CN115490681A - Triazine derivatives - Google Patents

Triazine derivatives Download PDF

Info

Publication number
CN115490681A
CN115490681A CN202211454323.9A CN202211454323A CN115490681A CN 115490681 A CN115490681 A CN 115490681A CN 202211454323 A CN202211454323 A CN 202211454323A CN 115490681 A CN115490681 A CN 115490681A
Authority
CN
China
Prior art keywords
virus
deuterium
pharmaceutically acceptable
substituted
prodrug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202211454323.9A
Other languages
Chinese (zh)
Other versions
CN115490681B (en
Inventor
吴劲梓
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ascletis Bioscience Co Ltd
Original Assignee
Ascletis Bioscience Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ascletis Bioscience Co Ltd filed Critical Ascletis Bioscience Co Ltd
Priority to CN202310320094.XA priority Critical patent/CN116496266A/en
Priority to US18/067,147 priority patent/US20240025885A1/en
Priority to PCT/IB2022/000765 priority patent/WO2024009120A1/en
Publication of CN115490681A publication Critical patent/CN115490681A/en
Application granted granted Critical
Publication of CN115490681B publication Critical patent/CN115490681B/en
Priority to TW112125246A priority patent/TW202402296A/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pulmonology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Triazine derivatives represented by the general formula I, pharmaceutically acceptable salts, deuterides, prodrugs or metabolites thereof:
Figure 708353DEST_PATH_IMAGE001
wherein R is 1 、R 2 、R 3 、R 4 、R a 、R b 、R x X, Y, Z, W, Q, m andh is as defined in the disclosure.

Description

Triazine derivatives
Technical Field
The present disclosure relates generally to the field of medicinal chemistry, and more particularly to triazine derivatives.
Background
Coronavirus (CoV) is a family of enveloped positive-strand RNA pathogenic viruses that can cause acute and chronic diseases including central nervous system disease, common cold, lower respiratory tract infections, and diarrhea. HcoV-229E and HcoV-OC43 are the first zoonotic virus strains discovered since 1995.
Upon entry into the host cell, the coronavirus is broken down to release the nucleocapsid and the viral genome. The host cell ribosomes translate the Open Reading Frames (ORFs) 1a and 1b of the viral genome into polyproteins pp1a and pp1b, respectively, for encoding 16 non-structural proteins (nsps), while the remaining ORFs encode structural and accessory proteins. 3C-like cysteine protease (3 Clpro) and papayaki cysteine protease (Plpro) catalyze PP cleavage to nsp2-16, which in turn forms the replication-transcription complex (RTC). The loss of activity of these proteases leads to the cessation of the viral life cycle. Also, the structure and function of 3Clpro is highly conserved among coronaviruses. Therefore, 3Clpro becomes a potential effective target for developing broad-spectrum coronavirus resistant medicines. The 3Clpro inhibitors reported so far include covalent peptidomimetic inhibitors and non-covalent small molecule inhibitors. Although the peptidomimetic covalent inhibitor has remarkable inhibitory activity on 3Clpro, the target selectivity of the covalent inhibitor is poor, and the problems of unpredictable toxic and side effects, poor metabolic stability and the like exist. The non-covalent small molecule inhibitor is a better choice, however, the currently reported non-covalent small molecule inhibitors are very poor, and have the problems of single structure, weak enzyme inhibition activity, poor drug forming property and the like.
Disclosure of Invention
In one aspect, the disclosure relates to triazine derivatives represented by general formula I, pharmaceutically acceptable salts, deuterons, prodrugs, or metabolites thereof:
Figure 235119DEST_PATH_IMAGE001
wherein
R 1 、R 2 、R 3 、R 4 Selected from H or D;
rx is selected from hydrogen, deuterium, cyano, alkyl, alkenyl, alkynyl; wherein alkyl, alkenyl, alkynyl may be substituted with 1 to 3 deuterium, halogen, hydroxy, cyano or alkoxy groups; ring A is a five-membered N-containing heteroaromatic ring, optionally substituted with m R a Substituted;
x, Y and Z are independently selected from C, N, O or S;
R a each independently selected from hydrogen, deuterium, halogen, nitro, cyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
m = 1、2、3、4；
R b selected from hydrogen, deuterium, halogen, cyano, substituted alkoxy;
h =2、3、4；
w or Q is selected from hydrogen, deuterium, halogen, substituted alkyl.
In another aspect, the present disclosure relates to triazine derivatives, pharmaceutically acceptable salts, deuterides, prodrugs, or metabolites thereof as shown below:
Figure 808707DEST_PATH_IMAGE002
Figure 939475DEST_PATH_IMAGE003
Figure 406228DEST_PATH_IMAGE004
。
in yet another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a triazine derivative, pharmaceutically acceptable salt, deuteron, prodrug, or metabolite thereof of the present disclosure, and a pharmaceutically acceptable carrier, diluent, or excipient.
In yet another aspect, the present disclosure relates to a method of treating and/or preventing a viral infectious disease comprising administering to a subject in need thereof a therapeutically effective amount or a prophylactically effective amount of a triazine derivative, a pharmaceutically acceptable salt, a deuteron, a prodrug or a metabolite thereof of the present disclosure, or a therapeutically effective amount or a prophylactically effective amount of a pharmaceutical composition comprising a triazine derivative, a pharmaceutically acceptable salt, a deuteron, a prodrug or a metabolite thereof of the present disclosure.
In another aspect, the present disclosure relates to a method of inhibiting a 3C-like cysteine protease (3 Clpro) by contacting an inhibitory effective amount of a triazine derivative of the present disclosure, a pharmaceutically acceptable salt, deuteron, prodrug or metabolite thereof, or a inhibitory effective amount of a pharmaceutical composition comprising a triazine derivative of the present disclosure, a pharmaceutically acceptable salt, deuteron, prodrug or metabolite thereof, with a 3C-like cysteine protease (3 Clpro).
In yet another aspect, the present disclosure relates to the use of a triazine derivative, a pharmaceutically acceptable salt, a deuterode, a prodrug, or a metabolite thereof of the present disclosure in the manufacture of a medicament for treating and/or preventing a viral infectious disease in a subject.
In yet another aspect, the present disclosure relates to the use of a triazine derivative, a pharmaceutically acceptable salt, a deuteron, a prodrug, or a metabolite thereof of the present disclosure in the preparation of a 3C-like cysteine protease (3 Clpro) inhibitor.
In another aspect, the present disclosure relates to triazine derivatives, pharmaceutically acceptable salts, deuterons, prodrugs, or metabolites thereof of the present disclosure for use in the treatment and/or prevention of viral infectious diseases.
In yet another aspect, the present disclosure relates to triazine derivatives, pharmaceutically acceptable salts, deuterides, prodrugs or metabolites thereof of the present disclosure for use in inhibiting a 3C-like cysteine protease (3 Clpro).
Detailed Description
In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.
Throughout this specification and the claims which follow, unless the disclosure requires otherwise, the words "comprise" and "comprise" are to be construed in an open, inclusive sense, i.e., "including but not limited to".
As used in this disclosure and the appended claims, a singular reference of an element without a numerical designation includes plural references unless the context clearly dictates otherwise.
Reference throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" means that a particular reference element, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
It should be understood that, as used in the specification of the present disclosure and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a sustained release tablet comprising "a pharmaceutically acceptable excipient" includes one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.
Definition of
Certain chemical groups named herein are identified above by shorthand symbols indicating the total number of carbon atoms found in the chemical group shown. E.g. C 7 -C 12 Alkyl describes an alkyl group as defined below having a total number of carbon atoms from 7 to 12, and C 4 -C 12 Cycloalkylalkyl describes cycloalkylalkyl groups defined below having a total number of 4 to 12 carbon atoms. The total number of carbon atoms in the shorthand notation does not include carbons that may be present in a substituent of the group.
Accordingly, unless indicated to the contrary, the following terms used in the specification and appended claims have the following meanings:
the term "oxo", as used in this disclosure, refers to an = O group.
The term "cyano," as used in this disclosure, refers to a-CN group.
The term "nitro", as used in this disclosure, means-NO 2 A group.
The term "halogen" as used in this disclosure refers to fluorine, chlorine, bromine or iodine.
The term "alkyl" as used in this disclosure refers to a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing no unsaturation, having from 1 to 12 carbon atoms, and which is attached to the rest of the molecule by a single bond. In certain embodiments, the alkyl group has 1 to 8 carbon atoms. In certain embodiments, the alkyl group has 1 to 6 carbon atoms. In certain embodiments, the alkyl group has 1 to 4 carbon atoms. In certain embodiments, illustrative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, and the like. In certain embodiments, alkyl groups may be optionally substituted, i.e., substituted or unsubstituted.
Whenever a group is described as "optionally substituted," that group may be unsubstituted or substituted with one or more of the substituents indicated. Likewise, when a group is described as "unsubstituted or substituted," if substituted, the substituents may be selected from one or more of the substituents shown. If no substituent is indicated, it is meant that the indicated "optionally substituted" or "substituted" group may be substituted with one or more groups individually or independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclic, aralkyl, heteroaralkyl, (heteroalicyclic) alkyl, hydroxy, protected hydroxy, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanate, isothiocyanato, nitro, silyl, thio, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, amino, monosubstituted amino and disubstituted amino and protected derivatives thereof.
The term "alkoxy" as used in this disclosure refers to the general formula-OR, wherein R is alkyl as defined above. In certain embodiments, alkoxy groups have 1 to 8 carbon atoms. In certain embodiments, alkoxy groups have 1 to 6 carbon atoms. In certain embodiments, alkoxy groups have 1 to 4 carbon atoms. In certain embodiments, illustrative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, and the like. In certain embodiments, an alkoxy group may be optionally substituted, i.e., substituted or unsubstituted.
The term "cycloalkyl" as used in this disclosure refers to a stable non-aromatic monocyclic or polycyclic alkyl group, consisting of only carbon and hydrogen atoms, which may contain a fused or bridged ring system, having from 3 to 18 carbon atoms, in certain embodiments from 3 to 15 carbon atoms, in certain embodiments from 3 to 10 carbon atoms, and which is saturated and attached to the rest of the molecule by a single bond. In certain embodiments, illustrative examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Illustrative examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, decahydronaphthyl, 7-dimethyl-bicyclo [2.2.1] heptanyl, and the like. In certain embodiments, cycloalkyl groups may be optionally substituted, i.e., substituted or unsubstituted.
The term "aryl" as used in this disclosure refers to an aromatic monocyclic or polycyclic hydrocarbon ring system, consisting only of hydrogen and carbon, and containing from 6 to 18 carbon atoms, wherein the ring system may be partially saturated. In certain embodiments, aryl is C 6 -C 14 And (3) an aryl group. In certain embodiments, aryl is C 6 -C 12 And (3) an aryl group. In certain embodiments, aryl is C 6 -C 10 And (3) an aryl group. In certain embodiments, illustrative examples of aryl groups include, but are not limited to, phenyl, naphthyl, and fluorenyl. In certain embodiments, an aryl group may be optionally substituted, i.e., substituted or unsubstituted.
As used in this disclosureThe term "heteroaryl" refers to a 5-to 18-membered aromatic ring group containing 1 to 17 carbon atoms and 1 to 10 heteroatoms selected from nitrogen, oxygen, and sulfur. For the purposes of this disclosure, heteroaryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atom in the heteroaryl group may be optionally oxidized; the nitrogen atoms may optionally be quaternized. In certain embodiments, the heteroaryl group may contain from 4 to 14 atoms in the ring. In certain embodiments, 5 to 10 atoms may be present in the ring of the heteroaryl group. In certain embodiments, 5 to 6 atoms may be present in the ring of the heteroaryl group. In certain embodiments, illustrative examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [2 ], [ solution ]b][1,4]Dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzodioxolyl, benzodioxanyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothiophenyl, benzotriazolyl, benzo [4,6 ] benzo]Imidazo [1,2-a]Pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, imidazopyridinyl, imidazopiperazinyl, imidazopiperidinyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyl, diazanaphthyl, diazolinyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-phenyl-1-ylH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, 2, 3-naphthyridinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thienyl. In certain embodiments, heteroaryl groups may be optionally substituted, i.e., substituted or unsubstituted.
The term "physiologically acceptable" as used in this disclosure defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.
The term "carrier" as used in this disclosure refers to a substance that effects the incorporation of a compound into a cell or tissue.
The term "excipient" as used in this disclosure refers to an inert substance added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding capacity, lubricity, disintegration capacity, and the like to the composition.
The term "diluent" as used in this disclosure refers to an ingredient in a pharmaceutical composition that is not pharmaceutically active but may be pharmaceutically necessary or desirable.
The term "mammal" as used in this disclosure is intended to include animals such as dogs, cats, cattle, sheep, horses, and humans. In certain embodiments, the mammal comprises a human.
The term "patient" as used in this disclosure refers to animals (e.g., humans), companion animals (e.g., dogs, cats or horses), and livestock (e.g., cattle, pigs and sheep). In certain embodiments, the patient is a mammal including a male and a female. In certain embodiments, the patient is a human.
The term "pharmaceutically acceptable" or "pharmaceutically acceptable" as used in this disclosure refers to carriers, diluents, excipients, and/or salts that must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The term "optional" or "optionally" as used in this disclosure means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
As used in this disclosure, a "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been recognized by the U.S. food and drug administration as being useful in humans or animals in a variety of forms that do not have side effects on the constituent pharmaceutical compositions.
The term "pharmaceutically acceptable salts" as used in this disclosure includes "acceptable acid addition salts" and "acceptable base addition salts".
"acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and are formed using inorganic or organic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like, such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucic acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, succinic acid, tartaric acid, stearic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, toluenesulfonic acid, and the like.
"acceptable base addition salts" refers to those salts which retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benzylamine, phenylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. In certain embodiments, the organic base is isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
Typically, crystallization will result in solvates of the compounds of the invention. The term "solvate" as used in the present disclosure refers to an aggregate comprising one or more molecules of a compound of the present disclosure and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present disclosure may exist in hydrate forms, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, and the like, as well as in the corresponding solvated forms. The compounds of the present disclosure may be true solvates, while in other cases, the compounds of the present disclosure may retain only incidental water or be a mixture of water plus a portion of incidental solvent.
The term "pharmaceutical composition" as used in this disclosure refers to a formulation of a compound described in this disclosure with a vehicle generally accepted in the art for delivery of bioactivating compounds to mammals such as humans. Such media include all pharmaceutically acceptable carriers, diluents or excipients.
As used in this disclosure, a "therapeutically effective amount" refers to an amount of a compound or combination of compounds that ameliorates, reduces, or eliminates a particular disease or condition and symptoms of a particular disease or condition, or avoids or delays the onset of a particular disease or condition or symptoms of a particular disease or condition. The amount of the compound described in this disclosure that constitutes a "therapeutically effective amount" will vary according to the compound, the disease state and its severity, and the age, weight, etc., of the mammal to be treated, but can be determined routinely by those skilled in the art, based on their own knowledge and this disclosure.
As used in this disclosure, "treating" or "treatment" encompasses treating a related disease or condition in a mammal, such as a human, suffering from the related disease or condition and includes:
(i) Preventing the occurrence of a disease or condition in a mammal, particularly when the mammal is susceptible to said disease condition but has not been diagnosed as having such a disease condition;
(ii) Inhibiting the disease or disease state, i.e., preventing its occurrence; or
(iii) Alleviating the disease or condition, i.e., causing regression or no progression of the disease or condition.
As used in this disclosure, the terms "disease" and "disease state" may be used interchangeably, or may be different, in that a particular disease or disease state may not have a known causative agent (and therefore cannot be explained by etiology), and thus is not recognized as a disease, but rather is considered an undesirable disease state or condition, in which a clinician has identified a more or less specific series of symptoms.
The compounds described in the present disclosure, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as I-or (S) -, or (D) -or (L) -, of amino acids, in terms of absolute stereochemistry. The present disclosure is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), I-and (S) -, or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column. When a compound described in this disclosure contains an olefinic double bond or other center of geometric asymmetry, unless otherwise indicated, it is meant that the compound includes both E and Z geometric isomers. Likewise, all tautomeric forms are also meant to be included.
"stereoisomers" refers to compounds consisting of the same atoms bonded by the same bonds, but having different three-dimensional structures that are not interchangeable. The present disclosure encompasses various stereoisomers and mixtures thereof.
"cis-trans isomers" refer to molecules of the same molecular formula that have different relative distances between adjacent atoms or groups of atoms due to hindered free rotation of bonds due to the presence of double bonds or rings.
"tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the compounds.
The term "prodrug" as used in this disclosure is intended to mean a compound that can be converted to the biologically active compound of the invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the disclosure. Prodrugs can be inactive when administered to a subject in need thereof, but are converted in vivo to the active compounds of the invention. Prodrugs are generally rapidly converted in vivo to the parent compound of the present disclosure, for example, by hydrolysis in blood. Prodrug compounds often provide the advantages of solubility, histocompatibility or delayed release in mammalian organisms (see Bundgard, h., design Prodrugs (1985), pp.7-9, 21-24, (Elsevier, amsterdam)). A discussion of prodrugs is provided in Higuchi, T.T., et al, "Pro-drugs as Novel Delivery Systems", A.C.S.Symphosium Series, vol.14 and Bioreversible Carriers in Drug Design, ed.Edward B.Roche, american pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.
The term "prodrug" as used in this disclosure is also intended to include any covalently bonded carriers that release the active compounds of the disclosure in vivo when these prodrugs are administered to a mammalian subject. Prodrugs of the compounds of the present disclosure may be prepared by modifying functional groups present on the compounds of the present disclosure in such a way that, in routine manipulation or in vivo, the modified species are cleaved from the parent compound of the present disclosure. Prodrugs include compounds of the present disclosure wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the compound of the present disclosure is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol functional groups, or amide derivatives of amine functional groups, and the like, in the compounds of the disclosure.
The present disclosure also encompasses in vivo metabolites of the disclosed compounds. These products are obtained by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compounds mainly due to the enzymatic process. Accordingly, the present disclosure includes compounds produced by a method comprising contacting a compound of the present disclosure with a mammal for a time sufficient to produce a metabolite thereof. Identification of metabolites is typically accomplished by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it at a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from urine, blood or other biological samples. These products are easy to isolate because they are labelled (others are isolated by using antibodies capable of binding to epitopes present in the metabolite). Metabolite structure is determined in a conventional manner, e.g., by MS, LC/MS or NMR analysis. Typically, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. So long as the metabolite products are not otherwise detectable in vivo, they may be used in assays for the administration of therapeutic doses of the compounds of the disclosure.
The term "isotope" as used in this disclosure refers to different species of the same element having the same proton number, different neutron numbers.
The term "abundance" as used in this disclosure refers to the atomic number percentage of a certain isotope in the natural element to which it belongs.
The term "natural abundance of isotopes" or "natural abundance" as used in this disclosure refers to the atomic number percentage of each isotope in a natural element that occurs in nature. For example, isotopic natural abundance of hydrogen: 1 H=99.985%， 2 h =0.015%. Isotopic natural abundance of oxygen: 16 O=99.76%， 17 O=0.04%， 18 O=0.20%。
the term "isotopic enrichment index" as used in the present disclosure refers to the ratio of the abundance of a certain isotope to the natural abundance of that isotope. For example, a deuterium atom with an isotopic enrichment index of 6000 refers to a deuterium atom with an abundance of 90%.
The term "hydrogen" ("H") as used in this disclosure refers to a compound derived from a compound having the natural abundance of an isotope 1 H (99.985%) and 2 h (0.015%) hydrogen.
The term "deuterium" ("D" and "D") as used in this disclosure refers to an isotope of hydrogen (H) having one proton and one neutron in the nucleus of the deuterium atom, with a natural abundance of the isotope of 0.015%. ' d x-y "refers to substitution with x to y deuterium atoms. For example, methoxy-d 3 Finger-tying CD 3 O-。
Detailed description of the preferred embodiments
In one aspect, the disclosure relates to triazine derivatives represented by general formula I, pharmaceutically acceptable salts, deuterides, prodrugs or metabolites thereof:
Figure 724077DEST_PATH_IMAGE005
wherein
R 1 、R 2 、R 3 、R 4 Selected from H or D;
rx is selected from hydrogen, deuterium, cyano, alkyl, alkenyl, alkynyl; wherein alkyl, alkenyl, alkynyl may be substituted with 1 to 3 deuterium, halogen, hydroxy, cyano or alkoxy groups; ring A is a five-membered N-containing heteroaromatic ring optionally substituted by mR of (A) to (B) a Substituted;
x, Y and Z are independently selected from C, N, O or S;
R a each independently selected from hydrogen, deuterium, halogen, nitro, cyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
m = 1、2、3、4；
R b selected from hydrogen, deuterium, halogen, cyano, substituted alkoxy;
h =2、3、4；
w or Q is selected from hydrogen, deuterium, halogen, substituted alkyl.
In certain embodiments, ring a is not a heteroaromatic ring containing three N.
In certain embodiments, R a Each independently selected from hydrogen, deuterium, halogen, cyano, C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, C 1 -C 4 Deuterated alkyl or C 3 -C 6 A cycloalkyl group.
In certain embodiments, R x Selected from C substituted by one or more deuterium, halogen 1 -C 4 An alkyl group.
In certain embodiments, R a Each independently selected from hydrogen, deuterium, halogen, cyano, methyl, isopropyl, cyclopropyl, -CF 3 、-CHF 2 or-CD 3 。
In certain embodiments, R x Is C substituted by one or more deuterium 1 -C 4 An alkyl group.
In certain embodiments, Q is Cl or Br; w is deuterium.
In certain embodiments, the five-membered heteroaromatic ring a is selected from:
Figure 301689DEST_PATH_IMAGE006
。
in certain embodiments, the five-membered heteroaromatic ring a is selected from:
Figure 21383DEST_PATH_IMAGE007
。
in certain embodiments, by R b The substituted benzene ring is selected from the group consisting of:
Figure 862300DEST_PATH_IMAGE008
。
in certain embodiments, by R b The substituted benzene ring is selected from the group consisting of:
Figure 464183DEST_PATH_IMAGE009
。
in certain embodiments, by R b The substituted benzene ring is selected from the group consisting of:
Figure 48748DEST_PATH_IMAGE010
。
in certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 200, i.e., the abundance of deuterium atoms as a substituent is 3%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 400, i.e., the abundance of deuterium atoms as a substituent is 6%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 666.67, i.e., the abundance of deuterium atoms as a substituent is 10%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 1000, i.e., the abundance of deuterium atoms as a substituent is 15%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 2000, i.e., the abundance of deuterium atoms as a substituent is 30%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 3333.33, i.e., the abundance of deuterium atoms as a substituent is 50%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 4000, i.e., the abundance of deuterium atoms as a substituent is 60%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 5000, i.e., the abundance of deuterium atoms as a substituent is 75%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 6000, i.e., the abundance of deuterium atoms as a substituent is 90%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 6333.33, i.e., the abundance of deuterium atoms as a substituent is 95%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 6466.67, i.e., the abundance of deuterium atoms as a substituent is 97%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 6533.33, i.e., the abundance of deuterium atoms as a substituent is 98%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 6566.67, i.e., the abundance of deuterium atoms as a substituent is 98.5%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 6600, i.e., the abundance of deuterium atoms as a substituent is 99%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 6633.33, i.e., the abundance of deuterium atoms as a substituent is 99.5%.
In certain embodiments, the deuterium atom as a substituent has an isotopic enrichment index of 6660, i.e., the abundance of deuterium atoms as a substituent is 99.9%.
In certain embodiments, the triazine derivative, pharmaceutically acceptable salt, isomer, prodrug, or metabolite thereof of the present disclosure has an abundance of deuterium atom as a substituent of at least 60%, while other isotopes have their natural abundance.
In certain embodiments, the triazine derivative, pharmaceutically acceptable salt, isomer, prodrug, or metabolite thereof of the present disclosure has an abundance of deuterium atom as a substituent of at least 75%, while other isotopes have their natural abundance.
In certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, isomers, prodrugs, or metabolites thereof of the present disclosure have an abundance of deuterium atoms as substituents of at least 90%, while other isotopes have their natural abundance.
In certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, isomers, prodrugs, or metabolites thereof of the present disclosure have an abundance of deuterium atoms as substituents of at least 95%, while other isotopes have their natural abundance.
In certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, isomers, prodrugs, or metabolites thereof of the present disclosure have an abundance of deuterium atoms as substituents of at least 97%, while other isotopes have their natural abundance.
In certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, isomers, prodrugs, or metabolites thereof of the present disclosure have an abundance of deuterium atoms as substituents of at least 98%, while other isotopes have their natural abundance.
In certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, isomers, prodrugs, or metabolites thereof of the present disclosure have an abundance of deuterium atoms as substituents of at least 98.5%, while other isotopes have their natural abundance.
In certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, isomers, prodrugs, or metabolites thereof of the present disclosure have an abundance of deuterium atoms as substituents of at least 99%, while other isotopes have their natural abundance.
In certain embodiments, the triazine derivative, pharmaceutically acceptable salt, isomer, prodrug, or metabolite thereof of the present disclosure has an abundance of deuterium atom as a substituent of at least 99.5%, while other isotopes have their natural abundance.
In another aspect, the present disclosure relates to triazine derivatives, pharmaceutically acceptable salts, deuterides, prodrugs, or metabolites thereof as shown below:
Figure 419686DEST_PATH_IMAGE011
Figure 431505DEST_PATH_IMAGE012
Figure 255104DEST_PATH_IMAGE013
。
in certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, deuterons, prodrugs, or metabolites thereof of the present disclosure have superior therapeutic effects on viral infectious diseases.
In certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, deuterons, prodrugs, or metabolites thereof of the present disclosure have superior therapeutic effects on coronavirus infectious diseases.
In certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, deuterons, prodrugs, or metabolites thereof of the present disclosure are 3Clpro non-covalent small molecule inhibitors with significant activity.
In certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, deuterons, prodrugs, or metabolites thereof of the present disclosure are effective in increasing blood levels, extending half-lives, and significantly reducing single dose.
Pharmaceutical composition
In yet another aspect, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a triazine derivative represented by formula I, a pharmaceutically acceptable salt, a deuteron, a prodrug, or a metabolite thereof,
Figure 643360DEST_PATH_IMAGE014
wherein
R 1 、R 2 、R 3 、R 4 Selected from H or D;
rx is selected from hydrogen, deuterium, cyano, alkyl, alkenyl, alkynyl; wherein alkyl, alkenyl, alkynyl may be substituted with 1 to 3 of deuterium, halogen, hydroxy, cyano or alkoxy; ring A is a five-membered N-containing heteroaromatic ring, optionally substituted with m R a Substituted;
x, Y and Z are independently selected from C, N, O or S;
R a each independently selected from hydrogen, deuterium, halogen, nitro, cyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
m = 1、2、3、4；
R b selected from hydrogen, deuterium, halogen, cyano, substituted alkoxy;
h =2、3、4；
w or Q is selected from hydrogen, deuterium, halogen, substituted alkyl,
and a pharmaceutically acceptable carrier, excipient or diluent.
In certain embodiments, the pharmaceutical compositions of the present disclosure comprise a physiologically acceptable surfactant, carrier, diluent, excipient, smoothing agent, suspending agent, film-forming substance, coating aid, or combination thereof, and a compound of the present disclosure, a pharmaceutically acceptable salt, deuteride, prodrug, or metabolite thereof. Acceptable carriers or diluents for therapeutic use are well known in the Pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, 18 th Ed., mack Publishing co., easton, PA (1990)), the entire contents of which are incorporated herein by reference.
Preservatives, stabilizers, dyes, sweeteners, flavoring agents, perfumes and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used.
In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methyl aluminate silicate, synthetic aluminum silicate, calcium carbonate, calcium hydrogen phosphate, calcium hydroxymethylcellulose, etc. can be used as excipients; magnesium stearate, talc, hardened oil, etc. can be used as the smoothing agent; coconut oil, olive oil, sesame oil, peanut oil, soybean can be used as suspension or lubricant; cellulose acetate phthalate, which is a derivative of a saccharide such as cellulose or a sugar, or a methyl acetate-methacrylate copolymer, which is a derivative of polyethylene, may be used as the suspension; and plasticizers such as phthalate esters and the like may be used as the suspending agent.
Suitable routes of administration may include, for example, oral, rectal, transmucosal, topical or enteral administration; parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections. The compounds can also be administered in sustained or controlled release dosage forms including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches and the like, for extended and/or timed, pulsatile administration at a predetermined rate.
The pharmaceutical compositions of the present disclosure may be manufactured in accordance with known procedures, for example, by means of conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, entrapping or tableting operations.
Thus, in accordance with the present disclosure, the pharmaceutical compositions employed may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Suitable formulations depend on the chosen route of administration. Any known techniques, carriers and excipients may be used as is appropriate and understood in the art.
Injections can be prepared in the following conventional forms: as a solution or suspension, a solid dosage form suitable for formulation as a solution or suspension prior to injection, or as an emulsion. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In addition, the injectable pharmaceutical composition may contain, if necessary, small amounts of non-toxic auxiliary substances such as wetting agents, pH buffering agents and the like. Physiologically suitable buffers include, but are not limited to, hank's solution, ringer's solution, or physiological saline buffer. If desired, absorption enhancing agents (e.g., liposomes) can be used.
For transmucosal administration, penetrants appropriate to the permeation barrier to be used in the formulation.
Pharmaceutical preparations for parenteral administration, for example by bolus injection or continuous infusion, comprise aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or carriers include fatty oils such as sesame oil and the like, or other organic oils such as soybean oil, grapefruit oil or almond oil and the like, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, for example, sodium hydroxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that enhance the solubility of the compound to produce a highly concentrated formulation. Formulations for injection and additional preservatives may be presented in unit dosage form, for example, in ampoules or in multi-dose containers. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
For oral administration, the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. A pharmaceutical preparation for oral administration can be obtained by: the active compound is mixed with a solid excipient, the resulting mixture is optionally ground and the mixture of granules is processed, if desired after addition of suitable auxiliaries, to obtain tablets or dragee cores. Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations, for example maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, for example cross-linked polyvinylpyrrolidone, agar or alginic acid or an alginate such as sodium alginate. The lozenge cores are suitably coated. For this purpose, concentrated sugar solutions may be used, which may optionally comprise gum arabic, talc, polyvinylpyrrolidone, carbopol gel (carbopol gel), polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings in order to identify or characterize different combinations of active compound doses. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings in order to identify or characterize different combinations of active compound doses.
Pharmaceutical formulations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, such as glycerol or sorbitol, and a plasticizer. Push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
For buccal administration, the compositions may be formulated in conventional manner into tablets or lozenges.
For administration by inhalation, the compounds for use in the present disclosure are conveniently delivered in the form of a spray from a pressurized pack or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The present disclosure also discloses various pharmaceutical compositions known in the pharmaceutical art for delivery including intraocular, intranasal, and otic. Penetrants suitable for such use are generally known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compounds in water-soluble form, for example as eye drops, or in the form of gellan gum or as hydrogels; ophthalmic ointments; ophthalmic suspensions, such as microparticles, suspensions comprising small polymeric particles, liposoluble formulations, and microspheres in a liquid carrier medium; and an ocular insert. These suitable pharmaceutical formulations are most often and preferably formulated as sterile, isotonic and buffered pharmaceutical formulations for stability and comfort. Pharmaceutical compositions for intranasal delivery may also include drops and sprays, which are generally prepared to mimic nasal secretions in many respects to ensure that normal ciliary action is maintained. As is well known to those skilled in the art, suitable formulations are most often and preferably isotonic, lightly buffered to maintain pH between 5.5 and 6.5, and they most often and preferably include an antimicrobial preservative and a suitable pharmaceutical stabilizer. Pharmaceutical formulations for intraaural delivery include suspensions and ointments that are applied topically in the ear. Common solvents for such otic formulations include glycerin and water.
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
In addition to the foregoing formulations, the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated using suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives such as a sparingly soluble salt.
For hydrophobic compounds, a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The common cosolvent system used is a VPD cosolvent system which is 3% w/v benzyl alcohol, 8% w/v the non-polar surfactant POLYSORBATE (POLYSORBATE) 80TM and 65% w/v polyethylene glycol 300 and the volume of solution is made up by absolute ethanol. Of course, the proportions of the co-solvent system can be varied considerably without destroying its solubility and toxicity characteristics. In addition, the co-solvent composition may be varied: for example, other low toxicity non-polar surfactants may be used in place of polysorbate 80TM; the size of the polyethylene glycol fragment can be changed; other biocompatible polymers such as polyvinylpyrrolidone and the like may be substituted for the polyethylene glycol; and other sugars or polysaccharides may be substituted for glucose.
Alternatively, other delivery systems for hydrophobic drug compounds may be employed. Well-known examples of delivery vehicles or carriers for hydrophobic drugs are liposomes and emulsions. Although usually at the expense of higher toxicity, certain organic solvents, such as dimethylsulfoxide, can also be employed. In addition, compounds may be delivered using sustained release systems, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Many sustained release materials are known and established by those skilled in the art. Sustained release capsules can release the compound over several weeks to 100 days, depending on their chemical nature.
Agents for intracellular administration are administered using techniques well known to those of ordinary skill in the art. For example, such agents may be encapsulated into liposomes. Upon formation of the liposomes, all molecules present in the aqueous solution are incorporated into the aqueous interior. The inclusion of the liposome is not only not affected by the external micro-environment, but also efficiently delivered to the cytoplasm due to the fusion of the liposome with the cell membrane. Liposomes may be coated with tissue-specific antibodies. The liposomes will be targeted to and selectively absorbed by the desired organ. Alternatively, small hydrophobic organic molecules can be administered directly intracellularly.
Methods of treatment and uses
In yet another aspect, the present disclosure relates to a method of treating and/or preventing a viral infectious disease, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a triazine derivative represented by formula I, a pharmaceutically acceptable salt, deuteron, prodrug or metabolite thereof, or a therapeutically or prophylactically effective amount of a pharmaceutical composition comprising a triazine derivative represented by formula I, a pharmaceutically acceptable salt, deuteron, prodrug or metabolite thereof:
Figure 868805DEST_PATH_IMAGE014
wherein
R 1 、R 2 、R 3 、R 4 Selected from H or D;
rx is selected from hydrogen, deuterium, cyano, alkyl, alkenyl, alkynyl; wherein alkyl, alkenyl, alkynyl may be substituted with 1 to 3 of deuterium, halogen, hydroxy, cyano or alkoxy; ring A is a five-membered N-containing heteroaromatic ring, optionally substituted with m R a Substituted;
x, Y and Z are independently selected from C, N, O or S;
R a each independently selected from hydrogen, deuterium, halogen, nitro, cyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
m = 1、2、3、4；
R b selected from hydrogen, deuterium, halogen, cyano, substituted alkoxy;
h =2、3、4；
w or Q is selected from hydrogen, deuterium, halogen, substituted alkyl.
In certain embodiments, illustrative examples of viruses that can be used in the present disclosure include, but are not limited to, middle east syndrome-associated coronavirus (MERS-CoV), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), influenza a virus, influenza b virus, novel coronavirus (covi-19), spanish influenza virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, poliovirus, rhinovirus, adenovirus, ebola virus, enterovirus, hepatitis a virus, hepatitis c virus, hepatitis e virus, enterovirus, HIV virus, echovirus, filovirus, measles virus, yellow fever virus, japanese encephalitis virus, west nile virus, newcastle disease virus, RS virus, vesicular stomatitis virus, mumps virus, dengue virus, coxsackie virus, rotavirus, or tobacco mosaic virus.
In certain embodiments, illustrative examples of individuals that can be used in the present disclosure include, but are not limited to, mammals.
In certain embodiments, the subject useful in the present disclosure is a human.
In certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, deuterons, prodrugs, or metabolites thereof of the present disclosure have superior therapeutic effects on coronavirus infectious diseases.
In another aspect, the present disclosure relates to a method of inhibiting a 3C-like cysteine protease (3 Clpro), comprising contacting a triazine derivative represented by formula I, a pharmaceutically acceptable salt, deuteron, prodrug, or metabolite thereof, or a pharmaceutical composition comprising a triazine derivative represented by formula I, a pharmaceutically acceptable salt, deuteron, prodrug, or metabolite thereof, in an amount effective to inhibit, with the 3C-like cysteine protease (3 Clpro):
Figure 851192DEST_PATH_IMAGE015
wherein
R 1 、R 2 、R 3 、R 4 Selected from H or D;
rx is selected from hydrogen, deuterium, cyano, alkyl, alkenyl, alkynyl; wherein alkyl, alkenyl, alkynyl may be substituted with 1 to 3 of deuterium, halogen, hydroxy, cyano or alkoxy; ring A is a five-membered N-containing heteroaromatic ring, optionally substituted with m R a Substituted;
x, Y, Z are each independently selected from C, N, O or S;
R a each independently selected from hydrogen, deuterium, halogen, nitro, cyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
m = 1、2、3、4；
R b selected from hydrogen, deuterium, halogen, cyano, substituted alkoxy;
h =2、3、4；
w or Q is selected from hydrogen, deuterium, halogen, substituted alkyl.
In certain embodiments, the triazine derivatives, pharmaceutically acceptable salts, deuterons, prodrugs, or metabolites thereof of the present disclosure are 3Clpro non-covalent small molecule inhibitors with significant activity.
In yet another aspect, the present disclosure relates to the use of a triazine derivative represented by general formula I, a pharmaceutically acceptable salt, a deuterode, a prodrug, or a metabolite thereof in the preparation of a medicament for treating and/or preventing a viral infectious disease in an individual:
Figure 427667DEST_PATH_IMAGE014
wherein
R 1 、R 2 、R 3 、R 4 Selected from H or D;
rx is selected from hydrogen, deuterium, cyano, alkyl, alkenyl, alkynyl; wherein alkyl, alkenyl, alkynyl may be substituted with 1 to 3 deuterium, halogen, hydroxy, cyano or alkoxy groups; ring A is a five-membered N-containing heteroaromatic ring, optionally substituted with m R a Substituted;
x, Y, Z are each independently selected from C, N, O or S;
R a each independently selected from hydrogen, deuterium, halogen, nitroCyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
m = 1、2、3、4；
R b selected from hydrogen, deuterium, halogen, cyano, substituted alkoxy;
h =2、3、4；
w or Q is selected from hydrogen, deuterium, halogen, substituted alkyl.
In yet another aspect, the present disclosure relates to the use of a triazine derivative represented by general formula I, a pharmaceutically acceptable salt, a deuteron, a prodrug, or a metabolite thereof, for the preparation of a 3C-like cysteine protease (3 Clpro) inhibitor:
Figure 354035DEST_PATH_IMAGE014
wherein
R 1 、R 2 、R 3 、R 4 Selected from H or D;
rx is selected from hydrogen, deuterium, cyano, alkyl, alkenyl, alkynyl; wherein alkyl, alkenyl, alkynyl may be substituted with 1 to 3 of deuterium, halogen, hydroxy, cyano or alkoxy; ring A is a five-membered heteroaromatic ring containing N and is substituted with m optional R a Substituted;
x, Y and Z are independently selected from C, N, O or S;
R a each independently selected from hydrogen, deuterium, halogen, nitro, cyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
m = 1、2、3、4；
R b selected from hydrogen, deuterium, halogen, cyano, substituted alkoxy;
h =2、3、4；
w or Q is selected from hydrogen, deuterium, halogen, substituted alkyl.
In another aspect, the present disclosure relates to triazine derivatives of formula I, pharmaceutically acceptable salts, deuterons, prodrugs or metabolites thereof for use in the treatment and/or prevention of viral infectious diseases:
Figure 433986DEST_PATH_IMAGE014
wherein
R 1 、R 2 、R 3 、R 4 Selected from H or D;
rx is selected from hydrogen, deuterium, cyano, alkyl, alkenyl, alkynyl; wherein alkyl, alkenyl, alkynyl may be substituted with 1 to 3 of deuterium, halogen, hydroxy, cyano or alkoxy; ring A is a five-membered heteroaromatic ring containing N and is substituted with m optional R a Substituted;
x, Y and Z are independently selected from C, N, O or S;
R a each independently selected from hydrogen, deuterium, halogen, nitro, cyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
m = 1、2、3、4；
R b selected from hydrogen, deuterium, halogen, cyano, substituted alkoxy;
h =2、3、4；
w or Q is selected from hydrogen, deuterium, halogen, substituted alkyl.
In yet another aspect, the present disclosure relates to triazine derivatives of formula I, pharmaceutically acceptable salts, deuterides, prodrugs or metabolites thereof, for use in inhibiting a 3C-like cysteine protease (3 Clpro):
Figure 53186DEST_PATH_IMAGE014
wherein
R 1 、R 2 、R 3 、R 4 Selected from H or D;
rx is selected from hydrogen, deuterium, cyano, alkyl, alkenyl, alkynyl; wherein alkyl, alkenyl, alkynyl may be substituted with 1 to 3 of deuterium, halogen, hydroxy, cyano or alkoxy; ring A is a five-membered heteroaromatic ring containing N and is substituted with m optional R a Substituted;
x, Y, Z are each independently selected from C, N, O or S;
R a each independently selected from hydrogen, deuterium, halogen, nitro, cyano, oxo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl;
m = 1、2、3、4；
R b selected from hydrogen, deuterium, halogen, cyano, substituted alkoxy;
h =2、3、4；
w or Q is selected from hydrogen, deuterium, halogen, substituted alkyl.
Method of administration
The compound or pharmaceutical composition can be administered to the patient by any suitable method. Non-limiting examples of methods of administration include (a) administration by oral route, including administration in capsules, tablets, granules, sprays, syrups, or other such forms; (b) By non-oral routes of administration, such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraaural, including administration in aqueous suspensions, oily formulations, and the like, or in drops, sprays, suppositories, salves, ointments, and the like; (c) The administration is carried out by subcutaneous injection, intraperitoneal injection, intravenous injection, intramuscular injection, intradermal injection, intraorbital injection, intravesicular injection, intraspinal injection, intrasternal injection and the like, and comprises the delivery of an infusion pump; (d) Local (locally) administration such as injection directly in the kidney region or heart region, for example by depot implantation; and I topical (topically) administration; a suitable mode of administration, as recognized by one skilled in the art, is contact of the compounds of the present invention with living tissue.
The most suitable route depends on the nature and severity of the disease state being treated. Those skilled in the art are also familiar with determining methods of administration (oral, intravenous, inhalation, subcutaneous, rectal, etc.), dosage forms, appropriate pharmaceutical excipients, and other matters relevant to the delivery of a compound to a subject in need thereof.
Pharmaceutical compositions suitable for administration include compositions which contain an effective amount of the active ingredient to achieve its intended effect. The dosage required for a therapeutically effective amount of the disclosed pharmaceutical composition depends on the route of administration, the type of animal being treated, including humans, and the physical characteristics of the particular animal under consideration. The dosage may be adjusted to achieve the desired effect, but this will depend on the following factors: body weight, diet, concurrent medication, and other factors recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to an amount of a compound effective to prevent, alleviate or ameliorate symptoms of a disease, or to prolong the lifespan of the subject being treated. The determination of a therapeutically effective amount is well within the practical capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.
As will be apparent to those skilled in the art, the dosage and specific mode of administration for in vivo administration will vary depending upon the age, weight and type of mammal being treated, the specific compound employed and the specific use of the compounds employed. The determination of effective dosage levels, i.e., the dosage levels necessary to determine the desired effect, can be accomplished by those skilled in the art using conventional pharmacological procedures. Generally, clinical use of the compounds in humans is initiated at lower dosage levels, with increasing dosage levels until the desired effect is achieved. Alternatively, using established pharmacological methods, acceptable in vitro studies can be used to establish effective dosages and routes of administration for the compositions identified by the methods.
In non-human animal studies, the use of potential compounds begins at higher dose levels with dose reduction until the desired effect is no longer achieved or the adverse side effects disappear. The dosage range may be broader depending on the desired effect and the therapeutic indication. In general, the dosage may be from about 10. Mu.g/kg body weight to 500mg/kg body weight, preferably from about 100. Mu.g/kg body weight to 200mg/kg body weight. Alternatively, as will be appreciated by those skilled in the art, the dose may be based on and calculated in accordance with the surface area of the patient.
The exact formulation, route of administration and dosage of the pharmaceutical compositions of the present invention can be selected by the physician in accordance with the condition of the patient. In general, the dosage range of the composition administered to a patient may be inAbout 0.5mg/kg to 1000mg/kg of patient body weight. The dosage may be administered once or twice or more times during one or more days alone, as required by the patient. Where human dosages of the compounds are established for at least certain conditions, the invention will employ those same dosages, or established human dosages in the range of about 0.1% to 500%, more preferably in the range of 25% to 250%. In the absence of a defined human dose, as in the case of the newly discovered pharmaceutical compounds, a suitable human dose can be derived from ED 50 Or ID 50 Values, or other suitable values from in vitro or in vivo studies, are extrapolated as quantified in toxicity studies and efficacy studies in animals.
It should be noted that due to toxicity and organ dysfunction, the attending physician will know how and when to terminate, interrupt or adjust administration. Conversely, if the clinical response is inadequate (to preclude toxicity), the attending physician will also know to adjust the treatment to higher levels. The size of the dose administered in the treatment of a condition of interest will vary with the severity of the disease state to be treated and the route of administration. The severity of the disease state can be assessed, for example, in part, by standard prognostic assessment methods. In addition, the dose and possibly dose frequency will also vary according to the age, weight, and response of the individual patient. Protocols comparable to those discussed above may be used in veterinary medicine.
While the exact dose can be determined on a drug-by-drug basis, in most cases, some generalizations can be made about the agent. The daily dosage regimen for an adult patient is, for example, an oral dose of from 0.1mg to 2000mg of each active ingredient, preferably from 1mg to 1000mg of each active ingredient, for example from 5 to 500mg of each active ingredient. In other embodiments, the intravenous, subcutaneous or intramuscular dose of each active ingredient used is from 0.01mg to 1000mg, preferably from 0.1mg to 800mg, for example from 1 to 200mg. In the case of administration of pharmaceutically acceptable salts, the dosage can be calculated as the free base. In certain embodiments, the composition is administered from 1 to 4 times daily. Alternatively, the compositions of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to 1000mg of each active ingredient per day. As will be appreciated by those skilled in the art, in certain circumstances, it may be necessary to administer the disclosed compounds in amounts exceeding or far exceeding the preferred dosage ranges described above in order to effectively and rapidly treat a rapidly developing disease or infection. In certain embodiments, the compound is administered during continuous treatment, e.g., for a week or weeks, or months or years.
The dose and dosage interval may be adjusted individually to provide plasma levels of the active moiety sufficient to maintain the modulating effect or Minimum Effective Concentration (MEC). The MEC for each compound was different, but MEC could be assessed from in vitro data. The required dose to achieve MEC depends on the individual characteristics and the route of administration. However, plasma concentrations can be determined using HPLC assays or bioassays.
Dosing intervals can also be determined using MEC values. The composition should be administered using a treatment regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably 30-90% of the time, and more preferably 50-90% of the time.
In the case of topical administration or selective absorption, the effective local concentration of the drug is independent of plasma concentration.
The amount of the composition to be administered will, of course, depend on the individual to be treated, on the weight of said individual, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.
The potency and toxicity of the compounds disclosed herein can be assessed using known methods. For example, the toxicology of a particular compound or a subset of such compounds sharing certain chemical moieties can be established by determining the toxicity of a cell line, e.g., a mammalian cell line and preferably a human cell line, in vitro. The results of such studies can generally predict toxicity in animals, such as mammals, or more specifically, in humans. Alternatively, toxicity of a particular compound in an animal model such as mouse, rat, rabbit or monkey can be determined using known methods. The potency of a particular compound can be determined using several recognized methods, such as in vitro methods, animal models, or human clinical trials. There are well-established in vitro models for almost every class of disease states, including but not limited to cancer, cardiovascular disease, and various immune dysfunctions. Similarly, acceptable animal models can be used to determine the efficacy of chemical drugs for treating these disease states. When selecting a model to determine efficacy, the skilled person is able to select an appropriate model, dosage and route of administration and treatment regimen under the guidance of the state of the art. Of course, human clinical trials can also be used to determine the efficacy of compounds in humans.
If desired, the compositions can be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The package may for example comprise a metal or plastic foil, such as a blister pack. The packaging or dispensing device may carry instructions for administration. The packaging or dispensing device may also carry a notice associated with the container, the notice being mandated by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, the notice reflecting approval by the agency of the pharmaceutical form for human or veterinary administration. Such notice, for example, may be a label approved by the U.S. food and drug administration for prescription drugs, or an approved product insert. Compositions comprising the compounds of the invention may also be prepared in a suitable container, placed in a compatible pharmaceutical carrier, and labeled for treatment of a given disease state.
Preparation of the Compounds
The following reaction schemes illustrate methods for preparing compounds of the present disclosure, i.e., compounds of formula I, or pharmaceutically acceptable salts, deuterons, prodrugs or metabolites thereof, in the form of stereoisomers, cis-trans isomers, tautomers, or mixtures thereof,
Figure 54640DEST_PATH_IMAGE014
wherein R is 1 、R 2 、R 3 、R 4 、R a 、R b 、R x X, Y, Z, W, Q, m and h are as defined in the disclosure.
It will be appreciated that combinations of substituents and/or variables of the formulae depicted in the description below are permissible only if such combinations result in stable compounds.
It will also be appreciated by those skilled in the art that in the processes described below, the functional groups of the intermediate compounds may need to be protected by suitable protecting groups. These functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxyl groups include trialkylsilyl or diaralkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl and the like. Suitable protecting groups for mercapto include-C (O) -R '' (wherein R '' is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acids include alkyl, aryl or aralkyl esters.
Protecting groups may be added or removed according to standard techniques known to those skilled in the art and as described herein.
The use of protecting groups is described in detail in Green, t.w.and p.g.m.wuts, protective group organic Synthesis (organic synthetic protecting groups) (1999), 3rd ed., wiley. The protecting group may also be a polymer resin, such as Wang resin or chlorinated 2-chlorotrityl methane resin.
One skilled in the art will also appreciate that while these protected derivatives of the compounds of the present disclosure may not be pharmacologically active themselves, they may be administered to a mammal and then metabolized in the body to form pharmacologically active compounds of the present disclosure. These derivatives may thus be described as "prodrugs". All prodrugs of the compounds of the present disclosure are included within the scope of the present disclosure.
The following reaction schemes illustrate methods for preparing the compounds of the present disclosure. It will be appreciated that those skilled in the art can prepare these compounds by analogous methods or by methods known to those skilled in the art. It will also be appreciated that those skilled in the art will be able to produce other compounds of formula I not explicitly illustrated below in a similar manner to that described below, using appropriate starting materials and modifying the synthesis parameters as required. In general, the starting components can be obtained from common commercial sources, or synthesized according to sources known to those skilled in the art or prepared as described herein.
In the reaction formulae below, the structures of the various groups are as defined in this disclosure.
Generally, the compounds of general formula I of the present disclosure can be synthesized following the general procedure as described in scheme 1 below.
Figure 581437DEST_PATH_IMAGE016
Reaction scheme 1
In equation 1, the structures of the groups are as defined in the disclosure. The compounds may each exist as stereoisomers, cis-trans isomers, tautomers, or mixtures thereof.
Hereinafter, the present disclosure will be explained in detail by the following examples in order to better understand various aspects of the present disclosure and advantages thereof. It should be understood, however, that the following examples are not limiting and are merely illustrative of certain embodiments of the present disclosure.
Examples
Although any person skilled in the art can prepare the compounds of the present application in accordance with the general techniques disclosed above, more detailed synthetic techniques for the compounds of the present application are provided elsewhere in the specification for convenience. In addition, all reagents and reaction conditions used in the synthesis are known to those skilled in the art and can be obtained from common commercial sources. For example, various reagents used in the examples, including deuterated reagents, are commercially available from Sigma-Aldrich Company Ltd. The various cell lines and enzymes used in the examples are commercially available, for example, from the cell bank of the committee for type culture collection of the academy of sciences of china.
Unless otherwise stated in the context of the present invention, 1 HNMR was measured using deuterated dimethyl sulfoxide at a frequency of 500MHz at about 20-30 ℃. Standard NMR abbreviations are used: s = singlet; d = double peak; dd = bimodal; t = triplet peak; q = quartet; p = quintuple; m = multiplet; br = broadband.
Preparation of example 1
Synthesis of Compound 1
Figure 515895DEST_PATH_IMAGE017
(1) Synthesis of Compound 1-C
Compound 1-A (1 g, 4.36 mmol) was dissolved in acetonitrile (25 mL), and to the above solution were added potassium carbonate (0.72 g, 5.23 mmol) and compound 1-B (1.09 g, 4.80 mmol), and the reaction was heated under reflux for 2 h. Cooling to room temperature, diluting the reaction solution with ethyl acetate, filtering, concentrating the filtrate, and purifying by column chromatography to obtain compound 1-C (1.55 g, 95%).
(2) Synthesis of Compound 1-D
To compound 1-C (1.50 g, 4.02 mmol) was added TFA (10 mL), the reaction was stirred at room temperature overnight, concentrated, slurried with isopropyl ether, filtered, the filter cake collected, and dried to give compound 1-D (1.15 g, 90%).
(3) Synthesis of Compound 1-F
Compound 1-D (1 g, 3.15 mmol) was dissolved in DMF (25 mL), to the above solution were added potassium carbonate (0.52 g, 3.78 mmol) and compound 1-E (0.46 g, 3.47 mmol), and the reaction was heated under reflux for 2 h. Cooling to room temperature, diluting the reaction solution with ethyl acetate, filtering, concentrating the filtrate, and purifying by column chromatography to obtain compound 1-F (1.13 g, 87%).
(4) Synthesis of Compound 1
To a solution of the compounds 1-F (700 mg, 1.70 mmol) and 1-G (345 mg, 1.87 mmol) in tetrahydrofuran at 0 ℃ was added dropwise a solution of LiHMDS in tetrahydrofuran (1M, 1.87 mL,1.87 mmol), stirred at 0 ℃ for 3 h, and then transferred to room temperature and stirred for 40 min. After completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine and freed from impuritiesWater Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography gave compound 1 (663 mg, 73%).
Preparation of example 2
Synthesis of Compound 16
Figure 305996DEST_PATH_IMAGE018
(1) Synthesis of Compound 16-C
Compound 1-A (1 g, 4.36 mmol) was dissolved in acetonitrile (25 mL), and to the above solution were added potassium carbonate (0.8 g, 5.79 mmol) and compound 16-B (1.10 g, 4.82 mmol), and the reaction was heated under reflux for 3 h. Cooling to room temperature, diluting the reaction solution with ethyl acetate, filtering, concentrating the filtrate, and purifying by column chromatography to obtain compound 1-C (1.6 g, 98%).
(2) Synthesis of Compound 16-D
To compound 16-C (1.6 g, 4.29 mmol) was added TFA (15 mL), the reaction was stirred at room temperature overnight, concentrated, slurried with isopropyl ether, filtered, the filter cake collected, and dried to afford compound 16-D (1.16 g, 85%).
(3) Synthesis of Compound 16-F
Compound 16-D (1.1 g, 3.47 mmol) was dissolved in DMF (30 mL), to the above solution were added potassium carbonate (0.6 g, 4.34 mmol) and compound 16-E (0.5 g, 3.74 mmol), and the reaction was heated under reflux for 1 h. Cooling to room temperature, diluting the reaction solution with ethyl acetate, filtering, concentrating the filtrate, and purifying by column chromatography to obtain compound 16-F (1.2 g, 83%).
(4) Synthesis of Compound 16
To a solution of compound 16-F (800 mg, 1.93 mmol) and 1-G (370 mg, 2.0 mmol) in tetrahydrofuran was added dropwise a solution of LiHMDS in tetrahydrofuran (1M, 2.1 mL,2.1 mmol) at 0 deg.C, stirred for 3 h while maintaining 0 deg.C, and then transferred to room temperature and stirred for 1 h. After completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine, and washed with anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography gave compound 16 (703 mg, 68%).
Preparation of example 3
Synthesis of Compound 24
Figure 591484DEST_PATH_IMAGE019
(1) Synthesis of Compound 24
To a solution of compound 16-F (750 mg, 1.81 mmol) and 24-G (360 mg, 1.98 mmol) in tetrahydrofuran at 0 ℃ was added dropwise a solution of LiHMDS in tetrahydrofuran (1M, 2.0 mL,2.0 mmol), stirred for 2 h at 0 ℃ and then transferred to room temperature for 1 h. After completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography gave compound 24 (652 mg, 67%).
The other compound synthesis method is as in example 1, only need to change the corresponding raw materials.
Preparation of example 4
Synthesis of Compound 25
Figure 859654DEST_PATH_IMAGE020
(1) Synthesis of Compound 25-C
Compound 1-A (1 g, 4.36 mmol) was dissolved in acetonitrile (25 mL), to the above solution were added potassium carbonate (0.72 g, 5.23 mmol) and compound 25-B (1.09 g, 4.80 mmol), and the reaction was heated under reflux for 2 h. Cooling to room temperature, diluting the reaction solution with ethyl acetate, filtering, concentrating the filtrate, and purifying by column chromatography to obtain compound 25-C (1.40 g, 85%).
(2) Synthesis of Compound 25-D
To compound 25-C (1.40 g, 3.75 mmol) was added TFA (10 mL), the reaction was stirred at room temperature overnight, concentrated, slurried with isopropyl ether, filtered, the filter cake collected, and dried to give compound 25-D (1.1 g, 91%).
(3) Synthesis of Compound 25-F
Compound 25-D (1 g, 3.15 mmol) was dissolved in DMF (25 mL), potassium carbonate (0.52 g, 3.78 mmol) and compound 25-E (0.37 g, 3.15 mmol) were added to the above solution, and the reaction was heated at 75 h. Cooling to room temperature, diluting the reaction solution with ethyl acetate, filtering, concentrating the filtrate, and purifying by column chromatography to obtain compound 25-F (1.10 g, 88%).
(4) Synthesis of Compound 25
To a solution of compound 25-F (700 mg, 1.75 mmol) and 24-G (350 mg, 1.93 mmol) in tetrahydrofuran at 0 ℃ was added dropwise a solution of LiHMDS in tetrahydrofuran (1M, 2.1 mL,2.1 mmol), stirred for 3 h while maintaining 0 ℃, then transferred to room temperature and stirred for 40 min. After completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography gave compound 25 (350 mg, 38%).
Preparation of example 5
Synthesis of Compound 70
Figure 914198DEST_PATH_IMAGE021
(1) Synthesis of Compound 70
To a solution of compound 25-F (700 mg, 1.75 mmol) and 70-G (408 mg, 1.93 mmol) in tetrahydrofuran at 0 ℃ was added dropwise a solution of LiHMDS in tetrahydrofuran (1M, 2.1 mL,2.1 mmol), stirred for 3 h while maintaining 0 ℃, then transferred to room temperature and stirred for 40 min. After completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography gave compound 70 (300 mg, 31%).
Preparation of example 6
Synthesis of Compound 110
Figure 875201DEST_PATH_IMAGE022
(1) Synthesis of Compound 110
To a solution of the compound 25-F (700 mg, 1.75 mmol) and 110-G (354 mg, 1.93 mmol) in tetrahydrofuran at 0 ℃ was added dropwise tetrahydrofuran of LiHMDSThe solution of pyran (1M, 2.1 mL,2.1 mmol), maintained at 0 ℃ for 3 h with stirring, was then transferred to room temperature with stirring for 40 min. After completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine, and washed with anhydrous Na 2 SO 4 Drying, filtration, concentration, column chromatography purification gave compound 110 (260 mg, 28%).
Other compound synthesis methods, as in example 4, only required the corresponding raw material change.
Figure 382405DEST_PATH_IMAGE023
Figure 188687DEST_PATH_IMAGE024
Figure 363317DEST_PATH_IMAGE025
Figure 244290DEST_PATH_IMAGE026
Figure 504370DEST_PATH_IMAGE027
Figure 114343DEST_PATH_IMAGE028
Figure 409058DEST_PATH_IMAGE029
Figure 446284DEST_PATH_IMAGE030
Figure 193660DEST_PATH_IMAGE031
Figure 607324DEST_PATH_IMAGE032
Figure 490966DEST_PATH_IMAGE033
Figure 964673DEST_PATH_IMAGE034
Figure 933766DEST_PATH_IMAGE035
Figure 885542DEST_PATH_IMAGE036
Figure 889270DEST_PATH_IMAGE037
Figure 2719DEST_PATH_IMAGE038
Figure 459108DEST_PATH_IMAGE039
Figure 214575DEST_PATH_IMAGE040
Figure 72809DEST_PATH_IMAGE041
Figure 891248DEST_PATH_IMAGE042
Figure 100513DEST_PATH_IMAGE043
Figure 128512DEST_PATH_IMAGE044
Figure 841253DEST_PATH_IMAGE045
Figure 827663DEST_PATH_IMAGE046
Figure 55382DEST_PATH_IMAGE047
Figure 355914DEST_PATH_IMAGE048
Figure 923161DEST_PATH_IMAGE049
Figure 80473DEST_PATH_IMAGE050
Figure 264330DEST_PATH_IMAGE051
Biological example 1
In vitro potency assay for the antiviral potency of potential antiviral compounds against SARS-CoV-2
1. Object(s) to
The in vitro antiviral activity of potential antiviral compounds on SARS-CoV-2 Oncuronte hCoV-19/USA/MD HP20874/2021 (B.1.1.529) strain and hCoV-19/USA/Chicago IL/2022 (BA.5.2) strain was evaluated in an in vitro cell infection system.
2. Material
2.1 Reference compound
The reference compound, ridciclovir, is provided by IITRI. Compounds were assayed by setting 8 concentration points, 3 replicate wells.
2.2 Cell lines
Human lung cancer cell lines Calu-3 cells were cultured in minimal essential medium (EMEM) containing 10% heat-inactivated fetal bovine serum (Gibco, cat # A3840001), 100U/ml penicillin and streptomycin.
2.3 Reagent and apparatus
The main reagents used in this experiment were anti-coronavirus Nucleoprotein (NP) monoclonal antibodies, peroxidase-conjugated goat anti-mouse IgG, ABTS peroxidase.
The main instruments used in this test were an microplate reader and an ELISA plate reader.
3. Method for producing a composite material
Calu-3 cells were seeded in 96-well plates containing different fold-by-fold dilutions of the compounds, while the ormikrong variant virus strain with MOI =0.01 was added. Washing the virus-containing supernatant after 1 hour of incubation, replacing it with a medium containing a double dilution of the compound, and adjusting the concentration of CO to 5. + -.2% 2 And (3) for 48 hours in a humidifying chamber at 37 +/-2 ℃. The absorbance at 402 nm was measured using a microplate reader.
Absorbance readings from each well were collected by SoftMaxPro software and imported into Microsoft Excel spreadsheet for further calculations. Outliers were detected by the Grubbs test built into Graphpad Prism 9. Percent Virus Reduction (PVR) calculation for each well used the formula and the median inhibitory concentration (EC) was calculated by calculating the concentration-response curve for each test article by 4-parameter nonlinear regression curve fitting 50 )。
Figure 165290DEST_PATH_IMAGE052
Biological example 2
Rat model pharmacokinetic Property testing
Oral administration: compounds were administered at a dose of 10 mg/kg with Solutol: PEG400: tween80: salt = 10. Continuously taking blood from fundus venous plexus 0.25 h,0.5 h,1 h,2 h,4 h,8 h,10 h,12 h and 24 h after administration, placing in an EP tube containing EDTA, centrifuging at 8000 rpm/min for 5min, taking upper layer plasma, freezing at-80 deg.C, and analyzing by LC-MS/MS
Intravenous administration: the compounds were dosed at 1 mg/kg with 10% DMSO/30% PEG400/60% water). Continuously collecting blood from fundus venous plexus at 0.0833 h,0.25 h,0.5 h,1 h,2 h,4 h,8 h,12 h and 24 h after administration, placing in an EP tube containing EDTA, centrifuging at 8000 rpm/min for 5min, collecting upper layer plasma, freezing at-80 deg.C, and analyzing by LC-MS/MS
According to the blood concentration-time data obtained by testing, the pharmacokinetic parameters are calculated by adopting WinNonlin software.
Figure 852623DEST_PATH_IMAGE053
Biological example 3
Cynomolgus pharmacokinetic Property testing
Oral administration: compounds were dosed at 2 mg/kg with Solutol: PEG400: tween80: salt = 10. Continuously taking blood and placing in an EP tube containing EDTA 0.25 h,0.5 h,1 h,2 h,4 h,8 h,10 h,12 h and 24 h after administration, centrifuging at 8000 rpm/min for 5min, taking upper layer plasma, freezing at-80 deg.C, and analyzing by LC-MS/MS
Intravenous administration: the compounds were dosed at 1 mg/kg with 10% DMSO/30% PEG400/60% water). Continuously taking blood and placing in an EP tube containing EDTA at 0.0833 h,0.25 h,0.5 h,1 h,2 h,4 h,8 h,12 h and 24 h after administration, centrifuging at 8000 rpm/min for 5min, taking upper layer plasma, freezing at-80 deg.C, and analyzing by LC-MS/MS
According to the blood concentration-time data obtained by testing, the pharmacokinetic parameters are calculated by adopting WinNonlin software.
Figure 180836DEST_PATH_IMAGE054
In the present disclosure, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions.
All patents, patent application publications, patent applications, and non-patent publications cited in this specification are herein incorporated by reference in their entirety.
From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the disclosure. Accordingly, the scope of the disclosure should be limited only by the attached claims.

Claims (17)

1. Triazine derivatives represented by the general formula I, pharmaceutically acceptable salts, deuterides, prodrugs or metabolites thereof:
Figure 53829DEST_PATH_IMAGE001
wherein
R 1 、R 2 、R 3 、R 4 Selected from H or D;
rx is selected from hydrogen, deuterium, cyano, C 1 -C 4 Alkyl radical, C 2 -C 4 Alkenyl radical, C 2 -C 4 Alkynyl; wherein alkyl, alkenyl, alkynyl may be substituted with 1 to 3 of deuterium, halogen, hydroxy, cyano or alkoxy; ring A is a five-membered N-containing heteroaromatic ring, optionally substituted with m R a Substituted;
x, Y and Z are independently selected from C, N, O or S;
R a each independently selected from hydrogen, deuterium, halogen, nitro, cyano or C substituted by 1 to 3 of deuterium, halogen, hydroxy, cyano 1 -C 4 Alkyl radical, C 3 -C 6 A cycloalkyl group;
m = 1、2、3、4；
R b selected from hydrogen, deuterium, halogen, cyano, substituted alkoxy;
h =2、3、4；
w or Q is selected from hydrogen, deuterium, halogen, C 1 -C 4 A substituted alkyl group.
2. The triazine derivative, pharmaceutically acceptable salt thereof, deuterogen, prodrug, or metabolite of claim 1, wherein ring a is not a heteroaromatic ring containing three N.
3. The triazine derivative, a pharmaceutically acceptable salt thereof, a deutero-compound, a prodrug, or a metabolite thereof according to claim 1, wherein
R a Each independently selected from hydrogen, deuterium, halogen, cyano, C 1 -C 4 Alkyl radical, C 1 -C 4 Haloalkyl, C 1 -C 4 Deuterated alkyl or C 3 -C 6 A cycloalkyl group;
R x selected from C substituted by one or more deuterium, halogen 1 -C 4 An alkyl group.
4. The triazine derivative, a pharmaceutically acceptable salt thereof, a deutero-compound, a prodrug, or a metabolite thereof according to claim 1, wherein
R a Each independently selected from hydrogen, deuterium, halogen, cyano, methyl, isopropyl, cyclopropyl, -CF 3 、-CHF 2 or-CD 3 ；
R x Is C substituted by one or more deuterium 1 -C 4 An alkyl group.
5. The triazine derivative, a pharmaceutically acceptable salt thereof, a deutero-compound, a prodrug, or a metabolite thereof according to claim 1, wherein
Q is Cl or Br;
w is deuterium.
6. The triazine derivative, pharmaceutically acceptable salt thereof, deuterogen, prodrug, or metabolite of claim 1, wherein the five-membered heteroaromatic ring a is selected from the group consisting of:
Figure 236549DEST_PATH_IMAGE002
。
7. the triazine derivative, pharmaceutically acceptable salt, deuteron, prodrug, or metabolite thereof of claim 6, wherein the five-membered heteroaromatic ring a is selected from the group consisting of:
Figure 281865DEST_PATH_IMAGE003
。
8. the triazine derivative, pharmaceutically acceptable salt thereof, deuteron, prodrug, or metabolite of claim 1, wherein R is substituted with R b The substituted benzene ring is selected from the group consisting of:
Figure 444119DEST_PATH_IMAGE004
。
9. the triazine derivative, pharmaceutically acceptable salt, deuteron, prodrug, or metabolite thereof of claim 8, wherein R is substituted with R b The substituted benzene ring is selected from the group consisting of:
Figure 258491DEST_PATH_IMAGE005
。
10. the triazine derivative, pharmaceutically acceptable salt thereof, deuteron, prodrug, or metabolite of claim 9, wherein R is substituted with R b The substituted benzene ring is selected from the group consisting of:
Figure 346533DEST_PATH_IMAGE006
。
11. a triazine derivative, a pharmaceutically acceptable salt, a deutero-compound, a prodrug, or a metabolite thereof as shown below:
Figure 879145DEST_PATH_IMAGE007
Figure 343625DEST_PATH_IMAGE008
Figure 278083DEST_PATH_IMAGE009
。
12. a pharmaceutical composition comprising a therapeutically effective amount of a triazine derivative, pharmaceutically acceptable salt, deuteride, prodrug or metabolite thereof according to any one of claims 1 to 11, and a pharmaceutically acceptable carrier, diluent or excipient.
13. Use of a triazine derivative, a pharmaceutically acceptable salt, deuterode, prodrug or metabolite thereof according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 12 for the preparation of a medicament for the treatment and/or prevention of a viral infectious disease in a subject.
14. The use of claim 13, wherein the virus is selected from the group consisting of middle east syndrome-associated coronavirus (MERS-CoV), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), influenza a virus, influenza b virus, novel coronavirus (SARS-CoV-2), spanish influenza virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, poliovirus, rhinovirus, adenovirus, ebola virus, enterovirus, hepatitis a virus, hepatitis c virus, hepatitis e virus, enterovirus, HIV virus, echovirus, filovirus, measles virus, yellow fever virus, japanese encephalitis virus, west nile virus, newcastle disease virus, RS virus, vesicular stomatitis virus, mumps virus, dengue virus, coxsackie virus, rotavirus, or tobacco mosaic virus.
15. The use of claim 13 or 14, wherein the subject is selected from a mammal.
16. The use of claim 15, wherein the mammal is a human.
17. Use of a triazine derivative, a pharmaceutically acceptable salt, deutero-compound, prodrug or metabolite thereof according to any one of claims 1 to 11, or a pharmaceutical composition according to claim 12 for the preparation of a 3C-like cysteine protease (3 CLpro) inhibitor.
CN202211454323.9A 2022-07-08 2022-11-21 Triazine derivatives Active CN115490681B (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN202310320094.XA CN116496266A (en) 2022-07-08 2022-11-21 Triazine derivatives
US18/067,147 US20240025885A1 (en) 2022-07-08 2022-12-16 Triazine derivatives and methods of use thereof
PCT/IB2022/000765 WO2024009120A1 (en) 2022-07-08 2022-12-16 Triazine derivatives and methods of use thereof
TW112125246A TW202402296A (en) 2022-07-08 2023-07-06 Triazine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210818971 2022-07-08
CN2022108189711 2022-07-08

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN202310320094.XA Division CN116496266A (en) 2022-07-08 2022-11-21 Triazine derivatives

Publications (2)

Publication Number Publication Date
CN115490681A true CN115490681A (en) 2022-12-20
CN115490681B CN115490681B (en) 2023-04-18

Family

ID=85116324

Family Applications (2)

Application Number Title Priority Date Filing Date
CN202310320094.XA Pending CN116496266A (en) 2022-07-08 2022-11-21 Triazine derivatives
CN202211454323.9A Active CN115490681B (en) 2022-07-08 2022-11-21 Triazine derivatives

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN202310320094.XA Pending CN116496266A (en) 2022-07-08 2022-11-21 Triazine derivatives

Country Status (1)

Country Link
CN (2) CN116496266A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023169572A1 (en) * 2022-03-10 2023-09-14 湖北九康通生物医药有限公司 Triazine compound, intermediate thereof, preparation method therefor and use thereof
WO2024009120A1 (en) * 2022-07-08 2024-01-11 Ascletis Bioscience Co., Ltd. Triazine derivatives and methods of use thereof
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170216257A1 (en) * 2013-06-21 2017-08-03 Zenith Epigenetics Ltd. Novel substituted bicyclic compounds as bromodomain inhibitors
CN113209087A (en) * 2020-02-05 2021-08-06 歌礼药业（浙江）有限公司 Pharmaceutical composition for inhibiting coronavirus and application thereof
WO2022021841A1 (en) * 2020-07-31 2022-02-03 四川大学 Novel coronavirus main protease inhibitor, and preparation method therefor and use thereof
CN114507221A (en) * 2022-04-21 2022-05-17 北京科翔中升医药科技有限公司 Triazine compound and application thereof in preparation of antiviral drugs
CN114539228A (en) * 2022-03-14 2022-05-27 药康众拓(江苏)医药科技有限公司 Triazine compound or pharmaceutically acceptable salt, isomer, pharmaceutical composition and application thereof
WO2022138987A1 (en) * 2021-04-14 2022-06-30 塩野義製薬株式会社 Triazine derivative having virus propagation inhibitory effect, and pharmaceutical composition containing same

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170216257A1 (en) * 2013-06-21 2017-08-03 Zenith Epigenetics Ltd. Novel substituted bicyclic compounds as bromodomain inhibitors
CN113209087A (en) * 2020-02-05 2021-08-06 歌礼药业（浙江）有限公司 Pharmaceutical composition for inhibiting coronavirus and application thereof
WO2022021841A1 (en) * 2020-07-31 2022-02-03 四川大学 Novel coronavirus main protease inhibitor, and preparation method therefor and use thereof
WO2022138987A1 (en) * 2021-04-14 2022-06-30 塩野義製薬株式会社 Triazine derivative having virus propagation inhibitory effect, and pharmaceutical composition containing same
CN114539228A (en) * 2022-03-14 2022-05-27 药康众拓(江苏)医药科技有限公司 Triazine compound or pharmaceutically acceptable salt, isomer, pharmaceutical composition and application thereof
CN114507221A (en) * 2022-04-21 2022-05-17 北京科翔中升医药科技有限公司 Triazine compound and application thereof in preparation of antiviral drugs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
*** 等: "治疗新型冠状病毒肺炎的国内临床试验化学药物简介", 《中国医药工业杂志》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11963967B2 (en) 2020-10-16 2024-04-23 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
WO2023169572A1 (en) * 2022-03-10 2023-09-14 湖北九康通生物医药有限公司 Triazine compound, intermediate thereof, preparation method therefor and use thereof
WO2024009120A1 (en) * 2022-07-08 2024-01-11 Ascletis Bioscience Co., Ltd. Triazine derivatives and methods of use thereof

Also Published As

Publication number Publication date
CN116496266A (en) 2023-07-28
CN115490681B (en) 2023-04-18

Similar Documents

Publication Publication Date Title
CN115490681B (en) Triazine derivatives
TWI625330B (en) Substituted polycyclic pyridone derivatives and prodrug thereof
CN115504968B (en) Triazine derivatives
EP2794565B1 (en) Hepatitis b antiviral agents
CN102838523A (en) Anti-enterovirus 71 (EV71) valerolactam compounds, preparation method and uses thereof
US11958830B2 (en) Protease inhibitors, preparation, and uses thereof
CN108473477A (en) The pyrimidine of aryl substitution for being used in influenza infection
EP3725785A1 (en) Glutarimide derivatives, use thereof, pharmaceutical composition based thereon and methods for producing glutarimide derivatives
CN112062800B (en) Phosphoramidate derivatives of nucleoside compounds and uses thereof
CA3200437A1 (en) Compounds for the treatment of sars
CN112010916B (en) Phosphoramidate derivatives of nucleoside compounds and uses thereof
CN115466225A (en) Amide compound, preparation method, pharmaceutical composition and application thereof
TWI832678B (en) Inhibitors of cysteine proteases and use thereof
EP2650292B1 (en) Thiazolamine derivative and use thereof as anti-picornaviral infection medicament
TW202402296A (en) Triazine derivatives
CN114805141A (en) 4-guanidinobenzoic acid aryl ester compound and application thereof in resisting SARS-CoV-2 virus
CN101239958A (en) Arylthioureas compounds with antivirus activity, preparation method and use thereof
CN113698383B (en) Piperazine compound and application thereof
CN115141206B (en) Alpha-lipoic acid lycorine conjugate and preparation method and application thereof
CN111960970A (en) Antitumor compounds
CN109134419A (en) A kind of 2,2- dimethyl -1,3- dioxolanes analog derivative, preparation method and use
WO2023085432A1 (en) Anti-sars-cov-2 drug
CN101602750A (en) (replacement) naphthyl, (replacement) aryl, piperazinyl amidine compounds
CN116621917A (en) Difluoro indole-spiro compound and preparation method and application thereof
CN117159538A (en) Methylisoindigo derivative as Mpro inhibitor and application thereof in antiviral drugs

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 40082299

Country of ref document: HK