CN106946909A - The nitro imidazole derivatives for the treatment of pulmonery tuberculosis disease - Google Patents

The nitro imidazole derivatives for the treatment of pulmonery tuberculosis disease Download PDF

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Publication number
CN106946909A
CN106946909A CN201610006632.8A CN201610006632A CN106946909A CN 106946909 A CN106946909 A CN 106946909A CN 201610006632 A CN201610006632 A CN 201610006632A CN 106946909 A CN106946909 A CN 106946909A
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methyl
milliliters
milligrams
equivalents
mms
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CN201610006632.8A
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Inventor
罗微
丁照中
黄志刚
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NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
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NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
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Priority to CN201610006632.8A priority Critical patent/CN106946909A/en
Priority to BR112017015744A priority patent/BR112017015744A2/en
Priority to US15/546,841 priority patent/US10227362B2/en
Priority to TW105102748A priority patent/TW201632533A/en
Priority to PCT/CN2016/072447 priority patent/WO2016119706A1/en
Priority to CN201680006991.1A priority patent/CN107207532B/en
Priority to JP2017540142A priority patent/JP6542900B2/en
Priority to EP16742768.1A priority patent/EP3252059A4/en
Priority to MX2017009810A priority patent/MX2017009810A/en
Priority to RU2017130546A priority patent/RU2675622C1/en
Publication of CN106946909A publication Critical patent/CN106946909A/en
Priority to ZA2017/05362A priority patent/ZA201705362B/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention discloses one kind replace nitro imidazole derivatives, its be mainly used in treat the relevant disease as caused by mycobacteria infections, such as mycobacterium tuberculosis, be particularly suitable for use in disease caused by drug resistant M mycobacterium.

Description

The nitro imidazole derivatives for the treatment of pulmonery tuberculosis disease
Bibliography：
The content of following document is incorporated herein by reference
U.S.patent NO.5,668,127
U.S.patent NO.6,087,358
JP 2005330266
WO 2004/033463
WO 2007/075872
WO 2008/140090
WO 2008/008480
WO 2009/120789
WO 2011/151320
WO 2011/093529
WO 2011/087995
WO 2011/014774
WO 2011/014776
WO 2013072903
Technical field
Replace nitro imidazole derivatives the present invention relates to one kind, it is mainly used in treatment as caused by mycobacteria infections Relevant disease, such as mycobacterium tuberculosis, disease caused by the drug resistance that is particularly suitable for use in conjugate branch bacillus.
Background technology
Mycobacterium tuberculosis is pathogen lungy.Blazon the whole world as one kind, and can be fatal infectious diseases, according to The World Health Organization is counted, and 8,000,000 people infection is about had more than every year, and 2,000,000 people die from tuberculosis.In past 10 years, tuberculosis Case is worldwide increased with 20% speed, and the amount of increase is especially notable in poverty-stricken area.If the trend develops like this Go down, cases of tuberculosis very likely continues to increase in next two decades with 41% amount of increase.Initial treatment with chemotherapy method it In 50 years afterwards, tuberculosis, which always is, is only second to AIDS, causes the main infection disease that adult is dead.It is lungy simultaneously Hair disease has triggered the appearance of many antibody-resistant bacterium, while reaching symbiosis with AIDS.HIV test is positive, and Crowd lungy is infected simultaneously, is had compared with the AIDS disease virus test crowd of being negative and is had more 30 times of probabilities and develop into activation Tuberculosis.For average, every three are died from the patient of AIDS, caused by just having a people to be tuberculosis.
The formula of the combination for the various medicaments that existing treatment use lungy US Department of Public Health is recommended, including head Isoniazid is first used, rifampin, pyrazinamide and ethambutol are combined two months, and isoniazid and rifampin are then used alone again Combination four months.Patient for having infected AIDS, the use of this kind of drug regimen need to be postponed until seven months.For infection The patient of multi-drug resistance tuberculosis, the drug regimen also need add remaining two wires medicament, such as streptomysin, kanamycins, amikacin, Capreomycin, 2-ethylisonicotinthionamide, seromycin, Ciprofloxacin and Ofloxacin.It is such to be used for multi-drug resistance tuberculosis (the usual course for the treatment of More than 2 years) patient combined therapy medicine, generally there is lower activity, and higher side effect compared to current market On first-line drug.
Therefore, exigence is such new either to aerobic (active) or anaerobism (incubation period or obstinate) Environment is respectively provided with the nitroimidazole and oxazole derivatives of high activity, is used as anti-tubercle bacillus drugs.Obviously, when can shorten treatment Between, the medicine of supervision frequency can be reduced again can bring the benefit of maximum.
Currently, Otsuka novel products Deltyba (delamanid) has been listed, and is treated as multi-drug resistance tuberculosis A kind of combination medicine, is approved for the treatment of adult, in view of considering in terms of resistance and tolerance.Equally, nitroimidazole oxazines Class compound PA-824 and TBA-354 (J.Org.Chem.53；8421-8439 (2010)) in terms of Mycobacterium tuberculosis is suppressed Show preferable in vitro and in vivo activity.The PA-824 mechanism of action is related to release (the Singh et of nitric oxide gas Al., Science 322；1392-1395 (2008)), and bacterium G6P phosphate dehydrogenase (FGD1) and it is auxiliary because Reduction step (Stover the et al., Nature 405 of sub (F420) intervention；962-966(2000)).Biochip technology pair The research of wild type mutagenic strain and FGD1 and F420 is found that the unknown work(being made up of 151 amino acid (17.37kDa) Can albumen, (Rv3547) seems to play a leading role to this series of reduction step, later by studying FA-824 reduction Also this hypothesis has been confirmed.TBA-354 is the nitroimidazole oxazines analog derivative developed by PA-824.Delamanid work It is to suppress the synthesis of methoxyl group and ketone group mycolic acid with mechanism, so as to kill bacterium, they are bacillus tubercle cell walls Important component.Nitro imidazole derivatives and treatment for tubercle bacillus are largely reported previously (U.S.Patent Nos.5,668,127and 6,087,358；Jiricek et al., WO 2007075872A2； Tsubochi et al., WO 2005042542A1 and WO 2004033463Al；JP 2005330266A；THOMPSON Et al., WO2011014776；MUSONDA et al., WO2013072903)
In the clinical development medicine of all anti-mycobacterium tuberculosis, nitro imidazole derivatives walk more and more forward, more next It is more attractive.It can be seen that for tuberculotherapy, multi-drug resistance tuberculosis treated from patent application above particularly Main patent formula following (1 and 2) shown in：
By research, two new bioactive molecule OPC-67683 (delamanid) and TBA- are obtained for treating tuberculosis 354 are developed, shown in structure following (3 and 4)：
Delamanid is the hydrogen of nitro-2-imidazo oxazole analog derivative, and the mainly biosynthesis by suppressing mycolic acid is sent out Raw effect, either shows very high activity to Multiple drug-resistan Tubercle bacillus in vitro or in vivo, on November 21st, 2013, Had ready conditions by the European human drugs committee (CHMP) and ratify Deltyba (Delamanid), 50 milligrams of thin membrane coated tablet is used for The treatment of Multiple drug-resistan Tubercle bacillus.It is formal in Europe listing on April 28th, 2014.2 month 1 day quilts of the Deltyba in 2008 Regard as Orphan drug.This invention address that a kind of new nitro glyoxaline compound of invention, for tuberculosis and multi-drug resistant knot The treatment of core disease.
Although OPC-67683 is proved to clinically have certain curative effect to multi-drug resistance tuberculosis treatment, in the course for the treatment of And have the space further optimized on cure rate, while also there is this needs, the present invention serves this, the nitroimidazole being related to Analog derivative is proven to have more excellent water solubility and pharmacokinetic property.It is expected that this improvement can bring preferably clinical table It is existing.
The content of the invention
The invention provides compound, its pharmaceutically acceptable salt or its stereoisomer shown in formula (I),
Wherein,
Ring A is 5~6 yuan of aryl or heteroaryl；
X is selected from N, C (R) or C；
R is selected from hydrogen, halogen, hydroxyl, cyano group, nitro, or selected from the following group optionally replaced by any substituent：Ammonia Base, C1-6Alkyl amino, the N, (C of N- bis-1-6Alkyl) amino, C1-6Alkyl, C1-6Miscellaneous alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-7Cycloalkanes Base, C3-7Heterocyclylalkyl, 5~7 yuan of aryl, 5~7 unit's heteroaryls；
V, W are separately selected from methylene ,-CH2CH2-, C (=O) ,-S (=O)-and-S (=O)2-, wherein, it is described Methylene and-CH2CH2- optionally replaced by 1 or 2 R；
Z is selected from the methylene optionally replaced by 1 or 2 R；
L be selected from singly-bound ,-O- ,-S-, N (R), C (R) (R) ,-C (=O)-,-C (=S)-,-S (=O)-or-S (=O )2-；
R1、R2Separately it is selected from hydrogen, halogen, hydroxyl, cyano group, nitro, or R1、R2Separately selected from optionally quilt The amino of any substituent substitution, C1-6Alkyl, C1-6Miscellaneous alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-7Cycloalkyl, C3-7Cycloalkyl- C1-6Alkyl-, C3-7Heterocyclylalkyl, 5~7 yuan of aryl or heteroaryl；
Optionally, the substituent R in the substituent R and V on Z is connected on same atom or atomic group, forms one 5 ~7 yuan of rings；
Optionally, construction unitIt can be replaced
R2It can also be vacancy；
M is selected from 1,2 or 3；
N is selected from 0,1,2 or 3；
" miscellaneous " represents hetero atom or hetero atom group, its be selected from-C (=O) NH- ,-NH- ,-C (=NH)-,-S (=O)2NH- ,-S (=O) NH- ,-O- ,-S-, N ,=O ,=S ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (= O)2- and-NHC (=O) NH-；
The number of hetero atom or hetero atom group is separately selected from 0,1,2 or 3.
In some schemes of the present invention, above-mentioned substituent and R are separately selected from：H、F、Cl、Br、I、OH、CN、NH2、 C1-4Alkyl, C1-4Miscellaneous alkyl, wherein, C1-4Alkyl or C1-4Miscellaneous alkyl optionally further by 0~3 halogen, OH and/or NH2Replaced.
In some schemes of the present invention, above-mentioned substituent is selected from：F、Cl、Br、I、CN、-CF3、-OCF3、-CH2CF3、OCH3、 (CH3)3COC (=O)-.
In some schemes of the present invention, above-mentioned R1And R2Hydrogen, halogen, cyano group are separately selected from, or selected from optionally being taken Generation：
In some schemes of the present invention, above-mentioned R1And R2Hydrogen, halogen, cyano group are separately selected from, or selected from optionally being taken Generation：
In some schemes of the present invention, above-mentioned R1And R2Separately it is selected from：
In some schemes of the present invention, above-mentioned R is selected from H, Cl, Br, I, OH, CN, NH2、Me、Et。
In some schemes of the present invention, above-mentioned ring A is selected from pyridine radicals, thiazolyl, oxazolyl, imidazole radicals, pyrimidine radicals.
In some schemes of the present invention, above-mentioned ring A is selected from：
In some schemes of the present invention, said structureIt is selected from：
In some schemes of the present invention, said structure unitIt is selected from：
In some schemes of the present invention, said structure unitIt is selected from：
Specifically, the compounds of this invention its be selected from：
Present invention also offers a kind of pharmaceutical composition, it includes formula (I) chemical combination of effective dose described in above-mentioned any one Thing, its pharmaceutically acceptable salt, optical isomer or pharmaceutically acceptable carrier.
Present invention also offers above-claimed cpd, its pharmaceutically acceptable salt or its optical isomer, or above-mentioned group Application of the compound in medicine of the treatment with prevention tubercle bacillus or other microorganism infections is prepared.
Present invention also offers the preparation method of formula (I) compound, comprise the following steps：
Wherein, LG2A suitable leaving group is represented, its dependent variable is as defined above.
In some schemes of the present invention, above-mentioned LG2Represent halogen.
Present invention also offers the intermediate for preparing formula (I) compound：
Wherein, LG1A suitable leaving group is represented, its dependent variable is as defined above.
In some schemes of the present invention, LG1Represent halogen.
Present invention also offers the intermediate for preparing formula (I) compound according to claim 1, including：
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 Implication goes to understand.When herein presented trade name, it is intended that refer to its corresponding commodity or its active component.
C1-12Selected from C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11And C12；C3-12Selected from C3、C4、C5、C6、C7、C8、C9、 C10、C11And C12。
C1-12Alkyl or miscellaneous alkyl, C3-12Ring group or heterocycle alkyl, by C3-12Cyclic hydrocarbon radical or the C of heterocycle alkyl substitution1-12Alkane Base or miscellaneous alkyl include but is not limited to：
C1-12Alkyl, C1-12Alkylamino, the N, (C of N- bis-1-12Alkyl) amino, C1-12Alkoxy, C1-12Alkanoyl, C1-12Alcoxyl Carbonyl, C1-12Alkyl sulphonyl, C1-12Alkyl sulphinyl, C3-12Cycloalkyl, C3-12Naphthene amino, C3-12Heterocycle alkylamino, C3-12Cycloalkyloxy, C3-12Cycloalkanoyl, C3-12Cycloalkyloxy group carbonyl, C3-12Naphthene sulfamide base, C3-12Cycloalkyl sulfenyl Base, 5~12 yuan of aryl or heteroaryl, 5~12 yuan of aralkyl or heteroarylalkyl；
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,；With
Phenyl, thiazolyl, xenyl, naphthyl, 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-triazoles base, 1, 2,4- triazolyls, 1,3,4- thiadiazolyl groups, 4H- pyranoses, pyridine radicals, piperidyl, Isosorbide-5-Nitrae-dioxane base, morpholinyl, pyridazine Base, pyrimidine radicals, pyrazinyl, piperazinyl, 1,3,5- trithiane bases, 1,3,5-triazines base, benzofuranyl, benzothienyl, Yin Diindyl base, benzimidazolyl, benzothiazolyl, purine radicals, quinolyl, isoquinolyl, cinnolines base or quinoxalinyl；
Term " pharmaceutically acceptable " adopted here, is to be directed to those compounds, material, composition and/or agent For type, they are within the scope of reliable medical judgment, it is adaptable to contact and use with the tissue of human and animal, without Excessive toxicity, excitant, 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 or alkali of relative nontoxic., can when in the compound of the present invention containing the functional group of acidity relatively To pass through the side contacted in pure solution or suitable atent solvent with the alkali of sufficient amount with the neutral form of this kind of compound Formula obtains base addition salts.Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salt. , can be by pure solution or suitable atent solvent when in the compound of the present invention containing the functional group of alkalescence relatively The mode contacted with the sour neutral form with this kind of compound of sufficient amount obtains acid-addition salts.Pharmaceutically acceptable sour 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 includes As acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, butanedioic 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.；Also 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 Science 66：1-19(1977)).Some specificization of the present invention Compound contains alkalescence and acid functional group, so as to be converted into any alkali or acid-addition salts.
Preferably, salt is contacted with alkali or acid in a usual manner, then separate parent compound, thus again in raw compounds Property form.The difference of the form of the parent fo of compound and its various salt is some 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 into Salt modifies the parent compound with the mode of alkali into salt.The example of pharmaceutically acceptable salt includes but is not limited to：Base The inorganic acid or acylate of such as amine, the alkali metal of acid group such as carboxylic acid or organic salt etc..Pharmaceutically acceptable salt bag Include the quaternary ammonium salt of conventional avirulent salt or parent compound, such as salt that nontoxic inorganic acid or organic acid is formed.Often The avirulent salt of rule includes but is not limited to those salt derived from inorganic acid and organic acid, described 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, many polygalacturonics, propionic acid, salicylic acid, stearic acid, Asia Acetic acid, butanedioic 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 is synthesized.Generally, the preparation method of such salt is：In the mixture of water or organic solvent or both, via trip Prepared from the appropriate alkali or acid reaction of these compounds and stoichiometry of acid or alkali form.It is generally preferable that ether, acetic acid The non-aqueous medias such as ethyl ester, ethanol, isopropanol or acetonitrile.
Except the form of salt, also there are prodrug forms in compound provided by the present invention.Compounds described herein The compound that chemical change is invented so as to conversion cost easily occurs in physiological conditions for prodrug.In addition, pro-drug can be with It is switched to the compound of the present invention in environment by chemistry or biochemical method in vivo.
Some 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.
Some 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 herein is come From Maehr, J.Chem.Ed.1985,62：114-120., 62 in 1985：114-120.Unless otherwise indicated, with wedge key and void Line key represents the absolute configuration of a Stereocenter.When compound described herein contain olefinic double bond or other geometry it is asymmetric in 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 have specific geometry or stereoisomer form.It is contemplated by the invention that all is this kind of Compound, including cis and trans isomers, (-)-and (+)-to enantiomer, (R)-and (S)-enantiomer, diastereoisomer, (D)-isomers, (L)-isomers, and its racemic mixture and other mixtures, such as enantiomter or diastereomer are rich The mixture of collection, all these mixtures are within the scope of the present invention.May be present in the substituents 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.
The chiral synthesis that can pass through or chiral reagent or other routine techniques prepares optically active (R)-with (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 is separated, and auxiliary group splits Open to provide pure required enantiomter.Or, when containing basic functionality (such as amino) or acidic functionality is (such as in molecule Carboxyl) when, with appropriate optically active acid or the salt of alkali formation diastereoisomer, then pass through side known in the field Method carries out diastereoisomer fractionation, then reclaims and obtains pure enantiomer.In addition, enantiomter and diastereoisomer Separate typically by what is completed using chromatography, the chromatography uses chiral stationary phase, and optionally with chemical derivatization It is combined and (carbaminate is for example generated by amine).
The compound of the present invention can include the original of unnatural proportions on the atom of one or more composition compounds Daughter isotope.For example, can use radioisotope labeled compound, such as tritium (3H), iodine-125 (125I) or C-14 (14C).This The conversion 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 dose active material of the present invention, do not disturb active matter The bioactivity of the matter and any preparation or the representational carrier of mounting medium that are had no toxic side effect to host or patient include Water, oil, vegetables and mineral matter, cream base, lotion base, ointment bases etc..These matrix include suspending agent, tackifier, transdermal rush Enter agent etc..Their preparation is well known to the technical staff in cosmetic field or topical remedy field.Other letters on carrier Breath, may be referred 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 prepare carrier, diluent and/or medium required for drug composition effective.
For medicine or pharmacologically active agents, term " effective dose " or " therapeutically effective amount " refer to nontoxic but can reached To the medicine or enough consumptions of medicament of Expected Results.For the peroral dosage form in the present invention, a kind of active material in composition " effective dose " when referring to be combined with another active material in said composition for the required consumption that produces a desired effect.Have The determination of effect amount varies with each individual, age and ordinary circumstance depending on acceptor, also depends in specific active material, case and closes Suitable effective dose can be determined by those skilled in the art according to routine test.
Term " active component ", " therapeutic agent ", " active material " or " activating agent " refers to a kind of chemical entities, and 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 weight The variant of hydrogen and hydrogen, if the valence state of specific atoms be it is normal and replace after compound be stable.When substituent is During ketone group (i.e.=O), it is meant that two hydrogen atoms are substituted.Ketone substitution is not occurred on aromatic radical.Term is " optionally substituted " refer to be substituted, it can not also be substituted, unless otherwise prescribed, the species and number of substituent in chemistry can be with Can be arbitrary on the basis of realization.
When any variable (such as R) the once above occurs in the composition or structure of compound, it is in each situation Under definition be all independent.If thus, for example, a group is replaced by 0-2 R, the group can be optionally At most replaced by two R, and the R under each case has independent option.In addition, the group of substituent and/or its variant Close and be just allowed in the case of stable compound can be only produced in such combination.
When the quantity of a linking group is 0, such as-(CRR)0-, it is singly-bound to represent the linking group.When wherein one When individual variable is selected from singly-bound, represents that two groups of its connection are joined directly together, such as the knot is represented when L represents singly-bound in A-L-Z Structure is actually A-Z.
When a substituent is vacancy, it is non-existent to represent the substituent, such as represents this when X is vacancy in A-X Structure is actually A.
Two atomic time on a ring can be cross connected to when the key of a substituent, this substituent can be with this Arbitrary atom on individual ring is mutually bonded.Chemical knot is connected to when not indicating it in cited substituent by which atom During the compound that structure formula includes but is not specifically mentioned, this substituent can be mutually bonded by its any atom.Substituent And/or combining for its variant is only just allowed in the case where such combination can produce the compound of stabilization.For example, Construction unitRepresent that it can send out in any one position on cyclohexyl or ring group diene Raw substitution.
The substituent of alkyl and miscellaneous alkyl atomic group is commonly referred to as " alkyl substituent ", and they 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, the number of substituent is 0~(2m '+1), its Middle m ' is the sum of carbon atom in this kind of atomic group.R ', R ", R " ', R " " and R " " ' preferred hydrogen, substituted or not independently of one another Substituted miscellaneous alkyl, substituted or unsubstituted aryl (such as by 1~3 aryl substituted with halogen), it is substituted or not by Substituted alkyl, alkoxy, thio alkoxy group or aralkyl.When the compound of the present invention includes more than one R group When, for example, each R group is independently to be subject to selection, there is more than one R ', R ", R " ', R " as worked as " and R " " ' These each groups during group.When R ' and R " is attached to same nitrogen-atoms, they can combine to form 5- with the nitrogen-atoms, 6- or 7- yuan of rings.For example ,-NR ' R " are intended to include but are not limited to 1- pyrrolidinyls and 4- morpholinyls.According to above-mentioned on substitution In the discussion of base, it will be understood by those skilled in the art that term " alkyl " is intended to include carbon atom bonding together in non-hydrogen group institute structure Into group, such as haloalkyl (such as-CF3、-CH2CF3) and acyl group (such as-C (O) CH3、-C(O)CF3、-C(O)CH2OCH3 Deng).
Similar to substituent 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 is the sum of open chemical valence on 0 to aromatic rings 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 thing includes more than one R group, for example, each R group is independently to be subject to selection, as when in the presence of more than one R ', R ", R " ', R " " and R " " ' group when these each groups.
Two substituents on the adjacent atom of aryl or heteroaryl ring can optionally by formula be-T-C (O)- (CRR ') q-U- substituent 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 substituents on the adjacent atom of aryl or heteroaryl ring can be-A optionally by formula (CH2) r B- substituent is replaced, wherein A and B independences 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 substituents on the adjacent atom of aryl or heteroaryl ring can be-A optionally by formula (CH2) r B- substituent is replaced, and wherein s and d are independently selected from 0~3 integer, and X is-O- ,-NR ' ,-S- ,-S (O)-、-S(O)2- or-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 " halo element " or " halogen " itself or the part as another substituent represent fluorine, Chlorine, bromine or iodine atom.In addition, term " haloalkyl " 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 haloalkyl is included 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 is not limited to：Methoxyl group, ethyoxyl, positive propoxy, isopropoxy, just Butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- amoxys." cycloalkyl " includes saturation ring group, such as cyclopropyl, ring Butyl or cyclopenta.3-7 cycloalkyl includes C3、C4、C5、C6And C7Cycloalkyl." alkenyl " includes the hydrocarbon of straight or branched configuration There are one or more carbon-to-carbon double bonds, such as vinyl and acrylic on any stable site on chain, the wherein 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 (i.e. containing heteroatomic atomic group), including Atom beyond carbon (C) and hydrogen (H) and containing 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 " represents substituted or unsubstituted cycloalkyl, Heterocyclylalkyl, cycloalkenyl group, heterocycle alkene Base, cycloalkynyl radical, heterocycle alkynyl, aryl or heteroaryl.So-called ring includes monocyclic, 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 yuan of rings " refer to surround 5~7 atoms of arrangement.Unless otherwise rule Fixed, the ring is optionally comprising 1~3 hetero atom.Therefore, " 5~7 yuan of rings " include such as phenyl, pyridine and piperidyl；The opposing party Face, term " 5~7 circle heterocycles alkyl ring " includes pyridine radicals and piperidyl, but does not include phenyl.Term " ring " is also included containing extremely The ring system of a few ring, each " ring " independently conforms to above-mentioned definition.
Unless otherwise prescribed, term " heterocycle " or " heterocyclic radical " mean it is stable containing hetero atom or hetero atom roll into a ball it is monocyclic, Bicyclic or three rings, they can be that saturation, part are undersaturated or undersaturated (aromatics), they comprising carbon atom and 1, 2nd, 3 or 4 ring hetero atoms independently selected from N, O and S, wherein above-mentioned any heterocycle, which can be fused on a phenyl ring, forms double Ring.Nitrogen and sulfur heteroatom can be optionally oxidized (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 substituents of defined mistake herein).The heterocycle can be attached to any hetero atom or carbon atom So as to form stable structure in side base.If the compound produced 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 scheme 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 scheme 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 stable 5,6,7 unit monocycles it is bicyclic or 7,8,9 or The aromatic rings of 10 membered bicyclic heterocyclic radicals, it comprising carbon atom and 1,2,3 or 4 ring hetero atoms 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 substituents of defined mistake herein).Nitrogen Can optionally it be oxidized (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.It is preferred that bridged ring include but is not limited to：One carbon atom, two carbon atoms, nitrogen-atoms, Two nitrogen-atoms and a carbon-to-nitrogen base.It is worth noting that, a bridge is always converted into three rings by monocyclic.In bridged ring, on ring Substituent can also be appeared on bridge.
The example of heterocyclic compound includes but is not limited to：Acridinyl, azocine base, benzimidazolyl, benzofuranyl, benzene And sulfydryl furyl, benzo mercaptophenyl, benzoxazolyl, benzoxazoles quinoline base, benzothiazolyl, BTA base, benzo Tetrazole radical, benzo isoxazolyl, benzisothia oxazolyl, benzimidazoline base, carbazyl, 4aH- carbazyls, carboline base, benzo two Hydrogen pyranose, chromene, cinnolines 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, oxadiazoles base, 1,2,3-oxadiazoles base, 1,2,4- oxadiazoles bases, 1,2,5- oxadiazoles bases, 1,3,4- oxadiazoles bases, evil 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, Pyridine radicals, 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-triazoles base, 1,2,4- triazolyls, 1,2,5- triazolyls, 1,3,4- triazolyls and xanthyl.Also 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 represents straight chain, the side chain or hydrocarbon atomic group of ring-type or its combination, Ke Yishi as a part for another substituent Fully saturated, unit or polynary undersaturated, can be monosubstituted, two substitutions or polysubstituted, can be monovalence (such as first Base), divalence (such as methylene) or multivalence (such as methine), divalence or polyad group can be included, with specified quantity Carbon atom (such as C1-C10Represent 1 to 10 carbon)." alkyl " includes but is not limited to aliphatic group and aryl radical, the aliphatic hydrocarbon Base includes chain and ring-type, is specifically including but not limited to alkyl, alkenyl, alkynyl, the aryl radical includes but is not limited to 6-12 The aryl radical of member, such as benzene, naphthalene.In certain embodiments, term " alkyl " represent straight chain or side chain atomic group or Combinations thereof, can be fully saturated, unit or polynary undersaturated, can include divalence and polyad group.Saturation The example of hydrocarbon atomic group includes but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, Zhong Ding Base, isobutyl group, cyclohexyl, (cyclohexyl) methyl, Cvclopropvlmethvl, and the original such as n-pentyl, n-hexyl, n-heptyl, n-octyl The homologue or isomers of son group.Unsaturated alkyl has one or more double or triple bonds, and the example includes but is not limited to second Alkenyl, 2- acrylic, cyclobutenyl, crotyl, 2- isopentene groups, 2- (butadienyl), 2,4- pentadienyls, 3- (Isosorbide-5-Nitraes-penta two Alkenyl), acetenyl, 1- and 3- propinyls, 3- butynyls, and higher level homologue and isomers.
Unless otherwise prescribed, term " miscellaneous alkyl " or its subordinate concept (such as miscellaneous alkyl, miscellaneous thiazolinyl, miscellaneous alkynyl, heteroaryl Base etc.) itself or combine straight chain, side chain or ring-type the hydrocarbon atomic group for representing stable with another term or it is combined, It is made up of the carbon atom and at least one hetero atom of certain amount.In certain embodiments, term " miscellaneous alkyl " itself or with Another term joint represents stable straight chain, side chain hydrocarbon atomic group or its composition, the carbon atom and extremely for having 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 is optionally quaternized.Hetero atom or hetero atom group can be located at miscellaneous alkyl any interior location (including The alkyl is attached to the position of molecule remainder).Example includes but is 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 it is continuous, for example- CH2-NH-OCH3。
Term " alkoxy ", " alkylamino " and " alkylthio group " (or thio alkoxy) belongs to idiomatic expression, refers to lead to respectively Cross those alkyl groups that an oxygen atom, amino or sulphur atom are connected to the remainder of molecule.
Unless otherwise prescribed, term " cyclic hydrocarbon radical ", " heterocycle alkyl " 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 heterocycle alkyl (such as miscellaneous alkyl, Heterocyclylalkyl), miscellaneous original Son can take up the position that the heterocycle is attached to molecule remainder.The example of cycloalkyl includes but is not limited to cyclopenta, hexamethylene Base, 1- cyclohexenyl groups, 3- cyclohexenyl groups, suberyl etc..The non-limiting examples of heterocyclic radical 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 " represents the aromatics hydrocarbon substituent of how unsaturated, can be monosubstituted, two substitutions Or it is polysubstituted, can be monovalence, divalence or multivalence, it can be monocyclic or polycyclic (such as 1 to 3 ring；Wherein at least one Individual ring is aromatics), they are fused together or are covalently attached.Term " heteroaryl " refers to containing one to four heteroatomic virtue Base (or ring).In an exemplary embodiment, hetero atom is selected from B, N, O and S, and wherein nitrogen and sulphur atom is optionally oxidized, nitrogen Atom is optionally quaternized.Heteroaryl can be connected to the remainder of molecule by hetero atom.The non-limit of aryl or heteroaryl Property embodiment processed includes phenyl, 1- naphthyls, 2- naphthyls, 4- xenyls, 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 3- pyrazoles Base, 2- imidazole radicals, 4- imidazole radicals, pyrazinyl, 2- oxazolyls, 4- oxazolyls, 2- phenyl -4- oxazolyls, 5- oxazolyls, the different evils of 3- Oxazolyl, 4- isoxazolyls, 5- isoxazolyls, 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, 2- furyls, 3- furyls, 2- thiophenes Fen base, 3- thienyls, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- benzothiazolyls, purine Base, 2- benzimidazolyls, 5- indyls, 1- isoquinolyls, 5- isoquinolyls, 2- quinoxalinyls, 5- quinoxalinyls, 3- quinolyls With 6- quinolyls.Any one above-mentioned aryl and the substituent of heteroaryl ring system are selected from acceptable substituent described below.
For simplicity, aryl (such as aryloxy group, arylthio, aralkyl) when being used in combination with other terms is included such as The aryl and heteroaryl ring of upper definition.Therefore, term " aralkyl " is intended to include those atomic group (examples that aryl is attached to alkyl 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 group.
Term " leaving group " refers to can be (such as affine to replace instead by substitution reaction by another functional group or atom Should) functional group that is replaced or atom.For example, representational 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 " protection group " includes but is not limited to " amino protecting group ", " hydroxyl protecting group " or " sulfhydryl protected base ".Term " amino protecting group " refers to the blocking group for being suitable for preventing the upper side reaction in ammonia nitrogen position.Representational amino protecting group includes But it is not limited to：Formoxyl；Acyl group, such as alkanoyl (such as acetyl group, tribromo-acetyl base 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 '-methoxyphenyl) methyl；Silicyl, such as trimethyl first silicon Alkyl (TMS) and t-butyldimethylsilyl (TBS) etc..Term " hydroxyl protecting group " refers to be suitable for preventing hydroxyl The protection group of side reaction.Representative hydroxyl protecting group includes but is not limited to：Alkyl, such as methyl, ethyl and the tert-butyl group；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 Embodiment and art technology that embodiment that face is enumerated, the combination of itself and other chemical synthesis process are formed Equivalent mode known to upper personnel, preferred embodiment including but not limited to embodiments of the invention.
Solvent used in the present invention can be obtained through commercially available.The abbreviation used below：Aq. it is water；Equivalent is to work as Amount；SEMCl is (2- (chloromethane epoxide) ethyl) trimethyl silane；I-PrOH is isopropanol；DCM is dichloromethane；PE is oil Ether；DMF is DMF, and EtOAc is ethyl acetate；EtOH is ethanol；MeOH is methanol, and THF is tetrahydrofuran It is；DMSO is dimethyl sulfoxide (DMSO)；AcOH is acetic acid；BOC is tertbutyloxycarbonyl, amido protecting group；Bn is benzyl；CuI is iodate It is cuprous；AcOCu is copper acetate；Pd(OH)2For palladium dydroxide；RT is room temperature；POCl3For POCl3；Boc2O is Boc acid anhydrides； Bn2NH is two benzyl group ammonia；(n-Bu)4Sn is tetra-n-butyl tin；DMAP is nitrogen nitrogen dimethylamino pyridine；(NH4)2CO3For ammonium carbonate； TFA is trifluoroacetic acid；TFAA is TFAA；TEA is triethylamine；DIBAl-H is diisobutyl aluminium hydride；NIS is N- iodine For succinimide；Pd(PPh3P)2Cl2For double (triphenylphosphine) palladium bichlorides；DAST is nitrogen nitrogen diethyl sulfur trifluoride；n-BuSn For normal-butyl tin；Pd(PPh3)4For four triphenyl phosphorus palladiums；LDA is lithium diisopropylamine；B(i-PrO)3For the isopropyl of boric acid three Ester；CsF is cesium fluoride；NaH is sodium hydride；TMSCF3For trimethyl trifluoromethyl silane；MS is molecular sieve；Cbz is benzyloxy carbonyl Base；TBDMS is tert-butyldimethyl silyl.
Compound nomenclature is either manually or by usingOr to use supplier's directory name on Vehicles Collected from Market.
Synthetic method
The compound of the present invention can be by a variety of synthetic methods well-known to those skilled in the art, by a series of It is prepared by synthesis step.The compound of the present invention can use synthetic method described below or flexible to synthesize.
It is preferred that method include but is not limited to following description.
Particularly, the compound of formula (I) can be by reaction intermediate formula (II), when LG1 represents suitable leaving group halogen When (such as chlorine, bromine, iodine) or its analog, it is made with suitable aryl boric acid or borate reaction；Or it is corresponding when LG1 represents boron When acid or borate, it is made with the reaction of fragrant halides, wherein needing to use suitable alkali (such as cesium fluoride, sodium carbonate, bicarbonate Sodium), suitable catalyst (such as Pd (dppf) Cl2, Pd (PPh3)4Deng), react in a suitable solvent (such as dioxane/water, Toluene etc.), according to reaction process 1, the reaction is carried out preferably under 80 degrees Celsius~120 degrees Celsius：
Reaction process 1
All variable-definitions such as formula (I).
Intermediate formula (II) can be by a variety of synthetic methods well-known to those skilled in the art according to popular response system It is standby.For example, the formula (II) of intermediate can be prepared according to reaction process 2：
Reaction process 2
Wherein variables L G1Represent a suitable leaving group, such as such as halogen, chlorine, bromine, iodine, boric acid or borate etc.. Variables L G2Represent a suitable leaving group, such as halogen (such as chlorine, bromine, iodine etc.).Other all variable-definitions such as formulas (I). The step A and step B of reaction process 2 are method of the ketone of benzyl protection with pyrroles in suitable solvent such as toluene by azeotropic Water is removed at a suitable temperature, it is then amide cyclised with acrylamide or propine.Step C is that the cyclisation product of previous step is being closed Aromatisation is carried out in the presence of suitable reagent such as bromine, it usually needs carried out under conditions of heating.Following step D is dehydrated The product that reagent (such as POCl3, tribromo oxygen phosphorus etc.) is obtained with upper step reacts, and is carried out generally between 110 to 130 degrees Celsius. Benzyl protecting group on step E, nitrogen-atoms usually requires to hydrogenate or chemically remove, and solvent is typically to use methanol or second Alcohol.Following step F, ring-opening reaction is generally in the presence of alkali, such as DIPEA in polar solvent (e.g., methanol, ethanol, isopropyl Alcohol) middle progress.Step G, at suitable alkali (such as sodium hydrogen, sodium acetate), suitable solvent (such as DMF or tert-butyl acetate) is present Under, obtain intermediate formula (II) compound of cyclization in 0 to 120 degrees Celsius of reactions.
Obviously in the front and rear reaction referred to, reaction product can be separated from reaction medium, whenever necessary can be with Purification process known to those skilled in the art is further used, is such as extracted, and Chromatographic purification.More clearly in the presence of one The reaction product of above enantiomer, the compound of formula (I) can be by separation method known to those skilled in the art, particularly Preparative chromatography, such as preparation HPLC, SFC etc. are separated into its isomer.
The compound of formula (I) equally can also be by being cyclized formula (III) compound by reaction stream under the effect of suitable alkali Journey 3 is directly prepared from：
Reaction process 3：
Wherein variables L G1Represent a suitable leaving group, such as such as halogen, chlorine, bromine, iodine, boric acid or borate etc.. Variables L G2Represent a suitable leaving group, such as such as halogen, chlorine, bromine, iodine etc..Other all variable-definitions such as formula above (I)。
Step A, when LG1 represents suitable leaving group halogen (such as chlorine, bromine, iodine or its analog), with suitable virtue Ylboronic acid or borate reaction；Or it is corresponding when LG1 represents boric acid or borate, reacted with fragrant halides, wherein needing Use suitable alkali (such as cesium fluoride, cesium carbonate, sodium carbonate, sodium acid carbonate), suitable catalyst (such as Pd (dppf) Cl2Deng), In a suitable solvent react (such as dioxane/water, toluene etc.), according to reaction process 1 above, the reaction more preferably in Carried out under 80 degrees Celsius~120 degrees Celsius.Benzyl protecting group on step B, nitrogen-atoms usually require hydrogenation or chemically Such as, ethyl chloroformate, methanol is removed, and the reaction is general to be carried out under 60 degrees Celsius~80 degrees Celsius.Step C, it is epoxidised The reaction of intermediate and nucleopilic reagent, it usually needs suitable alkali (such as DIPEA, sodium acetate etc.), in suitable solvent (such as first Alcohol, ethanol, isopropanol, tert-butyl alcohol etc.) under 80 degrees Celsius~100 degrees Celsius carry out.Next step D, in suitable alkali (such as Sodium hydrogen, sodium acetate) and suitable solvent (such as DMF or tert-butyl acetate) in, 0 to 120 degrees Celsius progress.
In addition, compound formula (I) can also be prepared by reaction process 4：
Reaction process 4：
Wherein X is C, variable PG1Represent suitable leaving group, such as tertbutyloxycarbonyl, benzyl, benzyloxycarbonyl group etc., LG2, LG3Represent a suitable leaving group, such as such as halogen, chlorine, bromine, iodine, nitrogen nitrogen dimethylamino methene etc..Other own Variable-definition such as formula (I).
Reaction process 4 includes piperidones or pyrrolidones and nitrogen nitrogen dimethyl with suitable protecting group on step A nitrogen Formamide dimethylacetal or suitable bromide reagent (bromine, bromo-succinimide, copper bromide, phenyl trimethicone amine tribromo Salt) react in the suitable solvent (such as toluene, dimethylbenzene, DMF), it usually needs higher temperature 50 to 140 degrees Celsius it Between.Next step B, obtained adduct and nucleopilic reagent suitable solvent (such as methanol, ethanol, isopropanol, the tert-butyl alcohol, DMF), carried out in the presence of suitable alkali (such as triethylamine, DIPEA etc.).Step C, protection group PG1Removal pass through hydrogenation or chemistry Method is completed.Step D, the reaction of epoxidised intermediate and nucleopilic reagent usually requires suitable alkali (such as DIPEA, sodium acetate Deng) progress under 80 degrees Celsius~100 degrees Celsius in suitable solvent (such as methanol, ethanol, isopropanol, tert-butyl alcohol etc.).Under One step E, in the presence of the suitable solvent (such as DMF or tert-butyl acetate) of suitable alkali (such as sodium hydrogen, sodium acetate), 0 to 120 Degree Celsius reaction i.e. obtain formula (I) compound.
Intermediate compound above in flow or can be bought in market is obtained, or can be according to known to those skilled in the art General reactions flow is prepared.Such as, the intermediate compound of formula (IV) can be prepared from according to reaction process 5：
Reaction process 5：
Variables L G2, LG3A suitable leaving group, such as halogen (such as chlorine, bromine, iodine, mesyl etc.) are represented respectively. Other all variable-definitions such as formulas (I).
Reaction process 5 is comprising step A allyl alcohols in corresponding (+) tartaric acid diisopropyl ester or (-) tartaric acid diisopropyl ester And aoxidized under conditions of tetraisopropyl titanate presence by dicumyl peroxide, the reaction is generally in suitable solvent (such as dichloro Methane, toluene) middle progress.The suitable alkali of upper protection group 4-Nitrobenzenesulfonyl chloride needs (such as triethylamine, diisopropyl ethyl amine, Nitrogen nitrogen dimethylamino pyridine), the reaction is generally carried out in -20 degrees Celsius~0 degree Celsius of temperature range.Following step B, It is that epoxy intermediate obtained above and raw material nitroimidazole are put together heating, reaction needs that epoxy, which is transferred to nitroimidazole, Suitable solvent (such as ethanol, isopropanol, the tert-butyl alcohol, tert-butyl acetate etc.), suitable alkali (such as diisopropyl ethyl amine, carbonic acid Potassium etc.), the reaction is generally carried out in 40 degrees Celsius~100 degrees Celsius of temperature range.Step C, same we can directly obtain To non-optical active formula (IV) midbody compound by the way that the epoxy with leaving group is obtained with nitroimidazole heating, this is anti- In requisition for suitable solvent (such as ethanol, isopropanol, the tert-butyl alcohol, tert-butyl acetate etc.), suitable alkali (such as diisopropyl ethyl Amine, sodium acetate etc.), the reaction is generally carried out in 40 degrees Celsius~100 degrees Celsius of temperature range.
In order to obtain the compound of the present invention, it is sometimes desirable to which those skilled in the art are right on the basis of existing embodiment Synthesis step or reaction process are modified or selected.
Compound shown in formula (I) compound itself can also pass through official well known in the art as shown in formula (I) It can roll into a ball and be transformed.
The chemical reaction of the specific embodiment of the invention is completed in a suitable solvent, and described solvent must be suitable for The chemical change and its required reagent and material of the present invention.In order to obtain the compound of the present invention, it is sometimes desirable to this area skill Art personnel modify or selected to synthesis step or reaction process on the basis of existing embodiment.
An important consideration factor in any synthetic route planning in this area is to be reactive functional groups (in the present invention Amino) the suitable protection group of selection.For trained practitioner, Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991) be this respect authority.The institute that the present invention is quoted There is bibliography incorporated herein on the whole.
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 Embodiment and art technology that embodiment that face is enumerated, the combination of itself and other chemical synthesis process are formed Equivalent mode known to upper personnel, preferred embodiment including but not limited to embodiments of the invention.
The present invention can be specifically described by embodiment below, these embodiments are not meant to any limit to the present invention System.
All solvents used in the present invention are commercially available, be can be used without being further purified.Reaction is usually lazy Under property nitrogen, carried out in anhydrous solvent.Proton magnetic resonance (PMR) data Ji Lu Bruker Avance III 400 (400MHz) On spectroscope, chemical shift is represented with (ppm) at tetramethylsilane low field.Mass spectrum is in the series of Agilent 1200 (＆ of Jia 6110 Determined on 1956A).LC/MS or Shimadzu MS include a DAD：SPD-M20A (LC) and Shimadzu Micromass 2020 detectors.Mass spectrograph is equipped with the electric spray ion source (ESI) operated under a positive or negative pattern.
Compound manually orSoftware is named, and commercial compound uses supplier's directory name.
With equipped with Shimadzu SIL-20A automatic samplers and Japanese Shimadzu DAD：The Shimadzu of SPD-M20A detectors LC20AB systems carry out efficient liquid phase chromatographic analysis, using Xtimate Cl8 (3m fillers, specification is 2.1 x 300mm) chromatogram Post.The method of 0-60AB_6 minutes：Using linear gradient, elution is started using 100%A (aqueous solution of the A as 0.0675%TFA), And terminate to elute using 60%B (MeCN solution of the B as 0.0625%TFA), whole process is 4.2 minutes, is then eluted with 60%B 1 minute.Chromatographic column releveling is reached 100 in 0.8 minute：0, total run time is 6 minutes.The method of 10-80AB_6 minutes：Should With linear gradient, elution is started using 90%A (aqueous solution of the A as 0.0675%TFA), and (B is 0.0625%TFA's using 80%B Acetonitrile solution) terminate elution, whole process is 4.2 minutes, is then eluted 1 minute with 80%B.By 0.8 point of chromatographic column releveling Clock reaches 90：10, total run time is 6 minutes.Column temperature is 50 DEG C, and flow velocity is 0.8mL/min.PDAD is scanned Wavelength is 200-400nm.
Thin-layer chromatographic analysis (TLC) are carried out on Sanpont-group silica GF254, ultraviolet lamp irradiation inspection is commonly used Spotting out, also inspects spot using other method in some cases, in these cases, (about 1g is added in 10g silica gel with iodine Iodine and being thoroughly mixed is formed), (dissolving about 1g vanillic aldehydes are in 100mL 10%H for vanillic aldehyde2SO4In be made), ninhydrin (from Aldrich is bought) or special developer (be thoroughly mixed (NH4)6Mo7O24·4H2O、5g(NH4)2Ce(IV)(NO3)6、450mL H2The dense H2SO of O and 50mL4And be made) expansion lamellae, inspect compound.Using Still, W.C.；Kahn, M.；And Mitra, M.Journal of Organic Chemistry, the similar approach of technology disclosed in 1978,43,2923-2925., Flash column chromatography is carried out on Silicycle 40-63 μm of (230-400 mesh) silica gel.Flash column chromatography or thin-layer chromatography it is conventional Solvent is the mixture of methylene chloride/methanol, ethyl acetate/methanol and hexane/ethyl acetate.
Carry out preparing chromatogram point using the gloomy UV/VIS-156 detectors of gill in the systems of Gilson-281Prep LC 322 Analysis, the chromatographic column used is Agella Venusil ASB PrepC18.5m, 150 x 21.2mm；Phenomenex Gemini C18、5m、150 x 30mm；Boston Symmetrix C18,5m, 150 x 30mm；Or Phenomenex Synergi C18、4m、150 x 30mm.When flow velocity is about 25mL/min, with the acetonitrile/water eluting compounds of low gradient, its Contain 0.05%HCl, 0.25%HCOOH or 0.5%NH in reclaimed water3·H2O, total run time is 8-15 minutes.
With with Agilent1260 automatic samplers and Agilent DAD：The Agilent of 1260 detectors 1260Infinity SFC systems carry out SFC analyses.Chromatographic column uses Chiralcel OD-H 250 x 4.6mm I.D., 5um Or the 250 x 4.6mm I.D. of x 4.6mm I.D., 5um or ChiralpakAD-H of Chiralpak AS-H 250, 5um.OD-H_5_40_2.35ML chromatographic condition：Chiralcel OD-H chromatographic columns (specification is 250 x 4.6mm I.D., 5um fillers), mobile phase is 40% ethanol (0.05%DEA)-CO2；Flow velocity is 2.35mL/min；Detection wavelength is 220nm.AS- H_3_40_2.35ML chromatographic conditions：Chiralpak AS-H chromatographic columns (specification is 250 x 4.6mm I.D., 5um fillers)；Stream Dynamic is mutually 40% methanol (0.05%DEA)-CO2；Flow velocity is 2.35mL/min, and Detection wavelength is 220nm.OD-H_3_40_ 2.35M chromatographic conditions：Chiralcel OD-H chromatographic columns (specification is 250 x 4.6mm I.D, 5um fillers), mobile phase is 40% methanol (0.05%DEA)-CO2, flow velocity is 2.35mL/min, and Detection wavelength is 220nm.AD-H_2_50_2.35ML chromatograms Condition：ChiralpakAD-H chromatographic columns (specification is 250 x 4.6mm I.D, 5um fillers), mobile phase is 50% methanol (0.1%MEA)-CO2, flow velocity is 2.35mL/min, and Detection wavelength is 220nm.
Preparative SFC analyses are carried out in the Pre-SFC systems of Waters Thar 80 using Gilson UV detectors, The chromatographic column used is Chiralcel OD-H (specification is 250 x 4.6mm I.D, 5m fillers) or ChiralpakAD-H (specification is 250 x 4.6mm I.D, 5m fillers).When flow velocity is about 40-80mL/min, with ethanol-titanium dioxide of low gradient Carbon or methanol-carbon dioxide eluting compounds, wherein methanol or ethanol contain 0.05%NH3·H2O, 0.05%DEA or 0.1%MEA, total run time is 20-30 minutes.
Below by embodiment, the present invention will be described in detail, but is not meant to any unfavorable limitation of the present invention.
The absolute steric configuration of the chiral centre carbon atom of some compounds or intermediate, or double bond configuration, not By experiment test.In this case, " A " is denoted as by the isomers that chiral preparation chromatographic isolation goes out first, be secondly separated What is gone out is denoted as " B ".Any one those skilled in the art can be carried out " A " and " B " isomers by some methods clear and definite Differentiation, such as NMR.The method is the method for the most suitably judging spatial configuration.
The example being set forth below prepared by method described herein as, separation and Expressive Features.Hereafter Example is only merely a part representative in the scope of the invention, rather than invention is all.It describe in detail herein The present invention, wherein also disclosing that its specific embodiment mode, to those skilled in the art, is not departing from spirit of the invention It will be apparent with various changes and modifications are carried out for the specific embodiment of the invention in the case of scope.
Key intermediate A, B and C preparation：
(S) -2- ((chloro- 7,8- dihydros -1,6- naphthyridines -6 (the 5H)-yls of 2-) methyl) -2- methyl -6- nitro -2,3- dihydros Imidazo [2,1-B] oxazole
Step 1：
1- benzyl -4- pyrrolidin-1-yl -3,6- dihydro -2H- pyridines
Into toluene (70.00 milliliters) solution of 1- benzyl -4- ketone (90.00 grams, 475.56 mMs, 1.00 equivalents) Under nitrogen protection pyrrolidines (33.82 grams, 475.56 mMs, 1.00 equivalents are added in 30 degrees Celsius.Mixture is taken the photograph 130 Stirred 12 hours under family name's degree.Then mixture is concentrated in vacuo, at 45 degrees Celsius, obtains 1- benzyl -4- pyrrolidin-1-yl -3, 6- dihydro -2H- pyridines (110.00 grams, crude product), are yellow solid, and it, which need not be further purified, is used for next step.
Step 2：
6- benzyls -1,3,4,5,7,8- hexahydro -1,6- benzodiazine -2- ketone
To 1- benzyl -4- pyrrolidin-1-yl -3,6- dihydro -2H- pyridines, (119.00 grams, 491.01 mMs, 1.00 work as Amount) toluene (80.00 milliliters) solution in added under 30 degrees Celsius propyl- 2- acrylamides (52.35 grams, 736.51 mMs, 1.50 equivalents), then mixture is stirred 12 hours under 130 degrees Celsius, mixture is cooled to 30 degrees Celsius, and 45 Degree Celsius it is concentrated under reduced pressure.Residue is washed with petroleum ether (100 milliliters), filtered, filter cake is concentrated in a vacuum, obtains 6- benzyls Base -1,3,4,5,7,8- hexahydro -1,6- benzodiazine -2- ketone (76.00 grams, 313.63 mMs, 63.88% yield) are yellow Color solid.
Step 3：
Tetrahydrochysene -1, the 6- naphthyridines -2- ketone of 6- benzyls 1,5,7,8
By 6- benzyls -1,3,4,5,7,8- hexahydro -1,6- benzodiazine -2- ketone (35.00 grams, 144.44 mMs, 1.00 Equivalent) it is dissolved in acetic acid (200.00 milliliters), under nitrogen protection in 0 degree Celsius of bromine added into the solution (23.08 Gram, 144.44 mMs, 1.00 equivalents) and acetic acid (200.00 milliliters) mixture.The mixture stirs 30 under 0 degree Celsius Minute, it is then heated to 110 degrees Celsius and stirs 12 hours.Mixture is cooled to 30 degrees Celsius, and it is dense in 45 degrees Celsius of decompressions Contracting.Residue is poured into the aqueous solution (70 milliliters) of sodium carbonate and stirred 10 minutes.Solid is filtered and petroleum ether (30 millis are used Rise) washing, vacuum drying obtains tetrahydrochysene -1, the 6- naphthyridines -2- ketone (35.00 grams, crude product) of 6- benzyls 1,5,7,8, is yellow solid. LCMS(ESI)m/z：241(M+1).
Step 4：
Chloro- 7,8- dihydros -5H-1, the 6- benzodiazines of 6- benzyls -2-
By tetrahydrochysene -1, the 6- naphthyridines -2- ketone of 6- benzyls 1,5,7,8 (35.00 grams, 145.65 mMs, 1.00 equivalents) in 30 Degree Celsius it is added portionwise in POCl3 (178.62 grams, 1.16 moles, 8.00 equivalents), stirs 10 minutes after adding, then 130 degrees Celsius are heated the mixture to stir 12 hours.Mixture is cooled down, trichlorine oxygen is removed in 50 degrees Celsius of vacuum distillations Phosphorus.Residue dchloromethane, and pouring into water (500 milliliters), by mixture with saturated sodium carbonate solution (500 milliliters) Alkalization.Aqueous phase is extracted (500 milliliters × 3) with dichloromethane.The organic phase of merging is washed with saturated brine (30 milliliters × 2), With anhydrous sodium sulfate drying, filter and be concentrated in vacuo.Residue purified by silica gel chromatography (petrol ether/ethyl acetate= 15/1,7/1) 6- benzyls -2- chloro- 7,8- dihydros -5H-1,6- benzodiazine (key intermediate A) (17.00 grams, 65.70, are obtained MM, 45.11% yield), it is yellow solid.1H NMR (400MHz, CDCl3) 7.41-7.30 (m, 5H), 7.26 (d, J= 8.0Hz, 1H), 7.10 (d, J=8.0Hz, 1H), 3.73 (s, 2H), 3.61 (s, 2H), 3.07-3.01 (m, 2H), 2.88-2.83 (m, 2H)
Step 5：
Tetrahydrochysene -1, the 6- benzodiazine hydrochlorides of 2- chloro- 5,6,7,8-
6- benzyls -2- chloro- 7,8 dihydro -5H-1,6- naphthyridines (15.00 grams, 57.97 mMs, 1.00 equivalents) is dissolved in two In chloroethanes (80.00 milliliters), 1- chloroethyls phosgene (12.43 grams, 86.96 mmoles are added in 0 degree Celsius under nitrogen protection You, 1.50 equivalents).Mixture is stirred 0.5 hour under 0 degree Celsius, 85 degrees Celsius is then heated to and stirs 12 hours.Will Mixture is concentrated, and is then dissolved in methanol (30.00 milliliters), and the mixture is stirred for 2 hours at 80 degrees Celsius.Will mixing Thing cold filtration, obtains tetrahydrochysene -1, the 6- benzodiazines of 2- chloro- 5,6,7,8- (6.30 grams of crude products), is white solid.Need not by it Being further purified is used for next step.
Step 6：
(S) chloro- 7,8- dihydros -1,6- naphthyridines -6 (the 5H)-yls of -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3-2-) - 2- methyl propan-2-ols
Tetrahydrochysene -1, the 6- benzodiazines of 2- chloro- 5,6,7,8- (11.00 grams, 65.24 mMs, 1.00 equivalents) and 2- is chloro- 1- [[(2S) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (14.20 grams, 65.24 mMs, 1.00 equivalents) are molten In ethanol (150.00 milliliters), nitrogen is adding nitrogen nitrogen diisopropylethylamine (21.08 in 15 degrees Celsius under protecting into the solution Gram, 163.10 mMs, 2.50 equivalents).Mixture is stirred 12 hours at 85 degrees Celsius.Then mixture is cooled into 15 to take the photograph Family name's degree, and be concentrated under reduced pressure in 60 degrees Celsius.Water (30 milliliters) is added into residue.Extracted with ethyl acetate (200 milliliters × 4) Take, the organic phase of merging is washed with saturated brine (100 milliliters × 2), with anhydrous sodium sulfate drying, filtering and vacuum concentration. Residue is by Silica gel chromatography (petrol ether/ethyl acetate=20/1,1/2) to obtain 1- (chloro- 7, the 8- dihydros -5H- of 2- 1,6- naphthyridines -6- bases) -3- (the chloro- 4- nitroimidazoles -1- bases of 2-)-the third propan-2-ol of -2- methyl (20.00 grams, 51.78 mMs, 79.37% yield), it is yellow solid.LCMS(ESI)m/z：386(M+1).
Step 7：
(S) -2- ((chloro- 7,8- dihydros -1,6- naphthyridines -6 (the 5H)-yls of 2-) methyl) -2- methyl -6- nitro -2,3- dihydros Imidazo [2,1-B] oxazole
By 1- (chloro- 7,8- dihydros -5H-1,6- naphthyridines-the 6- bases of 2-) -3- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- methyl - Propan-2-ol (9.00 grams, 23.30 mMs, 1.00 equivalents) is dissolved in DMF (80.00 milliliters) solution at -20 degrees Celsius in nitrogen Protection is lower to add NaH (1.12 grams, 46.60 mMs, 2.00 equivalents).By mixture -20 degrees Celsius stir 10 minutes, then - 5 degrees Celsius are warming up to, and is stirred 10 minutes, then proceedes to be warming up to 15 degrees Celsius, and be stirred for 10 minutes.Mixture is cold But to 0 degree Celsius, then mixture is added drop-wise in 0.25 mole of aqueous hydrochloric acid solution (400 milliliters), then mixture is used Sodium bicarbonate aqueous solution is alkalized to pH=7~8, and sediment is filtered and dried, obtain (S) -2- ((chloro- 7,8- dihydro -1 of 2-, 6- naphthyridines -6 (5H)-yl) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole (key intermediate B) (6.70 grams, 19.16 mMs, 82.22% yield), are yellow solid.1H NMR (400MHz, CDCl3) 7.52 (s, 1H), 7.27 (s, 1H), 7.12 (d, J=8.0Hz, 1H), 4.39 (d, J=9.6Hz, 1H), 3.96 (d, J=9.6Hz, 1H), 3.82 (q, J=15.3Hz, 2H), 3.14-3.03 (m, 2H), 3.02-2.85 (m, 3H), 2.80 (d, J=14.8Hz, 1H), 1.68 (s, 3H).LCMS(ESI)m/z：350(M+1).
(R) the chloro- 1- of -2- ((2- expoxy propane -2- bases) methyl) -4- nitro -1H- imidazoles
Step 1：
(S)-(2- methyl oxirane -2- bases) methyl -4- nitrobenzene-sulfonic acid esters
By 4A molecular sieve (15.00 grams) in DCM suspension (300.00 milliliters) solution nitrogen protection under in 10-30 Degree Celsius add 2- methyl propyl- 2- alkene -1- alcohol (15.00 grams, 208.02 mMs, 1.00 equivalents) and diisopropyl (2S, 3S) - Mixture is cooled to -10~0 degree Celsius, four isopropyls by tartaric acid diisopropyl ester (2.92 grams, 12.48 mMs, 0.06 equivalent) Epoxide titanium (3.55 grams, 12.48 mMs, 0.06 equivalent) be added dropwise in reactant mixture keep reaction temperature -15~- 5 degrees Celsius, then stir the mixture for 0.5 hour, (1- hydrogen peroxide -1- methyl-ethyls) benzene (63.32 grams, 416.03 mmoles You, 2.00 equivalents) it is added dropwise in the mixture, keep the temperature at after -15~-5 degrees Celsius, 3 hours, phosphorous acid front three The mixture of ester (25.83 grams, 208.02 mMs, 1.0 equivalents) is added to the reactant mixture, 20 at -15~-5 degrees Celsius 4- nitrobenzene sulfonyl chlorides (46.10 grams, 208.02 mMs, 1.00 equivalents) after minute, DMAP (1.27 grams, 10.40 mmoles You, 0.05 equivalent) it is added in reactant mixture, triethylamine is then added dropwise, and (25.81 grams, 208.02 mMs, 1.0 work as Amount), mixture is gradually stepped up into temperature to 20 degrees Celsius after adding, after 1 hour, water (100 milliliters) reaction is added to mixed Compound is simultaneously stirred 20 minutes, and filtering extracts filtrate (50 milliliters × 3) with dichloromethane.By the organic phase saturated salt of merging (30 milliliter * 1) washing of water, with anhydrous sodium sulfate drying, filtering and vacuum concentration.Residue is passed through into Silica gel chromatography (pillar height degree：250 millimeters, diameter：100 millimeters, 100-200 mesh silica gel, petrol ether/ethyl acetate=30/1,5/1), obtain [(S)-(2- methyl oxirane -2- bases) methyl -4- nitrobenzene-sulfonic acids ester (24.00 grams, 87.83 mMs, 42.22% production Rate), it is light yellow solid.1H NMR (400MHz, CDCl3)：δ 8.47-8.37 (m, 2H), 8.17-8.11 (m, 2H), 4.28 (d, J=10.9Hz, 1H), 4.04 (d, J=10.9Hz, 1H), 2.77-2.65 (m, 2H), 1.43-1.35 (m, 3H)
Step 2：
(R) the chloro- 1- of -2- ((2- expoxy propane -2- bases) methyl) -4- nitro -1H- imidazoles
To the chloro- 4- nitros -1H- imidazoles of 2- (20.00 grams, 135.57 mMs, 1.00 equivalents) and (S)-(2- methyl epoxies Ethane -2- bases) methyl -4- nitrobenzene-sulfonic acids ester (37.05 grams, 135.57 mMs, 1.00 equivalents) is at DMF (300.00 milliliters) Mixture in, add potassium carbonate (56.21 grams, 406.71 mMs, 3.00 equivalents) and deaerated with nitrogen and replace 3 times, then Mixture is stirred at 60 c 12 hours.Reactant mixture is concentrated to remove solvent under reduced pressure.Residue is dilute Release, with saturated sodium carbonate, (200 milliliters) neutralize and are extracted with ethyl acetate (50 milliliters × 3).By the organic layer saturation of merging Salt solution (50 milliliters × 2) is washed, dried over sodium sulfate, is filtered and is concentrated to give residue under reduced pressure.Residue passes through post color Spectrometry (SiO2, petrol ether/ethyl acetate=5/1,2/1), obtains (key intermediate C) (R) -2- chloro- 1- ((2- methyl epoxies Ethane -2- bases base) methyl) -4- nitro -1H- imidazoles (17.86 grams, 82.07 mMs, 60.54% yield) is yellow oily Thing.LCMS(ESI)m/z：218(M+1).
Embodiment 1
2- methyl -6- nitros -2- (((the 5H)-yl of 2- phenyl -7,8- dihydros -1,6- naphthyridines -6) methyl) -2,3- dihydro miaows Azoles simultaneously [2,1-B] oxazole
Step 1：
6- benzyl -2- phenyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
To the mixed solution of key intermediate A (1.10 grams, 4.25 mMs) dioxane/water (11 milliliters, 10/1) Middle addition potassium phosphate (2.23 grams, 10.51 mMs), phenylboric acid (1.03 grams, 8.45 mMs) and Pd (PPh3)4(734.00 Milligram, 635.19 micromoles), mixture is stirred 3 hours under 130 degrees Celsius.Mixture is filtered, filtrate is concentrated, it is residual Stay thing by Silica gel chromatography (petrol ether/ethyl acetate=10/0,10/1) obtain 6- benzyl -2- phenyl -7,8- dihydro - 5H-1,6- benzodiazine (750.00 milligrams, 58.75%), are white solid.H NMR (400MHz, CDCl3)：δ 7.96 (d, J =7.2Hz, 2H), 7.53-7.36 (m, 10H), 3.76 (s, 2H), 3.69 (s, 2H), 3.16 (t, J=5.9Hz, 2H), 2.93 (t, J=5.9Hz, 2H) .LCMS (ESI) m/z：301(M+1).LCMS(ESI)m/z：301(M+1).
Step 2：
2- phenyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
To the dichloro of 6- benzyl -2- phenyl -7,8- dihydro -5H-1,6- benzodiazines (375.00 milligrams, 1.25 mMs) In ethane solution (15 milliliters), 1- chloroethyls phosgene (232.02 milligrams, 1.62 mMs), the mixing are added at 0 degree Celsius Thing is stirred 15 minutes under 0 degree Celsius, is then heated to 85 degrees Celsius and is stirred 12 hours.Mixture is concentrated under reduced pressure, and to Methanol (15 milliliters) is added in residue, is then stirred for 1 hour at 60 degrees Celsius.Mixture is concentrated, 2- phenyl -5 are obtained, 6,7,8- tetrahydrochysene -1,6- naphthyridine hydrochlorides (340.00 milligrams, crude product), are white solid.LCMS(ESI)m/z：211(M+1).
Step 3：
1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- methyl -3- (2- phenyl -7,8- dihydros -1,6- naphthyridines -6 (5H)-yl) propan-2-ol
To 2- phenyl -5,6, the ethanol of 7,8- tetrahydrochysene -1,6- benzodiazine hydrochlorides (500.00 milligrams, 2.38 mMs) 2- chloro- 1- ((2- methyl oxirane -2- bases) methyl) -4- nitro -1H- imidazoles (672.69 millis are added in (5 milliliters) solution Gram, 3.09 mMs), mixture is stirred 6 hours under 70 degrees Celsius.Mixture is concentrated, residue passes through silica gel chromatograph Method purifying (petrol ether/ethyl acetate=20/1,2/1) obtains 1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- methyl -3- ((the 5H)-yl of 2- phenyl -7,8- dihydros -1,6- naphthyridines -6) propan-2-ol (600.00 milligrams of crude products), is yellow oil.LCMS (ESI)m/z：428(M+1).
Step 4：
2- methyl -6- nitros -2- (((the 5H)-yl of 2- phenyl -7,8- dihydros -1,6- naphthyridines -6) methyl) -2,3- dihydro miaows Azoles simultaneously [2,1-B] oxazole
To 1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- methyl -3- (2- phenyl -7,8- dihydros -1,6- naphthyridines -6 (5H)-yl) propan-2-ol (600.00 milligrams, 1.40 mMs) takes the photograph in 0 under nitrogen protection in the solution of DMF (10 milliliters) Family name's degree adds NaH (67.20 milligrams, 2.80 mMs).The mixture is stirred 1 hour under 0 degree Celsius.Mixture is added to and stirred In the water (40 milliliters) mixed, the solid separated out is filtered, and is recrystallized in ethyl acetate (50 milliliters), white solid is obtained, will It passes through chiral SFC (ChiralpakAD 250 × 30mmI.D.5um, Supercritical CO2/ EtOH (0.2%NH3H2O) =60/40,80ml/min, 220nm) split and obtain two chiral isomers, first obtained compound is 2- methyl -6- nitre Base -2- (((the 5H)-yl of 2- phenyl -7,8- dihydros -1,6- naphthyridines -6) methyl) -2-, 3- glyoxalidine simultaneously name by [2,1-B] oxazole For compound 1A (40.60 milligrams, 7.19%), second obtained compound 2- methyl -6- nitros -2- ((2- phenyl -7,8- Dihydro -1,6- naphthyridines -6 (5H)-yl) methyl) simultaneously [2,1-B] oxazole is named as compound 1B (48.10 millis to -2,3- glyoxalidine Gram, 8.48%).Nuclear-magnetism is all mutually：1H NMR (400MHz, CDCl3)：δ 7.94 (d, J=7.2Hz, 2H), 7.53-7.36 (m, 6H), 4.45 (d, J=10.0Hz, 1H), 3.97-3.86 (m, 3H), 3.16-2.99 (m, 5H), 2.81 (d, J=14.8Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：392(M+1).
Embodiment 2
2- methyl -6- nitros -2- ((2- (4- (trifluoromethoxy) phenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) Methyl) -2,3- dihydros simultaneously [2,1-B] oxazole
Step 1：
6- benzyls -2- (4- (trifluoromethoxy) phenyl) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
To key intermediate A (1.20 grams, 4.64 mMs, 1.00 equivalents) dioxane (5 milliliters) and water (0.5 milli Rise) mixed solution in add potassium phosphate (2.46 grams, 11.60 mMs, 2.50 equivalents), under nitrogen protection in 0 degree Celsius Add Pd (PPh3)4(536.18 milligrams, 464.00 micromoles, 0.10 equivalent), (4- (trifluoromethoxy) phenyl) boric acid (1.43 Gram, 6.96 mMs, 1.50 equivalents).Mixture is stirred at one hundred and twenty degrees centigrade 3 hours.Mixture is cooled down, and taken the photograph 50 Family name's degree is concentrated under reduced pressure, and residue is purified by Silica gel chromatography (petrol ether/ethyl acetate=50/1,15/1), obtains 6- Benzyl -2- (4- (trifluoromethoxy) phenyl) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines (1.30 grams, 3.38 mMs, 72.89% yield), it is yellow solid.LCMS(ESI)m/z：385(M+1).
Step 2：
2- (4- (trifluoromethoxy) phenyl) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
To 6- benzyls -2- (4- (trifluoromethoxy) phenyl) -5,6,7,8- tetrahydrochysene -1,6- benzodiazine (1.30 grams, 3.38 MM, 1.00 equivalents) dichloroethanes (20 milliliters) solution under nitrogen protection in 0 degree Celsius add 1- chlorine phosgenes (725.28 milligrams, 5.07 mMs, 1.50 equivalents).Mixture is stirred 0.5 hour under 15 degrees Celsius, 80 are then heated to Degree Celsius stirring 12 hours.Methanol (5 milliliters) is added into the mixture, and is stirred for after 4 hours, is cooled down, at 50 degrees Celsius Be concentrated under reduced pressure the mixture, by residue by Silica gel chromatography (methylene chloride/methanol=50/1,10/1), obtains 2- [4- (trifluoromethoxy) phenyl] -5,6,7,8- tetrahydrochysene -1,6- benzodiazine (500.00 milligrams, 1.70 mMs, 50.27% Yield), it is yellow solid.LCMS(ESI)m/z：295(M+1).
Step 3：
1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- methyl -3- (2- (4- (trifluoromethoxy) phenyl) -7,8- bis- Hydrogen -1,6- naphthyridines 6 (5H)-yl) propan-2-ol
To 2- [4- (trifluoromethoxy) phenyl] -5,6,7,8- tetrahydrochysene -1,6- benzodiazines (400.00 milligrams, 1.36 millis Mole, 1.00 equivalents) and the chloro- 1- of 2- [(2- methyl oxirane -2- bases) methyl] -4- nitroimidazoles (591.90 milligrams, 2.72 MM, 2.00 equivalents) in the solution of ethanol (10 milliliters) add DIPEA (74.00 milligrams, 572.58 micromoles, 0.42 work as Amount).Mixture is stirred at 80 degrees celsius 12 hours.Mixture is cooled down, and is concentrated under reduced pressure at 50 degrees Celsius, residue leads to Cross Silica gel chromatography (petrol ether/ethyl acetate=15/1,1/1), obtain 1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) - 2- methyl -3- (2- (4- (trifluoromethoxy) phenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines 6) propan-2-ol (500.00 millis Gram, crude product), it is yellow solid.LCMS(ESI)m/z：512(M+1).
Step 4：
2- methyl -6- nitros -2- ((2- (4- (trifluoromethoxy) phenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) Methyl) -2,3- dihydros simultaneously [2,1-B] oxazole
By 1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- methyl -3- (2- (4- (trifluoromethoxy) phenyl) -7,8- Dihydro -1,6- naphthyridines 6 (5H)-yl) (5.00 in the least in DMF for propan-2-ol (300.00 milligrams, 586.07 micromoles, 1.00 equivalents) Rise) NaH (28.13 milligrams, 1.17 mMs, 2.00 equivalents) is added under 0 degree Celsius under nitrogen protection in solution.The mixture Stirred 0.5 hour at 0 degree Celsius, the color of solution becomes red.In the mixture water (10 milliliters) will be added at 0 degree Celsius In, aqueous phase is extracted with ethyl acetate (50 milliliters × 4).The organic phase of merging is washed with saturated brine (20 milliliters × 2), With anhydrous sodium sulfate drying, filtering and vacuum concentration, residue preparative prepare chromatogram purification (GX-D；Boston Symmetrix C18 ODS-R 150*30mm*5um；Acetonitrile 24%-54%；Water (0.225%NH4OH)； The mixture (90 milligrams) of two kinds of isomers 25mL/min) is obtained, it is passed through into chiral SFC (250 × 30mm of ChiralpakAD I.D.5um, Supercritical CO2/ EtOH (0.2%NH3H2O)=60/40,70ml/min, 220nm) separation obtain two Individual chiral isomer, first obtained compound be 2- methyl -6- nitros -2- ((2- (4- (trifluoromethoxy) phenyl) -7, 8- dihydros -1,6- naphthyridines -6 (5H) base) methyl) simultaneously [2,1-B] oxazole is named as compound 2A (48.20 millis to -2,3- glyoxalidine Gram, 97.33 micromoles, 16.61% yield, 96% purity), second obtained compound 2- methyl -6- nitro -2- ((2- (4- (trifluoromethoxy) phenyl)-(5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2,3- glyoxalidine simultaneously dislike by [2,1-B] Azoles is named as compound 2B (33.40 milligrams, 67.02 micromoles, 11.44% yield, 95.4% purity).Nuclear-magnetism is all mutually：1H NMR (400MHz, CDCl3)：δ 7.98 (d, J=8.8Hz, 2H), 7.56-7.45 (m, 2H), 7.42-7.36 (m, 1H), 7.30 (d, J=8.4Hz, 2H), 4.43 (d, J=9.6Hz, 1H), 4.01-3.78 (m, 3H), 3.21-2.92 (m, 5H), 2.81 (d, J =14.8Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：476(M+1).
Embodiment 3
(S) -2- methyl -6- nitros -2- ((2- (3- (trifluoromethoxy) phenyl) -7,8- dihydros -1,6- naphthyridines -6 (5H) - Base) methyl) -2-, 3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (120.00 milligrams, 343.08 micromoles, 1.00 equivalents) and [3- (trifluoromethoxy) phenyl] Boric acid (70.65 milligrams, 343.08 micromoles, 1.00 equivalents) is dissolved in dioxane (5.00 milliliters) and water (500.00 microlitres) In, the solution adds Pd (dppf) Cl in 30 degrees Celsius under nitrogen protection2(25.10 milligrams, 34.31 micromoles, 0.10 works as Amount), sodium carbonate (90,91 milligrams, 857.70 micromoles, 2.5 equivalents).Mixture is stirred 12 hours at 110 degrees Celsius.Reaction After complete, mixture is cooled to 30 degrees Celsius, and be concentrated under reduced pressure at 45 degrees Celsius.Residue is poured into water (10 milliliters), and Stirring 5 minutes.Aqueous phase is extracted with ethyl acetate (30 milliliters × 3).The organic phase of merging is washed with saturated brine (10 milliliters × 2) Wash, then with anhydrous sodium sulfate drying, filter and be concentrated in vacuo.Residue purifies (petroleum ether/acetic acid by preparative thin-layer chromatography Ethyl ester=1/2.5) prepare chromatographic separation and purification (GX-D with preparative；Boston Symmetrix C18 ODS-R 150* 30mm*5um；Acetonitrile 24%-54%；Water (0.225%fomic acid) 25ml/min), obtain (S) -2- Methyl -6- nitros -2- ((2- (3- (trifluoromethoxy) phenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2,3- Glyoxalidine simultaneously [2,1-B] oxazoline compound 3 (12.00 milligrams, 24.62 micromoles, 7.18% yield, 97.54% purity),.1H NMR (400MHz, CDCl3)：δ 7.89-7.87 (d, J=8.03Hz, 1H), 7.84 (s, 1H), 7.52 (s, 1H), 7.51- 7.46 (m, 2H), 7.41 (d, J=8.16Hz, 1H), 7.27 (d, J=8.16Hz, 1H), 4.44 (d, J=9.66Hz, 1H), 3.97 (d, J=9.66Hz, 1H), 3.95-3.84 (m, 2H), 3.18-3.01 (m, 5H), 2.82 (d, J=14.81Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：476(M+1).
Embodiment 4
(S) -2- methyl -6- nitros -2- ((2- (2- (trifluoromethoxy) phenyl) -7,8- dihydros -1,6- naphthyridines -6 (5H) - Base) methyl) -2-, 3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (100.00 milligrams, 285.90 micromoles, 1.00 equivalents) and (2- (trifluoromethoxy) phenyl) Boric acid (70.65 milligrams, 343.08 micromoles, 1.20 equivalents) is dissolved in dioxane (5.00 milliliters) and water (500.00 microlitres) In mixed solution, the mixed solution is under the protection of nitrogen, and sodium carbonate are added in 15 degrees Celsius, and (60.61 milligrams, 571.80 micro- rub You, 2.00 equivalents), Pd (dppf) Cl2(20.92 milligrams, 28.59 micromoles, 0.10 equivalent).Mixed solution is Celsius 120 Degree stirring 12 hours.Mixed solution is cooled to 15 degrees Celsius after having reacted, filters and concentrates filter vacuum.Residue passes through Preparative prepares chromatographic separation and purification (GX-D；Boston Symmetrix C18 ODS-R 150*30mm*5um； Acetonitrile 24%-54%；Water (0.225%fomic acid)；25mL/min), (S) -2- methyl -6- nitre is obtained Base -2- ((2- (2- (trifluoromethoxy) phenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2-, 3- glyoxalidine And [2,1-B] oxazoline compound 4 (15.00 milligrams, 29.97 micromoles, 10.48% yield, 95% purity).1H NMR (400MHz, CDCl3)：δ 7.77 (d, J=2.8Hz, 1H), 7.55 (s, 1H), 7.49-7.31 (m, 5H), 4.45 (d, J= 9.6Hz, 1H), 4.01-3.82 (m, 3H), 3.23-2.93 (m, 5H), 2.83 (d, J=14.8Hz, 1H), 1.70 (s, 3H) .LCMS(ESI)m/z：476(M+1).
Embodiment 5
(S) -2- ((2- (2- fluorophenyls)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros - 2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
Tetrahydrochysene -1, the 6- benzodiazines of 6- benzyls -2- (2- fluorophenyls) -5,6,7,8-
By key intermediate A (1.50 grams, 5.80 mMs, 1.00 equivalents) and (2- fluorophenyls) boric acid (973.84 milligrams, 6.96 mMs, 1.20 equivalents) it is dissolved in the mixed solution of dioxane (20.00 milliliters) and water (5.00 milliliters), in nitrogen Protection under, add Pd (dppf) Cl2(424.39 milligrams, 580.00 micromoles, 0.10 equivalent) and sodium carbonate (1.23 grams, 11.60 mMs, 2.00 equivalents), then mixed solution is stirred 12 hours under 100 degrees Celsius.Reaction solution is concentrated under reduced pressure To remove solvent, 20 milliliters of residue diluted with water is simultaneously extracted with ethyl acetate (10 milliliters × 3).The organic layer of merging is used full Washed with salt solution (10 milliliters × 2), it is dried over sodium sulfate, filter and be concentrated under reduced pressure, obtain 6- benzyls -2- (2- fluorophenyls) -5, 6,7,8- tetrahydrochysenes 1,6- benzodiazines (1.39 grams, 4.37 mMs, 75.27% yield), are brown solid.
Step 2：
Tetrahydrochysene -1, the 6- benzodiazines of 2- (2- fluorophenyls) -5,6,7,8-
By tetrahydrochysene -1, the 6- benzodiazines of 6- benzyls -2- (2- fluorophenyls) -5,6,7,8- (1.39 grams, 4.37 mMs, 1.00 equivalents) it is dissolved in methanol (20.00 milliliters), Pd (OH) is added under the atmosphere of nitrogen2/ C (10%, 139 milligrams).Should Mixed solution is replaced 3 times with hydrogen.The mixed solution is heated to 50 degrees Celsius and in H2Stirring 12 is small under conditions of (50psi) When.Reactant mixture is filtered, filtrate decompression is concentrated, tetrahydrochysene -1, the 6- naphthalenes of crude product 2- (2- fluorophenyls) -5,6,7,8- are obtained Pyridine (1.05 grams, crude product).Crude product is used for next step without further purification.
Step 3：
(S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3- (2- (2- fluorophenyls) -7,8- dihydros -1,6- naphthyridines -6 (5H)-yl) -2- methyl propan-2-ols
By tetrahydrochysene -1, the 6- naphthyridines of 2- (2- fluorophenyls) -5,6,7,8- (300.00 milligrams, 1.31 mMs, 1.00 equivalents), (R) the chloro- 1- of -2- ((2- expoxy propane -2- bases) methyl) -4- nitro -1H- imidazoles (286.00 milligrams, 1.31 mMs, 1.00 Equivalent), DIPEA (507.91 milligrams, 3.93 mMs, 3.00 equivalents) is dissolved in the mixed solution in ethanol (20.00 milliliters) and used Nitrogen displacement three times.Then by mixed solution in the atmosphere of nitrogen under 80 degrees Celsius stir 12 hours.By reactant mixture It is concentrated under reduced pressure to remove solvent.Residue passes through Silica gel chromatography (silica, petrol ether/ethyl acetate=5/1,1/ 1) (S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3- (2- (2- fluorophenyls) -7,8- dihydros -1,6- naphthyridines -6 are obtained (5H)-yl) -2- methyl propan-2-ol (300.00 milligrams, 672.84 micromoles, 51.36% yield) is yellow solid.
Step 4：
(S) -2- ((2- (2- fluorophenyls)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros - 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3-, (2- (2- fluorophenyls) -7,8- dihydro -1,6- naphthalene are molten Liquid -6 (5H)-yl) -2- methyl propan-2-ol (300.00 milligrams, 672.84 micromoles, 1.00 equivalents) is dissolved in DMF (5.00 milliliters) In.The mixed solution adds NaH (32.30 milligrams, 807.41 micromoles, 1.20 equivalents) and at such a temperature under 0 degree Celsius Stirring 30 minutes.Reactant mixture is added to saturated ammonium chloride (20 milliliters) under 0 degree Celsius, then with 20 milliliters of dilutions of water, And (10 milliliters × 3) are extracted with DCM.The organic layer of merging is washed (10 milliliters × 2) with saturated brine, it is dried over sodium sulfate, It is filtered, and concentrated under reduced pressure to give residue.Residue prepares chromatographic separation and purification (GX-E by preparative；Innoval C18 150*30mm*5um；Acetonitrile 12%-42%；Water (0.225%fomic acid)；25mL/min) purify To (S) -2- ((2- (2- fluorophenyls)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros -2-, 3- bis- Hydrogen imidazo [2,1-B] oxazoline compound 5 (101.80 milligrams, 248.65 micromoles, 36.96% yield).1H NMR (400MHz, CDCl3)：δ 7.94-7.87 (m, 1H), 7.57-7.54 (m, 1H), 7.53 (s, 1H), 7.42-7.33 (m, 2H), 7.28-7.23 (m, 1H), 7.19-7.11 (m, 1H), 4.44 (d, J=8.0Hz, 1H), 3.96 (d, J=8.0Hz, 1H), 3.92- 3.83 (m, 2H), 3.22-3.08 (m, 2H), 3.08-2.94 (m, 3H), 2.82 (d, J=12.0Hz, 1H), 1.69 (s, 3H) .LCMS(ESI)m/z：409(M+1).
Embodiment 6
(S) -2- ((2- (3- fluorophenyls)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros - 2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
Tetrahydrochysene -1, the 6- benzodiazines of 6- benzyls -2- (3- fluorophenyls) -5,6,7,8-
By key intermediate A (1.50 grams, 5.80 mMs, 1.00 equivalents), (3- fluorophenyls) boric acid (973.36 milligrams, 6.96 mMs, 1.20 equivalents) it is dissolved in the mixed solution of dioxane (20.00 milliliters) and water (5.00 milliliters).The mixing Solution adds Pd (dppf) Cl under the protection of nitrogen2(424.17 milligrams, 579.71 micromoles, 0.10 equivalent) and sodium carbonate (1.23 grams, 11.59 mMs, 2.00 equivalents).Then it is small in 100 degrees Celsius of stirrings 12 by mixture under the atmosphere of nitrogen When.Reactant mixture is concentrated under reduced pressure to remove solvent.By 20 milliliters of residue diluted with water and be extracted with ethyl acetate (10 milli Rise × 3).The organic layer of merging is washed (10 milliliters × 2) with saturated brine, it is dried over sodium sulfate, filter and be concentrated under reduced pressure, obtain To tetrahydrochysene -1, the 6- benzodiazines of 6- benzyls -2- (3- fluorophenyls) -5,6,7,8- (1.40 grams, 4.40 mMs, 75.81% production Rate) brown solid
Step 2：
Tetrahydrochysene -1, the 6- benzodiazines of 2- (3- fluorophenyls) -5,6,7,8-
By tetrahydrochysene -1, the 6- benzodiazines of 6- benzyls -2- (3- fluorophenyls) -5,6,7,8- (1.40 grams, 4.40 mMs, 1.00 equivalents) it is dissolved in methanol (20.00 milliliters).Pd (OH) is added under the protection of nitrogen2/ C (10%, 140 milligrams).Should Mixed solution is replaced 3 times with hydrogen.By mixture in H250 degrees Celsius are heated under conditions of (50psi) to stir 12 hours.Will Mixture filters and concentrates filtrate decompression, obtains tetrahydrochysene -1, the 6- benzodiazines of crude product 2- (3- fluorophenyls) -5,6,7,8- (1.10 grams, crude product).Crude product is directly used in next step.Crude product is used for next step without further purification.
Step 3：
(S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3- (2- (3- fluorophenyls) -7,8- dihydros -1,6- naphthyridines -6 (5H)-yl) -2- methyl propan-2-ols
By tetrahydrochysene -1, the 6- benzodiazines of 2- (3- fluorophenyls) -5,6,7,8-, (300.00 milligrams, 1.31 mMs, 1.00 work as Amount), the chloro- 1- of (R) -2- ((2- expoxy propane -2- bases) methyl) -4- nitro -1H- imidazoles (286.00 milligrams, 1.31 mMs, 1.00 equivalents), DIPEA (507.91 milligrams, 3.93 mMs, 3.00 equivalents) is dissolved in ethanol (20.00 milliliters), by mixture Stirred 12 hours in 80 degrees Celsius under the protection of nitrogen.Reactant mixture is concentrated under reduced pressure.Residue passes through silica gel chromatography Purify (silica, petrol ether/ethyl acetate=5/1,1/1), obtain (S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) - (300.00 milligrams, 672.84 is micro- for -2- methyl propan-2-ol by 3- (2- (3- fluorophenyls)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) Mole, 51.36% yield) yellow solid.
Step 4：
(S) -2- ((2- (3- fluorophenyls)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros - 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3- (2- (3- fluorophenyls) -7,8- dihydro -1,6- phenodiazines Miscellaneous naphthalene -6 (5H)-yl) -2- methyl propan-2-ol (300.00 milligrams, 672.84 micromoles, 1.00 equivalents) be dissolved in DMF (5.00 milli Rise) in, under 0 degree Celsius, NaH (32.30 milligrams, 807.41 micromoles, 1.20 equivalents) is added into the mixed solution and is stirred Mix 30 minutes.Reactant mixture is quenched under 0 degree Celsius with saturated ammonium chloride solution (20 milliliters), then with water (20 milliliters) Dilution, and extracted (10 milliliters × 3) with DCM.The organic layer of merging is washed with saturated brine (10 milliliters × 2), through sodium sulphate Dry, filter and be concentrated to give residue under reduced pressure.Residue prepares chromatogram (GX-E by preparative；Phenomenex Synergi C18 150*30mm*4um；Acetonitrile 15%-45%；Water (0.13%HCl)；It is 25mL/min) pure Change, obtain (S) -2- ((2- (3- fluorophenyls)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros - 2-, 3- glyoxalidine simultaneously [2,1-B] oxazoline compound 6 (161.80 milligrams, 395.20 micromoles, 58.74% yield).1H NMR (400MHz, CDCl3)：δ 7.76-7.66 (m, 2H), 7.53 (s, 1H), 7.50 (d, J=8.0Hz, 1H), 7.46-7.37 (m, 2H), 7.14-7.06 (m, 1H), 4.44 (d, J=8.0Hz, 1H), 3.97 (d, J=12.0Hz, 1H), 3.92-3.82 (m, 2H), 3.20-3.08 (m, 2H), 3.07-2.95 (m, 3H), 2.82 (d, J=12.0Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z： 409(M+1).
Embodiment 7
(S) -2- ((2- (4- fluorophenyls)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros - 2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
Tetrahydrochysene -1, the 6- benzodiazines of 6- benzyls -2- (4- fluorophenyls) -5,6,7,8-
By key intermediate A (2.00 grams, 7.73 mMs, 1.00 equivalents) and (4- fluorophenyls) boric acid (1.08 grams, 7.73 MM, 1.00 equivalents) it is dissolved in the mixed solution of dioxane (20.00 milliliters) and water (2.00 milliliters).In the guarantor of nitrogen In addition sodium carbonate (1.64 grams, 15.46 mMs, 2.00 equivalents), Pd (dppf) Cl under 15 degrees Celsius under shield2(565.60 millis Gram, 773.00 micromoles, 0.10 equivalent).Mixed solution is stirred 12 hours at 110 degrees Celsius under nitrogen protection.React Mixed solution is cooled to 15 degrees Celsius afterwards, and is concentrated under reduced pressure at 50 degrees Celsius, water (20 milliliters), aqueous phase are added into residue (100 milliliters × 4) are extracted with dichloromethane, the organic phase of merging is washed, anhydrous sodium sulfate with saturated aqueous common salt (50 milliliters) Dry, filter and be concentrated in vacuo.Residue obtains 6- by Silica gel chromatography (petrol ether/ethyl acetate=20/1,5/1) Benzyl -2- (4- fluorophenyls) -7,8- dihydros -5H-1,6- benzodiazine (1.86 grams, 5.84 mMs, 75.57% yield) Huang Color solid.1H NMR (400MHz, CDCl3)：δ 8.00-7.89 (m, 2H), 7.47-7.30 (m, 7H), 7.15 (t, J=8.8Hz, 2H), (t, J=6.0Hz, the 2H) of 3.76 (s, 2H), 3.68 (s, 2H), 3.19-3.07 (m, 2H), 2.92
Step 2：
Tetrahydrochysene -1, the 6- benzodiazine hydrochlorides of 2- (4- fluorophenyls) -5,6,7,8-
By 6- benzyls -2- (4- fluorophenyls) -7,8- dihydros -5H-1,6- benzodiazine (1.86 grams, 5.84 mMs, 1.00 Equivalent) it is dissolved in dichloroethanes (20.00 milliliters).Under the protection of nitrogen 1- chloroethyls phosgene (1.25 is added in 0 degree Celsius Gram, 8.76 mMs, 1.50 equivalents).Mixture is stirred 0.5 hour under 0 degree Celsius.It is then heated to 85 degrees Celsius and stirs Mix 12 hours.Then mixture concentration is added into methanol (20.00 milliliters) to remove in solvent, residue, and mixture is existed 85 degrees Celsius are stirred for 2 hours.The mixed solution is filtered and dried, and obtains the tetrahydrochysenes -1,6- bis- of 2- (4- fluorophenyls) -5,6,7,8- The yellow solid of azanaphthalene hydrochloride (1.54 grams thick), is directly used in next step.
Step 3：
(S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3- (2- (4- fluorophenyls) -7,8- dihydros -1,6- naphthyridines -6 (5H)-yl) -2- methyl propan-2-ols
By tetrahydrochysene -1, the 6- benzodiazines of 2- (4- fluorophenyls) -5,6,7,8- (1.54 grams, 6.75 mMs, 1.00 equivalents) (1.47 grams, 6.75 mMs, 1.00 work as with the chloro- 1- of 2- [[(2S) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles Amount) it is dissolved in ethanol (20.00 milliliters).Under the protection of nitrogen DIPEA (2.18 grams, 16.88 mmoles are added in 15 degrees Celsius You, 2.50 equivalents).Mixture is cooled to 15 degrees Celsius by mixture after 80 degrees Celsius are stirred 12 hours, and at 60 degrees Celsius It is concentrated under reduced pressure.Residue by Silica gel chromatography (silica, petrol ether/ethyl acetate=20/1,1/3) by being obtained 1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -7,8- dihydros -5H-1,6- naphthyridines -6- bases] -2- methyl - The yellow solid of propan-2-ol (1.20 grams, 2.69 mMs, 39.87% yield).
Step 4：
(S) -2- ((2- (4- fluorophenyls)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros - 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By 1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -7,8- dihydros -5H-1,6- naphthyridines -6- Base] -2- methyl -propyl- 2- alcohol (1.20 grams, 2.69 mMs, 1.00 equivalents) is dissolved in DMF (10.00 milliliters), the mixed solution NaH (129.12 milligrams, 5.38 mMs, 2.00 equivalents) is added in -20 degrees Celsius under nitrogen protection, then by mixed solution Stir 10 minutes, then stirred 10 minutes under -5 degrees Celsius under -20 degrees Celsius, stirred 10 minutes under 15 degrees Celsius.It is residual Excess is purified by silica gel chromatography (petrol ether/ethyl acetate=20/1,1/3), and products therefrom is at methanol (20 milliliters), and 75 take the photograph Stirred 0.5 hour under family name's degree, be then cooled to 15 degrees Celsius, filtered and dry, obtain (S) -2- ((2- (4- fluorophenyls) -7,8- Dihydro -1,6- naphthyridines -6 (5H)-yl) methyl) -2- methyl -6-- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 7 (711.10mg, 1.72mmol, 63.99%yield, 99.1%purity).1H NMR (400MHz, CDCl3)：δ 7.93 (dd, J =8.8,5.5Hz, 2H), 7.52 (s, 1H), 7.48-7.42 (m, 1H), 7.40-7.33 (m, 1H), 7.14 (t, J=8.7Hz, 2H), 4.43 (d, J=9.6Hz, 1H), 4.02-3.78 (m, 3H), 3.22-2.90 (m, 5H), 2.81 (d, J=15.1Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：410(M+1).
Embodiment 8
(S) -2- ((2- (4- chlorphenyls)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros - 2,3- glyoxalidine simultaneously [2,1-B] oxazole
Under nitrogen protection in 15 degrees Celsius, by key intermediate B (100.00 milligrams, 285.90 micromoles, 1.00 work as Amount) and (4- chlorphenyls) boric acid (53.65 milligrams, 343.08 micromoles, 1.20 equivalents) be dissolved in dioxane (5.00 milliliters) and In the mixed solution of water (500.00 microlitres).Mixture is stirred at one hundred and twenty degrees centigrade 12 hours, be subsequently cooled to 15 Celsius Degree, filtering, filtrate is concentrated under reduced pressure at 50 degrees Celsius, and residue prepares chromatographic separation and purification (GX-D by preparative；Boston Symmetrix C18 ODS-R 150*30mm*5um；Acetonitrile 24%-54%；Water (0.225%fomic acid)；25mL/min) obtain (S) -2- ((2- (4- chlorphenyls)-(the 5H)-yl of 7,8- dihydros -1,6- benzodiazine -6) methyl) - 2- methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazole by compound 8 (10.80 milligrams, 24.26 micromoles, 8.49% Yield, 95.67% purity).1H NMR (400MHz, CDCl3)：δ 7.90 (d, J=8.4Hz, 2H), 7.55-7.34 (m, 5H), 4.43 (d, J=9.5Hz, 1H), 4.03-3.79 (m, 3H), 3.24-2.92 (m, 5H), 2.81 (d, J=14.8Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：426(M+1).
Embodiment 9
(S) -4- (6- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole -2- bases) methyl) -5,6,7, 8- tetrahydrochysenes 1,6- naphthyridines -2- bases) benzonitrile
By key intermediate B (120.00 milligrams, 343.08 micromoles, 1.00 equivalents) and (4- cyano-phenyls) boric acid (60.49 milligrams, 411.70 micromoles, 1.20 equivalents) are dissolved in dioxane (5.00 milliliters), in 30 under the protection of nitrogen Pd (dppf) Cl is added degree Celsius into the solution2(25.10 milligrams, 34.31 micromoles, 0.10 equivalent), sodium carbonate (90.91 Milligram, 857.70 micromoles, 2.5 equivalents).Mixture is stirred 12 hours at 110 degrees Celsius.30 degrees Celsius are then cooled to, And be concentrated under reduced pressure at 45 degrees Celsius, water (10 milliliters) is added into the residue.Aqueous phase be extracted with ethyl acetate (20 milliliters × 3).The organic phase of merging is washed with saturated brine (10 milliliters × 2), with anhydrous sodium sulfate drying, filtering and vacuum concentration.It is residual Excess then prepares chromatographic isolation pure by thin-layer chromatography (petrol ether/ethyl acetate=1/2.5) preliminary treatment by preparative Change (GX-D；Boston Symmetrix C18 ODS-R 150*30mm*5um；Acetonitrile 24%-54%；water (0.225%fomic acid)；25mL/min) obtain (S) -4- (6- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1- B] oxazole -2- bases) methyl) -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- bases) (9.60 milligrams, 23.05 micro- rub benzonitrile compound 9 You, 6.72% yield, 99.3% purity).1H NMR (400MHz, CDCl3)：δ 8.09-8.07 (d, J=8.28Hz, 2H), 7.76-7.74 (d, J=8.41Hz, 2H), 7.55 (d, J=8.03Hz, 1H), 7.52 (s, 1H), 7.43-7.41 (d, J= 8.03Hz, 1H), 4.43-4.41 (d, J=9.66Hz, 1H), 3.98-3.96 (d, J=9.54Hz, 1H), 3.92-3.84 (m, 2H), 3.17-3.00 (m, 5H), 2.82 (d, J=14.81Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：417(M+1).
Embodiment 10
(S) -2- methyl -6- nitros -2- ((2- (4- (trifluoromethyl) phenyl) -7,8- dihydros -1,6- naphthyridines -6 (5H) - Base) methyl) -2-, 3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (120.00 milligrams, 343.08 micromoles, 1.00 equivalents) and [4- (trifluoromethyl) phenyl] boron Sour (65.16 milligrams, 343.08 micromoles, 1.00 equivalents) are dissolved in mixing for dioxane (5.00 milliliters) and water (500.00 microlitres) In polymer solution, under the atmosphere of nitrogen in 15 degrees Celsius add sodium carbonate (72.73 milligrams, 686.17 micromoles, 2.00 work as Amount), Pd (dppf) Cl2(25.10 milligrams, 34.31 micromoles, 0.10 equivalent).The mixed solution stirs 12 under 110 degrees Celsius Hour, chromatographic separation and purification (Boston Symmetrix C18 ODS-R150*30mm*5um are prepared by preparative； Acetonitrile 24%-54%；Water (0.225%fomic acid)；25mL/min) obtain (S) -2- methyl -6- nitre - 2,3- glyoxalidine is simultaneously by base -2- ((2- (4- (trifluoromethyl) phenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) [2,1-B] oxazoline compound 10 (16.40 milligrams, 34.16 micromoles, 9.96% yield, 95.7% purity).1H NMR (400MHz, CDCl3)：δ 8.07 (d, J=8.0Hz, 2H), 7.72 (d, J=8.2Hz, 2H), 7.59-7.48 (m, 2H), 7.42 (d, J=8.0Hz, 1H), 4.44 (d, J=9.8Hz, 1H), 4.04-3.81 (m, 3H), 3.23-2.93 (m, 5H), 2.82 (d, J =14.8Hz, 1H), 1.70 (s, 3H) .LCMS (ESI) m/z：460(M+1).
Embodiment 11
(S) -2- ((2- (3- fluoro- 4- (trifluoromethoxy) phenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) - 2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (62.32 milligrams, 178.17 micromoles, 1.00 equivalents) and [the fluoro- 4- of 3- (trifluoromethoxy) Phenyl] boric acid (39.90 milligrams, 178.17 micromoles, 1.00 equivalents) is dissolved in dioxane (5.00 milliliters), in the guarantor of nitrogen Under shield Pd (dppf) Cl is added in 30 degrees Celsius2(13.04 milligrams, 17.82 micromoles, 0.10 equivalent), sodium carbonate (47.21 millis Gram, 445.42 micromoles, 2.5 equivalents).Cooled down after mixed solution is stirred 12 hours under 110 degrees Celsius, and at 45 degrees Celsius Under be concentrated under reduced pressure.Residue is poured into water (10 milliliters), and stirred 5 minutes.Aqueous phase be extracted with ethyl acetate (30 milliliters × 3).The organic phase of merging is washed with saturated brine (10 milliliters × 2), with anhydrous sodium sulfate drying, filtering and vacuum concentration.It is residual After excess is by thin-layer chromatography (petrol ether/ethyl acetate=1/2.5) preliminary treatment, then it is pure by preparative preparation chromatographic isolation Change (GX-E；Column：Innoval C18 150*30mm*5um；Acetonitrile 30%-60%；Water (0.225% fomic acid)；25mL/min)) obtain (S) -2- ((2- (3- fluoro- 4- (trifluoromethoxy) phenyl) -7,8- dihydro -1,6- naphthalenes Pyridine -6 (5H)-yl) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 11 (10.70 milligrams, 20.82 micromoles, 11.68% yield, 96% purity).1H NMR (400MHz, CDCl3)：δ 7.86 (dd, J=11.36, 2.07Hz, 1H), 7.85 (d, J=8.53Hz, 1H), 7.72 (s, 1H), 7.52-7.49 (m, 1H), 7.47-7.39 (m, 2H), 4.43 (d, J=9.66Hz, 1H), 3.96 (d, J=9.66Hz, 1H), 3.91-3.83 (m, 2H), 3.20-2.99 (m, 5H), 2.82 (d, J=14.93Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：494(M+1).
Embodiment 12
(S) -2- ((2- (3,4- difluorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitre Base 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (300.00 milligrams, 857.71 micromoles, 1.00 equivalents) and (3,4- difluorophenyl) boric acid (162.53 milligrams, 1.03 mMs, 1.20 equivalents) are dissolved in the mixing of dioxane (5.00 milliliters) and water (500.00 microlitres) In solution.Under the protection of nitrogen sodium carbonate (113.64 milligrams, 1.07 mMs, 2.50 equivalents), Pd are added in 30 degrees Celsius (dppf)Cl2(62.76 milligrams, 85.77 micromoles, 0.10 equivalent).Heat the mixture to 100 degrees Celsius and stirring 12 is small When, water (10 milliliters) is added in the mixed solution, aqueous phase is extracted with ethyl acetate (30 milliliters × 3) by cooling.By merging Organic phase is washed with saturated aqueous common salt (20 milliliters), with anhydrous sodium sulfate drying, is filtered and is concentrated in vacuo.Residue is passed through thin Chromatographic separation and purification (GX-D is being prepared by preparative after layer chromatography (petrol ether/ethyl acetate=1/1,0/1) preliminary treatment； Boston Symmetrix C18 ODS-R 150*30mm*5um；Acetonitrile 24%-54%；Water (0.225% Fomic acid), 25ml/min) obtain (S) -2- ((2- (3,4- difluorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) Methyl) -2- methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 12 (5.70 milligrams, 13.34 micromoles, 3.11% yield, 95.0% purity).1H NMR (400MHz, CDCl3)：δ 7.85 (ddd, J=11.83,7.83,2.13Hz, 1H), 7.83 (br.s., 1H), 7.52 (s, 1H), 7.46-7.44 (m, 1H), 7.39-7.37 (m, 1H), 7.26-7.21 (m, 1H), 4.43 (d, J=9.66Hz, 1H), 3.96 (d, J=9.54Hz, 1H), 3.90-3.82 (m, 2H), 3.11 (d, J= 14.93Hz, 2H), 3.01-2.99 (m, 3H), 2.83-2.79 (d, J=14.81Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/ z：428(M+1).
Embodiment 13
(S) -2- ((2- (2,4- difluorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitre Base -2-, 3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (300.00 milligrams, 857.71 micromoles, 1.00 equivalents) and (2,4- difluorophenyl) boric acid (162.53 milligrams, 1.03 mMs, 1.20 equivalents) are dissolved in the mixing of dioxane (5.00 milliliters) and water (500.00 microlitres) In solution, sodium carbonate (113.64 milligrams, 1.07 mMs, 2.50 equivalents) then is added in 30 degrees Celsius under nitrogen protection, Pd(dppf)Cl2(62.76 milligrams, 85.77 micromoles, 0.10 equivalent).It is then heated to 100 degrees Celsius and stirs 12 hours. Mixture is cooled to 30 degrees Celsius.Water (10 milliliters) is added in the mixture.Be extracted with ethyl acetate (30 milliliters × 3).The organic phase of merging is washed with saturated aqueous common salt (20mL), with anhydrous sodium sulfate drying, filters and is concentrated in vacuo.It is remaining Thing then prepares chromatogram (GX-D by silica gel chromatography (petrol ether/ethyl acetate=1/1,0/1) by preparative； Boston Symmetrix C18 ODS-R 150*30mm*5um；Acetonitrile 24%-54%；Water (0.225% Fomic acid), 25ml/min) obtain (S) -2- ((2- (2,4- difluorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) Methyl) -2- methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 13 (35.70 milligrams, 83.53 micromoles, 19.48% yield, 97.0% purity).1H NMR (400MHz, CDCl3)：δ 7.95-7.93 (td, J=8.78,6.65Hz, 1H), 7.53-7.50 (m, 2H), 7.38-7.36 (d, J=8.16Hz, 1H), 7.00-6.99 (td, J=8.03,2.76Hz, 1H), 6.93-6.88 (ddd, J=11.11,8.72,2.51Hz, 1H), 4.43 (d, J=9.66Hz, 1H), 3.96 (d, J=9.66Hz, 1H), 3.90-3.87 (m, 2H), 3.17-3.09 (m, 2H), 3.03-2.99 (m, 3H), 2.81 (d, J=14.81Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：428(M+1).
Embodiment 14
(S) -2- ((2- (3,5- difluorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitre Base -2-, 3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (200 milligrams, 571.80 micromoles, 1.00 equivalents) and (3,5- difluorophenyl) boric acid (628.98 micromoles, 1.10 equivalents) are dissolved in dioxane (5.00 milliliters), and Pd (dppf) Cl is added under the atmosphere of nitrogen2 (42 milligrams, 57.18 micromoles, 0.10 equivalent) and cesium fluoride (217 milligrams, 1.43 mMs, 2.50 equivalents).By mixture plus Heat is to 110 degrees Celsius and stirs 2 hours.Mixture is cooled to 20 DEG C, and is concentrated under reduced pressure.By residue diluted with water, aqueous phase It is extracted with ethyl acetate (20 milliliters × 3).The organic phase of merging is washed with saturated aqueous common salt (20 milliliters), anhydrous sodium sulfate is done It is dry, filter and be concentrated in vacuo.Residue is passed through into silica gel chromatography (pillar height degree：250 millimeters, diameter：100 millimeters, 100- 200 mesh silica gel, petrol ether/ethyl acetate=2/1,1/1) obtain (S) -2- ((2- (3,5- difluorophenyl) -7,8- dihydros -1,6- Naphthyridines -6 (5H)-yl) methyl) -2- methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 14 (26.00 milligrams, 59.62 micromoles, 10.43% yield).1H NMR (400MHz, CDCl3)：δ 7.52-7.46 (m, 4H), 7.41-7.39 (m, 1H), 6.84 (tt, J=8.67,2.31Hz, 1H), 4.43 (d, J=9.66Hz, 1H), 4.98-3.87 (m, 3H), 3.17-2.84 (m, 5H), 2.80 (d, J=14.81Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：428(M+1).
Embodiment 15
(S) -2- ((2- (the chloro- 2- fluorophenyls of 5-)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- Nitro 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (200.00 milligrams, 571.80 micromoles, 1.00 equivalents) and (the chloro- 2- fluoro-phenyls of 5-) boric acid (119.64 milligrams, 686.17 micromoles, 1.20 equivalents) are dissolved in the mixed of water (500.00 microlitres) and dioxane (3.00 milliliters) Close in solution, add Pd (dppf) Cl2(41.84 milligrams, 57.18 micromoles, 0.10 equivalent) and cesium fluoride (260.57 millis Gram, 1.72 mMs, 3.00 equivalents).By mixture in 110 degrees Celsius of stirred under nitrogen atmosphere 16 hours.It is concentrated in vacuo, it is remaining Thing prepares chromatographic separation and purification (GX-D by preparative；Boston Green ODS 150*30 5u；acetonitrile 40%-70%；Water (0.225%fomic acid)；25mL/min) obtain (S) -2- ((2- (the chloro- 2- fluorophenyls of 5-) -7, (the 5H)-yl of 8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-b] oxazoline compound 15 (40.09 milligrams, 88.24 micromoles, 15.43% yield, 97.7% purity).1H NMR (400MHz, CDCl3)：δ7.94 (dd, J=6.78,2.76Hz, 1H), 7.53-7.56 (m, 2H), 7.39 (d, J=8.00Hz, 1H), 7.32 (ddd, J=8.75, 4.17,2.76Hz, 1H), 7.10 (dd, J=10.42,8.78Hz, 1H), 4.44 (d, J=9.66Hz, 1H), 4.00-3.82 (m, 3H), 2.93-3.22 (m, 5H), 2.82 (d, J=14.81Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：444.0(M+1).
Embodiment 16
(S) -2- ((2- (2,3- difluorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1-b] oxazole
By key intermediate B (200.00 milligrams, 571.80 micromoles, 1.00 equivalents) and (2,3- difluorophenyl) boric acid (135.44 milligrams, 857.70 micromoles, 1.50 equivalents), cesium fluoride (173.71 milligrams, 1.14 mMs, 2.00 equivalents) is dissolved in In the mixed solution of water (300.00 microlitres) and dioxane (3.00 milliliters).By the mixed solution with after nitrogen displacement three times plus Enter Pd (dppf) Cl2(41.84 milligrams, 57.18 micromoles, 0.10 equivalent), and stirred 12 hours at 110 degrees Celsius.Residue Chromatographic separation and purification (GX-A is prepared by preparative；Phenomenex Gemini Cl8 250*5010u；acetonitrile 38%-68%；H2O (0.2%NH3.H2O)；25mL/min) obtain (S) -2- ((2- (2,3- difluorophenyl) -7,8- dihydro -1, 6- naphthyridines -6 (5H)-yl) methyl) -2- methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazole by compound 16 (28.00 Milligram, 65.51 micromoles, 11.46% yield).1H NMR (400MHz, DMSO-d6) δ 8.11 (s, 1H), 7.73-7.43 (m, 4H), 7.37-7.22 (m, 1H), 4.29 (s, 1H), 4.10 (d, J=10.54Hz, 1H), 3.85 (d, J=14.05Hz, 2H), 2.98 (d, J=3.76Hz, 6H), 1.60 (s, 3H) .LCMS (ESI) m/z：428.0(M+1).
Embodiment 17
(S) -2- ((2- (2,5- difluorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitre Base -2-, 3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (200.00 milligrams, 571.80 micromoles, 1.00 equivalents) and (2,5- difluorophenyl) boric acid (108.3 milligrams, 686.16 micromoles, 1.20 equivalents) are dissolved in the mixed solution of toluene (5.00 milliliters) and water (500.00 microlitres) In, add cesium fluoride (260.57 milligrams, 1.72 mMs, 3.00 equivalents), Pd in 30 degrees Celsius under the atmosphere of nitrogen (dppf)Cl2(41.84 milligrams, 57.18 micromoles, 0.10 equivalent), are then heated to 100 degrees Celsius and stir 12 hours.Will Mixture, which is cooled to after 30 degrees Celsius, is added to water (10 milliliters) in the mixture, and aqueous phase is extracted with ethyl acetate (30 milliliters ×3).The organic phase of merging is washed, anhydrous sodium sulfate drying with saturated aqueous common salt (20 milliliters), filters and is concentrated in vacuo.Will Residue by preparative by preparing chromatogram point again after silica gel chromatograph (petrol ether/ethyl acetate=1/1,0/1) preliminary treatment From purifying (GX-D；Boston Symmetrix C18 ODS-R 150*30mm*5um；Acetonitrile 24%-54%； Water (0.225%fomic acid), 25ml/min) obtain (S) -2- ((2- (2,5- difluorophenyl) -7,8- dihydros -1,6- Naphthyridines -6 (5H)-yl) methyl) -2- methyl -6- nitros -2-, 3- glyoxalidine simultaneously [2,1-B] oxazoline compound 17 (51.50 milli Gram, 118.69 micromoles, 20.76% yield, 98.5% purity).1H NMR (400MHz, CDCl3)：δ 7.71-7.60 (ddd, J =9.22,6.02,3.20Hz, 1H), 7.59 (dd, J=8.03,2.26Hz, 1H), 7.53 (s, 1H), 7.38 (d, J= 8.03Hz, 1H), 7.12-7.05 (m, 2H), 4.44 (d, J=9.66Hz, 1H), 3.98 (d, J=9.66Hz, 1H), 3.91- 3.84 (m, 2H), 3.16-3.09 (m, 2H), 3.04-3.00 (m, 3H), 2.83-2.80 (d, J=14.81Hz, 1H), 1.69 (s, 3H).LCMS(ESI)m/z：428(M+1).
Embodiment 18
(S) -2- ((2- (the chloro- 4- fluorophenyls of 3-)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- Nitro 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (300.00 milligrams, 857.71 micromoles, 1.00 equivalents), (the chloro- 4- fluoro-phenyls of 3-) boric acid (224.32 milligrams, 1.29 mMs, 1.50 equivalents), cesium fluoride (260.57 milligrams, 1.72 mMs, 2.00 equivalents) is dissolved in water In the mixed solution of (500.00 microlitres) and dioxane (5.00 milliliters), nitrogen protection is lower to add Pd (dppf) Cl2(62.76 Milligram, 85.77 micromoles, 0.10 equivalent), and stirred 12 hours under 110 degrees Celsius.After concentration, color is prepared by preparative Spectrum isolates and purifies (GX-G, Phenomenex Synergi C18150*30mm*4um, acetonitrile 45%-75%；H2O (+0.0022NH3.H2O)；25mL/min) obtain (S) -2- ((2- (the chloro- 4- fluorophenyls of 3-) -7,8- dihydros -1,6- naphthyridines -6 (5H)-yl) methyl) -2- methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 18 (90.00 milligrams, 202.77 Micromole, 23.64% yield).1H NMR (400MHz, DMSO-d6)：δ 8.27-8.18 (m, 1H), 8.10 (s, 1H), 8.09- 8.03 (m, 1H), 7.84-7.75 (m, 1H), 7.63-7.43 (m, 2H), 4.30 (d, J=10.67Hz, 1H), 4.16-4.06 (m, 1H), 3.82 (d, J=12.67Hz, 2H), 2.97 (d, J=3.51Hz, 6H), 1.60 (s, 3H) .LCMS (ESI) m/z：444.1 (M+1).
Embodiment 19
(S) -2- ((2- (the chloro- 2- fluorophenyls of 3-)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- Nitro 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (200.00 milligrams, 571.80 micromoles, 1.00 equivalents) and (the chloro- 2- fluoro-phenyls of 3-) boric acid (99.70 milligrams, 571.80 micromoles, 1.00 equivalents) are dissolved in the mixing of dioxane (3.00 milliliters) and water (500.00 microlitres) In solution, Pd (dppf) Cl is added2(41.84 milligrams, 57.18 micromoles, 0.10 equivalent) and cesium fluoride (260.57 milligrams, 1.72 mMs, 3.00 equivalents).Mixture is stirred 16 hours for 110 degrees Celsius under nitrogen protection, residue is led in concentration Cross preparative and prepare chromatographic separation and purification (GX-D；Boston Green ODS 150*30 5u；Acetonitrile 40%- 70%；Water (0.225%fomic acid)；25mL/min) obtain (S) -2- ((2- (the chloro- 2- fluorophenyls of 3-) -7,8- bis- Hydrogen -1,6- naphthyridines -6 (5H)-yl) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 19 (47.80 milligrams, 101.12 micromoles, 17.68% yield, 93.9% purity).1H NMR (400MHz, CDCl3)δ7.83-7.74 (m, 1H), 7.56-7.50 (m, 2H), 7.47-7.37 (m, 2H), 7.19 (td, J=7.91,0.88Hz, 1H), 4.43 (d, J= 9.66Hz, 1H), 3.99-3.86 (m, 3H), 3.24-2.91 (m, 5H), 2.82 (d, J=14.81Hz, 1H), 1.69 (s, 3H) .LCMS(ESI)m/z：444.1(M+1).
Embodiment 20
(S) -2- ((2- (the chloro- 3- fluorophenyls of 4-)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- Nitro 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (200 milligrams, 571.80 micromoles, 1.00 equivalents) and (the chloro- 3- fluoro-phenyls of 4-) boric acid (628.98 micromoles, 1.10 equivalents) are dissolved in dioxane (5.00 milliliters), and Pd (dppf) Cl is added under the protection of nitrogen2 (42 milligrams, 57.18 micromoles, 0.10 equivalent) and cesium fluoride (217 milligrams, 1.43 mMs, 2.50 equivalents).By mixture plus Mixture to 110 degrees Celsius and is cooled to 20 degrees Celsius by heat after stirring 2 hours, and is concentrated under reduced pressure.By residue diluted with water, Aqueous phase is extracted with ethyl acetate (20 milliliters × 3).The organic phase of merging is washed, anhydrous slufuric acid with saturated aqueous common salt (20 milliliters) Sodium is dried, and is filtered and is concentrated in vacuo.Residue prepares chromatographic separation and purification (Instrument by preparative：GX-D； Column：Boston Symmetrix C18 ODS-R 150*30mm*5um；Mobile phase：MeCN：25%-55%； H2O (+0.0023 HCOOH), Rate：25ml/min；Monitored Wavelength：220nm/254nm；Run length： 10min/15min；Column temperature：20 DEG C) obtain (S) -2- ((2- (the chloro- 3- fluorophenyls of 4-) -7,8- dihydro -1, 6- naphthyridines -6 (5H)-yl) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 20 (26.00 milli Gram, 52.72 micromoles, 9.22% yield).1H NMR (400MHz, CDCl3)：δ 7.81 (d, J=10.29Hz, 1H), 7.68 (d, J=8.78Hz, 1H), 7.52-7.38 (m, 4H), 4.43 (d, J=9.54Hz, 1H), 3.98-3.66 (m, 3H), 3.16-2.79 (m, 6H), 1.69 (s, 1H) .LCMS (ESI) m/z：444(M+1).
Embodiment 21
(S) -2- ((2- (the chloro- 5- fluorophenyls of 3-)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- Nitro 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (200 milligrams, 571.80 micromoles, 1.00 equivalents) and (the chloro- 5- fluoro-phenyls of 3-) boric acid (628.98 micromoles, 1.10 equivalents) are dissolved in dioxane (5.00 milliliters), and Pd (dppf) Cl is added under the protection of nitrogen2 (42 milligrams, 57.18 micromoles, 0.10 equivalent) and cesium fluoride (217 milligrams, 1.43 mMs, 2.50 equivalents).Mixed solution adds Heat to 110 degrees Celsius, and stir 2 hours after be cooled to 20 degrees Celsius, be concentrated under reduced pressure, by residue diluted with water, aqueous phase second Acetoacetic ester extracts (20 milliliters × 3).The organic phase of merging is washed, anhydrous sodium sulfate drying with saturated aqueous common salt (20 milliliters), Filter and be concentrated in vacuo, residue prepares chromatographic separation and purification (Instrument by preparative：GX-D；Column：Boston Symmetrix C18 ODS-R 150*30mm*5um；Mobile phase：MeCN：15%-45%；H2O(+ 0.0023HCOOH), Rate：25ml/min；Monitored Wavelength：220nm/254nm；Run length：10min/ 15min；Column temperature：20 DEG C) obtain (S) -2- ((2- (the chloro- 5- fluorophenyls of 3-) -7,8- dihydro -1,6- naphthalenes Pyridine -6 (5H)-yl) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 21 (88.00 milligrams, 193.70 micromoles, 33.88% yield).1H NMR (400MHz, CDCl3)：δ 7.76 (s, 1H), 7.59 (dt, J=9.47, 1.98Hz, 1H), 7.53 (s, 1H), 7.50-7.43 (m, 1H), 7.43-7.35 (m, 1H), 7.12 (dt, J=8.16,2.07Hz, 1H), 4.43 (d, J=9.66Hz, 1H), 3.98-3.68 (m, 3H), 3.34-2.88 (m, 5H), 2.82 (d, J=14.81Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：444(M+1).
Embodiment 22
(S) -2- ((2- (the chloro- 5- fluorophenyls of 2-)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- Nitro 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (200 milligrams, 571.80 micromoles, 1.00 equivalents) and (the chloro- 5- fluoro-phenyls of 2-) boric acid (628.98 micromoles, 1.10 equivalents) are dissolved in dioxane (5.00 milliliters), and Pd (dppf) Cl is added under the protection of nitrogen2 (42 milligrams, 57.18 micromoles, 0.10 equivalent) and cesium fluoride (217 milligrams, 1.43 mMs, 2.50 equivalents).By mixture plus Heat is to 110 degrees Celsius and stirs 2 hours.Mixture is cooled to 20 degrees Celsius, and is concentrated under reduced pressure.By residue diluted with water, Aqueous phase is extracted with ethyl acetate (20 milliliters × 3).The organic phase of merging is washed with saturated aqueous common salt (20mL), anhydrous sodium sulfate Dry, filter and be concentrated in vacuo.Residue prepares chromatographic separation and purification (Instrument by preparative：GX-D；Column： Boston Symmetrix C18 ODS-R 150*30mm*5um；Mobile phase：MeCN：35%-75%；H2O(+ 0.0023HCOOH), Rate：25ml/min；Monitored Wavelength：220nm/254nm；Run length：10min/ 15min；Column temperature：20 DEG C) obtain (S) -2- ((2- (the chloro- 5- fluorophenyls of 2-) -7,8- dihydro -1,6- naphthalenes Pyridine -6 (5H)-yl) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 22 (30.00 milligrams, 66.91 micromoles, 11.70% yield).1H NMR (400MHz, CDCl3)：δ 7.54 (s, 1H), 7.47-7.36 (m, 3H), 7.31 (dd, J=8.97,3.07Hz, 1H), 7.04 (td, J=8.22,3.14Hz, 1H), 4.44 (d, J=9.66Hz, 1H), 4.12- 3.68 (m, 3H), 3.36-2.91 (m, 5H), 2.83 (d, J=14.81Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：444 (M+1).
Embodiment 23
(S) -2- ((2- (the chloro- 2- fluorophenyls of 4-)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- Nitro 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (200.00 milligrams, 571.80 micromoles, 1.00 equivalents) and (the chloro- 2- fluoro-phenyls of 4-) boric acid (119.64 milligrams, 686.16 micromoles, 1.20 equivalents) are dissolved in the mixed of dioxane (3.00 milliliters) and water (500.00 microlitres) Close in solution.Nitrogen protection is lower to add Pd (dppf) Cl2(41.84 milligrams, 57.18 micromoles, 0.10 equivalent) and cesium fluoride (260.57 milligrams, 1.72 mMs, 3.00 equivalents).Mixture is stirred 16 hours at 110 degrees Celsius.Concentration, residue leads to Cross preparative and prepare chromatographic separation and purification (GX-G；Phenomenex Synergi C18 150*30mm*4um； Acetonitrile 24%-54%；Water (0.225%fomic acid)；25mL/min) obtaining (S) -2-, (((4- is chloro- by 2- 2- fluorophenyls)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1- B] oxazoline compound 23 (56.26 milligrams, 125.10 micromoles, 21.88% yield, 98.7% purity)1H NMR (400MHz, CDCl3)：δ 7.92 (t, J=8.41Hz, 1H), 7.57-7.50 (m, 2H), 7.38 (d, J=8.03Hz, 1H), 7.27-7.22 (m, 1H), 7.22-7.16 (m, 1H), 4.43 (d, J=9.66Hz, 1H), 4.0-3.81 (m, 3H), 3.23-2.90 (m, 5H), 2.81 (d, J=14.81Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：444.0(M+1).
Embodiment 24
(S) -2- ((2- (furans -3- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros - 2-3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (200.00 milligrams, 571.80 micromoles, 1.00 equivalents) and 3- furyl boronic acids (76.77 millis Gram, 686.16 micromoles, 1.20 equivalents) it is dissolved in the mixed solution of dioxane (5.00 milliliters) and water (500.00 microlitres), Sodium carbonate (121.21 milligrams, 1.14 mMs, 2.00 equivalents), Pd (PPh are added under nitrogen protection3)4(66.07 milligrams, 57.18 micromoles, 0.10 equivalent).Mixture is stirred 12 hours at 90 degrees Celsius.Mixture is cooled to 30 degrees Celsius, and It is concentrated under reduced pressure under 45 degrees Celsius, residue is preliminary by Silica gel chromatography (petrol ether/ethyl acetate=10/1,1/1) Processing, then prepares chromatographic separation and purification (GX-D by preparative；Boston Symmetrix C18 ODS-R150*30mm* 5um；MeCN：24%-54%；H2O(+0.0025FA)；25ml/min) obtain (S) -2- ((2- (furans -3- bases) -7,8- bis- Hydrogen -1,6- naphthyridines -6 (5H)-yl) methyl) -2- methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 24 (56.67 milligrams, 142.65 micromoles, 24.95% yield, 96% purity).1H NMR (400MHz, CDCl3)：δ 7.99 (s, 1H), 7.51 (s, 1H), 7.48 (t, J=1.69Hz, 1H), 7.31-7.29 (m, 1H), 7.28-7.24 (m, 1H), 6.87 (d, J =1.13Hz, 1H), 4.43 (d, J=9.66Hz, 1H), 3.95 (d, J=9.66Hz, 1H), 3.81 (m, 2H), 3.14-3.07 (m, 2H), 2.99-2.96 (m, 3H), 2.79 (d, J=14.81Hz, 1H), 1.68 (s, 3H) .LCMS (ESI) m/z：382(M+ 1).
Embodiment 25
(S) -2- ((2- (furans -2- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros - 2-3- glyoxalidine simultaneously [2,1-B] oxazole
By key intermediate B (150.00 milligrams, 428.85 micromoles, 1.00 equivalents) and tributyl (2- furyls) stannane (229.73 milligrams, 643.28 micromoles, 1.50 equivalents) are dissolved in dichloroethanes (10.00 milliliters), under nitrogen protection in 30 Degree Celsius add Pd (dppf) Cl2(31.38 milligrams, 42.89 micromoles, 0.10 equivalent), lithium chloride (6.09 milligrams, 143.76 Micromole, 1.00 equivalents).It is then heated to 120 degrees Celsius and stirs 12 hours.Mixture is cooled down and subtracted under 45 degrees Celsius Pressure concentration.Water (10 milliliters) is added in the mixture and stirred 5 minutes, aqueous phase is extracted with ethyl acetate (30 milliliters × 3). The organic phase of merging is washed with saturated brine (10mL × 2), anhydrous sodium sulfate drying, filtering and vacuum concentration, residue lead to Cross after silica gel chromatography (ethyl acetate) processing, chromatographic separation and purification (Instrument is then prepared by preparative：GX-D； Boston Symmetrix C18 ODS-R 150*30mm*5um；Acetonitrile 24%-54%；Water (0.225% fomic acid)；25ml/min) obtain (S) -2- ((2- (furans -2- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) first Base) -2- methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 25 (31.70 milligrams, 83.12 micromoles, 19.38% yield).1H NMR (400MHz, CDCl3)：7.53 (m, 1H), 7.52 (s, 1H), 7.47 (d, J=8.16Hz, 1H), 7.33 (d, J=8.16Hz, 1H), 6.99 (d, J=3.39Hz, 1H), 6.52 (dd, J=3.39,1.76Hz, 1H), 4.43 (d, J =9.54Hz, 1H), 3.95 (d, J=9.66Hz, 1H), 3.85 (d, J=14.18Hz, 2H), 3.09 (d, J=14.81Hz, 2H), 3.01-2.97 (m, 3H), 2.79 (d, J=14.81Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：382(M+1).
Embodiment 26
(S) -2- (((the 5H)-yl of 2- cyclopropyl -7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros -2,3- Glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
6- benzyl -2- cyclopropyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
By key intermediate A (1.50 grams, 5.80 mMs, 1.00 equivalents) and toluene cyclopropylboronic acid (647.69 milligrams, 7.54 mMs, 1.30 equivalents) it is dissolved in toluene (10.00 milliliters), double (1- gold are added in 30 degrees Celsius under the protection of nitrogen Firm alkyl)-butyl-phosphine (415.91 milligrams, 1.16 mMs, 0.20 equivalent), cesium carbonate (3.78 grams, 11.60 mMs, 2.00 equivalents) and Pd (OAc)2(130.22 milligrams, 580.00 micromoles, 0.10 equivalent).Then 100 are heated the mixture to take the photograph Family name's degree is simultaneously stirred 12 hours.Residue by silica gel chromatography (petrol ether/ethyl acetate=30/1) purify, obtain 6- benzyls- 2- cyclopropyl -7,8- dihydro -5H--1,6- benzodiazine (1.30 grams, 4.92 mMs, 84.79% yield), are yellow solid 。1H NMR (300MHz, CDCl3) 7.35-7.29 (m, 2H), 7.27 (s, 1H), 7.25-7.21 (m, 1H), 7.21-7.17 (m, 1H), 7.05 (d, J=7.9Hz, 1H), 6.71 (d, J=7.9Hz, 1H), 3.62 (s, 2H), 3.49 (s, 2H), 2.93-2.85 (m, 2H), 2.79-2.71 (m, 2H), 1.99-1.87 (m, 1H), 0.92-0.85 (m, 2H), 0.84-0.80 (m, 2H) .LCMS (ESI)m/z：265(M+1).
Step 2：
2- cyclopropyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazine hydrochlorides
By 6- benzyl -2- cyclopropyl -7,8- dihydro -5H-1,6- benzodiazine (200.00 milligrams, 756.54 micromoles, 1.00 equivalents) it is dissolved in dichloroethanes (10.00 milliliters), under nitrogen protection in addition 1- chlorine phosgenes under 0 degree Celsius (162.24 milligrams, 1.13 mMs, 1.50 equivalents).Mixture is stirred 20 minutes under 0 degree Celsius, 80 is then heated to and takes the photograph Family name's degree is simultaneously stirred 12 hours.After concentration, methanol (10.00 milliliters) is added in the mixture, and it is small at 75 degrees Celsius to be stirred for 2 When.Mixture is cooled down, and is concentrated under reduced pressure under 45 degrees Celsius.Residue is washed with dichloromethane (20mL × 3), filtered, Filtration cakes torrefaction obtains 2- cyclopropyl -5,6, and 7,8- tetrahydrochysene -1,6- benzodiazine hydrochlorides (170.00 milligrams, thick), are that yellow is consolidated Body, it is used for next step without further purification.
Step 3：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- (2- cyclopropyl -7,8- dihydro -5H-1,6- naphthyridines -6- bases) - 2- methyl -propyl- 2- alcohol
By 2- cyclopropyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazine hydrochloride (550.00 milligrams, 3.16 mMs, 1.00 Equivalent) and the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (893.94 milligrams, 4.11 mmoles You, 1.30 equivalents) be dissolved in ethanol (20.00 milliliters) solution, under nitrogen protection in 30 degrees Celsius add DIPEA (1.02 grams, 7.90 mMs, 2.50 equivalents).Mixture is stirred at this temperature 10 minutes, be then heated to 80 degrees Celsius and stirring 12 Hour.The mixture (20 milliliters) dilutions of water, aqueous phase is extracted with ethyl acetate (20 milliliters × 3).The organic phase of merging is used Saturated brine (10 milliliters × 2) is washed, with anhydrous sodium sulfate drying, filtering and vacuum concentration.Residue is passed through into silica gel chromatograph Method purifying (petrol ether/ethyl acetate=10/1,2/1) obtains (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- (2- rings third Base -7,8- dihydro -5H-1,6- naphthyridines -6- bases) -2- methyl -propyl- 2- alcohol (400.00 milligrams, crude product) is yellow solid.LCMS (ESI)m/z：392(M+1).
Step 4：
(S) -2- (((the 5H)-yl of 2- cyclopropyl -7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros -2,3- Glyoxalidine simultaneously [2,1-B] oxazole
By (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- (2- cyclopropyl -7,8- dihydro -5H-1,6- benzodiazine - 6- yls) -2- methyl -propyl- 2- alcohol (440.00 milligrams, 1.12 mMs, 1.00 equivalents) is dissolved in DMF (5.00 milliliters), in nitrogen Under the protection of gas NaH (67.37 milligrams, 1.68 mMs, 1.50 equivalents) is added in -45 degrees Celsius.By mixture -45 to - 15 degrees Celsius are stirred 2 hours.Residue is poured into saturated ammonium chloride (20 milliliters) aqueous solution, and stirred under 0 degree Celsius 20 minutes, aqueous phase was extracted with ethyl acetate (30 milliliters × 3).The organic phase of merging is washed with saturated brine (10 milliliters × 2), With anhydrous sodium sulfate drying, filtering and vacuum concentration.Residue prepares chromatographic separation and purification (GX-D by preparative；Boston Symmetrix C18 ODS-R 150*30mm*5um；Acetonitrile 20%-54%；Water (0.225%fomic acid)；25mL/min) obtain (S) -2- (((the 5H)-yl of 2- cyclopropyl -7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl - 6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 26 (157.10 milligrams, 442.05 micromoles, 39.47% production Rate).1H NMR (400MHz, CDCl3)：δ 7.51 (s, 1H), 7.16 (d, J=7.91Hz, 1H), 6.82 (d, J=8.03Hz, 1H), 4.42 (d, J=9.66Hz, 1H), 3.93 (d, J=9.54Hz, 1H), 3.79 (q, J=14.89Hz, 2H), 3.07-3.04 (m, 2H), 2.94-2.85 (m, 3H), 2.76 (d, J=14.81Hz, 1H), 2.03-2.01 (m, 1H), 1.66 (s, 3H), 0.98- 0.96 (m, 2H), 0.92-0.90 (m, 2H) .LCMS (ESI) m/z：356(M+1).
Embodiment 27
(S) -2- methyl -6- nitros -2- ((2- (trifluoromethyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) - 2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
Benzyl -4- pyrrolidin-1-yl -3,6- dihydro -2H- pyridines
By 1- benzyl -4- ketone (10.00 grams, 52.84 mMs, 1.00 equivalents) and pyrrolidines (4.51 grams, 63.41 mmoles You, 1.20 equivalents) it is dissolved in toluene (100mL), at 110 degrees Celsius with fraction water device water-dividing 4.5 hours, mixture is cooled down, it is dense Contract to obtain 1- benzyl -4- pyrrolidin-1-yl -3,6 dihydro -2H- pyridines (10.50 grams, crude product), is yellow oil, and it is without entering The purifying of one step is used for next step.
Step 2：
6- benzyls -2- (trifluoromethyl) -7,8- dihydros -5H-1,6- benzodiazine
By 1- benzyl -4- pyrrolidin-1-yl -3,6- dihydro -2H- pyridines (2.50 grams, 10.32 mMs, 1.00 equivalents) (E) -4- ethyoxyls -1,1, the fluoro- butyl- 3- alkene -2- ketone of 1- tri- (2.08 grams, 12.38 mMs, 1.20 equivalents) is dissolved in dioxy six In ring (30.00 milliliters), 100 degrees Celsius are heated to, and stir 4 hours.Then by ammonium acetate (2.39 grams, 30.96 mMs, 3.00 equivalents) add, and be stirred for 16 hours.Mixture is cooled down and is diluted with water.By (100 milliliters of ethyl acetate of aqueous phase × 3) extract.The organic phase of merging is washed with saturated aqueous common salt (100 milliliters), with anhydrous sodium sulfate drying, filtered and vacuum Concentration.Residue is passed through into silica gel chromatography (pillar height degree：300 millimeters, 40 millimeters of diameter, 100-200 mesh silica gel, petroleum ether/second The purifying of acetoacetic ester=30/1) obtains 6- benzyls -2- (trifluoromethyl) -7,8- dihydros -5H-1,6- benzodiazine (1.50 grams, 5.13 MM, 49.73% yield), it is yellow oil.1H NMR (400MHz, CDCl3) 7.46-7.29 (m, 7H), 3.75 (s, 2H), (t, J=5.96Hz, the 2H) of 3.70 (s, 2H), 3.15 (t, J=5.90Hz, 2H), 2.92
Step 3：
2- (trifluoromethyl) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
By 6- benzyls -2- (trifluoromethyl) -7,8- dihydros -5H-1,6- benzodiazine (1.50 grams, 5.13 mMs, 1.00 Equivalent) it is dissolved in methanol (20.00 milliliters), then the addition Pd/C (100.00 milligrams) into solution.By mixture at H2 (50psi) Lower stirring 16 hours.Mixture is filtered and concentrated, 2- (trifluoromethyl) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines is obtained (850.00 milligrams, crude product), are pale solid, and it need not be further purified in next step.
Step 4：
(S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- methyl -3- (2- (trifluoromethyl) -7,8- dihydros -1,6- Naphthyridines -6 (5H)-yl) propan-2-ol
By 2- (trifluoromethyl) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines (200.00 milligrams, 989.22 micromoles, 1.00 Equivalent) and the chloro- 1- of (R) -2- ((2- expoxy propane -2- bases) methyl) -4- nitro -1H- imidazoles (322.90 milligrams, 1.48 mmoles You, 1.50 equivalents) it is dissolved in ethanol (10.00 milliliters), DIPEA is added under nitrogen protection, and (127.85 milligrams, 989.22 micro- rub You, 1.00 equivalents).Heat the mixture to 80 degrees Celsius and stir 16 hours.Mixture is cooled down and is concentrated under reduced pressure, by remnants Thing is poured into water (50 milliliters), and (50mL × 3) are extracted with ethyl acetate.By the organic phase of merging with saturated aqueous common salt (50mL) Washing, with anhydrous sodium sulfate drying, filters and is concentrated in vacuo, obtain (S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- Methyl -3- (2- (trifluoromethyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) propan-2-ol (310.00 milligrams, crude product), is palm fibre Color grease.LCMS(ESI)m/z：420.1(M+1).
Step 5：
(S) -2- methyl -6- nitros -2- ((2- (trifluoromethyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) - 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- methyl -3- (2- (trifluoromethyl) -7,8- dihydro -1, 6- naphthyridines -6 (5H)-yl) propan-2-ol (100.00 milligrams, 238.21 micromoles, 1.00 equivalents) is dissolved in DMF (2.00 milliliters), Under nitrogen protection in addition NaH (19.06 milligrams, 476.42 micromoles, 2.00 equivalents) under -20 degrees Celsius.By mixture- Stirred 1 hour under 20 degrees Celsius.Mixture is poured into ice-water (w/w=1/1) (10 milliliters), and stirred 5 minutes.Aqueous phase is used Ethyl acetate extracts (10 milliliters × 3).By the organic phase anhydrous Na of merging2SO4 is dried, and is filtered and is concentrated in vacuo.Residue Chromatographic separation and purification (Instrument is prepared by preparative：GX-G；Column：Phenomenex Synergi C18 150* 30mm*4um；Mobile phase：MeCN：20%-60%；H2O(+0.0025FA)；Rate：25ml/min；Monitored Wavelength：220nm/254nm；Run length：10min/15min；Column temperature：30 DEG C) obtain (S) -2- methyl -6- nitros -2- ((2- (trifluoromethyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2,3- dihydros Imidazo [2,1-B] oxazoline compound 27 (42.00 milligrams, 108.47 micromoles, 45.54% yield, 99% purity).1H NMR (300MHz, CDCl3) 7.52-7.47 (m, 3H), 4.39 (d, J=9.8Hz, 1H), 3.99-3.89 (m, 3H), 3.14-3.84 (m, 5H), 2.82 (d, J=14.7Hz, 1H), 1.68 (s, 3H) .LCMS (ESI) m/z：384(M+1).
Embodiment 28
(S) -2- methyl -6- nitros -2- ((2- (piperidin-1-yl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) - 2,3- glyoxalidine are simultaneously [2,1-B]
Step 1：
6- benzyls -2- (1- piperidyls) -7,8- dihydros -5H-1,6- benzodiazine
By key intermediate A (500.00 milligrams, 1.93 mMs, 1.00 equivalents) and piperidines (328.68 milligrams, 3.86 millis Mole, 2.00 equivalents) it is dissolved in toluene (5.00 milliliters) solution, add sodium tert-butoxide in 30 degrees Celsius under the protection of nitrogen (370.95 milligrams, 3.86 mMs, 2.00 equivalents, Pd2(dba)3(88.37 milligrams, 96.5 micromoles, 0.05 equivalent), tertiary fourth Sodium alkoxide (741.92 milligrams, 7.72 mMs, 2.00 equivalents), Xphos (92.01 milligrams, 193.00 micromoles, 0.10 equivalent). Mixture is stirred 12 hours under 100 degrees Celsius, then cooled down, and be concentrated under reduced pressure under 45 degrees Celsius.Residue passes through silicon Glue chromatography purifies (petrol ether/ethyl acetate=20/1,5/1), obtains 6- benzyls -2- (1- piperidyls) -7,8- dihydros -5H- 1,6- benzodiazine (550.00 milligrams, 1.79 mMs, 92.70% yield), is yellow solid.1H NMR (400MHz, CDCl3) 7.43-7.39 (m, 2H), 7.39-7.33 (m, 2H), 7.33-7.29 (m, 1H), 7.09 (d, J=8.5Hz, 1H), 6.47 (d, J=8.5Hz, 1H), 3.71 (s, 2H), 3.52 (s, 2H), 3.51-3.46 (m, 4H), 2.91-2.87 (m, 2H), 2.84-2.80 (m, 2H), 1.67-1.61 (m, 6H) .LCMS (ESI) m/z：308(M+1).
Step 2：
Tetrahydrochysene -1, the 6- benzodiazines of 2- (1- piperidyls) -5,6,7,8-
By 6- benzyls -2- (1- piperidyls) -7,8- dihydros -5H-1,6- benzodiazine (500.00 milligrams, 1.63 mMs, 1.00 equivalents) it is dissolved in methanol (20.00 milliliters), add Pd/C (100.00 milligrams, 1.63 in 30 degrees Celsius under nitrogen protection MM, 1.00 equivalents).Mixture is existed, H2(50Psi), 18 hours are stirred under 30 degrees Celsius.By mixture filter and Be concentrated under reduced pressure under 45 degrees Celsius, obtain tetrahydrochysene -1, the 6- benzodiazines of 2- (1- piperidyls) -5,6,7,8- (410.00 milligrams, slightly Product), it is yellow solid, it is used for next step without further purification.
Step 3：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- methyl -3- [2- (1- piperidyls) -7,8- dihydros -5H-1,6- Benzodiazine -6- bases] propan-2-ol
By 2- (1- piperidyls) -5,6,7,8- tetrahydrochysene -1,6- benzodiazine (200.00 milligrams, 920.34 micromoles, 1.00 Equivalent) and the chloro- 1- of (R) -2- ((2- methyl oxirane -2- bases) methyl) -4- nitro -1H- imidazoles (300.41 milligrams, 1.38 MM, 1.50 equivalents) it is dissolved in ethanol (3.00 milliliters), DIPEA (59.47 millis are added in 30 degrees Celsius under nitrogen protection Gram, 460.17 micromoles, 0.50 equivalent).Mixture is stirred 12 hours at 80 degrees Celsius, cooling, and subtracted under 45 degrees Celsius Pressure concentration.Residue is by Silica gel chromatography (petrol ether/ethyl acetate=10/1,1/1), and obtaining (2S) -1-, (2- is chloro- 4- nitroimidazole -1- bases) -2- methyl -3- [2- (1- piperidyls) -7,8- dihydros -5H-1,6- naphthyridines -6- bases] propan-2-ol (200.00 milligrams, crude product), are yellow solid.
Step 4：
(S) -2- methyl -6- nitros -2- ((2- (piperidin-1-yl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) - 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- methyl -3- [2- (1- piperidyls) -7,8- dihydro -5H-1, 6- naphthyridines -6- bases] propan-2-ol (139.00 milligrams, 319.60 micromoles, 1.00 equivalents) is dissolved in DMF (5.00 milliliters), in nitrogen In addition NaH (25.57 milligrams, 639.20 micromoles, 2.00 equivalents) under -45 degrees Celsius under gas shielded.By mixture -45 Stirring adds water (3mL) under to -15 degrees Celsius after 1 hour, and the mixture is stirred 5 minutes.Aqueous phase is extracted with dichloromethane Take (20 milliliters × 3).The organic phase of merging is washed with saturated brine (10mL × 2), with anhydrous sodium sulfate drying, filtered and true Sky concentration.Residue prepares chromatogram point by preparative again after being handled by thin-layer chromatography (petrol ether/ethyl acetate=1/2.5) From purifying (GX-D；Boston Symmetrix C18 ODS-R 150*30mm*5um；Acetonitrile 24%-54%； Water (0.225%fomic acid)；25mL/min) obtain (S) -2- methyl -6- nitros -2- ((2- (piperidin-1-yl) -7, (the 5H)-yl of 8- dihydros -1,6- naphthyridines -6) methyl) -2,3- glyoxalidine simultaneously [2,1-B] oxazole by compound 28 (5.40 milligrams, 13.55 micromoles, 4.24% yield).1H NMR (400MHz, CDCl3)：δ 7.51 (s, 1H), 7.07 (d, J=8.66Hz, 1H), 6.46 (d, J=8.53Hz, 1H), 4.43 (d, J=9.66Hz, 1H), 3.91 (d, J=9.54Hz, 1H), 3.73-3.66 (m, 2H), 3.48 (br.S., 4H), 3.08-3.02 (m, 2H), 2.90-2.89 (m, 2H), 2.72 (d, J=14.81Hz, 2H), 1.65 (s, 3H), 1.63 (br.s., 6H) .LCMS (ESI) m/z：399(M+1).
Embodiment 29
(S) -2- methyl -6- nitros -2- ((2- (tetrahydrochysene -2H- pyrans -4- bases) -7,8- dihydros -1,6- naphthyridines -6 (5H) - Base) methyl base) -2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
6- benzyls -2- (3,6- dihydro -2H- pyrans -4- bases) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
By key intermediate A (1.33 grams, 5.14 mMs, 1.20 equivalents), 2- (3,6- dihydro -2H- pyrans -4- bases) - 4,4,5,5- tetramethyls -1,3, the ring of 2- dioxies boron penta (900.00 milligrams, 4.28 mMs, 1.00 equivalents) is dissolved in THF (20.00 Milliliter) and the mixed solution of water (5.00 milliliters) in, the mixed solution is protected into lower addition Pd (dppf) Cl in nitrogen2 (313.17 milligrams, 428.00 micromoles, 0.10 equivalent) and cesium carbonate (2.79 grams, 8.56 mMs, 2.00 equivalents), then will Mixture is stirred 12 hours at 80 degrees Celsius.Reactant mixture is concentrated under reduced pressure to remove solvent, by residue water (20 millis Rise) dilution, and (10 milliliters × 3) are extracted with ethyl acetate.The organic layer of merging is washed with saturated brine (10 milliliters × 2), It is dried over sodium sulfate, residue is filtered, and concentrated under reduced pressure to give, it is passed through into Silica gel chromatography (silica, PE: acetic acid Ethyl ester=5: 6- benzyls -2- (3,6- dihydro -2H- pyrans -4- bases) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines 1) are obtained (960.00 milligrams, 3.13 mMs, 73.20% yield) are white solid.LCMS(ESI)m/z：308(M+1).
Step 2：
2- (tetrahydrochysene -2H- pyrans -4- bases) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
By 6- benzyls -2- (3,6- dihydro -2H- pyrans -4- bases) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines (500.00 millis Gram, 1.62 mMs, 1.00) it is dissolved in methanol (10.00mL), Pd/C (10%, 0.05 gram) is added under the atmosphere of nitrogen.Will Mixed solution is replaced three times with hydrogen and stirred 12 hours under conditions of 28 degrees Celsius, H2 (50psi).By reactant mixture mistake Filter and concentrate filtrate decompression, obtain crude product 2- (tetrahydrochysene -2H- pyrans -4- bases) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines (400.00 milligrams, crude product), are colorless oil, and crude product is used for into next step without further purification.LCMS(ESI) m/z：219(M+1).
Step 3：
(S) -2- methyl -2- (((the 5H)-yl of 2- morpholino -7,8- dihydros -1,6- naphthyridines -6) methyl) -6- nitros -2,3- Glyoxalidine simultaneously [2,1-B] oxazole
By 2- (tetrahydrochysene -2H- pyrans -4- bases) -5,6,7,8- tetrahydrochysene -1,6- benzodiazine (350.00 milligrams, 1.60 mmoles You, 1.00 equivalents), the chloro- 1- of (R) -2- ((2- expoxy propane -2- bases) methyl) -4- nitro -1H- imidazoles (417.81 milligrams, 1.92 mMs, 1.20 equivalents), DIPEA (620.35 milligrams, 4.80 mMs, 3.00 equivalents) is added to ethanol (10.00 millis Rise) in, nitrogen is protected in 12 hours of stirring under 80 degrees Celsius.Reactant mixture is concentrated under reduced pressure, residue passes through silica gel color Spectrometry purifying (silica, methylene chloride/methanol=20/1) obtain (S) -2- methyl -2- ((2- morpholinoes -7,8- dihydro -1, 6- naphthyridines -6 (5H)-yl) methyl) -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole (530.00 milligrams, 1.22 mMs, 75.99% yield), it is yellow solid.1H NMR (400MHz, CDCl3) 8.06 (s, 1H), 7.29 (d, J=8.0Hz, 1H), 7.01 (d, J=8.0Hz, 1H), 4.13-4.07 (m, 2H), 4.06 (s, 2H), 3.92-3.72 (m, 2H), 3.62-3.49 (m, 2H), 3.15-2.89 (m, 5H), 2.74-2.50 (m, 2H), 1.89-1.84 (m, 4H), 1.21 (s, 3H) .LCMS (ESI) m/z： 436/438(M+1).
Step 4：
(S) -2- methyl -6- nitros -2- ((2- (tetrahydrochysene -2H- pyrans -4- bases) -7,8- dihydros -1,6- naphthyridines -6 (5H) - Base) methyl base) -2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (S) -2- methyl -2- (((the 5H)-yl of 2- morpholino -7,8- dihydros -1,6- naphthyridines -6) methyl) -6- nitro -2, Simultaneously [2,1-B] oxazole (530.00 milligrams, 1.22 mMs, 1.00 equivalents) is dissolved in DMF (5.00 milliliters) 3- glyoxalidine, NaH (58.56 milligrams, 1.46 mMs, 1.20 equivalents) is added under 0 degree Celsius.Mixture is stirred 20 minutes under 0 degree Celsius Saturated ammonium chloride (30 milliliters) is added afterwards to be quenched, and then with (10 milliliters) dilutions of water, and is extracted (10 milliliters × 3) with DCM.It will close And organic layer washed with saturated brine (10 milliliters × 2), it is dried over sodium sulfate, filter and concentrate under reduced pressure, residue is logical Cross preparative and prepare chromatographic separation and purification (GX-G；Phenomenex Synergi C18 150*30mm*4um； Acetonitrile 0%-30%；Water (0.225%fomic acid)；25mL/min) obtain (S) -2- methyl -6- nitre Base -2- ((2- (tetrahydrochysene -2H- pyrans -4- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl base) -2,3- glyoxalidine And [2,1-B] oxazoline compound 29 (300.00 milligrams, 751.05 micromoles, 61.56% yield).1H NMR (400MHz, CDCl3)：δ 7.52 (s, 1H), 7.27 (d, J=8.0Hz, 1H), 6.98 (d, J=8.0Hz, 1H), 4.42 (d, J=8.0Hz, 1H), 4.13-4.06 (m, 2H), 3.95 (d, J=12.0Hz, 1H), 3.89-3.75 (m, 2H), 3.60-3.51 (m, 2H), 3.15-3.04 (m, 2H), 3.01-2.87 (m, 4H), 2.79 (d, J=12.0Hz, 1H), 1.90-1.81 (m, 4H), 1.68 (s, 3H).LCMS(ESI)m/z：399(M+1).
Embodiment 30
(S) -2- methyl -2- (((the 5H)-yl of 2- morpholino -7,8- dihydros -1,6- naphthyridines -6) methyl) -6- nitros -2,3- Glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
4- (6- benzyl -7,8- dihydro -5H-1,6- benzodiazine -2- bases) morpholine
Under nitrogen protection in 30 degrees Celsius by key intermediate A (1.00 grams, 3.86 mMs, 1.00 equivalents) and morpholine (672.57 milligrams, 7.72 mMs, 2.00 equivalents) Pd2(dba)3(176.73 milligrams, 193.00 micromoles, 0.05 equivalent), uncle Sodium butoxide (741.92 milligrams, 7.72 mMs, 2.00 equivalents), and Xphos (184.01 milligrams, 386.00 micromoles, 0.10 works as Amount) it is dissolved in toluene (20.00 milliliters).Then 100 degrees Celsius are heated the mixture to and is stirred 12 hours.Mixture is cold But, and under 45 degrees Celsius it is concentrated under reduced pressure.Residue passes through Silica gel chromatography (petrol ether/ethyl acetate=20/1,1/ 1) 4- (6- benzyl -7,8- dihydro -5H-1,6- naphthyridines -2- bases) morpholine (1.10 grams, 3.56 mMs, 92.11% production, are obtained Rate), it is yellow solid.1H NMR (400MHz, CDCl3) 7.43-7.39 (m, 2H), 7.36 (t, J=7.3Hz, 2H), 7.31 (d, J=7.0Hz, 1H), 7.15 (d, J=8.4Hz, 1H), 6.45 (d, J=8.5Hz, 1H), 3.86-3.81 (m, 4H), 3.72 (s, 2H), 3.54 (s, 2H), 3.49-3.44 (m, 4H), 2.92-2.87 (m, 2H), 2.85-2.81 (m, 2H) .LCMS (ESI) m/z： 310(M+1).
Step 2：
4- (6- benzyls -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- bases) morpholine
By 4- (6- benzyl -7,8- dihydro -5H-1,6- benzodiazine -2- bases) morpholine (700.00 milligrams, 2.26 mMs, 1.00 equivalents) it is dissolved in methanol (20.00 milliliters), add Pd (OH)2/ C (10%, 20 milligrams).By the mixed solution hydrogen Gas is replaced three times and stirred 12 hours under conditions of 50 degrees Celsius, H2 (50psi).Reactant mixture is filtered, filtrate is concentrated, 4- (5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- bases) morpholine (400.00 milligrams, crude product) is obtained, is yellow solid.LCMS(ESI) m/z：220(M+1).
Step 3：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- methyl -3- (2- morpholino -7,8- dihydro -5H-1,6- naphthalenes Pyridine -6- bases) propan-2-ol
Under nitrogen protection in by 4- (5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- bases) morpholine, (250.00 in the least under 30 degrees Celsius Gram, 1.14 mMs, 1.00 equivalents) and the chloro- 1- of (R) -2- ((2- methyl oxirane -2- bases) methyl) -4- nitro -1H- miaows Azoles (198.46 milligrams, 912.00 micromoles, 0.80 equivalent) is dissolved in the tert-butyl alcohol (3.00 milliliters), adds DIPEA (147.34 Milligram, 1.14 mMs, 1.00 equivalents).Mixture is stirred at 80 degrees celsius 12 hours, cooled down, and under 45 degrees Celsius It is concentrated under reduced pressure.Residue is obtained into (2S) -1- (2- by Silica gel chromatography (petrol ether/ethyl acetate=10/1,2/1) Chloro- 4- nitroimidazoles -1- bases) -2- methyl -3- (base of 2- morpholino -7,8- dihydro -5H-1,6- naphthyridines -6) propan-2-ol (200.00 milligrams, 457.78 micromoles, 40.16% yield), are yellow solid.LCMS(ESI)m/z：437(M+1).
Step 4：
(S) -2- methyl -2- (((the 5H)-yl of 2- morpholino -7,8- dihydros -1,6- naphthyridines -6) methyl) -6- nitros -2,3- Glyoxalidine simultaneously [2,1-B] oxazole
By (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- methyl -3- (2- morpholino -7,8- dihydro -5H-1,6- naphthalenes The base of pyridine -6) propan-2-ol (200.00 milligrams, 457.78 micromoles, 1.00 equivalents) is dissolved in DMF (5.00 milliliters), protected in nitrogen Under shield NaH (36.62 milligrams, 915.56 micromoles, 2.00 equivalents) is added in -45 degrees Celsius.Mixture is Celsius in -45-15 The lower stirring of degree 2 hours.Then it is quenched with ammonium chloride (20 milliliters).Aqueous phase is extracted with ethyl acetate (30 milliliters × 3).By merging Organic phase is washed with saturated aqueous common salt (20 milliliters), with anhydrous sodium sulfate drying, is filtered and is concentrated in vacuo.Residue is by preparing Type prepares chromatographic separation and purification (GX-A；Phenomenex Gemini C18 250*50 10u；(0.05%ammonia-ACN)； 25mL/min) obtain (S) -2- methyl -2- (((the 5H)-yl of 2- morpholino -7,8- dihydros -1,6- naphthyridines -6) methyl) -6- nitros - 2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 30 (39.10 milligrams, 97.06 micromoles, 21.2% yield, 99.4% is pure Degree).1H NMR (400MHz, CDCl3)：δ 7.51 (s, 1H), 7.13 (d, J=8.53Hz, 1H), 6.45 (d, J=8.53Hz, 1H), 4.43 (d, J=9.66Hz, 1H), 3.93 (d, J=9.54Hz, 1H), 3.83-3.81 (m, 4H), 3.72-3.68 (m, 2H), 3.47-3.44 (m, 4H), 3.07-3.04 (m, 2H), 2.76 (ddd, J=12.02,7.18,4.77Hz, 1H) 2.75- 2.71 (m, 3H) 1.66 (s, 3H) .LCMS (ESI) m/z：401(M+1).
Embodiment 31
(S) -2- ((2- (4,4- difluoropiperdin -1- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- first Base -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
Benzyl -4,4- difluoro piperazine
1- benzyl -4- ketone (1.00 grams, 5.28 mMs, 1.00 equivalents) is dissolved in DCM (10.00 milliliters), in nitrogen In addition DAST (2.56 grams, 15.85 mMs, 3.00 equivalents) under zero degrees celsius under protection.Mixture is stirred under 0 degree Celsius Mix 0.5 hour, then heat to 15 degrees Celsius and stir 12 hours.Under 0 degree Celsius, the carbonic acid of saturation is added this mixture to In hydrogen sodium (60 milliliters) solution, then mixture is extracted (100mL × 4) with DCM.By the organic phase saturated aqueous common salt of merging (40 milliliters) washing, with anhydrous sodium sulfate drying, filter and be concentrated in vacuo, obtain 1- benzyls -4,4- difluoro-piperidin (1.20 grams, Crude product), it is black solid, it, which need not be further purified, is used for next step.1H NMR (400MHz, CDCl3)：δ 7.39-7.29 (m, 5H), 3.66-3.52 (m, 2H), 2.57 (t, J=5.3Hz, 4H), 2.02 (ddd, J=19.7,13.7, 5.8Hz, 4H)
Step 2：
4,4- difluoropiperdin hydrochlorides
1- benzyls -4,4- difluoro-piperidin (1.20 grams, 5.68 mMs, 1.00 equivalents) is dissolved in dichloroethanes (10.00 Milliliter) in, add 1- chloroethyls phosgene (1.22 grams, 8.52 mMs, 1.50 equivalents in zero degrees celsius under nitrogen protection. Mixture is stirred at such a temperature 0.5 hour.It is then heated to 85 degrees Celsius and stirs 12 hours.Mixture is concentrated, it is residual Methanol (10.00 milliliters) is added in excess, is then stirred for the mixture at 85 degrees Celsius 2 hours.Mixture is cooled down, It is concentrated under reduced pressure under 60 degrees Celsius, obtains 4,4- difluoropiperdins hydrochloride (580.00 milligrams thick), be black solid, it need not be entered The purifying of one step is used for next step.
Step 3：
6- benzyls -2- (4,4- difluoropiperdin -1- bases) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
Under nitrogen protection in 15 degrees Celsius by chloro- 7,8- dihydros -5H-1, the 6- benzodiazines of 6- benzyls -2- (1.03 grams, 3.98 mMs, 1.00 equivalents) and 4,4- difluoropiperdin (960.00 milligrams, 7.93 mMs, 1.99 equivalents) be dissolved in toluene In (15.00 milliliters) solution, sodium tert-butoxide (956.36 milligrams, 9.95 mMs, 2.50 equivalents), dicyclohexyl-[2- are being added (2,4,6- triisopropyl) phenyl] phosphine (284.65 milligrams, 597.10 micromoles, 0.15 equivalent), Pd2(dba)3(291.61 millis Gram, 318.45 micromoles, 0.08 equivalent).Mixture is stirred 12 hours at 110 degrees Celsius, cooling, and in 60 degrees Celsius of decompressions Concentration.Water (20 milliliters) is added in residue, aqueous phase is extracted (100 milliliters × 4) with dichloromethane.The organic phase of merging is used (50 milliliters) washings of saturated aqueous common salt, with anhydrous sodium sulfate drying, filter and are concentrated in vacuo.Obtain 6- benzyls -2- [4- (4,4- Two fluoro- 1- piperidyls) phenyl] -7,8- dihydros -5H-1,6- benzodiazine (700.00 milligrams, 1.67 mMs, 41.92% production Rate), it is yellow solid.1H NMR (400MHz, CDCl3)：δ 7.49-7.30 (m, 5H), 7.21-7.06 (m, 1H), 6.58-6.47 (m, 1H), 3.78-3.66 (m, 5H), 3.64-3.46 (m, 2H), 2.86 (dd, J=18.7,5.4Hz, 3H), 2.10-1.95 (m, 3H), 1.40-1.20 (m, 2H), 1.03-0.79 (m, 2H) .LCMS (ESI) m/z：344(M+1).
Step 4：
2- (4,4- difluoropiperdin -1- bases) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
By 6- benzyls -2- [4- (4,4- bis- fluoro- 1- piperidyls) phenyl] -7,8- dihydros -5H-1,6- benzodiazine (600.00 milligrams, 1.75 mMs, 1.00 equivalents) are dissolved in methanol (30.00mL), then add Pd under 15 degrees Celsius (OH)2/ C (24.22 milligrams, 174.98 micromoles, 0.10 equivalent).Stirring 12 is small under conditions of 60 degrees Celsius, H2 (50psi) When.Mixture is filtered and filtrate is concentrated, residue passes through Silica gel chromatography (petrol ether/ethyl acetate=10/1,1/ 10), obtaining 2- (4,4- difluoropiperdin -1- bases) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines, (250.00 milligrams, 987.01 micro- rub You, 56.40% yield), it is yellow solid.LCMS(ESI)m/z：254(M+1).
Step 5：
(S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3- (2- (4,4- difluoropiperdin -1- bases) -7,8- dihydro -1, 6-- naphthyridines -6 (5H)-yl) -2- methyl propan-2-ols
Under nitrogen protection in 15 degrees Celsius by 2- (4,4- bis- fluoro- 1- piperidyls) -5,6,7,8- tetrahydrochysene -1,6- diazas Naphthalene (100.00 milligrams, 394.80 micromoles, 1.00 equivalents) and the chloro- 1- of 2- [[(2S) -2- methyl oxirane -2- bases] first Base] -4- nitroimidazoles (85.91 milligrams, 394.80 micromoles, 1.00 equivalents), (127.56 milligrams, 987.00 micro- rub DIPEA You, 2.50 equivalents) it is dissolved in the tert-butyl alcohol (5.00 milliliters).Mixture is stirred 12 hours at 85 degrees Celsius, cooling, and taken the photograph 60 Family name's degree is concentrated, and residue is obtained into (S) -1- (2- by Silica gel chromatography (petrol ether/ethyl acetate=20/1,1/2) Chloro- 4- nitros -1H- imidazoles -1- bases) -3- (2- (4,4- difluoropiperdin -1- bases) -7,8- dihydros -1-, 6- naphthyridines -6 (5H) - Base) -2- methyl propan-2-ol (200.00 milligrams, crude product) is yellow oil.LCMS(ESI)m/z：471(M+1).
Step 6：
(S) -2- ((2- (4,4- difluoropiperdin -1- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- first Base -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4,4- bis- fluoro- 1- piperidyls) -7,8- dihydros -5H- The base of 1,6- naphthyridines -6] -2- methyl -propyl- 2- alcohol (200.00 milligrams, 424.72 micromoles, 1.00 equivalents) be dissolved in DMF (5.00 milli Rise) in, add NaH (20.39 milligrams, 849.44 micromoles, 2.00 equivalents) in -20 degrees Celsius under nitrogen protection.Will mixing Thing is stirred 10 minutes at -20 degrees Celsius, then heats to 0 degree Celsius, and is stirred 10 minutes, then by mixture at 15 degrees Celsius It is further stirred for after 10 minutes being quenched with saturated aqueous ammonium chloride (50mL), mixture is filtered, filtration cakes torrefaction obtains crude product, will Crude product prepares chromatographic separation and purification (GX-D by preparative；Boston Symmetrix C18 ODS-R 150*30mm*5 um；Acetonitrile 24%-54%；Water (0.225%fomic acid)；25mL/min) obtain (S) -2- ((2- (4, 4- difluoropiperdin -1- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitro -2,3- glyoxalidine And [2,1-B] oxazoline compound 31 (15.00 milligrams, 33.88 micromoles, 7.98% yield, 98.12% purity).1H NMR (400MHz, METHANOL-d4)：δ 7.81 (s, 1H), 7.21 (d, J=8.4Hz, 1H), 6.67 (d, J=8.4Hz, 1H), 4.40 (d, J=10.3Hz, 1H), 4.11 (d, J=10.3Hz, 1H), 3.75-3.61 (m, 6H), 3.11-2.98 (m, 2H), 2.95- (s, the 3H) .LCMS of 2.85 (m, 2H), 2.77-2.67 (m, 1H), 2.66-2.55 (m, 1H), 2.06-1.91 (m, 4H), 1.66 (ESI)m/z：435(M+1).
Embodiment 32
(S) -2- methyl -6- nitros -2- ((2- (3,4,5- trifluorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) Methyl) -2,3- glyoxalidine simultaneously [2,1-B] oxazole
Synthetic method such as embodiment 29.
(S) -2- methyl -6- nitros -2- ((2- (3,4,5- trifluorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) Methyl) -2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 32 (123.50 milligrams, 272.34 micromoles, 52.49% yield, 98.216% purity).1H NMR (400MHz, CDCl3) 7.68-7.59 (m, 2H), 7.52 (s, 1H), 7.46-7.37 (m, 2H), 4.43 (d, J=12.0Hz, 1H), 3.97 (d, J=8.0Hz, 1H), 3.95-3.81 (m, 2H), 3.24-2.92 (m, 5H), 2.82 (d, J=12.0Hz, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：446(M+1).
Embodiment 33
(S)-N- (4- fluorophenyls) -6- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole -2- bases) first Base) -5,6,7,8-, 8- tetrahydrochysene -1,6- benzodiazine -2- amine
Synthetic method such as embodiment 30.
(S)-N- (4- fluorophenyls) -6- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazo liter -2- bases) Methyl) -5,6-, 7,8- tetrahydrochysene -1,6- benzodiazine -2- amines 33 (9.50 milligrams, 22.09 micromoles, 6.79% production Rate, 98.7% purity).1H NMR (400MHz, CDCl3)：δ 8.47 (s, 1H), 7.97 (br.s., 1H), 7.53 (s, 1H), 7.25 (d, J=4.6Hz, 1H), 7.18 (d, J=8.5Hz, 1H), 7.05 (t, J=8.5Hz, 2H), 6.63 (d, J=8.5Hz, 1H), 4.41 (d, J=9.5Hz, 1H), 3.96 (d, J=9.8Hz, 1H), 3.79-3.65 (m, 2H), 3.12-3.04 (m, 2H), 2.94 (dd, J=6.3,11.4Hz, 1H), 2.88-2.73 (m, 3H), 1.67 (s, 3H) .LCMS (ESI) m/z：425(M+1).
Embodiment 34
(S) -2- ((2- (4- fluorophenoxies)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
Chloro- 7,8- dihydros -1,6- naphthyridines -6 (the 5H)-carboxylic acid tert-butyl esters of the tert-butyl group -2-
By tetrahydrochysene -1, the 6- benzodiazines of 2- chloro- 5,6,7,8- (850.00 milligrams, 4.14 mMs, 1.00 equivalents) and uncle Butoxy carbonyl tert-butyl carbonate (1.36 grams, 6.22 mMs of mixture, 1.50 equivalents) is dissolved in dichloromethane (15.00 milliliters) In the mixed solution of water (15.00 milliliters), sodium acid carbonate (1.04 grams, 12.43 mMs, 3.00 are added under 15 degrees Celsius Equivalent) by mixture 15 degrees Celsius stir 2 hours.Mixture is poured into water (30 milliliters), aqueous phase is extracted with ethyl acetate (50 milliliters × 3).The organic phase of merging is washed with saturated aqueous common salt (30 milliliters), with anhydrous sodium sulfate drying, filtered and true Sky concentration.Residue obtains the tert-butyl group -2- chloro- by Silica gel chromatography (petrol ether/ethyl acetate=50/1,30/1) (the 5H)-carboxylic acid tert-butyl ester of 7,8- dihydro -1,6- naphthyridines -6 (1.00 grams, 3.72 mMs, 89.75% yield), is white solid.
Step 2：
Chloro- 1- oxygen -7,8- dihydro -5H-1, the 6- naphthyridines -1--6- carboxylic acid, ethyl esters of the tert-butyl group -2-
By chloro- 7,8- dihydros -1,6- naphthyridines -6 (the 5H)-carboxylic acid tert-butyl esters of the tert-butyl group -2- (1.20 grams, 4.47 mMs, 1.00 equivalents) it is dissolved in chloroform (20.00 milliliters) solution, mixture is in addition metachloroperbenzoic acid (1.45 under 0 degree Celsius Gram, 6.71 mMs, 1.50 equivalents).Mixture is stirred 12 hours under 25 degrees Celsius.Then by mixture with saturation come sulphur Sour sodium (20 milliliters) is quenched, and (40 milliliters × 3) are extracted with dichloromethane.By the organic phase of merging saturated aqueous common salt (20 millis Rise) washing, with anhydrous sodium sulfate drying, filter and be concentrated in vacuo, obtain the tert-butyl group -2- chloro- 1- oxygen -7,8- dihydro -5H-1,6- Naphthyridines -1--6- carboxylic acid, ethyl esters (1.00 grams, 3.51 mMs, 78.52% yield), are yellow solid, are directly used in down One step.LCMS(ESI)m/z：285(M+1).
Step 3：
Tetrahydrochysene -1, the 6- benzodiazine -1- oxides of 6- (tert-butoxycarbonyl) -2- (4- fluorophenoxies) -5,6,7,8-
By chloro- 1- oxygen -7,8- dihydro -5H-1,6- benzodiazine-the 1--6- carboxylic acid, ethyl esters of the tert-butyl group -2- (600.00 millis Gram, 2.11 mMs, 1.00 equivalents) and 4- fluorophenols (283.46 milligrams, 2.53 mMs, 1.20 equivalents) be dissolved in DMF (3.00 Milliliter) in, add NaH (168.57 milligrams, 4.21 mMs, 2.00 equivalents in 0 degree Celsius under the protection of nitrogen.Will mixing Thing is cooled down after being stirred 12 hours at 70 degrees Celsius, and residue is poured into water (15 milliliters), be extracted with ethyl acetate (30 milliliters × 3).The organic phase of merging is simultaneously washed with saturated brine (20 milliliters), with anhydrous sodium sulfate drying, filtering and vacuum concentration, and will Residue obtains 6- (tert-butoxycarbonyl) -2- (4- fluorine with Silica gel chromatography (petrol ether/ethyl acetate=5/1,1/3) Phenoxy group) -5,6,7,8- tetrahydrochysene -1,6- benzodiazine -1- oxides (510.00 milligrams, 1.42 mMs, 67.07% production Rate), it is yellow solid.
Step 4：
The tert-butyl group -2- (4- fluorophenoxies)-(the 5H)-carboxylic acid tert-butyl ester of 7,8- dihydros -1,6- naphthyridines -6
By tetrahydrochysene -1, the 6- benzodiazine -1- oxides of 6- (tert-butoxycarbonyl) -2- (4- fluorophenoxies) -5,6,7,8- (410.00 milligrams, 1.14 mMs, 1.00 equivalents) are dissolved in ammonium chloride (3.00 milliliters) and THF (3.00 milliliters) mixed solution In, add zinc (745.45 milligrams, 11.40 mMs, 10.00 equivalents) in 0 degree Celsius under nitrogen protection.By mixture 15 Degree Celsius stirring 2 hours.Mixture is filtered, and filtrate is extracted with ethyl acetate (30 milliliters × 3).By the organic of merging Mutually washed with saturated aqueous common salt (20 milliliters), with anhydrous sodium sulfate drying, filter and be concentrated in vacuo.Then residue is passed through into silicon Glue chromatography purifying (petrol ether/ethyl acetate=20/1,10/1) obtains the tert-butyl group -2- (4- fluorophenoxies) -7,8- dihydro -1, 6- naphthyridines -6 (5H)-carboxylic acid tert-butyl ester (420.00 milligrams, crude product), is white solid.1H NMR (400MHz, CDCl3)：δ7.41 (d, J=8.4Hz, 1H), 7.12-7.05 (m, 4H), 6.66 (d, J=8.4Hz, 1H), 4.55 (s, 2H), 3.72 (t, J= 5.8Hz, 2H), 2.92-2.81 (m, 2H), 1.51 (s, 9H)
Step 5：
Tetrahydrochysene -1, the 6- benzodiazines of 2- (4- fluorophenoxies) -5,6,7,8-
By the tert-butyl group -2- (4- fluorophenoxies)-(5H)-carboxylic acid tert-butyl ester of 7,8- dihydros -1,6- naphthyridines -6 (200.00 millis Gram, 580.75 micromoles, 1.00 equivalents) it is dissolved in dichloromethane (1.00 milliliters) solution, add TFA under 15 degrees Celsius (66.24 milligrams, 580.75 micromoles, 1.00 equivalents) are stirred 1 hour.Then be concentrated under reduced pressure the mixture, obtains 2- (4- fluorobenzene Epoxide) -5,6,7,8- tetrahydrochysene -1,6- benzodiazines (177.00 milligrams, crude product, tfa salt) are yellow oil.
Step 6：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenoxies) -7,8- dihydros -5H-1,6- phenodiazine Miscellaneous naphthalene -6- bases] -2- methyl -propyl- 2- alcohol
By tetrahydrochysene -1, the 6- benzodiazines of 2- (4- fluorophenoxies) -5,6,7,8- (177.00 milligrams, 494.01 micromoles, 1.00 equivalents, tfa salt) be dissolved in the tert-butyl alcohol (2.00 milliliters) solution, under 15 degrees Celsius add DIPEA (191.54 milligrams, 1.48 mMs, 3.00 equivalents), the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (129.00 milligrams, 592.81 micromoles, 1.20 equivalents).Mixture is stirred 12 hours at 70 degrees Celsius, cooling, and taken the photograph 45 It is concentrated under reduced pressure under family name's degree.By residue by Silica gel chromatography (petrol ether/ethyl acetate=10/1,3/1) obtain (2S)- 1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- the fluorophenoxies)-base of 7,8- dihydros -5H-1,6- naphthyridines -6] -2- methyl - Propan-2-ol (130.00 milligrams, 281.46 micromoles, 56.97% yield), is yellow solid.LCMS(ESI)m/z：462(M+ 1).
Step 7：
(S) -2- ((2- (4- fluorophenoxies)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenoxies) -7,8- dihydro -5H-1,6- naphthalenes The base of pyridine -6] -2- methyl -propyl- 2- alcohol (160.00 milligrams, 346.42 micromoles, 1.00 equivalents) is dissolved in DMF (2.00 milliliters), Under nitrogen protection NaH (27.71 milligrams, 692.84 micromoles, 2.00 equivalents) is added in -45 degrees Celsius.By mixture -45 Stirred 1 hour under to 15 degrees Celsius.It is quenched with saturated ammonium chloride solution (20 milliliters), middle stirring 5 minutes.Aqueous phase ethyl acetate Extract (40 milliliters × 3).The organic phase of merging is washed with saturated aqueous common salt (30 milliliters), with anhydrous sodium sulfate drying, filtering And be concentrated in vacuo.Residue is prepared into chromatographic separation and purification (GX-G by preparative；Phenomenex Synergi Max-RP 250*80 10u；Acetonitrile 30%-60%；Water (0.225%fomic acid)；25mL/min) obtain (S)- 2- ((2- (4- fluorophenoxies)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitro -2,3- dihydro miaows Azoles simultaneously [2,1-B] oxazoline compound 34 (56.00 milligrams, 129.00 micromoles, 37.24% yield, 98% purity).1H NMR (400MHz, CDCl3)：δ 7.52 (s, 1H), 7.30 (br.s., 1H), 7.09 (s, 2H), 7.07 (d, J=1.9Hz, 2H), 6.60 (d, J=8.3Hz, 1H), 4.41 (d, J=9.8Hz, 1H), 3.95 (d, J=9.7Hz, 1H), 3.79 (q, J=14.9Hz, 2H), (s, the 3H) .LCMS of 3.11-3.03 (m, 2H), 2.93 (td, J=6.0,11.6Hz, 1H), 2.84-2.74 (m, 3H), 1.68 (ESI)m/z：426(M+1).
Embodiment 35
(S) -2- (3,4- difluorophenyl) -6- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole -2- Base) methyl) -5,6-, 7,8- tetrahydrochysene -1,6- benzodiazine -3- nitriles
Step 1：
The tert-butyl group -3- cyano group -2- oxos -1,2, (the 5H)-carboxylic acid tert-butyl ester of 7,8- tetrahydrochysene -1,6- naphthyridines -6
By (Z)-tert-butyl group 3- ((dimethylamino) methylene) -4- oxo-piperidine -1- carboxylic acid tert-butyl esters (16.00 grams, 62.91 mMs, 1.00 equivalents) be dissolved in DMF (120.00 milliliters), be added portionwise under 0 degree Celsius NaH (5.03 grams, 125.82 mMs, 2.00 equivalents) and stir 1 hour.Finish, mixture is stirred for 30 minutes in this temperature, then added 2- cyanoacetamides (5.55 grams, 66.06 mMs, 1.05 equivalents) are dissolved in DMF (80.00 milliliters), are added dropwise to mixing molten In liquid and keeping temperature is constant.Gained mixture is stirred 12 hours at 28 degrees Celsius.It is concentrated under reduced pressure, residue passes through silica gel color Spectrometry purifying (silica, DCM/ ethyl acetate=1/1,1: 5) purifying obtains tert-butyl group 3- cyano group -2- oxos -1,2,7,8- Tetrahydrochysene -1,6- naphthyridines -6 (5H)-carboxylic acid tert-butyl ester (1.00 grams, 3.63 mMs, 5.77% yield), it is dark brown solid.1H NMR (400MHz, DMSO-d6) 8.04 (s, 1H), 4.24 (s, 2H), 3.55 (t, J=4.0Hz, 2H), 2.64 (t, J= 4.0Hz, 2H), 1.42 (s, 9H)
Step 2：
Tetrahydrochysene -1, the 6- benzodiazine -3- nitriles of 2- chloro- 5,6,7,8-
By the tert-butyl group -3- cyano group -2- oxos -1,2, (the 5H)-carboxylic acid tert-butyl ester of 7,8- tetrahydrochysene -1,6- naphthyridines -6 (2.00 grams, 7.26 mMs, 1.00 equivalents) it is added in POCl3 (28.22 grams, 184.05 mMs, 25.35 equivalents).By mixture Stirred 3 hours at 110 degrees Celsius.Reactant mixture is poured into in 28 degrees Celsius of water (1500 milliliters), sodium carbonate is then added To pH=10.Mixture is extracted (500 milliliters × 3) with DCM.By the organic layer of merging with saturated aqueous common salt (500 milliliters × 2) Washing, it is dried over sodium sulfate, filter and be concentrated under reduced pressure, obtain tetrahydrochysene -1, the 6- benzodiazine -3- of crude product 2- chloro- 5,6,7,8- Nitrile (2.00 grams, crude product), is directly used in next step.
Step 3：
Chloro- 3- cyano group -7,8- dihydro -1,6- naphthyridines -6 (the 5H)-carboxylic acid tert-butyl esters of the tert-butyl group -2-
Tetrahydrochysene -1, the 6- benzodiazine -3- nitriles of 2- chloro- 5,6,7,8- (1.40 grams, 7.23 mMs, 1.00 equivalents) are dissolved in In the mixed solution of THF (20.00 milliliters) and water (10.00 milliliters), di-tert-butyl dicarbonic acid ester (3.16 grams, 14.46 are added MM, 2.00 equivalents) and sodium carbonate (2.30 grams, 21.69 mMs, 3.00 equivalents).Mixture is stirred under 25 degrees Celsius Mix 12 hours.Reactant mixture is concentrated under reduced pressure, residue DCM dilutes (20 milliliters), and extracted with DCM (20 milliliters × 3).The organic layer of merging is washed with saturated brine (20 milliliters × 2), it is dried over sodium sulfate, filter and be concentrated under reduced pressure, residue By Silica gel chromatography (silica, petrol ether/ethyl acetate=10/1,5/1) obtain the chloro- 3- cyano group of the tert-butyl group -2- - (the 5H)-carboxylic acid tert-butyl ester of 7,8- dihydro -1,6- naphthyridines -6 (700.00 milligrams, 2.38 mMs, 32.96% yield), is yellow Solid.1H NMR (300MHz, CDCl3) 7.74 (s, 1H), 4.61 (s, 2H), 3.75 (t, J=8.0Hz, 2H), 3.03 (t, J= 8.0Hz, 2H), 1.48 (s, 9H)
Step 4：
The tert-butyl group -3- cyano group -2- (3,4- difluorophenyl)-(the 5H)-carboxylic acid tert-butyl ester of 7,8- dihydros -1,6- naphthyridines -6
By chloro- 3- cyano group -7,8- dihydro -1,6- naphthyridines -6 (the 5H)-carboxylic acid tert-butyl esters of the tert-butyl group -2- (350.00 milligrams, 1.19 mMs, 1.00 equivalents), (3,4- difluorophenyl) boric acid (225.50 milligrams, 1.43 mMs, 1.20 equivalents), carbonic acid Caesium (775.45 milligrams, 2.38 mMs, 2.00 equivalents) is dissolved in the mixing of dioxane (10.00 milliliters) and water (4.00 milliliters) In solution, nitrogen protection is lower to add Pd (dppf) Cl2(87.07 milligrams, 119.00 micromoles, 0.10 equivalent), then will mixing Thing is stirred 12 hours at 110 degrees Celsius.Reactant mixture is concentrated under reduced pressure, residue DCM dilutes (20 milliliters), and uses DCM Extract (20 milliliters × 3).The organic layer of merging is washed with saturated brine (20 milliliters × 2), it is dried over sodium sulfate, filter and subtract Pressure concentration, residue obtains the tert-butyl group by Silica gel chromatography (silica, petrol ether/ethyl acetate=10/1,5/1) 3- cyano group -2- (3,4- difluorophenyl)-(the 5H)-carboxylic acid tert-butyl ester of 7,8- dihydros -1,6- naphthyridines -6 (420.00 milligrams, 1.13 millis Mole, 95.04% yield), it is yellow solid.1H NMR (400MHz, CDCl3) 8.53 (s, 1H), 8.32-8.25 (m, 1H), 8.24-8.19 (m, 1H), 7.31-7.22 (m, 1H), 4.65 (s, 2H), 3.81 (t, J=6.0Hz, 2H), 3.03 (t, J= 6.0Hz, 2H), 1.53 (s, 9H)
Step 5：
Tetrahydrochysene -1, the 6- benzodiazine -3- nitriles of 2- (3,4- difluorophenyl) -5,6,7,8-
By the tert-butyl group -3- cyano group -2- (3,4- difluorophenyl)-(5H)-carboxylic acid tert-butyl ester of 7,8- dihydros -1,6- naphthyridines -6 (246.00 milligrams, 662.39 micromoles, 1.00 equivalents) are dissolved in DCM (2.00 milliliters) solution, add TFA (75.52 millis Gram, 662.39 micromoles, 1.00 equivalents), mixture is stirred 1 hour under 25 degrees Celsius, be concentrated under reduced pressure to obtain product 2- (3,4- Difluorophenyl) -5,6,7,8- tetrahydrochysene -1,6- benzodiazine -3- nitriles (250.00 milligrams, crude product), it is not purified to be directly used in down One step.
Step 6：
(S) -6- (3- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- hydroxy-2-methyls propyl group) -2- (3,4- difluorobenzenes Base) -5,6-, 7,8- tetrahydrochysene -1,6- benzodiazine -3- nitriles
By tetrahydrochysene -1, the 6- benzodiazine -3- nitriles of 2- (3,4- difluorophenyl) -5,6,7,8-, (180.00 milligrams, 663.57 is micro- Mole, 1.00 equivalents) and the chloro- 1- of (R) -2- ((2- expoxy propane -2- bases) methyl) -4- nitro -1H- imidazoles (173.28 milligrams, 796.28 micromoles, 1.20 equivalents) it is dissolved in the tert-butyl alcohol (10.00 milliliters), add DIPEA (257.28 milligrams, 1.99 mmoles You, 3.00 equivalents).Mixture is stirred at 80 degrees celsius 12 hours.Reactant mixture is concentrated under reduced pressure, residue passes through silicon The purifying of glue chromatography (silica, petrol ether/ethyl acetate=5/1,1: 1) obtains (S) -6- (3- (chloro- 4- nitros -1H- miaows of 2- Azoles -1- bases) -2- hydroxy-2-methyls propyl group) -5,6-, 7,8- tetrahydrochysene -1,6- benzodiazine -3- nitriles of -2- (3,4- difluorophenyl) (230.00 milligrams, 470.47 micromoles, 70.90% yield), are yellow solid.LCMS(ESI)m/z：489/491(M+1/M+ 3).
Step 7：
(S) -2- (3,4- difluorophenyl) -6- ((2- methyl -6- nitros -2-, 3- glyoxalidine simultaneously [2,1-B] oxazole -2- Base) methyl) -5,6-, 7,8- tetrahydrochysene -1,6- benzodiazine -3- nitriles
By (S) -6- (3- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- hydroxy-2-methyls propyl group) -2- (3,4- difluoros Phenyl) -5,6,7,8- tetrahydrochysene -1,6- benzodiazine -3- nitriles (230.00 milligrams, 470.47 micromoles, 1.00 equivalents) are dissolved in DMF In (5.00 milliliters) solution, NaH (22.58 milligrams, 564.56 micromoles, 1.20 equivalents) is added under 0 degree Celsius.By mixture After being stirred 10 minutes under 0 degree Celsius, it is quenched with saturated ammonium chloride solution (20 milliliters), then with (20 milliliters) dilutions of water, and Extracted with DCM (20 milliliters × 3).The organic layer of merging is washed with saturated brine (20mL × 2), dried over sodium sulfate, filtering And be concentrated under reduced pressure, residue prepares chromatographic separation and purification (GX-F by preparative；Welch Ultimate AQ-C18150* 30mm*5um；Acetonitrile 43%-73%；Water (0.225%fomic acid)；25mL/min) (S) -2- (3, 4- difluorophenyls) -6- ((2- methyl -6- nitros -2-, 3- glyoxalidine simultaneously [2,1-B] oxazole -2- bases) methyl) -5,6,7,8- Tetrahydrochysene -1,6- benzodiazine -3- nitrile compounds 35 (20.90 milligrams, 42.91 micromoles, 9.12% yield, 92.884% is pure Degree).1H NMR (400MHz, CDCl3) 7.80-7.66 (m, 3H), 7.53 (s, 1H), 7.36-7.29 (m, 1H), 4.37 (d, J= 12.0Hz, 1H), 4.00 (d, J=8.0Hz, 1H), 3.93 (d, J=13.2Hz, 2H), 3.25-2.98 (m, 5H), 2.84 (d, J =16.0Hz, 1H), 1.70 (s, 3H) .LCMS (ESI) m/z：453(M+1).
Embodiment 36
(S) -2- ((the chloro- 2- of 3- (3,4- difluorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- first Base -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
Tetrahydrochysene -1, the 6- naphthyridines -2- ketone of 6- benzyl -3- chlorine 1,5,7,8
By 4- toluene sulfonic acides (4.30 grams, 24.98 mMs, 1.50 equivalents) and tetrahydrochysene -1, the 6- naphthalene of 6- benzyls 1,5,7,8 Pyridine -2- ketone (4.00 grams, 16.65 mMs, 1.00 equivalents) is dissolved in acetonitrile (30.00 milliliters), add NCS (3.33 grams, 24.98 mMs, 1.50 equivalents).The mixture is stirred 12 hours under 25 degrees Celsius.It is quenched with water, reactant mixture is used Ethyl acetate extracts (250 milliliters × 2).The organic layer of merging is concentrated under reduced pressure, residue passes through Silica gel chromatography (dioxy SiClx, petrol ether/ethyl acetate=3/1, methylene chloride/methanol=10/1) obtain 6- benzyls -3- chloro- 5,6,7,8- tetrahydrochysene -1, 6- naphthyridines -2 (1H) -one (220.00 milligrams, 750.37 micromoles, 29.43% yield), is white solid.LCMS(ESI)m/z： 275.1(M+1).
Step 2：
Chloro- 7,8- dihydros -5H--1, the 6- benzodiazine of 6- benzyls -2,3- bis-
By tetrahydrochysene -1, the 6- naphthyridines -2- ketone of 6- benzyl -3- chlorine 1,5,7,8, (700.00 milligrams, 2.55 mMs, 1.00 work as Amount) and POCl3 (3.33 grams, 21.73 mMs, 8.53 equivalents) be dissolved in toluene (5.00 milliliters), mixture is calorified 100 degrees Celsius are stirred 5 hours.Reactant mixture is poured into water (100 milliliters) under 25 degrees Celsius, by pH by being gradually added into Sodium carbonate liquor is adjusted to about 9, and (200 milliliters × 2) are extracted with ethyl acetate.The organic layer of merging is concentrated under reduced pressure, it is residual Excess obtains 6- benzyls -2,3- bis- by Silica gel chromatography (silica, petrol ether/ethyl acetate=80/1,20/1) Chloro- 7,8- dihydros -5H--1,6- benzodiazine (220.00 milligrams, 750.37 micromoles, 29.43% yield), is white solid. LCMS(ESI)m/z：293.0(M+1).
Step 3：
The chloro- 2- of 6- benzyls -3- (3,4- difluorophenyl) -7,8- dihydros -5H-1,6- benzodiazine
By chloro- 7,8- dihydros -5H-1, the 6- benzodiazine of 6- benzyls -2,3- bis- (200.00 milligrams, 682.15 micromoles, 1.00 equivalents), (3,4- difluorophenyl) boric acid (96.95 milligrams, 613.94 micromoles, 0.90 equivalent), cesium fluoride (207.24 millis Gram, 1.36 mMs, 2.00 equivalents) it is dissolved in the mixed solution of dioxane (3 milliliters) and water (300.00 microlitres), nitrogen is protected Shield is lower to add Pd (dppf) Cl2(49.91 milligrams, 68.22 micromoles, 0.10 equivalent), and by the mixture under 110 degrees Celsius Stirring 12 hours.It is concentrated in vacuo and residue is passed through into Silica gel chromatography (silica, petrol ether/ethyl acetate=50/ 1,20: 1) obtain the chloro- 2- of 6- benzyls -3- (3,4- difluorophenyl) -7,8 dihydro -5H-1,6- benzodiazines (170.00 milligrams, 458.44 micromoles, 67.21% yield), it is white solid.LCMS(ESI)m/z：370.9(M+1).
Step 4：
Tetrahydrochysene -1, the 6- benzodiazine hydrochlorides of the chloro- 2- of 3- (3,4- difluorophenyl) -5,6,7,8-
By the chloro- 2- of 6- benzyls -3- (3,4- difluorophenyl) -7,8- dihydros -5H-1,6- benzodiazine (140.00 milligrams, 377.54 micromoles, 1.00 equivalents) and 1- chloroethyl phosgenes solution (70.17 milligrams, 490.80 micromoles, 1.30 equivalents) It is dissolved in dichloroethanes (100.00 milliliters), and is stirred 12 hours at 80 degrees Celsius.Reactant mixture is concentrated under reduced pressure, then by first Alcohol (100.00 milliliters) is added in reactant mixture, is stirred 12 hours at 80 degrees celsius.The reactant mixture is depressurized dense Contracting, obtains tetrahydrochysene -1, the 6- benzodiazine hydrochlorides of the chloro- 2- of crude product 3- (3,4- difluorophenyl) -5,6,7,8- (140.00 millis Gram, slightly, hydrochloric acid), next step is used for without further purification.LCMS(ESI)m/z：280.9(M+1).
Step 5：
(2S) -1- [the chloro- 2- of 3- (3,4- difluorophenyl) -7,8- dihydros -5H-1,6- naphthyridines -6- bases] -3- (chloro- 4- nitre of 2- Base imidazoles -1- bases) -2- methyl -propyl- 2- alcohol
By tetrahydrochysene -1, the 6- benzodiazines of the chloro- 2- of 3- (3,4- difluorophenyl) -5,6,7,8-, (140.00 milligrams, 498.75 is micro- Mole, 1.00 equivalents) be dissolved in the tert-butyl alcohol (5.00 milliliters) solution, add DIPEA (161.15 milligrams, 1.25 mMs, 2.50 equivalents) and the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (130.24 milligrams, 598.50 micromoles, 1.20 equivalents).Mixture is stirred 12 hours under 100 degrees Celsius.Reactant mixture is concentrated under reduced pressure, Residue obtains (2S) -1- by Silica gel chromatography (silica, petrol ether/ethyl acetate=20/1,1/3), and [3- is chloro- 2- (3,4- difluorophenyl) -7,8- dihydros -5H-1,6- benzodiazine -6- bases] -3- (the chloro- 4 nitroimidazole -1- bases of 2-) -2- first Base -propyl- 2- alcohol (80.00 milligrams, 160.54 micromoles, 32.19% yield), is yellow solid.LCMS(ESI)m/z：499.8 (M+1).
Step 6：
(S) -2- ((the chloro- 2- of 3- (3,4- difluorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- first Base -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (2S) -1- [the chloro- 2- of 3- (3,4- difluorophenyl) -7,8- dihydro -5H-1,6- benzodiazine -6- bases] -3- (2- Chloro- 4- nitroimidazoles -1- bases) -2- methyl -propyl- 2- alcohol (80.00 milligrams, 160.54 micromoles, 1.00 equivalents) is dissolved in DMF (2.00 milliliters), NaH (3.85 milligrams, 160.54 micromoles, 1.00 equivalents) stirrings 30 minutes are added under -20 degrees Celsius, are connect And stir mixture 1 hour at 15 degrees Celsius.Reactant mixture is added in water (15 milliliters) at 0 degree Celsius and is quenched, so After be extracted with ethyl acetate (100 milliliters × 2).The organic layer of merging is concentrated under reduced pressure, residue prepares chromatogram by preparative Method purifies (GX-A, Phenomenex Gemini C18 250*50mm*10um, acetonitrile 50%-80%；0.05% ammonia-ACN；25mL/min) obtain (S) -2- ((chloro- 2- of 3- (3,4- difluorophenyl) -7,8- dihydros -1,6- naphthyridines -6 (5H)-yl) methyl) -2- methyl 6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 36 (17.80 milligrams, 38.38 Micromole, 23.91% yield, 99.580% purity).1H NMR (400MHz, CDCl3) 7.53 (s, 1H), 7.45 (s, 1H), 7.28-7.20 (m, 1H), 4.40 (d, J=9.8Hz, 1H), 4.03-3.79 (m, 3H), 3.22-3.07 (m, 2H), 3.05-2.75 (m, 4H), 1.69 (s, 3H) LCMS (ESI) m/z：462.1(M+1).
Embodiment 37
(S) -2- (((the 5H)-yl of 2- (3,4- difluorophenyl) -4- methyl -7,8- dihydros -1,6- naphthyridines -6) methyl) -2- first Base -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
6- benzyl -4- methyl -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2 (1H) -one
By 1- benzyl -4- ketone (10.00 grams, 52.84 mMs, 1.00 equivalents) and 3- oxos butyramide (5.88 grams, 58.12 mMs, 1.10 equivalents) stir 12 under 110 degrees Celsius in EATON ' S REAGENT (20.00 milliliters) mixture Hour.Saturated sodium bicarbonate aqueous solution (300 milliliters) is added this mixture to, pH value ＞ 7 is adjusted to, by aqueous layer with ethyl acetate Extract (200 milliliters × 4).The organic phase of merging is washed with saturated aqueous common salt (100 milliliters), with anhydrous sodium sulfate drying, mistake Filter and be concentrated in vacuo, residue is poured into acetone (100 milliliters), then filtered, filtration cakes torrefaction obtain 6- benzyl -4- methyl - 5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2 (1H) ketone (7.00 grams, 27.52 mMs, 52.09% yield), are white solid.1H NMR (400MHz, CDCl3)：δ 7.46-7.25 (m, 5H), 6.25 (br, s, 1H), 3.76 (s, 2H), 3.42 (br, s, 2H), 2.84-2.64 (m, 4H), 2.10 (s, 3H)
Step 2：
Chloro- 4- methyl -7,8- dihydro -5H-1, the 6- benzodiazines of 6- benzyls -2-
By 6- benzyl -4- methyl -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2 (1H) -one (7.80 grams, 30.67 mMs, 1.00 equivalents) it is added in POCl3 (97.44 grams, 635.49 mMs, 20.72 equivalents), stir 12 under 110 degrees Celsius Cooled down after hour, then add mixture to and be quenched in water (300 milliliters), stirred the mixture for 30 minutes, then by water layer Alkalized with sodium bicarbonate aqueous solution to pH ＞ 7.Mixture is extracted into (200 milliliters × 4) with DCM, with anhydrous sodium sulfate drying, mistake Filter and vacuum concentration, obtain chloro- 4- methyl -7,8- dihydro -5H-1, the 6- benzodiazines (5.00 grams, crude product) of 6- benzyls -2-, are Yellow solid.LCMS(ESI)m/z：273(M+1).
Step 3：
6- benzyls -2- (3,4- difluorophenyl) -4- methyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
Under nitrogen protection, in 15 degrees Celsius by chloro- 4- methyl -7,8- dihydro -5H-1, the 6- benzodiazines of 6- benzyls -2- (1.87 grams, 6.86 mMs, 1.00 equivalents) and (3,4- difluorophenyl) boric acid (1.30 grams, 8.23 mMs, 1.20 equivalents), Cesium fluoride (3.13 grams, 20.58 mMs, 3.00 equivalents) is dissolved in the mixed of dioxane (25.00 milliliters) and water (2.50 milliliters) Close in solution, add Pd (dppf) Cl2(501.95 milligrams, 686.00 micromoles, 0.10 equivalent), the mixture is taken the photograph 110 Stirred 12 hours under family name's degree.Add the mixture in water (10 milliliters), mixture is then extracted into (100 millis with dichloromethane Rise × 4).The organic phase of merging is washed with saturated aqueous common salt (100 milliliters), with anhydrous sodium sulfate drying, filters and vacuum is dense Contracting.Residue is obtained into 6- benzyls -2- (3,4- bis- by Silica gel chromatography (petrol ether/ethyl acetate=20/1,5/1) Fluorophenyl) -4- methyl -7,8- dihydro -5H-1,6- benzodiazine (1.30 grams, 3.71 mMs, 54.08% yield) are yellow Solid..1H NMR (400MHz, CDCl3)：δ 7.83 (ddd, J=2.1,7.8,11.7Hz, 1H), 7.66 (ddd, J=2.0, 4.2,6.3Hz, 1H), 7.46-7.30 (m, 6H), 7.27-7.18 (m, 1H), 3.83-3.78 (m, 2H), 3.64 (s, 2H), 3.11 (t, J=5.8Hz, 2H), 2.87 (t, J=5.9Hz, 2H), 2.23 (s, 3H)
Step 4：
2- (3,4- difluorophenyl) -4- methyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazine hydrochlorides
By 6- benzyls -2- (3,4- difluorophenyl) -4- methyl -7,8- dihydro -5H-1,6- naphthyridines (1.30 grams, 3.71 mmoles You, 1.00 equivalents) it is dissolved in dichloroethanes (20.00 milliliters), add 1- chlorine phosgenes in 15 degrees Celsius under nitrogen protection (795.63 milligrams, 5.57 mMs, 1.50 equivalents.Mixture is stirred 12 hours at 85 degrees Celsius.Then it is mixture is dense Methanol (20.00 milliliters) is added in contracting, residue, gained mixture is stirred for 2 hours at 85 degrees Celsius.By mixture mistake Filter, filter cake is collected, dry 2- (3,4- difluorophenyl) -4- methyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazine hydrochlorides (800.00 milligrams, 2.70 mMs, 72.67% yield), are white solid, are directly used in next step.
Step 5：
(S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3- (2- (3,4- difluorophenyl) -4- methyl -7,8- dihydro - (the 5H)-yl of 1,6-- naphthyridines -6) -2- methyl propan-2-ols
By 2- (3,4- difluorophenyl) -4- methyl -5,6,7,8- tetrahydrochysene -1,6- naphthyridine hydrochloride (800.00 milligrams, 2.70 MM, 1.00 equivalents) and the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (705.06 millis Gram, 3.24 mMs, 1.20 equivalents) it is dissolved in ethanol (20.00 milliliters) solution, under nitrogen protection in 15 degrees Celsius of additions DIPEA (872.37 milligrams, 6.75 mMs, 2.50 equivalents).Mixture is stirred 12 hours at 80 degrees Celsius, cooling, and 60 degrees Celsius are concentrated under reduced pressure, and residue is added in water (10 milliliters).Aqueous phase extracts (50 milliliters × 4) with dichloromethane, with anhydrous Sodium sulphate is dried, filtering and vacuum concentration, and residue is passed through into Silica gel chromatography (pillar height degree：250 millimeters, diameter：100 Millimeter, 100-200 mesh silica gel, petrol ether/ethyl acetate=20/1,1/1) obtain (S) -1- (chloro- 4- nitros -1H- imidazoles -1- of 2- Base) -3- ((the 5H)-yl of 2- (3,4- difluorophenyl) -4- methyl -7,8- dihydros -1,6-- naphthyridines -6) -2- methyl propan-2-ols (800.00 milligrams, 1.67 mMs, 62.00% yield), are yellow solid.LCMS(ESI)m/z：478(M+1).
Step 6：
(S) -2- (((the 5H)-yl of 2- (3,4- difluorophenyl) -4- methyl -7,8 dihydros -1,6- naphthyridines -6) methyl) -2- first Base -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3- (2- (3,4- difluorophenyl) -4- methyl -7,8- bis- Hydrogen -1,6-- naphthyridines -6 (5H)-yl) -2- methyl propan-2-ol (400.00 milligrams, 837.01 micromoles, 1.00 equivalents) is dissolved in DMF In (5.00 milliliters) solution, adding NaH in -20 degrees Celsius under nitrogen protection, (40.18 milligrams, 1.67 mMs, 2.00 work as Amount) stir 10 minutes, then heat to -5 degrees Celsius and stir 10 minutes.Then mixture is stirred for 10 points at 15 degrees Celsius Clock.Mixture is cooled to 0 degree Celsius, is quenched with saturated aqueous ammonium chloride (30mL).Then mixture is filtered, by filter cake Collection is dried to obtain crude product, and it purifies (GX-D by preparative preparative chromatography；Boston Symmetrix C18 ODS-R 150*30mm*5um；Acetonitrile 24%-54%；Water (0.225%fomic acid)；25mL/min) (S)- 2- (((the 5H)-yl of 2- (3,4- difluorophenyl) -4- methyl -7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl 6- nitro -2, 3- glyoxalidine simultaneously [2,1-B] oxazoline compound 37 (97.50 milligrams, 215.79 micromoles, 25.78% yield, 97.7% is pure Degree).1H NMR (400MHz, METHANOL-d4)：δ 7.88-7.78 (m, 2H), 7.71 (d, J=8.5Hz, 1H), 7.46 (s, 1H), 7.38-7.30 (m, 1H), 4.45 (d, J=10.5Hz, 1H), 4.14 (d, J=10.3Hz, 1H), 3.84 (s, 2H), (s, the 3H) .LCMS of 3.18-3.08 (m, 2H), 3.05-2.90 (m, 3H), 2.88-2.78 (m, 1H), 2.30 (s, 3H), 1.69 (ESI)m/z：442(M+1).
Embodiment 38
2- (3,4- difluorophenyl) -6- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole -2- bases) first Base)-(6H) -one of 7,8- dihydros -1-, 6- naphthyridines -5
Step 1：
Tetrahydrochysene -1, the 6- benzodiazine hydrochlorides of 2- chloro- 5,6,7,8-
Chloro- 7,8- dihydros -5H-1, the 6- benzodiazines of 6- benzyls -2- (2.70 grams, 10.43 mMs, 1.00 equivalents) is molten In dichloroethanes (50.00 milliliters), added under the protection of nitrogen in 15 degrees Celsius 1- chloroethyls phosgenes (2.24 grams, 15.65 mMs, 1.50 equivalents).Mixture is stirred 12 hours at 85 degrees Celsius.Then mixture is concentrated molten to remove Methanol (50.00 milliliters) is added in agent, residue, 80 degrees Celsius is then heated to and stirs 2 hours.By mixture mistake Filter, filter cake is collected and dry tetrahydrochysene -1, the 6- benzodiazine hydrochlorides of 2- chloro- 5,6,7,8- (2.00 grams, 9.75 mMs, 93.50% yield), it is white solid, is directly used in next step.
Step 2：
Chloro- 7,8- dihydros -5H-1, the 6- benzodiazine -6- carboxylic acid, ethyl esters of the tert-butyl group -2-
Tetrahydrochysene -1, the 6- benzodiazine hydrochlorides of 2- chloro- 5,6,7,8- (2.00 grams, 9.75 mMs, 1.00 equivalents) is molten In DCM (20.00 milliliters), adding triethylamine in 15 degrees Celsius under nitrogen protection, (2.47 grams, 24.38 mMs, 2.50 work as Amount) and di-tert-butyl dicarbonic acid ester (3.19 grams, 14.63 mMs, 1.50 equivalents).Mixture is small in 15 degrees Celsius of stirrings 12 When.Pour the mixture into water (30 milliliters), aqueous phase is extracted (100 milliliters × 4) with dichloromethane.The organic phase of merging is used (100 milliliters) washings of saturated aqueous common salt, with anhydrous sodium sulfate drying, filter and are concentrated in vacuo.Obtain chloro- 7, the 8- bis- of tert-butyl group 2- Hydrogen -5H-1,6- benzodiazine -6- carboxylic acid, ethyl esters (2.50 grams, 9.30 mMs, 95.41% yield), are white solid.LCMS (ESI)m/z：269(M+1).
Step 3：
Chloro- 5- oxos -7,8- dihydro -1, the 6- benzodiazine -6- carboxylic acid, ethyl esters of tert-butyl group 2-
By chloro- 7,8- dihydros -5H-1,6- benzodiazine-the 6- carboxylic acid, ethyl esters of the tert-butyl group -2- (2.30 grams, 8.56 mMs, 1.00 equivalents) in the mixed solution of acetonitrile (740.00 microlitres) and carbon tetrachloride (37.00 milliliters) and water (14.80 milliliters), Under nitrogen protection sodium metaperiodate (5.49 grams, 25.68 mMs, 3.00 equivalents) and RuCl are added in 15 degrees Celsius3(532.58 Milligram, 2.57 mMs, 0.30 equivalent.Mixture is stirred 12 hours at 15 degrees Celsius.By the mixture, to water is entered, (20 in the least Rise) in, then extracted (100 milliliters × 4), the organic phase of merging is washed with saturated aqueous common salt (100 milliliters), used with dichloromethane Anhydrous sodium sulfate drying, is filtered and is concentrated in vacuo, and residue is passed through into Silica gel chromatography (pillar height degree：250 millimeters, diameter： 100 millimeters, 100-200 mesh silica gel, petrol ether/ethyl acetate=20/1 to 10/1) obtain the chloro- 5- oxos -7,8- bis- of tert-butyl group 2- Hydrogen -1,6- benzodiazine -6- carboxylate methyl esters (1.80 grams, 6.37 mMs, 74.38% yield), are white solid.1H NMR (400MHz, CDCl3)：δ 8.38 (d, J=8.3Hz, 1H), 7.37 (d, J=8.0Hz, 1H), 4.13-4.04 (m, 2H), 3.24- 3.12 (m, 2H), 1.60 (s, 9H) .LCMS (ESI) m/z：283(M+1).
Step 4：
The tert-butyl group -2- (3,4- difluorophenyl) -5- oxo -7,8- dihydro -1,6- benzodiazine -6- carboxylic acid, ethyl esters
By tert-butyl group 2- chloro- 5- oxos -7,8- dihydro -1,6- benzodiazine -6- carboxylate methyl esters (1.80 grams, 6.37 mmoles You, 1.00 equivalents) it is dissolved in the mixed solution of dioxane (30.00 milliliters) and water (3.00 milliliters), add (3,4- difluoros Phenyl) boric acid (1.21 grams, 7.64 mMs, 1.20 equivalents), cesium fluoride (2.90 grams, 19.11 mMs, 3.00 equivalents). Under nitrogen protection Pd (dppf) Cl is added in 15 degrees Celsius2(466.09 milligrams, 637.00 micromoles, 0.10 equivalent).Will mixing Thing is stirred 12 hours under 110 degrees Celsius.Mixture is cooled to 15 degrees Celsius, is concentrated under reduced pressure.Water (20 millis are added in residue Rise), aqueous phase is extracted (100 milliliters × 4) with dichloromethane.The organic phase of merging is washed with saturated aqueous common salt (100 milliliters), used Anhydrous sodium sulfate drying, filters and is concentrated in vacuo.Residue is passed through into Silica gel chromatography (pillar height degree：250 millimeters, diameter： 100 millimeters, 100-200 mesh silica gel, petrol ether/ethyl acetate=20/1,10/1) obtain tert-butyl group 2- (3,4- difluorophenyl) -5- Oxo -7,8- dihydro -1,6- naphthyridines -6- carboxylate methyl esters (1.40 grams, 3.89 mMs, 60.99% yield), are white solid.1H NMR (400MHz, CDCl3)：δ 8.49 (d, J=8.3Hz, 1H), 7.99 (ddd, J=2.0,7.8,11.5Hz, 1H), 7.82 (ddd, J=2.0,4.1,6.4Hz, 1H), 7.73 (d, J=8.3Hz, 1H), 7.35-7.29 (m, 1H), 4.18-4.08 (m, 2H), 3.28 (t, J=6.4Hz, 2H), 1.62 (s, 10H)
Step 5：
2- (3,4- difluorophenyl) -7,8- dihydros -6H-1,6- benzodiazine -5- ketone
By the tert-butyl group -2- (3,4- difluorophenyl) -5- oxo -7,8- dihydro -1,6- benzodiazine -6- carboxylic acid, ethyl esters (500.00 milligrams, 1.39 mMs, 1.00 equivalents) are dissolved in hydrochloric ethyl acetate (10.00 milliliters), and the solution is Celsius 15 The lower stirring of degree 1 hour.Mixture is concentrated to dryness, 2- (3,4- difluorophenyl) -7,8- dihydros -6H-1,6- benzodiazine -5- is obtained Ketone (350.00 milligrams, 1.34 mMs, 96.76% yield), is white solid.LCMS(ESI)m/z：261(M+1).
Step 6：
2- (3,4- difluorophenyl) -6- [(2- methyl oxirane -2- bases) methyl] -7,8- dihydro -1,6- naphthyridines -5- ketone
To 2- (3,4- difluorophenyl)-(250.00 milligrams, 960.65 is micro- for 7,8- dihydros -6H-1,6- benzodiazine -5- ketone Mole, 1.00 equivalents) and 2- (chloromethyl) -2- Methyl-oxiranes (153.54 milligrams, 1.44 mMs, 1.50 equivalents) exist In DMF (3.00 milliliters) solution under nitrogen protection in 15 degrees Celsius add potassium tert-butoxides (215.59 milligrams, 1.92 mMs, 2.00 equivalents).Mixture is stirred 3 hours under 110 degrees Celsius.Add in water (10 milliliters), then will into the mixture Mixture is extracted with ethyl acetate (50 milliliters × 4).The organic phase of merging is washed with salt solution (50 milliliters), anhydrous sodium sulfate is used Dry, filter and be concentrated in vacuo, residue is passed through into Silica gel chromatography (pillar height degree：250 millimeters, 10 millimeters of diameter, 100- 200 mesh silica gel, petrol ether/ethyl acetate=20/1,1/1), obtain 2- (3,4- fluorophenyl) -6- [(2- methyl oxiranes -2- Base) methyl] -7,8- dihydro -1,6- naphthyridines -5- ketone (240.00 milligrams, crude product) is yellow solid.LCMS(ESI)m/z：331 (M+1).
Step 7：
6- [3- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- hydroxy-2-methyls-propyl group] -2- (3,4- difluorophenyl) -7,8- Dihydro -1,6- naphthyridines -5- ketone
By 2- (3,4- difluorophenyl) -6- [(2- methyl oxirane -2- bases) methyl] -7,8- dihydro -1,6- naphthyridines -5- (66.99 milligrams, 454.09 is micro- for ketone (150.00 milligrams, 454.09 micromoles, 1.00 equivalents) and the chloro- 4- nitros -1H- imidazoles of 2- Mole, 1.00 equivalents) it is dissolved in tert-butyl acetate (5.00 milliliters) solution, add sodium acetate in 15 degrees Celsius under nitrogen protection (37.25 milligrams, 454.09 micromoles, 1.00 equivalents).Mixture is stirred 3 hours at 110 degrees Celsius.Mixture is cooled down, And be concentrated under reduced pressure at 70 degrees Celsius, residue purifies (petrol ether/ethyl acetate=1/1) by preparative thin-layer chromatography method, obtains To 6- [3- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- hydroxy-2-methyls propyl group] -2- (3,4- difluorophenyl) -7,8- dihydro -1, 6- naphthyridines -5- ketone (40 milligrams, crude product), is white solid.LCMS(ESI)m/z：478(M+1).
Step 8：
2- (3,4- difluorophenyl) -6- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole -2- bases) first Base)-(6H) -one of 7,8- dihydros -1-, 6- naphthyridines -5
By 6- [3- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- hydroxy-2-methyls-propyl group] -2- (3,4- difluorophenyl) -7, 8- dihydro -1,6- naphthyridines -5- ketone (30.00 milligrams, 83.71 micromoles, 1.00 equivalents) is dissolved in DMF (2.00 milliliters) solution, NaH (4.02 milligrams, 167.42 micromoles, 2.00 equivalents) is added under -20 degrees Celsius of nitrogen protections, mixture is taken the photograph -20 Family name's degree is stirred 10 minutes, then heats to 0 degree Celsius, and is stirred 10 minutes, then is stirred 10 minutes at 15 degrees Celsius.By mixture Be cooled to 0 degree Celsius, be quenched with saturated aqueous ammonium chloride (20 milliliters), the mixture be extracted with ethyl acetate (30 milliliters × 4).The organic phase of merging is washed with salt solution (20 milliliters), with anhydrous sodium sulfate drying, filters and is concentrated in vacuo, residue leads to Cross preparative and prepare chromatogram purification (GX-D；Boston Symmetrix C18 ODS-R 150*30mm*5um； Acetonitrile 24%-54%；Water (0.225%fomic acid)；25mL/min), 2- (3,4- difluorobenzenes are obtained Base) -6- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole -2- bases) methyl) -7,8- dihydros -1,6- naphthyridines - 5 (6H) -one compounds 38 (8.00 milligrams, 18.12 micromoles, 21.65% yield).1H NMR (400MHz, METHANOL-d4)： δ 8.35 (d, J=8.3Hz, 1H), 8.13-8.02 (m, 1H), 7.91 (d, J=8.3Hz, 2H), 7.84 (s, 1H), 7.46-7.35 (m, 1H), 4.68-4.47 (m, 1H), 4.34-4.16 (m, 2H), 3.96-3.78 (m, 2H), 3.31-3.14 (m, 2H), 3.08- 2.96 (m, 1H), 1.76 (s, 3H) .LCMS (ESI) m/z：442(M+1).
Embodiment 39
(S) -2- ((2- (4- fluorophenyls) -6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-yl) methyl) -2- methyl - 6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
The bromo- 4- oxo-piperidines -1- benzyl chloroformates of 3-
To the ethyl acetate (10.00 of 4- oxo-piperidine -1- benzyl chloroformates (2.00 grams, 8.57 mMs, 1.00 equivalents) Milliliter) copper bromide (3.83 grams, 17.14 mMs, 2.00 equivalents) that adds under nitrogen protection in solution.By mixture 80 Degree Celsius stirring 1 hour.Mixture is filtered, and is concentrated under reduced pressure, the bromo- 4- oxo-piperidines -1- benzyl chloroformates (2.40 of 3- are obtained Gram, crude product), it is directly used in next step.
Step 2：
2- (4- fluorophenyls) -6,7- dihydro -4H- thiazoles simultaneously [5,4-c] pyridine -5- benzyl chloroformates
The bromo- 4- oxo-piperidines -1- benzyl chloroformates of 3- (2.40 grams, 7.69 mMs, 1.00 equivalents) and 4- fluorine is thio Benzamide (1.19 grams, 7.69 mMs, 1.00 equivalents), which is dissolved in, to be heated to 80 degrees Celsius in isopropanol (20.00 milliliters) and stirs Mix 2 hours.It is concentrated under reduced pressure, residue is passed through into Silica gel chromatography (pillar height degree：300 millimeters, 50 millimeters of diameter, 100-200 Mesh silica gel, petrol ether/ethyl acetate=30/1,5/1) obtain 2- (4- fluorophenyls) -6,7- dihydro -4H- thiazoles simultaneously [5,4-c] pyrrole Pyridine -5- benzyl chloroformates (1.20 grams, 3.26 mMs, 42.36% yield), are white solid.1H NMR (400MHz, CDCl3)：δ 8.12-7.73 (m, 2H), 7.49-7.31 (m, 5H), 7.19-7.06 (m, 2H), 5.22 (s, 2H), 4.78 (br.s., 2H), 3.89 (br.s., 2H), 2.98 (br.s., 2H)
Step 3：
2- (4- fluorophenyls) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine
By 2- (4- fluorophenyls) -6,7- dihydro -4H- thiazoles simultaneously [5,4-c] pyridine -5- benzyl chloroformate (1.20 grams, 3.26 MM, 1.00 equivalents) be dissolved in AcOH (5.00 milliliters) solution, at 20 degrees celsius add HBr acetum (48%, 5mL) solution, and stir 1 hour.Mixture is filtered, filter cake washed with ethyl acetate, be dried in vacuo, obtain 2- (4- fluorine Phenyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine (800.00 milligrams, 2.54 mMs, 77.85% yield), are yellow Solid, is directly used in next step.
Step 4：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -6,7- dihydro -4H- thiazoles simultaneously [5,4- C] pyridine -5- bases] -2- methyl -propyl- 2- alcohol
By the chloro- 1- of 2- [[(2S) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (150.00 milligrams, 689.31 micromoles, 1.10 equivalents) and 2- (4- fluorophenyls) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine (197.52 millis Gram, 626.64 micromoles, 1.00 equivalents) be dissolved in ethanol (5.00 milliliters) solution, then add DIPEA (202.47 milligrams, 1.57 mMs, 2.50 equivalents).Mixed solution is stirred at 80 degrees celsius 5 hours, cool down and be concentrated under reduced pressure, by residue It is diluted with water, and (30 milliliters × 3) is extracted with ethyl acetate.The organic phase of merging is washed with saturated aqueous common salt (30 milliliters), Anhydrous sodium sulfate drying is used again, and filtering and vacuum concentration obtain (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorine Phenyl) -6,7- dihydro -4H- thiazoles simultaneously [5,4-c] pyridine -5- bases] -2- methyl -propyl- 2- alcohol (250.00 milligrams, crude product), will It is directly used in next step.
Step 5
(S) -2- ((2- (4- fluorophenyls) -6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-yl) methyl) -2- methyl - 6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -6,7- dihydro -4H- thiazoles simultaneously [5, 4-c] pyridine -5- bases] -2- methyl -propyl- 2- alcohol (150.00 milligrams, 331.93 micromoles, 1.00 equivalents) be dissolved in DMF (3.00 milli Rise) in, NaH (26.55 milligrams, 663.86 micromoles, 2.00 equivalents) and stirring 30 are added in 0 degree Celsius under the protection of nitrogen Minute.Mixture is poured into ice-water (w/w=1/1) (20 milliliters) and stirred 10 minutes.Aqueous phase is extracted with ethyl acetate (20 milliliters × 3).The organic phase of merging is washed with saturated brine (20 milliliters), with anhydrous sodium sulfate drying, filters and vacuum is dense Contracting.Residue prepares chromatographic separation and purification (GX-A by preparative；Phenomenex Gemini C18 250*50 10u； 0.225%FA-ACN；Begin from 25to 55；Flow Rate (25ml/min)) obtain (S) -2- ((2- (4- fluorobenzene Base) -6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-yl) methyl) -2- methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1- B] oxazoline compound 39 (20.00 milligrams, 47.18 micromoles, 14.21% yield, 98% purity).1H NMR (400MHz, CDCl3)：δ 7.99-7.79 (m, 1H), 7.55 (s, 1H), 7.12 (t, J=8.7Hz, 2H), 4.42 (d, J=9.7Hz, 1H), 4.08-3.84 (m, 3H), 3.24-3.10 (m, 2H), 3.09-2.95 (m, 1H), 2.94-2.69 (m, 3H), 1.67 (s, 3H)； LCMS(ESI)m/z：416(M+1).
Embodiment 40
(2S) -2- [[2- (3,4- difluorophenyl) -6,7- dihydro -4H- thiazoles simultaneously [5,4-c] pyridine -5- bases] methyl] -2- Methyl -6- nitro -3H- imidazos [2,1-B] oxazole
Synthetic method such as embodiment 39.
(2S) -2- [[2- (3,4- difluorophenyl) -6,7- dihydro -4H- thiazoles simultaneously [5,4-c] pyridine -5- bases] methyl] -2- Methyl -6- nitro -3H- imidazos [2,1-B] oxazoline compound 40 (30.00 milligrams, 92.29 micromoles, 43.37%).1H NMR (300MHz, CDCl3)：δ 7.78-7.71 (m, 1H), 7.65-7.56 (m, 2H), 7.26-7.20 (m, 1H), 4.41 (d, J= 9.8Hz, 1H), 4.06-3.85 (m, 3H), 3.23-2.95 (m, 3H), 2.93-2.68 (m, 3H), 1.67 (s, 3H)；LCMS (ESI)m/z：434(M+1).
Embodiment 41
(S) -2- (3,4- difluorophenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole -2- Base) methyl) -4,5-, 6,7- tetrahydrochysene oxazoles simultaneously [5,4-c] pyridine
Step 1：
1- benzyl -3,6- dihydro -2H- pyridines
By 1- benzyls -1,2, it is molten that 3,6- tetrahydropyridines (53.00 grams, 211.89 mMs, 1.00 equivalents) are dissolved in methanol In liquid (500.00 milliliters), sodium borohydride (12.02 grams, 317.83 mMs, 1.50 equivalents) is added.Mixture is taken the photograph 25 Stirred 12 hours under family name's degree, be concentrated under reduced pressure, by residue diluted with water (250 milliliters), and be extracted with ethyl acetate (500 milliliters ×2).The organic layer of merging is concentrated under reduced pressure, 1- benzyl -3,6- dihydro -2H- pyridines (30.00 grams, crude product) are obtained, directly used In next step.
Step 2：
4- benzyls -7- oxa- -4- azabicyclos (4.1.0) heptane
It is under 25 degrees Celsius that 1- benzyl -3,6- dihydro -2H- pyridines (10.00 grams, 57.72 mMs, 1.00 equivalents) is molten In the mixed solution of Xie Shui (190.00 milliliters) and trifluoroacetic acid (24.02 grams, 210.68 mMs, 3.65 equivalents) and at this At a temperature of stir 1 hour, then will heat up to 35 degrees Celsius and add bromo-succinimide (20.55 grams, 115.44 mmoles You, 2.00 equivalents) stir 5 hours, 25 degrees Celsius are cooled to, NaOH (2.31 grams, 57.72 millis are added into mixed solution Mole, 1.00 equivalents) and acetonitrile (50.00 milliliters), stirring is concentrated under reduced pressure after 12 hours, to remove solvent.By residue second Acetoacetic ester extracts (500 milliliters × 2).The organic layer of merging is concentrated under reduced pressure, residue passes through Silica gel chromatography (titanium dioxide Silicon, petrol ether/ethyl acetate=10/1,3: 1) obtain 4- benzyls -7- oxa- -4- azabicyclos [4.1.0] heptane (5.00 grams, 26.42 mMs, 45.77% yield), it is yellow solid.
Step 3：
4- azido -1- Bezyl-piperidin -3- alcohol
By 4- benzyls -7- oxa- -4- azabicyclos (4.1.0) heptane (5.00 grams, 26.42 mMs, 1.00 equivalents) and Lithium perchlorate (2.81 grams, 26.42 mMs, 1.00 equivalents) is dissolved in acetonitrile (30.00 milliliters), is added under the protection of nitrogen Enter Sodium azide (2.23 grams, 34.35 mMs, 1.30 equivalents), be warming up to 80 degrees Celsius of 16 hours of stirring.Mixture is poured into In sodium bicarbonate aqueous solution (50 milliliters) and stir 10 minutes.Aqueous phase is extracted with ethyl acetate (50 milliliters × 3).By having for merging Machine is mutually washed with saturated aqueous common salt (50mL), anhydrous sodium sulfate drying, filtering and vacuum concentration obtain 4- azido -1- benzyls - Piperidin-3-ol (5.50 grams, crude product), is directly used in next step.
Step 4：
4- amino -1- benzyl piepridine -3- alcohol
4- azido -1- Bezyl-piperidin -3- alcohol (5.50 grams, 23.68 mMs, 1.00 equivalents) is dissolved in tetrahydrofuran In the mixed solution of (50.00 milliliters) and water (2.00 milliliters), be added portionwise under 15 degrees Celsius triphenyl phosphorus (12.42 grams, 47.36 mMs, 2.00 equivalents) and stir 16 hours, then it is concentrated in vacuo.Residue is purified into (post by silica gel partition method Highly：300 millimeters, diameter：50 millimeters, 100-200 mesh silica gel, the purification of methylene chloride/methanol=50/1) obtains 4- amino -1- Bezyl-piperidin -3- alcohol (3.40 grams, 16.48 mMs, 69.60% yield), is yellow solid.
Step 5：
N- (1- benzyl -3- hydroxy-4-piperidinyls base) -3,4- difluoro-benzam ides
By 4- amino -1- benzyl piepridine -3- alcohol (2.00 grams, 9.70 mMs, 1.00 equivalents) and 3,4- difluoro-benzoic acid (1.53 grams, 9.70 mMs, 1.00 equivalents) are dissolved in dichloromethane (30.00 milliliters) solution, then under 15 degrees Celsius Add EDCI (3.72 grams, 19.40 mMs, 2.00 equivalents), HOBT (2.62 grams, 19.40 mMs, 2.00 equivalents), three second Amine (3.93 grams, 38.80 mMs, 4.00 equivalents) is simultaneously stirred 12 hours.Then with (20 milliliters) dilutions of water, aqueous phase acetic acid Ethyl ester extracts (40 milliliters × 3).The organic phase of merging is washed, anhydrous sodium sulfate drying with salt solution (20 milliliters), filtered and true Sky concentration.By residue by TLC separation purify (petrol ether/ethyl acetate=10/1,1/3) obtain N- (1- benzyls- 3- hydroxy-4-piperidinyls base) -3,4- difluoro-benzam ides (1.70 grams, 4.91 mMs, 50.62% yield) are white solid 。1H NMR (400MHz, CDCl3)：δ 7.71-7.64 (m, 1H), 7.58-7.47 (m, 1H), 7.38-7.30 (m, 4H), 7.27- 7.21 (m, 1H), 6.11 (d, J=6.1Hz, 1H), 3.92-3.82 (m, 1H), 3.66 (dt, J=4.3,9.3Hz, 1H), 3.59 (s, 2H), 3.13 (dd, J=3.2,11.2Hz, 1H), 2.87 (d, J=11.8Hz, 1H), 2.21-2.13 (m, 1H), 2.11- 2.03 (m, 2H), 1.66 (dq, J=4.3,11.8Hz, 1H) .LCMS (ESI) m/z：347(M+1).
Step 6：
3,4- bis- fluoro- N- (3- hydroxy-4-piperidinyls base) benzamides
By N- (1- benzyl -3- hydroxy-4-piperidinyls base) -3,4- difluoro-benzam ides (1.70 grams, 4.91 mMs, 1.00 Equivalent) it is dissolved in methanol (50.00 milliliters), Pd (OH) is added under the protection of nitrogen2/ C (10%, 0.05 gram).Then hydrogen is used Gas is replaced three times, by mixture in H2(50PSI), is stirred 12 hours under 50 degrees Celsius.Reactant mixture is filtered and by filtrate Concentration, obtains the fluoro- N- of 3,4- bis- (3- hydroxy-4-piperidinyls base) benzamide (1.20 grams, crude product), it is without further purification For next step.LCMS(ESI)m/z：257(M+1).
Step 7：
4- [(3,4- difluoro benzoyl) amino] -3- hydroxy-piperdine -1- benzyl chloroformates
By benzyl chloroformate (878.75 milligrams, 5.15 mMs, 1.10 equivalents), 3,4- bis- fluoro- N- (3- hydroxyl -4- piperazines Piperidinyl) benzamide (1.20 grams, 4.68 mMs, 1.00 equivalents) is dissolved in dichloromethane (30.00 milliliters), then it is Celsius 15 Degree is lower to add triethylamine (1.42 grams, 14.04 mMs, 3.00 equivalents), and stirs 10 hours.Water (20 milliliters) is added to In mixture, aqueous phase is extracted with ethyl acetate (40 milliliters × 3).The organic phase of merging is washed with salt solution (30 milliliters), with nothing Aqueous sodium persulfate is dried, and is filtered and is concentrated in vacuo.Residue is isolated and purified by silica gel chromatography (petrol ether/ethyl acetate= 10/1,1/1) 4- [(3,4- difluoro benzoyl) amino] -3- hydroxy-piperdine -1- benzyl chloroformate (1.25 grams, 3.20 are obtained MM, 68.42% yield), it is white solid.LCMS(ESI)m/z：391(M+1).
Step 8：
4- [(3,4- difluoro benzoyl) amino] -3- oxo piperidine -1- benzyl chloroformates
By 4- [(3,4- difluoro benzoyl) amino] -3- hydroxy-piperdine -1- benzyl chloroformate (920.00 milligrams, 2.36 MM, 1.00 equivalents) it is dissolved in dichloromethane (30.00 milliliters) solution, then add DMP (3.00 grams, 7.08 at 15 degrees Celsius MM, 3.00 equivalents) and stir 3 hours.Then, residue is poured into the aqueous solution.Sodium hydrate aqueous solution (0.5N, 40 Milliliter), aqueous phase is extracted (60 milliliters × 3) with dichloromethane.The organic phase of merging is washed, anhydrous slufuric acid with salt solution (30 milliliters) Sodium is dried, and is filtered and is concentrated in vacuo.By residue by Silica gel chromatography (petrol ether/ethyl acetate=10/1,1/3) with 4- [(3,4- difluoro benzoyl) amino] -3- oxo piperidine -1- benzyl chloroformates (1.00 grams, crude product) are obtained, are yellow oil Shape thing.
Step 9：
2- (3,4- difluorophenyl) -6,7- dihydro -4H- oxazoles simultaneously [5,4-c] pyridine -5- benzyl chloroformates
In 15 degrees Celsius of dioxies to POCl3 (2.55 grams, 16.63 mMs, 5.38 equivalents) under the protection of nitrogen 4- [(3,4- difluoro benzoyl) amino] -3- hydroxy-piperdine -1- benzyl chloroformates are added in six rings (20.00 milliliters) solution (1.20 grams, 3.09 mMs, 1.00 equivalents).Then heat to 110 degrees Celsius and stir 3 hours.Then residue is fallen Enter in water (50 milliliters), and stir 5 minutes.Aqueous phase is extracted with ethyl acetate (60 milliliters × 3), the organic phase salt solution of merging (30 milliliters × 2) wash, with anhydrous sodium sulfate drying, after filtering and vacuum concentration, residue passes through Silica gel chromatography (two Silica, petrol ether/ethyl acetate=1/0,10/1) obtain 2- (3,4- difluorophenyl) -6,7- dihydro -4H- oxazoles simultaneously [5,4- C] pyridine -5- benzyl chloroformates (800.00 milligrams, 2.16 mMs, 69.90% yield) are yellow oil.1H NMR (400MHz, CDCl3)：δ 7.89-7.69 (m, 2H), 7.42-7.39 (m, 4H), 7.39-7.34 (m, 1H), 7.28-7.22 (m, 1H), 5.21 (s, 2H), 4.68 (br.s., 2H), 3.86 (br.s., 2H), 2.87-2.67 (m, 2H) .LCMS (ESI) m/z：371 (M+1).
Step 10：
The tetrahydrochysene oxazoles of 2- (3,4- difluorophenyl) -4,5,6,7- simultaneously [5,4-c] pyridine
By 2- (3,4- difluorophenyl) -6,7- dihydro -4H- oxazoles simultaneously [5,4-c] pyridine -5- benzyl chloroformates (800.00 Milligram, 2.16 mMs, 1.00 equivalents) it is dissolved in hydrobromic acid acetum (20 milliliters), and stirring 3 is small under 15 degrees Celsius When.Mixture is filtered, and filter cake is concentrated in a vacuum, the tetrahydrochysene oxazoles of 2- (3,4- difluorophenyl) -4,5,6,7- are obtained simultaneously [5,4-c] pyridine (450.00 milligrams, 1.42 mMs, 65.69% yield, hydrobromate), is yellow solid.LCMS(ESI) m/z：237(M+1).
Step 11：
[2- (3,4- difluorophenyl) -6,7- dihydro -4H- oxazoles are simultaneously by (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [5,4-C] pyridine -5- bases] -2- methyl -propyl- 2- alcohol
By the tetrahydrochysene oxazoles of 2- (3,4- difluorophenyl) -4,5,6,7- simultaneously [5,4-c] pyridine (200.00 milligrams, 630.66 is micro- Mole, 1.00 equivalents, hydrobromate) and the chloro- 1- of 2- (((2S) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (137.24 milligrams, 630.66 micromoles, 1.00 equivalents) are dissolved in the tert-butyl alcohol (15.00 milliliters) solution, add DIPEA (244.52 milligrams, 1.89 mMs, 3.00 equivalents).The mixture is stirred 12 hours at 80 degrees Celsius.Cooling, at 45 degrees Celsius Lower concentration, and residue with Silica gel chromatography (petrol ether/ethyl acetate=10/1,3/1) obtained into (2S) -1- (2- is chloro- 4- nitroimidazole -1- bases) -3- [2- (3,4- difluorophenyl) -6,7- dihydro -4H- oxazoles simultaneously [5,4-c] pyridine -5- bases] -2- first Base -propyl- 2- alcohol (166.00 milligrams, 365.78 micromoles, 58.00% yield), is yellow oil.LCMS(ESI)m/z：454 (M+1).
Step 12：
(S) -2- (3,4- difluorophenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole -2- Base) methyl) -4,5-, 6,7- tetrahydrochysene oxazoles simultaneously [5,4-c] pyridine
By (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (3,4- difluorophenyl) -6,7- dihydro -4H- oxazoles And [5,4-c] pyridine -5- bases] -2- methyl -propyl- 2- alcohol (166.00 milligrams, 365.78 micromoles, 1.00 equivalents) is dissolved in DMF In (3.00 milliliters) solution, under nitrogen protection, NaH (29.26 milligrams, 731.56 micromoles, 2.00 are added under -45 degrees Celsius Equivalent).Mixture is stirred 2 hours under -45-15 degrees Celsius.Then mixture is quenched with saturated ammonium chloride (20 milliliters). Aqueous phase is extracted with ethyl acetate (50 milliliters × 2).The organic phase of merging is washed with salt solution (20 milliliters × 2), anhydrous slufuric acid is used Sodium is dried, filtering and vacuum concentration.Then residue is prepared into chromatographic separation and purification (GX-D by preparative；Boston Green ODS 150*30 5u；Acetonitrile 42%-72%；Water (0.225%fomic acid)；25mL/min) Obtain (S) -2- (3,4- difluorophenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1-B] oxazole -2- bases) first Base) -4,5-, 6,7- tetrahydrochysene oxazoles simultaneously [5,4-c] pyridine compounds 41 (49.40 milligrams, 115.64 micromoles, 31.61% production Rate, 97.7% purity).1H NMR (400MHz, CDCl3)：δ 7.85-7.78 (m, 1H), 7.74 (dd, J=3.1,7.7Hz, 1H), 7.55 (s, 1H), 7.27-7.20 (m, 1H), 4.40 (d, J=9.7Hz, 1H), 3.97 (d, J=9.7Hz, 1H), 3.87 (s, 2H), 3.17-3.07 (m, 2H), 3.02-2.94 (m, 1H), 2.80 (d, J=14.9Hz, 1H), 2.65 (d, J=1.9Hz, 2H), 1.67 (s, 3H) .LCMS (ESI) m/z：418(M+1).
Embodiment 42
(S) -2- ((2- (4- fluorophenyls) -5,6- glyoxalidine simultaneously [1,2- α] pyrazine -7 (8H)-yl) methyl) -2- methyl - 6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
The bromo- 1- of 2- (4- fluorophenyls) ethyl ketone
1- (4- fluorophenyls) ethyl ketone (9.00 grams, 65.15 mMs, 1.00 equivalents) is dissolved in acetic acid (100.00 milliliters) In, 15 degrees Celsius addition bromines (10.41 grams, 65.15 mMs, 1.00 equivalents) and stir 20 minutes, then by gained Mixture is stirred 12 hours at 50 degrees Celsius, is concentrated under reduced pressure, and is adjusted with sodium carbonate liquor by pH to 9.Mixture acetic acid second Ester extracts (200 milliliters × 2).The organic layer of merging is concentrated under reduced pressure, residue is obtained and passes through Silica gel chromatography (pillar height Degree：250 millimeters, diameter：100 millimeters, 100-200 mesh silica gel, petrol ether/ethyl acetate=1/0) obtain 2- bromo- 1- (4- fluorobenzene Base) ethyl ketone (6.30 grams, 29.03 mMs, 44.56% yield) is white solid.LCMS(ESI)m/z：218.8(M+1).
Step 2：
3- chloropyrazine -2- amine
By 2,3- dichloropyrazines (5.00 grams, 33.56 mMs, 1.00 equivalents) and ammoniacal liquor (68.27 grams, 1.95 moles, 58.04 equivalents) mixing, stirred 12 hours under 85 degrees Celsius, be concentrated under reduced pressure, residue is passed through into Silica gel chromatography (post Highly：250 millimeters, diameter：100 millimeters, 100-200 mesh silica gel, petrol ether/ethyl acetate=50/1,20/1) obtain 3- chlorine pyrroles Piperazine -2- amine (700.00 milligrams, 5.40 mMs, 16.09% yield), is white solid.
Step 3：
The chloro- 2- of 8- (4- fluorophenyls) imidazo [1,2-a] pyrazine
Under 15 degrees Celsius, by the bromo- 1- of 2- (4- fluorophenyls) ethyl ketone (3.02 grams, 13.90 mMs, 1.20 equivalents) and 3- Chloropyrazine -2- amine (1.50 grams, 11.58 mMs, 1.00 equivalents) is dissolved in glycol dimethyl ether (20.00 milliliters), then Heat the mixture to 35 degrees Celsius and stir 12 hours.Mixture is concentrated, with Silica gel chromatography (pillar height degree：250 millis Rice, diameter：100 millimeters, 100-200 mesh silica gel, petrol ether/ethyl acetate=20/1,5/1), obtain 8- chloro- 2- (4- fluorobenzene Base) imidazo [1,2-a] pyrazine (900.00 milligrams, 3.63 mMs, 31.38% yield) is white solid.LCMS(ESI) m/z：247.9(M+1).
Step 4：
2- (4- fluorophenyls) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine hydrochloride
By the chloro- 2- of 8- (4- fluorophenyls) imidazo [1,2-a] pyrazine (900.00 milligrams, 3.63 mMs, 1.00 equivalents) It is dissolved in methanol (20.00 milliliters) solution, nitrogen protection is lower to add Pd/C.Then by mixed solution in 50 degrees Celsius, H2 Stirred 12 hours under conditions of (50psi).Reactant mixture is concentrated under reduced pressure, 2- (4- fluorophenyls) -5,6,7,8- tetrahydrochysenes is obtained Imidazo [1,2-a] pyrazine hydrochloride (850.00 milligrams, 2.93 mMs, 80.70% yield), is directly used in next step.
Step 5：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -6,8- dihydro -5H- imidazos [1,2- A] pyrazine -7- bases] -2- methyl -propyl- 2- alcohol
By 2- (4- fluorophenyls) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine hydrochloride (400.00 milligrams, 1.58 milli Mole, 1.00 equivalents) be dissolved in the tert-butyl alcohol (10.00 milliliters) solution, add DIPEA (509.42 milligrams, 3.94 mMs, 2.50 equivalents) and the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (514.65 milligrams, 2.36 MM, 1.50 equivalents).Mixture is warming up to 100 degrees Celsius and stirred 12 hours.The reaction solution pours into water (20 milliliters) In, then it is extracted with ethyl acetate (50 milliliters × 2).The organic layer of merging is concentrated to dryness.Residue is passed through into silica gel chromatograph Method purifies (pillar height degree：250 millimeters, diameter：100 millimeters, 100-200 mesh silica gel, petrol ether/ethyl acetate=5/1,1/3) To (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -6,8- dihydro -5H- imidazos [1,2-] pyrazine - 7- yls] -2- methyl -propyl- 2- alcohol (200 milligrams, 459.93 micromoles, 29.17% yield) is white solid.LCMS(ESI)m/ z：435.0(M+1)
Step 6：
(S) -2- ((2- (4- fluorophenyls) -5,6- glyoxalidine simultaneously [1,2- α] pyrazine -7 (8H)-yl) methyl) -2- methyl - 6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -6,8- dihydro -5H- imidazos [1, 2-] pyrazine -7- bases] -2- methyl -propyl- 2- alcohol (200.00 milligrams, 459.93 micromoles, 1.00 equivalents) be dissolved in DMF (3.00 milli Rise) in solution, NaH (11.04 milligrams, 459.93 micromoles, 1.00 equivalents) is added under -25 degrees Celsius and is stirred 1 hour.Will Mixture is poured under 0 degree Celsius in water (15 milliliters), is then extracted with ethyl acetate (30 milliliters × 2).By having for merging Machine layer is concentrated to dryness.Residue prepares chromatographic separation and purification (GX-B, Phenomenex Synergi C18 by preparative 150*30mm*4um, acetonitrile 20%-50%；0.1%TFA-ACN；25mL/min) obtain (S) -2- ((2- (4- fluorine Phenyl) -5,6- glyoxalidine simultaneously [1,2- α] pyrazine -7 (8H)-yl) methyl) -2- methyl -6- nitros 2,3- glyoxalidine simultaneously [2, 1-B] oxazoline compound 42 (70.60 milligrams, 176.28 micromoles, 38.33% yield, 99.476% purity).1H NMR (400MHz, METHANOL-d4)：δ 7.86 (s, 1H), 7.78 (s, 1H), 7.71 (dd, J=5.0,8.7Hz, 2H), 7.29 (t, J =8.7Hz, 2H), 4.47-4.38 (m, 1H), 4.31-4.05 (m, 5H), 3.30-3.09 (m, 3H), 1.70 (s, 3H) .LCMS (ESI)m/z：399.0(M+1).
Embodiment 43
(S) -2- ((2- (3,4- difluorophenyl) -5,6- glyoxalidine simultaneously [1,2- α] pyrazine -7 (8H)-yl) methyl) -2- Methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazole
Synthetic method such as embodiment 42.
(S) -2- ((2- (3,4- difluorophenyl) -5,6- glyoxalidine simultaneously [1,2- α] pyrazine -7 (8H)-yl) methyl) -2- Methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 43 (82.00 milligrams, 192.51 micromoles, 21.79% production Rate, 97.753% purity), it is yellow solid.1H NMR (400MHz, METHANOL-d4)：δ 7.85 (d, J=11.9Hz, 2H), 7.69-7.62 (m, 1H), 7.54-7.40 (m, 2H), 4.42 (d, J=10.7Hz, 1H), 4.31-4.06 (m, 5H), 3.30- 3.09 (m, 3H), 1.70 (s, 3H) .LCMS (ESI) m/z：417.0(M+1).
Embodiment 44
(S) -2- methyl -6- nitros -2- ((2- phenyl -7,8- dihydro pyrido [4,3-d] pyrimidine -6 (5H)-yl) first Base) -2,3- glyoxalidine simultaneously [2,1-B] oxazole
Step 1：
The tert-butyl group (3E) -3- (methylamino methylene) -4- oxo-piperidine -1- carboxylic acid tert-butyl esters
4- oxo-piperidine -1- t-butyl formates (5.00 grams, 25.09 mMs, 1.00 equivalents) are dissolved in dioxane In (30.00 milliliters), then adding 1,1- dimethoxys-N, N- dimethyl methylamine, (11.96 grams, 100.36 mMs, 4.00 work as Amount).Mixture is stirred 16 hours at 120 degrees Celsius, cooling, and be concentrated under reduced pressure at 50 degrees Celsius.By residue diluted with water (50 milliliters), and stir 20 minutes.Aqueous phase is extracted with ethyl acetate (50 milliliters × 3).By the organic phase saturated brine of merging (50 milliliters × 2) wash, with anhydrous sodium sulfate drying, filtering and vacuum concentration.Residue is isolated and purified by silica gel chromatograph (ethyl acetate/methanol=20/1) obtains the tertiary fourth of the tert-butyl group (3E) -3- (methylamino methylene) -4- oxo-piperidine -1- carboxylic acids Ester (3.00 grams, 11.80 mMs, 47.02% yield), is yellow oil.1H NMR (400MHz, CDCl3)：δ 7.51 (s, 1H), (s, the 9H) of 4.57 (s, 2H), 3.62 (t, J=4.0Hz, 1H), 3.13 (s, 7H), 2.46 (t, J=4.0Hz, 1H), 1.49
Step 2：
2- phenyl -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine -6- t-butyl formates
By the tert-butyl group (3E) -3- (methylamino methylene) -4- oxo-piperidine -1- carboxylic acid tert-butyl ester (3.00 grams, 11.80 MM, 1.00 equivalents) and benzamidine (1.85 grams, 11.80 mMs, 1.00 equivalents) be dissolved in ethanol (30.00 milliliters), then add Enter triethylamine (3.58 grams, 35.40 mMs, 3.00 equivalents).Mixture is stirred at 80 degrees celsius 2 hours, cooled down, decompression Concentration.By residue diluted with water (30 milliliters) and stir 20 minutes.Aqueous phase is extracted with ethyl acetate (30 milliliters × 3).It will close And organic phase washed with saturated brine (30 milliliters × 2), with anhydrous sodium sulfate drying, filter and be concentrated in vacuo, by residue (petrol ether/ethyl acetate=3/1) is isolated and purified by silica gel chromatograph and obtains 2- phenyl -7,8- dihydro -5H- pyridos [4,3- D] pyrimidine -6- t-butyl formates (2.10 grams, 6.74 mMs, 57.15% yield) are yellow solid.1H NMR (400MHz, CDCl3)：δ 8.54 (s, 1H), 8.46-8.36 (m, 2H), 7.54-7.44 (m, 3H), 4.64 (s, 2H), 3.80 (t, J= 4.0Hz, 2H), 3.03 (t, J=4.0Hz, 2H), 1.53 (s, 9H) .LCMS (ESI) m/z：312(M+1).
Step 3：
2- phenyl -5,6,7,8- tetrahydropyridines simultaneously [4,3-d] pyrimidine
By 2- phenyl -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine -6- t-butyl formates (500.00 milligrams, 1.61 millis Mole, 1.00 equivalents) it is dissolved in dichloromethane (1.00 milliliters), addition trifluoroacetic acid (183.09 milligrams, 1.61 mMs, 1.00 equivalents).Mixture is stirred 2 hours under 28 degrees Celsius, is concentrated under reduced pressure at 50 c, obtains 2- phenyl -5,6, The trifluoroacetate (800.00 milligrams, crude product) of 7,8- tetrahydropyridines simultaneously [4,3-d] pyrimidine, is yellow oil.The product is not It is used for next step through being further purified.
Step 4：
(S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- methyl -3- (2- phenyl -7,8- dihydropyridines [4,3-d] Pyrimidine -6- (5H)-yl) propan-2-ol
By 2- phenyl -5,6,7,8- tetrahydropyridines simultaneously [4,3-d] pyrimidine (340.00 milligrams, 1.61 mMs, 1.00 work as Amount) and the chloro- 1- of (R) -2- ((2- methyl oxirane -2- bases) methyl) -4- nitro -1H- imidazoles (420.42 milligrams, 1.93 millis Mole, 1.20 equivalents) be dissolved in ethanol (10.00 milliliters), then add DIPEA (623.99 milligrams, 4.83 mMs, 3.00 equivalents).Mixture is stirred 12 hours at 80 degrees Celsius, cooling is concentrated under reduced pressure, at 50 degrees Celsius.Residue is passed through Silica gel chromatograph isolates and purifies (petrol ether/ethyl acetate=2/1), obtain (S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) - 2- methyl -3- (2- phenyl -7,8- dihydropyridine [4,3-d] pyrimidine -6- (5H)-yl) propan-2-ol (650.00 milligrams, 1.52 millis Mole, 94.14% yield), it is yellow oil.1H NMR (400MHz, CDCl3) 8.46 (s, 1H), 8.43-8.36 (m, 2H), 8.06 (s, 1H), 7.52-7.45 (m, 3H), 4.10-4.06 (m, 2H), 3.96-3.78 (m, 2H), 3.19-2.99 (m, 4H), 2.77-2.56 (m, 2H), 1.22 (s, 3H) .LCMS (ESI) m/z：429/431(M+1).
Step 5：
(S) -2- methyl -6- nitros -2- ((2- phenyl -7,8- dihydro pyrido [4,3-d] pyrimidine -6 (5H)-yl) first Base) -2,3- glyoxalidine simultaneously [2,1-B] oxazole
By (S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of the 2-) -2- methyl -3- (dihydropyridines of 2- phenyl -78 [4,3-d] Pyrimidine -6 (5H)-yl) propan-2-ol (350.00 milligrams, 816.10 micromoles, 1.00 equivalents) is dissolved in DMF (5.00 milliliters), NaH (39.17 milligrams, 979.32 micromoles, 1.20 equivalents) is added in 0 degree Celsius and stir 30 minutes under nitrogen protection.Reaction Mixture is quenched with saturated ammonium chloride (20 milliliters), then with (10 milliliters) dilutions of water, and extracted with dichloromethane (10 milliliters × 3).The organic layer of merging is washed with saturated brine (10 milliliters × 2), it is dried over sodium sulfate, filter and be concentrated under reduced pressure, residue Chromatographic separation and purification (GX-E is prepared by preparative；Diamonsil 150*25mm*5um；Acetonitrile 20%- 50%；Water (0.225%fomic acid)；25mL/min) obtain (S) -2- methyl -6- nitros -2- ((2- phenyl -7,8- Dihydro pyrido [4,3-d] pyrimidine -6 (5H)-yl) methyl) -2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 44 (23.10 Milligram, 58.87 micromoles, 7.21% yield).1H NMR (400MHz, CDCl3)：δ 8.45 (s, 1H), 8.43-8.36 (m, 2H), 7.53 (s, 1H), 7.51-7.46 (m, 3H), 4.43-3.95 (m, 2H), 3.93-3.82 (m, 2H), 3.25-3.17 (m, 1H), (s, the 3H) .LCMS of 3.12 (d, J=16.0Hz, 1H), 3.05-2.89 (m, 3H), 2.83 (d, J=12.0Hz, 1H), 1.70 (ESI)m/z：393(M+1).
Embodiment 45
(S) -2- ((2- (4- fluorophenyls) -7,8- dihydro pyridos [4,3-d] pyrimidine -6 (5H)-yl) methyl) -2- methyl - 6- nitros -2-, 3- glyoxalidine simultaneously [2,1-B] oxazole
Synthetic method such as embodiment 44.
(S) -2- ((2- (4- fluorophenyls) -7,8- dihydro pyridos [4,3-d] pyrimidine -6 (5H)-yl) methyl) -2- methyl - 6- nitros -2-, 3- glyoxalidine simultaneously [2,1-B] oxazoline compound 45 (100.00 milligrams, 243.66 micromoles, 27.22% production Rate).1H NMR (400MHz, CDCl3)：δ 8.44-8.37 (m, 3H), 7.53 (s, 1H), 7.19-7.12 (m, 2H), 4.42-3.96 (m, 2H), 3.89-3.85 (m, 2H), 3.24-3.16 (m, 1H), 3.12 (d, J=16.0Hz, 1H), 3.03-2.87 (m, 3H), 2.83 (d, J=16.0Hz, 1H), 1.70 (s, 3H) .LCMS (ESI) m/z：411(M+1).
Embodiment 46
(S) -2- ((2- (3,4- difluorophenyl) -7,8- dihydro pyridos [4,3-d] pyrimidine -6 (5H)-yl) methyl) -2- Methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazole
Synthetic method such as embodiment 44.
(S) -2- ((2- (3,4- difluorophenyl) -7,8- dihydro pyridos [4,3-d] pyrimidine -6 (5H)-yl) methyl) -2- Methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 46 (20.80 milligrams, 47.05 micromoles, 7.06% production Rate, 96.9% purity).1H NMR (400MHz, CDCl3) 8.42 (s, 1H), 8.31-8.16 (m, 2H), 7.53 (s, 1H), 7.27- 7.21 (m, 1H), 4.39 (d, J=12.0Hz, 1H), 3.99 (d, J=12.0Hz, 1H), 3.93-3.82 (m, 2H), 3.26- 3.16 (m, 1H), 3.12 (d, J=16.0Hz, 1H), 3.04-2.88 (m, 3H), 2.83 (d, J=16.0Hz, 1H), 1.70 (s, 3H).LCMS(ESI)m/z：429(M+1).
Embodiment 47
(S) ((2- (4- (trifluoromethoxy) phenyl) -7,8- dihydro pyridos [4,3-d] are phonetic by -2- methyl -6- nitros -2- Pyridine -6 (5H)-yl) methyl) -2,3- glyoxalidine simultaneously [2,1-B] oxazole
Synthetic method such as embodiment 44.
(S) ((2- (4- (trifluoromethoxy) phenyl) -7,8- dihydro pyridos [4,3-d] are phonetic by -2- methyl -6- nitros -2- Pyridine -6 (5H)-yl) methyl) -2,3- glyoxalidine simultaneously [2,1-B] oxazoline compound 47 (26.70 milligrams, 56.04 micromoles, 5.75% yield).1H NMR (400MHz, CDCl3)：δ 8.49-8.41 (m, 3H), 7.53 (s, 1H), 7.31 (d, J=8.0Hz, 2H), 4.43-3.95 (m, 2H), 3.94-3.82 (m, 2H), 3.25-3.16 (m, 1H), 3.12 (d, J=16.0Hz, 1H), 3.04-2.89 (m, 3H), 2.83 (d, J=16.0Hz, 1H), 1.70 (s, 3H) .LCMS (ESI) m/z：477(M+1).
Embodiment 48
(S) -2- ((2- (3,5- difluorophenyl) -7,8- dihydro pyridos [4,3-d] pyrimidine -6 (5H)-yl) methyl) -2- Methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 44.
(S) -2- ((2- (3,5- difluorophenyl) -7,8- dihydro pyridos [4,3-d] pyrimidine -6 (5H)-yl) methyl) -2- Methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1b] azole compounds 48 (25.20 milligrams, 57.67 micromoles, 15.77% yield, 98.030% purity).1H NMR (400MHz, CDCl3) δ 8.35 (s, 1H), 7.91-7.83 (m, 2H), 7.43 (s, 1H), 6.86- 6.78 (m, 1H), 4.29 (d, J=8.0Hz, 1H), 3.89 (d, J=8.0Hz, 1H), 3.85-3.74 (m, 2H), 3.14-3.07 (m, 1H), 3.03 (d, J=16.0Hz, 1H), 2.96-2.79 (m, 3H), 2.75 (d, J=16.0Hz, 1H), 1.61 (s, 3H) .LCMS(ESI)m/z：429(M+1).
Embodiment 49
(S) -2- ((2- (3,5- difluorophenyl) -4- methoxyl groups -7,8- dihydro pyrido [4,3-d] pyrimidine -6 (5H)-yl) Methyl) -2- methyl 6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Step 1：
Ethyl 1- benzyl -4- oxo piperidine -3- carboxylate methyl esters
Into tetrahydrofuran (20.00 milliliters) solution of 1- benzyl -4- ketone (5.00 grams, 26.42 mMs, 1.00 equivalents) Disposably add sodium hydrogen (2.11 grams, 52.84 mMs, 2.00 equivalents) in 15 degrees Celsius under nitrogen protection.Mixture is existed Stirred 30 minutes under 15 degrees Celsius.Then diethyl carbonate (6.24 grams, 52.84 mMs, 2.00 equivalents) is added into this to mix In compound, and stirred 1 hour under 70 degrees Celsius.Mixture is poured into water (50 milliliters), and stirred 30 minutes.Aqueous phase second Acetoacetic ester (100 milliliters × 3) is extracted.The organic phase of merging is washed with salt solution (50 milliliters), with anhydrous sodium sulfate drying, filtering And be concentrated in vacuo.By residue by silica gel chromatography (petrol ether/ethyl acetate=30/1,10/1), ethyl 1- benzyls are obtained Base -4- oxo piperidine -3- carboxylic acid, ethyl esters (in 4.50 gram, 17.22 mMs, 65.18% yield) are yellow oil.
Step 2：
6- benzyls -2- (3,5- difluorophenyl) -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine -4- alcohol
To ethyl 1- benzyl -4- oxo piperidine -3- carboxylic acid, ethyl esters (1.20 grams, 4.59 mMs, 1.00 equivalents) and 3,5- Sodium methoxide is added in methanol (15.00 milliliters) solution of difluoro benzamidine (931.63 milligrams, 5.97 mMs, 1.30 equivalents) (496.13 milligrams, 9.18 mMs, 2.00 equivalents), mixture are stirred at 80 degrees celsius 2 hours.The mixture is concentrated to exist It is concentrated under reduced pressure under 45 degrees Celsius, residue is poured into water (50 milliliters), ethyl acetate (30 milliliters) and stirred 5 minutes, filtering, Dry cake obtains 6- benzyls -2- (3,5- difluorophenyl) -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine -4- alcohol (400.00 Milligram, 1.13 mMs, 24.66% yield), it is white solid.LCMS(ESI)m/z：354.1(M+1).
Step 3：
The chloro- 2- of 6- benzyls -4- (3,5- difluorophenyl) -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine
To 6- benzyls -2- (3,5- difluorophenyl) -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine -4- alcohol (720.00 millis Gram, 2.04 mMs, 1.00 equivalents) toluene (5.00 milliliters) solution in add POCl3 (2.77 grams, 18.07 mMs, 8.86 equivalents), mixture is stirred 2 hours at one hundred and twenty degrees centigrade, and mixture is poured into water (50 milliliters) and ethyl acetate (50 millis Rise) mixed solution in, be stirred for 5 minutes, filter, dry cake obtain the chloro- 2- of 6- benzyls -4- (3,5- difluorophenyl) - 7,8- dihydro -5H- pyridos [4,3-d] pyrimidines (540.00 milligrams, 1.45 mMs, 71.08% yield), are white solid.
Step 4：
6- benzyls -2- (3,5- difluorophenyl) -4- methoxyl groups -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine
To the chloro- 2- of 6- benzyls -4- (3,5- difluorophenyl) -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine (540.00 millis Gram, 1.45 mMs, 1.00 equivalents) methanol (10.00 milliliters) solution in add sodium methoxide (783.29 milligrams, 14.50 mmoles You, 10.00 equivalents), mixture is stirred 8 hours at 70 degrees Celsius, water (50 milliliters) is added in mixed solution and stirs 5 points Clock.Mixture is filtered, dry cake obtains 6- benzyls -2- (3,5- difluorophenyl) -4- methoxyl group -7,8- dihydro -5H- pyridines And [4,3-d] pyrimidine (410.00 milligrams, 1.12 mMs, 76.96% yield), it is white solid.1H NMR (400MHz, CDCl3) δ 7.90-7.83 (m, 2H), 7.34-7.29 (m, 3H), 7.27-7.16 (m, 2H), 6.80 (tt, J=2.4,8.7Hz, 1H), 3.98 (s, 3H), 3.68 (s, 2H), 3.48 (s, 2H), 2.92-2.85 (m, 2H), 2.78-2.70 (m, 2H)
Step 5：
2- (3,5- difluorophenyl) -4- methoxyl groups -5,6,7,8- tetrahydropyridines simultaneously [4,3-d] pyrimidine
To 6- benzyls -2- (3,5- difluorophenyl) -4- methoxyl groups -7,8- dihydro -5H- pyridos [4,3-d] pyrimidine In 0 degree Celsius of nitrogen protection in dichloroethanes (15.00 milliliters) solution of (410.00 milligrams, 1.12 mMs, 1.00 equivalents) Lower addition 1- chloroethyls phosgene (240.19 milligrams, 1.68 mMs, 1.50 equivalents).Mixture is stirred under 0 degree Celsius 30 minutes, and be heated to 90 degrees Celsius, after stirring 11.5 hours, mixture is concentrated under reduced pressure at 45 degrees Celsius, methanol (15 is added Milliliter), and stirred 2 hours under 90 degrees Celsius.Then in 45 degrees Celsius of mixtures that are concentrated under reduced pressure, dichloromethane (30mL) is added Into residue, and stir 30 minutes, filtering, collect filter cake and obtain 2- (3,5- difluorophenyl) -4- methoxyl groups -5,6,7,8-- Tetrahydropyridine simultaneously [4,3-d] pyrimidine (286.00 milligrams, 911.61 micromoles, 81.39% yield, hydrochloride), are white solid.
Step 6：
(2R) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (3,5- difluorophenyl) -4- methoxyl groups -7,8- dihydro - 5H- pyridos [4,3-d] pyrimidine -6- bases] -2- methyl -propyl- 2- alcohol
By 2- (3,5- difluorophenyl) -4- methoxyl groups -5,6,7,8- tetrahydropyridines simultaneously [4,3-d] pyrimidine (286.00 milligrams, 911.61 micromoles, 1.00 equivalents, hydrochloride) and the chloro- 1- of 2- [[(2S) -2- methyl oxirane -2- bases] methyl] -4- nitros Imidazoles (238.05 milligrams, 1.09 mMs, 1.20 equivalents) is dissolved in the tert-butyl alcohol (6.00 milliliters), is added under nitrogen protection Diisopropylamine (235.63 milligrams, 1.82 mMs, 2.00 equivalents).Mixture is stirred at 80 degrees celsius 12 hours.Will be mixed Compound is cooled to 15 degrees Celsius, then is concentrated under reduced pressure at 45 degrees Celsius.Residue isolates and purifies (diameter by silica gel chromatography：250 Millimeter, pillar height degree：100mm, 100-200 mesh silica gel, petrol ether/ethyl acetate=10/1,2/1), obtaining (2R) -1-, (2- is chloro- 4- nitroimidazole -1- bases) [simultaneously [4,3-d] are phonetic for 2- (3,5- difluorophenyl) -4- methoxyl group -7,8- dihydro -5H- pyridos by -3- Pyridine -6- bases] -2- methyl -propyl- 2- alcohol (400.00 milligrams, 808.28 micromoles, 88.66% yield) is yellow solid.1H NMR (400MHz, CDCl3) δ 8.02 (s, 1H), 8.00-7.91 (m, 2H), 6.92 (tt, J=2.3,8.6Hz, 1H), 4.11 (s, 3H), 4.07 (s, 2H), 3.82-3.67 (m, 2H), 3.63-3.51 (m, 2H), 3.02-2.98 (m, 2H), 2.77-2.57 (m, 2H), 1.35 (s, 3H)
Step 7：
(S) -2- ((2- (3,5- difluorophenyl) -4- methoxyl groups -7,8- dihydro pyrido [4,3-d] pyrimidine -6 (5H)-yl) Methyl) -2- methyl 6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
To (2R) -1- (the chloro- 4- nitro-imidazols -1- bases of 2-) -3- [2- (3,5- difluorophenyl) -4- methoxyl groups -7,8- bis- Hydrogen -5H- pyridos [4,3-d] pyrimidine -6- bases] and -2- methyl -propyl- 2- alcohol (200.00 milligrams, 404.14 micromoles, 1.00 work as Amount) DMF (3.00 milliliters) solution in added under the protection of -45 degrees Celsius of nitrogen sodium hydrogen (32.33 milligrams, 808.28 micromoles, 2.00 equivalents).Mixture is stirred 1 hour under -45-0 degrees Celsius.In the ammonium chloride (50 milliliters) for pouring the mixture into saturation And stir 5 minutes.Aqueous phase is extracted with ethyl acetate (100 milliliters × 2).The organic phase of merging is washed with salt solution (30 milliliters), With anhydrous sodium sulfate drying, filter and be concentrated in vacuo.Residue is washed with methanol (30 milliliters × 2), filtered, filter cake is collected and obtains To (S) -2- ((2- (3,5- difluorophenyl) -4- methoxyl groups -7,8- dihydro simultaneously [4,3-d] pyrimidine -6 (5H)-yl) methyl) -2- first Base -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles by compound 49 (39.00 milligrams, 81.08 micromoles, 20.06% yield, 95.3% purity).1H NMR (400MHz, CDCl3) δ 7.85 (d, J=7.7Hz, 2H), 7.43 (s, 1H), 6.80 (t, J= 8.0Hz, 1H), 4.29 (d, J=9.5Hz, 1H), 4.00 (s, 3H), 3.87 (d, J=9.3Hz, 1H), 3.72-3.56 (m, 2H), 3.11-2.98 (m, 2H), 2.89-2.67 (m, 4H), 1.60 (s, 3H) .LCMS (ESI) m/z：459.1(M+1).
Embodiment 50
(S) -2- ((2- (3,5- difluorophenyl) -5,6- dihydros-[1,2,4] triazol [1,5-a] pyrazine -7 (8H)-yl) Methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Step 1：
[1,2,4] triazol [1,5-a] pyrazine -2- amine
To pyrazine -2- amine (10.00 grams, 105.15 mMs, 1.00 equivalents) dioxane (200.00 milliliters) it is mixed Be added dropwise in polymer solution under the protection of 0~5 degree Celsius of nitrogen ethyl-N- (thio-methylene) carbamic acid (17.05 grams, 130.00 mMs, 1.24 equivalent are blended under 15 degrees Celsius and stirred 16 hours.Gained suspension is filtered, and uses dichloromethane (200 milliliters) washing, obtain ethyl-N- (pyrazine -2- bases thiocarbamoyl) t-butyl carbamate (13.60 grams, 60.11 mMs, 57.16% yield), it is faint yellow solid.1H NMR (400MHz, DMSO-d6) δ 12.08 (s, 1H), 11.79 (s, 1H), 9.68 (s, 1H), 8.51 (s, 2H), 4.24 (m, 2H), 1.27 (m, 3H)
Step 2：
[1,2,4] triazol [1,5-a] pyrazine -2- amine
To ethyl-N- (pyrazine -2- bases thiocarbamoyl) t-butyl carbamate (12.60 grams, 55.69 mMs, 1.00 equivalents) methanol (80.00 milliliters) and ethanol (80.00 milliliters) mixed solution in add hydroxylamine hydrochloride (6.97 grams, 100.24 mMs of mixtures, 1.80 equivalents) and diisopropylamine (17.76 grams, 137.55 mMs, 2.47 equivalents).Will be mixed Compound is stirred 16 hours at 65 degrees Celsius.Reactant mixture is concentrated into about 20 milliliters of volume under reduced pressure.Gained is suspended Liquid is filtered, and collects solid and with dichloromethane: (60: 1,90 milliliters) of ethanol is washed, and obtains [1,2,4] triazol [1,5-a] pyrrole Piperazine -2- amine (5.30 grams, 39.22 mMs, 70.43% yield), is white solid.1H NMR (400MHz, DMSO-d6)δ8.83 (s, 1H), 8.69-8.68 (d, J=4.3Hz, 1H), 7.97-7.96 (d, J=4.3Hz, 1H), 6.46 (s, 2H)
Step 3：
Bromo- [1,2,4] triazol [1, the 5-a] pyrazines of 2-
To copper bromide (1.98 grams, 8.88 mMs, 1.20 equivalents) and nitrite tert-butyl (1.14 grams, 11.10 mmoles You, 1.50 equivalents) acetonitrile (30 milliliters) solution under 65 degrees Celsius add [1,2,4] triazol [1,5a] pyrazine -2- amine (1.00 grams, 7.40 mMs, 1.00 equivalents).After adding, mixture is stirred 2 hours at such a temperature.Reactant mixture is existed Decompression is lower to be concentrated.By residue (150 milliliters) dilutions of ethyl acetate, with 1N hydrochloric acid (100 milliliters) and the ammonium chloride of saturation (100 milliliters) washings.Organic layer is dried through anhydrous Na 2SO4, filters and is concentrated to give residue under reduced pressure, by residue Pass through silica gel chromatography (silica, petrol ether/ethyl acetate=1: 1) purifying obtains bromo- [1,2, the 4] triazols [1,5- of 2- A] pyrazine (350.00 milligrams, 1.76 mMs, 23.77% yield) is faint yellow solid.1H NMR (300MHz, DMSO-d6)δ 9.38 (s, 1H), 9.10-9.09 (d, J=4.3Hz, 1H), 8.33-8.32 (d, J=4.3Hz, 1H)
Step 4：
2- bromo- 5,6,7,8- tetrahydrochysenes [1,2,4] triazol [1,5-a] pyrazine
To the ethanol of bromo- [1,2,4] triazol [1, the 5-a] pyrazines of 2- (350.00 milligrams, 1.76 mMs, 1.00 equivalents) The lithium borohydride (154.00 milligrams, 7.08 mMs, 4.02 equivalents) added in (10.00 milliliters) mixed solution.By mixture Stir 2 hours at 50 c.Reactant mixture is concentrated under reduced pressure, crude product is obtained, is white solid, its is direct For next step.LCMS(ESI)m/z：203/205(M+1)/(M+2).
Step 5：
Bromo- 5,6- dihydros [1,2,4] triazol [1,5-a] pyrazine -7 (the 8H)-carboxylic acid tert-butyl esters of tert-butyl group 2-
To 2- bromo- 5,6,7,8- tetrahydrochysenes [1,2,4] triazol [1,5-a] pyrazine (350.00 milligrams, 1.72 mMs, 1.00 equivalents) water (15.00 milliliters) solution in add sodium acid carbonate (144.82 milligrams, 1.72 mMs, 1.00 equivalents) and Boc2O (379.98 milligrams, 1.74 mMs, 1.01 equivalents).Mixture is stirred 0.5 hour under 10~20 degrees Celsius.To Water (50 milliliters) is added in reactant mixture, and (30 milliliters × 3) are extracted with ethyl acetate.By the organic layer of merging through anhydrous sulphur Sour sodium is dried, and is filtered and is concentrated under reduced pressure, obtain bromo- 6,8- dihydros -5H- [1,2,4] triazol [1, the 5-a] pyrazines of tert-butyl group 2- - 7- carboxylate methyl esters (600.00 milligrams, crude product), are faint yellow solid.1H NMR (300MHz, CDCl3) δ 4.72 (s, 2H), 4.23- 4.13 (m, 2H), 3.99-3.89 (m, 2H), 1.50 (s, 9H)
Step 6：
The tert-butyl group -2- (3,5- difluorophenyl) -5,6- dihydros-[1,2,4] triazol [1,5-a] pyrazine -7 (8H)-carboxylic acid The tert-butyl ester
To bromo- 6,8- dihydros -5H- [1,2,4] triazol [1, the 5- α] pyrazine -7- carboxylic acid, ethyl esters of tert-butyl group 2- (500.00 millis Gram, 1.65 mMs, 1.00 equivalents) and (3,5- difluorophenyl) boric acid (260.00 milligrams, 1.65 mMs, 1.00 equivalents) Under nitrogen protection-secondary property adds cesium carbonate (1.08 in the mixed solution of dioxane (10.00 milliliters) and water (1.00 milliliters) Gram, 3.30 mMs, 2.00 equivalents) and Pd (dppf) Cl2(60.00 milligrams, 82.00 micromoles, 0.05 equivalent).By mixture It is heated to 80 degrees Celsius and stirs 16 hours.The mixture is washed with water (30 milliliters), and aqueous phase is with ethyl acetate (30 milliliters × 2) Extraction.The organic phase of merging is dried with anhydrous Na 2SO4, is filtered and is concentrated in vacuo, obtains residue.Residue is passed through into silica gel Chromatography (SiO2, petrol ether/ethyl acetate=20/1~5: 1) purifies, obtains tert-butyl group 2- (3,5- difluorophenyl) -6,8- bis- Hydrogen -5H- [1,1,2,4] triazol [1,5-a] pyrazine -7- carboxylic acid, ethyl esters (310.00 milligrams, 921.69 micromoles, 55.86% production Rate), it is faint yellow solid.LCMS(ESI)m/z：337.1(M+1)
Step 7：
2- (3,5- difluorophenyl) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazol [1,5-a] pyrazine
To the tert-butyl group -2- (3,5- difluorophenyl) -6,8- dihydros -5H- [1,2,4] triazol [1,5-a] pyrazine -7- carboxylic acids Trifluoroacetic acid is added in dichloromethane (10.00 milliliters) solution of ethyl ester (310.00 milligrams, 921.69 micromoles, 1.00 equivalents) (3.06 grams, 26.84 mMs, 29.12 equivalents).Mixture is stirred 12 hours at 15 degrees Celsius.Reactant mixture is depressurized Concentration, obtains residue as dark brown solid, is directly used in next step.LCMS(ESI)m/z：237.1(M+1)
Step 8：
(S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3- (2- (3,5- difluorophenyl) -5,6- dihydros-[1,2,4] Triazol [1,5-a] pyrazine -7 (8H)-yl) -2- methyl propan-2-ols
To 2- (3,5- difluorophenyl) -5,6,7,8- tetrahydrochysenes-[1,2,4] triazol [1,5-a] pyrazine (550.00mg, 1.57mmol, 1.00eq, trifluoroacetate) the tert-butyl alcohol (10.00 milliliters) solution in add 2- chloro- 1- [[(2S) -2- methyl Oxirane -2- bases] methyl] -4- nitroimidazoles (250.00 milligrams, 1.15 mMs, 0.73 equivalent) and diisopropylamine (1.01 Gram, 7.85 mMs, 5.00 equivalents).Mixture is stirred at 80 degrees celsius 16 hours.By reactant mixture water (50 millis Rise) washing, and (30 milliliters × 2) are extracted with ethyl acetate.By the organic layer of merging through anhydrous sodium sulfate drying, filter and subtracting Pressure is concentrated to give residue.Residue is pure by silica gel chromatography (SiO2, petrol ether/ethyl acetate=3/1 to 1/5) Change, obtain (S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3- (2- (3,5- difluorophenyl) -5,6- dihydros-[1,2,4] Triazol [1,5-a] pyrazine -7 (8H)-yl) -2- methyl propan-2-ol (250.00 milligrams, 550.87 micromoles, 35.09% production Rate), it is light yellow oil.LCMS(ESl)m/z：454.1(M+1)
Step 9：
(S) -2- ((2- (3,5- difluorophenyl) -5,6- dihydros-[1,2,4] triazol [1,5-a] pyrazine -7 (8H)-yl) Methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
To (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (3,5- difluorophenyl) -6,8- dihydros -5H- [1,2, 4] triazol [1,5-a] pyrazine -7- bases] -2- methyl -propyl- 2- alcohol (100.00 milligrams, 220.35 micromoles, 1.00 equivalents) In DMF (5.00 milliliters) solution sodium hydrogen (20.00 milligrams, 500.00 micromoles, 2.27 are added under -50 degrees Celsius of nitrogen protections Equivalent).Mixture is stirred 0.5 hour at -50 degrees Celsius.Then 0 degree Celsius is heated the mixture to, other 0.5 is stirred small When.Reactant mixture is poured into saturated ammonium chloride solution (40 milliliters), then extracted with ethyl acetate (30 milliliters × 2).Will The organic layer anhydrous sodium sulfate of merging, filtering, and residue is concentrated to give under reduced pressure.Residue is passed through into preparative separation color Spectrum purifying, obtains (2S) -2- [[2- (3,5- difluorophenyl) -6,8- dihydros -5H- [1,2,4] triazol [1,5-a] pyrazine -7- Base] methyl] -2- methyl -6- nitro -3H- imidazos [2,1b] azoles (11.25 milligrams, 26.36 micromoles, 11.96% yield, 97.79% purity).1H NMR (400MHz, DMSO-d6) δ 8.42 (br.s., 1H), 8.10 (s, 1H), 7.55 (d, J=6.5Hz, 2H), 7.31 (br.s., 1H), 4.31 (d, J=10.8Hz, 1H), 4.22-4.15 (m, 1H), 4.10 (d, J=10.5Hz, 1H), 4.02-3.90 (m, 3H), 3.19-3.15 (m, 2H), 3.08-3.04 (m, 2H), 1.59 (s, 3H) .LCMS (ESI) m/z：418.2 (M+1).
Embodiment 51
(S) -2- ((2- (3,5- dichlorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitre Base -2-, 3 glyoxalidine simultaneously [2,1b] azoles
To key intermediate B (200.00 milligrams, 571.80 micromoles, 1.00 equivalents) and (3,5- dichlorophenyl) boric acid The mixing of the dioxane (5.00 milliliters) and water (500.00 microlitres) of (109.11 milligrams, 571.80 micromoles, 1.00 equivalents) It is disposable under nitrogen protection in solution to add Pd (dppf) Cl2(20.92 milligrams, 28.59 micromoles, 0.05 equivalent), fluorination Caesium (260.57 milligrams, 1.72 mMs, 3.00 equivalents).Mixture is stirred 6 hours under 100 degrees Celsius.Mixture is used Ethyl acetate dilutes, filtering and concentration.Residue is passed through into preparative separation chromatographic isolation (GX-F；Phenomenex Synergi C18 150*25*10um；0.225%FA-ACN；Begin from 52to 82；Flow Rate (25ml/min), obtain (S)- 2- ((2- (3,5- dichlorophenyl)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros -2-, 3 dihydros Imidazo [2,1b] azole compounds 51 (50.00 milligrams, 107.54 micromoles, 18.81% yield, 99% purity).1H NMR (400MHz, CDCl3) δ 7.86 (d, J=1.9Hz, 2H), 7.53 (s, 1H), 7.50-7.44 (m, 1H), 7.43-7.35 (m, 2H), 4.43 (d, J=9.7Hz, 1H), 4.07-3.66 (m, 3H), 3.30-2.88 (m, 5H), 2.82 (d, J=14.9Hz, 1H), 1.69 (s, 3H)；LCMS(ESI)m/z：460(M+1).
Embodiment 52
(S) -2- (((the 5H)-yl of 2- (3,5- difluorophenyl) -4- methyl -7,8- dihydros -1,6- naphthyridines -6) methyl) -2- first Base -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Step 1：
6- benzyl -4- methyl isophthalic acids, 5,7,8 tetrahydrochysene -1,6- naphthyridines -2- ketone
By 1- benzyl -4- ketone (4.00 grams, 21.14 mMs, 1.00 equivalents) and 3- oxos butyramide (2.35 grams, 23.25 MM, 1.10 equivalents) it is dissolved in Eton reagent (8.00 milliliters), stirred 12 hours at 110 degrees Celsius.Mixture is added to full In sodium bicarbonate aqueous solution (100 milliliters), control pH ＞ 7 extract aqueous layer with ethyl acetate (100 milliliters × 4).It will merge Organic phase washed with saturated brine (100 milliliters), with anhydrous sodium sulfate drying, filter and be concentrated in vacuo.Residue is used third (60 milliliters) washings of ketone, then filter, filter cake are collected and obtains 6- benzyl -4- methyl isophthalic acids, 5,7,8 tetrahydrochysene -1,6- naphthyridines -2- ketone (2.80 grams, 11.01 mMs, 52.08% yield), are white solid.1H NMR (400MHz, DMSO-d6)：δ 11.25 (br, S, 1H), 7.34 (d, J=4.3Hz, 4H), 7.27 (qd, J=4.1,8.6Hz, 1H), 5.99 (s, 1H), 3.66 (s, 2H), 3.26 (s, 2H), 2.61-2.52 (m, 4H), 1.95 (s, 3H)
Step 2：
Chloro- 4- methyl -7,8- dihydro -5H--1, the 6- benzodiazines of 6- benzyls -2-
By 6- benzyl -4- methyl isophthalic acids, (2.80 grams, 11.01 mMs, 1.00 work as 5,7,8 tetrahydrochysene -1,6- naphthyridines -2- ketone Amount) and the mixing of (9.00 milliliters) of POCl3 after, stirring 12 hours under 110 degrees Celsius.Mixture is added drop-wise to frozen water (100 Milliliter) in, then mixture is stirred 0.5 hour at 15 degrees Celsius.Then the sodium bicarbonate water of saturation is added into mixture Solution (100 milliliters) is until pH ＞ 7.Mixture is extracted (100 milliliters × 4) with dichloromethane.By the organic phase salt of merging The washing of (100 milliliters) of water, organic phase anhydrous sodium sulfate drying, filter and be concentrated in vacuo obtain the chloro- 4- methyl of 6- benzyls -2- - 7,8- dihydro -5H--1,6- benzodiazines (3.50 grams, crude product), are yellow solid.LCMS(ESI)m/z：273(M+1).
Step 3：
6- benzyls -2- (3,5- difluorophenyl) -4- methyl -7,8- dihydro -5H--1,6- benzodiazines
To chloro- 4- methyl -7,8- dihydro -5H--1, the 6- benzodiazines of 6- benzyls -2- (500.00 milligrams, 1.83 mMs, 1.00 equivalents) and (3,5- difluorophenyl) boric acid (346.77 milligrams, 2.20 mMs, 1.20 equivalents) dioxane (10.00 Milliliter) and water (1.00 milliliters) mixed solution in disposable 15 degrees Celsius of upper disposable addition cesium fluorides under nitrogen protection (694.94 milligrams, 4.58 mMs, 2.50 equivalents) and Pd (dppf) Cl2(133.90 milligrams, 183.00 micromoles, 0.10 works as Amount).Mixture is stirred 5 hours at 110 degrees Celsius.Water (10 milliliters) is added into the mixture, dichloromethane is then used (100 milliliters × 3) extract.The organic phase of merging is washed with salt solution (100 milliliters), with anhydrous sodium sulfate drying, filtered and true Sky concentration.Residue is passed through into Silica gel chromatography (pillar height degree：250 millimeters, diameter：100 millimeters, 100-200 mesh silica gel, Petrol ether/ethyl acetate=40/1 to 15/1), obtain 6- benzyls -2- (3,5- difluorophenyl) -4- methyl -7,8- dihydros -5H-- 1,6- benzodiazine (580.00 milligrams, 1.66 mMs, 90.45% yield), is white solid.1H NMR (300MHz, CDCl3)：δ 7.41 (d, J=6.8Hz, 2H), 7.32 (br, s, 3H), 7.27-7.16 (m, 3H), 6.78-6.65 (m, 1H), 3.70 (s, 2H), 3.55 (s, 2H), 3.08-2.95 (m, 2H), 2.83-2.71 (m, 2H), 2.14 (s, 3H)
Step 4：
2- (3,5- difluorophenyl) -4- methyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazine hydrochlorides
To 6- benzyls -2- (3,5- difluorophenyl) -4- methyl -7,8- dihydro -5H-1,6- naphthyridines (580.00 milligrams, 1.66 MM, 1.00 equivalents) dichloroethanes (15.00 milliliters) solution in disposable add 1- in 15 degrees Celsius under nitrogen protection Chlorine phosgene (354.98 milligrams, 2.48 mMs, 1.50 equivalents).Mixture is stirred 12 hours under 90 degrees Celsius.Then Mixture is concentrated to dryness, methanol (10.00 milliliters) is added in residue, it is small that at 90 degrees Celsius gained mixture is stirred for into 1 When.Mixture is concentrated to dryness, 2- (3,5- difluorophenyl) -4- methyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazines is obtained (400.00 milligrams, 1.35 mMs, 81.56% yield, hydrochloride) for white solid.
Step 5：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (3,5-difluor O phenyl) -4- methyl -7,8- bis- Hydrogen -5H--1,6- naphthyridines -6- bases] -2- methyl -propyl- 2- alcohol
By 2- (3,5- difluorophenyl) -4- methyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazines (400.00 milligrams, 1.35 millis Mole, 1.00 equivalents, hydrochloride) and the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (352.53 milligrams, 1.62 mMs, 1.20 equivalents) are mixed in the tert-butyl alcohol (8.00 milliliters), Celsius in 15 under nitrogen protection Degree is disposable to add diisopropylamine (436.19 milligrams, 3.38 mMs, 2.50 equivalents).Mixture is stirred under 100 degrees Celsius Mix 12 hours.Mixture is concentrated to dryness.Residue is passed through into Silica gel chromatography (pillar height degree：250 millimeters, diameter：100 Millimeter, 100-200 mesh silica gel, petrol ether/ethyl acetate=30/1 to 1/2), obtain (2S) -1- (chloro- 4- nitroimidazoles -1- of 2- Base) -3- [2- (3,5- difluorophenyl) -4- methyl -7,8- dihydro -5H-1,6- naphthyridines -6- bases] -2- methyl -propyl- 2- alcohol (260.00 milligrams, crude product), are yellow solid.LCMS(ESI)m/z：478(M+1).
Step 6：
(2S) -2- [[2- (3,5- difluorophenyl) -4- methyl -7,8- dihydro -5H-1,6- naphthyridines -6- bases] methyl] -2- first Base -6- nitro -3H- imidazos [2,1b] azoles
To (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (3,5- difluorophenyl) -4- methyl -7,8- dihydro - 5H-1,6- naphthyridines -6- bases] -2- methyl -propyl- 2- alcohol (260.00 milligrams, 544.06 micromoles, 1.00 equivalents) DMF (5.00 Milliliter) disposable in solution sodium hydrogen added under -20 degrees Celsius of nitrogen protections (43.60 milligrams, 1.09 mMs, 2.00 work as Amount).Mixture is stirred 10 minutes under -20 degrees Celsius, 0 degree Celsius is then heated to, and stirred 10 minutes, is then heated to 15 degrees Celsius, it is stirred for 10 minutes.Mixture is added drop-wise in ammonium chloride (20 milliliters), mixture is then filtered and collects filter Cake, obtains crude product.Crude product passes through alkaline preparative separation chromatographic separation and purification ((GX-D；Boston Symmetrix C18 ODS-R 150*30mm*5um；Acetonitrile 24%-54%；Water (0.225%NH4OH)；25mL/min)), obtain (2S yls) -2- [[2- (3,5- difluorophenyl) -4- methyl -7,8- dihydro -5H-1,6- naphthyridines -6- bases] methyl] -2- methyl -6- Nitro -3H- imidazos [2,1b] azole compounds 52 (60.00 milligrams, 135.51 micromoles, 24.91% yield, 99.7% is pure Degree).1H NMR (400MHz, CDCl3)：δ 7.56-7.45 (m, 3H), 7.31 (s, 1H), 6.87-6.77 (m, 1H), 4.44 (d, J =9.8Hz, 1H), 3.97 (d, J=9.5Hz, 1H), 3.88-3.71 (m, 2H), 3.20-2.81 (m, 6H), 2.25 (s, 3H), 1.70 (s, 3H) .LCMS (ESI) m/z：442(M+1).
Embodiment 53
(S) -2- ((2- (2- diuril azoles -3- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- Nitro 2,3- glyoxalidine simultaneously [2,1b] azoles
To (2S) -2- [(chloro- 7,8- dihydros -5H-1,6- naphthyridines-the 6- bases of 2-) case base phenethyl] -2- methyl -6- nitros - 3H- imidazos [2,1-b] oxazole (200.00 milligrams, 571.80 micromoles, 1.00 equivalents) and (the chloro- 3- thienyls of 2-) boric acid The mixing of the dioxane (3.00 milliliters) and water (300.00 microlitres) of (92.86 milligrams, 571.80 micromoles, 1.00 equivalents) is molten Cesium fluoride (173.71 milligrams, 1.14 mMs, 2.00 equivalents) and Pd (dppf) Cl are added in liquid2(8.37 milligrams, 11.44 is micro- Mole, 0.02 equivalent).Mixture is stirred 12 hours at 70 degrees Celsius.Water (50 milliliters) is added into reactant mixture to be quenched, Then it is extracted with ethyl acetate (50 milliliters × 3).The organic layer of merging is dried over sodium sulfate, filter and be concentrated to give under reduced pressure To residue.Residue is passed through into preparative separation chromatographic separation and purification (GX-F；Phenomenex Synergi C18 150*25* 10um；Acetonitrile 30%-60%；ACN (0.225%fomic acid)；25mL/min), (2S) -2- [[2- are obtained (the chloro- 3- thienyls of 2-) -7,8- dihydros -5H-1,6- naphthyridines -6- bases] methyl] -2- ethoxyl methyl case -6- nitro -3H- imidazoles And [2,1b] azole compounds 53 (26.30 milligrams, 59.55 micromoles, 10.41% yield, 97.8% purity).1H NMR (400MHz, METHANOL-d4)：δ 7.82 (s, 1H), 7.65 (d, J=6.15Hz, 2H), 7.39 (d, J=5.90Hz, 1H), 7.31 (d, J=5.77Hz, 1H), 4.42 (d, J=10.54Hz, 1H), 4.15 (d, J=10.54Hz, 1H), 3.95 (s, 2H), 3.25-2.81 (m, 6H), 1.69 (s, 3H) .LCMS (ESI) m/z：432.2(M+1).
Embodiment 54
(S) -2- methyl -6- nitros -2- ((2- (5- (trifluoromethyl) furans -2- bases) -7,8- dihydros -1,6- naphthyridines -6 (5H)-yl) methyl) -2,3- glyoxalidine simultaneously [2,1b] azoles
Step 1：
Methyl -6- benzyl -7,8- dihydro -5H--1,6- benzodiazine -2- carboxylic acids
To chloro- 7,8- dihydros -5H--1, the 6- benzodiazines of 6- benzyls -2- (5.00 grams, 19.32 mMs, 1.00 equivalents) Methanol (50.00 milliliters) solution in nitrogen protection is lower adds Pd (dppf) Cl2(706.96 milligrams, 966.00 micromoles, 0.05 Equivalent), triethylamine (3.65 grams, 36.07 mMs, 1.87 equivalents).Suspension is deaerated with carbon monoxide.By mixture one Stirred 12 hours under 80 degrees Celsius of carbonoxide (50Psi).Reactant mixture is concentrated to remove solvent under reduced pressure.By residue Dilution, is washed, and (500 milliliters × 2) are extracted with ethyl acetate with sodium carbonate (100 milliliters).By the organic layer of merging in decompression Lower concentration, obtains residue.Residue is separated by silica gel chromatography (SiO2, petrol ether/ethyl acetate=50/1~5: 1).Obtain 6- benzyl -7,8- dihydro -5H--1,6- benzodiazine -2- carboxylate methyl ester (3.00 grams, 10.63 mMs, 55.00% Yield), it is yellow solid.LCMS(ESI)m/z：283.2(M+1).
Step 2：
1- (6- benzyl -7,8- dihydro -5H-1,6- naphthyridines -2- bases) -2- dimethoxyphosphoryls-ethyl ketone
To methyl -6- benzyl -7,8- dihydro -5H--1,6- benzodiazine -2- carboxylate methyl esters (2.50 grams, 8.85 mMs, 1.00 equivalents) tetrahydrofuran (125.00 milliliters) solution under -78 degrees Celsius be added dropwise n-BuLi (2.5M's, 10.62 milli Rise, 3.00 equivalents), after 30 minutes completion of dropping, mixture is stirred 30 minutes in this temperature, then under -78 degrees Celsius plus Enter THF (125.00 millis of [methoxyl group (methyl) phosphoryl] epoxide methane (3.51 gram, 28.32 mMs, 3.20 equivalents) Rise) solution.Gained mixture is stirred 2 hours under -78 degrees Celsius.Ammonium chloride (30 is added into reaction under -78 degrees Celsius Milliliter) reaction is quenched, then it is extracted with ethyl acetate (400 milliliters × 2).The organic layer of merging is concentrated under reduced pressure, obtained Residue.Residue is isolated and purified by silica gel chromatography and (SiO2, petrol ether/ethyl acetate=3/1~0: 1), changed Compound 1- (6- benzyl -7,8- dihydro -5H--1,6- naphthyridines -2- bases) -2- dimethoxyphosphoryls-ethyl ketone (2.35 grams, 6.28 millis Mole, 70.93% yield), it is colorless solid.
Step 3：
(E) -4- (6- benzyl -7,8- dihydro -5-H-1,6- benzodiazine -2- bases) -4- oxos-but-2-ene acetoacetic ester
To 1- (6- benzyl -7,8- dihydro -5-H-1,6- benzodiazine -2- bases) -2- dimethoxyphosphoryls-ethyl ketone The addition potassium tert-butoxide (845.24 of (2.35 grams, 6.28 mMs, 1.00 equivalents) in dichloroethanes (30.00 milliliters) solution Milligram, 7.53 mMs, 1.20 equivalents) and 2- ethyls (2.56 grams, 12.55 mMs, 2.00 equivalents).Will mixing Thing is stirred 2 hours at -20 degrees Celsius.By residue by silica gel chromatography (SiO2, petrol ether/ethyl acetate=1/0~20: 1) separate, obtain compound ethyl (E) -4- (6- benzyl -7,8- dihydro -5-H-1,6- benzodiazine -2- bases) -4- oxos-butyl- 2- olefin(e) acids ethyl ester (1.50 grams, 4.28 mMs, 68.16% yield), is yellow solid.1H NMR (400MHz, CDCl3)：δ 8.48 (d, J=15.9Hz, 1H), 7.82 (d, J=7.9Hz, 1H), 7.41-7.22 (m, 6H), 6.92 (d, J=15.9Hz, 1H), 4.25-4.19 (m, 2H), 3.65 (d, J=16.9Hz, 4H), 3.12-3.00 (m, 2H), 2.83 (t, J=6.0Hz, 2H), 1.30-1.23 (m, 3H) .LCMS (ESI) m/z：351.1(M+1)
Step 4：
5- (6- benzyls -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- bases) -2- (trifluoromethyl) furans -3- carboxylic acid, ethyl esters
To TFAA (1.35 grams, 6.42 mMs, 1.50 equivalents) and triphenyl phosphorus (1.12 grams, 4.28 mMs, 1.00 equivalents) dichloromethane (15.00 milliliters) solution in add ethyl (E) -4- (6- benzyl -7,8- dihydro -5H-1,6- naphthalenes Pyridine -2- bases) -4- oxo but-2-enes acetoacetic ester (1.50 grams, 4.28 mMs, 1.00 equivalents).By mixture under 25 degrees Celsius Stirring 0.5 hour.Residue (SiO2, petrol ether/ethyl acetate=50/1~10: 1) is purified, changed by column chromatography Compound 5- (6- benzyls -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- bases) -2- (trifluoromethyl) furans -3- carboxylic acid, ethyl esters (1.30 grams, 3.02 mMs, 70.57% yield), obtain as yellow solid.
Step 5：
5- (6- benzyls -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- bases) -2- (trifluoromethyl) furans -3- carboxylic acid sodiums
To 5- (6- benzyl -7,8- dihydro -5-H-1,6- benzodiazine -2- bases) -2- (trifluoromethyl) furans -3- carboxylic acid second Hydrogen is added in the ethanol (7.00 milliliters) and water (7.00 milliliters) solution of ester (700.00 milligrams, 1.63 mMs, 1.00 equivalents) Sodium oxide molybdena (260.80 milligrams, 6.52 mMs, 4.00 equivalents).Mixture is stirred 12 hours under 25 degrees Celsius.Will reaction Mixture be concentrated under reduced pressure removing solvent obtain compound 5- (6- benzyls -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- bases) -2- (trifluoros Methyl) furans -3- carboxylic acid sodiums (1.00 grams, crude product) are yellow solid.
Step 6：
6- benzyls -2- [5- (trifluoromethyl) -2- furyls] -7,8- dihydros -5H-1,6- benzodiazine
To 5- (6- benzyls -5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- bases) -2- (trifluoromethyl) furans -3- carboxylic acid sodiums Copper sulphate (37.67 is added in N-methyl pyrrolidones (10.00 milliliters) solution of (1.00 grams, 2.36 mMs, 1.00 equivalents) Milligram, 236.00 micromoles, 0.10 equivalent).Mixture is stirred 2 hours under 150 degrees Celsius.Reactant mixture is depressurized dense Contracting removes solvent.Residue (silica, petrol ether/ethyl acetate=2: 1) obtains chemical combination by crossing to prepare plate and isolate and purify Thing 6- benzyls -2- [5- (trifluoromethyl) -2- furyls] -7,8- dihydros -5H--1,6- benzodiazine (500.00 milligrams, 1.40 MM, 59.12% yield), it is yellow solid.
Step 7：
2- [5- (trifluoromethyl) -2- furyls] -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
By 6- benzyls -2- [5- (trifluoromethyl) -2- furyls] -7,8- dihydros -5H-1,6- naphthyridines (600.00 milligrams, 1.67 mMs, 1.00 equivalents) and 1- chloroethyls phosgene (358.14 milligrams, 2.51 mMs, 1.50 equivalents) be dissolved in 1,2- In dichloroethanes (6.00 milliliters), mixture is stirred 12 hours at 80 degrees celsius.Reactant mixture is concentrated under reduced pressure with Solvent is removed, and adds methanol (6.00 milliliters).Mixture is stirred at 80 degrees celsius 12 hours.Reactant mixture is being subtracted Pressure concentrates to remove solvent.PH is adjusted to about 9 by being gradually added into sodium carbonate liquor, and (100 millis are extracted with ethyl acetate Rise × 2).The organic layer of merging is concentrated under reduced pressure, 2- [5- (trifluoromethyl) -2- furyls] -5 is obtained, 6,7,8- tetrahydrochysenes - 1,6- benzodiazine (200.00 milligrams, 745.63 micromoles, 44.65% yield), is white solid.LCMS(ESI)m/z： 269.1(M+1).
Step 8：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- methyl -3- [2- [5- (trifluoromethyl) -2- furyls] -7, 8- dihydros -5H--1,6- naphthyridines -6- bases] propan-2-ol
To 2- [5- (trifluoromethyl) -2- furyls] -5,6,7,8- tetrahydrochysene -1,6- benzodiazines (200.00 milligrams, 745.63 micromoles, 1.00 equivalents) the tert-butyl alcohol (5.00 milliliters) solution in, add diisopropylamine (192.73 milligrams, 1.49 milli Mole, 2.00 equivalents) and the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (178.48 millis Gram, 820.19 micromoles, 1.10 equivalents).Mixture is stirred 12 hours under 100 degrees Celsius.Residue is passed through into silica gel color Spectrometry (SiO2, petrol ether/ethyl acetate=10/1~1: 1) purify, obtain (2S) -1- (the chloro- 4- nitro-imidazols -1- bases of 2-) - 2- methyl -3- [2- [5- (trifluoromethyl) -2- furyls] -7,8- dihydros 5H-1,6- naphthyridines -6- bases] propan-2-ol (260.00 millis Gram, 535.16 micromoles, 71.77% yield), it is yellow solid.LCMS(ESI)m/z：486.2(M+1).
Step 9：
(S) -2- methyl -6- nitros -2- ((2- (5- (trifluoromethyl) furans -2- bases) -7,8- dihydros -1,6- naphthyridines -6 (5H)-yl) methyl) -2,3- glyoxalidine simultaneously [2,1b] azoles
To (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- methyl -3- [2- [5- (trifluoromethyl) -2- furyls] - 7,8- dihydro -5H--1,6- naphthyridines -6- bases] propan-2-ol (260.00 milligrams, 535.16 micromoles, 1.00 equivalents) DMF Sodium hydrogen (32.11 milligrams, 1.34 mMs, 2.50 equivalents) is added in (3.00 milliliters) solution under 0 degree Celsius, 10 minutes, will Mixture is stirred 50 minutes under 15 degrees Celsius.Reactant mixture is added into ammonium chloride (10 milliliters) at 0 degree Celsius to be quenched, then It is extracted with ethyl acetate (100 milliliters × 2).The organic layer of merging is washed with sodium chloride (20 milliliter * 1), concentrated under reduced pressure Obtain residue.Residue isolated and purified by preparative separation chromatography (GX-I, YMC-Actus ODS-AQ 100*30 5u, Acetonitrile 24%-54%；0.1%TFA-ACN；25mL/min), (S) -2- methyl -6- nitros -2- ((2- (5- are obtained (trifluoromethyl) furans -2- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2,3- glyoxalidine simultaneously [2,1b] azoles Compound 54 (48.00 milligrams, 105.28 micromoles, 19.67% yield, 98.561% purity).1H NMR (400MHz, CDCl3)：δ 7.59-7.55 (m, 1H), 7.52 (s, 1H), 7.42-7.34 (m, 1H), 7.11-7.01 (m, 1H), 6.94-6.84 (m, 1H), 4.48-4.37 (m, 1H), 4.03-3.78 (m, 3H), 3.26-2.73 (m, 6H), 1.69 (s, 3H) .LCMS (ESI) m/ z：450.2(M+1).
Embodiment 55
(S) -2- methyl -2- ((2- (4- methylthiazol -2- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) - 6- nitros 2,3- glyoxalidine simultaneously [2,1b] azoles
Step 1：
6- benzyls -5,6,7,8- tetrahydrochysene -1,6- benzodiazine -2- carboxylic acids
To chloro- 7,8- dihydros -5H--1, the 6- benzodiazines of 6- benzyls -2- (3.80 grams, 14.69 mMs, 1.00 equivalents) Triethylamine (2.00 milliliters) and methanol (20.00 milliliters) solution in nitrogen protection is lower adds Pd (dppf) Cl2(1.07 grams, 1.47 mMs, 0.10 equivalent).Suspension is deaerated under vacuo and purged with carbon monoxide, by mixture in carbon monoxide Stirred 12 hours at 80 DEG C under (50Psi).Filtering, concentration, silica gel chromatography (petroleum ether/acetic acid second is passed through by residue Ester=10/1,1/2), obtain 6- benzyls -5,6,7,8- tetrahydrochysene -1,6- benzodiazine -2- carboxylate methyl esters (3.90 grams, 13.81 millis Mole, 94.04% yield), it is yellow solid.1H NMR (400MHz, CDCl3) δ 7.93 (d, J=7.9Hz, 1H), 7.45 (d, J =7.9Hz, 1H), 7.42-7.30 (m, 5H), 4.01 (s, 3H), 3.75 (s, 2H), 3.71 (s, 2H), 3.18 (t, J=6.0Hz, 2H), 2.90 (t, J=6.0Hz, 2H)
Step 2：
6- benzyls -5,6,7,8- tetrahydrochysene -1,6- benzodiazine -2- formamides
Ammonia (4.58 grams, 269.20 mMs, 20.00 equivalents) is passed through methanol (50.00 milliliters) at -50 degrees Celsius, After 10 minutes, 6- benzyls -5,6,7,8- tetrahydrochysene -1,6- benzodiazine -2- carboxylate methyl esters are added into the solution at 15 degrees Celsius (3.80 grams, 13.46 mMs, 1.00 equivalents), mixture is stirred 120 minutes under 15 degrees Celsius.Reactant mixture is dense Contracting, obtains 6- benzyls -5,6,7,8- tetrahydrochysene -1,6- benzodiazine -2- formamides (3.30 grams, 12.34 mMs, 91.71% production Rate), it is yellow solid.1H NMR (400MHz, CDCl3) δ 7.97 (d, J=7.9Hz, 1H), 7.46 (d, J=7.9Hz, 1H), 7.43-7.30 (m, 5H), 3.75 (s, 2H), 3.70 (s, 2H), 3.09-3.02 (m, 2H), 2.93-2.84 (m, 2H)
Step 3：
6- benzyl -7,8- dihydro -5H--1,6- benzodiazine -2- thioformamides
To 6- benzyls -5,6, (1.50 grams, 5.61 mMs, 1.00 work as 7,8- tetrahydrochysene -1,6- benzodiazine -2- formamides Amount) tetrahydrofuran (30.00 milliliters) solution in add under nitrogen protection lawesson reagent (3.40 gram, 8.42 mMs, 1.50 equivalents).Mixture is stirred 4 hours at 80 DEG C.The mixture is concentrated to be concentrated under reduced pressure at 45 DEG C.Residue is passed through Silica gel chromatography (petrol ether/ethyl acetate=10/1,0/1), obtain 6- benzyl -7,8- dihydro -5H--1,6- benzodiazine - 2- thioformamides (780.00 milligrams, 2.75 mMs, 49.06% yield), are yellow solid.1H NMR (400MHz, CDCl3) δ 8.47 (d, J=8.0Hz, 1H), 7.45 (d, J=7.8Hz, 3H), 7.37 (d, J=7.5Hz, 3H), 3.96 (br.s., 2H), 3.84 (d, J=7.7Hz, 2H), 3.14 (br.s., 4H)
Step 4：
2- (6- benzyl -7,8- dihydro -5H-1,6- naphthyridines -2- bases) -4- methYl-thiazols
To 6- benzyl -7,8- dihydro -5H--1,6- benzodiazine -2- thioformamide (780.00 milligrams, 2.75 mmoles You, 1.00 equivalents) ethanol (15.00 milliliters) solution in add under nitrogen protection 1- chlorine propyl- 2- ketone (1.48 grams, 16.00 milli Mole, 5.82 equivalents).Mixture is stirred 12 hours at 80 DEG C.Mixture is concentrated under reduced pressure at 45 DEG C.Residue (oil Ether: ethyl acetate=10: 0 milliliter of Isosorbide-5-Nitrae) washing, filter, dry cake obtains 2- (6- benzyl -7,8- dihydro -5H-1,6- naphthyridines Pyridine -2- bases) -4- methYl-thiazols (719.00 milligrams, 2.24 mMs, 81.34% yield) are brown solid.1H NMR (400MHz, CDCl3) δ 7.91 (d, J=7.9Hz, 1H), 7.43-7.33 (m, 6H), 6.95 (s, 1H), 3.74 (s, 2H), 3.66 (s, 2H), 3.12-3.07 (m, 2H), 2.92-2.87 (m, 2H), 2.52 (s, 3H)
Step 5：
4- methyl -2- (5,6,7,8- tetrahydrochysene -1,6- benzodiazine -2- bases) thiazole
To 2- (6- benzyl -7,8- dihydro -5H-1,6- naphthyridines -2- bases) -4- methYl-thiazols (360.00 milligrams, 1.12 millis Mole, 1.00 equivalents) dichloroethanes (10.00 milliliters) solution in add 1- chloroethyl phosgenes under the protection of 0 DEG C of nitrogen (240.19 milligrams, 1.68 mMs, 1.50 equivalents).Mixture is stirred 12 hours at 100 DEG C, then mixture is cooled down It is concentrated under reduced pressure, methanol (15.00 milliliters) is added in residue, and is stirred 2 hours at 80 DEG C to 20 DEG C, then at 45 DEG C. 45 DEG C of mixtures that are concentrated under reduced pressure, dichloromethane (20 milliliters) is added in residue and stirred 10 minutes, filters and collects filter Cake obtain 4- methyl -2- (5,6,7,8- tetrahydrochysene -1,6- naphthyridines -2- bases) thiazole (150.00 milligrams, 560.16 micromoles, 50.01% yield, hydrochloric acid), it is white solid.1H NMR (300MHz, DMSO-d6) δ 7.98 (d, J=8.1Hz, 1H), 7.81 (d, J=8.1Hz, 1H), 7.43 (s, 1H), 4.33 (br.s., 2H), 3.47 (br.s., 2H), 3.18-3.14 (m, 2H), 2.44 (s, 3H)
Step 6：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- methyl -3- [2- (4- methylthiazol -2- bases) -7,8- dihydros - 5H--1-, 6- naphthyridines -6- bases] propan-2-ol
To 4- methyl -2- (5,6,7,8- tetrahydrochysene -1,6- benzodiazine -2- bases) thiazole, (150.00 milligrams, 560.16 micro- rub In that, 1.00 equivalents, HCl) and the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (146.28 Milligram, 672.19 micromoles, 1.20 equivalents) the tert-butyl alcohol (10.00 milliliters) solution in add diisopropylamine under nitrogen protection (144.79 milligrams, 1.12 mMs, 2.00 equivalents).Mixture is stirred 12 hours at 80 DEG C.The mixture subtracts at 45 DEG C Water (20 milliliters) is added in pressure concentration, residue, and is stirred 5 minutes.Aqueous phase is extracted with ethyl acetate (30 milliliters × 3).It will close And organic phase with salt solution (20 milliliters), with anhydrous sodium sulfate drying, filter and be concentrated in vacuo.Residue is thin by preparative Layer chromatography isolates and purifies (petrol ether/ethyl acetate=1/1), obtains (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- first Base -3- [2- (4- methylthiazol -2- bases) -7,8- dihydros -5H-1,6- naphthyridines -6- bases] propan-2-ol (73.00 milligrams, 162.61 Micromole, 29.03% yield), it is white solid.1H NMR (300MHz, CDCl3) δ 8.07 (s, 1H), 7.97 (d, J= 8.1Hz, 1H), 7.41 (d, J=8.1Hz, 1H), 6.99 (s, 1H), 4.07 (s, 2H), 3.98-3.81 (m, 2H), 3.18-3.04 (m, 4H), 2.76-2.67 (m, 1H), 2.54 (s, 3H), 2.07 (s, 1H), 1.22 (s, 3H)
Step 7：
(S) -2- methyl -2- ((2- (4- methylthiazol -2- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) - 6- nitros 2,3- glyoxalidine simultaneously [2,1b] azoles
To (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -2- methyl -3- [2- (4- methylthiazol -2- bases) -7,8- bis- Hydrogen -5H--1-, 6- naphthyridines -6- bases] propan-2-ol (73.00 milligrams, 162.61 micromoles, 1.00 equivalents) DMF (2.00 milliliters) It is disposable in solution to add sodium hydrogen (13.01 milligrams, 325.22 micromoles, 2.00 equivalents) under -45 DEG C of nitrogen protections.Will mixing Thing is stirred 10 minutes at -45-0 DEG C.Residue is poured into saturated ammonium chloride solution (30 milliliters) and stirred 5 minutes.Aqueous phase Extracted with ethyl acetate (50 milliliters × 3), the organic phase of merging is washed with salt solution (20 milliliters × 2), uses anhydrous anhydrous sodium sulfate Dry, filter and be concentrated in vacuo, residue separates (GX-F by preparative separation chromatography；Phenomenex Synergi C18 150*25*10um；Acetonitrile 32%-62%；Water (0.225%FA-ACN)；25mL/min) purify, obtain (S) -2- methyl -2- ((2- (4- methylthiazol -2- bases)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -6- nitro -2, 3- glyoxalidine simultaneously [2,1b] azoles by compound 55 (27.96 milligrams, 65.35 micromoles, 40.19% yield, 96.4% purity) 。1H NMR (400MHz, CDCl3) δ 7.94 (d, J=8.0Hz, 1H), 7.52 (s, 1H), 7.39 (d, J=8.0Hz, 1H), 6.97 (s, 1H), 4.43 (d, J=9.7Hz, 1H), 3.96 (d, J=9.5Hz, 1H), 3.93-3.80 (m, 2H), 3.19-3.07 (m, 2H), 3.06-2.90 (m, 3H), 2.80 (d, J=14.9Hz, 1H), 2.53 (s, 3H), 1.69 (s, 3H) .LCMS (ESI) m/z： 413.1(M+1).
Embodiment 56
(S) -2- ((2- (4- fluoro-2-methylbenzenes base)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl - 6- nitros 2,3- glyoxalidine simultaneously [2,1b] azoles
By key intermediate B (300.00 milligrams, 857.71 micromoles, 1.00 equivalents) and (the fluoro- 2- methylphenyls of 4-) boron Sour (198.07 milligrams, 1.29 mMs, 1.50 equivalents) are dissolved in dioxane (5.00 milliliters) and water (500.00 microlitres), plus Enter Pd (dppf) Cl2(31.38 milligrams, 42.89 micromoles, 0.05 equivalent) and cesium fluoride (260.57 milligrams, 1.72 mMs, 2.00 equivalents).Mixture is stirred 10 hours at 110 DEG C.Water (50 milliliters) is added into reactant mixture to be quenched, Ran Houyong Ethyl acetate (50 milliliters × 3) is extracted.The organic layer of merging is washed with saturated aqueous common salt (50 milliliters), it is dried over sodium sulfate, Filter and be concentrated to give residue under reduced pressure.Residue is isolated and purified into (GX-F by preparative separation chromatography； Phenomenex Synergi C18 150*25*10um；Acetonitrile 28%-49%；ACN (0.225%fomic acid)；25mL/min), (S) -2- ((2- (4- fluoro-2-methylbenzenes base)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) first is obtained Base) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles by compound 56 (104.70 milligrams, 239.60 micromoles, 27.93% yield, 96.9% purity).1H NMR (400MHz, CDCl3)：δ 7.54 (s, 1H), 7.38 (d, J=7.91Hz, 1H), 7.33 (dd, J=8.28,6.02Hz, 1H), 7.21-7.11 (m, 1H), 7.03-6.91 (m, 2H), 4.45 (d, J=9.66Hz, 1H), 4.03-3.80 (m, 3H), 3.22-2.92 (m, 5H), 2.83 (d, J=14.81Hz, 1H), 2.39-2.28 (s, 3H), 1.70 (s, 3H) .LCMS (ESI) m/z：424.1(M+1).
Embodiment 57
(S) -2- ((2- (4- fluorophenyls) -5,6- dihydros-[1,2,4] triazol [1,5-a] pyrazine -7 (8H)-yl) first Base) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 50.
(S) -2- ((2- (4- fluorophenyls) -5,6-2 hydrogen-[1,2,4] triazol [1,5-a] pyrazine -7 (8H)-yl) methyl) - 2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles by compound 57 (6.85 milligrams, 16.20 micromoles, 44.13% production Rate, 94.46% purity).1HNMR (400MHz, METHANOL-d4) δ 8.02-7.96 (m, 2H), 7.86-7.82 (m, 1H), 7.20-7.14 (m, 2H), 4.67-4.60 (m, 1H), 4.45-4.38 (m, 1H), 4.15 (s, 2H), 4.07 (s, 1H), 4.00 (s, 2H), 3.24-3.14 (m, 2H), 3.09-3.02 (m, 1H), 1.69-1.65 (m, 3H) .LCMS (ESI) m/z：400.1(M+1).
Embodiment 58
(S) -2- ((2- (the fluoro- 3- aminomethyl phenyls of 4-)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl - 6- nitros 2,3- glyoxalidine simultaneously [2,1b] azoles
By key intermediate B (100.00 milligrams, 285.90 micromoles, 1.00 equivalents) and (the fluoro- 3- methylphenyls of 4-) boron Sour (44.01 milligrams, 285.90 micromoles, 1.00 equivalents) are dissolved in dioxane (1.00 milliliters) and water (100.00 microlitres), plus Enter cesium fluoride (86.86 milligrams, 571.80 micromoles, 2.00 equivalents) and Pd (dppf) Cl2(20.92 milligrams, 28.59 micromoles, 0.10 equivalent).Mixture is stirred 10 hours at 110 DEG C.Water (50 milliliters) is added into reactant mixture to be quenched, Ran Houyong Ethyl acetate (50 milliliters × 3) is extracted.The organic layer of merging is washed with saturated aqueous common salt (50 milliliters), it is dried over sodium sulfate, Filter and be concentrated to give residue under reduced pressure, residue isolates and purifies (GX-G by preparative separation chromatography；Phenomenex Synergi Max-RP 250*8010u；Acetonitrile 20%-50%；ACN (0.225%fomic acid)；25mL/ Min), obtain (S) -2- ((2- (the fluoro- 3- aminomethyl phenyls of 4-)-(the 5H)-yl of 7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl - 6- nitros -2,3- glyoxalidine simultaneously [2,1-b] azoles (38.74 milligrams, 89.20 micromoles, 31.20% yield, 97.5% purity) Compound 58.1H NMR (400MHz, CDCl3)：δ 7.80 (d, J=7.53Hz, 1H), 7.74-7.68 (m, 1H), 7.53 (s, 1H), 7.47-7.43 (m, 1H), 7.38-7.34 (m, 1H), 7.08 (t, J=8.97Hz, 1H), 4.44 (d, J=9.66Hz, 1H), 4.02-3.79 (m, 3H), 3.22-2.91 (m, 5H), 2.81 (d, J=14.81Hz, 1H), 2.36 (s, 3H), 1.69 (s, 3H).LCMS(ESI)m/z：424.1(M+1).
Embodiment 59
(S) -2- (((the 5H)-yl of 2- cyclohexyl -7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros -2,3- Glyoxalidine simultaneously [2,11b] azoles
Step 1：
6- benzyls -2- (cyclohexene -1- bases) -7,8- dihydros -5H--1,6- benzodiazine
By 6- benzyls -2- chloro- 7,8- dihydros -5H--1,6- benzodiazine (200.00 milligrams, 772.95 micromoles, 1.00 Equivalent), cyclohexene -1- ylboronic acids (146.04 milligrams, 1.16 mMs, 1.50 equivalents), Pd (dppf) Cl2(56.56 milligrams, 77.30 micromoles, 0.10 equivalent) and cesium fluoride (234.82 milligrams, 1.55 mMs, 2.00 equivalents) be dissolved in dioxane In (4.00 milliliters) and water (0.4 milliliter), then stirred 12 hours at 110 DEG C under nitrogen protection.Reactant mixture is depressurized Concentration, water (10 milliliters) is added into residue, and extracted with (20 milliliters) of ethyl acetate.By the organic layer salt solution of merging (10 milliliters) washings, it is dried over sodium sulfate, filter and concentrate under reduced pressure, residue is isolated and purified by silica gel chromatograph (SiO2, petrol ether/ethyl acetate=20/1 to 10: 1), 6- benzyls -2- (cyclohexene -1- bases) -7,8- dihydro -5H--1 are obtained, 6- benzodiazines (160.00 milligrams, 525.57 micromoles, 68.00% yield), are yellow solid.1H NMR (300MHz, CDCl3) δ 7.36-7.11 (m, 6H), 7.05-6.99 (m, 1H), 6.54 (s, 1H), 3.64 (s, 2H), 3.53 (s, 2H), 3.01- 2.92 (m, 2H), 2.83-2.73 (m, 2H), 2.39 (br.s., 2H), 2.17 (d, J=6.2Hz, 2H), 1.77-1.66 (m, 2H), 1.65-1.55 (m, 2H)
Step 2：
2- cyclohexyl -5,6,7,8- tetrahydrochysene -1,6- benzodiazines
To 6- benzyls -2- (cyclohexene -1- bases) -7,8- dihydros -5H--1,6- benzodiazine (160.00 milligrams, 525.57 Micromole, 1.00 equivalents) methanol (5.00 milliliters) solution in add under nitrogen protection palladium dydroxide/carbon (7.38 milligrams, 52.55 micromoles, 0.10 equivalent).Suspension is deaerated, and with hydrogen displacement several times.By mixture under hydrogen (under 30psi) Stirring is reacted 12 hours at 15 DEG C.Reactant mixture is filtered, concentrates, obtains 2- cyclohexyl -5,6,7,8- tetrahydrochysenes -1,6- bis- Azanaphthalene (110.00 milligrams, 508.51 micromoles, 96.75% yield, 100% purity), is colorless oil.
Step 3：
(2R) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- (2- cyclohexyl -7,8- dihydro -5H-1,6- naphthyridines -6- bases) - 2- methyl -propyl- 2- alcohol
To 2- cyclohexyl -5,6, and 7,8- tetrahydrochysene -1,6- benzodiazines (110.00 milligrams, 508.51 micromoles, 1.00 work as Amount) ethanol (5.00 milliliters) solution in add diisopropylamine (131.44 milligrams, 1.02 mMs, 2.00 equivalents) and 2- it is chloro- 1- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (132.79 milligrams, 610.21 micromoles, 1.20 work as Amount).Mixture is stirred 12 hours at 80 DEG C.Reactant mixture is concentrated under reduced pressure, residue (20 milliliters) dilutions of water, and With (30 milliliters) extractions of ethyl acetate.The organic layer of merging is washed with salt solution (10 milliliters), it is dried over sodium sulfate, filter and It is concentrated under reduced pressure, residue isolates and purifies (silica, ethyl acetate) by preparative thin-layer chromatography, obtains (2R) -1- (2- Chloro- 4- nitroimidazoles -1- bases) -3- (2- cyclohexyl -7,8- dihydro -5H-1,6- naphthyridines -6- bases) -2- methyl -propyl- 2- alcohol (80.00 milligrams, 135.87 micromoles, 26.72% yield, 73.7% purity), are yellow solid.
Step 4：
(S) -2- (((the 5H)-yl of 2- cyclohexyl -7,8- dihydros -1,6- naphthyridines -6) methyl) -2- methyl -6- nitros -2,3- Glyoxalidine simultaneously [2,11b] azoles
To (2R) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- (2- cyclohexyl -7,8- dihydro -5H-1,6- naphthyridines -6- Base) -2- methyl propan-2-ol (80.00 milligrams, 184.36 micromoles, 1.00 equivalents) DMF (2.00 milliliters) solution at 0 DEG C Add sodium hydrogen (8.85 milligrams, 221.23 micromoles, 1.20 equivalents).Mixture is stirred 1 hour at 0 DEG C.By reactant mixture It is slowly added into the saturated ammonium chloride of cooling (10 milliliters), then with (20 milliliters) extractions of ethyl acetate.By the organic of merging Layer is washed with salt solution (10 milliliters × 2), dried over sodium sulfate, is filtered and is concentrated under reduced pressure, residue passes through preparative separation chromatography (Instrument：GX-D；Column：Boston Green ODS 150*30 5u；Mobile phase：20%-50%；H2O (+0.00225FA)；Rate：25ml/min；Monitored Wavelength：220nm/254nm；Run length：10min/ 15min；Column temperature：30 DEG C) purifying, obtain (S) -2- ((2- cyclohexyl -7,8- dihydros -1,6- naphthyridines -6 (5H)-yl) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,11b] azole compounds 59 (70.00 milligrams, 174.71 Micromole, 94.76% yield, 99.2% purity).1H NMR (400MHz, CDCl3) δ 7.52 (s, 1H), 7.30 (s, 1H), 7.00 (d, J=8.0Hz, 1H), 4.42 (d, J=9.7Hz, 1H), 3.94 (d, J=9.7Hz, 1H), 3.87-3.74 (m, 2H), 3.15- 2.90 (m, 5H), 2.84-2.67 (m, 2H), 2.02-1.72 (m, 5H), 1.67 (s, 3H), 1.52-1.23 (m, 5H) .LCMS (ESI)m/z：398.2(M+I).
Embodiment 60
(S) -2- ((2- (4- fluorophenyls) -7,7- dimethyl -6,7- thiazoline simultaneously [5,4-c] pyridine -5 (4H)-yl) first Base) -2- methyl 6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Step 1：
1- benzyl -3,3- lupetidine -4- ketone
Formaldehyde (18.26 grams, 225.00 mMs, 2.25 equivalents) is dissolved in ethanol (100.00 milliliters), Bian amine (10.72 grams, 100.00 mMs, 1.00 equivalents) are slowly added in the solution.Mixture is stirred 1 hour at 15 DEG C.So The mixture is slowly added into the ethanol of 3- methyl butyl- 2- ketone (8.61 grams, 100.00 mMs, 1.00 equivalents) afterwards In the reflux solution of (100.00 milliliters) and hydrochloric acid (9.20 milliliters).Mixture is stirred 12 hours at 80 DEG C.Then will be mixed Compound is cooled to 15 DEG C, then add diisopropylamine (14.22 grams, 110.00 mMs, 1.10 equivalents) and formaldehyde (2.44 grams, 30.00 mMs, 0.30 equivalent), and the mixture is stirred for 7 hours at 80 DEG C.By reactant mixture potassium hydroxide PH ＞ 10 are adjusted to, then with (200 milliliters) extractions of ethyl acetate.The organic layer of merging is washed with salt solution (100 milliliters), through sulphur Sour sodium is dried, and is filtered and is simultaneously being concentrated under reduced pressure, by residue by silica gel chromatography (SiO2, petrol ether/ethyl acetate=30/1~ 10: 1) purify, obtain 1- benzyls 3,3- lupetidine -4- ketone (10.00 grams, 46.02 mMs, 46.02% yield), is nothing Color grease.
Step 2：
3,3- lupetidine -4- ketone
By 1- benzyl -3,3- lupetidine -4- ketone (5.00 grams, 23.01 mMs, 1.00 equivalents) and 1- chloroethyl carbon Acyl chlorides (6.58 grams, 46.02 mMs, 2.00 equivalents) is dissolved in dichloroethanes (50.00 milliliters), by mixture degassing nitrogen Displacement 3 times, then mixture is stirred 12 hours, then concentrate mixture at 80 DEG C, adds methanol (50.00 milliliters), And stir the mixture at 80 DEG C other 4 hours.Reactant mixture concentration is removed into MeOH, by residue dichloromethane (20 milliliters) are washed and filtered, and are collected solid and are obtained 3,3- lupetidine -4- ketone (3.00 grams, 18.33 mMs, 79.67% Yield, hydrochloride), it is white solid.
1H NMR (400MHz, METHANOL-d4) δ 3.56 (t, J=6.7Hz, 1H), 3.37 (s, 1H), 3.25-3.07 (m, 1H), 3.01 (s, 1H), 2.76 (t, J=6.7Hz, 1H), 2.07-1.99 (m, 1H), 1.25 (s, 3H), 1.10 (d, J= 13.2Hz, 3H)
Step 3：
3,3- dimethyl -4- oxo-piperidine -1- benzyl carboxylates
To 3,3- lupetidine -4- ketone；The tetrahydrofuran of hydrochloride (1.00 grams, 6.11 mMs, 1.00 equivalents) In the mixed solution of (5.00 milliliters) and water (5.00 milliliters) sodium acid carbonate (1.28 grams, 15.28 mMs, 2.50 are added at 0 DEG C Equivalent) and CbzCl (1.25 grams, 7.33 mMs, 1.20 equivalents).Mixture is stirred 12 hours at 15 DEG C.The reaction is mixed Thing (20 milliliters) extractions of ethyl acetate.The organic layer of merging is washed with salt solution (10 milliliters × 2), dried over sodium sulfate, mistake Filter and be concentrated under reduced pressure, obtain 3,3- dimethyl -4- oxo-piperidine -1- benzyl carboxylates (1.60 grams, 4.81 mMs, 78.66% production Rate, 78.5% purity), it is colorless oil.1H NMR (400MHz, CDCl3) δ 7.35-7.25 (m, 6H), 5.11 (s, 2H), 3.72 (t, J=6.3Hz, 2H), 3.42 (br.s., 2H), 2.44 (br.s., 2H), 1.02 (br.s., 6H)
Step 4：
Bromo- 3, the 3- dimethyl -4- oxo-piperidines -1- carboxylic acids of benzyl 5-
To 3,3- dimethyl -4- oxo-piperidine -1- benzyl carboxylates (1.10 grams, 4.21 mMs, 1.10 equivalents) in THF The bromide (1.44 grams, 3.83 mMs, 1.00 equivalents) of phenyl trimethicone amine three is added in (10.00 milliliters) solution.By mixture Stirred 1 hour at 15 DEG C.Add water (10 milliliters) to be quenched, then with (20 milliliters) extractions of ethyl acetate.By the organic of merging Layer is washed with salt solution (10 milliliters), dried over sodium sulfate, is filtered and is concentrated under reduced pressure, obtains bromo- 3, the 3- dimethyl -4- of crude product 5- Oxo piperidine -1- benzyl carboxylates (1.40 grams, thick) are yellow oil, straight for next step.
Step 5：
2- (4- fluorophenyls) -7,7- dimethyl -4,6- thiazoline simultaneously [5,4-c] pyridine -5- benzyl formates
By bromo- 3, the 3- dimethyl -4- oxo piperidines -1- benzyl carboxylates of 5- (1.85 grams, 5.44 mMs, 1.00 equivalents), 4- fluoro thio benzamides (843.89 milligrams, 5.44 mMs, 1.00 equivalents) are dissolved in isopropanol (20.00 milliliters), mixture Deaerate and use nitrogen displacement 3 times, mixture is then reacted into 12 hours at 80 DEG C.By reactant mixture with water (20 milliliters) Dilution, and extracted with (40 milliliters) of ethyl acetate.The organic layer of merging is washed with salt solution 40 milliliters (20 milliliters × 2), through sulphur Sour sodium is dried, and is filtered and is simultaneously concentrated under reduced pressure, residue by silica gel chromatography (SiO2, petrol ether/ethyl acetate=20/1~ 10: 1) purify, obtain 2- (4- fluorophenyls) -7,7- dimethyl -4,6- thiazoline simultaneously [5,4-c] pyridine -5- benzyl formates (800.00 milligrams, 2.02 mMs, 37.09% yield), are colorless oil.
Step 6：
2- (4- fluorophenyls) -7,7- dimethyl -5,6- dihydro -4H- thiazoles simultaneously [5,4-c] pyridine
By 2- (4- fluorophenyls) -7,7- dimethyl -4,6- thiazoline simultaneously [5,4-c] pyridine -5- benzyl formates (500.00 Milligram, 1.26 mMs, 1.00 equivalents) it is dissolved in hydrogen bromide acetic acid solution (5.00mL), then nitrogen displacement exists mixture Stirred 2 hours at 15 DEG C.Reactant mixture concentration is removed into part acetic acid, solid is filtered, 2- (4- fluorophenyls) -7,7- is obtained Dimethyl -5,6- dihydro -4H- thiazoles simultaneously [5,4-c] pyridine (400.00 milligrams, 1.17 mMs, 92.86% yield, hydrobromic acid Salt), obtain as yellow solid.1H NMR (400MHz, CDCl3) δ 7.35-7.25 (m, 6H), 5.11 (s, 2H), 3.72 (t, J= 6.3Hz, 2H), 3.42 (br.s., 2H), 2.44 (br.s., 2H), 1.02 (br.s., 6H)
Step 6：
(2R) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -7,7- dimethyl -4,6- thiazolines And [5,4-C] pyridine -5- bases] -2- methyl -propyl- 2- alcohol
By 2- (4- fluorophenyls) -7,7- dimethyl -5,6- dihydro -4H- thiazoles simultaneously [5,4-c] pyridine (200.00 milligrams, 582.65 micromoles, 1.00 equivalents, hydrobromate), the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitre Base imidazoles (152.15 milligrams, 699.18 micromoles, 1.20 equivalents), diisopropylamine (225.91 milligrams, 1.75 mMs, 3.00 Equivalent) it is dissolved in ethanol (5.00 milliliters), nitrogen displacement, then mixture is stirred 12 hours at 80 DEG C.By reaction mixing Thing (10 milliliters) of water dilution, and with ethyl acetate (20 milliliters) extract.The organic layer of merging is washed with salt solution (10 milliliters), It is dried over sodium sulfate, filter and be concentrated under reduced pressure, residue is passed through into silica gel chromatography (SiO2, petrol ether/ethyl acetate=10/1 ~5/1) purify, obtain (2R) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -7,7- dimethyl -4,6- Thiazoline simultaneously [5,4-c] pyridine -5- bases] -2- methyl -propyl- 2- alcohol (200.00 milligrams, 416.71 micromoles, 71.52% production Rate), it is yellow oil.1H NMR (300MHz, CDCl3) δ 8.05 (s, 1H), 7.94-7.84 (m, 2H), 7.12 (t, J= 8.6Hz, 2H), 4.09-3.78 (m, 4H), 2.90-2.57 (m, 4H), 1.47-1.35 (m, 6H), 1.31-1.26 (m, 3H)
Step 7：
(S) -2- ((2- (4- fluorophenyls) -7,7- dimethyl -6,7- thiazoline simultaneously [5,4-c] pyridine -5 (4H)-yl) first Base) -2- methyl 6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
To (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -7,7- dimethyl -4,6- dihydro thiophenes Azoles simultaneously [5,4-C] pyridine -5- bases] -2- methyl -propyl- 2- alcohol (250.00 milligrams, 520.89 micromoles, 1.00 equivalents) DMF In (5.00 milliliters) solution, sodium hydrogen (31.25 milligrams, 781.33 micromoles, 1.50 equivalents) is added at 0 DEG C.By mixture 0 DEG C stirring 1 hour, reactant mixture is added in the saturated ammonium chloride of cooling (20 milliliters) and is quenched, E ethyl acetate is then used (20 milliliters) extractions.The organic layer of merging is washed with salt solution (10 milliliters), it is dried over sodium sulfate, filter and be concentrated under reduced pressure, Residue passes through preparative separation chromatography (Instrument：GX-D；Column：Boston Green ODS 150*30 5u； Mobile phase：58%-88%；ACN(+0.00225FA)；Rate：25ml/min；Monitored Wavelength： 220nm/254nm；Run length：10min/15min；Column temperature：30 DEG C of) purifying, obtain (S) -2- ((2- (4- fluorophenyls) -7,7- dimethyl -6,7- thiazoline simultaneously [5,4-c] pyridine -5 (4H)-yl) methyl) -2- methyl 6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azole compounds 60 (72.40 milligrams, 163.25 micromoles, 31.34% yield, 100% is pure Degree).1H NMR (400MHz, CDCl3) δ 7.87 (dd, J=5.3,8.8Hz, 1H), 7.52 (s, 1H), 7.11 (t, J=8.6Hz, 2H), 4.51 (d, J=9.7Hz, 1H), 3.96 (d, J=9.7Hz, 1H), 3.92-3.81 (m, 2H), 3.12 (d, J=15.1Hz, 1H), 2.89 (d, J=11.5Hz, 1H), 2.79 (d, J=15.1Hz, 1H), 2.66 (d, J=11.5Hz, 1H), 1.69 (s, 3H), 1.32 (s, 3H), 1.16 (s, 3H)；LCMS(ESI)m/z：444.2(M+1).
Embodiment 61
(S) -2- (4- fluorophenyls) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) - 4,5,6-, 7- tetrahydrochysene oxazole simultaneously [5,4-c] pyridine
Synthetic method such as embodiment 41.
(S) -2- (4- fluorophenyls) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) - 4,5,6-, 7- tetrahydrochysene oxazole simultaneously [5,4-c] pyridine by compound 61 (63.20 milligrams, 149.47 micromoles, 8.12% yield, 94.452% purity).1H NMR (400MHz, CDCl3) δ 7.94-7.86 (m, 2H), 7.46 (s, 1H), 7.06 (s, 2H), 4.35- 4.29 (m, 1H), 3.91-3.85 (m, 1H), 3.77 (s, 2H), 3.09-2.97 (m, 2H), 2.93-2.84 (m, 1H), 2.75- 2.67 (m, 1H), 2.56 (br.s., 2H), 1.58 (s, 3H) .LCMS (ESI) m/z：400.2(M+1).
Embodiment 62
(S) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) -2- (3,4,5- trifluoros Phenyl) -4-, 5,6,7- tetrahydrochysene oxazoles simultaneously [5,4-c] pyridine
Synthetic method such as embodiment 41.
(S) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) -2- (3,4,5- trifluoros Phenyl) -4-, 5,6,7- tetrahydrochysene oxazoles simultaneously [5,4-c] pyridine by compound 62 (222.70 milligrams, 484.42 micromoles, 42.49% yield, 94.7% purity).1H NMR (400MHz, CDCl3) δ 7.62 (t, J=7.2Hz, 2H), 7.55 (s, 1H), 4.45-4.35 (m, 1H), 3.98 (d, J=9.8Hz, 1H), 3.86 (s, 2H), 3.19-3.06 (m, 2H), 3.03-2.92 (m, 1H), 2.80 (d, J=14.8Hz, 1H), 2.70-2.58 (m, 2H), 1.68 (s, 3H) .LCMS (ESI) m/z：436(M+1).
Embodiment 63
(S) -2- methyl -6- nitros -2- ((2- (3,4,5- trifluorophenyl) -6,7- thiazolines simultaneously [5,4-c] pyridines -5 (4H)-yl) methyl base) -2,3- glyoxalidine simultaneously [2,1b] azoles
Step 1：
3,4,5- trifluoro-benzene thioamides
To tetrahydrofuran (80.00 millis of 3,4,5- benzamide trifluoroacetates (2.90 grams, 16.56 mMs, 1.00 equivalents) Rise) in solution, add lawesson reagent (7.37 grams, 18.22 mMs, 1.10 equivalents).Mixture is stirred 3 hours at 70 DEG C. By reactant mixture in the removing solvent that is concentrated under reduced pressure, by residue (200 milliliters) dilutions of water, and with (30 milliliters of ethyl acetate × 3) extract.The organic layer of merging is washed with saturated brine (30 milliliters × 2), it is dried over sodium sulfate, filter and under reduced pressure Concentration, by silica gel chromatography, (SiO2, petrol ether/ethyl acetate=5/1) purify, obtains 3,4,5- trifluoro-benzenes thio to residue Acid amides (4.35 grams, crude product), is yellow solid.
Step 2：
The bromo- 4- oxo-piperidines -1- benzyl carboxylates of 3-
To the chloroform of benzyl 4- oxo-piperidine -1- t-butyl formates (5.00 grams, 21.44 mMs, 1.00 equivalents) In (50.00 milliliters) solution, bromine (3.43 grams, 21.44 mMs, 1.00 equivalents) is added dropwise under 25 DEG C of nitrogen protections. Mixture is stirred 2 hours at 25 DEG C, the saturated sodium sulfite (100 milliliters) that reactant mixture adds cooling is quenched, then Extracted with dichloromethane (50 milliliters × 3).The organic layer of merging is washed with saturated sodium carbonate (100 milliliters × 2), through sodium sulphate Dry, filter and be concentrated under reduced pressure, obtain the bromo- 4- oxo-piperidines -1- benzyl carboxylates of crude product 3- (7.10 grams, crude product), be yellow Grease, is directly used in next step.
Step 3：
2- (3,4,5- trifluorophenyl) -6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-benzyl carboxylate
To the isopropanol of the bromo- 4- oxo-piperidines -1- benzyl carboxylates of base 3- (7.10 grams, 22.74 mMs, 1.00 equivalents) In (50.00 milliliters) solution, 3,4,5- trifluoro-benzenes thioamides (4.35 grams, 22.74 mMs, 1.00 equivalents) is added.Will be mixed Compound is stirred 12 hours at 80 DEG C, and concentrated reaction mixture removes solvent, and residue is passed through into silica gel chromatography (SiO2, stone Oily ether/ethyl acetate=5/1 to 1: 1, then in dichloromethane：Methanol=50：1) purify, obtain 2- (3,4,5- trifluoro-benzenes Base) -6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-benzyl carboxylate (1.00 grams, crude product) are yellow oil.LCMS (ESI)m/z：405(M+1).
Step 4：
2- (3,4,5- trifluorophenyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine
By 2- (3,4,5- trifluorophenyl) -6,7- thiazolines simultaneously [5,4-c] pyridine -5 (4H)-benzyl carboxylate (1.00 grams, 2.47 mMs, 1.00 equivalents) it is dissolved in hydrogen bromide acetic acid solution (3.00 milliliters).Mixture is stirred 2 hours at 25 DEG C. Reactant mixture is concentrated to remove solvent under reduced pressure, crude product 2- (3,4,5- trifluorophenyl) -4,5,6,7- tetrahydrochysenes is obtained Thiazole simultaneously [5,4-c] pyridine (1.00 grams, slightly, hydrobromate), is yellow solid, is directly used in next step.LCMS(ESI)m/ z：271(M+1).
Step 5：
(S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- methyl -3- (2- (3,4,5- trifluorophenyl) -6,7- bis- Hydrogen thiophene [5-, 4-c] pyridine -5 (4H)-yl) propan-2-ol
To 2- (3,4,5- trifluorophenyl) -4,5,6,7- tetrahydro-thiazoles simultaneously [5,4-c] pyridine (350.00 milligrams, 996.61 Micromole, 1.00 equivalents, hydrobromate) and (S) -2- chlorine 1- ((2- expoxy propane -2- bases) methyl) -4- nitro -1H- imidazoles In ethanol (10.00 milliliters) solution of (260.25 milligrams, 1.20 mMs, 1.20 equivalents), diisopropylamine (386.41 millis are added Gram, 2.99 mMs, 3.00 equivalents).Mixture is stirred 12 hours at 80 DEG C.Reactant mixture is concentrated under reduced pressure and removed Solvent is removed, residue (SiO2, petrol ether/ethyl acetate=5/1~1: 1) is purified by silica gel chromatography, obtains (S) -1- (2- Chloro- 4- nitros -1H- imidazoles -1- bases) -2- methyl -3- (2- (3,4,5- trifluorophenyl) -6,7- thiazolines simultaneously [5,4-c] pyrroles Pyridine -5 (4H)-yl) propan-2-ol (200.00 milligrams, 409.94 micromoles, 41.13% yield) is yellow solid.LCMS(ESI) m/z：488/490(M+1/M+3).
Step 6：
(S) -2- methyl -6- nitros -2- ((2- (3,4,5- trifluorophenyl) -6,7- thiazolines simultaneously [5,4-c] pyridines -5 (4H)-yl) methyl base) -2,3- glyoxalidine simultaneously [2,1b] azoles
To (S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -2- methyl -3- (2- (3,4,5- trifluorophenyl) -6,7- Dihydro thiophene [5-, 4-c] pyridine -5 (4H)-yl) propan-2-ol (100.00 milligrams, 204.97 micromoles, 1.00 equivalents) DMF In (2.00 milliliters) solution sodium hydrogen (9.84 milligrams, 245.96 micromoles, 1.20 equivalents) is added in 0 DEG C.Mixture is stirred at 0 DEG C Mix 30 minutes, add saturated ammonium chloride (50 milliliters) and reaction is quenched, and extracted with dichloromethane (10 milliliters × 3).By merging Organic layer is washed with saturated brine (10 milliliters × 2), dried over sodium sulfate, is filtered and is concentrated under reduced pressure, residue passes through preparative Separation chromatography (GX-F；Phenomenex Synergi C18 150*30mm*4um；Acetonitrile 50%-80%； Water (0.225%fomic acid)；Rate：25mL/min) purify, obtain (S) -2- methyl -6- nitros -2- ((2- (3,4, 5- trifluorophenyls) -6,7- thiazolines simultaneously [5,4-C] pyridine -5 (4H)-yl) methyl) -2,3- glyoxalidine simultaneously [2,1b] azoles Compound 63 (23.00 milligrams, 50.67 micromoles, 24.72% yield, 99.448% purity).1H NMR (400MHz, CDCl3)δ 7.60-7.48 (m, 3H), 4.41 (d, J=8.0Hz, 2H), 4.03-3.91 (m, 3H), 3.22-3.10 (m, 2H), 3.09-2.99 (m, 1H), 2.91-2.83 (m, 2H), 2.79 (d, J=16.0Hz, 2H), 1.68 (s, 3H) .LCMS (ESI) m/z：452(M+1).
Embodiment 64
(S) -2- (4- fluorophenyls) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) - 4,5,6-, 7- tetrahydrofuran simultaneously [3,2-c] pyridine
Step 1：
3- [2- (4- fluorophenyls) -2- oxo-ethyls] -4- oxo piperidine -1- benzyl carboxylates
By 4- oxo-piperidine -1- benzyl carboxylates (5.00 grams, 21.44 mMs, 1.00 equivalents) and pyrrolidines (6.10 grams, 85.76 mMs, 4.00 equivalents), TsOH.H2O (407.83 milligrams, 2.14 mMs, 0.10 equivalent) is dissolved in toluene (20.00 Milliliter) in, it is heated to 130 DEG C and stirs while using fraction water device water-dividing, after 12 hours, about 0.5 milliliter of water is separated out, dense at 50 DEG C Contract the mixture, crude product 4- pyrrolidin-1-yl -3,6- dihydro -2H- pyridine -1- benzyl carboxylates (7.00 grams, crude product), is palm fibre Color grease, it is disposable into toluene (15.00 milliliters) solution of the crude product (1.50 grams, 5.24 mMs, 1.00 equivalents) 2- bromo- 1- (4- fluorophenyls) ethyl ketone (1.14 grams, 5.24 mMs, 1.00 equivalents), mixture are added under 10 DEG C of nitrogen protections Stirred 12 hours at 10 DEG C, concentration, by residue by Silica gel chromatography (petrol ether/ethyl acetate=10/1,2/1), Obtain 3- [2- (4- fluorophenyls) -2- oxo-ethyls] -4- oxo piperidine -1- benzyl carboxylate (550.00 milligrams, 1.49 mmoles You, 28.41% yield), it is yellow oil.
Step 2：
2- (4- fluorophenyls) -6,7- dihydrofuran simultaneously [3,2-c] pyridine -5 (4H)-benzyl carboxylate
To 3- [2- (4- fluorophenyls) -2- oxo-ethyls] -4- oxo piperidine -1- benzyl carboxylate (400.00 milligrams, 1.08 MM, 1.00 equivalents) toluene (6.00 milliliters) solution in, disposably under nitrogen protection in 15 DEG C add POCl3s (1.81 grams, 11.80 mMs, 10.93 equivalents).Mixture is stirred 1 hour at 100 DEG C.Mixture is poured into water (30 millis Rise) in and stir 5 minutes.Aqueous phase is extracted with ethyl acetate (50mL × 3).The organic phase of merging is with salt solution (30 milliliters), with nothing Aqueous sodium persulfate is dried, and is filtered and is concentrated in vacuo, residue separates (petrol ether/ethyl acetate=1/0,10/ by silica gel chromatography 1) purify, obtain 2- (4- fluorophenyls) -6,7- dihydrofuran simultaneously [3,2-c] pyridine -5 (4H)-benzyl carboxylate (200.00 milligrams, 569.20 micromoles, 52.70% yield), it is yellow oil.
Step 3：
2- (4- fluorophenyls) -4,5,6,7- tetrahydrofurans simultaneously [3,2-c] pyridine
By 2- (4- fluorophenyls) -6,7- dihydrofuran simultaneously [3,2-c] pyridine -5 (4H)-benzyl carboxylate (233.00 milligrams, 663.12 micromoles, 1.00 equivalents) it is dissolved in hydrogen bromide acetic acid solution (5 milliliters, 92.08 mMs, 138.86 equivalents), will be mixed Compound is stirred 30 minutes at 15 DEG C.The mixture is concentrated at 45 DEG C, 2- (4- fluorophenyls) -4 is obtained, 5,6,7- tetrahydrofurans are simultaneously [3,2-c] pyridine (200.00 milligrams, slightly, hydrobromate), it is yellow solid.LCMS(ESI)m/z：218.1(M+1).
Step 4：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -6,7- dihydro -4H- furans simultaneously [3,2- C] pyridine -5- bases] -2- casees base phenethyl -propyl- 2- alcohol
To 2- (4- fluorophenyls) -4,5,6,7- tetrahydrofurans simultaneously [3,2-c] pyridine (197.71 milligrams, 663.12 micromoles, 1.00 equivalents, hydrobromate) and the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (158.73 Milligram, 729.43 micromoles, 1.10 equivalents) the tert-butyl alcohol (10.00 milliliters) solution in disposably add two under nitrogen protection Isopropylamine (171.40 milligrams, 1.33 mMs, 2.00 equivalents).Mixture is stirred 12 hours at 80 DEG C, in 45 DEG C of concentrations The mixture, residue is purified by silica gel chromatography (petrol ether/ethyl acetate=1/0,2/1), and obtaining (2S) -1-, (2- is chloro- 4- nitroimidazole -1- bases) -3- [2- (4- fluorophenyls) -6,7- dihydro -4H- furans simultaneously [3,2-c] pyridine -5- bases] -2- case base benzene Ethyl -propyl- 2- alcohol (190.00 milligrams, 436.93 micromoles, 65.89% yield), is yellow solid.1H NMR (400MHz, CDCl3) δ 8.08 (s, 1H), 7.64-7.57 (m, 2H), 7.12-7.04 (m, 2H), 6.39 (s, 1H), 4.07-4.02 (m, 2H), 3.65 (d, J=14.9Hz, 2H), 3.12-2.95 (m, 2H), 2.85-2.78 (m, 2H), 2.70 (d, J=14.1Hz, 1H), 2.54 (d, J=14.2Hz, 1H), 1.20 (s, 3H)
Step 5：
(S) -2- (4- fluorophenyls) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) - 4,5,6-, 7- tetrahydrofuran simultaneously [3,2-c] pyridine
To (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -6,7- dihydro -4H- furans simultaneously [3, 2-c] pyridine -5- bases] -2- methyl -propyl- 2- alcohol (190.00 milligrams, 436.93 micromoles, 1.00 equivalents) DMF (5.00 milli Rise) disposable in solution add sodium hydrogen (34.95 milligrams, 873.86 micromoles, 2.00 equivalents) under -45 DEG C of nitrogen protections.Will Mixture is stirred 10 minutes at -45-0 DEG C, and mixture is poured into saturated ammonium chloride (30 milliliters), and is stirred 5 minutes.Use second Acetoacetic ester (50 milliliters × 3) is extracted, and the organic phase of merging is washed with salt solution (30 milliliters), and with anhydrous sodium sulfate drying, filtering is simultaneously It is concentrated in vacuo, residue passes through preparative separation chromatography (GX-D；Boston Green ODS 150*30 5u； Acetonitrile 40%-70%；Water (0.225%fomic acid)；25mL/min) purify, obtain (S) -2- (4- fluorine Phenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) -4,5,6,7- tetrahydrofurans are simultaneously [3,2-c] pyridine compounds 64 (33.40 milligrams, 82.41 micromoles, 18.86% yield, 98.3% purity).1H NMR (400MHz, CDCl3) δ 7.58 (dd, J=5.3,8.8Hz, 2H), 7.54 (s, 1H), 7.06 (t, J=8.7Hz, 2H), 6.36 (s, 1H), 4.42 (d, J=9.5Hz, 1H), 3.94 (d, J=9.5Hz, 1H), 3.63 (s, 2H), 3.19-3.06 (m, 2H), 2.98-2.88 (m, 1H), 2.74 (d, J=14.9Hz, 1H), 2.71-2.56 (m, 2H), 1.67 (s, 3H) .LCMS (ESI) m/z： 399.1(M+1).
Embodiment 65
(S) -2- (3,4- difluorophenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) first Base) -4,5-, 6,7- tetrahydrochysene oxazoles simultaneously [4,5-c] pyridine
Step 1：
3- aminopyridine -4- alcohol
To 3- nitropyridine -4- alcohol (30.00 grams, 214.13 mMs, 1.00 equivalents) methanol (500.00 milliliters) and In DMF (10.00 milliliters) mixed solution it is disposable added under 15 DEG C of nitrogen protections palladium carbon (3.00 grams, 214.13 mMs, 1.00 equivalents).Mixture is stirred 4 hours under 15 DEG C of condition, hydrogen (25-40Psi), filtering, filtrate is concentrated to dryness, it is remaining Hydrochloric acid methanol (4N, 100mL) is added in thing, is then filtered mixture, filter cake is washed with dichloromethane (200 milliliters), overanxious And filter cake is collected, 3- aminopyridine -4- alcohol (31.00 grams, 211.50 mMs, 98.77% yield, hydrochloric acid) is obtained, is greyish white Color solid.1H NMR (400MHz, DMSO-d6) δ 14.44 (br, s, 1H), 7.96-7.84 (m, 2H), 7.27 (d, J=6.3Hz, 1H).
Step 2：
3,4- bis- fluoro- N- (4- hydroxyl -3- pyridine radicals) benzamides
To the dichloromethane of 3- aminopyridine -4- alcohol (15.00 grams, 102.34 mMs, 1.00 equivalents, hydrochloride) It is disposable under nitrogen protection in (200.00 milliliters) that triethylamine (41.42 grams, 409.36 mMs, 56.74 are added at 0 DEG C Milliliter, 4.00 equivalents).Then adding 3,4- difluoro benzoyl chlorides, (25.30 grams, 143.28 mMs, 17.94 milliliters, 1.40 work as Amount), obtained mixture is stirred 12 hours under 15 degrees Celsius.Mixture is filtered, filter cake is with dichloromethane (50 milliliters) Washing, obtains the fluoro- N- of 3,4- bis- (4- hydroxyl -3- pyridine radicals) benzamide (30.00 grams, crude product), is yellow solid.1H NMR (400MHz, DMSO-d6) δ 11.91 (br, s, 1H), 9.39 (s, 1H), 8.69 (br, s, 1H), 7.97 (ddd, J=2.1,7.8, 11.2Hz, 1H), 7.84-7.77 (m, 1H), 7.73 (d, J=5.1Hz, 1H), 7.62 (td, J=8.4,10.3Hz, 1H), 6.31 (d, J=7.0Hz, 1H) .LCMS (ESI) m/z：251(M+1).
Step 3：
2- (3,4- difluorophenyl) azoles simultaneously [4,5-c] pyridine
By carbon trichloride (35.48 grams, 149.88 mMs, 16.98 milliliters, 2.50 equivalents), triphenylphosphine (47.17 grams, 179.86 mMs, 3.00 equivalents) and triethylamine (48.53 grams, 479.62 mMs, 66.48 milliliters, 8.00 equivalents) be dissolved in two In chloromethanes (200.00 milliliters), mixture is stirred 0.5 hour at 15 degrees Celsius, and fluoro- N- (the 4- hydroxyls of 3,4- bis- are then added portionwise Base -3- pyridine radicals) benzamide (15.00 grams, 59.95 mMs, 1.00 equivalents).Then by gained mixture in 15 DEG C of stirrings 12 hours.This is added drop-wise to 1N hydrochloric acid in 0 DEG C of reactant mixture, water layer (100 milliliters × 3) are extracted into dichloromethane, then Water layer is adjusted to pH=8 with saturated sodium bicarbonate aqueous solution, water layer is extracted with dichloromethane (100 milliliters × 3), merging has Machine mutually uses salt water washing (100 milliliters), with anhydrous sodium sulfate drying, and filtering and vacuum concentration obtain 2- (3,4- difluorophenyl) Azoles simultaneously [4,5-c] pyridine (in 4.50 gram, 19.38 mMs, 32.33% yield), is yellow solid.1H NMR (400MHz, CDCl3) δ 9.13 (d, J=0.8Hz, 1H), 8.67-8.58 (m, 1H), 8.16-8.02 (m, 2H), 7.62-7.53 (m, 1H), 7.38 (td, J=8.4,9.3Hz, 1H) .LCMS (ESI) m/z：233(M+1).
Step 4：
5- benzyls -2- (3,4- difluorophenyl) azoles simultaneously [4,5-c] pyridine -5- bromides
To the acetonitrile of 2- (3,4- difluorophenyl) azoles simultaneously [4,5-c] pyridine (4.50 grams, 19.38 mMs, 1.00 equivalents) Bian bromine (16.57 grams, 96.90 mMs, 11.51 milliliters, 5.00 are added in (80.00 milliliters) solution in 0 DEG C under nitrogen protection Equivalent).Mixture is stirred 12 hours at 15 DEG C.Mixture is filtered, filter cake is collected, and obtains 5- benzyls -2- (3,4- difluorobenzenes Base) azoles simultaneously [4,5-c] pyridine -5- bromides (6.00 grams, 14.88 mMs, 76.78% yield) are white solid.1H NMR (400MHz, METHANOL-d4) δ 9.78 (s, 1H), 9.12 (d, J=7.0Hz, 1H), 8.46 (d, J=6.8Hz, 1H), 8.37-8.21 (m, 2H), 7.69-7.55 (m, 3H), 7.54-7.42 (m, 3H), 6.04-5.95 (m, 2H) .LCMS (ESI) m/z： 323(M+1).
Step 5：
5- benzyls -2- (3,4- difluorophenyl) -6,7- dihydro -4H- oxazoles simultaneously [4,5-c] pyridine
To 5- benzyls -2- (3,4- difluorophenyl) -6,7- dihydro -4H- oxazoles simultaneously [4,5-c] pyridine (5.00 grams, 12.40 MM, 1.00 equivalents) methanol (80.00 milliliters) solution in, at -10-5 DEG C nitrogen protection under add sodium borohydride (4.69 grams, 124.00 mMs, 10.00 equivalents).Mixture is stirred 12 hours at 15 DEG C.Water is added into the mixture (200 milliliters), are then extracted with ethyl acetate (200 milliliters × 4).The organic phase of merging is washed with saturated brine (100 milliliters) Wash, with anhydrous sodium sulfate drying, filter and be concentrated in vacuo.Residue is passed through into Silica gel chromatography (pillar height degree：250 millimeters, Diameter：100 millimeters, 100-200 mesh silica gel, petrol ether/ethyl acetate=20/1 to 5/1), obtain 5- benzyls -2- (3,4- difluoros Phenyl) -6,7- dihydro -4H- oxazoles simultaneously [4,5-c] pyridine (3.80 grams, crude product) are yellow oil.1H NMR (400MHz, CDCl3) δ 7.81 (ddd, J=2.1,7.6,11.0Hz, 1H), 7.77-7.72 (m, 1H), 7.43-7.30 (m, 5H), 7.28- 7.19 (m, 2H), 3.82-3.76 (m, 2H), 3.60-3.53 (m, 2H), 2.95-2.88 (m, 2H), 2.88-2.79 (m, 2H)
Step 6：
The tetrahydrochysene oxazoles of 2- (3,4- difluorophenyl) -4,5,6,7- simultaneously [4,5-c] pyridine hydrochloride
To 5- benzyls -2- (3,4- difluorophenyl) -6,7- dihydro -4H- oxazoles simultaneously [4,5-c] pyridine (3.80 grams, 11.64 MM, 1.00 equivalents) dichloroethanes (60.00 milliliters) solution in, disposably add 1- chloroethyls under the protection of 0 DEG C of nitrogen Phosgene (4.99 grams, 34.92 mMs, 3.00 equivalents).Mixture is stirred 12 hours at 100 DEG C.Mixture is concentrated Methanol (80 milliliters) is added in solvent, residue to remove, is then stirred for mixture at 80 DEG C 1 hour.Then will mixing Thing is concentrated to dryness, and ethyl acetate (50 milliliters) is added in residue, mixture is filtered, and is collected filter cake, is obtained 2- (3,4- difluoros Phenyl) -4,5,6,7- tetrahydrochysene oxazoles simultaneously [4,5-c] pyridine hydrochloride (3.80 grams, slightly, hydrochloride) is yellow solid.1H NMR (400MHz, DMSO-d6) δ 9.85 (br, s, 2H), 8.01-7.93 (m, 1H), 7.87-7.79 (m, 1H), 7.69-7.59 (m, 1H), 4.20 (br, s, 2H), 3.52-3.49 (m, 2H), 3.12-3.03 (m, 2H)
Step 7：
[2- (3,4- difluorophenyl) -6,7- dihydro -4H- oxazoles are simultaneously by (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- (4,5-] pyridine -5- bases] -2- methyl -propyl- 2- alcohol
To the tetrahydrochysene oxazoles of 2- (3,4- difluorophenyl) -4,5,6,7- simultaneously [4,5-c] pyridine (2.00 grams, 7.33 mMs, 1.00 equivalents, hydrochloride) and the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (1.60 grams, 7.33 mMs, 1.00 equivalents) the tert-butyl alcohol (30.00 milliliters) solution in, disposably under nitrogen protection in 15 DEG C add two Isopropylamine (2.37 grams, 18.34 mMs, 3.20 milliliters, 2.50 equivalents).Mixture is stirred 12 hours at 100 DEG C.Will be mixed Compound is concentrated to dryness, and residue passes through Silica gel chromatography (pillar height degree：250 millimeters, diameter：100 millimeters, 100-200 mesh silicon Glue, petrol ether/ethyl acetate=20/1 to 1/1), obtain (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (3,4- bis- Fluorophenyl) -6,7- dihydro -4H- oxazoles simultaneously [4,5-c] pyridine -5- bases] -2- methyl -propyl- 2- alcohol (1.00 grams, 2.20 mMs, 30.06% yield), it is yellow solid.LCMS(ESI)m/z：454(M+1).
Step 8：
(S) -2- (3,4- difluorophenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) first Base) -4,5-, 6,7- tetrahydrochysene oxazoles simultaneously [4,5-c] pyridine
To (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (3,4- difluorophenyl) -6,7- dihydro -4H- oxazoles And (4,5-] pyridine -5- bases] -2- methyl -propyl- 2- alcohol (1.00 grams, 2.20 mMs, 1.00 equivalents) DMF (10.00 milliliters) In solution it is disposable added under -5 DEG C of nitrogen protections sodium hydrogen (176.00 milligrams, 4.40 mMs, 60% purity, 2.00 work as Amount).Mixture is stirred 0.5 hour at -5 DEG C.Mixture is added drop-wise in ammonium chloride (100 milliliters) solution, filters and collects Filter cake, obtains crude product, and it is passed through into Silica gel chromatography (pillar height degree：250 millimeters, diameter：100 millimeters, 100-200 mesh Silica gel, petrol ether/ethyl acetate=20/1 to 1/1), obtain (S) -2- (3,4- difluorophenyl) -5- ((2- methyl -6- nitros - 2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) -4,5-, 6,7- tetrahydrochysene oxazoles simultaneously [4,5-c] pyridine (386.40 milligrams, 907.28 micromoles, 41.24% yield, 98.0% purity).1H NMR (400MHz, CDCl3) δ 7.80 (ddd, J=2.0,7.6, 10.9Hz, 1H), 7.74 (ddd, J=1.7,4.0,8.6Hz, 1H), 7.55-7.51 (m, 1H), 7.24 (td, J=8.3, 9.8Hz, 1H), 4.37 (d, J=9.7Hz, 1H), 3.96 (d, J=9.7Hz, 1H), 3.77-3.65 (m, 2H), 3.23 (td, J= 4.9,12.1Hz, 1H), 3.16 (d, J=15.1Hz, 1H), 2.94 (ddd, J=4.6,7.9,12.3Hz, 1H), 2.78 (d, J= 15.1Hz, 1H), 2.75-2.66 (m, 1H), 2.66-2.55 (m, 1H), 1.68 (s, 3H) .LCMS (ESI) m/z：418(M+1).
Embodiment 66
(S) -2- (4- fluorophenyls) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) - 4,5,6-, 7- tetrahydrochysene oxazole simultaneously [4,5-c] pyridine
Synthetic method such as embodiment 65.
(S) -2- (4- fluorophenyls) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) - 4,5,6-, 7- tetrahydrochysene oxazole simultaneously [4,5-c] pyridine by compound 66 (16.60 milligrams, 39.04 micromoles, 21.27% yield, 93.931% purity).1H NMR (400MHz, CDCl3) δ 7.94-7.84 (m, 2H), 7.45 (s, 1H), 7.09 (s, 2H), 4.32- (s, the 3H) .LCMS of 4.22 (m, 1H), 3.96-3.70 (m, 3H), 3.31-3.17 (m, 2H), 3.04-2.70 (m, 4H), 1.63 (ESI)m/z：400.2(M+1).
Embodiment 67
(S) -2- ((2- (4- fluorophenyls) -6,7- dihydros thiophene simultaneously [4,5-c] pyridine -5 (4H)-yl) methyl) -2- methyl -6- Nitro -2-, 3 glyoxalidine simultaneously [2,1b] azoles
Step 1：
N- (4- chloro-3-pyridyls base) fluoro- benzamides of -4-
Add into acetonitrile (20.00 milliliters) solution of 4- chloropyridine -3- amine (2.00 grams, 15.56 mMs, 1.00 equivalents) Entering pyridine (2.46 grams, 31.12 mMs, 2.00 equivalents) and 4- fluorobenzoyl chlorides, (2.71 grams, 17.12 mMs, 1.10 work as Amount).Mixture is stirred 2 hours at 20 DEG C.By the lower concentration of reactant mixture decompression.Then water (100 milliliters), Ran Houyong are added Dichloromethane extracts (200 milliliters × 3).The organic layer of merging is dried with sodium sulphate, filters and is concentrated under reduced pressure, N- (4- are obtained Chloro-3-pyridyl base) the fluoro- benzamides of -4- (3.20 gram, 12.77 mMs, 82.07% yield) are white solid.1H NMR (300MHz, CDCl3) δ 9.65 (s, 1H), 8.28 (d, J=5.27Hz, 1H), 8.12 (br.s., 1H), 7.93-7.83 (m, 2H), 7.33 (d, J=5.09Hz, 1H), 7.22-7.11 (m, 3H)
Step 2：
2- (4- fluorophenyls) thiazole simultaneously [4,5-c] pyridine
To the first of N- (4- chloro-3-pyridyls base) fluoro- benzamides of -4- (3.20 gram, 12.77 mMs, 1.00 equivalents) Lawesson reagent (3.62 grams, 8.94 mMs, 0.70 equivalent) is added in benzene (50.00 milliliters) solution.Mixture is stirred at 110 DEG C Mix 12 hours.Reactant mixture is concentrated, saturated sodium bicarbonate solution (100 milliliters) is added into residue, dichloro is then used Methane extracts (150 milliliters × 3).The organic layer of merging is dried over sodium sulfate, filter and be concentrated under reduced pressure, residue is passed through into silicon Glue chromatography purifies (pillar height degree：300 millimeters, 50 millimeters of diameter, 100-200 mesh silica gel, petrol ether/ethyl acetate=5/1,3/ 1,1/1) 2- (4- fluorophenyls) thiazole simultaneously [4,5-c] pyridine (1.50 grams, 6.51 mMs, 51.01% yield), are obtained, are white Color solid.1H NMR (400MHz, CDCl3) δ 9.28 (s, 1H), 8.46 (d, J=5.52Hz, 1H), 8.09-8.00 (m, 2H), 7.79 (d, J=5.40Hz, 1H), 7.21-7.09 (m, 2H)
Step 3：
5- benzyls -2- (4- fluorophenyls) thiazole simultaneously [4,5-c] pyridine -5- bromides
By 2- (4- fluorophenyls) thiazole simultaneously [4,5-c] pyridine (700.00 milligrams, 3.04 mMs, 1.00 equivalents) and Bian bromine (519.94 milligrams, 3.04 mMs, 1.00 equivalents) are dissolved in acetonitrile (5.00 milliliters), and mixture is in nitrogen displacement, Ran Hou Stirred 2 hours at 20 DEG C.Mixture is filtered, filter cake is washed with dichloromethane (20 milliliters).Collect filter cake, obtain 5- benzyls- 2- (4- fluorophenyls) thiazole simultaneously [4,5-c] pyridine -5- bromides (1.20 grams, 2.99 mMs, 98.36% yield), are white Color solid.
Step 4：
5- benzyls -2- (4- fluorophenyls) -4,5,6,7- tetrahydrochysenes [4,5-c] pyridine
To 5- benzyls -2- (4- fluorophenyls) thiazole simultaneously [4,5-c] pyridine -5- bromides (900.00 milligrams, 2.24 mmoles You, 1.00 equivalents) methanol (200.00 milliliters) solution in nitrogen protection it is lower add palladium dydroxide/carbon (157.28 milligrams, 1.12 mMs, 0.50 equivalent).Suspension is deaerated and changed 3 times with hydrogen.By mixture at hydrogen (50psi), 50 DEG C Stirring 12 hours.Reactant is filtered.Filtrate decompression is concentrated, 5- benzyls -2- (4- fluorophenyls) -4,5,6,7- tetrahydrochysenes is obtained [4,5-c] pyridine (580.00 milligrams, 1.79 mMs, 79.91% yield) is white solid.1H NMR (400MHz, METHANOL-d4) δ 8.01-7.91 (m, 2H), 7.68-7.51 (m, 5H), 7.23 (t, J=8.72Hz, 2H), 4.59 (s, 2H), 4.49-4.37 (m, 2H), 3.74 (br.s., 2H), 3.38-3.33 (m, 2H)
Step 5：
2- (4- fluorophenyls) -4,5,6,7- tetrahydrochysenes [4,5-c] pyridine
To 5- benzyls -2- (4- fluorophenyls) -6,7- dihydro -4H- thiazoles simultaneously [4,5-c] pyridine (600.00 milligrams, 1.85 milli Mole, 1.00 equivalents) dichloroethanes (5.00 milliliters) in, add 1- chloroethyls phosgene (396.74 milligrams, 2.78 mmoles You, 1.50 equivalents).Mixture is stirred 16 hours at 80 DEG C.Concentration removes dichloroethanes, and adds methanol (5.00 millis Rise), mixture is stirred 2 hours at 60 DEG C.Mixture is filtered and by filtration cakes torrefaction, obtains 2- (4- fluorophenyls) -4, 5,6,7- tetrahydrochysenes [4,5-c] pyridine (280.00 milligrams, 1.20 mMs, 64.60% yield) is white solid.LCMS(ESI) m/z：235(M+1).
Step 6：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -6,7- dihydro -4H- thiazoles simultaneously [4,5- C] pyridine -5- bases] -2- methyl -propyl- 2- alcohol
To 2- (4- fluorophenyls) -4, and 5,6,7- tetrahydrochysenes [4,5-c] pyridine (200.00 milligrams, 853.64 micromoles, 1.00 work as Amount) and the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] meter Yi Ji] -4- nitroimidazoles (222.91 milligrams, 1.02 mmoles You, 1.20 equivalents) the tert-butyl alcohol (2.00 milliliters) solution in add diisopropylamine (220.65 milligrams, 1.71 mMs, 2.00 work as Amount).Mixture is stirred 12 hours at 80 DEG C.Water (50 milliliters) is added into reactant mixture, is then extracted with ethyl acetate Take (50 milliliters × 3).The organic layer of merging is dried over sodium sulfate, filter and concentrate under reduced pressure, residue is passed through into silica gel Chromatography purifies (pillar height degree：300 millimeters, 50 millimeters of diameter, 100-200 mesh silica gel, petrol ether/ethyl acetate=5/1,3/1), Obtain (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -6,7- dihydro -4H- thiazoles simultaneously [4,5-c] pyrroles Pyridine -5- bases] -2- methyl -propyl- 2- alcohol (230.00 milligrams, 508.96 micromoles, 59.62% yield) is yellow solid.
Step 7：
(S) -2- ((2- (4- fluorophenyls) -6,7- dihydros thiophene simultaneously [4,5-c] pyridine -5 (4H)-yl) methyl) -2- methyl -6- Nitro -2-, 3 glyoxalidine simultaneously [2,1b] azoles
To (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4-fluorop phenyl) -6,7- dihydro -4H- thiazoles And the DMF (3.00 of [4,5- pyridine -5- bases] -2- methyl -propyl- 2- alcohol (230.00 milligrams, 508.96 micromoles, 1.00 equivalents) Milliliter) sodium hydrogen (40.72 milligrams, 1.02 mMs, 2.00 equivalents) is added in solution.Mixture is stirred 30 points at -45 DEG C Clock.Then it is stirred 30 minutes at 0 DEG C.Reactant mixture is added in saturated ammonium chloride solution (50 milliliters), then Extracted with ethyl acetate (50 milliliters × 3).The organic layer of merging is dried over sodium sulfate, filter and be concentrated to give under reduced pressure residual Excess.Residue passes through preparative separation chromatography (GX-I；Phenomenex Gemini 150*25mm*10um； Acetonitrile 36%-66%；ACN (0.225%fomic acid)；25mL/min) purify, obtain (S) -2- ((2- (4- Fluorophenyl) -6,7- dihydros thiophene simultaneously [4,5-c] pyridine -5 (4H)-yl) methyl) -2- methyl -6- nitros -2,3- glyoxalidine is simultaneously [2,1b] azoles is by compound 67 (84.60 milligrams, 200.99 micromoles, 39.49% yield, 98.7% purity).1H NMR (400MHz, CDCl3- d) δ 7.83-7.72 (m, 2H), 7.44 (s, 1H), 7.09-6.98 (m, 2H), 4.31 (d, J=9.66Hz, 1H), 3.92-3.72 (m, 3H), 3.16-3.01 (m, 2H), 2.84-2.52 (m, 4H), 1.60 (s, 3H) .LCMS (ESI) m/z： 416(M+1).
Embodiment 68
(S) -2- ((2- (3,4- difluorophenyl) -6,7- dihydros thiophene simultaneously [4,5-c] pyridine -5 (4H)-yl) methyl) -2- first Base -6- nitros 2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 67.
(S) -2- ((2- (3,4- difluorophenyl) -6,7- dihydros thiophene simultaneously [4,5-c] pyridine -5 (4H)-yl) methyl) -2- first Base -6- nitros 2,3- glyoxalidine simultaneously [2,1b] azole compounds 68 (75.10 milligrams, 171.19 micromoles, 32.18% yield, 98.8% purity).1H NMR (400MHz, CDCl3) δ 7.73 (ddd, J=2.2,7.6,11.0Hz, 1H), 7.62-7.56 (m, 1H), 7.53 (s, 1H), 7.26-7.17 (m, 1H), 4.39 (d, J=9.5Hz, 1H), 3.99-3.82 (m, 3H), 3.28-3.11 (m, 2H), 2.92-2.74 (m, 3H), 2.73-2.61 (m, 1H), 1.69 (s, 3H) .LCMS (ESI) m/z：434.2(M+1).
Embodiment 69
(S) -2- ((2- (4- fluorophenyls) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azoles
Step 1：
2,5- dihydro -1H- pyrroles
To the dichloro of tert-butyl group -2,5- pyrrolin -1- carboxylic acid tert-butyl esters (2.00 grams, 11.82 mMs, 1.00 equivalents) Trifluoroacetic acid (9.18 grams, 80.51 mMs, 6.81 equivalents) is added in methane (6.00 milliliters) solution, by mixture at 20 DEG C Stirring 1 hour.Mixture is concentrated under reduced pressure, and obtains crude product for dark brown grease.It is directly used in next step.
Step 2：
1- tosyl -2,5- dihydro -1H- pyrroles
To dichloromethane (10.00 millis of 2,5- dihydro -1H- pyrroles (2.16 grams, 11.79 mMs, 1.00 equivalents, TFA) Rise) in solution, add TosCl (2.70 grams, 14.15 mMs, 1.20 equivalents) and triethylamine (3.58 grams, 35.37 mMs, 3.00 equivalents.Mixture is stirred 16 hours at 20 DEG C.By reactant mixture with 1M watery hydrochloric acid (30 milliliters), saturation NaHCO 3 is molten Liquid (30mL) and salt solution (30mL) washing.By organic layer through anhydrous sodium sulfate drying, filter and be concentrated under reduced pressure, obtain 1- (to first Benzenesulfonyl) -2,5- pyrrolin (1.50 grams, 6.72 mMs, 56.98% yield) is brown solid.
Step 3：
The bromo- 1- tosyls pyrrolidines -3- alcohol of 4-
To the DMSO of 1- (p-toluenesulfonyl) -2,5- pyrrolin (1.50 grams, 6.72 mMs, 1.00 equivalents) In 0 DEG C of addition NBS, (1.79 grams, 10.08 mMs, 1.50 work as in batches in (10.00 milliliters) and acetonitrile (5.00 milliliters) solution Amount).Then mixture is stirred 16 hours at 15 DEG C.Water (50mL) is added into reactant mixture, and with ethyl acetate (30 Milliliter × 2) extract.The organic layer of merging is washed with salt solution (30 milliliters), through anhydrous sodium sulfate drying, filtered and under reduced pressure Concentration, residue passes through silica gel chromatography (SiO2, petrol ether/ethyl acetate=10: 1 to 3: 1) purify, obtain the bromo- 1- of 4- (right Tosyl) pyrrolidines -3- alcohol (1.58 grams, 4.93 mMs, 73.43% yield) be white solid.
Step 4：
The bromo- 1- tosyls pyrrolidines -3- ketone of 4-
To the dichloro of 4- bromo- 1- (p-toluenesulfonyl) pyrrolidines -3- alcohol (1.58 grams, 4.93 mMs, 1.00 equivalents) In methane (15.00 milliliters) solution, this Martin reagent (4.19 grams, 9.87 mMs, 2.00 equivalents) is worn in addition, then uses nitrogen Conversion, then stirs mixture 12 hours at 10~15 DEG C.By reactant mixture with sodium bicarbonate aqueous solution (50 milliliters × 2) wash, and extracted with ethyl acetate (30 milliliters × 2).By the organic layer of merging through anhydrous sodium sulfate drying, filter and subtracting Pressure concentration, (silica, petrol ether/ethyl acetate=10: 1 to 1: 1), obtain are isolated and purified by residue by silica gel chromatograph It is yellow to 4- bromo- 1- (p-toluenesulfonyl) pyrrolidines -3- ketone (980.00 milligrams, 3.08 mMs, 62.47% yield) Solid.1H NMR (300MHz, CDCl3) δ 7.69-7.61 (d, J=8.1Hz, 2H), 7.35-7.28 (d, J=7.8Hz, 2H), 4.32-4.25 (t, J=6.3Hz, 1H), 4.00-3.91 (m, 1H), 3.61 (s, 2H), 3.55-3.47 (m, 1H), 2.39 (s, 3H).
Step 5：
2- (4- fluorophenyls) -5- tosyls 4,5,6,6a tetrahydrochysene tetrahydrochysene -3aH- pyrrolo-es [3,4-d] thiazole 3a alcohol
Exist to 4- bromo- 1- (p-toluenesulfonyl) pyrrolidines -3- ketone (880.00 milligrams, 2.77 mMs, 1.00 equivalents) 4- fluoro thio benzamides (430.00 milligrams, 2.77 mMs, 1.00 equivalents) are added in DMF (12.00 milliliters) solution.Will be mixed Compound is stirred 16 hours at 60 DEG C.Reactant mixture is concentrated under reduced pressure, residue (10 milliliters) dilutions of ethyl acetate, mistake Filter, collects filter cake and the liquid after filtering is passed through into silica gel chromatography (SiO2, petrol ether/ethyl acetate=10: 1,3: 1) pure Change, obtain 2- (4- fluorophenyls) -5- tosyls 4,5,6,6a tetrahydrochysene tetrahydrochysene -3aH- pyrrolo-es [3,4-d] thiazole 3a alcohol (900.00 milligrams, 2.49 mMs), are pale solid.
Step 6：
2- (4- fluorophenyls) -5- tosyls -5,6- dihydro -4H- pyrrolo-es [3,4-D] thiazole
By 2- (4- fluorophenyls) -5- tosyls 4,5,6,6a tetrahydrochysene tetrahydrochysene -3aH- pyrrolo-es [3,4-d] thiazole 3a's Alcohol (900.00 milligrams, 2.29 mMs, 1.00 equivalents), methane sulfonyl chloride (444.00 milligrams, 3.88 mMs, 1.69 equivalents) It is dissolved in triethylamine (730.00 milligrams, 7.21 mMs, 3.15 equivalents) in dichloromethane (20.00 milliliters), mixture degassing And protected with nitrogen, then mixture is stirred 16 hours at 20 DEG C.Add water (50 milliliters), and with (30 milliliters of dichloromethane × 2) extract.By the organic layer anhydrous sodium sulfate drying of merging, filter and be concentrated under reduced pressure, residue is passed through into silica gel chromatography (SiO2, petrol ether/ethyl acetate=20: 1 to 1: 1) purify, obtain 2- (4- fluorophenyls) -5- tosyls -5,6- dihydro - 4H- pyrrolo-es [3,4-D] thiazole (600.00 milligrams, 1.11 mMs, 48.28% yield, 69% purity), is light yellow solid Body.
Step 7：
2- (4- fluorophenyls) -5,6- dihydro -4H- pyrrolo-es [3,4-D] thiazole
To 2- (4- fluorophenyls) -5- tosyls -5,6- dihydro -4H- pyrrolo-es [3,4-D] thiazole (550.00 milligrams, 1.01 mMs, 1.00 equivalents) water (3.00 milliliters) and AcOH (15.00 milliliters) mixed solution in add bromination acetate hydrogen it is molten Liquid (81.72 milligrams, 1.01 mMs, 1.00 equivalents).Mixture is stirred 1 hour at 20 DEG C.Reactant mixture is depressurized dense Contracting, then with the dilution of (50 milliliters) of water, and with ethyl acetate (50 milliliters) extract.By water layer be basified to NaOH regulation pH value= 11, then extracted with ethyl acetate (40 milliliters × 2), through anhydrous sodium sulfate drying, filter and be concentrated under reduced pressure, obtain 2- (4- fluorine Phenyl) -5,6- dihydro -4H- pyrrolo-es [3,4-D] thiazole (145.00 milligrams, 658.28 micromoles, 65.18% yield) is light Yellow solid.
Step 8：
(S) -1- (the chloro- 4- nitros -1H- imidazoles -1- bases of 2-) -3- (2- (4- fluorophenyls) -4H- pyrrolo-es [3,4-d] thiophenes Azoles -5 (6H)-yl) -2- methyl propan-2-ols
To 2- (4- fluorophenyls) -5,6- dihydro -4H- pyrrolo-es [3,4-D] thiazole (160.00 milligrams, 726.38 micromoles, 1.00 equivalents) 2- chloro- 1- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (158.00 are added in solution Milligram, 726.07 micromoles, 1.00 equivalents) and diisopropylamine (481.00 milligrams, 3.72 mMs, 5.12 equivalents).Will mixing Thing is stirred 16 hours at 80 DEG C.Water (50 milliliters) is added, and is extracted with ethyl acetate (30 milliliters × 2).By the organic of merging Layer is filtered and simultaneously concentrated under reduced pressure through anhydrous sodium sulfate drying, residue separated by preparative thin-layer chromatography (silica, Dichloromethane：Methanol=20: (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -4,6- bis- 1), are obtained Hydrogen pyrrolo- [3,4-d] thiazole -5- bases] -2- methyl -propyl- 2- alcohol (150.00 milligrams, 342.56 micromoles, 47.16% production Rate), it is faint yellow solid.
Step 9：
(S) -2- ((2- (4- fluorophenyls) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azoles
To (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3-, [2- (4- fluorophenyls) -4,6- pyrrolin is simultaneously [3,4-d] Thiazole -5- bases] -2- methyl -propyl- 2- alcohol (150.00 milligrams, 342.56 micromoles, 1.00 equivalents) DMF (5.00 milliliters) it is molten In liquid sodium hydrogen (30.00 milligrams, 750.00 micromoles, 2.19 equivalents) is added under 0 DEG C of nitrogen protection.Mixture is stirred at 0 DEG C Mix 1 hour.Reactant mixture is poured at 0 DEG C in saturated ammonium chloride solution (40 milliliters), then with (30 milliliters of ethyl acetate × 2) extract.By the organic layer anhydrous sodium sulfate drying of merging, filtering, and concentrate under reduced pressure, by residue acetic acid second Ester is purified, and obtains (2S) -2- [[2- (4- fluorophenyls) -4,6- pyrrolin simultaneously [3,4-d] thiazole -5- bases] methyl] -2- methyl 6- nitro -3H- imidazos [2,1b] azoles (17.71 milligrams, 40.90 micromoles, 11.94% yield, 92.71% purity).1H NMR (400MHz, CDCl3) δ 7.91-7.84 (m, 2H), 7.57 (s, 1H), 7.17-7.09 (t, J=8.4Hz, 2H), 4.53- 4.48 (d, J=9.6Hz, 1H), 4.20 (d, J=3.3Hz, 3H), 4.13-4.07 (m, 1H), 4.03-3.97 (m, J=9.6Hz, 1H), 3.42 (d, J=14.8Hz, 1H), 3.12 (d, J=14.8Hz, 1H), 1.64-1.60 (m, 3H) .LCMS (ESI) m/z： 402.10(M+1).
Embodiment 70
(S) -2- ((2- (3- fluorophenyls) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (3- fluorophenyls) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azole compounds 70 (67.10 milligrams, 165.99 micromoles, 48.46% yield, 99.3% is pure Degree).1H NMR (400MHz, CDCl3) δ 7.67-7.58 (m, 2H), 7.55 (s, 1H), 7.39 (dt, J=5.8,8.0Hz, 1H), 7.11 (dt, J=1.8,8.3Hz, 1H), 4.49 (d, J=9.7Hz, 1H), 4.26-4.17 (m, 3H), 4.14-4.06 (m, 1H), (s, the 3H) .LCMS of 3.98 (d, J=9.7Hz, 1H), 3.40 (d, J=14.8Hz, 1H), 3.11 (d, J=14.7Hz, 1H), 1.70 (ESI)m/z：402.2(M+1).
Embodiment 71
(S) -2- ((2- (3,4- difluorophenyl) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl - 6- nitros -2-, 3 glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (3,4- difluorophenyl) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl - 6- nitros -2-, 3 glyoxalidine simultaneously [2,1b] azole compounds 71 (49.80 milligrams, 115.42 micromoles, 21.05% yield, 97.2% purity).1H NMR (400MHz, CDCl3) δ 7.75 (ddd, J=2.2,7.5,11.0Hz, 1H), 7.65-7.58 (m, 1H), 7.56 (s, 1H), 7.25-7.19 (m, 1H), 4.49 (d, J=9.7Hz, 1H), 4.27-4.18 (m, 3H), 4.13-4.07 (m, 1H), 4.00 (d, J=9.7Hz, 1H), 3.42 (d, J=14.8Hz, 1H), 3.12 (d, J=14.7Hz, 1H), 1.72 (s, 3H).LCMS(ESI)m/z：420.2(M+1).
Embodiment 72
(S) -2- methyl -6- nitros -2- ((2- (4- (trifluoromethyl) phenyl) -4H- pyrrolo-es [3,4-d] thiazoles -5 (6H)-yl) methyl) -2-, 3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- methyl -6- nitros -2- ((2- (4- (trifluoromethyl) phenyl) -4H- pyrrolo-es [3,4-d] thiazoles -5 (6H)-yl) methyl) -2-, 3- glyoxalidine simultaneously [2,1b] azole compounds 72 (24.30 milligrams, 52.53 micromoles, 17.68% production Rate, 97.59% purity).1H NMR (400MHz, CDCl3) δ 8.01 (d, J=8.0Hz, 2H), 7.70 (d, J=8.3Hz, 2H), 7.57 (s, 1H), 4.50 (d, J=9.7Hz, 1H), 4.29-4.20 (m, 3H), 4.16-4.09 (m, 1H), 4.00 (d, J= 9.7Hz, 1H), 3.43 (d, J=14.8Hz, 1H), 3.13 (d, J=14.7Hz, 1H), 1.72 (s, 3H) .LCMS (ESI) m/z： 452.2(M+1).
Embodiment 73
(S) -2- methyl -6- nitros -2- ((2- (4- (trifluoromethoxy) phenyl) -4H- pyrrolo-es [3,4-d] thiazoles -5 (6H)-yl) methyl) -2-, 3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- methyl -6- nitros -2- ((2- (4- (trifluoromethoxy) phenyl) -4H- pyrrolo-es [3,4-d] thiazoles -5 (6H)-yl) methyl) -2-, 3- glyoxalidine simultaneously [2,1b] azole compounds 73 (46.00 milligrams, 97.82 micromoles, 16.43% production Rate, 99.4% purity).1H NMR (400MHz, CHLOROFORM-d)=7.96-7.89 (m, 1H), 7.56 (s, 1H), 7.31- 7.29 (m, 2H), 4.54-4.46 (m, 1H), 4.29-4.17 (m, 3H), 4.16-4.07 (m, 1H), 4.00 (d, J=9.7Hz, 1H), 3.42 (d, J=14.7Hz, 1H), 3.12 (d, J=14.7Hz, 1H), 1.72 (s, 3H) .LCMS (ESI) m/z：468.1(M +1).
Embodiment 74
(S) -2- ((2- (2- fluorophenyls) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (2- fluorophenyls) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azole compounds 74 (45.45 milligrams, 110.14 micromoles, 34.45% yield, 97.271% Purity).1H NMR (400MHz, CDCl3) δ 8.23-8.16 (m, 1H), 7.56 (s, 1H), 7.44-7.36 (m, 1H), 7.28- 7.17 (m, 2H), 4.51 (d, J=8.0Hz, 1H), 4.29-4.22 (m, 3H), 4.17-4.10 (m, 1H), 4.00 (d, J= 12.0Hz, 1H), 3.43 (d, J=16.0Hz, 1H), 3.13 (d, J=16.0Hz, 1H), 1.72 (s, 3H) .LCMS (ESI) m/z： 402(M+1).
Embodiment 75
(S) -2- ((2- (4- fluorophenyls) -5H- pyrrolo-es [3,4-d] thiazole -5- bases) methyl) -2- methyl -6- nitro -2, 3- glyoxalidine simultaneously [2,1b] azoles
By (2S) -2- [[2- (4- fluorophenyls) -4,6- pyrrolin simultaneously [3,4-d] thiazole -5- bases] methyl] -2- methyl - Ethyl acetate (30.00 millis of 6- nitro -3H- imidazos [2,1b] azoles (100.00 milligrams, 249.12 micromoles, 1.00 equivalents) Rise) solution in atmosphere in 80 DEG C stir 20 hours.Reactant mixture is concentrated under reduced pressure, residue passes through preparative thin-layer chromatography Isolate and purify (silica, dichloromethane: methanol=15: 1).Then washed with methanol (5mL), obtain (S) -2- ((2- (4- Fluorophenyl) -5H- pyrrolo-es [3,4-d] thiazole -5- bases) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles Compound 75 (12.30 milligrams, 30.40 micromoles, 12.20% yield, 98.7% purity).1H NMR (400MHz, DMSO-d6)δ 8.04 (s, 1H), 8.01-7.93 (m, 2H), 7.41-7.31 (m, 3H), 7.04 (d, J=1.8Hz, 1H), 4.69-4.54 (m, 2H), 4.29-4.16 (m, 2H), 1.56 (s, 3H) .LCMS (ESI) m/z：400.2(M+1).
Embodiment 76
(S) -2- ((2- (4- chlorphenyls) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (4- chlorphenyls) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azole compounds 76 (114.50 milligrams, 267.79 micromoles, 60.83% yield, 97.729% purity).1HNMR (400MHz, CDCl3) δ 7.83 (d, J=8.5Hz, 2H), 7.56 (s, 1H), 7.41 (d, J= 8.5Hz, 2H), 4.50 (d, J=9.5Hz, 1H), 4.29-4.16 (m, 3H), 4.14-4.05 (m, 1H), 4.00 (d, J= 9.8Hz, 1H), 3.42 (d, J=14.8Hz, 1H), 3.11 (d, J=14.8Hz, 1H), 1.71 (s, 3H) .LCMS (ESI) m/z： 418.2(M+1).
Embodiment 77
(S) -2- ((2- (the chloro- 4- fluorophenyls of 2-) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl - 6- nitros 2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (the chloro- 4- fluorophenyls of 2-) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl - 6- nitros 2,3- glyoxalidine simultaneously [2,1b] azole compounds 77 (38.00 milligrams, 85.78 micromoles, 27.01% yield, 98.384% purity).1H NMR (400MHz, CDCl3) δ 8.13-8.06 (m, 1H), 7.56 (s, 1H), 7.27-7.23 (m, 1H), 7.13-7.07 (m, 1H), 4.50 (d, J=8.0Hz, 1H), 4.30-4.20 (m, 3H), 4.18-4.09 (m, 1H), 4.00 (d, J =12.0Hz, 1H), 3.42 (d, J=12.0Hz, 1H), 3.13 (d, J=12.0Hz, 1H), 1.72 (s, 3H) .LCMS (ESI) m/ z：436/438(M+1/M+3).
Embodiment 78
(S) -2- ((2- (2,4- difluorophenyl) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl - 6- nitros -2-, 3 glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
S) -2- ((2- (2,4- difluorophenyl) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl -6- Nitro -2-, 3 glyoxalidine simultaneously [2,1b] azole compounds 78 (117.40 milligrams, 271.83 micromoles, 82.61% yield, 97.107% purity).1H NMR (400MHz, CDCl3) δ 8.23-8.14 (m, 1H), 7.56 (s, 1H), 7.03-6.92 (m, 2H), 4.50 (d, J=8.0Hz, 1H), 4.28-4.21 (m, 3H), 4.16-4.08 (m, 1H), 4.00 (d, J=12.0Hz, 1H), 3.42 (d, J=12.0Hz, 1H), 3.12 (d, J=12.0Hz, 1H), 1.72 (s, 3H) .LCMS (ESI) m/z：420(M+1).
Embodiment 79
(S) -2- ((2- (4- fluoro-2-methylbenzenes base) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- first Base -6- nitros 2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (4- fluoro-2-methylbenzenes base) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- first Base -6- nitros 2,3- glyoxalidine simultaneously [2,1b] azole compounds 79 (332.10 milligrams, 786.28 micromoles, 39.12% yield, 98.36% purity).1HNMR (400MHz, CDCl3) δ 7.65-7.54 (m, 2H), 7.05-6.92 (m, 2H), 4.56-4.46 (m, 1H), 4.31-4.17 (m, 3H), 4.15-4.09 (m, 1H), 4.03-3.97 (m, 1H), 3.47-3.35 (m, 1H), 3.20-3.06 (m, 1H), 2.56 (s, 3H), 1.72 (s, 3H) .LCMS (ESI) m/z：416.1(M+1).
Embodiment 80
(S) -2- ((2- (the fluoro- 2- methoxyphenyls of 4-) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- Methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (the fluoro- 2- methoxyphenyls of 4-) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- Methyl -6- nitros 2,3- glyoxalidine simultaneously [2,1b] azole compounds 80 (47.90 milligrams, 105.87 micromoles, 38.11% yield, 95.36% purity).1H NMR (400MHz, CHLOROFORM-d) δ=8.21-8.12 (m, 1H), 7.47 (s, 1H), 6.73- 6.61 (m, 2H), 4.43 (d, J=9.7Hz, 1H), 4.19-4.08 (m, 3H), 4.06-3.97 (m, 1H), 3.93 (s, 3H), (s, the 3H) .LCMS of 3.89 (d, J=9.7Hz, 1H), 3.32 (d, J=14.7Hz, 1H), 3.02 (d, J=14.8Hz, 1H), 1.62 (ESI)m/z：432.1(M+1).
Embodiment 81
(S) -2- ((2- (3,5- difluoro pyridine -2- bases) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- Methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (3,5- difluoro pyridine -2- bases) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- Methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azole compounds 81 (24.50 milligrams, 55.89 micromoles, 36.48% yield, 95.9% purity).1H NMR (400MHz, CDCl3) δ 8.30 (d, J=2.1Hz, 1H), 7.47 (s, 1H), 7.32-7.25 (m, 1H), 4.42 (d, J=9.7Hz, 1H), 4.25-4.13 (m, 3H), 4.10-4.03 (m, 1H), 3.90 (d, J=9.8Hz, 1H), 3.34 (d, J=14.7Hz, 1H), 3.05 (d, J=14.7Hz, 1H), 1.63 (s, 3H) .LCMS (ESI) m/z：421.1(M+1).
Embodiment 82
(S) -2- ((2- (5- fluorine pyridine -2- bases) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl - 6- nitros 2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (5- fluorine pyridine -2- bases) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl - 6- nitros 2,3- glyoxalidine simultaneously [2,1b] azole compounds 82 (970.60 milligrams, 2.37 mMs, 63.61% yield, 98.1% Purity).1H NMR (400MHz, CDCl3) δ 8.45 (d, J=2.8Hz, 1H), 8.11 (dd, J=4.5,8.7Hz, 1H), 7.56 (s, 1H), 7.51 (dt, J=2.8,8.4Hz, 1H), 4.51 (d, J=9.5Hz, 1H), 4.27-4.18 (m, 3H), 4.14-4.07 (m, 1H), 3.99 (d, J=9.7Hz, 1H), 3.42 (d, J=14.7Hz, 1H), 3.12 (d, J=14.8Hz, 1H), 1.72 (s, 3H).LCMS(ESI)m/z：403(M+1).
Embodiment 83
(S) -2- methyl -6- nitros -2- ((2- (2,4,5- trifluorophenyl) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H) - Base) methyl) -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- methyl -6- nitros -2- ((2- (2,4,5- trifluorophenyl) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H) - Base) methyl) -2,3- glyoxalidine simultaneously [2,1b] azole compounds 83 (50.80 milligrams, 114.98 micromoles, 14.54% yield, 99% purity).1H NMR (400MHz, CDCl3) δ 8.06 (ddd, J=6.8,8.8,10.9Hz, 1H), 7.61-7.49 (m, 1H), 7.12-7.01 (m, 1H), 4.50 (d, J=9.7Hz, 1H), 4.29-4.18 (m, 3H), 4.16-4.07 (m, 1H), 4.01 (d, J =9.7Hz, 1H), 3.42 (d, J=14.7Hz, 1H), 3.13 (d, J=14.8Hz, 1H), 1.72 (s, 3H) .LCMS (ESI) m/ z：438.0(M+1).
Embodiment 84
(S) -2- ((2- (3,5- difluorophenyl) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl - 6- nitros -2-, 3 glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (3,5- difluorophenyl) -4H- pyrrolo-es [3,4-d] thiazole -5 (6H)-yl) methyl) -2- methyl - 6- nitros -2-, 3 glyoxalidine simultaneously [2,1b] azole compounds 84 (48.70 milligrams, 115.57 micromoles, 27.67% yield, 99.53% purity).1H NMR (400MHz, CDCl3) δ 7.56 (s, 1H), 7.47-7.39 (m, 2H), 6.87 (tt, J=2.3, 8.7Hz, 1H), 4.49 (d, J=9.5Hz, 1H), 4.28-4.19 (m, 3H), 4.15-4.08 (m, 1H), 4.00 (d, J= 9.7Hz, 1H), 3.42 (d, J=14.8Hz, 1H), 3.12 (d, J=14.7Hz, 1H), 1.72 (s, 3H) .LCMS (ESI) m/z： 420.1(M+1)
Embodiment 85
(S)-N- (4- fluorophenyls)-N- methyl -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- Base) methyl) -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole -2- amine
Synthetic method such as embodiment 69.
(S)-N- (4- fluorophenyls)-N- methyl -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- Base) methyl) -5,6- dihydro -4H- pyrrolo-es [3,4-d] thiazole -2- amines 85 (27.10 milligrams, 62.20 micromoles, 14.52% yield, 98.8% purity).1H NMR (400MHz, CDCl3) δ 7.54 (s, 1H), 7.36-7.30 (m, 2H), 7.17- 7.08 (m, 2H), 4.48 (d, J=9.7Hz, 1H), 4.09-3.87 (m, 5H), 3.46 (s, 3H), 3.35 (d, J=14.7Hz, 1H), 3.04 (d, J=14.8Hz, 1H), 1.67 (s, 3H) .LCMS (ESI) m/z：431(M+1).
Embodiment 86
(S) -2- ((2- (4,4- difluoropiperdin -1- bases) -4H- pyrrolo-es (3,4-d] thiazole -5 (6H)-yl) methyl) -2- Methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (4,4- difluoropiperdin -1- bases) -4H- pyrrolo-es (3,4-d] thiazole -5 (6H)-yl) methyl) -2- Methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azole compounds 86 (9.30 milligrams, 20.98 micromoles, 13.31% yield, 96.2% purity).1H NMR (400MHz, CDCl3) δ 7.54 (s, 1H), 4.48 (d, J=9.7Hz, 1H), 4.08-4.00 (m, 3H), 3.98-3.85 (m, 2H), 3.66-3.58 (m, 4H), 3.35 (d, J=14.7Hz, 1H), 3.04 (d, J=14.8Hz, 1H), 2.15-2.02 (m, 4H), 1.68 (s, 3H) .LCMS (ESI) m/z：427.0(M+1).
Embodiment 87
(S) -2- ((2- (4- fluorophenyls) -5H- pyrrolo-es [3,4-d] pyrimidine -6 (7H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 44.
(S) -2- ((2- (4- fluorophenyls) -5H- pyrrolo-es [3,4-d] pyrimidine -6 (7H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azole compounds 87 (14.60 milligrams, 35.57 micromoles, 13.21% yield, 96.567% Purity).1H NMR (400MHz, CDCl3) δ 8.58 (s, 1H), 8.47-8.36 (m, 2H), 7.55 (s, 1H), 7.19-7.11 (m, 2H), 4.46 (d, J=8.0Hz, 1H), 4.28-4.11 (m, 4H), 4.00 (d, J=8.0Hz, 1H), 3.33 (d, J=12.0Hz, 1H), 3.11 (d, J=12.0Hz, 1H), 1.73 (s, 3H) .LCMS (ESI) m/z：397(M+1).
Embodiment 88
(S) -2- ((2- (4- fluorophenyls) -5H- pyrrolo-es [3,4-b] pyridine -6 (7H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azoles
Step 1：
Pyridine-2,3-dicarboxylic acid dimethyl ester
Pyridine-2,3-dicarboxylic acid (20.00 grams, 119.67 mMs, 1.00 equivalents) is molten in methanol (150.00 milliliters) The concentrated sulfuric acid (17.61 grams, 179.51 mMs, 9.57 milliliters, 1.50 equivalents) is added in liquid.Mixture is stirred 10 at 60 DEG C Hour.Add sodium carbonate liquor to adjust pH to about 9, extracted with ethyl acetate (200 milliliters × 2).The organic layer of merging is subtracted Pressure concentration, residue separated by silica gel chromatography (SiO2, petrol ether/ethyl acetate=20/1~3: 1), obtain pyridine -2, 3- dimethyl dicarboxylates (20.00 grams, 102.47 mMs, 85.63% yield), are white solid.
Step 2：
1- pyridine oxides -1--2,3- dimethyl dicarboxylate
To chloroform (160.00 millis of pyridine-2,3-dicarboxylic acid dimethyl ester (20.00 grams, 102.47 mMs, 1.00 equivalents) Rise) m-CPBA (28.74 grams, 133.21 mMs, 80% purity, 1.30 equivalents) is added in solution.By mixture at 60 DEG C Stirring 4 hours.Reactant mixture adds sodium bicarbonate aqueous solution (200 milliliters), and is extracted with dichloromethane (500 milliliters × 4). The organic layer of merging is concentrated under reduced pressure, washed with ethyl acetate (50mL), filter cake is collected by filtration and obtains 1- pyridine oxides -1-- 2,3- dimethyl dicarboxylates (17.50 grams, crude product), are white solid, are directly used in next step.
Step 3：
6- chloropyridine -2,3- dimethyl dicarboxylates
By 1- pyridine oxides -1--2,3- dimethyl dicarboxylate (14.00 grams, 66.30 mMs, 1.00 equivalents) two In the ring of oxygen six (140.00 milliliters) solution, adding POCl3, (50.83 grams, 331.50 mMs, 30.81 milliliters, 5.00 work as Amount).Mixture is stirred 2 hours at 100 DEG C.Reactant mixture is poured into water (100 milliliters) at 25 DEG C, by pH carbonic acid Sodium solution is adjusted to about 9, and is extracted with ethyl acetate (500 milliliters × 2).The organic layer of merging is concentrated under reduced pressure, residue leads to Cross Silica gel chromatography and (SiO2, petrol ether/ethyl acetate=40/1~10: 1), obtain 6- chloropyridines -2,3- dicarboxylic acids two Methyl esters (9.50 grams, 41.37 mMs, 62.40% yield), is yellow oil.
Step 4：
6- (4- fluorophenyls) pyridine-2,3-dicarboxylic acid dimethyl ester
By 6- chloropyridines -2,3- dimethyl dicarboxylate (5.00 grams, 21.78 mMs, 1.00 equivalents), (4- fluorophenyls) boron Sour (3.96 grams, 28.31 mMs, 1.30 equivalents), Pd (dppf) Cl2(796.65 milligrams, 1.09 mMs, 0.05 equivalent), Sodium carbonate (4.62 grams, 43.56 mMs, 2.00 equivalents) is dissolved in dioxane (30.00 milliliters) and H2O (400.00 microlitres) In, solution is deaerated and uses nitrogen displacement, and mixture is stirred into 10 hours at 80 DEG C.Reactant mixture is concentrated under reduced pressure removing Solvent, residue is separated by silica gel chromatography and (SiO2, petrol ether/ethyl acetate=30/1~10: 1), obtains 6- (4- fluorobenzene Base) pyridine-2,3-dicarboxylic acid dimethyl ester (5.00 grams, 17.29 mMs, 79.36% yield) is white solid.LCMS(ESI) m/z：290.2(M+1).
Step 5：
[6- (4- fluorophenyls) -2- (methylol) -3- pyridine radicals] methanol
To the first of 6- (4- fluorophenyls) pyridine-2,3-dicarboxylic acid dimethyl ester (5.00 grams, 17.29 mMs, 1.00 equivalents) In alcohol (100.00 milliliters) solution add calcium chloride (2.30 grams, 20.75 mMs, 1.20 equivalents) and sodium borohydride (6.54 grams, 172.90 mMs, 10.00 equivalents).Mixture is stirred 3 hours at 15 DEG C.The reactant mixture is with ethyl acetate (1L × 2) Extraction.The organic layer of merging is concentrated under reduced pressure, residue isolates and purifies (SiO2, petrol ether/ethyl acetate by silica gel chromatography =20/1~3: 1), obtain [6- (4- fluorophenyls) -2- (methylol) -3- pyridine radicals] methanol (3.50 grams, 15.01 mMs, 86.79% yield), it is white solid.
Step 6：
2,3- double (chloromethyl) -6- (4- fluorophenyls) pyridines
To [6- (4- fluorophenyls) -2- (methylol) -3- pyridine radicals] methanol (1.50 grams, 6.43 mMs, 1.00 equivalents) D dichloromethane (20.00 milliliters) solution in add thionyl chloride (19.68 grams, 165.42 mMs, 12.00 milliliters, 25.73 Equivalent).Mixture is stirred 0.5 hour at 0 DEG C.Reactant mixture is concentrated to removing solvent under reduced pressure, the double (chlorine of 2,3- are obtained Methyl) -6- (4- fluorophenyls) pyridine (2.00 grams, thick) is yellow oil.LCMS(ESI)m/z：270.1(M+1).
Step 7：
2- (4- fluorophenyls) -6- trityls -5,7- pyrrolin simultaneously [3,4-b) pyridine
To the DMF of double (chloromethyl) -6- (4- fluorophenyls) pyridines (2.00 grams, 7.40 mMs, 1.00 equivalents) of 2,3- Diisopropylamine (2.87 grams, 22.20 mMs, 3.88 milliliters, 3.00 equivalents) and trityl are added in (60.00 milliliters) solution Amine (2.88 grams, 11.10 mMs, 1.50 equivalents).Mixture is stirred 20 hours at 80 DEG C.By reactant mixture in decompression It is lower to concentrate to remove solvent.Residue is extracted with ethyl acetate (200 milliliters × 2).The organic layer of merging is concentrated under reduced pressure, residue Isolated and purified by silica gel chromatography and (SiO2, petrol ether/ethyl acetate=1/0~50: 1), obtain 2- (4- fluorophenyls) -6- three Benzyl -5,7- pyrrolin simultaneously [3,4-b] pyridine (1.50 grams, crude product), are white solid.1H NMR (400MHz, CDCl3)δ 7.80 (dd, J=5.4,8.8Hz, 2H), 7.53 (d, J=7.5Hz, 6H), 7.33 (s, 2H), 7.26-7.18 (m, 8H), 7.11 (d, J=7.3Hz, 4H), 7.03 (s, 2H), 4.04-3.90 (m, 4H)
Step 8：
2- (4- fluorophenyls) -6,7- dihydro -5H- pyrrolo-es [3,4-b] pyridine；2,2,2- trifluoroacetic acids
To 2- (4- fluorophenyls) -6- trityls -5,7- pyrrolin simultaneously [3,4-b] pyridine (1.50 grams, 3.29 mmoles You, 1.00 equivalents) methanol (7.00 milliliters) and chloroform (7.00 milliliters) solution in addition trifluoroacetic acid (10.78 grams, 94.54 MM, 7.00 milliliters, 28.74 equivalents).By mixture 0 DEG C stir 0.5 hour reactant mixture with water (150 milliliters × 2) wash.The aqueous phase of merging is concentrated under reduced pressure, 2- (4- fluorophenyls) -6,7- dihydro -5H- pyrrolo-es [3,4-b] pyridine is obtained；2, 2,2- trifluoroacetic acids (1.00 grams, crude product), are yellow solid.LCMS(ESI)m/z：215.2(M+1).
Step 9：
[2- (4- fluorophenyls) -5,7- pyrrolin is simultaneously [3,4-b] by (2S) -1- (the bromo- 4- nitro-imidazols -1- bases of 2-) -3- Pyridine -6- bases] -2- methyl -propyl- 2- alcohol
To 2- (4- fluorophenyls) -6,7- dihydro -5H- pyrrolo-es [3,4-b] pyridine；2,2,2- trifluoroacetic acids (1.00 grams, 3.05 mMs, 1.00 equivalents) the tert-butyl alcohol (50.00 milliliters) in addition diisopropylamine (1.18 grams, 9.14 mMs, 1.60 Milliliter, 3.00 equivalents) and the bromo- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (1.20 grams, 4.58 mMs, 1.50 equivalents).Mixture is stirred 10 hours at 40 DEG C.Reactant mixture is molten in the removing that is concentrated under reduced pressure Agent, (SiO2, petrol ether/ethyl acetate=10/1~3: (2S) -1- 1), is obtained by residue by post Silica gel chromatography (the bromo- 4- nitro-imidazols -1- bases of 2-) -3- [2- (4- fluorophenyls) -5,7--dihydropyrrolo [3,4-b] pyridine -6- bases] - 2- methyl -propyl- 2- alcohol (700.00 milligrams, crude product), is brown oil.LCMS(ESI)m/z：476.0(M+1).
Step 10：
(S) -2- ((2- (4- fluorophenyls) -5H- pyrrolo-es [3,4-b] pyridine -6 (7H)-yl) methyl) -2- methyl -6- nitre Base -2,3- glyoxalidine simultaneously [2,1b] azoles
To (2S) -1- (the bromo- 4- nitroimidazoles -1- bases of 2-) -3-, [2- (4- fluorophenyls) -5,7- pyrrolin is simultaneously [3,4-b] Pyridine -6- bases] -2- methyl -propyl- 2- alcohol (700.00 milligrams, 1.47 mMs, 1.00 equivalents) DMF (4.00 milliliters) solution Middle addition sodium hydrogen (70.54 milligrams, 2.94 mMs, 2.00 equivalents).Mixture is stirred 10 minutes at 0 DEG C.Reaction is mixed Compound is added at 0 DEG C in the aqueous solution of saturated ammonium chloride (200 milliliters), is filtered and dry cake, and filter cake passes through preparative TLC separation purifying (silica, DCM: methanol=15: 1), obtains (S) -2- ((2- (4- fluorophenyls) -5H- pyrrolo-es [3,4-b] pyridine -6- (7H)-yl) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azole compounds 88 (243.60 milligrams, 600.70 micromoles, 40.86% yield, 97.5% purity).1H NMR (400MHz, CDCl3)δ7.97- 7.89 (m, 2H), 7.55 (s, 3H), 7.21-7.11 (m, 2H), 4.58-4.46 (m, 1H), 4.34-4.08 (m, 4H), 4.04- 3.93 (m, 1H), 3.41-3.25 (m, 1H), 3.15-3.04 (m, 1H), 1.73 (s, 3H) .LCMS (ESI) m/z：396.2(M+ 1).
Embodiment 89
(S) -2- (4- fluorophenyls) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) - 5,6- dihydro -4H- pyrrolo-es (3,4-d) oxazoles
Step 1：
6- oxa- -3- azabicyclos [3.1.0] hexane -3- benzyl carboxylates
To the methanol of the bromo- 4- hydroxy-pyrrolidines -1- benzyl formates of 3- (7.50 grams, 24.99 mMs, 1.00 equivalents) NaOH is added in the mixed solution of (50.00 milliliters) and water (50.00 milliliters), and (1.50 grams, 37.49 mMs, 1.50 work as Amount).Mixture is stirred 12 hours at 20 DEG C.Water (200 milliliters) is added into mixture, then with (200 milliliters of ethyl acetate × 3) extract.The organic layer of merging is dried with sodium sulphate, filters and is concentrated under reduced pressure, 6- oxa- -3- azabicyclos are obtained [3.1.0] hexane -3- benzyl carboxylates (350.00 milligrams, 1.60 mMs, 95.81% yield), are slightly yellow grease.1H NMR (300MHz, CDCl3) δ 7.36-7.31 (m, 5H), 5.14-5.12 (m, 2H), 3.88 (t, J=12.90Hz, 1H), 3.68- 3.63 (m, 2H), 3.43-3.37 (m, 3H)
Step 2：
3- amino-4-hydroxies-pyrrolidines -1- benzyl carboxylates
By 6- oxa- -3- azabicyclos [3.1.0] hexane -3- benzyl carboxylates, (5.40 grams, 24.63 mMs, 1.00 work as Amount) and ammoniacal liquor (43.17 grams, 1.23 moles, 47.43 milliliters, 50.00 equivalents) mixing, then mixture is stirred at 100 DEG C Mix 16 hours.Mixture is concentrated under reduced pressure, obtain 3- amino-4-hydroxies-pyrrolidines -1- benzyl carboxylates (5.00 grams, 21.16 mMs, 85.92% yield), it is slightly yellow grease.
Step 3：
3- [(4- fluoro benzoyls) amino] -4- hydroxy-pyrrolidine -1- carboxylic acid benzyls
To benzyl 3- amino-4-hydroxies-pyrrolidines -1- t-butyl formates, (in 4.50 gram, 19.05 mMs, 1.00 work as Amount) and dichloromethane (50.00 milliliters) solution of 4- fluobenzoic acids (2.67 grams, 19.05 mMs, 1.00 equivalents) in addition HOBt (2.57 grams, 19.05 mMs, 1.00 equivalents), EDCI (7.30 grams, 38.10 mMs, 2.00 equivalents) and triethylamine (5.78 grams, 57.15 mMs, 7.92 milliliters, 3.00 equivalents).Mixture is stirred 12 hours at 20 DEG C.To reactant mixture Middle addition water (200 milliliters), and extracted with dichloromethane (150 milliliters × 3).The organic layer of merging is washed with saturated brine, It is dried over sodium sulfate, filter and be concentrated under reduced pressure, residue passes through silica gel chromatography (pillar height degree：300 millimeters, 50 millimeters of diameter, 100-200 mesh silica gel, petrol ether/ethyl acetate=5/1,2/1,0/1) purifying, obtain 3- [(4- fluoro benzoyls) amino] -4- Hydroxy-pyrrolidine -1- carboxylic acids benzyl (2.78 grams, 7.76 mMs, 40.73% yield) and 3- [(4- fluoro benzoyls) ammonia Base] -4- (4- fluoro benzoyls) epoxide-pyrrolidines -1- benzyl carboxylates (2.20 grams, 4.58 mMs, 24.04% yield), be Yellow is small (2.20 grams, 4.58 mMs, 24.04% yield), is faint yellow solid.1H NMR (400MHz, DMSO-d6)δ8.52 (d, J=6.40Hz, 1H), 7.92 (dd, J=6.90,5.77Hz, 2H), 7.38-7.36 (m, 5H), 7.30 (d, J=8.78Hz, 2H), 5.08-5.06 (m, 2H), 4.23-4.11 (m, 2H), 3.65-3.57 (m, 2H), 3.29-3.16 (m, 2H)
Step 4：
3- [(4- fluoro benzoyls) amino] -4- oxo-pyrrolis -1-CarboxylicAcid benzyl ester
To 3- [(4- fluoro benzoyls) amino] -4- hydroxy-pyrrolidine -1- benzyl carboxylates Ester (4.20 grams, 11.72 mMs, 1.00 equivalents) wears this Martin reagent in the solution of DCM (3.00 milliliters) in 0 DEG C of addition (9.94 grams, 23.44 mMs, 7.26 milliliters, 2.00 equivalents).Mixture is stirred 2 hours at 20 DEG C.Into reactant mixture Sodium sulfite solution (100ml) and sodium bicarbonate solution (100mL) are added, is extracted, will closed with dichloromethane (200 milliliters × 3) And organic layer washed with saturated aqueous common salt (200mL*1), it is dried over sodium sulfate, filter and be concentrated under reduced pressure, obtain 3- [(4- fluorine Benzoyl) amino] -4- oxo-pyrroli -1- benzyl carboxylates (4.00 grams, 11.22 mMs, 95.78% yield) are micro- Yellow oil.1H NMR (400 MHz, DMSO) δ 9.15 (d, J=6.52 Hz, 1H), 7.92 (dd, J=8.47,5.58 Hz, 2H), 7.41-7.33 (m, 7H), 5.15 (s, 2H), 4.51 (d, J=8.91 Hz, 1H), 4.09-3.77 (m, 3H), 3.40 (s, 1H)
Step 5：
2- (4- fluorophenyls) -4,6- pyrrolin simultaneously [3,4-d) oxazole -5- benzyl carboxylates
To benzyl 3- [(4- fluoro benzoyls) amino] -4- oxo-pyrroli -1- t-butyl formate (4.00 grams, 11.22 MM, 1.00 equivalents) in dioxane (5.00 milliliters) solution add POCl3 (9.62 gram, 62.74 mMs, 5.83 milliliters, 5.59 equivalents).Mixture is stirred 4 hours at 100 DEG C.The mixture is slowly added to H2O (200 after cooling Milliliter) in, filter and wash filter cake with dichloromethane (50 milliliters), collect filter cake and obtain 2- (4- fluorophenyls) -4,6- dihydros Pyrrolo- [3,4-d) oxazole -5- benzyl carboxylates (1.50 grams, 4.43 mMs, 39.48% yield) are brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.03 (dd, J=7.40,5.40 Hz, 2H), 7.44-7.36 (m, 7H), 5.18 (s, 2H), 4.68-4.60 (m, 2H), 4.50-4.41 (m, 2H)
Step 6：
2- (4- fluorophenyls) -5,6- dihydro -4H- pyrrolo-es [3,4-d) oxazole
By 2- (4- fluorophenyls) -4,6- pyrrolin simultaneously [3,4-d) oxazole -5- benzyl carboxylates (1.50 grams, 4.43 mmoles You, 1.00 equivalents) it is dissolved in hydrogen bromide acetic acid solution (7.17 grams, 88.60 mMs, 4.81 milliliters, 20.00 equivalents), 20 Stirred under nitrogen atmosphere 1 hour at DEG C.Mixture is concentrated under reduced pressure, dichloromethane (20 milliliters) and ethyl acetate (20 millis is added Rise), filter and be dried in vacuo filter cake, obtain2-(4- fluorophenyls) -5,6- dihydro -4H- pyrrolo-es [3,4-d) oxazole (1.00 grams, 3.51 mMs, 79.17% yield, hydrobromate), are black solid.1H NMR (300 MHz, DMSO) δ 8.07-7.89 (m, 2H), 7.48-7.27 (m, 2H), 4.58-4.23 (m, 4H)
Step 7：
(2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [simultaneously dislike 2- (4- fluorophenyls) -4,6- pyrrolin by [3,4-d] Azoles -5- bases] -2- methyl -propyl- 2- alcohol
To 2- (4- fluorophenyls) -5,6- dihydro -4H- pyrrolo-es [3,4-d) oxazole (1.00 grams, 3.51 mMs, 1.00 work as Amount, hydrobromate) and the chloro- 1- of 2- [[(2R) -2- methyl oxirane -2- bases] methyl] -4- nitroimidazoles (916.57 milligrams, 4.21 mMs, 1.20 equivalents) the tert-butyl alcohol (20.00 milliliters) solution in add diisopropylamine (906.60 milligrams, 7.01 mmoles You, 1.23 milliliters, 2.00 equivalents) mixture is stirred 12 hours at 80 DEG C.Not (50 milliliters) are added into reactant mixture, Then it is extracted with ethyl acetate (100 milliliters × 3).The organic layer of merging is dried over sodium sulfate, filter and concentrate under reduced pressure Obtain residue.Residue is passed through into Silica gel chromatography (pillar height degree：300 millimeters, 50 millimeters of diameter, 100-200 mesh silicon Glue, petrol ether/ethyl acetate=5/1,3/1,1/1), obtain (2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorine Phenyl) -4,6- pyrrolin simultaneously [3,4-d] oxazole -5- bases] -2- methyl -propyl- 2- alcohol (700.00 milligrams, 1.66 mMs, 47.28% yield), it is yellow solid.LCMS(ESI)m/z：422.1(M+1).
Step 8：
(S) -2- (4- fluorophenyls) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) - 5,6- dihydro -4H- pyrrolo-es (3,4-d) oxazoles
To ((2S) -1- (the chloro- 4- nitroimidazoles -1- bases of 2-) -3- [2- (4- fluorophenyls) -4,6- pyrrolin simultaneously [3,4- D] oxazole -5- bases] -2- methyl -propyl- 2- alcohol (700.00 milligrams, 1.66 mMs, 1.00 equivalents) DMF (5.00 milliliters) it is molten Sodium hydrogen (132.76 milligrams, 3.32 mMs, 60% purity, 2.00 equivalents) is added in liquid at -45 DEG C.By mixture -45 Stir 30 minutes, then stir it 30 minutes at 0 DEG C at DEG C.Reactant mixture is added to saturated ammonium chloride solution (150 Milliliter) in, then mixture is filtered, filter cake is passed through into preparative separation chromatography (GX-A；Phenomenex Gemini 150* 25mm*10um；Acetonitrile 40%-70%；Water (0.05%ammonia hydroxide v/v)；25mL/min) Purifying, obtains (S) -2- (4- fluorophenyls) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) first Base) -5,6- dihydro -4H- pyrrolo-es (3,4-d) oxazoline compound 89 (46.00 milligrams, 117.70 micromoles, 7.09% yield, 98.6% purity).1H NMR (400MHz, CDCl3) δ 7.98 (dd, J=8.85,5.33Hz, 2H), 7.56 (s, 1H), 7.15 (t, J=8.66Hz, 2H), 4.46 (d, J=9.66Hz, 1H), 4.11-3.89 (m, 5H), 3.42 (d, J=14.93Hz, 1H), 3.10 (d, J=14.81Hz, 1H), 1.70 (s, 3H) .LCMS (ESI) m/z：386.1(M+1).
Embodiment 90
(S) -2- (3,4- difluorophenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) first Base) and -5,6-- dihydro -4H- pyrrolo-es [3,4-d) oxazole
Synthetic method such as embodiment 89.
(S) -2- (3,4- difluorophenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) first Base) -5,6-- dihydro -4H- pyrrolo-es [3,4-d) oxazoline compound 90 (24.80 milligrams, 59.27 micromoles, 35.88% yield, 96.4% purity).1H NMR (400MHz, CDCl3) δ 7.84-7.77 (m, 1H), 7.77-7.71 (m, 1H), 7.56 (s, 1H), 7.27-7.21 (m, 1H), 4.45 (d, J=9.66Hz, 1H), 4.10-3.89 (m, 5H), 3.42 (d, J=14.93Hz, 1H), 3.10 (d, J=14.93Hz, 1H), 1.70 (s, 3H)
Embodiment 91
(S) -2- (2,4- difluorophenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) first Base) and -5,6-- dihydro -4H- pyrrolo-es [3,4-d) oxazole
Synthetic method such as embodiment 89.
(S) -2- (2,4- difluorophenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) first Base) -5,6-- dihydro -4H- pyrrolo-es [3,4-d) oxazoline compound 91 (31.30 milligrams, 75.82 micromoles, 24.48% yield, 97.7% purity).1HNMR (400MHz, CDCl3) δ 8.03-7.91 (m, 1H), 7.56 (s, 1H), 6.98 (d, J=8.2Hz, 2H), 4.49-4.42 (m, 1H), 4.16-3.89 (m, 5H), 3.48-3.37 (m, 1H), 3.17-3.03 (m, 1H), 1.70 (s, 3H).LCMS(ESI)m/z：404.1(M+1).
Embodiment 92
(S) -2- (3,5- difluoro pyridine -2- bases) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- Base) methyl) -5,6- dihydro -4H- pyrrolo-es [3,4-d) oxazole
Synthetic method such as embodiment 89.
(S) -2- (3,5- difluoro pyridine -2- bases) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- Base) methyl) -5,6- dihydro -4H- pyrrolo-es [3,4-d) oxazoline compound 92 (125.10 milligrams, 305.38 micromoles, 51.10% yield, 98.7% purity).1H NMR (400MHz, CDCl3) δ 8.48 (d, J=2.1Hz, 1H), 7.56 (s, 1H), 7.41 (ddd, J=2.3,7.8,10.0Hz, 1H), 4.43 (d, J=9.7Hz, 1H), 4.20-4.06 (m, 3H), 4.05-3.92 (m, 2H), 3.43 (d, J=14.8Hz, 1H), 3.13 (d, J=14.8Hz, 1H), 1.71 (s, 3H) .LCMS (ESI) m/z： 405.0(M+1).
Embodiment 93
(S) -2- (5- fluorine pyridine -2- bases) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) Methyl) and -5,6- dihydro -4H- pyrrolo-es [3,4-d) oxazole
Synthetic method such as embodiment 89.
(S) -2- (3,5- difluoro pyridine -2- bases) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- Base) methyl) -5,6- dihydro -4H- pyrrolo-es [3,4-d) oxazoline compound 93 (175.46 milligrams, 445.96 micromoles, 52.09% yield, 98.194% purity).1H NMR (400MHz, CDCl3) δ 8.56 (d, J=0.4Hz, 1H), 8.13-8.07 (m, 1H), 7.57-7.51 (m, 2H), 4.43 (d, J=12.0Hz, 1H), 4.19-4.02 (m, 3H), 4.01-3.92 (m, 2H), 3.42 (d, J=16.0Hz, 1H), 3.11 (d, J=16.0Hz, 1H), 1.70 (s, 3H) .LCMS (ESI) m/z：387(M+1).
Embodiment 94
(S) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) -2- (2,4,5- trifluoros Phenyl) and -5,6- dihydro -4H- pyrrolo-es [3,4-d) oxazole
Synthetic method such as embodiment 89.
(S) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) methyl) -2- (2,4,5- trifluoros Phenyl) and -5,6- dihydro -4H- pyrrolo-es [3,4-d) oxazoline compound 94 (491.75 milligrams, 1.14 mMs, 57.13% production Rate, 97.416% purity).1H NMR (400MHz, CDCl3) δ 7.89-7.74 (m, 1H), 7.57 (s, 1H), 7.15-7.02 (m, 1H), 4.50-4.39 (m, 1H), 4.14-3.90 (m, 5H), 3.48-3.38 (m, 1H), 3.16-3.07 (m, 1H), 1.71 (s, 3H).LCMS(ESI)m/z：422(M+1).
Embodiment 95
(S) -2- (3,5- difluorophenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) first Base) and -5,6-- dihydro -4H- pyrrolo-es [3,4-d) oxazole
Synthetic method such as embodiment 89.
(S) -2- (3,5- difluorophenyl) -5- ((2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles -2- bases) first Base) -5,6-- dihydro -4H- pyrrolo-es [3,4-d) oxazoline compound 95 (21.60 milligrams, 53.29 micromoles, 10.32% yield, 99.5% purity).1H NMR (400MHz, CDCl3) δ 7.56 (s, 1H), 7.54-7.48 (m, 2H), 6.95-6.83 (m, 1H), (s, the 3H) .LCMS of 4.43 (s, 1H), 4.15-3.88 (m, 5H), 3.41 (s, 1H), 3.10 (d, J=14.8Hz, 1H), 1.71 (ESI)m/z：404.2(M+1).
Embodiment 96
(S) -2- ((2- (4- fluorophenyls) -8,9- dihydro -5H- pyridos [3,2-c] azepine -6 (7H)-yl) methyl) -2- Methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 7.
(S) -2- ((2- (4- fluorophenyls) -8,9- dihydro -5H- pyridos [3,2-c] azepine -6 (7H)-yl) methyl) -2- Methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azole compounds 96 (85.50 milligrams, 196.26 micromoles, 36.10% production Rate, 97.2% purity).1H NMR (400MHz, CDCl3) δ 8.08-7.93 (m, 2H), 7.54-7.40 (m, 3H), 7.16 (t, J= 8.7Hz, 2H), 4.36 (d, J=9.5Hz, 1H), 4.03-3.84 (m, 3H), 3.31-3.15 (m, 4H), 2.96 (d, J= 15.3Hz, 1H), 2.54 (d, J=15.3Hz, 1H), 1.80 (br, s, 2H), 1.59 (s, 3H) .LCMS (ESI) m/z：424(M+ 1).
Embodiment 97
(S) -2- ((2- (4- fluorophenyls) -8,9- dihydro -5H- pyridos [2,3-d] azepine -7 (6H)-yl) methyl) -2- Methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 7.
(S) -2- ((2- (4- fluorophenyls) -8,9- dihydro -5H- pyridos [2,3-d] azepine -7 (6H)-yl) methyl) -2- Methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azole compounds 97 (23.80 milligrams, 50.02 micromoles, 9.20% yield, 89% purity).1H NMR (400MHz, CDCl3) δ 8.11-7.89 (m, 2H), 7.56-7.46 (m, 1H), 7.45-7.34 (m, 2H), 7.15 (t, J=8.7Hz, 2H), 4.36 (d, J=9.5Hz, 1H), 4.00-3.89 (m, 1H), 3.19-2.62 (m, 10H), 1.72-1.57 (m, 3H) .LCMS (ESI) m/z：424(M+1).
Embodiment 98
(2S) -2- ((2- (4- fluorophenyls) -6,7,8,9- tetrahydrochysene -5H--5,8-epiminocvclohepta [b] pyridine - 10- yls) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 7.
(2S) -2- ((2- (4- fluorophenyls) -6,7,8,9- tetrahydrochysene -5H--5,8-epiminocyclohepta [b] pyridine - 10- yls) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azole compounds 98A (30.26 milligrams, 69.49 micro- rub You, 32.79% yield, 100% purity).1H NMR (400MHz, CDCl3) δ 7.94-7.87 (m, 2H), 7.45 (s, 1H), 7.42-7.38 (m, 1H), 7.36-7.31 (m, 1H), 7.19-7.10 (m, 2H), 4.39 (d, J=9.7Hz, 1H), 4.06 (d, J =6.0Hz, 1H), 3.93 (d, J=9.7Hz, 1H), 3.63 (t, J=6.1Hz, 1H), 3.39 (dd, J=4.8,17.9Hz, 1H), 3.08 (d, J=14.7Hz, 1H), 2.75-2.64 (m, 2H), 2.29-2.08 (m, 2H), 1.83-1.78 (m, 1H), 1.73-1.63 (m, 4H) .LCMS (ESI) m/z：436.3(M+1).
(2S) -2- ((2- (4- fluorophenyls) -6,7,8,9- tetrahydrochysene -5H--5,8-epiminocyclohepta [b] pyridine - 10- yls) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azole compounds 98B (41.29 milligrams, 94.82 micro- rub You, 44.75% yield, 100% purity).1H NMR (400MHz, CDCl3) δ 7.97-7.90 (m, 2H), 7.55 (s, 1H), 7.50-7.45 (m, 1H), 7.42-7.37 (m, 1H), 7.19-7.11 (m, 2H), 4.50 (d, J=9.4Hz, 1H), 4.03 (d, J =6.0Hz, 1H), 3.94 (d, J=9.4Hz, 1H), 3.71-3.62 (m, 1H), 3.22 (d, J=14.6Hz, 1H), 2.99 (d, J =14.8Hz, 1H), 2.80 (d, J=14.8Hz, 1H), 2.67 (d, J=17.8Hz, 1H), 2.15 (d, J=11.7Hz, 1H), 2.05-1.93 (m, 1H), 1.76 (d, J=12.3Hz, 2H), 1.60 (s, 3H) .LCMS (ESI) m/z：436.3(M+1).
Embodiment 99
(2S) -2- ((tetrahydrochysene -4H-5,8-epiminocyclohepta [d] thiazole -9- of 2- (4- fluorophenyls) -5,6,7,8- Base) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(2S) -2- ((tetrahydrochysene -4H-5,8-epiminocyclohepta [d] thiazole -9- of 2- (4- fluorophenyls) -5,6,7,8- Base) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azole compounds 99A (3.70 milligrams, 8.26 micromoles, 2.47% yield, 98.594% purity).1H NMR (400MHz, CDCl3) δ 7.91-7.84 (m, 2H), 7.53 (s, 1H), 7.16- 7.09 (m, 2H), 4.35 (d, J=8.0Hz, 1H), 4.25 (d, J=4.0Hz, 1H), 3.95 (d, J=8.0Hz, 1H), 3.69- 3.63 (m, 1H), 3.38-3.27 (m, 1H), 3.04 (d, J=16.0Hz, 1H), 2.80 (d, J=16.0Hz, 1H), 2.56 (d, J =16.0Hz, 1H), 2.19-2.10 (m, 2H), 1.99-1.91 (m, 1H), 1.67 (s, 3H), 1.69-1.61 (m, 1H) .LCMS (ESI)m/z：442 (M+1) (2S) -2- ((2- (4- fluorophenyls) -5,6,7,8- tetrahydrochysene -4H-5,8-epiminocyclohepta [d] thiazole -9- bases) methyl) -2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azole compounds 99B (3.70 milligrams, 8.33 micromoles, 2.49% yield, 99.431% purity).1H NMR (400MHz, CDCl3) δ 7.94-7.85 (m, 2H), 7.56 (s, 1H), 7.17-7.09 (m, 2H), 4.45 (d, J=12.0Hz, 1H), 4.31-4.26 (m, 1H), 3.95 (d, J=8.0Hz, 1H), 3.68-3.60 (m, 1H), 3.23-3.14 (m, 1H), 3.07 (d, J=16.0Hz, 1H), 2.78 (d, J=12.0Hz, 1H), 2.61-2.53 (m, 1H), 2.21-2.09 (m, 1H), 1.96-1.86 (m, 2H), 1.61 (s, 3H), 1.57-1.53 (m, 1H).LCMS(ESI)m/z：442(M+1).
Embodiment 100
(S) -2- ((2- (4- fluorophenyls) -7,8- dihydro -4H- thiazoles simultaneously [4,5-d] azatropylidene -6 (5H)-yl) methyl) - 2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azoles
Synthetic method such as embodiment 69.
(S) -2- ((2- (4- fluorophenyls) -7,8- dihydro -4H- thiazoles simultaneously [4,5-d] azatropylidene -6 (5H)-yl) methyl) - 2- methyl -6- nitros -2,3- glyoxalidine simultaneously [2,1b] azole compounds 100 (35.30 milligrams, 77.62 micromoles, 10.33% production Rate, 94.431% purity).1H NMR (400MHz, CDCl3) δ 7.87-7.78 (m, 2H), 7.56 (s, 1H), 7.13-7.07 (m, 2H), 4.40 (d, J=8.0Hz, 2H), 3.97 (d, J=8.0Hz, 2H), 3.24 (d, J=16.0Hz, 2H), 3.17-3.09 (m, 1H), (s, the 3H) .LCMS (ESI) of 3.07-2.86 (m, 6H), 2.82 (d, J=16.0Hz, 2H), 2.76-2.66 (m, 1H), 1.67 m/z：430(M+1).
Pharmacological moieties
Part I：Killing Mycobacterium Tuberculosis Compound ira vitro drug effect is tested using H37Rv bacterial strains
On the test same day, dissolved compound is used as compound in pure DMSO (Sigma 276855-2L) to concentration 10mg/ml Mother liquor.30 μ l DMSO are added in the 2nd row to the 11st row hole of the orifice plate of v- bottoms 96 (Axygen-wipp02280).Plus 30 μ lization Compound mother liquor arranges hole in the 2nd, takes 30 μ l to add the 3rd row hole from the 2nd row hole after mixing and blows and beats mixing.Operated with this to the 10th Row.11st row not dosing, containing only 30 μ l DMSO.This is compound " motherboard ".From the 2nd row to the 11st row, correspondence compound concentration For 5,2.5,1.25,0.625,0.3125,0.156,0.078,0.039,0.02,0mg/ml.For the compound of good drug efficacy, fit When reduction test concentrations." daughter board " is used as using flat 96 orifice plate (Greiner 655090).98 μ are added in the hole of all daughter boards L 7H9 (Sigma M0178) culture medium.2 μ l compounds are drawn from motherboard to add in the daughter board of correspondence position.Daughter board A and H OK, the 1st and the 12nd row are containing only 7H9 culture mediums.
By the H37Rv inoculations in glycerine cryopreservation tube in the 7H9 culture mediums containing 0.05% Tween 80, in 37 DEG C, 200 Rpm shaking table in culture 4 week.Bacterium solution is washed twice and resuspension with the 7H9 culture mediums containing 0.05% Tween 80 In in same medium.The absorbance of bacterium solution is adjusted to OD using same culture medium550Between=0.4-0.5.Dispense this bacterium solution In micro centrifugal pipe and it is stored in -80 DEG C.Storage time is no more than 1 month.On the day of test, the bacterium solution of packing is thawed. It will be thawed after bacterium solution dilutes 20 times with 7H9 culture mediums and dilute 50 times again, totally 1000 times of dilutions, this bacterium solution will be used to be inoculated with daughter board. 100 μ l bacterium solutions are inoculated in each hole of daughter board, the 12nd row plus 100 μ l 7H9 culture mediums are not added with bacterium solution.
Test daughter board is put in 37 DEG C of incubators and cultivated, humidity maintains ＞ 80%.Start after one week, daily The 7H9 culture mediums that 12.5 μ l contain 20% Tween 80 are added into the 12nd row hole of a 1st row hole containing bacterium and one without bacterium It is blue (Invitrogen DAL1100) with 20 μ l Alamar, and continue to observe after cultivating 24 hours.Bacterium solution in the 1st row hole Can be blue when pink colour is reduced in 24 hours by the Alamar added, plus 7H9 culture mediums and Alamar containing 20% Tween 80 Indigo plant is in all holes on test board, and 37 DEG C are continued to measure fluorescent value after accompanying foster 24 hours.
Minimal inhibitory concentration (MIC) is defined as：The minimum medicine of Alamar indigo plant discolorations can be completely inhibited by observing by the naked eye Thing concentration, or the minimum drug concentration that 90% reduced form Alamar indigo plants are generated can be suppressed over by fluorescence photometer measurement.Part Compound test result is listed in table 1.
Part II：Killing Mycobacterium Tuberculosis is tested using mycobacterium bovis bcg bacterial strain TMC1019 (ATCC35737) On the method test same day of Compound ira vitro drug effect, dissolved compound is in pure DMSO (Sigma 276855-2L) to concentration 12.8mg/ml is used as compound stock solutions.Added in the 1st row to the 12nd row hole of the orifice plate of v- bottoms 96 (Axygen-wipp02280) 30μl DMSO.Plus 30 μ l compound stock solutions in the 1st arrange hole.Take 30 μ l to add the 2nd row hole from the 1st row hole and blow and beat mixing.With this Operation carries out 2 times of gradient dilutions to the 11st row.12nd row are not added with compound, containing only 30 μ l DMSO.In all A rows and H rows holes only Plus 30 μ l DMSO.This is compound " motherboard ".From the 1st row to the 12nd row, correspondence compound concentration is 6.4,3.2,1.6,0.8, 0.4,0.2,0.1,0.05,0.025,0.0125,0.00625 and 0mg/ml.For the compound of good drug efficacy, appropriate reduction test Concentration." daughter board " is used as using flat 96 orifice plate (Greiner 655090).98 μ l 7H9 are added in the hole of all daughter boards (Sigma M0178) culture medium.2 μ l compound solutions are drawn from motherboard to add in the daughter board of correspondence position.Daughter board A and H row And the 12nd row containing only 7H9 culture mediums and the DMSO of corresponding concentration.
Strain of BCG vaccine in glycerine cryopreservation tube is inoculated in the 7H9 fluid nutrient mediums containing 0.05% Tween 80, in 37 4 week of culture in degrees Celsius 200 rpms of shaking table.Bacterium solution is washed two with the 7H9 culture mediums containing 0.05% Tween 80 It is secondary and be resuspended in same medium.Using same culture medium by the absorbance of bacterium solution be adjusted to OD550=0.4-0.5 it Between.This bacterium solution is dispensed in micro centrifugal pipe and -80 DEG C are stored in.Storage time is no more than 1 month.On the day of test, it will divide The bacterium solution of dress is thawed.It will be thawed after bacterium solution dilutes 20 times with 7H9 culture mediums and dilute 50 times again, totally 1000 times of dilutions, this bacterium solution will For being inoculated with.100 μ l bacterium solutions are inoculated in each hole except A rows on daughter board.Only add 100 μ l 7H9 culture mediums in A rows hole, It is not added with bacterium solution.Final concentration of 64,32,16,8,4,2,1,0.5,0.25,0.125, the 0.0625 and 0 μ g/ml of test of medicine.Will Test daughter board is put in culture in 37 DEG C of incubators, and humidity maintains ＞ 80%.
Start after one week, add 12.5 μ l into an A rows hole without bacterium and a H rows hole containing bacterium daily 7H9 culture mediums and 20 μ l Alamar containing 20% Tween 80 are blue (Invitrogen DAL1100), and continue after cultivating 24 hours Observation.When the bacterium solution in H rows hole can by the Alamar added indigo plant when 24 is small it is interior be reduced to pink colour when, plus Alamar indigo plant in survey In all holes on test plate (panel), 37 DEG C are continued to accompany observation minimal inhibitory concentration (MIC) after foster 24 hours.
Minimal inhibitory concentration (MIC) is defined as, and the minimum medicine of Alamar indigo plant discolorations can be completely inhibited by observing by the naked eye Thing final concentration, or the minimum medicine final concentration that 90% reduced form Alamar indigo plants are generated can be suppressed over by fluorescence photometer measurement. Part of compounds testing result is listed in table 1.
Table 1：External work of the invention molecule in part to mycobacterium bovis bcg bacterial strain and Mycobacterium tuberculosis H37Rv bacterial strain Property.
+++：＜ 1；++：1~32；+：＞ 32
Test result indicate that, compound involved in the present invention is either to mycobacterium bovis bcg bacterial strain still to knot Core mycobacteria H37Rv bacterial strains have a good inhibitory activity, the essentially all equal ＜ 1ug/mL of molecule MIC, and The compound no cytotoxicity of the present invention.
Part III：Dynamic solubility and MDR1-MDCK cells two-way penetration assess experiment.Testing result such as table 2 It is shown.
1. dynamic solubility is tested：Weigh quantification compound sample to be dissolved in pure DMSO, final concentration of 10mM. will be by Compound is tried to add containing 96 orifice plates per hole 490uL buffer solutions with control compound (10mM DMSO mother liquors, per hole 10uL) In.Be vortexed 2 minutes after, sample panel on the oscillator at room temperature (22 ± 2 DEG C) be incubated 24 hours.Then transferase 12 00uL samples are arrived MultiScreen filters (polycarbonate membrane), with micropore vacuum manifold (millipore vacuum manifold) filtering simultaneously Collect filtrate.The concentration of compound in filtrate is determined with HPLC-UV.The UV standard solutions of 3 various concentrations are surveyed with solubility Test agent priority sample introduction.Each sample inserting needle 2 times, bring mark song into and calculate concentration, average.
2.MDR1-MDCK cells two-way penetration assesses experiment：People's P- glycoprotein (P- will permanently be expressed Glycoprotein MDR1-MDCK cell seedings) form the individual layer of convergence in 96 hole Insert cell plates, culture after 4-7 days Cell；Using assess fenoterol (hypotonicity label) and propranolol (high osmosis label) it is unidirectional (A → B) permeability, and a kind of Digoxin (P- glycoprotein substrates) two-way penetration verify the quality of cell monolayer.These three Control compound does two multiple holes.
The standard conditions of testing compound transport experiment are as follows：
- test concentrations：2 μM (DMSO≤1%)；
- repeat：N=3；
- direction：：Two-way transhipment, including A → B and B → A both directions；
- incubation time：Single time point, 2.5 hours；
- transport buffer：HBSS, pH7.4；
- incubation conditions：37 DEG C, 5%CO2, 95% relative humidity.
After incubation terminates, the sample solution in dosing holes (donor wells) and receiver hole (receiver wells) is taken Mixed immediately with containing the cold acetonitrile solution of interior target.And measure cell internalizing with the cold acetonitrile solution cell lysis of interior target is contained The accumulation amount of compound.Using LC/MS/MS methods analysis testing compound in all samples (on including initial dose liquid, dosing holes Clear liquid, reception liquid, cell pyrolysis liquid) in concentration.The concentration of testing compound with the ratio between its peak area and internal standard peak area come Represent.Table 2 lists the external dynamic solubility (Kinetic Solubility, KS) of candidate compound and in MDR1- Permeability data in MDCK cell monolayers.
Table 2：Part invention molecular dynamics solubility and MDR1-MDCK cell two-way penetration results
Obviously, aforementioned four candidate compound is superior to OPC-67683 on dynamic solubility, and good solubility is favourable In the absorption and the research of preparation of internal medicine；Again by permeability parameter, we are not difficult to find out, the molecule preferably gone out is High transmittance film molecule, with the obvious advantage compared to reference compound (OPC-67683), good permeance property further promotes medicine Absorb, the effect of the anti-mycobacterium tuberculosis reached.
Part IV：Internal pharmacokinetics
Rodent medicine after being injected intravenously and be administered orally with standard scheme test compound is for feature.It is specific next Say, the CD-1 male mices of 7 to 10 week old of candidate compound intravenous injection and oral administration in experiment.Oral formulations are 0.5% The suspension that is made into of Methyl cellulose；Intravenous formulations are ethanol/DMSO/ polyethylene glycol 400s/pure water (10: 10: 50: 30) The settled solution being made into.The sample of blood plasma and lung is collected, is analyzed in LC-MS/MS methods,
And medicine is calculated for parameter.The medicine of candidate compound 7 is shown in Table 3 for parameter.Table 3：Internal pharmacokinetic parameter
It is obvious that the newfound medicine of compound 7 is superior to reference compound (OPC-67683) for parameter, it is noticeable Be 7 pulmonary drug concentrations upon administration 1 hour significantly larger than reference compound (OPC-67683), reached reference compound More than 9 times.For the patient of pulmonary infection tubercle bacillus, higher drug exposure means better drug effect, this point It is very important.
By the active testing to H37Rv bacterial strains we have found that molecule involved in the present invention is respectively provided with preferable treating tuberculosis It will be seen that all molecules are respectively provided with basic nitrogen atom in mycobacteria Compound ira vitro drug effect, structure, can into salt, Be conducive to putting forward high molecular solubility, so as to be easier to carry out the research of preparation, the experimental data of solubility also confirms ours Assuming that.Testing permeability shows that most of molecules that we are had found are high transmittance film molecules, and this quasi-molecule is conducive in vivo Distribution and absorption, so as to be hopeful to obtain more preferable curative effect.Internal pharmacokinetic data is even more to have done further to test Card, the solubility collected, high permeability shows excellent lung's exposed amount in the compound 7 of one.In view of being collected into These data, we it is believed that these molecules will show than reference compound (OPC-67683) preferably drug effect, So as to benefit many patients.

Claims (10)

1. compound, its pharmaceutically acceptable salt or its optical isomer shown in formula (I),
Wherein,
Ring A is 5~6 yuan of aryl or heteroaryl；
X is selected from N, C (R) or C；
R is selected from hydrogen, halogen, hydroxyl, cyano group, nitro, or selected from the following group optionally replaced by any substituent：Amino, C1-6 Alkyl amino, the N, (C of N- bis-1-6Alkyl) amino, C1-6Alkyl, C1-6Miscellaneous alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-7Cycloalkyl, C3-7 Heterocyclylalkyl, 5~7 yuan of aryl, 5~7 unit's heteroaryls；
V, W are separately selected from methylene ,-CH2CH2-, C (=O) ,-S (=O)-and-S (=O)2-, wherein, the methylene Base and-CH2CH2- optionally replaced by 1 or 2 R；
Z is selected from the methylene optionally replaced by 1 or 2 R；
L be selected from singly-bound ,-O- ,-S-, N (R), C (R) (R) ,-C (=O)-,-C (=S)-,-S (=O)-or-S (=O)2-；
R1、R2Separately it is selected from hydrogen, halogen, hydroxyl, cyano group, nitro, or R1、R2Separately it is selected from and is optionally arbitrarily taken Amino, C for base substitution1-6Alkyl, C1-6Miscellaneous alkyl, C2-6Alkenyl, C2-6Alkynyl, C3-7Cycloalkyl, C3-7Cycloalkyl-C1-6Alkane Base-, C3-7Heterocyclylalkyl, 5~7 yuan of aryl or heteroaryl；
Optionally, the substituent R in the substituent R and V on Z is connected on same atom or atomic group, forms one 5~7 Yuan of rings；
Optionally, construction unitIt can be replaced
R2It can also be vacancy；
M is selected from 1,2 or 3；
N is selected from 0,1,2 or 3；
" miscellaneous " represents hetero atom or hetero atom group, its be selected from-C (=O) NH- ,-NH- ,-C (=NH)-,-S (=O)2NH- ,-S (= O) NH- ,-O- ,-S-, N ,=O ,=S ,-C (=O) O- ,-C (=O)-,-C (=S)-,-S (=O)-,-S (=O)2- and-NHC (=O) NH-；
The number of hetero atom or hetero atom group is separately selected from 0,1,2 or 3.
2. compound, its pharmaceutically acceptable salt or its optical isomer according to claim 1, wherein, the substitution Base and R are separately selected from：
H、F、Cl、Br、I、OH、CN、NH2、C1-4Alkyl, C1-4Miscellaneous alkyl, wherein, C1-4Alkyl or C1-4Miscellaneous alkyl is optionally entered One step is by 0~3 halogen, OH and/or NH2Replaced；
Preferably, the substituent is selected from：F、Cl、Br、I、CN、-CF3、-OCF3、-CH2CF3、OCH3、(CH3)3COC (=O)-.
3. compound according to claim 1 or claim 2, its pharmaceutically acceptable salt or its optical isomer, wherein, R1And R2 Hydrogen, halogen, cyano group are separately selected from, or selected from optionally substituted：
Preferably, R1And R2Hydrogen, halogen, cyano group are separately selected from, or selected from optionally substituted：
It is highly preferred that R1And R2Separately it is selected from：
4. compound according to claim 1 or claim 2, its pharmaceutically acceptable salt or its optical isomer, wherein, R is selected from H、Cl、Br、I、OH、CN、NH2、Me、Et。
5. compound according to claim 1 or claim 2, its pharmaceutically acceptable salt or its optical isomer, wherein, ring A choosings From pyridine radicals, thiazolyl, oxazolyl, imidazole radicals, pyrimidine radicals；
Preferably, ring A is selected from：
Preferably, structureIt is selected from：
6. compound according to claim 1 or claim 2, its pharmaceutically acceptable salt or its optical isomer, wherein, structure list MemberIt is selected from：
7. compound according to claim 1 or claim 2, its pharmaceutically acceptable salt or its optical isomer, wherein, construction unitIt is selected from：
8. compound according to claim 1 or claim 2, its pharmaceutically acceptable salt or its optical isomer, it is selected from：
9. a kind of pharmaceutical composition, it includes formula (I) compound of effective dose described in claim 1~8 any one, its pharmacy Upper acceptable salt, optical isomer or pharmaceutically acceptable carrier.
10. formula (I) compound, its pharmaceutically acceptable salt or its optics according to any one of claim 1~8 are different Structure body, or composition according to claim 9 are preparing treatment and prevention tubercle bacillus or the medicine of other microorganism infections Application in thing.
CN201610006632.8A 2015-01-29 2016-01-06 The nitro imidazole derivatives for the treatment of pulmonery tuberculosis disease Pending CN106946909A (en)

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CN201610006632.8A CN106946909A (en) 2016-01-06 2016-01-06 The nitro imidazole derivatives for the treatment of pulmonery tuberculosis disease
CN201680006991.1A CN107207532B (en) 2015-01-29 2016-01-28 The nitro imidazole derivatives for the treatment of pulmonery tuberculosis disease
US15/546,841 US10227362B2 (en) 2015-01-29 2016-01-28 Anti-pulmonary tuberculosis nitroimidazole derivative
TW105102748A TW201632533A (en) 2015-01-29 2016-01-28 The nitroimidazole derivative for anti- tuberculosis uberculosis
PCT/CN2016/072447 WO2016119706A1 (en) 2015-01-29 2016-01-28 Anti-pulmonary tuberculosis nitroimidazole derivative
BR112017015744A BR112017015744A2 (en) 2015-01-29 2016-01-28 compound having a structure of formula (i), a pharmaceutically acceptable salt thereof or an optical isomer thereof, pharmaceutical composition and use of the compound of formula (i) for the treatment and prevention of mycobacterium tuberculosis or other microbial infections
JP2017540142A JP6542900B2 (en) 2015-01-29 2016-01-28 Nitroimidazole derivatives for anti-pulmonary tuberculosis
EP16742768.1A EP3252059A4 (en) 2015-01-29 2016-01-28 Anti-pulmonary tuberculosis nitroimidazole derivative
MX2017009810A MX2017009810A (en) 2015-01-29 2016-01-28 Anti-pulmonary tuberculosis nitroimidazole derivative.
RU2017130546A RU2675622C1 (en) 2015-01-29 2016-01-28 Nitroimidazole derivative against pulmonary tuberculosis
ZA2017/05362A ZA201705362B (en) 2015-01-29 2017-08-08 Anti-pulmonary tuberculosis nitroimidazole derivative

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109503464A (en) * 2018-12-17 2019-03-22 天津药明康德新药开发有限公司 A kind of synthetic method of nitrogen-(Benzyloxycarbonylpiperidin -4- base) -2- (trifluoromethyl) benzamide
CN113264929A (en) * 2021-05-02 2021-08-17 润生药业有限公司 Preparation method of tiotropium bromide

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109503464A (en) * 2018-12-17 2019-03-22 天津药明康德新药开发有限公司 A kind of synthetic method of nitrogen-(Benzyloxycarbonylpiperidin -4- base) -2- (trifluoromethyl) benzamide
CN113264929A (en) * 2021-05-02 2021-08-17 润生药业有限公司 Preparation method of tiotropium bromide
CN113264929B (en) * 2021-05-02 2023-10-10 润生药业有限公司 Preparation method of tiotropium bromide

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