CN106946909A

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

Info

Publication number: CN106946909A
Application number: CN201610006632.8A
Authority: CN
Inventors: 罗微; 丁照中; 黄志刚
Original assignee: NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
Current assignee: NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
Priority date: 2016-01-06
Filing date: 2016-01-06
Publication date: 2017-07-14

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

Nitroimidazole derivatives against tuberculosis

Reference documents:

the contents of the following documents are 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

The invention relates to a substituted nitroimidazole derivative which is mainly used for treating related diseases caused by mycobacteria infection, such as mycobacterium tuberculosis, and is particularly suitable for diseases caused by drug-resistant combined mycobacteria.

Background

Mycobacterium tuberculosis is the causative agent of tuberculosis. As a globally widespread and life-threatening infectious disease, according to the statistics of the world health organization, about more than 800 million people are infected each year, and 200 million people die from tuberculosis. Over the past decade, tuberculosis cases have grown worldwide at a rate of 20%, with this rising amplitude being particularly pronounced in poverty-stricken areas. If this trend progresses as such, cases of tuberculosis will likely continue to grow at 41% rise in the next two decades. Tuberculosis has been second only to aids for fifty years after the initial application of chemotherapy, the leading infectious disease that causes death in adults. Tuberculosis causes the appearance of a plurality of drug-resistant strains, and simultaneously achieves a symbiotic relationship with AIDS. People who are positive in the HIV test and infected with tuberculosis have 30 times more probability of developing activated tuberculosis than people who are negative in the HIV test. On average, one of every three patients who die of aids is caused by tuberculosis.

The current treatment for tuberculosis employs a formulation of a combination of multiple agents recommended by the U.S. public health agency, including first two months with isoniazid, rifampin, pyrazinamide and ethambutol, and then four months with isoniazid and rifampin alone. For patients infected with AIDS, the use of the pharmaceutical composition needs to be delayed to seven months. For patients infected with multi-drug resistant tuberculosis, the pharmaceutical composition needs to be added with other second-line agents, such as streptomycin, kanamycin, amikacin, capreomycin, ethionamide, cycloserine, ciprofloxacin and ofloxacin. Such combination therapies for patients resistant to multidrug tuberculosis (typically over a2 year course of treatment) typically have lower activity and higher side effects than the first line drugs currently on the market.

Therefore, there is an urgent need for novel nitroimidazooxazole derivatives having high activity in both aerobic (active) and anaerobic (latent or recalcitrant) environments as anti-tubercle bacillus drugs. Clearly, drugs that both shorten treatment time and reduce frequency of supervision would provide the greatest benefit.

Currently, the Otsuka new product dellyba (delamanid) is marketed as a combination drug for multi-drug resistant tuberculosis treatment approved for adult treatment, in view of considerations of resistance and tolerance. Also, nitroimidazole oxazine compounds PA-824 and TBA-354 (J.org.chem.53; 8421-8439(2010)) showed better in vitro and in vivo activity in inhibiting Mycobacterium tuberculosis. The mechanism of action of PA-824 involves the release of nitric oxide gas (Singh et al, Science 322; 1392-. Gene chip technology studies of wild-type mutagenized strains with FGD1 and F420 revealed a protein of unknown function consisting of 151 amino acids (17.37kDa), (Rv3547) appeared to dominate this series of reduction steps, a hypothesis later documented by studies of FA-824 reduction. TBA-354 is a nitroimidazole oxazine derivative developed from PA-824. The mechanism of action of Delamanid is to inhibit the synthesis of methoxy and ketomycolic acids, thereby killing bacteria, which are important components of the cell wall of mycobacterium tuberculosis. Nitroimidazole derivatives and treatments for tubercle bacilli have been reported extensively previously (U.S. patent nos.5,668,127and 6,087,358; jiicek et Al, WO 2007075872a 2; Tsubochi et Al, WO 2005042542a1 and WO 2004033463 Al; JP 2005330266 a; thompson et Al, WO 2011014776; musnoda et Al, WO2013072903).

Nitroimidazole derivatives are becoming increasingly attractive in all anti-tubercle bacillus clinically developed drugs, moving forward. As can be seen from the above patent applications, the main patent formulas for the treatment of tuberculosis, in particular for the treatment of multi-drug resistant tuberculosis, are shown as follows (1 and 2):

through research, two new active molecules, OPC-67683(delamanid) and TBA-354, were developed for the treatment of tuberculosis, the structures of which are shown below (3 and 4):

delamanid is a nitro-2H-imidazooxazole derivative, has high activity in vitro and in vivo on multi-drug resistant mycobacterium tuberculosis mainly by inhibiting the biosynthetic action of mycolic acid, and is conditionally approved by European human pharmaceutical Committee (CHMP) on 11/21.2013 to Deltyba (Delamanid) and 50 mg of film coated tablets for treating the multi-drug resistant mycobacterium tuberculosis. Is formally marketed in europe in 2014 4 and 28. Delthyba was identified as an orphan drug on day 1 of 2 months of 2008. The invention aims to invent a novel nitroimidazole compound which is used for treating tuberculosis and multi-drug resistant tuberculosis.

Although OPC-67683 is proved to have certain curative effect on multi-drug resistant tuberculosis treatment in clinic, the invention has a space for further optimizing the treatment course and the cure rate, and the invention serves for the requirement that the related nitroimidazole derivatives are proved to have more excellent water solubility and pharmacokinetic properties. This improvement is expected to lead to better clinical performance.

Disclosure of Invention

The invention provides a compound shown in a formula (I), pharmaceutically acceptable salt or stereoisomer thereof,

wherein,

ring A is a 5-to 6-membered aryl or heteroaryl group;

x is selected from N, C (R) or C;

r is selected from hydrogen, halogen, hydroxyl, cyano, nitro, or from the following optionally substituted by any substituent: amino group, C_1-6Alkylamino, N-di (C)_1-6Alkyl) amino, C_1-6Alkyl radical, C_1-6Heteroalkyl group, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl, 5-to 7-membered aryl, 5-to 7-membered heteroaryl;

v, W are each independently selected from methylene, -CH₂CH₂-, C (═ O), -S (═ O) -and-S (═ O)₂-₂CH₂-optionally substituted with 1 or 2R;

z is selected from methylene optionally substituted with 1 or 2R;

l is selected from a single bond, -O-, -S-, n (r), C (r), (r), -C (═ O) -, -C (═ S) -, -S (═ O) -, or-S (═ O)₂-；

R₁、R₂Each independently selected from hydrogen, halogen, hydroxy, cyano, nitro, or R₁、R₂Each independently selected from amino optionally substituted with an optional substituent, C_1-6Alkyl radical, C_1-6Heteroalkyl group, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Cycloalkyl radical, C_3-7cycloalkyl-C_1-6Alkyl-, C_3-7Heterocycloalkyl, 5-to 7-membered aryl or heteroaryl;

optionally, a substituent R on Z and a substituent R on V are connected on the same atom or atomic group to form a 5-7-membered ring;

optionally, a structural unitCan be replaced by

R₂Or may be a void;

m is selected from 1, 2 or 3;

n is selected from 0, 1, 2 or 3;

"hetero" represents a heteroatom or heteroatom group selected from-C (═ O) 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 heteroatoms or groups of heteroatoms is independently selected from 0, 1, 2 or 3, respectively.

In some embodiments of the present invention, the above substituents and R are each independently selected from: H. f, Cl, Br, I, OH, CN, NH₂、C_1-4Alkyl radical, C_1-4Heteroalkyl group, wherein_1-4Alkyl or C_1-4The heteroalkyl group may optionally be further substituted with 0-3 halogens, OH and/or NH₂And (4) substituting.

In some embodiments of the present invention, the above substituents are selected from: F. cl, Br, I, CN, -CF₃、-OCF₃、-CH₂CF₃、OCH₃、(CH₃)₃COC(＝O)-。

In some embodiments of the invention, R is as defined above₁And R₂Each independently selected from hydrogen, halogen, cyano, or from optionally substituted:

in some aspects of the inventionR is₁And R₂Each independently selected from:

in some embodiments of the present invention, R is selected from H, Cl, Br, I, OH, CN, NH₂、Me、Et。

In some embodiments of the present invention, ring A is selected from pyridyl, thiazolyl, oxazolyl, imidazolyl, and pyrimidinyl.

In some embodiments of the invention, ring a is selected from:

in some embodiments of the invention, the above structureSelected from:

in some embodiments of the invention, the structural unitSelected from:

in particular, the compounds of the invention are selected from:

the present invention also provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, an optical isomer, or a pharmaceutically acceptable carrier thereof, as described in any of the above.

The invention also provides application of the compound, the pharmaceutically acceptable salt thereof, the optical isomer thereof or the composition in preparing medicaments for treating and preventing mycobacterium tuberculosis or other microbial infections.

The invention also provides a process for the preparation of a compound of formula (I) comprising the steps of:

wherein LG is₂Represents a suitable leaving group, the other variables being as defined above.

In some embodiments of the present invention, the LG is₂Represents halogen.

The present invention also provides intermediates for the preparation of compounds of formula (I):

wherein LG is₁Represents a suitable leaving group, the other variables being as defined above.

In some aspects of the invention, LG₁Represents halogen.

The present invention also provides intermediates for the preparation of compounds of formula (I) according to claim 1, comprising:

correlation definition

As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.

C_1-12Is selected from C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁And C₁₂；C_3-12Is selected from C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁And C₁₂。

C_1-12Alkyl or heteroalkyl, C_3-12Cyclic or heterocyclic hydrocarbon radicals, by C_3-12Cycloalkyl-or heterocycloalkyl-substituted C_1-12Alkyl or heteroalkyl groups include, but are not limited to:

C_1-12alkyl radical, C_1-12Alkylamino, N-di (C)_1-12Alkyl) amino, C_1-12Alkoxy radical, C_1-12Alkanoyl radical, C_1-12Alkoxycarbonyl, C_1-12Alkylsulfonyl radical, C_1-12Alkylsulfinyl radical, C_3-12Cycloalkyl radical, C_3-12Cycloalkylamino radical, C_3-12Heterocycloalkylamino, C_3-12Cycloalkoxy, C_3-12Cycloalkyl acyl, C_3-12Cycloalkanoyloxycarbonyl radical, C_3-12Cycloalkylsulfonyl radical, C_3-12Cycloalkylsulfinyl, 5-to 12-membered aryl or heteroaryl, 5-to 12-membered aralkyl or heteroaralkyl;

methyl, ethyl, n-propyl, isopropyl, -CH₂C(CH₃)(CH₃) (OH), cyclopropyl, cyclobutyl, propylmethylene, cyclopropanoyl, benzyloxy, trifluoromethyl, aminomethyl, hydroxymethyl, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl, ethoxy, acetyl, ethylsulfonyl, ethoxycarbonyl, 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)₂CH₃b, carrying out the following steps of; and

phenyl, thiazolyl, biphenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolinyl, pyrrolidinyl, 1, 3-oxypentacyclyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, thiazolyl, 1, 2, 3-oxazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 3, 4-thiadiazolyl, 4H-pyranyl, pyridyl, piperidyl, 1, 4-dioxanyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1, 3, 5-trithianyl, 1, 3, 5-triazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolyl, isoquinolyl, cinnolinyl or quinoxalinyl;

the term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical salts," Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.

Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.

As used herein, "pharmaceutically acceptable salts" belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, for example, salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.

The illustrations of mesomeric, ambiscientific and scientific, or enantiomerically pure compounds herein are from Maehr, j.chem.ed.1985, 62: 114-120. In 1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by wedge bonds and dashed bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomer unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C³H) Iodine-125 (¹²⁵I) Or C-14(¹⁴C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent, and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on the carrier, reference may be made to Remington: the Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), The contents of which are incorporated herein by reference.

The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.

The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including deuterium and hydrogen variants, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., ═ O), it means that two hydrogen atoms are substituted. The keto substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.

When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

When the number of one linking group is 0, e.g. - (CRR)₀-, represents that the linking group is a single bond. When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, for example, where L represents a single bond in A-L-Z means that the structure is actually A-Z.

When a substituent is absent, it indicates that the substituent is absent, e.g., when X is absent in A-X, it indicates that the structure is actually A.

When a substituent's bond can cross-link two atoms on a ring, such substituent can be bonded to any atom on the ring. When no atom is indicated in the listed substituents for connecting to a compound included in the general chemical structure but not specifically mentioned, such substituent may be bonded through any atom thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unitMeaning that it may be substituted at any position on the cyclohexyl or cyclyldiene.

Substituents for alkyl and heteroalkyl radicals are generally referred to as "alkyl substituents" and may be selected from, but are not limited to, one or more of the 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)₂And fluoro (C)₁-C₄) Alkyl, the number of substituents being 0 to (2m '+ 1), where m' is the total number of carbon atoms in such radicals. R ', R ", R'", R "" and R "" each independently preferably is hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy, thioalkoxy, or aralkyl. When a compound of the invention includes more than one R group, for example, each R group is independently selected, as are each of these groups when more than one R ', R ", R'", R "" and R "" groups are present. When R' and R "are attached to the same nitrogen atom, they may combine with the nitrogen atom to form a 5-, 6-or 7-membered ring. For example, -NR' R "is intended to include, but not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, those skilled in the art will appreciate that the term "alkyl" is intended to include groups consisting of carbon atoms bonded to non-hydrogen groups, such as haloalkyl (e.g., -CF)₃、-CH₂CF₃) And acyl (e.g., -C (O) CH)₃、-C(O)CF₃、-C(O)CH₂OCH₃Etc.).

Similar to the substituents described for the alkyl radicals, the aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" and are selected from, for example, -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)₂Fluorine (C)₁-C₄) Alkoxy and fluorine (C)₁-C₄) Alkyl, etc., the number of substituents being between 0 and the total number of open valences on the aromatic ring; wherein R ', R ", R'", R "" and R "" are independently preferably selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each R group is independently selected, as are each of these groups when more than one R ', R ", R'", R "" and R "" groups are present.

Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by a substituent of the formula-T-C (O) - (CRR ') q-U-, wherein T and U are independently selected from-NR-, -O-, CRR' -or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula-A (CH2) r B-, wherein A and B are independently selected from-CRR' -, -O-, -NR-, -S (O) -, S (O)₂-、-S(O)₂NR' -or a single bond, and r is an integer of 1 to 4. Optionally, one single bond on the new ring thus formed may be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula-A (CH2) r B-, wherein S and d are each independently an integer selected from 0 to 3, and X is-O-, -NR', -S-, -S (O)₂-or-S (O)₂NR' -. The substituents R, R ', R "and R'" are each independently preferably selected from hydrogen and substituted or unsubstituted (C)₁-C₆) An alkyl group.

Unless otherwise indicatedIt is specified that the term "halogenide" or "halogen" by itself or as part of another substituent denotes a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C)₁-C₄) Alkyl "is intended to include, but not be limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, and the like.

Examples of haloalkyl groups include, but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "alkoxy" represents the above alkyl group having the specified number of carbon atoms attached through an oxygen bridge. C_1-6Alkoxy radicals comprising C₁、C₂、C₃、C₄、C₅And C₆Alkoxy group of (2). Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy. "cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-7 cycloalkyl radicals including C₃、C₄、C₅、C₆And C₇A cycloalkyl group. "alkenyl" includes hydrocarbon chains in either a straight or branched configuration, wherein one or more carbon-carbon double bonds, such as ethenyl and propenyl, are present at any stable site along the chain.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

Unless otherwise specified, the term "hetero" denotes a heteroatom or a heteroatom group (i.e., a heteroatom-containing radical) including atoms other than carbon (C) and hydrogen (H) and radicals containing such heteroatoms, including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, ═ O, ═ S, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O)₂-, and optionally substituted-C (═ O) n (h) -, -C (═ NH) -, -S (═ O)₂N (h) -or-S (═ O) n (h) -.

Unless otherwise specified, "cyclic" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The term "ring" includes monocyclic, bicyclic, spiro, fused or bridged rings. The number of atoms in the ring is generally defined as the number of ring members, for example, "5 to 7 membered ring" means 5to 7 atoms arranged around the ring. Unless otherwise specified, the ring optionally contains 1-3 heteroatoms. Thus, "5 to 7 membered ring" includes, for example, phenyl, pyridine and piperidinyl; in another aspect, the term "5-to 7-membered heterocycloalkyl ring" includes pyridyl and piperidyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable heteroatom or heteroatom group containing monocyclic, bicyclic, or tricyclic ring which may be saturated, partially unsaturated, or unsaturated (aromatic), which contains carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p). The nitrogen atom may be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituents already defined herein). The heterocyclic ring may be attached to any heteroatom or carbon pendant group to form a stable structure. The heterocyclic rings described herein may be substituted at the carbon or nitrogen position if the resulting compound is stable. The nitrogen atoms in the heterocycle are optionally quaternized. In a preferred embodiment, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. In another preferred embodiment, the total number of S and O atoms in the heterocycle does not exceed 1. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" means a stable 5,6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic group aromatic ring comprising carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom may be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituents already defined herein). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p). It is noted that the total number of S and O atoms on the heteroaromatic ring does not exceed 1. Bridged rings are also included in the definition of heterocyclic. Bridged rings are formed when one or more atoms (i.e., C, O, N or S) connect two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In bridged rings, ring substituents may also be present on the bridge.

Examples of heterocyclic compounds include, but are not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2H, 6H-1, 5, 2-dithiazinyl, dihydrofuro [2, 3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatino, isobenzofuranyl, pyran, isoindolyl, indolyl, etc, Isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthine, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, Pyrazolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1, 2, 5-thiadiazinyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 3, 4-thiadiazolyl, thianthrenyl, thiazolyl, isothiazolylthiothienyl, thienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, 1, 2, 5-triazolyl, 1, 3, 4-triazolyl, and xanthenyl. Fused ring and spiro compounds are also included.

Unless otherwise specified, the term "hydrocarbyl" or its derivatives (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent, mean a straight, branched, or cyclic hydrocarbon radical or combination thereof, which may be fully saturated, mono-or poly-unsaturated, mono-, di-, or poly-substituted, may be mono-or di-or poly-valent (such as methine), may include di-or poly-valent radicals, having the specified number of carbon atoms (such as C)₁-C₁₀Representing 1 to 10 carbons). "hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl including linear and cyclic, specifically including, but not limited to, alkyl, alkenyl, alkynyl, and aromatic hydrocarbyl including, but not limited to, 6-12 membered aromatic hydrocarbyl such as benzene, naphthalene, and the like. In some embodiments, the term "hydrocarbyl" denotes a straight or branched chain radical or a combination thereof, which may be fully saturated, mono-or polyunsaturated, and may include divalent and polyvalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, and homologs or isomers of radicals such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl groups have one or more double or triple bonds, examples of which include, but are not limited to, ethenyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers.

Unless otherwise specified, the term "heterohydrocarbyl" or a subset thereof (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and the like) by itself or in combination with another term means a stable straight-chain, branched, or cyclic hydrocarbon radical, or combination thereof, consisting of a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl," by itself or in combination with another term, means a stable straight-chain, branched-chain hydrocarbon radical, or combination thereof, having a number of carbon atoms and at least one heteroatom constituent. In one exemplary embodiment, the heteroatoms are selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatom or heteroatom group may be located at any internal position of the heterohydrocarbyl group (including the position where the hydrocarbyl group is attached to the remainder of the molecule). Examples include, but are 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-OCH₃and-CH ═ CH-N (CH)₃)-CH₃. Up to two heteroatoms may be consecutive, e.g. -CH₂-NH-OCH₃。

The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in the conventional sense to refer to those alkyl groups attached to the rest of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.

Unless otherwise specified, the terms "cycloalkyl", "heterocycloalkyl", or a subset thereof (e.g., aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, etc.) by themselves or in combination with other terms, mean cyclized "alkyl", "heteroalkyl", respectively. Furthermore, in the case of a heterohydrocarbyl or heterocycloalkyi (e.g., heteroalkyl, heterocycloalkyl), a heteroatom may occupy the position of the heterocycle attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclyl groups include 1- (1, 2, 5, 6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran indol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl.

Unless otherwise specified, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent which may be mono-, di-or poly-substituted, and may be mono-, di-or polyvalent, and which may be monocyclic or polycyclic (e.g., 1 to 3 rings; wherein at least one ring is aromatic), fused together or covalently linked. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In one illustrative example, the heteroatom is selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroaryl group may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-oxazolyl, 2-thiazolyl, 2-pyridyl, 4-pyridyl, and the like, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalyl, 5-quinoxalyl, 3-quinolyl, and 6-quinolyl. The substituents for any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

For simplicity, aryl when used in combination with other terms (e.g., aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like), including those alkyl groups in which a carbon atom (e.g., methylene) has been replaced by, for example, an oxygen atom, such as phenoxymethyl, 2-pyridyloxymethyl 3- (1-naphthyloxy) propyl and the like.

The term "leaving group" refers to a functional group or atom that can be substituted by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetyloxy, and the like.

The term "protecting group" includes, but is not limited to, "amino protecting group," hydroxyl protecting group, "or" thiol protecting group. The term "amino protecting group" refers to a protecting group suitable for use in preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: a formyl group; acyl, for example alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups, such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups, such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.

The solvent used in the present invention can be commercially available. Abbreviations used below: aq. is water; equivalent is equivalent; SEMCl is (2- (chloromethoxy) ethyl) trimethylsilane; i-PrOH is isopropanol; DCM is dichloromethane; PE is petroleum ether; DMF is N, N-dimethylformamide, EtOAc is ethyl acetate; EtOH is ethanol; MeOH is methanol and THF is tetrahydrofuran; DMSO is dimethyl sulfoxide; AcOH is acetic acid; BOC is tert-butyloxycarbonyl, amino group protected group; bn is benzyl; CuI is cuprous iodide; AcOCu is copper acetate; pd (OH)₂Is palladium hydroxide; RT is room temperature; POCl₃Is phosphorus oxychloride; boc₂O is Boc anhydride; bn₂NH is dibenzyl amino; (n-Bu)₄Sn is tetra-n-butyltin; DMAP is N-dimethylamino pyridine; (NH)₄)₂CO₃Is ammonium carbonate; TFA is trifluoroacetic acid; TFAA is trifluoroacetic anhydride; TEA is triethylamine; DIBAL-H is diisobutylaluminum hydride; NIS is N-iodosuccinimide; pd (PPh)₃P)₂Cl₂Bis (triphenylphosphine) palladium chloride; DAST is nitrogen, diethyl sulfur trifluoride; n-BuSn is n-butyltin; pd (PPh)₃)₄Is tetratriphenylphosphine palladium; LDA is lithium diisopropylamide; b (i-PrO)₃Is triisopropyl borate; CsF is cesium fluoride; NaH is sodium hydride; TMSCF₃Is trimethyl trifluoromethyl silane; MS is a molecular sieve; cbz is benzyloxycarbonyl; TBDMS is tert-butyldimethylsilyl.

The compounds are named manually or by useOr for current use of supplier catalog names on the market.

Synthesis method

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, through a series of synthetic steps. The compounds of the present invention may be synthesized using synthetic methods described below or variations thereof.

Preferred methods include, but are not limited to, the following.

In particular, compounds of formula (I) may be prepared from reaction intermediates of formula (II) when LG1 represents a suitable leaving group halogen (e.g. chloro, bromo, iodo) or an analogue thereof, with a suitable arylboronic acid or boronic ester; or when LG1 represents a boronic acid or boronic ester, with an aromatic halide, in which the presence of a suitable base (such as caesium fluoride, sodium carbonate, sodium bicarbonate), a suitable catalyst (such as Pd (dppf) Cl₂，Pd(PPh₃)₄Etc.), in a suitable solvent (e.g., dioxane/water, toluene, etc.), preferably at 80-120 degrees celsius, according to scheme 1:

reaction scheme 1

All variables are defined as formula (I).

The intermediate of formula (II) may be prepared according to conventional reactions by a variety of synthetic methods well known to those skilled in the art. For example, the intermediate of formula (II) can be prepared according to reaction scheme 2:

reaction scheme 2

Wherein the variable LG₁Represents a suitable leaving group, for example halogen, such as chlorine, bromine, iodine, boronic acid or boronic ester, and the like. Variable LG₂Represents a suitable leaving group such as halogen (e.g. chloro, bromo, iodo, etc.). All other variables are defined as formula (I). Steps A and B of scheme 2 are performed by azeotroping a benzyl protected ketone with pyrrole in a suitable solvent such as toluene at a suitable temperatureThe water is removed and then cyclized with acrylamide or propynamide. Step C is the aromatization of the cyclization product of the previous step under the action of a suitable reagent such as liquid bromine, usually under heating. The following step D, in which a dehydrating agent (e.g., phosphorus oxychloride, phosphorus oxybromide, etc.) is reacted with the product obtained in the previous step, is usually carried out at a temperature of between 110 and 130 ℃. Step E, the benzyl protecting group on the nitrogen atom usually needs to be hydrogenated or chemically removed, and the solvent is usually methanol or ethanol. Following step F, the ring-opening reaction is typically carried out in a polar solvent (e.g., methanol, ethanol, isopropanol) in the presence of a base, such as DIPEA. And G, reacting at 0-120 ℃ in the presence of a suitable base (such as sodium hydrogen and sodium acetate) and a suitable solvent (such as DMF or tert-butyl acetate) to obtain the ring-closed intermediate compound shown as the formula (II).

It is clear that in the reactions mentioned hereinbefore and hereinafter, the reaction product may be isolated from the reaction medium and, if desired, further purified by purification methods well known to those skilled in the art, such as extraction, and chromatography. It will be further apparent that for reaction products in which more than one enantiomer is present, the compounds of formula (I) may be separated into their isomers by separation methods well known to those skilled in the art, in particular by preparative chromatography, such as preparative HPLC, SFC, and the like.

The compounds of formula (I) can likewise be prepared directly from scheme 3 by cyclisation of the compounds of formula (III) under the action of a suitable base:

reaction scheme 3:

wherein the variable LG₁Represents a suitable leaving group, for example halogen, such as chlorine, bromine, iodine, boronic acid or boronic ester, and the like. Variable LG₂Represents a suitable leaving group, for example halogen, such as chlorine, bromine, iodine, etc. All other variables are as defined above for formula (I).

Step a, when LG1 represents a suitable leaving group halogen (e.g. chloro, bromo, iodo or the like), with a suitable arylboronic acid or boronic ester; or correspondingly when LG1 represents a boronic acid or boronic ester, with an aromatic halide, in which a suitable base (such as caesium fluoride, caesium carbonate, sodium bicarbonate), a suitable catalyst (such as Pd (dppf) Cl, is used₂Etc.), in a suitable solvent (e.g., dioxane/water, toluene, etc.), more preferably at 80-120 deg.c, according to scheme 1 above. In step B, the benzyl protecting group on the nitrogen atom is usually hydrogenated or chemically removed by, for example, chloroethyl chloroformate, methanol, and the reaction is generally carried out at 60 ℃ to 80 ℃. Step C, the reaction of the epoxidized intermediate with the nucleophile typically requires a suitable base (e.g., DIPEA, sodium acetate, etc.) in a suitable solvent (e.g., methanol, ethanol, isopropanol, tert-butanol, etc.) at 80-100 ℃. The next step D is carried out in a suitable base (e.g. sodium hydrogen, sodium acetate) and a suitable solvent (e.g. DMF or t-butyl acetate) at 0 to 120 degrees celsius.

In addition, the compounds of formula (I) can also be prepared by reaction scheme 4:

reaction scheme 4:

wherein X is C, variable PG₁Represents a suitable leaving group, such as tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, etc., LG₂，LG₃Represents a suitable leaving group, for example halogen, such as chloro, bromo, iodo, azodimethylaminomethylenyl and the like. All other variables are defined as formula (I).

Reaction scheme 4 comprises step A of piperidone or pyrrolidone having a suitable protecting group at the nitrogen with N-dimethylformamide dimethyl acetal or a suitable brominating agent (liquid bromine, bromosuccinimide, cupric bromide, benzene)Trimethyl amine tribromide) in a suitable solvent (e.g., toluene, xylene, DMF), generally requires relatively high temperatures of between 50 and 140 degrees celsius. In the next step B, the adduct obtained is reacted with a nucleophile in the presence of a suitable solvent (e.g.methanol, ethanol, isopropanol, tert-butanol, DMF), a suitable base (e.g.triethylamine, DIPEA, etc.). Step C, protecting group PG₁Removal of (a) is accomplished by hydrogenation or chemical means. Step D, the reaction of the epoxidized intermediate with the nucleophile typically requires a suitable base (e.g., DIPEA, sodium acetate, etc.) in a suitable solvent (e.g., methanol, ethanol, isopropanol, tert-butanol, etc.) at 80-100 ℃. The next step E, reaction in the presence of a suitable base (e.g. sodium hydrogen, sodium acetate) and a suitable solvent (e.g. DMF or t-butyl acetate) at 0 to 120 degrees celsius provides the compound of formula (I).

The intermediate compounds of the preceding schemes are either commercially available or may be prepared according to general reaction schemes well known to those skilled in the art. For example, an intermediate compound of formula (IV) can be prepared according to reaction scheme 5:

reaction scheme 5:

variable LG₂，LG₃Each represents a suitable leaving group such as halogen (e.g., chloro, bromo, iodo, methylsulfonyl, etc.). All other variables are defined as formula (I).

Scheme 5 comprises step A oxidizing allyl alcohol with cumene peroxide in the presence of the corresponding diisopropyl (+) or (-) tartrate and tetraisopropyl titanate, usually in a suitable solvent (e.g., dichloromethane, toluene). The p-nitrobenzenesulfonyl chloride as the protecting group requires a suitable base (e.g., triethylamine, diisopropylethylamine, azadimethylaminopyridine), and the reaction is usually carried out at a temperature ranging from-20 ℃ to 0 ℃. In the next step B, epoxy transfer to nitroimidazole is carried out by heating the epoxy intermediate obtained above together with the nitroimidazole starting material, and the reaction is carried out in the presence of a suitable solvent (e.g., ethanol, isopropanol, t-butanol, t-butyl acetate, etc.), a suitable base (e.g., diisopropylethylamine, potassium carbonate, etc.), and usually at a temperature of 40 ℃ to 100 ℃. Step C, also we can directly obtain the intermediate compound of formula (IV) which is not optically active by heating epoxy with leaving group and nitroimidazole, the reaction requires a suitable solvent (such as ethanol, isopropanol, tert-butanol, tert-butyl acetate, etc.), a suitable base (such as diisopropylethylamine, sodium acetate, etc.), the reaction is usually carried out at a temperature of 40-100 ℃.

In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.

The compounds of formula (I) may also be derived from compounds of formula (I) which themselves are converted by functional groups well known in the art.

The chemical reactions of the embodiments of the present invention are carried out in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.

An important consideration in any synthetic route planning in the art is the selection of suitable protecting groups for reactive functional groups, such as amino groups in the present invention. Greene and Wuts (protective groups In Organic Synthesis, Wiley and Sons, 1991) are the authorities of this area for trained practitioners. All references cited herein are incorporated herein in their entirety.

The present invention will be specifically described below by way of examples, which are not intended to limit the present invention in any way.

All solvents used in the present invention are commercially available and can be used without further purification. The reaction is generally carried out under inert nitrogen in an anhydrous solvent. Proton NMR data were recorded on a Bruker Avance III 400(400MHz) spectrometer with chemical shifts expressed as (ppm) at the low field of tetramethylsilane. Mass spectra were measured on an agilent 1200 series plus 6110(& 1956A). LC/MS or Shimadzu MS contain a DAD: SPD-M20A (LC) and Shimadzu Micromass2020 detector. The mass spectrometer was equipped with an electrospray ion source (ESI) operating in either positive or negative mode.

The compound is made by hand orThe software names, and the commercial compounds are under the supplier catalog name.

Using a sample prepared with a Shimadzu SIL-20A autosampler and a Japanese Shimadzu DAD: HPLC analysis was performed using an Shimadzu LC20AB system from SPD-M20A detector using an Xtimate Cl8(3M packing, 2.1X 300mm specification) column. Method 0-60AB — 6 min: the elution was started with 100% a (a is 0.0675% TFA in water) and ended with 60% B (B is 0.0625% TFA in MeCN) using a linear gradient, with the entire procedure being 4.2 min followed by 1 min of 60% B. The column was equilibrated for a further 0.8 min to 100: 0 and a total run time of 6 minutes. Method for 10-80 AB-6 minutes: elution was started with 90% a (a is 0.0675% TFA in water) and ended with 80% B (B is 0.0625% TFA in acetonitrile) using a linear gradient, with the entire procedure being 4.2 min followed by 80% B for 1 min. The column was equilibrated for a further 0.8 min to 90: 10, total run time 6 minutes. The column temperature was 50 ℃ and the flow rate was 0.8 mL/min. The scanning wavelength of the diode array detector is 200-400 nm.

Thin Layer Chromatography (TLC) was performed on a Sanpont-group silica gel GF254, spots were detected by irradiation with a UV light lamp, and in some cases by other methods, in these cases iodine (about 1g iodine was added to 10g silica gel and mixed thoroughly), vanillin (about 1g vanillin dissolved in 100mL 10% H)₂SO₄Prepared in (r)), ninhydrin (available from Aldrich) or special color developer (mixed thoroughly (NH)₄)₆Mo₇O₂₄·4H₂O、5g(NH₄)₂Ce(IV)(NO₃)₆、450mLH₂O and 50mL concentrated H2SO₄Prepared) thin layer plates were spread and the compounds were examined. Still, w.c. was used; kahn, m.; and Mitra, M.journal of Organic Chemistry, 1978, 43, 2923-. Common solvents for flash or thin layer chromatography are mixtures of dichloromethane/methanol, ethyl acetate/methanol and hexane/ethyl acetate.

Preparative chromatography was performed on a Gilson-281Prep LC 322 system using a Gilson UV/VIS-156 detector using an Agella Venusil ASB PrepC18.5m, 150X 21.2mm chromatography column; phenomenex Gemini C18, 5m, 150 x 30 mm; boston Symmetrix C18, 5m, 150 x 30 mm; or Phenomenex Synergi C18, 4m, 150X 30 mm. Eluting the compound with a low gradient of acetonitrile/water containing 0.05% HCl, 0.25% HCOOH or 0.5% NH at a flow rate of about 25mL/min₃·H₂O, total run time 8-15 minutes.

Using an Agilent1260 autosampler and Agilent DAD: 1260 Agilent1260Infinity SFC System of Detector SFC for SFC analysis. The chromatographic column adopts Chiralcel OD-H250 x 4.6mm I.D., 5um or Chiralpak AS-H250 x 4.6mm I.D., 5um or Chiralpak AD-H250 x 4.6mm I.D., 5 um. Chromatographic conditions of OD-H-5-40-2.35 ML: chiralcel OD-H chromatographic column (250X 4.6mm I.D., 5um packing) with 40% ethanol (0.05% DEA) -CO as mobile phase₂(ii) a The flow rate is 2.35 mL/min; the detection wavelength was 220 nm. AS-H _3_40_2.35ML chromatographic conditions: a Chiralpak AS-H chromatography column (specification 250 x 4.6mm i.d., 5um packing); the mobile phase was 40% methanol (0.05% DEA) -CO₂(ii) a The flow rate was 2.35mL/min and the detection wavelength was 220 nm. OD-H _3_40_2.35M chromatographic conditions: chiralcel OD-H chromatographic column (250X 4.6mm I.D, 5um packing) with 40% methanol (0.05% DEA) -CO as mobile phase₂The flow rate was 2.35mL/min, and the detection wavelength was 220 nm. AD-H _2_50_2.35ML chromatographic conditions: ChiralpakAD-H chromatographic column (specification 250X 4.6mm I.D, 5um packing) with 50% methanol (0.1% MEA) -CO as mobile phase₂The flow rate was 2.35mL/min, and the detection wavelength was 220 nm.

Preparative SFC analyses were performed on a Waters THar 80 Pre-SFC system using a Gilson UV detector using either Chiralcel OD-H (250X 4.6mm I.D, 5m packing) or ChiralpakAD-H (250X 4.6mm I.D, 5m packing). Eluting the compound with a low gradient of ethanol-carbon dioxide or methanol-carbon dioxide at a flow rate of about 40-80mL/min, wherein the methanol or ethanol contains 0.05% NH₃·H₂O, 0.05% DEA or 0.1% MEA, for a total run time of 20-30 minutes.

The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention.

The absolute steric configuration of the chiral center carbon atom, or the configuration of the double bond, of certain compounds or intermediates has not been tested experimentally. In this case, the isomer first separated by chiral preparative chromatography is designated "A" and the second separated is designated "B". One of skill in the art can clearly distinguish between the "A" and "B" isomers by certain methods, such as NMR. This method is the most suitable method for judging the stereoconfiguration.

The examples set forth below are all prepared, isolated and characterized by the methods described herein. The following examples are merely representative of the scope of the invention, and are not intended to be exhaustive. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Preparation of key intermediates a, B and C:

(S) -2- ((2-chloro-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

1-benzyl-4-pyrrolidin-1-yl-3, 6-dihydro-2H-pyridine

To a solution of 1-benzyl-4-one (90.00 g, 475.56 mmol, 1.00 eq) in toluene (70.00 ml) at 30 ℃ under nitrogen protection was added pyrrolidine (33.82 g, 475.56 mmol, 1.00 eq. the mixture was stirred at 130 ℃ for 12H then the mixture was concentrated in vacuo at 45 ℃ to give 1-benzyl-4-pyrrolidin-1-yl-3, 6-dihydro-2H-pyridine (110.00 g, crude) as a yellow solid which was used in the next step without further purification.

Step 2:

6-benzyl-1, 3, 4, 5, 7, 8-hexahydro-1, 6-naphthyridin-2-one

To a solution of 1-benzyl-4-pyrrolidin-1-yl-3, 6-dihydro-2H-pyridine (119.00 g, 491.01 mmol, 1.00 eq) in toluene (80.00 ml) was added prop-2-enamide (52.35 g, 736.51 mmol, 1.50 eq) at 30 degrees celsius, then the mixture was stirred at 130 degrees celsius for 12 hours, cooled to 30 degrees celsius, and concentrated at 45 degrees celsius under reduced pressure. The residue was washed with petroleum ether (100ml), filtered and the filter cake was concentrated in vacuo to give 6-benzyl-1, 3, 4, 5, 7, 8-hexahydro-1, 6-naphthyridin-2-one (76.00 g, 313.63 mmol, 63.88% yield) as a yellow solid.

And step 3:

6-benzyl-1, 5, 7, 8-tetrahydro-1, 6-naphthyridin-2-one

6-benzyl-1, 3, 4, 5, 7, 8-hexahydro-1, 6-naphthyridin-2-one (35.00 g, 144.44 mmol, 1.00 eq.) was dissolved in acetic acid (200.00 ml), and a mixture of liquid bromine (23.08 g, 144.44 mmol, 1.00 eq.) and acetic acid (200.00 ml) was added to the solution at 0 deg.C under nitrogen protection. The mixture was stirred at 0 ℃ for 30 minutes and then heated to 110 ℃ and stirred for 12 hours. The mixture was cooled to 30 degrees celsius and concentrated under reduced pressure at 45 degrees celsius. The residue was poured into an aqueous solution of sodium carbonate (70 ml) and stirred for 10 minutes. The solid was filtered and washed with petroleum ether (30ml) and dried in vacuo to give 6-benzyl 1, 5, 7, 8 tetrahydro-1, 6-naphthyridin-2-one (35.00 g, crude) as a yellow solid. LCMS (ESI) m/z: 241(M +1).

And 4, step 4:

6-benzyl-2-chloro-7, 8-dihydro-5H-1, 6-naphthyridine

Reacting 6-benzyl-1, 5, 7, 8-tetrahydro-1, 6-naphthyridin-2-one (35.00 g, 145.65 mmol, 1.00 eq) was added portionwise to phosphorus oxychloride (178.62 g, 1.16 mol, 8.00 eq) at 30 ℃ and stirred for 10 minutes after addition was complete, then the mixture was heated to 130 ℃ and stirred for 12 hours the mixture was cooled, the phosphorus oxychloride was distilled off under reduced pressure at 50 ℃ the residue was diluted with dichloromethane and poured into water (500 ml), the mixture was basified with saturated sodium carbonate solution (500 ml), the aqueous phase was extracted with dichloromethane (500 ml × 3), the combined organic phase was washed with saturated brine (30ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 15/1, 7/1) to give 6-benzyl-2-chloro-7, 8-dihydro-5H-1, 6-naphthyridine (key a) (17.00 g, 65.70 mmol, 45.11% yield as a 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).

And 5:

2-chloro-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride

6-benzyl-2-chloro-7, 8-dihydro-5H-1, 6-naphthyridine (15.00 g, 57.97 mmol, 1.00 eq) was dissolved in dichloroethane (80.00 ml) and 1-chloroethylcarbonyl chloride (12.43 g, 86.96 mmol, 1.50 eq) was added at 0 deg.C under nitrogen protection. The mixture was stirred at 0 degrees celsius for 0.5 hours, then heated to 85 degrees celsius and stirred for 12 hours. The mixture was concentrated and then dissolved in methanol (30.00ml) and the mixture was stirred at 80 ℃ for an additional 2 hours. The mixture was cooled and filtered to give 2-chloro-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (6.30 g crude) as a white solid. It was used in the next step without further purification.

Step 6:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3-2-chloro-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol

2-chloro-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (11.00 g, 65.24 mmol, 1.00 eq) and 2-chloro-1- [ [ (2S) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (14.20 g, 65.24 mmol, 1.00 eq) were dissolved in ethanol (150.00 mL) and to this solution was added azodiisopropylethylamine (21.08 g, 163.10 mmol, 2.50 eq) at 15 deg.C under nitrogen protection. The mixture was stirred at 85 ℃ for 12 hours. The mixture was then cooled to 15 degrees celsius and concentrated under reduced pressure at 60 degrees celsius. Water (30ml) was added to the residue. Extraction with ethyl acetate (200 ml × 4) and the combined organic phases were washed with saturated brine (100ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 20/1, 1/2) to give 1- (2-chloro-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) -3- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-propan-2-ol (20.00 g, 51.78 mmol, 79.37% yield) as a yellow solid. LCMS (ESI) m/z: 386(M +1).

And 7:

1- (2-chloro-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) -3- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-propan-2-ol (9.00 g, 23.30 mmol, 1.00 eq) was dissolved in DMF (80.00 mL) solution at-20 deg.C under nitrogen protection with addition of NaH (1.12 g, 46.60 mmol)Mole, 2.00 equivalents). The mixture was stirred at-20 ℃ for 10 minutes, then warmed to-5 ℃ and stirred for 10 minutes, then further warmed to 15 ℃ and stirred for another 10 minutes. Cooling the mixture to 0 ℃, then adding the mixture dropwise to 0.25 mol aqueous hydrochloric acid (400 ml), then basifying the mixture with aqueous sodium bicarbonate to pH 7-8, filtering and drying the precipitate to obtain (S) -2- ((2-chloro-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B)]Oxazole (key intermediate B) (6.70 g, 19.16 mmol, 82.22% yield) as a 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) -2-chloro-1- ((2-oxidopropan-2-yl) methyl) -4-nitro-1H-imidazole

Step 1:

(S) - (2-Methyloxieth-2-yl) methyl-4-nitrobenzenesulfonate

Adding 2-methylpropan-2-en-1-ol (15.00 g, 208.02 mmol, 1.00 equiv.) and diisopropyl (2S, 3S) -tartrate diisopropyl ester (2.92 g, 12.48 mmol, 0.06 equiv.) at 10-30 ℃ under nitrogen protection in a suspension (300.00 ml) solution of DCM (15.00 g) of 4A, cooling the mixture to-10-0 ℃, dropwise adding titanium tetraisopropoxide (3.55 g, 12.48 mmol, 0.06 equiv.) to the reaction mixture to maintain the reaction temperature at-15 to-5 ℃, and then mixingThe compound was stirred for 0.5 h, (1-hydroperoxy-1-methyl-ethyl) benzene (63.32 g, 416.03 mmol, 2.00 eq) was added dropwise to the mixture, the temperature was maintained at-15 to-5 ℃ after 3h, a mixture of trimethyl phosphite (25.83 g, 208.02 mmol, 1.0 eq) was added to the reaction mixture at-15 to-5 ℃ after 20 min, 4-nitrobenzenesulfonyl chloride (46.10 g, 208.02 mmol, 1.00 eq), DMAP (1.27 g, 10.40 mmol, 0.05 eq) was added dropwise to the reaction mixture, followed by triethylamine (25.81 g, 208.02 mmol, 1.0 eq), the mixture was gradually warmed to 20 ℃ after addition, after 1h, water (100ml) was added to the reaction mixture and stirred for 20 min, filtration, the filtrate was extracted with dichloromethane (50ml 4833) and the combined organic phases were washed with saturated salts (30 g, filtered with water) and the residue was purified by silica gel column chromatography (6783-200 mm), the filtrate was purified by vacuum column chromatography using ethyl acetate (200 mm ) and silica gel as a white solid, after 3h, the reaction was purified by silica gel column chromatography, and the reaction was purified by vacuum.¹H NMR(400MHz，CDCl₃)：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) -2-chloro-1- ((2-oxidopropan-2-yl) methyl) -4-nitro-1H-imidazole

To a mixture of 2-chloro-4-nitro-1H-imidazole (20.00 g, 135.57 mmol, 1.00 eq) and (S) - (2-methyloxiran-2-yl) methyl-4-nitrobenzenesulfonate (37.05 g, 135.57 mmol, 1.00 eq) in DMF (300.00 ml) was added potassium carbonate (56.21 g, 406.71 mmol, 3.00 eq) degassed and replaced 3 times with nitrogen, and the mixture was stirred at 60 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted, neutralized with saturated sodium carbonate (200 ml) and extracted with ethyl acetate (50ml × 3). The combined organic layers were washed with saturated brine (50ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate 5/1, 2/1) to give (key intermediate C) (R) -2-chloro-1- ((2-methyloxiran-2-yl) methyl) -4-nitro-1H-imidazole (17.86 g, 82.07 mmol, 60.54% yield) as a yellow oil. LCMS (ESI) m/z: 218(M +1).

Example 1

2-methyl-6-nitro-2- ((2-phenyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

6-benzyl-2-phenyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

To a mixed solution of key intermediate a (1.10 g, 4.25 mmol) in dioxane/water (11 ml, 10/1) was added potassium phosphate (2.23 g, 10.51 mmol), phenylboronic acid (1.03 g, 8.45 mmol) and Pd (PPh)₃)₄(734.00 mg, 635.19 micromoles) and the mixture was stirred at 130 degrees celsius for 3 hours. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/0, 10/1) to give 6-benzyl-2-phenyl-7, 8-dihydro-5H-1, 6-naphthyridine (750.00 mg, 58.75%) as a white solid. H NMR (400MHz, CDCl)₃)：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-tetrahydro-1, 6-naphthyridine

To a solution of 6-benzyl-2-phenyl-7, 8-dihydro-5H-1, 6-naphthyridine (375.00 mg, 1.25 mmol) in dichloroethane (15 ml) was added 1-chloroethylcarbonyl chloride (232.02 mg, 1.62 mmol) at 0 degrees celsius and the mixture was stirred at 0 degrees celsius for 15 minutes, then heated to 85 degrees celsius and stirred for 12 hours. The mixture was concentrated under reduced pressure, and methanol (15 ml) was added to the residue, followed by stirring at 60 ℃ for another 1 hour. The mixture was concentrated to give 2-phenyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (340.00 mg, crude) as a white solid. LCMS (ESI) m/z: 211(M +1).

And step 3:

1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2-phenyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) propan-2-ol

To a solution of 2-phenyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (500.00 mg, 2.38 mmol) in ethanol (5 ml) was added 2-chloro-1- ((2-methyloxiran-2-yl) methyl) -4-nitro-1H-imidazole (672.69 mg, 3.09 mmol) and the mixture was stirred at 70 ℃ for 6 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 20/1, 2/1) to give 1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2-phenyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) propan-2-ol (600.00 mg crude) as a yellow oil. LCMS (ESI) m/z: 428(M +1).

And 4, step 4:

To a solution of 1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2-phenyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) propan-2-ol (600.00 mg, 1.40 mmol) in DMF (10 ml) under nitrogen at 0 degrees celsius NaH (67.20 mg, 2.80 mmol) was added the mixture stirred at 0 degrees celsius for 1 hour the mixture was added to stirred water (40 ml), the precipitated solid was filtered and recrystallized in ethyl acetate (50ml) to give a white solid which was passed through SFC (chiralpak ad 250 × 30mm i.d.5um, Supercritical CO₂/EtOH(0.2％NH₃H₂O) ═ 60/40, 80ml/min, 220nm) to give two chiral isomers, the first compound obtained being 2-methyl-6-nitro-2- ((2-phenyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-, 3-dihydroimidazo [2, 1-B]Oxazole designated Compound 1A (40.60 mg, 7.19%) to give a second compound, 2-methyl-6-nitro-2- ((2-phenyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B]The oxazole was designated compound 1B (48.10 mg, 8.48%). The nuclear magnetism is the same as:¹H NMR(400MHz，CDCl₃)：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).

example 2

2-methyl-6-nitro-2- ((2- (4- (trifluoromethoxy) phenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydro [2, 1-B ] oxazole

Step 1:

6-benzyl-2- (4- (trifluoromethoxy) phenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

To a mixed solution of critical intermediate a (1.20 g, 4.64 mmol, 1.00 eq) in dioxane (5 ml) and water (0.5 ml) was added potassium phosphate (2.46 g, 11.60 mmol, 2.50 eq) and Pd (PPh) was added at 0 ℃ under nitrogen protection (PPh)₃)₄(536.18 mg, 464.00 micromoles, 0.10 equivalents), (4- (trifluoromethoxy) phenyl) boronic acid (1.43 g, 6.96 mmol, 1.50 equivalents). The mixture was stirred at 120 ℃ for 3 hours. The mixture was cooled and concentrated at 50 degrees celsius under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 50/1, 15/1) to give 6-benzyl-2- (4- (trifluoromethoxy) phenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (1.30 g, 3.38 mmol, 72.89% yield) as a yellow solid. LCMS (ESI) m/z: 385(M +1).

Step 2:

2- (4- (trifluoromethoxy) phenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

To a solution of 6-benzyl-2- (4- (trifluoromethoxy) phenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (1.30 g, 3.38 mmol, 1.00 eq) in dichloroethane (20ml) was added 1-chlorocarbonyl chloride (725.28 mg, 5.07 mmol, 1.50 eq) at 0 ℃ under nitrogen. The mixture was stirred at 15 ℃ for 0.5 hour, then heated to 80 ℃ and stirred for 12 hours. Methanol (5 ml) was added to the mixture and after stirring for a further 4 hours, cooling, the mixture was concentrated at 50 ℃ under reduced pressure and the residue was purified by silica gel chromatography (dichloromethane/methanol ═ 50/1, 10/1) to give 2- [4- (trifluoromethoxy) phenyl ] -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (500.00 mg, 1.70 mmol, 50.27% yield) as a yellow solid. LCMS (ESI) m/z: 295(M +1).

And step 3:

1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2- (4- (trifluoromethoxy) phenyl) -7, 8-dihydro-1, 6-naphthyridine 6(5H) -yl) propan-2-ol

To a solution of 2- [4- (trifluoromethoxy) phenyl ] -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (400.00 mg, 1.36 mmol, 1.00 eq) and 2-chloro-1- [ (2-methyloxiran-2-yl) methyl ] -4-nitroimidazole (591.90 mg, 2.72 mmol, 2.00 eq) in ethanol (10 ml) was added DIPEA (74.00 mg, 572.58 micromole, 0.42 eq). The mixture was stirred at 80 ℃ for 12 hours. The mixture was cooled and concentrated at 50 ℃ under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 15/1, 1/1) to give 1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2- (4- (trifluoromethoxy) phenyl) -7, 8-dihydro-1, 6-naphthyridine 6(5H) -yl) propan-2-ol (500.00 mg, crude) as a yellow solid. LCMS (ESI) m/z: 512(M +1).

And 4, step 4:

1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2- (4- (trifluoromethoxy) phenyl) -7, 8-dihydro-1, 6-naphthyridine 6(5H) -yl) propan-2-ol (300.00 mg, 586.07 micromoles, 1.00 equiv) was added to a DMF (5.00 ml) solution at 0 deg.C under nitrogen protection with NaH (28.13 mg, 1.17 mmol, 2.00 equiv.) the mixture was stirred at 0 deg.C for 0.5H, the color of the solution turned red, the mixture was added to water (10 ml) at 0 deg.C, the aqueous phase was extracted with ethyl acetate (50ml × 4), the combined organic phases were washed with saturated brine (20ml × 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo, the preparative chromatographic purification (GX-SyD; storage diamond 18-150 mm-ODS 24 mm; 225% -225% NH-water; 3.54%₄OH) 25mL/min) to give a mixture of the two isomers (90 mg) which was passed through chiral SFC (ChiralpakAD 250 × 30mmI. D.5um, Supercritical CO₂/EtOH(0.2％NH₃H₂O) ═ 60/40, 70ml/min, 220nm) to give two chiral isomers, the first compound obtained was 2-methyl-6-nitro-2- ((2- (4- (trifluoromethoxy) phenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) yl) methyl) -2, 3-dihydroimidazo [2, 1-B) group]The oxazole was designated compound 2A (48.20 mg, 97.33 micromoles, 16.61% yield, 96% purity) to give a second compound, 2-methyl-6-nitro-2- ((2- (4- (trifluoromethoxy) phenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B ] -]The oxazole was designated compound 2B (33.40 mg, 67.02 micromole, 11.44% yield, 95.4% purity). The nuclear magnetism is the same as:¹HNMR(400MHz，CDCl₃)：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).

example 3

(S) -2-methyl-6-nitro-2- ((2- (3- (trifluoromethoxy) phenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (120.00 mg, 343.08 micromoles, 1.00 eq.) and [3- (trifluoromethoxy) phenyl]Boric acid (70.65 mg, 343.08 micromoles, 1.00 eq) was dissolved in dioxane (5.00 ml) and water (500.00 μ l), and the solution was charged with Pd (dppf) Cl at 30 deg.C under nitrogen blanket₂(25.10 mg, 34.31 micromole, 0.10 eq), sodium carbonate (90, 91 mg, 857.70 micromole, 2.5 eq.) the mixture was stirred at 110 ℃ for 12 hours after completion of the reaction, the mixture was cooled to 30 ℃ and concentrated at 45 ℃ under reduced pressure, the residue was poured into water (10 ml) and stirred for 5 minutes the aqueous phase was extracted with ethyl acetate (30ml × 3), the combined organic phases were washed with saturated brine (10ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate 1/2.5) and preparative chromatographic separation purification (GX-D; Boston Symmetrix C18 ODS-R150 mm 30mm 5 um; acetonitrile 24% -54%; water (0.225% mica acid)25ml/min) to give (S) -2-methyl-2- (3-nitro) -2-phenyl) -2- (3-dihydro-2H) -2-methoxy-2-5H-phenyl) -2- (6-dihydro-2-1-5H) and 2-dihydro-2-naphthyl-2H- ((8-5 m) and 2H) to give (2-5-dihydro-naphthyl) imidazole, 2-]Oxazole compound 3(12.00 mg, 24.62. mu. mol, 7.18% yield, 97.54% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 4

(S) -2-methyl-6-nitro-2- ((2- (2- (trifluoromethoxy) phenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (100.00 mg, 285.90 micromoles, 1.00 equivalents) and (2- (trifluoromethoxy) phenyl) boronic acid (70.65 mg, 343.08 micromoles, 1.20 equivalents) were dissolved in a mixed solution of dioxane (5.00 mL) and water (500.00 microliters) and sodium carbonate (60.61 mg, 571.80 micromoles, 2.00 equivalents), Pd (dppf) Cl, was added to the mixed solution at 15 ℃ under nitrogen protection₂(20.92 mg, 28.59 micromoles, 0.10 equiv.). The mixed solution was stirred at 120 ℃ for 12 hours. After the reaction was complete, the mixed solution was cooled to 15 ℃, filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative chromatography (GX-D; Boston symmetry C18 ODS-R150X 30mm X5 um; acetonitrile 24% -54%; water (0.225% fomic acid); 25mL/min) to give (S) -2-methyl-6-nitro-2- ((2- (2- (trifluoromethoxy) phenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-, 3-dihydroimidazo [2, 1-B ] -2]Oxazole compound 4(15.00 mg, 29.97 micromole, 10.48% yield, 95% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 5

(S) -2- ((2- (2-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

6-benzyl-2- (2-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

Key intermediate A (1.50 g, 5.80 mmol, 1.00 eq.) and (2-fluorophenyl) boronic acid (973.84 mg, 6.96 mmol, 1.20 eq.) were dissolved in a mixed solution of dioxane (20.00 mL) and water (5.00 mL) and Pd (dppf) Cl was added under nitrogen protection₂(424.39 mg, 580.00 micromoles, 0.10 equivalents) and sodium carbonate (1.23 g, 11.60 mmol, 2.00 equivalents) and the combined solution was then stirred at 100 degrees celsius for 12 hours the reaction was concentrated under reduced pressure to remove the solvent, the residue was diluted with water to 20ml and extracted with ethyl acetate (10ml × 3), the combined organic layers were washed with saturated brine (10ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-benzyl-2- (2-fluorophenyl) -5, 6, 7, 8-tetrahydro 1, 6-naphthyridine (1.39 g, 4.37 mmol, 75.27% yield) as a brown solid.

Step 2:

2- (2-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

6-benzyl-2- (2-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (1.39 g, 4.37 mmol, 1.00 eq) was dissolved in methanol (20.00 ml) and Pd (OH) was added under nitrogen atmosphere₂C (10%, 139 mg). The mixed solution was replaced with hydrogen gas 3 times. The mixed solution was heated to 50 ℃ and at H₂(50psi) stirringStirring for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product 2- (2-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (1.05 g, crude). The crude product was used in the next step without further purification.

And step 3:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (2-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol

2- (2-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (300.00 mg, 1.31 mmol, 1.00 eq), (R) -2-chloro-1- ((2-oxetan-2-yl) methyl) -4-nitro-1H-imidazole (286.00 mg, 1.31 mmol, 1.00 eq), DIPEA (507.91 mg, 3.93 mmol, 3.00 eq) were dissolved in ethanol (20.00 ml) and the mixed solution was replaced with nitrogen three times. The mixed solution was then stirred at 80 degrees celsius for 12 hours under an atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate 5/1, 1/1) to give (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (2-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol (300.00 mg, 672.84 micromoles, 51.36% yield) as a yellow solid.

And 4, step 4:

The (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (2-fluorophenyl) -7, 8-dihydro-1, 6-naphthalen-ol-6 (5H) -yl) -2-methylpropan-2-ol (300.00 mg,672.84 micromoles, 1.00 equiv) in DMF (5.00 mL) the mixed solution was added NaH (32.30 mg, 807.41 micromoles, 1.20 equiv) at 0 deg.C and stirred for 30 minutes at this temperature the reaction mixture was added saturated ammonium chloride (20mL) at 0 deg.C, then diluted with 20mL of water and extracted with DCM (10mL × 3). the combined organic layers were washed with saturated brine (10mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by preparative chromatography (GX-E; Innoval C18150 mm 30mm 5 um; acetonile trien 12% -42%; water (0.225% fomic acid); 25mL/min) to give (S) -2- ((2- (2-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-nitro-2-imidazole-2-and 2-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl-2-nitro-2-imidazole and 2-B-2-dihydro-1, 2-E]Oxazole compound 5(101.80 mg, 248.65 micromole, 36.96% yield).¹H NMR(400MHz，CDCl₃)：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).

Example 6

(S) -2- ((2- (3-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

6-benzyl-2- (3-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

Key intermediate a (1.50 g, 5.80 mmol, 1.00 eq), (3-fluorophenyl) boronic acid (973.36 mg, 6.96 mmol, 1.20 eq) was dissolved in a mixed solution of dioxane (20.00 ml) and water (5.00 ml). Adding Pd (dppf) Cl into the mixed solution under the protection of nitrogen₂(424.17 mg, 579.71 micromoles, 0.10 equivalents) and sodium carbonate (1.23 g, 11.59 mmol, 2.00 equivalents) the mixture was then stirred at 100 ℃ under nitrogen for 12 hours the reaction mixture was concentrated under reduced pressure to remove the solvent the residue was diluted with water to 20ml and extracted with ethyl acetate (10ml × 3) the combined organic layers were washed with saturated brine (10ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-benzyl-2- (3-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (1.40 g, 4.40 mmol, 75.81% yield) as a brown solid

Step 2:

2- (3-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

6-benzyl-2- (3-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (1.40 g, 4.40 mmol, 1.00 eq) was dissolved in methanol (20.00 ml). Adding Pd (OH) under the protection of nitrogen₂C (10%, 140 mg). The mixed solution was replaced with hydrogen gas 3 times. Mixing the mixture in H₂(50psi) heated to 50 degrees Celsius and stirred for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product 2- (3-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (1.10 g, crude). The crude product was used directly in the next step. The crude product was used in the next step without further purification.

And step 3:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (3-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol

2- (3-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (300.00 mg, 1.31 mmol, 1.00 eq), (R) -2-chloro-1- ((2-oxetan-2-yl) methyl) -4-nitro-1H-imidazole (286.00 mg, 1.31 mmol, 1.00 eq), DIPEA (507.91 mg, 3.93 mmol, 3.00 eq) were dissolved in ethanol (20.00 ml), and the mixture was stirred at 80 ℃ for 12 hours under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate 5/1, 1/1) to give (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (3-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol (300.00 mg, 672.84 micromoles, 51.36% yield) as a yellow solid.

And 4, step 4:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (3-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol (300.00 mg, 672.84 micromole, 1.00 equiv.) was dissolved in DMF (5.00 mL) and to this mixture was added NaH (32.30 mg, 807.41 micromole, 1.20 equiv.) and stirred for 30 minutes at 0 deg.C the reaction mixture was quenched with saturated ammonium chloride solution (20mL) at 0 deg.C, then diluted with water (20mL) and extracted with DCM (10mL × 3), the combined organic layers were washed with saturated brine (10mL × 2), dried over sodium sulfate residue, filtered and concentrated under reduced pressure to afford preparative chromatography (GX-E; phenomeneXSynergi C18150 mm 30 mm; Aceton. sub.4. under reduced pressure15% -45% of itrile; water (0.13% HCl); 25mL/min) to obtain (S) -2- ((2- (3-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2-, 3-dihydroimidazo [2, 1-B)]Oxazole compound 6(161.80 mg, 395.20 micromole, 58.74% yield).¹H NMR(400MHz，CDCl₃)：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).

Example 7

(S) -2- ((2- (4-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

6-benzyl-2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

Key intermediate a (2.00 g, 7.73 mmol, 1.00 eq) and (4-fluorophenyl) boronic acid (1.08 g, 7.73 mmol, 1.00 eq) were dissolved in a mixed solution of dioxane (20.00 ml) and water (2.00 ml). Sodium carbonate (1.64 g, 15.46 mmol, 2.00 eq.) in Pd (dppf) Cl was added at 15 deg.C under nitrogen₂(565.60 mg, 773.00 micromoles, 0.10 equiv.). The mixed solution was stirred at 110 ℃ for 12 hours under nitrogen. After the reaction, the mixed solution was cooled to 15 ℃ and concentrated under reduced pressure at 50 ℃ to give a residueWater (20ml) was added, the aqueous phase was extracted with dichloromethane (100ml × 4), the combined organic phases were washed with saturated brine (50ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 20/1, 5/1) to give 6-benzyl-2- (4-fluorophenyl) -7, 8-dihydro-5H-1, 6-naphthyridine (1.86 g, 5.84 mmol, 75.57% yield) as a yellow solid.¹H NMR(400MHz，CDCl₃)：8.00-7.89(m，2H)，7.47-7.30(m，7H)，7.15(t，J＝8.8Hz，2H)，3.76(s，2H)，3.68(s，2H)，3.19-3.07(m，2H)，2.92(t，J＝6.0Hz，2H).

Step 2:

2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride

6-benzyl-2- (4-fluorophenyl) -7, 8-dihydro-5H-1, 6-naphthyridine (1.86 g, 5.84 mmol, 1.00 eq) was dissolved in dichloroethane (20.00 mL). 1-chloroethylcarbonyl chloride (1.25 g, 8.76 mmol, 1.50 eq.) was added at 0 deg.C under nitrogen. The mixture was stirred at 0 ℃ for 0.5 h. Then heated to 85 degrees celsius and stirred for 12 hours. The mixture was then concentrated to remove the solvent, methanol (20.00 ml) was added to the residue, and the mixture was stirred at 85 ℃ for an additional 2 hours. The combined solution was filtered and dried to give 2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (1.54 g crude) as a yellow solid which was used directly in the next step.

And step 3:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (4-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol

2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (1.54 g, 6.75 mmol, 1.00 eq) and 2-chloro-1- [ [ (2S) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (1.47 g, 6.75 mmol, 1.00 eq) were dissolved in ethanol (20.00 ml). DIPEA (2.18 g, 16.88 mmol, 2.50 eq) was added at 15 degrees celsius under nitrogen. After the mixture was stirred at 80 ℃ for 12 hours, the mixture was cooled to 15 ℃ and concentrated at 60 ℃ under reduced pressure. The residue was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate 20/1, 1/3) to give 1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] -2-methyl-propan-2-ol (1.20 g, 2.69 mmol, 39.87% yield) as a yellow solid.

And 4, step 4:

1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl]-2-methyl-propan-2-ol (1.20 g, 2.69 mmol, 1.00 equiv) was dissolved in DMF (10.00ml), and NaH (129.12 mg, 5.38 mmol, 2.00 equiv) was added to the mixed solution at-20 ℃ under nitrogen protection, then the mixed solution was stirred for 10min at-20 ℃, then for 10min at-5 ℃ and for 10min at 15 ℃. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 20/1, 1/3) and the resulting product was stirred in methanol (20ml), 75 ℃ for 0.5H, then cooled to 15 ℃, filtered and dried to give (S) -2- ((2- (4-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] o]Oxazole compound 7(711.10mg, 1.72mmol, 63.99% yield, 99.1% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 8

(S) -2- ((2- (4-chlorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (100.00 mg, 285.90 micromoles, 1.00 eq) and (4-chlorophenyl) boronic acid (53.65 mg, 343.08 micromoles, 1.20 eq) were dissolved in a mixed solution of dioxane (5.00 ml) and water (500.00 μ l) at 15 degrees celsius under nitrogen. The mixture was stirred at 120 ℃ for 12 hours, then cooled to 15 ℃ and filtered, the filtrate was concentrated at 50 ℃ under reduced pressure, and the residue was purified by preparative chromatography (GX-D; Boston symmetry C18 ODS-R150X 30mm X5. mu.m; acetonitrile 24% -54%; water (0.225% fomicacid); 25mL/min) to give (S) -2- ((2- (4-chlorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] -2]Oxazole compound 8(10.80 mg, 24.26 micromole, 8.49% yield, 95.67% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 9

(S) -4- (6- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazol-2-yl) methyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) benzonitrile

Key intermediate B (120.00 mg, 343.08 micromoles, 1.00 eq.) and (4-cyanophenyl) boronic acid (60.49 mg, 411.70 micromoles, 1.20 eq.) were dissolved in dioxane (5.00 ml) and Pd (dppf) Cl was added to the solution at 30 deg.C under nitrogen protection₂(25.10 mg, 34.31 micromoles, 0.10 equivalents), sodium carbonate (90.91 mg, 857.70 micromoles, 2.5 equivalents), the mixture was stirred at 110 ℃ for 12 hours, then cooled to 30 ℃ and concentrated at 45 ℃ under reduced pressure, water (10 mL) was added to the residue, the aqueous phase was extracted with ethyl acetate (20mL × 3), the combined organic phases were washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was initially treated by thin layer chromatography (petroleum ether/ethyl acetate 1/2.5), followed by preparative chromatographic separation and purification (GX-D; Boston symmetry C18-R150 ODS 30mm 5 um; acetonitrile 24% -54%; water (0.225% mic acid; 25mL/min) to give (S) -4- (6-methyl-6-nitro-2-imidazole [ 2-dihydro-imidazole, 1-2B- ((1-2-dihydro-2B, 2-B-5) and]oxazol-2-yl) methyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) benzonitrile compound 9(9.60 mg, 23.05. mu. mol, 6.72% yield, 99.3% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 10

(S) -2-methyl-6-nitro-2- ((2- (4- (trifluoromethyl) phenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (120.00 mg, 343.08 micromoles, 1.00 eq.) and [4- (trifluoromethyl) phenyl]Boric acid (65.16 mg, 343.08 micromoles, 1.00 eq) was dissolved in a mixture solution of dioxane (5.00 ml) and water (500.00 μ l), and sodium carbonate (72.73 mg, 686.17 micromoles, 2.00 eq), pd (dppf) Cl, was added at 15 degrees celsius under nitrogen at 15 degrees celsius₂(25.10 mg, 34.31 micromole, 0.10 equiv.). The mixed solution was stirred at 110 ℃ for 12 hours and purified by preparative chromatography (Boston symmetry C18 ODS-R150 30mm 5 um; acetonitrile 24% -54%; water (0.225% fomic acid); 25mL/min) to give (S) -2-methyl-6-nitro-2- ((2- (4- (trifluoromethyl) phenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B ] -2]Oxazole compound 10(16.40 mg, 34.16 micromole, 9.96% yield, 95.7% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 11

(S) -2- ((2- (3-fluoro-4- (trifluoromethoxy) phenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (62.32 mg, 178.17 micromole, 1.00 equiv.)) And [ 3-fluoro-4- (trifluoromethoxy) phenyl group]Boric acid (39.90 mg, 178.17 micromoles, 1.00 eq) was dissolved in dioxane (5.00 ml) and Pd (dppf) Cl was added at 30 deg.C under nitrogen protection₂(13.04 mg, 17.82 micromoles, 0.10 eq), sodium carbonate (47.21 mg, 445.42 micromoles, 2.5 eq), the mixed solution was stirred at 110 ℃ for 12 hours, cooled and concentrated under reduced pressure at 45 ℃ the residue was poured into water (10 mL) and stirred for 5 minutes the aqueous phase was extracted with ethyl acetate (30mL × 3), the combined organic phases were washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the residue was subjected to preliminary treatment by preparative chromatography (petroleum ether/ethyl acetate 1/2.5) to yield (S) -2- ((2- (3-fluoro-4- (trifluoromethoxy) phenyl) -7, 8-dihydro-naphthyridine) -1-60%; water (0.225% fomicroinid); 25mL/min) to give (S) -2- (3-fluoro-4- (trifluoromethyl) phenyl) -7, 6-dihydro-naphthyridine-1, 6-2-methyl) -2H-2-5-dihydro-2-imidazole [ 1-2H, 6-methyl-2-5 ] and 2-nitro-2H (2-5-methyl-2-imidazole)]Oxazole compound 11(10.70 mg, 20.82 micromole, 11.68% yield, 96% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 12

(S) -2- ((2- (3, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (300.00 mg, 857.71 micromoles, 1.00 equiv.) and (3, 4-difluorophenyl) boronic acid (162.53 mmol)G, 1.03 mmol, 1.20 eq) was dissolved in a mixed solution of dioxane (5.00 ml) and water (500.00 μ l). Sodium carbonate (113.64 mg, 1.07 mmol, 2.50 eq.), Pd (dppf) Cl was added at 30 deg.C under nitrogen₂(62.76 mg, 85.77 micromoles, 0.10 eq.) the mixture is heated to 100 ℃ and stirred for 12 hours, cooled, water (10 ml) is added to the mixed solution, the aqueous phase is extracted with ethyl acetate (30ml × 3.) the combined organic phases are washed with saturated brine (20ml), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo, the residue is initially treated by thin-layer chromatography (petroleum ether/ethyl acetate ═ 1/1, 0/1) and then purified by preparative chromatography (GX-D; Boston Symmetrix C18 ODS-R150: 30mm 5 um; acetonitrile 24% -54%; water (0.225% fomic acid), 25ml/min) to give (S) -2- ((2- (3, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydro-2-B-1, 3-dihydro-1B-2-B-1-5H-yl) methyl-6-nitro-2, 3-imidazole and 2-B-dihydro-2-B-l-5 mg]Oxazole compound 12(5.70 mg, 13.34 micromole, 3.11% yield, 95.0% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 13

(S) -2- ((2- (2, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2-, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (300.00 mg, 857.71 micromoles, 1.00 equiv) and (2, 4-difluorophenyl) boronic acid (162.53 mg, 1.0)3 mmol, 1.20 eq) was dissolved in a mixed solution of dioxane (5.00 ml) and water (500.00. mu.l), followed by the addition of sodium carbonate (113.64 mg, 1.07 mmol, 2.50 eq), Pd (dppf) Cl at 30 ℃ under nitrogen protection₂(62.76 mg, 85.77 micromoles, 0.10 equivalents) then heated to 100 degrees celsius and stirred for 12 hours the mixture is cooled to 30 degrees celsius, water (10 mL) is added to the mixture, extracted with ethyl acetate (30mL × 3), the combined organic phases are washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue is purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 1/1, 0/1), followed by preparative chromatography (GX-D; Boston' S macrothrix C18 ODS-R150: -30 mm 5 um; acetotriole 24% -54%; (water (0.225% fomic acid), 25mL/min) to give (S) -2- ((2- (2, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydro-imidazo [2, 3-B ] 2, 3-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl-2, 2-dihydro-B-2, 2-D-C-5 m]Oxazole compound 13(35.70 mg, 83.53 micromole, 19.48% yield, 97.0% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 14

(S) -2- ((2- (3, 5-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2-, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (200 mg, 571.80 micromoles, 1.00 equivalents) and (3, 5-difluorophenyl) boronic acid (628) were added.98 micromoles, 1.10 equivalents) was dissolved in dioxane (5.00 ml) and Pd (dppf) Cl was added under nitrogen₂(42 mg, 57.18 micromoles, 0.10 equivalents) and cesium fluoride (217 mg, 1.43 mmol, 2.50 equivalents). The mixture is heated to 110 ℃ and stirred for 2 hours the mixture is cooled to 20 ℃ and concentrated under reduced pressure the residue is diluted with water, the aqueous phase is extracted with ethyl acetate (20ml × 3). the combined organic phase is washed with saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo the residue is purified by chromatography on silica gel (column height: 250 mm, diameter: 100 mm, 100-mesh 200-mesh silica gel, petroleum ether/ethyl acetate ═ 2/1, 1/1) to give (S) -2- ((2- (3, 5-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] -2, 1-B]Oxazole compound 14(26.00 mg, 59.62 micromoles, 10.43% yield).¹H NMR(400MHz，CDCl₃)：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).

Example 15

(S) -2- ((2- (5-chloro-2-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (200.00 mg, 571.80 micromoles, 1.00 equiv.) and (5-chloro-2-fluoro-phenyl) boronic acid (119.64 mg, 686.17 micromoles, 1.20 equiv.) were dissolved in a mixed solution of water (500.00. mu.L) and dioxane (3.00 mL), and Pd (dppf) Cl was added₂(41.84 mg, 57.18 micromoles, 0.10 equivalents) and cesium fluoride (260.57 mg, 1.72mmol, 3.00 equivalents). The mixture was stirred at 110 degrees celsius under nitrogen for 16 hours. TrueConcentrating in air, and separating and purifying the residue by preparative chromatography (GX-D; Boston Green ODS 150 x 305 u; acetonitrile 40% -70%; water (0.225% fomic acid); 25mL/min) to give (S) -2- ((2- (5-chloro-2-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-b)]Oxazole compound 15(40.09 mg, 88.24 micromole, 15.43% yield, 97.7% purity).¹H NMR(400MHz，CDCl₃)：7.94(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).

Example 16

(S) -2- ((2- (2, 3-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-b ] oxazole

Key intermediate B (200.00 mg, 571.80 micromoles, 1.00 equivalents) and (2, 3-difluorophenyl) boronic acid (135.44 mg, 857.70 micromoles, 1.50 equivalents), cesium fluoride (173.71 mg, 1.14 mmol, 2.00 equivalents) were dissolved in a mixed solution of water (300.00 μ l) and dioxane (3.00 ml). The mixed solution was replaced with nitrogen three times, and Pd (dppf) Cl was added₂(41.84 mg, 57.18 micromoles, 0.10 equivalents) and stirred at 110 degrees celsius for 12 hours. The residue was purified by preparative chromatography (GX-A; Phenomenex Gemini Cl 8250. about.5010 u; acetonitrile 38% -68%; H)₂O(0.2％NH₃.H₂O); 25mL/min) to give (S) -2- ((2- (2, 3-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ]]Oxazole Compound 16(28.00 mmol)G, 65.51 micromoles, 11.46% yield).¹H NMR(400MHz，DMSO-d₆)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).

Example 17

(S) -2- ((2- (2, 5-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2-, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (200.00 mg, 571.80 micromoles, 1.00 equiv.) and (2, 5-difluorophenyl) boronic acid (108.3 mg, 686.16 micromoles, 1.20 equiv.) were dissolved in a mixed solution of toluene (5.00 mL) and water (500.00. mu.L), and cesium fluoride (260.57 mg, 1.72mmol, 3.00 equiv.), Pd (dppf) Cl, was added at 30 ℃ under nitrogen at 30 ℃₂(41.84 mg, 57.18 micromoles, 0.10 eq.), then heated to 100 ℃ and stirred for 12 hours after cooling the mixture to 30 ℃ water (10 ml) was added to the mixture, the aqueous phase was extracted with ethyl acetate (30ml × 3), the combined organic phases were washed with saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 1/1, 0/1) followed by preparative chromatography (GX-D; Boston Symmetrix C18 ODS-R150: 30mm 5 um; acetoitrile 24% -54%; water (0.225% fomic acid), 25ml/min) to give (S) -2- ((2- (2, 5-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-nitro-2-imidazole [2, 2-dihydro-2- (2, 5-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-nitro-2-dihydro-2-imidazole [2, 3-dihydro-2-B ] -]Oxazole compound 17(51.50 mg, 118.69 micromoles, 20.76% yield, 98.5% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 18

(S) -2- ((2- (3-chloro-4-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (300.00 mg, 857.71 micromoles, 1.00 eq), (3-chloro-4-fluoro-phenyl) boronic acid (224.32 mg, 1.29 mmol, 1.50 eq), cesium fluoride (260.57 mg, 1.72mmol, 2.00 eq) were dissolved in a mixed solution of water (500.00. mu.l) and dioxane (5.00 ml) and Pd (dppf) Cl was added under nitrogen protection₂(62.76 mg, 85.77 micromoles, 0.10 equiv.) and stirred at 110 deg.C for 12 hours. Concentrating, separating and purifying by preparative chromatography (GX-G, Phenomenex Synergi C18150 x 30mm x 4um, acetonitrile 45% -75%; H₂O(+0.0022NH₃.H₂O); 25mL/min) to obtain (S) -2- ((2- (3-chloro-4-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B)]Oxazole compound 18(90.00 mg, 202.77 micromole, 23.64% yield).¹H NMR(400MHz，DMSO-d₆)：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).

Example 19

(S) -2- ((2- (3-chloro-2-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (200.00 mg, 571.80 micromoles, 1.00 equiv.) and (3-chloro-2-fluoro-phenyl) boronic acid (99.70 mg, 571.80 micromoles, 1.00 equiv.) were dissolved in a mixed solution of dioxane (3.00 mL) and water (500.00. mu.L), and Pd (dppf) Cl was added₂(41.84 mg, 57.18 micromoles, 0.10 equivalents) and cesium fluoride (260.57 mg, 1.72mmol, 3.00 equivalents). The mixture was stirred at 110 ℃ for 16H under nitrogen, concentrated and the residue purified by preparative chromatography (GX-D; Boston Green ODS 150 x 305 u; acetonitrile 40% -70%; water (0.225% fomic acid); 25mL/min) to give (S) -2- ((2- (3-chloro-2-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] -2]Oxazole compound 19(47.80 mg, 101.12 micromole, 17.68% yield, 93.9% purity).¹H NMR(400MHz，CDCl₃)7.83-7.74(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).

Example 20

(S) -2- ((2- (4-chloro-3-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (200 mg, 571.80 micromoles, 1.00 eq.) and (4-chloro-3-fluoro-phenyl) boronic acid (628.98 micromoles, 1.10 eq.) were dissolved in dioxane (5.00 ml) and Pd (dppf) Cl was added under nitrogen protection₂(42 mg, 57.18 micromoles, 0.10 equivalents) and cesium fluoride (217 mg, 1.43 mmol, 2.50 equivalents). The mixture was heated to 110 ℃ and stirred for 2 hours, then cooled to 20 ℃ and concentrated under reduced pressure, the residue was diluted with water, the aqueous phase was extracted with ethyl acetate (20ml × 3). the combined organic phases were washed with saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was purified by preparative chromatography (Instrument: GX-D; Column: Boston symprix C18 ODS-R150: 30mm 5 um; Mobile phase: MeCN: 25% -55%; H₂O (+0.0023HCOOH), Rate: 25 ml/min; monitored wavelet: 220nm/254 nm; run length: 10min/15 min; column temperature: (S) -2- ((2- (4-chloro-3-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B) is obtained at 20 ℃]Oxazole compound 20(26.00 mg, 52.72 micromole, 9.22% yield).¹H NMR(400MHz，CDCl₃)：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).

Example 21

(S) -2- ((2- (3-chloro-5-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (200 mg, 571.80 micromoles, 1.00 equivalents) and (3-chloro-5-fluoro-phenyl) boronic acid (628.98 micromoles, 1.10 equivalents) were dissolved in dioxahexakisTo the loop (5.00 ml), Pd (dppf) Cl was added under nitrogen protection₂(42 mg, 57.18 micromoles, 0.10 equivalents) and cesium fluoride (217 mg, 1.43 mmol, 2.50 equivalents). the mixed solution was heated to 110 ℃ and stirred for 2 hours, cooled to 20 ℃, concentrated under reduced pressure, the residue was diluted with water, the aqueous phase was extracted with ethyl acetate (20ml × 3). the combined organic phases were washed with saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by preparative chromatography (Instrument: GX-D; Column: Boston Symmetrix C18-R150. mu.30 mm 5. mu.m; Mobile phase: MeCN: 15% -45%; H.H.₂O (+0.0023HCOOH), Rate: 25 ml/min; monitored wavelet: 220nm/254 nm; run length: 10min/15 min; column temperature: (S) -2- ((2- (3-chloro-5-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B) is obtained at 20 ℃]Oxazole compound 21(88.00 mg, 193.70 micromole, 33.88% yield).¹H NMR(400MHz，CDCl₃)：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).

Example 22

(S) -2- ((2- (2-chloro-5-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (200 mg, 571.80 micromoles, 1.00 eq.) and (2-chloro-5-fluoro-phenyl) boronic acid (628.98 micromoles, 1.10 eq.) were dissolved in dioxane (5.00 ml) and Pd (dppf) Cl was added under nitrogen protection₂(42 mg, 57.18. mu.m)Moles, 0.10 equivalents) and cesium fluoride (217 mg, 1.43 mmol, 2.50 equivalents). the mixture was heated to 110 degrees Celsius and stirred for 2 hours, the mixture was cooled to 20 degrees Celsius and concentrated under reduced pressure, the residue was diluted with water, the aqueous phase was extracted with ethyl acetate (20mL × 3). the combined organic phases were washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.the residue was purified by preparative chromatography (Instrument: GX-D; Column: Boston symmetry C18 ODS-R150: 30mm 5 um; Mobile phase: MeCN: 35% -75%; H.H.₂O (+0.0023HCOOH), Rate: 25 ml/min; monitored wavelet: 220nm/254 nm; run length: 10min/15 min; column temperature: (S) -2- ((2- (2-chloro-5-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B) is obtained at 20 ℃]Oxazole compound 22(30.00 mg, 66.91 micromole, 11.70% yield).¹H NMR(400MHz，CDCl₃)：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).

Example 23

(S) -2- ((2- (4-chloro-2-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (200.00 mg, 571.80 micromoles, 1.00 eq) and (4-chloro-2-fluoro-phenyl) boronic acid (119.64 mg, 686.16 micromoles, 1.20 eq) were dissolved in a mixed solution of dioxane (3.00 ml) and water (500.00 μ l). Adding Pd (dppf) Cl under the protection of nitrogen₂(41.84 mg, 57.18 micromoles, 0.10 equiv.) and cesium fluoride (260.57 mg, 1.72mmol, 300 equivalents). The mixture was stirred at 110 ℃ for 16 hours. Concentrating, separating and purifying the residue by preparative chromatography (GX-G; Phenomenex Synergi C18150 x 30mm 4 um; acetonitrile 24% -54%; water (0.225% fomic acid); 25mL/min) to give (S) -2- ((2- (4-chloro-2-fluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ]]Oxazole compound 23(56.26 mg, 125.10 micromoles, 21.88% yield, 98.7% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 24

(S) -2- ((2- (furan-3-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2-3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (200.00 mg, 571.80 micromoles, 1.00 equiv.) and 3-furylboronic acid (76.77 mg, 686.16 micromoles, 1.20 equiv.) were dissolved in a mixed solution of dioxane (5.00 mL) and water (500.00. mu.L), and sodium carbonate (121.21 mg, 1.14 mmol, 2.00 equiv.), Pd (PPh) were added under nitrogen protection₃)₄(66.07 mg, 57.18 micromoles, 0.10 equiv.). The mixture was stirred at 90 degrees celsius for 12 hours. The mixture was cooled to 30 ℃ and concentrated under reduced pressure at 45 ℃ and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1, 1/1) initially followed by preparative chromatography (GX-D; Boston symmetry C18 ODS-R150: 30mm 5 um; MeCN: 24% -54%; H₂O (+0.0025 FA); 25ml/min) to give (S) -2- ((2- (furan-3-yl) -7, 8-Dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B]Oxazole compound 24(56.67 mg, 142.65 micromoles, 24.95% yield, 96% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 25

(S) -2- ((2- (furan-2-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2-3-dihydroimidazo [2, 1-B ] oxazole

Key intermediate B (150.00 mg, 428.85 micromoles, 1.00 equiv.) and tributyl (2-furyl) stannane (229.73 mg, 643.28 micromoles, 1.50 equiv.) were dissolved in dichloroethane (10.00mL) and Pd (dppf) Cl was added at 30 deg.C under nitrogen protection₂(31.38 mg, 42.89 micromoles, 0.10 equivalents), lithium chloride (6.09 mg, 143.76 micromoles, 1.00 equivalents) then heated to 120 degrees Celsius and stirred for 12 hours the mixture is cooled and concentrated under reduced pressure at 45 degrees Celsius, water (10 mL) is added to the mixture and stirred for 5 minutes, the aqueous phase is extracted with ethyl acetate (30mL × 3), the combined organic phases are washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue is treated with silica gel chromatography (ethyl acetate) followed by preparative chromatographic separation and purification (Instrument: GX-D; Boston symmetry C18-R150: 30mm ODS 5 um; acetotriele 24% -54%; water (0.225% mic acid); 25mL/min) to give (S) -2- ((2- (furan-2-yl) -7, 8-dihydro-1-6-naphthyridine) -6-methyl-2-nitro) -2-methyl-6H-nitro-22, 3-dihydroimidazo [2, 1-B]Oxazole compound 25(31.70 mg, 83.12 micromole, 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).

Example 26

(S) -2- ((2-cyclopropyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

6-benzyl-2-cyclopropyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

Key intermediate A (1.50 g, 5.80 mmol, 1.00 eq) and toluene cyclopropylboronic acid (647.69 mg, 7.54 mmol, 1.30 eq) were dissolved in toluene (10.00ml) and bis (1-adamantyl) -butyl-phosphine (415.91 mg, 1.16 mmol, 0.20 eq), cesium carbonate (3.78 g, 11.60 mmol, 2.00 eq) and Pd (OAc) were added at 30 degrees Celsius under nitrogen₂(130.22 mg, 580.00 micromoles, 0.10 equiv.). The mixture was then heated to 100 degrees celsius and stirred for 12 hours. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 30/1) to give 6-benzyl-2-cyclopropyl-7, 8-dihydro-5H-1, 6-naphthyridine (1.30 g, 4.92 mmol,84.79% yield) as a 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-tetrahydro-1, 6-naphthyridine hydrochloride

6-benzyl-2-cyclopropyl-7, 8-dihydro-5H-1, 6-naphthyridine (200.00 mg, 756.54 micromoles, 1.00 equiv.) was dissolved in dichloroethane (10.00mL) and 1-chlorocarbonyl chloride (162.24 mg, 1.13 mmol, 1.50 equiv.) was added at 0 deg.C under nitrogen. The mixture was stirred at 0 ℃ for 20 minutes, then heated to 80 ℃ and stirred for 12 hours. After concentration, methanol (10.00ml) was added to the mixture and stirred at 75 ℃ for an additional 2 hours. The mixture was cooled and concentrated under reduced pressure at 45 ℃. The residue was washed with dichloromethane (20mL × 3), filtered and the filter cake was dried to give 2-cyclopropyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (170.00 mg, crude) as a yellow solid which was used in the next step without further purification.

And step 3:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- (2-cyclopropyl-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) -2-methyl-propan-2-ol

2-cyclopropyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (550.00 mg, 3.16 mmol, 1.00 eq.) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (893.94 mg, 4.11 mmol, 1.30 eq.) were dissolved in a solution of ethanol (20.00 ml) and DIPEA (1.02 g, 7.90 mmol, 2.50 eq.) was added at 30 deg.C under nitrogen. The mixture was stirred at this temperature for 10 minutes, then heated to 80 degrees celsius and stirred for 12 hours. The mixture was diluted with water (20ml) and the aqueous phase was extracted with ethyl acetate (20ml × 3). The combined organic phases were washed with saturated brine (10ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1, 2/1) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- (2-cyclopropyl-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) -2-methyl-propan-2-ol (400.00 mg, crude) as a yellow solid. LCMS (ESI) m/z: 392(M +1).

And 4, step 4:

Dissolving (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- (2-cyclopropyl-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) -2-methyl-propan-2-ol (440.00 mg, 1.12 mmol, 1.00 equiv.) in DMF (5.00 mL), adding NaH (67.37 mg, 1.68 mmol, 1.50 equiv.) at-45 ℃ under nitrogen protection, stirring the mixture at-45 to-15 ℃ for 2 hours, pouring the residue into a saturated aqueous solution of ammonium chloride (20mL) and stirring at 0 ℃ for 20 minutes, extracting the aqueous phase with ethyl acetate (30mL of × 3), washing the combined organic phases with saturated saline (10mL of × 2), drying with anhydrous sodium sulfate, filtering and vacuum concentrating the residue, purifying by preparative chromatography (GX-D; Synmrix 18% C18-25% acetonitrile R25% to 25mm S2- ((25% S-225 mm) to obtain a mixtureCyclopropyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B]Oxazole compound 26(157.10 mg, 442.05 micromole, 39.47% yield).¹H NMR(400MHz，CDCl₃)：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).

Example 27

(S) -2-methyl-6-nitro-2- ((2- (trifluoromethyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

benzyl-4-pyrrolidin-1-yl-3, 6-dihydro-2H-pyridine

1-benzyl-4-one (10.00 g, 52.84 mmol, 1.00 equiv.) and pyrrolidine (4.51 g, 63.41 mmol, 1.20 equiv.) were dissolved in toluene (100mL), and water was divided over a water trap at 110 deg.C for 4.5H, the mixture was cooled and concentrated to give 1-benzyl-4-pyrrolidin-1-yl-3, 6-dihydro-2H-pyridine (10.50 g, crude) as a yellow oil which was used in the next step without further purification.

Step 2:

6-benzyl-2- (trifluoromethyl) -7, 8-dihydro-5H-1, 6-naphthyridine

1-benzyl-4-pyrrolidin-1-yl-3, 6-dihydro-2H-pyridine (2.50 g, 10.32 mmol, 1.00 eq) and (E) -4-ethoxy-1, 1, 1-trifluoro-but-3-en-2-one (2.08 g, 12.38 mmol, 1.20 eq) were dissolved in dioxane (30.00ml), heated to 100 ℃ and stirred for 4H, then ammonium acetate (2.39 g, 30.96 mmol, 3.00 eq) was added and stirred for 16H, the mixture was cooled and diluted with water, the aqueous phase was extracted with ethyl acetate (100ml ×), the combined organic phases were washed with saturated brine (100ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the oil was purified by silica gel (column height: 300mm, diameter 40 mm, 100ml 200 mesh silica gel, petroleum ether/ethyl acetate ═ 6- (32 ml) -benzyl-3H-2-naphthyridine-1, 6-5% yield, 6.2 g-dihydro-naphthalene (6.2 g, 6.2.7-5 g, 6-5 mg) and yellow oil was obtained as yellow oil.¹H NMR(400MHz，CDCl₃)7.46-7.29(m，7H)，3.75(s，2H)，3.70(s，2H)，3.15(t，J＝5.90Hz，2H)，2.92(t，J＝5.96Hz，2H).

And step 3:

2- (trifluoromethyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

6-benzyl-2- (trifluoromethyl) -7, 8-dihydro-5H-1, 6-naphthyridine (1.50 g, 5.13 mmol, 1.00 eq) was dissolved in methanol (20.00 ml) and Pd/C (100.00 mg) was added to the solution. The mixture was stirred under H2(50psi) for 16 hours. The mixture was filtered and concentrated to give 2- (trifluoromethyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (850.00 mg, crude) as an off-white solid, which was used in the next step without further purification.

And 4, step 4:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2- (trifluoromethyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) propan-2-ol

2- (trifluoromethyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (200.00 mg, 989.22 micromoles, 1.00 equiv.) and (R) -2-chloro-1- ((2-oxetan-2-yl) methyl) -4-nitro-1H-imidazole (322.90 mg, 1.48 mmol, 1.50 equiv.) were dissolved in ethanol (10.00ml) and DIPEA (127.85 mg, 989.22 micromoles, 1.00 equiv.) was added under nitrogen. The mixture was heated to 80 degrees celsius and stirred for 16 hours. The mixture was cooled and concentrated under reduced pressure, and the residue was poured into water (50mL) and extracted with ethyl acetate (50mL × 3). The combined organic phases were washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2- (trifluoromethyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) propan-2-ol (310.00 mg, crude) as a brown oil. LCMS (ESI) m/z: 420.1(M +1).

And 5:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2- (trifluoromethyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) propan-2-ol (100.00 mg, 238.21 micromoles, 1.00 equivalents) was dissolved in DMF (2.00 mL) and NaH (19.06 mg, 476.42 micromoles, 2.00 equivalents) was added at-20 deg.C under nitrogen. The mixture was stirred at-20 ℃ 1The mixture was poured into ice-water (w/w ═ 1/1) (10 ml) and stirred for 5 minutes, the aqueous phase was extracted with ethyl acetate (10ml × 3), the combined organic phases were extracted with anhydrous Na₂SO4 was dried, filtered and concentrated in vacuo. The residue was isolated and purified by preparative chromatography (Instrument: GX-G; Column: Phenomenex synergy C18150: 30 mm. about.4. mu.m; Mobile phase: MeCN: 20% -60%; H₂O (+0.0025 FA); and (3) Rate: 25 ml/min; MonitordWavelength: 220nm/254 nm; run length: 10min/15 min; column temperature: (S) -2-methyl-6-nitro-2- ((2- (trifluoromethyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B) is obtained at 30 DEG C]Oxazole compound 27(42.00 mg, 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).

Example 28

(S) -2-methyl-6-nitro-2- ((2- (piperidin-1-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B ]

Step 1:

6-benzyl-2- (1-piperidinyl) -7, 8-dihydro-5H-1, 6-naphthyridine

Key intermediate a (500.00 mg, 1.93 mmol, 1.00 eq) and piperidine (328.68 mg, 3.86 mmol, 2.00 eq) were dissolved in a solution of toluene (5.00 ml) and sodium tert-butoxide (370.95) was added at 30 degrees celsius under nitrogen protectionMg, 3.86 mmol, 2.00 eq, Pd₂(dba)₃(88.37 mg, 96.5 micromole, 0.05 equivalent), sodium tert-butoxide (741.92 mg, 7.72 mmol, 2.00 equivalent), Xphos (92.01 mg, 193.00 micromole, 0.10 equivalent). The mixture was stirred at 100 degrees celsius for 12 hours, then cooled and concentrated at 45 degrees celsius under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 20/1, 5/1) to give 6-benzyl-2- (1-piperidinyl) -7, 8-dihydro-5H-1, 6-naphthyridine (550.00 mg, 1.79 mmol, 92.70% yield) as a 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:

2- (1-piperidinyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

6-benzyl-2- (1-piperidinyl) -7, 8-dihydro-5H-1, 6-naphthyridine (500.00 mg, 1.63 mmol, 1.00 eq) was dissolved in methanol (20.00 mL) and Pd/C (100.00 mg, 1.63 mmol, 1.00 eq) was added at 30 deg.C under nitrogen. Mixing the mixture in₂(50Psi), stirred at 30 ℃ for 18 hours. The mixture was filtered and concentrated under reduced pressure at 45 degrees celsius to give 2- (1-piperidinyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (410.00 mg, crude) as a yellow solid which was used in the next step without further purification.

And step 3:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [2- (1-piperidinyl) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] propan-2-ol

2- (1-piperidinyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (200.00 mg, 920.34 micromoles, 1.00 eq) and (R) -2-chloro-1- ((2-methyloxiran-2-yl) methyl) -4-nitro-1H-imidazole (300.41 mg, 1.38 mmol, 1.50 eq) were dissolved in ethanol (3.00 ml) and DIPEA (59.47 mg, 460.17 micromoles, 0.50 eq) was added at 30 ℃ under nitrogen. The mixture was stirred at 80 ℃ for 12 hours, cooled and concentrated at 45 ℃ under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1, 1/1) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [2- (1-piperidinyl) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] propan-2-ol (200.00 mg, crude) as a yellow solid.

And 4, step 4:

(S) -2-methyl-6-nitro-2- ((2- (piperidin-1-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B ] oxazole

Mixing (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [2- (1-piperidinyl) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl]Propan-2-ol (139.00 mg, 319.60. mu. mol, 1.00 eq) was dissolved in DMF (5.00 mL), NaH (25.57 mg, 639.20. mu. mol, 2.00 eq) was added at-45 ℃ under nitrogen protection, the mixture was stirred at-45 to-15 ℃ for 1 hour before water (3mL) was added and the mixture was stirred for 5 minutes, the aqueous phase was extracted with dichloromethane (20mL × 3), the combined organic phases were washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was purified by thin layer chromatography (petroleum ether/ethyl acetate ═ 1/2.5) followed by preparative chromatographic separation (GX-D; Boston Symmetrix ODS 18-R150. 30 mm.5 um; ac24% -54% of etonitrile; water (0.225% fomic acid); 25mL/min) to obtain (S) -2-methyl-6-nitro-2- ((2- (piperidin-1-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B ]]Oxazole compound 28(5.40 mg, 13.55 micromole, 4.24% yield).¹H NMR(400MHz，CDCl₃)：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).

Example 29

(S) -2-methyl-6-nitro-2- ((2- (tetrahydro-2H-pyran-4-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

6-benzyl-2- (3, 6-dihydro-2H-pyran-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

Key intermediate A (1.33 g, 5.14 mmol, 1.20 equiv.), 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxolane (900.00 mg, 4.28 mmol, 1.00 equiv.) was dissolved in a mixed solution of THF (20.00 mL) and water (5.00 mL), and the mixed solution was added with Pd (dppf) Cl under nitrogen protection₂(313.17 mg, 428.00 micromoles, 0.10 equivalents) and cesium carbonate (2.79 g, 8.56 mmol, 2.00 equivalents), and the mixture was stirred at 80 degrees celsius for 12 hours. Mixing the reactionThe material was concentrated under reduced pressure to remove the solvent, the residue diluted with water (20ml) and extracted with ethyl acetate (10ml × 3). the combined organic layers were washed with saturated brine (10ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (silica, PE: ethyl acetate 5: 1) to give 6-benzyl-2- (3, 6-dihydro-2H-pyran-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (960.00 mg, 3.13 mmol, 73.20% yield) as a white solid lcms (esi) M/z: 308(M +1).

Step 2:

2- (tetrahydro-2H-pyran-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

6-benzyl-2- (3, 6-dihydro-2H-pyran-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (500.00 mg, 1.62 mmol, 1.00) was dissolved in methanol (10.00mL) and Pd/C (10%, 0.05 g) was added under a nitrogen atmosphere. The mixed solution was replaced three times with hydrogen and stirred at 28 degrees celsius, H2(50psi) for 12 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 2- (tetrahydro-2H-pyran-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (400.00 mg, crude) as a colorless oil, which was used in the next step without further purification. LCMS (ESI) m/z: 219(M +1).

And step 3:

(S) -2-methyl-2- ((2-morpholino-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

2- (tetrahydro-2H-pyran-4-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (350.00 mg)1.60 mmol, 1.00 eq), (R) -2-chloro-1- ((2-oxetan-2-yl) methyl) -4-nitro-1H-imidazole (417.81 mg, 1.92 mmol, 1.20 eq), DIPEA (620.35 mg, 4.80 mmol, 3.00 eq) was added to ethanol (10.00ml) and stirred at 80 ℃ for 12 hours under nitrogen. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (silica, dichloromethane/methanol ═ 20/1) to give (S) -2-methyl-2- ((2-morpholino-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -6-nitro-2, 3-dihydroimidazo [2, 1-B ]]Oxazole (530.00 mg, 1.22 mmol, 75.99% yield) as a 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).

And 4, step 4:

Mixing (S) -2-methyl-2- ((2-morpholino-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -6-nitro-2, 3-dihydroimidazo [2, 1-B ]]Oxazole (530.00 mg, 1.22 mmol, 1.00 eq) was dissolved in DMF (5.00 mL), NaH (58.56 mg, 1.46 mmol, 1.20 eq) was added at 0 degrees celsius, the mixture was stirred at 0 degrees celsius for 20 minutes and quenched by addition of saturated ammonium chloride (30mL), then diluted with water (10 mL) and extracted with DCM (10mL × 3), the combined organic layers were washed with saturated brine (10mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure, the residue was purified by preparative chromatography (GX-G; Phenomenex synergy C18150 x 30mm 4 um; acetonitrile 0% -30%; water (0.225% fomic acid); 25mL/min) to obtain (S) -2-methyl-6-nitro-2- ((2- (tetrahydro-2H-pyran-4-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B)]Oxazole compound 29(300.00 mg, 751.05 micromole, 61.56% yield).¹H NMR(400MHz，CDCl₃)：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).

Example 30

Step 1:

4- (6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridin-2-yl) morpholine

Critical intermediate a (1.00 g, 3.86 mmol, 1.00 eq) and morpholine (672.57 mg, 7.72 mmol, 2.00 eq) Pd at 30 ℃ under nitrogen blanket₂(dba)₃(176.73 mg, 193.00 micromole, 0.05 eq), sodium tert-butoxide (741.92 mg, 7.72 mmol, 2.00 eq), Xphos (184.01 mg, 386.00 micromole, 0.10 eq) was dissolved in toluene (20.00 ml). The mixture was then heated to 100 degrees celsius and stirred for 12 hours. The mixture was cooled and concentrated under reduced pressure at 45 ℃. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 2)0/1, 1/1) to give 4- (6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridin-2-yl) morpholine (1.10 g, 3.56 mmol, 92.11% yield) as a 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-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) morpholine

4- (6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridin-2-yl) morpholine (700.00 mg, 2.26 mmol, 1.00 eq) was dissolved in methanol (20.00 ml) and Pd (OH) was added₂C (10%, 20 mg). The mixed solution was replaced three times with hydrogen and stirred at 50 degrees celsius, H2(50psi) for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give 4- (5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) morpholine (400.00 mg, crude) as a yellow solid. LCMS (ESI) m/z: 220(M +1).

And step 3:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- (2-morpholino-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) propan-2-ol

4- (5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) morpholine (250.00 mg, 1.14 mmol, 1.00 eq) and (R) -2-chloro-1- ((2-methyloxiran-2-yl) methyl) -4-nitro-1H-imidazole (198.46 mg, 912.00 μmol, 0.80 eq) were dissolved in t-butanol (3.00 mL) at 30 ℃ under nitrogen and DIPEA (147.34 mg, 1.14 mmol, 1.00 eq) was added. The mixture was stirred at 80 ℃ for 12 hours, cooled, and concentrated at 45 ℃ under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1, 2/1) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- (2-morpholino-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) propan-2-ol (200.00 mg, 457.78 micromoles, 40.16% yield) as a yellow solid. LCMS (ESI) m/z: 437(M +1).

And 4, step 4:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- (2-morpholino-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) propan-2-ol (200.00 mg, 457.78 micromoles, 1.00 equiv.) was dissolved in DMF (5.00 mL), NaH (36.62 mg, 915.56 micromoles, 2.00 equiv.) was added at-45 deg.C under nitrogen, the mixture was stirred at-45-15 deg.C for 2 hours, then quenched with ammonium chloride (20mL), the aqueous phase was extracted with ethyl acetate (30mL × 3), the combined organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was chromatographically purified by preparative chromatography (GX-A; Phennex Gemini C50 u 5010; (0.05% monatin-ACN), 25 mL/2-methyl-3- (2-morpholino-2H-6-morpholino) -2-dihydro-2-morpholino-2-dihydro-2H-2-dihydro-2-]Oxazole compound 30(39.10 mg, 97.06 micromoles, 21.2% yield, 99.4% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 31

(S) -2- ((2- (4, 4-Difluoropiperidin-1-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

benzyl-4, 4-difluoropiperazine

1-benzyl-4-one (1.00 g, 5.28 mmol, 1.00 eq) was dissolved in DCM (10.00mL), DAST (2.56 g, 15.85 mmol, 3.00 eq) was added at zero degrees Celsius under nitrogen protection, the mixture was stirred at 0 degrees Celsius for 0.5 h, then warmed to 15 degrees Celsius and stirred for 12 h, the mixture was added to a saturated solution of sodium bicarbonate (60 mL) at 0 degrees Celsius, then the mixture was extracted with DCM (100mL × 4), the combined organic phases were washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1-benzyl-4, 4-difluoro-piperidine (1.20 g, crude product as a black solid which was used in the next step without further purification.¹H NMR(400MHz，CDCl₃)：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-Difluoropiperidine hydrochloride

1-benzyl-4, 4-difluoro-piperidine (1.20 g, 5.68 mmol, 1.00 eq) was dissolved in dichloroethane (10.00ml), 1-chloroethylcarbonyl chloride (1.22 g, 8.52 mmol, 1.50 eq) was added at zero degrees centigrade under nitrogen protection, the mixture was stirred at this temperature for 0.5 h, then heated to 85 ℃ and stirred for 12 h, the mixture was concentrated, methanol (10.00ml) was added to the residue, the mixture was then stirred at 85 ℃ for an additional 2h, the mixture was cooled and concentrated at 60 ℃ under reduced pressure to give 4, 4-difluoropiperidine hydrochloride (580.00 mg crude) as a black solid which was used in the next step without further purification.

And step 3:

6-benzyl-2- (4, 4-difluoropiperidin-1-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

6-benzyl-2-chloro-7, 8-dihydro-5H-1, 6-naphthyridine (1.03 g, 3.98 mmol, 1.00 eq.) and 4, 4-difluoropiperidine (960.00 mg, 7.93 mmol, 1.99 eq.) were dissolved in a solution of toluene (15.00 ml) at 15 deg.C under nitrogen, and sodium tert-butoxide (956.36 mg, 9.95 mmol, 2.50 eq.) dicyclohexyl- [2- (2, 4, 6-triisopropyl) phenyl ] was added]Phosphine (284.65 mg, 597.10 micromoles, 0.15 equivalents), Pd₂(dba)₃(291.61 mg, 318.45 micromoles, 0.08 eq.) the mixture is stirred at 110 ℃ for 12 hours, cooled and concentrated at 60 ℃ under reduced pressure, water (20ml) is added to the residue, the aqueous phase is extracted with dichloromethane (100ml × 4), the combined organic phases are washed with saturated brine (50ml), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to give 6-benzyl-2- [4- (4, 4-difluoro-1-piperidinyl) phenyl ] 1]-7, 8-dihydro-5H-1, 6-naphthyridine (700.00 mg, 1.67 mm)Mol, 41.92% yield) as a yellow solid.¹H NMR(400MHz，CDCl₃)：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).

And 4, step 4:

2- (4, 4-Difluoropiperidin-1-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

Reacting 6-benzyl-2- [4- (4, 4-difluoro-1-piperidyl) phenyl]-7, 8-dihydro-5H-1, 6-naphthyridine (600.00 mg, 1.75 mmol, 1.00 eq.) was dissolved in methanol (30.00mL) and Pd (OH) was added at 15 deg.C₂C (24.22 mg, 174.98 micromoles, 0.10 equiv). Stirring was carried out at 60 ℃ for 12 hours under H2(50 psi). The mixture was filtered and the filtrate was concentrated and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1, 1/10) to give 2- (4, 4-difluoropiperidin-1-yl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (250.00 mg, 987.01 micromoles, 56.40% yield) as a yellow solid. LCMS (ESI) m/z: 254(M +1).

And 5:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (4, 4-difluoropiperidin-1-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol

2- (4, 4-difluoro-1-piperidinyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (100.00 mg, 394.80 micromoles, 1.00 equivalents) and 2-chloro-1- [ [ (2S) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (85.91 mg, 394.80 micromoles, 1.00 equivalents), DIPEA (127.56 mg, 987.00 micromoles, 2.50 equivalents) were dissolved in t-butanol (5.00 ml) at 15 deg.C under nitrogen. The mixture was stirred at 85 ℃ for 12H, cooled and concentrated at 60 ℃ and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate-20/1, 1/2) to give (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (4, 4-difluoropiperidin-1-yl) -7, 8-dihydro-1-, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol (200.00 mg, crude) as a yellow oil. LCMS (ESI) m/z: 471(M +1).

Step 6:

Mixing (S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4, 4-difluoro-1-piperidinyl) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl]-2-methyl-propan-2-ol (200.00 mg, 424.72 micromoles, 1.00 equiv) was dissolved in DMF (5.00 ml) and NaH (20.39 mg, 849.44 micromoles, 2.00 equiv) was added at-20 ℃ under nitrogen. The mixture was stirred at-20 ℃ for 10 minutes, then warmed to 0 ℃ and stirred for 10 minutes, then the mixture was quenched with saturated aqueous ammonium chloride (50mL) after stirring at 15 ℃ for an additional 10 minutes, the mixture was filtered, the filter cake was dried to give a crude product, which was purified by preparative chromatography (GX-D; Boston symmetry C18 ODS-R150 30mm 5 um; acetonitrile 24% -54%; water (0.225% fomic acid); 25mL/min) to give (S) -2- ((2- (4, 4-difluoropiperidin-1-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B]Oxazole compound 31(15.00 mg, 33.88 micromole, 7.98% yield, 98.12% purity).¹H NMR(400MHz，METHANOL-d4)：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)，2.95-2.85(m，2H)，2.77-2.67(m，1H)，2.66-2.55(m，1H)，2.06-1.91(m，4H)，1.66(s，3H).LCMS(ESI)m/z：435(M+1).

Example 32

(S) -2-methyl-6-nitro-2- ((2- (3, 4, 5-trifluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B ] oxazole

The synthesis was as in example 29.

(S) -2-methyl-6-nitro-2- ((2- (3, 4, 5-trifluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B)]Oxazole compound 32(123.50 mg, 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).

Example 33

(S) -N- (4-fluorophenyl) -6- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazol-2-yl) methyl) -5, 6, 7, 8-, 8-tetrahydro-1, 6-naphthyridin-2-amine

The synthesis was as in example 30.

(S) -N- (4-fluorophenyl) -6- ((2-methyl-6-nitro)-2, 3-dihydroimidazo [2, 1-B]oxazo l-2-yl) methyl) -5, 6-, 7, 8-tetrahydro-1, 6-naphthyridin-2-amine compound 33(9.50 mg, 22.09 micromole, 6.79% yield, 98.7% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 34

(S) -2- ((2- (4-fluorophenoxy) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

tert-butyl-2-chloro-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester

2-chloro-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (850.00 mg, 4.14 mmol, 1.00 eq) and tert-butyloxycarbonyl carbonate (1.36 g, mixture 6.22 mmol, 1.50 eq) were dissolved in a mixed solution of dichloromethane (15.00 ml) and water (15.00 ml), and sodium bicarbonate (1.04 g, 12.43 mmol, 3.00 eq) was added at 15 deg.C. The mixture was poured into water (30ml) and the aqueous phase was extracted with ethyl acetate (50ml × 3). The combined organic phases were washed with saturated brine (30ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 50/1, 30/1) to give tert-butyl-2-chloro-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester (1.00 g, 3.72 mmol, 89.75% yield) as a white solid.

Step 2:

tert-butyl-2-chloro-1-oxo-7, 8-dihydro-5H-1, 6-naphthyridin-1-ium-6-carboxylic acid ethyl ester

Tert-butyl-2-chloro-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester (1.20 g, 4.47 mmol, 1.00 eq) was dissolved in chloroform (20.00 ml) and the mixture was added to m-chloroperoxybenzoic acid (1.45 g, 6.71 mmol, 1.50 eq) at 0 deg.C. The mixture was stirred at 25 ℃ for 12 hours. The mixture was then quenched with saturated sodium sulfate (20ml) and extracted with dichloromethane (40 ml × 3). The combined organic phases were washed with saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give tert-butyl-2-chloro-1-oxo-7, 8-dihydro-5H-1, 6-naphthyridin-1-ium-6-carboxylic acid ethyl ester (1.00 g, 3.51 mmol, 78.52% yield) as a yellow solid which was used directly in the next step. LCMS (ESI) m/z: 285(M +1).

And step 3:

6- (tert-Butoxycarbonyl) -2- (4-fluorophenoxy) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-1-oxide

Tert-butyl-2-chloro-1-oxo-7, 8-dihydro-5H-1, 6-naphthyridin-1-ium-6-carboxylic acid ethyl ester (600.00 mg, 2.11 mmol, 1.00 eq) and 4-fluorophenol (283.46 mg, 2.53 mmol, 1.20 eq) were dissolved in DMF (3.00 ml), NaH (168.57 mg, 4.21 mmol, 2.00 eq) was added at 0 ℃ under nitrogen protection, the mixture was stirred at 70 ℃ for 12 hours and then cooled, the residue was poured into water (15 ml), the combined organic phases were extracted with ethyl acetate (30ml × 3), washed with saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 5/1, 1/3) to give 6- (tert-butoxycarbonyl) -2- (4-fluorophenoxy) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-1-oxide (510.00 mg, 1.42 mmol, 67.07% yield) as a yellow solid.

And 4, step 4:

tert-butyl-2- (4-fluorophenoxy) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester

6- (tert-butoxycarbonyl) -2- (4-fluorophenoxy) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-1-oxide (410.00 mg, 1.14 mmol, 1.00 eq) was dissolved in a mixed solution of ammonium chloride (3.00 ml) and THF (3.00 ml), zinc (745.45 mg, 11.40 mmol, 10.00 eq) was added at 0 deg.C under nitrogen protection, the mixture was stirred at 15 deg.C for 2 hours, the mixture was filtered, and the filtrate was extracted with ethyl acetate (30ml ×), the combined organic phases were washed with saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.¹H NMR(400MHz，CDCl₃)：7.41(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).

And 5:

2- (4-fluorophenoxy) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

Tert-butyl-2- (4-fluorophenoxy) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester (200.00 mg, 580.75 micromoles, 1.00 eq) was dissolved in dichloromethane (1.00 ml) and TFA (66.24 mg, 580.75 micromoles, 1.00 eq) was added at 15 degrees celsius and stirred for 1 hour. The mixture was then concentrated under reduced pressure to give 2- (4-fluorophenoxy) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (177.00 mg, crude, TFA salt) as a yellow oil.

Step 6:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenoxy) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] -2-methyl-propan-2-ol

2- (4-fluorophenoxy) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (177.00 mg, 494.01 micromole, 1.00 eq, TFA salt) was dissolved in a solution of tert-butanol (2.00 ml) and DIPEA (191.54 mg, 1.48 mmol, 3.00 eq), 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (129.00 mg, 592.81 micromole, 1.20 eq) was added at 15 deg.C. The mixture was stirred at 70 ℃ for 12 hours, cooled and concentrated at 45 ℃ under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1, 3/1) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenoxy) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] -2-methyl-propan-2-ol (130.00 mg, 281.46 micromoles, 56.97% yield) as a yellow solid. LCMS (ESI) m/z: 462(M +1).

And 7:

Mixing (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenoxy) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl]-2-methyl-propan-2-ol (160.00 mg, 346.42 micromoles, 1.00 equiv.) is dissolved in DMF (2.00 mL), NaH (27.71 mg, 692.84 micromoles, 2.00 equiv.) is added at-45 ℃ under nitrogen protection, the mixture is stirred at-45 to 15 ℃ for 1 hour, quenched with saturated ammonium chloride solution (20mL), stirred for 5 minutes, the aqueous phase is extracted with ethyl acetate (40 mL × 3), the combined organic phases are washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue is chromatographed by preparative chromatography (GX-G; Phenomenex synergy Max-RP250 Max-8010 u; acetonitrile 30% -60%; water (0.225% fomic acid); 25mL/min) to give (S) -2- ((2- (4-fluorophenoxy) -7, 8-dihydro-1, 6-naphthyridine) -1H-6-methyl-2-imidazole (2-methyl-2-nitro-2B, 2-B-2-nitro-2-B-2-methyl-imidazole (5-6-2-nitro-2-B, 2-B) is obtained]Oxazole compound 34(56.00 mg, 129.00 micromoles, 37.24% yield, 98% purity).¹H NMR(400MHz，CDCl₃)：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)，3.11-3.03(m，2H)，2.93(td，J＝6.0，11.6Hz，1H)，2.84-2.74(m，3H)，1.68(s，3H).LCMS(ESI)m/z：426(M+1).

Example 35

(S) -2- (3, 4-difluorophenyl) -6- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazol-2-yl) methyl) -5, 6-, 7, 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile

Step 1:

tert-butyl-3-cyano-2-oxo-1, 2, 7, 8-tetrahydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester

Tert-butyl (Z) -tert-butyl 3- ((dimethylamino) methylene) -4-oxopiperidine-1-carboxylate (16.00 g, 62.91 mmol, 1.00 eq) is dissolved in DMF (120.00 ml), NaH (5.03 g, 125.82 mmol, 2.00 eq) is added portionwise at 0 degrees celsius and stirred for 1 hour. After the addition was complete, the mixture was stirred at this temperature for a further 30 minutes, then 2-cyanoacetamide (5.55 g, 66.06 mmol, 1.05 eq) was added dissolved in DMF (80.00 ml) and added dropwise to the mixed solution with the temperature being maintained. The resulting mixture was stirred at 28 ℃ for 12 hours. Concentrated under reduced pressure and the residue purified by silica gel chromatography (silica, DCM/ethyl acetate ═ 1/1, 1: 5) to give tert-butyl 3-cyano-2-oxo-1, 2, 7, 8-tetrahydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester (1.00 g, 3.63 mmol, 5.77% yield) as a 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:

2-chloro-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile

Tert-butyl-3-cyano-2-oxo-1, 2, 7, 8-tetrahydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester (2.00 g, 7.26 mmol, 1.00 eq) was added to phosphorus oxychloride (28.22 g, 184.05 mmol, 25.35 eq). The mixture was stirred at 110 ℃ for 3 hours. The reaction mixture was poured into 28 ℃ water (1500 ml) and sodium carbonate was added to pH 10. The mixture was extracted with DCM (500 ml × 3). The combined organic layers were washed with saturated brine (500 ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product 2-chloro-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile (2.00 g, crude) which was used directly in the next step.

And step 3:

tert-butyl-2-chloro-3-cyano-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester

2-chloro-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile (1.40 g, 7.23 mmol, 1.00 eq) was dissolved in a mixed solution of THF (20.00 ml) and water (10.00ml), di-tert-butyl dicarbonate (3.16 g, 14.46 mmol, 2.00 eq) and sodium carbonate (2.30 g, 21.69 mmol, 3.00 eq) were added, the mixture was stirred at 25 ℃ for 12 hours, the reaction mixture was concentrated under reduced pressure, the residue was diluted with DCM (20ml), and extracted with DCM (20ml × 3), the combined organic layers were washed with saturated brine (20ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate 10/1, 5/1) to give tert-butyl-2-chloro-3-cyano-7, 8-dihydro-1, 6-naphthyridine-3-carboxylic acid (96.00 mg ) as a yellow solid, yield of 700.30%.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).

And 4, step 4:

tert-butyl-3-cyano-2- (3, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester

Tert-butyl-2-chloro-3-cyano-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester (350.00 mg, 1.19 mmol, 1.00 eq), (3, 4-difluorophenyl) boronic acid (225.50 mg, 1.43 mmol, 1.20 eq), cesium carbonate (775.45 mg, 2.38 mmol, 2.00 eq) were dissolved in a mixed solution of dioxane (10.00ml) and water (4.00 ml), Pd (dppf) Cl was added under nitrogen protection₂(87.07 mg, 119.00 micromoles, 0.10 eq), then the mixture is stirred at 110 ℃ for 12H the reaction mixture is concentrated under reduced pressure, the residue is diluted with DCM (20ml) and extracted with DCM (20ml × 3.) the combined organic layers are washed with saturated brine (20ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue is purified by silica gel chromatography (silica, petroleum ether/ethyl acetate ═ 10/1, 5/1) to give tert-butyl 3-cyano-2- (3, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester (420.00 mg, 1.13 mmol, 95.04% yield) as a 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).

And 5:

2- (3, 4-difluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile

Tert-butyl-3-cyano-2- (3, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester (246.00 mg, 662.39 micromoles, 1.00 equivalents) was dissolved in DCM (2.00 ml) solution and TFA (75.52 mg, 662.39 micromoles, 1.00 equivalents) was added and the mixture was stirred at 25 ℃ for 1 hour and concentrated under reduced pressure to give the product 2- (3, 4-difluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile (250.00 mg, crude) which was used in the next step without purification.

Step 6:

(S) -6- (3- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-hydroxy-2-methylpropyl) -2- (3, 4-difluorophenyl) -5, 6-, 7, 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile

2- (3, 4-difluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile (180.00 mg, 663.57 micromoles, 1.00 eq.) and (R) -2-chloro-1- ((2-oxetan-2-yl) methyl) -4-nitro-1H-imidazole (173.28 mg, 796.28 micromoles, 1.20 eq.) were dissolved in t-butanol (10.00mL) and DIPEA (257.28 mg, 1.99 mmol, 3.00 eq.) was added. The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate 5/1, 1: 1) to give (S) -6- (3- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-hydroxy-2-methylpropyl) -2- (3, 4-difluorophenyl) -5, 6-, 7, 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile (230.00 mg, 470.47 micromoles, 70.90% yield) as a yellow solid. LCMS (ESI) m/z: 489/491(M +1/M +3).

And 7:

(S) -2- (3, 4-difluorophenyl) -6- ((2-methyl-6-nitro-2-, 3-dihydroimidazo [2, 1-B ] oxazol-2-yl) methyl) -5, 6-, 7, 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile

The (S) -6- (3- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-hydroxy-2-methylpropyl) -2- (3, 4-difluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-Naphthyridine-3-carbonitrile (230.00 mg, 470.47 micromoles, 1.00 equiv.) was dissolved in DMF (5.00 mL), NaH (22.58 mg, 564.56 micromoles, 1.20 equiv.) was added at 0 deg.C and the mixture was stirred at 0 deg.C for 10 minutes, quenched with saturated ammonium chloride solution (20mL), then diluted with water (20mL) and extracted with DCM (20mL × 3). the combined organic layers were washed with saturated brine (20mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative chromatography (GX-F; Welch Umate AQ-C18150 mm 30mm 5. mu.m.; acetonitrile 43% -73%; water (0.225% fomicrid); 25 mL/min.) to give (S) -2- (3, 4-difluorophenyl) -6- ((2-methyl-6-nitro-2-, 3-2-dihydroimidazo [ 2.1.B ] (S) -2, 1-dihydroimidazo [ B ] (2, 1.]Oxazol-2-yl) methyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile compound 35(20.90 mg, 42.91 micromoles, 9.12% yield, 92.884% purity).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).

Example 36

(S) -2- ((3-chloro-2- (3, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

6-benzyl-3-chloro-1, 5, 7, 8-tetrahydro-1, 6-naphthyridin-2-one

4-Methylbenzenesulfonic acid (4.30 g, 24.98 mmol, 1.50 equivalents) and 6-benzyl 1, 5, 7, 8-tetrahydro-1, 6-naphthyridin-2-one (4.00 g, 16.65 mmol, 1.00 equivalents) were dissolved in acetonitrile (30.00ml), and NCS (3.33 g, 24.98 mmol, 1.50 equivalents) was added. The mixture was stirred at 25 ℃ for 12 hours. Quenched with water and the reaction mixture was extracted with ethyl acetate (250 ml × 2). The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate 3/1, dichloromethane/methanol 10/1) to give 6-benzyl-3-chloro-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2 (1H) -one (220.00 mg, 750.37 micromoles, 29.43% yield) as a white solid. LCMS (ESI) m/z: 275.1(M +1).

Step 2:

6-benzyl-2, 3-dichloro-7, 8-dihydro-5H-1, 6-naphthyridine

6-benzyl-3-chloro-1, 5, 7, 8-tetrahydro-1, 6-naphthyridin-2-one (700.00 mg, 2.55 mmol, 1.00 eq.) and phosphorus oxychloride (3.33 g, 21.73 mmol, 8.53 eq.) were dissolved in toluene (5.00 ml) and the mixture was stirred at 100 ℃ for 5 hours. The reaction mixture was poured into water (100ml) at 25 ℃, the pH adjusted to about 9 by gradual addition of sodium carbonate solution, and extracted with ethyl acetate (200 ml × 2). The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate 80/1, 20/1) to give 6-benzyl-2, 3-dichloro-7, 8-dihydro-5H-1, 6-naphthyridine (220.00 mg, 750.37 micromoles, 29.43% yield) as a white solid. LCMS (ESI) m/z: 293.0(M +1).

And step 3:

6-benzyl-3-chloro-2- (3, 4-difluorophenyl) -7, 8-dihydro-5H-1, 6-naphthyridine

6-benzyl-2, 3-dichloro-7, 8-dihydro-5H-1, 6-naphthyridine (200.00 mg, 682.15 micromole, 1.00 eq), (3, 4-difluorophenyl) boronic acid (96.95 mg, 613.94 micromole, 0.90 eq), cesium fluoride (207.24 mg, 1.36 mmol, 2.00 eq) were dissolved in a mixed solution of dioxane (3ml) and water (300.00. mu.l), Pd (dppf) Cl was added under nitrogen protection₂(49.91 mg, 68.22 micromoles, 0.10 equiv.) and the mixture was stirred at 110 degrees celsius for 12 hours. The residue was concentrated in vacuo and purified by silica gel chromatography (silica, petroleum ether/ethyl acetate: 50/1, 20: 1) to give 6-benzyl-3-chloro-2- (3, 4-difluorophenyl) -7, 8 dihydro-5H-1, 6-naphthyridine (170.00 mg, 458.44 micromoles, 67.21% yield) as a white solid. LCMS (ESI) m/z: 370.9(M +1).

And 4, step 4:

3-chloro-2- (3, 4-difluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride

A solution of 6-benzyl-3-chloro-2- (3, 4-difluorophenyl) -7, 8-dihydro-5H-1, 6-naphthyridine (140.00 mg, 377.54 micromoles, 1.00 equivalents) and 1-chloroethylcarbonyl chloride (70.17 mg, 490.80 micromoles, 1.30 equivalents) was dissolved in dichloroethane (100.00 ml) and stirred at 80 degrees celsius for 12 hours. The reaction mixture was concentrated under reduced pressure, and methanol (100.00 ml) was added to the reaction mixture, followed by stirring at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give the crude product 3-chloro-2- (3, 4-difluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (140.00 mg, crude, hydrochloric acid) which was used in the next step without further purification. LCMS (ESI) m/z: 280.9(M +1).

And 5:

(2S) -1- [ 3-chloro-2- (3, 4-difluorophenyl) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] -3- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-propan-2-ol

3-chloro-2- (3, 4-difluorophenyl) -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (140.00 mg, 498.75 micromoles, 1.00 equivalents) was dissolved in a solution of t-butanol (5.00 ml) and DIPEA (161.15 mg, 1.25 mmol, 2.50 equivalents) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (130.24 mg, 598.50 micromoles, 1.20 equivalents) were added. The mixture was stirred at 100 degrees celsius for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate-20/1, 1/3) to give (2S) -1- [ 3-chloro-2- (3, 4-difluorophenyl) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] -3- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-propan-2-ol (80.00 mg, 160.54 micromoles, 32.19% yield) as a yellow solid. LCMS (ESI) m/z: 499.8(M +1).

Step 6:

Reacting (2S) -1- [ 3-chloro-2- (3, 4-difluorophenyl) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl]-3- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-propan-2-ol (80.00 mg, 160.54 micromoles, 1.00 equivalents) was dissolved in DMF (2.00 ml), NaH (3.85 mg, 160.54 micromoles, 1.00 equivalents) was added at-20 ℃ and stirred for 30 minutes, followed by stirring the mixture for 1 hour at 15 ℃. The reaction mixture was quenched by addition to water (15 ml) at 0 deg.C and then with ethyl acetateExtraction (100mL × 2). the combined organic layers were concentrated under reduced pressure and the residue was purified by preparative chromatography (GX-A, Phenomenex Gemini C18250 x 50mm x 10um, acetonitrile 50% -80%; 0.05% amonia-ACN; 25mL/min) to give (S) -2- ((3-chloro-2- (3, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl 6-nitro-2, 3-dihydroimidazo [2, 1-B ] -2]Oxazole compound 36(17.80 mg, 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).

Example 37

(S) -2- ((2- (3, 4-difluorophenyl) -4-methyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

6-benzyl-4-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2 (1H) -one

A mixture of 1-benzyl-4-one (10.00 g, 52.84 mmol, 1.00 equiv.) and 3-oxobutanamide (5.88 g, 58.12 mmol, 1.10 equiv.) in EATON' S REAGENT (20.00 mL) was stirred at 110 deg.C for 12 h, the mixture was added to saturated aqueous sodium bicarbonate (300 mL), adjusted to pH > 7, the aqueous layer was extracted with ethyl acetate (200 mL × 4), the combined organic phases were washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo,the residue was poured into acetone (100ml), then filtered and the filter cake was dried to give 6-benzyl-4-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2 (1H) one (7.00 g, 27.52 mmol, 52.09% yield) as a white solid.¹HNMR(400MHz，CDCl₃)：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:

6-benzyl-2-chloro-4-methyl-7, 8-dihydro-5H-1, 6-naphthyridine

6-benzyl-4-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2 (1H) -one (7.80 g, 30.67 mmol, 1.00 equiv.) was added to phosphorus oxychloride (97.44 g, 635.49 mmol, 20.72 equiv.), stirred at 110 deg.C for 12 hours and then cooled, then the mixture was quenched by addition to water (300 mL), the mixture was stirred for 30 minutes, and then the aqueous layer was basified to pH > 7 with aqueous sodium bicarbonate. The mixture was extracted with DCM (200 ml × 4), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 6-benzyl-2-chloro-4-methyl-7, 8-dihydro-5H-1, 6-naphthyridine (5.00 g, crude) as a yellow solid. LCMS (ESI) m/z: 273(M +1).

And step 3:

6-benzyl-2- (3, 4-difluorophenyl) -4-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

6-benzyl-2-chloro-4-methyl-7, 8-dihydro-5H-1, 6-naphthyridine (1.87 g, 6.86 mmol, 1.00 equiv.) and (3, 4-difluorophenyl) boronic acid (1.30 g, 8.23 mmol, 1.20 equiv.) were added to cesium fluoride (3.13 g, 20.58 mmol) at 15 deg.C under nitrogen3.00 eq) was dissolved in a mixed solution of dioxane (25.00 ml) and water (2.50 ml), and Pd (dppf) Cl was added₂(501.95 mg, 686.00 micromoles, 0.10 equivalents), the mixture is stirred at 110 ℃ for 12 hours the mixture is added to water (10 ml) and the mixture is then extracted with dichloromethane (100ml ×.) the combined organic phases are washed with saturated brine (100ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.¹H NMR(400MHz，CDCl₃)：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).

And 4, step 4:

2- (3, 4-difluorophenyl) -4-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride

6-benzyl-2- (3, 4-difluorophenyl) -4-methyl-7, 8-dihydro-5H-1, 6-naphthyridine (1.30 g, 3.71 mmol, 1.00 equiv.) was dissolved in dichloroethane (20.00 mL), 1-chlorocarbonyl chloride (795.63 mg, 5.57 mmol, 1.50 equiv.) was added at 15 deg.C under nitrogen protection, the mixture was stirred at 85 deg.C for 12 hours, the mixture was then concentrated, methanol (20.00 mL) was added to the residue, the resulting mixture was stirred at 85 deg.C for an additional 2 hours, the mixture was filtered, the filter cake was collected, dried to give 2- (3, 4-difluorophenyl) -4-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (800.00 mg, 2.70 mmol, 72.67% yield) as a white solid, which was used directly in the next step.

And 5:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (3, 4-difluorophenyl) -4-methyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol

2- (3, 4-difluorophenyl) -4-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (800.00 mg, 2.70 mmol, 1.00 eq) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (705.06 mg, 3.24 mmol, 1.20 eq) were dissolved in a solution of ethanol (20.00 ml) and DIPEA (872.37 mg, 6.75 mmol, 2.50 eq) was added at 15 deg.C under nitrogen. The mixture was stirred at 80 ℃ for 12 h, cooled and concentrated at 60 ℃ under reduced pressure and the residue was taken up in water (10 ml). The aqueous phase was extracted with dichloromethane (50ml × 4), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100 mesh silica gel, petroleum ether/ethyl acetate ═ 20/1, 1/1) to give (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (3, 4-difluorophenyl) -4-methyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol (800.00 mg, 1.67 mmol, 62.00% yield) as a yellow solid. LCMS (ESI) m/z: 478(M +1).

Step 6:

(S) -2- ((2- (3, 4-difluorophenyl) -4-methyl-7, 8 dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

Mixing (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (3, 4-difluorophenyl) -4-methyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) -2-methylpropan-2-ol (400.00)Mg, 837.01 micromoles, 1.00 eq) was dissolved in a solution of DMF (5.00 ml), NaH (40.18 mg, 1.67 mmol, 2.00 eq) was added at-20 ℃ under nitrogen and stirred for 10min, then warmed to-5 ℃ and stirred for 10 min. The mixture was then stirred at 15 ℃ for an additional 10 minutes. The mixture was cooled to 0 ℃ and quenched with saturated aqueous ammonium chloride (30 mL). The mixture was then filtered and the filter cake was collected and dried to give a crude product which was purified by preparative chromatography (GX-D; Boston symmetry C18 ODS-R150 x 30mm x 5 um; acetonitrile 24% -54%; water (0.225% fomic acid); 25mL/min) to give (S) -2- ((2- (3, 4-difluorophenyl) -4-methyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl 6-nitro-2, 3-dihydroimidazo [2, 1-B ] -2]Oxazole compound 37(97.50 mg, 215.79 micromole, 25.78% yield, 97.7% purity).¹H NMR(400MHz，METHANOL-d₄)：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)，3.18-3.08(m，2H)，3.05-2.90(m，3H)，2.88-2.78(m，1H)，2.30(s，3H)，1.69(s，3H).LCMS(ESI)m/z：442(M+1).

Example 38

2- (3, 4-difluorophenyl) -6- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazol-2-yl) methyl) -7, 8-dihydro-1-, 6-naphthyridin-5 (6H) -one

Step 1:

2-chloro-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride

6-benzyl-2-chloro-7, 8-dihydro-5H-1, 6-naphthyridine (2.70 g, 10.43 mmol, 1.00 eq.) was dissolved in dichloroethane (50.00 ml) and 1-chloroethylcarbonyl chloride (2.24 g, 15.65 mmol, 1.50 eq.) was added at 15 deg.C under nitrogen. The mixture was stirred at 85 ℃ for 12 hours. The mixture was then concentrated to remove the solvent, and methanol (50.00 ml) was added to the residue, which was then heated to 80 ℃ and stirred for 2 hours. The mixture was filtered and the filter cake was collected and dried to give 2-chloro-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (2.00 g, 9.75 mmol, 93.50% yield) as a white solid which was used directly in the next step.

Step 2:

tert-butyl-2-chloro-7, 8-dihydro-5H-1, 6-naphthyridine-6-carboxylic acid ethyl ester

2-chloro-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride (2.00 g, 9.75 mmol, 1.00 eq.) was dissolved in DCM (20.00 mL) and triethylamine (2.47 g, 24.38 mmol, 2.50 eq.) and di-tert-butyl dicarbonate (3.19 g, 14.63 mmol, 1.50 eq.) were added at 15 deg.C under nitrogen. The mixture was stirred at 15 ℃ for 12 hours. The mixture was poured into water (30ml) and the aqueous phase was extracted with dichloromethane (100ml × 4). The combined organic phases were washed with saturated brine (100ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Tert-butyl 2-chloro-7, 8-dihydro-5H-1, 6-naphthyridine-6-carboxylic acid ethyl ester (2.50 g, 9.30 mmol, 95.41% yield) was obtained as a white solid. LCMS (ESI) m/z: 269(M +1).

And step 3:

tert-butyl 2-chloro-5-oxo-7, 8-dihydro-1, 6-naphthyridine-6-carboxylic acid ethyl ester

Tert-butyl-2-chloro-7, 8-dihydro-5H-1, 6-naphthyridine-6-carboxylic acid ethyl ester (2.30 g, 8.56 mmol, 1.00 equiv.) was added to a mixed solution of acetonitrile (740.00 μ l) and carbon tetrachloride (37.00 ml) and water (14.80 ml) under nitrogen at 15 deg.C with sodium periodate (5.49 g, 25.68 mmol, 3.00 equiv.) and RuCl₃(532.58 mg, 2.57 mmol, 0.30 eq. the mixture was stirred at 15 ℃ for 12 h. the mixture was taken up in water (20ml) and then extracted with dichloromethane (100ml × 4), the combined organic phases were washed with saturated brine (100ml), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo, and the residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-mesh silica gel, petroleum ether/ethyl acetate 20/1 to 10/1) to give tert-butyl 2-chloro-5-oxo-7, 8-dihydro-1, 6-naphthyridine-6-carboxylic acid methyl ester (1.80 g, 6.37 mmol, 74.38% yield) as a white solid.¹H NMR(400MHz，CDCl₃)：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).

And 4, step 4:

tert-butyl-2- (3, 4-difluorophenyl) -5-oxo-7, 8-dihydro-1, 6-naphthyridine-6-carboxylic acid ethyl ester

Tert-butyl 2-chloro-5-oxo-7, 8-dihydro-1, 6-naphthyridine-6-carboxylic acid methyl ester (1.80 g, 6.37 mmol, 1.00 equiv.) was dissolved in a mixed solution of dioxane (30.00ml) and water (3.00 ml), and (3, 4-difluorophenyl) boronic acid (1.21 g, 7.64 mmol, 1.20 equiv.) and cesium fluoride (2.90 g, 19.11 mmol, 3.00 equiv.) were added. Pd (dppf) Cl was added at 15 ℃ under nitrogen₂(466.09 mg, 637.00 micromoles, 0.10 equiv.). Mixing the mixtureAfter stirring at 110 ℃ for 12 h, the mixture was cooled to 15 ℃ and concentrated under reduced pressure, water (20ml) was added to the residue, the aqueous phase was extracted with dichloromethane (100ml ×), the combined organic phases were washed with saturated brine (100ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-.¹H NMR(400MHz，CDCl₃)：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)

And 5:

2- (3, 4-difluorophenyl) -7, 8-dihydro-6H-1, 6-naphthyridin-5-one

Ethyl tert-butyl-2- (3, 4-difluorophenyl) -5-oxo-7, 8-dihydro-1, 6-naphthyridine-6-carboxylate (500.00 mg, 1.39 mmol, 1.00 eq) was dissolved in ethyl acetate hydrochloride (10.00ml) and the solution was stirred at 15 ℃ for 1 hour. The mixture was concentrated to dryness to give 2- (3, 4-difluorophenyl) -7, 8-dihydro-6H-1, 6-naphthyridin-5-one (350.00 mg, 1.34 mmol, 96.76% yield) as a white solid. LCMS (ESI) m/z: 261(M +1).

Step 6:

2- (3, 4-difluorophenyl) -6- [ (2-methyloxiran-2-yl) methyl ] -7, 8-dihydro-1, 6-naphthyridin-5-one

To a solution of 2- (3, 4-difluorophenyl) -7, 8-dihydro-6H-1, 6-naphthyridin-5-one (250.00 mg, 960.65 micromoles, 1.00 eq) and 2- (chloromethyl) -2-methyl-oxirane (153.54 mg, 1.44 mmol, 1.50 eq) in DMF (3.00 ml) was added potassium tert-butoxide (215.59 mg, 1.92 mmol, 2.00 eq) at 15 degrees celsius under nitrogen. The mixture was stirred at 110 ℃ for 3 hours. To the mixture was added water (10 ml), and the mixture was extracted with ethyl acetate (50ml × 4). The combined organic phases were washed with brine (50ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by chromatography on silica gel (column height: 250 mm, 10 mm diameter, 100 mesh silica gel, petroleum ether/ethyl acetate ═ 20/1, 1/1) to give 2- (3, 4-fluorophenyl) -6- [ (2-methyloxiran-2-yl) methyl ] -7, 8-dihydro-1, 6-naphthyridin-5-one (240.00 mg, crude) as a yellow solid. LCMS (ESI) m/z: 331(M +1).

And 7:

6- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methyl-propyl ] -2- (3, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-5-one

2- (3, 4-difluorophenyl) -6- [ (2-methyloxiran-2-yl) methyl ] -7, 8-dihydro-1, 6-naphthyridin-5-one (150.00 mg, 454.09 micromole, 1.00 eq) and 2-chloro-4-nitro-1H-imidazole (66.99 mg, 454.09 micromole, 1.00 eq) were dissolved in a solution of tert-butyl acetate (5.00 ml) and sodium acetate (37.25 mg, 454.09 micromole, 1.00 eq) was added at 15 deg.C under nitrogen. The mixture was stirred at 110 ℃ for 3 hours. The mixture was cooled and concentrated at 70 ℃ under reduced pressure and the residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate-1/1) to give 6- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methylpropyl ] -2- (3, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-5-one (40 mg, crude) as a white solid. LCMS (ESI) m/z: 478(M +1).

And 8:

Reacting 6- [3- (2-chloro-4-nitroimidazol-1-yl) -2-hydroxy-2-methyl-propyl]-2- (3, 4-difluorophenyl) -7, 8-dihydro-1, 6-naphthyridin-5-one (30.00 mg, 83.71 micromoles, 1.00 equiv.) is dissolved in a solution of DMF (2.00 mL), NaH (4.02 mg, 167.42 micromoles, 2.00 equiv.) is added at-20 ℃ under nitrogen protection, the mixture is stirred at-20 ℃ for 10 minutes, then warmed to 0 ℃ and stirred for 10 minutes, then stirred at 15 ℃ for 10 minutes, the mixture is cooled to 0 ℃ and quenched with saturated aqueous ammonium chloride (20mL), the mixture is extracted with ethyl acetate (30mL × 4), the combined organic phases are washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue is purified by preparative chromatography (GX-D; Boston Symmrix C18 ODS-R150 30mm 5; acornitrole 24% -54%; 2.3-5% methyl imidazole-2- (3-5 mL) and 2-5-nitro-2-5-2-mL- ((6-methyl-2-5-one, 3-one]Oxazol-2-yl) methyl) -7, 8-dihydro-1, 6-naphthyridin-5 (6H) -one compound 38(8.00 mg, 18.12 micromoles, 21.65% yield).¹H NMR(400MHz，METHANOL-d₄)：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).

Example 39

(S) -2- ((2- (4-fluorophenyl) -6, 7-dihydrothiazolo [5, 4-c ] pyridin-5 (4H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

3-bromo-4-oxopiperidine-1-carboxylic acid benzyl ester

To a solution of benzyl 4-oxopiperidine-1-carboxylate (2.00 g, 8.57 mmol, 1.00 eq) in ethyl acetate (10.00ml) was added copper bromide (3.83 g, 17.14 mmol, 2.00 eq) under nitrogen. The mixture was stirred at 80 ℃ for 1 hour. The mixture was filtered and concentrated under reduced pressure to give benzyl 3-bromo-4-oxopiperidine-1-carboxylate (2.40 g, crude) which was used directly in the next step.

Step 2:

benzyl 2- (4-fluorophenyl) -6, 7-dihydro-4H-thiazolo [5, 4-c ] pyridine-5-carboxylate

Benzyl 3-bromo-4-oxopiperidine-1-carboxylate (2.40 g, 7.69 mmol, 1.00 eq) and 4-fluorothiobenzamide (1.19 g, 7.69 mmol, 1.00 eq) were dissolved in isopropanol (20.00 ml) and heated to 80 ℃ and stirred for 2 hours. Concentrated under reduced pressure, and the residue was purified by silica gel chromatography (column height: 300mm, diameter 50mm, 100-mesh 200-mesh silica gel, petroleum ether/ethyl acetate 30/1, 5/1) to give 2- (4-fluorophenyl) -6, 7-dihydro-4H-thiazolo [5, 4-c)]Pyridine-5-carboxylic acidBenzyl ester (1.20 g, 3.26 mmol, 42.36% yield) as a white solid.¹H NMR(400MHz，CDCl₃)：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).

And step 3:

2- (4-fluorophenyl) -4, 5,6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

Benzyl 2- (4-fluorophenyl) -6, 7-dihydro-4H-thiazolo [5, 4-c ] pyridine-5-carboxylate (1.20 g, 3.26 mmol, 1.00 eq.) was dissolved in AcOH (5.00 mL), and a solution of HBr in acetic acid (48%, 5mL) was added at 20 deg.C and stirred for 1 hour. The mixture was filtered, the filter cake washed with ethyl acetate and dried in vacuo to give 2- (4-fluorophenyl) -4, 5,6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (800.00 mg, 2.54 mmol, 77.85% yield) as a yellow solid, which was used directly in the next step.

And 4, step 4:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -6, 7-dihydro-4H-thiazolo [5, 4-c ] pyridin-5-yl ] -2-methyl-propan-2-ol

2-chloro-1- [ [ (2S) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (150.00 mg, 689.31 micromoles, 1.10 equivalents) and 2- (4-fluorophenyl) -4, 5,6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (197.52 mg, 626.64 micromoles, 1.00 equivalents) were dissolved in a solution of ethanol (5.00 mL) and DIPEA (202.47 mg, 1.57 mmol, 2.50 equivalents) was added. The mixed solution was stirred at 80 ℃ for 5 hours, cooled and concentrated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate (30ml × 3). The combined organic phases were washed with saturated brine (30ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -6, 7-dihydro-4H-thiazolo [5, 4-c ] pyridin-5-yl ] -2-methyl-propan-2-ol (250.00 mg, crude) which was used directly in the next step.

Step 5

Mixing (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -6, 7-dihydro-4H-thiazolo [5, 4-c)]Pyridin-5-yl]-2-methyl-propan-2-ol (150.00 mg, 331.93 micromoles, 1.00 equiv) was dissolved in DMF (3.00 ml), NaH (26.55 mg, 663.86 micromoles, 2.00 equiv) was added at 0 ℃ under nitrogen and stirred for 30 min the mixture was poured into ice-water (w/w ═ 1/1) (20ml) and stirred for 10min the aqueous phase was extracted with ethyl acetate (20ml × 3) the combined organic phases were washed with saturated brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the residue was purified by preparative chromatography (GX-a; Phenomenex Gemini C18250 x 0 u; 0.225% FA-ACN; Begin from 25to 55; Flow Rate (25ml/min)) to give (S) -2- ((2- (4-fluorophenyl) -6, 7-dihydrothiazolo [5, 4-5014C) and (25ml/min) yield (S) -2- ((2- (4-fluorophenyl) -6, 7-dihydrothiazolo [5, 4-C5014-C)]Pyridin-5 (4H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B]Oxazole compound 39(20.00 mg, 47.18 micromole, 14.21% yield, 98% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 40

(2S) -2- [ [2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-thiazolo [5, 4-c ] pyridin-5-yl ] methyl ] -2-methyl-6-nitro-3H-imidazo [2, 1-B ] oxazole

The synthesis was as in example 39.

(2S) -2- [ [2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-thiazolo [5, 4-c ]]Pyridin-5-yl]Methyl radical]-2-methyl-6-nitro-3H-imidazo [2, 1-B]Oxazole compound 40(30.00 mg, 92.29 micromole, 43.37%).¹HNMR(300MHz，CDCl₃)：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).

EXAMPLE 41

(S) -2- (3, 4-difluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazol-2-yl) methyl) -4, 5-, 6, 7-tetrahydrooxazolo [5, 4-c ] pyridine

Step 1:

1-benzyl-3, 6-dihydro-2H-pyridines

1-benzyl-1, 2, 3, 6-tetrahydropyridine (53.00 g, 211.89 mmol, 1.00 eq) was dissolved in methanol solution (500.00 ml) and sodium borohydride (12.02 g, 317.83 mmol, 1.50 eq) was added. The mixture was stirred at 25 ℃ for 12 h, concentrated under reduced pressure, the residue diluted with water (250 ml) and extracted with ethyl acetate (500 ml × 2). The combined organic layers were concentrated under reduced pressure to give 1-benzyl-3, 6-dihydro-2H-pyridine (30.00 g, crude) which was used directly in the next step.

Step 2:

4-benzyl-7-oxa-4-azabicyclo [4.1.0] heptane

1-benzyl-3, 6-dihydro-2H-pyridine (10.00 g, 57.72 mmol, 1.00 equiv.) is dissolved in a mixed solution of water (190.00 ml) and trifluoroacetic acid (24.02 g, 210.68 mmol, 3.65 equiv.) at 25 degrees celsius and stirred at that temperature for 1 hour, then the temperature is raised to 35 degrees celsius and bromosuccinimide (20.55 g, 115.44 mmol, 2.00 equiv.) is added and stirred for 5 hours, the temperature is lowered to 25 degrees celsius, sodium hydroxide (2.31 g, 57.72 mmol, 1.00 equiv.) and acetonitrile (50.00 ml) are added to the mixed solution, and after stirring for 12 hours, concentration under reduced pressure is performed to remove the solvent. The residue was extracted with ethyl acetate (500 ml × 2). The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate 10/1, 3: 1) to give 4-benzyl-7-oxa-4-azabicyclo [4.1.0] heptane (5.00 g, 26.42 mmol, 45.77% yield) as a yellow solid.

And step 3:

4-azido-1-benzyl-piperidin-3-ol

4-benzyl-7-oxa-4-azabicyclo [4.1.0] heptane (5.00 g, 26.42 mmol, 1.00 eq.) and lithium perchlorate (2.81 g, 26.42 mmol, 1.00 eq.) were dissolved in acetonitrile (30.00ml), sodium azide (2.23 g, 34.35 mmol, 1.30 eq.) was added under nitrogen protection, and the mixture was stirred at 80 ℃ for 16 hours. The mixture was poured into aqueous sodium bicarbonate (50ml) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (50ml × 3). The combined organic phases were washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4-azido-1-benzyl-piperidin-3-ol (5.50 g, crude) which was used directly in the next step.

And 4, step 4:

4-amino-1-benzylpiperidin-3-ols

4-azido-1-benzyl-piperidin-3-ol (5.50 g, 23.68 mmol, 1.00 equiv.) was dissolved in a mixed solution of tetrahydrofuran (50.00 ml) and water (2.00 ml), triphenylphosphine (12.42 g, 47.36 mmol, 2.00 equiv.) was added in portions at 15 deg.C and stirred for 16 hours, then concentrated in vacuo. The residue was purified by silica gel separation (column height: 300mm, diameter: 50mm, 100-mesh 200-mesh silica gel, dichloromethane/methanol: 50/1) to give 4-amino-1-benzyl-piperidin-3-ol (3.40 g, 16.48 mmol, 69.60% yield) as a yellow solid.

And 5:

n- (1-benzyl-3-hydroxy-4-piperidinyl) -3, 4-difluoro-benzamide

4-amino-1-benzylpiperidin-3-ol (2.00 g, 9.70 mmol, 1.00 equiv.) and 3, 4-difluorobenzoic acid (1.53 g, 9.70 mmol, 1.00 h.Amount) was dissolved in dichloromethane (30.00ml) and EDCI (3.72 g, 19.40 mmol, 2.00 eq) was added at 15 degrees celsius, triethylamine (3.93 g, 38.80 mmol, 4.00 eq) was stirred for 12 hours then diluted with water (20ml), the aqueous phase was extracted with ethyl acetate (40 ml × 3), the combined organic phases were washed with brine (20ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was purified by thin layer chromatography (petroleum ether/ethyl acetate 10/1, 1/3) to give N- (1-benzyl-3-hydroxy-4-piperidinyl) -3, 4-difluoro-benzamide (1.70 g, 4.91 mmol, 50.62% yield) as a white solid.¹H NMR(400MHz，CDCl3)：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-difluoro-N- (3-hydroxy-4-piperidinyl) benzamides

N- (1-benzyl-3-hydroxy-4-piperidinyl) -3, 4-difluoro-benzamide (1.70 g, 4.91 mmol, 1.00 eq) was dissolved in methanol (50.00 ml) and Pd (OH) was added under nitrogen protection₂C (10%, 0.05 g). Then replaced three times with hydrogen and the mixture was taken up in H₂(50PSI), stirring at 50 ℃ for 12 hours. The reaction mixture was filtered and the filtrate was concentrated to give 3, 4-difluoro-N- (3-hydroxy-4-piperidinyl) benzamide (1.20 g, crude) which was used in the next step without further purification. LCMS (ESI) m/z: 257(M +1).

And 7:

4- [ (3, 4-difluorobenzoyl) amino ] -3-hydroxy-piperidine-1-carboxylic acid benzyl ester

Benzyl chloroformate (878.75 mg, 5.15 mmol, 1.10 eq), 3, 4-difluoro-N- (3-hydroxy-4-piperidinyl) benzamide (1.20 g, 4.68 mmol, 1.00 eq) were dissolved in dichloromethane (30.00ml), triethylamine (1.42 g, 14.04 mmol, 3.00 eq) was added at 15 degrees celsius, and stirred for 10 hours. Water (20ml) was added to the mixture and the aqueous phase was extracted with ethyl acetate (40 ml × 3). The combined organic phases were washed with brine (30ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1, 1/1) to give benzyl 4- [ (3, 4-difluorobenzoyl) amino ] -3-hydroxy-piperidine-1-carboxylate (1.25 g, 3.20 mmol, 68.42% yield) as a white solid. LCMS (ESI) m/z: 391(M +1).

And 8:

4- [ (3, 4-difluorobenzoyl) amino ] -3-oxo-piperidine-1-carboxylic acid benzyl ester

Benzyl 4- [ (3, 4-difluorobenzoyl) amino ] -3-hydroxy-piperidine-1-carboxylate (920.00 mg, 2.36 mmol, 1.00 eq) was dissolved in a solution of dichloromethane (30.00ml) and DMP (3.00 g, 7.08 mmol, 3.00 eq) was added at 15 degrees celsius and stirred for 3 hours. The residue was then poured into an aqueous solution. Aqueous sodium hydroxide (0.5N, 40 ml) and the aqueous phase extracted with dichloromethane (60 ml × 3). The combined organic phases were washed with brine (30ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1, 1/3) to give benzyl 4- [ (3, 4-difluorobenzoyl) amino ] -3-oxo-piperidine-1-carboxylate (1.00 g, crude) as a yellow oil.

And step 9:

benzyl 2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [5, 4-c ] pyridine-5-carboxylate

To a solution of phosphorus oxychloride (2.55 g, 16.63 mmol, 5.38 equivalents) in dioxane (20.00 ml) was added 4- [ (3, 4-difluorobenzoyl) amino at 15 deg.C under nitrogen]Benzyl-3-hydroxy-piperidine-1-carboxylate (1.20 g, 3.09 mmol, 1.00 eq.) then warmed to 110 ℃ and stirred for 3 hours then the residue was poured into water (50ml) and stirred for 5 minutes the aqueous phase was extracted with ethyl acetate (60 ml × 3), the combined organic phases were washed with brine (30ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate 1/0, 10/1) to give 2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [5, 4-c ] -5]Benzyl pyridine-5-carboxylate (800.00 mg, 2.16 mmol, 69.90% yield) as a yellow oil.¹H NMR(400MHz，CDCl₃)：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:

2- (3, 4-difluorophenyl) -4, 5,6, 7-tetrahydrooxazolo [5, 4-c ] pyridine

Benzyl 2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [5, 4-c ] pyridine-5-carboxylate (800.00 mg, 2.16 mmol, 1.00 eq) was dissolved in acetic acid hydrobromide solution (20ml) and stirred at 15 deg.C for 3H. The mixture was filtered and the filter cake was concentrated in vacuo to give 2- (3, 4-difluorophenyl) -4, 5,6, 7-tetrahydrooxazolo [5, 4-c ] pyridine (450.00 mg, 1.42 mmol, 65.69% yield, hydrobromide) as a yellow solid. LCMS (ESI) m/z: 237(M +1).

Step 11:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [5, 4-C ] pyridin-5-yl ] -2-methyl-propan-2-ol

2- (3, 4-difluorophenyl) -4, 5,6, 7-tetrahydrooxazolo [5, 4-c ] pyridine (200.00 mg, 630.66 μmol, 1.00 eq, hydrobromide) and 2-chloro-1- [ (2S) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (137.24 mg, 630.66 μmol, 1.00 eq) were dissolved in a solution of t-butanol (15.00 ml) and DIPEA (244.52 mg, 1.89 mmol, 3.00 eq) was added. The mixture was stirred at 80 ℃ for 12 hours. Cooled, concentrated at 45 degrees celsius, and the residue purified by silica gel chromatography (petroleum ether/ethyl acetate-10/1, 3/1) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [5, 4-c ] pyridin-5-yl ] -2-methyl-propan-2-ol (166.00 mg, 365.78 micromoles, 58.00% yield) as a yellow oil. LCMS (ESI) m/z: 454(M +1).

Step 12:

Mixing (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [5, 4-c ]]Pyridin-5-yl]-2-methyl-propan-2-ol (166.00 mg, 365.78 micromoles, 1.00 equiv.) is dissolved in DMF (3.00 mL) solution and NaH (29.26 mg, 731.56 micromoles, 2.00 equiv.) is added at-45 ℃ under nitrogen protection and the mixture is stirred at-45-15 ℃ for 2 hours then the mixture is quenched with saturated ammonium chloride (20 mL.) the aqueous phase is extracted with ethyl acetate (50mL × 2). the combined organic phases are washed with brine (20mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue is chromatographed by preparative chromatography (GX-D; BostonGreen 150 x 305 u; ODS 42% -72%; water (0.225% mic acid); 25mL/min) to give (S) -2- (3, 4-difluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydro-imidazole [2, 1B ] 2-dihydroimidazole]Oxazol-2-yl) methyl) -4, 5-, 6, 7-tetrahydrooxazolo [5, 4-c]Pyridine compound 41(49.40 mg, 115.64 micromoles, 31.61% yield, 97.7% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 42

(S) -2- ((2- (4-fluorophenyl) -5, 6-dihydroimidazo [1, 2-a ] pyrazin-7 (8H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

2-bromo-1- (4-fluorophenyl) ethanone

1- (4-fluorophenyl) ethanone (9.00 g, 65.15 mmol, 1.00 equiv.) was dissolved in acetic acid (100.00 ml), liquid bromine (10.41 g, 65.15 mmol, 1.00 equiv.) was added at 15 deg.C and stirred for 20 minutes, then the resulting mixture was stirred at 50 deg.C for 12 hours, concentrated under reduced pressure, and the pH was adjusted to 9 with sodium carbonate solution. The mixture was extracted with ethyl acetate (200 ml × 2). The combined organic layers were concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-mesh 200-mesh silica gel, petroleum ether/ethyl acetate ═ 1/0) to give 2-bromo-1- (4-fluorophenyl) ethanone (6.30 g, 29.03 mmol, 44.56% yield) as a white solid. LCMS (ESI) m/z: 218.8(M +1).

Step 2:

3-chloropyrazin-2-amines

2, 3-dichloropyrazine (5.00 g, 33.56 mmol, 1.00 eq) and ammonia (68.27 g, 1.95 mol, 58.04 eq) were mixed, stirred at 85 ℃ for 12 hours, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-mesh 200-mesh silica gel, petroleum ether/ethyl acetate 50/1, 20/1) to give 3-chloropyrazin-2-amine (700.00 mg, 5.40 mmol, 16.09% yield) as a white solid.

And step 3:

8-chloro-2- (4-fluorophenyl) imidazo [1, 2-a ] pyrazine

2-bromo-1- (4-fluorophenyl) ethanone (3.02 g, 13.90 mmol, 1.20 equivalents) and 3-chloropyrazin-2-amine (1.50 g, 11.58 mmol, 1.00 equivalents) were dissolved in ethylene glycol dimethyl ether (20.00 ml) at 15 degrees Celsius, and then the mixture was heated to 35 degrees Celsius and stirred for 12 hours. The mixture was concentrated and purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-mesh 200-mesh silica gel, petroleum ether/ethyl acetate 20/1, 5/1) to give 8-chloro-2- (4-fluorophenyl) imidazo [1, 2-a ] pyrazine (900.00 mg, 3.63 mmol, 31.38% yield) as a white solid. LCMS (ESI) m/z: 247.9(M +1).

And 4, step 4:

2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydroimidazo [1, 2-a ] pyrazine hydrochloride

Reacting 8-chloro-2- (4-fluorophenyl) imidazo [1, 2-a]Pyrazine (900.00 mg, 3.63 mmol, 1.00 eq) was dissolved in methanol (20.00 ml) and Pd/C was added under nitrogen. The mixed solution was then brought to 50 degrees Celsius, H₂(50psi) for 12 hours. The reaction mixture was concentrated under reduced pressure to give 2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydroimidazo [1, 2-a]Pyrazine hydrochloride (850.00 mg, 2.93 mmol, 80.70% yield) was used directly in the next step.

And 5:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -6, 8-dihydro-5H-imidazo [1, 2-a ] pyrazin-7-yl ] -2-methyl-propan-2-ol

2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydroimidazo [1, 2-a ] pyrazine hydrochloride (400.00 mg, 1.58 mmol, 1.00 equivalent) was dissolved in t-butanol (10.00ml) and DIPEA (509.42 mg, 3.94 mmol, 2.50 equivalents) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (514.65 mg, 2.36 mmol, 1.50 equivalents) were added. The mixture was warmed to 100 degrees celsius and stirred for 12 hours. The reaction solution was poured into water (20ml), followed by extraction with ethyl acetate (50ml × 2). The combined organic layers were concentrated to dryness. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-mesh 200-mesh silica gel, petroleum ether/ethyl acetate 5/1, 1/3) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -6, 8-dihydro-5H-imidazo [1, 2- ] pyrazin-7-yl ] -2-methyl-propan-2-ol (200 mg, 459.93 micromole, 29.17% yield) as a white solid. LCMS (ESI) m/z: 435.0(M +1)

Step 6:

The (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -6, 8-dihydro-5H-imidazo [1, 2-]Pyrazin-7-yl]-2-methyl-propan-2-ol (200.00 mg, 459.93 micromoles, 1.00 equiv) was dissolved in a solution of DMF (3.00 mL), NaH (11.04 mg, 459.93 micromoles, 1.00 equiv) was added at-25 ℃ and stirred for 1 hour the mixture was poured into water (15 mL) at 0 ℃ and then extracted with ethyl acetate (30mL × 2) the combined organic layers were concentrated to dryness the residue was purified by preparative chromatography (GX-B, Phenomenex synergy C18150 mm 30mm 4um, acetonitrile 20% -50%; 0.1% TFA-ACN; 25mL/min) to give (S) -2- ((2- (4-fluorophenyl) -5, 6-dihydroimidazo [1, 2- α ] m]Pyrazin-7 (8H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B]Oxazole compound 42(70.60 mg, 176.28 micromoles, 38.33% yield, 99.476% purity).¹H NMR(400MHz，METHANOL-d₄)：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).

Example 43

(S) -2- ((2- (3, 4-difluorophenyl) -5, 6-dihydroimidazo [1, 2-alpha ] pyrazin-7 (8H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

The synthesis was as in example 42.

(S) -2- ((2- (3, 4-difluorophenyl) -5, 6-dihydroimidazo [1, 2- α)]Pyrazin-7 (8H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B]Oxazole compound 43(82.00 mg, 192.51 micromoles, 21.79% yield, 97.753% purity) as a yellow solid.¹H NMR(400MHz，METHANOL-d₄)：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).

Example 44

(S) -2-methyl-6-nitro-2- ((2-phenyl-7, 8-dihydropyrido [4, 3-d ] pyrimidin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B ] oxazole

Step 1:

tert-butyl (3E) -3- (methylaminomethylene) -4-oxopiperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25.09 mmol, 1.00 eq) was dissolved in dioxane (30.00ml) and 1, 1-dimethoxy-N, N-dimethylmethylamine (11.96 g, 100.36 mmol, 4.00 eq) was added, the mixture was stirred at 120 ℃ for 16 h, cooled and concentrated at 50 ℃ under reduced pressure, the residue was diluted with water (50ml) and stirred for 20 min, the aqueous phase was extracted with ethyl acetate (50ml × 3), the combined organic phases were washed with saturated brine (50ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was purified by silica gel chromatography (ethyl acetate/methanol 20/1) to give tert-butyl (3E) -3- (methylaminomethylene) -4-oxopiperidine-1-carboxylic acid tert-butyl ester (3.00 g, 11.80 mmol, 47.02% yield) as a yellow oil.¹H NMR(400MHz，CDCl₃)：7.51(s，1H)，4.57(s，2H)，3.62(t，J＝4.0Hz，1H)，3.13(s，7H)，2.46(t，J＝4.0Hz，1H)，1.49(s，9H).

Step 2:

2-phenyl-7, 8-dihydro-5H-pyrido [4, 3-d ] pyrimidine-6-carboxylic acid tert-butyl ester

Tert-butyl (3E) -3- (methylaminomethylene) -4-oxopiperidine-1-carboxylic acid tert-butyl ester (3.00 g, 11.80 mmol, 1.00 equiv.) and benzamidine (1.85 g, 11.80 mmol, 1.00 equiv.) are dissolved in ethanol (30.00ml), triethylamine (3.58 g, 35.40 mmol, 3.00 equiv.) is added and the mixture is stirred at 80 ℃ for 2 hours, cooled, concentrated under reduced pressure, the residue is diluted with water (30ml) and stirred for 20 minutes, the aqueous phase is extracted with ethyl acetate (30ml × 3), the combination is combinedThe organic phase of (a) was washed with saturated brine (30ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 3/1) to give 2-phenyl-7, 8-dihydro-5H-pyrido [4, 3-d ═]Pyrimidine-6-carboxylic acid tert-butyl ester (2.10 g, 6.74 mmol, 57.15% yield) as a yellow solid.¹H NMR(400MHz，CDCl₃)：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).

And step 3:

2-phenyl-5, 6, 7, 8-tetrahydropyrido [4, 3-d ] pyrimidine

Tert-butyl 2-phenyl-7, 8-dihydro-5H-pyrido [4, 3-d ] pyrimidine-6-carboxylate (500.00 mg, 1.61 mmol, 1.00 eq) was dissolved in dichloromethane (1.00 ml) and trifluoroacetic acid (183.09 mg, 1.61 mmol, 1.00 eq) was added. The mixture was stirred at 28 ℃ for 2h and concentrated at 50 ℃ under reduced pressure to give the trifluoroacetate salt of 2-phenyl-5, 6, 7, 8-tetrahydropyrido [4, 3-d ] pyrimidine (800.00 mg, crude) as a yellow oil. The product was used in the next step without further purification.

And 4, step 4:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2-phenyl-7, 8-dihydropyridine [4, 3-d ] pyrimidin-6- (5H) -yl) propan-2-ol

2-phenyl-5, 6, 7, 8-tetrahydropyrido [4, 3-d ] is reacted with a catalyst]Pyrimidine (340.00 mg, 1.61 mmol, 1.00 eq.) and (R) -2-chloro-1- ((2-methyloxiran-2-yl)) Methyl) -4-nitro-1H-imidazole (420.42 mg, 1.93 mmol, 1.20 eq) was dissolved in ethanol (10.00ml) and DIPEA (623.99 mg, 4.83 mmol, 3.00 eq) was added. The mixture was stirred at 80 ℃ for 12 hours, cooled, concentrated under reduced pressure, and concentrated at 50 ℃. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 2/1) to give (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2-phenyl-7, 8-dihydropyridine [4, 3-d ]]Pyrimidin-6- (5H) -yl) propan-2-ol (650.00 mg, 1.52 mmol, 94.14% yield) as a 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).

And 5:

Mixing (S) -1- (2-chloro-4-nitro-1H-imidazole-1-yl) -2-methyl-3- (2-phenyl-78 dihydropyridine [4, 3-d ]]Pyrimidin-6 (5H) -yl) propan-2-ol (350.00 mg, 816.10 micromoles, 1.00 eq) was dissolved in DMF (5.00 mL), NaH (39.17 mg, 979.32 micromoles, 1.20 eq) was added at 0 degrees celsius under nitrogen and stirred for 30 minutes the reaction mixture was quenched with saturated ammonium chloride (20mL), then diluted with water (10 mL) and extracted with dichloromethane (10mL × 3), the combined organic layers were washed with saturated brine (10mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative chromatography (GX-E; Diamonsil 150 x 25mm 5 um; acetonitrile 20% -50%; water (0.225% fomic acid); 25mL/min) to afford (S) -2-methyl-6-nitro-2- ((2-phenyl-7, 8-dihydropyrido [4, 3-d ] to (S) -2-methyl-6-nitro-2- ((2-phenyl-7, 8-dihydropyrido [4, 3-d ] 2-d)]Pyrimidin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B]Oxazole conversionCompound 44(23.10 mg, 58.87 micromoles, 7.21% yield).¹H NMR(400MHz，CDCl₃)：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)，3.12(d，J＝16.0Hz，1H)，3.05-2.89(m，3H)，2.83(d，J＝12.0Hz，1H)，1.70(s，3H).LCMS(ESI)m/z：393(M+1).

Example 45

(S) -2- ((2- (4-fluorophenyl) -7, 8-dihydropyrido [4, 3-d ] pyrimidin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2-, 3-dihydroimidazo [2, 1-B ] oxazole

The synthesis was as in example 44.

(S) -2- ((2- (4-fluorophenyl) -7, 8-dihydropyrido [4, 3-d)]Pyrimidin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2-, 3-dihydroimidazo [2, 1-B]Oxazole compound 45(100.00 mg, 243.66 micromole, 27.22% yield).¹H NMR(400MHz，CDCl₃)：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).

Example 46

(S) -2- ((2- (3, 4-difluorophenyl) -7, 8-dihydropyrido [4, 3-d ] pyrimidin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-B ] oxazole

The synthesis was as in example 44.

(S) -2- ((2- (3, 4-difluorophenyl) -7, 8-dihydropyrido [4, 3-d)]Pyrimidin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1-B]Oxazole compound 46(20.80 mg, 47.05 micromole, 7.06% yield, 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).

Example 47

(S) -2-methyl-6-nitro-2- ((2- (4- (trifluoromethoxy) phenyl) -7, 8-dihydropyrido [4, 3-d ] pyrimidin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B ] oxazole

The synthesis was as in example 44.

(S) -2-methyl-6-nitro-2- ((2- (4- (trifluoromethoxy) phenyl) -7, 8-dihydropyrido [4, 3-d)]Pyrimidin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1-B]Oxazole compound 47(26.70 mg, 56.04 micromole, 5.75% yield).¹H NMR(400MHz，CDCl₃)：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).

Example 48

(S) -2- ((2- (3, 5-difluorophenyl) -7, 8-dihydropyrido [4, 3-d ] pyrimidin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 44.

(S) -2- ((2- (3, 5-difluorophenyl) -7, 8-dihydropyrido [4, 3-d)]Pyrimidin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b]Azole compound 48(25.20 mg, 57.67 micromoles, 15.77% yield, 98.030% purity).¹H NMR(400MHz，CDCl₃)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).

Example 49

(S) -2- ((2- (3, 5-difluorophenyl) -4-methoxy-7, 8-dihydropyrido [4, 3-d ] pyrimidin-6 (5H) -yl) methyl) -2-methyl 6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

Step 1:

ethyl 1-benzyl-4-oxo-piperidine-3-carboxylic acid methyl ester

To a solution of 1-benzyl-4-one (5.00 g, 26.42 mmol, 1.00 eq) in tetrahydrofuran (20.00 ml) was added sodium hydrogen (2.11 g, 52.84 mmol, 2.00 eq) in one portion at 15 deg.C under nitrogen. The mixture was stirred at 15 ℃ for 30 minutes. Diethyl carbonate (6.24 g, 52.84 mmol, 2.00 eq) was then added to the mixture and stirred at 70 ℃ for 1 hour. The mixture was poured into water (50ml) and stirred for 30 minutes. The aqueous phase was extracted with ethyl acetate (100ml × 3). The combined organic phases were washed with brine (50ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 30/1, 10/1) to give ethyl 1-benzyl-4-oxo-piperidine-3-carboxylate (4.50 g, 17.22 mmol, 65.18% yield) as a yellow oil.

Step 2:

6-benzyl-2- (3, 5-difluorophenyl) -7, 8-dihydro-5H-pyrido [4, 3-d ] pyrimidin-4-ol

To a solution of ethyl 1-benzyl-4-oxo-piperidine-3-carboxylate (1.20 g, 4.59 mmol, 1.00 eq) and 3, 5-difluorobenzamidine (931.63 mg, 5.97 mmol, 1.30 eq) in methanol (15.00 ml) was added sodium methoxide (496.13 mg, 9.18 mmol, 2.00 eq) and the mixture was stirred at 80 ℃ for 2 h. The mixture was concentrated under reduced pressure at 45 degrees celsius, the residue poured into water (50ml), ethyl acetate (30ml) and stirred for 5 minutes, filtered and the filter cake dried to give 6-benzyl-2- (3, 5-difluorophenyl) -7, 8-dihydro-5H-pyrido [4, 3-d ] pyrimidin-4-ol (400.00 mg, 1.13 mmol, 24.66% yield) as a white solid. LCMS (ESI) m/z: 354.1(M +1).

And step 3:

6-benzyl-4-chloro-2- (3, 5-difluorophenyl) -7, 8-dihydro-5H-pyrido [4, 3-d ] pyrimidine

To a solution of 6-benzyl-2- (3, 5-difluorophenyl) -7, 8-dihydro-5H-pyrido [4, 3-d ] pyrimidin-4-ol (720.00 mg, 2.04 mmol, 1.00 eq) in toluene (5.00ml) was added phosphorus oxychloride (2.77 g, 18.07 mmol, 8.86 eq) and the mixture was stirred at 120 ℃ for 2H, the mixture was poured into a mixed solution of water (50ml) and ethyl acetate (50ml), which was stirred for 5 minutes, filtered, and the filter cake was dried to give 6-benzyl-4-chloro-2- (3, 5-difluorophenyl) -7, 8-dihydro-5H-pyrido [4, 3-d ] pyrimidine (540.00 mg, 1.45 mmol, 71.08% yield) as a white solid.

And 4, step 4:

6-benzyl-2- (3, 5-difluorophenyl) -4-methoxy-7, 8-dihydro-5H-pyrido [4, 3-d ] pyrimidine

To 6-benzyl-4-chloro-2- (3, 5-difluorophenyl) -7, 8-dihydro-5H-pyrido [4, 3-d]Sodium methoxide (783.29 mg, 14.50 mmol, 10.00 equivalents) was added to a solution of pyrimidine (540.00 mg, 1.45 mmol, 1.00 equivalents) in methanol (10.00 ml), the mixture was stirred at 70 ℃ for 8 hours, and water (50ml) was added to the mixed solution and stirred for 5 minutes. The mixture was filtered and the filter cake was dried to give 6-benzyl-2- (3, 5-difluorophenyl) -4-methoxy-7, 8-dihydro-5H-pyrido [4, 3-d]Pyrimidine (410.00 mg, 1.12 mmol, 76.96% yield) as a white solid.¹H NMR(400MHz，CDCl₃)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).

And 5:

2- (3, 5-difluorophenyl) -4-methoxy-5, 6, 7, 8-tetrahydropyrido [4, 3-d ] pyrimidine

To a solution of 6-benzyl-2- (3, 5-difluorophenyl) -4-methoxy-7, 8-dihydro-5H-pyrido [4, 3-d ] pyrimidine (410.00 mg, 1.12 mmol, 1.00 eq) in dichloroethane (15.00 ml) was added 1-chloroethylcarbonyl chloride (240.19 mg, 1.68 mmol, 1.50 eq) at 0 degrees celsius under nitrogen. The mixture was stirred at 0 ℃ for 30 minutes and heated to 90 ℃ and after stirring for 11.5 hours, the mixture was concentrated at 45 ℃ under reduced pressure, methanol (15 ml) was added and stirred at 90 ℃ for 2 hours. The mixture was then concentrated at 45 degrees celsius under reduced pressure, dichloromethane (30mL) was added to the residue and stirred for 30 minutes, filtered, and the filter cake was collected to give 2- (3, 5-difluorophenyl) -4-methoxy-5, 6, 7, 8-tetrahydropyrido [4, 3-d ] pyrimidine (286.00 mg, 911.61 micromoles, 81.39% yield, hydrochloride salt) as a white solid.

Step 6:

(2R) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 5-difluorophenyl) -4-methoxy-7, 8-dihydro-5H-pyrido [4, 3-d ] pyrimidin-6-yl ] -2-methyl-propan-2-ol

2- (3, 5-difluorophenyl) -4-methoxy-5, 6, 7, 8-tetrahydropyrido [4, 3-d]Pyrimidine (286.00 mg, 911.61 micromoles, 1.00 equivalents, hydrochloride salt) and 2-chloro-1- [ [ (2S) -2-methyloxiran-2-yl]Methyl radical]-4-nitroimidazole (238.05 mg, 1.09 mmol, 1.20 equiv.) was dissolved in tert-butanol (6.00 ml) and diisopropylamine (235.63 mg, 1.82 mmol, 2.00 equiv.) was added under nitrogen. The mixture was stirred at 80 ℃ for 12 hours. The mixture was cooled to 15 ℃ and concentrated under reduced pressure at 45 ℃. The residue was chromatographed on silica gelSeparation and purification (diameter: 250 mm, column height: 100mm, 100-mesh 200-mesh silica gel, petroleum ether/ethyl acetate 10/1, 2/1) to give (2R) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 5-difluorophenyl) -4-methoxy-7, 8-dihydro-5H-pyrido [4, 3-d)]Pyrimidin-6-yl]-2-methyl-propan-2-ol (400.00 mg, 808.28 micromole, 88.66% yield) as a yellow solid.¹HNMR(400MHz，CDCl₃)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).

And 7:

To (2R) -1- (2-chloro-4-nitro-imidazol-1-yl) -3- [2- (3, 5-difluorophenyl) -4-methoxy-7, 8-dihydro-5H-pyrido [4, 3-d]Pyrimidin-6-yl]-2-methyl-propan-2-ol (200.00 mg, 404.14 micromole, 1.00 eq) in DMF (3.00 ml) under-45 ℃ nitrogen protection was added sodium hydrogen (32.33 mg, 808.28 micromole, 2.00 eq.) the mixture was stirred at-45-0 ℃ for 1 hour, the mixture was poured into saturated ammonium chloride (50ml) and stirred for 5 minutes, the aqueous phase was extracted with ethyl acetate (100ml × 2), the combined organic phases were washed with brine (30ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was washed with methanol (30ml × 2), filtered, and the filter cake was collected to give (S) -2- ((2- (3, 5-difluorophenyl) -4-methoxy-7, 8-dihydro [4, 3-d ] di-hydro [4, 3-d ] (S) and was filtered]Pyrimidin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Oxazole compound 49(39.00 mg, 81.08 micromoles, 20.06% yield, 95.3% purity).¹H NMR(400MHz，CDCl₃)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).

Example 50

(S) -2- ((2- (3, 5-difluorophenyl) -5, 6-dihydro- [1, 2, 4] triazolo [1, 5-a ] pyrazin-7 (8H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

Step 1:

[1, 2, 4] triazolo [1, 5-a ] pyrazin-2-amine

To a solution of pyrazine-2-amine (10.00 g, 105.15 mmol, 1.00 eq) in dioxane (200.00 ml) was added dropwise ethyl-N- (thiomethylene) carbamate (17.05 g, 130.00 mmol, 1.24 eq) under nitrogen protection at 0-5 degrees celsius, mixing was stirred at 15 degrees celsius for 16 hours the resulting suspension was filtered and washed with dichloromethane (200 ml) to give ethyl-N- (pyrazin-2-ylthiocarbamoyl) carbamic acid tert-butyl ester (13.60 g, 60.11 mmol, 57.16% yield) as a pale yellow solid.¹H NMR(400MHz，DMSO-d₆)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] triazolo [1, 5-a ] pyrazin-2-amine

To a mixed solution of ethyl-N- (pyrazin-2-ylthiocarbamoyl) carbamic acid tert-butyl ester (12.60 g, 55.69 mmol, 1.00 eq) in methanol (80.00 ml) and ethanol (80.00 ml) were added hydroxylamine hydrochloride (6.97 g, 100.24 mmol mixture, 1.80 eq) and diisopropylamine (17.76 g, 137.55 mmol, 2.47 eq). The mixture was stirred at 65 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to a volume of about 20 ml. The resulting suspension was filtered, the solid collected and washed with dichloromethane/ethanol (60: 1, 90 ml) to give [1, 2, 4]]Triazolo [1, 5-a]Pyrazin-2-amine (5.30 g, 39.22 mmol, 70.43% yield) as a white solid.¹H NMR(400MHz，DMSO-d₆)8.83(s，1H)，8.69-8.68(d，J＝4.3Hz，1H)，7.97-7.96(d，J＝4.3Hz，1H)，6.46(s，2H)

And step 3:

2-bromo- [1, 2, 4] triazolo [1, 5-a ] pyrazines

To a solution of copper bromide (1.98 g, 8.88 mmol, 1.20 equivalents) and tert-butyl nitrite (1.14 g, 11.10 mmol, 1.50 equivalents) in acetonitrile (30ml) was added [1, 2, 4] at 65 degrees celsius]Triazolo [1, 5a ]]Pyrazin-2-amine (1.00 g, 7.40 mmol, 1.00 eq). After the addition was complete, the mixture was stirred at this temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (150 ml) and washed with 1N hydrochloric acid (100ml) and saturated ammonium chloride (100 ml). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate 1: 1) to give 2-bromo- [1, 2, 4]Triazolo [1, 5-a]Pyrazine (350.00 mg, 1.76 mmol, 23.77% yield) as a light yellow solid.¹H NMR(300MHz，DMSO-d₆)9.38(s，1H)，9.10-9.09(d，J＝4.3Hz，1H)，8.33-8.32(d，J＝4.3Hz，1H)

And 4, step 4:

2-bromo-5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [1, 5-a ] pyrazines

To a mixed solution of 2-bromo- [1, 2, 4] triazolo [1, 5-a ] pyrazine (350.00 mg, 1.76 mmol, 1.00 eq) in ethanol (10.00 ml) was added lithium borohydride (154.00 mg, 7.08 mmol, 4.02 eq). The mixture was stirred at 50 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a white solid, which was used directly in the next step. LCMS (ESI) m/z: 203/205(M +1)/(M +2).

And 5:

tert-butyl 2-bromo-5, 6-dihydro [1, 2, 4] triazolo [1, 5-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester

To 2-bromo-5, 6, 7, 8-tetrahydro [1, 2, 4]]Triazolo [1, 5-a]To a solution of pyrazine (350.00 mg, 1.72 mmol, 1.00 eq) in water (15.00 ml) was added sodium bicarbonate (144.82 mg, 1.72 mmol, 1.00 eq) and Boc₂O (379.98 mg, 1.74 mmol, 1.01 eq.) the mixture was stirred at 10-20 ℃ for 0.5H, water (50ml) was added to the reaction mixture and extracted with ethyl acetate (30ml × 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 2-bromo-6, 8-dihydro-5H- [1, 2, 4] dihydro-l]Triazolo [1, 5-a]Pyrazine-7-carboxylic acid methyl ester (600.00 mg, crude) as a light yellow solid.¹H NMR(300MHz，CDCl₃)4.72(s，2H)，4.23-4.13(m，2H)，3.99-3.89(m，2H)，1.50(s，9H)

Step 6:

tert-butyl-2- (3, 5-difluorophenyl) -5, 6-dihydro- [1, 2, 4] triazolo [1, 5-a ] pyrazine-7 (8H) -carboxylic acid tert-butyl ester

To tert-butyl 2-bromo-6, 8-dihydro-5H- [1, 2, 4]Triazolo [1, 5- α]Cesium carbonate (1.08 g, 3.30 mmol, 2.00 equiv.) and pd (dppf) Cl were added sequentially to a mixed solution of dioxane (10.00 ml) and water (1.00 ml) of pyrazine-7-carboxylic acid ethyl ester (500.00 mg, 1.65 mmol, 1.00 equiv.) and (3, 5-difluorophenyl) boronic acid (260.00 mg, 1.65 mmol, 1.00 equiv.) under nitrogen protection₂(60.00 mg, 82.00 micromole, 0.05 eq.) the mixture is heated to 80 ℃ and stirred for 16 hours, the mixture is washed with water (30ml), the aqueous phase is extracted with ethyl acetate (30ml × 2), the combined organic phases are dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue which is purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 20/1-5: 1) to give tert-butyl 2- (3, 5-difluorophenyl) -6, 8-dihydro-5H- [1, 1, 2, 4]Triazolo [1, 5-a]Pyrazine-7-carboxylic acid ethyl ester (310.00 mg, 921.69 micromoles, 55.86% yield) as a light yellow solid. LCMS (ESI) m/z: 337.1(M +1)

And 7:

2- (3, 5-difluorophenyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyrazines

To a solution of ethyl tert-butyl-2- (3, 5-difluorophenyl) -6, 8-dihydro-5H- [1, 2, 4] triazolo [1, 5-a ] pyrazine-7-carboxylate (310.00 mg, 921.69 micromole, 1.00 eq) in dichloromethane (10.00 ml) was added trifluoroacetic acid (3.06 g, 26.84 mmol, 29.12 eq). The mixture was stirred at 15 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to give the residue as a dark brown solid, which was used directly in the next step. LCMS (ESI) m/z: 237.1(M +1)

And 8:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (3, 5-difluorophenyl) -5, 6-dihydro- [1, 2, 4] triazolo [1, 5-a ] pyrazin-7 (8H) -yl) -2-methylpropan-2-ol

To a solution of 2- (3, 5-difluorophenyl) -5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [1, 5-a ] pyrazine (550.00mg, 1.57mmol, 1.00eq, trifluoroacetate) in tert-butanol (10.00 ml) was added 2-chloro-1- [ [ (2S) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (250.00 mg, 1.15 mmol, 0.73 eq) and diisopropylamine (1.01 g, 7.85 mmol, 5.00 eq). The mixture was stirred at 80 ℃ for 16 hours. The reaction mixture was washed with water (50ml) and extracted with ethyl acetate (30ml × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 3/1 to 1/5) to give (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (3, 5-difluorophenyl) -5, 6-dihydro- [1, 2, 4] triazolo [1, 5-a ] pyrazin-7 (8H) -yl) -2-methylpropan-2-ol (250.00 mg, 550.87 micromole, 35.09% yield) as a light yellow oil. LCMS (ESl) m/z: 454.1(M +1)

And step 9:

To (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 5-difluorophenyl) -6, 8-dihydro-5H- [1, 2, 4]Triazolo [1, 5-a]Pyrazin-7-yl]-2-methyl-propan-2-ol (100.00 mg, 220.35 micromoles, 1.00 equiv.) in DMF (5.00ml) under nitrogen protection at-50 ℃ sodium hydrogen (20.00 mg, 500.00 micromoles, 2.27 equiv.) the mixture is stirred at-50 ℃ for 0.5H then the mixture is heated to 0 ℃ and stirred for an additional 0.5H pouring the reaction mixture into saturated ammonium chloride solution (40 ml) then extracted with ethyl acetate (30ml × 2) the combined organic layers are over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which is purified by preparative separation chromatography to give (2S) -2- [ [2- (3, 5-difluorophenyl) -6, 8-dihydro-5H- [1, 2, 4] 1]Triazolo [1, 5-a]Pyrazin-7-yl]Methyl radical]-2-methyl-6-nitro-3H-imidazo [2, 1b]Oxazole (11.25 mg, 26.36 micromoles, 11.96% yield, 97.79% purity).¹H NMR(400MHz，DMSO-d₆)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).

Example 51

(S) -2- ((2- (3, 5-dichlorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2-, 3 dihydroimidazo [2, 1b ] oxazole

To a mixture of critical intermediate B (200.00 mg, 571.80 micromoles, 1.00 equiv.) and dioxane (5.00mL) and water (500.00. mu.L) of (3, 5-dichlorophenyl) boronic acid (109.11 mg, 571.80 micromoles, 1.00 equiv.) was addedPd (dppf) Cl is added into the mixed solution in one portion under the protection of nitrogen₂(20.92 mg, 28.59 micromoles, 0.05 eq), cesium fluoride (260.57 mg, 1.72 mmol, 3.00 eq). The mixture was stirred at 100 ℃ for 6 hours. The mixture was diluted with ethyl acetate, filtered and concentrated. The residue was chromatographed by preparative separation (GX-F; Phenomenex Synergic 18150 x 25 x 10 um; 0.225% FA-ACN; Begin from 52to 82; Flow Rate (25ml/min) to give (S) -2- ((2- (3, 5-dichlorophenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2-, 3-dihydroimidazo [2, 1b ] -2]Azole compound 51(50.00 mg, 107.54 micromoles, 18.81% yield, 99% purity).¹H NMR(400MHz，CDCl₃)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).

Example 52

(S) -2- ((2- (3, 5-difluorophenyl) -4-methyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

Step 1:

6-benzyl-4-methyl-1, 5, 7, 8 tetrahydro-1, 6-naphthyridin-2-one

1-benzyl-4-one (4.00 g, 21.14 mmol, 1.00 eq.) and 3-oxobutanamide (2.35 g, 23.25 mmol, 1.10 eq.) were dissolved in Eton's reagent (8.00 ml) and stirred at 110 deg.C for 12 h. Adding the mixture to saturationAqueous sodium bicarbonate (100ml), pH controlled > 7, aqueous layer was extracted with ethyl acetate (100ml × 4), the combined organic phases were washed with saturated brine (100ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was washed with acetone (60 ml), then filtered and the cake collected to give 6-benzyl-4-methyl-1, 5, 7, 8 tetrahydro-1, 6-naphthyridin-2-one (2.80 g, 11.01 mmol, 52.08% yield) as a white solid.¹H NMR(400MHz，DMSO-d₆)：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:

6-benzyl-2-chloro-4-methyl-7, 8-dihydro-5H-1, 6-naphthyridine

6-benzyl-4-methyl-1, 5, 7, 8-tetrahydro-1, 6-naphthyridin-2-one (2.80 g, 11.01 mmol, 1.00 eq.) and phosphorus oxychloride (9.00 ml) were mixed and stirred at 110 ℃ for 12 hours. The mixture was added dropwise to ice water (100ml), and then the mixture was stirred at 15 ℃ for 0.5 hour. Saturated aqueous sodium bicarbonate (100ml) was then added to the mixture until pH > 7. The mixture was extracted with dichloromethane (100ml × 4). The combined organic phases were washed with brine (100ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 6-benzyl-2-chloro-4-methyl-7, 8-dihydro-5H-1, 6-naphthyridine (3.50 g, crude) as a yellow solid. LCMS (ESI) m/z: 273(M +1).

And step 3:

6-benzyl-2- (3, 5-difluorophenyl) -4-methyl-7, 8-dihydro-5H-1, 6-naphthyridine

To a mixed solution of dioxane (10.00 ml) of 6-benzyl-2-chloro-4-methyl-7, 8-dihydro-5H-1, 6-naphthyridine (500.00 mg, 1.83 mmol, 1.00 eq) and (3, 5-difluorophenyl) boronic acid (346.77 mg, 2.20 mmol, 1.20 eq) and water (1.00 ml) was added cesium fluoride (694.94 mg, 4.58 mmol, 2.50 eq) and pd (dppf) Cl in one portion at 15 degrees celsius under nitrogen protection₂(133.90 mg, 183.00 micromoles, 0.10 equivalents.) the mixture is stirred at 110 ℃ for 5 hours.water (10 ml) is added to the mixture, which is then extracted with dichloromethane (100ml × 3. the combined organic phases are washed with brine (100ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. the residue is purified by silica gel chromatography (column height: 250 mm, diameter: 100mm, 100-mesh silica gel, petroleum ether/ethyl acetate 40/1 to 15/1) to give 6-benzyl-2- (3, 5-difluorophenyl) -4-methyl-7, 8-dihydro-5H-1, 6-naphthyridine (580.00 mg, 1.66 mmol, 90.45% yield) as a white solid.¹H NMR(300MHz，CDCl₃)：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)

And 4, step 4:

2- (3, 5-difluorophenyl) -4-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine hydrochloride

To a solution of 6-benzyl-2- (3, 5-difluorophenyl) -4-methyl-7, 8-dihydro-5H-1, 6-naphthyridine (580.00 mg, 1.66 mmol, 1.00 eq) in dichloroethane (15.00 ml) was added 1-chlorocarbonyl chloride (354.98 mg, 2.48 mmol, 1.50 eq) in one portion at 15 degrees celsius under nitrogen. The mixture was stirred at 90 degrees celsius for 12 hours. The mixture was then concentrated to dryness, methanol (10.00 ml) was added to the residue, and the resulting mixture was stirred at 90 ℃ for an additional 1 hour. The mixture was concentrated to dryness to give 2- (3, 5-difluorophenyl) -4-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (400.00 mg, 1.35 mmol, 81.56% yield, hydrochloride salt) as a white solid.

And 5:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 5-difluoro-O-phenyl) -4-methyl-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] -2-methyl-propan-2-ol

2- (3, 5-difluorophenyl) -4-methyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (400.00 mg, 1.35 mmol, 1.00eq, hydrochloride salt) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (352.53 mg, 1.62 mmol, 1.20 eq) were mixed in tert-butanol (8.00 ml) and diisopropylamine (436.19 mg, 3.38 mmol, 2.50 eq) was added in one portion at 15 deg.C under nitrogen. The mixture was stirred at 100 degrees celsius for 12 hours. The mixture was concentrated to dryness. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100mm, 100-mesh 200-mesh silica gel, petroleum ether/ethyl acetate 30/1 to 1/2) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 5-difluorophenyl) -4-methyl-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] -2-methyl-propan-2-ol (260.00 mg, crude) as a 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-naphthyridin-6-yl ] methyl ] -2-methyl-6-nitro-3H-imidazo [2, 1b ] oxazole

To (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 5-difluorophenyl) -4-methyl-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl]A solution of-2-methyl-propan-2-ol (260.00 mg, 544.06 micromoles, 1.00 equiv) in DMF (5.00ml) was added sodium hydrogen (43.60 mg, 1.09 mmol, 2.00 equiv) in one portion at-20 degrees celsius under nitrogen. The mixture was stirred at-20 ℃ for 10 minutes, then heated to 0 ℃ and stirred for 10 minutes, then heated to 15 ℃ and stirred for another 10 minutes. The mixture was added dropwise to ammonium chloride (20 ml), then the mixture was filtered and the filter cake was collected to give the crude product. The crude product was purified by basic preparative separation chromatography ((GX-D; Boston symmetry C18 ODS-R150 30mm 5 um; acetonitrile 24% -54%; water (0.225% NH)₄OH); 25mL/min)) to give (2S-yl) -2- [ [2- (3, 5-difluorophenyl) -4-methyl-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl)]Methyl radical]-2-methyl-6-nitro-3H-imidazo [2, 1b]Azole compound 52(60.00 mg, 135.51 micromoles, 24.91% yield, 99.7% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 53

(S) -2- ((2- (2-chlorothiazol-3-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] oxazole

To (2S) -2- [ (2-chloro-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) phenyl ethyl]-2-methyl-6-nitro-3H-imidazo [2, 1-b]Dioxane (3.00 mL) of oxazole (200.00 mg, 571.80 micromole, 1.00 equivalent) and (2-chloro-3-thienyl) boronic acid (92.86 mg, 571.80 micromole, 1.00 equivalent) and water (300.00 micromole, 1.00 equivalent)L) was added cesium fluoride (173.71 mg, 1.14 mmol, 2.00 eq) and pd (dppf) Cl₂(8.37 mg, 11.44 micromoles, 0.02 eq.) the mixture is stirred at 70 ℃ for 12 hours, quenched by the addition of water (50mL) to the reaction mixture, then extracted with ethyl acetate (50mL × 3.) the combined organic layers are dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which is purified by preparative separation chromatography (GX-F; Phenomenex Synergi C18150 25. mu.10. mu.m; acetonitrile 30% -60%; ACN (0.225% fomic acid); 25mL/min) to give (2S) -2- [ [2- (2-chloro-3-thienyl) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) acid]Methyl radical]-2-ethoxymethyl-6-nitro-3H-imidazo [2, 1b ] s]Azole compound 53(26.30 mg, 59.55 micromoles, 10.41% yield, 97.8% purity).¹H NMR(400MHz，METHANOL-d₄)：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).

Example 54

(S) -2-methyl-6-nitro-2- ((2- (5- (trifluoromethyl) furan-2-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2, 3-dihydroimidazo [2, 1b ] oxazole

Step 1:

methyl-6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridine-2-carboxylic acid

To 6-benzyl-2-chloro-7, 8-dihydro-5H-1, 6-naphthyridine (5.00 g)19.32 mmole, 1.00 eq) in methanol (50.00 ml) was added Pd (dppf) Cl under nitrogen protection₂(706.96 mg, 966.00 micromoles, 0.05 eq), triethylamine (3.65 g, 36.07 mmol, 1.87 eq.) the suspension was degassed with carbon monoxide the mixture was stirred at 80 degrees c for 12 hours under carbon monoxide (50 Psi.) the reaction mixture was concentrated under reduced pressure to remove the solvent the residue was diluted, washed with sodium carbonate (100ml) and extracted with ethyl acetate (500 ml × 2.) the combined organic layers were concentrated under reduced pressure to give a residue which was separated by silica gel chromatography (SiO2, petroleum ether/ethyl acetate ═ 50/1-5: 1) to give methyl 6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridine-2-carboxylate (3.00 g, 10.63 mmol, 55.00% yield) as a yellow solid lcms (esi) M/z: 283.2(M +1).

Step 2:

1- (6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridin-2-yl) -2-dimethoxyphosphoryl-ethanone

To a solution of methyl-6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridine-2-carboxylate (2.50 g, 8.85 mmol, 1.00 eq) in tetrahydrofuran (125.00 ml) was added n-butyllithium (2.5M, 10.62 ml, 3.00 eq) dropwise at-78 degrees celsius, after 30 minutes of addition, the mixture was stirred at this temperature for 30 minutes, and then a solution of [ methoxy (methyl) phosphoryl ] oxymethane (3.51 g, 28.32 mmol, 3.20 eq) in THF (125.00 ml) was added at-78 degrees celsius. The resulting mixture was stirred at-78 ℃ for 2 hours. The reaction was quenched by the addition of ammonium chloride (30ml) to the reaction at-78 ℃ and then extracted with ethyl acetate (400 ml × 2). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 3/1-0: 1) to give compound 1- (6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridin-2-yl) -2-dimethoxyphosphoryl-ethanone (2.35 g, 6.28 mmol, 70.93% yield) as a colorless solid.

And step 3:

(E) -4- (6-benzyl-7, 8-dihydro-5-H-1, 6-naphthyridin-2-yl) -4-oxo-but-2-enoic acid ethyl ester

To a solution of 1- (6-benzyl-7, 8-dihydro-5-H-1, 6-naphthyridin-2-yl) -2-dimethoxyphosphoryl-ethanone (2.35 g, 6.28 mmol, 1.00 eq) in dichloroethane (30.00 ml) was added potassium tert-butoxide (845.24 mg, 7.53 mmol, 1.20 eq) and ethyl 2-oxoacetate (2.56 g, 12.55 mmol, 2.00 eq). The mixture was stirred at-20 ℃ for 2 hours. The residue was separated by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 1/0-20: 1) to give the compound ethyl (E) -4- (6-benzyl-7, 8-dihydro-5-H-1, 6-naphthyridin-2-yl) -4-oxo-but-2-enoic acid ethyl ester (1.50 g, 4.28 mmol, 68.16% yield) as a yellow solid.¹H NMR(400MHz，CDCl₃)：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)

And 4, step 4:

5- (6-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) -2- (trifluoromethyl) furan-3-carboxylic acid ethyl ester

To a solution of trifluoroacetic anhydride (1.35 g, 6.42 mmol, 1.50 equivalents) and triphenylphosphine (1.12 g, 4.28 mmol, 1.00 equivalents) in dichloromethane (15.00 ml) was added ethyl (E) -4- (6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridin-2-yl) -4-oxobut-2-enoic acid ethyl ester (1.50 g, 4.28 mmol, 1.00 equivalents). The mixture was stirred at 25 ℃ for 0.5 h. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate 50/1-10: 1) to give the compound ethyl 5- (6-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) -2- (trifluoromethyl) furan-3-carboxylate (1.30 g, 3.02 mmol, 70.57% yield) as a yellow solid.

And 5:

sodium 5- (6-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) -2- (trifluoromethyl) furan-3-carboxylate

To a solution of ethyl 5- (6-benzyl-7, 8-dihydro-5-H-1, 6-naphthyridin-2-yl) -2- (trifluoromethyl) furan-3-carboxylate (700.00 mg, 1.63 mmol, 1.00 eq) in ethanol (7.00 ml) and water (7.00 ml) was added sodium hydroxide (260.80 mg, 6.52 mmol, 4.00 eq). The mixture was stirred at 25 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent to give the compound sodium 5- (6-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) -2- (trifluoromethyl) furan-3-carboxylate (1.00 g, crude) as a yellow solid.

Step 6:

6-benzyl-2- [5- (trifluoromethyl) -2-furyl ] -7, 8-dihydro-5H-1, 6-naphthyridine

To a solution of sodium 5- (6-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) -2- (trifluoromethyl) furan-3-carboxylate (1.00 g, 2.36 mmol, 1.00 eq) in azomethylpyrrolidone (10.00 ml) was added copper sulfate (37.67 mg, 236.00 micromole, 0.10 eq). The mixture was stirred at 150 degrees celsius for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by separation on a preparative plate (silica, petroleum ether/ethyl acetate 2: 1) to give the compound 6-benzyl-2- [5- (trifluoromethyl) -2-furyl ] -7, 8-dihydro-5H-1, 6-naphthyridine (500.00 mg, 1.40 mmol, 59.12% yield) as a yellow solid.

And 7:

2- [5- (trifluoromethyl) -2-furyl ] -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine

6-benzyl-2- [5- (trifluoromethyl) -2-furyl ] -7, 8-dihydro-5H-1, 6-naphthyridine (600.00 mg, 1.67 mmol, 1.00 eq.) and 1-chloroethylcarbonyl chloride (358.14 mg, 2.51 mmol, 1.50 eq.) were dissolved in 1, 2-dichloroethane (6.00 ml) and the mixture was stirred at 80 ℃ for 12H. The reaction mixture was concentrated under reduced pressure to remove the solvent, and methanol (6.00 ml) was added. The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The pH was adjusted to about 9 by gradual addition of sodium carbonate solution and extracted with ethyl acetate (100ml × 2). The combined organic layers were concentrated under reduced pressure to give 2- [5- (trifluoromethyl) -2-furyl ] -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (200.00 mg, 745.63 micromoles, 44.65% yield) as a white solid. LCMS (ESI) m/z: 269.1(M +1).

And 8:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [2- [5- (trifluoromethyl) -2-furyl ] -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl ] propan-2-ol

To a solution of 2- [5- (trifluoromethyl) -2-furyl ] -5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (200.00 mg, 745.63 micromoles, 1.00 equivalents) in t-butanol (5.00ml) were added diisopropylamine (192.73 mg, 1.49 mmol, 2.00 equivalents) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (178.48 mg, 820.19 micromoles, 1.10 equivalents). The mixture was stirred at 100 degrees celsius for 12 hours. The residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 10/1 ═ 1: 1) to give (2S) -1- (2-chloro-4-nitro-imidazol-1-yl) -2-methyl-3- [2- [5- (trifluoromethyl) -2-furyl ] -7, 8-dihydro 5H-1, 6-naphthyridin-6-yl ] propan-2-ol (260.00 mg, 535.16 micromoles, 71.77% yield) as a yellow solid. LCMS (ESI) m/z: 486.2(M +1).

And step 9:

To (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [2- [5- (trifluoromethyl) -2-furyl]-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl]To a solution of propan-2-ol (260.00 mg, 535.16 micromoles, 1.00 eq) in DMF (3.00 mL) at 0 ℃ was added sodium hydrogen (32.11 mg, 1.34 mmol, 2.50 eq) for 10min, the mixture was stirred at 15 ℃ for 50 min the reaction mixture was quenched at 0 ℃ by addition of ammonium chloride (10 mL) and then extracted with ethyl acetate (100mL × 2) the combined organic layers were washed with sodium chloride (20 mL 1) and concentrated under reduced pressure to give a residue which was purified by preparative separation chromatography (GX-I, YMC-Actus ODS-AQ 100: -305 u, acetonitrile 24% -54%; 0.1% TFA-ACN; 25mL/min) to give (S) -2-methyl-6-nitro-2- ((2- (5- (trifluoromethyl) furan-2-yl) -7, 8-dihydro-1, 6-naphthyridine) -5H-methyl) -2-imidazole [2, 3.5H-dihydro-2-imidazole, 2 b ] and 2-d]Azole compound 54(48.00 mg, 105.28 μm)Mole, 19.67% yield, 98.561% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 55

(S) -2-methyl-2- ((2- (4-methylthiazol-2-yl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -6-nitro 2, 3-dihydroimidazo [2, 1b ] oxazole

Step 1:

6-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-2-carboxylic acid

To a solution of 6-benzyl-2-chloro-7, 8-dihydro-5H-1, 6-naphthyridine (3.80 g, 14.69 mmol, 1.00 eq) in triethylamine (2.00 ml) and methanol (20.00 ml) under nitrogen protection was added Pd (dppf) Cl₂(1.07 g, 1.47 mmol, 0.10 equiv.). The suspension was degassed under vacuum and purged with carbon monoxide and the mixture was stirred under carbon monoxide (50Psi) at 80 ℃ for 12 hours. Filtration and concentration and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1, 1/2) to give methyl 6-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-2-carboxylate (3.90 g, 13.81 mmol, 94.04% yield) as a yellow solid.¹H NMR(400MHz，CDCl₃)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-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-2-carboxamide

Ammonia (4.58 g, 269.20 mmol, 20.00 equiv.) was bubbled through methanol (50.00 ml) at-50 deg.C, after 10 minutes, 6-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-2-carboxylic acid methyl ester (3.80 g, 13.46 mmol, 1.00 equiv.) was added to the solution at 15 deg.C and the mixture was stirred for 120 minutes at 15 deg.C. The reaction mixture was concentrated to give 6-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-2-carboxamide (3.30 g, 12.34 mmol, 91.71% yield) as a yellow solid.¹H NMR(400MHz，CDCl₃)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).

And step 3:

6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridine-2-thiocarboxamide

To a solution of 6-benzyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine-2-carboxamide (1.50 g, 5.61 mmol, 1.00 eq) in tetrahydrofuran (30.00 ml) was added lawson's reagent (3.40 g, 8.42 mmol, 1.50 eq) under nitrogen. The mixture was stirred at 80 ℃ for 4 hours. The mixture was concentrated at 45 ℃ under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1, 0/1) to give 6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridine-2-carbothioamide (780.00 mg, 2.75 mmol, 49.06% yield) as a yellow solid.¹H NMR(400MHz，CDCl₃)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).

And 4, step 4:

2- (6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridin-2-yl) -4-methyl-thiazole

To a solution of 6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridine-2-carbothioamide (780.00 mg, 2.75 mmol, 1.00 eq) in ethanol (15.00 ml) was added 1-chloroprop-2-one (1.48 g, 16.00 mmol, 5.82 eq) under nitrogen. The mixture was stirred at 80 ℃ for 12 hours. The mixture was concentrated at 45 ℃ under reduced pressure. The residue was washed with (petroleum ether: ethyl acetate 10: 1, 40 ml), filtered and the filter cake was dried to give 2- (6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridin-2-yl) -4-methyl-thiazole (719.00 mg, 2.24 mmol, 81.34% yield) as a brown solid.¹H NMR(400MHz，CDCl₃)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).

And 5:

4-methyl-2- (5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) thiazole

To a solution of 2- (6-benzyl-7, 8-dihydro-5H-1, 6-naphthyridin-2-yl) -4-methyl-thiazole (360.00 mg, 1.12 mmol, 1.00 eq) in dichloroethane (10.00 ml) was added 1-chloroethylcarbonyl chloride (240.19 mg, 1.68 mmol, 1.50 eq) under nitrogen protection at 0 ℃. The mixture was stirred at 100 ℃ for 12 hours, and then the mixture was cooledCooled to 20 ℃ and concentrated under reduced pressure at 45 ℃ and methanol (15.00 ml) was added to the residue and stirred at 80 ℃ for 2 hours. The mixture was concentrated at 45 ℃ under reduced pressure, dichloromethane (20 ml) was added to the residue and stirred for 10 minutes, filtered and the filter cake was collected to give 4-methyl-2- (5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) thiazole (150.00 mg, 560.16 micromoles, 50.01% yield, hydrochloric acid) as a white solid.¹H NMR(300MHz，DMSO-d₆)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- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [2- (4-methylthiazol-2-yl) -7, 8-dihydro-5H- - -1-, 6-naphthyridin-6-yl ] propan-2-ol

To 4-methyl-2- (5, 6, 7, 8-tetrahydro-1, 6-naphthyridin-2-yl) thiazole (150.00 mg, 560.16 micromoles, 1.00eq, HCl) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl]Methyl radical]-4-nitroimidazole (146.28 mg, 672.19 micromole, 1.20 equivalents) in t-butanol (10.00 ml) under nitrogen atmosphere diisopropylamine (144.79 mg, 1.12 mmol, 2.00 equivalents) is added, the mixture is stirred at 80 ℃ for 12 hours, the mixture is concentrated at 45 ℃ under reduced pressure, water (20 ml) is added to the residue and stirred for 5 minutes, the aqueous phase is extracted with ethyl acetate (30ml × 3), the combined organic phases are dried with brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue is purified by preparative thin layer chromatography (petroleum ether/ethyl acetate ═ 1/1) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [2- (4-methylthiazol-2-yl) -7, 8-dihydro-5H-1, 6-naphthyridin-6-yl)]Propan-2-ol (73.00 mg, 162.61 micromoles, 29.03% yield) as a white solid.¹H NMR(300MHz，CDCl₃)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).

And 7:

To (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -2-methyl-3- [2- (4-methylthiazol-2-yl) -7, 8-dihydro-5H- - -1-, 6-naphthyridin-6-yl]To a solution of propan-2-ol (73.00 mg, 162.61 micromoles, 1.00 eq) in DMF (2.00 mL) was added sodium hydrogen (13.01 mg, 325.22 micromoles, 2.00 eq) in one portion under nitrogen protection at-45 ℃ the mixture was stirred for 10min at-45-0 ℃ the residue was poured into saturated ammonium chloride solution (30mL) and stirred for 5min the aqueous phase was extracted with ethyl acetate (50mL × 3), the combined organic phases were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue was purified by preparative separation chromatography (GX-F; phenomenx Synergi C18150 x 25 x 10 um; acetonitrile 32% -62%; water (0.225% FA-ACN); 25mL/min) to give (S) -2-methyl-2- (4-methylthiazol-2-7, 8-dihydronaphthyridine) -1, 6-2-dihydro-naphthyridine (1.5-2-methyl-2-yl) and 2-nitro-2-d-2-3 b]Oxazole compound 55(27.96 mg, 65.35 micromole, 40.19% yield, 96.4% purity).¹H NMR(400MHz，CDCl₃)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).

Example 56

(S) -2- ((2- (4-fluoro-2-methylphenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] oxazole

Key intermediate B (300.00 mg, 857.71 micromoles, 1.00 equiv.) and (4-fluoro-2-methyl-phenyl) boronic acid (198.07 mg, 1.29 mmol, 1.50 equiv.) were dissolved in dioxane (5.00mL) and water (500.00. mu.L) and Pd (dppf) Cl was added₂(31.38 mg, 42.89 micromoles, 0.05 eq) and cesium fluoride (260.57 mg, 1.72 mmol, 2.00 eq.) the mixture was stirred at 110 ℃ for 10 hours, quenched by the addition of water (50mL) and then extracted with ethyl acetate (50mL × 3) the combined organic layers were washed with saturated brine (50mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue, the residue was purified by preparative separation chromatography (GX-F; Phenomenex Synergi C18150 25 x 10 um; acetonitrile 28% -49%; ACN (0.225% fomicacid); 25mL/min) to give (S) -2- ((2- (4-fluoro-2-methylphenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] 2]Oxazole compound 56(104.70 mg, 239.60 micromoles, 27.93% yield, 96.9% purity).¹H NMR(400MHz，CDCl₃)：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).

Example 57

(S) -2- ((2- (4-fluorophenyl) -5, 6-dihydro- [1, 2, 4] triazolo [1, 5-a ] pyrazin-7 (8H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 50.

(S) -2- ((2- (4-fluorophenyl) -5, 6-2H- [1, 2, 4)]Triazolo [1, 5-a]Pyrazin-7 (8H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ]]Oxazole compound 57(6.85 mg, 16.20 micromole, 44.13% yield, 94.46% purity).¹HNMR(400MHz，METHANOL-d₄)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).

Example 58

(S) -2- ((2- (4-fluoro-3-methylphenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] oxazole

Key intermediate B (100.00 mg, 285.90 micromoles, 1.00 equivalents) and (4-fluoro-3-methyl-phenyl) boronic acid (44.01 mg, 285.90 micromoles, 1.00 equivalents) were dissolved in dioxane (1.00 mL) and water (100.00 microliters), and cesium fluoride (86.86 mg, 571.80 micromoles, 2.00 equivalents) and Pd (dppf) Cl were added₂(20.92 mg, 28.59 micromoles, 0.10 eq.) the mixture is stirred at 110 ℃ for 10 hours, quenched by the addition of water (50ml) to the reaction mixture, then extracted with ethyl acetate (50ml × 3), the combined organic layers are washed with saturated brine (50ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which is purified by preparative separation chromatography (GX-G; Phenomenex Synerg)i Max-RP 250 × 8010 u; 20% -50% of acetonitrile; ACN (0.225% fomic acid); 25mL/min) to give (S) -2- ((2- (4-fluoro-3-methylphenyl) -7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1-b)]Oxazole (38.74 mg, 89.20 micromole, 31.20% yield, 97.5% purity) compound 58.¹H NMR(400MHz，CDCl₃)：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).

Example 59

(S) -2- ((2-cyclohexyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 11b ] oxazole

Step 1:

6-benzyl-2- (cyclohexen-1-yl) -7, 8-dihydro-5H-1, 6-naphthyridine

6-benzyl-2-chloro-7, 8-dihydro-5H-1, 6-naphthyridine (200.00 mg, 772.95 micromoles, 1.00 equiv.), cyclohexen-1-ylboronic acid (146.04 mg, 1.16 mmol, 1.50 equiv.), Pd (dppf) Cl₂(56.56 mg, 77.30 micromoles, 0.10 equiv.) and cesium fluoride (234.82 mg, 1.55 mmol, 2.00 equiv.) were dissolved in dioxane (4.00 ml) and water (0.4 ml) and then stirred under nitrogen at 110 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure, and water (10 ml) was added to the residue, followed by addition of acetic acidExtraction with ethyl ester (20 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate ═ 20/1 to 10: 1) to give 6-benzyl-2- (cyclohexen-1-yl) -7, 8-dihydro-5H-1, 6-naphthyridine (160.00 mg, 525.57 micromoles, 68.00% yield) as a yellow solid.¹H NMR(300MHz，CDCl₃)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-tetrahydro-1, 6-naphthyridine

To a solution of 6-benzyl-2- (cyclohexen-1-yl) -7, 8-dihydro-5H-1, 6-naphthyridine (160.00 mg, 525.57 micromoles, 1.00 equivalents) in methanol (5.00ml) under nitrogen was added palladium hydroxide on carbon (7.38 mg, 52.55 micromoles, 0.10 equivalents). The suspension was degassed and replaced several times with hydrogen. The mixture was reacted under hydrogen (30 psi) with stirring at 15 ℃ for 12 hours. The reaction mixture was filtered and concentrated to give 2-cyclohexyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (110.00 mg, 508.51 micromoles, 96.75% yield, 100% purity) as a colorless oil.

And step 3:

(2R) -1- (2-chloro-4-nitroimidazol-1-yl) -3- (2-cyclohexyl-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) -2-methyl-propan-2-ol

To a solution of 2-cyclohexyl-5, 6, 7, 8-tetrahydro-1, 6-naphthyridine (110.00 mg, 508.51 micromoles, 1.00 equivalents) in ethanol (5.00ml) was added diisopropylamine (131.44 mg, 1.02 mmol, 2.00 equivalents) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (132.79 mg, 610.21 micromoles, 1.20 equivalents). The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (20 ml) and extracted with ethyl acetate (30 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (silica, ethyl acetate) to give (2R) -1- (2-chloro-4-nitroimidazol-1-yl) -3- (2-cyclohexyl-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) -2-methyl-propan-2-ol (80.00 mg, 135.87 micromoles, 26.72% yield, 73.7% purity) as a yellow solid.

And 4, step 4:

To a solution of (2R) -1- (2-chloro-4-nitroimidazol-1-yl) -3- (2-cyclohexyl-7, 8-dihydro-5H-1, 6-naphthyridin-6-yl) -2-methylpropan-2-ol (80.00 mg, 184.36 micromole, 1.00 eq) in DMF (2.00 ml) at 0 deg.C was added sodium hydrogen (8.85 mg, 221.23 micromole, 1.20 eq.) the mixture was stirred at 0 deg.C for 1 hour, the reaction mixture was slowly added to cooled saturated ammonium chloride (10 ml) and then extracted with ethyl acetate (20 ml). the combined organic layers were washed with brine (10 ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was chromatographed by preparative separation (Instrument: GX-D; Column: Boston Green 150 ODS 305 u; Mobile: 20% -50%; H₂O(+0.00225FA)；Rate：25ml/min；Monitored Wavelength：220nm/254nm；Run length：10min/15min；Column temperature: purifying at 30 ℃ to obtain (S) -2- ((2-cyclohexyl-7, 8-dihydro-1, 6-naphthyridin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 11b ]]Azole compound 59(70.00 mg, 174.71 micromoles, 94.76% yield, 99.2% purity).¹H NMR(400MHz，CDCl₃)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).

Example 60

(S) -2- ((2- (4-fluorophenyl) -7, 7-dimethyl-6, 7-dihydrothiazolo [5, 4-c ] pyridin-5 (4H) -yl) methyl) -2-methyl 6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

Step 1:

1-benzyl-3, 3-dimethylpiperidin-4-one

Formaldehyde (18.26 g, 225.00 mmol, 2.25 eq) was dissolved in ethanol (100.00 ml) and benzylamine (10.72 g, 100.00 mmol, 1.00 eq) was added slowly to the solution. The mixture was stirred at 15 ℃ for 1 hour. The mixture was then slowly added to a refluxing solution of 3-methylbutan-2-one (8.61 g, 100.00 mmol, 1.00 eq.) in ethanol (100.00 ml) and hydrochloric acid (9.20 ml). The mixture was stirred at 80 ℃ for 12 hours. The mixture was then cooled to 15 ℃, diisopropylamine (14.22 g, 110.00 mmol, 1.10 equiv.) and formaldehyde (2.44 g, 30.00 mmol, 0.30 equiv.) were then added and the mixture was stirred at 80 ℃ for a further 7 hours. The reaction mixture was adjusted to pH > 10 with potassium hydroxide and then extracted with ethyl acetate (200 ml). The combined organic layers were washed with brine (100ml), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 30/1-10: 1) to give 1-benzyl 3, 3-dimethylpiperidin-4-one (10.00 g, 46.02 mmol, 46.02% yield) as a colorless oil.

Step 2:

3, 3-dimethylpiperidin-4-one

1-benzyl-3, 3-dimethylpiperidin-4-one (5.00 g, 23.01 mmol, 1.00 eq) and 1-chloroethylcarbonyl chloride (6.58 g, 46.02 mmol, 2.00 eq) were dissolved in dichloroethane (50.00 ml), the mixture was degassed and replaced with nitrogen 3 times, then the mixture was stirred at 80 ℃ for 12 hours, then the mixture was concentrated, methanol (50.00 ml) was added and the mixture was stirred at 80 ℃ for an additional 4 hours. The reaction mixture was concentrated to remove MeOH, the residue was washed with dichloromethane (20 ml) and filtered, and the solid was collected to give 3, 3-dimethylpiperidin-4-one (3.00 g, 18.33 mmol, 79.67% yield, hydrochloride salt) as a white solid.

¹H NMR(400MHz，METHANOL-d₄)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).

And step 3:

3, 3-dimethyl-4-oxopiperidine-1-carboxylic acid benzyl ester

To a mixed solution of 3, 3-dimethylpiperidin-4-one, hydrochloride salt (1.00 g, 6.11 mmol, 1.00 equiv) in tetrahydrofuran (5.00ml) and water (5.00ml) was added sodium bicarbonate (1.28 g, 15.28 mmol, 2.50 equiv) and CbzCl (1.25 g, 7.33 mmol, 1.20 equiv) at 0 deg.c and the mixture was stirred at 15 deg.c for 12 hours the reaction mixture was extracted with ethyl acetate (20 ml) the combined organic layers were washed with brine (10 ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give benzyl 3, 3-dimethyl-4-oxopiperidine-1-carboxylate (1.60 g, 4.81 mmol, 78.66% yield, 78.5% purity) as a colorless oil.¹H NMR(400MHz，CDCl₃)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)

And 4, step 4:

benzyl 5-bromo-3, 3-dimethyl-4-oxopiperidine-1-carboxylic acid

To a solution of benzyl 3, 3-dimethyl-4-oxopiperidine-1-carboxylate (1.10 g, 4.21 mmol, 1.10 eq) in THF (10.00 ml) was added phenyltrimethylamine tribromide (1.44 g, 3.83 mmol, 1.00 eq). The mixture was stirred at 15 ℃ for 1 hour. Water (10 ml) was added to quench, followed by extraction with ethyl acetate (20 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude 5-bromo-3, 3-dimethyl-4-oxo-piperidine-1-carboxylic acid benzyl ester (1.40 g, crude) as a yellow oil which was used straight on to the next step.

And 5:

benzyl 2- (4-fluorophenyl) -7, 7-dimethyl-4, 6-dihydrothiazolo [5, 4-c ] pyridine-5-carboxylate

Benzyl 5-bromo-3, 3-dimethyl-4-oxo-piperidine-1-carboxylate (1.85 g, 5.44 mmol, 1.00 eq), 4-fluorothiobenzamide (843.89 mg, 5.44 mmol, 1.00 eq) were dissolved in isopropanol (20.00 ml), the mixture was degassed and replaced 3 times with nitrogen, and the mixture was then reacted at 80 ℃ for 12 hours. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (40 ml). The combined organic layers were washed with 40 ml of brine (20 ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate ═ 20/1-10: 1) to give benzyl 2- (4-fluorophenyl) -7, 7-dimethyl-4, 6-dihydrothiazolo [5, 4-c ] pyridine-5-carboxylate (800.00 mg, 2.02 mmol, 37.09% yield) as a colorless oil.

Step 6:

2- (4-fluorophenyl) -7, 7-dimethyl-5, 6-dihydro-4H-thiazolo [5, 4-c ] pyridine

2- (4-fluorophenyl) -7, 7-dimethyl-4, 6-dihydrothiazolo [5, 4-c)]Benzyl pyridine-5-carboxylate (500.00 mg, 1.26 mmol, 1.00 eq) was dissolved in acetic acid hydrogen bromide solution (5.00mL), replaced with nitrogen, and the mixture was stirred at 15 ℃ for 2 hours. The reaction mixture was concentrated to remove a portion of the acetic acid and the solid was filtered to give 2- (4-fluorophenyl) -7, 7-dimethyl-5, 6-dihydro-4H-thiazolo [5, 4-c ]]Pyridine (400.00 mg, 1.17 mmol, 92.86% yield, hydrobromide) was obtained as a yellow solid.¹H NMR(400MHz，CDCl₃)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- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -7, 7-dimethyl-4, 6-dihydrothiazolo [5, 4-C ] pyridin-5-yl ] -2-methyl-propan-2-ol

2- (4-fluorophenyl) -7, 7-dimethyl-5, 6-dihydro-4H-thiazolo [5, 4-c)]Pyridine (200.00 mg, 582.65 micromoles, 1.00 equivalents, hydrobromide), 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl]Methyl radical]-4-nitroimidazole (152.15 mg, 699.18 micromole, 1.20 equivalents), diisopropylamine (225.91 mg, 1.75 mmol, 3.00 equivalents) were dissolved in ethanol (5.00ml), replaced with nitrogen, and the mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (20 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 10/1-5/1) to give (2R) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -7, 7-dimethyl-4, 6-dihydrothiazolo [5, 4-c)]Pyridin-5-yl]2-methyl-propan-2-ol (200.00 mg, 416.71 micromole, 71.52% yield) as a yellow oil.¹H NMR(300MHz，CDCl₃)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).

And 7:

To (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -7, 7-dimethyl-4, 6-dihydrothia-neAzolo [5, 4-C]Pyridin-5-yl]To a solution of-2-methyl-propan-2-ol (250.00 mg, 520.89 micromoles, 1.00 equiv) in DMF (5.00ml) was added sodium hydrogen (31.25 mg, 781.33 micromoles, 1.50 equiv) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour, and the reaction mixture was quenched by addition to cooled saturated ammonium chloride (20 ml) and then extracted with ethyl E acetate (20 ml). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative separation chromatography (Instrument: GX-D; Column: Boston Green ODS 150 x 305 u; Mobile phase: 58% -88%; ACN (+0.00225 FA); Rate: 25 ml/min; Monitored wavelet: 220nm/254 nm; Run length: 10min/15 min; Column temperature: 30 ℃) to give (S) -2- ((2- (4-fluorophenyl) -7, 7-dimethyl-6, 7-dihydrothiazolo [5, 4-c ])]Pyridin-5 (4H) -yl) methyl) -2-methyl 6-nitro-2, 3-dihydroimidazo [2, 1b]Oxazole compound 60(72.40 mg, 163.25 micromoles, 31.34% yield, 100% purity).¹H NMR(400MHz，CDCl₃)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).

Example 61

(S) -2- (4-fluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -4, 5, 6-, 7-tetrahydrooxazolo [5, 4-c ] pyridine

The synthesis was as in example 41.

(S) -2- (4-fluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1 b)]Azole-2-yl) methyl) -4, 5, 6-, 7-tetrahydrooxazolo [5, 4-c]Pyridine compound 61(63.20 mg, 149.47 micromoles, 8.12% yield, 94.452% purity).¹H NMR(400MHz，CDCl₃)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).

Example 62

(S) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -2- (3, 4, 5-trifluorophenyl) -4-, 5, 6, 7-tetrahydrooxazolo [5, 4-c ] pyridine

The synthesis was as in example 41.

(S) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1 b)]Oxazol-2-yl) methyl) -2- (3, 4, 5-trifluorophenyl) -4-, 5, 6, 7-tetrahydrooxazolo [5, 4-c]Pyridine compound 62(222.70 mg, 484.42 micromoles, 42.49% yield, 94.7% purity).¹H NMR(400MHz，CDCl₃)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).

Example 63

(S) -2-methyl-6-nitro-2- ((2- (3, 4, 5-trifluorophenyl) -6, 7-dihydrothiazolo [5, 4-c ] pyridin-5 (4H) -yl) methyl) -2, 3-dihydroimidazo [2, 1b ] oxazole

Step 1:

3, 4, 5-trifluorobenzenethioamides

To a solution of 3, 4, 5-trifluorobenzamide (2.90 g, 16.56 mmol, 1.00 eq) in tetrahydrofuran (80.00 ml) was added lawson's reagent (7.37 g, 18.22 mmol, 1.10 eq). The mixture was stirred at 70 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was diluted with water (200 ml) and extracted with ethyl acetate (30ml × 3). The combined organic layers were washed with saturated brine (30ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate ═ 5/1) to give 3, 4, 5-trifluorobenzenethioamide (4.35 g, crude) as a yellow solid.

Step 2:

3-bromo-4-oxopiperidine-1-carboxylic acid benzyl ester

To a solution of benzyl 4-oxopiperidine-1-carboxylic acid tert-butyl ester (5.00 g, 21.44 mmol, 1.00 eq) in chloroform (50.00 ml) was added liquid bromine (3.43 g, 21.44 mmol, 1.00 eq) dropwise at 25 ℃ under nitrogen. The mixture was stirred at 25 ℃ for 2 hours, and the reaction mixture was quenched by addition of cooled saturated sodium sulfite (100ml) and then extracted with dichloromethane (50ml × 3). The combined organic layers were washed with saturated sodium carbonate (100ml × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude product benzyl 3-bromo-4-oxopiperidine-1-carboxylate (7.10 g, crude) as a yellow oil which was used directly in the next step.

And step 3:

benzyl 2- (3, 4, 5-trifluorophenyl) -6, 7-dihydrothiazolo [5, 4-c ] pyridine-5 (4H) -carboxylate

To a solution of benzyl 3-bromo-4-oxopiperidine-1-carboxylate (7.10 g, 22.74 mmol, 1.00 eq) in isopropanol (50.00 ml) was added 3, 4, 5-trifluorobenzenethioamide (4.35 g, 22.74 mmol, 1.00 eq). The mixture was stirred at 80 ℃ for 12H, the reaction mixture was concentrated to remove the solvent and the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 5/1 to 1: 1, then dichloromethane: methanol 50: 1) to give benzyl 2- (3, 4, 5-trifluorophenyl) -6, 7-dihydrothiazolo [5, 4-c ] pyridine-5 (4H) -carboxylate (1.00 g, crude) as a yellow oil. LCMS (ESI) m/z: 405(M +1).

And 4, step 4:

2- (3, 4, 5-trifluorophenyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine

Benzyl 2- (3, 4, 5-trifluorophenyl) -6, 7-dihydrothiazolo [5, 4-c ] pyridine-5 (4H) -carboxylate (1.00 g, 2.47 mmol, 1.00 equiv.) was dissolved in acetic acid hydrobromide solution (3.00 ml). The mixture was stirred at 25 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent to give the crude product 2- (3, 4, 5-trifluorophenyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (1.00 g, crude, hydrobromide) as a yellow solid, which was used directly in the next step. LCMS (ESI) m/z: 271(M +1).

And 5:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2- (3, 4, 5-trifluorophenyl) -6, 7-dihydrothia [5-, 4-c ] pyridin-5 (4H) -yl) propan-2-ol

To a solution of 2- (3, 4, 5-trifluorophenyl) -4, 5, 6, 7-tetrahydrothiazolo [5, 4-c ] pyridine (350.00 mg, 996.61 micromoles, 1.00eq, hydrobromide) and (S) -2-chloro 1- ((2-oxidopropan-2-yl) methyl) -4-nitro-1H-imidazole (260.25 mg, 1.20 mmol, 1.20 eq) in ethanol (10.00 ml) was added diisopropylamine (386.41 mg, 2.99 mmol, 3.00 eq). The mixture was stirred at 80 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent and the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 5/1-1: 1) to give (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2- (3, 4, 5-trifluorophenyl) -6, 7-dihydrothiazolo [5, 4-c ] pyridin-5 (4H) -yl) propan-2-ol (200.00 mg, 409.94 micromoles, 41.13% yield) as a yellow solid. LCMS (ESI) m/z: 488/490(M +1/M +3).

Step 6:

To (S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -2-methyl-3- (2- (3, 4, 5-trifluorophenyl) -6, 7-dihydrothia [5-, 4-c)]Pyridin-5 (4H) -yl) propan-2-ol (100.00 mg, 204.97 micromoles, 1.00 equivalents) in DMF (2.00 ml) was added sodium hydrogen (9.84 mg, 245.96 micromoles, 1.20 equivalents) at 0 ℃.The combined organic layers were washed with saturated brine (10 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by preparative separation chromatography (GX-F; Phenomenex Synergi C18150 x 30mm x 4 um; acetonitrile 50% -80%; water (0.225% fomic acid); Rate: 25mL/min) to give (S) -2-methyl-6-nitro-2- ((2- (3, 4, 5-trifluorophenyl) -6, 7-dihydrothiazolo [5, 4-C)]Pyridin-5 (4H) -yl) methyl) -2, 3-dihydroimidazo [2, 1b]Azole compound 63(23.00 mg, 50.67 micromoles, 24.72% yield, 99.448% purity).¹H NMR(400MHz，CDCl₃)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).

Example 64

(S) -2- (4-fluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -4, 5, 6-, 7-tetrahydrofuro [3, 2-c ] pyridine

Step 1:

3- [2- (4-fluorophenyl) -2-oxo-ethyl ] -4-oxo-piperidine-1-carboxylic acid benzyl ester

Benzyl 4-oxopiperidine-1-carboxylate (5.00 g, 21.44 mmol, 1.00 eq) and pyrrolidine (6.10 g, 85.76 mmol, 4.00 eq), tsoh.h2o (407.83 mg, 2.14 mmol, 0.10 eq) were dissolved in toluene (20.00 ml), heated to 130 ℃ and stirred while dividing with a water separator, after 12 hours about 0.5 ml of water was separated off, the mixture was concentrated at 50 ℃ and the crude benzyl 4-pyrrolidin-1-yl-3, 6-dihydro-2H-pyridine-1-carboxylate (7.00 g, crude) was added as a brown oil, to a solution of the crude (1.50 g, 5.24 mmol, 1.00 eq) in toluene (15.00 ml) at 10 ℃ in one portion under nitrogen protection 2-bromo-1- (4-fluorophenyl) ethanone (1.14 g, 5.24 mmol, 1.00 eq), the mixture was stirred at 10 ℃ for 12 h, concentrated and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 10/1, 2/1) to give benzyl 3- [2- (4-fluorophenyl) -2-oxo-ethyl ] -4-oxo-piperidine-1-carboxylate (550.00mg, 1.49 mmol, 28.41% yield) as a yellow oil.

Step 2:

2- (4-fluorophenyl) -6, 7-dihydrofuro [3, 2-c ] pyridine-5 (4H) -carboxylic acid benzyl ester

To a solution of benzyl 3- [2- (4-fluorophenyl) -2-oxo-ethyl ] -4-oxo-piperidine-1-carboxylate (400.00 mg, 1.08 mmol, 1.00 eq) in toluene (6.00 ml) was added phosphorus oxychloride (1.81 g, 11.80 mmol, 10.93 eq) in one portion at 15 ℃ under nitrogen. The mixture was stirred at 100 ℃ for 1 hour. The mixture was poured into water (30ml) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (50 mL. times.3). The combined organic phases were dried over anhydrous sodium sulfate with brine (30ml), filtered and concentrated in vacuo, and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate: 1/0, 10/1) to give benzyl 2- (4-fluorophenyl) -6, 7-dihydrofuro [3, 2-c ] pyridine-5 (4H) -carboxylate (200.00 mg, 569.20 micromoles, 52.70% yield) as a yellow oil.

And step 3:

2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydrofuro [3, 2-c ] pyridine

Benzyl 2- (4-fluorophenyl) -6, 7-dihydrofuro [3, 2-c ] pyridine-5 (4H) -carboxylate (233.00 mg, 663.12 micromoles, 1.00 equivalents) was dissolved in acetic acid hydrobromide solution (5ml, 92.08 mmol, 138.86 equivalents) and the mixture was stirred at 15 ℃ for 30 min. The mixture was concentrated at 45 ℃ to give 2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydrofuro [3, 2-c ] pyridine (200.00 mg, crude, hydrobromide) as a yellow solid. LCMS (ESI) m/z: 218.1(M +1).

And 4, step 4:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -6, 7-dihydro-4H-furo [3, 2-c ] pyridin-5-yl ] -2-boxylphenylethyl-propan-2-ol

To 2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydrofuro [3, 2-c ]]Pyridine (197.71 mg, 663.12 micromoles, 1.00 equivalents, hydrobromide) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl]Methyl radical]-4-nitroimidazole (158.73 mg, 729.43 micromole, 1.10 equivalents) in tert-butanol (10.00 ml) diisopropylamine (171.40 mg, 1.33 mmol, 2.00 equivalents) was added in one portion under nitrogen protection. The mixture was stirred at 80 ℃ for 12H, the mixture was concentrated at 45 ℃ and the residue was purified by silica gel chromatography (petroleum ether/ethyl acetate ═ 1/0, 2/1) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -6, 7-dihydro-4H-furo [3, 2-c)]Pyridin-5-yl]-2-boxylphenylethyl-propan-2-ol (190.00 mg, 436.93 micromoles, 65.89% yield) as a yellow solid.¹H NMR(400MHz，CDCl₃)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).

And 5:

To (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -6, 7-dihydro-4H-furo [3, 2-c)]Pyridin-5-yl]-2-methyl-propan-2-ol (190.00 mg, 436.93 micromoles, 1.00 equiv) in DMF (5.00mL) was added sodium hydrogen (34.95 mg, 873.86 micromoles, 2.00 equiv) in one portion at-45 ℃ under nitrogen protection, the mixture was stirred at-45-0 ℃ for 10 minutes, the mixture was poured into saturated ammonium chloride (30mL) and stirred for 5 minutes, extracted with ethyl acetate (50mL × 3), the combined organic phases were washed with brine (30mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, and the residue was purified by preparative separation chromatography (GX-D; Boston Green ODS 150. multidot.305 u; acetonitrile 40% -70%; water (0.225% mic acid); 25mL/min) to give (S) -2- (4-fluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] 2, 1 b)]Oxazol-2-yl) methyl) -4, 5, 6, 7-tetrahydrofuro [3, 2-c]Pyridine compound 64(33.40 mg, 82.41 micromoles, 18.86% yield, 98.3% purity).¹H NMR(400MHz，CDCl₃)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).

Example 65

(S) -2- (3, 4-difluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -4, 5-, 6, 7-tetrahydrooxazolo [4, 5-c ] pyridine

Step 1:

3-aminopyridin-4-ols

To a mixed solution of 3-nitropyridin-4-ol (30.00 g, 214.13 mmol, 1.00 eq) in methanol (500.00 ml) and DMF (10.00 ml) was added palladium on carbon (3.00 g, 214.13 mmol, 1.00 eq) in one portion under nitrogen protection at 15 ℃. The mixture was stirred under conditions of 15 ℃ under hydrogen (25-40Psi) for 4 hours, filtered, the filtrate concentrated to dryness, methanol hydrochloride (4N, 100mL) was added to the residue, then the mixture was filtered, the filter cake was washed with dichloromethane (200 mL), filtered and the filter cake was collected to give 3-aminopyridin-4-ol (31.00 g, 211.50 mmol, 98.77% yield, hydrochloric acid) as an off-white solid.¹H NMR(400MHz，DMSO-d₆)14.44(br，s，1H)，7.96-7.84(m，2H)，7.27(d，J＝6.3Hz，1H).

Step 2:

3, 4-difluoro-N- (4-hydroxy-3-pyridinyl) benzamide

To 3-aminopyridin-4-ol (15.00 g, 102.34 mmol, 1.00eq, hydrochloride) in dichloromethane (200.00 ml) was added triethylamine (41.42 g, 409.36 mmol, 56.74 ml, 4.00 eq) in one portion at 0 ℃ under nitrogen protection. 3, 4-difluorobenzoyl chloride (25.30 g, 143.28 mmol, 17.94 ml, 1.40 equiv.) was then added and the resulting mixture was stirred at 15 ℃ for 12 h. The mixture was filtered and the filter cake was washed with dichloromethane (50ml) to give3, 4-difluoro-N- (4-hydroxy-3-pyridinyl) benzamide (30.00 g, crude) was a yellow solid.¹H NMR(400MHz，DMSO-d₆)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).

And step 3:

2- (3, 4-difluorophenyl) oxazolo [4, 5-c ] pyridine

Hexachloroethane (35.48 g, 149.88 mmol, 16.98 ml, 2.50 equivalents), triphenylphosphine (47.17 g, 179.86 mmol, 3.00 equivalents) and triethylamine (48.53 g, 479.62 mmol, 66.48 ml, 8.00 equivalents) were dissolved in dichloromethane (200.00 ml), the mixture was stirred at 15 ℃ for 0.5 h, then 3, 4-difluoro-N- (4-hydroxy-3-pyridinyl) benzamide (15.00 g, 59.95 mmol, 1.00 equivalents) was added in portions, the resulting mixture was stirred at 15 ℃ for 12 h, the reaction mixture was added dropwise to 1N hydrochloric acid at 0 ℃, the aqueous layer was extracted with dichloromethane (100ml × 3), the aqueous layer was then adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, the aqueous layer was extracted with dichloromethane (100ml × 3), the combined organic phases were washed with brine (100ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 2- (3, 4-difluorophenyl) and [ 5-c ] was obtained]Pyridine (4.50 g, 19.38 mmol, 32.33% yield) as a yellow solid.¹H NMR(400MHz，CDCl₃)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).

And 4, step 4:

5-benzyl-2- (3, 4-difluorophenyl) oxazolo [4, 5-c ] pyridin-5-ium bromide

To 2- (3, 4-difluorophenyl) oxazolo [4, 5-c]Benzyl bromide (16.57 g, 96.90 mmol, 11.51 ml, 5.00 equiv.) was added to a solution of pyridine (4.50 g, 19.38 mmol, 1.00 equiv.) in acetonitrile (80.00 ml) at 0 ℃ under nitrogen. The mixture was stirred at 15 ℃ for 12 hours. The mixture was filtered and the filter cake collected to give 5-benzyl-2- (3, 4-difluorophenyl) oxazolo [4, 5-c]Pyridin-5-ium bromide (6.00 g, 14.88 mmol, 76.78% yield) as a white solid.¹HNMR(400MHz，METHANOL-d₄)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).

And 5:

5-benzyl-2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [4, 5-c ] pyridine

To the solution of 5-benzyl-2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [4, 5-c]Pyridine (5.00 g, 12.40 mmol, 1.00 eq) in methanol (80.00 ml) is added sodium borohydride (4.69 g, 124.00 mmol, 10.00 eq) under nitrogen at-10-5 deg.C, the mixture is stirred at 15 deg.C for 12 hours, water (200 ml) is added to the mixture, which is then extracted with ethyl acetate (200ml × 4), the combined organic phases are washed with saturated brine (100ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the residue is purified by silica gel chromatography (column height: 250 mm, diameter: 100mm, 100-mesh silica gel, petroleum ether/ethyl acetate 20/1 to 5/1) to give 5-benzyl-2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [4, 5-c ]]Pyridine (3.80 g, crude) as a yellow oil.¹H NMR(400MHz，CDCl₃)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:

2- (3, 4-difluorophenyl) -4, 5, 6, 7-tetrahydrooxazolo [4, 5-c ] pyridine hydrochloride

To the solution of 5-benzyl-2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [4, 5-c]To a solution of pyridine (3.80 g, 11.64 mmol, 1.00 eq) in dichloroethane (60.00 ml) was added 1-chloroethylcarbonyl chloride (4.99 g, 34.92 mmol, 3.00 eq) in one portion under nitrogen protection at 0 ℃. The mixture was stirred at 100 ℃ for 12 hours. The mixture was concentrated to remove the solvent, methanol (80 ml) was added to the residue, and the mixture was stirred at 80 ℃ for another 1 hour. The mixture was then concentrated to dryness, ethyl acetate (50ml) was added to the residue, the mixture was filtered, and the filter cake was collected to give 2- (3, 4-difluorophenyl) -4, 5, 6, 7-tetrahydrooxazolo [4, 5-c ]]Pyridine hydrochloride (3.80 g, crude, hydrochloride) as a yellow solid.¹H NMR(400MHz，DMSO-d₆)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).

And 7:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [4, 5- ] pyridin-5-yl ] -2-methyl-propan-2-ol

To a solution of 2- (3, 4-difluorophenyl) -4, 5, 6, 7-tetrahydrooxazolo [4, 5-c ] pyridine (2.00 g, 7.33 mmol, 1.00eq, hydrochloride) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (1.60 g, 7.33 mmol, 1.00 eq) in tert-butanol (30.00 ml) was added diisopropylamine (2.37 g, 18.34 mmol, 3.20 ml, 2.50 eq) in one portion under nitrogen at 15 ℃. The mixture was stirred at 100 ℃ for 12 hours. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100mm, 100 mesh silica gel, petroleum ether/ethyl acetate 20/1 to 1/1) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [4, 5-c ] pyridin-5-yl ] -2-methyl-propan-2-ol (1.00 g, 2.20 mmol, 30.06% yield) as a yellow solid. LCMS (ESI) m/z: 454(M +1).

And 8:

To (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (3, 4-difluorophenyl) -6, 7-dihydro-4H-oxazolo [4, 5-]Pyridin-5-yl]To a solution of-2-methyl-propan-2-ol (1.00 g, 2.20 mmol, 1.00 eq) in DMF (10.00 ml) was added sodium hydrogen (176.00 mg, 4.40 mmol, 60% purity, 2.00 eq) in one portion at-5 ℃ under nitrogen protection. The mixture was stirred at-5 ℃ for 0.5 h. The mixture was added dropwise to a solution of ammonium chloride (100ml), filtered and the filter cake was collected to give a crude product, which was purified by silica gel chromatography (column height: 250 mm, diameter: 100mm, 100-mesh 200-mesh silica gel, petroleum ether/ethyl acetate: 20/1 to 1/1) to give (S) -2- (3, 4-difluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] a]Oxazol-2-yl) methyl) -4, 5-, 6, 7-tetrahydrooxazolo [4, 5-c]Pyridine (386.40 mg, 907.28 micromoles, 41.24% yield, 98.0% purity).¹H NMR(400MHz，CDCl₃)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).

Example 66

(S) -2- (4-fluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -4, 5, 6-, 7-tetrahydrooxazolo [4, 5-c ] pyridine

The synthesis was as in example 65.

(S) -2- (4-fluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1 b)]Oxazol-2-yl) methyl) -4, 5, 6-, 7-tetrahydrooxazolo [4, 5-c]Pyridine compound 66(16.60 mg, 39.04 micromole, 21.27% yield, 93.931% purity).¹H NMR(400MHz，CDCl₃)7.94-7.84(m，2H)，7.45(s，1H)，7.09(s，2H)，4.32-4.22(m，1H)，3.96-3.70(m，3H)，3.31-3.17(m，2H)，3.04-2.70(m，4H)，1.63(s，3H).LCMS(ESI)m/z：400.2(M+1).

Example 67

(S) -2- ((2- (4-fluorophenyl) -6, 7-dihydrothia [4, 5-c ] pyridin-5 (4H) -yl) methyl) -2-methyl-6-nitro-2-, 3 dihydroimidazo [2, 1b ] oxazole

Step 1:

n- (4-chloro-3-pyridinyl) -4-fluoro-benzamide

To a solution of 4-chloropyridin-3-amine (2.00 g, 15.56 mmol, 1.00 eq) in acetonitrile (20.00 ml) was added pyridine (2.46 g, 31.12 mmol, 2.00 eq) and 4-fluorobenzoyl chloride (2.71 g, 17.12 mmol, 1.10 eq.) the mixture was stirred at 20 ℃ for 2h, the reaction mixture was concentrated under reduced pressure, then water (100ml) was added, then dichloromethane was extracted (200ml × 3). the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give N- (4-chloro-3-pyridinyl) -4-fluoro-benzamide (3.20 g, 12.77 mmol, 82.07% yield) as a white solid.¹HNMR(300MHz，CDCl₃)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-fluorophenyl) thiazolo [4, 5-c ] pyridine

To a solution of N- (4-chloro-3-pyridyl) -4-fluoro-benzamide (3.20 g, 12.77 mmol, 1.00 eq) in toluene (50.00 ml) was added lawson's reagent (3.62 g, 8.94 mmol, 0.70 eq.) the mixture was stirred at 110 ℃ for 12 h the reaction mixture was concentrated, to the residue was added saturated sodium bicarbonate solution (100ml) and then extracted with dichloromethane (150 ml × 3). the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (column height: 300 mmSilica gel of 100 meshes and diameter of 50 mm, petroleum ether/ethyl acetate 5/1, 3/1, 1/1) to obtain 2- (4-fluorophenyl) thiazolo [4, 5-c)]Pyridine (1.50 g, 6.51 mmol, 51.01% yield) as a white solid.¹H NMR(400MHz，CDCl₃)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).

And step 3:

5-benzyl-2- (4-fluorophenyl) thiazolo [4, 5-c]Pyridin-5-ium bromides

2- (4-fluorophenyl) thiazolo [4, 5-c ] pyridine (700.00 mg, 3.04 mmol, 1.00 equivalent) and benzyl bromide (519.94 mg, 3.04 mmol, 1.00 equivalent) were dissolved in acetonitrile (5.00ml), and the mixture was replaced with nitrogen and then stirred at 20 ℃ for 2 hours. The mixture was filtered and the filter cake was washed with dichloromethane (20 ml). The filter cake was collected to give 5-benzyl-2- (4-fluorophenyl) thiazolo [4, 5-c ] pyridin-5-ium bromide (1.20 g, 2.99 mmol, 98.36% yield) as a white solid.

And 4, step 4:

5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro [4, 5-c ] pyridine

To 5-benzyl-2- (4-fluorophenyl) thiazolo [4, 5-c]To a solution of pyridin-5-ium bromide (900.00 mg, 2.24 mmol, 1.00 eq) in methanol (200.00 ml) was added palladium hydroxide on carbon (157.28 mg, 1.12 mmol, 0.50 eq) under nitrogen. The suspension was degassed and switched 3 times with hydrogen. The mixture was stirred under hydrogen (50psi), 50 ℃ for 12 hours. The reaction was filtered. Concentrating the filtrate under reduced pressure to obtain 5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro [4, 5-c]Pyridine (580.00 mg, 1.79 mmol, 79.91% yield) was a white solid.¹H NMR(400MHz，METHANOL-d₄)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).

And 5:

2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro [4, 5-c ] pyridine

To 5-benzyl-2- (4-fluorophenyl) -6, 7-dihydro-4H-thiazolo [4, 5-c ] pyridine (600.00 mg, 1.85 mmol, 1.00 eq) in dichloroethane (5.00ml) was added 1-chloroethylcarbonyl chloride (396.74 mg, 2.78 mmol, 1.50 eq). The mixture was stirred at 80 ℃ for 16 hours. The dichloroethane was removed by concentration, methanol (5.00ml) was added, and the mixture was stirred at 60 ℃ for 2 hours. The mixture was filtered and the filter cake was dried to give 2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro [4, 5-c ] pyridine (280.00 mg, 1.20 mmol, 64.60% yield) as a white solid. LCMS (ESI) m/z: 235(M +1).

Step 6:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -6, 7-dihydro-4H-thiazolo [4, 5-c ] pyridin-5-yl ] -2-methyl-propan-2-ol

To a solution of 2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro [4, 5-c ] pyridine (200.00 mg, 853.64 micromoles, 1.00 equivalents) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] miroethyl ] -4-nitroimidazole (222.91 mg, 1.02 mmol, 1.20 equivalents) in t-butanol (2.00 ml) was added diisopropylamine (220.65 mg, 1.71 mmol, 2.00 equivalents). The mixture was stirred at 80 ℃ for 12 hours. Water (50ml) was added to the reaction mixture, followed by extraction with ethyl acetate (50ml × 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (column height: 300 mm, diameter 50 mm, 100-mesh 200-mesh silica gel, petroleum ether/ethyl acetate 5/1, 3/1) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -6, 7-dihydro-4H-thiazolo [4, 5-c ] pyridin-5-yl ] -2-methyl-propan-2-ol (230.00 mg, 508.96 micromoles, 59.62% yield) as a yellow solid.

And 7:

To (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluoro-phenyl) -6, 7-dihydro-4H-thiazolo [4, 5-pyridin-5-yl]-2-methyl-propan-2-ol (230.00 mg, 508.96 micromoles, 1.00 equiv.) in DMF (3.00 mL) was added sodium hydrogen (40.72 mg, 1.02 micromoles, 2.00 equiv.) the mixture was stirred at-45 ℃ for 30 minutes then it was stirred at 0 ℃ for 30 minutes the reaction mixture was added to saturated ammonium chloride solution (50mL) then extracted with ethyl acetate (50mL × 3) the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by preparative separation chromatography (GX-I; Phenomenex Gemini 150 mm 25mm 10 um; acetonitrile 36% -66%; ACN (0.225% micacid); 25mL/min) to give (S) -2- ((2- (4-fluorophenyl) -6, 7-dihydrothia [4, 5-c ] -%]Pyridin-5 (4H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Oxazole compound 67(84.60 mg, 200.99 micromoles, 39.49% yield, 98.7% purity).¹H NMR(400MHz，CDCl₃-d)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).

Example 68

(S) -2- ((2- (3, 4-difluorophenyl) -6, 7-dihydrothia [4, 5-c ] pyridin-5 (4H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 67.

(S) -2- ((2- (3, 4-difluorophenyl) -6, 7-dihydrothia [4, 5-c)]Pyridin-5 (4H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b]Oxazole compound 68(75.10 mg, 171.19 micromoles, 32.18% yield, 98.8% purity).¹H NMR(400MHz，CDCl₃)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).

Example 69

(S) -2- ((2- (4-fluorophenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

Step 1:

2, 5-dihydro-1H-pyrroles

To a solution of tert-butyl-2, 5-dihydropyrrole-1-carboxylate (2.00 g, 11.82 mmol, 1.00 eq) in dichloromethane (6.00 ml) was added trifluoroacetic acid (9.18 g, 80.51 mmol, 6.81 eq) and the mixture was stirred at 20 ℃ for 1 h. The mixture was concentrated under reduced pressure to give the crude product as a dark brown oil. Used directly in the next step.

Step 2:

1-tosyl-2, 5-dihydro-1H-pyrrole

To a solution of 2, 5-dihydro-1H-pyrrole (2.16 g, 11.79 mmol, 1.00eq, TFA) in dichloromethane (10.00 mL) was added TosCl (2.70 g, 14.15 mmol, 1.20 eq) and triethylamine (3.58 g, 35.37 mmol, 3.00 eq the mixture was stirred at 20 ℃ for 16H, the reaction mixture was washed with 1M dilute hydrochloric acid (30mL), saturated NaHCO 3 solution (30mL) and brine (30mL), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1- (p-toluenesulfonyl) -2, 5-dihydropyrrole (1.50 g, 6.72 mmol, 56.98% yield) as a brown solid.

And step 3:

4-bromo-1-tosylpyrrolidin-3-ol

To a solution of 1- (p-toluenesulfonyl) -2, 5-dihydropyrrole (1.50 g, 6.72 mmol, 1.00 eq) in DMSO (10.00 ml) and acetonitrile (5.00ml) was added NBS (1.79 g, 10.08 mmol, 1.50 eq) in portions at 0 ℃. The mixture was then stirred at 15 ℃ for 16 hours. Water (50mL) was added to the reaction mixture, and extracted with ethyl acetate (30mL × 2). The combined organic layers were washed with brine (30ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate ═ 10: 1 to 3: 1) to give 4-bromo-1- (p-toluenesulfonyl) pyrrolidin-3-ol (1.58 g, 4.93 mmol, 73.43% yield) as a white solid.

And 4, step 4:

4-bromo-1-tosylpyrrolidin-3-one

To a solution of 4-bromo-1- (p-toluenesulfonyl) pyrrolidin-3-ol (1.58 g, 4.93 mmol, 1.00 eq) in dichloromethane (15.00 ml) was added dessimutan reagent (4.19 g, 9.87 mmol, 2.00 eq) and then switched over with nitrogen, the mixture was then stirred at 10-15 ℃ for 12 h, the reaction mixture was washed with aqueous sodium bicarbonate (50ml × 2) and extracted with ethyl acetate (30ml × 2), the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (silica, petroleum ether/ethyl acetate 10: 1 to 1: 1) to give 4-bromo-1- (p-toluenesulfonyl) pyrrolidin-3-one (980.00 mg, 3.08 mmol, 62.47% yield) as a yellow solid.¹H NMR(300MHz，CDCl₃)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).

And 5:

2- (4-fluorophenyl) -5-tosyl 4, 5, 6, 6a tetrahydro-3 aH-pyrrolo [3, 4-d ] thiazole 3a alcohol

To a solution of 4-bromo-1- (p-toluenesulfonyl) pyrrolidin-3-one (880.00 mg, 2.77 mmol, 1.00 eq) in DMF (12.00 ml) was added 4-fluorothiobenzamide (430.00 mg, 2.77 mmol, 1.00 eq). The mixture was stirred at 60 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (10 ml), filtered, the filter cake was collected and the filtered liquid was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 10: 1, 3: 1) to give 2- (4-fluorophenyl) -5-tosyl 4, 5, 6, 6a tetrahydro-3 aH-pyrrolo [3, 4-d ] thiazole 3a as an off-white solid in alcohol (900.00 mg, 2.49 mmol).

Step 6:

2- (4-fluorophenyl) -5-tosyl-5, 6-dihydro-4H-pyrrolo [3, 4-D ] thiazole

The alcohol of 2- (4-fluorophenyl) -5-tosyl 4, 5, 6, 6a tetrahydro-3 aH-pyrrolo [3, 4-d ] thiazole 3a (900.00 mg, 2.29 mmol, 1.00 equivalent), methanesulfonyl chloride (444.00 mg, 3.88 mmol, 1.69 equivalent) and triethylamine (730.00 mg, 7.21 mmol, 3.15 equivalents) were dissolved in dichloromethane (20.00 ml), the mixture was degassed and protected with nitrogen, and then the mixture was stirred at 20 ℃ for 16 hours. Water (50ml) was added and extracted with dichloromethane (30ml × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate ═ 20: 1 to 1: 1) to give 2- (4-fluorophenyl) -5-tosyl-5, 6-dihydro-4H-pyrrolo [3, 4-D ] thiazole (600.00 mg, 1.11 mmol, 48.28% yield, 69% purity) as a light yellow solid.

And 7:

2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [3, 4-D ] thiazole

To a mixed solution of 2- (4-fluorophenyl) -5-tosyl-5, 6-dihydro-4H-pyrrolo [3, 4-D ] thiazole (550.00mg, 1.01 mmol, 1.00 eq) in water (3.00 ml) and AcOH (15.00 ml) was added a hydrogen bromide acetic acid solution (81.72 mg, 1.01 mmol, 1.00 eq). The mixture was stirred at 20 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure, then diluted with water (50ml), and extracted with ethyl acetate (50 ml). The aqueous layer was basified with NaOH to adjust pH to 11, then extracted with ethyl acetate (40 ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [3, 4-D ] thiazole (145.00 mg, 658.28 μmol, 65.18% yield) as a light yellow solid.

And 8:

(S) -1- (2-chloro-4-nitro-1H-imidazol-1-yl) -3- (2- (4-fluorophenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) -2-methylpropan-2-ol

To a solution of 2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [3, 4-D ] thiazole (160.00 mg, 726.38 micromoles, 1.00 equivalents) was added 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (158.00 mg, 726.07 micromoles, 1.00 equivalents) and diisopropylamine (481.00 mg, 3.72 mmol, 5.12 equivalents). The mixture was stirred at 80 ℃ for 16 hours. Water (50ml) was added and extracted with ethyl acetate (30ml × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by preparative thin layer chromatography (silica, dichloromethane: methanol ═ 20: 1) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -4, 6-dihydropyrrolo [3, 4-d ] thiazol-5-yl ] -2-methyl-propan-2-ol (150.00 mg, 342.56 micromoles, 47.16% yield) as a light yellow solid.

And step 9:

To (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -4, 6-dihydropyrrolo [3, 4-d)]Thiazol-5-yl]-2-methyl-propan-2-ol (150.00 mg, 342.56 micromoles, 1.00 equiv.) in DMF (5.00mL) at 0 deg.C under nitrogen addition sodium hydrogen (30.00 mg, 750.00 micromoles, 2.19 equiv.) the mixture is stirred at 0 deg.C for 1 hour the reaction mixture is poured at 0 deg.C into saturated ammonium chloride solution (40 mL) and then extracted with ethyl acetate (30mL × 2. the combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure and the residue is purified with ethyl acetate to give (2S) -2- [ [2- (4-fluorophenyl) -4, 6-dihydropyrrolo [3, 4-d ]]Thiazol-5-yl]Methyl radical]-2-methyl-6-nitro-3H-imidazo [2, 1b]Oxazole (17.71 mg, 40.90 micromoles, 11.94% yield, 92.71% purity).¹HNMR(400MHz，CDCl₃)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).

Example 70

(S) -2- ((2- (3-fluorophenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (3-fluorophenyl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] e]Azole compound 70(67.10 mg, 165.99 micromoles, 48.46% yield, 99.3% purity).¹H NMR(400MHz，CDCl₃)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)，3.98(d，J＝9.7Hz，1H)，3.40(d，J＝14.8Hz，1H)，3.11(d，J＝14.7Hz，1H)，1.70(s，3H).LCMS(ESI)m/z：402.2(M+1).

Example 71

(S) -2- ((2- (3, 4-difluorophenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2-, 3 dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (3, 4-difluorophenyl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2-, 3 dihydroimidazo [2, 1b ]]Azole compound 71(49.80 mg, 115.42 micromoles, 21.05% yield, 97.2% purity).¹H NMR(400MHz，CDCl₃)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).

Example 72

(S) -2-methyl-6-nitro-2- ((2- (4- (trifluoromethyl) phenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2-methyl-6-nitro-2- ((2- (4- (trifluoromethyl) phenyl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-, 3-dihydroimidazo [2, 1b ] s]Oxazole compound 72(24.30 mg, 52.53 micromole, 17.68% yield, 97.59% purity).¹H NMR(400MHz，CDCl₃)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).

Example 73

(S) -2-methyl-6-nitro-2- ((2- (4- (trifluoromethoxy) phenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2-methyl-6-nitro-2- ((2- (4- (trifluoromethoxy) phenyl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-, 3-dihydroimidazo [2, 1b ] s]Azole compound 73(46.00 mg, 97.82 micromole, 16.43% yield, 9)9.4% 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).

Example 74

(S) -2- ((2- (2-fluorophenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (2-fluorophenyl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] e]Azole compound 74(45.45 mg, 110.14 micromoles, 34.45% yield, 97.271% purity).¹H NMR(400MHz，CDCl₃)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).

Example 75

(S) -2- ((2- (4-fluorophenyl) -5H-pyrrolo [3, 4-d ] thiazol-5-yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

Reacting (2S) -2- [ [2- (4-fluorobenzene)Yl) -4, 6-dihydropyrrolo [3, 4-d]Thiazol-5-yl]Methyl radical]-2-methyl-6-nitro-3H-imidazo [2, 1b]A solution of oxazole (100.00 mg, 249.12 micromoles, 1.00 eq) in ethyl acetate (30.00 ml) was stirred in air at 80 ℃ for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (silica, dichloromethane: methanol 15: 1). Then washed with methanol (5mL) to give (S) -2- ((2- (4-fluorophenyl) -5H-pyrrolo [3, 4-d)]Thiazol-5-yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Azole compound 75(12.30 mg, 30.40 micromolar, 12.20% yield, 98.7% purity).¹H NMR(400MHz，DMSO-d₆)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).

Example 76

(S) -2- ((2- (4-chlorophenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (4-chlorophenyl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] e]Azole compound 76(114.50 mg, 267.79 micromoles, 60.83% yield, 97.729% purity).¹HNMR(400MHz，CDCl₃)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).

Example 77

(S) -2- ((2- (2-chloro-4-fluorophenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (2-chloro-4-fluorophenyl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] e]Azole compound 77(38.00 mg, 85.78 micromoles, 27.01% yield, 98.384% purity).¹H NMR(400MHz，CDCl₃)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).

Example 78

(S) -2- ((2- (2, 4-difluorophenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2-, 3 dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

S) -2- ((2- (2, 4-difluorophenyl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2-, 3 dihydroimidazo [2, 1b ]]Azole compound 78(117.40 mg, 271.83 micromoles, 82.61% yield, 97.107% purity).¹H NMR(400MHz，CDCl₃)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).

Example 79

(S) -2- ((2- (4-fluoro-2-methylphenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (4-fluoro-2-methylphenyl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] e]Azole compound 79(332.10 mg, 786.28 micromoles, 39.12% yield, 98.36% purity).¹HNMR(400MHz，CDCl₃)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).

Example 80

(S) -2- ((2- (4-fluoro-2-methoxyphenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (4-fluoro-2-methoxyphenyl) -4H-pyrrolo [3, 4-d)]Thiazole-5 (6H) -yl)Methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b]Azole compound 80(47.90 mg, 105.87 micromoles, 38.11% yield, 95.36% purity).¹H NMR(400MHz，CHLOROFORM-d)＝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)，3.89(d，J＝9.7Hz，1H)，3.32(d，J＝14.7Hz，1H)，3.02(d，J＝14.8Hz，1H)，1.62(s，3H).LCMS(ESI)m/z：432.1(M+1).

Example 81

(S) -2- ((2- (3, 5-difluoropyridin-2-yl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (3, 5-difluoropyridin-2-yl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] e]Azole compound 81(24.50 mg, 55.89 micromole, 36.48% yield, 95.9% purity).¹H NMR(400MHz，CDCl₃)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).

Example 82

(S) -2- ((2- (5-fluoropyridin-2-yl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (5-Fluoropyridin-2-yl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro 2, 3-dihydroimidazo [2, 1b ] e]Azole compound 82(970.60 mg, 2.37 mmol, 63.61% yield, 98.1% purity).¹H NMR(400MHz，CDCl₃)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).

Example 83

(S) -2-methyl-6-nitro-2- ((2- (2, 4, 5-trifluorophenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2-methyl-6-nitro-2- ((2- (2, 4, 5-trifluorophenyl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2, 3-dihydroimidazo [2, 1b ] s]Azole compound 83(50.80 mg, 114.98 micromoles, 14.54% yield, 99% purity).¹H NMR(400MHz，CDCl₃)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).

Example 84

(S) -2- ((2- (3, 5-difluorophenyl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2-, 3 dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (3, 5-difluorophenyl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2-, 3 dihydroimidazo [2, 1b ]]Azole compound 84(48.70 mg, 115.57 micromoles, 27.67% yield, 99.53% purity).¹H NMR(400MHz，CDCl₃)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)

Example 85

(S) -N- (4-fluorophenyl) -N-methyl-5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] thiazol-2-amine

The synthesis was as in example 69.

(S) -N- (4-fluorophenyl) -N-methyl-5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1 b)]Oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d]Thiazole-2-amine compound 85(27.10 mg, 62.20 micromoles, 14.52% yield, 98.8% purity).¹H NMR(400MHz，CDCl₃)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).

Example 86

(S) -2- ((2- (4, 4-difluoropiperidin-1-yl) -4H-pyrrolo [3, 4-d ] thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (4, 4-Difluoropiperidin-1-yl) -4H-pyrrolo [3, 4-d)]Thiazol-5 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] e]Azole compound 86(9.30 mg, 20.98 micromoles, 13.31% yield, 96.2% purity).¹H NMR(400MHz，CDCl₃)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).

Example 87

(S) -2- ((2- (4-fluorophenyl) -5H-pyrrolo [3, 4-d ] pyrimidin-6 (7H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 44.

(S) -2- ((2- (4-fluorophenyl) -5H-pyrrolo [3, 4-d)]Pyrimidin-6 (7H) -yl) formazan2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] radical]Azole compound 87(14.60 mg, 35.57 micromole, 13.21% yield, 96.567% purity).¹H NMR(400MHz，CDCl₃)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).

Example 88

(S) -2- ((2- (4-fluorophenyl) -5H-pyrrolo [3, 4-b ] pyridin-6 (7H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

Step 1:

pyridine-2, 3-dicarboxylic acid dimethyl ester

Pyridine-2, 3-dicarboxylic acid (20.00 g, 119.67 mmol, 1.00 eq.) was added to a solution of concentrated sulfuric acid (17.61 g, 179.51 mmol, 9.57 ml, 1.50 eq.) in methanol (150.00 ml). The mixture was stirred at 60 ℃ for 10 hours. Sodium carbonate solution was added to adjust the pH to about 9 and extracted with ethyl acetate (200ml × 2). The combined organic layers were concentrated under reduced pressure and the residue was chromatographed on silica gel (SiO2, petroleum ether/ethyl acetate 20/1-3: 1) to give dimethyl pyridine-2, 3-dicarboxylate (20.00 g, 102.47 mmol, 85.63% yield) as a white solid.

Step 2:

1-Pyridin-1-ium-2, 3-dicarboxylic acid dimethyl ester

To a solution of dimethyl pyridine-2, 3-dicarboxylate (20.00 g, 102.47 mmol, 1.00 eq) in chloroform (160.00 ml) was added m-CPBA (28.74 g, 133.21 mmol, 80% purity, 1.30 eq). The mixture was stirred at 60 ℃ for 4 hours. The reaction mixture was added with aqueous sodium bicarbonate (200 ml) and extracted with dichloromethane (500 ml × 4). The combined organic layers were concentrated under reduced pressure, washed with ethyl acetate (50mL), and the filter cake was collected by filtration to give dimethyl 1-pyridin-1-ium-2, 3-dicarboxylate (17.50 g, crude) as a white solid which was used directly in the next step.

And step 3:

6-chloropyridine-2, 3-dicarboxylic acid dimethyl ester

To a solution of dimethyl 1-pyrid-1-oxide-2, 3-dicarboxylate (14.00 g, 66.30 mmol, 1.00 eq) in dioxane (140.00 ml) was added phosphorus oxychloride (50.83 g, 331.50 mmol, 30.81 ml, 5.00 eq). The mixture was stirred at 100 ℃ for 2 hours. The reaction mixture was poured into water (100ml) at 25 ℃, the pH was adjusted to about 9 with sodium carbonate solution, and extracted with ethyl acetate (500 ml × 2). The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 40/1-10: 1) to give dimethyl 6-chloropyridine-2, 3-dicarboxylate (9.50 g, 41.37 mmol, 62.40% yield) as a yellow oil.

And 4, step 4:

6- (4-fluorophenyl) pyridine-2, 3-dicarboxylic acid dimethyl ester

Dimethyl 6-chloropyridine-2, 3-dicarboxylate (5.00 g, 21.78 mmol, 1.00 eq), (4-fluorophenyl) boronic acid (3.96 g, 28.31 mmol, 1.30 eq), Pd (dppf) Cl₂(796.65 mg, 1.09 mmol, 0.05 eq), sodium carbonate (4.62 g, 43.56 mmol, 2.00 eq) was dissolved in dioxane (30.00 ml) and H2O (400.00 μ l), the solution was degassed and replaced with nitrogen, and the mixture was stirred at 80 ℃ for 10 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was separated by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 30/1-10: 1) to give dimethyl 6- (4-fluorophenyl) pyridine-2, 3-dicarboxylate (5.00 g, 17.29 mmol, 79.36% yield) as a white solid. LCMS (ESI) m/z: 290.2(M +1).

And 5:

[6- (4-fluorophenyl) -2- (hydroxymethyl) -3-pyridyl ] methanol

To a solution of dimethyl 6- (4-fluorophenyl) pyridine-2, 3-dicarboxylate (5.00 g, 17.29 mmol, 1.00 eq) in methanol (100.00 ml) was added calcium chloride (2.30 g, 20.75 mmol, 1.20 eq) and sodium borohydride (6.54 g, 172.90 mmol, 10.00 eq). The mixture was stirred at 15 ℃ for 3 hours. The reaction mixture was extracted with ethyl acetate (1L. times.2). The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 20/1-3: 1) to give [6- (4-fluorophenyl) -2- (hydroxymethyl) -3-pyridyl ] methanol (3.50 g, 15.01 mmol, 86.79% yield) as a white solid.

Step 6:

2, 3-bis (chloromethyl) -6- (4-fluorophenyl) pyridine

To a solution of [6- (4-fluorophenyl) -2- (hydroxymethyl) -3-pyridyl ] methanol (1.50 g, 6.43 mmol, 1.00 eq) in D dichloromethane (20.00 ml) was added thionyl chloride (19.68 g, 165.42 mmol, 12.00 ml, 25.73 eq). The mixture was stirred at 0 ℃ for 0.5 h. The reaction mixture was concentrated under reduced pressure to remove the solvent to give 2, 3-bis (chloromethyl) -6- (4-fluorophenyl) pyridine (2.00 g, crude) as a yellow oil. LCMS (ESI) m/z: 270.1(M +1).

And 7:

2- (4-fluorophenyl) -6-trityl-5, 7-dihydropyrrolo [3, 4-b ] pyridine

To a solution of 2, 3-bis (chloromethyl) -6- (4-fluorophenyl) pyridine (2.00 g, 7.40 mmol, 1.00 eq) in DMF (60.00 ml) were added diisopropylamine (2.87 g, 22.20 mmol, 3.88 ml, 3.00 eq) and tritylamine (2.88 g, 11.10 mmol, 1.50 eq.) the mixture was stirred at 80 ℃ for 20 h, the reaction mixture was concentrated under reduced pressure to remove the solvent, the residue was extracted with ethyl acetate (200ml × 2), the combined organic layers were concentrated under reduced pressure, the residue was purified by silica gel chromatography (SiO2, petroleum ether/ethyl acetate 1/0-50: 1) to give 2- (4-fluorophenyl) -6-trityl-5, 7-dihydropyrrolo [3, 4-b ] -]Pyridine (1.50 g, crude) as a white solid.¹H NMR(400MHz，CDCl₃)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).

And 8:

2- (4-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b ] pyridine; 2, 2, 2-trifluoroacetic acid

To a solution of 2- (4-fluorophenyl) -6-trityl-5, 7-dihydropyrrolo [3, 4-b ] pyridine (1.50 g, 3.29 mmol, 1.00 eq) in methanol (7.00 ml) and chloroform (7.00 ml) was added trifluoroacetic acid (10.78 g, 94.54 mmol, 7.00 ml, 28.74 eq). The mixture was stirred at 0 ℃ for 0.5 h, the reaction mixture was washed with water (150 ml. times.2). Concentrating the combined aqueous phases under reduced pressure to obtain 2- (4-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b ] pyridine; 2, 2, 2-trifluoroacetic acid (1.00 g, crude) as a yellow solid. LCMS (ESI) m/z: 215.2(M +1).

And step 9:

(2S) -1- (2-bromo-4-nitro-imidazol-1-yl) -3- [2- (4-fluorophenyl) -5, 7-dihydropyrrolo [3, 4-b] Pyridin-6-yl]-2-methyl-propan-2-ol

To 2- (4-fluorophenyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b ] pyridine; to tert-butanol (50.00 ml) in 2, 2, 2-trifluoroacetic acid (1.00 g, 3.05 mmol, 1.00 eq) were added diisopropylamine (1.18 g, 9.14 mmol, 1.60 ml, 3.00 eq) and 2-bromo-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (1.20 g, 4.58 mmol, 1.50 eq). The mixture was stirred at 40 ℃ for 10 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent and the residue was purified by column silica gel chromatography (SiO2, petroleum ether/ethyl acetate 10/1-3: 1) to give (2S) -1- (2-bromo-4-nitro-imidazol-1-yl) -3- [2- (4-fluorophenyl) -5, 7-dihydropyrolo [3, 4-b ] pyridin-6-yl ] -2-methyl-propan-2-ol (700.00 mg, crude) as a brown oil. LCMS (ESI) m/z: 476.0(M +1).

Step 10:

(S) -2- ((2- (4-fluorophenyl) -5H-pyrrolo [3, 4-b)]Pyridin-6 (7H) -yl) methyl) -2-methyl-6-nitro Radical-2, 3-dihydroimidazo [2, 1b]Azole

To (2S) -1- (2-bromo-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -5, 7-dihydropyrrolo [3, 4-b)]Pyridin-6-yl]To a solution of-2-methyl-propan-2-ol (700.00 mg, 1.47 mmol, 1.00 eq) in DMF (4.00 ml) was added sodium hydrogen (70.54 mg, 2.94 mmol, 2.00 eq). The mixture was stirred at 0 ℃ for 10 minutes. The reaction mixture was added to a saturated aqueous solution of ammonium chloride (200 ml) at 0 ℃, filtered and the filter cake was dried and purified by preparative thin layer chromatography (silica, DCM: methanol ═ 15: 1) to give (S) -2- ((2- (4-fluorophenyl) -5H-pyrrolo [3, 4-b)]Pyridin-6- (7H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Azole compound 88(243.60 mg, 600.70 micromoles, 40.86% yield, 97.5% purity).¹H NMR(400MHz，CDCl₃)7.97-7.89(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).

Example 89

(S) -2- (4-fluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole

Step 1:

6-oxa-3-azabicyclo [3.1.0]Hexane-3-Carboxylic acid benzyl ester

To a mixed solution of benzyl 3-bromo-4-hydroxy-pyrrolidine-1-carboxylate (7.50 g, 24.99 mmol, 1.00 equiv) in methanol (50.00 ml) and water (50.00 ml) was added sodium hydroxide (1.50 g, 37.49 mmol, 1.50 equiv.) the mixture was stirred at 20 ℃ for 12 hours, water (200 ml) was added to the mixture, followed by extraction with ethyl acetate (200ml × 3). the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-oxa-3-azabicyclo [ 3.1.0.]Hexane-3-carboxylic acid benzyl ester (350.00 mg, 1.60 mmol, 95.81% yield) as a yellowish oil.¹HNMR(300MHz，CDCl₃)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-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester

Benzyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate (5.40 g, 24.63 mmol, 1.00 eq.) and ammonia (43.17 g, 1.23 mol, 47.43 ml, 50.00 eq.) were mixed and the mixture was stirred at 100 ℃ for 16 h. The mixture was concentrated under reduced pressure to give benzyl 3-amino-4-hydroxy-pyrrolidine-1-carboxylate (5.00 g, 21.16 mmol, 85.92% yield) as a yellowish oil.

And step 3:

3- [ (4-fluorobenzoyl) amino ] -4-hydroxy-pyrrolidine-1-carboxylic acid benzyl ester

To a solution of benzyl 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (4.50 g, 19.05 mmol, 1.00 eq) and 4-fluorobenzoic acid (2.67 g, 19.05 mmol, 1.00 eq) in dichloromethane (50.00 ml) were added HOBt (2.57 g, 19.05 mmol, 1.00 eq), EDCI (7.30 g, 38.10 mmol, 2.00 eq) and triethylamine (5.78 g, 57.15 mmol, 7.92 ml, 3.00 eq). the mixture was stirred at 20 ℃ for 12 hours, water (200 ml) was added to the reaction mixture and extracted with dichloromethane (150 ml, ×). the combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel (column height: 300 mm, diameter 50 mm, 100mm, 200 mesh silica gel, petroleum ether/ethyl acetate ═ 36 2/1, 0/1- [ (363-366335) chromatography to give amino-fluorobenzoic acid tert-butyl ester]-4-hydroxy-pyrrolidine-1-carboxylic acid benzyl (2.78 g, 7.76 mmol, 40.73% yield) and 3- [ (4-fluorobenzoyl) amino]Benzyl-4- (4-fluorobenzoyl) oxy-pyrrolidine-1-carboxylate (2.20 g, 4.58 mmol, 24.04% yield) was small yellow (2.20 g, 4.58 mmol, 24.04% yield) as a light yellow solid.¹H NMR(400MHz，DMSO-d₆)8.52(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).

And 4, step 4:

3- [ (4-fluorobenzoyl) amino]-4-oxo-pyrrolidine-1-Carboxy radicalAcid benzyl ester

To 3- [ (4-fluorobenzoyl) amino]Benzyl-4-hydroxy-pyrrolidine-1-carboxylate (4.20 g, 11.72 mmol, 1.00 eq) in DCM (3.00 ml) was added dessimutant reagent (9.94 g, 23.44 mmol, 7.26 ml, 2.00 eq) at 0 ℃. The mixture was stirred at 20 ℃ for 2 hours. To the reaction mixtureTo the mixture was added sodium sulfite solution (100mL) and sodium bicarbonate solution (100mL), extracted with dichloromethane (200mL × 3), and the combined organic layers were washed with saturated brine (200mL × 1), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3- [ (4-fluorobenzoyl) amino group]-4-oxo-pyrrolidine-1-carboxylic acid benzyl ester (4.00 g, 11.22 mmol, 95.78% yield) as a yellowish oil.¹H NMR(400 MHz，DMSO)9.15(d，J＝6.52 Hz，1H)，7.92(dd，J＝8.47，5.58Hz，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).

And 5:

2- (4-fluorophenyl) -4, 6-dihydropyrrolo [3, 4-d ] oxazole-5-carboxylic acid benzyl ester

To benzyl 3- [ (4-fluorobenzoyl) amino]-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4.00 g, 11.22 mmol, 1.00 eq) to dioxane (5.00ml) was added phosphorus oxychloride (9.62 g, 62.74 mmol, 5.83 ml, 5.59 eq). The mixture was stirred at 100 ℃ for 4 hours. After cooling the mixture was added slowly to H2O (200 mL), filtered and the filter cake was washed with dichloromethane (50mL) and the filter cake was collected to give benzyl 2- (4-fluorophenyl) -4, 6-dihydropyrrolo [3, 4-d ] oxazole-5-carboxylate (1.50 g, 4.43 mmol, 39.48% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d)₆)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-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole

Benzyl 2- (4-fluorophenyl) -4, 6-dihydropyrrolo [3, 4-d ] oxazole-5-carboxylate (1.50 g, 4.43 mmol, 1.00 eq) was dissolved in acetic acid hydrobromide (7.17 g, 88.60 mmol, 4.81 ml, 20.00 eq) and stirred at 20 ℃ under nitrogen for 1 hour. The mixture was concentrated under reduced pressure, dichloromethane (20 ml) and ethyl acetate (20 ml) were added, filtered and the filter cake was dried under vacuum to give2-(4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole (1.00 g, 3.51 mmol, 79.17% yield, hydrobromide) as a black solid.¹H NMR(300 MHz，DMSO)8.07-7.89(m，2H)，7.48-7.27(m，2H)，4.58-4.23(m，4H)

And 7:

(2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -4, 6-dihydropyrrolo [3, 4-d ] oxazol-5-yl ] -2-methyl-propan-2-ol

To a solution of 2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole (1.00 g, 3.51 mmol, 1.00eq, hydrobromide) and 2-chloro-1- [ [ (2R) -2-methyloxiran-2-yl ] methyl ] -4-nitroimidazole (916.57 mg, 4.21 mmol, 1.20 eq) in tert-butanol (20.00 ml) was added diisopropylamine (906.60 mg, 7.01 mmol, 1.23 ml, 2.00 eq) and the mixture was stirred at 80 ℃ for 12H. To the reaction mixture was added water (50ml), followed by extraction with ethyl acetate (100 ml. times.3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (column height: 300 mm, diameter 50 mm, 100-mesh 200-mesh silica gel, petroleum ether/ethyl acetate 5/1, 3/1, 1/1) to give (2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -4, 6-dihydropyrrolo [3, 4-d ] oxazol-5-yl ] -2-methyl-propan-2-ol (700.00 mg, 1.66 mmol, 47.28% yield) as a yellow solid. LCMS (ESI) m/z: 422.1(M +1).

And 8:

(S) -2- (4-fluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d) oxazole

To ((2S) -1- (2-chloro-4-nitroimidazol-1-yl) -3- [2- (4-fluorophenyl) -4, 6-dihydropyrrolo [3, 4-d)]Oxazol-5-yl]To a solution of-2-methyl-propan-2-ol (700.00 mg, 1.66 mmol, 1.00 eq) in DMF (5.00ml) was added sodium hydrogen (132.76 mg, 3.32 mmol, 60% purity, 2.00 eq) at-45 ℃. The mixture was stirred at-45 ℃ for 30 minutes, then at 0 ℃ for 30 minutes. The reaction mixture was added to a saturated ammonium chloride solution (150 mL), the mixture was then filtered, and the filter cake was purified by preparative separation chromatography (GX-A; Phenomenex Gemini 150 x 25mm x 10 um; acetonitrile 40% -70%; water (0.05% ammonia hydroxide v/v); 25mL/min) to give (S) -2- (4-fluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ])]Oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d) oxazole compound 89(46.00 mg, 117.70 micromole, 7.09% yield, 98.6% purity).¹H NMR(400MHz，CDCl₃)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).

Example 90

(S) -2- (3, 4-difluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole

The synthesis was as in example 89.

(S) -2- (3, 4-difluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1 b)]Oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole compound 90(24.80 mg, 59.27 micromole, 35.88% yield, 96.4% purity).¹H NMR(400MHz，CDCl₃)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).

Example 91

(S) -2- (2, 4-difluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole

The synthesis was as in example 89.

(S) -2- (2, 4-difluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1 b)]Oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole compound 91(31.30 mg, 75.82 micromole, 24.48% yield, 97.7% purity).¹HNMR(400MHz，CDCl₃)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).

Example 92

(S) -2- (3, 5-Difluoropyridin-2-yl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole

The synthesis was as in example 89.

(S) -2- (3, 5-Difluoropyridin-2-yl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1 b)]Oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole compound 92(125.10 mg, 305.38 micromole, 51.10% yield, 98.7% purity).¹H NMR(400MHz，CDCl₃)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).

Example 93

(S) -2- (5-Fluoropyridin-2-yl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole

The synthesis was as in example 89.

(S) -2- (3, 5-Difluoropyridin-2-yl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1 b)]Oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole compound 93(175.46 mg, 445.96 micromole, 52.09% yield, 98.194% purity).¹H NMR(400MHz，CDCl₃)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).

Example 94

(S) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -2- (2, 4, 5-trifluorophenyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole

The synthesis was as in example 89.

(S) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1 b)]Oxazol-2-yl) methyl) -2- (2, 4, 5-trifluorophenyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole compound 94(491.75 mg, 1.14 mmol, 57.13% yield, 97.416% purity).¹H NMR(400MHz，CDCl₃)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).

Example 95

(S) -2- (3, 5-difluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole

The synthesis was as in example 89.

(S) -2- (3, 5-difluorophenyl) -5- ((2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1 b)]Oxazol-2-yl) methyl) -5, 6-dihydro-4H-pyrrolo [3, 4-d ] oxazole Compound 95(21.60 mg, 53.29. mu. mol, 10.32% yield, 99.5% purity).¹H NMR(400MHz，CDCl₃)7.56(s，1H)，7.54-7.48(m，2H)，6.95-6.83(m，1H)，4.43(s，1H)，4.15-3.88(m，5H)，3.41(s，1H)，3.10(d，J＝14.8Hz，1H)，1.71(s，3H).LCMS(ESI)m/z：404.2(M+1).

Example 96

(S) -2- ((2- (4-fluorophenyl) -8, 9-dihydro-5H-pyrido [3, 2-c ] azepin-6 (7H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 7.

(S) -2- ((2- (4-fluorophenyl) -8, 9-dihydro-5H-pyrido [3, 2-c)]Aza-6 (7H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Azole compound 96(85.50 mg, 196.26 micromoles, 36.10% yield, 97.2% purity).¹H NMR(400MHz，CDCl₃)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).

Example 97

(S) -2- ((2- (4-fluorophenyl) -8, 9-dihydro-5H-pyrido [2, 3-d ] azepin-7 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 7.

(S) -2- ((2- (4-fluorophenyl) -8, 9-dihydro-5H-pyrido [2, 3-d)]Aza-7 (6H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Azole compound 97(23.80 mg, 50.02 micromole, 9.20% yield, 89% purity).¹H NMR(400MHz，CDCl₃)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).

Example 98

(2S) -2- ((2- (4-fluorophenyl) -6, 7, 8, 9-tetrahydro-5H- -5, 8-epiminoclohepta [ b ]]Pyridine- 10-yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Azole

The synthesis was as in example 7.

(2S) -2- ((2- (4-fluorophenyl) -6, 7, 8, 9-tetrahydro-5H-5, 8-epizochytripta [ b ]]Pyridin-10-yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Azole compound 98A (30.26 mg, 69.49 micromoles, 32.79% yield, 100% purity).¹H NMR(400MHz，CDCl₃)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-fluorophenyl) -6, 7, 8, 9-tetrahydro-5H-5, 8-epizochytripta [ b ]]Pyridin-10-yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Azole Compound 98B (41.29 mg)94.82 micromoles, 44.75% yield, 100% purity).¹H NMR(400MHz，CDCl₃)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).

Example 99

(2S) -2- ((2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydro-4H-5, 8-epizochytohepta [ d ] thiazol-9-yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(2S) -2- ((2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydro-4H-5, 8-epizochytripta [ d ]]Thiazol-9-yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Azole compound 99A (3.70 mg, 8.26 micromole, 2.47% yield, 98.594% purity).¹H NMR(400MHz，CDCl₃)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), s/z: 442(M +1). (2S) -2- ((2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydro-4H-5, 8-epinocyclohexepta [ d)]Thiazol-9-yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Azole compound 99B (3.70 mg, 8.33 micromole, 2.49% yield, 99.431% purity).¹H NMR(400MHz，CDCl₃)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).

Example 100

(S) -2- ((2- (4-fluorophenyl) -7, 8-dihydro-4H-thiazolo [4, 5-d ] azepin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b ] oxazole

The synthesis was as in example 69.

(S) -2- ((2- (4-fluorophenyl) -7, 8-dihydro-4H-thiazolo [4, 5-d)]Azepin-6 (5H) -yl) methyl) -2-methyl-6-nitro-2, 3-dihydroimidazo [2, 1b]Azole compound 100(35.30 mg, 77.62 micromoles, 10.33% yield, 94.431% purity).¹H NMR(400MHz，CDCl₃)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)，3.07-2.86(m，6H)，2.82(d，J＝16.0Hz，2H)，2.76-2.66(m，1H)，1.67(s，3H).LCMS(ESI)m/z：430(M+1).

Pharmacological moieties

A first part: in vitro efficacy of anti-mycobacterium tuberculosis compounds using strain H37Rv

On the day of testing, the compound was dissolved in pure DMSO (Sigma 276855-2L) to a concentration of 10mg/ml as compound stock. Mu.l DMSO was added to the wells from column 2to column 11 of a v-bottom 96 well plate (Axygen-wipp 02280). Adding 30 μ l of compound mother liquor into the 2 nd row of holes, mixing uniformly, taking 30 μ l from the 2 nd row of holes, adding into the 3 rd row of holes, and blowing, beating and mixing uniformly. Thereby operating on column 10. Column 11 contains no drug, 30. mu.l DMSO only. This is the compound "master". From column 2to column 11, the corresponding compound concentrations were 5, 2.5, 1.25, 0.625, 0.3125, 0.156, 0.078, 0.039, 0.02, 0 mg/ml. For compounds with good efficacy, the test concentration was appropriately reduced. Flat-bottomed 96-well plates (Greiner 655090) were used as "daughter plates". 98 μ l of 7H9(Sigma M0178) medium was added to the wells of all the daughter plates. 2 μ l of compound was pipetted from the master plate into the daughter plate at the corresponding position. Daughter plate A and H rows, columns 1 and 12 contained only 7H9 medium.

The H37Rv strain in the glycerol vial was inoculated into 7H9 medium containing 0.05% Tween 80 and cultured at 37 ℃ for 4 weeks on a shaker at 200 rpm. The broth was washed twice with 7H9 medium containing 0.05% tween 80 and resuspended in the same medium. The absorbance of the bacterial solution was adjusted to OD using the same medium₅₅₀0.4-0.5. The bacterial solution was dispensed into a microcentrifuge tube and stored at-80 ℃. The storage time is not more than 1 month. On the day of testing, the dispensed bacterial solution was thawed. The thawed bacteria solution was diluted 20-fold with 7H9 medium and then 50-fold and 1000-fold, and was used to inoculate daughter plates. Mu.l of the inoculum was inoculated into each well of the daughter plate, and 100. mu.l of 7H9 medium was added to column 12 without the inoculum.

The test daughter plates were incubated in an incubator at 37 ℃ with humidity maintained at > 80%. Starting after one week, 12.5. mu.l of 7H9 medium containing 20% Tween 80 and 20. mu.l of Alamar blue (Invitrogen DAL1100) were added to one row of wells 1 containing bacteria and one row of wells 12 containing no bacteria daily and observed after further culturing for 24 hours. When the added Alamar blue was reduced to pink within 24 hours by the inoculum from the well in column 1, the fluorescence was measured after adding 7H9 medium containing 20% Tween 80 and Alamar blue to all wells on the test plate and incubating for a further 24 hours at 37 ℃.

The Minimum Inhibitory Concentration (MIC) was defined as: the minimum drug concentration that completely inhibits Alamar blue discoloration by visual observation or that inhibits more than 90% of reduced Alamar blue production as measured by fluorometry. The results of the partial compound assay are shown in Table 1.

A second part: method for testing in vitro efficacy of anti-mycobacterium tuberculosis compounds using mycobacterium bovis bcg strain TMC1019(ATCC35737) on the day of testing, the dissolved compounds were dissolved in pure DMSO (Sigma 276855-2L) to a concentration of 12.8mg/ml as compound stock solutions. Mu.l DMSO was added to the wells of column 1 to column 12 of a v-bottom 96 well plate (Axygen-wipp 02280). Add 30. mu.l of compound stock to well in column 1. Add 30. mu.l from well 1 to well 2 and blow and mix well. This operation was followed by 2-fold gradient dilution to column 11. Column 12 contained 30. mu.l DMSO without compound. Only 30. mu.l DMSO was added to wells in all rows A and H. This is the compound "master". From column 1 to column 12, the corresponding compound concentrations were 6.4, 3.2, 1.6, 0.8, 0.4, 0.2, 0.1, 0.05, 0.025, 0.0125, 0.00625 and 0 mg/ml. For compounds with good efficacy, the test concentration was appropriately reduced. Flat-bottomed 96-well plates (Greiner 655090) were used as "daughter plates". 98 μ l of 7H9(Sigma M0178) medium was added to the wells of all the daughter plates. 2. mu.l of the compound solution was pipetted from the master plate into the daughter plate at the corresponding position. Daughter boards a and H rows and column 12 contained only 7H9 medium and the corresponding concentration of DMSO.

The BCG strain in glycerol frozen tube was inoculated in 7H9 liquid medium containing 0.05% Tween 80 and cultured in a shaker at 37 ℃ and 200 rpm for 4 weeks. The broth was washed twice with 7H9 medium containing 0.05% tween 80 and resuspended in the same medium. The absorbance of the bacterial suspension was adjusted to 0.4 to 0.5 by using the same medium. The bacterial solution was dispensed into a microcentrifuge tube and stored at-80 ℃. The storage time is not more than 1 month. On the day of testing, the dispensed bacterial solution was thawed. The thawed bacterial suspension was diluted 20-fold with 7H9 medium and then 50-fold, and a total dilution of 1000-fold, and was used for inoculation. 100 μ l of the inoculum was inoculated into each well on the daughter plate except row A. Only 100. mu.l of 7H9 medium was added to the wells in row A, and no bacterial solution was added. The final concentrations tested for the drugs were 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625 and 0 μ g/ml. The test daughter plates were incubated in an incubator at 37 ℃ with humidity maintained at > 80%.

Starting after one week, 12.5. mu.l of 7H9 medium containing 20% Tween 80 and 20. mu.l of Alamar blue (Invitrogen DAL1100) were added daily to one row A well without bacteria and one row H well with bacteria and observed after further incubation for 24 hours. When the added Alamar blue can be reduced to pink color within 24 hours by the bacterial liquid in the H-row holes, the Alamar blue is added into all the holes on the test plate, and the Minimum Inhibitory Concentration (MIC) is observed after the culture is continued for 24 hours at 37 ℃.

The Minimum Inhibitory Concentration (MIC) is defined as the minimum final concentration of drug that completely inhibits Alamar blue discoloration by visual observation or that inhibits more than 90% of reduced Alamar blue production as measured by fluorimetry. The results of the partial compound assay are shown in Table 1.

Table 1: partial invention molecules have in vitro activity against mycobacterium bovis bcg strain and mycobacterium tuberculosis H37Rv strain.

+++：＜1；++：1～32；+：＞32

Experimental results show that the related compound has good inhibitory activity to both mycobacterium bovis BCG strains and mycobacterium tuberculosis H37Rv strains, the minimum inhibitory concentration of all molecules is less than 1ug/mL basically, and the compound has no cytotoxicity.

And a third part: kinetic solubility and MDR1-MDCK cell two-way permeability assessment experiment. The results are shown in Table 2.

1. Kinetic solubility test: samples of the weighed compounds were dissolved in pure DMSO at a final concentration of 10mM. the test compounds and control compounds (10mM DMSO stock, 10uL per well) were added to 96-well plates containing 490uL buffer per well. After vortexing for 2 minutes, the sample plates were incubated for 24 hours at room temperature (22. + -. 2 ℃) on a shaker. Then transfer 200uL sample to MultiScreen filter plate (polycarbonate membrane), filter with microporous vacuum manifold (millipore vacuum manifold) and collect the filtrate. The concentration of the compound in the filtrate was determined by HPLC-UV. The sample introduction was performed sequentially for 3 UV standard solutions of different concentrations and the solubility test samples. Each sample was inserted 2 times, and the concentration was calculated by introducing standard curve and averaging.

MDR1-MDCK cell bidirectional permeability assessment experiment: MDR1-MDCK cells permanently expressing human P-glycoprotein (P-glycoprotein) are planted on a 96-hole Insert cell plate, and after being cultured for 4-7 days, a converged monolayer of cells are formed; the quality of the monolayer was verified by evaluating the one-way (a → B) permeability of fenoterol (low permeability marker) and propranolol (high permeability marker), and the two-way permeability of Digoxin (a P-glycoprotein substrate). The three control compounds were duplicate.

The standard conditions for the test compound transport experiments are as follows:

-test concentration: 2 mu M (DMSO is less than or equal to 1%);

-repeating: n is 3;

-direction: : bidirectional transport, including both A → B and B → A directions;

-incubation time: single time point, 2.5 hours;

-a transport buffer: HBSS, pH7.4;

-incubation conditions: 37 ℃ and 5% CO₂95% relative humidity.

After the incubation was complete, the sample solutions in the dosing wells (donor wells) and the receiving wells (receiver wells) were immediately mixed with a cold acetonitrile solution containing the internal standard. The amount of accumulation of the compound within the cells was measured by lysing the cells with a cold acetonitrile solution containing an internal standard. The concentration of the test compound in all samples (including initial liquid administration, supernatant from administration well, receiver, cell lysate) was analyzed by LC/MS/MS method. The concentration of the test compound is expressed as the ratio of its peak area to the peak area of the internal standard. Table 2 lists the in vitro Kinetic Solubility (KS) of candidate compounds and permeability data in MDR1-MDCK monolayers.

Table 2: partial invention molecular kinetic solubility and MDR1-MDCK cell bidirectional permeability results

Obviously, the four candidate compounds are superior to OPC-67683 in dynamic solubility, and the good solubility is beneficial to the absorption of the medicine in vivo and the research of the preparation; similarly, through the permeability parameters, the optimized molecules are high-permeability membrane molecules, and compared with a reference compound (OPC-67683), the advantages are obvious, the good permeability further promotes the absorption of the medicine, and the good effect of resisting the mycobacterium tuberculosis is achieved.

The fourth part: pharmacokinetics in vivo

Rodent pharmacokinetic profiles following intravenous and oral administration of compounds were tested in standard protocols. Specifically, the candidate compound was administered intravenously and orally to CD-1 male mice 7 to 10 weeks old in the experiment. The oral preparation is a suspension prepared from 0.5% of methyl fiber; the intravenous injection is a clear solution prepared from ethanol/DMSO/polyethylene glycol 400/purified water (10: 50: 30). Plasma and lung samples were collected and analyzed by LC-MS/MS,

and calculating the pharmacokinetic parameters. The pharmacokinetic parameters for candidate compound 7 are shown in table 3. Table 3: in vivo pharmacokinetic parameters

It is clear that the newly discovered pharmaceutical parameters of compound 7 are all superior to the reference compound (OPC-67683), and it is noted that the pulmonary drug concentration of 7 is much higher than the reference compound (OPC-67683) 1 hour after administration, which is more than 9 times higher than the reference compound. For patients with pulmonary tuberculosis infection, it is important that higher drug exposure means better efficacy.

Through activity tests of the H37Rv strain, the molecules related to the invention are found to have better in-vitro drug effect of the mycobacterium tuberculosis resistant compound, and structurally, the molecules have basic nitrogen atoms and can form salts, which is beneficial to improving the solubility of the molecules, so that research on preparations is easier to develop, and experimental data of the solubility also testifies our hypothesis. Permeability tests show that most of the molecules found by the inventor are high-permeability membrane molecules, and the molecules are favorable for distribution and absorption in vivo, so that better curative effect is hopefully achieved. Further validation of in vivo pharmacokinetic data was carried out, with compound 7, which incorporates good solubility, high permeability, and excellent lung exposure. In view of these data collected, we have reason to believe that these molecules will exhibit better potency than the reference compound (OPC-67683), thus benefiting a wide range of patients.

Claims

1. A compound shown in a formula (I), pharmaceutically acceptable salt thereof or an optical isomer thereof,

wherein,

ring A is a 5-to 6-membered aryl or heteroaryl group;

x is selected from N, C (R) or C;

r is selected from hydrogen, halogen, hydroxyl, cyano, nitro or selected from optional substituted groupSubstituted with the following groups: amino group, C_1-6Alkylamino, N-di (C)_1-6Alkyl) amino, C_1-6Alkyl radical, C_1-6Heteroalkyl group, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl, 5-to 7-membered aryl, 5-to 7-membered heteroaryl;

z is selected from methylene optionally substituted with 1 or 2R;

optionally, a structural unitCan be replaced by

R₂Or may be a void;

m is selected from 1, 2 or 3;

n is selected from 0, 1, 2 or 3;

2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein the substituents and R are each independently selected from the group consisting of:

H、F、Cl、Br、I、OH、CN、NH₂、C_1-4alkyl radical, C_1-4Heteroalkyl group, wherein_1-4Alkyl or C_1-4The heteroalkyl group may optionally be further substituted with 0-3 halogens, OH and/or NH₂Substituted;

preferably, the substituents are selected from: F. cl, Br, I, CN, -CF₃、-OCF₃、-CH₂CF₃、OCH₃、(CH₃)₃COC(＝O)-。

3. The compound, a pharmaceutically acceptable salt thereof, or an optical isomer thereof according to claim 1 or 2, wherein R₁And R₂Each independently selected from hydrogen, halogen, cyano, or from optionally substituted:

preferably, R₁And R₂Each independently selected from hydrogen, halogen, cyano, or from optionally substituted:

more preferably, R₁And R₂Each independently selected from:

4. the compound, a pharmaceutically acceptable salt thereof, or an optical isomer thereof according to claim 1 or 2, wherein R is selected from H, Cl, Br, I, OH, CN, NH₂、Me、Et。

5. The compound of claim 1 or 2, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein ring a is selected from the group consisting of pyridyl, thiazolyl, oxazolyl, imidazolyl, pyrimidinyl;

preferably, ring a is selected from:

preferably, the structureSelected from:

6. the compound, a pharmaceutically acceptable salt thereof, or an optical isomer thereof according to claim 1 or 2, wherein the structural unitSelected from:

7. the compound, a pharmaceutically acceptable salt thereof, or an optical isomer thereof according to claim 1 or 2, wherein the structural unitSelected from:

8. the compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or an optical isomer thereof, selected from the group consisting of:

9. a pharmaceutical composition comprising an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, an optical isomer, or a pharmaceutically acceptable carrier thereof, as claimed in any one of claims 1-8.

10. Use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or an optical isomer thereof according to any of claims 1-8, or a composition according to claim 9, for the manufacture of a medicament for the treatment and prevention of mycobacterium tuberculosis or other microbial infections.