CN108239074A - Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition - Google Patents

Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition Download PDF

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Publication number
CN108239074A
CN108239074A CN201611204309.8A CN201611204309A CN108239074A CN 108239074 A CN108239074 A CN 108239074A CN 201611204309 A CN201611204309 A CN 201611204309A CN 108239074 A CN108239074 A CN 108239074A
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alkyl
compound
amino
halogen
bases
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CN108239074B (en
Inventor
许恒
陈晓光
林松文
季鸣
吴德雨
王春阳
吕元皓
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Institute of Materia Medica of CAMS
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Application filed by Institute of Materia Medica of CAMS filed Critical Institute of Materia Medica of CAMS
Priority to AU2017389818A priority patent/AU2017389818B2/en
Priority to EP17886474.0A priority patent/EP3560921A4/en
Priority to PCT/CN2017/118771 priority patent/WO2018121550A1/en
Priority to JP2019534817A priority patent/JP7077323B2/en
Priority to CA3174865A priority patent/CA3174865A1/en
Priority to EP22213583.2A priority patent/EP4169917A1/en
Priority to CA3174890A priority patent/CA3174890A1/en
Priority to US16/473,901 priority patent/US11534443B2/en
Priority to EP22213594.9A priority patent/EP4169918A1/en
Priority to CN201780075753.0A priority patent/CN110382490A/en
Priority to CA3048546A priority patent/CA3048546A1/en
Publication of CN108239074A publication Critical patent/CN108239074A/en
Publication of CN108239074B publication Critical patent/CN108239074B/en
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Priority to AU2022202886A priority patent/AU2022202886B2/en
Priority to AU2022202885A priority patent/AU2022202885B2/en
Priority to JP2022081738A priority patent/JP7384536B2/en
Priority to JP2022081736A priority patent/JP7384535B2/en
Priority to US17/944,151 priority patent/US20230113478A1/en
Priority to US17/944,149 priority patent/US20230110550A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The present invention relates to quinazoline compounds and preparation method thereof, purposes and pharmaceutical compositions.The quinazoline compounds are by formula (I) Suo Shi, it is 3 kinases of phosphatidylinositols (PI3K) inhibitor, can be used for preventing and/or treat with the relevant disease of PI3K activity, such as cancer, immunity disease, angiocardiopathy, viral infection, inflammation, metabolism/endocrine dysfunction or neurological disease.

Description

Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of quinazoline compounds and preparation method thereof, purposes and drug Composition.
Background technology
Phosphatidyl-inositol 3-kinase (phosphatidylinositol 3-kinase, PI3K) belongs to lipid kinase family, According to the difference of its structure, adjustment effect and lipid substrate specificity, it is divided into three categories (I, II and III).Research at present is most To be deep for I class PI3K, it includes 4 hypotypes (PI3K α, PI3K β, PI3K δ and PI3K γ), wherein PI3K α and PI3K β two A hypotype is widely present in various types of cells, and another two hypotype PI3K δ and PI3K γ are then mainly distributed in leucocyte (Vanhaesebroeck etc., Trends Biochem Sci., 2005,30 (4)：194-204).As receptor tyrosine kinase (RTK) and the major downstream effector of g protein coupled receptor (GPCR), PI3K is by being catalyzed phosphatidylinositols -4,5- diphosphonic acid (PIP2) phosphatidylinositols -3,4,5- triphosphoric acids (PIP3), so as to which the signal of various growth factors and cell factor be passed are generated It is directed at intracellular.PIP3 can activate serine/threonine protein kitase (protein kinase for intracellular second messenger B, AKT) and downstream effector include mammal rapamycin target point protein (Mammalian Target of Rapamycin, mTOR) and regulate and control various kinds of cell function.
Exception/the overacfivity for the signal path that PI3K is mediated is related to a variety of diseases.Such as PI3K is to the hair of tumour Raw, evolution has critical effect, and the particularly gene PIK3CA of coding p110 α is in most of tumours such as mammary gland The appearance such as cancer, lung cancer, intestinal cancer, oophoroma, incidence cancer, gastric cancer, prostate cancer, the cancer of the brain, liver cancer, tumor in digestive tract and leukaemia A large amount of amplifications and variation (Zhao etc., Nat.Drug Discov.Rev.2009,8:627-644).FDA has approved PI3K within 2014 δ inhibitor Idelalisib (Gilead) is non-suddenly for treating chronic lymphocytic leukemia (CLL), recurrent follicular B cells Strange gold lymthoma (FL) and recurrent small lymphocyte lymthoma (SLL).Also some PI3K inhibitor are carrying out antitumor The clinical test of aspect, such as BKM120 (Novartis, III phase), BAY 80-6946 (Bayer, III phase), PF-05212384 (Pfizer, II phase) etc..In addition to tumour, PI3K is to inflammation, immune conditions, cardiovascular disease, virus infection, metabolism/endocrine Dysfunction and neurological disease also have important adjustment effect, some compounds such as GSK2269557 (face by chronic obstructive pulmonary disease Bed the II phases), GSK2126458 (idiopathic pulmonary fibrosis, clinical I phase), UCB-5857 (primary Sjogren's syndrome, clinical II Phase) and RV-1729 (chronic obstructive pulmonary disease, clinical I phase) etc. had enter into clinical experimental stage for these diseases.
PI3K has become the drug targets to have a great attraction, but also needs to research and develop safer and more effective PI3K inhibitor For prevention and/or treating cancer, immunity disease, angiocardiopathy, viral infection, inflammation, metabolism/endocrine dysfunction Or neurological disease.
Invention content
The object of the present invention is to provide a kind of new PI3K inhibitor, to I class PI3K, including PI3K α, PI3K β, PI3K γ and/or PI3K δ, particularly PI3K α have stronger inhibitory activity, thus to the disease mediated by PI3K, such as cancer, immunity Disease, angiocardiopathy, viral infection, inflammation, metabolism/endocrine dysfunction or neurological disease have preferably prevent and/ Or therapeutic effect.
On the one hand, the present invention provides a kind of formula (I) compound represented, its stereoisomer, geometric isomer, changes Isomers or pharmaceutically acceptable salt：
Wherein
R1Selected from C1-3Alkyl, C1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from a singly-bound or C1-3Alkylidene, wherein the C1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from halogen or C1-3Alkyl；
R2Selected from C1-3Alkyl, 3-7 members cycloalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl are optionally by one It is a or multiple selected from following group substitution：Halogen, C1-3Alkyl, amino, C1-3Alkyl amino, two (C1-3Alkyl) amino, trifluoro Methyl, difluoromethyl, cyano or C1-3Alkoxy；
Ring A is selected from 3-7 members cycloalkyl or 3-7 membered heterocycloalkyls；
R3Selected from C1-3Alkyl, halogen, cyano, trifluoromethyl, C1-3Alkoxy, C1-3Hydroxy alkyl, C1-3Alkyl amino or Two (C1-3Alkyl) amino；
M is 0,1,2,3 or 4；When m is 2,3 or 4, R3It can be identical or different group.
Preferably, the present invention provides compound shown in a kind of formula (I), its stereoisomer, mutually geometric isomer, variations Structure body or pharmaceutically acceptable salt：
Wherein
R1Selected from C1-3Alkyl, C1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from a singly-bound or C1-3Alkylidene, wherein the C1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from halogen or C1-3Alkyl；
R2Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally selected from following group by least one Substitution：Halogen, C1-3Alkyl, amino, C1-3Alkyl amino, two (C1-3) alkyl amino, trifluoromethyl, difluoromethyl, cyano or C1-3Alkoxy；
Ring A is 3-7 member cycloalkyl；
R3Selected from C1-3Alkyl, halogen, cyano, trifluoromethyl, C1-3Alkoxy, C1-3Hydroxy alkyl, C1-3Alkyl amino or Two (C1-3Alkyl) amino；
M is 0,1,2,3 or 4；When m is 2,3 or 4, R3It can be identical or different group.
Preferably, the present invention provides compound shown in a kind of formula (I), its stereoisomer, mutually geometric isomer, variations Structure body or pharmaceutically acceptable salt：
Wherein
R1For C1-3Alkyl, C1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from a singly-bound or C1-3Alkylidene, wherein the C1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from halogen or C1-3Alkyl；
R2Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally selected from following base by one or more Group's substitution：Halogen, C1-3Alkyl, amino, C1-3Alkyl amino, two (C1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C1-3Alkoxy；
Ring A is 3-7 membered heterocycloalkyls；
R3Selected from C1-3Alkyl, halogen, cyano, trifluoromethyl, C1-3Alkoxy, C1-3Hydroxy alkyl, C1-3Alkyl amino or Two (C1-3Alkyl) amino；
M is 0,1,2,3 or 4；When m is 2,3 or 4, R3It can be identical or different group.
It is further preferred that the present invention provides compound shown in a kind of formula (I), its stereoisomer, geometric isomer, Tautomer or pharmaceutically acceptable salt：
Wherein
R1Selected from C1-3Alkyl, C1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from a singly-bound or C1-3Alkylidene, wherein the C1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from halogen or C1-3Alkyl；
R2Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally selected from following base by one or more Group's substitution：Halogen, C1-3Alkyl, amino, C1-3Alkyl amino, two (C1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C1-3Alkoxy；
Ring A is selected from：
R3It is each independently selected from C1-3Alkyl, halogen, cyano, trifluoromethyl, C1-3Alkoxy, C1-3Hydroxy alkyl, C1-3 Alkyl amino or two (C1-3Alkyl) amino；
M is 0,1,2,3 or 4；When m is 2,3 or 4, R3It can be identical or different group.
Specifically, it is as follows according to currently preferred compound：
On the other hand, the present invention also provides the compound, its stereoisomer, geometric isomer, tautomers Preparation method, include the following steps：
(1) using compound A as starting material, by bromo-reaction prepare compound B；
(2) compound C is obtained by the reaction with triphosgene in compound B；
(3) compound C and N, O- dimethyl hydroxylamine hydrochloride reaction prepare compound D；
(4) compound E is obtained by methyl-magnesium-bromide attack by compound D；
(5) compound E and 50% amino nitrile reactant aqueous solution obtain the compound F with quinazoline skeleton；
(6) compound F is cyclized through 2,5- acetyl butyryls and protects, and obtains compound G；
(7) compound G reacts removing methyl with alchlor, obtains versatile intermediates H；
(8) intermediate H is reacted with alcohol generation Mitsunobu or is reacted with halides, obtains compound I；
(9) compound I is deprotected to obtain compound J through hydroxylamine hydrochloride；
(10) using sodium hydrogen or pyridine as alkali, compound K is obtained by the reaction with halogenated alkane or alkyl acyl chlorine in compound J；
(11) under Suzuki reaction conditions, the pyridine -3- pinacol borates of compound K and substitution are coupled to obtain described Compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt.
In another aspect, the present invention also provides a kind of pharmaceutical composition, described pharmaceutical composition include the compound, its Stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt and optional pharmaceutically acceptable load Body and/or excipient；Preferably, described pharmaceutical composition is also included except the compound, its stereoisomer, geometrical isomerism One or more preventions and/or treating cancer, immunity disease except body, tautomer or pharmaceutically acceptable salt, Angiocardiopathy, viral infection, inflammation, metabolism/endocrine dysfunction or neurological disease active constituents of medicine；Preferably, Described pharmaceutical composition is to be pharmaceutically acceptable for prevention and/or treating cancer, immunity disease, cardiovascular disease, virus Infection, inflammation, metabolism/endocrine dysfunction or neurological disease pharmaceutical preparation.
Another aspect, the present invention also provides a kind of pharmaceutical preparations, and it includes at least one compound, its solids Isomers, geometric isomer, tautomer or pharmaceutically acceptable salt and optional pharmaceutically acceptable carrier or/ Or excipient；Preferably, the pharmaceutical preparation is selected from following pharmaceutical dosage form：Parenteral formulation, such as inject solution Or suspension；Enteral drug-delivery preparation, such as oral preparation, such as tablet or capsule；Local administration preparation, for example, lotion, gel, Ointment, emulsion, pernasal preparation, suppository, percutaneous drug administration preparation or eye-drops preparations.
Another aspect, the present invention also provides the compound, its stereoisomer, geometric isomer, tautomers Or pharmaceutically acceptable salt or described pharmaceutical composition prepare for prevent and/or treating cancer, immunity disease, Angiocardiopathy, viral infection, inflammation, metabolism/endocrine dysfunction or neurological disease drug in purposes.In other words, The present invention provides a kind of prevention and/or treating cancer, immunity disease, angiocardiopathy, viral infection, inflammation, metabolism/interior The method of secretory functional disturbance or neurological disease, this method include giving subject's prevention in need and/or therapeutically effective amount The compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt or the medicine Compositions.
Part term used in the present invention is defined as follows below, other undefined terms have technical field Meaning well known to technical staff.
Halogen refers to fluorine, chlorine, bromine or iodine.
C1-3Alkylidene refers to the linear chain or branch chain bivalent hydrocarbon radical with the saturation of 1-3 carbon atom.The example of such group Including but not limited to：Methylene (- CH2), ethylidene (- CH2CH2), propylidene (- CH2CH2CH2-)。
C1-3Alkyl refers to the straight chain and attachment radical of saturated aliphatic alkyl group with 1 to 3 carbon atom.The example of such group Including but not limited to：Methyl, ethyl, propyl, isopropyl.
3-7 member cycloalkyl refers to the monocyclic, condensed of the saturation with 3 to 7 carboatomic ring atoms, loop coil or multiring structure.It is such The example of group includes but not limited to：Cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl and suberyl.
3-7 membered heterocycloalkyls refer to that saturation with 3 to 7 annular atoms or part are unsaturated (there are one having i.e. in ring Or multiple double bonds and/or three key) carbon ring group, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)m(wherein m is 0 Integer to 2) hetero atom, but do not include the loop section of-O-O- ,-O-S- or-S-S-, remaining annular atom is carbon.3-7 members are satisfied It is included but are not limited to the specific example of Heterocyclylalkyl：Oxirane base, aziridine base, azetidinyl, oxygen Azetidinyl, Thietane base, dihydrofuran base, tetrahydrofuran base, tetrahydro-thienyl, pyrrolidinyl, imidazolidinyl, pyrrole Oxazolidinyl, oxazole alkyl, isoxazole alkyl, thiazolidinyl, isothiazole alkyl, 1,4- dioxanes base, 1,3- dioxas Cyclohexyl, 1,3- dithians base, piperidyl, morpholinyl, piperazinyl, dihydro pyranyl, THP trtrahydropyranyl, tetrahydrochysene thiophene It mutters base etc.；It is preferred that oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, piperidyl, morpholinyl, piperazinyl.
C1-3Alkoxy refers to-O- alkyl, and wherein the alkyl contains 1 to 3 carbon atom and is straight chain, branch or ring-type.This The example of class group includes but not limited to：Methoxyl group, ethyoxyl, positive propoxy, isopropoxy or ring propoxyl group.
Aryl refers to monocyclic or bicyclic aromatic carbocylic groups, usually has 6-10 carbon atom；Such as phenyl or Naphthalene.It is preferred that phenyl.
Heteroaryl refers to monocyclic 5- or 6- member aromatic heterocycle bases, including but not limited to：5- unit's heteroaryls：Furyl, Thienyl, pyrrole radicals, oxazolyl, isoxazolyls, thiazolyl, isothiazolyl, imidazole radicals, pyrazolyl, triazolyl (1,2,4- triazoles Base, 1,3,4- triazolyls or 1,2,3- triazolyls), thiadiazolyl group (1,3,4- thiadiazolyl groups, 1,2,5- thiadiazolyl groups, 1,2,3- Thiadiazolyl group or 1,2,4- thiadiazolyl groups) are He oxadiazolyl (1,3,4- oxadiazolyls, 1,2,5- oxadiazolyls, 1,2,3- Evil bis- Oxazolyl or 1,2,4- oxadiazolyls) and 6- unit's heteroaryls：Pyridyl group, pyrimidine radicals, pyrazinyl and pyridazinyl and bicyclic group Group, such as benzofuranyl, benzothienyl, indazolyl, purine radicals, quinolyl, isoquinolyl, phthalazinyl, naphthyridines base, quinoline Quinoline base (chinocalinyl), quinazolyl, cinnoline base, pteridyl, indolizine base, indyl, isoindolyl.Preferred heteroaryl Group is thienyl, thiazolyl, pyridyl group, pyrimidine radicals.
Singly-bound refers to that two groups of its connection are connected directly, for example when L represents singly-bound in O-L-R represents structure reality On be O-R.
" optionally " mean event described later or environment can with but need not occur, the explanation include the event or Environment generation or not spot occasion.For example, " alkyl being optionally optionally substituted by halogen " mean halogen can with but necessarily deposit Include the situation that alkyl is optionally substituted by halogen and the situation that alkyl is not optionally substituted by halogen in, the explanation.
If group, such as " R3" be portrayed as in formula " floating " " on ring A：
Refer to " R3" any atom of ring system is attributable to, as long as forming rock-steady structure, it is believed that an annular atom in annular atom On be depicted, imply or clearly defined hydrogen is substituted.
Compound of the present invention can contain one or more chiral centres, be deposited with different stereoisomeric forms in any ratio .All stereoisomeric forms in any ratio of the compounds of this invention, including but not limited to diastereoisomer, enantiomter and resistance turn different Structure body and their mixture (such as racemic mixture) are within the scope of the present invention.
Compound of the present invention includes its geometric isomer.For example, if the compound of the present invention contains double bond Or geometric isomer may be present in condensed ring, these compounds, then the mixture of the cis- of them, trans forms and cis and trans It is included within the scope of the present invention.
Compound of the present invention includes its tautomer.Tautomer refers to what is mutually converted via low energy barrier The constitutional isomer of different-energy, such as keto-enol and imine-enamine tautomerism.
Compound of the present invention further includes its compound isotopically labelled, wherein one or more atoms are naturally sent out Existing have same atoms ordinal number but the atom of different atomic masses or mass number substitutes.Example includes but not limited to：Hydrogen is same Position element2H and3H；Carbon isotope11C、13C and14C；Chlorine isotope36Cl；Fluorine isotope18F；Iodine isotope123I and125I；The same position of nitrogen Element13N and15N；Oxygen isotope15O、17O and18O；Phosphorus isotope32P and sulfur isotope35S。
The various hydrates and solvate and its polymorphic of compound or its salt of the present invention (polymorphisms) it is intended to be included within the scope of the present invention.
The prodrug of compound of the present invention is intended to be included within the scope of the present invention.Certain of compound of the present invention A little derivatives itself have weaker pharmacological activity or a no pharmacological activity, but when these derivatives are given in vivo or to on body When, they can be converted to the compound of the present invention with pharmacological activity for example, by modes such as hydrolytic cleavages, these Derivative is known as " prodrug ".Further information about prodrug purposes can be in Pro-drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series (T.Higuchi and W.Stella) and Bioreversible Carriers in Drug Design,Pergamon Press,1987(ed.E.B.Roche,American Pharmaceutical Association) in find.
Compound of the present invention includes its pharmaceutically acceptable salt.Pharmaceutically acceptable salt refers to for pharmacy Salt upper acceptable and that there is the pharmacological activity needed for parent compound.Berge et al. is in J.Pharma.Sci., and 1977, Pharmaceutically acceptable salt is described in detail in 66,1-19, the document is incorporated herein by reference.Institute of the present invention The compound stated can contain enough acidic-groups, enough basic groups or the functional group for having both both types, and Correspondingly pharmaceutically acceptable salt is formed with some inorganic or organic bases or inorganic and organic acid reaction.It is pharmaceutically acceptable Salt example include sulfate, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, single hydrogen orthophosphate, It is dihydrogen orthophosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromate, hydriodate, acetate, propionate, caprate, pungent Hydrochlorate, acrylates, formates, isobutyrate, caproate, enanthate, propiolate, oxalates, malonate, succinic acid Salt, suberate, sebacate, fumarate, maleate, butine -1,4- diacid salts, hexin -1,6- diacid salts, benzoic acid Salt, chloro-benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, methoxy benzoic acid salt, adjacent benzene Diformate, sulfonate, xylenesulfonate, phenylacetate, phenpropionate, benzenebutanoic acid salt, citrate, lactate, γ-hydroxyl Base butyrate, oxyacetate, tartrate, methane sulfonates, propane sulfonic acid salt, naphthalene -1- sulfonate, naphthalene-2-sulfonic acid salt and almond Hydrochlorate.
Compound of the present invention as drug in use, be typically in the form of pharmaceutical composition be administered.Therefore, The pharmaceutical composition of compound and pharmaceutically acceptable carrier of the present invention, diluent or excipient is also included within this hair Bright range.Carrier used herein, auxiliary agent, excipient include being suitable for the arbitrary and all molten of desired particular dosage form Agent, diluent or other liquid excipients, dispersant or suspending agent, surfactant, isotonic agent, thickener or emulsifier are prevented Rotten agent, solid binder, lubricant etc..In Remington：The Science and Practice of Pharmacy, 21st Edition, 2005, ed.D.B.Troy, Lippincott Williams＆Wilkins, Philadelphia and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988- In 1999, Marcel Dekker, New York, various carriers and use for preparing pharmaceutically acceptable composition are disclosed In the known technology of its preparation, their content is all incorporated by reference herein.
Composition of the present invention can be administered by being suitable for any approach of illness to be treated.Particularly pass through with following Form is administered：It is parenteral, such as with Injectable solution or suspended form；It is enteral such as oral, such as with tablet or capsule Dosage form formula；Part, such as in the form of lotion, gel, ointment or emulsion or with nose or suppository form.Local application be for example using In skin.Another form of local administration is to deliver medicine to eye.
Pharmaceutical composition can be applied with solid, semisolid, liquid or gaseous form or can be in dry powder, such as Lyophilized form.Pharmaceutical composition can be packaged as the form convenient for transmitting, including such as solid dosage forms, such as capsule, anther sac, sachet Agent, gelatin, paper, tablet, suppository, granule, pill, lozenge and pastille.The type of packaging will generally depend on administration method.Also contain The preparation and percutaneous preparation of the implantable sustained release of lid.
It can include but not limited to as some examples of the material of pharmaceutically acceptable carrier：Ion-exchanger, oxidation Aluminium, aluminum stearate, lecithin, serum proteins (such as human serum albumins), buffer substance (such as phosphate), glycine, Sorbic acid or potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte (such as sulfuric acid milt egg In vain, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt), colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, poly- third Olefin(e) acid ester, wax class, polyethylene-polyoxypropylene block copolymer, lanolin, carbohydrate (such as lactose, dextrose and saccharose), starch (such as cornstarch and potato starch), cellulose and its derivates, such as sodium carboxymethylcellulose, ethyl cellulose and vinegar Acid cellulose；Powdered tragacanth；Malt；Gelatin；Talcum powder；Excipient, such as cocoa butter and suppository wax；Oils, such as spend Oil generation, cottonseed oil；Safflower oil；Sesame oil；Olive oil；Corn oil and soybean oil；Glycol, such as propylene glycol or polyethylene glycol；Ester Class, such as ethyl oleate and ethyl laurate；Agar；Buffer, such as magnesium hydroxide and aluminium hydroxide；Alginic acid；Apyrogeneity Water；Isotonic saline solution；Ringer's solution；Ethyl alcohol；And phosphate buffer and other nontoxic compatible lubricants, such as the moon Osmanthus base sodium sulphate and magnesium stearate.According to the judgement of formulation scientist, there may also be colorant, releasing agent, packets in the composition Clothing agent, sweetener, flavoring agent and aromatic, preservative and antioxidant.
Compound of the present invention can be used alone or with other treatments disease of the present invention or illness (such as Cancer) therapeutic agent use.In certain embodiments, compound of the present invention is with having anti-hyperproliferation property Or second of compound for treatment height proliferative diseases (such as cancer) is combined or in medicine composition as connection Treatment is closed in dosage regimen to combine.The second compound of pharmaceutical combination preparations or Dosing schedules preferably has and this hair The activity of the bright compound complementation, so that they will not mutually have an adverse effect.Such compound is suitably by terms of Drawing purpose, effectively amount is present in combination.In one embodiment, the compound of the present invention and other antineoplastic Internet of Things It closes.The antitumor drug includes：Alkylating agents include but are not limited to cyclophosphamide, mustargen, melphalan, chlorambucil, card not Take charge of spit of fland；Metal platinum class includes but are not limited to carboplatin, cis-platinum, oxaliplatin；Topoisomerase enzyme inhibitor, including but not only limit In Topotecan, camptothecine, topotecan, Irinotecan；Antibiotics include but are not limited to fennel ciclamicin, D actinomycin D D, daunorubicin, adriamycin, mitoxantrone, bleomycin, plicamycin；Anti- micro-pipe or antimitotic agent, including but not only It is limited to taxol, vinorelbine, docetaxel, Doxorubicin；Antimetabolic species include but are not limited to fluorouracil, first ammonia Pterin, cytarabine, mercaptopurine (mecaptopurine), thioguanine and gemcitabine；Antibody class includes but are not limited to Trastuzumab, bevacizumab；Steroids, include but are not limited to Letrozole (Letrazole), R 83842 (vorazole), he not Western fragrant, Toremifene, fulvestrant, Flutamide, Nilutamide, Triptorelin；Kinase inhibitor class, EGFR kinase inhibitor, Include but are not limited to Gefitinib (gefitinib), Tarceva (erlotinib), Lapatinib (lapatinib), Ah Method replaces Buddhist nun (afatinib)；VEGFR inhibitor includes but are not limited to Sorafenib (Sorafenib), Rui Gefeini (Regorafenib), Sutent (Sunitinib), card it is rich for Buddhist nun (Cabozantinib), pazopanib (Pazopanib), Vande Thani (vandetanib), pazopanib (axitinib)；ALK inhibitor includes but are not limited to gram azoles for Buddhist nun (Crizotinib), Ceritinib (ceritinib), Alectinib；Bcr-Abl inhibitor includes but are not limited to her horse and replaces Buddhist nun (Imatinib), pa receive for Buddhist nun (Ponatinib), nilotinib (Nilotinib), Dasatinib (Dasatinib)；BTK Inhibitor includes but are not limited to replace Buddhist nun (Ibrutinib) according to Shandong；B-RAF inhibitor, includes but are not limited to Wei Luofeini (Vemurafenib)；Cell cycle protein dependent kinase CDK4/6 inhibitor, Pa Boxini (Palbociclib)；MTOR presses down Preparation includes but are not limited to rapamycin (rapamycin), everolimus (everolimus)；Deacetylase inhibitor, Include but are not limited to Vorinostat (vorinostat)；PD1/PDL1 antibody, Keytruda (Pembrolizumab), Opdivo(Nivolumab)。
Description of the drawings
Fig. 1 is tumor growth curve, which show embodiment 4 to human gastric cancer HGC-27 in nude mice by subcutaneous heteroplastic transplantation knurl Growth inhibition effect.
Specific embodiment
The following is specific embodiments of the present invention, and technical scheme of the present invention is further described, but this hair Bright protection domain is not limited to these embodiments.It is every to be included in without departing substantially from the change of present inventive concept or equivalent substitute In protection scope of the present invention.
In the examples below, annotated unless otherwise structural formula or chemical name, have the molecule at single chiral center with Racemic mixture form exists.It is annotated unless otherwise structural formula or chemical name, those have two or more chiralitys The molecule at center exists in the form of the racemic mixture of diastereoisomer.Single enantiomter/diastereoisomer can To be obtained by method known to those skilled in the art.
Preparation method
Compound of the present invention can be closed according to synthetic schemes herein and/or technology well known in the art Into.For example, compound provided by the invention can be prepared according to following universal synthesis method.
Universal synthesis method
Specifically, in universal synthesis method, quinazoline compounds of the present invention can be reacted by 11 steps to be prepared. For example, starting material A is converted into compound B through bromo-reaction, compound C is obtained by the reaction with triphosgene.Compound C and N, O- Compound D is obtained by the reaction in dimethyl hydroxylamine hydrochloride, by methyl-magnesium-bromide attack generation compound E.Compound E and 50% ammonia Base nitrile reactant aqueous solution obtains the compound F with quinazoline skeleton, then protects its amino by being cyclized with 2,5- acetyl butyryls Group.Gained compound G reacts removing methyl with alchlor, obtains versatile intermediates H.Intermediate H occurs with various alcohol Mitsunobu is reacted or is reacted with various halides, is obtained compound I, is deprotected to obtain compound J through hydroxylamine hydrochloride. Using sodium hydrogen or pyridine as alkali, compound K is obtained by the reaction with halogenated alkane or alkyl acyl chlorine in compound J.In art technology Under Suzuki reaction conditions known to personnel, compound K and the pyridine -3- pinacol borates of substitution are coupled to obtain compound 1- 15。
Embodiment
Prepare embodiment
Compound of the present invention can be according to one or more synthetic schemes herein and/or skill well known in the art Art synthesizes.Those skilled in the art will appreciate that the synthetic method for the certain embodiments being described in detail in the present invention, can hold It is readily adapted for synthesis other embodiment.In some embodiments, compound as described herein can by it is well known that The appropriately combined of synthetic method prepare.Many starting materials and other reagents are purchased from commercial supplier, such as A Faai Sha (China) Chemical Co., Ltd. is easily prepared using synthetic method commonly used in the art.
1It is recorded on the instrument that H H NMR spectroscopies operate under 400MHz or 500MHz.H H NMR spectroscopies obtain in the form of a solution (with Ppm is reported), use CDCl3(7.26ppm) or DMSO-d6(2.50ppm) or internal standard tetramethylsilane (0.00ppm) are as reference Standard.When reporting peak multiplicity, following abbreviation is used：S (unimodal), d (bimodal), t (triplet), q (quartet), m is (multiple Peak), br (broad peak), dd (double doublet), dt (double triplets).The coupling Changshu provided is in terms of hertz (Hz).
When needing, (R)-and (S)-isomers of non-restrictive illustrative compound, if it does, this field can be passed through Method known to technical staff is split, such as by forming diastereomeric salt or compound, can for example, by crystallization and Separation；By forming diastereoisomerism derivative, can be detached for example, by crystallization or chromatography；Make an enantiomter With enantiomter specific reagent selective reaction, modified and unmodified enantiomter is then detached；Or Such as chromatographic isolation is carried out in the chiral environment of chiral chromatographic column.Alternatively, specific enantiomter can be by using Optical activity reagent, substrate, catalyst or solvent carry out asymmetric syntheses or by asymmetric transformation by an enantiomter Another is converted into prepare.
In following preparation method and example, " Ac " refers to acetyl group, and " Me " refers to methyl, and " Et " refers to ethyl, " Ph " Refer to phenyl, " H2O " refers to water, and " PE " refers to petroleum ether, and " EtOAc " refers to ethyl acetate, and " MeOH " refers to methanol, " EtOH " Refer to ethyl alcohol, " DMF " refers to n,N-Dimethylformamide, " CDCl3" refer to deuterochloroform, " DMSO-d6" refer to that deuterated diformazan is sub- Sulfone, " NMP " refer to 1-Methyl-2-Pyrrolidone, and " DCM " refers to dichloromethane, and " DCE " refers to 1,2- dichloroethanes, and " THF " is Refer to tetrahydrofuran, " HCl " refers to hydrochloric acid, and " TsOH " refers to p-methyl benzenesulfonic acid, " AlCl3" refer to alchlor, " TEA " refers to three Ethamine, " NBS " refer to N- bromo-succinimides, " Na2SO4" refer to sodium sulphate, " K2CO3" refer to potassium carbonate, " MeMgBr " is Refer to methyl-magnesium-bromide, " DEAD " refers to diethyl azodiformate, " PPh3" refer to triphenylphosphine, " PdCl2(dppf) " refer to [1,1'- bis- (diphenylphosphino) ferrocene] palladium chloride, " Ar " refers to argon gas, and " M " refers to molarity, and " rt " refers to Room temperature, " min " refer to minute, and " h " refers to hour, and " mL " refers to milliliter, and " mmol " refers to mM, and " μM " refers to micromole, " nM " refers to nanomole, and " DEG C " refers to degree Celsius.
The preparation of versatile intermediates (H)
Step 1：The preparation of the bromo- 3- methoxy benzoic acids (B) of 2- amino -5-
In 20min 2- amino -3- methoxy benzoic acids (A) are added to by NBS (28.04g, 157.5mmol) points 5 batches In the solution of (25.08g, 150mmol) in DMF (200mL).2h is stirred at room temperature in the reaction mixture of generation.Use water (2L) diluted reaction mixture, is extracted (500mL × 4) with EtOAc.Conjunction is washed with water (500mL × 3) and saline solution (500mL) And organic layer, use anhydrous Na2SO4Dry, filtering, being concentrated to give product crude product (B), (35g, yield are for dark brown solid 95%) it, is directly used in without further purification in next step.
1H NMR(400MHz,DMSO-d6) δ 7.42 (d, J=2.2Hz, 1H), 7.07 (d, J=2.2Hz, 1H), 3.84 (s, 3H)。
Step 2：[the preparation of -2,4 (1H)-diketone (C) of 1,3] oxazines of the bromo- 8- methoxyl groups -2H- benzos [d] of 6-
By compound (B) (35g, 142.2mmol) and triphosgene (32mg, 107.8mmol) in anhydrous THF (350mL) Mixture reflux 3h.After being cooled to room temperature, the solid of generation is collected by filtration, with PE/EtOAc solution (1:1, v/v, 200mL) Washing is dried to obtain product (C) as faint yellow solid (30.78g, yield 80%).
1H NMR(400MHz,DMSO-d6) δ 11.43 (s, 1H), 7.56 (d, J=2.0Hz, 1H), 7.55 (d, J= 2.0Hz,1H),3.92(s,3H)。
Step 3：The bromo- N of 2- amino -5-, the preparation of 3- Dimethoxy-N-methyls benzamide (D)
By compound (C) (30.78g, 113.12mmol), N, O- dimethyl hydroxylamine hydrochlorides (16.55g, 169.68mmol) it is refluxed overnight with mixtures of the TEA (26.7mL, 192.3mmol) in dioxane (300mL).Decompression is steamed Remove volatile matter.With water (500mL) diluted reaction mixture, extracted with EtOAc (200mL × 3).With water (200mL × 2) and salt The organic layer that water (200mL) washing merges, uses anhydrous Na2SO4It is dry, it filters, concentration.Residue through flash column chromatography (silica gel, PE/EtOAc=4:1, v/v) purifying obtains product (D) as yellow oil (29.73g, yield 91%).
1H NMR(400MHz,DMSO-d6) δ 7.01 (d, J=2.0Hz, 1H), 6.97 (d, J=2.0Hz, 1H), 5.10 (br s,2H),3.82(s,3H),3.53(s,3H),3.22(s,3H)。
Step 4：The preparation of 1- (the bromo- 3- methoxyphenyls of 2- amino -5-) ethyl ketone (E)
At -20 DEG C in argon gas atmosphere to compound (D) (29.73g, 103mmol) in anhydrous tetrahydro furan (300mL) Solution in, methyl-magnesium-bromide (1M tetrahydrofuran solutions, 206mL, 206mmol) is slowly added dropwise in 30min.By the anti-of generation Mixture is answered to stir 30min at -20 DEG C, is then quenched with saturated aqueous ammonium chloride.With water (1L) diluted reaction mixture, It is extracted with EtOAc (300mL × 3).The organic layer merged is washed with water (300mL × 2) and saline solution (300mL), use is anhydrous Na2SO4It is dry, it filters, concentration.Residue is through flash column chromatography (silica gel, PE/EtOAc=15:1, v/v) purifying obtains product (E) it is yellow oil (6.5g, yield 26%).
1H NMR(400MHz,DMSO-d6) δ 7.50 (d, J=2.0Hz, 1H), 7.08 (d, J=2.0Hz, 1H), 7.04 (s, 2H),3.84(s,3H),2.51(s,3H)。
Step 5：The preparation of the bromo- 8- methoxyl groups -4- methylquinazolins -2- amine (F) of 6-
By compound (E) (7.41g, 30.36mmol) and concentrated hydrochloric acid (10mL) in 50% amino nitrile aqueous solution (74mL) Mixture stir 15min at 120 DEG C.Reaction mixture is cooled to room temperature, is diluted with water (300mL), production is collected by filtration Raw solid is washed with water (100mL) and ethyl alcohol (30mL), and being dried to obtain product (F), (8.00g, yield are for faint yellow solid 98%).
1H NMR(400MHz,DMSO-d6) δ 7.67 (d, J=2.0Hz, 1H), 7.20 (d, J=2.0Hz, 1H), 6.90 (br s,2H),3.88(s,3H),2.67(s,3H)。
Step 6：The preparation of the bromo- 2- of 6- (2,5- dimethyl -1H- pyrroles -1- bases) -8- methoxyl group -4- methylquinazolins (G)
By compound (F) (8.00g, 29.84mmol), 2,5- acetyl butyryls (13.61g, 119.36mmol) and to toluene sulphur Mixture of the sour monohydrate (0.568g, 2.98mmol) in NMP (80mL) and toluene (80mL) reflux water-dividing at 160 DEG C 6h.Reaction mixture is cooled to room temperature, decompression boils off toluene, is diluted with water (400mL), is extracted (100mL × 3) with EtOAc. The organic layer merged is washed with water (100mL × 3) and saline solution (100mL), uses anhydrous Na2SO4It is dry, it filters, concentration.Residual Object is through flash column chromatography (silica gel, PE/EtOAc=30:1, v/v) it is that (8.95g, yield are yellow solid that purifying, which obtains product (G), 87%).
1H NMR(400MHz,DMSO-d6) δ 8.04 (d, J=1.8Hz, 1H), 7.57 (d, J=1.8Hz, 1H), 5.84 (s, 2H),4.01(s,3H),2.92(s,3H),2.30(s,6H)。
Step 7：The preparation of the bromo- 2- of 6- (2,5- dimethyl -1H- pyrroles -1- bases) -4- methylquinazolin -8- phenol (H)
AlCl is added in into solution of the compound (G) (3.27g, 9.56mmol) in DCE (300mL)3(3.83g, 28.68mmol).The reaction mixture of generation is stirred into 1.5h at 80 DEG C.Reaction mixture is cooled to room temperature, uses water (300mL) dilutes, and is extracted (300mL × 2) with DCM.The organic layer merged is washed with water (200mL) and saline solution (100mL), is used Anhydrous Na2SO4It is dry, it filters, concentration.Residue is through flash column chromatography (silica gel, PE/EtOAc=50:1, v/v) purifying is produced Object (H) is yellow solid (2.41g, yield 77%).
1H NMR(400MHz,DMSO-d6) δ 10.64 (s, 1H), 7.93 (d, J=2.0Hz, 1H), 7.44 (d, J= 2.0Hz,1H),5.84(s,2H),2.91(s,3H),2.29(s,6H)。
Embodiment 1：N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) Quinazoline -6- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (1)
Step 1：The bromo- 2- of 6- (2,5- dimethyl -1H- pyrroles -1- bases) -4- methyl -8- ((tetrahydrochysene -2H- pyrans -4- bases) Oxygroup) quinazoline (I-1) preparation
At room temperature in argon gas atmosphere to the compound (H) (3.322g, 10mmol) that stirred, triphenylphosphine (3.148g, It 12mmol) and in solution of the tetrahydrochysene -2H- pyrans -4- alcohol (1.226g, 12mmol) in anhydrous tetrahydro furan (50mL) adds in even Nitrogen dicarboxylate (2.09g, 12mmol).The reaction mixture of generation is stirred at room temperature overnight.Add in silica gel (10g), by evaporated under reduced pressure in the mixture of generation.Residue is through flash column chromatography (silica gel, PE/EtOAc=10:1, v/v) it is pure Change obtains product (I-1) as yellow oil (2.097g, yield 50%).
1H NMR(400MHz,DMSO-d6) δ 8.04 (d, J=1.9Hz, 1H), 7.70 (d, J=1.8Hz, 1H), 5.86 (s, 2H), 5.01-4.91 (m, 1H), 3.94-3.80 (m, 2H), 3.56 (ddd, J=11.2,8.0,3.2Hz, 2H), 2.92 (s, 3H),2.36(s,3H),2.09–1.94(m,2H),1.77–1.65(m,2H)。
Step 2：The preparation of the bromo- 4- methyl -8- of 6- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinazoline -2- amine (J-1)
By compound (I-1) (2.082g, 5.0mmol) and hydroxylamine hydrochloride (1.734g, 25mmol) in ethyl alcohol (40mL) and Mixture in water (4mL) is refluxed overnight.It dilutes, the mixture evaporated under reduced pressure of generation with unsaturated carbonate hydrogen with water (100mL) Sodium water solution neutralizes, and is extracted with DCM (50mL × 3).The organic layer merged is washed with water (50mL) and saline solution (50mL), with nothing Water Na2SO4It is dry, it filters, concentration.Residue is through flash column chromatography (silica gel, DCM/MeOH=50:1, v/v) purifying obtains product (J-1) it is yellow oil (0.667g, yield 39%).
1H NMR(400MHz,DMSO-d6) δ 7.68 (d, J=2.0Hz, 1H), 7.36 (d, J=2.0Hz, 1H), 6.85 (s, 2H),4.82–4.73(m,1H),3.94–3.87(m,2H),3.53–3.45(m,2H),2.65(s,3H),2.05–1.96(m, 2H),1.68–1.58(m,2H)。
MS(ESI+)m/z 337.8,339.8[M+H]+。
Step 3：The system of the bromo- N of 6-, 4- dimethyl -8- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinazoline -2- amine (K-1) It is standby
Sodium hydrogen (60% is scattered in mineral oil, 153mg, 3.82mmol) is added to compound (J-1) (517mg) at 0 DEG C In the solution of DMF (50mL).The reaction mixture of generation is stirred into 30min at 0 DEG C, then add in iodomethane (217mg, 1.53mmol).The reaction mixture of generation is stirred at room temperature 3 hours.Reaction mixture is released with water (250mL), with 2M salt Acid neutralizes, and is extracted with ethyl acetate (50mL × 3).The organic layer merged is washed with water (50mL × 2) and saline solution (50mL), is used Anhydrous sodium sulfate is dried, and is filtered, concentration.Residue is through flash chromatography column (silica gel, DCM/EtOAc=4:1) purifying obtains product (K-1) it is yellow solid (113mg, 21%).
1H NMR(400MHz,DMSO-d6) δ 7.74 (d, J=1.8Hz, 1H), 7.39 (d, J=1.8Hz, 1H), 7.34 (q, J=4.8Hz, 1H), 4.94-4.76 (m, 1H), 3.99-3.82 (m, 2H), 3.53-3.43 (m, 2H), 2.88 (d, J=4.8Hz, 3H),2.66(s,3H),2.06–1.88(m,2H),1.77–1.57(m,2H)。
Step 4：N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinolines Oxazoline -6- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (1)
By compound (K-1) (35mg, 0.1mmol), N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls -1,3,2- dioxies Heterocycle pentaborane -2- bases) pyridin-3-yl) -2,4- difluorobenzenesulfonamides (51mg, 0.12mmol) and 2M wet chemicals The mixture degassing of (0.15mL, 0.63mmol) in Isosorbide-5-Nitrae-dioxane (7mL), then adds in PdCl2(dppf) (8mg, 0.01mmol).Reaction mixture degassing and backfilled with argon (three cycles) by generation, then at 100 DEG C in argon gas atmosphere Stir 5h.Reaction mixture is cooled to room temperature, is diluted with ethyl acetate (30mL) and water (30mL), being acidified to pH with hydrochloric acid is 5-6.Two-phase is detached, (30mL × 2) water layer is extracted with ethyl acetate.Having for merging is washed with water (50mL) and saline solution (50mL) Machine layer, is dried with anhydrous sodium sulfate, is filtered, concentration.Residue is through preparing thin-layer chromatography (silica gel, methylene chloride/methanol=20: 1, v/v) purifying obtains product (1) as yellow solid (40mg, yield 70%).
1H NMR(400MHz,DMSO-d6) δ 10.28 (s, 1H), 8.42 (d, J=2.0Hz, 1H), 7.93 (d, J= 2.0Hz, 1H), 7.83-7.66 (m, 2H), 7.63-7.53 (m, 1H), 7.50 (s, 1H), 7.28 (q, J=4.0Hz, 1H), 7.21 (dt, J=8.4,2.0Hz, 1H), 4.97-4.88 (m 1H), 4.01-3.88 (m, 2H), 3.64 (s, 3H), 3.53-3.44 (m, 2H), 2.91 (d, J=4.4Hz, 3H), 2.76 (s, 3H), 2.08-1.90 (m, 2H), 1.81-1.63 (m, 2H).
MS(ESI+)m/z 572.2[M+H]+。
Embodiment 2：N- (5- (2- (ethylamino) -4- methyl -8- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinazoline - 6- yls) -2- methoxypyridine -3- bases) -2,4 difluorobenzene sulfonamide (2)
Step 1：The bromo- N- ethyls -4- methyl -8- of 6- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinazoline -2- amine (K-2) Preparation
According to the method for step 3 in embodiment 1, by compound (J-1) and iodoethane prepare compound (K-2).
1H NMR(400MHz,DMSO-d6) δ 7.73 (d, J=1.6Hz, 1H), 7.41 (br s, 1H), 7.38 (d, J= 1.6Hz,1H),4.90–4.78(m,1H),3.98–3.82(m,2H),3.52–3.43(m,2H),3.43–3.33(m,2H), 2.66 (s, 3H), 2.02-1.90 (m, 2H), 1.73-1.61 (m, 2H), 1.17 (t, J=7.2Hz, 3H).
Step 2：N- (5- (2- (ethylamino) -4- methyl -8- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinazoline -6- Base) -2- methoxypyridine -3- bases) -2,4 difluorobenzene sulfonamide (2) preparation
According to the method for step 4 in embodiment 1, by compound (K-2) and N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide prepare compound (2).
1H NMR(400MHz,DMSO-d6) δ 10.28 (s, 1H), 8.42 (d, J=2.1Hz, 1H), 7.93 (d, J= 2.3Hz, 1H), 7.80-7.69 (m, 2H), 7.59 (ddd, J=10.4,9.6,2.4Hz, 1H), 7.49 (d, J=1.2Hz, 1H), 7.35 (t, J=5.0Hz, 1H), 7.26-7.16 (m, 1H), 4.95-4.87 (m, 1H), 3.98-3.89 (m, 2H), 3.64 (s, 3H), 3.52-3.36 (m, 4H), 2.75 (s, 3H), 2.05-1.92 (m, 2H), 1.80-1.63 (m, 2H), 1.19 (t, J= 7.1Hz,3H)。
MS(ESI+)m/z 586.2[M+H]+。
Embodiment 3：N- (5- (2- ((the third methyl of ring) amino) -4- methyl -8- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinolines Oxazoline -6- bases) -2- methoxypyridine -3- bases) -2,4 difluorobenzene sulfonamide (3)
Step 1：The bromo- N- of 6- (the third methyl of ring) -4- methyl -8- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinazoline -2- amine (K-3) preparation
According to the method for step 3 in embodiment 1, by compound (J-1) and ring the third methyl bromide prepare compound (K-3).
1H NMR(400MHz,DMSO-d6) δ 7.73 (s, 1H), 7.51 (br s, 1H), 7.37 (d, J=1.7Hz, 1H), 4.88-4.78 (m, 1H), 3.95-3.83 (m, 2H), 3.55-3.39 (m, 2H), 3.24 (t, J=6.3Hz, 2H), 2.66 (s, 3H),2.03–1.91(m,2H),1.74–1.59(m,2H),1.15–1.06(m,1H),0.45–0.35(m,2H),0.27(q,J =4.4Hz, 2H).
Step 2：N- (5- (2- ((the third methyl of ring) amino) -4- methyl -8- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinoline azoles Quinoline -6- bases) -2- methoxypyridine -3- bases) -2,4 difluorobenzene sulfonamide (3) preparation
According to the method for step 4 in embodiment 1, by compound (K-3) and N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide prepare compound (3).
1H NMR(400MHz,DMSO-d6) δ 10.28 (s, 1H), 8.43 (d, J=2.4Hz, 1H), 7.94 (d, J= 2.4Hz, 1H), 7.80-7.70 (m, 2H), 7.63-7.55 (m, 1H), 7.48 (d, J=1.2Hz, 1H), 7.45 (br s, 1H), 7.22 (dt, J=8.4,2.0Hz, 1H), 4.96-4.86 (m, 1H), 4.00-3.89 (m, 2H), 3.64 (s, 3H), 3.54-3.42 (m, 2H), 3.28 (t, J=6.4Hz, 2H), 2.76 (s, 3H), 2.06-1.94 (m, 2H), 1.80-1.63 (m, 2H), 1.21- 1.05 (m, 1H), 0.50-0.38 (m, 2H), 0.29 (q, J=4.8Hz, 2H).
MS(ESI+)m/z 612.2[M+H]+。
Embodiment 4：(R)-N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- bases) oxygroup) Quinazoline -6- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (4)
Step 1：(R) the bromo- 2- of -6- (2,5- dimethyl -1H- pyrroles -1- bases) -4- methyl -8- ((tetrahydrofuran -3- bases) Oxygroup) quinazoline (I-4) preparation
According to the method for step 1 in embodiment 1, by compound (H) and (S)-tetrahydrofuran -3- alcohol prepare compounds (I- 4)。
1H NMR(400MHz,CDCl3) δ 7.82 (d, J=1.6Hz, 1H), 7.22 (d, J=1.6Hz, 1H), 5.91 (s, 2H),5.22–5.14(m,1H),4.18–3.94(m,4H),2.91(s,3H),2.45(s,6H),2.33–2.26(m,2H)。
Step 2：(R) preparation of the bromo- 4- methyl -8- of -6- ((tetrahydrofuran -3- bases) oxygroup) quinazoline -2- amine (J-4)
According to the method for step 2 in embodiment 1, by compound (I-4) prepare compound (J-4).1H NMR(400MHz, DMSO-d6) δ 7.69 (d, J=2.0Hz, 1H), 7.21 (d, J=2.0Hz, 1H), 6.89 (s, 2H), 5.25-5.18 (m, 1H), 3.97–3.83(m,3H),3.80–3.72(m,1H),2.66(s,3H),2.33–2.21(m,1H),2.05–1.93(m,1H)。
Step 3：(R) the bromo- N of -6-, 4- dimethyl -8- ((tetrahydrofuran -3- bases) oxygroup) quinazoline -2- amine (K-4)
According to the method for step 3 in embodiment 1, by compound (J-4) prepare compound (K-4).
1H NMR(400MHz,DMSO-d6) δ 7.72 (d, J=2.0Hz, 1H), 7.34 (q, J=4.8Hz, 1H), 7.25 (s, 1H), 5.32-5.22 (m, 1H), 3.96-3.86 (m, 3H), 3.81-3.73 (m, 1H), 2.87 (d, J=4.8Hz, 3H), 2.66 (s,3H),2.28–2.15(m,1H),2.11–1.98(m,1H)。
Step 4：(R)-N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- bases) oxygroup) quinolines Oxazoline -6- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (4)
According to the method for step 4 in embodiment 1, by compound (K-4) and N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide prepare compound (4).
1H NMR(400MHz,DMSO-d6) δ 10.28 (s, 1H), 8.44 (d, J=2.2Hz, 1H), 7.96 (d, J= 2.2Hz, 1H), 7.80-7.70 (m, 2H), 7.63-7.54 (m, 1H), 7.38 (s, 1H), 7.29 (q, J=4.8Hz, 1H), 7.25–7.17(m,1H),5.43–5.36(m,1H),4.00–3.89(m,3H),3.83–3.76(m,1H),3.64(s,3H), 2.91 (d, J=4.8Hz, 3H), 2.76 (s, 3H), 2.28-2.15 (m, 1H), 2.15-2.02 (m, 1H).
MS(ESI+)m/z 558.2[M+H]+。
Embodiment 5：(R)-N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- bases) oxygroup) Quinazoline -6- bases) pyridin-3-yl) -2- chlorine 4- fluorobenzenesulfonamides (5)
According to the method for step 4 in embodiment 1, by compound (K-4) and N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) the chloro- 4- fluorobenzenesulfonamides prepare compounds (5) of -2-.
1H NMR(400MHz,DMSO-d6) δ 10.17 (s, 1H), 8.42 (d, J=2.4Hz, 1H), 7.94 (dd, J=8.8, 6.0Hz, 1H), 7.90 (d, J=2.4Hz, 1H), 7.76 (dd, J=8.8,2.6Hz, 1H), 7.69 (d, J=1.6Hz, 1H), 7.40-7.32 (m, 2H), 7.29 (q, J=4.8Hz, 1H), 5.42-5.35 (m, 1H), 4.00-3.89 (m, 3H), 3.79 (dt, J =8.0,4.4Hz, 1H), 3.66 (s, 3H), 2.90 (d, J=4.8Hz, 3H), 2.75 (s, 3H), 2.28-2.15 (m, 1H), 2.14–2.04(m,1H).
MS(ESI+)m/z 574.1[M+H]+。
Embodiment 6：(R)-N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- bases) oxygroup) Quinazoline -6- bases) pyridin-3-yl) -5- chlorothiophene -2- sulfonamide (6)
According to the method for step 4 in embodiment 1, by compound (K-4) and N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) -5- chlorothiophene -2- sulfonamide prepare compounds (6).
1H NMR(400MHz,DMSO-d6) δ 10.33 (s, 1H), 8.48 (d, J=2.4Hz, 1H), 7.96 (d, J= 2.4Hz, 1H), 7.73 (d, J=1.6Hz, 1H), 7.42-7.38 (m, 2H), 7.29 (t, J=4.8Hz, 1H), 7.25 (d, J= 4.4Hz, 1H), 5.43-5.36 (m, 1H), 4.00-3.90 (m, 3H), 3.80 (dt, J=8.0,4.4Hz, 1H), 3.75 (s, 3H), 2.91 (d, J=4.8Hz, 3H), 2.77 (s, 3H), 2.30-2.16 (m, 1H), 2.15-2.05 (m, 1H).
Embodiment 7：(S)-N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- bases) oxygroup) Quinazoline -6- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (7)
Step 1：(S) the bromo- 2- of -6- (2,5- dimethyl -1H- pyrroles -1- bases) -4- methyl -8- ((tetrahydrofuran -3- bases) Oxygroup) quinazoline (I-7) preparation
According to the method for step 1 in embodiment 1, by compound (H) and (R)-tetrahydrofuran -3- alcohol prepare compounds (I- 7)。
1H NMR(400MHz,DMSO-d6) δ 8.05 (d, J=1.8Hz, 1H), 7.58 (d, J=1.8Hz, 1H), 5.85 (s, 2H),5.38–5.31(m,1H),4.06–3.75(m,4H),2.92(s,3H),2.34(s,6H),2.32–2.24(m,1H), 2.13–2.02(m,1H).。
Step 2：(S) preparation of the bromo- 4- methyl -8- of -6- ((tetrahydrofuran -3- bases) oxygroup) quinazoline -2- amine (J-7)
According to the method for step 2 in embodiment 1, by compound (I-7) prepare compound (J-7).
1H NMR(400MHz,DMSO-d6) δ 7.69 (d, J=2.0Hz, 1H), 7.21 (d, J=2.0Hz, 1H), 6.90 (s, 2H),5.25–5.18(m,1H),3.97–3.82(m,3H),3.80–3.72(m,1H),2.66(s,3H),2.33–2.21(m, 1H),2.05–1.95(m,1H)。
Step 3：(S) system of the bromo- N of -6-, 4- dimethyl -8- ((tetrahydrofuran -3- bases) oxygroup) quinazoline -2- amine (K-7) It is standby
According to the method for step 3 in embodiment 1, by compound (J-7) prepare compound (K-7).
1H NMR(400MHz,DMSO-d6) δ 7.72 (d, J=2.0Hz, 1H), 7.34 (q, J=4.8Hz, 1H), 7.25 (s, 1H), 5.32-5.22 (m, 1H), 3.96-3.86 (m, 3H), 3.77 (dt, J=8.2,4.6Hz, 1H), 2.87 (d, J=4.8Hz, 3H),2.66(s,3H),2.27–2.17(m,1H),2.09–1.99(m,1H)。
Step 4：(S)-N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- bases) oxygroup) quinolines Oxazoline -6- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (7) preparation
According to the method for step 4 in embodiment 1, by compound (K-7) prepare compound (7).
1H NMR(400MHz,DMSO-d6) δ 10.28 (s, 1H), 8.44 (d, J=2.4Hz, 1H), 7.97 (d, J= 2.4Hz, 1H), 7.80-7.70 (m, 2H), 7.59 (ddd, J=10.4,9.2,2.4Hz, 1H), 7.38 (s, 1H), 7.29 (q, J =4.8Hz, 1H), 7.22 (dt, J=8.4,2.4Hz, 1H), 5.43-5.36 (m, 1H), 4.03-3.87 (m, 3H), 3.79 (dt, J=8.2,4.6Hz, 1H), 3.64 (s, 3H), 2.91 (d, J=4.8Hz, 3H), 2.76 (s, 3H), 2.28-2.16 (m, 1H), 2.15–2.04(m,1H)。
MS(ESI+)m/z 558.2[M+H]+。
Embodiment 8：N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrochysene -2H- pyrans -4- bases) methoxies Base) quinazoline -6- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (8)
Step 1：The bromo- 2- of 6- (2,5- dimethyl -1H- pyrroles -1- bases) -4- methyl -8- ((tetrahydrochysene -2H- pyrans -4- bases) Methoxyl group) quinazoline (I-8) preparation
According to the method for step 1 in embodiment 1, chemical combination is prepared by compound (H) and (tetrahydrochysene -2H- pyrans -4- bases) methanol Object (I-8),.
1H NMR(400MHz,DMSO-d6) δ 8.02 (d, J=1.9Hz, 1H), 7.55 (d, J=1.9Hz, 1H), 5.85 (s, 2H), 4.07 (d, J=6.2Hz, 2H), 3.94-3.86 (m, 2H), 3.36 (dt, J=11.6,2.0Hz, 2H), 2.91 (s, 3H), 2.35(s,6H),2.19–2.03(m,1H),1.78–1.69(m,2H),1.52–1.37(m,2H)。
Step 2：The preparation of the bromo- 4- methyl -8- of 6- ((tetrahydrochysene -2H- pyrans -4- bases) methoxyl group) quinazoline -2- amine (J-8)
According to the method for step 2 in embodiment 1, by compound (I-8) prepare compound (J-8).1H NMR(400MHz, DMSO-d6) δ 7.65 (d, J=2.0Hz, 1H), 7.22 (d, J=2.0Hz, 1H), 6.83 (s, 2H), 3.95 (d, J=6.7Hz, 2H),3.92–3.84(m,2H),3.40–3.32(m,2H),2.65(s,3H),2.14–1.99(m,1H),1.78–1.69(m, 2H),1.43–1.28(m,2H)。
Step 3：The bromo- N of 6-, 4- dimethyl -8- ((tetrahydrochysene -2H- pyrans -4- bases) methoxyl group) quinazoline -2- amine (K-8) It prepares
According to the method for step 3 in embodiment 1, by compound (J-8) prepare compound (K-8).
1H NMR(400MHz,DMSO-d6) δ 7.66 (d, J=2.0Hz, 1H), 7.28 (q, J=4.8Hz, 1H), 7.24 (d, J=1.4Hz, 1H), 3.98 (d, J=6.8Hz, 2H), 3.94-3.84 (m, 2H), 3.35 (dt, J=11.6,2.0Hz, 2H), 2.87 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 2.16-2.02 (m, 1H), 1.80-1.71 (m, 2H), 1.39 (qd, J= 12.4,4.4Hz, 2H).
Step 4：N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrochysene -2H- pyrans -4- bases) methoxyl group) Quinazoline -6- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (8) preparation
According to the method for step 4 in embodiment 1, by compound (K-8) and N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide prepare compound (8).
1H NMR(400MHz,DMSO-d6) δ 10.27 (s, 1H), 8.44 (d, J=2.0Hz, 1H), 7.95 (d, J= 2.0Hz, 1H), 7.76 (dt, J=8.6,6.3Hz, 1H), 7.65 (d, J=1.6Hz, 1H), 7.63-7.54 (m, 1H), 7.37 (s, 1H), 7.28-7.17 (m, 2H), 4.08 (d, J=6.4Hz, 2H), 3.95-3.87 (m, 2H), 3.64 (s, 3H), 3.37 (dt, J=11.6,2.0Hz, 2H), 2.90 (d, J=4.8Hz, 3H), 2.75 (s, 3H), 2.19-2.05 (m, 1H), 1.85- 1.74(m,2H),1.49–1.35(m,2H)。
MS(ESI+)m/z 586.2[M+H]+。
Embodiment 9：N- (5- (8- ((2,2- dimethyl tetrahydro -2H- pyrans -4- bases) oxygroup) -4- methyl -2- (methylamino) Quinazoline -6- bases) -2- methoxypyridine -3- bases) -2,4 difluorobenzene sulfonamide (9)
Step 1：The bromo- 2- of 6- (2,5- dimethyl -1H- pyrroles -1- bases) -8- ((2,2- dimethyl tetrahydro -2H- pyrans -4- Base) oxygroup) -4- methylquinazolins (I-9) preparation
According to the method for step 1 in embodiment 1, prepared by compound (H) and 2,2- dimethyl tetrahydro -2H- pyrans -4- alcohol Compound (I-9).
1H NMR(400MHz,CDCl3) δ 7.81 (d, J=1.9Hz, 1H), 7.29 (d, J=1.9Hz, 1H), 4.85-4.76 (m,1H),4.03–3.95(m,1H),3.80–3.70(m,1H),2.91(s,3H),2.44(s,6H),2.17–2.08(m,1H), 2.08–1.99(m,1H),1.92–1.75(m,2H),1.34(s,3H),1.28(s,3H)。
Step 2：The bromo- 8- of 6- ((2,2- dimethyl tetrahydro -2H- pyrans -4- bases) oxygroup) -4- methylquinazolin -2- amine (J- 9) preparation
According to the method for step 2 in embodiment 1, by compound (I-9) prepare compound (J-9).1H NMR(500MHz, DMSO-d6) δ 7.67 (d, J=1.5Hz, 1H), 7.36 (d, J=1.5Hz, 1H), 6.83 (s, 2H), 4.95-4.84 (m, 1H), 3.80–3.61(m,2H),2.66(s,3H),2.06–1.94(m,2H),1.54–1.39(m,2H),1.24(s,3H),1.21(s, 3H)。
Step 3：The bromo- 8- of 6- ((2,2- dimethyl tetrahydro -2H- pyrans -4- bases) oxygroup)-N, 4- dimethyl quinazolines -2- The preparation of amine (K-9)
According to the method for step 3 in embodiment 1, by compound (J-9) prepare compound (K-9).
1H NMR(400MHz,DMSO-d6) δ 7.72 (d, J=2.0Hz, 1H), 7.35 (d, J=2.0Hz, 1H), 7.32 (q, J=4.8Hz, 1H), 5.04-4.92 (m, 1H), 3.78 (dt, J=12.0,4.4Hz, 1H), 3.58 (t, J=10.0Hz, 1H), 2.87 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 2.01-1.83 (m, 2H), 1.67-1.43 (m, 2H), 1.29 (s, 3H), 1.17(s,3H)。
Step 4：N- (5- (8- ((2,2- dimethyl tetrahydro -2H- pyrans -4- bases) oxygroup) -4- methyl -2- (methylamino) quinolines Oxazoline -6- bases) -2- methoxypyridine -3- bases) -2,4 difluorobenzene sulfonamide (9) preparation
According to the method for step 4 in embodiment 1, by compound (K-9) and N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide prepare compound (9).
1H NMR(400MHz,DMSO-d6) δ 10.28 (s, 1H), 8.43 (d, J=2.4Hz, 1H), 7.94 (d, J= 2.4Hz, 1H), 7.79-7.71 (m, 2H), 7.59 (ddd, J=10.4,9.2,2.4Hz, 1H), 7.46 (d, J=1.8Hz, 1H), 7.27 (q, J=4.8Hz, 1H), 7.25-7.18 (m, 1H), 5.16-4.97 (m, 1H), 3.85-3.76 (m, 1H), 3.64 (s, 3H), 3.62-3.53 (m, 1H), 2.90 (d, J=4.8Hz, 3H), 2.76 (s, 3H), 2.04-1.91 (m, 2H), 1.66-1.50 (m,2H),1.29(s,3H),1.18(s,3H)。
MS(ESI+)m/z 600.2[M+H]+。
Embodiment 10：N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- bases) methoxyl group) quinolines Oxazoline -6- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (10)
Step 1：The bromo- 2- of 6- (2,5- dimethyl -1H- pyrroles -1- bases) -4- methyl -8- ((tetrahydrofuran -3- bases) methoxies Base) quinazoline (I-10) preparation
According to the method for step 1 in embodiment 1, by compound (H) and (tetrahydrofuran -3- bases) methanol prepare compound (I-10)。
1H NMR(400MHz,DMSO-d6) δ 8.03 (d, J=1.6Hz, 1H), 7.58 (d, J=1.6Hz, 1H), 5.85 (s, 2H), 4.23-4.08 (m, 2H), 3.88-3.75 (m, 2H), 3.69 (dd, J=14.8,7.6Hz, 1H), 3.62 (dd, J=8.6, 5.6Hz,1H),2.92(s,3H),2.84–2.71(m,1H),2.35(s,6H),2.12–2.00(m,1H),1.81–1.70(m, 1H)。
Step 2：The preparation of the bromo- 4- methyl -8- of 6- ((tetrahydrofuran -3- bases) methoxyl group) quinazoline -2- amine (J-10)
According to the method for step 2 in embodiment 1, by compound (I-10) prepare compound (J-10).
1H NMR(400MHz,DMSO-d6) δ 7.67 (d, J=2.0Hz, 1H), 7.26 (d, J=2.0Hz, 1H), 6.86 (s, 2H), 4.08-3.95 (m, 2H), 3.84-3.74 (m, 2H), 3.67 (dt, J=8.0,6.6Hz, 1H), 3.59 (dd, J=8.6, 5.0Hz,1H),2.78–2.68(m,1H),2.66(s,3H),2.09–1.98(m,1H),1.75–1.65(m,1H)。
Step 3：The system of the bromo- N of 6-, 4- dimethyl -8- ((tetrahydrofuran -3- bases) methoxyl group) quinazoline -2- amine (K-10) It is standby
According to the method for step 3 in embodiment 1, by compound (J-10) prepare compound (K-10).
1H NMR(400MHz,DMSO-d6) δ 7.68 (d, J=2.0Hz, 1H), 7.30 (d, J=4.8Hz, 1H), 7.28 (d, J=1.7Hz, 1H), 4.18-4.07 (m, 1H), 4.07-3.96 (m, 1H), 3.87-3.76 (m, 2H), 3.74-3.58 (m, 2H), 2.87 (d, J=4.8Hz, 3H), 2.78-2.68 (m, 1H), 2.66 (s, 3H), 2.10-1.96 (m, 1H), 1.82-1.68 (m, 1H)。
Step 4：N- (2- methoxyl groups -5- (4- methyl -2- (methylamino) -8- ((tetrahydrofuran -3- bases) methoxyl group) quinoline azoles Quinoline -6- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide (10) preparation
According to the method for step 4 in embodiment 1, by compound (K-10) prepare compound (10).
1H NMR(400MHz,DMSO-d6) δ 10.27 (s, 1H), 8.44 (d, J=2.1Hz, 1H), 7.96 (d, J= 2.2Hz, 1H), 7.75 (dt, J=8.6,6.4Hz, 1H), 7.68 (d, J=1.6Hz, 1H), 7.63-7.53 (m, 1H), 7.41 (s, 1H), 7.28-7.16 (m, 2H), 4.26-4.16 (m, 1H), 4.11 (dd, J=9.2,8.0Hz, 1H), 3.89-3.79 (m, 2H), 3.70 (dt, J=8.0,6.4Hz, 2H), 3.63 (s, 3H), 2.90 (d, J=4.8Hz, 3H), 2.82-2.70 (m, 4H), 2.12–2.00(m,1H),1.85–1.72(m,1H)。
MS(ESI+)m/z 572.2[M+H]+。
Embodiment 11：N- (5- (8- (cyclohexyl oxygroup) -4- methyl -2- (methylamino) quinazoline -6- bases) -2- methoxyl groups Pyridin-3-yl) -2,4 difluorobenzene sulfonamide (11)
Step 1：The bromo- 8- of 6- (cyclohexyl oxygroup) -2- (2,5- dimethyl -1H- pyrroles -1- bases) -4- methylquinazolins (I- 11) preparation
By compound (H) (1.661g, 5mmol), cyclohexyl bromide (8.15g, 50mmol) and potassium carbonate in seal pipe The reaction mixture of (6.91g, 50mmol) in acetonitrile (40mL) is refluxed overnight.After the mixture of generation is cooled to room temperature, Filtering.Silica gel (5g) is added in into filtrate, by evaporated under reduced pressure in the mixture of generation.Residue through flash column chromatography (silica gel, PE/EtOAc=100:1, v/v) purifying obtains product (I-11) as yellow oil (1.7g, yield 82%).
1H NMR(500MHz,DMSO-d6) δ 8.00 (d, J=2.0Hz, 1H), 7.61 (d, J=2.0Hz, 1H), 5.85 (s, 2H),4.79–4.72(m,1H),2.91(s,3H),2.35(s,6H),1.95–1.86(m,2H),1.79–1.70(m,2H), 1.69–1.57(m,2H),1.56–1.31(m,4H)。
Step 2：The preparation of the bromo- 8- of 6- (cyclohexyl oxygroup) -4- methylquinazolin -2- amine (J-11)
According to the method for step 2 in embodiment 1, by compound (I-11) prepare compound (J-11).1H NMR (400MHz,DMSO-d6) δ 7.64 (d, J=2.0Hz, 1H), 7.25 (d, J=2.0Hz, 1H), 6.83 (s, 2H), 4.58-4.45 (m,1H),2.65(s,3H),2.04–1.95(m,2H),1.82–1.67(m,2H),1.65–1.27(m,6H)。
Step 3：The preparation of the bromo- 8- of 6- (cyclohexyl oxygroup)-N, 4- dimethyl quinazoline -2- amine (K-11)
According to the method for step 3 in embodiment 1, by compound (J-11) prepare compound (K-11).
1H NMR(400MHz,DMSO-d6) δ 7.70 (d, J=2.0Hz, 1H), 7.34-7.25 (m, 2H), 4.69-4.54 (m, 1H), 2.87 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 1.98-1.86 (m, 2H), 1.82-1.71 (m, 2H), 1.61- 1.45(m,3H),1.41–1.27(m,3H)。
Step 4：N- (5- (8- (cyclohexyl oxygroup) -4- methyl -2- (methylamino) quinazoline -6- bases) -2- methoxyl group pyrroles Pyridine -3- bases) -2,4 difluorobenzene sulfonamide (11) preparation
According to the method for step 4 in embodiment 1, by compound (K-11) and N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide prepare compound (11).
1H NMR(400MHz,DMSO-d6) δ 10.28 (s, 1H), 8.42 (d, J=2.4Hz, 1H), 7.92 (d, J= 2.4Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.70 (d, J=1.2Hz, 1H), 7.59 (ddd, J=10.4,9.2, 2.4Hz, 1H), 7.41 (d, J=1.2Hz, 1H), 7.28-7.18 (m, 2H), 4.76-4.66 (m, 1H), 3.65 (s, 3H), 2.91 (d, J=4.8Hz, 3H), 2.75 (s, 3H), 2.04-1.91 (m, 2H), 1.88-1.73 (m, 2H), 1.67-1.47 (m, 3H), 1.39–1.27(m,3H)。
MS(ESI+)m/z 570.2[M+H]+。
Embodiment 12：N- (5- (8- (cyclopentyloxy) -4- methyl -2- (methylamino) quinazoline -6- bases) -2- methoxyl groups Pyridin-3-yl) -2,4 difluorobenzene sulfonamide (12)
Step 1：6- bromo- 8- (cyclopentyloxy) -2- (2,5- dimethyl -1H- pyrroles -1- bases) -4- methylquinazolins (I- 12) preparation
According to the method for step 1 in embodiment 11, by compound (H) and cyclopentyl bromide prepare compound (I-12).
1H NMR(500MHz,DMSO-d6) δ 8.00 (d, J=1.5Hz, 1H), 7.53 (d, J=1.5Hz, 1H), 5.85 (s, 2H),5.18–5.09(m,1H),2.91(s,3H),2.34(s,6H),2.03–1.92(m,2H),1.89–1.80(m,2H), 1.80–1.70(m,2H),1.69–1.58(m,2H)。
Step 2：The preparation of 6- bromo- 8- (cyclopentyloxy) -4- methylquinazolin -2- amine (J-12)
According to the method for step 2 in embodiment 1, by compound (I-12) prepare compound (J-12).
1H NMR(400MHz,DMSO-d6) δ 7.64 (d, J=2.0Hz, 1H), 7.16 (d, J=2.0Hz, 1H), 6.83 (s, 2H),5.00–4.94(m,1H),2.65(s,3H),2.04–1.91(m,2H),1.80–1.68(m,4H),1.66–1.53(m, 2H)。
Step 3：The preparation of 6- bromo- 8- (cyclopentyloxy)-N, 4- dimethyl quinazoline -2- amine (K-12)
According to the method for step 3 in embodiment 1, by compound (J-12) prepare compound (K-12).
1H NMR(400MHz,DMSO-d6) δ 7.66 (d, J=2.0Hz, 1H), 7.27 (q, J=4.8Hz, 1H), 7.20 (s, 1H), 5.11-4.98 (m, 1H), 2.87 (d, J=4.8Hz, 3H), 2.66 (s, 3H), 1.98-1.85 (m, 2H), 1.84-1.68 (m,4H),1.68–1.53(m,2H)。
Step 4：N- (5- (8- (cyclopentyloxy) -4- methyl -2- (methylamino) quinazoline -6- bases) -2- methoxyl group pyrroles Pyridine -3- bases) -2,4 difluorobenzene sulfonamide (12) preparation
According to the method for step 4 in embodiment 1, by compound (K-12) prepare compound (12).
1H NMR(400MHz,DMSO-d6) δ 10.28 (s, 1H), 8.43 (d, J=2.4Hz, 1H), 7.92 (d, J= 2.4Hz, 1H), 7.76 (dt, J=8.6,6.4Hz, 1H), 7.67 (d, J=1.6Hz, 1H), 7.64-7.55 (m, 1H), 7.32 (s, 1H), 7.27-7.17 (m, 2H), 5.20-5.13 (m, 1H), 3.65 (s, 3H), 2.90 (d, J=4.8Hz, 3H), 2.75 (s, 3H),1.99–1.87(m,2H),1.87–1.75(m,4H),1.69–1.55(m,2H)。
MS(ESI+)m/z 556.2[M+H]+。
Embodiment 13：N- (5- (8- cyclobutoxy group -4- methyl -2- (methylamino) quinazoline -6- bases) -2- methoxypyridines - 3- yls) -2,4 difluorobenzene sulfonamide (13)
Step 1：The bromo- 8- cyclobutoxy groups -2- of 6- (2,5- dimethyl -1H- pyrroles -1- bases) -4- methylquinazolins (I-13) Preparation
According to the method for step 1 in embodiment 11, by compound (H) and cyclobutyl bromine prepare compound (I-13).
1H NMR(400MHz,DMSO-d6) δ 8.02 (d, J=1.9Hz, 1H), 7.35 (d, J=1.9Hz, 1H), 5.85 (s, 2H), 4.98 (p, J=7.0Hz, 1H), 2.91 (s, 3H), 2.60-2.51 (m, 2H), 2.33 (s, 6H), 2.19-2.05 (m, 2H),1.92–1.77(m,1H),1.77–1.64(m,1H)。
Step 2：The preparation of the bromo- 8- cyclobutoxy groups -4- methylquinazolins -2- amine (J-13) of 6-
According to the method for step 2 in embodiment 1, by compound (I-13) prepare compound (J-13).1H NMR (400MHz,DMSO-d6) δ 7.65 (d, J=2.0Hz, 1H), 7.00 (d, J=2.0Hz, 1H), 6.89 (s, 2H), 4.81 (p, J =7.0Hz, 1H), 2.65 (s, 3H), 2.49-2.42 (m, 2H), 2.16-2.00 (m, 2H), 1.89-1.57 (m, 2H)
Step 3：The bromo- 8- cyclobutoxy groups of 6- -- N, 4- dimethyl quinazoline -2- amine (K-13)
According to the method for step 3 in embodiment 1, by compound (J-13) prepare compound (K-13).
1H NMR(400MHz,DMSO-d6) δ 7.65 (d, J=2.0Hz, 1H), 7.30 (br s, 1H), 7.01 (d, J= 1.6Hz, 1H), 4.84 (p, J=7.2Hz, 1H), 2.88 (d, J=4.8Hz, 3H), 2.65 (s, 3H), 2.49-2.42 (m, 2H), 2.19–2.03(m,2H),1.89–1.75(m,1H),1.74–1.58(m,1H)。
Step 4：N- (5- (8- cyclobutoxy group -4- methyl -2- (methylamino) quinazoline -6- bases) -2- methoxypyridines -3- Base) -2,4 difluorobenzene sulfonamide (13)
According to the method for step 4 in embodiment 1, by compound (K-13) and N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide prepare compound (13).
1H NMR(400MHz,DMSO-d6) δ 10.29 (s, 1H), 8.41 (d, J=2.4Hz, 1H), 7.91 (d, J= 2.4Hz, 1H), 7.77 (dt, J=8.6,6.4Hz, 1H), 7.59 (ddd, J=10.4,9.2,2.4Hz, 1H), 7.31-7.17 (m, 2H), 7.14 (d, J=1.2Hz, 1H), 5.05-4.88 (m, 1H), 3.66 (s, 3H), 2.91 (d, J=4.8Hz, 3H), 2.75(s,3H),2.55–2.45(m,2H),2.22–2.09(m,2H),1.90–1.78(m,1H),1.76–1.61(m,1H)。
MS(ESI+)m/z:542.2[M+H]+。
Embodiment 14：N- (6- (5- ((2,4 difluorobenzene base) sulfoamido) -6- methoxypyridine -3- bases) -4- methyl - 8- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinazoline -2- bases) acetamide (14)
Step 1：N- (the bromo- 4- methyl -8- of 6- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinazoline -2- bases) acetamide (K- 14) preparation
At room temperature by chloroacetic chloride (234mg, 3mmol) be added to compound (J-1) (338mg, 1mmol) and pyridine (396mg, 5mmol) in the mixture in DMF (10mL).4h is stirred at room temperature in the reaction mixture of generation.It is diluted with water (50mL) Reaction mixture, it is 5 to be acidified to pH value with 2M aqueous hydrochloric acid solutions, is extracted with ethyl acetate (30mL × 3).With water (30mL × 2) The organic layer merged with saline solution (30mL) washing, is dried with anhydrous sodium sulfate, is filtered, concentration.Residue is through flash chromatography column (silica gel, methylene chloride/methanol=70:1) purifying obtains product (K-14) as yellow solid (290mg, 76%).
1H NMR(400MHz,DMSO-d6) δ 10.57 (s, 1H), 7.94 (d, J=2.0Hz, 1H), 7.61 (d, J= 2.0Hz,1H),5.07–4.94(m,1H),3.93–3.85(m,2H),3.55–3.47(m,2H),2.81(s,3H),2.34(s, 3H),2.09–1.93(m,2H),1.74–1.58(m,2H)。
Step 2：N- (6- (5- ((2,4 difluorobenzene base) sulfoamido) -6- methoxypyridine -3- bases) -4- methyl -8- ((tetrahydrochysene -2H- pyrans -4- bases) oxygroup) quinazoline -2- bases) acetamide (14) preparation
According to the method for step 4 in embodiment 1, by compound (K-14) and N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) -2,4 difluorobenzene sulfonamide prepare compound (14).
1H NMR(400MHz,DMSO-d6) δ 10.55 (s, 1H), 10.32 (s, 1H), 8.52 (d, J=2.0Hz, 1H), 8.06 (d, J=2.0Hz, 1H), 7.91 (d, J=1.0Hz, 1H), 7.76 (dt, J=8.6,6.8Hz, 1H), 7.69 (d, J= 1.0Hz, 1H), 7.64-7.55 (m, 1H), 7.22 (dt, J=8.8,2.4Hz, 1H), 5.16-5.07 (m, 1H), 3.96-3.89 (m,2H),3.65(s,3H),3.58–3.45(m,2H),2.91(s,3H),2.36(s,3H),2.09–1.99(m,2H),1.79– 1.63(m,2H)。
MS(ESI+)m/z:600.2[M+H]+。
Embodiment 15：N- (6- (6- methoxyl groups -5- (methylsulfonyl amido) pyridin-3-yl) -4- methyl -8- ((tetrahydrochysene -2H- Pyrans -4- bases) oxygroup) quinazoline -2- bases) acetamide (15)
According to the method for step 4 in embodiment 1, by compound (K-14) and N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridin-3-yl) Methanesulfomide prepare compound (15).
1H NMR(400MHz,DMSO-d6) δ 10.55 (s, 1H), 9.39 (s, 1H), 8.51 (d, J=2.3Hz, 1H), 8.04 (d, J=2.3Hz, 1H), 7.93 (d, J=1.7Hz, 1H), 7.70 (d, J=1.7Hz, 1H), 5.16-5.08 (m, 1H), 3.99 (s,3H),3.97–3.87(m,2H),3.55–3.47(m,2H),3.10(s,3H),2.91(s,3H),2.36(s,3H),2.11– 1.98(m,2H),1.78–1.64(m,2H)。
MS(ESI+)m/z 502.2[M+H]+。
Pharmacological activity is evaluated
Embodiment 16：Biochemistry detects PI3K alpha actives
Using vitro kinase check and evaluation the compound of the present invention to the efficiency of PI3K α.Using based on the cold of luciferase Light detection measures the kinase activity of PI3K- α by detecting in kinase reaction generated ADP levels.Kinase-GloTMSwash Enzyme detection kit is purchased from Promega companies.All detections carry out at room temperature, use OptiPlateTM- 384 whites 384 Orifice plate.PI3K alpha kinases come from Invitrogen.Substrate is PIP2 (Invitrogen).Kinase buffer liquid includes 50mM Hepes (pH 7.5), 3mM MgCl2, 100mM NaCl, 1mM EGTA, 0.03%CHAPS and 2mM DTT.By in kinase buffer liquid PI3K alpha kinases are diluted to 6.6nM and prepare PI3K alpha kinase solution.Substrate solution includes 100 μM of PIP2 and 50 μM of ATP.It will treat It surveys compound and 10mM is diluted in 100%DMSO, 3 times of serial dilutions are then pressed in 100%DMSO into 10 various concentrations. Then the compound being diluted in 100%DMSO is diluted 25 times in 1 × kinase buffer liquid.By the 2.5 diluted compounds of μ L The PI3K alpha kinase solution of solution and 2.5 μ L are added in each hole of 384 orifice plates.Started instead by the substrate solution added in per 5 μ L of hole Should, end reaction volume be a concentration of 25 μM of 10 μ L, ATP, a concentration of 50 μM of PIP2, a concentration of 1.65nM of PI3K alpha kinases.By plate It covers and carries out reaction 1 hour in room temperature, then add in the kinases Kinase-Glo per 10 μ L of holeTMReagent terminates reaction.It will Plate is incubated 15 minutes, then reads cold light in 2104 multiple labeling micropore board detector plate reader of EnVision.
Percentage is inhibited to be calculated based on the following formula：
Inhibit %=100- (max-sample RLU)/(max-min) * 100.
Wherein sample RLU are the cold light reading under given compound concentration, and min refers to the reading of DMSO controls, max Refer to the reading of no enzyme activity control.The IC of compound is calculated by using in XLfit programs in Excel50, the results are shown in Table 1.
Table 1：PI3K alpha kinase inhibitory activity
Embodiment 17：Mtt assay measures the survival rate of tumour cell
After the human lung carcinoma cell NCI-H460 of exponential phase is digested with 0.25% pancreas enzyme -EDTA, it is configured to certain dense The single cell suspension of degree is inoculated in 96 orifice plates by 1200/hole, per hole add in 100 μ L, for 24 hours after, add in the to be measured of various concentration Compound and the fresh culture of coordinative solvent control, add 100 μ L (DMSO final concentrations per hole<0.2%), each test-compound If 6-9 concentration group, every group sets three parallel holes.In 5%CO2, continue to cultivate 96h at 37 DEG C, add in that 20 μ L are fresh to be matched per hole The PBS solution of the MTT containing 5mg/mL of system, continues after cultivating 4h, abandons supernatant, and it is heavy that 150 μ L DMSO dissolving MTT first hairpins are added in per hole It forms sediment, after microoscillator shakes mixing, OD value (optical density, OD) is measured under the conditions of wavelength 570nm, And the tumour cell handled using DMSO solvents calculates suppression of the untested compound to growth of tumour cell as control group with following equation Rate processed, and pass through SPSS16.0 and calculate IC50：
Inhibiting rate (%)=(ODControl- ODCompound)/ODControl× 100%
Wherein, ODControlFor the mean OD value of control group, ODControlTo give the mean OD value under compound concentration.
It the results are shown in Table 2.
Table 2：To the antiproliferative activity of human lung carcinoma cell NCI-H460
Embodiment 18：Nude mouse xenograft efficacy study
Human gastric cancer HGC-27 tumour cells are collected under aseptic condition, cell density is adjusted to 1 × 10 with sterile saline6 A/mL takes 0.2mL to be inoculated in nude mice armpit dorsal sc, treats tumour growth to diameter 1cm sizes, takes out, is cut under aseptic condition The tumor mass of 1mm × 1mm sizes is uniformly inoculated in nude mice armpit dorsal sc.Treat tumour growth to 100~300mm after two weeks3Afterwards, Animal is grouped at random, starts that (being denoted as the 0th day) is administered.Untested compound is administered orally daily.It weighs in twice a week simultaneously With the length and width of vernier caliper measurement tumour, nude mice after 20 days is dislocated and put to death, removed tumor tissues, weigh and clap by administration According to.Tumor control rate is finally calculated, antitumor action intensity is evaluated with tumor control rate, the results are shown in Table 3 and Fig. 1.
Gross tumor volume is calculated according to the following formula：
Gross tumor volume=(a × b2)/2, a and b represents knurl length and width respectively.
Tumor growth inhibition percentage is calculated according to the following formula：Tumor growth inhibition (%)=(1-T/C) × 100, T is Untested compound group gross tumor volume, C are solvent control group gross tumor volume.
Tumour regression percentage is calculated according to the following formula：100 × (final gross tumor volume-primary tumor volume)/initial Gross tumor volume.
3. embodiment 4 of table to human gastric cancer HGC-27 nude mice by subcutaneous heteroplastic transplantation knurl growth inhibition effect
Pharmacological activity is summarized：
All embodiments all show PI3K alpha kinases strong inhibitory activity, IC50Value is respectively less than 11nM.All implementations Example all shows human lung carcinoma cell NCI-H460 strong antiproliferative activity, IC50Value is respectively less than 5 μM.Wherein, embodiment 4 There is significant inhibiting effect in the growth of nude mice by subcutaneous heteroplastic transplantation knurl to human gastric cancer HGC-27.

Claims (9)

1. a kind of formula (I) compound represented, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable Salt：
Wherein
R1Selected from C1-3Alkyl, C1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from a singly-bound or C1-3Alkylidene, wherein the C1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from halogen or C1-3Alkyl；
R2Selected from C1-3Alkyl, 3-7 members cycloalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl are optionally by least one It is a to replace selected from following group：Halogen, C1-3Alkyl, amino, C1-3Alkyl amine group, two (C1-3Alkyl) amido, trifluoromethyl, Difluoromethyl, cyano or C1-3Alkoxy；
Ring A is selected from 3-7 members cycloalkyl or 3-7 membered heterocycloalkyls；
R3Selected from C1-3Alkyl, halogen, cyano, trifluoromethyl, C1-3Alkoxy, the C of hydroxyl substitution1-3Alkyl, C1-3Alkyl amine group or Two (C1-3Alkyl) amido；
M is 0,1,2,3 or 4；When m is 2,3 or 4, R3It can be identical or different group.
2. compound according to claim 1, its stereoisomer, geometric isomer, tautomer pharmaceutically may be used The salt of receiving：
Wherein
R1Selected from C1-3Alkyl, C1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from a singly-bound or C1-3Alkylidene, wherein the C1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from halogen or C1-3Alkyl；
R2Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally replaced by least one selected from following group： Halogen, C1-3Alkyl, amino, C1-3Alkyl amino, two (C1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C1-3Alcoxyl Base；
Ring A is 3-7 member cycloalkyl；
R3Selected from C1-3Alkyl, halogen, cyano, trifluoromethyl, C1-3Alkoxy, C1-3Hydroxy alkyl, C1-3Alkyl amino or two (C1-3 Alkyl) amino；
M is 0,1,2,3 or 4；When m is 2,3 or 4, R3It can be identical or different group.
3. compound according to claim 1, its stereoisomer, geometric isomer, tautomer pharmaceutically may be used The salt of receiving：
Wherein
R1Selected from C1-3Alkyl, C1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from a singly-bound or C1-3Alkylidene, wherein the C1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from halogen or C1-3Alkyl；
R2Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally replaced by least one selected from following group： Halogen, C1-3Alkyl, amino, C1-3Alkyl amino, two (C1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C1-3Alcoxyl Base；
Ring A is 3-7 membered heterocycloalkyls；
R3Selected from C1-3Alkyl, halogen, cyano, trifluoromethyl, C1-3Alkoxy, C1-3Hydroxy alkyl, C1-3Alkyl amino or two (C1-3 Alkyl) amino；
M is 0,1,2,3 or 4；When m is 2,3 or 4, R3It can be identical or different group.
4. compound according to claim 3, its stereoisomer, geometric isomer, tautomer pharmaceutically may be used The salt of receiving：
Wherein
R1Selected from C1-3Alkyl, C1-3Alkyl-carbonyl or Cvclopropvlmethvl；
L is selected from a singly-bound or C1-3Alkylidene, wherein the C1-3Alkylidene is optionally replaced by one or more Ra；
Ra is selected from halogen or C1-3Alkyl；
R2Selected from phenyl or thienyl, wherein the phenyl and thienyl are optionally replaced by least one selected from following group： Halogen, C1-3Alkyl, amino, C1-3Alkyl amino, two (C1-3Alkyl) amino, trifluoromethyl, difluoromethyl, cyano or C1-3Alcoxyl Base；
Ring A is selected from：
R3Selected from C1-3Alkyl, halogen, cyano, trifluoromethyl, C1-3Alkoxy, C1-3Hydroxy alkyl, C1-3Alkyl amino or two (C1-3 Alkyl) amino；
M is 0,1,2,3 or 4；When m is 2,3 or 4, R3It can be identical or different group.
5. according to claim 1-4 any one of them compound, its stereoisomer, geometric isomer, tautomer or Pharmaceutically acceptable salt, wherein the compound is selected from：
6. a kind of pharmaceutical composition, it includes at least one compound according to any one of claim 1 to 5, it is vertical Body isomers, geometric isomer, tautomer or pharmaceutically acceptable salt and optional pharmaceutically acceptable carrier And/or excipient.
7. pharmaceutical composition according to claim 6 is also included except the compound, its stereoisomer, geometry are different Active constituents of medicine except structure body, tautomer or pharmaceutically acceptable salt.
8. according to claim 1-5 any one of them compound, its stereoisomer, geometric isomer, tautomer or Pharmaceutical composition described in pharmaceutically acceptable salt or according to claim 6 or 7 is preparing for preventing and/or treat Purposes in the drug of disease kinase mediated PI3K.
9. according to claim 1-5 any one of them compound, its stereoisomer, geometric isomer, tautomer or Pharmaceutical composition described in pharmaceutically acceptable salt or according to claim 6 or 7 is preparing for preventing and/or treat cancer Disease, immunity disease, angiocardiopathy, viral infection, inflammation, metabolism/endocrine dysfunction or neurological disease drug in Purposes.
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CN110382490A (en) * 2016-12-26 2019-10-25 中国医学科学院药物研究所 Quinazoline compounds and preparation method thereof, purposes and pharmaceutical composition
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CN111646973A (en) * 2019-03-04 2020-09-11 中国医学科学院药物研究所 Polysubstituted quinazoline derivative and preparation method, pharmaceutical composition and application thereof
CN111646973B (en) * 2019-03-04 2022-07-19 中国医学科学院药物研究所 Polysubstituted quinazoline derivative and preparation method, pharmaceutical composition and application thereof
CN113620976A (en) * 2020-05-09 2021-11-09 中国医学科学院药物研究所 Thiazolopyrimidine compound and preparation method, application and pharmaceutical composition thereof
CN113620976B (en) * 2020-05-09 2023-09-26 中国医学科学院药物研究所 Thiazolopyrimidine compound, preparation method, application and pharmaceutical composition thereof

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