CN117126153A - New coronavirus inhibitor, preparation method, pharmaceutical composition and application thereof - Google Patents

New coronavirus inhibitor, preparation method, pharmaceutical composition and application thereof Download PDF

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CN117126153A
CN117126153A CN202210545003.8A CN202210545003A CN117126153A CN 117126153 A CN117126153 A CN 117126153A CN 202210545003 A CN202210545003 A CN 202210545003A CN 117126153 A CN117126153 A CN 117126153A
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hydrogen
pharmaceutically acceptable
added
independently selected
halogen
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冯文化
杨柳
马春英
郑艺璇
李磊
李小宝
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Institute of Materia Medica of CAMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The application belongs to the technical field of medicines and mainly relates to coronavirus M pro Protease inhibitors, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, in particular for the treatment or prophylaxis of coronavirus infections.

Description

New coronavirus inhibitor, preparation method, pharmaceutical composition and application thereof
Technical Field
The application belongs to the technical field of medicines and mainly relates to coronavirus M pro Protease inhibitors, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, in particular for the treatment or prophylaxis of coronavirus infections.
Background
Based on the high prevalence, broad distribution and rapid variability of coronaviruses. Vaccines have certain limitations in front of evolving coronaviruses, and therefore, there is an urgent need to develop highly specific and potent drugs against coronavirus targets, which are of great importance for the treatment and prevention of coronavirus epidemics and recurrence.
Coronaviruses are subfamilies of the orthocoronaviridae that belong to the order of the order coronaviridae. The coronavirus genome comprises 6-12 Open Reading Frames (ORFs), the first of which (ORF 1 a/b) is used to directly translate two polyproteins pp1a and pp1ab, which are cleaved by 3CL protease (M pro ) Functionalized into 16 nonstructural proteins (nsps). The protease is also called M pro Or papain-like protease (PLP). These functional nsp4 to nsp16 are linked by M pro Cleavage releases important roles responsible for replication and transcription of the viral genome, and other roles such as protein translation, cleavage, modification, and nucleic acid synthesis. Thus, M is suppressed pro Can effectively block viral RNA replication and transcription, and further block viral proliferation.
And the comparison of gene sequences shows that M pro of three coronaviruses of SARS-CoV-2, SARS-CoV and MERS-CoV show high structural similarity and conservation. The amino acid sequence of M pro of the three shows that the similarity can be up to 96.1%. M without homology in human pro Proteases, which make M pro The protease becomes an ideal specific antiviral target spot and can be used for developing anti-coronavirus medicaments capable of inhibiting proliferation of various coronaviruses.
However, no available M has been reported so far pro The aim of the present inventors was therefore to propose coronavirus M with good activity pro Protease inhibitors and are useful in the treatment or prevention of coronavirus infections.
Disclosure of Invention
The object of the present application is to develop a medicament for the treatment or prevention of novel coronavirus infections.
The present inventors have found, through intensive studies, that N1- ((pyridinyl-3-) thiazol-4) -phenylenediamine derivatives of the following general formula I have inhibitory activity against new coronaviruses and are less toxic and thus can be used as a medicament for treating or preventing coronavirus infection.
To this end, a first aspect of the application relates to compounds of the general formula I and stereoisomers thereof, and pharmaceutically acceptable salts thereof
1. A compound represented by the general formula (I) and stereoisomers thereof or pharmaceutically acceptable salts thereof,
R 1 independently selected from hydrogen, halogen or C 1-10 Straight-chain or branched alkyl, trifluoromethyl or C 1-10 Linear or branched alkoxy groups;
R 2 independently selected from hydrogen, halogen or C 1-10 Straight-chain or branched alkyl, trifluoromethyl or C 1-10 Linear or branched alkoxy groups;
R 3 independently selected from hydrogen, halogen or C 1-10 Straight-chain or branched alkyl, trifluoromethyl or C 1-10 Straight or branched chain alkoxy groups.
R 4 Independently selected from hydrogen, halogen or C 1-10 Straight-chain or branched alkyl, trifluoromethyl or C 1-10 Linear or branched alkoxy groups;
R 5 independently selected from
a) Substituted or unsubstituted C 1-10 A linear or branched alkyl group, said substituent being selected from I, cl, br or F;
b)-CO-R 6 a group, wherein R is 6 Independently selected from H or phenyl optionally substituted with at least one heteroatom, six membered heteroaryl, or phenyl substituted with at least one five or six membered heterocyclyl, six membered heteroaryl.
2. A compound according to claim 1, wherein the compound is preferably,
when R is 1 Is methyl, R 2 、R 3 、R 4 Is hydrogen, R 5 Among the specific compounds having the meaning described in b) above,
R 6 the radicals being selected from
(i) Phenyl or substituted variants thereof, bearing any combination of one or more substituents at any one ring position, e.g. halogen, C 1-10 Alkyl, trifluoromethyl and C 1-10 An alkoxy group;
(ii)R 7 、R 8 substituted aminomethylphenyl wherein R is 7 、R 8 Selected from aryl groups, e.g. phenyl groups, or substituted variants thereof, bearing any combination of one or more substituents, e.g. halogen, C, at any ring position 1-10 Alkyl, trifluoromethyl and C 1-10 An alkoxy group; heteroaryl, e.g. 2, 3 or 4-pyridyl, which may additionally bear any combination of one or more substituents, e.g. halogen, C 1-10 Alkyl, trifluoromethyl and C 1-10 An alkoxy group.
3. A compound according to claim 2, and stereoisomers thereof, and pharmaceutically acceptable salts thereof, more preferably,
when R is 1 Is methyl, R 2 、R 3 、R 4 Is hydrogen, R 5 In the particular compounds having the meaning described in b) above, R 6 Independently selected from hydrogen, 4-tert-butylphenyl, 4-tert-butyl-3-methoxyphenyl, 2-morpholinophenyl, 2-morpholino-4-pyridinyl;
when R is 1 Is methyl, R 2 、R 3 、R 4 Is hydrogen, R 5 In the particular compounds having the meaning described in b) above, R 6 In particular compounds whose radicals have the meanings described in (iii) above,
R 7 、R 8 independently selected from hydrogen, 3, 5-dimethylmorpholinyl, 4- (furan-2-carbonyl) piperazin-1-yl, 4-methanesulfonyl) piperazinyl, 4-formylpiperazinyl, 4-phenylbutyryl, morpholinyl;
4. a compound according to claim 3, most preferably,
a further aspect of the application relates to a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound according to any one of the first aspect of the application and stereoisomers thereof, pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.
The application also provides the use of a compound according to any one of the first aspect of the application, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of the eighth aspect of the application, in the manufacture of a medicament for the treatment or prophylaxis of a coronavirus infection. Among them, coronaviruses include HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory virus coronavirus (MERS) novel coronavirus SARS-CoV-2.
Summary of The Invention
Various aspects and features of the application are described further below.
All documents cited herein are incorporated by reference in their entirety and are incorporated by reference herein to the extent they are not inconsistent with this application. Furthermore, various terms and phrases used herein have a common meaning known to those skilled in the art, and even though they are still intended to be described and explained in greater detail herein, the terms and phrases used herein should not be construed to be inconsistent with the ordinary meaning in the sense of the present application. The following are definitions of various terms used in the present application, which are applicable to terms used throughout the specification of the present application unless otherwise specified in the specific context.
As used herein, the term "alkyl" refers to an alkyl group having the indicated number of carbon atoms, which is a straight or branched chain alkyl group, and which may include its sub-groups, e.g., where "C" is mentioned 1-10 Alkyl "when it is alsoMay include C 1-10 Alkyl, C 2-8 Alkyl, C 1-7 Alkyl groups and the like, and specific groups such as n-hexyl, n-heptyl, octyl, decyl, and the like.
The term "stereoisomer" is well known in the art in reference to a given compound and refers to another compound having the same formula, wherein the atoms constituting the other compound are spatially oriented in a different manner, but wherein the atoms of the other compound are identical to the atoms of the given compound in atomic and other atomic junctions (e.g., enantiomers, diastereomers and geometric isomers), see, e.g., morrison and Boyde Organic Chemistry,1983, 4 th edition, allnnandBacon. Boston, mass, p.123.
The application is described as "C 1-10 Alkyl "is a straight or branched chain alkyl of 1 to 10 carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, sec-butyl, pentyl, neopentyl, hexyl and the like.
"C" as described in the present application 1-10 Alkoxy "is a straight or branched chain alkoxy of 1 to 10 carbon atoms and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.
"halogen" as used herein includes fluorine, chlorine, bromine, iodine atoms.
Said aryl, aryl C 1-6 Alkyl, C 3-8 Cycloalkyl, heteromonocyclic group C 1-6 Alkyl, bridged ring radicals or R 9 And R is 10 The amino atom to which it is attached forming a heteromonocyclic group may be further substituted by a substituent selected from the group consisting of hydroxy, amino, carboxyl, halogen, mercapto, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 1-6 Alkanoyl, di (C) 1-6 Alkyl) amino, C 1-6 Alkylamino group C 1-6 Alkyl, C 1-6 Alkylcarbonyl, C 1-6 Alkylcarbonyloxy, C 1-6 Alkoxycarbonyl group, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di (C) 1-6 Alkyl) sulfamoyl, sulfamoyl C 1-6 Alkyl, C 1-6 Alkylamido C 1-6 Alkylamino group C 1-6 Alkanoyl, di (C) 1-6 Alkyl) amino C 1-6 Alkanoyl, amino C 1-6 Alkanoyl, amino C 1-6 Alkylacyl C 1-6 Alkyl or C substituted by hydroxy, amino, halogen 1-6 Alkyl or C 1-6 An alkoxy group.
With respect to any of the above groups containing one or more substituents, it will of course be appreciated that such groups do not include any substitution or substitution patterns that are stereoisomers and/or that are not synthetically feasible. Furthermore, the compounds of the present application include all stereochemical isomers resulting from the substitution of these compounds.
"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted" means that one group may or may not be substituted with the described substituent.
Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases include, but are not limited to: sodium, potassium, ammonium lithium, calcium and magnesium salts. Salts from organic bases include, but are not limited to; primary, secondary and tertiary amines, substituted amines (including naturally substituted amines), and salts of cyclic amines, including: isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine ethylenediamine, glucosamine, N-alkyl glucosamine, theobromine purine, piperazine, piperidine and N-ethyl pyridine. It will also be appreciated that other carboxylic acid derivatives will use the practice of the present application, for example, carboxylic acid amides, including formamide, lower alkyl formamide, di (lower alkyl) formamide, and the like.
Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts from mineral acids include: nicotinic acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts from organic acids include: acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
The compounds of the application generally comprise one or more chiral centers. The present application is therefore intended to include racemic compounds, diastereomers, enantiomers and mixtures enriched in one or more stereoisomers. The scope of the application as described and claimed includes the racemic forms of the compounds as well as the individual enantiomers and non-racemic compounds thereof.
As used herein, the term "effective amount" refers to the amount of a drug that achieves treatment and/or prevention of a disease or disorder described herein in a subject.
The term "pharmaceutical composition" as described herein, which may also refer to "composition", may be used to effect treatment and/or prophylaxis of a disease or condition described herein in a subject, particularly a mammal.
As used herein, the term "subject" may refer to a patient or other animal, particularly a mammal, such as a human, dog, monkey, cow, horse, etc., who receives a compound of formula I of the application or a pharmaceutical composition thereof to treat and/or prevent a disease or condition described herein.
As used herein, the term "disease and/or disorder" refers to a physical state of the subject that is associated with the disease and/or disorder of the present application. For example, the diseases and/or conditions of the present application may refer to a physical condition, such as a condition that is inflammatory in the lung, or a condition, such as a condition that manifests as pneumonia. The physical and disease states are not distinguished herein, or may be referred to interchangeably, e.g. "pulmonary inflammation" and "pneumonia".
As described herein, "%" refers to weight/weight percent, particularly where solid materials are described, unless otherwise indicated. Of course, in describing a liquid substance, the "%" may refer to a weight/volume percentage (in the case of a solid being dissolved in a liquid) or may refer to a volume/volume percentage (in the case of a liquid being dissolved in a liquid).
The term "pharmaceutically acceptable" as used herein, for example when describing a "pharmaceutically acceptable salt", means that the salt is not only physiologically acceptable to the subject, but may also refer to synthetic materials of pharmaceutical use, such as salts formed as intermediates in the preparation of chiral separations, which, although not directly administered to the subject, may still play a role in obtaining the end products of the present application.
In a further aspect the application also relates to pharmaceutical compositions comprising the compounds of the application as active ingredient. The pharmaceutical compositions may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use may be made by combining the compounds of the application with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present application are typically present in the pharmaceutical compositions thereof in an amount of 0.1 to 95% by weight.
The compounds of the present application or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory, cutaneous, vaginal, rectal, etc.
The dosage form may be a liquid, solid or semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloid solution) emulsion (including o/w type, w/o type and compound emulsion), suspension, injection (including water injection, powder injection and transfusion) eye drops, nasal drops, lotion, liniment and the like, and the solid dosage forms can be tablets (including common tablets, enteric-coated tablets, buccal tablet dispersible tablets, chewable tablets, effervescent tablets and orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric-coated capsules), granules, powder, pellets, dripping pills, suppositories, films, patches, gas (powder) foggies, sprays and the like; the semisolid dosage form may be an ointment, gel, paste, or the like.
The compound of the application can be prepared into common preparations and also into sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For the preparation of the compounds of the present application into tablets, various excipients known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, cosolvents. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium hydrogen phosphate calcium sulfate, calcium carbonate, etc., and the wetting agent can be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, honey, dextrose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.: the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, sodium carboxymethyl cellulose, sodium bicarbonate, citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc., and the lubricant and cosolvent can be pulvis Talci, silicon dioxide, stearic acid, tartaric acid, liquid paraffin, polyethylene glycol, etc.
The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets.
In order to prepare the administration unit into a capsule, the compound of the present application as an active ingredient may be mixed with a diluent and a cosolvent, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient of the compound can be prepared into particles or pellets by mixing with a diluent, an adhesive and a disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binder wetting agents, and disintegrants used to prepare tablets of the compounds of the application may also be used dry to prepare capsules of the compounds of the application.
For the preparation of the compound of the present application into injection, water, ethanol, isopropanol, propylene glycol or their mixture may be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator commonly used in the art may be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-B-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc., and the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetic acid, etc. For example, mannitol, glucose, etc. can be added as propping agent for preparing lyophilized powder for injection.
In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.
For the purpose of administration, the drug or the pharmaceutical composition of the present application can be administered by any known administration method to enhance the therapeutic effect.
The dosage of the pharmaceutical composition of the present application may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. Generally, the compounds of the present application are suitably administered in a daily dosage range of from 0.001 to 150mg/Kg of body weight, preferably from 01 to 100mg/Kg of body weight, more preferably from 1 to 60mg/Kg of body weight and most preferably from 2 to 30mg/Kg of body weight. The above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means.
The compounds or compositions of the present application may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present application has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual circumstances.
Detailed Description
The present application will be further described by the following examples, however, the scope of the present application is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the application without departing from the spirit and scope thereof. The present application generally and/or specifically describes the materials used in the test as well as the test methods. Although many materials and methods of operation are known in the art for accomplishing the objectives of the present application, the present application will be described in as much detail herein.
For all of the following examples, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structure of the compound was determined by nuclear magnetic resonance spectroscopy (NMR) and/or Mass Spectrometry (MS) mp. was the melting point given in degrees celsius, temperature uncorrected.
The structure of the compounds was determined by nuclear magnetic resonance hydrogen spectroscopy (HMR) and Mass Spectrometry (MS). The nuclear magnetic resonance hydrogen spectral shift (8) is given in parts per million (ppm). The nuclear magnetic resonance hydrogen spectrum is measured by a Mercury-600 nuclear magnetic resonance apparatus, tritiated dimethyl sulfoxide (DMS 0-d 6) or deuterated chloroform is used as a solvent, and Tetramethylsilane (TMS) or 3- (trimethylsilyl) sodium deuteropate (TSP) is used as an internal standard.
High resolution mass spectra were determined using an Agilent1100series lc/MSD trap mass spectrometer liquid chromatography-mass spectrometer.
The electronic balance adopts a Yanasome-300 type electronic balance in Japan.
Column chromatography generally uses 200-300 mesh or 300-400 mesh silica gel as a carrier.
The anhydrous solvents were all treated by standard methods. Other reagents were all commercially available in analytical purity.
Preparation example
Synthetic route of preparation example
N- ((2-methyl-5-nitrobenzene) aminothioacyl) acetamide (MT-1)
Ammonium thiocyanate (8.855 g,0.116 mol) was dissolved in 120ml of acetone and heated under stirring in an oil bath at 40 ℃. Acetyl chloride (8.412 ml,0.118 mol) was added dropwise via a constant pressure dropping funnel, as a white solid formed. Stirring for about 30min after the completion of the dropwise addition, and TLC monitoring. Cooled to room temperature, 135ml of acetone solution in which 2-methyl-5-nitroaniline (15.0 g,0.0985 mol) was dissolved was added, and after the addition, stirred at room temperature and monitored by TLC. After the raw materials are reacted completely, 225ml of water is added to precipitate solid, and the solid is filtered by vacuum suction, washed with water and n-hexane to obtain 23.402g of pale yellow solid with the yield of 93.8%. The product is directly put into the next step for use without further purification.
1 H NMR(500MHz,DMSO-d6)δ12.38(s,1H),11.72(s,1H),8.68(s, 1H),8.07(dd,J＝8.4,2.4Hz,1H),7.59(d,J＝8.4Hz,1H),2.33(s,3H), 2.19(s,3H). 13C NMR(126MHz,DMSO)δ180.3,173.3,145.9,141.8, 138.3,131.9,121.7,121.2,24.3,18.3.
2.2-bromo-1- (pyridine-3) ethanone (MT-Br)
500ml of a single-necked flask was placed in an ice bath, 3-acetylpyridine (5 ml,0.0455 mol) was added, and 33% HBr solution (18.32 ml,0.050 mol) was added. 16.0g of pyridinium tribromide was dispersed in about 200ml of glacial acetic acid, the above solution was added in portions, and after addition, the mixture was stirred at room temperature, a yellow solid precipitated and monitored by TLC. After the raw materials are reacted completely, 500ml of diethyl ether is added and stirred for 10min, and then the mixture is subjected to vacuum filtration, diethyl ether washing and methanol washing to obtain 8.932g of white solid with the yield of 98.1%.
1 H NMR(400MHz,TFA)δ9.69(s,1H),9.30(d,J＝8.3Hz,1H), 9.23(s,1H),8.45–8.30(m,1H),4.70(s,2H). 13 C NMR(101MHz, TRIFLUOROACETIC_)δ147.1,144.5,142.7,133.1,128.0,118.5,115.7, 112.9,110.1,27.6.
N- (2-methyl-5-nitrophenyl) -4- (pyridin-3-yl) thiazol-2-amine (MT-2)
N- ((2-methyl-5-nitrobenzene) aminothioacyl) acetamide (MT-1) (3.245 g, 0.0128 mol) was taken in a 250ml bottle and K2CO3 (8.855 g,0.0640 mol) was added and the solution turned yellow and stirred for 10min. 2-bromo-1- (pyridine-3) ethanone (MT-Br) (3.0 g,0.0107 mol) was dispersed in about 10ml methanol and added dropwise to the above solution, followed by stirring at room temperature and TLC monitoring. After the raw materials are reacted completely, about 50ml of water is added into the solution, solids are separated out, and the solution is subjected to vacuum filtration, water washing and diethyl ether washing to obtain 3.12g of yellow solid with the yield of 93.4%. 1 H NMR (500MHz,DMSO-d6)δ9.76(s,1H),9.55(s,1H),9.12(s,1H),8.46(d,J ＝4.9Hz,1H),8.21(d,J＝8.0Hz,1H),7.73(d,J＝8.3Hz,1H),7.60(d,J ＝3.0Hz,1H),7.49–7.26(m,2H),2.37(s,3H). 13 C NMR(126MHz, DMSO)δ164.1,147.4,146.7,146.3,145.8,140.3,134.6,134.5,131.6, 131.0,124.9,116.7,112.9,107.7,19.0.
4.6-methyl-N1- (4- (pyridin-3-yl) thiazol-2-yl) benzene-1, 3-diamine (MT-3)
SnCl2 (1.912 g,10.0 mmol) was added to 15ml of concentrated hydrochloric acid under ice bath. N- (2-methyl-5-nitrophenyl) -4- (pyridin-3-yl) thiazol-2-amine (MT-2) (500 mg,1.60 mmol) was added to the above solution in one portion, and after the addition, the reaction was carried out at room temperature, followed by TLC monitoring. After the raw materials are reacted completely, the mixture is moved to an ice bath for cooling, solid is precipitated, the mixture is filtered under reduced pressure and washed with water, and 899mg of light green solid is obtained, and the yield is 88.6%. 1H NMR(500MHz,DMSO-d6)δ 9.16(s,1H),9.06(d,J＝2.2Hz,1H),8.46(dd,J＝4.7,1.6Hz,1H),8.18 (dt,J＝8.0,1.9Hz,1H),7.39(dd,J＝8.0,4.8Hz,1H),7.34(s,1H),7.06 (d,J＝2.3Hz,1H),6.84(d,J＝8.0Hz,1H),6.27(dd,J＝8.1,2.3Hz,1H), 4.91(s,2H),2.08(s,3H). 13 C NMR(101MHz,DMSO)δ167.1,148.7, 147.6,147.5,147.4,140.0,133.3,131.4,130.8,124.1,117.2,110.9,108.4, 104.4,17.5.
6.4- (((3R, 5S) -3, 5-dimethylmorpholino) methyl) benzoic acid (MT-G1)
In a single-necked flask, sodium triacetoxyborohydride (2.933 g,0.014 mol) was added under ice bath, and 30ml of chloroform was added. To the solution was added cis-2, 6-dimethylmorpholine (907 ul, 0.0073 mol) and p-aldehyde benzoic acid (1.0 g,0.0067 mol). After the addition, the mixture was stirred overnight at room temperature and monitored by TLC. After the completion of the reaction, water was added, pH was adjusted to 7 with sodium hydrogencarbonate solution, the aqueous layer was extracted three times with ethyl acetate, pH was then adjusted to acidity, extraction was performed with n-butanol, concentration by rotary evaporation, and filtration to give 750mg of a white solid with a yield of 45.2%. 1 H NMR(500MHz, Methanol-d4)δ8.03(d,J＝7.8Hz,2H),7.50(d,J＝7.9Hz,2H),3.76 (d,J＝8.0Hz,5H),3.00–2.77(m,2H),1.99(t,J＝10.9Hz,2H),1.16(d, J＝6.4Hz,7H). 13 C NMR(126MHz,Methanol-d4)δ169.3,140.1,131.7, 129.4,71.0,61.7,58.3,17.8.
7.4- (((3R, 5S) -3, 5-Dimethylmorpholino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) thiazol-2-yl) amino) phenyl) benzamide (MT-Z1)
In a two-necked flask, 4- (1-methyl-2-piperazinyl) methylbenzoic acid (200 mg,0.65 mmol) was charged under argon, and 8ml of methylene chloride, triethylamine (194.54 ul,1.40 mmo) was added via syringel) was added with thionyl chloride (70.8 ul,0.976 mmol) and a solid was formed, and the reaction was stirred at room temperature for 1h. Another two-necked flask was charged with 6-methyl-N1- (4- (3-pyridyl) thiazol-2-yl) benzene-1, 3-diamine (73.5 mg,0.26 mmol) dissolved in dichloromethane 8ml and triethylamine (194.54 ul,1.40 mmol) was added. The above solution was slowly added by syringe under ice bath, and after the addition was completed, the solution was stirred at room temperature and monitored by TLC. After the reaction was completed, about 4ml of methanol and 10ml of water were added, and the mixture was stirred for 10 minutes to separate the liquid. The aqueous layer was adjusted to pH 8 with 10% sodium hydroxide solution, about 4ml of methanol, 10ml of methylene chloride was added thereto, and stirred for 10 minutes. Separating, washing an organic layer with water, washing saturated saline, concentrating by rotary evaporation, and separating and purifying by a Flash column to obtain 106mg of a product with the yield of 29.3%. 1 H NMR(500MHz,CDCl3)δ 9.12(s,1H),8.56(d,J＝4.5Hz,1H),8.34(s,1H),8.18(d,J＝8.1Hz,1H), 8.11(s,1H),7.91(s,1H),7.55(d,J＝7.5Hz,2H),7.35(dd,J＝8.0,4.8Hz, 2H),7.27–7.19(m,3H),6.93(s,1H),3.87(s,2H),3.69(s,2H),2.82(s, 2H),2.36(s,3H),1.93(s,2H),1.17(d,J＝6.3Hz,6H). 13 C NMR(101 MHz,Chloroform-d)δ165.9,165.6,148.7,148.3,147.5,138.9,137.2, 133.4,131.4,130.5,129.6,127.2,124.2,124.2,123.6,115.6,111.5, 103.8,71.5,62.4,59.2,19.1,17.4.
8.4- ((4- (furan-2-carbonyl) piperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) thiazol-2-yl) amino) phenyl) benzamide (MT-Z3)
In a two-necked flask, 4- ((4- (furan-2-carbonyl) piperazinyl-1) methyl) benzoic acid (278.1 mg,0.88 mmol) was added, argon protected, 8ml dichloromethane, triethylamine (270 ul,1.947 mmol) were added via syringe, and after addition of thionyl chloride (77 ul,1.062 mmol) a solid was formed, and the reaction was stirred at room temperature for 1h. Another two-necked flask was charged with 6-methyl-N1- (4- (3-pyridyl) thiazol-2-yl) benzene-1, 3-diamine (200 mg, 0.706 mmol) dissolved in dichloromethane 8ml and triethylamine (270 ul,1.947 mmol) was added. The above solution was slowly added by syringe under ice bath, and after the addition was completed, the solution was stirred at room temperature and monitored by TLC. After the reaction was completed, about 4ml of methanol and 10ml of water were added, and the mixture was stirred for 3 minutes to separate the liquid. The aqueous layer was adjusted to pH 8 with 10% sodium hydroxide solution, about 4ml of methanol, 10ml of methylene chloride,stirring for 10min. Separating, washing an organic layer with water, washing saturated saline, concentrating by rotary evaporation, and separating and purifying by a Flash column to obtain 88mg of a product with the yield of 21.5%. 1 H NMR(500 MHz,CDCl3)δ9.1(s,1H),8.6(s,1H),8.3(d,J＝2.1Hz,1H),8.2(d,J ＝7.9Hz,1H),8.1(s,1H),7.9(d,J＝7.8Hz,2H),7.5(d,J＝7.6Hz,3H), 7.4(dd,J＝7.9,4.8Hz,1H),7.3–7.2(m,3H),7.0(d,J＝3.5Hz,1H),6.9 (s,1H),6.5(dd,J＝3.5,1.8Hz,1H),3.9(s,4H),3.7(s,2H),2.6(t,J＝5.1 Hz,4H),2.4(s,3H). 13 C NMR(101MHz,Chloroform-d)δ165.9,165.6, 159.1,148.6,148.3,147.8,147.5,143.7,138.9,137.2,134.2,133.5, 131.4,130.5,129.5,127.3,124.3,123.6,116.5,115.7,111.6,111.3, 103.8,62.3,53.1,29.7,17.4.
N- (4-methyl-3- ((4- (pyridin-3-yl) thiazol-2-yl) amino) phenyl) -4- ((4- (methylsulfonyl) piperazin-1-yl) methyl) benzamide (MT-Z5)
In a two-necked flask, 4- ((4- (methylsulfonyl) piperazin-1-yl) methyl) benzoic acid (200 mg,0.67 mmol) was added, protected by argon, 8ml of dichloromethane, triethylamine (121 ul,0.871 mmol) was added via syringe, and after addition of thionyl chloride (53.5 ul,0.737 mmol) a solid was formed and the reaction was stirred at room temperature for 1h. Another two-necked flask was charged with 6-methyl-N1- (4- (3-pyridyl) thiazol-2-yl) benzene-1, 3-diamine (94.6 mg,0.335 mmol) in 8ml of dichloromethane and triethylamine (121 ul,0.871 mmol) was added. The above solution was slowly added by syringe under ice bath, and after the addition was completed, the solution was stirred at room temperature and monitored by TLC. After the reaction was completed, about 4ml of methanol and 10ml of water were added, and the mixture was stirred for 3 minutes to separate the liquid. The aqueous layer was adjusted to pH 8 with 10% sodium hydroxide solution, about 4ml of methanol, 10ml of methylene chloride was added thereto, and stirred for 10 minutes. Separating, washing the organic layer with water, washing with saturated saline, concentrating by rotary evaporation, and separating and purifying by a Flash column to obtain 94mg of product with the yield of 50%. 1 H NMR(500 MHz,Methanol-d4)δ9.11(d,J＝2.2Hz,1H),8.50(d,J＝2.2Hz,1H), 8.45(dd,J＝4.9,1.6Hz,1H),8.37(dt,J＝8.0,2.0Hz,1H),7.94(d,J＝ 7.9Hz,2H),7.52(d,J＝8.0Hz,2H),7.49–7.40(m,2H),7.36(dd,J＝8.2, 2.2Hz,1H),7.26(s,1H),7.25(d,J＝2.3Hz,1H),3.67(s,2H),3.27(t,J＝ 5.0Hz,5H),2.87(s,3H),2.62–2.58(m,4H),2.36(s,3H). 13 C NMR(101 MHz,Chloroform-d)δ165.8,165.4,148.5,148.3,147.4,138.9,137.1, 134.3,133.5,131.4,130.5,129.8,129.5,127.4,124.1,123.6,115.6, 111.4,103.8,62.0,52.3,45.7,34.4,17.4.
10.4- ((4-formylpiperazin-1-yl) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) thiazol-2-yl) amino) phenyl) benzamide (MT-Z6)
In a two-necked flask, 4- ((4-formylpiperazin-1-yl) methyl) benzoic acid (175.8 mg,0.708mmol) was added, and 8ml of methylene chloride, triethylamine (211.6 ul, 1.803 mmol) and thionyl chloride (56.5 ul,0.779 mmol) were added via syringe under argon gas, followed by solid formation and the reaction was stirred at room temperature for 1h. Another two-necked flask was charged with 6-methyl-N1- (4- (3-pyridyl) thiazol-2-yl) benzene-1, 3-diamine (100 mg,0.354 mmol) dissolved in dichloromethane 8ml and triethylamine (211.6 ul, 1.323 mmol) was added. The above solution was slowly added by syringe under ice bath, and after the addition was completed, the solution was stirred at room temperature and monitored by TLC. After the reaction was completed, about 4ml of methanol and 10ml of water were added, and the mixture was stirred for 3 minutes to separate the liquid. The aqueous layer was adjusted to pH 8 with 10% sodium hydroxide solution, about 4ml of methanol, 10ml of methylene chloride was added thereto, and stirred for 10 minutes. Separating, washing an organic layer with water, washing saturated saline, concentrating by rotary evaporation, and separating and purifying by a Flash column to obtain 45mg of a product with the yield of 24.8%. 1 H NMR (500MHz,CDCl3)δ9.1(s,1H),8.6(d,J＝4.8Hz,1H),8.4(s,1H),8.2 (d,J＝8.1Hz,1H),8.1(s,1H),7.9(d,J＝7.1Hz,2H),7.5(d,J＝8.0Hz, 2H),7.4(q,J＝7.6Hz,2H),7.3–7.2(m,1H),3.5(s,2H),3.2(s,4H),2.5 (d,J＝14.3Hz,3H),2.4(s,3H),1.4(t,J＝7.4Hz,9H). 13 C NMR(101 MHz,CDCl3)δ165.5,160.8,148.6,148.2,147.4,138.9,137.1,134.1, 133.6,131.4,129.4,129.3,127.3,127.3,124.1,123.6,115.5,111.3,103.8, 62.3,52.3,45.5,17.4.
11.2,2,2-trifluoro-N- (4-methyl-3- ((4- (pyridin-3-yl) thiazol-2-yl) amino) phenyl) acetamide (MT-Z7)
In a two-necked flask, 6-methyl-N1- (4- (3-pyridyl) thiazol-2-yl) benzene-1, 3-diamine (100 mg,0.0035 mmol) was dissolved in methylene chloride (8 ml), triethylamine (73.8 ul, 0.551 mmol) was added, trifluoroacetic anhydride (78.1 mg,0.0037 mmol) was added under ice bath at 0℃in a roomThe reaction was stirred at temperature and monitored by TLC. After the reaction is completed, water is added to adjust the pH to 7-8, dichloromethane extraction, rotary evaporation concentration and Flash column separation and purification are carried out, thus obtaining 97.3mg of product with the yield of 73.1%. 1 H NMR(500MHz,Methanol-d4)δ9.19–9.05(m,1H), 8.55(d,J＝4.0Hz,1H),8.52–8.23(m,2H),7.52–7.43(m,1H),7.27(t, J＝5.2Hz,3H),3.41–3.34(m,2H),2.40–2.29(m,3H). 13 C NMR(101 MHz,Methanol-d4)δ166.2,155.3,155.0,147.2,147.1,146.3,139.5, 134.84,134.1,131.3,130.6,125.9,123.8,115.7,113.1,104.4,16.4.
N- (4-methyl-3- ((4- (pyridin-3-yl) thiazol-2-yl) amino) phenyl) -4-oxo-4-phenylbutanamide (MT-Z8)
In a two-necked flask, 3-benzoylpropionic acid (200 mg,1.122 mmol) was dissolved in dichloromethane 15ml, EDCI (321.7 mg,1.683 mmol), HOBt (369.2 mg,1.739 mg), triethylamine (280 ul,2.02 mmol) was added under ice-bath, and after disappearance of the starting material, 6-methyl-N1- (4- (3-pyridinyl) thiazol-2-yl) benzene-1, 3-diamine (100 mg,0.354 mmol) was added and monitored by TLC. After the reaction of the raw materials is completed, the raw materials are washed by saturated sodium bicarbonate solution, dried by anhydrous sodium sulfate, filtered and concentrated, and separated and purified by a Flash column to obtain 47mg of a product with the yield of 30.1%. 1 H NMR(500MHz,DMSO-d6)δ10.02(s,1H),9.40(s,1H), 9.15(s,1H),8.48(s,2H),8.36(d,J＝7.9Hz,1H),8.03(d,J＝7.7Hz,2H), 7.67(t,J＝7.2Hz,1H),7.56(t,J＝7.6Hz,2H),7.48(s,1H),7.37(d,J＝ 8.0Hz,1H),7.24–7.09(m,2H),3.37(d,J＝5.8Hz,3H),2.76(s,2H), 2.25(s,3H). 13 C NMR(101MHz,DMSO-d6)δ199.4,170.6,166.0, 148.1,147.4,147.0,137.1,134.1,133.6,131.0,131.0,129.2,128.4, 124.3,123.4,114.5,112.1,18.0.
16.4- (tert-butyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) thiazol-2-yl) amino) phenyl) benzamide (MT-0816)
In a two-necked flask, 4-t-butylbenzoic acid (126 mg,0.708 mmol) was added under argon, 8ml of methylene chloride, triethylamine (127.9 ul,0.921 mmol) and thionyl chloride (56.5 ul,0.779 mmol) were added via syringe, and the reaction was stirred at room temperature and monitored by TLC. Another two-necked flask was taken and charged with 6-methyl-N1- (4- (3-pyridyl) thiazol-2-yl) benzene-1, 3-diamine (73.5 mg,0.26 mmo)l) dissolved in dichloromethane 8ml triethylamine (194.54 ul,1.40mmol) was added. The above solution was slowly added by syringe under ice bath, and after the addition was completed, the solution was stirred at room temperature and monitored by TLC. After the reaction was completed, about 4ml of methanol and 10ml of water were added, and the mixture was stirred for 3 minutes to separate the liquid. The aqueous layer was adjusted to pH 8 with 10% sodium hydroxide solution, about 4ml of methanol, 10ml of methylene chloride was added thereto, and stirred for 10 minutes. Separating, washing an organic layer with water, washing saturated saline, concentrating by rotary evaporation, and separating and purifying by a Flash column to obtain 76mg of a product with the yield of 24.2%. 1 H NMR(500MHz,CDCl3)δ9.2(s,1H),8.6 (s,1H),8.5(d,J＝7.7Hz,1H),8.5(s,1H),8.1(s,1H),7.9(d,J＝8.1Hz, 2H),7.6(s,1H),7.6(d,J＝8.1Hz,2H),7.3(d,J＝8.0Hz,1H),7.2(d,J＝ 8.2Hz,1H),7.0(s,1H),2.4(s,3H),1.4(s,10H).
17.4- (tert-butyl) -3-methoxy-N- (4-methyl-3- ((4- (pyridin-3-yl) thiazol-2-yl) amino) phenyl) benzamide (MT-0819)
In a two-necked flask, 3-methoxy-4-tert-butylbenzoic acid (295 mg,1.416 mmol) was added under argon, 8ml of dichloromethane, triethylamine (255.9 ul,1.841 mmol) were added via syringe, and after addition of thionyl chloride (113.0 ul, 1.578 mmol), the reaction was stirred at room temperature and monitored by TLC. Another two-necked flask was charged with 6-methyl-N1- (4- (3-pyridyl) thiazol-2-yl) benzene-1, 3-diamine (200 mg, 0.706 mmol) dissolved in dichloromethane 8ml and triethylamine (255.9 ul,1.841 mmol) was added. The above solution was slowly added by syringe under ice bath, and after the addition was completed, the solution was stirred at room temperature and monitored by TLC. After the reaction was completed, about 4ml of methanol and 10ml of water were added, and the mixture was stirred for 3 minutes to separate the liquid. The aqueous layer was adjusted to pH 8 with 10% sodium hydroxide solution, about 4ml of methanol, 10ml of methylene chloride was added thereto, and stirred for 10 minutes. Separating, washing an organic layer with water, washing saturated saline, concentrating by rotary evaporation, and separating and purifying by a Flash column to obtain 85mg of a product with the yield of 25.4%. 1 H NMR(500MHz,DMSO-d6)1H NMR(500MHz,CDCl3)δ9.13(s,1H),8.58(s,1H),8.35(s,1H),8.26 (d,J＝7.9Hz,1H),8.00(s,1H),7.52(d,J＝1.7Hz,1H),7.46–7.32(m, 3H),7.25(s,2H),6.96(s,1H),3.95(s,3H),2.37(s,3H),1.43(s,9H). 13 C NMR(101MHz,Chloroform-d)δ166.2,165.7,159.0,147.5,147.4, 146.5,142.7,138.7,137.3,134.4,133.7,131.4,126.7,124.3,118.0, 115.8,111.6,110.8,104.1,55.3,35.2,29.5,17.4.
N- (4-methyl-3- ((4- (pyridin-3-yl) thiazol-2-yl) amino) phenyl) -4- (morpholinomethyl) benzamide (MT-0820)
In a two-necked flask, 4-morpholinomethylbenzoic acid (235 mg,1.062 mmol) was added under argon, 8ml of dichloromethane and triethylamine (127.9ul,0.921 mmol) were added via syringe, and after addition of thionyl chloride (82.2 ul,1.133 mmol), the reaction was stirred at room temperature and monitored by TLC. Another two-necked flask was charged with 6-methyl-N1- (4- (3-pyridyl) thiazol-2-yl) benzene-1, 3-diamine (200 mg, 0.706 mmol) dissolved in dichloromethane 8ml and triethylamine (196.9 ul,1.416 mmol) was added. The above solution was slowly added by syringe under ice bath, and after the addition was completed, the solution was stirred at room temperature and monitored by TLC. After the reaction was completed, about 4ml of methanol and 10ml of water were added, and the mixture was stirred for 3 minutes to separate the liquid. The aqueous layer was adjusted to pH 8 with 10% sodium hydroxide solution, about 4ml of methanol, 10ml of methylene chloride was added thereto, and stirred for 10 minutes. Separating, washing the organic layer with water, washing with saturated saline, concentrating by rotary evaporation, and separating and purifying by a Flash column to obtain 113mg of a product with the yield of 32.9%. 1 H NMR(500MHz,CDCl3)δ9.2– 9.1(m,1H),8.6–8.6(m,1H),8.4(s,1H),8.2(d,J＝7.9Hz,1H),8.0(s, 1H),7.9(d,J＝7.8Hz,2H),7.6(d,J＝7.7Hz,2H),7.4(dd,J＝7.9,4.8 Hz,1H),7.3(s,2H),6.9(s,1H),3.8(s,4H),3.7(s,2H),2.6(s,4H),2.4(s, 4H). 13 C NMR(101MHz,Chloroform-d)δ165.8,165.5,148.6,148.3, 147.5,138.9,137.2,133.5,131.4,130.5,129.9,127.3,124.1,123.6, 115.6,111.4,103.8,66.4,62.6,53.4,17.4.
N- (4-methyl-3- ((4- (pyridin-3-yl) thiazol-2-yl) amino) phenyl) -2-morpholinobenzamide (MT-0822)
In a two-necked flask, 2- (4-morpholinyl) benzoic acid (293.5 mg,1.416 mmol) was added, protected by argon, 8ml dichloromethane, triethylamine (255.9ul,1.841 mmol) were added via syringe and after addition of thionyl chloride (113.0 ul, 1.554 mmol) l turned yellow immediately, the reaction was stirred at room temperature and monitored by TLC. Another two-necked flask was taken and charged with 6-methyl-N1- (4- (3-pyridyl) thiazol-2-yl) benzene-1, 3-diamine (200 mg, 0.706 mmol) in dichloromethane 8ml triethylamine (255.9 ul,1.841 mmol) was added. The above solution was slowly added by syringe under ice bath, and after the addition was completed, the solution was stirred at room temperature and monitored by TLC. After the reaction was completed, about 4ml of methanol and 10ml of water were added, and the mixture was stirred for 3 minutes to separate the liquid. The aqueous layer was adjusted to pH 8 with 10% sodium hydroxide solution, about 4ml of methanol, 10ml of methylene chloride was added thereto, and stirred for 10 minutes. Separating, washing an organic layer with water, washing saturated saline, concentrating by rotary evaporation, and separating and purifying by a Flash column to obtain 86mg of a product with the yield of 25.8%. 1 H NMR(500MHz,CDCl3) δ12.1(s,1H),9.1(d,J＝2.1Hz,1H),8.6(d,J＝4.8Hz,1H),8.5(d,J＝ 2.1Hz,1H),8.3(dd,J＝7.8,1.6Hz,1H),8.3(d,J＝7.9Hz,1H),7.5(d,J ＝7.3Hz,1H),7.5–7.3(m,5H),7.3(d,J＝8.1Hz,2H),7.0(s,1H),4.0(t, J＝4.5Hz,4H),3.1(t,J＝4.5Hz,4H),2.4(s,3H). 13 C NMR(101MHz, Chloroform-d)δ165.8,164.1,150.5,148.2,148.0,147.1,138.9,137.8, 133.9,132.7,132.1,131.5,130.6,127.9,125.6,123.7,123.3,120.5, 115.0,110.6,103.9,67.3,53.7,17.4.
N- (4-methyl-3- ((4- (pyridin-3-yl) thiazol-2-yl) amino) phenyl) -2-morpholinyl nicotinamide (MT-0824)
In a two-necked flask, 4-morpholino nicotinic acid (221.2 mg,1.062 mmol) was added, protected by argon, 8ml of dichloromethane, triethylamine (196.9 ul,1.416 mmol) were added via syringe, and after addition of thionyl chloride (87.35 ul,1.204 mmol), l turned yellow immediately, the reaction was stirred at room temperature and monitored by TLC. Another two-necked flask was charged with 6-methyl-N1- (4- (3-pyridyl) thiazol-2-yl) benzene-1, 3-diamine (200 mg, 0.706 mmol) dissolved in dichloromethane (8 ml), and triethylamine (196.9 ul,1.416mmol) was added. The above solution was slowly added by syringe under ice bath, and after the addition was completed, the solution was stirred at room temperature and monitored by TLC. After the reaction was completed, about 4ml of methanol and 10ml of water were added, and the mixture was stirred for 3 minutes to separate the liquid. The aqueous layer was adjusted to pH 8 with 10% sodium hydroxide solution, about 4ml of methanol, 10ml of methylene chloride was added thereto, and stirred for 10 minutes. Separating, washing the organic layer with water, washing with saturated saline, concentrating by rotary evaporation, and separating and purifying by a Flash column to obtain 104mg of the product with the yield of 31.1%. 1 H NMR(500MHz,CDCl3)δ11.1(s,1H), 9.2(s,1H),8.6(d,J＝7.8Hz,1H),8.5(dt,J＝10.9,2.8Hz,3H),8.3(d,J ＝7.9Hz,1H),7.4(q,J＝5.2Hz,1H),7.3(dd,J＝8.2,2.1Hz,1H),7.3(s, 1H),7.3(d,J＝2.0Hz,1H),7.3–7.2(m,1H),7.0(s,1H),3.9(t,J＝4.7 Hz,4H),3.3(t,J＝4.7Hz,4H),2.4(s,3H). 13 C NMR(101MHz, Chloroform-d)δ165.5,163.2,160.0,152.7,150.4,148.0,147.9,146.9, 140.7,139.0,137.3,134.1,131.5,123.8,123.5,122.0,120.3,114.6, 110.2,104.0,67.1,52.0,17.4.
Examples antiviral Activity experiments
New coronavirus activity inhibition assay
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Experimental results
As shown in the table, the compounds MT-Z7 and MT-0820 have certain activity, and MT-Z8 and MT-0819 have better activity on novel coronaviruses, and the IC50 value is 2.294umol/L. The compound MT-Z1 has stronger antiviral activity to the novel coronavirus in experiments, the IC50 value is 0.661umol/L, and the activity is doubled compared with that of the macitenib.

Claims (8)

1. A compound represented by the general formula (I) and stereoisomers thereof or pharmaceutically acceptable salts thereof,
R 1 independently selected from hydrogen, halogen or C 1-10 Straight-chain or branched alkyl, trifluoromethyl or C 1-10 Linear or branched alkoxy groups;
R 2 independently selected from hydrogen, halogen or C 1-10 Straight-chain or branched alkyl, trifluoromethyl or C 1-10 Linear or branched alkoxy groups;
R 3 independently selected from hydrogen, halogen or C 1-10 Straight-chain or branched alkyl, trifluoromethyl or C 1-10 Straight or branched chain alkoxy groups.
R 4 Independently selected from hydrogen, halogen or C 1-10 Straight-chain or branched alkyl, trifluoromethyl or C 1-10 Linear or branched alkoxy groups;
R 5 independently selected from
a) Substituted or unsubstituted C 1-10 A linear or branched alkyl group, said substituent being selected from I, cl, br or F;
b)-CO-R 6 a group, wherein R is 6 Independently selected from H or phenyl optionally substituted with at least one heteroatom, six membered heteroaryl, or phenyl substituted with at least one five or six membered heterocyclyl, six membered heteroaryl.
2. The compound according to claim 1, wherein, when R 1 Is methyl, R 2 、R 3 、R 4 Is hydrogen, R 5 Among the specific compounds having the meaning described in b) above,
R 6 the radicals being selected from
(i) Phenyl or substituted variants thereof, bearing any combination of one or more substituents at any one ring position, e.g. halogen, C 1-10 Alkyl, trifluoromethyl and C 1-10 An alkoxy group;
(ii)R 7 、R 8 substituted aminomethylphenyl wherein R is 7 、R 8 Selected from aryl groups, e.g. phenyl groups, or substituted variants thereof, bearing any combination of one or more substituents, e.g. halogen, C, at any ring position 1-10 Alkyl, trifluoromethyl and C 1-10 An alkoxy group; heteroaryl, e.g. 2, 3 or 4-pyridyl, which may additionally bear any combination of one or more substituents, e.g. halogen, C 1-10 Alkyl, trifluoromethyl and C 1-10 An alkoxy group.
3. A compound according to claim 2, wherein
When R is 1 Is methyl, R 2 、R 3 、R 4 Is hydrogen, R 5 In the particular compounds having the meaning described in b) above, R 6 Independently selected from hydrogen, 4-tert-butylphenyl, 4-tert-butyl-3-methoxyphenyl, 2-morpholinophenyl, 2-morpholino-4-pyridinyl;
when R is 1 Is methyl, R 2 、R 3 、R 4 Is hydrogen, R 5 In the particular compounds having the meaning described in b) above, in the particular compounds having the meaning described in (iii) above for the R6 group,
R 7 、R 8 independently selected from the group consisting of hydrogen, 3, 5-dimethylmorpholinyl, 4- (furan-2-carbonyl) piperazin-1-yl, 4-methanesulfonyl) piperazinyl, 4-formylpiperazinyl, 4-phenylbutyryl, morpholinyl.
4. A compound according to any one of claims 1-3, and stereoisomers thereof, which are chemically acceptable salts, characterized in that said compound is a compound having the structure:
5. a compound according to any one of claims 1 to 4, as well as stereoisomers, chemically acceptable salts thereof, characterized in that the compound is a compound of stereoisomers, pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.
6. A pharmaceutical composition comprising a compound according to any one of claims 1-4, a pharmaceutically acceptable salt or isomer thereof and other pharmaceutically active ingredients.
7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt or isomer thereof, together with one or more pharmaceutically acceptable carriers and/or diluents, in any pharmaceutically acceptable dosage form.
8. Use of a compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt or isomer thereof for the manufacture of a medicament for the treatment and/or prophylaxis of novel coronavirus infectious diseases, in particular Covid-19.
CN202210545003.8A 2022-05-19 2022-05-19 New coronavirus inhibitor, preparation method, pharmaceutical composition and application thereof Pending CN117126153A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115867278A (en) * 2020-04-10 2023-03-28 Ab科学有限公司 Use of masitinib for treating 2019 coronavirus disease (COVID-19)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115867278A (en) * 2020-04-10 2023-03-28 Ab科学有限公司 Use of masitinib for treating 2019 coronavirus disease (COVID-19)

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