CN113717201B - (+/-) -Marinopyrole A derivative and preparation method and application thereof - Google Patents

(+/-) -Marinopyrole A derivative and preparation method and application thereof Download PDF

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CN113717201B
CN113717201B CN202111087070.1A CN202111087070A CN113717201B CN 113717201 B CN113717201 B CN 113717201B CN 202111087070 A CN202111087070 A CN 202111087070A CN 113717201 B CN113717201 B CN 113717201B
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秦勇
宋灏
肖玉梅
何艳
廖瑜琳
王文静
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Zhien Biotechnology Co ltd
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Abstract

The invention relates to a (+/-) -Marinopyrole A derivative shown as a formula 3, an optical isomer, a racemate or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, a method for preparing the compound and application of the compound in preparing antibacterial drugs.

Description

(+/-) -Marinopyrole A derivative and preparation method and application thereof
Technical Field
The invention relates to a (+/-) -marinopyrole A derivative, a preparation method and application thereof.
Background
Methicillin-resistant staphylococcus aureus is a unique strain derived from staphylococcus aureus varieties, can cause severe infections of various tissues and organs such as human epidermis, soft tissues, mucous membranes, bones, joints and the like, and can resist methicillin and cephalosporin antibiotics containing beta-lactam structures. Since the first discovery by Jevons of the interns in 1961 of Methicillin-resistant staphylococcus aureus (MRSA), the bacterium spread at an alarming rate worldwide, at least one hundred thousand people are hospitalized with MRSA infection every year, and due to its extremely broad transmission route, epidemic outbreaks in hospitals and communities are common. Due to the characteristics of heterogeneous drug resistance, broad-spectrum drug resistance, special growth, inherent drug resistance and acquired drug resistance, MRSA infection has become the three most difficult infectious diseases worldwide together with hepatitis B and acquired immune deficiency syndrome, and Community-associated MRSA (Community-associated MRSA, CA-MRSA) and vancomycin-resistant (VRE) reports appear in recent years, thereby seriously threatening public health and safety. Therefore, the search for the development of drugs having high antibacterial activity has become one of the research hotspots in the fields of medical health and drug development.
In recent years, scientists have discovered some new compounds with clinical application value through the research on the drug resistance mechanism of MRSA, and the current drugs for treating MRSA infection can be divided into the following categories according to different antibacterial mechanisms (Malina, s.i.; andres, r.; hartmut, l.curr. Opin. Crit. Care 2005,11,481): (I) glycopeptide antibiotics. Glycopeptide antibiotics are the main drugs for treating MRSA infection at present, and represent drugs such as vancomycin (vancomycin), norvancomycin (norvancomycin), teicoplanin (teicoplanin), telavancin, oritavancin and dalbavancin; (di), oxazolidinone antibiotics, the main representative drug of which is linezolid. The drug is also the first oxazolidinone antibiotic approved for clinical use (Prasad, j.v.n.v.curr.opin.microbiol.2007,10, 454); (III), beta-lactam antibiotics which are the most researched medicines for resisting MRSA infection at present, and representative medicines comprise ceftobiprole, ceftaroline and the like; (IV), lipopeptide antibiotics, the representative drug of which is daptomycin (daptomycin). The unique mechanism of action of daptomycin greatly reduces the likelihood of resistance to it by bacteria (Raja, A.; laBonte, J.; lebbos, J.; kirkpatrick, P., nature Rev. Drug Discov.2003,2, 943); (penta), glycyltetracyclines, the representative drug being tigecycline; (VI) compound preparation. According to the guidelines for treating methicillin-resistant staphylococcus aureus (MRSA) infection of adults and children issued by the american Society for Infectious Diseases (IDSA), proposed treatment protocols are proposed for different types and stages of CA-MRAS or Skin and soft tissue infections (Skin and soft tissue infections, SSTI), and from the administration categories, suggested antibiotics include vancomycin, daptomycin, linezolid, clindamycin, and telavancin, and combinations or single doses are considered according to clinical symptoms (clinin infection dis.2011,52 (3): e 18-55).
Although several new drugs for treating MRSA infections are developed successively by each major pharmaceutical company, vancomycin, which has been used clinically for many years, remains the first line drug and the last line of defense for treating MRSA infections to date. In recent years, with the emergence of vancomycin-resistant MRSA cases and the gradual manifestation of toxic and side effects of various drugs, the search for drug candidates having anti-MRSA activity with a novel skeleton is one of important directions in the field of antibiotic research in recent years.
The structural modification of active natural products is one of the important ways to find new drugs. Marinpyrole A is a marine natural product with a dipyrrole heterocyclic skeleton, is extracted and separated from marine actinomycetes CNQ-418 by William Fenical subject group in 2008, and is racemized in toluene at high temperature to obtain (+/-) -Marinpyrole A, and the antibacterial activity of Marinpyrole A is screened, so that the Marinpyrole A has very rich biological activity and is resistant to the biological activityThe activity of methicillin-resistant Staphylococcus aureus (MRSA) is remarkable, and the MICs of (-) -marinopyrole A and (+) -marinopyrole A to MRSA 90 Are 0.61. Mu.M and 0.31. Mu.M, respectively (MIC of vancomycin) 90 0.14-0.27 μ M), is a star molecule with good drug development prospects (William Fenical et al organic lett.2008,10,629). In view of such important development value of such natural products, since the discovery of marinopyrole a, its synthesis and biological activity have been receiving much attention, there have been many groups of subjects who have completed the total synthesis of (±) -marinopyrole a, some of which have also performed the serial synthesis of derivatives thereof and completed further studies on biological activity.
Figure BDA0003265949310000031
In 2013, the Qinyong subject group reports that marinopyrole A is used as a lead compound, more than 70 derivatives are successfully synthesized, antibacterial activity screening is carried out on the compounds, and a plurality of derivatives are found to show low nanomolar inhibitory activity on drug-resistant strains such as methicillin-resistant staphylococcus epidermidis (MRSE), methicillin-sensitive bacteria (MSSA) and methicillin-resistant staphylococcus aureus (MRSA).
Figure BDA0003265949310000032
a Methicillin-competent Staphylococcus aureus (Methicillin-sensitive Staphylococcus aureus)
b Methicilin-resistant Staphylococcus aureus
c Methicillin-resistant Staphylococcus epidermidis
d Vancomycin-resistant Staphylococcus aureus (Vancomycin resistant Staphylococcus aureus)
e Enterococcus (Enterococcus faecalis)
f The related data are provided by the antibiotic research institute of Sichuan province
Wherein the 4,4' -position of the phenyl ring has a CF 3 The substituted compound 2 has better inhibitory activity to the three strains than that of a natural product marinopyrole A and vancomycin, the inhibitory activity is respectively 64 times, 8 times and 4 times that of the vancomycin, and the substituted compound also has good inhibitory activity to vancomycin-resistant staphylococcus aureus (WHO-3), and is a new skeleton antibiotic candidate with great clinical development value (Mar. Drugs 2013,11,2927, CN101786979B.
Disclosure of Invention
The inventors of the present invention synthesized (±) -marinoprole a derivatives represented by formula 3, which have antibacterial activity against methicillin-resistant staphylococcus aureus (MRSA).
Accordingly, the present invention provides, in a first aspect, a compound represented by formula 3, an optical isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof,
Figure BDA0003265949310000041
wherein, the first and the second end of the pipe are connected with each other,
1) X is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is C 1-6 Alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, substituted with R 3 Substituted C 1-6 Alkyl radical, by R 3 Substituted 4-10 membered heteroaryl or substituted by R 3 Substituted 4-10 membered heterocyclyl, R 3 Is hydroxy, hydroxy-substituted C 1-6 Alkyl, halogen, C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, amino or amino substituted C 1-6 An alkyl group; or alternatively
2) X is an N atom, R 1 And R 2 Each independently is C 1-6 Alkyl, or R 1 And R 2 Form a 4-10 membered heteroaryl, 4-10 membered heterocyclyl with the N atom to which they are attached 4 Substituted 4-10 membered heteroaryl or by R 4 Substituted 4-10 membered heterocyclyl, R 4 Is hydroxy, halogen, C 1-6 Alkyl, carboxylRadical, carboxyl-substituted C 1-6 Alkyl, amino-substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, benzyl, phenyl or 5-6 membered heteroaryl.
The second aspect of the present invention provides a pharmaceutical composition, comprising at least one compound represented by formula 3 according to the first aspect of the present invention, an optical isomer, racemate or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. The compound represented by the formula 3, an optical isomer, a racemate, or a pharmaceutically acceptable salt thereof is present in a therapeutically effective amount (e.g., an amount effective for treating bacterial infection or a disease caused by bacterial infection).
A third aspect of the present invention provides a method for preparing a compound represented by formula 3, an optical isomer, a racemate, or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention, comprising:
reacting compound 2 with a nucleophile represented by formula 4 in an aprotic solvent,
Figure BDA0003265949310000051
wherein R is 1 And R 2 Is defined as described in the present invention.
The fourth aspect of the present invention provides the use of a compound represented by formula 3, an optical isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention for the preparation of a medicament for antibacterial or therapeutic treatment of bacterial infection or a disease caused by bacterial infection.
The fifth aspect of the present invention provides a compound represented by formula 3, an optical isomer thereof, a racemate thereof or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention, which is used for antisepsis or for the treatment of bacterial infection or diseases caused by bacterial infection.
A sixth aspect of the invention provides a method of treating a bacterial infection or a disease caused by a bacterial infection, comprising: administering an effective amount of the compound of formula 3, optical isomers, racemates or pharmaceutically acceptable salts thereof according to the first aspect of the present invention to a subject in need thereof.
In certain embodiments, R in formula 3 3 Is hydroxy, hydroxy-substituted C 1-6 Alkyl, halogen, C 1-4 Alkyl, carboxyl substituted C 1-4 Alkyl, amino or amino substituted C 1-4 An alkyl group.
In certain embodiments, R in formula 3 4 Is hydroxy, halogen, C 1-4 Alkyl, carboxyl substituted C 1-4 Alkyl, amino-substituted C 1-4 Alkyl, hydroxy-substituted C 1-4 Alkyl, benzyl, phenyl or 5-6 membered heteroaryl.
In certain embodiments, R in formula 3 3 Is carboxyl, amino, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, carboxymethyl, carboxyethyl, carboxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl.
In certain embodiments, R in formula 3 3 Is carboxyl or amino.
In certain embodiments, R in formula 3 4 Is C 1-4 Alkyl, carboxy substituted C 1-4 Alkyl, benzyl or 5-6 membered heteroaryl.
In certain embodiments, R in formula 3 4 Is benzyl, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, carboxymethyl, carboxyethyl, carboxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, phenyl or pyridin-4-yl.
In certain embodiments, R in formula 3 4 Is benzyl, isobutyl, methyl, carboxymethyl or pyridin-4-yl.
In certain embodiments, X in formula 3 is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is C 1-4 Alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, substituted with R 3 Substituted C 1-4 Alkyl radical, by R 3 Substituted 4-10 membered heteroaryl or by R 3 Substituted 4-10 membered heterocyclyl, R 3 Definitions are as described herein.
In certain embodiments, X in formula 3Is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is C 1-4 Alkyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl or by R 3 Substituted C 1-4 Alkyl radical, R 3 Definitions are as described herein.
In certain embodiments, X in formula 3 is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is 4-10 membered heteroaryl, 4-10 membered heterocyclyl or substituted with R 3 Substituted C 1-6 Alkyl radical, R 3 Definitions are as described herein.
In certain embodiments, X in formula 3 is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is 5-10 membered heteroaryl, 5-10 membered heterocyclyl or substituted with R 3 Substituted C 1-4 Alkyl radical, R 3 Definitions are as described herein.
In certain embodiments, X in formula 3 is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is methyl, ethyl, n-propyl, n-butyl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, substituted by R 3 Substituted methyl, by R 3 Substituted ethyl radical, by R 3 Substituted n-propyl or by R 3 Substituted n-butyl, R 3 Definitions are as described herein.
In certain embodiments, X in formula 3 is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is 5-10 membered heteroaryl, 5-10 membered heterocyclyl, or 3 Substituted methyl, by R 3 Substituted ethyl radical, by R 3 Substituted n-propyl or by R 3 Substituted n-butyl, R 3 Definitions are as described herein.
In certain embodiments, X in formula 3 is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is pyrido [3,2-D][1,3]Thiazol-2-yl, thiophen-2-yl, benzothiazol-2-yl, thiazolo [4,5-b ]]Pyridin-2-yl, 3-aminopropyl, 2-hydroxyethyl, 3-hydroxypropyl, carboxymethyl or carboxyethyl.
In certain embodiments, X in formula 3 is a N atom, R 1 And R 2 Each independently is C 1-4 Alkyl, or R 1 And R 2 Form, together with the N atom to which they are attached, a 4-10 membered heteroaryl, a 4-10 membered heterocyclyl, a 4 Substituted 4-10 membered heteroaryl or by R 4 Substituted 4-10 membered heterocyclyl, R 4 Definitions are as described herein.
In certain embodiments, X in formula 3 is a N atom, R 1 And R 2 Each independently is C 1-4 Alkyl, or R 1 And R 2 Form, together with the N atom to which they are attached, a 5-10 membered heteroaryl, a 5-10 membered heterocyclyl, a 4 Substituted 5-10 membered heteroaryl or substituted by R 4 Substituted 5-10 membered heterocyclyl, R 4 Definitions are as described herein.
In certain embodiments, X in formula 3 is a N atom, R 1 And R 2 Each independently being methyl, ethyl, n-propyl, n-butyl, or R 1 And R 2 Form, together with the N atom to which they are attached, a morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, piperazinyl, 1,2, 4-triazolyl, hexahydropyridinyl, 1, 5-dihydro-pyrazolo [3,4-d]Pyrimidin-4-yl or piperidinyl, said morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, piperazinyl, 1,2, 4-triazolyl, hexahydropyridyl, 4-oxo-1, 5-dihydro-pyrazolo [3,4-d]Pyrimidin-1-yl or piperidinyl optionally substituted with R 4 Substituted, R 4 Definitions are as described herein.
In certain embodiments, X in formula 3 is a N atom, R 1 And R 2 Each independently being methyl, or R 1 And R 2 With the N atom to which they are attached form morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, 1-benzylpiperazinyl, 1,2, 4-triazol-1-yl, hexahydropyridyl, N-isobutylpiperazinyl, N-methylpiperazinyl, piperazinyl, 1- (4-pyridyl) piperazinyl, 4-oxo-1, 5-dihydro-pyrazolo [3,4-d]Pyrimidin-1-yl or N- (carboxymethyl) piperidinyl.
In certain embodiments, the compound of formula 3 is selected from:
Figure BDA0003265949310000071
Figure BDA0003265949310000081
Figure BDA0003265949310000091
in certain embodiments, the method of the third aspect of the present invention wherein compound 2 is reacted with a nucleophile represented by formula 4 in an aprotic solvent and in the presence of a base.
In certain embodiments, the aprotic solvent of the present invention is selected from dichloromethane, trichloromethane, acetonitrile, dimethylsulfoxide, N-Dimethylformamide (DMF), N-diethylformamide, N-methylpyrrolidone (NMP), tetrahydrofuran, 2-methyltetrahydrofuran, or any combination thereof.
In certain embodiments, the base of the present invention is potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, triethylamine, or pyridine.
In certain embodiments, the base of the present invention is potassium carbonate.
In certain embodiments, the nucleophile of formula 4 according to the present invention is selected from the group consisting of: morpholine, dimethylamine, 2-mercaptobenzothiazole, tetrahydropyrrole, 2-mercaptothiazole, 2-mercaptothiophene, thiomorpholine, 1-benzylpiperazine, piperidine, N-isobutylpiperazine, N-methylpiperazine, thiazolo [4,5-b ] pyridine-2 (3H) -thione, tert-butyl (3-mercaptopropyl) carbamic acid, piperazine, 1- (4-pyridyl) piperazine, allopurin, ethyl thioglycolate.
In certain embodiments, the antibiotic of the present invention is resistant to methicillin-resistant staphylococcus aureus (MRSA). In certain embodiments, the bacterial infection described herein is a methicillin-resistant staphylococcus aureus (MRSA) infection. In certain embodiments, the disease caused by a bacterial infection according to the present invention is a methicillin-resistant staphylococcus aureus (MRSA) infection, such as a skin infection, a soft tissue infection, and the like.
In certain embodiments, the subjects described herein are mammalian subjects and human subjects, including male and female subjects and including newborn, infant, juvenile, adolescent, adult and geriatric subjects, and including various ethnic and ethnic groups, including, but not limited to, white, black, asian, indian and hispanic.
The compounds of the present invention may be used both as such and in the form of their pharmaceutically acceptable salts. The pharmaceutically acceptable salt of the compound shown in the formula 3 comprises a salt formed by pharmaceutically acceptable inorganic acid or organic acid, or pharmaceutically acceptable inorganic base or organic base. Examples of suitable acid addition salts include salts with hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, pamoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, tannic, and the like. Examples of suitable base addition salts include salts with sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, procaine, and the like. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art. When referring to the compounds of the present invention, the compounds of formula 3 and pharmaceutically acceptable salts thereof are included herein.
The pharmaceutical composition comprises the compound shown in the formula 3, optical isomer, racemate or pharmaceutically acceptable salt thereof and a conventional pharmaceutical carrier and/or excipient. The pharmaceutical composition of the present invention can be prepared into various dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections according to conventional methods in the art, and administered by routes such as oral or parenteral routes.
It should be noted that the dosage and method of administration of the compound of formula 3, its optical isomer, racemate, or pharmaceutically acceptable salt according to the present invention depend on a variety of factors, including the age, body weight, sex, physical health, nutritional status, activity intensity of the compound, administration time, metabolic rate, severity of the disease, and subjective judgment of the treating physician. The preferred dosage is between 0.001-1000mg/kg body weight/day.
Definition of
In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Meanwhile, in order to better understand the present invention, the following provides definitions and explanations of related terms.
The term "optionally" as used herein means that the event or circumstance described therein occurs or does not occur, and if a substituent is described as "optionally substituted with" … the substituent may or may not be substituted.
Unless indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.
The term "hydroxy" as used herein means-OH.
The term "amino" as used herein means-NH 2 。
The term "carboxy" as used herein refers to-C (O) OH.
The term "halogen" as used herein refers to fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine.
The term "C" as used in the present invention 1 -C 6 Alkyl "refers to a saturated straight or branched chain monovalent hydrocarbon radical having 1 to 6 carbon atoms, including C 1-5 Alkyl radical, C 1-4 Alkyl radical, C 1-3 Alkyl radical, C 1-2 Alkyl radical, C 2-5 Alkyl radical, C 2-4 Alkyl groups, and the like. ' C 1 -C 6 Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, hexyl and the like. "C 1 -C 4 Typical examples of alkyl groups "include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,Tert-butyl, and the like.
The term "4-10 membered heteroaryl" as used herein refers to a heteroaromatic ring group having 4-10 ring members, including monocyclic heteroaromatic rings and polycyclic aromatic rings in which a monocyclic aromatic ring is fused to one or more other aromatic rings. "4-to 10-membered heteroaryl" has one or two or more heteroatoms selected from O, S or N, preferably at least one nitrogen atom. Also included within the scope of the term "heteroaryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic), wherein the linking group or point is on the aromatic or non-aromatic ring. The "4-10 membered heteroaryl" may be oxo. For example, a "4-10 membered heteroaryl" as described herein contains 1-2 heteroatoms, e.g., at least one nitrogen atom, e.g., 1 nitrogen, oxygen or sulfur atom, or 1 nitrogen and 1 oxygen atom. The "4-to 10-membered heteroaryl group" includes "5-to 8-membered heteroaryl group", "5-to 7-membered heteroaryl group", "5-to 6-membered heteroaryl group", "5-to 10-membered nitrogen-containing heteroaryl group", "5-to 7-membered nitrogen-containing heteroaryl group", "5-to 8-membered nitrogen-containing heteroaryl group", "5-to 6-membered nitrogen-containing heteroaryl group" and the like, wherein nitrogen atoms in some of the nitrogen-containing heteroaryl groups can be oxidized to form an N-oxide. Those skilled in the art will recognize these nitrogen-containing heteroaryl ring groups which are capable of forming N-oxides. The "4-to 10-membered heteroaryl" has, for example, 5 to 6 ring members. Typical examples of "4-10 membered heteroaryl" include, but are not limited to, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzothiazolyl, pyrimidinyl, benzoxazolyl, thiadiazolyl, benzimidazolyl, imidazopyridinyl, thiazolyl, 1, 5-dihydro-pyrazolo [3,4-d ] pyrimidinyl, 4-oxo-1, 5-dihydro-pyrazolo [3,4-d ] pyrimidin-4-yl, and the like.
The term "4-to 10-membered heterocyclic group" as used herein means a saturated or partially saturated monocyclic or bicyclic or multiple condensed cyclic group having at least one heteroatom (e.g., 1,2, 3,4 or 5) which is a nitrogen atom, an oxygen atom and/or a sulfur atom, and having 4 to 10 ring atoms and no aromaticity. The "4-to 10-membered heterocyclic group" may be oxo. For example, a "4-10 membered heterocyclyl" as described herein contains 1-2 heteroatoms, e.g. at least one nitrogen atom, e.g. 1 nitrogen, oxygen or sulfur atom, or 1 nitrogen and 1 oxygen atom. The "4-to 10-membered heterocyclic group" includes "4-to 8-membered heterocyclic group", "4-to 7-membered heterocyclic group", "5-to 6-membered heterocyclic group", "5-to 10-membered nitrogen-containing heterocyclic group", "5-to 7-membered nitrogen-containing heterocyclic group", "5-to 8-membered nitrogen-containing heterocyclic group", "5-to 6-membered nitrogen-containing heterocyclic group" and the like, wherein nitrogen atoms in some of the nitrogen-containing heterocyclic groups can be oxidized to form an N-oxide. Those skilled in the art will recognize these nitrogen-containing heterocyclic groups which are capable of forming N-oxides. Specific examples of "4-10 membered heterocyclyl" include, but are not limited to: tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, hexahydropyridyl, piperazinyl, thiazinyl, piperidinyl, thiomorpholinyl, morpholinyl, and the like.
The term "pharmaceutically acceptable" as used herein means that the substance described therein is not only physiologically acceptable to the subject, but also pharmaceutically valuable. For example, when "pharmaceutically acceptable salt" is described, it is meant that the salt is not only physiologically acceptable to the subject, but may also refer to a synthetic substance of pharmaceutical value.
The term "pharmaceutically acceptable carrier and/or excipient" as used herein refers to carriers and/or excipients that are pharmacologically and/or physiologically compatible with the subject and active ingredient, and are well known in the art (see, e.g., remington's Pharmaceutical sciences. Edded by Gennaro AR, 19th. Pennsylvania. Typical pharmaceutically acceptable carriers and/or excipients include, for example, microcrystalline cellulose, starch, crospovidone, povidone, polyvinylpyrrolidone, maltitol, citric acid, sodium dodecylsulfonate, or magnesium stearate, and the like.
The term "effective amount" as used herein refers to an amount effective to achieve the intended purpose. For example, an amount effective to treat a disease (e.g., a bacterial infection or a disease caused by a bacterial infection) refers to an amount that reduces or eliminates a disease state or condition. It is within the ability of those skilled in the art to determine such an effective amount.
As used herein, the term "about" means within an acceptable standard error of the specified value as recognized by one of ordinary skill in the art, e.g., within ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, ± 0.5%, ± 0.1%, ± 0.05% or ± 0.01% of the specified value.
The compound provided by the invention is subject to the structural formula of the compound if the name and the structural formula are inconsistent.
The invention has the beneficial technical effects
The compound shown in the formula 3 has strong antibacterial activity on gram-positive bacteria such as methicillin-resistant staphylococcus aureus (MRSA) and the like.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
The starting compound 2 used in the following examples can be referred to in mar, drugs 2013,11,2927-2948; doi:10.3390/md 11082927.
The compound shown in the formula 3 can be prepared by adopting a general synthesis method in the embodiment of the invention.
The general synthesis method comprises adding compounds 2 and K into test tube under argon protection 2 CO 3 And a nucleophile, dried DMF or NMP is added, the reaction solution is stirred at 65-80 deg.C (e.g., 75 deg.C) with DMF as solvent or 80-120 deg.C (e.g., 80 deg.C or 100 deg.C) with NMP as solvent overnight, and the reaction is monitored by LC-MS. After the reaction is completed, saturated NH is used 4 Quenching with Cl aqueous solution, extracting with ethyl acetate for three times, combining organic layers, adding water and saturated saltThe water was washed once each. Anhydrous Na for organic phase 2 SO 4 Drying and vacuum concentrating to obtain crude product. The crude product is purified by silica gel column chromatography and/or preparative HPLC. Samples from compound spectra and assay purity data were collected by preparative HPLC (b)
Figure BDA0003265949310000131
Prep Silica OBD TM 30X 100 mm) or by recrystallization purification.
EXAMPLE 1 preparation of Compounds 3-4
Figure BDA0003265949310000141
The crude product was prepared by reference to the general synthesis using compound 2 (30.0 mg, 46.4. Mu. Mol,1.0 eq) as the reaction starting material, morpholine (80.8. Mu.L, 928. Mu. Mol,20.0 eq) as the nucleophile and NMP as the solvent. The crude product was purified by Silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 8) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: n-hexane: isopropanol (v: v) = 95. Purity =99.7791%; IR (neat): v max ＝3097,2971,2860,1636,1594,1481,1410,1332,1310,1170,1129,1066,948,864,737cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.57(s,1H),11.03(s,1H),10.89(s,1H),8.10(d,J＝8.0Hz,1H),7.83(d,J＝8.0Hz,1H),7.34(d,J＝8.4Hz,1H),7.31(s,1H),7.22(s,1H),6.99(d,J＝8.4Hz,1H),6.95(s,1H),3.49–3.38(m,4H),2.96–2.92(m,2H),2.59–2.56(m,2H)； 13 C NMR(150MHz,Acetone-d 6 )δ186.0,185.9,161.6,160.9,143.7,136.2(q,J＝39.45Hz),135.9(q,J＝39.6Hz),133.7,133.0,131.2,126.0,124.8,124.5,124.5(q,J＝270Hz),124.4,123.8,124.2(q,J＝271.5Hz),120.8,116.4,116.2,115.3,114.9,110.6,106.6,67.2,67.2,51.1,51.1；HRMS(m/z):[M-H] - calcd.For C 28 H 17 Cl 3 F 6 N 3 O 5 - ,694.0143；found,694.0130。
EXAMPLE 2 preparation of Compounds 3-5
Figure BDA0003265949310000142
Compound 2 (200mg, 310. Mu. Mol,1.0 eq), dimethylamine (2M in tetrahydrofuran) (0.300mL, 465. Mu. Mol,1.5 eq), cuprous iodide (2.95mg, 15.5. Mu. Mol,0.05 eq), potassium phosphate anhydrous (65.8mg, 310. Mu. Mol,1.0 eq), and N, N' -bis (2, 4, 6-trimethoxyphenyl) oxamide (65.2mg, 15.5. Mu. Mol,0.5 eq) were dissolved in 20mL dry Dimethylsulfoxide (DMSO) and reacted overnight at 100 ℃ and the next day the starting materials were completely reacted by LC-MS. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with saturated brine (2X 20 mL), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: acetone (v: v) = 15. IR (neat): v max ＝3264,2924,1636,1591,1499,1410,1335,1169,1130,965,848,927,865cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.52(s,1H),11.13(s,1H),10.73(s,1H),8.08(d,J＝8.0Hz,1H),7.80(d,J＝8.4Hz,1H),7.33(d,J＝8.8Hz,1H),7.30(s,1H),7.23(s,1H),6.99(d,J＝8.0Hz,1H),6.91(s,1H),2.46(s,6H)； 13 C NMR(150MHz,Acetone-d 6 )δ185.6,185.3,161.7,160.8,145.9,136.0(q,J＝29.25Hz),135.7(q,J＝29.25Hz),133.5,133.5,132.8,125.2,124.8,124.7,124.5(q,J＝270Hz),124.3(q,J＝270Hz),124.1,124.1,120.5,116.3,116.1,115.3,114.8,110.5,105.8,41.9,41.9；HRMS(m/z):[M-H] - calcd.For C 26 H 15 Cl 3 F 6 N 3 O 4 - ,652.0038；found,652.0038。
EXAMPLE 3 preparation of Compounds 3-6
Figure BDA0003265949310000151
Compound 2 (50.0 mg, 77.8. Mu. Mol,1.0 eq) was used asReaction initiator, K 2 CO 3 (108mg, 0.778mmol, 10.0eq) as a base, pyrido [3,2-D][1,3]Thiazole-2-thiol (130mg, 0.778mmol, 10.0eq) as a nucleophilic reagent and DMF as a solvent, and a crude product is prepared by referring to a general synthesis method. The crude product was purified by Silica gel column chromatography (petroleum ether: ethyl acetate (v: v) =10: 1-3) to obtain compound 3-6 (41.6mg, 69%) as a pale yellow powder, and a portion of the sample was further subjected to normal phase preparative HPLC (Prep Silica OBD TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: mobile phase n-hexane: isopropanol (v: v) = 90-15-80) purification for profile collection and determination of purity data at 25 ℃. Purity: 96.0824%; IR (neat) v max ＝2924,2857,1638,1605,1414,1333,1173,1136,1068,946,929,868cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ10.88(s,1H),8.19(d,J＝8.0Hz,1H),7.83(d,J＝8.0Hz,1H),7.76(d,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.45–7.40(m,2H),7.36–7.31(m,2H),7.25(s,1H),7.15(s,1H),6.93(d,J＝8.0Hz,1H)； 13 C NMR(100MHz,Acetone-d 6 )δ187.2,184.2,165.1,161.7,159.2,154.5,136.6(q,J＝33Hz),136.5,135.4(q,J＝32Hz),135.0,134.1,131.8,127.3,125.9,125.7,125.6,124.8,124.7,124.4,124.3(q,J＝270Hz),124.2(q,J＝270Hz),122.9,122.9,122.2,121.1,120.5,116.6,116.3,115.6,114.6,111.2；HRMS(m/z):[M-H] - calcd.For C 31 H 13 Cl 3 F 6 N 3 O 4 S 2 - ,773.9323；found,773.9315。
EXAMPLE 4 preparation of Compounds 3-7
Figure BDA0003265949310000161
Compound 2 (50.0 mg, 77.8. Mu. Mol,1.0 eq) was used as the reaction starting material, K 2 CO 3 (53.7mg, 0.389mmol, 5.0eq) as a base, tetrahydropyrrole (125. Mu.L, 1.56mmol, 20.0eq) as a nucleophile and NMP as a solvent to prepare a crude product with reference to a general synthetic method. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 5),taking part of the sample, and performing normal phase preparative HPLC (Prep Silica OBD) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: n-hexane: isopropanol (v: v) = 90. Purity: 99.3917%; IR (neat) v max ＝3235,2962,1635,1590,1494,1478,1410,1337,1168,1127,1065,861,786,739,705,683cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.45(s,1H),11.28(s,1H),10.38(s,1H),7.98(d,J＝8.0Hz,1H),7.66(d,J＝8.0Hz,1H),7.29(d,J＝8.0Hz,1H),7.25(d,J＝12.0Hz,2H),7.00(d,J＝8.0Hz 1H),6.88(s,1H),3.19–3.12(m,2H),2.88–2.84(m,2H),1.84–1.67(m,4H)； 13 C NMR(150MHz,Acetone-d 6 )δ185.0,183.3,161.7,159.7,144.9,135.5(q,J＝30Hz),135.3(q,J＝30Hz),133.1,132.1,126.2,126.1,125.2,125.0,125.0,124.5(q,J＝270Hz),124.4(q,J＝270Hz),124.1,120.9,116.3,116.1,115.1,114.4,111.5,102.4,50.9,50.9,26.3,26.3；HRMS(m/z):[M-H] - calcd.For C 29 H 19 Cl 3 F 6 N 3 O 4 - ,692.0351；found,692.0345。
EXAMPLE 5 preparation of Compounds 3-8
Figure BDA0003265949310000171
Compound 2 (50.0 mg, 77.8. Mu. Mol,1.0 eq) was used as the reaction starting material, K 2 CO 3 (108mg, 0.778mmol, 10.0eq) as a base, 2-mercaptothiazole (91.2mg, 0.778mmol, 10.0eq) as a nucleophilic reagent, and DMF as a solvent, and the crude product is prepared by referring to a general synthetic method. The crude product was purified by Silica gel column chromatography (petroleum ether: ethyl acetate (v: v) =8: 1-3) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: mobile phase n-hexane: isopropanol (v: v) = 90-15-80) purification for profile collection and determination of purity data at 25 ℃. Purity: 99.6474%; IR (neat): v max ＝2960,1638,1603,1506,1406,1334,1173,11301,1055,1014,946,791cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.59(s,1H),10.88(s,1H),10.18(s,1H),8.09(d,J＝8.0Hz,1H),7.63(d,J＝8.0Hz,1H),7.61(d,J＝4.0Hz,1H),7.53(d,J＝4.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.34(s,1H),7.19(s,1H),7.16(s,1H),7.02-6.99(m,1H)； 13 C NMR (150MHz,Acetone-d 6 )δ187.1,184.0,161.7,161.5,159.0,144.4,136.7(q,J＝33Hz),135.4(q,J＝33Hz),134.1,134.0,131.8,127.3,125.9,125.8,124.9,124.4(q,J＝270Hz),124.3,124.3(q,J＝270Hz),123.8,122.9,121.5,120.7,116.3,116.3,115.5,114.6,111.0；HRMS(m/z):[M-H] - calcd.For C 27 H 11 Cl 3 F 6 N 3 O 4 S 2 - ,723.9166；found,723.9161。
EXAMPLE 6 preparation of Compounds 3-9
Figure BDA0003265949310000181
Compound 2 (60.1mg, 92.9. Mu. Mol,1.0 eq) was used as the reaction starting material, K 2 CO 3 (128mg, 929. Mu. Mol,10.0 eq) as a base, 2-mercaptothiophene (108mg, 929. Mu. Mol,10.0 eq) as a nucleophile and DMF as a solvent, the crude product was prepared by reference to general synthetic methods. The crude product was purified by Silica gel column chromatography (petroleum ether: ethyl acetate (v: v) =10: 1-4) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: n-hexane: isopropanol (v: v) = 95. Purity: 98.6780%; IR (neat) v max ＝3230,2972,1636,1596,1505,1406,1333,1170,1129,1066,944,866,737,701cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.64(s,1H),10.92(s,1H),10.18(s,1H),8.02(d,J＝8.4Hz,1H),7.63(d,J＝8.0Hz,1H),7.53(dd,J＝5.2,2.0Hz,1H),7.32(t,J＝2.8Hz,2H),7.18(s,1H),7.03(s,1H),6.95(s,1H),6.94(d,J＝2.8Hz,1H),6.93–6.91(m,1H)； 13 C NMR(100MHz,Acetone-d 6 )δ187.0,184.6,161.8,159.5,136.5(q,J＝32.4Hz),135.5(q,J＝32.1Hz),135.1,134.0,132.5,132.2,131.9,131.1,130.0,128.9,128.5,125.6,125.5,124.4(q,J＝270.6Hz),124.3(q,J＝270.5Hz),124.3,122.0,121.6,121.0,116.5,116.1,115.5,114.7,111.2；HRMS(m/z):[M-H] - calcd.For C 28 H 12 Cl 3 F 6 N 2 O 4 S 2 - ,722.9214；found,722.9203。
EXAMPLE 7 preparation of Compounds 3-10
Figure BDA0003265949310000182
The crude product was prepared by reference to general synthetic procedures using compound 2 (100mg, 155. Mu. Mol,1.0 eq) as the reaction starting material, thiomorpholine (0.31. Mu.L, 3.1mmol,20.0 eq) as the nucleophile and NMP as the solvent. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 5). Purity =99.7515%; IR (neat) v max ＝2924,1333,2173,1134,749cm –1 ； 1 H NMR(400MHz,Methanol-d 4 )δ7.67(d,J＝8.0Hz,1H),7.62(d,J＝8.0Hz,1H),7.25–5.23(m,2H),7.13(s,1H),6.93(d,J＝8.0Hz,1H),6.62(s,1H),3.19-3.14(m,2H),2.95–1.90(m,2H),2.48–2.43(m,2H),2.32–2.29(m,2H)； 13 C NMR(100MHz,Methanol-d 4 )δ185.5,185.4,160.0,159.2,146.2,136.2(q,J＝30Hz),135.4(q,J＝30Hz),132.8,132.1,128.5,127.5,126.4,125.9,125.6,125.6,125.0(q,J＝270Hz),124.7(q,J＝270Hz),124.2,121.2,116.5,114.7,114.6,111.6,107.8,53.7,53.7,28.7,28.7；HRMS(m/z):[M-H] - calcd.For C 28 H 17 Cl 3 F 6 N 3 O 4 S - ,709.9915；found,709.9909。
EXAMPLE 8 preparation of Compounds 3-11
Figure BDA0003265949310000191
The crude product was prepared by reference to the general synthetic method using compound 2 (100mg, 155. Mu. Mol,1.0 eq) as the reaction starting material, 1-benzylpiperazine (516mg, 3.1mmol, 20.0eq) as the nucleophile, and NMP as the solvent. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 8). Purity: 99.9052 percent; IR (neat) v max ＝2904,1674,1594,11332,1310,962,740cm –1 ； 1 H NMR(400MHz,Methanol-d 4 )δ7.67(d,J＝8.0Hz,1H),7.63(d,J＝8.0Hz,1H),7.32–7.27(m,5H),7.23(d,J＝8.0Hz,2H),7.11(s,1H),6.91(d,J＝8.0Hz,1H),6.61(s,1H),3.52(s,2H),3.03–3.00(m,2H),2.76–2.72(m,2H),2.36–2.30(m,4H)； 13 C NMR(150MHz,Methanol-d 4 )δ185.5,185.3,160.1,159.3,145.2,137.7,136.2(q,J＝30Hz),135.4(q,J＝30Hz),132.9,132.2,130.7,129.4,128.7,128.4,127.3,126.1,126.1,125.8,125.6,125.0(q,J＝270Hz),124.8(q,J＝270Hz),124.3,121.6,121.4,116.5,116.3,114.7,114.7,111.4,107.3,63.8,54.0,54.0,50.6,50.6；HRMS(m/z):[M-H] - calcd.For C 35 H 24 Cl l3 F 6 N 4 O 4 - ,783.0773；found,783.0775。
EXAMPLE 9 preparation of Compounds 3-12
Figure BDA0003265949310000201
The compounds 3-9 (40.0 mg, 55.2. Mu. Mol,1.0 eq) prepared in example 6 and m-chloroperoxybenzoic acid (78.7 mg, 456. Mu. Mol,8.0 eq) were dissolved in 4mL of dry dichloromethane and reacted overnight at room temperature (25 ℃ C.), LC-MS showed complete reaction of the starting materials, and saturated Na was added to the reaction mixture 2 S 2 O 3 The reaction was quenched with aqueous solution, extracted with dichloromethane (4 × 8 mL), dried over anhydrous sodium sulfate, filtered with suction and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) =4Products 3 to 12 (33.8mg, 81%). Taking part of the sample, and performing normal phase preparative HPLC (Prep Silica OBD) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: 25 ℃, n-hexane: isopropanol = 90-15-80) for profile acquisition and determination of purity data. Purity: 99.1410%; IR (neat) v max ＝3255,1638,1605,1504,1400,1330,1127,1066,946,869,725cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.50(s,1H),10.74(s,1H),10.08(s,1H),8.04(dd,J＝5.2,1.6Hz,1H),7.94(d,J＝8.8Hz,1H),7.78(d,J＝8.0Hz,1H),7.58(dd,J＝4.0,1.6Hz,1H),7.32(s,1H),7.30(s,1H),7.22–7.17(m,2H),7.10(s,1H),7.08(d,J＝8.0Hz,1H)； 13 C NMR(100MHz,Acetone-d 6 )δ188.0,184.6,161.4,159.5,142.4,137.0,136.8(q,J＝31.6Hz),135.4(q,J＝32.2Hz),135.4,134.3,134.2,132.0,131.9,129.0,126.8,126.0,124.8,124.4(q,J＝271Hz),124.3(q,J＝270Hz),123.8,121.7,120.9,119.6,116.6,116.3,115.6,114.8,112.5；HRMS(m/z):[M-H] - calcd.For C 28 H 12 Cl 3 F 6 N 2 O 6 S 2 - ,754.9112；found,754.9102。
EXAMPLE 10 preparation of Compounds 3-13
Figure BDA0003265949310000211
Referring to the synthesis method of the compounds 3 to 5 in example 3, compound 2 (300.0 mg, 464. Mu. Mol,1.0 eq), 1,2, 4-triazole (641mg, 9.28mmol,20.0 eq), cuprous iodide (26.5 mg, 139. Mu. Mol,0.3 eq), anhydrous potassium phosphate (197mg, 928. Mu. Mol,2.0 eq) and N, N' -bis (2, 4, 6-trimethoxyphenyl) oxamide (39.0 mg, 92.8. Mu. Mol,0.2 eq) were dissolved in 25mL of dried DMSO and reacted at 100 ℃ to give a crude product. The crude product was purified by Silica gel column chromatography (petroleum ether: ethyl acetate (v: v) =4: 1-1) to obtain 3 to 13 (16.0 mg, 25%) as a pale yellow powder, and a part of the sample was further subjected to normal phase preparative HPLC (Prep Silica OBD) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: 25 ℃, n-hexane: isopropanol (v: v) =90Purity data. Purity: 99.3317%; IR (neat): v max ＝3128,1735,1637,1603,1505,1331,1170,1126,1066,1003,946,866,781cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.44(s,1H),10.76(s,1H),10.11(s,1H),8.62(s,1H),8.13(s,1H),7.94(d,J＝8.0Hz,1H),7.90(d,J＝8.4Hz,1H),7.33(s,1H),7.31(s,1H),7.20(s,1H),7.16(s,1H),7.10(d,J＝8.0Hz,1H)； 13 C NMR(100MHz,Acetone-d 6 )δ186.9,184.3,161.3,159.7,154.2,148.0,136.5(q,J＝32.0Hz),135.7(q,J＝33.0Hz),133.7,134.2,132.1,129.9,129.7,128.5,125.9,125.7,124.8,123.1,120.1,120.3,116.5,116.3,115.3,114.9,111.6,111.4；HRMS(m/z):[M-H] - calcd.For C 26 H 11 Cl 3 F 6 N 5 O 4 - ,675.9786；found,675.9780。
EXAMPLE 11 preparation of Compounds 3-14
Figure BDA0003265949310000221
Compound 2 (50.0 mg, 77.8. Mu. Mol,1.0 eq) was used as the reaction initiator, K 2 CO 3 (53.7mg, 0.389mmol, 5eq) as base, piperidine (140. Mu.L, 1.56mmol, 20.0eq) as nucleophile and NMP as solvent, referred to general synthetic methods to prepare the crude product. The crude product was purified by Silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 5) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: 25 ℃, n-hexane: isopropanol (v: v) = 90. Purity: 99.4094%; IR (neat) v max ＝2929 1637,1593,1483,1412,1337,1177,1135.79,1068,1028,949,864,797cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.52(s,1H),11.07(s,1H),8.09(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.31(s,1H),7.23(s,1H),6.96(d,J＝8.0Hz,1H),6.96(s,1H),2.91–2.86(m,1H),2.57–2.52(m,2H),1.39–1.29(m,7H)； 13 C NMR(150MHz,Acetone-d 6 )δ186.1,185.6,161.6,161.3,145.6,136.1(q,J＝30Hz),135.8(q,J＝30Hz),133.6,133.0,125.6,124.9,124.8,124.5(q,J＝270Hz),124.4,124.3(q,J＝270Hz),124.1,123.5,120.7,116.4,116.0,115.3,114.8,110.7,106.3,52.0,52.0,26.6,26.6,24.4；HRMS(m/z):[M-H] - calcd.For C 28 H 17 Cl 3 F 6 N 3 O 4 - ,678.0194；found,678.0181。
EXAMPLE 12 preparation of Compounds 3-15
Figure BDA0003265949310000222
Compound 2 (200mg, 311. Mu. Mol,1.0 eq) was used as the reaction starting material, K 2 CO 3 (216mg, 1.56mmol,5.0 eq) as a base, N-isobutylpiperazine (0.963mL, 6.22mmol,20.0 eq) as a nucleophile, NMP as a solvent, and reference a general synthetic method to prepare the crude product. The crude product was purified by Silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 3) to give 3 to 15 (113mg, 49%) as a pale yellow powder, and a portion of the sample was further subjected to normal phase preparative HPLC (Prep Silica OBD TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: n-hexane: isopropanol (v: v) = 90. Purity: 98.1727%; IR (neat): v max ＝2927,2853,1636,1593,1481,1411,1331,1171,1128,1067,863cm –1 ； 1 H NMR(600MHz,Acetone-d 6 )δ8.06(d,J＝8.4Hz,1H),7.99(d,J＝8.4Hz,1H),7.30(d,J＝8.4Hz,1H),7.25(s,1H),7.16(s,1H),6.97(d,J＝7.8Hz,1H),6.91(m,1H),3.19(m,2H),3.00(m,2H),2.75(m,4H),2.56(m,2H),1.98(m,1H),0.92(d,J＝6.6Hz,6H)； 13 C NMR(100MHz,Acetone-d 6 )δ185.9,184.3,161.6,160.5,144.1,136.7,135.7(q,J＝32Hz),135.3(q,J＝32Hz),135.2,133.8,133.6,126.5,124.9,124.7,124.6(q,J＝270Hz),124.5(q,J＝270Hz),122.7,121.6,116.2,116.0,115.2,115.2,110.3,106.7,66.5,54.4,54.4,49.3,25.2,25.2,20.6,20.6；HRMS(m/z):[M-H] - calcd.For C 32 H 26 Cl 3 F 6 N 4 O 4 S - ,749.0929；found,749.0933。
EXAMPLE 13 preparation of Compounds 3-16
Figure BDA0003265949310000231
Compound 2 (50.0 mg, 77.8. Mu. Mol,1.0 eq) was used as the reaction starting material, K 2 CO 3 (108mg, 0.778mmol, 10.0eq) as a base, 2-mercaptobenzothiazole (130mg, 0.778mmol, 10.0eq) as a nucleophilic reagent, and DMF as a solvent, and the crude product was prepared by reference to a general synthetic method. The crude product was purified by Silica gel column chromatography (petroleum ether: ethyl acetate (v: v) =10 1-3) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: mobile phase n-hexane: isopropanol (v: v) = 90-15-80) purification for profile collection and determination of purity data at 25 ℃. Purity: 96.0824%; IR (neat): v max ＝2924,2857,1638,1605,1414,1333,1173,1136,1068,946,929,868cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ10.88(s,1H),8.19(d,J＝8.0Hz,1H),7.83(d,J＝8.0Hz,1H),7.76(d,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.45–7.40(m,2H),7.36–7.31(m,2H),7.25(s,1H),7.15(s,1H),6.93(d,J＝8.0Hz,1H)； 13 C NMR(100MHz,Acetone-d 6 )δ187.2,184.2,165.1,161.7,159.2,154.5,136.6(q,J＝33Hz),136.5,135.4(q,J＝32Hz),135.0,134.1,131.8,127.3,125.9,125.7,125.6,124.8,124.7,124.4,124.3(q,J＝270Hz),124.2(q,J＝270Hz),122.9,122.9,122.2,121.1,120.5,116.6,116.3,115.6,114.6,111.2；HRMS(m/z):[M-H] - calcd.For C 31 H 13 Cl 3 F 6 N 3 O 4 S 2 - ,773.9323；found,773.9315。
Dissolving compounds 3-35 (90.1mg, 0.116mmol,1.0 eq) and m-chloroperoxybenzoic acid (201mg, 1.16mmol,10.0 eq) in 10mL dry dichloromethane, reacting at room temperature (25 ℃) for 6 days, detecting by LC-MS to show that the reaction of the raw materials is complete, adding the mixture into the reaction solutionSaturated Na 2 S 2 O 3 Aqueous solution quenching, dichloromethane extraction (3 × 20 mL), drying over anhydrous sodium sulfate, suction filtration concentration to give crude product, which was purified by Silica gel column chromatography (petroleum ether: ethyl acetate (v: v) =8, 1-4) to give yellow powder compound 3-16 (28.1mg, 30%), a portion of which was taken for further purification by normal phase preparative HPLC (Prep Silica OBD TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: 25 ℃, n-hexane: isopropanol (v: v) =90: 98.4919%.
IR:(neat):ν max ＝3005,1275,1261,1174,797,764,750cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.5(s,1H),10.71(s,1H),10.21,(s,1H),8.23–8.21(m,1H),7.99(d,J＝8.0Hz,1H),7.93–7.90(m,1H),7.74(d,J＝8.0Hz,1H),7.67–7.63(m,2H),7.32(m,2H),7.21(s,1H),7.16(s,1H),7.10(d,J＝12.0Hz,1H)； 13 C NMR(150MHz,Acetone-d 6 )δ188.0,184.7,166.8,161.5,160.0,153.4,137.8,136.9(q,J＝30Hz),136.1,135.7(q,J＝30Hz),134.4,132.3,129.3,128.8,128.5,126.5,126.0,125.3,124.7,124.4(q,J＝270Hz),124.3(q,J＝271Hz),123.9,123.8,123.4,121.3,119.5,116.7,116.3,115.6,114.9,113.1；HRMS(m/z):[M-Na] - calcd.For C 31 H 13 Cl 3 F 6 N 3 O 6 S 2 - ,805.9221；found,805.9214。
EXAMPLE 14 preparation of Compounds 3-17
Figure BDA0003265949310000251
The crude product was prepared by reference to general synthetic procedures using compound 2 (100mg, 155. Mu. Mol,1.0 eq) as the starting material for the reaction, N-methylpiperazine (0.35mL, 3.1mol,20.0 eq) as the nucleophile, and NMP as the solvent. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 8). Purity: 100 percent; IR (eat):ν max ＝2978,1484,1316,1130,1066,861,707cm –1 ； 1 H NMR(400MHz,Methanol-d 4 )δ7.70(t,J＝8.0Hz,2H),7.22(d,J＝8.0Hz,2H),7.12(s,1H),6.94(d,J＝8.0Hz,1H),6.64(s,1H),3.10-3.07(m,2H),2.87-2.86(m,2H),2.45–2.40(m,4H),2.34(s,3H)； 13 C NMR(150MHz,Methanol-d 4 )δ185.5,185.2,160.0,159.4,144.8,135.9(q,J＝30Hz),134.2(q,J＝30Hz),133.1,133.1,132.3,132.3,128.3,128.3,127.5,126.7,125.7,123.9,123.9,116.4,116.4,115.1,114.7,111.3,107.4,55.8,55.8,50.1,50.1,45.7；HRMS(m/z):[M-H] - calcd.For C 29 H 20 Cl 3 F 6 N 4 O 4 - ,707.0460；found,707.0486。
EXAMPLE 15 preparation of Compounds 3-18
Figure BDA0003265949310000252
Compound 2 (70mg, 109. Mu. Mol,1.0 eq) was used as the reaction starting material, K 2 CO 3 (105mg, 763. Mu. Mol,7.0 eq) as base, thiazolo [4,5-b]Pyridine-2 (3H) -thiones (Thiazolo [4,5-b ]]pyridine-2-thiol) (138mg, 1.09mmol,10.0 eq) as a nucleophile and DMF as a solvent were reacted at 75 ℃ to give the crude product by reference to a general synthetic method. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 5). Purity: 99.3992%; IR (neat) v max ＝2927,2856,1638,1605,1505,1414,1384,1329,1170,1129,1067,944,928,867,782cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ10.9(s,1H),8.55(dd,J＝4.4,1.2Hz,1H),8.31(dd,J＝8.0,1.2Hz,1H),8.18(d,J＝8.4Hz,1H),7.58(d,J＝8Hz,1H),7.39(d,J＝8.4Hz,1H),7.35(s,1H),7.33-7.29(m,1H),7.26(s,1H),7.13(s,1H),6.95(d,J＝8.4Hz,1H)； 13 C NMR(100MHz,Acetone-d 6 )δ187.3,184.0,170.9,165.0,161.7,159.2,148.9,136.6(q,J＝32Hz),135.6,135.2(q,J＝32Hz),134.2,132.1,131.4,130.4,127.7(q,J＝196Hz),127.5(q,J＝195Hz),126.4,125.7,125.0,124.7,124.6,124.4,123.0,120.7,120.6,116.5,116.2,115.6,115.0,111.0；HRMS(m/z):[M-H] - calcd.For C 30 H 12 Cl 3 F 6 N 4 O 4 S 2 - ,774.9275；found,774.9276。
EXAMPLE 16 preparation of Compounds 3-19
Figure BDA0003265949310000261
Compound 2 (50.0 mg, 77.8. Mu. Mol,1.0 eq) was used as the reaction initiator, K 2 CO 3 (108mg, 0.778mmol, 10.0eq) as a base, tert-butyl (3-mercaptopropyl) carbamic acid (149mg, 0.778mmol, 10.0eq) as a nucleophilic reagent, and DMF as a solvent, and referring to a general synthetic method, a crude product is prepared. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 8) to give compound 3-29 (46.0 mg, 74%) as a pale yellow powder; IR (neat) v max ＝3119.39,2979.28,2934.62,1681.17,1637.17,1595.35,1505.36,1405.48,1332.02,1305.32,1230.00,1128.56,1165,41,944.45,865.73,782.53,738.33,574.78cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.6(s,1H),10.96(s,1H),10.1(s,1H),8.07(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.35-7.32(m,2H),7.16(s,1H),7.04(s,1H),6.94(d,J＝8.0Hz,1H),3.00(q,J＝20Hz,2H),2.70–2.65(m,1H),2.55–2.50(m,1H),1.56–1.46(m,2H),1.40–1.38(m,12H)； 13 C NMR(150MHz,Acetone-d 6 )δ186.7,184.6,161.7,159.3,156.7,136.3(q,J＝30Hz),135.3(q,J＝30Hz),134.0,132.4,132.4,131.9,126.0,125.8,125.6,124.5,124.4(q,J＝270Hz),124.4(q,J＝270Hz),122.4,122.0,120.7,116.4,116.0,115.4,114.5,110.8,78.6,39.5,33.7,30.9,28.6,28.6,28.6；HRMS(m/z):[M-H] - calcd.For C 32 H 256 Cl 3 F 6 N 3 O 6 S - ,798.0439；found,798.0429。
Dissolving compound 3-29 (140mg, 0.175mmol, 1.0eq) in 13mL dichloromethane, adding 1.3mL trifluoromethanesulfonic acid, reacting at 25 ℃ for 1h, detecting by TLC that the raw material reaction is complete, and returning to the reactionThe reaction solution was quenched by addition of saturated aqueous sodium bicarbonate, extracted with dichloromethane (3X 15 mL), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by Silica gel column chromatography (dichloromethane: methanol (v: v) = 20) to obtain compound 3-19 (83.3mg, 68%) as a pale yellow powder, and a portion of the sample was further subjected to normal phase preparative HPLC (Prep Silica OBD TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: n-hexane: isopropanol (v: v) = 80. Purity: 100.0000%; IR (neat) v max ＝2961,1958,1507,1407,1332,1258,1068,1014,945,867,796cm –1 ； 1 H NMR(400MHz,Methanol-d 4 )δ7.92(d,J＝8.0Hz,1H),7.72(d,J＝8.0Hz,1H),7.12–7.10(m,2H),7.07(s,1H),6.95(d,J＝8.0Hz,1H),6.85(s,1H),2.81–2.78(m,2H),2.66–2.65(m,2H),1.75–1.71,(m,2H)； 13 C NMR(150MHz,Methanol-d 4 )δ187.0,184.3,160.4,160.0,135.8(q,J＝30Hz),135.2(q,J＝30Hz),134.5,133.9,133.1,130.7,130.3,129.52,127.2,127.1,125.3,125.2(q,J＝270Hz),124.9(q,J＝270Hz),122.0,120.2,116.8,115.9,115.0,114.96,111.3,39.0,32.3,28.3；HRMS(m/z):[M-H] - calcd.For C 27 H 17 Cl 3 F 6 N 3 O 4 S - ,697.9915；found,697.9910。
EXAMPLE 17 preparation of Compounds 3-20
Figure BDA0003265949310000271
Compound 2 (90.2mg, 141. Mu. Mol,1.0 eq) was used as the reaction starting material, K 2 CO 3 (39mg, 282. Mu. Mol,2.0 eq) as a base, 2-tert-butoxycarbonylaminoethanethiol (250mg, 1.41mmol,10.0 eq) as a nucleophile, and DMF as a solvent were prepared as a crude product by reference to general synthetic procedures. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) =10: 1-2); IR (neat) v max ＝2977,1688,1637,1600,1505,1406,1332,1168,1130,1066,944,866,738cm –1 ； 1 H NMR(600MHz,Acetone-d 6 )δ12.58(s,1H),10.96(s,1H),10.08(s,1H),8.05(d,J＝7.8Hz,1H),7.62(d,J＝7.8Hz,1H),7.34(d,J＝8.4Hz,1H),7.32(s,1H),7.16(s,1H),7.06(s,1H),6.96(d,J＝7.8Hz,1H),5.96(s,1H),3.09-3.00(m,2H),2.81-2.77(m,1H),2.64-2.59(m,1H),1.37(s,9H)； 13 C NMR(150MHz,Acetone-d 6 )δ186.6,184.5,161.7,159.2,156.3,136.3(q,J＝32.4Hz),135.2(q,J＝32.6Hz),133.9,132.5,131.9,131.8,127.1,126.0,125.7,124.4,124.4(q,J＝270Hz),124.3(q,J＝271.5Hz),122.3,122.0,120.7,116.4,116.1,115.5,114.5,110.9,79.0,41.0,35.8,28.5,28.5,28.5；HRMS(m/z):[M-H] - calcd.For C 31 H 22 Cl 3 F 6 N 3 O 6 S - ,784.0283；found,784.0269。
Dissolving the compound 3-30 (80.0mg, 102. Mu. Mol,1.0 eq) in 8mL of dichloromethane, adding 0.8mL of trifluoromethanesulfonic acid, reacting at 25 ℃ for 5h, detecting by TLC that the raw material has completely reacted, adding a saturated aqueous solution of sodium bicarbonate to the reaction solution, quenching, extracting with dichloromethane (4X 10 mL), combining the organic phases, drying over anhydrous sodium sulfate, vacuum-filtering and concentrating to obtain a crude product, and purifying the crude product by Silica gel column chromatography (dichloromethane: methanol (v: v) =20, 1.0.1% ammonia water) to obtain a pale yellow powder compound 3-20 (8.99mg, 13%), wherein a part of the sample is further subjected to normal-phase preparative HPLC (Prep silicon OBD) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: n-hexane: isopropanol (v: v) = 85. Purity =99.8986%; IR (neat) v max ＝2936,1601,1506,1408,1331,1170,1128,944,866,738cm –1 ； 1 H NMR(600MHz,Methanol-d 4 )δ7.74(d,J＝8.4Hz,1H),7.67(d,J＝8.4Hz,1H),7.15(s,1H),7.14(s,1H),7.05(s,1H),6.94(d,J＝7.8Hz,1H),6.84(s,1H),2.98–2.89(m,2H),2.87–2.76(m,2H)； 13 C NMR(150MHz,Methanol-d 4 )δ186.8,184.4,160.0,159.3,135.9(q,J＝32.55Hz),135.2(q,J＝32.1Hz),134.7,133.0,132.8,129.5,129.0,127.4,126.6,125.1(q,J＝271.5Hz),124.9(q,J＝271.5Hz),124.0,122.5,121.9,120.7,116.2,115.9,115.5,114.9,111.3,40.5,33.7；HRMS(m/z):[M-H] - calcd.For C 26 H 15 Cl 3 F 6 N 3 O 4 S - ,683.9759；found,683.9748。
EXAMPLE 18 preparation of Compounds 3-21
Figure BDA0003265949310000291
Compound 2 (50.1mg, 77.8. Mu. Mol,1.0 eq) was used as the reaction starting material, K 2 CO 3 (53.7mg, 0.389mmol,5.0 eq) as base, anhydrous piperazine (134mg, 1.56mmol,20.0 eq) as nucleophile and NMP as solvent, referenced to general synthetic methods to prepare the crude product. The crude product was purified by silica gel column chromatography (dichloromethane: methanol (v: v) = 20) to obtain yellow powdery compound 3-21 (31.2mg, 58%), 30mg of which was taken and 5mL of methanol was added for recrystallization to obtain 13mg of a pale yellow pure product and 17mg of a mother liquor, and a spectrum was collected and purity data was measured. Purity of the pure product: 99.2190 percent; IR (neat): v max ＝2849,1595,1578,1474,1377,1342,1006,860cm –1 ； 1 H NMR(400MHz,Methanol-d 4 )δ7.99(d,J＝8.0Hz,1H),7.73(d,J＝8.0Hz,1H),7.17–7.15(m,2H),7.10(s,1H),6.98(d,J＝8.4Hz,1H),6.72(s,1H),3.29-3.16(m,4H),2.93–2.85(m,4H)； 13 C NMR(150MHz,Methanol-d 4 )δ185.9,184.7,160.2,159.9,144.2,135.5(q,J＝30Hz),135.4(q,J＝30Hz),134.0,132.7,132.7,129.9,128.7,127.9,126.3,125.2(q,J＝270Hz),125.0(q,J＝270Hz),124.9,122.4,116.5,116.1,115.3,114.8,110.9,107.6,48.7,48.7,45.6,45.6；HRMS(m/z):[M-H] - calcd.For C 28 H 18 Cl 3 F 6 N 4 O 4 - ,693.0303；found,693.0301。
EXAMPLE 19 preparation of Compounds 3-22
Figure BDA0003265949310000301
Compound 2 (200mg, 311. Mu. Mol,1.0 eq) was used as the reaction starting material, 1- (4-pyridyl) piperazine (295. Mu.L, 4.67mmol,15.0 eq) was used as the nucleophile, NMP was used as the solvent,the crude product is prepared by referring to a general synthetic method. The crude product was purified by silica gel column chromatography (dichloromethane: methanol (v: v) = 30) to obtain a light yellow powder of compound 3-22 (98mg, 41%). Purity =99.6606%; IR (neat) v max ＝2925,1645,1474,1331,1221,1121,941,926,873cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ8.29(d,J＝8Hz,1H),8.05(d,J＝7.6Hz,3H),7.29–7.24(m,4H),7.16(s,1H),7.09(s,1H),6.99(d,J＝8.8Hz,1H),3.79(d,J＝4.8Hz,4H),2.96(d,J＝5.2Hz,4H)； 13 C NMR(100MHz,Acetone-d 6 )δ187.8,183.0,161.5,160.0,156.8,144.01,136.4(q,J＝32Hz),134.8(q,J＝32Hz),134.7,134.7,134.2,132.3,131.5,130.3,128.7,125.0(q,J＝270Hz),124.6,124.4(q,J＝271Hz),124.2,121.4,118.4,117.1,116.2,115.3,114.3,109.8,109.67,108.4,108.4,49.5,49.5,46.3,46.3；HRMS(m/z):[M-H] - calcd.For C 33 H 21 Cl 3 F 6 N 5 O 4 S - ,770.0569；found,770.0601。
EXAMPLE 20 preparation of Compounds 3-23
Figure BDA0003265949310000302
Compound 2 (50.0 mg, 77.8. Mu. Mol,1.0 eq) was used as the reaction initiator, K 2 CO 3 (108mg, 0.778mmol, 10.0eq) as a base, 2-hydroxyethylthiol (55.2. Mu.L, 0.778mmol, 10.0eq) as a nucleophilic reagent, and DMF as a solvent, and the crude product was prepared by reference to a general synthetic method. The crude product was purified by Silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 4. Purity: 99.8935%; IR (neat) v max ＝2924,1637,1598,1506,1407,1333,1171,1129,944,866cm –1 ；1H NMR(400MHz,Acetone-d6)δ12.6(s,1H),10.96(s,1H),10.14(s,1H),8.06(d,J＝8.0Hz,1H),7.63(d,J＝8.0Hz,1H),7.35–7.32(m,2H),7.15(s,1H),7.04(s,1H),6.94(dd,J＝0.8,8.0Hz,1H),3.87(t,J＝5.2Hz,1H),3.49–3.43(m,2H),2.80–2.74(m,1H),2.68–2.62(m,1H)； 13 C NMR(150MHz,Acetone-d 6 )δ186.6,184.5,161.7,159.3,136.3(q,J＝30Hz),135.2(q,J＝30Hz),134.0,132.6,132.3,131.8,126.0,125.8,125.6,124.5,124.4(q,J＝270Hz),124.3(q,J＝270Hz),122.0,122.0,120.7,116.5,116.0,115.5,114.5,110.8,61.7,38.7；HRMS(m/z):[M-H] - calcd.For C 26 H 14 Cl 3 F 6 N 2 O 5 S - ,684.9599；found,684.9593。
Dissolving compound 3-31 (80.2mg, 0.117mmol,1.0 eq) and m-chloroperoxybenzoic acid (201mg, 1.17mmol,10.0 eq) in 10mL dry dichloromethane, reacting at 25 deg.C for 24h, detecting by LC-MS to show complete reaction of raw materials, adding saturated Na into the reaction solution 2 S 2 O 3 The aqueous solution was quenched, extracted with dichloromethane (3 × 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by Silica gel column chromatography (petroleum ether: acetone (v: v) = 3-1 TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: n-hexane: isopropanol (v: v) = 85-20-75) purification for profile collection and assay purity data. Purity: 99.3794%; IR (neat): v max =2925,1606,1410,1331,1169,1138,1068,947,750,626cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ10.79(s,1H),7.95(d,J＝8.0Hz,1H),7.70(d,J＝8.0Hz,1H),7.33–7.20(m,2H),7.18(s,1H),7.12–7.10(m,2H),4.00–3.99(m,1H),3.93(q,J＝20Hz,2H),3.51–3.416(m,2H)； 13 C NMR(150MHz,Acetone-d 6 )δ188.2,184.5,161.6,159.0,136.8(q,J＝33Hz),135.2(q,J＝31.5Hz),134.34,134.3,131.9,131.0,126.9,126.5,124.7,124.4(q,J＝271.5Hz),124.3,124.3(q,J＝271.5Hz),121.2,121.0,119.5,116.6,116.4,115.5,114.7,112.6,59.9,56.0；HRMS(m/z):[M-H] - calcd.For C 26 H 14 Cl 3 F 6 N 2 O 7 S - ,716.9597；found,716.9493。
EXAMPLE 21 preparation of Compounds 3-24
Figure BDA0003265949310000321
The crude product was prepared by reference to the general synthetic method using compound 2 (100mg, 155. Mu. Mol,1.0 eq) as the reaction starting material, allopurin (423mg, 3.1mmol, 20.0eq) as the nucleophile, and NMP as the solvent. The crude product was purified by silica gel column chromatography (petroleum ether: acetone (v: v) = 8. Purity: 99.7027%; IR (neat) v max ＝2925,1725,1605,1408,1333,1132cm –1 ； 1 H NMR(600MHz,Acetone-d 6 )δ10.81(m,2H),8.52(s,1H),8.04–8.02(m,2H),7.89(d,J＝6.0Hz,1H),7.33–7.31(m,2H),7.20(s,1H),7.15(s,1H),7.08(d,J＝6.0Hz,1H)； 13 C NMR(100MHz,Acetone-d 6 )δ186.8,184.3,161.2,161.1,159.7,158.6,149.0,136.4(q,J＝33Hz),135.5(q,J＝33Hz),134.0,133.7,132.3,132.2,129.6,126.2,126.0,124.9,124.5(q,J＝270Hz),124.4(q,J＝271Hz)；123.2,120.9,120.3,116.5,116.1,115.4,115.0,111.3,111.2,110.1；HRMS(m/z):[M-H] - calcd.For C 29 H 12 Cl 3 F 6 N 6 O 5 - ,742.9844；found,742.9844。
EXAMPLE 22 preparation of Compounds 3-25
Figure BDA0003265949310000322
Compound 2 (30.0 mg, 46.4. Mu. Mol,1.0 eq) was used as the reaction starting material, K 2 CO 3 (52.1mg, 464. Mu. Mol,10.0 eq) as a base, 3-mercapto-1-propanol (40.1. Mu.L, 464. Mu. Mol,10.0 eq) as a nucleophile, and DMF as a solvent were prepared to give the crude product by reference to general synthetic methods. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) =5: 1-3) to obtain 3-32 (20.9mg, 64%) as a pale yellow powder, and a portion of the product was sampledThe product was further purified by normal phase preparative HPLC (Prep Silica OBD) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: 25 ℃, mobile phase: n-hexane: isopropanol (v: v) = 90. Purity: 99.4647 percent; IR (neat) v max ＝3132,2942,2885,1702,1636,1597,1505,1405,1332,1127,1066,944,866,738cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.59(s,1H),10.98(s,1H),10.15(s,1H),8.08(d,J＝8.4Hz,1H),7.65(d,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.33(s,1H),7.16(s,1H),7.05(s,1H),6.93(d,J＝8.4Hz,1H),3.59(t,J＝5.2Hz,1H),3.50-3.39(m,2H),2.78-2.71(m,1H),2.61-2.54(m,1H),1.61-1.41(m,2H)； 13 C NMR(150MHz,Acetone-d 6 )δ186.7,184.7,161.7,159.5,136.3(q,J＝32.2Hz),135.3(q,J＝32.2Hz),134.0,132.5,132.3,131.9,125.9,125.8,125.4,124.4(q,J＝270Hz),124.4,123.4(q,J＝270Hz),122.4,122.1,120.8,116.5,116.0,115.5,114.5,110.7,60.1,33.3,33.0；HRMS(m/z):[M-H] - calcd.For C 27 H 16 Cl 3 F 6 N 2 O 5 S - ,698.9755；found,698.9742。
Compounds 3-32 (40.0mg, 57.1. Mu. Mol,1.0 eq) and m-chloroperoxybenzoic acid (98.4mg, 571. Mu. Mol,10.0 eq) were dissolved in 4mL of dry dichloromethane, the reaction was carried out overnight at 25 ℃ and the LC-MS detection on the next morning indicated that the reaction of the starting materials was complete, and saturated Na was added to the reaction mixture 2 S 2 O 3 The aqueous solution was quenched, extracted with dichloromethane (4 × 8 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by Silica gel column chromatography (petroleum ether: acetone (v: v) = 3-1 TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: 25 ℃, n-hexane: isopropanol (v: v) = 90. Purity =98.6657%; IR (neat): v max ＝3457,3057,2971,2891,1638,1607,1505,1404,1327,1157,1117,1064,944,784,735cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ12.42(s,1H),10.79(s,1H),9.97(s,1H),7.95(d,J＝8.0Hz,1H),7.69(d,J＝8.0Hz,1H),7.33(s,1H),7.31(s,1H),7.18(s,1H),7.12(s,1H),7.11(d,J＝4.0Hz,1H),3.86(t,J＝4.8Hz,1H),3.61(q,J＝5.6Hz,2H),3.44–3.24(m,2H),1.94–1.83(m,2H)； 13 C NMR(100MHz,Acetone-d 6 )δ188.1,184.5,161.5,159.0,136.8(q,J＝32.4Hz),135.3(q,J＝32.3Hz),134.5,134.2,131.8,130.6,126.8,126.5,124.8,124.4(q,J＝271Hz),124.4,124.3(q,J＝271Hz),121.3,121.1,119.5,116.6,116.5,115.7,114.7,112.7,60.2,54.8,26.2；HRMS(m/z):[M-H] - calcd.For C 27 H 16 Cl 3 F 6 N 2 O 7 S - ,730.9653；found,730.9647。
EXAMPLE 23 preparation of Compounds 3-26
Figure BDA0003265949310000341
Compound 3-21 (100mg, 0.144mmol, 1.0eq) was dissolved in 5mL of acetonitrile, and K was added 2 CO 3 (99.4mg, 0.720mmol, 5.0eq), ethyl bromoacetate (20.0. Mu.L, 0.173mmol, 1.2eq), stirring at 25 ℃ for 4h, TLC to show completion of the reaction, and saturated NH was added to the reaction mixture 4 Aqueous Cl solution was quenched. Extraction with ethyl acetate (3 × 15 mL), drying over anhydrous sodium sulfate, filtration and concentration gave a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate (v: v) = 5) to give compound 3-33 (76.5mg, 68%) as a yellow powder. IR (neat) v max ＝2927,2854.,1747,1636,1595,1481,1334,1201,1170,1131,1067.,863,709cm –1 ； 1 H NMR(400MHz,Acetone-d 6 )δ11.01(s,1H),8.09(d,J＝8.0Hz,1H),7.83(d,J＝12.0Hz,1H),7.33(d,J＝8.0Hz,1H),7.30(s,1H),7.22(s,1H),6.99–6.97(m,1H),6.94(s,1H),4.13(q,J＝8Hz,2H),3.19(s,2H),2.98-2.97(m,2H),2.65–2.62(m,2H),2.46–2.41(m,4H),1.23(t,J＝12Hz,3H)； 13 C NMR(150MHz,Acetone-d 6 )δ185.8,185.8,170.4,161.6,160.9,144.4,136.0(q,J＝30Hz),135.8(q,J＝30Hz),133.6,132.9,125.9,124.8,124.6,124.5(q,J＝270Hz),124.3(q,J＝270Hz),123.9,123.9,120.8,116.4,116.3,116.0,115.2,114.9,110.6,106.6,60.7,59.5,53.1,53.1,50.8,50.8,14.6；HRMS(m/z):[M-H] - calcd.For C 32 H 24 Cl 3 F 6 N 4 O 6 - ,779.0671；found,779.0657。
Dissolving the compound 3-33 (100mg, 0.128mmol, 1.0eq) in 8mL of dichloromethane, adding 1.5mL of 1M NaOH aqueous solution, reacting at 25 ℃ for 2h, showing by LC-MS that the raw material is completely reacted, adding dilute hydrochloric acid to quench the reaction, extracting with dichloromethane liquid (3 × 15 mL), combining organic phases, drying with anhydrous sodium sulfate, carrying out suction filtration and concentration to obtain a crude product, purifying the crude product by silica gel column chromatography (dichloromethane: methanol (v: v) = 10) to obtain a yellow powder compound 3-26 (54.0mg, 56%), taking 30mg of the yellow powder compound, adding 5mL of acetone to recrystallize, obtaining 7mg of a light yellow pure compound 3-26 and 22mg of a mother solution, collecting a spectrum and determining purity data. Purity of the pure product: 99.2646%; IR (neat): v max ＝2923,2854,1600,1333,1259,1173,1020,798cm –1 ； 1 H NMR(600MHz,Methanol-d 4 )δ7.67(d,J＝12.0Hz,1H),7.58(d,J＝12.0Hz,1H),7.24-7.23(m,2H),7.14(s,1H),6.99(d,J＝12.0Hz,1H),6.65(s,1H),3.56(s,2H),3.31-3.28(m,2H),3.13–3.07(m,6H)； 13 C NMR(150MHz,Methanol-d 4 )δ185.6,184.8,169.7,159.2,158.8,143.2,135.8(q,J＝30Hz),135.4(q,J＝30Hz),132.5,132.2,128.4,128.1,127.3,125.8,125.2,125.0(q,J＝270Hz),124.8(q,J＝270Hz),123.7,121.3,116.8,116.5,114.7,114.4,111.5,108.0,59.8,53.9,53.9,48.6,48.6；HRMS(m/z):[M-H] - calcd.For C 30 H 20 Cl 3 F 6 N 4 O 6 - ,751.0358；found,751.0349。
EXAMPLE 24 preparation of Compounds 3-27
Figure BDA0003265949310000351
Preparation of crude Compounds 3-34 by reference to general Synthesis procedure, starting with Compound 2 (30.0 mg, 46.4. Mu. Mol,1.0 eq), K 2 CO 3 (52.0 mg, 464. Mu. Mol,10.0 eq) as base, ethylthioglycolate (152. Mu.L, 1.39mmol,30.0 eq) as nucleophile, dissolved in a mixture of 3mL dry acetonitrile and 0.3mL DMFThe solvent was stirred at room temperature overnight and then reacted at 74 ℃ until the reaction was complete. The crude product was purified by Silica gel column chromatography (petroleum ether: ethyl acetate (v: v) =8: 1-6) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: n-hexane: isopropanol (v: v) = 95. Purity: 98.6505%; IR (neat) v max ＝3210,2981,1732,1710,1637,1598,1505,1407,1333,1170,1127,1066,945,866,789cm –1 ；
1 H NMR(400MHz,Acetone-d 6 )δ10.96(s,1H),8.05(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.35(d,J＝8.8Hz,1H),7.33(s,1H),7.16(s,1H),7.05(s,1H),6.96(d,J＝8.4Hz,1H),4.02(q,J＝6.8Hz,2H),3.33(q,J＝16.0Hz,2H),1.16(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,Acetone-d 6 )δ186.8,184.5,168.6,161.8,159.3,136.4(q,J＝48.45Hz),135.3(q,J＝48.45Hz),134.0,132.8,131.9,130.7,125.8,125.6,122.5,124.4(q,J＝270.6Hz),124.3(q,J＝270.5Hz),124.3,122.8,121.7,120.8,116.5,116.1,115.5,114.6,110.9,62.1,37.3,14.3；HRMS(m/z):[M-H] - calcd.For C 28 H 16 Cl 3 F 6 N 2 O 6 S - ,726.9704；found,726.9692。
Compound 3-34 (39.9mg, 54.9 μmol,1.0 eq) was dissolved in 2mL of dichloromethane, 0.3ml of 2N NaOH aqueous solution was added thereto, reaction was carried out at 25 ℃ for 2h, lc-MS showed completion of the starting material reaction, pH =2-3 was adjusted with dilute hydrochloric acid, extraction was carried out several times with a mixed solution of chloroform: isopropanol =10 TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: n-hexane: isopropanol (v: v) = 85-20-75) purification for profile collection and assay purity data. Purity:99.2190％；IR:(neat):ν max ＝3164,2974,1709,1638,1595,1505,1407,1333,1129,1066,988,866cm –1 ； 1 H NMR(600MHz,Acetone-d 6 )δ12.54(s,1H),10.97(s,1H),10.11(s,1H),8.03(d,J＝7.8Hz,1H),7.63(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),7.32(s,1H),7.17(s,1H),7.03(s,1H),6.96(d,J＝8.4Hz,1H),3.42(dd,J＝44.4,15.0Hz,2H)； 13 C NMR(150MHz,Acetone-d 6 )δ186.8,184.4,169.5,161.8,159.2,136.4(q,J＝32.25Hz),135.2(q,J＝32.25Hz),134.0,132.7,131.8,131.2,127.1,125.9,125.7,124.4(q,J＝271.5Hz),124.4(q,J＝270Hz),124.3,122.5,121.8,120.7,116.4,116.1,115.5,114.5,111.1,37.3；HRMS(m/z):[M-H] - calcd.For C 26 H 12 Cl 3 F 6 N 2 O 6 S - ,698.9391；found,698.9344。
EXAMPLE 25 preparation of Compounds 3-28
Figure BDA0003265949310000371
Compound 2 (20.0 mg, 31.0. Mu. Mol,1.0 eq) was used as the reaction initiator, K 2 CO 3 (52.0 mg, 310. Mu. Mol,10.0 eq) as a base, 3-mercaptopropionic acid (54.0. Mu.L, 620. Mu. Mol,20.0 eq) as a nucleophile, and DMF as a solvent were prepared to give the crude product by reference to general synthetic procedures. The crude product was purified by Silica gel column chromatography (dichloromethane: methanol (v: v) =45 1-40) TM 5 μm, 30X 100mm column, flow rate: 25mL/min, temperature: 25 ℃, n-hexane: isopropanol (v: v) =90: 96.3462%; IR (neat) v max ＝3245,2922,2854,1637,1599,1408,1335,1172,1133,1067,946,866,784cm –1 ； 1 H NMR(600MHz,Acetone-d 6 )δ10.94(s,1H),8.07(d,J＝8.4Hz,1H),7.66(d,J＝7.8Hz,1H),7.34(d,J＝8.4Hz,1H),7.31(s,1H),7.14(s,1H),7.04(s,1H),6.94(d,J＝7.8Hz,1H),2.86-2.70(m,2H),2.46-2.34(m,2H)； 13 C NMR(100MHz,Acetone-d 6 )δ186.7,184.3,172.4,161.6,159.2,136.2(q,J＝32.2Hz),135.1(q,J＝32.2Hz),134.1,132.0,131.9,128.5,126.3,126.0,125.7,124.6,123.1,122.4,121.8,120.9,120.4,116.5,115.9,115.4,114.7,110.8,34.6,31.5；HRMS(m/z):[M-H] - calcd.For C 27 H 14 Cl 3 F 6 N 2 O 6 S - ,712.9548；found,712.9549。
Example 26 in vitro antibacterial Activity test
The experimental strains used were: methicillin-resistant staphylococcus aureus (MRSA) 8 strains (all the strains are clinical isolated pathogenic bacteria collected in 2016-2018 Chengdu area, and are identified by a VITEK-60 automatic microorganism identifier and then re-identified by a conventional method in a laboratory in a collection unit); and (3) quality control of the strains: staphylococcus aureus ATCC29213 (commercially available, stored in the laboratory).
Culture conditions and bacterial liquid preparation: conventional MH medium (purchased from Beijing Oobo Star Biotechnology Limited liability company, lot number: 20180216, formulation: peptone 1%, beef powder 0.3%, naCl 0.5%, agar powder 1.2%), incubating at 35-37 deg.C for 24h, separating and purifying single colony of each bacterium by agar plate-drawing method before experiment, culturing at 37 deg.C, picking single colony, and preparing about 0.5 McLee unit (about 10) by McLeeb method 8 CFU/ml), and diluting the suspension by 100 times to obtain final concentration of about 10 6 CFU/ml。。
The experimental method comprises the following steps: the two-fold dilution of agar recommended by the national Committee for standardization of Clinical laboratories (Clinical and Laboratory Standards Institute CLSI) was used.
The concentration of the experimental drug is generally set to be within the range of 0.008-128 mu g/ml by two-fold dilution, and is properly adjusted according to the experimental result. The test drugs in this experiment included the compounds prepared in examples 1-25 of this invention, compound 2, and vancomycin. The compounds prepared in examples 1-25 of the present invention and compound 2 were made up in DMSO at a concentration of 1.92mg/ml for use immediately before use. Vancomycin is vancomycin hydrochloride for injection (purchased from Dalian Meiren biotechnology Co., ltd., M0208A), and is prepared into 1.92mg/ml concentration with sterile distilled water for standby use before use.
Adding 1ml of 1.92mg/ml test solution into a sterile plate, adding 14ml of melted MH culture medium at 50 ℃, uniformly mixing, then diluting twice to ensure that the final concentration of the medicaments in each plate is 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.015 and 0.008 mu g/ml in sequence, and cooling. Inoculating diluted bacteria liquid on the prepared MH agar plate by using a multi-point inoculator, wherein the inoculation amount of each point is about 10 4 And (3) covering the CFU with a dish cover, putting the CFU into an incubator for culture according to the culture condition of 7.3, and observing by naked eyes after the culture is finished, wherein the lowest sample concentration without bacterial growth in the dish is the Minimum Inhibitory Concentration (MIC). In each experiment, a standard strain is used as a quality control strain, and a blank bacteria control without any sample and a vehicle bacteria control with DMSO are set. The results are shown in Table 1.
TABLE 1 results of antimicrobial tests of the compounds against clinically isolated MRSA strains
Figure BDA0003265949310000381
Figure BDA0003265949310000391
The results show that the compounds 3-4 to 3-28 prepared in the examples of the present invention have strong antibacterial activity against methicillin-resistant staphylococcus aureus (MRSA).
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention and not to limit it; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art will understand that: modifications to the specific embodiments of the invention or equivalent substitutions for parts of the technical features may be made; without departing from the spirit of the present invention, it is intended to cover all aspects of the invention as defined by the appended claims.

Claims (26)

1. A compound represented by the general formula 3, a racemate thereof or a pharmaceutically acceptable salt thereof,
Figure FDA0003866427550000011
wherein, the first and the second end of the pipe are connected with each other,
1) X is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is C 1-6 Alkyl radical, by R 3 Substituted C 1-6 Alkyl, pyrido [3,2-D][1,3]Thiazol-2-yl, thiophen-2-yl, benzothiazol-2-yl, or thiazolo [4,5-b ]]Pyridin-2-yl, R 3 Is hydroxy, halogen, carboxy or amino; or alternatively
2) X is an N atom, R 1 And R 2 Each independently is C 1-6 Alkyl, or R 1 And R 2 Form, together with the N atom to which they are attached, a morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, piperazinyl, 1,2, 4-triazolyl, 4-oxo-1, 5-dihydro-pyrazolo [3,4-d]Pyrimidin-4-yl or piperidinyl, said morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, piperazinyl, 1,2, 4-triazolyl, 4-oxo-1, 5-dihydro-pyrazolo [3,4-d ]]Pyrimidin-4-yl or piperidinyl optionally substituted with R 4 Substituted, R 4 Is hydroxy, halogen, C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, amino-substituted C 1-6 Alkyl, hydroxy-substituted C 1-6 Alkyl, benzyl, phenyl or pyridin-4-yl.
2. The compound of claim 1, racemate or a pharmaceutically acceptable salt thereof, wherein:
R 4 is hydroxy, halogen, C 1-4 Alkyl, carboxyl substituted C 1-4 Alkyl, amino-substituted C 1-4 Alkyl, hydroxy-substituted C 1-4 Alkyl, benzyl, phenyl or pyridin-4-yl.
3. The compound of claim 1, racemate or a pharmaceutically acceptable salt thereof, wherein: r 3 Is carboxyl, amino or hydroxyl.
4. The compound of claim 1, racemate or a pharmaceutically acceptable salt thereof, wherein: r 3 Is carboxyl or amino.
5. The compound of claim 1, racemate or a pharmaceutically acceptable salt thereof, wherein: r is 4 Is C 1-4 Alkyl, carboxy substituted C 1-4 Alkyl, benzyl or pyridin-4-yl.
6. The compound of claim 1, racemate or a pharmaceutically acceptable salt thereof, wherein: r 4 Is benzyl, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, carboxymethyl, carboxyethyl, carboxypropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, phenyl or pyridin-4-yl.
7. The compound of claim 1, racemate or a pharmaceutically acceptable salt thereof, wherein: r 4 Is benzyl, isobutyl, methyl, carboxymethyl or pyridin-4-yl.
8. The compound of claim 1, 3 or 4, racemate or a pharmaceutically acceptable salt thereof, wherein:
x is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is C 1-4 Alkyl radical, by R 3 Substituted C 1-4 Alkyl, pyrido [3,2-D][1,3]Thiazol-2-yl, thiophen-2-yl, benzothiazol-2-yl, or thiazolo [4,5-b ]]Pyridin-2-yl, R 3 As defined in claim 1, 3 or 4.
9. The compound of claim 1, 3 or 4, racemate or a pharmaceutically acceptable salt thereof, wherein: x is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is pyrido [3,2-D][1,3]Thiazol-2-yl, thiophen-2-yl, benzothiazol-2-yl, thiazolo [4,5-b ]]Pyridin-2-yl or quiltR 3 Substituted C 1-6 Alkyl radical, R 3 As defined in claim 1, 3 or 4.
10. The compound of claim 1, 3 or 4, racemate or a pharmaceutically acceptable salt thereof, wherein: x is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is pyrido [3,2-D][1,3]Thiazol-2-yl, thiophen-2-yl, benzothiazol-2-yl, thiazolo [4,5-b ]]Pyridin-2-yl or by R 3 Substituted C 1-4 Alkyl radical, R 3 As defined in claim 1, 3 or 4.
11. The compound of claim 1, 3 or 4, racemate or a pharmaceutically acceptable salt thereof, wherein: x is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is methyl, ethyl, n-propyl, n-butyl, pyrido [3,2-D ]][1,3]Thiazol-2-yl, thiophen-2-yl, benzothiazol-2-yl, thiazolo [4,5-b ]]Pyridin-2-yl radical of formula (I) 3 Substituted methyl, by R 3 Substituted ethyl radical, by R 3 Substituted n-propyl or by R 3 Substituted n-butyl, R 3 As defined in claim 1, 3 or 4.
12. The compound of claim 1, 3 or 4, racemate or a pharmaceutically acceptable salt thereof, wherein: x is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is pyrido [3,2-D][1,3]Thiazol-2-yl, thiophen-2-yl, benzothiazol-2-yl, thiazolo [4,5-b ]]Pyridin-2-yl radical of formula (I) 3 Substituted methyl, by R 3 Substituted ethyl radical, by R 3 Substituted n-propyl or by R 3 Substituted n-butyl, R 3 As defined in claim 1, 3 or 4.
13. The compound of claim 1, racemate or a pharmaceutically acceptable salt thereof, wherein: x is an S atom or-S (O) 2 -，R 1 Is absent, R 2 Is pyrido [3,2-D][1,3]Thiazol-2-yl, thiophen-2-yl, benzothiazol-2-yl, thiazolo [4,5-b ]]Pyridin-2-yl, 3-aminopropyl, 2-hydroxyethyl, 3-hydroxypropyl, carboxymethyl or carboxyethyl.
14. The compound of claim 1,2, 5, 6 or 7, racemate or a pharmaceutically acceptable salt thereof, wherein:
x is an N atom, R 1 And R 2 Each independently is C 1-4 Alkyl, or R 1 And R 2 Form, together with the N atom to which they are attached, a morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, piperazinyl, 1,2, 4-triazolyl, 4-oxo-1, 5-dihydro-pyrazolo [3,4-d]Pyrimidin-4-yl or piperidinyl, said morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, piperazinyl, 1,2, 4-triazolyl, 4-oxo-1, 5-dihydro-pyrazolo [3,4-d]Pyrimidin-4-yl or piperidinyl optionally substituted with R 4 Substituted, R 4 As defined in claim 1,2, 5, 6 or 7.
15. The compound of claim 1,2, 5, 6 or 7, racemate or a pharmaceutically acceptable salt thereof, wherein: x is an N atom, R 1 And R 2 Each independently being methyl, ethyl, n-propyl, n-butyl, or R 1 And R 2 Form, together with the N atom to which they are attached, a morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, piperazinyl, 1,2, 4-triazolyl, 4-oxo-1, 5-dihydro-pyrazolo [3,4-d]Pyrimidin-4-yl or piperidinyl, said morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, piperazinyl, 1,2, 4-triazolyl, 4-oxo-1, 5-dihydro-pyrazolo [3,4-d]Pyrimidin-4-yl or piperidinyl optionally substituted with R 4 Substituted, R 4 As defined in claim 1,2, 5, 6 or 7.
16. The compound of claim 1, racemate or a pharmaceutically acceptable salt thereof, wherein: x is an N atom, R 1 And R 2 Each independently being methyl, or R 1 And R 2 Form a morpholinyl, tetrahydropyrrolyl, or,Thiomorpholinyl, 1-benzylpiperazinyl, 1,2, 4-triazol-1-yl, piperidinyl, N-isobutylpiperazinyl, N-methylpiperazinyl, piperazinyl, 1- (4-pyridinyl) piperazinyl, 4-oxo-1, 5-dihydro-pyrazolo [3,4-d]Pyrimidin-4-yl or N- (carboxymethyl) piperidinyl.
17. The compound of claim 1, racemate or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
Figure FDA0003866427550000031
Figure FDA0003866427550000041
Figure FDA0003866427550000051
18. a pharmaceutical composition comprising at least one compound, racemate or pharmaceutically acceptable salt according to any one of claims 1 to 17, and one or more pharmaceutically acceptable carriers or excipients.
19. A process for preparing a compound of formula 3, racemate or pharmaceutically acceptable salt according to any one of claims 1 to 17, comprising:
reacting compound 2 with a nucleophile represented by formula 4 in an aprotic solvent,
Figure FDA0003866427550000052
wherein R is 1 And R 2 Is as defined in any one of claims 1 to 17.
20. The method of claim 19, wherein compound 2 is reacted with a nucleophile represented by formula 4 in an aprotic solvent and in the presence of a base.
21. The process of claim 20, wherein the aprotic solvent is selected from dichloromethane, chloroform, acetonitrile, dimethylsulfoxide, N-dimethylformamide, N-diethylformamide, N-methylpyrrolidinone, tetrahydrofuran, 2-methyltetrahydrofuran, or any combination thereof.
22. The process of claim 20, wherein the base is potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, triethylamine, or pyridine.
23. The process of claim 22, wherein the base is potassium carbonate.
24. Use of a compound according to any one of claims 1 to 17, a racemate or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment of bacterial infections or diseases caused by bacterial infections.
25. The use of claim 24, wherein the bacterial infection is a methicillin-resistant staphylococcus aureus infection and the disease caused by the bacterial infection is a methicillin-resistant staphylococcus aureus infection.
26. The use of claim 25, wherein the disease caused by methicillin-resistant staphylococcus aureus infection is a skin infection or a soft tissue infection.
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