CN105461711B - Pyrido [1,2-a] pyrimidinone analogues as PI3K inhibitor - Google Patents

Pyrido [1,2-a] pyrimidinone analogues as PI3K inhibitor Download PDF

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CN105461711B
CN105461711B CN201410271282.9A CN201410271282A CN105461711B CN 105461711 B CN105461711 B CN 105461711B CN 201410271282 A CN201410271282 A CN 201410271282A CN 105461711 B CN105461711 B CN 105461711B
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alkyl
compound
group
acid
pharmaceutically acceptable
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CN105461711A (en
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吴成德
于涛
陈曙辉
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to EP15810067.7A priority patent/EP3159341B8/en
Priority to PCT/CN2015/081518 priority patent/WO2015192760A1/en
Priority to JP2017518397A priority patent/JP6680774B2/en
Priority to CN201580027396.1A priority patent/CN106470992B/en
Priority to CA2951971A priority patent/CA2951971A1/en
Priority to AU2015276699A priority patent/AU2015276699B2/en
Priority to KR1020177000523A priority patent/KR102495840B1/en
Priority to US15/319,726 priority patent/US9856256B2/en
Priority to ES15810067T priority patent/ES2754264T3/en
Priority to EA201790016A priority patent/EA032642B1/en
Priority to TW104119646A priority patent/TWI628180B/en
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Abstract

The invention discloses a kind of pyrido [1,2-a] pyrimidinone analogues as PI3K inhibitor, in particular it relates to compound or its pharmaceutically acceptable salt shown in formula (I).

Description

Pyrido [1,2-a] pyrimidinone analogues as PI3K inhibitor
Technical field
The present invention relates to a kind of pyrido [1,2-a] pyrimidinone analogues as PI3K inhibitor, specifically, the present invention It is related to compound or its pharmaceutically acceptable salt shown in formula (I).
Background technology
PI3K accesses are the places that variation is occurred most frequently in human cancer cell, can lead to the proliferation of cell, activation, amplification letter Number.
PI3K kinases (phosphatidyl-inositol 3-kinase, PI3Ks) belongs to lipid kinase family, being capable of phosphorylation phosphatidylinositols The 3 ' ends-OH of inositol ring.Phosphatidyl-inositol 3-kinase (phosphatidylinositol-3-kinase, PI3K) be it is a kind of by The fat kinases of regulator subunit p85 or p101 and catalytic subunit p110 compositions, by being catalyzed phosphatidylinositols 4,5- diphosphonic acid (phosphatidylinositol4,5-bisphosphate, PIP2) phosphoric acid turns to phosphatidylinositols 3,4,5- triphosphoric acids (phosphatidylinositol3,4,5-trisphosphate, PIP3) and activate the Akt in downstream etc. to the increasing to cell It grows, survive and is metabolized etc. and play a crucial role.Therefore inhibit 3 kinases of phosphate acyl inositol, PI3K accesses can be influenced, to inhibit The proliferation of cancer cell and activation.
PTEN Tumor Suppressor Gene (phosphatase and tension homolog deleted on Chromosome ten) so that PIP3 dephosphorylations is generated PIP2, to realize that the negativity of PI3K/Akt signal paths is adjusted, inhibit Cell Proliferation and promotion Apoptosis.Frequently generation and PTEN are lacked in cancer in cancer for PI3K gene mutations and amplification Deng all prompt PI3K and tumorigenic substantial connection.
Invention content
The purpose of the present invention is to provide compound or its pharmaceutically acceptable salt shown in formula (I),
Wherein,
It can be by structural unitIt replaces with
E is selected from optionally by R3Substituted C1-6Alkyl, C3-10Cyclic hydrocarbon radical or heterocyclic hydrocarbyl；
In L and Q, one is selected from-C (Rd1)(Rd2)-,-C (=O) N (Rd3)-、-N(Rd4)-,-C (=NRd5- S)-, (=O)2N(Rd6)-,-S (=O) N (Rd7)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2- Or-N (Rd8) C (=O) N (Rd9)-, another be selected from singly-bound or-C (Rd1)(Rd2)-；
A, T is separately selected from N or C (Rt)；
X, 0 or 1 in Y, Z is selected from N, remaining is selected from C (Rt)；
B is selected from-C (Rd1)(Rd2)-,-C (=O) N (Rd3)-、-N(Rd4)-,-C (=NRd5- S)-, (=O)2N(Rd6)-、-S (=O) N (Rd7)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2Or-N (Rd8)C (=O) N (Rd9)-；
Hetero atom or hetero atom group are separately selected from-C (=O) N (Rd3)-、-N(Rd4)-,-C (=NRd5)-,-S (= O)2N(Rd6)-,-S (=O) N (Rd7)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O )2And/or-N (Rd8) C (=O) N (Rd9)-；
m1Separately it is selected from 0,1,2 or 3；
R1-3In one be selected fromRemaining be selected from H, F, Cl, Br, I, CN, OH, SH, NH2, CHO, COOH, or selected from optionally by R01Substituted C1-10Alkyl or miscellaneous alkyl, C3-10Cyclic hydrocarbon radical or heterocyclic hydrocarbyl, by C3-10 Cyclic hydrocarbon radical or the C of heterocyclic hydrocarbyl substitution1-10Alkyl or miscellaneous alkyl；
D1Selected from singly-bound ,-C (Rd1)(Rd2)-,-C (=O) N (Rd3)-、-N(Rd4)-,-C (=NRd5- S)-, (=O)2N (Rd6)-,-S (=O) N (Rd7)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2Or- N(Rd8) C (=O) N (Rd9)-；
D2Selected from-C (Rd1)(Rd2)-；
D3Selected from-N (Rd4)-,-C (=O) N (Rd4)-、-N(Rd4) C (=O)-,-N (Rd4) C (=O) O- ,-N (Rd4) OC (= O)-、-N(Rd4) C (=O) N (Rd4- S)-, (=O)-,-S (=O)2,-S (=O)2N(Rd6)-,-S (=O) N (Rd7)-；
R4Selected from H, or selected from optionally by R01Substituted C1-10Alkyl or miscellaneous alkyl, C3-10Cyclic hydrocarbon radical or heterocyclic hydrocarbyl, quilt C3-10Cyclic hydrocarbon radical or the C of heterocyclic hydrocarbyl substitution1-10Alkyl or miscellaneous alkyl；
N is selected from 1,2,3,4,5 or 6；
Optionally, any two R1Between, the same D2In Rd1With Rd2Between, two D2Between, R4With a D2Between Or R4With D3Between be commonly connected to form one or two 3,4,5 or 6 yuan of carbocyclic ring or miscellaneous on same carbon atom or hetero atom Ring；
Rt、Rd1、Rd2Separately it is selected from H, F, Cl, Br, I, CN, OH, SH, NH2, CHO, COOH, C (=O) NH2、S (=O) NH2, S (=O)2NH2, or selected from optionally by R01Substituted C1-10Alkyl or miscellaneous alkyl, C3-10Cyclic hydrocarbon radical or heterocyclic hydrocarbyl, By C3-10Cyclic hydrocarbon radical or the C of heterocyclic hydrocarbyl substitution1-10Alkyl or miscellaneous alkyl；
R01Selected from F, Cl, Br, I, CN, OH, SH, NH2、CHO、COOH、R02；
R02Selected from C1-10Alkyl, C1-10Alkylamino, N, bis- (C of N-1-10Alkyl) amino, C1-10Alkoxy, C1-10Alkanoyl, C1-10Alkoxy carbonyl group, C1-10Alkyl sulphonyl, C1-10Alkyl sulphinyl, C3-10Naphthenic base, C3-10Naphthene amino, C3-10Heterocycle alkane Amino, C3-10Cycloalkyloxy, C3-10Cycloalkanoyl, C3-10Cycloalkoxycarbonyl, C3-10Naphthene sulfamide base, C3-10Naphthenic base Asia sulphur Acyl group, 5-6 membered unsaturated heterocycles base, 6-12 members aryl or heteroaryl；
Hetero atom or hetero atom group are separately selected from-C (=O) N (Rd3)-、-N(Rd4)-,-C (=NRd5)-,-S (= O)2N(Rd6)-,-S (=O) N (Rd7)-,-O- ,-S- ,=O ,=S ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (= O)-,-S (=O)2And/or-N (Rd8) C (=O) N (Rd9)-；
Rd3-d9Separately it is selected from H, OH, NH2、R02；
R02Optionally by R001Substitution；
R001Selected from F, Cl, Br, I, CN, OH, N (CH3)2、NH(CH3)、NH2, CHO, COOH, trifluoromethyl, aminomethyl, hydroxyl Methyl, methyl, methoxyl group, formoxyl, methoxycarbonyl group, mesyl, methylsulfinyl；
R01、R001, hetero atom or hetero atom group number separately be selected from 0,1,2 or 3.
In the scheme of the present invention, above-mentioned E is selected from by R3Substituted C1-6Alkyl or C3-6Naphthenic base, R3Number be selected from 0,1,2 or 3 or E is selected from
Wherein,
G1~5In 0,1,2 or 3 be selected from N, remaining be selected from C (R3)；
G6Selected from-C (R3)(R3)-,-C (=O) N (R3a)-、-N(R3a)-,-C (=NR3a- S)-, (=O)2N(R3a)-、-S (=O) N (R3a)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2Or-N (R3a)C (=O) N (R3a)-；
G7~9In 0,1 or 2 be selected from N, remaining be selected from C (R3)；
G10~16In 0,1,2,3 or 4 be selected from N, remaining be selected from C (R3)；
G17Selected from N or C (R3)；
G18~22In 0,1,2 or 3 be selected from-C (=O) N (R3a)-、-N(R3a)-,-C (=NR3a- S)-, (=O)2N (R3a)-,-S (=O) N (R3a)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2Or- N(R3a) C (=O) N (R3a)-, remaining be selected from-C (R3)(R3)-；
R3aSelected from C1-10Alkyl, C1-10Alkyl acyl, C1-10Alkoxy carbonyl group, C1-10Alkyl sulphonyl, C1-10Alkyl sulfenyl Base, C3-10Naphthenic base, C3-10Cycloalkanoyl, C3-10Cycloalkoxycarbonyl, C3-10Naphthene sulfamide base, C3-10Naphthenic base sulfenyl Base, 5-6 membered unsaturated heterocycles base, 6-10 members aryl or heteroaryl；
Remaining variables are as defined in claim 1.
In the scheme of the present invention, above-mentioned E is selected from optionally by R3Substituted methyl, ethyl, propyl,
In the scheme of the present invention, above-mentioned E is selected from
In the scheme of the present invention, in above-mentioned L and Q, one is selected from-S (=O)2NH- ,-S (=O)2-、-NH-、-NHC (=O) NH-, another is selected from singly-bound ,-CH2-。
In the scheme of the present invention, 0 or 1 in above-mentioned X, Y, Z is selected from N, remaining is selected from CH, C (CH3)、C(CF3)、 CCl、CF。
In the scheme of the present invention, above-mentioned A, T are separately selected from N, CH, C (CH3)、C(CF3),CCl,CF；Or Person, B are selected from NH, N (CH3) or N (CF3)。
In the scheme of the present invention, above-mentioned any two R1Between, the same D2In Rd1With Rd2Between, two D2It Between, R4With a D2Between or R4With D3Between formed ring be selected from：
In the scheme of the present invention, above-mentioned R1-3In one be selected fromRemaining is selected from H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、ORa、N(Rb)(Rc), optionally by RdSubstituted C1-3Alkyl or cyclopropyl；
D1Selected from singly-bound ,-C (Re)(Re)-,-C (=O) N (Ra)-、-N(Ra)-,-C (=NRa- S)-, (=O)2N(Ra)-、- S (=O) N (Ra)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2Or-N (Ra)C (=O) N (Ra)-；
D2Selected from-C (Ra)(Ra)-；
N is selected from 1,2,3,4,5 or 6；
Ra、Rb、RcSeparately it is selected from H, optional RdSubstituted C1-6Alkyl or C3-6Naphthenic base；
ReSelected from H, optional RdSubstituted C1-6Alkyl or alkoxy, optional RdSubstituted C3-6Naphthenic base or cycloalkyloxy；
RdSelected from F, Cl, Br, I, CN, OH, CHO, COOH, CH3、CF3、CH3O、CH3CH2O,RdNumber be selected from 0,1,2 or 3；
Optionally, any two R1Between, the same D2In RaWith RaBetween, two D2Between or RaWith a D2It Between be commonly connected to form one or two 3,4,5 or 6 yuan of carbocyclic rings or oxa- rings on same carbon atom or oxygen atom, wherein oxygen is former The number of son is 1 or 2.
In the scheme of the present invention, above-mentioned any two R1Between, the same D2In RaWith RaBetween, two D2It Between or RaWith a D2Between formed ring be selected from cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, oxetanylmethoxy, 1,3- dioxies Five ring groups.
In the scheme of the present invention, above-mentioned R1-3In one be selected from
Remaining be selected from H, F, Cl、Br、I、CN、OH、NH2, it is methyl, ethyl, propyl, methoxyl group, ethyoxyl, methylamino, dimethylamino, halogenated methyl, halogenated Ethyl, halopropyl, aminomethyl, aminoethyl, aminopropyl, cyclopropyl.
In the scheme of the present invention, above compound or its pharmaceutically acceptable salt are selected from：
Related definition：
Unless otherwise indicated, following term used herein and phrase are intended to following meanings.One specific term Or phrase it is especially define in the case of should not be considered as it is uncertain or unclear, and should be according to common Meaning goes to understand.When herein presented trade name, it is intended that refer to its corresponding commodity or its active constituent.
C1-10Selected from C1、C2、C3、C4、C5、C6、C7、C8、C9And C10；C3-10Selected from C3、C4、C5、C6、C7、C8、C9And C10。
C1-10Alkyl or miscellaneous alkyl, C3-10Ring group or heterocyclic hydrocarbyl, by C3-10Cyclic hydrocarbon radical or the C of heterocyclic hydrocarbyl substitution1-10Alkane Base or miscellaneous alkyl include but not limited to：
C1-10Alkyl, C1-10Alkylamino, N, bis- (C of N-1-10Alkyl) amino, C1-10Alkoxy, C1-10Alkanoyl, C1-10Alcoxyl Carbonyl, C1-10Alkyl sulphonyl, C1-10Alkyl sulphinyl, C3-10Naphthenic base, C3-10Naphthene amino, C3-10Heterocycle alkylamino, C3-10Cycloalkyloxy, C3-10Cycloalkanoyl, C3-10Cycloalkyloxy group carbonyl, C3-10Naphthene sulfamide base, C3-10Naphthenic base sulfenyl Base；
Methyl, ethyl, n-propyl, isopropyl ,-CH2C(CH3)(CH3) (OH), cyclopropyl, cyclobutyl, propylmethylene, Ring propiono, benzyloxy, trifluoromethyl, aminomethyl, methylol, methoxyl group, formoxyl, methoxycarbonyl group, mesyl, methyl are sub- Sulfonyl, ethyoxyl, acetyl group, ethylsulfonyl, carbethoxyl group, dimethylamino, diethylamino, Dimethylaminocarbonyl, Diethylaminocarbonyl；
N(CH3)2,NH(CH3),-CH2CF3,-CH2CH2CF3,-CH2CH2F,-CH2CH2S (=O)2CH3,-CH2CH2CN,-CH2CH(OH)(CH3)2,- CH2CH(F)(CH3)2,-CH2CH2F,-CH2CF3,-CH2CH2CF3,-CH2CH2NH2,-CH2CH2OH,-CH2CH2OCH3,- CH2CH2CH2OCH3,-CH2CH2N(CH3)2,-S (=O)2CH3,-CH2CH2S (=O)2CH3,
Phenyl, thiazolyl, xenyl, naphthalene, cyclopenta, furyl, 3- pyrrolinyls, pyrrolidinyl, 1,3- oxygen five rings Base, pyrazolyl, 2- pyrazolinyls, pyrazolidinyl, imidazole radicals, oxazolyl, thiazolyl, 1,2,3- oxazolyls, 1,2,3- triazolyls, 1, 2,4- triazolyls, 1,3,4- thiadiazolyl groups, 4H- pyranoses, pyridyl group, piperidyl, 1,4- dioxane base, morpholinyl, pyridazine Base, pyrimidine radicals, pyrazinyl, piperazinyl, 1,3,5- trithianes base, cyanuro 1,3,5, benzofuranyl, benzothienyl, Yin Diindyl base, benzimidazolyl, benzothiazolyl, purine radicals, quinolyl, isoquinolyl, cinnoline base or quinoxalinyl；
Methyl, ethyl, propyl, methoxyl group, ethyoxyl, methylamino, dimethylamino, halogenated methyl, halogenated ethyl, halogenated third Base, aminomethyl, aminoethyl, aminopropyl, cyclopropyl；With
Term " pharmaceutically acceptable " adopted here is to be directed to those compounds, material, composition and/or agent For type, they are suitable for contacting use with the tissue of human and animal within the scope of reliable medical judgment, without Excessive toxicity, irritation, allergic reaction or other problems or complication match with rational interests/Hazard ratio.
Term " pharmaceutically acceptable salt " refers to the salt of the compounds of this invention, by present invention discover that have specific substitution It is prepared by the compound of base and the acid of relative nontoxic or alkali.It, can when in the compound of the present invention containing relatively acid functional group To pass through the side for using the alkali of sufficient amount to be contacted with the neutral form of this kind of compound in pure solution or suitable atent solvent Formula obtains base addition salts.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt. It, can be by pure solution or suitable atent solvent when in the compound of the present invention containing relatively alkaline functional group Acid-addition salts are obtained with the mode that the acid of sufficient amount is contacted with the neutral form of this kind of compound.Pharmaceutically acceptable acid addition The example of salt includes inorganic acid salt, and the inorganic acid includes such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate radical, phosphoric acid, phosphorus A sour hydrogen radical, dihydrogen phosphate, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid etc.；And acylate, the organic acid include As acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, Phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, the tartaric acid acid similar with methanesulfonic acid etc.；Further include amino acid (such as Arginine etc.) salt, and such as glucuronic acid organic acid salt (referring to Berge et al., " Pharmaceutical Salts",Journal of Pharmaceutical Science66:1-19(1977)).Certain specific chemical combination of the present invention Object contains alkalinity and acid functional group, so as to be converted into any alkali or acid-addition salts.
Preferably, so that salt is contacted with alkali or acid in a usual manner, then detach parent compound, thus again in raw compounds Property form.The forms of the parent fo of compound and its various salt is the difference is that certain physical properties, such as in polarity Different solubility in solvent.
" pharmaceutically acceptable salt " used herein belongs to the derivative of the compounds of this invention, wherein by with acid at Salt modifies the parent compound with alkali at the mode of salt.The example of pharmaceutically acceptable salt includes but not limited to：Base Such as the inorganic acid or acylate of amine, the alkali metal of acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt packet The quaternary ammonium salt of conventional avirulent salt or parent compound is included, such as nontoxic inorganic acid or organic acid are formed by salt.Often The avirulent salt of rule includes but not limited to the salt that those are derived from inorganic acid and organic acid, the inorganic acid or organic acid choosing From Aspirin, 2- ethylenehydrinsulfonic acids, acetic acid, ascorbic acid, benzene sulfonic acid, benzoic acid, bicarbonate radical, carbonic acid, lemon Lemon acid, edetic acid(EDTA), ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic, hydrobromic acid, salt Acid, hydriodate, hydroxyl, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecyl sodium sulfonate, maleic acid, malic acid, mandelic acid, first Alkyl sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, poly galacturonic, propionic acid, salicylic acid, stearic acid, Asia Acetic acid, succinic acid, sulfamic acid, p-aminobenzene sulfonic acid, sulfuric acid, tannin, tartaric acid and p-methyl benzenesulfonic acid.
The pharmaceutically acceptable salt of the present invention can pass through conventional chemical side by the parent compound containing acid group or base Method synthesizes.Under normal circumstances, the preparation method of such salt is：In the mixture of water or organic solvent or both, via trip It is reacted with the alkali appropriate of stoichiometry or acid to prepare from these compounds of acid or alkali form.It is generally preferable that ether, acetic acid The non-aqueous medias such as ethyl ester, ethyl alcohol, isopropanol or acetonitrile.
In addition to the form of salt, there is also prodrug forms for compound provided by the present invention.Compounds described herein Chemical change easily occurs in physiological conditions for prodrug to be converted to the compound of the present invention.In addition, pro-drug can be with The compound of the present invention is switched to by chemistry or biochemical method in environment in vivo.
Certain compounds of the present invention can exist with nonsolvated forms or solvation form, including hydrate shape Formula.In general, solvation form is suitable with non-solvated form, it is intended to be included within the scope.The present invention's Certain compounds can exist with polycrystalline or amorphous form.
Certain compounds of the present invention can have asymmetric carbon atom (optical centre) or double bond.It is racemic modification, non-right Isomers, geometric isomer and single isomers is reflected to be included within the scope of the present invention.
The diagrammatic representation of the compound of raceme, ambiscalemic and scalemic or enantiomer-pure is come herein From Maehr, J.Chem.Ed.1985,62:114-120.1985,62：114-120.Unless otherwise indicated, with wedge key and void Line key indicates the absolute configuration of a Stereocenter.When compound described herein contains in olefinic double bond or other geometry asymmetry The heart, unless otherwise prescribed, they include E, Z geometric isomer.Similarly, all tautomeric forms are included in the present invention Within the scope of.
The compound of the present invention may exist specific geometry or stereoisomer form.It is contemplated by the invention that all is this kind of Compound, including cis and trans isomer, (-)-and (+)-to enantiomer, (R)-and (S)-enantiomer, diastereoisomer, (D)-isomers, (L)-isomers and its racemic mixture and other mixtures, such as enantiomter or diastereomer richness The mixture of collection, all these mixtures are within the scope of the present invention.May be present in the substituent groups such as alkyl it is other not Symmetric carbon atom.All these isomers and their mixture, are included within the scope of the present invention.
Can by chiral synthesis or chiral reagent or other routine techniques prepare optically active (R)-and (S)- Isomers and D and L isomers.If expecting a kind of enantiomer of certain compound of the invention, asymmetric syntheses can be passed through Or prepared by the derivatization with chiral auxiliary, wherein gained non-enantiomer mixture detached, and auxiliary group is split It opens to provide pure required enantiomter.Alternatively, when containing basic functionality (such as amino) or acidic functionality (such as in molecule Carboxyl) when, the salt of diastereoisomer is formed with optically active acid appropriate or alkali, then passes through known in the field point One step crystallizing or chromatography carry out diastereoisomer fractionation, and then recycling obtains pure enantiomer.In addition, enantiomter and The separation of diastereoisomer is typically to be completed by using chromatography, and the chromatography uses chiral stationary phase, and optionally Ground is combined (such as generating carbaminate by amine) with chemical derivatization.
The compound of the present invention can include the original of unnatural proportions on one or more atoms for constituting the compound Daughter isotope.For example, radioisotope labeled compound can be used, such as tritium (3H), iodine-125 (125I) or C-14 (14C).This The transformation of all isotopics of the compound of invention, no matter radioactivity whether, be included within the scope of the present invention.
Term " pharmaceutically acceptable carrier " is to refer to deliver effective quantity active material of the present invention, do not interfere active matter The bioactivity of the matter and any preparation or the representative carrier of mounting medium that have no toxic side effect to host or patient include Water, oil, vegetables and minerals, cream base, lotion base, ointment bases etc..These matrix include suspending agent, tackifier, transdermal rush Into agent etc..Their preparation is well known to the technical staff in cosmetic field or topical remedy field.Other letters about carrier Breath, can refer to Remington:The Science and Practice of Pharmacy,21st Ed., Lippincott, Williams&Wilkins (2005), the content of the document are incorporated herein by reference.
Term " excipient " typically refers to carrier, diluent and/or medium required for preparing drug composition effective.
For drug or pharmacologically active agents, term " effective quantity " or " therapeutically effective amount " refer to nontoxic but can reach To the drug of desired effect or enough dosages of medicament.For the peroral dosage form in the present invention, a kind of active material in composition " effective quantity " refer to when another active material is combined in the composition for the required dosage that achieves the desired results.Have The determination of effect amount varies with each individual, and depends on age and the ordinary circumstance of receptor, also depends on specific active material, closed in case Suitable effective quantity can be determined by those skilled in the art according to routine test.
Term " active constituent ", " therapeutic agent ", " active material " or " activating agent " refer to a kind of chemical entities, it can have The therapeutic purpose disorder of effect ground, disease or illness.
Term " substituted " refers to that any one or more hydrogen atoms in specific atoms are substituted with a substituent, including are weighed The variant of hydrogen and hydrogen, as long as the compound after the valence state of specific atoms is normal and substitution is stable.When substituent group is When ketone group (i.e.=O), it is meant that two hydrogen atoms are substituted.Ketone substitution does not occur on aromatic radical.Term is " optionally substituted " refer to that can be substituted, it can not also be substituted, unless otherwise prescribed, the type and number of substituent group in chemistry can be with It can be arbitrary on the basis of realization.
When any variable (such as R) occurs in the composition of compound or structure more than primary, in every case Under definition be all independent.Thus, for example, if a group is replaced by 0-2 R, the group can be optionally At most replaced by two R, and R in each case has independent option.In addition, the group of substituent group and/or its variant It closes and is only just allowed in the case where such combination will produce stable compound.
When the key of a substituent group can be cross connected to two atomic time on a ring, this substituent group can be with this Arbitrary atom on a ring is mutually bonded.When not indicating it is connected to chemical knot by which atom in cited substituent group Structure general formula include but be not specifically mentioned compound when, this substituent group can be mutually bonded by its any atom.Substituent group And/or the combination of its variant is only just allowed in the case where such combination will produce stable compound.
Alkyl and miscellaneous alkyl atomic group (including be commonly known as alkylidene, alkenyl, sub- miscellaneous alkyl, miscellaneous thiazolinyl, alkynyl, Those of naphthenic base, Heterocyclylalkyl, cycloalkenyl group and heterocycloalkenyl group) substituent group be commonly referred to as " alkyl substituent ", it Can be selected from but not limited to one or more of following groups：- R ' ,-OR ' ,=O ,=NR ' ,=N-OR ' ,-NR ' R " ,- SR ', halogen ,-SiR ' R " R " ', OC (O) R ' ,-C (O) R ' ,-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、 NR’C(O)NR”R”’、-NR”C(O)2R ' ,-NR " " '-C (NR ' R " R " ')=NR " ", NR " " C (NR ' R ")=NR " ' ,-S (O) R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2With fluoro (C1-C4) alkyl, substituent group Number is 0~(2m '+1), and wherein m ' is the sum of carbon atom in this kind of atomic group.R', R ", R " ', R " " and R " " ' it is respectively independent The preferred hydrogen in ground, substituted or unsubstituted miscellaneous alkyl, substituted or unsubstituted aryl (such as are replaced by 1~3 halogen Aryl), substituted or unsubstituted alkyl, alkoxy, thio alkoxy group or aralkyl.When the compound of the present invention packet When including more than one R group, for example, each R group is independently to be subject to selection, as when there are more than one R', R ", R " ', R " " and R " " ' group when each of these groups.When R' and R " is attached to the same nitrogen-atoms, they can be with The nitrogen-atoms combines and forms 5-, 6- or 7- membered rings.For example,-NR'R " is intended to include but are not limited to 1- pyrrolidinyls and 4- morpholines Base.According in the above-mentioned discussion about substituent group, it will be understood by those skilled in the art that term " alkyl " is intended to include carbon atom It is bonded to the group that non-hydrogen group is constituted, such as halogenated alkyl (such as-CF3、-CH2CF3) and acyl group (such as-C (O) CH3、-C (O)CF3、-C(O)CH2OCH3Deng).
Similar to substituent group described in alkyl radicals, aryl and heteroaryl substituent are commonly referred to collectively as " aryl substituent ", Selected from such as-R ' ,-OR ' ,-NR ' R " ,-SR ' ,-halogen ,-SiR ' R " R " ', OC (O) R ' ,-C (O) R ' ,-CO2R ' ,-CONR ' R " ,-OC (O) NR ' R " ,-NR " C (O) R ', NR ' C (O) NR " R " ' ,-NR " C (O) 2R ' ,-NR " " '-C (NR ' R " R " ')=NR " ", NR " " C (NR ' R ")=NR " ' ,-S (O) R ' ,-S (O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2、 Fluorine (C1-C4) alkoxy and fluorine (C1-C4) alkyl etc., the quantity of substituent group be 0 to open chemical valence on aromatic rings sum Between；Wherein R ', R ", R " ', R " " and R " " ' preferably independently be selected from hydrogen, substituted or unsubstituted alkyl, it is substituted or not by Substituted miscellaneous alkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.When the chemical combination of the present invention When object includes more than one R group, for example, each R group is independently to be subject to selection, as when there are more than one R ', R ", R " ', R " " and R " " ' group when each of these groups.
Two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-T-C (O)-by general formula The substituent group of (CRR ') q-U- is replaced, wherein T and U independently selected from-NR- ,-O-, CRR'- or singly-bound, q be 0 to 3 it is whole Number.Alternatively, two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-A by general formula (CH2) substituent group of r B- is replaced, and wherein A and B are independent selected from-CRR '-,-O- ,-NR- ,-S- ,-S (O)-, S (O)2-、- S(O)2NR '-or singly-bound, r are 1~4 integers.Optionally, a singly-bound on the new ring being consequently formed could alternatively be double Key.Alternatively, two substituent groups on the adjacent atom of aryl or heteroaryl ring can be optionally-A by general formula (CH2) substituent group of r B- is replaced, and wherein s and d are independently selected from 0~3 integer, and X is-O- ,-NR ' ,-S- ,-S (O)-、-S(O)2Or-S (O)2NR'-.Substituent R, R ', R " and R " ' preferably separately are selected from hydrogen and are substituted or are not taken (the C in generation1-C6) alkyl.
Unless otherwise prescribed, term " halogenated element " or " halogen " itself or the part as another substituent group indicate fluorine, Chlorine, bromine or iodine atom.In addition, term " halogenated alkyl " is intended to include monohaloalkyl alkyl and multi-haloalkyl.For example, term " halogen Generation (C1-C4) alkyl " be intended to include but are not limited to trifluoromethyl, 2,2,2- trifluoroethyls, 4- chlorobutyls and 3- bromopropyls etc. Deng.
The example of halogenated alkyl includes but are not limited to：Trifluoromethyl, trichloromethyl, pentafluoroethyl group and five chloroethyls. " alkoxy " represents the abovementioned alkyl with given number carbon atom connected by oxygen bridge.C1-6Alkoxy includes C1、C2、C3、 C4、C5And C6Alkoxy.The example of alkoxy includes but not limited to：Methoxyl group, ethyoxyl, positive propoxy, isopropoxy, just Butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- amoxys." naphthenic base " includes saturation ring group, such as cyclopropyl, ring Butyl or cyclopenta.3-7 naphthenic base includes C3、C4、C5、C6And C7Naphthenic base." alkenyl " includes the hydrocarbon of straight chain or branched chain There are one or more carbon-to-carbon double bonds, such as vinyl and acrylic wherein on stabilization site any on the chain in chain.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine.
Unless otherwise prescribed, " miscellaneous " the expression hetero atom of term or hetero atom group (containing heteroatomic atomic group), including Atom other than carbon (C) and hydrogen (H) and contain these heteroatomic atomic groups, such as including oxygen (O), nitrogen (N), sulphur (S), silicon (Si), germanium (Ge), aluminium (Al), boron (B) ,-O- ,-S- ,=O ,=S ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (= O) ,-S (=O)2, and optionally by substituted-C (=O) N (H)-,-N (H)-,-C (=NH)-,-S (=O)2N (H)-or-S (=O) N (H)-.
Unless otherwise prescribed, " ring " indicates substituted or unsubstituted naphthenic base, Heterocyclylalkyl, cycloalkenyl group, heterocycle alkene Base, cycloalkynyl radical, heterocycle alkynyl, aryl or heteroaryl.So-called ring includes monocycle, connection ring, loop coil and ring or bridged ring.It is former on ring The number of son is generally defined as first number of ring, for example, " 5~7 membered ring " refers to surrounding 5~7 atoms of arrangement.Unless otherwise rule Fixed, which optionally includes 1~3 hetero atom.Therefore, " 5~7 membered ring " includes such as phenylpyridine and piperidyl；Another party Face, term " 5~7 membered heterocycloalkyl ring " include pyridyl group and piperidyl, but do not include phenyl.Term " ring " further includes containing extremely The ring system of a few ring, each " ring " independently conform to above-mentioned definition.
Unless otherwise prescribed, term " heterocycle " or " heterocycle " mean the stable monocycle rolled into a ball containing hetero atom or hetero atom, Bicyclic or tricyclic, they can be saturation, part it is undersaturated or undersaturated (aromatics), they include carbon atom and 1, 2,3 or 4 ring hetero atoms independently selected from N, O and S, wherein above-mentioned arbitrary heterocycle can be fused to formation pair on a phenyl ring Ring.Nitrogen and sulfur heteroatom can be optionally by oxidation (i.e. NO and S (O) p).Nitrogen-atoms can be it is substituted or unsubstituted (i.e. N or NR, wherein R are H or other substituent groups of defined mistake herein).The heterocycle can be attached to any hetero atom or carbon atom Stable structure is formed in side group.If the compound generated is stable, carbon potential can occur for heterocycle as described herein Or the substitution on nitrogen position.Miscellaneous ring nitrogen is optionally quaternized.One preferred embodiment is, when S in heterocycle and O atom When sum is more than 1, these hetero atoms are not adjacent to each other.Another preferred embodiment is that the sum of S and O atom is no more than in heterocycle 1.As used herein, term " aromatic heterocyclic group " or " heteroaryl " mean 5,6,7 stable unit monocycles it is bicyclic or 7,8,9 or The aromatic rings of 10 membered bicyclic heterocycles, it includes carbon atom and 1,2,3 or 4 ring hetero atom independently selected from N, O and S.Nitrogen Atom can be substituted or unsubstituted (i.e. N or NR, wherein R are H or other substituent groups of defined mistake herein).Nitrogen It can be optionally by oxidation (i.e. NO and S (O) p) with sulfur heteroatom.It is worth noting that, the sum of S and O atom does not surpass on aromatic heterocycle Cross 1.Bridged ring is also contained in the definition of heterocycle.When one or more atoms (i.e. C, O, N or S) connect two non-conterminous carbon originals Bridged ring is formed when son or nitrogen-atoms.Preferably bridged ring includes but not limited to：One carbon atom, two carbon atoms, a nitrogen-atoms, Two nitrogen-atoms and a carbon-to-nitrogen base.It is worth noting that, monocycle is always converted into tricyclic by a bridge.In bridged ring, on ring Substituent group can also appear on bridge.
The example of heterocyclic compound includes but not limited to：Acridinyl, azocine base, benzimidazolyl, benzofuranyl, benzene And sulfydryl furyl, benzo mercaptophenyl, benzoxazolyl, benzoxazoles quinoline base, benzothiazolyl, benzotriazole base, benzo Tetrazole radical, benzo isoxazolyl, benzisothia oxazolyl, benzimidazoline base, carbazyl, 4aH- carbazyls, carboline base, benzo two Hydrogen pyranose, chromene, cinnoline base decahydroquinolyl, 2H, 6H-1,5,2- dithiazine base, dihydrofuran simultaneously [2,3-b] tetrahydrofuran Base, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazole radicals, 1H- indazolyls, indoles alkenyl, indolinyl, middle nitrogen Indenyl, indyl, 3H- indyls, isatino bases, isobenzofuran-base, pyrans, isoindolyl, iso-dihydro-indole-group, different Yin Diindyl base, indyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridines base, octahydro isoquinoline Quinoline base, 1,2,3- oxadiazoles base, 1,2,4- oxadiazoles base, 1,2,5- oxadiazoles base, 1,3,4- oxadiazoles base, is disliked at oxadiazoles base Oxazolidinyl, oxazolyl, isoxazolyl, hydroxyindole base, pyrimidine radicals, phenanthridinyl, phenanthroline, azophenlyene, phenthazine, benzo xanthine Base, phenol oxazines base, phthalazinyl, piperazinyl, piperidyl, piperidone base, 4- piperidone bases, piperonyl, pteridyl, purine radicals, pyrrole Mutter base, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido oxazole, pyridine-imidazole, pyridothiazole, Pyridyl group, pyrimidine radicals, pyrrolidinyl, pyrrolinyl, 2H- pyrrole radicals, pyrrole radicals, pyrazolyl, quinazolyl, quinolyl, 4H- quinolines Piperazine base, quinoxalinyl, quininuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazole radical, 6H-1,2,5- thiophenes Diazine, 1,2,3- thiadiazolyl groups, 1,2,4- thiadiazolyl groups, 1,2,5- thiadiazolyl groups, 1,3,4- thiadiazolyl groups, thianthrene group, thiophene Oxazolyl, isothiazolyl thienyl, thienyl, thieno oxazolyl, thiophene benzothiazolyl, Thienoimidazole base, thienyl, triazine Base, 1,2,3- triazolyls, 1,2,4- triazolyls, 1,2,5- triazolyls, 1,3,4- triazolyls and xanthyl.Further include condensed ring and spiral shell Cycle compound.
Unless otherwise prescribed, term " alkyl " or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl etc.) sheet Body indicates straight chain, branch or cricoid hydrocarbon atomic group or combinations thereof, Ke Yishi as a part of of another substituent group Fully saturated, unit or polynary undersaturated can be monosubstituted, two substitutions or polysubstituted, may include divalent or more Valence atomic group, carbon atom (such as C with specified quantity1-C10Indicate 1 to 10 carbon)." alkyl " includes but not limited to aliphatic hydrocarbon Base and aryl radical, the aliphatic group include chain and ring-type, are specifically including but not limited to alkyl, alkenyl, alkynyl, the virtue Fragrant alkyl includes but not limited to aryl radical of 6-12 members, such as benzene, naphthalene etc..In some embodiments, term " alkyl " indicates Straight chain or branch atomic group or combination thereof can be fully saturated, units or polynary undersaturated, may include Divalent and polyad group.The example of saturated hydrocarbons atomic group includes but not limited to methyl, ethyl, n-propyl, isopropyl, positive fourth Base, tertiary butyl, isobutyl group, sec-butyl, isobutyl group, cyclohexyl, (cyclohexyl) methyl, Cvclopropvlmethvl and n-pentyl, just oneself The homologue or isomers of the atomic groups such as base, n-heptyl, n-octyl.Unsaturated alkyl has one or more double or triple bonds, The example includes but not limited to vinyl, 2- acrylic, cyclobutenyl, crotyl, 2- isopentene groups, 2- (butadienyl), 2,4- Pentadienyl, 3- (Isosorbide-5-Nitrae-pentadienyl), acetenyl, 1- and 3- propinyls, 3- butynyls and more advanced homologue and different Structure body.
Unless otherwise prescribed, term " miscellaneous alkyl " or its subordinate concept (such as miscellaneous alkyl, miscellaneous thiazolinyl, miscellaneous alkynyl, heteroaryl Base etc.) itself or combine indicating the straight chain of stabilization, branch or cricoid hydrocarbon atomic group with another term or combinations thereof, It is made of the carbon atom and at least one hetero atom of certain amount.In some embodiments, term " miscellaneous alkyl " itself or with Another term joint indicates stable straight chain, branch hydrocarbon atomic group or combinations thereof object, there is the carbon atom and extremely of certain amount Few hetero atom composition.In an exemplary embodiment, hetero atom be selected from B, O, N and S, wherein nitrogen and sulphur atom optionally by Oxidation, nitrogen heteroatom are optionally quaternized.Hetero atom B, O, N and S can be located at miscellaneous alkyl any interior location (including this Alkyl is attached to the position of molecule rest part).Example includes but not limited to-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、- CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3,-CH=CH-O- CH3、-CH2- CH=N-OCH3With-CH=CH-N (CH3)-CH3.At most two hetero atoms can be continuous, such as-CH2-NH- OCH3。
Term " alkoxy ", " alkylamino " and " alkylthio group " (or thio alkoxy) belongs to idiomatic expression, refers to logical respectively It crosses an oxygen atom, amino or sulphur atom and is connected to those of rest part of molecule alkyl group.
Unless otherwise prescribed, term " cyclic hydrocarbon radical ", " heterocyclic hydrocarbyl " or its subordinate concept (such as aryl, heteroaryl, ring Alkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycloalkenyl, cycloalkynyl radical, heterocycle alkynyl etc.) itself or combine with other terms distinguish table Show " alkyl ", " miscellaneous alkyl " of cyclisation.In addition, for miscellaneous alkyl or heterocyclic hydrocarbyl (such as miscellaneous alkyl, Heterocyclylalkyl), miscellaneous original Son can take up the position that the heterocycle is attached to molecule rest part.The example of naphthenic base includes but not limited to cyclopenta, hexamethylene Base, 1- cyclohexenyl groups, 3- cyclohexenyl groups, suberyl etc..The non-limiting examples of heterocycle include 1- (1,2,5,6- tetrahydropyridines Base), 1- piperidyls, 2- piperidyls, 3- piperidyls, 4- morpholinyls, morpholinyl, tetrahydrofuran -2- bases, tetrahydrofuran indoles - 3- bases, thiophane -2- bases, thiophane -3- bases, 1- piperazinyls and 2- piperazinyls.
Unless otherwise prescribed, term " aryl " indicates the aromatics hydrocarbon substituent of how unsaturated, can be monosubstituted, two substitutions Or it is polysubstituted, it can be monocycle or polycyclic (preferably 1 to 3 ring), they are fused together or are covalently attached.Term is " miscellaneous Aryl " refers to containing one to four heteroatomic aryl (or ring).In an exemplary embodiment, hetero atom be selected from B, N, O and S, wherein nitrogen and sulphur atom are optionally aoxidized, and nitrogen-atoms is optionally quaternized.Heteroaryl can be connected to point by hetero atom The rest part of son.The non-limiting embodiment of aryl or heteroaryl includes phenyl, 1- naphthalenes, 2- naphthalenes, 4- xenyls, 1- pyrroles Cough up base, 2- pyrrole radicals, 3- pyrrole radicals, 3- pyrazolyls, 2- imidazole radicals, 4- imidazole radicals, pyrazinyl, 2- oxazolyls, 4- oxazolyls, 2- Phenyl -4- oxazolyls, 5- oxazolyls, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- thiazolyls, 4- thiazolyls, 5- Thiazolyl, 2- furyls, 3- furyls, 2- thienyls, 3- thienyls, 2- pyridyl groups, 3- pyridyl groups, 4- pyridyl groups, 2- pyrimidines Base, 4- pyrimidine radicals, 5- benzothiazolyls, purine radicals, 2- benzimidazolyls, 5- indyls, 1- isoquinolyls, 5- isoquinolyls, 2- quinoxalinyls, 5- quinoxalinyls, 3- quinolyls and 6- quinolyls.The substituent group of above-mentioned any one aryl and heteroaryl ring system Selected from acceptable substituent group described below.
For simplicity, aryl when being used in combination with other terms (such as aryloxy group, arylthio, aralkyl) includes such as The aryl and heteroaryl ring of upper definition.Therefore, term " aralkyl " is intended to include that aryl is attached to those of alkyl atomic group (example Such as benzyl, phenethyl, pyridylmethyl), including wherein carbon atom (such as methylene) by such as oxygen atom replace that A little alkyl, such as phenoxymethyl, 2- pyridine oxygen methyls 3- (1- naphthoxys) propyl etc..
Term " leaving group " refers to can by substitution reaction, (such as affine substitution be anti-by another functional group or atom Answer) functional group that is replaced or atom.For example, representative leaving group includes triflate；Chlorine, bromine, iodine；Sulphonic acid ester Base, such as methanesulfonates, tosylate, brosylate, p-methyl benzenesulfonic acid ester；Acyloxy, such as acetoxyl group, trifluoro second Acyloxy etc..
Term " protecting group " includes but not limited to " amino protecting group ", " hydroxyl protection base " or " sulfhydryl protected base ".Term " amino protecting group " refers to suitable for the blocking group for preventing side reaction on ammonia nitrogen position.Representative amino protecting group includes But it is not limited to：Formoxyl；Acyl group, such as alkanoyl (such as acetyl group, trichloroacetyl or trifluoroacetyl group)；Alkoxy carbonyl Base, such as tert-butoxycarbonyl (Boc)；Arylmethoxycarbonyl groups, such as benzyloxycarbonyl group (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc)；Aryl Methyl, such as benzyl (Bn), trityl (Tr), 1,1- bis--(4'- methoxyphenyls) methyl；Silicyl, such as trimethyl first silicon Alkyl (TMS) and t-butyldimethylsilyl (TBS) etc..Term " hydroxyl protection base " refers to suitable for prevention hydroxyl The protecting group of side reaction.Representative hydroxyl protection base includes but not limited to：Alkyl, such as methyl, ethyl and tertiary butyl；Acyl group, example Such as alkanoyl (such as acetyl group)；Aryl methyl, such as benzyl (Bn), to methoxy-benzyl (PMB), 9- fluorenyl methyls (Fm) and two Phenyl methyl (benzhydryl, DPM)；Silicyl, such as trimethyl silyl (TMS) and t-butyldimethylsilyl (TBS) etc..
The compound of the present invention can be prepared by a variety of synthetic methods well-known to those skilled in the art, including under The combination of specific implementation mode that face is enumerated, itself and other chemical synthesis process is formed by embodiment and art technology Equivalent replacement mode known to upper personnel, preferred embodiment include but not limited to the embodiment of the present invention.
All solvents used in the present invention are commercially available, and can be used without being further purified.Reaction is usually lazy Under property nitrogen, carried out in anhydrous solvent.Proton magnetic resonance (PMR) data are recorded in Bruker Avance III400 (400MHz) On spectroscope, chemical shift is indicated with (ppm) at tetramethylsilane low field.Mass spectrum is in 1200 series of Agilent plus 6110 (& It is measured on 1956A).LC/MS or Shimadzu MS include a DAD：SPD-M20A (LC) and Shimadzu Micromass2020 detectors.There are one the electric spray ion sources (ESI) operated under positive or negative pattern for mass spectrograph outfit.
The present invention uses following initialisms：Aq represents water；HATU represents O-7- azepine benzos triazol-1-yl)-N, N, N', N'- tetramethylurea hexafluorophosphates；EDC represents N- (3- dimethylaminopropyls)-N'- ethyl-carbodiimide hydrochlorides；m- CPBA represents 3- chloroperoxybenzoic acids；Eq represents equivalent, equivalent；CDI represents carbonyl dimidazoles；DCM represents dichloromethane；PE generations Table petroleum ether；DIAD represents diisopropyl azo-2-carboxylic acid；DMF represents n,N-Dimethylformamide；DMSO represents dimethyl sulfoxide； EtOAc represents ethyl acetate；EtOH represents ethyl alcohol；MeOH represents methanol；CBz represents benzyloxycarbonyl group, is a kind of amine protecting group group； It is a kind of amine protecting group group that BOC, which represents tert-butyl carbonyl,；HOAc represents acetic acid；NaCNBH3Represent sodium cyanoborohydride；R.t. generation Table room temperature；O/N is represented overnight；THF represents tetrahydrofuran；Boc2O represents two carbonic ester of di-t-butyl；TFA represents trifluoro second Acid；DIPEA represents diisopropyl ethyl amine；SOCl2Represent thionyl chloride；CS2Represent carbon disulfide；TsOH is represented to toluene sulphur Acid；NFSI represents N- fluoro- N- (benzenesulfonyl) benzsulfamide；NCS represents 1- chlorine pyrrolidine-2,5-diones；n-Bu4NF represents fluorine Change tetrabutylammonium；IPrOH represents 2- propyl alcohol；Mp represents fusing point.
Compound manually orSoftware is named, and commercial compound uses supplier's directory name.
Specific implementation mode
In order to which the present invention is described in more detail, following Examples are provided, but the scope of the present invention is not limited to this.
Flow 1：
Reaction condition：A) tert-butyldimethyl silyl chlorine, 1 hydrogen-imidazoles；B) 1- tert-butoxies-N, N, N', N'- tetramethyls two Aminomethane, heating；C) 2- amidos -5- bromopyridines, acetic acid, heating；D) acetic acid, microwave；E) potassium carbonate, DMF, heating；F) R boron Fat (boric acid), 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides, potassium carbonate, dioxane, water, heating.G) mesyl chloride, three Ethamine, dichloromethane, 0 degree；H) 4,4- difluoropiperdins, diisopropylethylamine, acetonitrile, heating.
Embodiment 1
N- (5- (3- (2- (bis- fluoro- 1- piperidyls of 4,4-) ethyoxyl) -4- oxo-pyridins simultaneously [1,2-a] pyrimidin-7-yl] - 2- methoxypyridines -3-] -2,4- dimethylthiazole -5- sulfonamide
A) 2- ((tert-butyldimethyl silyl) oxygen) ethyl acetate
Ethyl glycolate (100g, 961mmol) and 1 hydrogen-imidazoles (130g, 1.9mol) are dissolved in dichloromethane (1L) to be placed in In three neck round bottom flask, 0 degree of lower addition tert-butyldimethyl silyl chlorine (158g, 1mol), mixture is stirred at room temperature 8 hours, It washes (1L*3), sodium sulphate drying is concentrated to give title compound as yellow oil (195g, 93%).
1H NMR(400MHz,CDCl3)ppmδ4.14-4.09(m,4H),1.20-1.16(t,3H),0.83(s,9H), 0.01(s,6H).
B) (Z)-ethyl 2- ((tert-butyldimethyl silyl) oxygen) -3- (dimethylamino) acrylate
By 2- ((tert-butyldimethyl silyl) oxygen) ethyl acetate (96g, 0.44mol) and 1- tert-butoxies-N, N, N', N'- Two aminomethane of tetramethyl (91.9g, 0.53mol) stirs 24 hours at reflux.Concentrate mixture, Liquid Residue silica gel Column chromatography purifies to obtain title compound as yellow oil (80g, 66.6%).
1H NMR(400MHz,CDCl3)ppmδ6.68(s,1H),4.13-4.11(q,2H),2.96(s,6H),1.28- 1.24(t,3H),0.95(s,9H),0.14(s,6H).
C) (Z)-ethyl 3- ((5- bromopyridine -2- bases) amido) -2- ((tert-butyldimethyl silyl) oxygen) acrylate
By (Z)-ethyl 3- ((5- bromopyridine -2- bases) amido) -2- ((tert-butyldimethyl silyl) oxygen) acrylate (80g, It 293mmol) is dissolved in acetic acid (800mL) with 2- amido -5- bromopyridines (50.6g, 293mmol), stirring 2 hours under 80 degree.It is dense Contracting mixture, residue are dissolved in ethyl acetate (500mL), with sodium carbonate liquor (500mL) and saturated salt solution (500mL) Wash, sodium sulphate is dry, concentration, gained residue with silica gel chromatography obtain title compound as yellow oil (74g, 63.0%).
1H NMR(400MHz,CDCl3)ppmδ8.24(s,1H),7.75-7.72(d,1H),7.63-7.60(d,1H), 6.75-6.72(d,1H),6.57-6.54(d,1H),4.25-4.20(q,2H),1.34-1.30(t,3H),1.02(s,9H), 0.22(s,6H).
D) -4 hydrogen of the bromo- 3- hydroxyls of 7--pyrido [1,2-a] pyrimidin-4-one
By (Z)-ethyl 3- ((5- bromopyridine -2- bases) amido) -2- ((tert-butyldimethyl silyl) oxygen) acrylate (2g* 34,169mmol) it is dissolved in acetic acid (13mL*34), the lower stirring 4 hours of 140 degree of microwave.Mixture is concentrated, residue is dissolved in ethyl alcohol In (50mL*34), title compound (20.4g, 50%) is obtained by filtration.
1H NMR(400MHz,CDCl3)ppmδ8.98(s,1H),8.14(s,1H),8.00-7.98(d,1H),7.79- 7.77(d,1H).
E) the bromo- 3- of 7- (2- ethoxys) -4H- pyridos [1,2-a] pyrimidin-4-one
By ethylene bromohyrin (933mg, 7.47mmol), bromo- 3- hydroxyls -4H- pyridos [1, the 2-a] pyrimidin-4-ones of 7- (600mg, 2.49mmol) and potassium carbonate (1.03g, 7.47mmol) are dissolved in n,N-Dimethylformamide (10mL), nitrogen protection Lower 110 degree are stirred to react 1 hour.LCMS shows that the reaction was complete.Crude product is obtained after reaction solution is concentrated.Crude product is directly used in next Step.
F) N- (5- (3- (2- ethoxys) -4- oxo 4H- pyridos [1,2-a] pyrimidin-7-yl) -2- methoxypyridines -3- Base) -2,4- dimethylthiazole -5- sulfonamide
The bromo- 3- of 7- (2- ethoxys) -4H- pyridos [1,2-a] pyrimidin-4-ones (704mg, 2.49mmol) are dissolved in two In six ring of oxygen (10mL) and water (2mL), N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls -1,3,2- di (hetero) oxygen pentaborane-is added 2- yls) pyridin-3-yl) -2,4- dimethylthiazole -5- sulfonamide (1.06g, 2.49mmol), potassium carbonate (687mg, 4.97mmol) and 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides (50mg).Reaction solution is stirred to react 3 hours under 100 degree. LCMS shows that the reaction was complete.Crude product will be obtained after reaction solution filtering and concentrating, crude product purifies to obtain with preparative high performance liquid chromatography White solid title product (500mg, 40%).
1H NMR(400MHz,CDCl3)ppmδ9.09(s,1H),8.24(s,1H),8.18(d,1H),8.01(d,1H), 7.80-7.67(m,1H),4.28-4.22(m,2H),4.01-3.92(m,5H),2.65(s,3H),2.56(s,3H).
G) 2- ((7- (5- (2,4- dimethylthiazole 2,4- dimethylthiazole -5- sulfoamidos) -6- methoxypyridines -3- Base) -4- oxo -4H- pyridos [1,2-a] pyrimidin-3-yl) oxygroup) ethyl methane sulfonate ester
By N- (5- (3- (2- hydroxyl-oxethyls) -4- oxo -4H- pyridos [1,2-a] pyrimidin-7-yl) pyridin-3-yl) - 2,4- dimethylthiazole -5- sulfonamide (50.00mg, 99.30umol) and triethylamine (20.10mg, 198.60umol) are dissolved in In dichloromethane, 0 degree of lower addition methane sulfonyl chloride (13.65mg, 119.16umol).It is stirred to react under 0 degree 1 hour.TLC is shown The reaction was complete, and dichloromethane (10mL) and water (8mL) are added into reaction solution.Organic phase is washed with saturated salt solution (10mL), nothing Aqueous sodium persulfate is dried, and filtering is concentrated to give crude product.Crude product is purified to obtain faint yellow solid shape title compound with silica gel column chromatography Object (55mg, 95.2%).
1H NMR(400MHz,CDCl3) ppm δ 9.08 (d, J=1.10Hz, 1H), 8.54 (d, J=2.43Hz, 1H), 8.21 (s,1H),7.67-7.79(m,3H),4.58-4.66(m,2H),4.43-4.50(m,2H),4.01(s,3H),3.17(s,3H), 2.74(s,3H),2.46(s,3H).
H) N- (5- (3- (2- (bis- fluoro- 1- piperidyls of 4,4-) ethyoxyl) -4- oxo-pyridins simultaneously [1,2-a] pyrimidine -7- Base] -2- methoxypyridines -3-] -2,4- dimethylthiazole -5- sulfonamide
By 2- ((7- (5- (2,4- dimethylthiazole 2,4- dimethylthiazole -5- sulfoamidos) -6- methoxypyridines -3- Base) -4- oxo -4H- pyridos [1,2-a] pyrimidin-3-yl) oxygroup) ethyl methane sulfonate ester (50.00mg, 85.96umol) and 4, 4- difluoropiperdins (12.50mg, 103.16umol) are dissolved in acetonitrile (2mL), addition diisopropylethylamine (22.22mg, 171.93umol).50 degree are stirred to react 12 hours.Liquid chromatography mass spectrometric shows that the reaction was complete.It will be obtained after reaction solution filtering and concentrating thick Product.Crude product is purified to obtain faint yellow solid shape title product (15.00mg, 28.77%) with preparative high performance liquid chromatography.
1H NMR(400MHz,CD3OD) ppm δ 9.11 (d, J=1.51Hz, 1H), 8.30 (d, J=2.26Hz, 1H), 8.27 (s, 1H), 8.01-8.11 (m, 2H), 7.74 (d, J=9.29Hz, 1H), 4.35 (t, J=5.40Hz, 2H), 3.89 (s, 3H), 2.94-2.97 (m, 2H), 2.78 (d, J=5.02Hz, 4H), 2.64 (s, 3H), 2.49 (s, 3H), 1.98-2.05 (m, 4H)
Following 5 compounds have also been synthesized with reference to the preparation method of embodiment 1：
Flow 2:
Reaction condition：A) 2- morpholines ethyl alcohol, dibromo triphenylphosphine, dichloromethane；B) the bromo- 3- hydroxyls -4H- pyridos of 7- [1,2-a] pyrimidin-4-one, potassium carbonate, n,N-Dimethylformamide；C) 2- methoxyl groups -5- (4,4,5,5- tetramethyls -1,3,2- Dioxy boron -2- bases) pyridine) -3- amine, 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides, potassium carbonate, dioxane, water, heating； D) R bases sulfonic acid chloride, pyridine.
Embodiment 7
2,4- dimethyl-N -s (2- methoxyl groups -5- (3- (2- morpholines ethyoxyl) -4- oxo -4H- pyridos [1,2-a] Pyrimidin-4-one -7- bases) pyridin-3-yl) benzsulfamide
A) 4- (2- bromoethyls) morpholine hydrobromate
Under nitrogen protection, molten to the dichloromethane (80mL) dissolved with 2- morpholines ethyl alcohol (4g, 30.49mmol) under 0 degree Dibromo triphenylphosphine (15.45g, 36.59mmol) is added portionwise in liquid.Mixed liquor stirs 18 hours under 15 degree.The reaction was complete Afterwards, reaction solution filters, and filter cake is dried under reduced pressure to obtain near-white solid (5.1g, 60.8%) after being washed with dichloromethane.
1H NMR(400MHz,CDCl3) ppm δ 4.06 (d, J=12.2Hz, 2H), 3.89-3.75 (m, 4H), 3.71- 3.63 (m, 2H), 3.56 (d, J=12.5Hz, 2H), 3.28-3.18 (m, 2H)
B) the bromo- 3- of 7- (2- morpholines ethyoxyl) -4H- pyridos [1,2-a] pyrimidin-4-one
Under nitrogen protection, by bromo- 3- hydroxyls -4H- pyridos [1, the 2-a] pyrimidin-4-ones (1g, 4.15mmol) of 7-, 4- (2- bromoethyls) morpholine hydrobromate (1.14g, 4.15mmol) and potassium carbonate (1.72g, 12.45mmol) are placed in N, N- diformazans It is stirred 2 hours in base formamide (80mL) and under 120 degree.After the completion of reaction, reaction solution concentration removes N, N- dimethyl formyls Amine.Dichloromethane is added in concentrate and filters.The solid product (1.3g, 88.4%) in brown is obtained after filtrate is concentrated.
1H NMR(400MHz CDCl3) ppm δ 9.03 (d, J=1.7Hz, 1H), 8.07 (s, 1H), 7.51 (dd, J=2.2, 9.5Hz, 1H), 7.45-7.29 (m, 1H), 4.24 (t, J=5.7Hz, 2H), 3.75-3.56 (m, 4H), 2.78 (t, J= 5.6Hz,2H),2.62-2.47(m,4H)
C) 7- (5- amino -6- methoxypyridine -3- bases) -3- (2- morpholines ethyoxyl) -4H- pyridos [1,2-a] are phonetic Pyridine -4- ketone
Under nitrogen protection, to dissolved with the bromo- 3- of 7- (2- morpholines ethyoxyl) -4H- pyridos [1,2-a] pyrimidin-4-one (100mg, 0.28mmol), 2- methoxyl groups -5- (4,4,5,5- tetramethyls -1,3,2- dioxy boron -2- bases) pyridine) -3- amine It is added 1,1 '-bis- (two in dioxane (5mL) mixed liquor of (46mg, 0.31mmol) and potassium carbonate (117mg, 0.85mmol) Phenylphosphine) ferrocene palladium bichloride (8mg, 0.008mmol) and water (1mL).This mixed liquor is under nitrogen protection in 90 degree of lower stirrings 18 hours.After the completion of reaction, reaction solution is extracted with dichloromethane.Organic phase concentrates after being dried over anhydrous sodium sulfate.Gained slightly produces Product purify to obtain near-white solid (23.82mg, 22.06%) through preparative thin-layer chromatography and preparation scale liquid chromatogram method.
1H NMR(400MHz,CDCl3) ppm δ 9.13 (d, J=1.5Hz, 1H), 8.46 (d, J=2.5Hz, 1H), 8.19 (s, 1H), 7.86 (dd, J=2.5,8.5Hz, 1H), 7.79 (dd, J=2.0,9.0Hz, 1H), 7.72-7.64 (m, 1H), 6.89 (d, J=8.5Hz, 1H), 4.33 (t, J=5.5Hz, 2H), 4.01 (s, 3H), 3.82-3.66 (m, 4H), 2.87 (t, J= 5.8Hz,2H),2.62(br.s.,4H)
D) 2,4- dimethyl-N -s (2- methoxyl groups -5- (3- (2- morpholines ethyoxyl) -4- oxo -4H- pyridos [1,2- A] pyrimidin-4-one -7- bases) pyridin-3-yl) benzsulfamide
To dissolved with 7- (5- amino -6- methoxypyridine -3- bases) -3- (2- morpholines ethyoxyl) -4H- pyridos [1,2- A] pyrimidin-4-one (100.00mg, 251.62umol) pyridine (3mL) solution in be added dropwise 2- methyl -4- fluorophenylsulfonyl chlorides (61.8mg,301.94umol).Reaction solution stirs 18 hours under 18 degree.After reaction, pyridine removes under reduced pressure.Residue is molten In dichloromethane and with water and saturated common salt water washing.Organic phase is concentrated to give crude product after being dried over anhydrous sodium sulfate.This is thick Product purifies to obtain the solid product (23.16mg, 16.11%) in yellow through preparation scale liquid chromatogram method.
1H NMR(400MHz,CDCl3) ppm δ 8.97 (s, 1H), 8.16 (s, 1H), 8.03 (d, J=2.2Hz, 1H), 7.91 (d, J=8.1Hz, 1H), 7.82 (d, J=2.0Hz, 1H), 7.65 (d, J=1.0Hz, 2H), 7.16 (d, J=8.1Hz, 1H), 7.10 (s, 1H), 4.31 (t, J=5.6Hz, 2H), 3.99 (s, 3H), 3.82-3.66 (m, 4H), 2.86 (t, J= 5.6Hz, 2H), 2.64 (s, 3H), 2.61 (d, J=4.2Hz, 4H), 2.33 (s, 3H)
Following 13 compounds have also been synthesized with reference to the preparation method of embodiment 7：
Flow 3:
Reaction condition：A) methane sulfonyl chloride, triethylamine, dichloromethane；B) potassium carbonate, n,N-Dimethylformamide；c)N- (2- methoxyl groups -5- (4,4,5,5-t tetramethyl -1,3,2- dioxaborinate -2- bases) pyridin-3-yl) -2,4- dimethylthiazoles - 5- sulfonamide, palladium, potassium carbonate, dioxane, water, heating.
Embodiment 21
N- (2- methoxyl groups -5- (4- oxos -3- (2- (2- oxo-pyrrolidine -1- bases) ethyoxyl) -4H- pyridos [1,2- A] pyrimidin-7-yl) pyridin-3-yl) -2,4- dimethylthiazole -5- sulfonamide
A) 2- (2- oxo-pyrrolidine -1- bases) ethyl methanesulfonate
Under 0 degree, to dissolved with 1- (2- hydroxyethyls) pyrrolidin-2-one (500.00mg, 3.87mmol) and triethylamine Methane sulfonyl chloride (531.97mg, 4.64mmol) is added in dichloromethane (5mL) solution of (1.17g, 11.61mmol).Reaction Liquid stirs 1 hour under 0 degree.After the completion of reaction, reaction solution water and salt water washing.Organic phase is dried over anhydrous sodium sulfate rear dense Contracting obtains yellow oily crude product (470.00mg, 58.60%).
1H NMR(400MHz,CDCl3) δ 4.35 (t, J=5.1Hz, 2H), 3.62 (t, J=5.1Hz, 2H), 3.51 (t, J =7.1Hz, 2H), 3.03 (s, 3H), 2.40 (t, J=8.1Hz, 2H), 2.06 (quin, J=7.6Hz, 2H)
B) the bromo- 3- of 7- (2- (2- oxo-pyrrolidine -1- bases) ethyoxyl) -4H- pyridos [1,2-a] pyrimidin-4-one
Under nitrogen protection, will added with bromo- 3- hydroxyls -4H- pyridos [1, the 2-a] pyrimidin-4-ones of 7- (100.00mg, 414.87umol), 2- (2- oxo-pyrrolidine -1- bases) ethyl methanesulfonates (257.94mg, 1.24mmol) and potassium carbonate N,N-dimethylformamide (10mL) mixed liquor of (229.36mg, 1.66mmol) stirs 18 hours under 120 degree.Reaction is completed Afterwards, reaction solution concentrates.Concentrate obtained after purification through silica gel chromatographic column yellow oily product (210.00mg, 79.05%, purity： 55%).
1H NMR(400MHz,CDCl3) δ 9.02 (d, J=1.7Hz, 1H), 8.03 (s, 1H), 7.51 (dd, J=2.1, 9.4Hz, 1H), 7.44-7.37 (m, 1H), 4.23 (t, J=5.1Hz, 2H), 3.67 (s, 2H), 3.62 (t, J=7.0Hz, 2H), 2.34 (t, J=8.0Hz, 2H), 2.10-1.86 (m, 2H)
C) N- (2- methoxyl groups -5- (4- oxos -3- (2- (2- oxo-pyrrolidine -1- bases) ethyoxyl) -4H- pyridos [1, 2-a] pyrimidin-7-yl) pyridin-3-yl) -2,4- dimethylthiazole -5- sulfonamide
Under nitrogen protection, to added with the bromo- 3- of 7- (2- (2- oxo-pyrrolidine -1- bases) ethyoxyl) -4H- pyridos [1, 2-a] pyrimidin-4-one (210.00mg, 327.96umol), N- (2- methoxyl groups -5- (4,4,5,5-t tetramethyl -1,3,2- dioxies Miscellaneous borine -2- bases) pyridin-3-yl) -2,4- dimethylthiazole -5- sulfonamide (145.19mg, 327.96umol) and potassium carbonate Bis- (diphenylphosphine) the ferrocene palladium bichlorides of 1,1'- are added in dioxane (5mL) mixed liquor of (135.98mg, 983.87umol) (2.40mg, 3.28umol) and water (1mL).Under nitrogen protection, mixed liquor stirs 18 hours under 90 degree.After the completion of reaction, Reaction solution concentrates.Concentration residue through preparative thin-layer chromatography purify to obtain yellow solid target compound (60.07mg, 30.41%).
1H NMR(400MHz,CDCl3) δ 8.98 (s, 1H), 8.20-8.06 (m, 3H), 7.92 (d, J=2.2Hz, 1H), 7.68 (d, J=1.1Hz, 2H), 7.58 (s, 1H), 7.28 (d, J=2.4Hz, 1H), 7.20-7.09 (m, 1H), 4.32 (t, J= 5.1Hz, 2H), 4.00 (s, 3H), 3.84-3.65 (m, 4H), 2.42 (t, J=8.0Hz, 2H), 2.08 (quin, J=7.6Hz, 2H)
Following 15 compounds have also been synthesized with reference to the preparation method of embodiment 21：
Flow 4：
Reaction condition：A) 1,2- Bromofumes, potassium carbonate, DMF, heating；B) bis- fluoro- N- of 2,4- (2- methoxyl groups -5- (4, 4,5,5- tetramethyls -1,3,2- di (hetero) oxygen pentaborane -2- bases) pyridin-3-yl) benzsulfamide, 1,1 '-bis- (diphenylphosphines) two cyclopentadienyl Iron palladium bichloride, potassium carbonate, dioxane, water, heating；C) 1H- pyrazoles, cesium carbonate, acetonitrile, heating.
Embodiment 37
Bis- fluoro- N- of 2,4- (2- methoxyl groups -5- (4- oxos -3- (2- pyrazoles -1- ethyoxyls) pyrido [1,2-a] pyrimidines - 7- yls) pyridin-3-yl) benzsulfamide
A) the bromo- 3- of 7- (2- bromine oxethyls) pyrido [1,2-a] pyrimidin-4-one
By the bromo- 3- Hydroxy-pyridines of 7- simultaneously [1,2-a] pyrimidin-4-one (600.00mg, 2.49mmol) and glycol dibromide (1.40g, 7.47mmol) is dissolved in DMF (10mL), and potassium carbonate (1.03g, 7.47mmol) is added.100 degree are stirred to react 1.5 Hour.TLC shows that the reaction was complete, and reaction solution is cooled to room temperature.Purified to obtain brown solid title with silica gel column chromatography Compound (550.00mg, 63.5%).
1H NMR(400MHz,CDCl3) ppm δ 9.10 (s, 1H), 8.20 (s, 1H), 7.61 (dd, J=9.54,1.71Hz, 1H), 7.49 (d, J=9.54Hz, 1H), 4.49 (t, J=6.36Hz, 2H), 3.66 (t, J=6.36Hz, 2H)
B) N- (5- (3- (2- bromine oxethyls) -4- oxo -4H- pyridos [1,2-a] pyrimidin-7-yl) -2- methoxyl group pyrroles Pyridine -3- bases) -2,4 difluorobenzene sulfonamide
The bromo- 3- of 7- (2- bromine oxethyls) pyrido [1,2-a] pyrimidin-4-ones (550.00mg, 1.58mmol) are dissolved in In dioxane (15mL) and water (2mL), 2,4-, bis- fluoro- N- (2- methoxyl groups -5- (4,4,5,5- tetra- are added under nitrogen protection Methyl-1,3,2- di (hetero) oxygen pentaborane -2- bases) pyridin-3-yl) benzsulfamide (673.67mg, 1.58mmol), potassium carbonate (436.74mg, 3.16mmol) and 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides (117.20mg, 158.00umol).90 degree It is stirred to react 1.5 hours.Liquid chromatography mass spectrometric shows that the reaction was complete.Crude product will be obtained after reaction solution filtering and concentrating.Crude product silicagel column Chromatography purifies to obtain faint yellow solid shape title product (250.00mg, 27.89%).
1H NMR(400MHz,CDCl3) ppm δ 9.03 (s, 1H), 8.24 (s, 1H), 8.12 (d, J=2.20Hz, 1H), 7.89-7.98(m,2H),7.68-7.76(m,2H),7.32(br.s.,1H),6.99-7.06(m,1H),6.90-6.98(m, 1H), 4.52 (t, J=6.24Hz, 2H), 3.98 (s, 3H), 3.69 (t, J=6.36Hz, 2H)
C) ((4- oxos -3- (2- pyrazoles -1- ethyoxyls) pyrido [1,2-a] is phonetic by 2- methoxyl groups -5- by bis- fluoro- N- of 2,4- Pyridine -7- bases) pyridin-3-yl) benzsulfamide
By N- (5- (3- (2- bromine oxethyls) -4- oxo -4H- pyridos [1,2-a] pyrimidin-7-yl) -2- methoxyl group pyrroles Pyridine -3- bases) -2,4 difluorobenzene sulfonamide (50.00mg, 88.13umol) and 1H- pyrazoles (9.00mg, 132.20umol) dissolving In acetonitrile (0.5mL), cesium carbonate (57.43mg, 176.26umol) is added.70 degree are stirred to react 2 hours.Liquid chromatography mass spectrometric is shown The reaction was complete.Crude product will be obtained after reaction solution filtering and concentrating.Crude product is purified to obtain yellow solid with preparative high performance liquid chromatography Shape title product (15.00mg, 30.69%).
1H NMR(400MHz,CDCl3) ppm δ 9.00 (d, J=0.98Hz, 1H), 8.11 (d, J=2.20Hz, 1H), 7.87-7.99(m,3H),7.61-7.73(m,3H),7.49-7.57(m,1H),7.34(br.s.,1H),6.98-7.06(m, 1H), 6.90-6.98 (m, 1H), 6.26 (t, J=1.96Hz, 1H), 4.57 (dd, J=10.88,4.28Hz, 4H), 3.97 (s, 3H).
Following 3 compounds have also been synthesized with reference to the preparation method of embodiment 37：
Flow 5:
Reaction condition：A) methane sulfonyl chloride, triethylamine, dichloromethane, 0 degree is arrived room temperature；B) potassium carbonate, DMF, heating；c)R Boron fat (boric acid), 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides, potassium carbonate, dioxane, water, heating；D) hydrochloric acid-acetic acid Ethyl ester, ethyl acetate, room temperature.
Embodiment 41
Bis- fluoro- N- of 2,4- (2- methoxyl groups -5- (4- oxos -3- (piperidines -4- oxygroups) -4H- pyridos [1,2-a] pyrimidines - 7- yls) pyridin-3-yl) benzsulfamide
A) tertiary butyl 4- ((methylsulfonyl) oxygen) piperidines -1- carboxylates
Tertiary butyl 4- hydroxy piperidine -1- carboxylates (1g, 4.97mmol) and triethylamine (1g, 9.95mmol) are dissolved in dichloro In methane (4mL), 0 degree of lower dropwise addition methane sulfonyl chloride (1g, 8.72mmol).Reaction solution is warmed to room temperature lower stirring instead after dripping It answers 2 hours.Reaction solution is poured into ice water and is quenched, is extracted with dichloromethane, organic phase is washed with saturated common salt, anhydrous sodium sulfate Dry, filtering obtains red solid title compound (1.6g, crude product) after concentrating filtrate.
B) tertiary butyl 4- ((bromo- 4- oxos -4H- pyridos [1,2-a] pyrimidin-3-yls of 7-) oxygen) piperidines -1- carboxylates
By tertiary butyl 4- ((methylsulfonyl) oxygen) piperidines -1- carboxylates (200mg, 0.72mmol), the bromo- 3- hydroxyls -4H- pyrroles of 7- Simultaneously [1,2-a] pyrimidin-4-one (115mg, 0.48mmol) and potassium carbonate (198mg, 1.43mmol) are dissolved in N, N- dimethyl methyls for pyridine In amide (2mL), it is stirred to react 2 hours for 120 degree under nitrogen protection.It adds water in reaction solution, is extracted with ethyl acetate, have Machine is mutually washed with saturated common salt, and anhydrous sodium sulfate drying, filtering obtains crude product after concentrating filtrate.Crude product silica gel column chromatography Method purifies to obtain red solid title compound (170mg, 84%).
1H NMR(400MHz,CDCl3)ppmδ9.14-9.10(m,1H),8.17(s,1H),7.65-7.59(m,1H), 7.53-7.47(m,1H),4.90-4.88(m,1H),3.85(m,2H),3.71-3.70(m,2H),1.95(s,3H),1.47(s, 9H).
C) tertiary butyl 4- ((7- (5- (2,4 difluorobenzene sulfonamide) -6- methoxypyridine -3- bases) -4- oxo -4H- pyridines And [1,2-a] pyrimidin-3-yl) oxygen) piperidines -1- carboxylates
By tertiary butyl 4- ((bromo- 4- oxos -4H- pyridos [1,2-a] pyrimidin-3-yls of 7-) oxygen) piperidines -1- carboxylates (130mg, 0.3mmol), 2,4- bis- fluoro- N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls -1,3,2- di (hetero) oxygen pentaboranes -2- Base) pyridin-3-yl) benzsulfamide (130mg, 0.3mmol), potassium carbonate (85mg, 0.61umol) and 1,1 '-bis- (diphenylphosphines) Ferrocene palladium bichloride (22mg, 0.03mmol) is dissolved in dioxane (2mL) and water (0.4mL).Reaction solution is in nitrogen protection It is stirred to react 2 hours for 100 degree under microwave condition.Crude product is purified to obtain Red oil title compound with silica gel column chromatography (80mg, 30%).
D) ((4- oxos -3- (piperidines -4- oxygroups) -4H- pyridos [1,2-a] are phonetic by 2- methoxyl groups -5- by bis- fluoro- N- of 2,4- Pyridine -7- bases) pyridin-3-yl) benzenesulfonamide, hydrochloride
By tertiary butyl 4- ((7- (5- (2,4 difluorobenzene sulfonamide) -6- methoxypyridine -3- bases) -4- oxo -4H- pyridines And [1,2-a] pyrimidin-3-yl) oxygen) piperidines -1- carboxylates (28mg, 0.043mmol) are dissolved in ethyl acetate (2mL), it is added Hydrochloric acid/ethyl acetate (15mL).Reaction solution is spent at room temperature to be stirred to react 1 hour.Reaction solution is filtered, solid obtains palm fibre after being spin-dried for Color solid-like title product (7.4mg, 29%).
1H NMR(400MHz,CD3OD)ppmδ9.24(s,1H),8.47-8.46(m,2H),8.37(s,1H),8.13(s, 1H),7.97-7.86(m,2H),7.26-7.21(m,1H),7.12-7.08(m,1H),4.85-4.84(m,1H),3.86(s, 1H),3.55-3.50(m,2H),3.31-3.25(m,2H),2.19(s,4H).
Following 3 compounds have also been synthesized with reference to the preparation method of embodiment 41：
Flow 6:
Reaction condition：A) the chloro- 3- nitropyridines of the bromo- 2- of 5-, R alcohol, potassium hydroxide, potassium carbonate, 2- (2- methoxyl group ethoxies Base)-N, N- bis- [2- (2- methoxy ethoxies) ethyl] ethamine, toluene；B) 4,4,5,5- tetramethyls -2- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborinate -2- bases) -1,3,2- dioxaborinates, 1,1'- bis- (diphenylphosphine) ferrocene palladium bichlorides, acetic acid Potassium, dioxane, heating；C) Pd/C, methanol；D) the chloro- pyridos of the bromo- 3- of 7- [1,2-a] pyrimidin-4-one, 1,1'- bis- (hexichol Base phosphorus) ferrocene palladium bichloride, potassium carbonate, dioxane, water, heating；E) 2,4- difluoro chlorides, pyridine；F) hydrochloric acid/dioxy Six rings, dioxane.
Embodiment 45
N- [5- (chloro- 4- oxos -4H- pyridos [1,2-a] pyrimidin-7-yls of 3-) -2- (3- (methylamino) propoxyl group) pyrroles Pyridine -3- bases] two fluoro- benzsulfamides of -2,4-
A) (3- ((the bromo- 3- nitropyridines -2- bases of 5-) oxygen) propyl) (methyl) t-butyl carbamate
To the toluene (30mL) added with potassium hydroxide (723mg, 12.89mmol) and potassium carbonate (1.78g, 12.89mmol) The chloro- 3- nitropyridines (1.8g, 7.58mmol) of the bromo- 2- of 5-, (3- hydroxypropyls) (methyl) carbamic acid uncle are added in mixed liquor Butyl ester (1.72g, 9.1mmol) and 2- (2- methoxy ethoxies)-N, N- bis- [2- (2- methoxy ethoxies) ethyl] ethamine (245mg,0.758mmol).Mixed liquor stirs 18 hours in 15 degree under nitrogen protection.After having reacted, reaction solution filtering, filtrate Through silica gel chromatograph column purification (PE after concentration:EA=20:1-4:1) yellow oily target compound (1.5g, 50%) is obtained.
1H NMR(400MHz,CDCl3) ppm δ 8.40 (d, J=2.0Hz, 1H), 8.36 (d, J=2.2Hz, 1H), 4.47 (t, J=6.1Hz, 2H), 3.40 (t, J=6.8Hz, 2H), 2.87 (s, 3H), 2.03 (s, 2H), 1.41 (s, 9H)
B) methyl (3- ((3- nitros -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborinate -2- bases) pyridine -2- bases) Oxygen) propyl) t-butyl carbamate
Under nitrogen protection, to added with (3- ((the bromo- 3- nitropyridines -2- bases of 5-) oxygen) propyl) (methyl) carbamic acid uncle Butyl ester (1.5g, 3.84mmol), 4,4,5,5- tetramethyls -2- (4,4,5,5- tetramethyl -1,3,2- dioxaborinate -2- bases) - The dioxane (30mL) of 1,3,2- dioxaborinates (1.17g, 4.61mmol) and potassium acetate (1.13g, 11.53mmol) mixes Bis- (diphenylphosphine) the ferrocene palladium bichlorides (97mg, 0.11mmol) of 1,1'- are added in liquid.This mixed liquor is under nitrogen protection in 80 Degree stirring 18 hours.After the completion of reaction after testing, reaction solution filtering obtains yellow oil after filtrate concentration through Silica gel chromatography Shape crude product (0.9g, 53%).
1H NMR(400MHz,CDCl3) ppm8.65 (d, J=1.5Hz, 1H), 8.55 (d, J=1.5Hz, 1H), 4.52 (t, J=5.7Hz, 2H), 3.41 (t, J=6.8Hz, 2H), 2.87 (s, 3H), 2.04 (br.s., 2H), 1.41 (s, 9H), 1.33 (s,12H).
C) (3- ((3- amino -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborinate -2- bases) pyridine -2- bases) oxygen) third Base) (methyl) t-butyl carbamate
To dissolved with methyl (3- ((3- nitros -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborinate -2- bases) pyridine -2- Base) oxygen) propyl) and t-butyl carbamate (900mg, 2.06mmol) methanol (10mL) solution in be added Pd/C (90.00mg). Mixed liquor stirs 4 hours in 15 degree under an atmosphere of hydrogen.After the completion of reaction after testing, reaction solution filtering obtains after filtrate concentration Yellow oily crude product (870mg, 95%).
1H NMR(400MHz,CDCl3) ppm δ 7.93 (s, 1H), 7.21 (s, 1H), 4.41 (t, J=6.0Hz, 2H), 3.39(br.s.,2H),2.85(br.s.,3H),2.00(br.s.,2H),1.41(br.s.,9H),1.31(s,12H).
D) (3- ((3- amino -5- (chloro- 4- oxos -4H- pyridos [1,2-a] pyrimidin-7-yls of 3-) pyridine -2- bases) oxygen) Propyl) (methyl) t-butyl carbamate
Under nitrogen protection, in room temperature to added with the bromo- 3- of 7- chloro- pyrido [1,2-a] pyrimidin-4-one (503mg, 1.94mmol), (3- ((3- amino -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborinate -2- bases) pyridine -2- bases) oxygen) third Base) (methyl) t-butyl carbamate (790mg, 1.94mmol) and sodium carbonate (1M, 4.85mL, 4.85mmol) dioxane Bis- (diphenylphosphine) the ferrocene palladium bichlorides (17mg, 0.019mmol) of 1,1'- are added in (10mL) mixed liquor.This mixed liquor is in nitrogen It is stirred 18 hours in 80 degree under gas shielded.After the completion of reaction after testing, reaction solution filtering, filtrate subtracts after being dried over anhydrous sodium sulfate Pressure concentration.Residue obtains yellow solid target compound (600mg, 67%) through silica gel chromatographic column after purification.
1H NMR(400MHz,CDCl3) δ 9.18 (d, J=1.7Hz, 1H), 8.48 (s, 1H), 7.97 (dd, J=2.1, 9.2Hz, 1H), 7.84-7.66 (m, 2H), 7.13 (d, J=1.7Hz, 1H), 4.45 (br.s., 2H), 3.43 (br.s., 2H), 2.88 (br.s., 3H), 2.05 (t, J=6.5Hz, 2H), 1.43 (s, 9H)
E) (3- ((5- (chloro- 4- oxos -4H- pyridos [1,2-a] pyrimidin-7-yls of 3-) -3- (2,4 difluorobenzene sulfonamide) Pyridine -2- bases) oxygen) propyl) (methyl) t-butyl carbamate
To added with (3- ((3- amino -5- (chloro- 4- oxos -4H- pyridos [1,2-a] pyrimidin-7-yls of 3-) pyridine -2- bases) Oxygen) propyl) (methyl) t-butyl carbamate (600mg, 1.3mmol) pyridine (5mL) mixed liquor in 2,4 difluorobenzene is added Sulfonic acid chloride (333mg, 1.57mmol).Mixed liquor reacts 18 hours under 15 degree.After the completion of reaction, reaction solution concentration.Residue It is dissolved in dichloromethane and with water, salt water washing.Organic phase concentrates after being dried over anhydrous sodium sulfate.Gains are pure through silica gel chromatography Change obtains yellow solid target compound (404mg, 48%).
F) N- [5- (chloro- 4- oxos -4H- pyridos [1,2-a] pyrimidin-7-yls of 3-) -2- (3- (methylamino) propoxyl group) Pyridin-3-yl] two fluoro- benzsulfamides of -2,4-
To (3- ((5- (chloro- 4- oxos -4H- pyridos [1,2-a] pyrimidin-7-yls of 3-) -3- (2,4 difluorobenzene sulfonamide) Pyridine -2- bases) oxygen) propyl) and (methyl) t-butyl carbamate (450mg, 0.43mmol) dioxane (30mL) solution in Hydrochloric acid/dioxane solution (4mL) mixed liquors are added to stir 3 hours under 15 degree.After the completion of reaction, reaction solution concentration.To dense Sodium bicarbonate aqueous solution is added in contracting residue.Sediment, which filters out, to be drained, and dichloromethane is used in combination to wash to obtain pale-yellow solid Target product (175.56mg, 75.9%).
1H NMR(400MHz,DMSO-d6) δ 8.81 (d, J=1.5Hz, 1H), 8.56 (s, 1H), 8.13 (dd, J=2.0, 9.3Hz, 1H), 8.02-7.89 (m, 1H), 7.85-7.73 (m, 2H), 7.47 (d, J=2.2Hz, 1H), 7.33-7.21 (m, 1H), 7.19-7.09 (m, 1H), 4.29 (t, J=5.4Hz, 2H), 3.20-3.08 (m, 2H), 2.72 (s, 3H), 2.08 (m, 2H).
Following 5 compounds have also been synthesized with reference to the preparation method of embodiment 45：
Flow 7：
Reaction condition：A) diethyl ethoxymethylenemalonate, ethyl alcohol, heating；B) tribromo oxygen phosphorus, heating；c)DIBAL- H, tetrahydrofuran, -5-0 degree；D) manganese dioxide, dioxane, heating；E) morpholine, acetic acid sodium borohydride, acetic acid, methanol add Heat；F) N- [2- methoxyl groups -5- (4,4,5,5- tetramethyl -1,3,2- di (hetero) oxygen pentaborane -2- bases) pyridin-3-yl] -2,4- two Methyl -5- sulfonamide, 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides, potassium carbonate, dioxane, water, heating.
Embodiment 51
N- (2- methoxyl groups -5- (3- (morpholine methyl) -4- oxo -4H- pyridos [1,2-a] pyrimidin-7-yl) pyridines - 3- yls) -2,4- dimethylthiazole -5- sulfonamide
A) 2- (((5- bromopyridine -2- bases) amino) methylene) diethyl malonate
By 2- amido -5- bromopyridines (1.72g, 9.94mmol) and diethyl ethoxymethylenemalonate (4.51g, It 20.87mmol) is placed in round-bottomed flask, 130 degree are stirred to react 2 hours.TLC shows that the reaction was complete, and mixture is cooled to 25 Degree, filtering, filter cake obtain white solid title compound (3.14g, 92%) after being eluted with petroleum ether (20mL*3).
1H NMR(400MHz,CDCl3) ppm δ 11.10 (d, J=12.47Hz, 1H), 9.06 (d, J=12.72Hz, 1H), 8.38 (d, J=2.20Hz, 1H), 7.74 (dd, J=8.56,2.45Hz, 1H), 6.76 (d, J=8.56Hz, 1H), 4.21- 4.34 (m, 4H), 1.35 (dt, J=16.02,7.15Hz, 6H)
B) bromo- 4- oxos -4H- pyridos [1,2-a] pyrimidine -3- carboxylic acid, ethyl esters of 7-
By 2- (((5- bromopyridine -2- bases) amino) methylene) diethyl malonates (21.76g, 63.41mmol) and tribromo Oxygen phosphorus (54.54g, 190.23mmol) is placed in round-bottomed flask, and 80 degree are stirred to react 4 hours.TLC shows that the reaction was complete, will mix It closes object and is cooled to 25 degree, be slowly added into ice water.Aqueous sodium carbonate is added into mixture, adjusts pH to 8 or so.With two Chloromethanes (300mL*3) extracts, and organic phase is washed with saturated salt solution (200mL*2), anhydrous sodium sulfate drying, filtering, after concentration Obtain white solid title compound (18.8g, 99.8%).
1H NMR(400MHz,CDCl3) ppm δ 9.36 (d, J=1.98Hz, 1H), 9.03 (s, 1H), 7.97 (dd, J= 9.26,1.98Hz, 1H), 7.67 (d, J=9.26Hz, 1H), 4.42 (q, J=7.06Hz, 2H), 1.41 (t, J=7.06Hz, 3H).
C) the bromo- 3- of 7- (methylol) -4H- pyrido [1,2-a] pyrimidin-4-one
Bromo- 4- oxos -4H- pyridos [1,2-a] pyrimidine -3- carboxylic acid, ethyl esters (5.00g, 16.83mmol) of 7- are dissolved in Tetrahydrofuran (150mL) is placed in three neck round bottom, and DIBAL-H is added dropwise into said mixture under -5 degree Toluene (50mL) solution of (50.49mmol).By the lower stirring 2 hours of 0 degree of reaction solution.TLC shows that the reaction was complete, into reaction solution It is slowly added to saturated aqueous ammonium chloride, is extracted with ethyl acetate (200mL*3), is washed with saturated salt solution (200mL*2), it is anhydrous Sodium sulphate is dried, and filtering is concentrated to give crude product.Crude product is purified to obtain brick-red solid shape title compound with silica gel column chromatography (1.1g, 25.6%).
1H NMR(400MHz,CDCl3) ppm δ 9.15 (d, J=1.96Hz, 1H), 8.39 (s, 1H), 7.98 (dd, J= 9.54,2.20Hz, 1H), 7.59 (d, J=9.29Hz, 1H), 4.64 (s, 2H)
D) bromo- 4- oxos -4H- pyridos [1,2-a] pyrimidine -3- formaldehyde of 7-
7- bromo- 3- (methylol) -4H- pyridos [1,2-a] pyrimidin-4-ones (0.7g, 2.74mmol) are dissolved in dioxy Six rings (15mL) are placed in 50mL round-bottomed flasks, and manganese dioxide (2.39g, 27.44mmol) is added.80 degree are stirred to react 3 hours. TLC shows that the reaction was complete, and reaction solution is cooled to room temperature.Reaction solution is diluted with dichloromethane (50mL), filtering.Filtrate is concentrated Obtain yellow solid title compound (0.6g, 86.5%).
1H NMR(400MHz,CDCl3) ppm δ 10.38 (s, 1H), 9.39 (d, J=2.21Hz, 1H), 8.90 (s, 1H), 8.06 (dd, J=9.26,2.21Hz, 1H), 7.73 (d, J=9.26Hz, 1H)
E) the bromo- 3- of 7- (morpholine methyl) -4H- pyridos [1,2-a] pyrimidin-4-one
Bromo- 4- oxos -4H- pyridos [1,2-a] pyrimidine -3- formaldehyde (88.00mg, 347.75umol) of 7- are dissolved in methanol (4mL) is placed in mother 10mL and refers in bottle, be added morpholine (45.44mg, 521.63umol) and AcOH (41.77mg, 695.51umol).50 degree are stirred 2 hours.Acetic acid sodium borohydride (294.81mg, 1.39mmol) is added into above-mentioned reaction solution, Continue stirring 12 hours under 50 degree.TLC shows that the reaction was complete, and reaction solution is cooled to room temperature.Purified with silica gel column chromatography Obtain yellow solid title compound (45mg, 40%).
1H NMR(400MHz,CDCl3) ppm δ 9.13 (d, J=1.71Hz, 1H), 8.38 (s, 1H), 7.70 (dd, J= 9.41,2.08Hz, 1H), 7.49 (d, J=9.29Hz, 1H), 3.68-3.73 (m, 4H), 3.62 (s, 2H), 2.57 (br.s., 4H).
F) N- (2- methoxyl groups -5- (3- (morpholine methyl) -4- oxo -4H- pyridos [1,2-a] pyrimidin-7-yl) pyrroles Pyridine -3- bases) -2,4- dimethylthiazole -5- sulfonamide
The bromo- 3- of 7- (morpholine methyl) -4H- pyridos [1,2-a] pyrimidin-4-ones (60.00mg, 185.09umol) is molten N- [2- methoxyl groups -5- (4,4,5,5- tetramethyls-are added in dioxane (3mL) and water (0.5mL) in solution under nitrogen protection 1,3,2- di (hetero) oxygen pentaborane -2- bases) pyridin-3-yl] -2,4- dimethylthiazole -5- sulfonamide (86.60mg, 203.60umol), potassium carbonate (51.16mg, 370.18umol) and 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides (13.54mg,18.51umol).80 degree are stirred to react 2 hours.Liquid chromatography mass spectrometric shows that the reaction was complete.After reaction solution filtering and concentrating Obtain crude product.Crude product is purified to obtain yellow solid title product (50.00mg, 50%) with preparative high performance liquid chromatography.
1H NMR(400MHz,CDCl3) ppm δ 9.23 (s, 1H), 8.42 (s, 1H), 8.20 (d, J=1.76Hz, 1H), 8.06 (s, 1H), 7.90 (dd, J=9.04,1.76Hz, 1H), 7.77 (d, J=9.04Hz, 1H), 4.00 (s, 3H), 3.76 (t, J=4.41Hz, 4H), 3.65 (s, 2H), 2.66 (s, 3H), 2.59 (s, 7H)
Following 1 compound has also been synthesized with reference to the preparation method of embodiment 51：
Flow 8:
Condition：A) malonyl chloride, dichloromethane, room temperature；B) phosphorus oxychloride, reflux；C) N- (2- hydroxypropyls) morpholine, sodium Hydrogen, tetrahydrofuran, 0 degree is arrived room temperature；D) R boron fat (boric acid), 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides, potassium carbonate, dioxy Six rings, water, heating.
Embodiment 53
((2- (2- morpholines ethyoxyl) -4- oxo -4H- pyridos [1,2-a] are phonetic by 2- methoxyl groups -5- by the fluoro- N- of the chloro- 4- of 2- Pyridine -7- bases) pyridin-3-yl) benzsulfamide
A) bromo- 2- hydroxyls -4H- pyridos [1,2-a] pyrimidin-4-ones of 7-
2- amino -5- bromopyridines (1.0g, 5.7mmol) are dissolved in dichloromethane (10mL) to be placed in 50mL round-bottomed flasks, 0 Degree is lower to be added dropwise malonyl chloride (977mg, 6.9mmol).Reaction solution is risen to 15 degree after dripping, reaction is stirred to react 48 at 15 degree Hour.LCMS shows that the reaction was complete.Reaction solution is filtered, filter cake obtains yellow solid mark after being eluted with dichloromethane (20mL) Inscribe compound (1.4g, 100%).
B) chloro- 4H- pyridos [1,2-a] pyrimidin-4-ones of the bromo- 2- of 7-
Bromo- 2- hydroxyls -4H- pyridos [1,2-a] pyrimidin-4-ones (900mg, 3.73mmol) of 7- are dissolved in phosphorus oxychloride (8mL) is placed in 50mL round-bottomed flasks, and 110 degree are stirred to react 18 hours.LCMS shows that the reaction was complete.Reaction solution is cooled to room Temperature is poured slowly into normal-temperature water (50mL) and is quenched, and is extracted with ethyl acetate (20mL*3), and organic phase is dried with anhydrous sodium sulfate, Filtering, crude product is obtained after filtrate is concentrated.Crude product is purified to obtain yellow solid title compound with silica gel column chromatography (300mg, 31%).
1H NMR(400MHz,DMSO-d6)ppmδ8.99(d,1H),8.21(dd,1H),7.65(d,1H),6.56(s, 1H).
C) the bromo- 2- of 7- (2- morpholines ethyoxyl) -4H- pyridos [1,2-a] pyrimidin-4-one
N- (2- hydroxypropyls) morpholines (404mg, 3.08mmol) are dissolved in tetrahydrofuran (5mL) and are placed in 50mL round-bottomed flasks In, sodium hydrogen (308mg, 7.71mmol, 60% purity) is added under 0 degree, is stirred to react 30 minutes under 0 degree, the bromo- 2- (2- of 7- are added dropwise Morpholine ethyoxyl) -4H- pyridos [1,2-a] pyrimidin-4-one (200mg, 770umol).Reaction solution is risen to 15 degree, stirring Reaction 3 hours.TLC shows that the reaction was complete.Reaction solution is poured slowly into ice water (50mL) and is quenched, with ethyl acetate (20mL*3) Extraction, organic phase are dried with anhydrous sodium sulfate, filter, crude product is obtained after filtrate is concentrated.Crude product is pure with thin layer chromatography is prepared Change obtains title compound (40mg, 14%).
D) the fluoro- N- of the chloro- 4- of 2- (2- methoxyl groups -5- (2- (2- morpholines ethyoxyl) -4- oxo -4H- pyridos [1,2-a] Pyrimidin-7-yl) pyridin-3-yl) benzsulfamide
The bromo- 2- of 7- (2- morpholines ethyoxyl) -4H- pyridos [1,2-a] pyrimidin-4-one (70mg, 197umol) is dissolved In dioxane (5mL) and water (1mL), the fluoro- N- of the chloro- 4- of 2- (2- methoxyl groups -5- (4,4,5,5- tetramethyls -1,3,2- is added Di (hetero) oxygen pentaborane -2- bases) pyridin-3-yl benzsulfamide (87mg, 197umol), potassium carbonate (54mg, 395umol) and 1,1 ' - Bis- (diphenylphosphine) ferrocene palladium bichlorides (7mg).Reaction solution is stirred to react 3 hours for 100 degree under nitrogen protection.LCMS is shown instead It should be complete.Crude product is obtained after reaction solution is concentrated.Crude product is purified to obtain white solid title with preparative high performance liquid chromatography Product (50mg, 42%).
1H NMR(400MHz,CDCl3)ppmδ9.08(d,1H),8.14(dd,1H),8.09(d,1H),7.90(d,1H), 7.87(dd,1H),7.58(d,2H),7.28(d,1H),7.19-7.12(m,1H),5.86(s,1H),4.58-4.48(m,2H), 3.99(s,3H),3.76(br.s.,4H),2.85(br.s.,2H),2.62(br.s.,3H).
Flow 9:
Reaction condition：A) triphosgene, triethylamine, 2,4- dimethyl -5- amino-thiazols, 0 degree；Anhydrous methylene chloride, room temperature； B) 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides, potassium acetate, duplex pinacol borate, anhydrous dioxane, heating；c) 1- (2- methoxyl group -5- bromopyridine -3- bases) -3- (2,4- dimethylthiazole -5- bases) urea, 1,1'- bis- (di-t-butyl phosphines) two cyclopentadienyl Iron palladium chloride, three hypophosphite monohydrate potassium, tetrahydrofuran, water, heating.
Embodiment 54
1- (2,4- dimethylthiazole -5- bases) -3- (2- methoxyl groups -5- (3- (2- morpholinoethyls) -4- oxo -4H- pyrroles Pyridine simultaneously [1,2-a] pyrimidin-7-yl) pyridin-3-yl) urea
A) 1- (2- methoxyl group -5- bromopyridine -3- bases) -3- (2,4- dimethylthiazole -5- bases) urea
By -5 bromopyridine (100.00mg, 492.52umol) of 2- methoxyl group -3- amidos, triethylamine (498.38mg, It 4.93mmol) is placed in 10mL three neck round bottom with anhydrous methylene chloride (5mL), three is slowly added dropwise under 0 degree, nitrogen protection Reaction 2 hours is stirred at room temperature in phosgene (438.47mg, 1.48mmol) dichloromethane solution (1mL).Add under 0 degree, nitrogen protection Enter 2,4- dimethyl -5- aminothiazoles (162.20mg, 985.04umol), reaction is stirred at room temperature overnight.Liquid chromatography mass spectrometric is shown instead Should be complete, water (50mL) is added into mixture, is extracted with dichloromethane (50mL*3), merges organic phase, uses saturated salt solution (50mL*2) wash, anhydrous sodium sulfate drying, filter, concentration, with silica gel chromatography obtain title compound (85.00mg, 48%).
1H NMR(400MHz,CD3OD)ppmδ8.57(d,1H),7.82(d,1H),4.02(s,3H),2.56(s,3H), 2.26(s,3H).
B) (3- (2- morpholinoethyls) -4- oxo -4H- pyridos [1,2-a] pyrimidin-7-yl) boric acid
By the bromo- 3- of 7- (2- morpholinoethyls) -4H- pyridos [1,2-a] pyrimidin-4-one (200.00mg, It 564.65umol) is placed in 10mL round-bottomed flask with long necks, is dissolved at room temperature in dioxane (3mL), then protected in nitrogen Shield is lower to be added duplex pinacol borate (430.16mg, 1.69mmol), and potassium acetate (221.57mg, 2.26mmol), 1,1'- is bis- (diphenylphosphino) ferrocene palladium chloride (41.32mg, 56.47umol).Mixture is placed in 100 degree to react 2 hours.Liquid phase Mass spectrum shows that the reaction was complete.Reaction solution is diluted with ethyl acetate (20mL), is used in combination water (20mL*3) to extract, water phase merges concentration Title compound (120.00mg, crude product) is obtained, crude product is not purified to be directly used as reacting in next step.
C) 1- (2,4- dimethylthiazole -5- bases) -3- (2- methoxyl groups -5- (3- (2- morpholinoethyls) -4- oxos -4H- Pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) urea
To 3- (2- morpholinoethyls) -4- oxo -4H- pyridos [1,2-a] pyrimidin-7-yl) and boric acid (120.00mg, slightly Product) tetrahydrofuran (4mL) and water (1mL) solution in 1- (2- methoxyl group -5- bromopyridine -3- bases) -3- (2,4- dimethyl is added Thiazole -5- bases) urea (30.00mg, 83.98umol), three hypophosphite monohydrate potassium (38.68mg, 167.96umol), 1,1'- bis- (two uncles Butyl phosphine) ferrocene palladium chloride (5.47mg, 8.40umol), mixture reacts 5 hours at 80 degree.Liquid chromatography mass spectrometric display reaction Completely.Crude product will be obtained after reaction solution filtering and concentrating.Crude product is purified to obtain title product with preparative high performance liquid chromatography (24.00mg, 52%).
1H NMR(400MHz,DMSO-d6)ppmδ8.92(d,1H),8.73(d,1H),8.18(s,1H),8.13(d,1H), 8.01–8.03(m,1H),7.66(d,1H),4.19–4.22(m,2H),4.01(s,3H),3.54–3.56(m,4H),2.67– 2.70(m,2H),2.45–2.49(m,7H),2.23(s,3H).
Following 1 compound has also been synthesized with reference to the preparation method of embodiment 54：
Flow 10:
Reaction condition：A) thionyl chloride, dichloromethane, room temperature；B) 7- (5- amino -6- methoxypyridine -3- bases) -3- (2- morpholines ethyoxyl) -4H- pyridos [1,2-a] pyrimidin-4-one, DMF, heating.
Embodiment 56
Nitrogen-(2- methoxyl groups -5- (- 4 pyridinium hydroxide of 3- (2- morpholinoes ethyoxyl) -4- oxos simultaneously [1,2-a] pyrimidin-7-yl) Pyridin-3-yl) -2,4- dimethylthiazole -5- formamides
A) 2,4- dimethylthiazoles -5- formyl chlorides
2,4- dimethylthiazole -5- carboxylic acids (50.0mg, 0.318mmol) and dichloromethane (2mL) are placed in 10mL round bottoms In flask, addition thionyl chloride (378.43mg, 3.18mmol) is stirred to react 1 hour at room temperature under 0 degree.TLC display reactions Completely.Black solid title compound is obtained after mixture is concentrated, and without further purification, directly carries out next step reaction.
B) nitrogen-(2- methoxyl groups -5- (- 4 pyridinium hydroxide of 3- (2- morpholinoes ethyoxyl) -4- oxos simultaneously [1,2-a] pyrimidine -7- Base) pyridin-3-yl) -2,4- dimethylthiazole -5- formamides
By 2,4- dimethylthiazole -5- formyl chlorides (50.0mg, 0.284mmol), 7- (5- amino -6- methoxypyridines -3- Base) -3- (2- morpholinoes ethyoxyl) -4 hydrogen-pyrido [1,2-a] pyrimidin-4-one (113.1mg, 0.284mmol), DMF (0.5mL) is placed in 10mL round-bottomed flasks, and 60 degree are stirred to react 0.5 hour.TLC shows that the reaction was complete, and reaction solution is cooled to Room temperature is purified to obtain title compound (10g, 80%) with preparation thin layer chromatography board.
1H NMR(400MHz,CD3OD)ppmδ9.19(s,1H),8.82(d,1H),8.35-8.37(m,1H),8.16- 8.19(m,1H),7.81(d,1H),4.50-4.52(m,2H),4.13(s,3H),3.97(s,4H),3.59(s,1H),3.49 (s,1H),2.73(d,1H).
Following 1 compound has also been synthesized with reference to the preparation method of embodiment 56：
Flow 11:
Reaction condition：A) triethylamine, diphenyl phosphate azide, the tert-butyl alcohol, heating；B) hydrochloric acid-ethyl acetate, room temperature；c) Chlorosulfonic acid, heating；D) pyridine, 2,4- dimethyl -5- aminothiazoles, dioxane, heating；E) sodium nitrite, concentrated hydrochloric acid, ice Bath；F) sodium methoxide, methanol, heating；G) duplex Knit-the-brows any alcohol borates, 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides, acetic acid Potassium, dioxane, heating；H) (3- (2- morpholines ethyoxyl) -4- oxo -4H- pyridos [1,2-a] pyrimidin-7-yl) boric acid, 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides, potassium carbonate, dioxane, water, heating.
Embodiment 58
N- (2,4- dimethylthiazole -5- bases) -2- methoxyl groups -5- (3- (2- morpholines ethyoxyl) -4- oxos -4H-4H- Pyrido [1,2-a] pyrimidin-7-yl) pyridine -3- sulfonamide
A) tertiary butyl (2,4- dimethylthiazole -5- bases) carbamate
By 2,4- dimethylthiazole -5- carboxylic acids (700.00mg, 4.45mmol), diphenyl phosphate azide (1.65g, 6.00mmol), triethylamine (1.13g, 11.13mmol) and the tert-butyl alcohol (35mL) are placed in 100mL round bottom single-necked flasks, and 85 degree are stirred It mixes 4 hours .TLC of reaction and shows that the reaction was complete, reaction solution is cooled to room temperature, H is added thereto2O (20mL), ethyl acetate extraction It takes three times, merges organic phase, anhydrous sodium sulfate drying is filtered, and filtrate is spin-dried for, and obtained crude product is purified with silica gel column chromatography To title compound (900.00mg, 88.54%).
1H NMR(400MHz,DMSO-d6)δ9.46(br.s.,1H),2.46(s,3H),2.14(s,3H),1.43(s, 9H).
B) 2,4- dimethyl -5- aminothiazole hydrochlorides
Tertiary butyl (2,4- dimethylthiazole -5- bases) carbamate is dissolved in hydrochloric acid-ethyl acetate (10mL), room Temperature stirring is spin-dried for after 1 hour, and obtained crude product is beaten to obtain title compound (700mg) with ethyl acetate.
1H NMR(400MHz,DMSO-d6)δ2.66(s,3H),2.19(s,3H).
C) the bromo- 3- sulphonyl chloropyridines of 2- amino -5-
Chlorosulfonic acid (136.18g, 57.80mmol) is placed in 250mL round bottom three-necked bottles, -15 degree, nitrogen protection are cooled to Under, 2- amino -5- bromopyridines (10.00g, 57.80mmol) are added dropwise thereto.After being added dropwise, will gradually it heat up in its oil bath To 160 degree of heating stirrings 5 hours.After reaction, it is cooled to room temperature, is poured slowly into ice, wait for that ice-out is complete, precipitation is consolidated Body washs to obtain title compound (10.00g, 63.72%) through filtering, ice water
1H NMR(400MHz,DMSO-d6) δ 8.27 (d, J=2.3Hz, 1H), 8.08 (d, J=2.0Hz, 1H)
D) the bromo- N- of 2- amino -5- (2,4- dimethylthiazole -5- bases) pyridine -3- sulfonamide
The dioxane (3mL) that the bromo- 3- sulphonyl chloropyridines (164.90mg, 607.33mmol) of 2- amino -5- will be contained is molten Liquid is placed in 50mL three-necked round bottom flask, is cooled to 0 degree, and pyridine (196.00mg, 2.48mmol) and 2,4- diformazans are added thereto Base -5- aminothiazoles hydrochloride (100.00mg, 607.33mmol).Reaction solution is gradually increased to be stirred at room temperature 2 hours, then adds Heat is reacted 1 hour to 50 degree.After reaction, it is cooled to room temperature to be dissolved in (two in the mixed solution of dichloromethane and methanol Chloromethanes：Methanol=20:1) it is filtered after, stirring 30 minutes, obtained filtrate is spin-dried for, and obtained crude product silica gel column chromatography is pure Change obtains title compound (60.00mg, 27.20%).
1H NMR(400MHz,CD3OD) δ 8.27 (d, J=2.5Hz, 1H), 7.81 (d, J=2.5Hz, 1H), 2.56 (s, 3H),2.06(s,3H).
E) the bromo- N- of the chloro- 5- of 2- (2,4- dimethylthiazole -5- bases) pyridine -3- sulfonamide
By the bromo- N- of 2- amino -5- (2,4- dimethylthiazole -5- bases) pyridine -3- sulfonamide (100.00mg, It 275.29umol) is placed in the round-bottomed flask of 25mL, is cooled to 0 degree, concentrated hydrochloric acid (7mL) is added thereto.Then under the conditions of 0 degree The aqueous solution (855.00mg, 12.39mmol, 1.5mL) of sodium nitrite is added dropwise thereto.After being added dropwise, it is warmed to room temperature Stirring 1 hour, filtering, the sodium bicarbonate solution tune pH value that filtrate is saturated to 8.After acquired solution is spin-dried for, it is dissolved in dichloromethane With (dichloromethane in the mixed solution of methanol：Methanol=10:1) it is filtered after, stirring 30 minutes, obtained filtrate is spin-dried for, and obtains Crude product obtain title compound (30.00mg, 28.48%) with thin layer chromatography.
1H NMR(400MHz,CD3OD) δ 8.76 (d, J=2.3Hz, 1H), 8.40 (d, J=2.5Hz, 1H), 2.55 (s, 3H),2.17(s,3H).
F) the bromo- N- of 2- methoxyl groups -5- (2,4- dimethylthiazole -5- bases) pyridine -3- sulfonamide
Will contain the bromo- N- of the chloro- 5- of 2- (2,4- dimethylthiazole -5- bases) pyridine -3- sulfonamide (30.00mg, It 78.39umol) is placed in closed microwave tube with the methanol solution of sodium methoxide (10.00mg, 185.19umol), is heated to 110 Degree stirring 3 hours.After completion of the reaction, it is cooled to room temperature, saturated sodium bicarbonate (5mL), dichloromethane extraction is added thereto Three times, merge organic phase, anhydrous sodium sulfate drying, filtering is spin-dried for obtaining title compound (20.00mg, 67.45%).
1H NMR(400MHz,CD3OD) δ 8.24 (d, J=2.5Hz, 1H), 8.10 (d, J=2.5Hz, 1H), 3.97 (s, 3H),2.44(s,3H),2.06(s,3H).
G) (3- (2- morpholines ethyoxyl) -4- oxo -4H- pyridos [1,2-a] pyrimidin-7-yl) boric acid
Will contain the bromo- 3- of 7- (2- morpholines ethyoxyl) -4H-4- oxo pyridines simultaneously [1,2-a] pyrimidine (80.00mg, 225.86umol), duplex Knit-the-brows any alcohol borate (172.06mg, 677.58umol), 1,1 '-bis- (diphenylphosphine) ferrocene chlorinations Dioxane (3mL) solution of palladium (49.58mg, 67.76umol) and potassium acetate (66.50mg, 677.58umol) is placed in 50mL Round bottom single-necked flask in, be heated under nitrogen protection 80 degree stir 1 hour.After reaction, water (5mL) is added thereto, Ethyl acetate extracts three times, and water phase is spin-dried for, and the mixed solution of obtained crude product dichloromethane and methanol is beaten (dichloromethane： Methanol=20:1) title compound (60.00mg, 83.24%), is obtained by filtration.
1H NMR(400MHz,CD3OD) δ 9.00 (br.s., 1H), 8.23 (s, 1H), 8.00 (d, J=7.8Hz, 1H), 7.53 (d, J=8.3Hz, 1H), 4.31 (br.s., 2H), 3.73 (br.s., 4H), 2.87 (br.s., 2H), 2.65 (br.s., 4H),1.22(s,4H).
H) N- (2,4- dimethylthiazole -5- bases) -2- methoxyl groups -5- (3- (2- morpholines ethyoxyl) -4- oxos -4H- 4H- pyridos [1,2-a] pyrimidin-7-yl) pyridine -3- sulfonamide
By the bromo- N- of 2- methoxyl groups -5- (2,4- dimethylthiazole -5- bases) pyridine -3- sulfonamide (20.00mg, 52.87umol), (3- (2- morpholines ethyoxyl) -4- oxo -4H- pyridos [1,2-a] pyrimidin-7-yl) boric acid (60.00mg, 188.02umol), 1,1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides (3.87mg, 5.29umol) and potassium carbonate (21.92mg, It 158.61umol) is dissolved in dioxane (3mL) and water (0.3mL), under nitrogen protection, reaction solution is heated to 80 degree of stirrings 1 Hour.After reaction, solution is spin-dried for, obtained crude product preparative high performance liquid chromatography purifies to obtain title compound (5.00mg, 16.51%).
1H NMR(400MHz,CD3OD) δ 9.14 (s, 1H), 8.64 (s, 1H), 8.39 (d, J=2.5Hz, 1H), 8.26 (s, 1H), 8.03 (d, J=11.3Hz, 1H), 7.74 (d, J=9.3Hz, 1H), 4.35 (t, J=5.4Hz, 2H), 4.10 (s, 3H), 3.76-3.69 (m, 4H), 2.88 (t, J=5.5Hz, 2H), 2.66 (br.s., 4H), 2.44 (s, 3H), 2.11 (s, 3H)；MS (ESI)m/z:573(M+H+).
Flow 12:
Reaction condition：A) carbonyl dimidazoles, acetonitrile, heating；B) 4- (2- chloroethyls) morpholine, cesium carbonate, dimethyl sulfoxide, Heating；C) bis- fluoro- N- of 2,4- (2- methoxyl groups -5- (4,4,5,5- tetramethyl -1,3,2- dioxo boron -2- bases) pyridin-3-yl) Benzsulfamide, [1,1 '-bis- (diphenylphosphine) ferrocene] palladium bichloride, potassium carbonate, dioxane, water, heating.
Embodiment 59
Bis- fluoro- N- of 2,4- (2- methoxyl groups -5- (three nitrogen of 2- (2- morpholines ethyl) -3- oxo -2,3- dihydros-[1,2,4] Azoles [4,3-a] pyridine -6- bases) pyrimidin-3-yl) benzsulfamide
A) bromo- [1,2,4] triazole [4,3-a] pyridine -3 (2H) -one of 6-
The bromo- 2- hydrazono-s -1,2- dihydropyridines (5.00g, 26.59mmol) of 5- and acetonitrile (100mL) are placed in 250mL Round bottom single-necked flask in, then under conditions of nitrogen protection be added carbonyl dimidazoles (4.75g, 29.29mmol).It will reaction Solution is placed in 80 degree and reacts 2 hours.Solid is precipitated in filtering, and acetonitrile (20mL) is then added and is beaten purifying, is obtained by filtration titled Close object (3.90g, 68.53%).
1H NMR(400MHz,DMSO-d6)δ12.63(br.s.,1H),8.07(s,1H),7.28-7.19(m,2H)
B) the bromo- 2- of 6- (2- morpholines ethyl)-[1,2,4] triazole [4,3-a] pyridine -3 (2H) -one
Bromo- [1,2,4] triazole [4,3-a] pyridine -3 (2H) -one (1.00g, 4.67mmol) of 6- are dissolved in diformazan Asia In sulfone (10mL), cesium carbonate (3.80g, 11.68mmol) and 4- (2- chloroethyls) morphine (1.40g, 9.34mmol) is added, obtains It is stirred at room temperature 16 hours to solution.It filters, water (10mL) is added in filtrate and then is extracted with ethyl acetate three times after reaction, Merge organic phase, anhydrous sodium sulfate drying, filtering is spin-dried for, crude product obtains title compound with column chromatography separating purification (500.00mg, 32.72%)
1H NMR(400MHz,DMSO-d6) δ 8.14 (s, 1H), 7.38-7.19 (m, 2H), 4.02 (t, J=6.5Hz, 2H), 3.53-3.49 (m, 4H), 2.68 (t, J=6.3Hz, 2H), 2.41 (br.s., 4H)
C) bis- fluoro- N- of 2,4- (2- methoxyl groups -5- (2- (2- morpholines ethyl) -3- oxo -2,3- dihydros-[1,2,4] three Nitrogen azoles [4,3-a] pyridine -6- bases) pyrimidin-3-yl) benzsulfamide
By the bromo- 2- of 6- (2- morpholines ethyl)-[1,2,4] triazole [4,3-a] pyridine -3 (2H) -one (100.00mg, 305.64umol), 2,4-, bis- fluoro- N- [2- methoxyl groups -5- (4,4,5,5- tetramethyls -1,3,2- dioxy boryl -2- bases) -3- Pyridyl group] benzsulfamide (130.28mg, 305.64umol), potassium carbonate (42.24mg, 305.64umol) and 1,1 '-bis- (hexichol Base phosphine) ferrocene palladium bichloride (223.64mg, 305.64umol) is dissolved in dioxane (1.5mL) and water (0.3mL).In nitrogen Under conditions of gas shielded, above-mentioned reaction solution is placed in 80 degree and is reacted 2 hours.After reaction, it is spin-dried for, obtains crude product and prepare height Effect liquid phase chromatogram method purifies to obtain title compound (50.00mg, 29.93%).
1H NMR(400MHz,CD3OD) δ 7.99-7.92 (m, 1H), 7.84 (s, 1H), 7.75 (d, J=2.0Hz, 1H), 7.60 (d, J=2.0Hz, 1H), 7.50-7.43 (m, 1H), 7.27 (d, J=9.5Hz, 1H), 7.08-6.95 (m, 2H), 4.18 (t, J=6.3Hz, 2H), 3.88 (s, 3H), 3.71-3.64 (m, 4H), 2.88-2.83 (m, 2H), 2.58 (br.s., 4H)
Flow 13:
Reaction condition：A) Ethyl formate, sodium hydrogen, glycol dimethyl ether, heating；B) 5- bromopyridines -2- amine, ammonium acetate add Heat；C) tribromo oxygen phosphorus, heating；D) cesium carbonate, acetonitrile, heating；E) R boric acid (borate), 1,1 '-bis- (diphenylphosphine) ferrocene Palladium bichloride, potassium carbonate, dioxane, water, heating.
Embodiment 60
((3- (2- dionins quinoline) -4- oxo -4H- pyridos [1,2-a] are phonetic by 2- methoxyl groups -5- by the fluoro- N- of the chloro- 4- of 2- Pyridine -7- bases) pyridin-3-yl) benzsulfamide
A) (E)-(- 3 (2H)-alkenylene of 2- oxo-dihydros furans) sodium methoxide
Slowly the 500mL round bottoms equipped with glycol dimethyl ether (96mL) are added portionwise in sodium hydrogen (0.93g, 23.23mmol) In flask.Dihydrofuran -2 (3H) -one (2g, 23.23mmol) and Ethyl formate is added dropwise under stirring into said mixture Glycol dimethyl ether (12mL) solution of (1.72g, 23.23mmol), then adds ethyl alcohol (0.15mL).Reaction solution is at 60 degree It is stirred to react 16 hours.Mixture is cooled to 25 degree, filtering, filter cake obtains yellow green after being eluted with ethyl acetate (20mL*3) Solid-like title compound (2.1g, 66%).
1H NMR(400MHz,D2O)ppmδ8.45-8.31(m,1H),4.27(t,2H),2.71(t,2H).
B) (E) -3- (((5- bromopyridine -2- bases) amino) methylene alkenyl) dihydrofuran -2 (3H) -one
By (E)-(- 3 (2H)-alkenylene of 2- oxo-dihydros furans) sodium methoxide (1.42g, 10.4mmol), 5- bromopyridines -2- Amine (1.2g, 6.94mmol) and ammonium acetate (2.67g, 34.68mmol) are placed in 50mL round-bottomed flasks, and 120 degree to be stirred to react 1 small When.Liquid chromatography mass spectrometric shows that the reaction was complete, and reaction solution is cooled to room temperature, and is poured slowly into ice water, there is solid precipitation, filters, filter Cake obtains crude solid title compound after being eluted with water (20mL*3), then obtains gray scales with petroleum ether (30mL) mashing again Inscribe compound (1.4g, 75%).
1H NMR(400MHz,CDCl3)ppmδ8.29(d,1H),8.02(d,1H),7.74(dd,1H),6.79(d,1H), 4.44(t,2H),2.90(dt,2H).
C) the bromo- 3- of 7- (2- bromoethyls) -4H- pyridos [1,2-a] pyrimidin-4-one
By (E) -3- (((5- bromopyridine -2- bases) amino) methylene alkenyl) dihydrofuran -2 (3H) -one (1.4g, It 5.2mmol) is placed in 50mL round-bottomed flasks with tribromo oxygen phosphorus (6.98g, 24.35mmol), 80 degree are stirred to react 1.5 hours.Liquid Phase mass spectrum shows that the reaction was complete, and reaction solution is cooled to room temperature, and is poured slowly into ice water, adjusts pH value to 8, uses dichloromethane (20mL*3) is extracted, and organic phase is washed with saturated common salt, and anhydrous sodium sulfate drying is concentrated to give yellow solid title compound (1.2g, 69%).
1H NMR(400MHz,CDCl3)ppmδ9.17(d,1H),8.27(s,1H),7.74(dd,1H),7.54(d,1H), 3.73(t,2H),3.21(t,2H).
D) the bromo- 3- of 7- (2- dionins quinoline) -4H- pyridos [1,2-a] pyrimidin-4-one
By the bromo- 3- of 7- (2- bromoethyls) -4H- pyridos [1,2-a] pyrimidin-4-one (0.2g, 0.6mmol), morpholine (78.73mg, 0.9mmol) and cesium carbonate (0.59g, 1.81mmol) are placed in 50mL round-bottomed flasks, and 70 degree to be stirred to react 12 small When.Liquid chromatography mass spectrometric shows that the reaction was complete, and reaction solution is cooled to room temperature, and adds water, is extracted with dichloromethane (20mL*3), organic phase It is washed with saturated common salt, anhydrous sodium sulfate drying is concentrated to give crude oil title compound, is directly used in and reacts in next step.
E) ((3- (2- dionins quinoline) -4- oxo -4H- pyridos [1,2-a] are phonetic by 2- methoxyl groups -5- by the fluoro- N- of the chloro- 4- of 2- Pyridine -7- bases) pyridin-3-yl) benzsulfamide
The bromo- 3- of 7- (2- dionins quinoline) -4H- pyridos [1,2-a] pyrimidin-4-one (0.59mmol) is dissolved in dioxy In six rings (2mL) and water (0.4mL), the chloro- 4- of 2- fluoro- N- (2- methoxyl groups -5- (4,4,5,5- tetramethyls are added under nitrogen protection Base -1,3,2- di (hetero) oxygen pentaborane -2- bases) pyridin-3-yl) benzsulfamide (0.59mmol), potassium carbonate (1.18mmol) and 1, 1 '-bis- (diphenylphosphine) ferrocene palladium bichlorides (22mg).Mixture is placed under the conditions of microwave reaction and is reacted 1 hour for 100 degree.Liquid Phase mass spectrum shows that the reaction was complete.Crude product will be obtained after reaction solution filtering and concentrating.Crude product silica gel column chromatography and preparation efficient liquid phase Chromatography purifies to obtain title product.
1H NMR(400MHz,CDCl3)ppmδ9.08(s,1H),8.29(s,1H),8.17-8.09(m,2H),7.94(d, 1H),7.85-7.77(m,1H),7.75-7.68(m,1H),7.28(d,1H),7.18-7.12(m,1H),4.00(s,3H), 3.79(br.s.,3H),2.93(br.s.,1H).
1 vitro enzyme active testing of experimental example
PI3K (p110 α) kinase activity is surveyed by following two test methods respectively in all embodiments of the invention Examination.
Method one：
Reaction buffer：HEPES50mM (pH7.0), NaN30.02%, BSA0.01%, Orthovanadate0.1mM, 1%DMSO
Detection buffer:HEPES10mM (pH7.0), BSA0.02%, KF0.16M, EDTA4mM
Reaction enzyme：The ends N- expressed in insect cell are sub- with the people source recombinant full-lenght PI3K p110 α that His is marked The p85 α subunits (molecular weight=83.6kDa) of base (molecular weight=128.4kDa) and not tape label
Reaction substrate：10 μM of PIP2 substrates (PI (4,5) P2)
Reaction condition：P2 and 10 μM of ATP of 10 μM of PI (4,5)
Reaction step：
1. getting out substrate in the reaction solution of fresh configuration.
2. kinases is added in substrate reactions liquid, gently mix.
3. utilizing Acoustic technologies (Echo550；Nanoliter rang) it is dissolved in the compound turn of 100%DMSO It moves into kinase reaction liquid, is incubated at room temperature 10 minutes
4. the ATP of suitable concentration is added in the reaction system.
5.30 DEG C of incubation half an hours
6. terminate liquid, which is added, terminates reaction.
7. detection mixture is added and is incubated overnight.
8. being detected using homogeneous phase time discrimination fluorescence (HTRF) method.(excitation wavelength 320nm, measurement in 615nm and The ratio of 665nm launch wavelengths reading).
Method two：
ADP-Glo experimental methods
Diluted chemical compound：
3 times of gradient dilution untested compounds, totally 10 concentration points (10000nM to 0.5nM).
Experimental method：
It shifts in 50nL compounds to reaction plate (PerkinElmer#6007299), 3uL enzymes/substrate mixture is added 2uL ATP solution is added after being incubated 20min in (0.33nM PI3Kalpha, Millipore#14-602-K/166.5uM PIP2) (100uM) starting reaction after reacting at room temperature 2 hours, is added 5uL ADP-Glo reagents and terminates kinase reaction, be incubated at room temperature 60 points Clock digests remaining unreacted ATP completely, and 10uL kinase assay reagents are added, and incubation at room temperature after forty minutes, is read on Envision Take fluorescence.PIP2, ATP, ADP-Glo reagent and kinase assay reagent are all from ADP-Glo kinase assay kits (Promega# V1792)。
Data analysis：
IC50 (Model205, XL-fit, iDBS) is calculated using 4 parameter fitting method of standard.
MTOR kinase activities are tested by following test method respectively in all embodiments of the invention.
Reaction buffer：20mM Hepes(pH7.5),10mM MgCl2,2mM MnCl2, 1mM EGTA, 0.02% Brij35,0.02mg/ml BSA,0.1mM Na3VO4, 2mM DTT, 2%DMSO.
Reaction enzyme：The ends N- expressed in insect cell recombinate mTOR segment (amino acid with the people source that GST is marked 1360-2549, molecular weight=163.9kDa)
Reaction substrate：People source recombinant full-lenght 4EBP1 that the ends N- expressed in bacterium are marked with His (molecular weight= 13.6kDa)
Reaction condition：3 μM of 4EBP1 and 10 μM of ATP
Reaction step：
1. reaction substrate and other response factors are added in freshly prepared reaction buffer.
2. kinases is added in substrate reactions liquid, gently mix.
3. utilizing Acoustic technologies (Echo550；Nanoliter rang) it is dissolved in the compound turn of 100%DMSO It moves into kinase reaction liquid, is incubated at room temperature 20 minutes.
4. suitable concentration is added in the reaction system32P-ATP。
5. being incubated two hours in room temperature.
6. detecting kinase activity using P81filter-binding methods.
Experimental result is shown in Table 3：
3 vitro enzyme active testing result of table
Note：A≤1nM；1nM<B≤50nM；50nM<C≤200nM；200nM<D；NT expressions are not surveyed.
2 cell in vitro active testing of experimental example
Experimental procedure and method：
1. by MCF-7 cells with every hole 2.5 × 104A density kind into 96 orifice plates (culture solution used need to be containing The complete culture solution of 10%FBS).
2. second day takes the culture solution in hole away, by some concentration (preliminary screening) or a series of concentration (IC50It surveys Examination) compound be dissolved in the culture solution without serum, 96 orifice plate culture cell 2 hours is added.
3. insulin is dissolved in the culture solution without serum, cell culture 30 minutes is added, insulin is final concentration of 10 mcg/mls.
4. wait for reaction, prepare lysate as follows：
A) enhancement solution (Enhancer Solution) needs to take out in refrigerator in advance and melt.
B) enhancement solution (Enhancer Solution) lysis buffer (Lysis Buffer) of 5X is diluted 10 times, It is prepared into concentration lysate.
C) concentration lysate is diluted 5 times with distilled water, lysate is made.
5. the culture solution in hole is exhausted, it is used in combination the rapid rinses of PBS primary.
6. 150 microlitres of freshly prepared lysates are added in each hole, then room temperature is shaken 10 minutes.
7. after confirming that all cells have all fallen off, lysate is transferred to cell fragment in 1.5 milliliters of pipes together.
8. being vortexed several times, lysate and cell is made to be thoroughly mixed, mixed liquor is then centrifuged 10 points at 4 DEG C with 12000g Clock.
9. calculating the number of the ELISA-one microplate items of needs.The microplate item having more is removed from frame, puts back to storage It deposits in bag and is sealed.Before microplate item, first with 200 microlitres of distilled water rinses once each hole, to remove anti-corrosion above Agent.
10. 50 microlitres of antibody mixed liquor is added into each hole.(antibody mixed liquor be by by intermediary antibody reagent and Enzyme label antibody reagent equal proportion mixes, and not be vortexed when paying attention to preparing antibody mixed liquor)
11. 25 microlitres of product of cell lysis are added into each hole of ELISA-One microplates.It is firmly micro- with adhesive closure membrane cover Plate is incubated 1 hour in microplate concussion instrument at room temperature.
12. each hole is washed 3 times with 150 microlitres of 1X cleaning buffer solutions.After last time washes, by the cleaning buffer solution in hole It pumps.If desired, 1X cleaning buffer solutions can be allowed to stop longest in microplate 30 minutes, prepare substrate mixing to set apart Liquid.
13. Substrate cocktail Ying Suiyong with.100 microlitres of Substrate cocktails are added into each hole, then use masking foil Microplate is sealed, is incubated 10 minutes in microplate concussion instrument at room temperature.
14. 10 microlitres of terminate liquids are added into each hole, then slightly (5-10 seconds) mixing is once in microplate concussion instrument.
15. assembling corresponding ELISA-One filters group, fluorescence signal intensity is read.
Experimental result is shown in Table 4：
4 cell in vitro active testing result of table
Note：A≤50nM；50nM < B≤100nM；100nM < C≤250nM；D>250nM.
Conclusion：The compounds of this invention is notable to PI3K inhibiting effect, but has weaker inhibiting effect to mTOR.

Claims (14)

1. compound or its pharmaceutically acceptable salt shown in formula (I),
Wherein,
It can be by structural unitIt replaces with
E is selected from optionally by R3Substituted C1-6Alkyl, C3-10Cyclic hydrocarbon radical or heterocyclic hydrocarbyl；
In L and Q, one is selected from-C (Rd1)(Rd2)-,-C (=O) N (Rd3)-、-N(Rd4)-,-C (=NRd5- S)-, (=O)2N (Rd6)-,-S (=O) N (Rd7)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2Or- N(Rd8) C (=O) N (Rd9)-, another be selected from singly-bound or-C (Rd1)(Rd2)-；
A, T is separately selected from N or C (Rt)；
X, 0 or 1 in Y, Z is selected from N, remaining is selected from C (Rt)；
B is selected from-C (Rd1)(Rd2)-,-C (=O) N (Rd3)-、-N(Rd4)-,-C (=NRd5- S)-, (=O)2N(Rd6- S)-, (=O) N(Rd7)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2Or-N (Rd8) C (=O) N (Rd9)-；
m1Separately it is selected from 0,1,2 or 3；
R1-3In one be selected fromRemaining is selected from H, F, Cl, Br, I, CN, OH, SH, NH2、CHO、 COOH, or selected from optionally by R01Substituted C1-10Alkyl or miscellaneous alkyl, C3-10Cyclic hydrocarbon radical or heterocyclic hydrocarbyl, by C3-10Cyclic hydrocarbon radical or The C of heterocyclic hydrocarbyl substitution1-10Alkyl or miscellaneous alkyl；
D1Selected from singly-bound ,-C (Rd1)(Rd2)-,-C (=O) N (Rd3)-、-N(Rd4)-,-C (=NRd5- S)-, (=O)2N(Rd6)-、- S (=O) N (Rd7)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2Or-N (Rd8)C (=O) N (Rd9)-；
D2Selected from-C (Rd1)(Rd2)-；
D3Selected from-N (Rd4)-,-C (=O) N (Rd4)-、-N(Rd4) C (=O)-,-N (Rd4) C (=O) O- ,-N (Rd4) OC (= O)-、-N(Rd4) C (=O) N (Rd4- S)-, (=O)-,-S (=O)2,-S (=O)2N(Rd6)-,-S (=O) N (Rd7)-；
R4Selected from H, or selected from optionally by R01Substituted C1-10Alkyl or miscellaneous alkyl, C3-10Cyclic hydrocarbon radical or heterocyclic hydrocarbyl, by C3-10Ring Alkyl or the C of heterocyclic hydrocarbyl substitution1-10Alkyl or miscellaneous alkyl；
N is selected from 1,2,3,4,5 or 6；
Optionally, any two R1Between, the same D2In Rd1With Rd2Between, two D2Between, R4With a D2Between or R4With D3Between be commonly connected to form one or two 3,4,5 or 6 yuan of carbocyclic rings or heterocycles on same carbon atom or hetero atom；
Rt、Rd1、Rd2Separately it is selected from H, F, Cl, Br, I, CN, OH, SH, NH2, CHO, COOH, C (=O) NH2, S (=O) NH2, S (=O)2NH2, or selected from optionally by R01Substituted C1-10Alkyl or miscellaneous alkyl, C3-10Cyclic hydrocarbon radical or heterocyclic hydrocarbyl, by C3-10 Cyclic hydrocarbon radical or the C of heterocyclic hydrocarbyl substitution1-10Alkyl or miscellaneous alkyl；
R01Selected from F, Cl, Br, I, CN, OH, SH, NH2、CHO、COOH、R02；
R02Selected from C1-10Alkyl, C1-10Alkylamino, N, bis- (C of N-1-10Alkyl) amino, C1-10Alkoxy, C1-10Alkanoyl, C1-10Alkane Oxygen carbonyl, C1-10Alkyl sulphonyl, C1-10Alkyl sulphinyl, C3-10Naphthenic base, C3-10Naphthene amino, C3-10Heterocycle alkylamino, C3-10Cycloalkyloxy, C3-10Cycloalkanoyl, C3-10Cycloalkoxycarbonyl, C3-10Naphthene sulfamide base, C3-10Cycloalkylsulfinyl, 5-6 membered unsaturated heterocycles base, 6-12 members aryl or heteroaryl；
Hetero atom or hetero atom group are separately selected from-C (=O) N (Rd3)-、-N(Rd4)-,-C (=NRd5- S)-, (=O)2N (Rd6)-,-S (=O) N (Rd7)-,-O- ,-S- ,=O ,=S ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2And/or-N (Rd8) C (=O) N (Rd9)-；
Rd3-d9Separately it is selected from H, OH, NH2、R02；
R02Optionally by R001Substitution；
R001Selected from F, Cl, Br, I, CN, OH, N (CH3)2、NH(CH3)、NH2, CHO, COOH, trifluoromethyl, aminomethyl, methylol, Methyl, methoxyl group, methoxycarbonyl group, mesyl, methylsulfinyl；
R01、R001The number of hetero atom or hetero atom group is separately selected from 0,1,2 or 3.
2. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, wherein E is selected from by R3It takes The C in generation1-6Alkyl or C3-6Naphthenic base, R3Number be selected from selected from 0,1,2 or 3 or E
Wherein,
G1~5In 0,1,2 or 3 be selected from N, remaining be selected from C (R3)；
G6Selected from-C (R3)(R3)-,-C (=O) N (R3a)-、-N(R3a)-,-C (=NR3a- S)-, (=O)2N(R3a- S)-, (=O) N(R3a)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2Or-N (R3a) C (=O) N (R3a)-；
G7~9In 0,1 or 2 be selected from N, remaining be selected from C (R3)；
G10~16In 0,1,2,3 or 4 be selected from N, remaining be selected from C (R3)；
G17Selected from N or C (R3)；
G18~22In 0,1,2 or 3 be selected from-C (=O) N (R3a)-、-N(R3a)-,-C (=NR3a- S)-, (=O)2N(R3a)-、-S (=O) N (R3a)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2Or-N (R3a)C (=O) N (R3a)-, remaining be selected from-C (R3)(R3)-；
R3aSelected from C1-10Alkyl, C1-10Alkyl acyl, C1-10Alkoxy carbonyl group, C1-10Alkyl sulphonyl, C1-10Alkyl sulphinyl, C3-10Naphthenic base, C3-10Cycloalkanoyl, C3-10Cycloalkoxycarbonyl, C3-10Naphthene sulfamide base, C3-10Cycloalkylsulfinyl, 5- 6 membered unsaturated heterocycle bases, 6-10 members aryl or heteroaryl；
Remaining variables are as defined in claim 1.
3. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 2, wherein E is selected from optionally quilt R3Substituted methyl, ethyl, propyl,
4. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 3, wherein E is selected from
5. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, wherein in L and Q, one Selected from-S (=O)2NH- ,-S (=O)2,-NH- ,-NHC (=O) NH-, another be selected from singly-bound ,-CH2-。
6. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, wherein 0 in X, Y, Z Or 1 be selected from N, remaining be selected from CH, C (CH3)、C(CF3)、CCl、CF。
7. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, wherein A, T are independently Ground is selected from N, CH, C (CH3)、C(CF3),CCl,CF；Alternatively, B is selected from NH, N (CH3) or N (CF3)。
8. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, wherein any two R1It Between, the same D2In Rd1With Rd2Between, two D2Between, R4With a D2Between or R4With D3Between formed ring be selected from：
9. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, wherein R1-3In one It is selected fromRemaining is selected from H, F, Cl, Br, I, CN, OH, SH, NH2、CHO、COOH、ORa、N(Rb) (Rc), optionally by RdSubstituted C1-3Alkyl or cyclopropyl；D1Selected from singly-bound ,-C (Re)(Re)-,-C (=O) N (Ra)-、-N (Ra)-,-C (=NRa- S)-, (=O)2N(Ra)-,-S (=O) N (Ra)-,-O- ,-S- ,-C (=O) O- ,-C (=O)-,-C (= S)-,-S (=O)-,-S (=O)2Or-N (Ra) C (=O) N (Ra)-；D2Selected from-C (Ra)(Ra)-；
N is selected from 1,2,3,4,5 or 6；
Ra、Rb、RcSeparately it is selected from H, optional RdSubstituted C1-6Alkyl or C3-6Naphthenic base；
ReSelected from H, optional RdSubstituted C1-6Alkyl or alkoxy, optional RdSubstituted C3-6Naphthenic base or cycloalkyloxy；
RdSelected from F, Cl, Br, I, CN, OH, NH2、CHO、COOH、CH3、CF3、CH3O、CH3CH2O,RdNumber be selected from 0,1,2 or 3；
Optionally, any two R1Between, the same D2In RaWith RaBetween, two D2Between or RaWith a D2Between it is common It is connected on same carbon atom or oxygen atom and forms one or two 3,4,5 or 6 yuan of carbocyclic ring or oxa- rings, the wherein number of oxygen atom Mesh is 1 or 2.
10. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 9, wherein any two R1 Between, the same D2In RaWith RaBetween, two D2Between or RaWith a D2Between formed ring be selected from cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, oxetanylmethoxy, 1,3- dioxolane bases.
11. compound or its pharmaceutically acceptable salt shown in the formula (I) according to claim 1~10 any one, In, R1-3In one be selected from Remaining is selected from H, F, Cl, Br, I, CN, OH, NH2, methyl, Ethyl, propyl, methoxyl group, ethyoxyl, propoxyl group, methylamino, dimethylamino, halogenated methyl, halogenated ethyl, halopropyl, ammonia Methyl, aminoethyl, aminopropyl, cyclopropyl.
12. compound or its pharmaceutically acceptable salt shown in formula (I) according to claim 1, are selected from：
13. compound or its pharmaceutically acceptable salt shown in formula (I) as described in claim 1 benefit from suppression in preparation treatment Purposes in the drug of the disease of PI3K processed.
14. purposes according to claim 13, wherein described benefit from inhibits the disease of PI3K to be selected from tumour.
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US15/319,726 US9856256B2 (en) 2014-06-17 2015-06-16 Pyridino[1,2-A]pyrimidone analogue used as P13K inhibitor
JP2017518397A JP6680774B2 (en) 2014-06-17 2015-06-16 Pyrido [1,2-a] pyrimidone analogues as PI3K inhibitors
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CA2951971A CA2951971A1 (en) 2014-06-17 2015-06-16 Pyridino[1,2-a]pyrimidone analogue used as pi3k inhibitor
AU2015276699A AU2015276699B2 (en) 2014-06-17 2015-06-16 Pyridino[1,2-a]pyrimidone analogue used as PI3K inhibitor
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PCT/CN2015/081518 WO2015192760A1 (en) 2014-06-17 2015-06-16 Pyridino[1,2-a]pyrimidone analogue used as pi3k inhibitor
ES15810067T ES2754264T3 (en) 2014-06-17 2015-06-16 Pyridin [1,2-a] pyrimidone analog used as PI3K inhibitor
EA201790016A EA032642B1 (en) 2014-06-17 2015-06-16 PYRIDINO[1,2-a]PYRIMIDONE ANALOGUES USED AS PI3K INHIBITORS
KR1020177000523A KR102495840B1 (en) 2014-06-17 2015-06-16 Pyridino[1,2-a]pyrimidone analogue used as pi3k inhibitor
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