CN113214288A - Benzo [1,3] oxazine-oxazolidinone compound and preparation method and application thereof - Google Patents

Benzo [1,3] oxazine-oxazolidinone compound and preparation method and application thereof Download PDF

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CN113214288A
CN113214288A CN202010080053.4A CN202010080053A CN113214288A CN 113214288 A CN113214288 A CN 113214288A CN 202010080053 A CN202010080053 A CN 202010080053A CN 113214288 A CN113214288 A CN 113214288A
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CN113214288B (en
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黄海洪
张东峰
吴永奇
鲁海嘉
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention discloses benzo [1,3]]An oxazine-oxazolidinone compound, a preparation method and application thereof, belonging to the technical field of medicine. In particular to the application in preparing the medicine for treating and/or preventing infectious diseases, in particular to the application in infectious diseases caused by gram-positive bacteria, mycobacterium tuberculosis and the like. In particular to a compound shown as a formula (I), a stereoisomer thereof, pharmaceutically acceptable salts thereof and a medicament containing the compoundCompositions, methods of use, and methods of making these compounds, wherein X1、X2、R1、R2、R3As described in the specification.

Description

Benzo [1,3] oxazine-oxazolidinone compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines. In particular to a benzo [1,3] oxazine-oxazolidinone compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition taking the compound as an active ingredient, and applications of the compound and the pharmaceutical composition in treating and/or preventing infectious diseases, particularly infectious diseases caused by gram-positive bacteria, mycobacterium tuberculosis and the like.
Background
Bacterial resistance is exacerbated by the long-term use of antibiotics in the clinic, which causes bacterial mutation and resistance, and their inappropriate use in medical and agricultural production. The World Health organization published a list of 12 bacteria or bacterial families that most require antibiotics in 2017 (World Health organization. WHO publications list of bacteria for the World new antibiotics are used for the purpose of new genetic new. geneva: WHO,2017.), and drug-resistant bacterial infections have become a significant problem threatening human Health. Therefore, the search for antibacterial agents having new structures and new mechanisms is urgent.
Oxazolidinone antibacterial agents exert antibacterial action by inhibiting bacterial protein synthesis, and their mechanism of action is different from that of conventional antibiotics, so that cross-resistance rarely occurs. Linezolid, the first drug to be marketed in 2000, is used for the treatment of multidrug resistance G+Bacteria causing infections, which have also been shown to have anti-mycobacterium tuberculosis activity (j. antipicrob. chemither., 2009,64,388-391) and are used in the form of off-label for the treatment of drug-resistant tuberculosis. Tedizolid was marketed in 2014 for the treatment of acute skin infections (eur.j.med.chem.,2011,46, 1027-. However, the long-term use of the medicines can inhibit the synthesis of mitochondrial protein and generate bone marrow toxicity; has an inhibitory effect on monoamine oxidase, resulting in neurotoxicity (Expert Review of Anti-inflammatory Therapy,2016,14, 901-915). Meanwhile, the compounds have short half-life and quick in-vivo clearance, so that the dosage of the compounds is large, and the problems limit the clinical application of oxazolidinone antibacterial drugs. Therefore, there is a need to develop novel antibacterial agents with stronger activity.
Disclosure of Invention
The invention aims to solve the technical problem of providing a benzo [1,3] oxazine-oxazolidinone compound which has a novel structure, low toxicity and strong activity, and particularly has strong inhibitory activity on gram-positive bacteria and mycobacterium tuberculosis.
Therefore, the invention provides a compound shown in a general formula (I) and an isomer thereof, or a pharmaceutically acceptable salt thereof in a first aspect,
Figure BDA0002379968460000021
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
R1is-NHR4、-NHCOR4、-NHCSR4、-NHSO2R4、-NHCOOR4、-NHCSOR4、-NHCONHR4、-NHCSNHR4；
R4Independently selected from H, substituted or unsubstituted straight or branched C1-C4Alkyl, substituted or unsubstituted 3-6 membered cycloalkyl;
the R is4Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
R2、R3independently selected from H, F, Cl, Br, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-8 membered non-aromatic heterocyclyl;
R2、R3the 5-6 membered heteroaryl or 5-8 membered non-aromatic heterocyclyl group of (a) contains at least one heteroatom selected from N, O, S;
R2、R3the substituted or unsubstituted substituents described in (1) may optionally be selected from the following groups: F. cl, Br, -OH, ═ O, -NO2、-CN、-NH2、-CF3、-OR5、COR5、-NHCOR5、-CONR5R6、-COOR5Wherein R is5And R6Each independently is a straight or branched chain C1-C6An alkyl group;
or R2、R3The substituted or unsubstituted substituents recited in (1) are optionally selected from the group consisting of: straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical, C3-C6Cycloalkyl, said straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical or C3-C6The cycloalkyl group is optionally substituted with: -OH, -CN, -NH25-6 membered aromatic ring or 5-6 membered non-aromatic heterocyclic ring;
or R2、R3The substituted or unsubstituted substituents recited in (1) are optionally selected from the group consisting of: a 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S, C1-C3Alkyl-substituted 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S or oxygen-substituted 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S.
Preferably, the compound shown in the formula (I) and isomers thereof, or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
R1is-NHR4、-NHCOR4、-NHCSR4、-NHSO2R4、-NHCOOR4、-NHCSOR4、-NHCONHR4、-NHCSNHR4；
R4Independently selected from H, substituted or unsubstituted straight or branched C1-C4Alkyl, substituted or unsubstituted 3-6 membered cycloalkyl;
the R is4In (1) substituted or unsubstituted substituentMay optionally be selected from the following groups: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
R2is H, F, Cl or Br, R3Is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl;
or R3Is H, F, Cl or Br, R2Is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl;
R2、R3the substituted or unsubstituted substituents described in (1) may optionally be selected from the following groups: F. cl, Br, -OH, ═ O, -NO2、-CN、-NH2、-CF3、-OR5、COR5、-NHCOR5、-CONR5R6、-COOR5Wherein R is5And R6Each independently is a straight or branched chain C1-C6An alkyl group;
or R2、R3The substituted or unsubstituted substituents recited in (1) are optionally selected from the group consisting of: straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical, C3-C6Cycloalkyl, said straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical or C3-C6The cycloalkyl group is optionally substituted with: -OH, -CN, -NH25-6 membered aromatic ring or 5-6 non-aromatic heterocycle;
or R2、R3The substituted or unsubstituted substituents recited in (1) are optionally selected from the group consisting of: a 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S, C1-C3Alkyl-substituted 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S or oxygen-substituted 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S.
Preferably, the compound represented by formula (I) and isomers thereof, or pharmaceutically acceptable salts thereof, is represented by general formula (II):
Figure BDA0002379968460000041
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
R1is-NHR4、-NHCOR4、-NHCSR4、-NHSO2R4、-NHCOOR4、-NHCSOR4、-NHCONHR4、-NHCSNHR4；
R4Independently selected from H, substituted or unsubstituted straight or branched C1-C4Alkyl, substituted or unsubstituted 3-6 membered cycloalkyl;
the R is4Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
R2is H, F, Cl or Br, R3Is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl;
or R3Is H, F, Cl or Br, R2Is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl;
R2、R3the substituted or unsubstituted substituents described in (1) may optionally be selected from the following groups: F. cl, Br, -OH, ═ O, -NO2、-CN、-NH2、-CF3、-OR5、COR5、-NHCOR5、-CONR5R6、-COOR5Wherein R is5And R6Each independently is a straight or branched chain C1-C6An alkyl group;
or R2、R3The substituted or unsubstituted substituents recited in (1) are optionally selected from the group consisting of: straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical, C3-C6Cycloalkyl, said straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical or C3-C6The cycloalkyl group is optionally substituted with: -OH, -CN, -NH25-6 membered aromatic ring or 5-6 non-aromatic heterocycle;
or R2、R3The substituted or unsubstituted substituents recited in (1) are optionally selected from the group consisting of: a 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S, C1-C3Alkyl-substituted 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S or oxygen-substituted 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S.
Preferably, the compound shown in the formula (II) and isomers thereof, or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
R1is-NHR4、-NHCOR4、-NHCSR4、-NHSO2R4、-NHCOOR4、-NHCSOR4、-NHCONHR4、-NHCSNHR4；
R4Independently selected from H, substituted or unsubstituted straight or branched C1-C4Alkyl, substituted or unsubstituted 3-6 membered cycloalkyl;
the R is4Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
R2、R3independently selected from H, F, Cl, Br, -OH, -NO2、-CN、-NH2、-CF3、
Figure BDA0002379968460000051
Figure BDA0002379968460000061
Preferably, the compound shown in the formula (II) and isomers thereof, or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
R1is-NH2、-NHCH3、
Figure BDA0002379968460000062
Figure BDA0002379968460000063
R2、R3Independently selected from H, F,
Figure BDA0002379968460000064
Figure BDA0002379968460000071
Preferably, the compound represented by formula (II) and isomers thereof, or pharmaceutically acceptable salts thereof, is represented by general formula (III):
Figure BDA0002379968460000072
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
R1is-NHR4、-NHCOR4、-NHCSR4、-NHSO2R4、-NHCOOR4、-NHCSOR4、-NHCONHR4、-NHCSNHR4；
R4Independently selected from H, substituted or unsubstituted straight or branched C1-C4Alkyl, substituted or unsubstituted 3, 4,5 or 6 membered cycloalkyl;
the R is4Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
R3h, F, Cl or Br;
r represents 1,2,3, 4 or 5 substituents which are the same or different and are each independently selected from the following groups: F. cl, Br, -OH, -NO2、-CN、-NH2、-CF3、-OR5、COR5、-NHCOR5、-CONR5R6、-COOR5Wherein R is5And R6Each independently is a straight or branched chain C1-C6An alkyl group;
or R represents 1,2,3, 4 or 5 substituents which are the same or different and are each independently selected from the following groups: straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical, C3、C4、C5Or C6Cycloalkyl, said straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical or C3、C4、C5Or C6The cycloalkyl group is optionally substituted with: F. cl, Br, -OH, ═ O, -NO2、-CN、-NH2、-CF3Morpholinyl, thiomorpholinyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; wherein said substituted or unsubstituted group is selected from: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
or R represents 1,2,3, 4 or 5 substituents which are the same or different and are each independently selected from the following groups: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinylA linyl group, a substituted or unsubstituted piperidinyl group, a substituted or unsubstituted piperazinyl group; wherein the substituted or unsubstituted substituents are selected from: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group.
Preferably, the compound represented by formula (II) and isomers thereof, or pharmaceutically acceptable salts thereof, is represented by general formula (IV):
Figure BDA0002379968460000091
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
z is N, Y is C, W is C, or Y is N, W is C, Z is C, or W is N, Y is C, Z is C;
R1is-NHR4、-NHCOR4、-NHCSR4、-NHSO2R4、-NHCOOR4、-NHCSOR4、-NHCONHR4、-NHCSNHR4；
R4Independently selected from H, substituted or unsubstituted straight or branched C1-C4Alkyl, substituted or unsubstituted 3, 4,5 or 6 membered cycloalkyl;
the R is4Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
R3h, F, Cl or Br;
r represents 1,2,3, 4 or 5 substituents which are the same or different and are each independently selected from the following groups: F. cl, Br, -OH, -NO2、-CN、-NH2、-CF3、-OR5、COR5、-NHCOR5、-CONR5R6、-COOR5Wherein R is5And R6Each independently is a straight or branched chain C1-C6An alkyl group;
or R represents 1,2,3, 4 or 5 substituents which are the same or different and are each independently selected from the following groups: straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical, C3、C4、C5Or C6Cycloalkyl, said straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical or C3、C4、C5Or C6The cycloalkyl group is optionally substituted with: F. cl, Br, -OH, ═ O, -NO2、-CN、-NH2、-CF3Morpholinyl, thiomorpholinyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; wherein the substituted or unsubstituted substituents are selected from: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
or R represents 1,2,3, 4 or 5 substituents which are the same or different and are each independently selected from the following groups: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolylSubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl; wherein the substituted or unsubstituted substituents are selected from: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group.
The pharmaceutically acceptable salts described in the present invention are salts of the compounds of the present invention with an acid selected from the group consisting of: hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, tartaric acid, maleic acid, fumaric acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, malonic acid, succinic acid, malic acid, benzenesulfonic acid, or trifluoroacetic acid.
A compound according to any one of the first aspect of the present invention, which is the subject compound of the present invention prepared in the examples (represented by structural formula or described by systematic name) and stereoisomers thereof, and pharmaceutically acceptable salts thereof.
A compound according to any one of the first aspect of the invention, which is a compound selected from:
Figure BDA0002379968460000101
Figure BDA0002379968460000111
Figure BDA0002379968460000121
Figure BDA0002379968460000131
Figure BDA0002379968460000141
Figure BDA0002379968460000151
in a second aspect, the present invention provides methods for preparing compounds according to any one of the first aspect of the invention, but these methods do not limit the invention in any way. Such as reaction solvent, catalyst, base, reaction temperature, etc., are not limited to the following explanation. The compounds of the invention may also be prepared using any method selected from the combination of various synthetic methods described in the specification or known in the art, which combinations are readily available to those skilled in the art.
The preparation of a compound according to any one of the first aspect of the invention comprises the steps of:
Figure BDA0002379968460000152
in particular, the method comprises the following steps of,
(1) and reacting the compound shown in the formula F with N-bromosuccinimide (NBS) in acetonitrile to obtain the compound shown in the formula G.
(2) The compound of formula G reacts with methanol under acidic (such as sulfuric acid) conditions at 20-100 ℃ to obtain the compound of formula H.
(3) The compound of formula H reacts with ammonia water in a solvent (such as methanol and ethanol) at the temperature of 20-60 ℃ to obtain the compound of formula J.
(4) The amide carbonyl group in the compound of formula J is first reduced to CH2The reducing agent can be lithium aluminum hydride and borane, the solvent is tetrahydrofuran and dichloromethane, and the reaction temperature is 20-90 ℃; followed by reaction with benzyloxycarbonyl chloride (CbzCl) in the presence of a base (e.g., sodium bicarbonate, sodium carbonate,triethylamine, etc.) to obtain the compound of formula K.
(5) The compound of formula K reacts with the compound of formula L in a solvent (such as toluene, benzene) under the acidic condition (such as p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, sulfuric acid) at 80-140 ℃ to obtain the compound of formula M.
(6) The compound of formula M is subjected to removal of p-methoxybenzyl (PMB) in a solvent (such as acetonitrile, tetrahydrofuran, 1, 4-dioxane or water or a mixture thereof) under the action of ceric ammonium nitrate to obtain a compound of formula N.
(7) Compounds of formula N and (BOC)2Reacting O with base (such as triethylamine, diisopropylethylamine, and sodium carbonate) and catalyst (such as 4-dimethylaminopyridine) to obtain compound of formula O.
(8) And (3) reacting the compound of the formula O in a solvent (such as methanol, ethanol, tetrahydrofuran and dichloromethane) under the condition of alkalinity (such as cesium carbonate, sodium carbonate and potassium carbonate) to obtain the compound of the formula A.
(9) A compound of the formula A and R2B(OH)2Or R2Substituted boronic acid pinacol ester or nitrogen-containing non-aromatic heterocycle on a metallic palladium catalyst (e.g., tetrakistriphenylphosphine palladium, [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, [1, 1' -bis (diphenylphosphino) ferrocene]And (2) reacting palladium dichloride-dichloromethane complex, palladium acetate) and a base (such as cesium carbonate, potassium carbonate, sodium phosphate and potassium fluoride) in a solvent (such as 1, 4-dioxane, DMSO, tetrahydrofuran, ethanol or water or a mixture thereof) under the protection of inert gas to obtain the compound of the formula B.
(10) And (3) removing the BOC protecting group of the compound of the formula B under an acidic condition (such as trifluoroacetic acid and hydrochloric acid) to obtain the compound of the formula C.
(11) The compound of formula C is reacted with a corresponding electrophile in the presence of a base (e.g. triethylamine, diisopropylethylamine, sodium carbonate) to give the compound of formula (I).
(12) The compound of formula A is subjected to BOC protecting group removal under acidic (such as trifluoroacetic acid and hydrochloric acid) conditions to obtain a compound of formula D.
(13) The compound of formula D is reacted with a corresponding electrophile in the presence of a base (e.g. triethylamine, diisopropylethylamine, sodium carbonate) to give a compound of formula E.
(14) Compounds of formula E and R2B(OH)2Or R2Substituted boronic acid pinacol ester or nitrogen-containing non-aromatic heterocycle on a metallic palladium catalyst (e.g., tetrakistriphenylphosphine palladium, [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, [1, 1' -bis (diphenylphosphino) ferrocene]Reacting palladium dichloride-dichloromethane complex, palladium acetate) and a base (such as cesium carbonate, potassium carbonate, sodium phosphate, potassium fluoride) in a solvent (such as 1, 4-dioxane, DMSO, tetrahydrofuran, ethanol or water or a mixture thereof) under the protection of inert gas to obtain the compound of the formula (I).
Or taking the compound of the formula A' as a raw material, and obtaining the compound of the formula (I) through the steps.
Figure BDA0002379968460000171
A' compound of the formula
Figure BDA0002379968460000172
Is prepared from the raw materials by the method.
By using
Figure BDA0002379968460000173
Replacing the compound of the formula L, and obtaining the compound shown in the formula (II) through the steps.
In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the first aspect of the present invention and stereoisomers thereof, pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable excipients.
The fourth aspect of the present invention provides the use of the compound of the first aspect of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the third aspect of the present invention for the manufacture of a medicament for the treatment and/or prevention of infectious diseases, particularly infectious diseases caused by gram-positive bacteria, mycobacterium tuberculosis, and the like.
Any aspect of the invention or any one of the aspects having features is equally applicable to any other aspect or any one of the other aspects as long as they are not mutually inconsistent, although appropriate modifications to the respective features may be made as necessary when applicable to each other. In the present invention, for example, reference to "any of the first aspects of the invention" means any sub-aspect of the first aspects of the invention, and in other respects similarly referred to, has similar meaning.
Detailed description of the invention:
various aspects and features of the disclosure are described further below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure. The following are definitions of various terms used herein, which apply to the terms used throughout the specification of the present application unless otherwise specified in specific instances.
The compounds of the present invention have asymmetric centers and the compounds of the present invention containing asymmetrically substituted atoms can be isolated in optically active or racemic forms, and one skilled in the art knows how to prepare optically active forms, such as by racemate resolution or synthesis from optically active starting materials. Unless a particular stereochemistry or isomeric form is specifically indicated, the present invention includes all chiral, diastereomeric and racemic forms. Processes for preparing the compounds of the invention and intermediates thereof are part of this invention. All tautomers of the compounds of the invention also belong to the invention.
The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers, atropisomers, and the like.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R or S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes D and L or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in either racemic or enantiomerically enriched forms, such as the (R) -, (S) -, (R, S) -, (S, R) -, (R, R) -or (S, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on the differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The term "substituted" means that any one or more hydrogen atoms on a particular atom in a given structure is replaced with a particular substituent, provided that the valency of the particular atom is normal and the resulting compound is stable after the substitution. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
The carbon atom content of each hydrocarbon-containing moiety is indicated by a prefix indicating the minimum and maximum number of carbon atoms in that moiety. Ci-CjDenotes a moiety having an integer "i" (inclusive of i) to an integer "j" (inclusive of j) carbon atoms. Thus, for example, C1-C4Alkyl means alkyl having 1 to 4 (including 1,2,3 and 4) carbon atoms, in particular methyl, ethyl, C3Alkyl and C4An alkyl group.
As used herein, the term "alkyl" refers to an alkyl group having the specified number of carbon atoms, which is a straight or branched chain alkyl group, and which may include a sub-group thereof, such as the reference to "C1-C4When "alkyl", it may also include C1-C3Alkyl radical, C1-C2Alkyl radical, C2-C4Alkyl radical, C3-C4Alkyl, etc., and specific groups such as methyl, ethyl, n-propyl, isopropyl. The terms "alkoxy" and "alkylamino" are used in their conventional expressions to refer to an alkyl group attached to the remainder of the molecule through an oxygen atom or an amine group, respectively, wherein the alkyl group is as described herein. Alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, and the like. Alkylamino groups include, but are not limited to, methylamino, ethylamino, isopropylamino, n-propylamino, and the like.
The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms, including, but not limited to, trifluoromethyl, difluoromethyl, and the like.
As used herein, the terms "halo," "halogen atom," "halo," and the like, denote fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having the number of ring carbon atoms specified, and which may include sub-groups thereof, such as for example, references to a "3-6 membered cycloalkyl group or C3-C6The cycloalkyl group "when used herein refers to a cycloalkyl group having 3 to 6 (inclusive of 3, 4,5 and 6) carbon atoms, which may also include groups of the sub-range represented by 3-5 membered cycloalkyl, 4-6 membered cycloalkyl, and the like, as well as specific groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
As used herein, the term "heterocyclyl" refers to a cyclic heteroalkyl group having the indicated number of ring atoms, including monocyclic or fused ring groups, having from 4 to 10 ring atoms in the ring, wherein one or two ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, with the remaining ring atoms being carbon. These rings may also have one or more double bonds, but these rings do not have a completely conjugated pi-electron system. Heterocyclyl groups include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, 1, 2-dihydropyridinyl, morpholinyl, thiomorpholinyl, hexahydropyrimidyl, piperazinyl, homopiperazinyl, 1, 3-benzoxazinyl, oxazolidinyl, homopiperidinyl, and the like.
As used herein, the term "heteroaryl" refers herein to an aromatic group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur, and nitrogen. For example, "5-6 membered heteroaryl" includes 5 membered heteroaryl and 6 membered heteroaryl. Wherein 5-membered heteroaryl includes, but is not limited to, imidazolyl, furyl, thienyl, pyrrolyl, triazolyl, tetrazolyl, pyrazolyl (e.g., 2-pyrazolyl), thiazolyl, isothiazolyl, oxazolyl, isoxazolyl. 6-membered heteroaryl groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3, 5-triazinyl, and the like.
As used herein, the term "ring" means a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. The so-called ring includes fused rings. The number of atoms on a ring is generally defined as the number of ring members, e.g., "3-6 membered ring" means 3-6 atoms arranged around the ring.
"protecting group" refers to a class of substituents that, when reacted with a functional group, are typically used to block or protect the particular functionality of the functional group. For example, "protecting group for amino" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl and ethoxycarbonyl. Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group.
As used herein, the term "effective amount" refers to an amount of a drug that achieves the desired treatment of a disease or disorder described herein in a subject.
As used herein, the term "pharmaceutically acceptable" when describing a "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but may also refer to a synthetic substance of pharmaceutical value, e.g., a salt formed as an intermediate in order to effect chiral resolution, which salt may play a role in achieving the end product of the invention, although such intermediate salt may not be directly administered to the subject.
As used herein, the term "pharmaceutical composition" may also refer to a "composition" that may be used to effect treatment of a disease or disorder described herein in a subject, particularly a mammal.
"treatment" of a disease includes:
(1) preventing the disease, i.e., causing the clinical symptoms of the disease not to occur in a mammal exposed to or susceptible to the disease but who has not experienced or exhibited symptoms of the disease,
(2) inhibiting the disease, i.e., preventing or reducing the progression of the disease or its clinical symptoms,
(3) alleviating the disease, i.e., causing the recovery of the disease or its clinical symptoms.
"therapeutically effective amount" refers to the amount of a compound that is sufficient to effect treatment of a disease when administered to a mammal for the treatment of the disease. The therapeutically effective amount will vary depending on the compound, the disease to be treated and its severity, as well as the age, weight, sex, etc., of the mammal. A therapeutically effective amount may also refer to any amount of the compound sufficient to achieve a desired beneficial effect, including preventing, inhibiting, or ameliorating a disease as described in (1) - (3) above. For example, the amount of the compound may be between 0.1 and 250mg/kg, or preferably, 0.5 and 100mg/kg, or more preferably, 1 and 50mg/kg, or even more preferably, 2 and 20 mg/kg. Preferably, the amount of the compound is administered to the mammal twice daily. More preferably, the amount of the compound is administered to the mammal once daily. More preferably, the amount of the compound is administered to the mammal once weekly or once biweekly.
As used herein, the term "disease and/or disorder" refers to a physical condition of the subject that is associated with the disease and/or disorder of the present invention. For example, the disease and/or disorder of the present invention refers to an infectious disease.
As used herein, the term "subject" can refer to a patient or other animal, particularly a mammal, e.g., a human, dog, monkey, cow, horse, etc., that receives a compound of formula I of the invention or a pharmaceutical composition thereof for treating a disease or disorder described herein.
In still another aspect, the present invention relates to pharmaceutical compositions containing the compounds of the present invention as active ingredients. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compound of the present invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, and solubilizers. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and cosolvent may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
To encapsulate the administration unit, the active ingredient of the compound of the present invention may be mixed with a diluent and a cosolvent, and the mixture may be directly placed in a hard capsule or soft capsule. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The diluents, binders, wetting agents, disintegrants, and cosolvents used to prepare the compound tablets of the present invention can also be used to prepare capsules of the compounds of the present invention.
For preparing the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture can be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator, and osmotic pressure regulator commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
The beneficial technical effects are as follows:
the compound not only has a brand new structural framework, but also has strong activities of resisting gram-positive bacteria and mycobacterium tuberculosis. Of these 11 compounds, the Minimal Inhibitory Concentration (MIC) against Mycobacterium tuberculosis in vitro was less than 1 μ g/mL. The Minimum Inhibitory Concentration (MIC) of 13 compounds against staphylococcus aureus in vitro is less than or equal to 1 mug/mL, wherein the activity of 11 compounds against staphylococcus aureus in vitro is stronger than that of vancomycin. The Minimum Inhibitory Concentration (MIC) of 9 compounds against Bacillus subtilis in vitro is less than or equal to 1 mug/mL.
The compounds of the invention also have strong antibacterial activity against drug-resistant strains. The Minimum Inhibitory Concentration (MIC) of 7 compounds on drug-resistant mycobacterium tuberculosis is less than 1 mu g/mL, and the activity of the compounds is stronger than that of isoniazid and rifampicin. Meanwhile, the 7 compounds have strong antibacterial activity on methicillin-resistant staphylococcus aureus, vancomycin-resistant enterococcus and methicillin-resistant staphylococcus epidermidis.
In addition, the compounds of the invention have low Vero cytotoxicity (IC)50Greater than 40 μ g/mL), showing good safety.
In conclusion, the invention provides benzo [1,3] oxazine-oxazolidinone compounds with novel structures, strong activity and low toxicity, and the compounds can be used for preventing and treating diseases caused by infection of sensitive or drug-resistant gram-positive bacteria and mycobacterium tuberculosis.
Detailed Description
The present invention will be described in detail by the following examples, but is not intended to limit the present invention in any way. 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.
For all of the following examples, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structure of the compounds is determined by nuclear magnetic resonance spectroscopy (NMR) and/or Mass Spectrometry (MS). Melting point (Mp) is the melting point given in ° c.
Preparation examples section
The structure of the compound is shown by nuclear magnetic resonance hydrogen spectrum (1H NMR), Mass Spectroscopy (MS) or carbon Spectroscopy (C: (M)13C NMR). The nuclear magnetic resonance hydrogen spectral shift (δ) is given in parts per million (ppm). The coupling constant (J) is in Hertz (Hz). NMR spectra were measured using a Mercury-400 or Brucker-500 NMR spectrometer, deuterated chloroform (CDCl)3) Or deuterated dimethyl sulfoxide (DMSO-d)6) As solvent Tetramethylsilane (TMS) was used as internal standard. The melting point was measured using a Yanaco model M.P-500D melting point tester, Japan, and the temperature was not corrected. The high resolution mass spectrum was measured using an Agilent 1100series LC/MSD trap mass spectrometer. The electronic balance used was a Sartorius BSA323S type electronic balance. The column chromatography generally uses 300-400 mesh silica gel as a carrier. The anhydrous solvents were all processed by standard methods. Other reagents were all commercially available analytical grade.
The invention employs the following abbreviations:
THF is tetrahydrofuran. DCM is dichloromethane. PE is petroleum ether. DMSO is dimethyl sulfoxide.
MeOH is methanol. NBS is N-bromosuccinimide. DMF is N, N-dimethylformamide.
BTC is triphosgene. EDCI is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
HOBt is 1-hydroxybenzotriazole. X-PHOS is 2-dicyclohexyl phosphonium-2, 4, 6-triisopropyl biphenyl.
Preparation example
Preparation example 1
Preparation of 5- (hydroxymethyl) -3- (4-methoxybenzyl) oxazolidin-2-one (intermediate 1)
Figure BDA0002379968460000241
3-amino-1, 2-propanediol (25.0g, 274.7mmol) was dissolved in 350mL of methanol, magnesium sulfate (66.1g,274.7mmol) and p-methoxybenzaldehyde (37.4g,274.7mmol) were added, stirring was carried out overnight at room temperature the next day, sodium borohydride (11.4g,302.2mmol) was added slowly under ice bath, stirring was carried out for 5h and suction filtration was carried out, the filter cake was washed, and the filtrate was concentrated to dryness. The concentrate was dissolved directly in THF (400mL), sodium carbonate (101.9g,961.5mmol) was added under ice-bath followed by BTC (26.9g,90.7mmol) slowly, stirring for 72h, suction filtration, the cake washed with THF, 500mL water was added to the filtrate, after DCM extraction the organic layer was washed with brine, dried over sodium sulfate overnight, filtered, concentrated to dryness, 80mL mixed solvent (PE: DCM ═ 1:1) was added, stirring for 2h, suction filtration gave intermediate 1, 42.0g of white solid, yield: 62.6 percent.
HR-MS(ESI):m/z[M+H]+Calculated value C12H16NO4238.1079; found 238.1069.
1H NMR(400MHz,CDCl3)δ:7.20(dd,J＝8.8,2.0Hz,2H),6.88(dd,J＝8.8,2.0Hz,2H),4.60-4.54(m,1H),4.41(d,J＝14.4Hz,1H),4.33(d,J＝14.8Hz,1H),3.83(dd,J＝13.2,3.2Hz,1H),3.81(s,3H),3.62(dd,J＝12.8,4.8Hz,1H),3.42(t,J＝8.8Hz,1H),3.28(dd,J＝8.8,6.8Hz,1H).
13C NMR(125MHz,CDCl3)δ:159.4,157.8,129.5,127.6,114.2,73.4,63.2,55.3,47.7,45.0.
Preparation example 2
Preparation of (S) -5- (hydroxymethyl) -3- (4-methoxybenzyl) oxazolidin-2-one (intermediate 2)
Figure BDA0002379968460000251
The reaction was carried out in the same manner as in preparation example 1 except for replacing 3-amino-1, 2-propanediol in the preparation of intermediate 1 with (S) -3-amino-1, 2-propanediol to give intermediate 2 as a white solid (38.0 g, yield 58.4%).
Preparation example 3
Preparation of 3- (4-methoxybenzyl) -5-formyl-oxazolidin-2-one (intermediate 3)
Figure BDA0002379968460000252
Dissolving the intermediate 1(1.0g and 4.2mmol) in 15mL of ultra-dry tetrahydrofuran, dissolving oxalyl chloride (0.72mL and 8.4mmol) in 10mL of ultra-dry tetrahydrofuran, placing the mixture in a low-temperature reactor at-78 ℃ under the protection of argon, slowly dropwise adding a tetrahydrofuran solution (diluted by the same volume) of DMSO (1.2mL and 16.8mmol) after the internal temperature is reduced to-70 ℃, controlling the internal temperature not to exceed-55 ℃, reacting for 10min after the dropwise adding is finished, dropwise adding the tetrahydrofuran solution of the intermediate 1 dissolved in advance into the active intermediate, and controlling the temperature not to exceed-55 ℃. After the addition, the reaction is carried out for 20-30 min. Dried triethylamine (2.0mL, 14.7mmol) was dissolved in super dry tetrahydrofuran (diluted in equal volume) and slowly added to the reaction mixture at a temperature not exceeding-60 ℃. After the addition was completed, the reaction was carried out for 15 min. Moving to room temperature, adding water to quench when the internal temperature rises to zero centigrade, washing the reaction solution twice with water and once with salt solution. Drying over sodium sulfate and column chromatography (methanol: dichloromethane ═ 1: 99) afforded intermediate 3as a white solid, 0.89g, 89.8% yield.
Preparation example 4
Preparation of (S) -3- (4-methoxybenzyl) -5-formyl-oxazolidin-2-one (intermediate 4)
Figure BDA0002379968460000261
The reaction was carried out by the method in preparation example 3 using intermediate 2 as a starting material to give intermediate 4 as a white solid in an amount of 0.92g with a yield of 92.8%.
Examples
Example 1
Preparation of 5- ((3S,3aS) -3- (aminomethyl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-7-yl) picoline nitrile (Compound 1)
Figure BDA0002379968460000262
The first step is as follows: preparation of 5-bromo-4-fluoro-2-hydroxybenzoic acid (intermediate 5)
Dissolving 4-fluorosalicylic acid (23.8g,152.7mmol) in acetonitrile (250mL), sequentially adding concentrated sulfuric acid (8.7mL) and NBS (28.5g,160.3mmol), stirring at room temperature for 1h, concentrating the reaction solution to near dryness, suction filtering, washing the filter cake with water, and drying under an infrared lamp to obtain an intermediate 5, 30.0g of a white solid, yield: 83.8 percent.
LC-MS(ESI):m/z[M-H]-Calculated value C7H3BrFO3: 232.9250 and 234.9229; measured value: 232.9147, and 234.9111.
1H NMR(400MHz,DMSO-d6)δ:8.01(d,J＝8.0Hz,1H),7.05(dd,J＝10.4,2.8Hz,1H).
The second step is that: preparation of methyl 5-bromo-4-fluoro-2-hydroxybenzoate (intermediate 6)
After dissolving intermediate 5(29.0g,123.4mmol) in methanol (300mL), adding concentrated sulfuric acid (10.0mL), reacting at 85 ℃ for 32 hours, concentrating the reaction solution to dryness, redissolving dichloromethane, washing the organic phase with water, saturated aqueous sodium bicarbonate solution and brine in succession, drying over anhydrous sodium sulfate, filtering and concentrating to obtain intermediate 6 as a white solid (28.0g, yield: 91.1 percent.
LC-MS(ESI):m/z[M+H]-Calculated value C8H7BrFO3: 248.9563 and 250.9542; measured value: 248.9546, and 250.9527.
1H NMR(400MHz,CDCl3)δ:10.91(d,J＝1.6Hz,1H),8.04(d,J＝7.6Hz,1H).6.76(d,J＝9.6Hz,1H)，3.96(s,3H).
The third step: preparation of 5-bromo-4-fluoro-2-hydroxybenzamide (intermediate 7)
Dissolving intermediate 6(28.0g,112.4mmol) in methanol (150.0mL), adding 30% ammonia water (300.0mL), reacting at 55 ℃ under a sealed condition for 6 hours, adding water (300.0mL) after the reaction is finished, precipitating a white solid, performing suction filtration, washing a filter cake with water, and drying by an infrared lamp to obtain intermediate 7, wherein the white solid is 24.0g, and the yield is as follows: 91.3 percent.
LC-MS(ESI):m/z[M+H]+Calculated value C7H6BrFNO2: 233.9566 and 235.9545; measured value: 233.9558, and 235.9520.
1H NMR(400MHz,DMSO-d6)δ:13.54(s,1H),8.47(s,1H),8.25(d,J＝8.0Hz,1H),8.09(s,1H),6.95(d,J＝10.4Hz,1H).
The fourth step: preparation of benzyl (5-bromo-4-fluoro-2-hydroxybenzyl) carbamate (intermediate 8)
Dissolving the intermediate 7(12.0g,51.2mmol) in dry tetrahydrofuran (100.0mL), slowly adding borane dimethyl sulfide (230.4mmol) dropwise under the protection of argon, reacting at 85 ℃ for 5 hours, cooling to room temperature after the reaction is finished, slowly adding methanol dropwise until no gas is generated, stirring for 30 minutes, and concentrating to dryness. The residue was dissolved in a mixed solvent of tetrahydrofuran (100.0mL) and water (20.0mL), sodium bicarbonate (8.6g,102.4mmol) was added under ice-bath conditions, benzyl chloroformate (7.2mL,51.2mmol) was further added, water was added after 2 hours of reaction, water was added after dichloromethane extraction three times, the organic phases were combined and washed twice with water in sequence, brine was washed once and concentrated to dryness, the residue was redissolved in a mixed solvent of tetrahydrofuran (100.0mL) and water (20.0mL), lithium hydroxide monohydrate (6.5g,153.6mmol) was added after two hours of reaction, water was added, dichloromethane extraction was performed, the organic phases were combined, washed twice with water in sequence, saturated brine was washed once with anhydrous sodium sulfate column chromatography and filtration were performed, and silica gel (petroleum ether/dichloromethane ═ 1/1) gave intermediate 8, 13.1g of white solid, yield 72.0%.
LC-MS(ESI):m/z[M+H]+Calculated value C15H14BrFNO3: 354.0141 and 356.0121; measured value: 354.0125, and 356.0104.
1H NMR(400MHz,CDCl3)δ:9.15(s,1H),7.38-7.32(m,5H),7.22(d,J＝8.0Hz,1H),6.74(d,J＝10.0Hz,1H),5.47(brs,1H),5.14(s,2H),4.21(d,J＝6.8Hz,2H).
The fifth step: preparation of benzyl (S) -6-bromo-7-fluoro-2- ((S) -3- (4-methoxybenzyl) -2-oxooxazolidin-5-yl) -2H-benzo [ e ] [1,3] oxazine-3 (4H) -carboxylate (intermediate 9)
Dissolving the intermediate 8(5.5g,15.5mmol) and the intermediate 4(9.2g,39.1mmol) in toluene (60.0mL), adding a catalyst p-toluenesulfonic acid monohydrate (0.3g,1.6mmol), carrying out heat preservation reaction in a 135 ℃ oil bath for 6 hours, separating generated water by adopting a water separator, cooling to room temperature after the reaction is finished, washing the reaction solution with water, and concentrating to obtain brown oily matter. After silica gel column chromatography (petroleum ether/ethyl acetate 4/1), intermediate 9 was obtained as a white solid, 4.4g, yield 49.4%.
LC-MS(ESI):m/z[M+H]+Calculated value C27H25BrFN2O6: 571.0880 and 573.0860; measured value: 571.0879 and 573.0859
1H NMR(400MHz,acetone-d6)δ:7.52(d,J＝7.6Hz,1H),7.44-7.34(m,5H),7.21(d,J＝8.0Hz,2H),6.89(d,J＝8.4Hz,2H),6.78(d,J＝9.6Hz,1H),6.05(d,J＝8.4Hz,1H),5.21(dd,J＝12.4,14.0Hz,2H),5.07(d,J＝17.6Hz,1H),4.86(td,J＝5.2,8.4Hz,1H),4.46(d,J＝17.2Hz,1H),4.38(d,J＝14.4Hz,1H),4.32(d,J＝14.8Hz,1H),3.78(s,3H),3.62(t,J＝9.2Hz,1H),3.49(dd,J＝5.2,9.2Hz,1H).
And a sixth step: preparation of benzyl (S) -6-bromo-7-fluoro-2- ((S) -2-oxooxazolidin-5-yl) -2H-benzo [ e ] [1,3] oxazine-3 (4H) -carboxylate (intermediate 10)
Intermediate 9(3.4g,5.9mmol) was dissolved in a mixed solvent of acetonitrile and water (acetonitrile: 85.0mL, water: 9.5mL), ceric ammonium nitrate (12.9g,23.6mmol) was added, after stirring at room temperature for 2 hours, 200mL of water was added, the organic phases were combined after extraction with dichloromethane three times, washed with water twice, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and subjected to silica gel column chromatography (dichloromethane/methanol ═ 100/1) to give intermediate 10 as a white solid, 2.1g, yield 78.1%.
LC-MS(ESI):m/z[M+H]+Calculated value C19H17BrFN2O5: 451.0305 and 453.0284; measured value: 451.0318 and 453.0296
1H NMR(400MHz,acetone-d6)δ:7.55(d,J＝7.6Hz,1H),7.45-7.42(m,2H),7.39-7.33(m,3H),6.83(d,J＝10.0Hz,1H),6.69(s,1H),6.18(d,J＝8.4Hz,1H),5.24(dd,J＝12.4,15.6Hz,2H),5.10(d,J＝17.2Hz,1H),4.95(td,J＝5.6,8.8Hz,1H),4.49(d,J＝17.2Hz,1H),3.77(td,J＝0.8,9.2Hz,1H),3.70-3.66(m,1H).
The seventh step: preparation of benzyl (S) -6-bromo-2- ((S) -3- (tert-butoxycarbonyl) -2-oxooxazolidin-5-yl) -7-fluoro-2H-benzo [ e ] [1,3] oxazine-3 (4H) -carboxylate (intermediate 11)
After intermediate 10(2.2g,4.8mmol) was dissolved in dichloromethane (20.0mL), triethylamine (1.0mL,7.3mmol), di-tert-butyl dicarbonate (1.2g,5.7mmol) and 4-dimethylaminopyridine (49.0mg,0.1mmol) were added successively, and the reaction was stirred at room temperature for 2 hours, the reaction mixture was washed twice with water, once with brine, dried over anhydrous sodium sulfate, filtered, and subjected to silica gel column chromatography (petroleum ether/dichloromethane ═ 6/4) to obtain intermediate 11 as a white solid (2.1g, yield 78.1%).
LC-MS(ESI):m/z[M+Na]+Calculated value C24H24BrFN2NaO7: 573.0649 and 575.0628; measured value: 573.0637 and 575.0617
1H NMR(400MHz,acetone-d6)δ:7.56(d,J＝7.6Hz,1H),7.44-7.41(m,2H),7.40-7.32(m,3H),6.89(d,J＝9.6Hz,1H),6.28(d,J＝8.8Hz,1H),5.23(dd,J＝12.4,16.0Hz,2H),5.11(d,J＝17.2Hz,1H),4.98-4.92(m,1H),4.50(d,J＝16.8Hz,1H),4.16-4.08(m,2H),1.50(s,9H).
Eighth step: preparation of tert-butyl ((3S,3aS) -7-bromo-6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 12)
Intermediate 11(2.1g,3.8mmol) was dissolved in anhydrous methanol (20mL), cesium carbonate (4.5g,7.6mmol) was added, stirring was carried out at room temperature for 3 hours, water (200.0mL) was added, a white solid was precipitated, suction filtration was carried out, the cake was washed with water, and infrared lamp drying was carried out to give intermediate 12 as a white solid 1.4g, yield 88.6%.
LC-MS(ESI):m/z[M+Na]+Calculated values: 439.0281 and 441.0260 found: 439.0265 and 441.0246
1H NMR(400MHz,CDCl3)δ:7.26(d,J＝7.2Hz,1H),6.71(d,J＝9.2Hz,1H),5.45(s,1H),4.88(brs,1H),4.77(d,J＝16.4Hz,1H),4.64-4.61(m,1H),4.37(d,J＝16.4Hz,1H),3.62-3.48(m,2H),1.44(s,9H)
The ninth step: preparation of tert-butyl ((3S,3aS) -7- (6-cyanopyridin-3-yl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 13)
Intermediate 12(270.0mg,0.65mmol), 2-cyanopyridine-5-boronic acid pinacol ester (194.0mg,0.84mmol), tetrakistriphenylphosphine palladium (74.8mg,0.06mmol) and sodium carbonate (137.3mg,1.30mmol) were charged into a three-necked reaction flask, a mixed solvent of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under an argon atmosphere, the reaction was carried out at 100 ℃ for 5 hours, after completion of the reaction, the reaction mixture was cooled to room temperature, water (20mL) was added, methylene chloride was extracted three times, the organic layers were combined, washed successively three times with water, once with saturated saline solution, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (methylene chloride/methanol ═ 100/1) to obtain intermediate 13 as an off-white solid 240.0mg with a yield of 84.1%.
LC-MS(ESI):m/z[M+H]+Calculated value C22H22FN4O5: 441.1574, respectively; measured value: 441.1572
1H NMR(400MHz,CDCl3)δ:8.83(s,1H),7.97-7.94(m,1H),7.77(dd,J＝0.8,8.0Hz,1H),7.17(d,J＝8.0Hz,1H),6.79(d,J＝11.2Hz,1H),5.56(s,1H),4.9(brs,1H),4.86(d,J＝16.8Hz,1H),4.67(t,J＝4.8Hz,1H),4.47(d,J＝16.4Hz,1H),3.65-3.50(m,2H),1.45(s,9H).
The tenth step: preparation of 5- ((3S,3aS) -3- (aminomethyl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-7-yl) picoline nitrile (Compound 1)
Intermediate 13(240.0mg,0.54mmol) was dissolved in dichloromethane (15.0mL), trifluoroacetic acid (4.0mL) was added under ice-bath conditions, after reaction for 3 hours with incubation, the reaction solution was neutralized with saturated aqueous sodium bicarbonate solution to neutrality, the reaction solution was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate and subjected to silica gel column chromatography (dichloromethane/methanol 100/2, containing 5% o ammonia in methanol) to give compound 1 as an off-white solid (175 mg, yield 94.3%).
LC-MS(ESI):m/z[M+H]+Calculated value C17H14FN4O3: 341.1050, respectively; measured value: 341.1039
1H NMR(400MHz,CDCl3)δ:8.84(s,1H),7.96(dt,J＝2.0,8.0Hz,1H),7.76(dd,J＝0.8,8.4Hz,1H),7.19(d,J＝8.0Hz,1H),6.80(d,J＝11.2Hz,1H),5.41(d,J＝1.2Hz,1H),4.86(d,J＝16.4Hz,1H),4.61(td,J＝1.2,5.2Hz,1H),4.52(d,J＝16.4Hz,1H),3.18-3.06(m,2H).
13C NMR(125MHz,CDCl3)δ:159.1(d,JC-F＝250Hz),156.2,154.4(d,JC-F＝12.5Hz),150.6,136.7,134.3,132.5,128.2,118.6(d,JC-F＝13.8Hz),117.2,116.0,106.4(d,JC-F＝25Hz),84.0,81.0,42.7,39.9.
Example 2
Preparation of N- ((3S,3aS) -7- (6-cyanopyridin-3-yl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (compound 2)
Figure BDA0002379968460000301
Compound 1(310.0mg,0.91mmol) was dissolved in dichloromethane (15.0mL), triethylamine (190.0. mu.L, 1.4mmol) was added under ice-bath conditions, acetyl chloride (84.0. mu.L, 1.2mmol) was added slowly, and the reaction was incubated for 2 hours. The reaction mixture was washed twice with water, once with saturated brine, dried over sodium sulfate, and subjected to silica gel column chromatography (dichloromethane/methanol ═ 100/1) to give compound 2 as an off-white solid (305 mg, yield 87.6%).
LC-MS(ESI):m/z[M+H]+Calculated value C19H16FN4O4: 383.1156, respectively; measured value: 383.1146
1H NMR(400MHz,CDCl3)δ:8.83(s,1H),7.95(dt,J＝2.0,8.0Hz,1H),7.76(dd,J＝0.8,8.0Hz,1H),7.16(d,J＝8.4Hz,1H),6.79(d,J＝11.2Hz,1H),5.89(t,J＝6.4Hz,1H),5.50(d,J＝1.2Hz,1H),4.85(d,J＝16.4Hz,1H),4.70(t,J＝4.8Hz,1H),4.49(d,J＝16.4Hz,1H),3.72(t,J＝5.2Hz,2H),2.05(s,3H).
13C NMR(100MHz,CDCl3)δ:171.2,159.2(d,JC-F＝248.0Hz),156.3,150.6,136.8,134.2,132.5,128.2,128.1(d,JC-F＝4.0Hz),118.8(d,JC-F＝14.0Hz),117.2,115.8,106.5(d,JC-F＝26.0Hz),83.8,78.9,40.2,40.1,23.2.
Example 3
Preparation of N- ((3S,3aS) -6-fluoro-7- (6-methoxypyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (compound 3)
Figure BDA0002379968460000311
The first step is as follows: preparation of N- (((3S,3aS) -7-bromo-6-fluoro-1-carbonyl-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (intermediate 14)
Dissolving intermediate 12(210.0mg,0.5mmol) in dichloromethane (10.0mL), adding trifluoroacetic acid (3.0mL) under ice bath condition, keeping the temperature for reaction for 3h, then completing the reaction, neutralizing the reaction liquid with saturated sodium bicarbonate aqueous solution under ice bath condition to be neutral, extracting with dichloromethane for three times, combining organic phases, drying with anhydrous sodium sulfate, filtering, placing the filtrate in ice bath again, adding triethylamine (105.0 muL, 0.8mmol), then adding acetyl chloride (46.0 muL, 0.7mmol), keeping the temperature for reaction for two hours, completing the reaction, washing the reaction liquid twice, washing with saturated saline solution once, drying with anhydrous sodium sulfate, and carrying out column chromatography on silica gel to obtain intermediate 14, white solid 140mg, yield 77.3%
LC-MS(ESI):m/z[M+H]+Calculated value C13H13BrFN2O4: 359.0043 and 361.0022; found 359.0028 and 361.0002
1H NMR(400MHz,CDCl3)δ:7.26(d,J＝7.2Hz,1H),6.70(d,J＝8.8Hz,2H),5.89(t,J＝6.4Hz,1H),5.39(d,J＝0.8Hz,1H),4.76(d,J＝16.8Hz,1H),4.67-4.64(m,1H),4.40(d,J＝16.4Hz,1H),3.70-3.66(m,2H),2.03(s,3H).
The second step is that: preparation of N- ((3S,3aS) -6-fluoro-7- (6-methoxypyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (compound 3)
Intermediate 14(95.0mg,0.26mmol), 2-methoxy-5-pyridineboronic acid (61.0mg,0.40mmol), tetrakistriphenylphosphine palladium (41.6mg,0.04mmol) and sodium carbonate (56.2mg,0.5mmol) were charged into a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under argon protection to obtain compound 3as an off-white solid 78.0mg in a yield of 75.9% according to the preparation method of intermediate 13 in example 1.
LC-MS(ESI):m/z[M+H]+ calculated value C19H19FN3O5: 388.1309, respectively; measured value: 388.1294
1H NMR(400 MHz,CDCl3)δ:8.25(s,1 H),7.69(d,J＝8.4 Hz,1 H),7.07(d,J＝8.4 Hz,1 H),6.80(d,J＝8.8 Hz,1 H),6.72(d,J＝11.2 Hz,1 H),6.15(s,1 H),5.43(s,1H),4.80(d,J＝16.8 Hz,1 H),4.68(t,J＝4.8 Hz,1 H),4.47(d,J＝16.8 Hz,1 H),3.97(s,3 H),3.70(t,J＝5.2 Hz,2 H),2.04(s,3 H).
13C NMR(100 MHz,CDCl3)δ:171.1,163.7,159.0(d,JC-F＝248.0 Hz),156.4,152.4(d,JC-F＝12.0 Hz),146.4(d,JC-F＝3.0Hz),139.0(d,JC-F＝3.0Hz),127.8(d,JC-F＝5.0Hz),124.0,120.9(d,JC-F＝15.0Hz),115.1(d,JC-F＝4.0Hz),110.7,106.0(d,JC-F＝26.0Hz),83.6,78.9,53.6,40.3,40.2,23.1.
Example 4
Preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-1-one (Compound 4)
Figure BDA0002379968460000321
The first step is as follows: preparation of tert-butyl ((3S,3aS) -6-fluoro-7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 15)
Intermediate 12(220.0mg,0.5mmol), 2- (2-methyl-2H-tetrazol-5-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (287.1mg,0.6mmol), tetrakistriphenylphosphine palladium (50.0mg,0.05mmol) and sodium carbonate (101.8mg,0.96mmol) were charged into a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under argon to obtain intermediate 15 as an off-white solid at 150.0mg in a yield of 57.0% according to the method for preparing intermediate 9 in example 1.
LC-MS(ESI):m/z[M+H]+Calculated value C23H25FN7O5: 498.1901, respectively; measured value: 498.1878
1H NMR(400MHz,CDCl3)δ:8.87(s,1H),8.30(d,J＝8.0Hz,1H),7.98(dt,J＝8.0,1.6Hz,1H),7.20(d,J＝8.0Hz,1H),6.77(d,J＝11.2Hz,1H),5.53(s,1H),4.92-4.85(m,2H),4.68-4.66(m,1H),4.48(d,J＝16.4Hz,1H),4.47(s,3H),3.64-3.51(m,2H),1.44(s,9H).
The second step is that: preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-1-one (Compound 4)
Intermediate 15(170.0mg,0.34mmol) was dissolved in dichloromethane (10.0mL), and trifluoroacetic acid (3.0mL) was added under ice-bath conditions to follow the procedure for the preparation of compound 1 in example 1 to give compound 4 as an off-white solid 85.0mg, yield 62.5%.
LC-MS(ESI):m/z[M+H]+Calculated value C18H17FN7O3: 398.1377, respectively; measured value: 398.1353
1H NMR(400MHz,CDCl3)δ:8.88(s,1H),8.30(dd,J＝0.8,8.0Hz,1H),7.99(dt,J＝8.0,1.6Hz,1H),7.22(d,J＝8.0Hz,1H),6.79(d,J＝10.8Hz,1H),5.40(d,J＝1.6Hz,1H),4.87(d,J＝16.4Hz,1H),4.61(td,J＝5.6,1.2Hz,1H),4.53(d,J＝16.4Hz,1H),4.47(s,3H),3.17-3.05(m,2H),1.27(s,2H).
13C NMR(100MHz,CDCl3)δ:164.8,159.2(d,JC-F＝248.0Hz),156.4,153.6(d,JC-F＝12.0Hz),149.9(d,JC-F＝3.0Hz),145.7,137.1,132.1,128.2(d,JC-F＝4.0Hz),122.1,119.9(d,JC-F＝4.0Hz),115.7,106.3(d,JC-F＝25.0Hz),84.0,81.5,42.9,40.1,39.8.
Example 5
Preparation of N- ((3S,3aS) -6-fluoro-7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 5)
Figure BDA0002379968460000331
Compound 4(45.0mg,0.11mmol) was dissolved in dichloromethane (15mL), triethylamine (24.0. mu.L, 0.17mmol) was added under ice bath conditions, acetyl chloride (10.0. mu.L, 0.15mmol) was slowly added, and compound 5 was obtained as an off-white solid at 44mg, yield 88.5% according to the preparation method of compound 2 in example 2.
LC-MS(ESI):m/z[M+H]+Calculated value C20H19FN7O4: 440.1483, respectively; measured value: 440.1455
1H NMR(400MHz,CDCl3)δ:8.85(s,1H),8.30(d,J＝8.4Hz,1H),7.98(dt,J＝8.4,2.0Hz,1H),7.20(d,J＝8.0Hz,1H),6.77(d,J＝10.8Hz,1H),6.27(t,J＝2.0Hz,1H),5.48(d,J＝1.2Hz,1H),4.84(d,J＝16.4Hz,1H),4.70(d,J＝4.8Hz,1H),4.50(d,J＝16.8Hz,1H),4.46(s,3H),3.73-3.70(m,2H),2.05(s,3H).
13C NMR(100MHz,CDCl3)δ:171.2,164.7,159.2(d,JC-F＝248.0Hz),156.4,153.4(d,JC-F＝12.0Hz),149.8,145.6,137.1(d,JC-F＝4.0Hz),132.0,128.1(d,JC-F＝5.0Hz),122.0,120.0(d,JC-F＝14.0Hz),115.5(d,JC-F＝3.0Hz),106.2(d,JC-F＝25.0Hz),83.7,78.9,40.2,40.1,40.0,23.1.
Example 6
Preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7- (6-morpholin-pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-1-one (Compound 6)
Figure BDA0002379968460000341
The first step is as follows: preparation of tert-butyl ((3S,3aS) -6-fluoro-7- (6-morpholinopyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 16)
Intermediate 12(200.0mg,0.48mmol), 6- (4-morpholinyl) -3-pyridineboronic acid (119.7mg,0.58mmol), tetrakistriphenylphosphine palladium (50mg,0.05mmol) and sodium carbonate (101.6mg,0.96mmol) were charged into a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under argon protection to obtain intermediate 16 as an off-white solid 160.0mg with a yield of 66.7% according to the preparation method of intermediate 9 in example 1.
LC-MS(ESI):m/z[M+H]+Calculated value C25H30FN4O6: 501.2149, respectively; measured value: 501.2126
1H NMR(400MHz,CDCl3)δ:8.30(s,1H),7.65(d,J＝8.8Hz,1H),7.07(d,J＝8.4Hz,1H),6.73-6.68(m,2H),5.47(s,1H),4.91(t,J＝5.2Hz,1H),4.81(d,J＝16.4Hz,1H),4.65(t,J＝4.8Hz,1H),4.44(d,J＝16.4Hz,1H),3.84(t,J＝4.8Hz,4H),3.57-3.55(m,6H),1.44(s,9H).
The second step is that: preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7- (6-morpholin-pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-1-one (Compound 6)
Intermediate 16(150.0mg,0.30mmol) was dissolved in dichloromethane (10.0mL), and trifluoroacetic acid (3.0mL) was added under ice-bath conditions to follow the procedure for the preparation of compound 1 in example 1 to give compound 6 as an off-white solid 93.0mg, yield 77.5%.
LC-MS(ESI):m/z[M+Na]+Calculated value C20H21FN4NaO4: 423.1445, respectively; measured value: 423.1428
1H NMR(400MHz,CDCl3)δ:8.31(s,1H),7.65(dt,J＝8.8,2.0Hz,1H),7.09(d,J＝8.0Hz,1H),6.74-6.68(m,2H),5.34(d,J＝1.2Hz,1H),4.82(d,J＝16.4Hz,1H),4.59(td,J＝5.6,1.2Hz,1H),4.49(d,J＝16.4Hz,1H),3.84(d,J＝4.8Hz,4H),3.56(d,J＝4.4Hz,4H),3.16-3.04(m,2H),1.54(brs,2H).
13C NMR(100MHz,CDCl3)δ:159.0(d,JC-F＝247.0Hz),158.7,156.4,152.1(d,JC-F＝12.0Hz),147.5(d,JC-F＝3.0Hz),137.8(d,JC-F＝4.0Hz),127.4(d,JC-F＝5.0Hz),121.2(d,JC-F＝15.0Hz),120.7,115.2(d,JC-F＝4.0Hz),106.4,105.9(d,JC-F＝26.0Hz),83.8,81.0,66.8,45.5,42.9,40.1.
Example 7
Preparation of N- ((3S,3aS) -6-fluoro-7- (6-morpholinopyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (compound 7)
Figure BDA0002379968460000351
Compound 6(50.0mg,0.12mmol) was dissolved in dichloromethane (15.0mL), triethylamine (26. mu.L, 0.19mmol) was added under ice-bath conditions, then acetyl chloride (11.5. mu.L, 0.16mmol) was added slowly, and compound 7 was obtained as an off-white solid 50.0mg with a yield of 90.6% according to the preparation method of compound 2 in example 2.
LC-MS(ESI):m/z[M+H]+Calculated value C22H24FN4O5: 443.1731, respectively; measured value: 443.1721
1H NMR(400MHz,CDCl3)δ:8.29(s,1H),7.63(d,J＝8.8Hz,1H),7.06(d,J＝8.4Hz,1H),6.72-6.67(m,2H),6.26(s,1H),5.42(s,1H),4.79(d,J＝16.4Hz,1H),4.67(t,J＝4.4Hz,1H),4.46(d,J＝16.4Hz,1H),3.83(d,J＝4.4Hz,4H),3.69(t,J＝5.2Hz,2H),3.55(t,J＝4.4Hz,4H),2.03(s,3H).
13C NMR(100MHz,CDCl3)δ:171.16,159.0(d,JC-F＝247.0Hz),158.7,156.5,152.5(d,JC-F＝12.0Hz),147.4,137.8(d,JC-F＝3.0Hz),127.5(d,JC-F＝5.0Hz),121.3(d,JC-F＝15.0Hz),120.6,115.0(d,JC-F＝4.0Hz),106.4,105.9(d,JC-F＝26.0Hz),83.6,78.9,66.7,45.5,40.2,23.1
Example 8
Preparation of N- ((3S,3aS) -6-fluoro-1-oxo-7- (pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 8)
Figure BDA0002379968460000352
Intermediate 14(130.0mg,0.36mmol), 3-pyridineboronic acid (58.0mg,0.47mmol), tetrakistriphenylphosphine palladium (41.6mg,0.04mmol) and sodium carbonate (77mg,0.73mmol) were charged into a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under argon protection to obtain compound 8 as an off-white solid 90.0mg with a yield of 69.2% according to the preparation method of intermediate 13 in example 1.
LC-MS(ESI):m/z[M+H]+Calculated value C18H17FN3O4: 358.1203, respectively; measured value: 358.1186
1H NMR(400MHz,CDCl3)δ:8.72(s,1H),8.59(s,1H),7.81(d,J＝7.2Hz,1H),7.39-7.36(m,1H),7.14(d,J＝8.4Hz,1H),6.75(d,J＝11.2Hz,1H),6.25(s,1H),5.46(d,J＝0.8Hz,1H),4.82(d,J＝16.4Hz,1H),4.69(t,J＝4.8Hz,1H),4.48(d,J＝16.4Hz,1H),3.71(t,J＝5.6Hz,1H),2.04(s,3H),
Example 9
Preparation of N- ((3S,3aS) -6-fluoro-1-oxo-7- (pyridin-4-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 9)
Figure BDA0002379968460000361
Intermediate 14(130.0mg,0.36mmol), 4-pyridineboronic acid (58.0mg,0.47mmol), tetrakistriphenylphosphine palladium (41.6mg,0.04mmol) and sodium carbonate (77.0mg,0.73mmol) were charged into a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9mL) and water (1.5mL) was added under argon protection to obtain compound 9 as an off-white solid 86.0mg in 66.2% yield according to the preparation method of intermediate 13 in example 1.
LC-MS(ESI):m/z[M+H]+Calculated value C18H17FN3O4: 358.1203, respectively; measured value: 358.1186
1H NMR(400MHz,CDCl3)δ:8.65(d,J＝4.4Hz,2H),7.42(d,J＝4.4Hz,2H),7.18(d,J＝8.0Hz,1H),6.75(d,J＝11.2Hz,1H),6.26(t,J＝5.6Hz,1H),5.48(s,1H),4.82(d,J＝16.4Hz,1H),4.69(t,J＝4.4Hz,1H),4.48(d,J＝16.4Hz,1H),3.71(t,J＝5.2Hz,2H),2.04(s,3H).
Example 10
Preparation of N- ((3S,3aS) -6-fluoro-1-oxo-7-phenyl-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 10)
Figure BDA0002379968460000362
Intermediate 14(80mg,0.22mmol), phenylboronic acid (41.0mg,0.33mmol), tetrakistriphenylphosphine palladium (25.0mg,0.02mmol) and sodium carbonate (47.0mg,0.44mmol) were charged into a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under argon protection to obtain compound 10 as an off-white solid 65.0mg in 81.7% yield according to the preparation method of intermediate 13 in example 1.
LC-MS(ESI):m/z[M+H]+Calculated value C19H18FN2O4: 357.1251, respectively; measured value: 357.1235
1H NMR(400MHz,CDCl3)δ:7.48-7.36(m,5H),7.12(d,J＝8.0Hz,1H),6.72(d,J＝10.8Hz,1H),6.17(t,J＝5.2Hz,1H),5.43(s,1H),4.80(d,J＝16.4Hz,1H),4.69(d,J＝4.8Hz,1H),4.47(d,J＝16.0Hz,1H),3.72-3.69(m,2H),2.04(s,3H).
13C NMR(100MHz,CDCl3)δ:171.1,159.0(d,JC-F＝249.0Hz),156.4,152.1(d,JC-F＝12.0Hz),134.9,128.8(d,JC-F＝3.0Hz),128.5,128.3(d,JC-F＝5.0Hz),127.7,124.3(d,JC-F＝14.0Hz),114.8(d,JC-F＝4.0Hz),105.8(d,JC-F＝26.0Hz),83.6,78.9,40.2,23.1.
Example 11
Preparation of 4- ((3S,3aS) -3- (aminomethyl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-7-yl) benzonitrile (Compound 11)
Figure BDA0002379968460000371
The first step is as follows: preparation of tert-butyl ((3S,3aS) -7- (4-cyanophenyl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 17)
Intermediate 12(150.0mg,0.36mmol), 4-cyanophenylboronic acid (68.7mg,0.47mmol), tetrakistriphenylphosphine palladium (41.6mg,0.04mmol) and sodium carbonate (76.2mg,0.72mmol) were charged into a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under argon protection to obtain intermediate 17 as an off-white solid (140.0mg, 88.6% yield) according to the preparation method of intermediate 13 in example 1.
LC-MS(ESI):m/z[M+Na]+Calculated value C23H22FN3NaO5: 462.1441, respectively; measured value: 462.1436
1H NMR(400MHz,CDCl3)δ:7.71(dd,J＝1.6,6.4Hz,2H),7.59(dd,J＝1.6,8.4Hz,2H),7.13(d,J＝8.0Hz,1H),6.75(d,J＝11.2Hz,1H),5.23(s,1H),4.93(t,J＝5.2Hz,1H),4.83(d,J＝16.8Hz,1H),4.66(d,J＝4.4Hz,1H),4.45(d,J＝16.4Hz,1H),3.63-3.52(m,2H),1.44(s,9H).
The second step is that: preparation of 4- ((3S,3aS) -3- (aminomethyl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-7-yl) benzonitrile (Compound 11)
Intermediate 17(130.0mg,0.28mmol) was dissolved in dichloromethane (10.0mL), and trifluoroacetic acid (3.0mL) was added under ice-bath conditions to follow the procedure for the preparation of compound 1 in example 1 to give compound 11 as an off-white solid 85.3mg, yield 84.7%.
LC-MS(ESI):m/z[M+H]+Calculated value C18H15FN3O3: 340.1097, respectively; measured value: 340.1082
1H NMR(400MHz,CDCl3)δ:7.73(dd,J＝2.0,6.4Hz,2H),7.59(dd,J＝1.6,8.8Hz,2H),7.16(d,J＝8.0Hz,1H),6.76(d,J＝11.2Hz,1H),5.38(d,J＝1.2Hz,1H),4.84(d,J＝16.4Hz,1H),4.61(td,J＝1.2,5.6Hz,1H),4.50(d,J＝16.4Hz,1H),3.17-3.05(m,2H),1.57(brs,2H).
13C NMR(100MHz,CDCl3)δ:158.9(d,JC-F＝249.0Hz),156.3,153.6(d,JC-F＝12.0Hz),139.6,132.4,129.5(d,JC-F＝3.0Hz),128.3(d,JC-F＝4.0Hz),122.1(d,JC-F＝14.0Hz),118.7,115.5(d,JC-F＝4.0Hz),111.4,106.2(d,JC-F＝26.0Hz),83.9,81.0,42.8,40.0.
Example 12
Preparation of N- ((3S,3aS) -7- (4-cyanophenyl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 12)
Figure BDA0002379968460000381
Compound 11(65.0mg,0.19mmol) was dissolved in dichloromethane (15.0mL), triethylamine (53.3. mu.L, 0.38mmol) was added under ice-bath conditions, and acetyl chloride (27.4. mu.L, 0.38mmol) was slowly added to obtain compound 12 as an off-white solid in 58.0mg, 79.5% yield according to the preparation method of compound 2 in example 2.
LC-MS(ESI):m/z[M+H]+Calculated value C20H17FN3O4: 382.1203, respectively; measured value: 382.1194
1H NMR(400MHz,CDCl3)δ:7.72(dd,J＝2.0,6.8Hz,2H),7.58(dd,J＝1.6,8.4Hz,2H),7.13(d,J＝8.0Hz,1H),6.75(d,J＝10.8Hz,1H),5.96(t,J＝6.0Hz,1H),5.47(d,J＝1.2Hz,1H),4.82(d,J＝16.4Hz,1H),4.69(td,J＝1.2,4.2Hz,1H),4.47(d,J＝16.4Hz,1H),3.72-3.69(m,2H),2.04(s,3H).
13C NMR(100MHz,CDCl3)δ:171.1,159.0(d,JC-F＝249.0Hz),156.3,153.4(d,JC-F＝12.0Hz),139.6,132.4,129.5(d,JC-F＝3.0Hz),128.2(d,JC-F＝10.0Hz),122.3(d,JC-F＝14.0Hz),118.7,115.4(d,JC-F＝3.0Hz),111.4,106.2(d,JC-F＝26.0Hz),83.7,78.9,40.3,40.2,23.2.
Example 13
Preparation of (3S,3aS) -7- (4-acetylphenyl) -3- (aminomethyl) -6-fluoro-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 13)
Figure BDA0002379968460000382
The first step is as follows: preparation of tert-butyl ((3S,3aS) -7- (4-acetylphenyl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 18)
Intermediate 12(220.0mg,0.53mmol), 4-acetylphenylboronic acid (112.4mg,0.69mmol), tetrakistriphenylphosphine palladium (61.3mg,0.05mmol) and sodium carbonate (111.8mg,1.06mmol) were charged to a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under argon protection to afford intermediate 18 as an off-white solid 215.0mg in 89.2% yield according to the procedure for preparation of intermediate 13 in example 1.
LC-MS(ESI):m/z[M+H]+Calculated value C24H26FN2O6: 457.1775, respectively; measured value: 457.1765
1H NMR(400MHz,CDCl3)δ:8.02(dd,J＝1.6,6.8Hz,2H),7.58(dd,J＝2.0,8.8Hz,2H),7.16(d,J＝8.0Hz,1H),6.75(d,J＝11.2Hz,1H),5.51(s,1H),4.90(t,J＝4.8Hz,1H),4.84(d,J＝16.4Hz,1H),4.66(td,J＝1.2,4.8Hz,1H),4.46(d,J＝16.4Hz,1H),3.64-3.51(m,2H),2.64(s,3H),1.45(s,3H).
The second step is that: preparation of (3S,3aS) -7- (4-acetylphenyl) -3- (aminomethyl) -6-fluoro-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 13)
Intermediate 18(200.0mg,0.44mmol) was dissolved in dichloromethane (10.0mL), and trifluoroacetic acid (3.0mL) was added under ice-bath conditions, followed by the procedure for the preparation of compound 1 in example 1, to give compound 13 as an off-white solid (130.0mg, yield 83.3%).
LC-MS(ESI):m/z[M+H]+Calculated value C19H18FN2O4: 357.1251, respectively; measured value: 357.1237
1H NMR(400MHz,CDCl3)δ:8.02(dd,J＝2.0,6.8Hz,2H),7.58(dd,J＝1.6,8.4Hz,2H),7.18(d,J＝8.4Hz,1H),6.75(d,J＝11.2Hz,1H),5.37(d,J＝1.2Hz,1H),4.84(d,J＝16.4Hz,1H),4.61(td,J＝1.6,5.6Hz,1H),4.51(d,J＝16.4Hz,1H),3.17-3.04(m,2H),2.64(s,3H),1.64(s,2H).
13C NMR(100MHz,CDCl3)δ:197.7,159.0(d,JC-F＝249.0Hz),156.3,153.1(d,JC-F＝12.0Hz),139.7(d,JC-F＝2.0Hz),136.1,129.0,128.9,128.6,128.4,128.3,122.9(d,JC-F＝14.0Hz),115.3(d,JC-F＝3.0Hz),106.0(d,JC-F＝25.0Hz),83.9,81.0,42.82,40.0,26.7.
Example 14
Preparation of N- ((3S,3aS) -7- (4-acetylphenyl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 14)
Figure BDA0002379968460000391
Compound 13(85.0mg,0.24mmol) was dissolved in dichloromethane (15.0mL), triethylamine (49.6. mu.L, 0.36mmol) was added under ice-bath conditions, acetyl chloride (22. mu.L, 0.31mmol) was slowly added, and compound 17 was obtained as an off-white solid in 78.0mg, yield 82.1% according to the preparation method of compound 2 in example 2.
LC-MS(ESI):m/z[M+H]+Calculated value C21H20FN2O5: 399.1356, respectively; measured value: 399.1336
1H NMR(400MHz,CDCl3)δ:8.02(d,J＝8.0Hz,2H),7.58(d,J＝7.2Hz,2H),7.16(d,J＝8.0Hz,1H),6.74(d,J＝11.2Hz,1H),5.97(s,1H),5.45(s,1H),4.83(d,J＝16.4Hz,1H),4.69(t,J＝4.8Hz,1H),4.48(d,J＝16.0Hz,1H),3.77-3.65(m,2H),2.64(s,3H),2.04(s,3H).
13C NMR(100MHz,CDCl3)δ:197.8,171.3,159.0(d,JC-F＝249.0Hz),156.4,153.0(d,JC-F＝12.0Hz),139.6,136.1,129.0,128.9,128.3(d,JC-F＝4.0Hz),123.0(d,JC-F＝14.0Hz),115.1(d,JC-F＝3.0Hz),106.0(d,JC-F＝26.0Hz),83.7,79.0,40.21,40.17,26.7,23.1.
Example 15
Preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7- (4-morpholinylphenyl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-1-one (Compound 15)
Figure BDA0002379968460000401
The first step is as follows: preparation of tert-butyl ((3S,3aS) -6-fluoro-7- (4-morpholinylphenyl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 19)
Intermediate 12(200.0mg,0.48mmol), 4- (4-morpholinyl) phenylboronic acid (119.5mg,0.58mmol), tetrakistriphenylphosphine palladium (50.0mg,0.05mmol) and sodium carbonate (101.6mg,0.96mmol) were charged into a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under argon protection to obtain intermediate 19 as an off-white solid 195.0mg in 81.6% yield according to the preparation method of intermediate 13 in example 1.
LC-MS(ESI):m/z[M+H]+ calculated value C26H31FN3O6: 500.2197, respectively; measured value: 500.2172
1H NMR(400MHz,CDCl3)δ:7.41(dd,J＝1.6,8.8Hz,2H),7.10(d,J＝8.4Hz,1H),6.98(d,J＝8.4Hz,2H),6.70(d,J＝10.8Hz,1H),5.46(s,1H),4.90(t,J＝5.2Hz,1H),4.81(d,J＝16.0Hz,1H),4.65(td,J＝12,4.8Hz,1H),4.43(d,J＝16.0Hz,1H),3.89(t,J＝4.8Hz,4H),3.58-3.54(m,2H),3.22(t,J＝4.8Hz,4H),1.45(s,9H).
The second step is that: preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7- (4-morpholinylphenyl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-1-one (Compound 15)
Intermediate 19(160.0mg,0.32mmol) was dissolved in dichloromethane (10.0mL), and trifluoroacetic acid (3.0mL) was added under ice-bath conditions to follow the procedure for the preparation of compound 1 in example 1 to give compound 15 as an off-white solid 85.0mg with a yield of 66.4%.
LC-MS(ESI):m/z[M+H]+ calculated value C21H23FN3O4: 400.1673, respectively; measured value: 400.1648
1H NMR(400MHz,CDCl3)δ:7.40(d,J＝8.0Hz,2H),7.11(d,J＝8.4Hz,1H),6.83(d,J＝8.8Hz,2H),6.70(d,J＝11.2Hz,1H),5.34(s,1H),4.81(d,J＝16.4Hz,1H),4.62(s,1H),4.48(d,J＝16.4Hz,1H),3.88(t,J＝4.8Hz,4H),3.22-3.06(m,6H),1.60(brs,2H).
13C NMR(100MHz,CDCl3)δ:158.9(d,JC-F＝246.0Hz),156.4,151.7(d,JC-F＝12.0Hz),150.7,129.6,129.5,127.8(d,JC-F＝5.0Hz),126.1,123.9(d,JC-F＝14.0Hz),115.4,114.9(d,JC-F＝3.0Hz),105.7(d,JC-F＝27.0Hz),83.7,80.83,66.86,49.0,42.8,40.1.
Example 16
Preparation of N- ((3S,3aS) -6-fluoro-7- (4-morpholinophenyl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 16)
Figure BDA0002379968460000411
Compound 15(60.0mg,0.15mmol) was dissolved in dichloromethane (15.0mL), triethylamine (31. mu.L, 0.23mmol) was added under ice-bath conditions, then acetyl chloride (13.8. mu.L, 0.20mmol) was added slowly, and compound 19 was obtained as an off-white solid 52.0mg with a yield of 78.3% according to the preparation method of compound 2 in example 2.
LC-MS(ESI):m/z[M+H]+Calculated value C23H25FN3O5: 442.1778, respectively; measured value: 442.1757
1H NMR(400MHz,CDCl3)δ:7.39(d,J＝7.6Hz,2H),7.08(d,J＝8.4Hz,1H),6.95(d,J＝8.8Hz,2H),6.68(d,J＝10.8Hz,1H),6.54(brs,1H),5.41(s,1H),4.77(d,J＝16.4Hz,1H),4.67(t,J＝4.8Hz,1H),4.45(d,J＝16.4Hz,1H),3.87(d,J＝4.8Hz,4H),3.68(t,J＝4.8Hz,2H),3.19(d,J＝4.8Hz,4H),2.03(s,3H).
13C NMR(100MHz,CDCl3)δ:171.3,158.9(d,JC-F＝247.0Hz),156.6,151.6(d,JC-F＝12.0Hz),150.6,129.6,129.5,127.8(d,JC-F＝5.0Hz),126.1,124.0(d,JC-F＝15.0Hz),115.4,114.8(d,JC-F＝4.0Hz),105.8(d,JC-F＝26.0Hz),83.6,79.0,66.8,49.0,40.3,40.2,23.0.
Example 17
Preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7- (pyrimidin-5-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 17)
Figure BDA0002379968460000412
The first step is as follows: preparation of tert-butyl ((3S,3aS) -6-fluoro-1-oxo-7- (pyrimidin-5-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 20)
Intermediate 12(200.0mg,0.48mmol), 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (118.8mg,0.58mmol), palladium tetrakistriphenylphosphine (50.0mg,0.05mmol) and sodium carbonate (101.6mg,0.96mmol) were charged into a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under argon protection to obtain intermediate 20 as an off-white solid at 75.2mg in 66.7% yield according to the preparation method of intermediate 13 in example 1.
LC-MS(ESI):m/z[M+H]+Calculated value C20H22FN4O5: 417.1574, respectively; measured in factThe value: 417.1586
1H NMR(400MHz,CDCl3)δ:9.21(s,1H),8.88(d,J＝1.2Hz,2H),7.16(d,J＝8.0Hz,1H),6.80(d,J＝10.8Hz,1H),5.55(s,1H),4.90-4.84(m,2H),4.67(t,J＝4.8Hz,1H),4.47(d,J＝16.8Hz,1H),3.65-3.52(m,2H),1.45(s,9H).
The second step is that: preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7- (pyrimidin-5-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 17)
Intermediate 20(140.0mg,0.34mmol) was dissolved in dichloromethane (10.0mL), and trifluoroacetic acid (3.0mL) was added under ice-bath conditions to follow the procedure for the preparation of compound 1 in example 1 to give compound 17 as an off-white solid 80.0mg with a yield of 74.5%.
LC-MS(ESI):m/z[M+H]+Calculated value C15H14FN4O3: 317.1050, respectively; measured value: 317.1039
1H NMR(400MHz,CDCl3)δ:9.20(s,1H),8.87(d,J＝1.2Hz,2H),7.17(d,J＝8.0Hz,1H),6.81(d,J＝11.2Hz,1H),5.40(d,J＝1.6Hz,1H),4.86(d,J＝16.4Hz,1H),4.61(td,J＝1.6,5.2Hz,1H),4.52(d,J＝16.4Hz,1H),3.17-3.05(m,2H),1.42(brs,2H).
13C NMR(100MHz,CDCl3)δ:159.1(d,JC-F＝249.0Hz),157.7,156.3,156.2,156.1,154.0(d,JC-F＝12.0Hz),129.1(d,JC-F＝2.0Hz),127.9(d,JC-F＝4.0Hz),116.9(d,JC-F＝15.0Hz),116.0(d,JC-F＝3.0Hz),106.3(d,JC-F＝26.0Hz),84.0,81.0,42.8,39.9.
Example 18
Preparation of N- ((3S,3aS) -6-fluoro-1-oxo-7- (pyrimidin-5-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 18)
Figure BDA0002379968460000421
Compound 17(50.0mg,0.16mmol) was dissolved in dichloromethane (15.0mL), triethylamine (33. mu.L, 0.24mmol) was added under ice-bath conditions, and acetyl chloride (15. mu.L, 0.21mmol) was then added slowly to afford compound 18 as an off-white solid in 50.0mg, 88.3% yield, according to the preparation method of compound 2 in example 2.
LC-MS(ESI):m/z[M+H]+Calculated value C17H16FN4O4: 359.1156, respectively; measured value: 359.1150
1H NMR(400MHz,CDCl3)δ:9.20(s,1H),8.87(d,J＝1.2Hz,2H),7.16(d,J＝8.0Hz,1H),6.79(d,J＝10.8Hz,1H),6.21(t,J＝6.4Hz,1H),5.50(d,J＝1.2Hz,1H),4.84(d,J＝16.4Hz,1H),4.70(t,J＝4.8Hz,1H),4.50(d,J＝16.4Hz,1H),3.72-3.69(m,2H),2.04(s,3H).
13C NMR(100MHz,CDCl3)δ:171.2,159.1(d,JC-F＝248.8Hz),157.6,156.3,156.2,156.1,153.9(d,JC-F＝12.2Hz),129.1(d,JC-F＝1.9Hz),127.8(d,JC-F＝4.3Hz),117.1(d,JC-F＝15.1Hz),115.8(d,JC-F＝3.6Hz),106.4(d,JC-F＝25.5Hz),83.8,78.9,40.2,40.1,23.1.
Example 19
Preparation of N- ((3S,3aS) -6-fluoro-7- (1- (2-hydroxyacetyl) -1,2,3, 6-tetrahydropyridin-4-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 19)
Figure BDA0002379968460000431
The first step is as follows: preparation of tert-butyl 4- ((3S,3aS) -3- (acetamidomethyl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-7-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (intermediate 21)
Intermediate 14(140mg,0.39mmol), N-t-butoxycarbonyl-1, 2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (132mg,0.43mmol), tetrakistriphenylphosphine palladium (45.0mg,0.04mmol) and sodium carbonate (82.7mg,0.78mmol) were charged into a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9mL) and water (1.5mL) was added under an argon atmosphere to obtain intermediate 21 as an off-white solid at 130.0mg in a yield of 72.3% according to the preparation method of intermediate 13 in example 1.
LC-MS(ESI):m/z[M+Na]+ calculated value C23H28FN3NaO6: 484.1860, respectively; measured value: 484.1844
1H NMR(400MHz,CDCl3)δ:6.93(d,J＝8.4Hz,1H),6.60(d,J＝11.6Hz,1H),5.93(s,1H),5.86(s,1H),5.37(d,J＝1.2Hz,1H),4.74(d,J＝16.4Hz,1H),4.65(t,J＝4.8Hz,1H),4.40(d,J＝16.4Hz,1H),4.06-4.04(m,2H),3.75-3.59(m,4H),2.44(brs,2H),2.03(s,3H),1.49(s,9H).
The second step is that: preparation of N- ((3S,3aS) -6-fluoro-7- (1- (2-hydroxyacetyl) -1,2,3, 6-tetrahydropyridin-4-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 19)
Dissolving the intermediate 21(130.0mg,0.28mmol) in dichloromethane (10.0mL), adding trifluoroacetic acid (3.0mL) under an ice bath condition, carrying out heat preservation reaction for 3 hours, then completing the reaction, neutralizing the reaction solution with saturated sodium bicarbonate aqueous solution under the ice bath condition to be neutral, extracting with dichloromethane for three times, combining organic phases, drying with anhydrous sodium sulfate, filtering, and carrying out spin drying to obtain colorless oil. The oil was redissolved in DMF (4.0mL), glycolic acid (31.9mg,0.42mmol), EDCI (81.0mg,0.42mmol), HOBt (56.8mg,0.42mmol) and triethylamine (98.7mL,0.71mmol) were sequentially added, stirred at room temperature for 8 hours, the reaction solution was extracted three times with dichloromethane after ice water addition, the organic phases were combined, washed once with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous salt solution, dried over anhydrous sodium sulfate, filtered and chromatographed on a silica gel column to give compound 19 as an off-white solid 55.0mg with a yield of 46.6%.
LC-MS(ESI):m/z[M+H]+Calculated value C20H23FN3O6: 420.1571, respectively; measured value: 420.1558
1H NMR(400MHz,CDCl3)δ:6.91(d,J＝8.0Hz,1H),6.61(dd,J＝3.2,11.6Hz,1H),6.17(t,J＝6.4Hz,1H),5.91-5.84(m,1H),5.40(s,1H),4.74(d,J＝16.4Hz,1H),4.65(t,J＝4.8Hz,1H),4.40(d,J＝16.4Hz,1H),4.28-4.19(m,3H),3.93-3.92(m,1H),3.85(t,J＝5.6Hz,1H),3.69-3.66(m,3H),3.45(t,J＝5.6Hz,1H),2.52(brs,2H),2.02(s,3H).
Example 20
Preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7-morpholine-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 20)
Figure BDA0002379968460000441
The first step is as follows: preparation of tert-butyl ((3S,3aS) -6-fluoro-7-morpholin-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 22)
Intermediate 12(300mg,0.72mmol), morpholine (125.0mg,1.44mmol), X-PHOS (103.0mg,0.22mmol), palladium acetate (24.2g,0.11mmol) and cesium carbonate (351.6mg,1.08mmol) were added to toluene (15.0mL), reacted at 100 ℃ for 6 hours under argon protection, filtered with suction, and subjected to silica gel column chromatography (petroleum ether/ethyl acetate: 90/30) to give intermediate 22 as an off-white solid 134.0mg in 44.1% yield.
LC-MS(ESI):m/z[M+H]+Calculated value C20H27FN3O6: 424.1884, respectively; measured value: 424.1870
1H NMR(400MHz,CDCl3)δ:6.67-6.62(m,2H),5.38(s,1H),4.87(s,1H),4.73(d,J＝16.4Hz,1H),4.61(t,J＝4.8Hz,1H),4.37(d,J＝16.4Hz,1H),3.87(d,J＝4.8Hz,4H),3.56-3.49(m,2H),3.01(d,J＝4.8Hz,4H),1.44(s,9H).
The second step is that: preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7-morpholine-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 20)
Intermediate 22(140.0mg,0.33mmol) was dissolved in dichloromethane (10mL), and trifluoroacetic acid (3mL) was added under ice-bath conditions to follow the procedure for the preparation of compound 1 in example 1 to give compound 20 as an off-white solid in 75.0mg, 70.3% yield.
LC-MS(ESI):m/z[M+H]+Calculated value C15H19FN3O4: 324.1360, respectively; measured value: 324.1347
1H NMR(400MHz,CDCl3)δ:6.66-6.62(m,2H),5.25(d,J＝1.6Hz,1H),4.74(d,J＝16.4Hz,1H),4.55(td,J＝1.2,4.8Hz,1H),4.41(d,J＝16.4Hz,1H),3.86(d,J＝4.8Hz,4H),3.14-2.99(m,6H),1.37(brs,2H).
13C NMR(100MHz,CDCl3)δ:156.5,155.0(d,JC-F＝246.6Hz),147.5(d,JC-F＝11.6Hz),135.7(d,JC-F＝9.7Hz),116.3(d,JC-F＝4.3Hz),114.4(d,JC-F＝3.7Hz),106.4(d,JC-F＝24.1Hz),83.6,81.0,67.0,51.4,51.3,42.9,40.2.
Example 21
Preparation of N- ((3S,3aS) -6-fluoro-7-morpholin-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 21)
Figure BDA0002379968460000451
Compound 20(60.0mg,0.14mmol) was dissolved in dichloromethane (15mL), and triethylamine (39mL,0.28mmol) was added under ice-bath conditions, followed by slow addition of acetyl chloride (17mL,0.24mmol) to afford compound 21 as an off-white solid, 58.4mg, 86.1% yield, according to the procedure for preparation of compound 2 in example 2.
LC-MS(ESI):m/z[M+H]+Calculated value C17H21FN3O5: 366.1465, respectively; measured value: 366.1453
1H NMR(400MHz,CDCl3)δ:6.65-6.59(m,2H),6.32(s,1H),5.33(d,J＝1.2Hz,1H),4.70(d,J＝16.4Hz,1H),4.63(t,J＝5.2Hz,1H),4.38(d,J＝16.4Hz,1H),3.85(d,J＝4.8Hz,4H),3.67(t,J＝5.6Hz,2H),2.98(d,J＝4.8Hz,4H),2.02(s,3H).
13C NMR(100MHz,CDCl3)δ:171.2,156.6,155.1(d,JC-F＝246.0Hz),147.4(d,JC-F＝11.0Hz),135.9(d,JC-F＝9.0Hz),116.3(d,JC-F＝4.0Hz),114.3(d,JC-F＝3.0Hz),106.5(d,JC-F＝24.0Hz),83.5,79.0,67.0,51.4,51.3,40.4,40.3,23.1.
Example 22
Preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7-thiomorpholine-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 22)
Figure BDA0002379968460000452
The first step is as follows: preparation of tert-butyl ((3S,3aS) -6-fluoro-1-oxo-7-thiomorpholine-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 23)
Intermediate 12(200.0mg,0.48mmol), thiomorpholine (99mg,0.96mmol), X-PHOS (69mg,0.14mmol), palladium acetate (16g,0.07mmol) and cesium carbonate (234.4mg,0.72mmol) were added to toluene (15mL) according to the preparation method of intermediate 22 in example 20 to give intermediate 23 as a pale yellow solid 46.0mg with a yield of 21.8%.
LC-MS(ESI):m/z[M+H]+Calculated value C20H27FN3O5S: 440.1655, respectively; measured value: 440.1650
1H NMR(400MHz,CDCl3)δ:6.65-6.59(m,2H),5.37(s,1H),4.94(brs,1H),4.71(d,J＝16.4Hz,1H),4.59(td,J＝1.2,4.8Hz,1H),4.35(d,J＝16.4Hz,1H),3.54-3.51(m,2H),3.21(d,J＝4.8Hz,4H),2.79(d,J＝4.8Hz,4H),1.43(s,9H).
The second step is that: preparation of (3S,3aS) -3- (aminomethyl) -6-fluoro-7-thiomorpholine-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 22)
Intermediate 23(160mg,0.36mmol) was dissolved in dichloromethane (10mL), and trifluoroacetic acid (3mL) was added under ice-bath conditions, followed by the procedure for the preparation of compound 1 in example 1, to give compound 22 as an off-white solid 83.0mg, yield 70.5%.
LC-MS(ESI):m/z[M+H]+Calculated value C15H19FN3O3S: 340.1131, respectively; measured value: 340.1107
1H NMR(400MHz,CDCl3)δ:6.67-6.61(m,2H),5.25(d,J＝1.6Hz,1H),4.73(d,J＝16.4Hz,1H),4.54(td,J＝1.2,4.8Hz,1H),4.40(d,J＝16.4Hz,1H),3.23(d,J＝4.8Hz,4H),3.13-3.01(m,2H),2.80(d,J＝4.8Hz,4H),1.39(s,2H).
13C NMR(100MHz,CDCl3)δ:160.3(d,JC-F＝247.0Hz),156.46,147.8(d,JC-F＝12.0Hz),136.8(d,JC-F＝10.0Hz),117.9(d,JC-F＝40.0Hz),114.4(d,JC-F＝40.0Hz),106.3(d,JC-F＝24.0Hz),83.6,81.0,53.7,42.9,40.1,28.1.
Example 23
Preparation of N- ((3S,3aS) -6-fluoro-1-oxo-7-thiomorpholine-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 23)
Figure BDA0002379968460000461
Compound 22(60.0mg,0.18mmol) was dissolved in dichloromethane (15mL), triethylamine (37. mu.L, 0.27mmol) was added under ice-bath conditions, and acetyl chloride (15. mu.L, 0.21mmol) was then added slowly to afford compound 23 as an off-white solid in 50.0mg, 74.6% yield, according to the preparation method of compound 2 in example 2.
LC-MS(ESI):m/z[M+H]+Calculated value C17H21FN3O4S: 382.1237, respectively; measured value: 382.1220
1H NMR(400MHz,CDCl3)δ:6.64-6.59(m,2H),6.35(s,1H),5.33(d,J＝1.2Hz,1H),4.70(d,J＝16.4Hz,1H),4.62(t,J＝4.8Hz,1H),4.37(d,J＝16.4Hz,1H),3.67(t,J＝5.2Hz,2H),3.20(d,J＝4.8Hz,4H),3.79(d,J＝4.8Hz,4H),2.01(s,3H).
13C NMR(100MHz,CDCl3)δ:171.2,156.5,155.3(d,JC-F＝247.0Hz),147.6(d,JC-F＝12.0Hz),136.9(d,JC-F＝10.0Hz),117.8(d,JC-F＝4.0Hz),114.2(d,JC-F＝4.0Hz),106.3(d,JC-F＝24.0Hz),83.4,79.0,53.7,53.6,40.3,40.2,28.1,23.0.
Example 24
Preparation of 5- ((3S,3aS) -3- (aminomethyl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-7-yl) picoline nitrile (Compound 24)
Figure BDA0002379968460000471
The first step is as follows: preparation of tert-butyl ((3S,3aS) -7-bromo-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 24)
Intermediate 24 was obtained as a white solid with a yield of 72.7% by reference to the preparation method of intermediate 12 in example 1 using salicylic acid as a starting material.
1H NMR(500MHz,CDCl3)δ:7.28(d,J＝8.5Hz,1H),7.22(s,1H),6.78(d,J＝9.0Hz,1H),5.40(s,1H),4.87(brs,1H),4.78(d,J＝17.0Hz,1H),4.63(t,J＝5.0Hz,1H),4.40(d,J＝17.0Hz,1H),3.65–3.45(m,2H),1.44(s,9H).
LC-MS(ESI):m/z[M+Na]+Calculated value C16H19BrN2NaO5421.0375 and 423.0355; measured value: 421.0364, and 423.0343.
The second step is that: preparation of tert-butyl ((3S,3aS) -7- (6-cyanopyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 25)
After adding intermediate 24(200mg, 0.5mmol), sodium carbonate (106mg, 1mmol), palladium tetrakistriphenylphosphine (8mg), 2-cyanopyridine-5-boronic acid pinacol ester (138mg, 0.6mmol) in a 50mL two-necked flask, DMSO/water (6: 1) was injected into the above system under Ar protection, and heated at 100 ℃ under reflux for 5 h. TLC monitored the reaction was complete and the reaction was cooled to room temperature, diluted with water, extracted three times with dichloromethane, the organic phases combined, washed 1 time with saturated brine, dried over anhydrous sodium sulfate and chromatographed on silica gel (dichloromethane/methanol ═ 100/1) to give intermediate 25 as a white solid 187mg, 88.6% yield.
1H NMR(400MHz,CDCl3)δ:8.88(dd,J＝2.4,0.8Hz,1H),7.94(dd,J＝8.0,2.4Hz,1H),7.75(dd,J＝8.0,0.8Hz,1H),7.43(dd,J＝8.4,2.0Hz,1H),7.35–7.29(m,1H),7.05(d,J＝8.4Hz,1H),5.52(s,1H),4.89(d,J＝16.8Hz,2H),4.68(td,J＝4.8,1.2Hz,1H),4.52(d,J＝16.8Hz,1H),3.61-3.55(m,2H),1.45(s,9H).
LC-MS(ESI):m/z[M+H]+ calculated value C22H23N4O5: 423.1668, respectively; measured value: 423.1658.
the third step: preparation of 5- ((3S,3aS) -3- (aminomethyl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-7-yl) picoline nitrile (Compound 24)
After adding intermediate 25(187mg, 0.44mmol), dichloromethane (6mL), and trifluoroacetic acid (2.5mL) to a 25mL single-neck flask, the mixture was stirred at room temperature for 1 h. TLC after the reaction was completed, saturated sodium bicarbonate solution was added dropwise to the above system in ice bath. After neutralizing the system to neutrality, the mixture was extracted 3 times with dichloromethane, the organic phases were combined, washed with saturated brine 1 time, dried over anhydrous sodium sulfate, and subjected to silica gel column chromatography (dichloromethane/methanol ═ 100/3) to give compound 24 as a white solid (98 mg, yield 69.1%).
1H NMR(500MHz,CDCl3)δ:8.89(s,1H),7.94(d,J＝8.0Hz,1H),7.75(d,J＝7.5Hz,1H),7.44(d,J＝8.5Hz,1H),7.34(s,1H),7.06(d,J＝8.5Hz,1H),5.39(s,1H),4.90(d,J＝17.0Hz,1H),4.74–4.46(m,2H),3.24–2.98(m,2H),1.54(s,2H).
13C NMR(400MHz,CDCl3)δ:156.38,153.50,149.23,138.79,134.43,132.13,130.21,128.46,127.40,125.73,120.07,119.23,117.28,83.84,81.08,42.83,40.36.
LC-MS(ESI):m/z[M+H]+ calculated value C17H15O3N4323.1139; found 323.1130.
Example 25
Preparation of N- (((3S,3aS) -7- (6-cyanopyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 25)
Figure BDA0002379968460000481
After compound 24(77mg, 0.24mmol), dichloromethane (6mL), triethylamine (67. mu.L, 0.48mmol) and acetyl chloride (34. mu.L, 0.48mmol) were added to a 25mL single-necked flask, the mixture was stirred at room temperature for 2 hours. TLC monitored completion of the reaction, reaction mixture was washed with water 3 times, saturated brine 1 time, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to give compound 25 as a white solid 81mg with 92.7% yield.
1H NMR(400MHz,CDCl3)δ:8.88(s,1H),7.94(d,J＝8.4Hz,1H),7.75(d,J＝8.0Hz,1H),7.43(d,J＝8.4Hz,1H),7.32(s,1H),7.05(d,J＝8.4Hz,1H),5.87(s,1H),5.46(s,1H),4.88(d,J＝16.8Hz,1H),4.71(t,J＝4.8Hz,1H),4.54(d,J＝16.8Hz,1H),3.72-3.69(m,2H),2.05(s,3H).
13C NMR(400MHz,CDCl3)δ:171.16,156.36,153.36,149.22,138.78,134.48,132.13,130.33,128.48,127.49,125.65,119.89,119.28,117.27,83.62,78.94,40.54,40.28,23.12.
LC-MS(ESI):m/z[M+H]+Calculated value C19H17O4N4365.1244; found 365.1240.
Example 26
Preparation of (3S,3aS) -3- (aminomethyl) -7- (pyridin-4-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-1-one (Compound 26)
Figure BDA0002379968460000491
The first step is as follows: preparation of tert-butyl ((3S,3aS) -1-oxo-7- (pyridin-4-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 26)
Starting from intermediate 24(200mg, 0.50mmol), pyridine-4-boronic acid (74mg, 0.6mmol), a similar procedure was followed as in intermediate 25 to give intermediate 26 as an off-white solid 141mg with a yield of 71.0%.
1H NMR(500MHz,CDCl3)δ:8.65(s,2H),7.48-7.44(m,3H),7.36(s,1H),7.01(d,J＝8.5Hz,1H),5.50(s,1H),4.96(s,1H),4.88(d,J＝17.0Hz,1H),4.69-4.67(m,1H),4.51(d,J＝17.0Hz,1H),3.60-3.55(m,2H),1.45(s,9H).
LC-MS(ESI):m/z[M+H]+Calculated value C21H24N3O5: 398.1716, respectively; measured value: 398.1717.
the second step is that: preparation of (3S,3aS) -3- (aminomethyl) -7- (pyridin-4-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-1-one (Compound 26)
Using intermediate 26 as a starting material (141mg, 0.35mmol), the similar procedure as in compound 24 was used to give compound 26 as a white solid, 101mg, 97.1% yield.
1H NMR(500MHz,CDCl3)δ:8.64(d,J＝5.5Hz,2H),7.49–7.38(m,4H),7.02(d,J＝8.5Hz,1H),5.37(s,1H),4.89(d,J＝16.5Hz,1H),4.69–4.47(m,2H),3.23–2.99(m,2H),1.54(s,2H).
13C NMR(400MHz,CDCl3)δ:156.43,153.16,150.32,147.18,132.52,127.05,125.37,121.20,119.62,118.81,83.77,81.06,42.88,40.44.
LC-MS(ESI):m/z[M+H]+Calculated value C16H16O3N3298.1186; found 298.1176.
Example 27
Preparation of N- (((3S,3aS) -1-oxo-7- (pyridin-4-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 27)
Figure BDA0002379968460000501
Using compound 26 as a starting material (69mg, 0.23mmol), the similar procedure as in compound 25 was performed by silica gel column chromatography (dichloromethane/methanol-100/3) to give compound 27 as a white solid (54 mg, 69.2% yield).
1H NMR(400MHz,CDCl3)δ:8.65(s,2H),7.49–7.44(m,3H),7.36–7.35(m,1H),7.01(d,J＝8.4Hz,1H),6.18(s,1H),5.44(d,J＝1.2Hz,1H),4.87(d,J＝16.8Hz,1H),4.70(td,J＝1.2,5.6Hz,1H),4.54(d,J＝16.8Hz,1H),3.73-3.70(m,2H),2.05(s,3H).
13C NMR(400MHz,CDCl3)δ:171.10,156.43,153.06,150.21,147.27,132.60,127.14,125.29,121.27,119.45,118.87,83.56,78.98,40.60,40.27,23.11.
LC-MS(ESI):m/z[M+H]+ calculated value C18H18O4N3340.1292; found 340.1287.
Example 28
Preparation of (3S,3aS) -3- (aminomethyl) -7- (pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-1-one (Compound 28)
Figure BDA0002379968460000502
The first step is as follows: preparation of tert-butyl (((3S,3aS) -1-oxo-7- (pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 27)
Starting from intermediate 24(200mg, 0.50mmol), pyridine-3-boronic acid (74mg, 0.6mmol), a similar procedure was followed as in intermediate 25 to give intermediate 27 as a white solid, 135mg, 67.9% yield.
1H NMR(500MHz,CDCl3)δ:8.79(s,1H),8.58(d,J＝5.0Hz,1H),7.82(d,J＝8.0Hz,1H),7.41(d,J＝8.5Hz,1H),7.36(dd,J＝8.0,4.5Hz,1H),7.29(s,1H),7.01(d,J＝8.0Hz,1H),5.48(s,1H),4.96(s,1H),4.88(d,J＝16.5Hz,1H),4.68(t,J＝5.0Hz,1H),4.51(d,J＝16.5Hz,1H),3.59-3.56(m,2H),1.45(s,9H).
LC-MS(ESI):m/z[M+H]+Calculated value C21H24N3O5: 398.1716, respectively; measured value: 398.1715.
the second step is that: preparation of (3S,3aS) -3- (aminomethyl) -7- (pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-1-one (Compound 28)
Using the similar procedure as in compound 24, starting from intermediate 27 (121mg, 0.30mmol), compound 28 was obtained as a white solid 22mg with a yield of 24.7%.
1H NMR(400MHz,CDCl3)δ:8.78(d,J＝2.4Hz,1H),8.58(dd,J＝5.2,2.0Hz,1H),7.81(dt,J＝8.4,1.6Hz,1H),7.41(dd,J＝8.4,2.4Hz,1H),7.35(dd,J＝8.0,4.8Hz,1H),7.30(d,J＝2.4Hz,1H),7.01(d,J＝8.4Hz,1H),5.35(s,1H),4.88(d,J＝16.8Hz,1H),4.65(t,J＝5.2Hz,1H),4.56(d,J＝16.8Hz,1H),3.18-3.06(m,2H),1.75(brs,2H).
13C NMR(400MHz,CDCl3)δ:156.47,152.42,148.44,147.99,135.62,134.03,132.35,127.19,125.41,123.60,119.63,118.77,83.73,81.02,42.89,40.48.
LC-MS(ESI):m/z[M+H]+Calculated value C16H16O3N3298.1186; found 298.1175.
Example 29
Preparation of N- (((3S,3aS) -1-oxo-7- (pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 29)
Figure BDA0002379968460000511
Using compound 28 as a starting material (20mg, 0.07mmol), the similar procedure as in compound 25 was used to give compound 29 as a pale yellow solid, 25mg, 100% yield.
1H NMR(400MHz,CDCl3)δ:8.80(s,1H),8.59(s,1H),7.83(d,J＝8.0Hz,1H),7.41-7.36(m,2H),7.29(d,J＝2.4Hz,1H),7.01(dd,J＝8.4,1.6Hz,1H),6.27(s,1H),5.44(s,1H),4.87(d,J＝16.8Hz,1H),4.71(t,J＝5.2Hz,1H),4.54(d,J＝16.8Hz,1H),3.79–3.61(m,2H),2.05(s,3H).
13C NMR(400MHz,CDCl3)δ:171.10,156.47,152.38,148.07,147.64,135.83,134.38,132.27,127.28,125.34,123.77,119.49,118.85,83.53,78.97,40.63,40.28,23.11.
LC-MS(ESI):m/z[M+H]+ calculated value C18H18O4N3340.1292; found 340.1285.
Example 30
Preparation of (3S,3aS) -7- (4-acetylphenyl) -3- (aminomethyl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-1-one (Compound 30)
Figure BDA0002379968460000521
The first step is as follows: preparation of tert-butyl (((3S,3aS) -7- (4-acetylphenyl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 28)
Similar procedure as in intermediate 25 was used starting from intermediate 24(200mg, 0.50mmol), 4-acetylphenylboronic acid (99mg, 0.6mmol) to give intermediate 28 as a pale yellow solid 189mg with a yield of 86.3%.
1H NMR(400MHz,CDCl3)δ:8.02(d,J＝8.4Hz,2H),7.62(d,J＝8.4Hz,2H),7.46(dd,J＝8.8,2.4Hz,1H),7.34(d,J＝2.4Hz,1H),7.00(d,J＝8.8Hz,1H),5.49(s,1H),4.91(s,1H),4.88(d,J＝16.8Hz,1H),4.69–4.66(m,1H),4.51(d,J＝16.8Hz,1H),3.61-3.56(m,2H),2.64(s,3H),1.45(s,9H).
LC-MS(ESI):m/z[M+Na]++Calculated value C24H26N2NaO6: 461.1689, respectively; measured value: 461.1678.
the second step is that: preparation of (3S,3aS) -7- (4-acetylphenyl) -3- (aminomethyl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-1-one (Compound 30)
Using intermediate 28 as a starting material (176mg, 0.40mmol), a similar procedure as in compound 24 was used to give compound 30 as a white solid, 108mg, 80.0% yield.
1H NMR(500MHz,CDCl3)δ:8.02(d,J＝8.0Hz,2H),7.62(d,J＝8.0Hz,2H),7.46(d,J＝8.5Hz,1H),7.36(s,1H),7.01(d,J＝8.5Hz,1H),5.36(s,1H),4.88(d,J＝17.0Hz,1H),4.63-4.6(m,1H),4.56(d,J＝17.0Hz,1H),3.17-3.05(m,2H),2.64(s,3H),1.48(brs,2H).
13C NMR(400MHz,CDCl3)δ:197.68,156.47,152.53,144.59,135.78,134.36,129.01,127.30,126.82,125.52,119.45,118.61,83.74,81.11,42.93,40.49,26.67.
LC-MS(ESI):m/z[M+H]+Calculated value C19H19O4N2339.1339; found 339.1343.
Example 31
Preparation of N- (((3S,3aS) -7- (4-acetylphenyl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 31)
Figure BDA0002379968460000531
Using the similar procedure as in compound 25, starting from compound 30 (65mg, 0.19mmol), compound 31 was obtained in the form of a white solid (78 mg) with a yield of 100%.
1H NMR(400MHz,CDCl3)δ:8.01(d,J＝8.4Hz,2H),7.61(d,J＝8.4Hz,2H),7.45(dd,J＝8.8,2.4Hz,1H),7.33(d,J＝2.0Hz,1H),6.99(d,J＝8.4Hz,1H),6.09(s,1H),5.42(s,1H),4.86(d,J＝16.4Hz,1H),4.75–4.66(m,1H),4.53(d,J＝16.4Hz,1H),3.84–3.59(m,2H),2.64(s,3H),2.05(s,3H).
13C NMR(400MHz,CDCl3)δ:197.70,171.07,156.47,152.39,144.58,135.79,134.49,129.01,127.38,126.83,125.43,119.26,118.65,83.52,78.96,40.66,40.28,26.68,23.12.
LC-MS(ESI):m/z[M+H]+ calculated value C21H21O5N2381.1445; found 381.1440.
Example 32
Preparation of 4- ((3S,3aS) -3- (aminomethyl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-7-yl) benzonitrile (Compound 32)
Figure BDA0002379968460000532
The first step is as follows: preparation of tert-butyl ((3S,3aS) -7- (4-cyanophenyl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 29)
Starting from intermediate 24(200mg, 0.50mmol), 4-cyanophenylboronic acid (89mg, 0.6mmol), the similar procedure used in intermediate 25 gave intermediate 29 as a white solid (179 mg, 84.8% yield).
1H NMR(400MHz,CDCl3)δ:7.71(d,J＝8.4Hz,2H),7.61(d,J＝8.4Hz,2H),7.42(dd,J＝8.8,2.4Hz,1H),7.30(d,J＝2.4Hz,1H),7.01(d,J＝8.8Hz,1H),5.49(s,1H),4.88(d,J＝16.4Hz,2H),4.71–4.64(m,1H),4.50(d,J＝16.4Hz,1H),3.60-3.55(m,2H),1.45(s,9H).
LC-MS(ESI):m/z[M+Na]+ calculated value C23H23N3NaO5: 444.1535, respectively; measured value: 444.1528.4- ((3S,3aS) -3- (aminomethyl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e)]Oxazolo [4,3-b][1,3]Preparation of oxazin-7-yl) benzonitrile (Compound 32)
Using the similar procedure as in compound 24, starting from intermediate 29 (150mg, 0.36mmol), compound 32 was obtained as a white solid 92mg with a yield of 79.6%.
1H NMR(400MHz,CDCl3)δ:7.72(d,J＝8.4Hz,2H),7.62(d,J＝8.4Hz,2H),7.42(dd,J＝8.4,2.0Hz,1H),7.32(d,J＝2.0Hz,1H),7.02(d,J＝8.4Hz,1H),5.37(s,1H),4.88(d,J＝16.8Hz,1H),4.66–4.60(m,1H),4.56(d,J＝16.8Hz,1H),3.23–3.00(m,2H),1.49(brs,2H).
13C NMR(400MHz,CDCl3)δ:156.44,152.85,144.51,133.62,132.69,127.33,125.56,119.62,118.85,118.79,110.85,83.77,81.10,42.89,40.44.
LC-MS(ESI):m/z[M+H]+ calculated value C18H16O3N3322.1186; found 322.1189.
Example 33
Preparation of N- (((3S,3aS) -7- (4-cyanophenyl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 33)
Figure BDA0002379968460000541
Using the similar procedure as in compound 25, starting from compound 32 (62mg, 0.19mmol), compound 33 was obtained as a white solid in 59mg with a yield of 85.5%.
1H NMR(400MHz,CDCl3)δ:7.71(d,J＝8.8Hz,2H),7.61(d,J＝8.8Hz,2H),7.42(dd,J＝8.4,2.0Hz,1H),7.30(d,J＝2.0Hz,1H),7.00(d,J＝8.4Hz,1H),5.96(s,1H),5.43(s,1H),4.86(d,J＝16.8Hz,1H),4.72-4.69(m,1H),4.53(d,J＝16.8Hz,1H),3.83–3.59(m,2H),2.05(s,3H).
13C NMR(400MHz,CDCl3)δ:171.04,156.42,152.73,144.51,133.78,132.72,127.38,125.49,119.45,118.87,110.89,83.57,78.96,40.64,40.31,23.17.
LC-MS(ESI):m/z[M+H]+Calculated value C20H18O4N3364.1292; found 364.1279.
Example 34
Preparation of (3S,3aS) -3- (aminomethyl) -7-morpholino-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 34)
Figure BDA0002379968460000551
The first step is as follows: preparation of tert-butyl (((3S,3aS) -7-morpholino-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 30)
After adding intermediate 24(400mg, 1mmol), cesium carbonate (489mg, 1.5mmol), palladium acetate (34mg, 0.15mmol), and 2-dicyclohexyl-p-2, 4, 6-triisopropylbiphenyl (143mg, 0.3mmol) to a 25mL two-necked flask, toluene (5mL) was injected into the above system under Ar protection, morpholine (175. mu.L, 2mmol) was dissolved in toluene (10mL) and the above system was then heated and refluxed at 120 ℃ for 5 hours. TLC monitored the reaction was complete, the reaction was cooled to rt, filtered through celite, the filtrate was concentrated and chromatographed on silica gel (dichloromethane/methanol-100/5) to give intermediate 30, 283mg of yellow oil in 65.9% yield.
1H NMR(400MHz,CDCl3)δ:6.84(d,J＝8.8Hz,1H),6.79(dd,J＝8.8,2.8Hz,1H),6.60(d,J＝2.8Hz,1H),5.33(s,1H),4.92(s,1H),4.76(d,J＝16.8Hz,1H),4.61(td,J＝4.8,1.2Hz,1H),4.40(d,J＝16.8Hz,1H),3.90–3.82(m,4H),3.55-3.52(m,2H),3.11–3.01(m,4H),1.44(s,9H).
LC-MS(ESI):m/z[M+H]+Calculated value C20H28N3O6: 406.1978, respectively; measured value: 406.1983.
the second step is that: preparation of (3S,3aS) -3- (aminomethyl) -7-morpholino-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 34)
Using a similar procedure as in compound 25, starting from intermediate 30 (267mg, 0.66mmol), compound 34 was obtained as a yellow solid, 154mg, 76.6% yield.
1H NMR(400MHz,CDCl3)δ:6.83(d,J＝8.8Hz,1H),6.77(d,J＝8.4Hz,1H),6.59(s,1H),5.23(s,1H),4.75(d,J＝16.4Hz,1H),4.59(brs,1H),4.44(d,J＝16.4Hz,1H),3.86–3.83(m,4H),3.72(q,J＝7.2Hz,1H),3.13(s,1H),3.06-3.04(m,4H),1.67(brs,2H).
13C NMR(400MHz,CDCl3)δ:156.61,146.98,146.06,119.43,118.54,116.98,113.68,83.59,80.92,66.89,50.22,42.92,40.75.LC-MS(ESI):m/z[M+H]+Calculated value C15H20O4N3306.1148; found 306.1148.
Example 35
Preparation of N- (((3S,3aS) -7-morpholino-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 35)
Figure BDA0002379968460000561
Using the similar procedure as in compound 25, starting from compound 34 (74mg, 0.24mmol), compound 35 was obtained as a yellow solid (82 mg) with a yield of 98.8%.
1H NMR(400MHz,CDCl3)δ:6.83(d,J＝9.2Hz,1H),6.79(dd,J＝9.2,2.8Hz,1H),6.59(s,1H),5.92(t,J＝6.0Hz,1H),5.27(d,J＝1.2Hz,1H),4.75(d,J＝16.8Hz,1H),4.66-4.63(m,1H),4.42(d,J＝16.8Hz,1H),3.90–3.82(m,4H),3.78-3.71(m,1H),3.65–3.58(m,1H),3.10–3.00(m,4H),2.03(s,3H).
13C NMR(400MHz,CDCl3)δ:170.88,156.54,119.25,118.65,117.22,113.70,83.37,78.90,66.82,50.33,40.90,40.32,23.13.
LC-MS(ESI):m/z[M+H]+ calculated value C17H22O5N3348.1554; found 348.1554.
Example 36
Preparation of (3S,3aS) -3- (aminomethyl) -7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-1-one (Compound 36)
Figure BDA0002379968460000562
The first step is as follows: preparation of t-butyl ((3S,3aS) -7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl)) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 31)
Starting from intermediate 24(200mg, 0.50mmol), 2- (2-methyl-2H-tetrazol-5-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (173mg, 0.6mmol), the similar procedure as in intermediate 25 gave intermediate 31 as a white solid of 129mg in 53.8% yield.
1H NMR(500MHz,CDCl3)δ:8.93(s,1H),8.29(d,J＝8.0Hz,1H),7.99(dd,J＝8.0,2.0Hz,1H),7.48(d,J＝8.5Hz,1H),7.36(s,1H),7.04(d,J＝8.5Hz,1H),5.50(s,1H),4.90(d,J＝16.5Hz,2H),4.69–4.67(m,1H),4.53(d,J＝16.5Hz,1H),4.47(s,3H),3.61–3.57(m,2H),1.45(s,9H).
LC-MS(ESI):m/z[M+H]+ calculated value C23H26N7O5: 480.1995, respectively; measured value: 480.1992. the second step is that: (3S,3aS) -3- (aminomethyl) -7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ]]Oxazolo [4,3-b][1,3]Preparation of oxazin-1-ones (Compound 36)
Using a similar procedure as in compound 24, starting from intermediate 31 (125mg, 0.26mmol), compound 36 was obtained as a white solid at 64mg in 64.7% yield.
1H NMR(400MHz,CDCl3)δ:8.94(d,J＝2.4Hz,1H),8.30(d,J＝8.0Hz,1H),7.99(dd,J＝8.0,2.4Hz,1H),7.48(dd,J＝8.4,2.4Hz,1H),7.38(s,1H),7.05(d,J＝8.4Hz,1H),5.37(s,1H),4.91(d,J＝16.8Hz,1H),4.63-4.62(m,1H),4.59(d,J＝17.2Hz,1H),4.47(s,3H),3.18-3.06(m,2H),1.53(brs,2H).
13C NMR(400MHz,CDCl3)δ:164.78,156.44,152.82,148.39,145.35,136.70,134.93,131.53,127.26,125.48,122.30,119.80,118.93,83.78,81.11,42.91,40.46,39.74.
LC-MS(ESI):m/z[M+H]+ calculated value C18H18O3N7380.1466; found 380.1465.
Example 37
Preparation of N- (((3S,3aS) -7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 37)
Figure BDA0002379968460000571
Using compound 36 as a starting material (34mg, 0.09mmol), the similar procedure as in compound 25 was used to give compound 37 as a white solid in 35mg with a yield of 92.6%.
1H NMR(400MHz,CDCl3)δ:8.93(s,1H),8.29(d,J＝8.4Hz,1H),7.99(dd,J＝8.0,2.0Hz,1H),7.47(d,J＝8.4Hz,1H),7.35(s,1H),7.04(d,J＝8.8Hz,1H),5.97(s,1H),5.44(s,1H),4.89(d,J＝16.8Hz,1H),4.71(t,J＝4.8Hz,1H),4.56(d,J＝16.8Hz,1H),4.47(s,3H),3.75-3.69(m,2H),2.05(s,3H).
13C NMR(400MHz,CDCl3)δ:171.00,164.74,156.39,152.69,148.36,145.33,136.69,134.97,131.63,127.35,125.39,122.31,119.61,118.98,83.55,78.92,40.63,40.30,39.75,23.14.
LC-MS(ESI):m/z[M+H]+Calculated value C20H20O4N7422.1571; found 422.1571.
Example 38
Preparation of 5- ((3S,3aS) -3- (aminomethyl) -6, 8-difluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-7-yl) picoline nitrile (Compound 38)
Figure BDA0002379968460000581
The first step is as follows: preparation of tert-butyl ((3S,3aS) -7-bromo-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 32)
Intermediate 32 was obtained in a yield of 74.7% as a white solid of 660mg, according to the preparation method of intermediate 12 in example 1, using 4, 6-difluorosalicylic acid as a starting material.
1H NMR(400MHz,CDCl3)δ:6.58(dd,J＝8.8,2.0Hz,1H),5.51(s,1H),4.90(brs,1H),4.85(d,J＝16.8Hz,1H),4.68–4.56(m,1H),4.35(d,J＝17.2Hz,1H),3.68–3.39(m,2H),1.44(s,9H).
LC-MS(ESI):m/z[M+Na]+Calculated value C16H17BrF2N2NaO5: 457.0181 and 459.0161; measured value: 457.0165, and 459.0159.
The second step is that: preparation of tert-butyl ((3S,3aS) -7- (6-cyanopyridin-3-yl) -6, 8-difluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 33)
Similar procedure as in intermediate 25 was used starting from intermediate 32(195mg, 0.45mmol), 2-cyanopyridine-5-boronic acid pinaster (124mg, 0.54mmol) to give intermediate 33 as a white solid 107mg with 51.9% yield.
1H NMR(400MHz,CDCl3)δ:8.78(d,J＝2.4Hz,1H),7.91(ddt,J＝8.0,2.4,1.2Hz,1H),7.79(dd,J＝8.0,0.8Hz,1H),6.65(dd,J＝10.4,2.0Hz,1H),5.61(s,1H),4.90(d,J＝16.8Hz,2H),4.67(td,J＝5.2,1.2Hz,1H),4.38(d,J＝16.8Hz,1H),3.70–3.46(m,2H),1.45(s,9H).
LC-MS(ESI):m/z[M+H]+Calculated value C22H21F2N4O5: 459.1475, respectively; measured value: 459.1480.
the third step: preparation of 5- ((3S,3aS) -3- (aminomethyl) -6, 8-difluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-7-yl) picoline nitrile (Compound 38)
Using the similar procedure as in compound 24, starting from intermediate 33 (107mg, 0.23mmol), compound 38 was obtained as a white solid in 90mg, 109% yield.
1H NMR(400MHz,CDCl3)δ:8.79(s,1H),7.92(dd,J＝8.4,0.8Hz,1H),7.79(d,J＝8.0Hz,1H),6.67(dd,J＝10.4,1.6Hz,1H),5.44(d,J＝1.2Hz,1H),4.91(d,J＝17.2Hz,1H),4.63-4.60(m,1H),4.45(d,J＝17.2Hz,1H),3.12(qd,J＝13.6,5.2Hz,2H),1.35(brs,2H).
LC-MS(ESI):m/z[M+H]+Calculated value C17H13O3N4F2359.0950; found 359.0960.
Example 39
Preparation of N- (((3S,3aS) -7- (6-cyanopyridin-3-yl) -6, 8-difluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 39)
Figure BDA0002379968460000591
Using the similar procedure as in compound 25, starting from compound 38 (44mg, 0.12mmol), compound 39 was obtained as a white solid in 56mg with a yield of 112%.
1H NMR(400MHz,CDCl3)δ:8.75(s,1H),7.88(d,J＝8.0Hz,1H),7.77(d,J＝8.0Hz,1H),6.63(d,J＝10.8Hz,1H),6.11(s,1H),5.54(s,1H),4.85(d,J＝17.2Hz,1H),4.68(t,J＝4.8Hz,1H),4.39(d,J＝17.2Hz,1H),3.82-3.52(m,2H),2.02(s,3H).
LC-MS(ESI):m/z[M+H]+Calculated value C19H15O4N4F2401.1056; found 401.1060.
Example 40
Preparation of (3S,3aS) -3- (aminomethyl) -6, 8-difluoro-7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 40)
Figure BDA0002379968460000592
The first step is as follows: preparation of tert-butyl ((3S,3aS) -6, 8-difluoro-7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 35)
Starting from intermediate 32(195mg, 0.45mmol), 2- (2-methyl-2H-tetrazol-5-yl) -5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (155mg, 0.54mmol), a similar procedure as in intermediate 25 gave intermediate 34 as a white solid, 190mg, 81.9% yield.
1H NMR(400MHz,CDCl3)δ:8.83(s,1H),8.32(dd,J＝8.0,0.8Hz,1H),7.95-7.93(m,1H),6.64(dd,J＝10.4,1.6Hz,1H),5.60(s,1H),5.04-5.01(m,1H),4.90(d,J＝17.2Hz,1H),4.68(td,J＝4.8,0.8Hz,1H),4.48(s,3H),4.40(d,J＝17.6Hz,1H),3.66-3.52(m,2H),1.45(s,9H).
LC-MS(ESI):m/z[M+H]+Calculated value C23H24F2N7O5: 516.1807, respectively; measured value: 516.1811.
the second step is that: preparation of (3S,3aS) -3- (aminomethyl) -6, 8-difluoro-7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (Compound 40)
Using intermediate 34 as a starting material (190mg, 0.37mmol), the similar procedure as in compound 24 gave compound 40 as a white solid, 90mg, 58.6% yield.
1H NMR(400MHz,CDCl3)δ:8.84(s,1H),8.33(d,J＝8.0Hz,1H),7.94(d,J＝8.4Hz,1H),6.66(dd,J＝10.4,2.0Hz,1H),5.43(d,J＝1.2Hz,1H),4.91(d,J＝17.2Hz,1H),4.63(t,J＝5.6Hz,1H),4.47-4.44(m,4H),3.12(qd,J＝13.6,4.8Hz,2H),1.43(bras,2H).
LC-MS(ESI):m/z[M+H]+Calculated value C18H16O3N7F2416.1277; found 416.1281.
EXAMPLE 41
Preparation of N- (((3S,3aS) -6, 8-difluoro-7- (6- (2-methyl-2H-tetrazol-5-yl) pyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 41)
Figure BDA0002379968460000601
Using the similar procedure as in compound 25, starting from compound 40 (47mg, 0.11mmol), compound 41 was obtained in the form of a white solid (73 mg, 146% yield).
1H NMR(400MHz,CDCl3)δ:8.82(s,1H),8.32(d,J＝8.4Hz,1H),7.95(dd,J＝8.0,2.0Hz,1H),6.65(dd,J＝10.4,2.0Hz,1H),6.39(t,J＝6.0Hz,1H),5.55(s,1H),4.88(d,J＝16.8Hz,1H),4.72(t,J＝4.8Hz,1H),4.48(s,3H),4.44(d,J＝16.8Hz,1H),3.80-3.66(m,2H),2.06(s,3H).
LC-MS(ESI):m/z[M+H]+Calculated value C20H18O4N7F2458.1383; found 458.1393.
Example 42
Preparation of N- (((3S,3aS) -6, 8-difluoro-7- (6-methoxypyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 42)
Figure BDA0002379968460000611
The first step is as follows: preparation of tert-butyl (((3S,3aS) -6, 8-difluoro-7- (6-methoxypyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 35)
Intermediate 35 was obtained in a yield of 40.2% using intermediate 32(250mg, 0.57mmol), 6-methoxypyridine-3-boronic acid (106mg, 0.69mmol) as the starting material and a similar procedure as in intermediate 25, as a yellow solid, 106 mg.
1H NMR(500MHz,CDCl3)δ:8.22(s,1H),7.62(d,J＝9.0Hz,1H),6.83(d,J＝8.5Hz,1H),6.59(d,J＝10.0Hz,1H),5.54(s,1H),4.93(t,J＝6.5Hz,1H),4.87(d,J＝17.0Hz,1H),4.66(t,J＝5.0Hz,1H),4.37(d,J＝17.0Hz,1H),3.98(s,3H),3.57(dt,J＝27.5,5.5Hz,2H),1.45(s,9H).
LC-MS(ESI):m/z[M+H]+Calculated value C22H24F2N3O6: 464.1633, respectively; measured value: 464.1629.
the second step is that: preparation of (3S,3aS) -3- (aminomethyl) -6, 8-difluoro-7- (6-methoxypyridin-3-yl) -3,3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-1-one (intermediate 36)
Using the similar procedure as in compound 24, intermediate 35 (106mg, 0.23mmol) was used as the starting material to give intermediate 36 as a white solid in 58mg, 69.0% yield.
1H NMR(400MHz,CDCl3)δ:8.22(s,1H),7.62(d,J＝8.4Hz,1H),6.83(d,J＝8.8Hz,1H),6.60(dd,J＝10.4,2.0Hz,1H),5.38(s,1H),4.87(d,J＝17.2Hz,1H),4.60(t,J＝5.6Hz,1H),4.43(d,J＝16.8Hz,1H),3.98(s,3H),3.11(qd,J＝13.2,4.8Hz,2H),1.34(s,2H).
LC-MS(ESI):m/z[M+]+Calculated value C17H16O4N3F2364.1103; found 364.1100.
The third step: preparation of N- (((3S,3aS) -6, 8-difluoro-7- (6-methoxypyridin-3-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 42)
Using intermediate 36 as a starting material (38mg, 0.10mmol), a similar procedure as in compound 25 was used to give compound 42 as a white solid in 35mg, 85.3% yield.
1H NMR(400MHz,CDCl3)δ:8.21(s,1H),7.62(d,J＝8.8Hz,1H),6.83(d,J＝8.8Hz,1H),6.59(dd,J＝10.0,1.6Hz,1H),6.29(d,J＝6.0Hz,1H),5.50(s,1H),4.84(d,J＝16.8Hz,1H),4.70(t,J＝4.8Hz,1H),4.42(d,J＝16.8Hz,1H),3.98(s,3H),3.83-3.59(m,2H),2.04(s,3H).
LC-MS(ESI):m/z[M+]+Calculated value C19H18O5N3F2406.1209; found 406.1212.
Example 43
Preparation of N- (3S,3aS) -7- (4-acetylphenyl) -6, 8-difluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 43)
Figure BDA0002379968460000621
The first step is as follows: preparation of tert-butyl (((3S,3aS) -7- (4-acetylphenyl) -6, 8-difluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 37)
Similar procedure as in intermediate 25 was used starting from intermediate 32(250mg, 0.57mmol), 4-acetylphenylboronic acid (113mg, 0.69mmol) to give intermediate 37 as a white solid 117mg in 43.3% yield.
1H NMR(500MHz,CDCl3)δ:8.03(d,J＝7.5Hz,2H),7.52(d,J＝8.0Hz,2H),6.60(d,J＝10.5Hz,1H),5.57(s,1H),5.01(t,J＝7.0Hz,1H),4.87(d,J＝17.0Hz,1H),4.67(t,J＝4.5Hz,1H),4.38(d,J＝17.0Hz,1H),3.64-3.52(m,2H),2.64(s,3H),1.45(s,9H).
LC-MS(ESI):m/z[M+Na]+Calculated value C24H24F2N2NaO6: 497.1500, respectively; measured value: 497.1488.
the second step is that: preparation of (3S,3aS) -7- (4-acetylphenyl) -3- (aminomethyl) -6, 8-difluoro-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-1-one (intermediate 38)
Using the similar procedure as in compound 24, intermediate 37 (117mg, 0.25mmol) was used as the starting material to give intermediate 38 as a pale yellow solid, 46mg, 48.9% yield.
1H NMR(400MHz,CDCl3)δ:8.04(d,J＝8.8Hz,2H),7.53(d,J＝8.4Hz,2H),6.62(dd,J＝10.4,2.0Hz,1H),5.40(d,J＝1.2Hz,1H),4.89(d,J＝16.8Hz,1H),4.61(dt,J＝5.2,1.2Hz,1H),4.44(d,J＝16.8Hz,1H),2.64(s,3H),1.35(s,2H).
LC-MS(ESI):m/z[M+H]+Calculated value C19H17O4N2F2375.1151; found 375.1150.
The third step: preparation of N- (3S,3aS) -7- (4-acetylphenyl) -6, 8-difluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 43)
Using intermediate 38 as a starting material (46mg, 0.12mmol), a similar procedure as in compound 25 was used to give compound 43 as a white solid in 35mg at 70.0% yield.
1H NMR(400MHz,CDCl3)δ:8.03(d,J＝8.0Hz,2H),7.52(d,J＝8.0Hz,2H),6.60(d,J＝10.0Hz,1H),6.29(s,1H),5.52(s,1H),4.85(d,J＝17.2Hz,1H),4.70(s,1H),4.42(d,J＝17.2Hz,1H),3.72(d,J＝19.2Hz,2H),2.64(s,3H),2.05(s,3H).
LC-MS(ESI):m/z[M+H]+Calculated value C21H19O5N2F2417.1257; found 417.1255.
Example 44
Preparation of 4- ((3S,3aS) -3- (aminomethyl) -6, 8-difluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-7-yl) benzonitrile (Compound 44)
Figure BDA0002379968460000631
The first step is as follows: preparation of tert-butyl (((3S,3aS) -7- (4-cyanophenyl) -6, 8-difluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 35)
Similar procedure as in intermediate 25 was used starting from intermediate 32(200mg, 0.46mmol), 4-cyanophenylboronic acid (81mg, 0.55mmol) to give intermediate 39 as a yellow solid 148mg with a yield of 70.5%.
1H NMR(400MHz,CDCl3)δ:7.74(d,J＝8.4Hz,2H),7.53(d,J＝8.8Hz,2H),6.61(dd,J＝10.4,1.6Hz,1H),5.58(s,1H),4.88(d,J＝17.2Hz,2H),4.67(td,J＝4.8,1.2Hz,1H),4.37(d,J＝17.2Hz,1H),3.71-3.42(m,2H),1.45(s,9H).
LC-MS(ESI):m/z[M+H]+Calculated values: c23H22F2N3O5: 458.1528, respectively; measured value: 458.1524.
the second step is that: preparation of 4- ((3S,3aS) -3- (aminomethyl) -6, 8-difluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-7-yl) benzonitrile (Compound 44)
Using the intermediate 35 as a starting material (148mg, 0.32mmol), a similar procedure as in compound 24 was used to give compound 44 as a white solid at 98mg with a yield of 86.0%.
1H NMR(400MHz,CDCl3)δ:7.74(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),6.62(dd,J＝10.8,2.0Hz,1H),5.41(s,1H),4.89(d,J＝17.2Hz,1H),4.63-4.60(m,1H),4.44(d,J＝16.8Hz,1H),3.18-3.04(m,2H),1.37(s,2H).
LC-MS(ESI):m/z[M+H]+Calculated value C18H14O3N3F2358.0998; found 358.0994.
Example 45
Preparation of N- (((3S,3aS) -7- (4-cyanophenyl) -6, 8-difluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazolo [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 45)
Figure BDA0002379968460000641
Using the similar procedure as in compound 25, starting from compound 44 (48mg, 0.13mmol), compound 45 was obtained as a white solid in 42mg, 80.8% yield.
1H NMR(400MHz,CDCl3)δ:7.74(d,J＝8.0Hz,2H),7.53(d,J＝8.4Hz,2H),6.61(dd,J＝10.4,1.6Hz,1H),6.24(t,J＝6.4Hz,1H),5.53(s,1H),4.85(d,J＝17.2Hz,1H),4.70(t,J＝4.4Hz,1H),4.41(d,J＝17.2Hz,1H),3.80-3.59(m,2H),2.05(s,3H).
LC-MS(ESI):m/z[M+]+Calculated value C20H16O4N3F2400.1103; found 400.1098.
Example 46
Preparation of N- ((3S,3aS) -6- (6-cyanopyridin-3-yl) -7-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (compound 46)
Figure BDA0002379968460000642
The first step is as follows: preparation of tert-butyl ((3S,3aS) -6-bromo-7-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 40)
Starting from 2-hydroxy-4-bromo-5-fluorobenzamide, the procedure for the preparation of intermediate 12 in example 1 was referenced to afford intermediate 40 as a white solid in 2.2g, yield: 81.5 percent.
LC-MS(ESI):m/z[M+Na]+Calculated value C16H18BrFN2NaO5: 439.0281 and 441.0260; measured value: 439.0256 and 441.0236
1H NMR(400MHz,CDCl3)δ:7.11(d,J＝6.0Hz,1H),6.86(d,J＝8.0Hz,1H),5.40(s,1H),4.95(s,1H),4.75(d,J＝16.8Hz,1H),4.62(t,J＝4.8Hz,1H),4.35(d,J＝16.8Hz,1H),3.56-3.51(m,2H),1.43(s,9H).
The second step is that: preparation of tert-butyl ((3S,3aS) -6- (6-cyanopyridin-3-yl) -7-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 41)
Intermediate 40(180.0mg,0.43mmol) and 2-cyanopyridine-5-boronic acid pinacol ester (129.0mg,0.56mmol), tetrakistriphenylphosphine palladium (46.0mg,0.04mmol), sodium carbonate (91.0mg,0.86mmol) were charged into a three-necked reaction flask, and a mixed solvent of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under argon atmosphere, which was prepared using the preparation of intermediate 13 in example 1 to give intermediate 41, 160.0mg of a white solid, yield: 84.2 percent.
LC-MS(ESI):m/z[M+H]+Calculated value C22H22FN4O5: 441.1574, respectively; measured value: 41.1574.
1H NMR(400MHz,CDCl3)δ:8.56(s,1H),8.01-7.97(m,1H),7.78(dd,J＝0.8,8.0Hz,1H),7.01-6.98(m,2H),5.49(s,1H),4.90(s,1H),4.86(d,J＝17.2Hz,1H),4.66(t,J＝4.8Hz,1H),4.47(d,J＝17.2Hz,1H),3.64-3.52(m,2H),1.45(s,9H).
the third step: preparation of 5- ((3S,3aS) -3- (aminomethyl) -7-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-6-yl) picoline nitrile (intermediate 42)
Intermediate 41(150.0mg,0.43mmol) was dissolved in dichloromethane (15.0mL), and trifluoroacetic acid (4.0mL) was added under ice-bath conditions to afford intermediate 42 as a white solid 91.0mg, yield: 78.4 percent.
LC-MS(ESI):m/z[M+H]+Calculated value C17H14FN4O3: 341.1050, respectively; measured value: 341.1042.
1H NMR(400MHz,CDCl3)δ:8.86(s,1H),8.01-7.98(m,1H),7.78(dd,J＝0.8,8.0Hz,1H),7.02-7.00(m,2H),5.35(d,J＝1.2Hz,1H),4.87(d,J＝17.6Hz,1H),4.56(td,J＝1.2,5.2Hz,1H),4.53(d,J＝17.2Hz,1H),3.17-3.05(m,2H),1.49(brs,2H).
13C NMR(100MHz,CDCl3)δ:156.3,154.7(d,JC-F＝244.0Hz),150.7(d,JC-F＝4.0Hz),148.9(d,JC-F＝2.0Hz),136.9(d,JC-F＝4.0Hz),134.1,133.0,128.2,123.9,121.8(d,JC-F＝8.0Hz),119.1(d,JC-F＝2.0Hz),117.1,114..4(d,JC-F＝26.0Hz),83.9,81.1,42.8,40.3.
the fourth step: preparation of N- ((3S,3aS) -6- (6-cyanopyridin-3-yl) -7-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (compound 46)
Intermediate 42(80.0mg,0.24mmol) was dissolved in dichloromethane (15.0mL), triethylamine (49 μ L,0.36mmol) was added under ice bath conditions followed by slow addition of acetyl chloride (22 μ L,0.31mmol), and compound 46 was obtained using the preparation method of compound 2 in example 2 as a white solid 68.0mg, yield: 75.5 percent.
LC-MS(ESI):m/z[M+H]+Calculated value C19H16FN4O4: 383.1156, respectively; measured value: 383.1141.
1H NMR(400MHz,CDCl3)δ:8.85(s,1H),8.00-7.97(m,1H),7.78(d,J＝8.0Hz,1H),7.00-6.97(m,2H),5.99(s,1H),5.44(d,J＝1.2Hz,1H),4.85(d,J＝17.2Hz,1H),4.69(td,J＝1.2,5.2Hz,1H),4.49(d,J＝17.2Hz,1H),3.72-3.69(m,2H),2.02(s,9H).
13C NMR(100MHz,CDCl3)δ:171.1,156.3,154.8(d,JC-F＝245.0Hz),150.7(d,JC-F＝4.0Hz),148.8(d,JC-F＝2.0Hz),137.0(d,JC-F＝4.0Hz),134.0,133.0,128.2,124.0(d,JC-F＝15.9Hz),121.6(d,JC-F＝8.0Hz),119.2(d,JC-F＝3.0Hz),117.1,114..4(d,JC-F＝25.0Hz),83.7,79.0,40.5,40.2,23.1.
example 47
Preparation of N- ((3S,3aS) -7-fluoro-6-morpholin-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 47)
Figure BDA0002379968460000661
The first step is as follows: preparation of tert-butyl ((3S,3aS) -7-fluoro-6-morpholin-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) carbamate (intermediate 43)
Intermediate 40(90.0mg,0.22mmol), morpholine (38mg,0.43mmol), X-PHOS (31.0mg,0.07mmol), palladium acetate (7.3mg,0.03mmol), cesium carbonate (106.0mg,0.32mmol) were added to toluene (10.0mL) according to the preparation method of intermediate 22 in example 20 to give intermediate 43 as a pale yellow solid, 35.0mg, yield 38.3%.
LC-MS(ESI):m/z[M+H]+Calculated value C20H27FN3O6: 424.1884, respectively; measured value: 424.1871.
1H NMR(400MHz,CDCl3)δ:6.77(d,J＝12.4Hz,1H),6.45(d,J＝7.6Hz,1H),5.24(d,J＝1.6Hz,1H),4.71(d,J＝16.4Hz,1H),4.54(t,J＝5.2Hz,1H),4.38(d,J＝16.4Hz,1H),3.85(d,J＝4.8Hz,4H),3.55-3.52(m,2H),3.06-3.03(m,4H),1.44(s,9H).
the second step is that: preparation of (3S,3aS) -3- (aminomethyl) -7-fluoro-6-morpholine-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-1-one (intermediate 44)
Intermediate 43(110.0mg,0.26mmol) was dissolved in dichloromethane (15.0mL), and trifluoroacetic acid (4.0mL) was added under ice-bath conditions to afford intermediate 44 as a white solid 72.0mg, yield: 85.7 percent.
LC-MS(ESI):m/z[M+H]+Calculated value C15H19FN3O4: 324.1360, respectively; measured value: 324.1349.
1H NMR(400MHz,CDCl3)δ:6.66(d,J＝12.4Hz,1H),6.45(d,J＝7.6Hz,1H),5.24(d,J＝1.6Hz,1H),4.71(d,J＝16.4Hz,1H),4.53(td,J＝1.2,5.6Hz,1H),4.38(d,J＝16.4Hz,1H),3.85(d,J＝4.8Hz,4H),3.12-3.00(m,6H),1.25(brs,2H).
13C NMR(100MHz,CDCl3)δ:156.5,151.1(d,JC-F＝241.0Hz),148.5(d,JC-F＝2.0Hz),140.1(d,JC-F＝10.0Hz),113.6(d,JC-F＝23.0Hz),119.2(d,JC-F＝7.0Hz),108.0(d,JC-F＝3.0Hz),83.7,81.1,66.9,50.8,50.7,43.0,40.0.
the third step: preparation of N- ((3S,3aS) -7-fluoro-6-morpholin-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 47)
Intermediate 44(45.0mg,0.14mmol) was dissolved in dichloromethane (15.0mL), triethylamine (29 μ L,0.21mmol) was added under ice bath conditions followed by slow addition of acetyl chloride (13 μ L,0.18mmol), and compound 47 was obtained as a white solid 44.0mg, yield using the preparation method of compound 2 in example 2: 86.3 percent.
LC-MS(ESI):m/z[M+H]+Calculated value C17H21FN3O5: 366.1465, respectively; measured value: 366.1443.
1H NMR(400MHz,CDCl3)δ:6.76(d,J＝12.0Hz,1H),6.48(d,J＝7.2Hz,1H),5.93(brs,1H),5.30(d,J＝1.2Hz,1H),4.70(d,J＝16.4Hz,1H),4.63(t,J＝4.8Hz,1H),4.36(d,J＝16.4Hz,1H),3.87(d,J＝4.8Hz,4H),3.75-3.60(m,2H),3.07-3.04(m,4H),2.03(s,3H).
13C NMR(100MHz,CDCl3)δ:170.9,156.4,151.1(d,JC-F＝241.0Hz),150.8,148.3(d,JC-F＝2.0Hz),113.5(d,JC-F＝24.0Hz),111.9(d,JC-F＝7.0Hz),108.2(d,JC-F＝3.0Hz),83.5,78.9,66.8,50.8,50.7,40.3,40.2,23.2.
example 48
Preparation of N- ((3S,3aS) -6-fluoro-7- (1-methyl-1H-pyrazol-4-yl) -1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazole [4,3-b ] [1,3] oxazin-3-yl) methyl) acetamide (Compound 48)
Figure BDA0002379968460000671
Intermediate 14(70.0mg,0.19mmol), 1-methylpyrazole-4-boronic acid pinacol ester (51.4mg,0.25mmol), tetratriphenylphosphine palladium (23.1mg,0.02mmol) and sodium carbonate (40.3mg,0.38mmol) were charged into a three-necked reaction flask, and a mixed solution of dimethyl sulfoxide (9.0mL) and water (1.5mL) was added under an argon atmosphere, followed by the procedure for the preparation of intermediate 13 in example 1, to give compound 48 as an off-white solid 35.0mg with a yield of 49.8%.
LC-MS(ESI):m/z[M+H]+Calculated value C17H18FN4O4: 361.1312, respectively; measured value: 361.13041H NMR(400MHz,DMSO-d6)δ:7.80(t,J＝6.0Hz,1H),7.58(d,J＝2.4Hz,1H),7.34(s,1H),7.12(d,J＝8.4Hz,1H),6.45(d,J＝12.0Hz,1H),5.09(s,1H),4.22-4.4.15(m,2H),4.06(d,J＝16.4Hz,1H),3.42(s,3H),2.99-2.96(m,2H),1.41(s,3H).
Example 49
Preparation of N- ((3S,3aS) -7- (6-cyanopyridin-3-yl) -6-fluoro-1-oxo-3, 3 a-dihydro-1H, 9H-benzo [ e ] oxazol [4,3-b ] [1,3] oxazin-3-yl) methyl) cyclopropylamide (Compound 49)
Figure BDA0002379968460000681
Compound 1(41.0mg,0.12mmol) was dissolved in dichloromethane (15.0mL), triethylamine (25. mu.L, 0.18mmol) was added under ice-bath conditions, and then propionyl chloride (14.5. mu.L, 0.16mmol) was added slowly, and the reaction was completed after 2 hours of incubation. The reaction mixture was washed twice with water, once with saturated brine, dried over sodium sulfate, and subjected to silica gel column chromatography (dichloromethane/methanol: 100/1) to give compound 49 as an off-white solid (35.0 mg, yield 83.3%).
LC-MS(ESI):m/z[M+H]+Calculated value C21H18FN4O4: 409.1312, respectively; measured value: 409.1291
1H NMR(400MHz,Acetone-d6)δ:8.90-8.89(m,1H),8.21-8.18(m,1H),8.03(dd,J＝0.8,8.0Hz,1H),7.75(t,J＝5.6Hz,1H),7.60(d,J＝8.4Hz,1H),6.90(d,J＝11.6Hz,1H),5.67(d,J＝0.8Hz,1H),4.82(d,J＝16.8Hz,1H),4.72(t,J＝5.6Hz,1H),4.59(d,J＝16.8Hz,1H),3.65-3.59(m,2H),1.65-1.59(m,1H),0.79-0.76(m,1H),0.70-0.66(m,1H).
Experimental example: biological activity assay
Experimental example 1 in vitro anti-tubercular Activity test
The experimental method comprises the following steps: sterile 96-well plates (Falcon 3072; Becton Dickinson, Lincoln Park, n.j.), test compounds were dissolved in DMSO to make a primary solution with a concentration of 5mg/mL, 199 μ L of 7H9 medium and1 μ L of the primary solution of the compound were added to the highest concentration well, mixed well, and diluted 2-fold sequentially to the remaining wells, the final concentration of the compound was: 25. 12.5, 6.25, 3.125, 1.56, 0.78, 0.39, 0.2, 0.1, 0.05, 0.025 μ g/mL. Selecting Mycobacterium tuberculosis H37RvCulturing for 2-3 weeks to obtain bacterial suspension, and inoculating to a culture medium containing 0.05Culturing in 7H9 culture medium containing Tween80 and ADC 10% at 37 deg.C for 1-2 weeks until the turbidity is McFarland1 (equivalent to 10)7CFU/mL), 1: after 20 dilutions, 100. mu.L of each well was added to the suspension to a final concentration of 106CFU/mL. Each plate was plated with 2 growth control wells containing no antimicrobial, and the 96-well plates were incubated at 37 ℃. Adding 20 μ L of 10 × Alamar Blue and 5% Tween 8050 μ L of mixed solution into growth control wells after 7 days, incubating at 37 deg.C for 24 hours, adding the above amount of Alamar Blue and Tween80 mixed solution into each experimental drug well if the color changes from Blue to pink, incubating at 37 deg.C for 24 hours, recording the color of each well, measuring 590nm fluorescence value by using microplate reader, calculating MIC90。
TABLE 1 MIC values for in vitro anti-Mycobacterium tuberculosis Activity of some of the compounds (. mu.g/mL)
Compound (I) Mycobacterium tuberculosis H37Rv
Compound 1 0.257
Compound 2 0.4
Compound 3 7.7
Compound 4 0.517
Compound 5 0.98
Compound (I)8 0.488
Compound 9 0.494
Compound 11 0.99
Compound 12 1.15
Compound 13 0.97
Compound 14 1.69
Compound 19 1.56
Compound 38 0.498
Compound 39 1.88
Compound 40 0.744
Compound 41 1.665
Compound 44 0.989
As can be seen from the data in Table 1, the compounds of the present invention have excellent in vitro anti-Mycobacterium tuberculosis activity.
Experimental example 2 in vitro antibacterial Activity test
The experimental method comprises the following steps: the Minimum Inhibitory Concentration (MIC) of the compound of the present invention against the strain was determined by agar double dilution. Dissolving the experimental compound by DMSO, diluting the solution to a required concentration by sterile distilled water, adding a culture medium into a culture dish containing the compound, and uniformly mixing to ensure that the final concentration of the compound in the culture dish is as follows: 64. 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125. mu.g/mL. The bacteria were inoculated on the surface of agar plates containing different concentrations of the compound, at about 10 bacteria/spot6CFU/mL, incubation for 16 hours at 37 ℃ and observation result, taking the minimum concentration of the compound contained in the aseptically grown plate culture medium as the minimum inhibitory concentration of the compound to the bacteria.
TABLE 2 MIC values for in vitro antibacterial Activity of some of the Compounds (. mu.g/mL)
Compound (I) Staphylococcus aureus 29213 Bacillus subtilis 168
Compound 2 0.125 0.125
Compound 3 0.125 0.5
Compound 5 0.125 0.125
Compound 7 0.5 1
Compound 10 0.125 0.5
Compound 12 0.125 0.125
Compound 14 0.125 0.125
Compound 16 0.5 2
Compound 18 0.5 2
Compound 19 0.5 1
Compound 21 2 8
Compound 23 1 8
Compound 25 0.5 1
Compound 27 1 4
Compound 29 2 4
Ampicillin 0.25 0.25
Vancomycin 1 0.25
As can be seen from the data in table 2, the compounds of the present invention have good in vitro antibacterial activity.
Experimental example 3 cytotoxicity test
The experimental method comprises the following steps: and digesting the Vero cells cultured to the logarithmic phase for 2-3 min by using 0.25% pancreatin, sucking a digestive juice, adding a proper amount of culture solution, uniformly mixing, taking 20 mu L, counting under a microscope by using a blood cell counter, and preparing cell suspension with a proper concentration for later use. Meanwhile, 5g/L MTT solution is prepared by PBS (phosphate buffered solution), and the MTT solution is filtered and sterilized for later use. The test drug was dissolved in DMSO, diluted 50-fold with medium to the highest concentration tested, and then serially diluted 1: 3 in 96-well plates with 6 concentrations of each compound, with a maximum concentration of 64 μ g/mL, 6 parallel wells per concentration, 50 μ L/well in medium. The prepared cell suspension is inoculated into a 96-well plate, 50 mu L/well, the cell concentration is 4 multiplied by 105one/mL. Simultaneously provided with cell pairs without medicineControl wells and media blank wells. After 48 hours of incubation, 10. mu.L/well of MTT was added and incubation was continued for 4 hours. Taking out the culture plate, carefully discarding the culture medium in the wells, adding 100 μ L of DMSO into each well, shaking until the formazan particles are completely dissolved, and measuring the Optical Density (OD) at 570nm with an enzyme linked immunosorbent assay detector570). Percent (%) cell inhibition ═ cell control OD570Value-addition medicine OD570Value)/(cell control OD570Value-blank OD570Value)]X 100%. Dose-response curve fitting was performed using origin7.0 software to calculate the concentration (IC) at which each compound inhibited 50% of cells50)。
TABLE 3 cytotoxicity of some of the compounds
Figure BDA0002379968460000711
As is clear from the data in Table 3, the compounds of the present invention showed very low cytotoxicity and high safety.
Experimental example 4 in vitro anti-drug-resistant Mycobacterium tuberculosis Activity of Compounds
The specific test method was carried out by referring to the screening method in Experimental example 1 of the present invention.
TABLE 4 in vitro anti-drug-resistant tubercle bacillus Activity of some of the Compounds
Figure BDA0002379968460000712
aIsoniazid, streptomycin, rifampin, ethambutol, rifapentine, resistant strains to aminosalicylic acid and ofloxacin;bisoniazid, streptomycin, rifampin, ethambutol, aminosalicylic acid, prothiocypyrronide, and capreomycin resistant strains;
as can be seen from the data in Table 4, the compounds of the present invention are resistant to clinically isolated multidrug-resistant Mycobacterium tuberculosis 13946aAnd 14862bHas strong antibacterial activity.
Experimental example 5 in vitro anti-drug-resistant bacterium Activity of Compound
The specific test method was carried out by referring to the screening method in Experimental example 2 of the present invention.
TABLE 5 in vitro anti-drug-resistant bacteria Activity of some of the Compounds
Figure BDA0002379968460000713
Figure BDA0002379968460000721
aMethicillin-resistant staphylococcus aureus;bvancomycin-resistant staphylococcus aureus XN 108;cvancomycin-resistant enterococci;dmethicillin-resistant staphylococcus epidermidis 8709.
As can be seen from the data in Table 5, the compounds of the present invention have strong antibacterial activity against drug-resistant strains.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (13)

1. A compound of formula (I) and isomers, or pharmaceutically acceptable salts thereof:
Figure FDA0002379968450000011
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
R1is-NHR4、-NHCOR4、-NHCSR4、-NHSO2R4、-NHCOOR4、-NHCSOR4、-NHCONHR4、-NHCSNHR4；
R4Independently selected from H, substituted or unsubstituted straight or branched C1-C4Alkyl, substituted or unsubstituted 3-6 membered cycloalkyl;
the R is4Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
R2、R3independently selected from H, F, Cl, Br, substituted or unsubstituted phenyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-8 membered non-aromatic heterocyclyl;
R2、R3the 5-6 membered heteroaryl or 5-8 membered non-aromatic heterocyclyl group of (a) contains at least one heteroatom selected from N, O, S;
R2、R3the substituted or unsubstituted substituents described in (1) may optionally be selected from the following groups: F. cl, Br, -OH, ═ O, -NO2、-CN、-NH2、-CF3、-OR5、COR5、-NHCOR5、-CONR5R6、-COOR5Wherein R is5And R6Each independently is a straight or branched chain C1-C6An alkyl group;
or R2、R3The substituted or unsubstituted substituents recited in (1) are optionally selected from the group consisting of: straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical, C3-C6Cycloalkyl, said straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical or C3-C6The cycloalkyl group is optionally substituted with: -OH, -CN, -NH25-6 membered aromatic ringOr 5-6 non-aromatic heterocyclic ring;
or R2、R3The substituted or unsubstituted substituents recited in (1) are optionally selected from the group consisting of: a 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S, C1-C3Alkyl-substituted 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S or oxygen-substituted 5-6 aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S.
2. A compound according to claim 1 and isomers thereof, or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
R1is-NHR4、-NHCOR4、-NHCSR4、-NHSO2R4、-NHCOOR4、-NHCSOR4、-NHCONHR4、-NHCSNHR4；
R4Independently selected from H, substituted or unsubstituted straight or branched C1-C4Alkyl, substituted or unsubstituted 3-6 membered cycloalkyl;
the R is4Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
R2is H, F, Cl or Br, R3Is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstitutedSubstituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl;
or R3Is H, F, Cl or Br, R2Is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl;
R2、R3the substituted or unsubstituted substituents described in (1) may optionally be selected from the following groups: F. cl, Br, -OH, ═ O, -NO2、-CN、-NH2、-CF3、-OR5、COR5、-NHCOR5、-CONR5R6、-COOR5Wherein R is5And R6Each independently is a straight or branched chain C1-C6An alkyl group;
or R2、R3The substituted or unsubstituted substituents recited in (1) are optionally selected from the group consisting of: straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical, C3-C6Cycloalkyl, said straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical or C3-C6Cycloalkyl group optionallySubstituted with the following groups: -OH, -CN, -NH25-6 membered aromatic ring or 5-6 non-aromatic heterocycle;
or R2、R3The substituted or unsubstituted substituents recited in (1) are optionally selected from the group consisting of: a 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S, C1-C3Alkyl-substituted 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S or oxygen-substituted 5-6 membered aromatic or 5-6 membered non-aromatic heterocyclic group containing at least one heteroatom selected from N, O or S.
3. The compound according to claim 2, which is represented by the general formula (II):
Figure FDA0002379968450000031
wherein, X1、X2、R1、R2、R3As defined in claim 2.
4. A compound according to claim 3 and isomers thereof, or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
R1is-NHR4、-NHCOR4、-NHCSR4、-NHSO2R4、-NHCOOR4、-NHCSOR4、-NHCONHR4、-NHCSNHR4；
R4Independently selected from H, substituted or unsubstituted straight or branched C1-C4Alkyl, substituted or unsubstituted 3-6 membered cycloalkyl;
the R is4Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
R2、R3independently selected from H, F, Cl, Br, -OH, -NO2、-CN、-NH2、-CF3、
Figure FDA0002379968450000032
Figure FDA0002379968450000033
Figure FDA0002379968450000041
5. The compound according to claim 4 and isomers thereof, or pharmaceutically acceptable salts thereof,
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
R1is-NH2、-NHCH3、
Figure FDA0002379968450000042
Figure FDA0002379968450000043
R2、R3Independently selected from H, F,
Figure FDA0002379968450000044
Figure FDA0002379968450000045
Figure FDA0002379968450000051
6. The compound according to claim 3, which is represented by the general formula (III):
Figure FDA0002379968450000052
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
R1is-NHR4、-NHCOR4、-NHCSR4、-NHSO2R4、-NHCOOR4、-NHCSOR4、-NHCONHR4、-NHCSNHR4；
R4Independently selected from H, substituted or unsubstituted straight or branched C1-C4Alkyl, substituted or unsubstituted 3, 4,5 or 6 membered cycloalkyl;
the R is4Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
R3h, F, Cl or Br;
r represents 1,2,3, 4 or 5 substituents which are identical or different and are eachIndependently selected from the group consisting of: F. cl, Br, -OH, -NO2、-CN、-NH2、-CF3、-OR5、COR5、-NHCOR5、-CONR5R6、-COOR5Straight or branched chain C1-C6Alkyl, straight or branched C1-C6Alkylamino radical, in which R5And R6Each independently is a straight or branched chain C1-C6An alkyl group;
or R represents 1,2,3, 4 or 5 substituents which are the same or different and are each independently selected from the following groups: straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical, C3、C4、C5Or C6Cycloalkyl, said straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical or C3、C4、C5Or C6The cycloalkyl group is optionally substituted with: F. cl, Br, -OH, ═ O, -NO2、-CN、-NH2、-CF3、-OCF3Morpholinyl, thiomorpholinyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; wherein said substituted or unsubstituted group is selected from: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
or R represents 1,2,3, 4 or 5 substituents which are the same or different and are each independently selected from the following groups: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, and the like,Substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl; wherein the substituted or unsubstituted substituents are selected from: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group.
7. The compound according to claim 3, which is represented by the general formula (IV):
Figure FDA0002379968450000071
wherein the content of the first and second substances,
X1、X2independently selected from H, F, Cl, Br, straight or branched chain C1-C3Alkyl, straight or branched C1-C3Alkoxy or halo straight or branched C1-C3An alkyl group;
z is N, Y is C, W is C, or Y is N, W is C, Z is C, or W is N, Y is C, Z is C;
R1is-NHR4、-NHCOR4、-NHCSR4、-NHSO2R4、-NHCOOR4、-NHCSOR4、-NHCONHR4、-NHCSNHR4；
R4Independently selected from H, substituted or unsubstituted straight or branched C1-C4Alkyl, substituted or unsubstituted 3, 4,5 or 6 membered cycloalkyl;
the R is4Wherein the substituted or unsubstituted substituents may optionally be selected from the group consisting of:F、Cl、Br、-OH、-NH2、-NO2、-CN、-CF3、-OCF3straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group;
R3h, F, Cl or Br;
r represents 1,2,3, 4 or 5 substituents which are the same or different and are each independently selected from the following groups: F. cl, Br, -OH, -NO2、-CN、-NH2、-CF3、-OR5、COR5、-NHCOR5、-CONR5R6、-COOR5Wherein R is5And R6Each independently is a straight or branched chain C1-C6An alkyl group;
or R represents 1,2,3, 4 or 5 substituents which are the same or different and are each independently selected from the following groups: straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical, C3、C4、C5Or C6Cycloalkyl, said straight or branched C1-C6Alkyl, straight or branched C1-C6Alkylamino radical or C3、C4、C5Or C6The cycloalkyl group is optionally substituted with: F. cl, Br, -OH, ═ O, -NO2、-CN、-NH2、-CF3、-OCF3Morpholinyl, thiomorpholinyl, substituted or unsubstituted triazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl; wherein said substituted or unsubstituted group is selected from: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group.
Or R represents 1,2,3, 4 or 5 substituents which are the sameOr are different and are each independently selected from the following groups: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl; wherein the substituted or unsubstituted substituents are selected from: F. cl, Br, -OH, -NH2、-NO2、-CN、-CF3、-OCF3Straight or branched chain C1-C3Alkyl, halogenated straight or branched C1-C3Alkyl, straight or branched C1-C3Alkoxy or straight or branched C1-C3An alkylamino group.
8. A compound according to claim 1 and stereoisomers thereof, or pharmaceutically acceptable salts thereof, which is selected from the following compounds:
Figure FDA0002379968450000081
Figure FDA0002379968450000091
Figure FDA0002379968450000101
Figure FDA0002379968450000111
Figure FDA0002379968450000121
9. the compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt of the compound represented by the general formula (I) is a salt of the compound with hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, tartaric acid, maleic acid, fumaric acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, acetic acid, malonic acid, succinic acid, malic acid, benzenesulfonic acid, or trifluoroacetic acid.
10. A process for the preparation of a compound according to any one of claims 1 to 8, comprising the steps of:
Figure FDA0002379968450000131
reacting the compound shown in the formula F with N-bromosuccinimide (NBS) in acetonitrile to obtain a compound shown in a formula G; reacting the compound shown in the formula G with methanol under an acidic condition to obtain a compound shown in a formula H; reacting the compound shown in the formula H with ammonia water to obtain a compound shown in the formula J; the amide carbonyl group in the compound of formula J is first reduced to CH2Then reacting with benzyloxycarbonyl chloride (CbzCl) to obtain a compound of formula K; reacting a compound shown in a formula K with a compound shown in a formula L under an acidic condition to obtain a compound shown in a formula M; removing p-methoxybenzyl (PMB) from the compound of the formula M under the action of ceric ammonium nitrate to obtain a compound of a formula N; compounds of formula N and (BOC)2Reacting O to obtain a compound shown in the formula O; reacting the compound of the formula O under alkaline conditions to obtain a compound of a formula A;
a compound of the formula A and R2B(OH)2Or R2Reacting substituted boronic acid pinacol ester or a nitrogen-containing non-aromatic heterocycle in a solvent under the protection of inert gas under the conditions of a metal palladium catalyst and alkali to obtain a compound shown in a formula B; in the acidic barRemoving the BOC protecting group under the component to obtain a compound shown in the formula C; reacting the compound of the formula C with a corresponding electrophilic reagent to obtain a compound of a formula (I);
or removing BOC protecting group from the compound of the formula A under an acidic condition to obtain a compound of a formula D; reacting the compound shown in the formula D with a corresponding electrophilic reagent to obtain a compound shown in the formula E; compounds of formula E and R2B(OH)2Or R2Reacting substituted boronic acid pinacol ester or nitrogen-containing non-aromatic heterocycle in a solvent under the protection of inert gas under the conditions of a metal palladium catalyst and alkali to obtain a compound shown in a formula (I);
by using
Figure FDA0002379968450000132
And replacing the compound of the formula L to obtain the compound shown in the formula (II).
11. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of any one of claims 1-8 and its isomer, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable adjuvants.
12. Use of a compound according to any one of claims 1 to 8, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 for the preparation of a medicament for the treatment and/or prevention of infectious diseases.
13. Use according to claim 12, characterized in that the infectious disease is an infection caused by gram-positive bacteria or mycobacterium tuberculosis.
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