[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN116284133B - Novel six-membered heterocyclic derivative, and pharmaceutical composition and application thereof - Google Patents

Novel six-membered heterocyclic derivative, and pharmaceutical composition and application thereof Download PDF

Info

Publication number
CN116284133B
CN116284133B CN202310279520.XA CN202310279520A CN116284133B CN 116284133 B CN116284133 B CN 116284133B CN 202310279520 A CN202310279520 A CN 202310279520A CN 116284133 B CN116284133 B CN 116284133B
Authority
CN
China
Prior art keywords
alkyl
formula
compound
pcdd115
novel
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.)
Active
Application number
CN202310279520.XA
Other languages
Chinese (zh)
Other versions
CN116284133A (en
Inventor
侯雯
潘伟
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.)
Nanjing Zhihe Medical Technology Co ltd
Original Assignee
Nanjing Zhihe Medical Technology 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 Nanjing Zhihe Medical Technology Co ltd filed Critical Nanjing Zhihe Medical Technology Co ltd
Publication of CN116284133A publication Critical patent/CN116284133A/en
Application granted granted Critical
Publication of CN116284133B publication Critical patent/CN116284133B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • 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
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems

Landscapes

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

Abstract

The invention discloses a novel six-membered heterocyclic derivative, a pharmaceutical composition and application thereof, wherein the novel six-membered heterocyclic derivative is shown in a formula (I), and definition of each substituent is detailed in the specification; the compound can be used for preparing antiviral drugs.

Description

Novel six-membered heterocyclic derivative, and pharmaceutical composition and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a novel six-membered heterocyclic derivative, a pharmaceutical composition and application thereof.
Background
Coronavirus disease-19 (covd-19, also known as SARS-CoV-2) is a new acute respiratory infectious disease, which is triggered by SARS-CoV-2 (also known as 2019-nCoV), and since then, coronaviruses have gradually become a research hotspot in the virology field.
Prior art 3CLpro inhibitors include covalent peptidomimetic inhibitors represented by PF-07321332 developed by the company Condui and non-covalent, non-peptidomimetic small molecule inhibitors represented by S-217622 developed by the company Shongai, japan. PF-07321332 is a substrate for CYP3A4 and is metabolically unstable and must be taken together with the CYP3A4 enzyme inhibitor ritonavir. Changes in the activity of the CYP3A4 enzyme affect the metabolism of Paxlovid, and thus affect the effectiveness and safety of Paxlovid. S-217622 gets rid of dependence on P450 enzyme inhibitors (such as ritonavir), realizes new crown of single drug treatment, expands the applicable crowd range without taking precautions against pharmacological reaction of other drugs needing to be taken at the same time due to the inhibition effect of the P450 enzyme. However, the currently reported non-covalent small molecule inhibitors are still very deficient, and have the problems of single structure, weak enzyme inhibition activity, high cytotoxicity and the like. There is an urgent need for specific inhibitors with different mechanisms of action to combat SARS-CoV-2 infection.
Disclosure of Invention
The inventor develops a novel six-membered heterocyclic derivative, and the compound can be used for preparing antiviral drugs.
In one aspect, the present invention provides a novel six-membered heterocyclic derivative, tautomer, stereoisomer, solvate and pharmaceutically acceptable salts thereof, as shown in (I):
in the formula (I) of the present invention,
n 1 selected from 1, 2, 3, or 4;
X 1 and X 2 Independently selected from O, S or =n-R a The method comprises the steps of carrying out a first treatment on the surface of the Wherein,
R a selected from hydrogen, the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
R 1 selected from hydrogen, the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
R 2a and R is 2b Independently selected from hydrogen, quiltOr a plurality of groups a substituted or unsubstituted with the following groups: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl, or R 2a And R is 2b Together with the oxygen or sulfur atom, form c=o or c=s;
R 3 Selected from the following groups, substituted or unsubstituted with one or more groups a: C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
R 4 selected from the group consisting ofWherein,
m1 is selected from 0, 1, 2, or 3;
R b selected from hydrogen,The following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl; wherein,
R d selected from hydrogen, the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
R c selected from halogen, cyano, nitro,The following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl; wherein,
R d selected from hydrogen, the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
R e1 And R is e2 Independently selected from hydrogen,The following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl; wherein R is d Selected from hydrogen, the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
R 5 selected from the group consisting ofWherein,
m 2 and m 3 Independently selected from 0, 1, 2, 3, or 4, and when m 2 Or m 3 When any one is 0, W is directly connected with N;
R g1 and Rg 2 Each independently selected from hydrogen, the following substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
w is selected fromWherein,
Y 1、 Y 2 and Y 3 Each independently selected from O or S;
R f1 and R is f2 Each independently selected from the group consisting of cations, hydrogen, or the following substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C18 aryl, C6-C18 heteroaryl; or,
R f1 And R is f2 Is connected with P and R together f1 、R f2 O which are respectively connected together form a multi-ring;
R f3 selected from hydroxy, quilt groupsA is a substituted or unsubstituted group of: C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkenyloxy, C1-C8 alkylthio, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkoxy, C6-C18 aryl, C6-C18 aryloxy, C6-C18 heteroaryl, C6-C18 heteroaryloxy;
R f4 and R is f5 Each independently selected from hydrogen, the following substituted or unsubstituted with group a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl;
the group A is: halogen, cyano, nitro, trifluoromethyl, C1-C8 alkyl, C3-C8 cycloalkyl, guanidino, C1-C8 alkoxy, C6-C18 aryl, C6-C18 aryloxy,
Wherein,
R h1 and R is h2 Independently selected from hydrogen, C1-C8 alkyl, halogenated C1-C8 alkyl, hydroxyC 1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkyloxycarbonyl, C1-C8 alkyloxycarbonylalkyl, C6-C18 aryl, C6-C18 heteroaryl;
R i selected from the group consisting of hydrogen, C1-C8 alkyl, halogenated C1-C8 alkyl, hydroxyC 1-C8 alkyl, C3-C8 cycloalkyl, non-aromatic heterocyclyl, non-aromatic heteroepoxy, C6-C18 aryl, C6-C18 heteroaryl;
R j Selected from the group consisting of hydrogen, C1-C8 alkyl, halogenated C1-C8 alkyl, hydroxyC 1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkyloxycarbonyl, C1-C8 alkyloxycarbonylalkyl, C6-C18 aryl, C6-C18 heteroaryl;
in some embodiments, the present invention provides a novel six-membered heterocyclic derivative, tautomer, stereoisomer, solvate, and pharmaceutically acceptable salts thereof, as shown in formula (II):
the substituents in formula (II) are as defined above.
In some embodiments, the present invention provides a novel six-membered heterocyclic derivative, tautomer, stereoisomer, solvate, and pharmaceutically acceptable salts thereof, according to formula (iii):
the substituents in formula (III) are as defined above.
In some embodiments, the present invention provides a novel six-membered heterocyclic derivative, tautomer, stereoisomer, solvate, and pharmaceutically acceptable salt thereof, according to formula (iv):
the substituents in formula (IV) are as defined above.
In some embodiments, the present invention provides a novel six-membered heterocyclic derivative, tautomer, stereoisomer, solvate, and pharmaceutically acceptable salts thereof, according to formula (v):
the substituents in formula (V) are as defined above.
In some embodiments, in formulas (I) - (v) above, n1 is selected from 1, 2, or 3;
in some more specific embodiments, in formulas (I) - (v) above, n1 is 1;
in some more specific embodiments, in formulas (I) - (v) above, n1 is 2.
In some embodiments, in formulas (I) - (ii) above, X1 is selected from S;
in some embodiments, in formulas (I) - (ii) above, X1 is selected from =n-R a The method comprises the steps of carrying out a first treatment on the surface of the Wherein,
in some embodiments, R as described above a Selected from hydrogen, the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
preferably, in some specific embodiments, R as described above a Selected from hydrogen, C1-C8 alkyl substituted or unsubstituted with one or more groups A;
more preferably, in some more specific embodiments, R as described above a Selected from hydrogen, C1-C8 alkyl.
In some embodiments, in formulas (I) - (v) above, X1 is selected from O.
In some embodiments, in formulas (I) - (V) above, R 1 Selected from hydrogen, the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
In some more specific embodiments, in formulas (I) - (V) above, R 1 Selected from hydrogen, C1-C8 alkyl substituted or unsubstituted with one or more groups A.
In some embodiments, in formulas (I) - (V) above, R 2a And R is 2b Each independently selected from hydrogen, the following substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C6-C18 aryl, non-aromatic heterocyclic group;
in some more specific embodiments, in formulas (I) - (V) above, R 2a And R is 2b Each independently selected from hydrogen, C1-C8 alkyl substituted or unsubstituted with one or more groups A;
in some more specific embodiments, in formulas (I) - (V) above, R 2a And R is 2b Are all hydrogen;
in some more specific embodiments, in formulas (I) - (V) above, R 2a Is hydrogen, R 2b C1-C8 alkyl which is optionally substituted by one or more groups A;
in some more specific embodiments, in formulas (I) - (V) above, R 2a And R is 2b Are each C1-C8-alkyl substituted or unsubstituted by one or more groups A.
In some embodiments, in formulas (I) - (V) above, R 3 Selected from the following groups, substituted or unsubstituted with one or more groups a: a C6-C18 aryl, heteroaryl, non-aromatic heterocyclic group;
In some more specific embodiments, in formulas (I) - (V) above, R 3 Selected from C6-C18 aryl substituted or unsubstituted with one or more groups A;
in some more specific embodiments, in formulas (I) - (V) above, R 3 Selected from heteroaryl groups substituted or unsubstituted with one or more groups a;
in some more specific embodiments, in formulas (I) - (V) above, R 3 Is phenyl substituted with one or more groups A.
In some embodiments, in formula (I) above, R 4 Selected from the group consisting of Wherein,
in some embodiments, m1 is selected from 0, 1, 2, or 3;
preferably, in some specific embodiments, m1 above is selected from 0, 1, or 2;
more preferably, in some more specific embodiments, m1 above is 0 or 1.
In some embodiments, R as described above b Selected from hydrogen,The following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkeneA radical, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclic radical;
wherein R is as described above d Selected from hydrogen, the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
Preferably, in some specific embodiments, R as described above b Selected from hydrogen, The following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
wherein R is as described above d As defined above;
more preferably, in some more specific embodiments, R as described above b Selected from hydrogen,The following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C6-C18 aryl, heteroaryl;
wherein R is as described above d As defined above;
in some embodiments, in formula (I) above, R is as described above c Selected from halogen, cyano, nitro, The following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl; wherein,
r is as described above d As defined above;
r is as described above e1 And R is e2 Independently selected from hydrogen,The following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
preferably, in some specific embodiments, R as described above c Selected from halogen, cyano, nitro, C1-C8 alkyl substituted or unsubstituted with one or more groups A; wherein,
r is as described above d As defined above;
more preferably, in some more specific embodiments, R as described above c Selected from halogen, cyano, nitro, hydroxy, amino, trifluoromethyl;
in some embodiments, in formulas (I) - (V) above, R 4 Is thatWherein,
m1、R b and R is c Respectively as defined above.
In some embodiments, in formulas (I) - (V) above, R 5 Is thatWherein,
in some embodiments, in formulas (I) - (V) above, m is as defined above 2 Selected from 0, 1, 2, or 3;
preferably, in some more specific embodiments, m2 is selected from 0, 1, or 2, and when m2 is 0, m3 is 0, where P is directly attached to N;
in some embodiments, in formulas (I) - (V) above, m is as defined above 3 Selected from 0, 1, 2, or 3;
preferably, in some more specific embodiments, m3 above is selected from 0, 1, or 2, when m3 is 0, then P is directly attached to N;
in some embodiments, in formulas (I) - (V) above, R is as described above g1 And Rg 2 Each independently selected from hydrogen, the following substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
Preferably, in some more specific embodiments, R as described above g1 And Rg 2 Are all hydrogen;
preferably, in some more specific embodiments, R as described above g1 Is hydrogen, rg 2 Selected from the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
preferably, in some more specific embodiments, R as described above g1 And Rg 2 Are each selected from the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl, non-aromatic heterocyclyl;
in some embodiments, in formulas (I) - (III) above, W isWherein,
in some embodiments, in formulas (I) - (III) above, Y is as described above 1 Selected from O or S;
in some more specific embodiments, Y as described above 1 Is O;
in some more specific embodiments, Y as described above 1 S is the same as the original formula;
in some embodiments, in formulas (I) - (III) above, R is as described above f1 And R is f2 Are each independently selected from cations, hydrogen,Or the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkylamino, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C6-C18 aryl, C6-C18 heteroaryl; or,
R f1 And R is f2 Is connected with P and R together f1 、R f2 O which are respectively connected together form a multi-ring;
preferably, in some more specific embodiments, R as described above f1 And R is f2 Are independently selected from Li + 、Na + 、K + 、Zn + 、Mg 2+ 、Ca 2+ 、Ag + Ammonium ion, or N (C) 1 -C 4 -alkyl group 4 + ；
Preferably, in some more specific embodiments, R as described above f1 And R is f2 Each independently selected from hydrogen, or the following groups substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C1-C8 alkylamino, C3-C8 cycloalkyl, C6-C18 aryl;
preferably, in some more specific embodiments, R f1 And R is f2 Is connected with P and R together f1 、R f2 O which are respectively connected together form a 5-7 membered ring;
in some embodiments, in formulas (I) - (II) and/or (IV) above, W isWherein,
in some embodiments, in formulas (I) - (II) and/or (IV) above, Y is as described above 2 Selected from O or S;
in some more specific embodiments, Y as described above 2 Is O;
in some more specific embodiments, Y as described above 2 S is the same as the original formula;
in some embodiments, in formulas (I) - (II) and/or (IV) above, R is as defined above f3 Selected from the following groups, substituted or unsubstituted with group a: C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkenyloxy C1-C8 alkylthio, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-) C8 cycloalkoxy, C3-C8 heterocycloalkyl, C3-C8 heterocycloalkoxy, C6-C18 aryl, C6-C18 aryloxy, C6-C18 heteroaryl, C6-C18 heteroaryloxy;
in some embodiments, in formulas (I) - (II) and/or (V) above, W isWherein,
in some embodiments, in formulas (I) - (II) and/or (V) above, Y is as described above 2 Selected from O or S;
in some more specific embodiments, Y as described above 2 Is O;
in some more specific embodiments, Y as described above 2 S is the same as the original formula;
in some embodiments, in formulas (I) - (II) and/or (V) above, R is as described above f4 And R is f5 Each independently selected from hydrogen, the following substituted or unsubstituted with group a: C1-C8 alkyl, C3-C8 cycloalkyl, heterocycloalkyl, C6-C18 aryl, heteroaryl;
the group A is: halogen, cyano, nitro, trifluoromethyl, C1-C8 alkyl, C3-C8 cycloalkyl, guanidino, C1-C8 alkoxy, C6-C18 aryl, C6-C18 aryloxy,
Wherein,
r is as described above h1 And R is h2 Independently selected from hydrogen, C1-C8 alkyl, halogenated C1-C8 alkyl, hydroxyC 1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkyloxycarbonyl, C1-C8 alkyloxycarbonylalkyl, C6-C18 aryl, C6-C18 heteroaryl;
r is as described above i Selected from hydrogen, C1-C8 alkyl, halogenated C1-C8 alkyl, hydroxyC 1-C8 alkyl, C3-C8 cycloalkyl, and non-aromatic Heterocyclyl, non-aromatic heteroepoxy, C6-C18 aryl, C6-C18 heteroaryl;
r is as described above j Selected from the group consisting of hydrogen, C1-C8 alkyl, halogenated C1-C8 alkyl, hydroxyC 1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkyloxycarbonyl, C1-C8 alkyloxycarbonylalkyl, C6-C18 aryl, C6-C18 heteroaryl;
in some embodiments, the novel six-membered heterocyclic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof provided herein are selected from the following:
in another aspect, in some embodiments, the present invention provides pharmaceutical compositions comprising the novel six-membered heterocyclic derivatives, tautomers, stereoisomers, solvates, and pharmaceutically acceptable salts thereof, as described above.
In some embodiments, the invention discloses a pharmaceutical composition, which is composed of the compound, isomer or pharmaceutically acceptable salt thereof of the invention as an active ingredient or a main active ingredient, and a pharmaceutically acceptable carrier.
In some embodiments, the present invention provides that the above pharmaceutical compositions are useful for the treatment and prevention of diseases associated with antiviral disorders.
In some embodiments, the present invention provides the use of the above pharmaceutical composition for the preparation of an antiviral drug.
In yet another aspect, the present invention provides a pharmaceutical composition comprising the above for use in the treatment of any viral-caused disease in a human or animal; such viruses include, but are not limited to: arenaviridae, filoviridae, and coronaviridae, and the like, including, but not limited to, adenovirus, rhinovirus, hepatitis a virus, hepatitis c virus, pneumo virus b, pneumo virus c, HIV virus, polio virus, measles virus, ebola virus, coxsackie virus, west nile virus, smallpox virus, yellow fever virus, dengue virus, influenza virus, lassa virus, respiratory syncytial virus, severe acute respiratory syndrome virus, parainfluenza virus, coronavirus, and the like.
Further, the influenza viruses include, but are not limited to, influenza a virus, influenza b virus, and the like;
further, the above coronaviruses include, but are not limited to, SARS virus, MERS virus, covd-19 virus, etc.;
in some embodiments, the novel six-membered heterocyclic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof of the invention may be prepared as pharmaceutical compositions for administration to a patient in a variety of suitably selected modes of administration, including systemic, e.g., oral, inhaled or parenteral, intravenous, intramuscular, transdermal or subcutaneous and the like.
In some embodiments, the novel six-membered heterocyclic derivatives, tautomers, stereoisomers, solvates and pharmaceutically acceptable salts thereof of the invention may be prepared as formulations of pharmaceutical compositions including, but not limited to, tablets, capsules or solutions for oral administration, or solutions, sprays, emulsions, ointments, emulsions or gels for transdermal administration.
Compared with the control compound ZJT1, the anti-novel coronavirus activity of the compound disclosed by the invention is obviously improved, and simultaneously, the cardiotoxicity is greatly reduced.
Compared with a control compound ZJT1, the compound disclosed by the invention enhances lung targeting, shows good effect of passing through a blood brain barrier, and is more beneficial to resisting lung virus infection and brain infection caused by the lung virus infection.
More unexpectedly, the compounds of the present invention are able to reduce the distribution in the liver, thereby reducing the risk of hepatotoxicity during use against pulmonary viral infections and the resulting brain infections.
The compound disclosed by the invention can be used as an antiviral drug with a novel structure.
Definition:
the following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
Certain compounds of the invention may exist in unsolvated forms or solvated forms such as, for example, hydrated, ethanolic forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.
The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include aluminum, sodium, potassium, calcium, manganese, iron, ammonium, organic ammonia, or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
The term "alkyl" means a saturated aliphatic radical, including straight and branched chain groups, alkyl groups which may be substituted or unsubstituted. When substituted alkyl, the substituent is preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents.
The term "alkenyl" means an aliphatic radical having an unsaturated carbon-carbon double bond, and includes straight and branched chain alkyl groups which may be substituted or unsubstituted. The carbon-carbon double bond may be one or more.
The term "cycloalkyl" means a single or fused ring of all carbons ("fused" ring means that each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system), wherein one or more of the rings does not have a fully attached pi-electron system, examples of cycloalkyl (without limitation) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cycloheptatriene. Cycloalkyl groups may be substituted and unsubstituted.
The term "cycloalkenyl" comprises a non-aromatic, monocyclic or polycyclic ring group of 3 to 1 0 carbon atoms having at least 1 carbon-carbon double bond. As one embodiment, there may be mentioned C3-C8 cycloolefins. As another embodiment, a C3 to C7 cycloalkenyl group may be mentioned. The monocyclic cycloolefin includes cyclopentenyl and cyclohexenyl, and the polycyclic cycloolefin includes norbornenyl and indenyl.
The term "aryl" means an all-carbon monocyclic or fused multicyclic group of 1 to 12 carbon atoms having a fully conjugated pi-electron system. Non-limiting examples of aryl groups are phenyl, naphthyl and anthracenyl. Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and even more preferably one or two.
The term "arylalkyl" denotes an alkyl group substituted with an aryl group.
The term "heteroaryl" means a multi-atom monocyclic or fused ring radical containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C, additionally having a fully conjugated pi-electron system. Non-limiting examples of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine, and carbazole.
The term "alkoxy" refers to a group in which an alkyl group is attached to oxygen, where the alkyl group may be straight chain, branched or cyclic alkyl.
The term "alkenyloxy" refers to an alkenyl group attached to oxygen, where the alkenyl group may be straight chain, branched or cyclic alkyl.
The term "alkylthio" refers to a group in which an alkyl group is attached to sulfur, where the alkyl group may be straight chain, branched or cyclic.
The term "hydroxy" denotes an-OH group.
The term "amino" means-NH 2 A group.
The term "halogen" means fluorine, chlorine, bromine or iodine.
The term "non-aromatic heterocyclic group" means a 1-valent group produced by a 4-to 7-membered non-aromatic ring having at least 1 nitrogen atom, oxygen atom, and/or sulfur atom in the ring.
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium representative of a carrier capable of delivering an effective amount of the active agents of the present invention, which does not interfere with the biological activity of the active agents and which does not have toxic or side effects to the host or patient, including water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like.
The term "stereoisomer" refers to a compound that has the same chemical constitution but differs in the arrangement of atoms or groups in space.
The term "solvate" refers to certain compounds that may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms, which are equivalent to unsolvated forms, are intended to be encompassed within the scope of the present invention.
The numerical ranges, e.g., "C1-C8", referred to in this application mean that the group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 8 carbon atoms.
The compounds herein may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
Detailed Description
A number of exemplary methods for preparing the compounds of the present invention are provided in the examples below. The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention. Certain compounds of the invention can be used as intermediates for preparing other compounds of the invention, all of which have structures determined by MS.
Materials SM1, 2,4, 5-trifluorobenzyl bromide, 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride, and 6-chloro-2-methyl-2H-indazol-5-amine are all commercially available; various commonly used dissolving agents and catalysts are commercially available.
Example 1: synthesis of Compound ZJT1
The reaction formula:
the preparation method comprises the following steps:
step 1: preparation of Compound ZJT 1-03:
starting material SM1 (22.9 g,0.10 mol), potassium carbonate (18.0 g,0.13 mol) and 1- (bromomethyl) -2.4,5-trifluorobenzene (24.8 g,0.11 mol) were added sequentially to acetonitrile (250 mL) and the system stirred at 80℃for 2 hours. The reaction system was cooled to room temperature, and then ethyl acetate was added to the system for dilution, followed by stirring for 1 hour. The system was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound ZJT1-03 (27.0 g), yield 72.3%. ESI-MS (+): m/z= 374.20.
Step 2: preparation of Compound ZJT 1-02:
a mixture of trifluoroacetic acid (60 mL) of the compound ZJT1-03 (25.0 g,67.0 mmol) was stirred at room temperature for 18 hours, concentrated under reduced pressure, the residue was slurried with toluene under reflux for 1 hour, cooled to room temperature, filtered, and the cake was slurried with isopropyl ether for 1 hour, filtered, and dried to obtain the compound ZJT1-02 (18.5 g) in 86.8% yield. ESI-MS (+): m/z= 318.05.
Step 3: preparation of Compound ZJT 1-01:
compound ZJT1-02 (18.0 g,56.7 mmol), 3- (chloromethyl) -1-methyl-1H-1, 2, 4-triazole hydrochloride (14.3 g,85.1 mol), and potassium carbonate (23.5 g,170.1 mol) were successively added to N, N-dimethylformamide (250 mL), and the system was stirred at 60℃for 4 hours. After the TLC detection, the system is cooled to room temperature, added with NH4Cl aqueous solution and stirred for 30 minutes, filtered, and the filter cake is washed with water and dried. Purification by silica gel column chromatography gave compound ZJT1-01 (9.9 g) in 42.3% yield. ESI-MS (+): m/z= 413.09.
Step 4: preparation of compound ZJT 1:
compound ZJT1-01 (9.5 g,23.04 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (5.45 g,30 mmol) are added sequentially to tetrahydrofuran (200 mL), cooled to 0deg.C, and then 1mol/L of lithium bistrimethylsilylamino tetrahydrofuran solution (LHMDS, 46.1mL,46.1 mmol) is added dropwise. After the completion of the dropwise addition, the reaction system was stirred at 0℃for 2.5 hours, warmed to room temperature, stirred for 1 hour, and NH was added 4 The reaction was quenched with aqueous Cl. The system was extracted 3 times with ethyl acetate, the organic phases were combined, washed with saturated aqueous sodium chloride, separated, and the organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound ZJT1 (4.39 g) in a yield of 35.8%. ESI-MS (+): m/z= 532.12.1H NMR (400 MHz, DMSO-d 6) δ11.32 (1H, s), 9.10 (1H, s), 8.19 (1H, s), 7.52 (1H, s), 7.31-7.44 (2H, m), 7.23 (1H, m), 5.05 (2H, s), 4.83 (2H, s), 3.94 (3H, s), 3.69 (3H, s).
Example 2: synthesis of Compound PCDD115-01
The reaction formula:
the preparation method comprises the following steps:
step 1: preparation of Compound PCDD 115-0101:
under the protection of nitrogen, the compound ZJT1 (4.24 g,8.0 mmol) is dissolved in N, N-dimethylformamide (80 mL), sodium hydride (0.56 g,24.0 mmol) is slowly added, stirring is carried out at room temperature for 1 hour, di-tert-butyl chloromethyl phosphate (6.20 g,24.0 mmol) is added, reaction is continued at room temperature for 12 hours, ice water (150 mL) is added, ethyl acetate extraction (200 mL×2) is carried out, the organic phases are combined, anhydrous sodium sulfate is dried, concentrated, and the remainder is purified and separated by a column to obtain the compound PCDD115-0101 (2.03 g), the yield: 33.7%. ESI-MS (+): m/z= 754.23.
Step 2: preparation of Compound PCDD 115-01:
under the protection of nitrogen, the compound PCDD115-0101 (2.00 g,2.53 mmol) is dissolved in acetonitrile (50 mL), trifluoroacetic acid (5.0 mL) is added, nitrogen is heated to 60 ℃ for reaction for 2 hours, the system is concentrated, acetonitrile is added into the residue for concentration again, and the trifluoroacetic acid is removed as much as possible; the residue was then dissolved in methylene chloride (25 mL), methyl tert-butyl ether (120 mL) was slowly added dropwise under ice-bath, the temperature was maintained under stirring for 3 hours, filtration, and elution with methyl tert-butyl ether gave compound PCDD115-01 (0.72 g), yield: 44.3%. ESI-MS (-) m/z= 640.10.
Example 3: synthesis of Compound PCDD115-03
The reaction formula:
the preparation method comprises the following steps:
compound PCDD115-01 (0.20 g,0.3 mmol) was dissolved in acetonitrile (10 mL), thionyl chloride (0.11 g,0.9 mmol) was added, the temperature was reduced to 0-5℃under a nitrogen atmosphere at 60℃for 2 hours, ethanol (1 mL) and triethylamine (0.12 g,1.2 mmol) were slowly added, the reaction was continued under a nitrogen atmosphere at 60℃for 2 hours, the temperature was reduced to room temperature, the concentration, the product was dissolved in dichloromethane, water washing, the organic phase was dried, filtered, concentrated, and the remainder was prepared and separated from the liquid phase to give compound PCDD115-03 (65.7 mg), yield was 30.2%. ESI-MS (+): m/z= 698.28.
Example 4: synthesis of Compound PCDD115-05
The reaction formula:
the preparation method comprises the following steps:
step 1: compound PCDD115-0502 preparation:
under the protection of nitrogen, the compound ZJT1 (2.66 g,5.0 mmol) is dissolved in tetrahydrofuran (50 mL), sodium hydroxide (1.0 g,25 mmol) is added, then formaldehyde aqueous solution (35-40%, 2.5 g) is slowly added, the temperature is raised to 55 ℃ for 8h of reaction, TLC detection reaction is complete, the system is concentrated, water and methylene dichloride are added, shaking is carried out, the liquid phase is separated, the methylene dichloride is extracted again, the methylene dichloride phase is combined, anhydrous sodium sulfate is dried, filtration is carried out, and residues are purified and separated by a column, thus obtaining the compound PCDD115-0502 (1.42 g), and the yield is 50.5%. ESI-MS (+): m/z= 562.35.
Step 2: compound PCDD115-0501 preparation:
the compound PCDD115-0502 (1.12 g,2.0 mmol), naH (96 mg,4.0 mmol), di-tert-butyl chloromethyl phosphate (1.56 g,6.0 mmol) and potassium iodide (0.48 g,3.0 mmol) were added sequentially to N, N-dimethylformamide (50 mL) at room temperature. After the reaction was completed by TLC at 50-55℃for 24 hours, 200mL of ethyl acetate was added to the system, followed by washing with water and saturated brine, followed by separation of an organic phase, drying over anhydrous sodium sulfate, filtration, concentration and column chromatography, whereby Compound PCDD115-0501 (0.54 g) was obtained in 34.4% yield. ESI-MS (+): m/z= 784.25.
Step 3: preparation of Compound PCDD 115-05:
referring to the procedure of step 2 in example 2, compound PCDD115-05 (0.12 g) was produced in a yield of 37.5%. ESI-MS (-) m/z= 670.10.
Example 5: synthesis of Compound PCDD115-06
The reaction formula:
the preparation method comprises the following steps:
with reference to the procedure in example 3, compound PCDD115-06 (0.16 g) was produced in a yield of 36.5%. ESI-MS (+): m/z= 728.16.
Example 6: synthesis of Compound PCDD115-07
The reaction formula:
the preparation method comprises the following steps:
step 1: synthesis of Compound PCDD115-0701
Freshly distilled phosphorus oxychloride (10.0 g,65.2 mmol) was dissolved in cold diethyl ether (80 mL) under argon, then anhydrous triethylamine (13.2 g,130.4 mmol) was added, cooled to 0-5℃after the addition was completed, and then diethyl ether solution (150 mL) in which 1, 3-propanediol (5.0 g,65.2 mmol) was slowly added dropwise to the system. After the addition was completed, the system was stirred overnight at room temperature. The system was filtered, rinsed with diethyl ether, and the filtrate was concentrated to give cyclophosphamide chloride (compound PCDD115-0701,9.3 g) in 91.1% yield.
Step 2: synthesis of Compound PCDD115-07
Compound PCDD115-0502 (0.56 g,1 mmol) was dissolved in dry dichloromethane (50 mL) at 0-5℃under nitrogen, and then compound PCDD115-0701 (0.31 g,2 mmol) and 1-methylimidazole (0.17 g,2 mmol) were added sequentially to the system with stirring. After the addition was complete, stirring was continued at room temperature for 16h and tlc monitored complete. The system was concentrated, and the residue was dissolved in methylene chloride (30 mL) and washed once with saturated aqueous sodium bicarbonate and water, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column to isolate compound PCDD115-07 (0.25 g) in 36.7% yield. ESI-MS (+): m/z= 682.12.
Example 7: synthesis of Compound PCDD115-10
The reaction formula:
the preparation method comprises the following steps:
adding the compound PCDD115-01 (0.32 g,0.5 mmol) into (15 mL) ethanol, cooling to 0-10 ℃, dropwise adding 5mL of aqueous solution of sodium bicarbonate (0.08 g,1.0 mmol), carrying out a temperature maintaining reaction, after the reaction is finished, distilling off ethanol at 20-30 ℃ under reduced pressure, adding acetone (10 mL), crystallizing, filtering, and drying to obtain the compound PCDD115-10 (0.25 g), wherein the yield is 72.8%. ESI-MS (+): m/z= 640.08.
Example 8: synthesis of Compound PCDD115-11
The reaction formula:
the preparation method comprises the following steps:
the compound PCDD115-10 (1.7 g,2.5 mmol) is added into water (10 mL), 2mL of aqueous solution with magnesium chloride (0.13 g,1.3 mmol) is added dropwise at 20-30 ℃ for reaction at a maintenance temperature for 2h, ethanol (50 mL) is added for natural crystallization, filtration and drying to obtain the compound PCDD115-11 (1.32 g) with the yield of 79.5%. ESI-MS (+): m/z= 640.10.
Example 9: synthesis of Compound PCDD115-16
The reaction formula:
the preparation method comprises the following steps:
step 1: synthesis of Compound PCDD115-1601
Tetrahydrofuran (500 mL), ZJT1 (5.32 g,20 mmol) and 0.12mol tetrabenzyl pyrophosphate (605 g,12 mmol) were sequentially added to the reaction flask under a nitrogen atmosphere, the temperature of the system was lowered to about 0 ℃, a solution of sodium bis (trimethylsilyl) amide (3.7 g,20 mmol) in tetrahydrofuran (40 mL) was added dropwise to the system, and after the dropwise addition was completed, the reaction was continued for 1 hour at a temperature of the system. The reaction was quenched with saturated sodium bicarbonate solution and extracted with methyl tert-butyl ether. The organic layer was washed with a saturated sodium hydrogencarbonate solution (200 mL), a saturated sodium hydrogencarbonate solution (200 mL) and a saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give PCDD115-1601 (6.87 g) in 86.7% yield. ESI-MS (+): m/z= 792.17.
Step 2: synthesis of Compound PCDD115-16
Under nitrogen atmosphere, adding the compound PCDD115-1601 (4.0 g,5 mmol) into methanol (100 mL), stirring uniformly at normal temperature, slowly dropwise adding a borane-pyridine complex (2.5 mmol) into the mixed system, keeping the reaction for 2h after the dropwise addition, concentrating the system under reduced pressure until a small amount of solvent remains (about one fifth of the solvent remains) after the reaction is finished, adding deionized water (200 mL), stirring continuously, slowly precipitating crystals, filtering, and recrystallizing the solid with water/methanol again to obtain the compound PCDD115-16 (1.88 g) with the yield of 61.4%. ESI-MS (-) m/z= 610.07.
Example 10: synthesis of Compound PCDD115-20
The reaction formula:
the preparation method comprises the following steps:
to the reaction flask was added compound ZJT1 (0.27 g,0.5 mmol), cesium carbonate (0.33 g,1 mmol), sodium iodide (0.19 g,1.25 mmol), N, N-dimethylacetamide (10 mL) and water (40 mL) under nitrogen atmosphere, and the system was stirred and warmed to 60℃and a solution of chloromethyl dimethyl carbonate (0.09 g,0.75 mmol) in N, N-dimethylacetamide (5 mL) was added. The system reacts for 8 hours at 55 ℃, is cooled to room temperature, is added with ethyl acetate, is washed by saturated ammonium chloride, water and saturated saline water in sequence, is separated into liquid and is dried by anhydrous sodium sulfate; the organic phase was concentrated and evaporated to dryness, and the residue was purified by column to give compound PCDD115-20 (0.12 g) in a yield of 38.7%. ESI-MS (+): m/z= 620.13.
Example 11: synthesis of Compound PCDD115-21
The reaction formula:
the preparation method comprises the following steps:
under the protection of nitrogen, the compound ZJT1 (0.53 g,1.0 mmol) is dissolved in N, N-dimethylformamide (30 mL), sodium hydrogen (0.08 g,2.0 mmol) is added, stirring is carried out at room temperature for 1 hour, methyl chloride pivalate (0.30 g,2.0 mmol) is slowly added under the nitrogen atmosphere, reaction is carried out at room temperature for 6 hours, water is added into the system, dichloromethane is used for extraction for 3 times, the organic phases are combined, anhydrous sodium sulfate is dried, concentration is carried out, and the residue is separated by column chromatography to obtain the compound PCDD115-21 (0.21 g), and the yield is 32.5%. ESI-MS (+): m/z= 646.19.
Example 12: synthesis of Compound PCDD115-23
The reaction formula:
the preparation method comprises the following steps:
step 1: synthesis of Compound PCDD115-2301
Chloromethyl chloroformate (5.4 g,45 mmol) was added to methylene chloride (50 mL), cooled to 0 ℃, and a solution of dimethylamine in tetrahydrofuran (25 mL) was slowly added dropwise thereto, and the system was allowed to react at room temperature for 24 hours. Concentrated to dryness, dichloromethane and water were added, the organic phase was separated and washed 3 times with 5% NaHCO3 solution. The organic phase was concentrated to dryness to give Compound PCDD115-2301 (2.35 g) in 37.8% yield. ESI-MS (+): m/z= 138.02.
Step 2: synthesis of Compound PCDD115-23
Compound ZJT1 (0.27 g,0.5 mmol), naH (24 mg,1.0 mmol), PCDD115-2301 (0.21 g,1.5 mmol) and potassium iodide (0.12 g,0.75 mmol) are added sequentially to N, N-dimethylformamide (30 mL) at room temperature. After the reaction was completed by TLC at 50-55℃for 24 hours, ethyl acetate (200 mL) was added to the reaction system, followed by washing with water, washing with saturated brine, separating out an organic phase, drying over anhydrous sodium sulfate, filtering, concentrating, and column-chromatography to give Compound PCDD115-23 (80 mg) in 25.3% yield. ESI-MS (+): m/z= 633.16.
Example 13: synthesis of Compound PCDD115-24
The reaction formula:
the preparation method comprises the following steps:
with reference to the procedure in example 10, compound PCDD115-24 (0.17 g) was produced in a yield of 32.1%. ESI-MS (+): m/z= 650.14.
Example 14: synthesis of Compound PCDD115-25
The reaction formula:
the preparation method comprises the following steps:
step 1: preparation of the Compound methyl 1-chloroethyl carbonate
1-chloroethyl chloroformate (14.3 g,0.1 mol) was added to anhydrous dichloromethane (300 mL), methanol (6.4 g,0.2 mol) was added, and pyridine (15.8 g,0.2 mol) was added dropwise with cooling in cold water, followed by stirring for 2 hours. The system was taken up in dichloromethane (200 mL) and the organic layer was washed twice with 2N hydrochloric acid, once with separation of the organic layer, anhydrous sodium sulfate, drying, filtration, and concentration to dryness under reduced pressure gave compound 1-chloroethyl methyl carbonate (9.9 g) in 71.4% yield. Directly used in the next step.
Step 2: preparation of Compound PCDD115-25
Referring to the synthesis procedure of example 11, substitution of chloromethyl pivalate with 1-chloroethyl methyl carbonate produced compound PCDD115-25 (128 mg) in 31.6% yield. ESI-MS (+): m/z= 664.17.
The following examples were synthesized in the same manner as in the above examples, using commercially available compounds or intermediate compounds appropriately synthesized from the commercially available compounds.
Example 15: determination of anti-coronavirus Activity
Vero E6 cells were seeded in 96-well plates and placed in 5% CO 2 Culturing at 37 ℃. During the cell index growth period, maintaining liquid containing test compound and positive control medicine in different dilutions is added, and 3 compound wells are set in each concentration while normal cell control wells are set. After the sample is added, the culture is carried out for 72 hours, and the cells of the sample are carried out by a CPE methodToxicity test.
Further, vero E6 cells were inoculated into 96-well cell culture plates at 37℃with 5% CO 2 Culturing in incubator for 24 hr, removing culture solution, adding 0.1 pfu/cell complex number of recombinant COVID-19 virus solution expressing green fluorescent protein (COVID-19 RFP), culturing at 37deg.C in 5% CO2 for 3 hr, removing virus solution, washing the top surface of Vero E6 cells with 500 μL 1×PBS for 3 times, and removing residual virus; the maintenance solution containing the test compound and the positive control agent at different dilutions was added and the culture was continued for 48h. The antiviral test of the tested sample is carried out by a CPE method, and when the pathological change degree (CPE) of the virus control group reaches 4+, the cytopathic change degree (CPE) of each group is observed.
The cells were assessed by fluorescence imaging of the cell cultures for infection with the virus and the level of intracellular viral replication. The half-toxic concentration of the sample on cells (CC 50) and the effective concentration of the drug (EC 50) to suppress 50% of the cytopathic effect were calculated by the Reed-Muench method, respectively, and the Therapeutic Index (TI) was calculated as CC50/EC 50. The results are shown in Table 1.
TABLE 1 determination of anti-coronavirus Activity
The above data indicate that the disclosed compounds all have more prominent activity against the COVID-19 virus and higher therapeutic index than the positive control compound ZJT1, wherein PCDD115-10, PCDD115-16, PCDD115-20, and PCDD115-24 are 3 times that of ZJT 1. These results indicate that the disclosed compounds treat diseases of coronaviridae infections with smaller doses and lower side effects.
Example 16: hERG assay
To investigate the risk of QT interval prolongation by test compounds, the effect of delayed rectifier k+ current (IKr) on important roles in ventricular repolarization was studied using CHO cells expressing the human ether-a-go-go related gene (hERG) channel.
The IKr induced by the depolarization stimulus given 2 seconds +50mV and the repolarization stimulus given 2 seconds-50 mV was further given using a fully automatic patch clamp system after the cells were maintained at a membrane potential of-80 mV by whole cell patch clamp method recording. After the generated current was stabilized, a test compound solution dissolved in an extracellular solution (NaCl: 137mmol/L, KCl:4mmol/L, caCl2:1.8mmol/L, mgCl2-6H2O:1mmol/L, glucose: 10mmol/L, HEPES:10mmol/L, pH 7.4.4) was applied to the cells at room temperature for 10 minutes. From the resulting IKr, the absolute value of the maximum tail current was measured using analytical software with reference to the current value of the resting membrane potential. Further, the inhibition ratio with respect to the maximum tail current before application of the test compound was calculated, and the influence of the test substance on IKr was evaluated in comparison with the vehicle-applied group (0.1% dmso solution). The results are shown in Table 2.
Average inhibition at 100. Mu. Mol/L of Compound of Table 2
Numbering of compounds Inhibition ratio (%) Numbering of compounds Inhibition ratio (%)
PCDD115-01 15.1 PCDD115-17 20.6
PCDD115-02 22.3 PCDD115-18 21.4
PCDD115-03 18.3 PCDD115-19 19.6
PCDD115-04 23.6 PCDD115-20 17.5
PCDD115-05 17.6 PCDD115-21 15.8
PCDD115-06 15.5 PCDD115-22 19.7
PCDD115-07 16.8 PCDD115-23 17.2
PCDD115-08 23.1 PCDD115-24 16.5
PCDD115-09 22.6 PCDD115-25 16.9
PCDD115-10 18.5 PCDD115-26 20.6
PCDD115-11 17.5 PCDD115-27 22.4
PCDD115-12 19.6 PCDD115-28 21.3
PCDD115-13 22.3 PCDD115-29 20.6
PCDD115-14 24.1 PCDD115-30 25.6
PCDD115-15 20.2 ZJT1 35.2
PCDD115-16 18.6 /
The inhibition rate of the compound disclosed by the invention on IKr is obviously smaller than that of a control compound ZJT1 at 100 mu mol/L, and compared with ZJT4, the inhibition rate is between 042 and 0.68, which shows that the compound disclosed by the invention has lower cardiotoxicity than the compound ZJT 1. Demonstrating that the disclosed compounds have greatly reduced cardiotoxicity.
Example 17: tissue distribution test
80 male Long Evans rats were randomly assigned to 5 groups, group A (16, randomly assigned to 4 groups, each group of 4, 4 groups of rats were each given 2mg/kg of compound PCDD 115-03) by gavage, group B (16, randomly assigned to 4 groups, each group of 4, 4 groups of rats were each given 2mg/kg of compound PCDD 115-20) by gavage, group C (16, randomly assigned to 4 groups, each group of 4, 4 groups of rats were each given 2mg/kg of compound PCDD 115-21) by gavage, group D (16, randomly assigned to 4 groups, each group of 4, 4 groups of rats were each given 2mg/kg of compound PCDD 115-23) by gavage, and group E (16, each group of 4, 4 groups of rats were each given 2mg/kg of compound ZJT1 by gavage). Fasted for 12 hours before the experiment, and the water is freely drunk; unified feeding is performed 2h after administration. 4 rats were anesthetized after 1.0h, 4.0h, 8.0h and 12.0h, respectively, and liver, lung and brain tissue samples were collected and the distribution of the analyte in each tissue was determined by HPLC-MS/MS (the analyte was ZJT 1). The results are shown in Table 3.
TABLE 3 tissue distribution of test substances after oral administration of Compound (2 mg/kg) to rats
BLQ: below the lower quantization limit (< 0.015. Mu.g/g).
The in vivo tissue distribution test data of rats show that the lung tissue concentration is highest in each time point of oral administration of the compounds PCDD115-03, PCDD115-20, PCDD115-21 and PCDD115-23 disclosed by the invention, and the distribution of the object to be tested in the lung and the brain is greater than that of the control compound ZJT1; comparison of the data from lung and liver tissue distribution shows that the disclosed compounds are more targeted in the lung and reduced distribution in the liver. This demonstrates that the compounds of the invention have better lung tissue targeting, can break through the blood brain barrier into brain tissue, and more unexpectedly, the compounds of the invention can reduce the distribution in the liver, thereby being more beneficial to resisting pulmonary virus infection and the resulting brain infection, and simultaneously reducing the risk of liver toxicity.
While the invention has been described with reference to the preferred embodiments, it is not intended to limit the invention thereto, and it is to be understood that other modifications and improvements may be made by those skilled in the art without departing from the spirit and scope of the invention, which is therefore defined by the appended claims.

Claims (10)

1. A novel six-membered heterocyclic derivative represented by formula (I):
in the formula (I) of the present invention,
n 1 selected from 1;
X 1 and X 2 Are all selected from O;
R 1 selected from quiltSubstituted C1-C8 alkyl, wherein R j Selected from hydrogen, C1-C8 alkyl;
R 2a and R is 2b Are all selected from hydrogen;
R 3 selected from C6-C18 aryl substituted with one or more fluorine atoms;
R 4 selected from the group consisting ofWherein,
m1 is selected from 0, 1, 2, or 3;
R b selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl;
R c selected from halogen;
R 5 selected from the group consisting ofWherein,
m 2 and m 3 Independently selected from 0, 1, 2, 3, or 4, and when m 2 Or m 3 When any one is 0, W is directly connected with N atoms;
R g1 and R is g2 Each independently selected from hydrogen, C1-C8 alkyl;
w is selected fromWherein,
Y 1、 Y 2 and Y 3 Each independently selected from O or S;
R f1 and R is f2 Each independently selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl; or,
R f1 and R is f2 Is connected with P and R together f1 、R f2 O which are respectively connected together form a multi-ring;
R f3 selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkenyloxy, C1-C8 alkylthio, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy;
R f4 and R is f5 Each independently selected from hydrogen, C1-C8 alkyl.
2. The novel six-membered heterocyclic derivative as described in claim 1, which has the structure as shown in the formula (II):
the definition of the substituents in formula (II) is as defined in formula (I) of claim 1.
3. The novel six-membered heterocyclic derivative as described in claim 1 or 2, which has the structure represented by the formula (iii):
the substituents in formula (III) are as defined in formula (I) of claim 1.
4. The novel six-membered heterocyclic derivative as described in claim 1 or 2, which has the structure of formula (iv):
the substituents in formula (IV) are as defined in formula (I) of claim 1.
5. The novel six-membered heterocyclic derivative as described in claim 1 or 2, which has the structure of formula (v):
the substituents in formula (V) are as defined in formula (I) of claim 1.
6. A novel six-membered heterocyclic derivative selected from the following compounds:
7. a pharmaceutical composition comprising the novel six-membered heterocyclic derivative as described in any one of claims 1 to 6.
8. Use of a novel six-membered heterocyclic derivative as described in any one of claims 1 to 6, or a pharmaceutical composition as described in claim 7 for the preparation of an anti-coronavirus drug.
9. The use as claimed in claim 8, wherein the medicament is prepared for oral, inhalation or parenteral administration for the prophylaxis and/or treatment of diseases caused by coronaviruses by intravenous, intramuscular, transdermal or subcutaneous administration.
10. The use as claimed in claim 8, wherein the coronavirus is selected from SARS virus, MERS virus, covd-19 virus.
CN202310279520.XA 2022-03-24 2023-03-21 Novel six-membered heterocyclic derivative, and pharmaceutical composition and application thereof Active CN116284133B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210300939 2022-03-24
CN2022103009394 2022-03-24

Publications (2)

Publication Number Publication Date
CN116284133A CN116284133A (en) 2023-06-23
CN116284133B true CN116284133B (en) 2024-03-29

Family

ID=86830268

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310279520.XA Active CN116284133B (en) 2022-03-24 2023-03-21 Novel six-membered heterocyclic derivative, and pharmaceutical composition and application thereof

Country Status (1)

Country Link
CN (1) CN116284133B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024031089A1 (en) 2022-08-05 2024-02-08 Gilead Sciences, Inc. Sars-cov2 main protease inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103153968A (en) * 2010-08-10 2013-06-12 盐野义制药株式会社 Triazine derivative and pharmaceutical compound that contains same and exhibits analgesic activity
CN116730988A (en) * 2022-03-10 2023-09-12 湖北九康通生物医药有限公司 Triazine compound, intermediate thereof, preparation method and application thereof
CN116782904A (en) * 2021-09-28 2023-09-19 盐野义制药株式会社 Pharmaceutical composition containing triazine derivative

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103153968A (en) * 2010-08-10 2013-06-12 盐野义制药株式会社 Triazine derivative and pharmaceutical compound that contains same and exhibits analgesic activity
CN116782904A (en) * 2021-09-28 2023-09-19 盐野义制药株式会社 Pharmaceutical composition containing triazine derivative
CN116730988A (en) * 2022-03-10 2023-09-12 湖北九康通生物医药有限公司 Triazine compound, intermediate thereof, preparation method and application thereof

Also Published As

Publication number Publication date
CN116284133A (en) 2023-06-23

Similar Documents

Publication Publication Date Title
JP7413419B2 (en) (S)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[1,5-A]pyrimidine-3-carboxamide Crystal forms, their preparation and their uses
CN115960088B (en) Novel coronavirus main protease inhibitor and preparation method and application thereof
CN114057702B (en) Novel inhibitor of coronavirus main protease and preparation method and application thereof
CA3142030A1 (en) Compounds useful to treat influenza virus infections
EP3816163A1 (en) Cell necrosis inhibitor, preparation method therefor and use thereof
TW201213329A (en) Pyrazine derivatives as ENaC blockers
JP2015536940A (en) Antiviral phosphonate analogs and methods for their production
CN115806570B (en) Peptoid derivative, pharmaceutical composition and application thereof
CN116284133B (en) Novel six-membered heterocyclic derivative, and pharmaceutical composition and application thereof
EP3965753A1 (en) Dhodh inhibitors and their use as antiviral agents
CN115710297A (en) Novel nucleotide derivatives, and pharmaceutical composition and application thereof
CN115135646B (en) Substituted polycyclic compounds, pharmaceutical compositions and uses thereof
CN108794517B (en) Arginase inhibitor and preparation method and application thereof
CA3211820A1 (en) Isoquinolone compound and use thereof
CN115361999B (en) 2- [ 2-Methylazetidin-1-yl ] -4-phenyl-6- (trifluoromethyl) -pyrimidine compounds
CN108350007B (en) Substituted adenine compound and pharmaceutical composition thereof
US20220211704A1 (en) Inhibitors of human immunodeficiency virus replication
CN113603689B (en) Polycyclic pyridone compounds, pharmaceutical compositions and uses thereof
CN111484541A (en) Dinucleotide precursor medicine and its preparing method
CN116462728B (en) Purine nucleoside derivative for resisting virus infection, pharmaceutical composition and application thereof
CN109705015A (en) Histon deacetylase (HDAC) inhibitor and preparation method thereof and purposes
JP7452903B2 (en) Entecavir monophosphate alanine amide phenol ester and its pharmaceutical uses
WO2016034637A1 (en) Derivatives of macrocyclic n-aryl-tricyclopyrimidine-2-amine polyethers as inhibitors of ftl3 and jak
RU2793918C2 (en) Cell necrosis inhibitor, method for its production and application
AU2022359222A1 (en) A new class of 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