CN118994004A - Application of (+) -sclerotiorin derivative in antimycobacterial medicine - Google Patents

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and in particular to the use of a (+)-sclerotiorin derivative in inhibiting anti-mycobacterial activity. The compound of formula (I) has a selective inhibitory effect on mycobacteria (Mycobacterium tuberculosis, Mycobacterium marinum and Mycobacterium smegmatis), is ineffective against other fungi and bacteria, and has no cytotoxicity. This class of compounds has a significant inhibitory effect on bacterial biofilms, and can produce a synergistic effect when used in combination with positive drugs. The present invention provides an anti-mycobacterial drug, characterized in that the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof is used to treat diseases caused by mycobacteria.

Description

Application of (+) -sclerotiorin derivative in antimycobacterial medicine

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to (+) -sclerotiorin derivatives, a composition and application thereof, wherein the compounds or the composition have the application of selectively inhibiting the activity of mycobacterium and can be used for preventing or treating diseases caused by mycobacterium bacteria.

Background

Mycobacteria include a broad class of gram-positive, rod-shaped, acid stain-positive bacteria, including many important human health-damaging pathogens such as Mycobacterium tuberculosis, mycobacterium marinum, mycobacterium smegmatis, and the like. They can cause a number of diseases such as cough, bronchitis, pneumonia and emphysema to cystic fibrosis, tuberculosis and even death. In 2021, the number of deaths caused by tuberculosis reaches 160 ten thousand cases, and the drug resistance to first-line drugs such as isoniazid and rifampicin is increasingly serious (who. Global tuberculosis report 2022,2023). Thus, there is a global need for safer, more effective new drugs for the treatment of mycobacterial bacterial infections.

(+) -Sclerotiorin was originally a polyketide natural product isolated from fungi Penicillium sclerotiorum and its derivatives showed a wide range of biological activities such as antifungal activity, cytotoxic activity, enzyme inhibitory activity (Lin L.et,al.J.Agr.Food Chem.,2012,60,4480-4491;Hai Y.,et,al.Eur.J.Med.Chem.2022,232,114166;Somoza,A.D.,et al.Org.Lett.,2012,14,972-975). but up to now, no (+) -Sclerotiorin derivatives with selective antimycobacterial activity in vitro have been reported. The patent aims at finding a compound which can keep the high antimycobacterial activity and has good selectivity and can be used as a medicine for clinical application.

Disclosure of Invention

The following is merely a general description of some aspects of the invention and is not limited in this regard. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification is different from that of the cited document, the disclosure of the present specification controls.

The invention provides a novel (+) -sclerotiorin derivative which is used for preventing or treating infectious diseases caused by mycobacterium, such as pulmonary tuberculosis, bone tuberculosis, lymphoid tuberculosis, lumbar tuberculosis, thoracic tuberculosis, breast tuberculosis, swimming pool granuloma, pulmonary infection, lymph node infection and bruley ulcer. The compound has the advantages of remarkable activity, stable property, good safety, remarkable synergistic effect with the commercially available positive drugs, and good kinetic property, thus having better clinical application prospect.

The invention also provides pharmaceutical compositions comprising these compounds and methods of using these compounds or compositions in the treatment of the above-described diseases in mammals, especially humans.

Specifically:

in one aspect, the present invention relates to a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,

Wherein:

R ₁ is a substituted or unsubstituted biphenyl, biphenyl ether, terphenyl, 4- (1-naphthyl) phenyl or 4-pyridineamide fragment, wherein the benzene ring and the pyridine ring may each independently be optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, F, cl, br, I, hydroxy, amino, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl or 5-6 membered heteroaryl. R ₂ is substituted or unsubstituted acetoxy, cinnamate, pyridine acrylate, heterocyclic acrylate, benzoate, picolinate, and heterocyclic formate, wherein the benzene ring and pyridine ring may each independently be optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, cl, br, I, hydroxy, amino, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl, or 5-6 membered heteroaryl.

The compound of claim 1, wherein R ₁ is R ₂ is hydroxy, acetoxy, substituted or unsubstituted

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the present disclosure.

In some embodiments, the pharmaceutical compositions of the present invention further comprise a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.

In another aspect, the invention relates to a compound or pharmaceutical composition of the disclosure for use in the prevention or treatment of infectious diseases caused by mycobacteria in a mammal, including a human; wherein the infectious disease comprises tuberculosis, bone tuberculosis, lymphoid tuberculosis, lumbar tuberculosis, thoracic tuberculosis, breast tuberculosis, swimming pool granuloma, pneumonia, lymph node infection, and bruley ulcer.

Biological test results show that the compounds provided by the invention can inhibit the growth of mycobacterium.

Any of the embodiments of any of the aspects of the invention may be combined with other embodiments, provided that they do not contradict. Furthermore, in any of the embodiments of any of the aspects of the present invention, any technical feature may be applied to the technical feature in other embodiments as long as they do not contradict.

The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, and "March's Advanced Organic Chemistry"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.

"Stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"Chiral" is a molecule that has properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.

"Enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.

"Diastereoisomers" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.

Many organic compounds exist in 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 and S are used to represent the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. One 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 can occur when there is no stereoselectivity or stereospecificity during a chemical reaction.

Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, 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 be present in the form of one of the possible isomers or mixtures thereof, for example racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.

Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Principles of Asymmetric Synthesis(2^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012);Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972);Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007).

The compounds of the invention may be optionally substituted with one or more substituents, as described in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with substituents described herein. Unless otherwise indicated, a substituted group may have a substituent 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, then the substituents may be the same or different at each position.

The term "unsubstituted" means that the specified group does not carry a substituent.

The term "optionally substituted with … …" may be used interchangeably with the term "unsubstituted or substituted with … …," i.e., the structure is unsubstituted or substituted with one or more substituents described herein. Substituents described herein include, but are not limited to D, F, cl, br, I, N ₃、CN、NO₂、OH、SH、NH₂, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

In addition, unless explicitly indicated otherwise, the description used in this disclosure of the manner in which "each … is independently" and "… is independently" and "… is independently" are to be understood in a broad sense as meaning that the particular choices expressed between the same symbols in different groups do not affect each other, or that the particular choices expressed between the same symbols in the same groups do not affect each other.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C _1-6 alkyl" refers specifically to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl, and C ₆ alkyl.

In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein refers to a saturated, straight or branched chain monovalent hydrocarbon group, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1 to 20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 3 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃), ethyl (Et, -CH ₂CH₃), n-propyl (n-Pr, -CH ₂CH₂CH₃), isopropyl (i-Pr, -CH (CH ₃)₂), N-butyl (n-Bu, -CH ₂CH₂CH₂CH₃), isobutyl (i-Bu, -CH ₂CH(CH₃)₂), sec-butyl (s-Bu, -CH (CH ₃)CH₂CH₃), tert-butyl (t-Bu, -C (CH ₃)₃), N-pentyl (-CH ₂CH₂CH₂CH₂CH₃), 2-pentyl (-CH (CH ₃)CH₂CH₂CH₃), 3-pentyl (-CH (CH ₂CH₃)₂), 2-methyl-2-butyl (-C (CH ₃)₂CH₂CH₃)), 3-methyl-2-butyl (-CH (CH ₃)CH(CH₃)₂), 3-methyl-1-butyl (-CH ₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (-CH ₂CH(CH₃)CH₂CH₃), n-hexyl (-CH ₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (-CH (CH ₃)CH₂CH₂CH₂CH₃), 3-hexyl (-CH (CH ₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (-C (CH ₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (-CH (CH ₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (-CH (CH ₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (-C (CH ₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (-CH (CH ₂CH₃)CH(CH₃)₂), 2, 3-dimethyl-2-butyl (-C (CH ₃)₂CH(CH₃)₂)), 3, 3-dimethyl-2-butyl (-CH (CH ₃)C(CH₃)₃), n-heptyl, n-octyl, and the like).

The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃), ethoxy (EtO, -OCH ₂CH₃), 1-propoxy (n-PrO, n-propoxy, -OCH ₂CH₂CH₃), 2-propoxy (i-PrO, i-propoxy, -OCH (CH ₃)₂), 1-butoxy (n-BuO, n-butoxy, -OCH ₂CH₂CH₂CH₃), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂CH(CH₃)₂), 2-butoxy (s-BuO, s-butoxy, -OCH (CH ₃)CH₂CH₃), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH ₃)₃), 1-pentoxy (n-pentoxy, -OCH ₂CH₂CH₂CH₂CH₃), 2-pentoxy (-OCH (CH ₃)CH₂CH₂CH₃), 3-pentoxy (-OCH (CH ₂CH₃)₂), 2-methyl-2-butoxy (-OC (CH ₃)₂CH₂CH₃), 3-methyl-2-butoxy (-OCH (CH ₃)CH(CH₃)₂), 3-methyl-l-butoxy (-OCH ₂CH₂CH(CH₃)₂), 2-methyl-l-butoxy (-OCH ₂CH(CH₃)CH₂CH₃), and the like.

The term "haloalkyl" means an alkyl group substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, trifluoromethyl, 2, 3-tetrafluoropropyl, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic cyclic hydrocarbon group containing 3 to 12 carbon atoms. In one embodiment, cycloalkyl groups contain 7 to 12 carbon atoms; in yet another embodiment, cycloalkyl groups contain 3 to 8 carbon atoms; in yet another embodiment, cycloalkyl groups contain 3 to 6 carbon atoms. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

The term "heterocyclyl" refers to a saturated or partially unsaturated, non-aromatic, mono-, bi-or tricyclic ring containing 3 to 12 ring atoms, at least one of which is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise indicated, heterocyclyl groups may be attached to other groups in the molecule through carbon atoms, may also be attached to other groups in the molecule through nitrogen atoms, and the-CH ₂ -group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazanyl, homopiperazinyl, homopiperidinyl, diazepinyl, oxepinyl, thiepinyl, oxazanyl, oxazalinkBasic, diazaRadical, thiazas-2-Oxa-5-azabicyclo [2.2.1] hept-5-yl. Examples of the substitution of the-CH ₂ -group in the heterocyclyl by-C (=o) -include, but are not limited to, 2-oxo-pyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl and pyrimidinedionyl. Examples of sulfur atoms in the heterocyclic group that are oxidized include, but are not limited to, sulfolane, 1-dioxothiomorpholino. The heterocyclyl group may be optionally substituted with one or more substituents described herein.

The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.

The term "halogen" or "halogen atom" refers to a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br) or an iodine atom (I).

The term "cyano" or "CN" means a cyano structure, which group may be attached to other groups.

The term "aryl" means a mono-or polyvalent mono-, bi-or tricyclic full-carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring is aromatic and has one or more points of attachment to the remainder of the molecule. In one embodiment, aryl groups are monovalent or polyvalent carbocyclic ring systems consisting of 6 to 10 ring atoms and containing at least one aromatic ring therein. Examples of aryl groups may include phenyl, naphthyl and anthracenyl. The aryl groups may independently be optionally substituted with one or more substituents described herein.

The term "heteroaryl" means a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one aromatic ring contains one or more heteroatoms and has one or more points of attachment to the remainder of the molecule. The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, heteroaryl is a heteroaryl consisting of 5-12 atoms comprising 1,2, 3, or 4 heteroatoms independently selected from O, S and N; in another embodiment, heteroaryl is a 5-6 atom composition heteroaryl comprising 1,2, 3, or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, oxadiazolyl (e.g., 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl), oxazolyl (e.g., 1,2,3, 4-oxazolyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, isothiazolyl, 2-thiadiazolyl (e.g., 1,3, 4-thiadiazolyl, 1,2, 3-thiadiazolyl), 1,2, 5-thiadiazolyl) Thiazolyl (e.g., 1,2,3, 4-Thiazolyl), tetrazolyl (e.g., 2H-1,2,3, 4-tetrazolyl, 1H-1,2,3, 4-tetrazolyl), triazolyl (e.g., 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl), 2-thienyl, 3-thienyl, 1H-pyrazolyl (e.g., 1H-pyrazol-3-yl) 1H-pyrazol-4-yl, 1H-pyrazol-5-yl), N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), 3-pyridyl, 4-pyrimidinyl, 5-pyrimidinyl, and the like, 2-pyrazinyl, triazinyl (e.g., 1,3, 5-triazine), tetrazinyl (e.g., 1,2,4, 5-tetrazine, 1,2,3, 5-tetrazine); the following bicyclic rings are also included, but are in no way limited to: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo [1,2-a ] pyridinyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, and the like.

As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in document ：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoic acid salts, bisulfate salts, borates, butyric acid salts, camphoric acid salts, cyclopentylpropionates, digluconate, dodecylsulfate, ethanesulfonate, formate, fumaric acid salts, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodic acid salts, 2-hydroxy-ethanesulfonate, lactobionic acid salts, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with suitable bases include the alkali metal, alkaline earth metal, ammonium and N ⁺(C_1-4 alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C _1-8 sulphonates and aromatic sulphonates.

"Solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.

When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the invention may be associated with a water molecule, such as a monohydrate; in other embodiments, one of the present compound molecules may be associated with more than one water molecule, such as a dihydrate, and in still other embodiments, one of the present compound molecules may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological effectiveness of the compounds in a non-hydrated form.

The term "treating" any disease or disorder as used herein refers to all slowing, interrupting, arresting, controlling or stopping the progression of the disease or disorder, but does not necessarily mean that the symptoms of all diseases or disorders are all absent, and includes prophylactic treatment of such symptoms, particularly in patients susceptible to such diseases or disorders. In some embodiments, ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.

The term "therapeutically effective amount" or "therapeutically effective dose" as used herein refers to an amount of a compound of the invention that is capable of eliciting a biological or medical response in an individual (e.g., reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to an individual, is effective for: (1) At least partially alleviating, inhibiting, preventing and/or ameliorating a mycobacterial infection. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that is effective to at least partially reduce or inhibit mycobacterial infection when administered to a cell, or organ, or non-cellular biological material, or medium.

The terms "administration" and "administering" of a compound as used herein should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need thereof. It will be appreciated that one skilled in the art may have an effect on mycobacterial infections by treating a patient currently suffering from such a disorder, or prophylactically treating a patient suffering from such a disorder, with an effective amount of a compound of the invention.

The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of such terms in relation to pharmaceutical compositions includes products comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any products that result directly or indirectly from mixing, compounding or aggregation of any two or more ingredients, or from decomposition of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

Description of the Compounds of the invention

The invention discloses (+) -sclerotiorin derivatives, stereoisomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, pharmaceutical preparations and compositions thereof, which can be used for preventing or treating infectious diseases caused by mycobacterium, such as phthisis, bone tuberculosis, lymphoid tuberculosis, lumbar tuberculosis, thoracic tuberculosis, breast tuberculosis, swimming pool granuloma, lung infection, lymph node infection and bruley ulcer.

In one aspect, the present invention relates to a compound of formula (I) or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),

R ₁ is a substituted or unsubstituted biphenyl, biphenyl ether, terphenyl, 4- (1-naphthyl) phenyl or 4-pyridineamide fragment, wherein the benzene ring and the pyridine ring may each independently be optionally substituted with 1,2, 3 or 4 substituents selected from deuterium, F, cl, br, I, hydroxy, amino, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl or 5-6 membered heteroaryl. R ₂ is substituted or unsubstituted cinnamate, pyridine acrylate, heterocyclic acrylate, benzoate, picolinate, and heterocycloformate, wherein the benzene ring and pyridine ring may each independently be optionally substituted with 1,2, 3, or 4 substituents selected from deuterium, F, cl, br, I, hydroxy, amino, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl, or 5-6 membered heteroaryl; in some embodiments, R ₁ is R ₂ is hydroxy, acetoxy, substituted or unsubstituted

In some embodiments, the invention relates to compounds of one of the following, or stereoisomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, but in no way limited to these compounds:

The disclosed compounds may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention is intended to encompass all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof, such as racemic mixtures, as part of the present invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.

The compounds of formula (I) may exist in different tautomeric forms and all such tautomers are included within the scope of the invention.

The compounds of formula (I) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, and may be an intermediate for preparing and/or purifying the compound of formula (I) and/or for separating enantiomers of the compound of formula (I).

Pharmaceutically acceptable acid addition salts may be formed from the reaction of a compound of the present disclosure with an inorganic or organic acid, such as acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline salt, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodite/iodide, isethionate, lactate, lactobionic aldehyde, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, stearate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactoate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

Pharmaceutically acceptable base addition salts may be formed from the compounds of the present disclosure by reaction with inorganic or organic bases.

Inorganic bases from which salts may be derived include, for example, ammonium salts and metals of groups I to XII of the periodic Table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts may be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine and tromethamine.

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of other suitable salts can be found in the nature, selection and application (Handbook of Pharmaceutical Salts：Properties,Selection,and Use)",Stahl and Wermuth(Wiley-VCH,Weinheim,Germany,2002).

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include both solvated and unsolvated forms of the presently disclosed compounds.

Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and ¹²⁵ I.

In another aspect, the compounds of the invention include isotopically enriched compounds defined herein, for example, those in which a radioisotope, such as ³H、¹⁴ C and ¹⁸ F, is present, or those in which a non-radioisotope, such as ² H and ¹³ C, is present. Such isotopically enriched compounds are useful in metabolic studies (using ¹⁴ C), kinetic studies (using, for example, ² H or ³ H), detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays, or in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation of the present invention using a suitable isotopically labelled reagent in place of the one previously used unlabelled reagent.

Furthermore, substitution of heavier isotopes, particularly deuterium (i.e., ² H or D), may afford certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopically enriched factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, e.g. D ₂ O, acetone-D ₆、DMSO-d₆.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The present invention provides a pharmaceutical composition comprising a compound of the present disclosure, such as the compounds listed in the examples; and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.

The present invention provides methods of treating, preventing or ameliorating a disease or disorder comprising administering a safe and effective amount of a combination comprising a compound of the present disclosure and one or more therapeutically active agents. Wherein the combination comprises one or more agents for preventing or treating a disease including tuberculosis, granuloma in swimming pool, pulmonary infection, lymph node infection, brucellosis, which are different from the compounds disclosed in the present invention in active ingredients.

Drugs for preventing or treating tuberculosis, granuloma in swimming pools, lung infections, lymph node infections, bruley ulcers include, but are not limited to: isoniazid, rifampin, ethambutol, pyrazinamide, streptomycin, para-ammonia salicylic acid, ethionamide, calicheamicin, li Fuding, bedaquiline, protomanib, triclosan, delamanib, and linezolid, or any combination thereof.

The dosage of the active ingredient in the compositions of the present invention may vary, but the amount of active ingredient must be such that an appropriate dosage form is obtained. The active ingredient may be administered to patients (animals and humans) in need of such treatment in a dosage that provides optimal pharmaceutical efficacy. The selected dosage depends on the desired therapeutic effect, on the route of administration and the duration of the treatment. The dosage will vary from patient to patient depending on the nature and severity of the disease, the weight of the patient, the particular diet of the patient, the concurrent medication, and other factors that will be recognized by those skilled in the art. The dosage range is typically about 0.5mg to 1.0g per patient per day, and may be administered in single or multiple doses. In one embodiment, the dosage ranges from about 0.5mg to 500mg per patient per day; in another embodiment about 0.5mg to 200mg per patient per day; in yet another embodiment about 5mg to 50mg per patient per day.

It will also be appreciated that certain compounds of the invention may exist in free form and for use in therapy, or if appropriate in the form of pharmaceutically acceptable derivatives thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adducts or derivatives that provide, directly or indirectly, the compounds of the invention or metabolites or residues thereof when administered to a patient in need thereof.

The disclosed pharmaceutical or pharmaceutical compositions may be prepared and packaged in bulk (bulk) form, wherein a safe and effective amount of the compound of formula (I) may be extracted and then administered to a patient in powder or syrup form. Typically, the patient is administered at a dosage level of between 0.0001 and 10mg/kg body weight per day to obtain an effective effect. Alternatively, the pharmaceutical compositions disclosed herein may be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I). When prepared in unit dosage form, the presently disclosed pharmaceutical compositions may generally contain, for example, from 0.5mg to 1g, or from 1mg to 700mg, or from 5mg to 100mg of a presently disclosed compound.

When the pharmaceutical compositions of the present invention contain one or more other active ingredients in addition to the compound of the present invention, the compound weight ratio of the compound of the present invention to the second active ingredient may vary and will depend on the effective dose of each ingredient. Typically, an effective dose of each is used. Thus, for example, when a compound of the present invention is mixed with another agent, the weight ratio of the compound of the present invention to the other agent typically ranges from about 1000:1 to about 1:1000, such as from about 200:1 to about 1:200. Mixtures of the compounds according to the invention with other active ingredients are generally also within the abovementioned ranges, but in each case an effective dose of each active ingredient should be used.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle associated with consistency of administration dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would greatly reduce the efficacy of the disclosed compounds and interactions that would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form selected. Furthermore, pharmaceutically acceptable excipients may be selected according to their particular function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients that can aid in the production of stable dosage forms can be selected. Certain pharmaceutically acceptable excipients that facilitate carrying or transporting the disclosed compounds from one organ or portion of the body to another organ or portion of the body when administered to a patient may be selected. Certain pharmaceutically acceptable excipients that enhance patient compliance may be selected.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants, and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation.

The skilled artisan will know and be familiar with the art to which they will be able to select the appropriate amount of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there are a number of resources available to the skilled person, who describe pharmaceutically acceptable excipients and are used to select the appropriate pharmaceutically acceptable excipient. Examples include Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(the American Pharmaceutical Association and the Pharmaceutical Press).

Various carriers for formulating pharmaceutically acceptable compositions, and well-known techniques for their preparation, are disclosed in Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York, the contents of each of which are incorporated herein by reference. In addition to any conventional carrier medium that is incompatible with the compounds of the present invention (e.g., produces any adverse biological effect or otherwise interacts in a deleterious manner with any of the other components of the pharmaceutically acceptable composition), its use is contemplated as falling within the scope of the present invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Thus, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof, which process comprises mixing the various ingredients. Pharmaceutical compositions comprising the compounds of the present disclosure may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) Oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) Parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patch tablets; (4) rectal administration, such as suppositories; (5) inhalations, such as aerosols, solutions and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

The pharmaceutical compositions provided herein may be provided in compressed tablets, developed tablets, chewable lozenges, instant tablets, reconstituted tablets, or enteric tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, aminated shellac, and cellulose acetate phthalate. Dragees are dragee-enclosed compressed tablets that can facilitate masking of unpleasant tastes or odors and prevent oxidation of the tablet. The film coated tablet is a compressed tablet covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating imparts the same general characteristics as the sugar coating. The composite tablet is a compressed tablet prepared through more than one compression cycle, and comprises a multi-layer tablet and a compression coated or dry coated tablet.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or particulate form alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical composition provided by the invention can be provided in a soft capsule or a hard capsule, and can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as a Dry Filled Capsule (DFC), consists of two segments, one segment being filled into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. Liquid, semi-solid and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. patent nos.4,328,245;4,409,239 and 4,410,545 prepared as described. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in the form of pellets in another liquid, which may be oil-in-water or water-in-oil. The emulsion may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcohol solution may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, for example, acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example sucrose, and may also contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for accurate and convenient administration.

Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredient provided herein and a secondary mono-or poly-alkylene glycol, including: 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further include one or more antioxidants such as Butylated Hydroxytoluene (BHT), butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulphite, sodium metabisulfite, thiodipropionic acid and esters thereof, and dithiocarbamates.

Dosage unit formulations for oral administration may be microencapsulated, as appropriate. It may also be formulated in an extended-release or sustained-release composition, for example, by coating or embedding the particulate material in a polymer, wax or the like.

The oral pharmaceutical compositions provided by the present invention may also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micelle dosage forms may be prepared using the methods described in U.S. Pat. No.6,350,458.

The pharmaceutical compositions provided herein may be provided in non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and carbon dioxide sources.

Coloring and flavoring agents may be used in all of the above dosage forms.

The disclosed compounds may also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparaginol or palmitoyl residue substituted polyoxyethylene polylysine. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.

The pharmaceutical compositions provided herein may be formulated in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

The pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

The pharmaceutical compositions provided herein may be administered parenterally, by injection, infusion or implantation, for topical or systemic administration. Parenteral administration as used in the present invention includes intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for making solutions or suspensions in liquids prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in the art of pharmaceutical sciences (see Remington: THE SCIENCE and Practice of Pharmacy, supra).

Pharmaceutical compositions contemplated for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water miscible vehicles, non-aqueous vehicles, antimicrobial or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, freezing point depressants, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

Suitable aqueous vehicles include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, medium chain triglycerides of hydrogenated soybean oil and coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N-dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercuric agents, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and glucose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants are those as described herein, including bisulfites and sodium metabisulfites. Suitable local anesthetics include, but are not limited to procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene tax refund sorbitol monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin and sulfobutyl ether 7-beta-cyclodextrinCyDex,Lenexa,KS)。

The pharmaceutical compositions provided by the invention can be formulated for single or multiple dose administration. The single dose formulation is packaged in ampules, vials or syringes. The multi-dose parenteral formulation must contain antimicrobial agents at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.

In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including lyophilized powder and subcutaneous injection tablets, which are reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile dry insoluble product reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a sterile ready-to-use emulsion.

The pharmaceutical compositions may be formulated as suspensions, solids, semi-solids, or thixotropic liquids for administration as an implanted depot. In one embodiment, the disclosed pharmaceutical compositions are dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.

Suitable internal matrices include polymethyl methacrylate, polymethyl butyl acrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate for coaches.

Suitable external polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxy ethanol copolymers.

In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for inhaled administration to a patient, such as dry powder, aerosol, suspension or solution compositions. In one embodiment, the disclosed pharmaceutical compositions can be formulated into dosage forms suitable for administration by inhalation to a patient using dry powders. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for administration by inhalation to a patient via a nebulizer. Dry powder compositions for delivery to the lungs by inhalation typically comprise a finely powdered compound as disclosed herein and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. The fine powder can be prepared by, for example, micronization and grinding. In general, reduced size (e.g., micronized) compounds may be defined by a D ₅₀ value (e.g., measured by laser diffraction) of about 1 to 10 microns.

Aerosols may be formulated by suspending or dissolving the presently disclosed compounds in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134 a), 1-difluoroethane (HFA-152 a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227 a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the disclosed compounds are typically administered to patients by means of Metered Dose Inhalers (MDI). Such devices are known to those skilled in the art that aerosols may contain additional pharmaceutically acceptable excipients that may be used by MDIs, such as surfactants, lubricants, co-solvents, and other excipients, to improve the physical stability of the formulation, improve valve characteristics, improve solubility, or improve taste.

Pharmaceutical compositions suitable for transdermal administration may be formulated as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch by ion permeation, as generally described in Pharmaceutical Research,3 (6), 318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with water or oil bases, with appropriate thickening and/or gelling agents and/or solvents. Such a base may include water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickening and gelling agents used according to the nature of the matrix include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or nonionic emulsifiers.

Lotions may be formulated with water or oil and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

The topical powders may be formed in the presence of any suitable powder base such as talc, lactose or starch. Drops may be formulated with an aqueous or nonaqueous base containing one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Topical formulations may be administered by application to the affected area one or more times per day; a occlusive dressing covering the skin is preferably used. The adhesive reservoir system may allow for continuous or prolonged administration.

Use of the compounds and compositions of the invention

The disclosed compounds or pharmaceutical compositions may be used in the preparation of a medicament for the treatment, prevention, amelioration, control or alleviation of infectious diseases caused by mycobacteria bacteria in a mammal, including a human.

In particular, the compounds of the present invention are useful as agents for the prevention or treatment of infectious diseases caused by mycobacteria including tuberculosis, bone tuberculosis, lymphoid tuberculosis, lumbar tuberculosis, thoracic tuberculosis, breast tuberculosis, swimming pool granuloma, pulmonary infection, lymph node infection, bruley ulcers.

The compounds or compositions of the present invention may be applied to, but are in no way limited to, the use of an effective amount of a compound or composition of the present invention to prevent, treat or ameliorate a disease caused by mycobacteria in a mammal, including a human being, when administered to a patient.

The compounds and pharmaceutical compositions of the present invention are useful for veterinary treatment of mammals, in addition to human therapy, in pets, in animals of introduced species and in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

Therapeutic method

In one embodiment, the presently disclosed methods of treatment comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Embodiments of the present disclosure include methods of treating the above-mentioned diseases by administering to a patient in need thereof a safe and effective amount of a compound of the present disclosure or a pharmaceutical composition comprising the compound of the present disclosure.

In one embodiment, the presently disclosed compounds or pharmaceutical compositions comprising the presently disclosed compounds may be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion and includes intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin, intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, the presently disclosed compounds or pharmaceutical compositions comprising the presently disclosed compounds may be administered orally. In another embodiment, the presently disclosed compounds or pharmaceutical compositions comprising the presently disclosed compounds may be administered by inhalation. In yet another embodiment, the presently disclosed compounds or compounds comprising the presently disclosed compounds may be administered intranasally.

In one embodiment, the presently disclosed compounds or pharmaceutical compositions comprising the presently disclosed compounds may be administered at one time or, depending on the dosing regimen, at several times at different time intervals over a specified period of time. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be performed until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the presently disclosed compounds, or pharmaceutical compositions comprising the presently disclosed compounds, depend on the pharmacokinetic properties of the compounds, such as dilution, distribution, and half-life, which can be determined by the skilled artisan. Furthermore, suitable dosing regimens for the presently disclosed compounds or pharmaceutical compositions comprising the presently disclosed compounds, including the duration of time for which the regimen is practiced, depend on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and the like, among other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that adjustment of the regimen may be required for the individual patient's response to the regimen, or as the individual patient needs to change over time.

The presently disclosed compounds may be administered simultaneously with, or before or after, one or more other therapeutic agents. The compounds of the present invention may be administered separately from other therapeutic agents by the same or different routes of administration, or in pharmaceutical compositions therewith.

For individuals of about 50-70kg, the presently disclosed pharmaceutical compositions and combinations may be in unit dosage form containing about 1-1000mg, or about 1-500mg, or about 1-250mg, or about 1-150mg, or about 0.5-100mg, or about 1-50mg of the active ingredient. The therapeutically effective amount of a compound, pharmaceutical composition or combination thereof is dependent on the species, weight, age and condition of the individual, the disease (disorder) or disease (disorder) being treated or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of the respective active ingredients required to prevent, treat or inhibit the disease (disorder) or the progression of the disease (disease).

The dose characteristics cited above have been demonstrated in vitro and in vivo tests using advantageous mammals (e.g. mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof. The compounds disclosed are used in vitro in the form of solutions, for example aqueous solutions, and also in the form of suspensions or aqueous solutions, for example, in the intestine in vivo, parenterally, in particular intravenously.

In one embodiment, a therapeutically effective dose of a compound of the present disclosure is from about 0.1mg to about 2,000mg per day. The pharmaceutical composition thereof should provide a dose of the compound of about 0.1mg to about 2,000mg. In a particular embodiment, the pharmaceutical dosage unit form prepared can provide from about 1mg to about 2,000mg, from about 10mg to about 1,000mg, from about 20mg to about 500mg, or from about 25mg to about 250mg of the primary active ingredient or a combination of the primary ingredients per dosage unit form. In a particular embodiment of the present invention, the pharmaceutical dosage unit form prepared can provide about 10mg,20mg,25mg,50mg,100mg,250mg,500mg,1000mg or 2000mg of the main active ingredient.

Furthermore, the compounds disclosed herein may be administered in prodrug form. In the present invention, a "prodrug" of a disclosed compound of the present invention is a functional derivative that, upon administration to a patient, ultimately releases the disclosed compound of the present invention in vivo. When a compound of the present disclosure is administered in a prodrug form, one skilled in the art can practice one or more of the following modes: (a) altering the in vivo onset time of the compound; (b) altering the duration of in vivo action of the compound; (c) altering in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for the preparation of prodrugs include variants of compounds that cleave chemically or enzymatically in vivo. These variants, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

General synthetic procedure

For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.

In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined for formula (I), unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.

The examples described below are given unless otherwise indicated that all temperatures are given in degrees celsius. Reagents were purchased from commercial suppliers such as ALDRICH CHEMICAL Company, arco Chemical Company AND ALFA CHEMICAL Company and used without further purification unless otherwise indicated. The general reagents are purchased from Shandong chemical plant, guangdong chemical reagent plant, guangzhou chemical reagent plant, tianjin good-apartment chemical Co., tianjin Fuchen chemical reagent plant, wuhan Xinhua Yuan technology development Co., qingdao Teng chemical reagent Co., and Qingdao ocean chemical plant.

The anhydrous methylene dichloride is obtained by reflux drying of calcium hydride. Ethyl acetate and petroleum ether are dried in advance by anhydrous sodium sulfate.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant.

Nuclear magnetic resonance spectra were recorded using a Bruker 400MHz or 500MHz or 600MHz nuclear magnetic resonance spectrometer with CDCl ₃、DMSO-d₆、CD₃ OD or acetone-d ₆ as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlet ), d (doublet, doublet), t (triplet, doublet), m (multiplet ), br (broadened, broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constants are expressed in hertz (Hz).

The following abbreviations are used throughout the present invention:

CDCl ₃ deuterated chloroform

Methanol-d ₄ deuterated Methanol

DMAP 4-dimethylaminopyridine

EDC & HCl 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

Mg

Mmol millimoles

M mol per liter

Degree centigrade

MeOH methanol

ML of

Rt room temperature

Typical synthetic procedures for preparing the disclosed compounds are shown in synthetic scheme 1 below. Wherein R ₁ and R ₂ have the meanings described in the present invention, unless otherwise specified.

Synthesis scheme 1

The corresponding aniline reagent (1.14 mmol) and potassium carbonate (15.8 mg,0.11 mmol) were initially dissolved in 10mL triethylamine, and after heating in a 35℃water bath for 10 minutes compound (+) -sclerotiorin (150.0 mg,0.38 mmol) was added. The whole reaction system was then stirred for a further 2 hours and monitored by thin layer chromatography during the reaction until a new red product appeared. After the reaction, the reaction mixture is quenched by saturated ammonium chloride solution, ethyl acetate is added to extract the reaction solution for more than three times, and the organic phases are combined and spin-dried to obtain the corresponding product R ₂ which is acetoxy (OAc).

100Mg of the acetoxy group-containing product obtained in the previous step was dissolved in 6mL of methanol solution, and 500. Mu.L of 1M aqueous sodium hydroxide solution was then added. The reaction was stirred at room temperature for 0.5 hours. The reaction mixture was quenched with saturated ammonium chloride solution and the system was neutralized with 1M dilute hydrochloric acid solution. Then, the reaction solution is extracted by ethyl acetate, and the organic phase is collected and dried by spin to obtain the corresponding product of R ₂ which is hydroxyl (OH).

The above product (0.17 mmol), DMAP (20.7 mg,0.17 mmol) and EDC. HCl (130.4 mg,0.68 mmol) were dissolved in 15mL anhydrous dichloromethane, a further drop of triethylamine was added and after stirring for 5min at 40℃in a water bath, the corresponding carboxylic reagent (0.68 mmol) was slowly added. The reaction was stirred for 1-3 hours and monitored during the reaction using thin layer chromatography until a new less polar red product appeared. After the reaction is finished, adding saturated ammonium chloride solution to terminate the reaction, extracting with dichloromethane three times, separating an organic phase, and concentrating under reduced pressure to obtain a crude extract, thereby obtaining the corresponding compound with R ₂ as other ester groups.

The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further described below in conjunction with the examples.

Examples

Example 1:

(R)-2-([1,1'-biphenyl]-4-yl)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl acetate( Compound 1)

Red powder; the yield is 85％;m.p.163–165℃.¹H NMR(500MHz,CDCl₃,J in Hz)δ7.88(s,1H),7.78-7.73(m,2H),7.63(d,J＝7.2Hz,2H),7.55-7.49(m,2H),7.36(d,J＝7.2Hz,2H),7.18(s,1H),6.99(d,J＝14.8Hz,1H),6.92(m,1H),5.68(overlapped,2H),2.49-2.30(m,1H),2.19(s,3H),1.60(s,3H),1.53(s,3H),1.47-1.35(m,1H),1.34-1.31(m,1H),0.99(d,J＝6.7Hz,3H),0.85(t,J＝7.3Hz,3H).¹³C NMR(125MHz,CDCl₃)δ193.7,185.1,170.1,147.8,147.4,143.9,143.1,141.1,139.3,138.9,131.8,130.0,129.1,129.1,128.6,128.6,128.4,128.4,127.1,127.1,126.8,116.2,115.3,114.4,109.9,84.7,34.9,29.9,29.6,20.2,20.1,12.2,11.9.HRESIMS m/z 542.2096[M+H]⁺(calcd for C₃₃H₃₃ClNO₄ ⁺,542.2098).

Example 2:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(4'-fluoro-[1,1'-biphenyl]-4-yl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl acetate( Compound 2)

Red powder with yield of 81％;m.p.135–137℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.86(s,1H),7.70(d,J＝8.0Hz,2H),7.62–7.56(m,2H),7.35(d,J＝8.0Hz,2H),7.21–7.13(overlapped,3H),6.96(d,J＝15.5Hz,1H),5.73–5.60(overlapped,2H),2.45–2.34(m,1H),2.18(s,3H),1.59(s,3H),1.53(s,3H),1.44–1.36(m,1H),1.33–1.25(m,1H),0.98(d,J＝6.6Hz,3H),0.84(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ193.9,184.8,170.3,162.0(d,¹J_C-F＝248.1Hz),148.1,147.6,144.1,143.4,142.1,141.2,139.5,135.3,135.3,131.9,129.0,129.0,128.6,127.1,127.1,116.4,116.4,116.1,114.6,110.1,103.6,84.9,35.1,30.1,23.3,20.4,20.3,12.4,12.1.HRESIMS m/z 560.2017[M+H]⁺(calcd for C₃₃H₃₂ClFNO₄ ⁺,560.2004).

Example 3:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(4'-fluoro-[1,1'-biphenyl]-4-yl)-7-hydroxy-7-methylisoquinoline-6,8(2H,7H)-dione( Compound 3

Red powder with yield of 47％;m.p.119–123℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.87(s,1H),7.71(d,J＝8.0Hz,2H),7.62–7.57(m,2H),7.37(d,J＝8.0Hz,2H),7.19(t,J＝8.4Hz,2H),7.15(s,1H),7.00(d,J＝15.6Hz,1H),5.75–5.67(overlapped,2H),4.11(s,1H),2.45–2.36(m,1H),1.61(s,3H),1.54(s,3H),1.42–1.39(m,1H),1.33–1.31(m,1H),0.98(d,J＝6.6Hz,3H),0.85(t,J＝7.5Hz,3H).¹³C NMR(100MHz,CDCl₃)δ196.5,188.2,160.4,148.5,148.1,145.5,143.8,142.3,140.3,139.4,132.0,129.1,129.0,128.7,128.7,127.1,127.1,116.4,116.4,116.3,116.2,115.6,109.5,101.0,83.7,35.2,30.1,29.6,20.3,12.5,12.1.HRESIMS m/z 518.1907[M+H]⁺(calcd for C₃₁H₃₀ClFNO₃ ⁺,518.1898).

Example 4:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(4'-fluoro-[1,1'-biphenyl]-4-yl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl cinnamate( Compound 4)

Red powder with yield of 40％;m.p.136–138℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ7.96–7.91(overlapped,3H),7.86–7.81(m,2H),7.75–7.68(overlapped,5H),7.48–7.44(overlapped,3H),7.32–7.26(overlapped,2H),7.24–7.16(overlapped,2H),6.65(d,J＝16.0Hz,1H),5.86(d,J＝15.7Hz,1H),5.78(d,J＝9.7Hz,1H),2.51–2.41(m,1H),1.57(s,3H),1.56(s,3H),1.45–1.38(m,1H),1.34–1.29(m,1H),0.97(d,J＝6.6Hz,3H),0.83(t,J＝7.5Hz,3H).¹³C NMR(100MHz,CDCl₃)δ193.7,184.2,165.9,148.8,147.7,146.7,144.7,143.4,142.3,142.2,140.9,135.3,133.2,131.5,130.0,130.0,130.0,130.0,129.9,129.9,129.3,129.3,129.1,129.1,128.5,128.5,118.0,118.0,116.8,116.6,115.2,109.6,103.0,86.1,35.5,30.7,23.6,20.5,12.4,12.2.HRESIMS m/z 648.2297[M+H]⁺(calcd for C₄₀H₃₆ClFNO₄ ⁺,648.2317).

Example 5:

(R)-5-chloro-2-(4'-chloro-[1,1'-biphenyl]-4-yl)-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl acetate( Compound 5

Red powder with yield of 82％;m.p.120–121℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.85(s,1H),7.71(d,J＝8.6Hz,2H),7.55(d,J＝8.5Hz,2H),7.45(d,J＝8.6Hz,2H),7.35(d,J＝8.5Hz,2H),7.16(s,1H),6.96(d,J＝15.5Hz,1H),5.69–5.62(overlapped,2H),2.44–2.35(m,1H),2.17(s,3H),1.59(s,3H),1.53(s,3H),1.45–1.37(m,1H),1.34–1.28(m,1H),0.97(d,J＝6.6Hz,3H),0.84(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ193.8,184.8,170.3,148.1,147.5,144.0,143.4,141.8,141.2,139.7,137.5,134.8,131.9,129.4,129.4,128.6,128.6,128.5,128.5,127.1,127.1,116.3,114.6,110.1,103.6,84.9,35.1,30.1,23.3,20.4,20.3,12.4,12.1.HRESIMS m/z 576.1720[M+H]⁺(calcd for C₃₃H₃₂Cl₂NO₄ ⁺,576.1708).

Example 6:

(R)-5-chloro-2-(4'-chloro-[1,1'-biphenyl]-4-yl)-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-hydroxy-7-methylisoquinoline-6,8(2H,7H)-dione( Compound 6

Red powder with yield of 74％;m.p.120–121℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.86(s,1H),7.72(d,J＝8.1Hz,2H),7.55(d,J＝8.3Hz,2H),7.46(d,J＝8.3Hz,2H),7.39(d,J＝8.1Hz,2H),7.14(s,1H),7.00(d,J＝15.5Hz,1H),5.74–5.66(overlapped,2H),4.12(s,1H),2.47–2.37(m,1H),1.61(s,3H),1.54(s,3H),1.47–1.38(m,1H),1.34–1.28(m,1H),1.00(d,J＝6.6Hz,3H),0.84(t,J＝7.5Hz,3H).¹³C NMR(100MHz,CDCl₃)δ196.5,188.2,148.5,148.1,145.4,143.8,142.0,140.3,139.6,137.5,134.9,132.0,129.5,129.5,128.7,128.7,128.6,128.6,127.1,127.1,116.3,115.6,109.5,101.0,83.7,35.1,30.1,29.6,20.3,12.5,12.1.HRESIMS m/z 534.1614[M+H]⁺(calcd for C₃₁H₃₀Cl₂NO₃ ⁺,534.1603).

Example 7:

(R)-5-chloro-2-(4'-cyano-[1,1'-biphenyl]-4-yl)-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl acetate( Compound 7

Red powder with yield of 73％;m.p.123–125℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.84(s,1H),7.81–7.72(overlapped,6H),7.74(d,J＝8.5Hz,2H),7.15(s,1H),6.97(d,J＝15.5Hz,1H),5.71–5.61(overlapped,2H),2.44–2.34(m,1H),2.16(s,3H),1.58(s,3H),1.53(s,3H),1.44–1.36(m,1H),1.34–1.27(m,1H),0.97(d,J＝6.6Hz,3H),0.84(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ193.8,184.9,170.3,148.2,147.3,143.8,143.5,141.0,141.0,140.7,133.0,133.0,131.9,131.9,129.0,129.0,128.0,128.0,127.4,127.4,118.6,116.2,114.7,112.3,110.2,103.9,84.9,35.1,30.1,23.2,20.4,20.3,12.4,12.1.HRESIMS m/z 567.2033[M+H]⁺(calcd for C₃₄H₃₂ClN₂O₄ ⁺,567.2051).

Example 8:

4'-((R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-hydroxy-7-methyl-6,8-dioxo-7,8-dihydroisoquinolin-2(6H)-yl)-[1,1'-biphenyl]-4-carbonitrile( Compound 8)

Red powder with yield of 69％;m.p.113–116℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.86(s,1H),7.82-7.72(overlapped,6H),7.45(d,J＝8.2Hz,2H),7.15(s,1H),7.01(d,J＝15.5Hz,1H),5.74-5.64(overlapped,2H),4.10(s,1H),2.45-2.35(m,1H),1.61(s,3H),1.54(s,3H),1.45-1.38(m,1H),1.35-1.29(m,1H),0.99(d,J＝6.6Hz,3H),0.85(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ196.3,188.3,148.7,147.9,145.2,144.0,143.5,141.2,140.6,140.1,133.1,133.1,131.9,129.0,129.0,128.0,128.0,127.4,127.4,118.6,116.2,115.7,112.4,109.6,101.3,83.7,35.2,30.1,29.6,20.3,12.5,12.1.HRESIMS m/z 525.1934[M+H]⁺(calcd for C₃₂H₃₀ClN₂O₃ ⁺,525.1945).

Example 9:

(R)-5-chloro-2-(4'-cyano-[1,1'-biphenyl]-4-yl)-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl cinnamate( Compound 9

Red powder with yield of 48％;m.p.135–138℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ8.06-8.01(overlapped,4H),7.95-7.92(overlapped,3H),7.78(d,J＝8.1Hz,2H),7.75-7.70(overlapped,3H),7.47-7.44(overlapped,3H),7.25-7.18(overlapped,2H),6.65(d,J＝16.0Hz,1H),5.86(d,J＝15.7Hz,1H),5.78(d,J＝9.8Hz,1H),2.49-2.42(m,1H),1.57(s,3H),1.56(s,3H),1.43-1.38(m,1H),1.34-1.31(m,1H),0.97(d,J＝6.6Hz,3H),0.83(t,J＝7.4Hz,3H).¹³C NMR(100MHz,Acetone-d₆)δ193.6,184.3,165.9,148.8,147.7,146.7,144.7,144.5,143.5,142.2,142.0,141.3,135.3,133.8,133.8,133.8,133.2,131.5,129.9,129.9,129.7,129.7,129.3,129.3,128.9,128.9,128.8,128.8,119.2,118.0,115.2,112.6,109.7,103.2,86.1,35.5,30.7,23.6,20.5,12.4,12.2.HRESIMS m/z 655.2350[M+H]⁺(calcd for C₄₁H₃₆ClN₂O₄ ⁺,655.2364).

Example 10:

(R)-5-chloro-2-(4'-cyano-[1,1'-biphenyl]-4-yl)-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl isonicotinate( Compound 10

Red powder with yield of 40％;m.p.130–132℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ8.86-8.83(overlapped,2H),8.07-8.00(overlapped,5H),7.95-7.90(overlapped,4H),7.83-7.79(overlapped,2H),7.28-7.22(overlapped,2H),5.87(d,J＝15.7Hz,1H),5.79(d,J＝9.8Hz,1H),2.50-2.43(m,1H),1.69(s,3H),1.58(s,3H),1.44-1.38(m,1H),1.34-1.31(m,1H),0.97(d,J＝6.6Hz,3H),0.83(t,J＝7.4Hz,3H).¹³C NMR(125MHz,Acetone-d₆)δ193.2,183.5,164.6,151.8,151.8,149.1,147.9,145.1,144.5,143.8,142.5,141.9,141.3,137.2,133.8,133.8,133.8,133.2,129.7,129.7,128.9,128.8,128.8,123.5,123.5,119.2,117.9,115.1,112.6,109.8,102.8,87.5,35.6,30.7,23.7,20.5,12.4,12.2.HRESIMS m/z 630.2181[M+H]⁺(calcd for C₃₈H₃₃ClN₃O₄ ⁺,630.2160).

Example 11:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(4'-methoxy-[1,1'-biphenyl]-4-yl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl acetate( Compound 11

Red powder with yield of 80％;m.p.116–119℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.87(s,1H),7.69(d,J＝8.5Hz,2H),7.56(d,J＝8.7Hz,2H),7.31(d,J＝8.7Hz,2H),7.17(s,1H),7.04–6.95(overlapped,3H),5.71–5.65(overlapped,2H),3.87(s,3H),2.44–2.35(m,1H),2.17(s,3H),1.59(s,3H),1.52(s,3H),1.44-1.37(m,1H),1.34-1.25(m,1H),0.97(d,J＝6.6Hz,3H),0.84(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ193.9,184.8,170.3,160.1,147.9,147.7,144.2,143.3,142.7,141.3,138.9,132.0,131.5,128.4,128.4,128.2,128.2,126.9,126.9,116.5,114.7,114.7,114.6,110.0,103.4,84.9,55.6,35.1,30.1,23.3,20.4,20.3,12.4,12.1.HRESIMS m/z 572.2217[M+H]⁺(calcd for C₃₄H₃₅ClNO₅ ⁺,572.2204).

Example 12:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-hydroxy-2-(4'-methoxy-[1,1'-biphenyl]-4-yl)-7-methylisoquinoline-6,8(2H,7H)-dione( Compound 12

Red powder with yield of 83％;m.p.130–131℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.88(s,1H),7.71(d,J＝9.8Hz,2H),7.57(d,J＝10.1Hz,2H),7.33(d,J＝9.8Hz,2H),7.15(s,2H),7.05-6.99(overlapped,3H),5.75-5.67(overlapped,2H),4.12(s,1H),3.88(s,3H),2.45-2.37(m,1H),1.61(s,3H),1.54(s,3H),1.43-1.38(m,1H),1.35-1.30(m,1H),0.98(d,J＝6.6Hz,3H),0.84(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ196.5,188.1,160.2,148.4,148.2,145.6,143.8,142.9,140.4,138.7,132.0,131.5,128.4,128.4,128.2,128.2,126.9,126.9,116.4,115.6,114.7,114.7,109.5,100.8,83.7,55.6,35.1,30.1,29.6,20.3,12.5,12.1.HRESIMS m/z 530.2109[M+H]⁺(calcd for C₃₂H₃₃ClNO₄ ⁺,530.2098).

Example 13:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-hydroxy-7-methyl-2-(4-(pyridin-4-yl)phenyl)isoquinoline-6,8(2H,7H)-dione( Compound 13

Red powder with yield of 49％;m.p.132-133℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ8.73(s,2H),7.90-7.79(overlapped,3H),7.62-7.51(overlapped,2H),7.46(d,J＝8.3Hz,2H),7.15(s,1H),7.01(d,J＝15.6Hz,1H),5.75-5.64(overlapped,2H),4.12(br,1H),2.45-2.36(m,1H),1.61(s,3H),1.54(s,3H),1.45-1.39(m,1H),1.34-1.29(m,1H),0.98(d,J＝6.6Hz,3H),0.85(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ196.4,188.3,150.8,148.7,148.7,147.9,146.3,145.2,144.0,140.9,140.2,140.1,131.9,128.9,128.9,128.9,127.5,127.5,127.5,116.2,115.7,109.6,101.3,83.7,35.2,30.1,29.6,20.3,12.5,12.1.HRESIMS m/z 501.1951[M+H]⁺(calcd for C₃₀H₃₀ClN₂O₃ ⁺,501.1945).

Example 14:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-methyl-6,8-dioxo-2-(4-phenoxyphenyl)-2,6,7,8-tetrahydroisoquinolin-7-yl acetate( Compound 14

Red powder with yield of 84％;m.p.163–165℃.¹H NMR(500MHz,CDCl₃,J in Hz)δ7.82(s,1H),7.42(t,J＝7.8Hz,2H),7.22(overlapped,3H),7.14(s,1H),7.09(overlapped,4H),6.96(d,J＝15.6Hz,1H),5.67(d,J＝9.8Hz,1H),5.63(d,J＝15.6Hz,1H),2.49-2.40(m,1H),2.18(s,3H),1.59(s,3H),1.56(s,3H),1.48-1.36(m,1H),1.35-1.25(m,1H),0.99(d,J＝6.6Hz,3H),0.85(t,J＝7.4Hz,3H).¹³C NMR(125MHz,CDCl₃)δ193.7,184.6,170.1,158.9,155.6,147.9,147.6,143.9,143.1,141.2,134.7,131.7,130.1,130.1,128.0,128.0,124.7,119.8,119.8,119.0,119.0,116.1,114.3,109.9,109.8,84.7,34.9,30.0,23.1,20.2,20.1,12.2,11.9.HRESIMS m/z 558.2053[M+H]⁺(calcd for C₃₃H₃₃ClNO₅ ⁺,558.2047).

Example 15:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(4-(4-fluorophenoxy)phenyl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl acetate( Compound 15

Red powder with yield of 87％;m.p.123-126℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.79(s,1H),7.21(d,J＝8.8Hz,2H),7.13-7.02(overlapped,7H),6.92(d,J＝15.9Hz,1H),5.68-5.59(overlapped,2H),2.45-2.35(m,1H),2.15(s,3H),1.56(s,3H),1.55(s,3H),1.44-1.36(m,1H),1.35-1.26(m,1H),0.97(d,J＝6.6Hz,3H),0.84(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ193.8,184.7,170.2,159.2,158.5(d,¹J_C-F＝244.1Hz),151.4,148.0,147.7,144.1,143.3,141.3,134.9,131.9,128.2,128.2,121.7,121.6,118.7,118.7,117.1,116.8,116.2,114.5,109.9,103.4,84.8,35.1,30.1,23.2,20.3,20.3,12.4,12.0.HRESIMS m/z 576.1962[M+H]⁺(calcd for C₃₃H₃₂ClFNO₅ ⁺,576.1953).

Example 16:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(4-(4-fluorophenoxy)phenyl)-7-hydroxy-7-methylisoquinoline-6,8(2H,7H)-dione( Compound 16

Red powder with yield of 64％;m.p.110-113℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.81(s,1H),7.26-7.23(overlapped,2H),7.14-7.03(overlapped,7H),6.97(d,J＝15.6Hz,1H),5.72-5.62(overlapped,2H),4.10(s,1H),2.47-2.37(m,1H),1.60(s,3H),1.57(s,3H),1.45-1.39(m,1H),1.35-1.29(m,1H),0.98(d,J＝6.6Hz,3H),0.85(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ196.5,188.1,159.4,158.5(d,¹J_C-F＝243.1Hz),151.4,148.5,148.3,145.5,143.8,140.4,134.8,131.9,128.2,128.2,121.7,121.6,118.8,118.8,117.2,116.9,116.2,115.5,109.4,100.8,83.7,35.2,30.1,29.6,20.3,12.4,12.1.HRESIMS m/z 534.1855[M+H]⁺(calcd for C₃₁H₃₀ClFNO₄ ⁺,534.1847).

Example 17:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(4-(3-fluorophenoxy)phenyl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl acetate( Compound 17

Red powder with yield of 77％;m.p.115-118℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.82(s,1H),7.40-7.32(m,1H),7.30-7.26(overlapped,2H),7.17-7.12(overlapped,3H),6.99-6.89(overlapped,2H),6.87-6.82(m,1H),6.80-6.75(m,1H),5.66(d,J＝9.8Hz,1H),5.59(d,J＝15.6Hz,1H),2.45-2.37(m,1H),2.18(s,3H),1.59(s,3H),1.56(s,3H),1.45-1.38(m,1H),1.34-1.28(m,1H),0.98(d,J＝6.6Hz,3H),0.85(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ193.9,184.9,170.4,158.1,148.2,147.7,144.0,143.4,141.3,135.6,131.9,131.1,128.4,128.4,119.9,119.9,116.2,115.1,114.5,111.8,111.6,110.0,107.5,107.3,103.6,84.9,35.1,30.1,23.3,20.4,20.3,12.4,12.1.HRESIMS m/z 576.1944[M+H]⁺(calcd for C₃₃H₃₂ClFNO₅ ⁺,576.1953).

Example 18:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(4-(2-methoxyphenoxy)phenyl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl acetate( Compound 18

Red powder with yield of 89％;m.p.133-135℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.85(s,1H),7.24-6.95(overlapped,10H),5.71-5.64(overlapped,2H),3.84(s,3H),2.49-2.39(m,1H),2.19(s,3H),1.60(s,3H),1.58(s,3H),1.47-1.40(m,1H),1.37-1.30(m,1H),1.00(d,J＝6.6Hz,3H),0.87(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ193.9,184.6,170.2,159.4,151.6,147.9,147.8,144.2,143.3,143.2,141.5,134.2,131.9,127.8,127.8,126.4,122.2,121.5,117.5,117.5,116.3,114.4,113.1,109.8,103.1,84.8,55.9,35.0,30.1,23.2,20.3,20.3,12.3,12.0.HRESIMS m/z 588.2162[M+H]⁺(calcd for C₃₄H₃₅ClNO₆ ⁺,588.2153).

Example 19:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-hydroxy-2-(4-(2-methoxyphenoxy)phenyl)-7-methylisoquinoline-6,8(2H,7H)-dione( Compound 19

Red powder with yield of 41％;m.p.139-140℃.¹H NMR(400MHz,CDCl₃,J in Hz)δ7.84(s,1H),7.25-7.18(overlapped,3H),7.13-7.09(overlapped,2H),7.06-6.97(overlapped,5H),5.62-5.72(overlapped,2H),4.12(s,1H),3.82(s,3H),2.46-2.37(m,1H),1.60(s,3H),1.56(s,3H),1.43-1.40(m,1H),1.33-1.30(m,1H),0.99(d,J＝6.6Hz,3H),0.85(t,J＝7.4Hz,3H).¹³C NMR(100MHz,CDCl₃)δ193.8,188.1,159.6,151.7,148.4,145.6,143.7,143.4,140.6,136.6,132.0,127.9,127.9,126.5,122.3,122.3,121.6,117.7,117.7,116.3,113.1,113.1,109.3,100.6,83.7,56.0,35.2,30.1,29.6,20.3,12.4,12.1.HRESIMS m/z 546.2057[M+H]⁺(calcd for C₃₂H₃₃ClNO₅ ⁺,546.2047).

Example 20:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-methyl-2-(4-(naphthalen-2-yl)phenyl)-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl cinnamate( Compound 20

Red powder with yield of 37％;m.p.127-130℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ8.05-8.00(overlapped,3H),7.87(d,J＝5.1Hz,1H),7.81-7.69(overlapped,7H),7.63-7.52(overlapped,4H),7.47-7.44(overlapped,3H),7.26-7.21(overlapped,2H),6.66(d,J＝16.1Hz,1H),5.95(d,J＝15.7Hz,1H),5.79(d,J＝9.7Hz,1H),2.54-2.46(m,1H),1.66(s,3H),1.59(s,3H),1.45-1.40(m,1H),1.36-1.32(m,1H),0.98(d,J＝6.7Hz,3H),0.85(t,J＝7.4Hz,3H).¹³C NMR(100MHz,Acetone-d₆)δ193.7,184.2,165.9,148.9,147.7,146.7,144.8,143.4,143.2,142.3,140.9,139.4,135.3,134.9,133.2,132.4,132.4,132.2,131.5,129.9,129.9,129.4,129.3,129.3,129.3,128.1,128.1,128.0,127.4,127.0,126.4,126.1,118.1,118.0,115.2,109.7,103.0,86.1,35.6,30.7,23.6,20.5,12.4,12.2.HRESIMS m/z 680.2546[M+H]⁺(calcd for C₄₄H₃₉ClNO₄ ⁺,680.2562).

Example 21:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-methyl-2-(4-(naphthalen-2-yl)phenyl)-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl isonicotinate( Compound 21

Red powder with yield of 35％;m.p.134-136℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ8.84(d,J＝6.0Hz,2H),8.09(s,1H),8.02(t,J＝7.6Hz,2H),7.91(d,J＝6.0Hz,2H),7.86(d,J＝8.4Hz,1H),7.83-7.75(overlapped,4H),7.65-7.61(m,1H),7.59-7.50(m,3H),7.29-7.23(overlapped,2H),5.96(d,J＝15.7Hz,1H),5.81(d,J＝9.7Hz,1H),2.54-2.46(m,1H),1.71(s,3H),1.66(s,3H),1.46-1.40(m,1H),1.36-1.31(m,1H),0.99(d,J＝6.7Hz,3H),0.85(t,J＝7.4Hz,3H).¹³C NMR(100MHz,Acetone-d₆)δ193.3,183.5,164.6,151.8,151.8,149.2,147.9,145.2,143.7,143.3,142.6,140.8,139.4,137.2,134.9,133.3,132.4,132.4,132.2,129.4,129.3,128.1,128.1,128.0,127.4,127.0,126.4,126.1,123.5,123.5,118.0,115.1,109.8,102.6,87.6,35.6,30.7,23.7,20.5,12.4,12.2.HRESIMS m/z 655.2352[M+H]⁺(calcd for C₄₁H₃₆ClN₂O₄ ⁺,655.2358).

Example 22:

(R)-2-([1,1':4',1"-terphenyl]-4-yl)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl acetate( Compound 22

Red powder with yield of 52％;m.p.130-133℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ8.00(d,J＝8.7Hz,2H),7.93(s,1H),7.89(d,J＝8.4Hz,2H),7.82(d,J＝8.4Hz,2H),7.76–7.71(m,4H),7.50(t,J＝7.7Hz,2H),7.42–7.38(m,1H),7.19(d,J＝15.7Hz,1H),7.16(s,1H),5.86(d,J＝15.7Hz,1H),5.77(d,J＝9.7Hz,1H),2.48–2.41(m,1H),2.07(s,3H),1.57(s,3H),1.48(s,3H),1.42–1.38(m,1H),1.34–1.32(m,1H),0.97(d,J＝6.6Hz,3H),0.83(t,J＝7.4Hz,3H).¹³C NMR(100MHz,Acetone-d₆)δ193.7,184.3,170.0,148.9,147.6,144.7,143.4,142.7,142.2,141.7,141.0,140.9,139.0,133.2,129.9,129.9,129.1,129.1,128.5,128.5,128.5,128.4,128.4,128.4,128.4,128.4,127.7,127.7,118.0,115.1,109.6,86.0,35.5,30.7,23.5,20.5,20.2,12.4,12.2.HRESIMS m/z 618.2398[M+H]⁺(calcd for C₃₉H₃₇ClNO₄ ⁺,618.2406).

Example 23:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(isonicotinamido)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl acetate( Compound 23

Red powder with yield of 70％;m.p.149-152℃.¹H NMR(500MHz,CDCl₃,J in Hz)δ8.81(s,2H),7.91-7.80(overlapped,3H),7.05-6.97(overlapped,2H),6.24(d,J＝15.6Hz,1H),5.71(d,J＝9.6Hz,1H),2.47-2.40(m,1H),2.00(s,3H),1.72(s,3H),1.51(s,3H),1.44-1.38(m,1H),1.34-1.28(m,1H),0.97(d,J＝6.6Hz,3H),0.85(t,J＝7.4Hz,3H).¹³C NMR(125MHz,CDCl₃)δ192.2,184.7,170.9,165.0,151.0,151.0,150.2,149.4,145.8,145.5,142.8,132.3,132.3,121.6,121.6,121.6,115.4,113.2,109.3,85.5,35.2,30.1,23.4,20.4,20.3,12.6,12.1.HRESIMS m/z 510.1784[M+H]⁺(calcd for C₂₇H₂₉ClN₃O₅ ⁺,510.1790).

Example 24:

N-((R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-7-hydroxy-7-methyl-6,8-dioxo-7,8-dihydroisoquinolin-2(6H)-yl)isonicotinamide( Compound 24

Red powder with yield of 61％;m.p.136-138℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ8.85(s,2H),8.08(s,1H),7.96(d,J＝6.1Hz,2H),7.27(d,J＝15.7Hz,1H),7.09(s,1H),6.45(d,J＝15.7Hz,1H),5.80(d,J＝9.7Hz,1H),2.55-2.43(m,1H),1.76(s,3H),1.46(s,3H),1.44-1.36(m,1H),1.34-1.30(m,1H),0.97(d,J＝6.6Hz,3H),0.83(t,J＝7.4Hz,3H).¹³C NMR NMR(100MHz,Acetone-d₆)δ196.4,188.5,165.7,151.6,151.6,151.6,150.3,148.5,145.4,145.3,143.0,139.2,133.4,133.4,122.4,122.4,116.3,114.7,108.5,102.3,84.0,35.6,20.5,12.6,12.2.HRESIMS m/z 468.1686[M+H]⁺(calcd for C₂₅H₂₇ClN₃O₄ ⁺,468.1685).

Example 25:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(isonicotinamido)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl cinnamate( Compound 25

Red powder with yield of 55％;m.p.150-151℃.¹H NMR(400MHz,Methanol-d₄,J in Hz)δ8.84(s,2H),8.18(s,1H),8.05(d,J＝5.5Hz,2H),7.62(d,J＝16.0Hz,1H),7.58–7.52(m,2H),7.37–7.33(overlapped,3H),7.21(s,1H),7.14(d,J＝15.7Hz,1H),6.54(d,J＝16.0Hz,1H),6.24(d,J＝15.7Hz,1H),5.71(d,J＝9.8Hz,1H),2.46-2.38(m,1H),1.70(s,3H),1.55(s,3H),1.41–1.35(m,1H),1.30–1.23(m,1H),0.92(d,J＝6.6Hz,3H),0.79(t,J＝7.4Hz,3H).¹³C NMR(100MHz,Methanol-d₄)δ193.9,186.1,167.2,166.1,151.3,150.4,150.4,150.0,148.0,146.8,146.8,144.4,141.8,135.5,133.7,131.9,130.1,130.1,130.1,129.5,129.5,123.8,117.4,116.7,114.3,110.4,103.9,86.1,36.3,31.1,23.7,20.5,12.6,12.3.HRESIMS m/z 598.2107[M+H]⁺(calcd for C₃₄H₃₃ClN₃O₅ ⁺,598.2103).

Example 26:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(isonicotinamido)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl(E)-3-(thiophen-3-yl)acrylate( Compound 26

Red powder with yield of 48％;m.p.125-128℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ9.03-8.99(m,2H),8.29-8.25(m,2H),8.03(s,1H),7.90-7.88(m,1H),7.79(d,J＝15.7Hz,1H),7.58-7.56(m,1H),7.49-7.46(m,1H),7.30(d,J＝15.8Hz,1H),7.17(s,1H),6.77(d,J＝15.8Hz,1H),6.45(d,J＝15.8Hz,1H),5.82(d,J＝9.7Hz,1H),2.54-2.47(m,1H),1.82(s,3H),1.72(s,3H),1.43-1.40(m,1H),1.36-1.33(m,1H),0.98(d,J＝6.7Hz,3H),0.84(t,J＝7.4Hz,3H).¹³C NMR(150MHz,Acetone-d₆)δ192.6,183.3,166.0,163.3,150.6,148.5,147.7,145.2,144.9,144.5,138.6,138.2,133.5,130.1,128.4,128.4,126.1,125.8,125.8,117.4,115.0,115.0,108.9,103.3,88.1,55.0,35.6,30.7,23.7,20.5,12.6,12.2.HRESIMS m/z 604.1662[M+H]⁺(calcd for C₃₂H₃₁ClN₃O₅S⁺,604.1667).

Example 27:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(isonicotinamido)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl isonicotinate( Compound 27

Red powder with yield of 50％;m.p.143-145℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ8.83(s,4H),8.22(s,1H),7.94-7.88(overlapped,4H),7.29(d,J＝15.7Hz,1H),7.18(s,1H),6.45(d,J＝15.7Hz,1H),5.82(d,J＝9.8Hz,1H),2.54-2.47(m,1H),1.76(s,3H),1.70(s,3H),1.44-1.38(m,1H),1.36-1.30(m,1H),0.98(d,J＝6.7Hz,3H),0.84(t,J＝7.4Hz,3H).¹³C NMR(100MHz,Acetone-d₆)δ192.7,183.8,165.8,164.6,151.8,151.8,151.8,151.7,151.7,150.2,148.7,145.4,145.4,144.6,144.1,139.3,137.0,133.3,123.5,122.3,115.4,114.6,109.1,103.7,87.3,35.6,30.7,23.6,20.5,12.6,12.2.HRESIMS m/z 573.1901[M+H]⁺(calcd for C₃₁H₃₀ClN₄O₅ ⁺,573.1899).

Example 28:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(isonicotinamido)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl 1H-pyrazole-5-carboxylate( Compound 28

Red powder with yield of 23％;m.p.143-145℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ11.19(s,1H),8.82–8.77(m,1H),8.05(s,1H),7.94(d,J＝2.4Hz,1H),7.90-7.86(m,1H),7.79(d,J＝2.4Hz,1H),7.28(d,J＝15.8Hz,1H),7.15(s,1H),6.94–6.83(overlapped,2H),6.41(d,J＝15.8Hz,1H),5.80(d,J＝9.8Hz,1H),2.51–2.46(m,1H),1.72(s,3H),1.63(s,3H),1.45–1.40(m,1H),1.33–1.30(m,1H),0.97(d,J＝6.6Hz,3H),0.83(t,J＝7.4Hz,3H).¹³C NMR(150MHz,Acetone-d₆)δ193.1,184.4,166.4,161.7,151.5,150.3,148.2,148.2,144.8,144.3,144.3,133.3,133.3,133.3,123.8,123.8,115.3,115.0,109.3,108.9,108.9,107.3,86.1,35.6,30.7,23.6,20.5,12.5,12.2.HRESIMS m/z 562.1831[M+H]⁺(calcd for C₂₉H₂₉ClN₅O₅ ⁺,562.1852).

Example 29:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(isonicotinamido)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl oxazole-4-carboxylate( Compound 29

Red powder with yield of 43％;m.p.143-145℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ8.85–8.82(m,2H),8.73(d,J＝1.0Hz,1H),8.32(d,J＝1.0Hz,1H),8.18(s,1H),7.94–7.92(m,2H),7.30(d,J＝15.8Hz,1H),7.16(s,1H),6.46(d,J＝15.8Hz,1H),5.82(d,J＝9.8Hz,1H),2.53–2.48(m,1H),1.77(s,3H),1.63(s,3H),1.45–1.42(m,1H),1.39–1.35(m,1H),0.98(d,J＝6.6Hz,3H),0.83(t,J＝7.4Hz,3H).¹³C NMR(150MHz,Acetone-d₆)δ193.0,184.1,165.8,160.2,153.4,151.7,151.7,150.0,148.4,146.6,145.2,144.2,144.0,139.3,133.4,133.0,122.3,122.3,115.4,114.8,109.0,104.0,86.6,35.6,30.7,23.7,20.5,12.6,12.2.HRESIMS m/z 563.1712[M+H]⁺(calcd for C₂₉H₂₈ClN₄O₆ ⁺,563.1692).

Example 30:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(isonicotinamido)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl thiazole-4-carboxylate( Compound 30

Red powder with yield of 50％;m.p.142-143℃.¹H NMR(400MHz,Acetone-d₆,J in Hz)δ9.03(d,J＝2.0Hz,1H),8.86-8.77(m,2H),8.59(d,J＝2.0Hz,1H),8.21(s,1H),7.91(d,J＝6.0Hz,2H),7.28(d,J＝15.7Hz,1H),7.16(s,1H),6.43(d,J＝15.7Hz,1H),5.82(d,J＝9.7Hz,1H),2.55–2.42(m,1H),1.76(s,3H),1.66(s,3H),1.45–1.37(m,1H),1.34–1.29(m,1H),0.97(d,J＝6.6Hz,3H),0.84(t,J＝7.4Hz,3H).¹³C NMR(100MHz,Acetone-d₆)δ192.9,184.3,165.8,160.5,155.7,151.6,151.6,150.4,148.5,147.5,145.4,144.7,144.1,139.2,133.4,130.4,122.3,122.3,115.5,114.7,109.1,103.7,86.7,35.6,30.7,23.7,20.5,12.6,12.2.HRESIMS m/z 579.1456[M+H]⁺(calcd for C₂₉H₂₈ClN₄O₅S⁺,579.1469).

Example 31:

(R)-5-chloro-3-((S,1E,3E)-3,5-dimethylhepta-1,3-dien-1-yl)-2-(isonicotinamido)-7-methyl-6,8-dioxo-2,6,7,8-tetrahydroisoquinolin-7-yl quinoline-6-carboxylate( Compound 31

Red powder with yield of 50％;m.p.156-159℃.¹H NMR(400MHz,Methanol-d₄,J in Hz)δ9.01-8.98(m,1H),8.80-8.78(m,1H),8.76-8.70(m,2H),8.55(d,J＝8.9Hz,1H),8.36-8.32(m,1H),8.21(s,1H),8.12(d,J＝8.9Hz,1H),7.97-7.92(overlapped,2H),7.67-7.63(m,1H),7.41(s,1H),7.24(d,J＝15.8Hz,1H),6.48(d,J＝15.8Hz,1H),5.79(d,J＝9.8Hz,1H),2.54-2.48(m,1H),1.78(s,3H),1.77(s,3H),1.48-1.43(m,1H),1.37-1.33(m,1H),1.01(d,J＝6.7Hz,3H),0.88(t,J＝7.4Hz,3H).¹³C NMR(150MHz,Methanol-d₄)δ194.6,184.4,173.6,166.1,153.9,151.7,150.9,150.9,149.3,147.7,145.9,143.8,139.9,133.8,133.0,133.0,130.4,130.4,129.8,129.8,129.1,128.8,123.6,123.5,123.5,116.8,115.6,110.8,87.0,36.3,31.2,24.0,20.6,12.6,12.3.HRESIMS m/z 623.2048[M+H]⁺(calcd for C₃₅H₃₂ClN₄O₅ ⁺,623.2061).

EXAMPLE 32 anti-Mycobacterium test

Test purpose: test compounds were tested for their inhibitory effect on mycobacterium tuberculosis, mycobacterium marinum and mycobacterium smegmatis.

1) Test strain:

Mycobacterium tuberculosis Mycobacterium tuberculosis ATCC 25177, mycobacterium marinum Mycobacterium marinum and Mycobacterium smegmatis Mycobacterium smegmatis.

2) The detection method comprises the following steps:

To the assay plate, 198. Mu.L of a 1000-fold diluted Mycobacterium solution (OD ₅₅₀. Mu.L of about 0.225 to 0.275) was inoculated, and then 2. Mu.L of the prepared compound working solution was added. The detection plate is placed in a 37 ℃ incubator for 10 to 12 days. Then, 12.5. Mu.L of 7H9+20% Tween 80 medium and 20. Mu.L of Alamar blue solution were added, and the culture was continued for 24 hours. DMSO served as solvent and growth control. 200. Mu.L of medium was placed in wells around the assay plate as a medium control. Rifampicin and isoniazid were used as positive controls and assayed in triplicate.

Determination of MIC ₉₀ values: inhibition and MIC ₉₀ values were determined by visual inspection of Alamar blue for discoloration or by fluorescent detection (Ex/Em, 530nm/590 nm) to determine bacterial growth.

Results:

TABLE 1 inhibitory Effect of the Compounds of the invention on Mycobacterium genus bacteria

Note 1: in the tables, in M.tuberculosis activity, "A" means that the MIC ₉₀ value is less than or equal to 1. Mu.M, "B" means that the MIC ₉₀ value is between 1 and 15. Mu.M, "C" means that the MIC ₉₀ value is between 15 and 25. Mu.M, and "D" means that the MIC ₉₀ value is greater than 25. Mu.M; in M.marinum activity, "A" means that the MIC ₉₀ value is between 10 and 40. Mu.M, "B" means that the MIC ₉₀ value is between 40 and 80. Mu.M, "C" means that the MIC ₉₀ value is between 80 and 100. Mu.M, and "D" means that the MIC ₉₀ value is greater than 100. Mu.M; in M.smegmatis, a value of 1-15. Mu.M for "A" means that a MIC ₉₀ value is between 15-30. Mu.M for "B" means that a MIC ₉₀ value is between 30-50. Mu.M for "C" means that a MIC ₉₀ value is between 30-50. Mu.M for "D" means that a MIC ₉₀ value is greater than 50. Mu.M. In addition, compounds a, B, C, D, E, F, G, H, I, J, K, L, M were tested in parallel for activity against three mycobacteria in the present invention.

And (2) injection: the invention tests in parallel that R ₁ is aliphatic hydrocarbon, phenyl and heterocycle substituted compound in the preparation process, namely compound ACompound BCompound CCompound DCompound ECompound FCompound GCompound HCompound ICompound JCompound KCompound LCompound MFor control.

Through in vitro activity screening of three mycobacteria bacteria, the compound of the invention has strong antibacterial activity on the three mycobacteria bacteria, is superior to isoniazid and rifampicin which are positive medicines or equivalent to positive medicines to a certain extent, and is obviously superior to compounds A, B, C, D, E, F, G, H, I, J, K, L and M. Therefore, the compound has a great potential application prospect in inhibiting the growth of mycobacterium.

Example 33 other antibacterial Activity test

Test purpose: the compounds were tested for their antibacterial effect against other gram-negative bacteria, gram-negative bacteria and fungi and whether the compounds of the invention selectively inhibited mycobacterial growth was investigated.

1) Test strain:

Coli ESCHERICHIA COLI, staphylococcus aureus Staphylococcus aureus, pseudomonas aeruginosa Pseudomonas aeruginosa and candida albicans Canidia Albicans

2) The detection method comprises the following steps:

The strain is selected on a solid culture medium to be cultured in a ventilated culture flask at 37 ℃ until the logarithmic phase of growth and the density is 1.0X10 ⁷/ml. It was diluted to 1:25 (4X 10 ⁵/ml) in medium before testing for activity. The sample solution was prepared using DMSO and filtered through a 0.22 μm filter. In the test, 198. Mu.L of culture medium was added to the first row of the 96-well plate, and the volume of bacterial liquid in the remaining wells was 100. Mu.L. 2 mu L of the sample solution to be measured is added to each well in the first row, 8 concentrations are diluted in an equal gradient, and then 100 mu L of bacterial liquid is added to each well. After incubation at 32 ℃ for 60 hours, the concentration of the last row of clarified wells was recorded as the minimum inhibitory concentration MIC ₉₀, as observed visually from the back of the 96-well plate. The experiment uses ciprofloxacin and amphotericin B as positive control, DMSO as blank control, bacterial liquid as negative control, and three parallel experiments are set.

Determination of MIC ₉₀ values: the inhibition effect and MIC ₉₀ values were determined by visual inspection from the back of the 96-well plate, recording the clear wells to determine if bacteria were growing.

Results:

Compounds 1-31 of the present invention were not significantly active against all four strains tested at 50. Mu.M concentration.

Through in vitro activity screening of four other gram-negative bacteria, gram-negative bacteria and fungi, the compound disclosed by the invention has stronger activity of inhibiting mycobacteria, is superior to isoniazid and rifampicin which are positive medicines or equivalent to positive medicines to a certain extent, and has certain selectivity and is ineffective to other fungi and bacteria. Therefore, the compound has good potential application prospect in the aspect of selectively inhibiting the growth of mycobacterium.

Example 34 combination drug sensitivity test

Test purpose: the effect of the compound on the combined action of the positive control isoniazid on the mycobacterium marinum is tested, and whether the compound has the potential of being combined with the positive control or not is studied.

2) The detection method comprises the following steps:

according to the checkerboard test, specifically based on MIC data of the compound and isoniazid, 4 x MIC, 2 x MIC, 1/2 x MIC, 1/4 x MIC, 1/8 x MIC and 1/16 x MIC of two drug concentrations were combined 7x7 in 96-well plates added with bacterial solutions using checkerboard dilution, the 96-well plates were placed in a 32 ℃ incubator, the results were observed and recorded after 48 hours, and each well was repeatedly assayed three times.

The combined effect was evaluated using a graded inhibitory concentration index (FICI) with the formula given below, if the lowest inhibitory concentration for drug A was designated MIC _A and the lowest inhibitory concentration for drug B was designated MIC _B, the MICs for the two drugs alone were each designated A, B. Then its calculation formula is as follows: fici=mic _A/A+MIC_B/B. The determination of the combined effect is as follows: ① FICI is less than or equal to 0.5, and the synergism is achieved; ② FICI is more than 0.5 and less than or equal to 1, adding; ③ FICI is more than 1 and less than or equal to 2, and is irrelevant; ④ FICI > 2, antagonism.

Results:

TABLE 2 Effect of the combination of the Compounds of the invention with isoniazid on the combined action of Mycobacterium marinum

Compounds of formula (I)

FICI

Compounds of formula (I)

FICI

Compounds of formula (I)

FICI

Compounds of formula (I)

FICI

1

C

12

A

23

A

Compound C

D

2

B

13

A

24

A

Compound D

D

3

B

14

C

25

A

Compound E

D

4

A

15

B

26

A

Compound F

D

5

B

16

B

27

A

Compound G

D

6

B

17

A

28

B

Compound H

D

7

A

18

A

29

A

Compound I

D

8

B

19

A

30

A

Compound J

D

9

B

20

A

31

A

Compound K

D

10

A

21

A

Compound A

D

Compound L

D

11

B

22

A

Compound B

D

Compound M

D

Note that: in the table, "A" means that the FICI value is less than or equal to 0.5, "B" means that the IC ₅₀ value is between 0.5 and 1. Mu.M, "C" means that the IC ₅₀ value is between 1 and 2, and "D" means that the FICI value is greater than 2. In addition, the invention tests the combined action effect of the compounds A, B, C, D, E, F, G, H, I, J, K, L, M on the sea mycobacteria in parallel when combined with isoniazid.

Through the combined action evaluation, the compound can generate more obvious synergistic or additive action when being combined with isoniazid, and the compounds A, B, C, D, E, F, G, H, I, J, K, L and M can not generate synergistic action. Therefore, the compound has a great potential application prospect in the aspect of combined administration with a positive medicine.

In conclusion, the compound disclosed by the invention has excellent selective mycobacterium growth inhibition activity, can generate remarkable synergistic effect when being used in combination with a positive medicine, and has further research value and wide development prospect.

Finally, it should be noted that there are other ways to implement the invention. Accordingly, the embodiments of the present invention are to be construed as illustrative, not restrictive of the invention, but may be modified and equivalents added to the scope of the invention as defined by the appended claims. All publications or patents cited herein are incorporated by reference.

Claims (9)

1. A (+) -sclerotiorin derivative is disclosed, which is a compound shown in formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof,

Wherein:

r ₁ is a substituted or unsubstituted biphenyl, biphenyl ether, terphenyl, 4- (1-naphthyl) phenyl or 4-pyridineamide fragment, wherein the benzene ring and the pyridine ring may each independently be optionally substituted with 1,2, 3 or 4 substituents selected from deuterium, F, cl, br, I, hydroxy, amino, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl or 5-6 membered heteroaryl. R ₂ is substituted or unsubstituted cinnamate, pyridine acrylate, heterocyclic acrylate, benzoate, picolinate, and heterocycloformate, wherein the benzene ring and pyridine ring may each independently be optionally substituted with 1,2, 3, or 4 substituents selected from deuterium, F, cl, br, I, hydroxy, amino, cyano, nitro, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl, or 5-6 membered heteroaryl.

2. The compound of claim 1, wherein R ₁ is R ₂ is hydroxy, acetoxy, substituted or unsubstituted

3. A compound according to claim 1, having the structure of one of the following or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:

4. a pharmaceutical composition comprising a compound according to any one of claims 1-3.

5. The pharmaceutical composition of claim 4, further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.

6. A combination of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to any one of claims 4 to 5, together with one or more therapeutically active agents. The combination is characterized in that the combination comprises one or more medicines for preventing or treating mycobacteria bacterial infectious diseases, and the active ingredients of the medicines are different from the compounds disclosed by the invention, specifically rifampicin, isoniazid, ethambutol, protomanib, bedaquiline, triclosan, streptomycin, pyrazinamide, p-ammonia salicylic acid, ethionine, frizzled, li Fuding, delamanib and linezolid.

7. Use of a compound according to any one of claims 1-3 or a pharmaceutical composition according to any one of claims 4-6 for the manufacture of a medicament for the treatment of a mammal, including a human, infected with a mycobacterium species.

8. The use according to claim 7, wherein the mycobacterium genus bacteria comprise mycobacterium tuberculosis Mycobacterium tuberculosis, mycobacterium marinum Mycobacterium marinum and mycobacterium smegmatis Mycobacterium smegmatis.

9. The use according to claim 7, wherein the bacterial infectious disease of the genus mycobacterium is tuberculosis, bone tuberculosis, lymphoid tuberculosis, lumbar tuberculosis, thoracic tuberculosis, breast tuberculosis, swimming pool granuloma, pulmonary infection, lymph node infection, bruley ulcer.