WO2021129799A1 - Influenza virus replication inhibitor and use thereof - Google Patents

Influenza virus replication inhibitor and use thereof Download PDF

Info

Publication number
WO2021129799A1
WO2021129799A1 PCT/CN2020/139363 CN2020139363W WO2021129799A1 WO 2021129799 A1 WO2021129799 A1 WO 2021129799A1 CN 2020139363 W CN2020139363 W CN 2020139363W WO 2021129799 A1 WO2021129799 A1 WO 2021129799A1
Authority
WO
WIPO (PCT)
Prior art keywords
atoms
group
compound
ring
och
Prior art date
Application number
PCT/CN2020/139363
Other languages
French (fr)
Chinese (zh)
Inventor
张英俊
任青云
罗慧超
殷俊俊
范钰新
莫玉峰
乔明明
李中乐
Original Assignee
广东东阳光药业有限公司
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 广东东阳光药业有限公司 filed Critical 广东东阳光药业有限公司
Publication of WO2021129799A1 publication Critical patent/WO2021129799A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a class of new compounds as inhibitors of influenza virus replication and a method for preparing them, a pharmaceutical composition containing the compound, and the use of the compound and the pharmaceutical composition in the treatment of influenza. More specifically, the compounds of the present invention can be used as inhibitors of influenza virus cap-dependent endonuclease (cap-dependent endonuclease).
  • Influenza (hereinafter referred to as influenza) is an acute respiratory infectious disease that seriously harms human health. It is caused by influenza virus and has the characteristics of high prevalence, widespread epidemic, and rapid spread. Influenza virus can cause severe symptoms such as pneumonia or heart and lung failure in the elderly and children with weakened immune system and some patients with immune disorders.
  • the flu virus was first discovered by the British Wilson Smith in 1933 and was called H1N1. H stands for hemagglutinin; N stands for neuraminidase. The numbers represent different types. Since its discovery, the influenza virus has caused multiple pandemics worldwide, and an outbreak will occur in about ten years, causing huge losses globally. The influenza virus epidemic can cause 250,000 to 500,000 deaths and 3 million to 5 million severe cases each year. A total of about 5% to 15% of people worldwide are infected. The cause of each pandemic is the emergence of new virus strains in humans.
  • Influenza viruses are RNA viruses of the Orthomyxoviridae family and belong to the genus Influenza viruses. According to the antigenic characteristics and genetic characteristics of virus particle nucleoprotein (NP) and matrix protein (M), influenza viruses are mainly divided into three types: A, B, and C, also known as A, B, and C three types. Type III viruses have similar biochemical and biological characteristics. Virus particles are 80-120nm in diameter, and are usually approximately spherical, but may appear in filamentous form. The virus consists of three layers, the inner layer is the viral nucleocapsid, containing nucleoprotein (NP), P protein and RNA. NP is a soluble antigen (S antigen) with type specificity and stable antigenicity.
  • S antigen soluble antigen
  • P protein may be a polymerase required for RNA transcription and replication.
  • the middle layer is the viral envelope, which is composed of a layer of lipids and a layer of membrane protein (MP). MP has stable antigenicity and type specificity.
  • the outer layer is a radial protrusion composed of two different glycoproteins, namely hemagglutinin (H) and neuraminidase (N). H can cause erythrocyte agglutination, which is a tool for viruses to absorb on the surface of sensitive cells.
  • N can hydrolyze mucus proteins and hydrolyze the N-acetylneuraminic acid at the end of the receptor-specific glycoprotein on the cell surface. It is the virus that leaves the cell surface after the virus has replicated. Tool of. Both H and N have mutation characteristics, so there is only strain-specific antigenicity, and its antibodies have a protective effect.
  • Type A influenza virus has one species, type A influenza virus. Wild waterbirds are the natural hosts of a large number of influenza A viruses. Sometimes the virus can spread to other species and cause a devastating outbreak in poultry or lead to a human influenza pandemic. Among the three types of influenza, type A virus is the most virulent human pathogen that causes most serious diseases. It can be transmitted to other species and cause a large-scale epidemic of human influenza. Based on the antibody response to these viruses, influenza A viruses can be subdivided into different serotypes.
  • H1N1 causing Spanish influenza in 1918
  • H2N2 causing Asian influenza in 1957
  • H3N2 causing Hong Kong influenza in 1968
  • H5N1 2007-08
  • H7N7 with rare potential for zoonotic disease
  • H1N2 endemic in humans and pigs
  • H9N2, H7N2, H7N3, and H10N7
  • Influenza B virus has one species, influenza B virus, which often causes local influenza epidemics, does not cause a pandemic influenza outbreak, and is only found in humans and seals. This type of influenza virus mutates at a rate 2-3 times slower than type A, so its genetic diversity is low, and there is only one type B influenza serotype. Due to the lack of antigen diversity, humans usually acquire a certain degree of influenza B immunity at an early age. However, due to the mutation of the influenza B strain, it is impossible for humans to be permanently immune. However, due to the low rate of antigen change of influenza B virus strains, combined with its restricted host changes (inhibiting cross-species antigen transition), to ensure that influenza B pandemic does not occur.
  • Influenza C virus has one species. Influenza C virus, which mostly exists in scattered form, mainly invades infants and young children. Generally, it does not cause influenza epidemics and can infect humans and pigs.
  • RNA polymerase is composed of PB1, PB2 and PA subunits.
  • the PB1 subunit is mainly involved in the replication process of the viral genome;
  • the PB2 subunit is mainly responsible for binding to the host pro-mRNA cap structure and assisting in the cleavage process of the endonuclease;
  • the PA subunit is a key protein in the life cycle of the influenza virus, which has Endonuclease activity is an enzyme necessary for the synthesis of viral mRNA.
  • the structure of influenza virus mRNA needs to have both a 5'cap structure and a 3'-poly(A) tail that can be recognized by the host cell's translation system.
  • the 5'cap structure is 10-13 nucleotides (ie cap-snatching) cut from the 5'end of the host cell pro-mRNA by the endonuclease activity of the PA subunit of RNA polymerase. It is an influenza virus Required for transcription initiation. Cap-snatching is a key event in the life cycle of influenza virus. There is no similar time and corresponding enzymes in the host cell. Therefore, endonuclease inhibitors for cap-snatching can selectively block the transcription process of influenza virus, which is harmful to the host. The cells do not affect.
  • Vaccination and the use of antiviral drugs are important means to deal with the influenza pandemic.
  • due to the strong antigenic variation of influenza viruses it is basically impossible to produce vaccines on a large scale before the pandemic.
  • Currently available antiviral therapy agents M2 ion channel blockers amantadine and rimantadine, and neuraminidase inhibitors Oseltamivir (Oseltamivir), Zanamivir (Zanamivir), Peramivir (Peramivir) And Laninamivir (Laninamivir).
  • Oseltamivir Oseltamivir
  • Zanamivir Zanamivir
  • Peramivir Peramivir
  • Laninamivir Laninamivir
  • Baloxavir marboxil a new anti-influenza agent with a new mechanism of action, has been on the market. It inhibits the synthesis of viral mRNA by inhibiting cap-dependent endonuclease (cap-dependent endonuclease), and ultimately inhibits virus proliferation. Other compounds to treat influenza through this mechanism of action are still urgently needed by scientists.
  • the present invention provides a new class of compounds as inhibitors of influenza virus RNA polymerase, more specifically, the present invention provides a class of new compounds as inhibitors of influenza virus cap-dependent endonuclease (cap-dependent endonuclease)
  • caps-dependent endonuclease Such compounds and their compositions can be used to prepare drugs for the prevention, treatment or alleviation of viral infections in patients.
  • the compound of the present invention can not only inhibit influenza virus very well, but also has lower cytotoxicity, better in vivo pharmacokinetic properties and in vivo pharmacodynamic properties, and better liver properties. Microsomal stability. Therefore, the compound provided by the present invention has better druggability than the existing similar compounds.
  • the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, or pharmaceutical compound represented by formula (I).
  • a compound which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, or pharmaceutical compound represented by formula (I).
  • Acceptable salts or their prodrugs
  • E is CR 10 , C or N;
  • Ring Cy is a C 3-8 carbocyclic ring, a heterocyclic ring composed of 3-8 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-8 atoms, wherein the C 3-8 carbocyclic ring, 3-
  • the 8-atom heterocyclic ring, the C 6-10 aromatic ring and the 5-8 atom heteroaromatic ring are each independently unsubstituted or substituted by 1, 2, 3, or 4 R x ; the 3-
  • the 8-atom heterocyclic ring and the 5-8 atom heteroaromatic ring each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O or S;
  • any two R x and the atoms connected to them form a C 3-6 carbon ring, a heterocyclic ring composed of 3-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms, wherein
  • Each R a , R b , R c and Rd are independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- Heterocyclic group composed of 6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group , C 3-6 cycloalkyl, 3-6 heterocyclic group, C 6-10 aryl and 5-6 heteroaryl are each independently unsubstituted or by 1, 2 or 3 Substituted by a substituent, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 1-6 haloalkoxy, C 1-6 alkoxy or
  • R c , R d and the nitrogen atoms connected to them together form a heterocyclic ring composed of 3-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 3-6 atoms and The heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
  • the compound does not include the following compounds:
  • the ring Cy is a C 3-7 carbocyclic ring, a 5-atom heterocyclic ring, a 6-atom heterocyclic ring, a 7-atom heterocyclic ring, a C 6-10 aromatic ring, 5 atoms Consisting of a heteroaromatic ring, a heteroaromatic ring consisting of 6 atoms or a heteroaromatic ring consisting of 7 atoms, wherein the C 3-7 carbon ring, a 5-atom heterocyclic ring, a 6-atom heterocyclic ring, A heterocyclic ring composed of 7 atoms, a C 6-10 aromatic ring, a heteroaromatic ring composed of 5 atoms, a heteroaromatic ring composed of 6 atoms, and a heteroaromatic ring composed of 7 atoms are each independently unsubstituted or 1 , 2, 3, or 4 R x ; the 5-atom heterocyclic ring, 6-atom heterocyclic ring, 7-atom heterocyclic ring, 7-atom
  • ring Cy is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dithiocyclopentane, dioxocyclopentane, pyrrolidine, dihydropyrrole, pyrazole , Dihydropyrazole, imidazolidine, dihydroimidazole, piperidine, tetrahydropyridine, dihydropyridine, morpholine, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro- 2H-1,4-thiazine, thiomorpholine, dihydrothiazine, piperazine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, tetrahydrothiopyran , Dihydrothiopyran,
  • any 2 R x and the atoms connected to them together form a C 3-6 carbon ring, a heterocyclic ring formed by 5-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms, wherein
  • each R a, R b, R c and R d are independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl , Heterocyclic group composed of 5-6 atoms, phenyl group or heteroaryl group composed of 5-6 atoms, wherein the methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl , Cyclobutyl, heterocyclic group consisting of 5-6 atoms, phenyl group and heteroaryl group consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2 or 3 substituents, the Substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl
  • R c , R d and their connected nitrogen atoms together form a heterocyclic ring composed of 5-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 5-6 atoms and
  • the heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.
  • any 2 R x and the atoms connected to them form cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, morpholine, thio Morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, Pyrazine, pyridazine or 1,3,5-triazine, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piper
  • the compound of the present invention is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, Pharmaceutically acceptable salts or their prodrugs,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , E and ring Cy have the definitions described in the present invention.
  • the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention, and optionally, further comprising a pharmaceutically acceptable adjuvant.
  • the pharmaceutical composition provided by the present invention further comprises one or more other therapeutic agents.
  • the other therapeutic agents of the present invention are selected from anti-influenza virus agents or vaccines.
  • the other therapeutic agent of the present invention is Amantadine, Rimantadine, Oseltamivir, Zanamivir, Peramivir , Laninamivir (Laninamivir), Laninamivir Octanoate Hydrate (Laninamivir Octanoate Hydrate), Favipiravir (Favipiravir), Arbidol (Arbidol), Ribavirin (Ribavirin), Sita Flynn, Ingavirin, Fludase, CAS No. 1422050-75-6, Pimodivir, Baloxavir marboxil, FluMist Quadrivalent, Quadrivalent, or ) Or a combination of them.
  • the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
  • the present invention provides the use of the compound or the pharmaceutical composition in the preparation of a medicine, wherein the medicine is used to prevent, treat or alleviate viral infectious diseases in patients.
  • the viral infection is an influenza virus infection.
  • the present invention provides the use of the compound or the pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to inhibit the RNA polymerase of influenza virus.
  • the RNA polymerase is a cap-dependent endonuclease.
  • the present invention includes all stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs of the compounds of the present invention.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal to be treated with it.
  • the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention also includes solvated and unsolvated forms thereof.
  • the compounds of the present invention may contain several asymmetric centers or the form of racemate mixtures as generally described.
  • the present invention further includes racemic mixtures, partial racemic mixtures, and separated enantiomers and diastereomers.
  • the compound of the present invention may exist in one form of possible isomers, rotamers, atropisomers, and tautomers or in the form of a mixture thereof.
  • the present invention may further include the isomers of the compounds of the present invention. Mixtures of isomers, rotamers, atropisomers, tautomers, or partial mixtures of isomers, rotamers, atropisomers, tautomers, or separated Isomers, rotamers, atropisomers, tautomers.
  • the compounds of the present invention include compounds defined in the present invention that are labeled with various isotopes, for example, radioactive isotopes such as 3 H, 14 C and 18 F are present, or non-radioactive isotopes are present, Such as 2 H and 13 C compounds.
  • radioactive isotopes such as 3 H, 14 C and 18 F are present, or non-radioactive isotopes are present, Such as 2 H and 13 C compounds.
  • the present invention relates to a method for the preparation, separation and purification of the compound contained in formula (I) or formula (II).
  • subject used in the present invention refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (such as humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.
  • subject and patient used in the present invention are used interchangeably.
  • the terms “subject” and “patient” refer to animals (for example, birds or mammals such as chickens, quails, or turkeys), especially “mammals” including non-primates (for example, cattle, pigs, etc.) , Horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans.
  • the subject is a non-human animal, such as a domestic animal (e.g., horse, cow, pig, or sheep) or a pet (e.g., dog, cat, guinea pig, or rabbit).
  • "patient” refers to a human being.
  • the present invention also includes isotopically-labeled compounds of the present invention, which are the same as those described in the present invention except for the fact that one or more atoms are replaced by an atom whose atomic mass or mass number is different from the natural common atomic mass or mass number.
  • Exemplary isotopes that can also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.
  • the compounds of the present invention containing the aforementioned isotopes and/or other isotopes of other atoms and pharmaceutically acceptable salts of the compounds are all included in the scope of the present invention.
  • Isotope-labeled compounds of the present invention such as radioisotopes, such as 3 H and 14 C, incorporated into the compounds of the present invention can be used for drug and/or substrate tissue distribution analysis. Due to the ease of preparation and detection, tritiated, i.e. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred.
  • substitution with heavy isotopes, such as deuterium, or 2 H can provide some therapeutic advantages derived from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Therefore, it may be preferable in some situations.
  • stereoisomers refers to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .
  • stereochemistry definitions and rules used in the present invention generally follow SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry” of Organic Compounds", John Wiley&Sons, Inc., New York, 1994.
  • the compounds of the present invention may contain asymmetric centers or chiral centers, and therefore exist in different stereoisomeric forms. It is expected that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and their mixtures such as racemic mixtures, It is also included in the scope of the present invention.
  • any asymmetric atom (for example, carbon, etc.) in the compound of the present invention may exist in a racemic or enantiomerically enriched form, for example, in (R)- or (S)-configuration.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the substituents on the atoms with unsaturated double bonds may exist in the form of cis-(Z)- or trans-(E)-.
  • the compound of the present invention can be one of the possible isomers or a mixture of them, such as racemates and diastereomer mixtures (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be in the cis or trans (cis- or trans-) configuration .
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • racemate of any final product or intermediate obtained can be resolved into optical enantiomers by a method familiar to those skilled in the art using known methods, for example, by performing diastereomeric salts of the obtained diastereomers. Separate.
  • the racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high performance liquid chromatography
  • enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • keto-enol tautomerism include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • the compound of the present invention may exist in one form of possible isomers, rotamers, atropisomers, and tautomers, or in the form of mixtures thereof,
  • they are substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.
  • nitrogen oxide means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxide.
  • N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms.
  • oxidants such as hydrogen peroxide or peracid (for example, peroxycarboxylic acid)
  • MCPBA m-chloroperbenzoic acid
  • solvate refers to an association formed by one or more solvent molecules with the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • the term "metabolite” refers to the product obtained by the metabolism of a specific compound or its salt in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage, etc. of the administered compound.
  • the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
  • pharmaceutically acceptable salt refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or through other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionic acid Salt, picrate
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also intends to contemplate any quaternary ammonium salts formed by compounds containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • prodrug represents the conversion of a compound into a compound represented by formula (I) or formula (II) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the parent structure in the blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group.
  • prodrugs please refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a specific substituent.
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples.
  • optionally substituted by can be used interchangeably with the term "unsubstituted or substituted by”, that is, the structure is unsubstituted or substituted by one or more substituents described in the present invention .
  • an optional substituent group can be substituted at each substitutable position of the group.
  • substituents selected from specific groups then the substituents can be substituted at each position with the same or different substitutions.
  • C 1-6 alkyl specifically refers to independently disclosed C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • C 1 -4 alkyl specifically refers to independently disclosed C 1 alkyl (methyl), C 2 alkyl (ethyl), C 3 alkyl (ie propyl, including n-propyl and isopropyl), C 4 alkane Group (ie, butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • alkyl or "alkyl group” used in the present invention means a saturated linear or branched monovalent hydrocarbon radical containing 1-20 carbon atoms.
  • the alkyl group contains 1-8 carbon atoms, that is, C 1-8 alkyl; in some embodiments, the alkyl group contains 1-6 carbon atoms, that is, C 1-6 alkane
  • the alkyl group contains 1-4 carbon atoms, ie, C 1-4 alkyl; in some embodiments, the alkyl group contains 1-2 carbon atoms.
  • the alkyl group is optionally substituted with one or more substituents described in the present invention.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2
  • alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one carbon-carbon sp 2 double bond, wherein the alkenyl group may be optionally substituted by one or Multiple substituents described in the present invention are substituted, including the positioning of "cis” and “tans", or the positioning of "E” and "Z".
  • the alkenyl group contains 2-8 carbon atoms, ie C 2-8 alkenyl; in some embodiments, the alkenyl group contains 2-6 carbon atoms, ie C 2-6 alkenyl Group; In some embodiments, the alkenyl group contains 2-4 carbon atoms, ie C 2-4 alkenyl.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more One of the substituents described in this invention is substituted.
  • the alkynyl group contains 2-8 carbon atoms, ie C 2-8 alkynyl; in some embodiments, the alkynyl group contains 2-6 carbon atoms, ie C 2-6 alkynyl In some embodiments, an alkynyl group contains 2-4 carbon atoms, ie, C 2-4 alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 1 -Butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octyne Kee, wait.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, that is, -O-alkyl, where the alkyl group has the meaning as described in the present invention.
  • the alkoxy group contains 1-12 carbon atoms, namely C 1-12 alkoxy; in some embodiments, the alkoxy group contains 1-6 carbon atoms, namely C 1 -6 alkoxy; in some embodiments, the alkoxy group contains 1-4 carbon atoms, ie, C 1-4 alkoxy; in some embodiments, the alkoxy group contains 1-3 Carbon atom, namely C 1-3 alkoxy.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butan Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 1-
  • alkylamino includes “N-alkylamino” and "N,N-dialkylamino” in which the amino groups are each independently substituted with one or two alkyl groups.
  • the alkylamino group is an alkylamino group with one or two Ci-6 alkyl groups attached to the nitrogen atom, that is, a Ci -6 alkylamino group.
  • the alkylamino group is an alkylamino group with one or two C 1-4 alkyl groups attached to the nitrogen atom, that is, a C 1-4 alkylamino group.
  • the alkylamino group is an alkylamino group with one or two C 1-3 alkyl groups attached to the nitrogen atom, that is, a C 1-3 alkylamino group.
  • one or two alkylamino C 1-2 alkyl groups attached to the alkylamino group on the nitrogen atom i.e., C 1-2 alkylamino.
  • Suitable alkylamino groups can be monoalkylamino or dialkylamino. Examples of this include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), and N,N-dimethylamino. Amino, N,N-diethylamino, etc.
  • Carbocyclic group or "carbocyclic ring” means a monovalent or multivalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms.
  • Carbobicyclic groups include spirocarbonbicyclic groups, fused carbobicyclic groups, and bridged carbon bicyclic groups.
  • the number of carbon atoms is 3-12, ie C 3-12 carbocyclyl; in other embodiments, the number of carbon atoms is 3-10, ie C 3-10 carbocyclyl ; In other embodiments, the number of carbon atoms is 3-8, that is, C 3-8 carbocyclic group; in other embodiments, the number of carbon atoms is 3-6, that is, C 3-6 carbon Cyclic; in other embodiments, the number of carbon atoms is 3-7, that is, C 3-7 carbocyclyl; in other embodiments, the number of carbon atoms is 3-6, that is, C 3- 6 carbocyclic group.
  • carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1- Cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl Cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
  • cycloalkyl refers to a monovalent or multivalent non-aromatic saturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3-14 ring atoms.
  • the cycloalkyl group contains 3-12 carbon atoms, that is, C 3-12 cycloalkyl; in some embodiments, the cycloalkyl group contains 3-8 carbon atoms, that is, C 3-8 cycloalkane. Group; In some embodiments, the cycloalkyl group contains 3-6 carbon atoms, that is, a C 3-6 cycloalkyl group.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • the cycloalkyl group is optionally substituted with one or more substituents described in the present invention.
  • aryl or "aromatic ring” are used interchangeably herein and refer to monocyclic, bicyclic, and tricyclic rings containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms
  • the carbocyclic ring system in which at least one ring system is aromatic, and each ring system contains a ring composed of 3-7 atoms, and has one or more attachment points connected to the rest of the molecule.
  • aryl groups may include phenyl, naphthyl, and anthracenyl.
  • the aryl group may be optionally substituted with one or more substituents described in the present invention.
  • heteroatom refers to O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or on the nitrogen atom in the heterocycle
  • the form in which hydrogen is substituted for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidinyl) NR, R are the substituents described in the present invention).
  • heterocyclic group refers to a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 3-14 ring atoms, wherein at least one ring atom is selected from heteroatoms, and the heteroatoms have the characteristics of the present invention The meaning described.
  • the “heterocyclic group” can be fully saturated or contain one or more degrees of unsaturation, but it cannot have an aromatic ring.
  • the terms “heterocyclyl”, “heterocyclic” and “heterocyclic” are used interchangeably herein.
  • the heterocyclic group is a heterocyclic group consisting of 3-10 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S and N, that is, a heterocyclic group consisting of 3-10 atoms
  • the heterocyclic group is a heterocyclic group consisting of 3-8 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, namely 3 -8-atom heterocyclic group
  • the heterocyclic group is a heterocyclic group consisting of 5-8 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N Cyclic group is a heterocyclic group consisting of 5-8 atoms; in some embodiments, the heterocyclic group is 3-6 containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N
  • a heterocyclic group composed of ring atoms that is, a heterocyclic group composed of 3-6 atoms; in some embodiments, a heterocyclic group composed of 3-6 atoms
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, dihydropyrrolyl (2-pyrrolinyl, 3-pyrrolinyl), dihydropyrazolyl, pyrazolidinyl, dihydroimidazolyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-di Oxycyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridyl, Dihydropyridyl, morpholinyl, dihydrooxazinyl, thiomorph
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like.
  • the heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • heteroaryl means a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 5-10 ring atoms, or 5-8 ring atoms, or 5-6 ring atoms, in which at least one ring The system is aromatic, and at least one ring contains one or more heteroatoms, and the heteroatoms have the definition described in the present invention.
  • heteroaryl means a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 5-10 ring atoms, or 5-8 ring atoms, or 5-6 ring atoms, in which at least one ring The system is aromatic, and at least one ring contains one or more heteroatoms, and the heteroatoms have the definition described in the present invention.
  • heteroaryl “heteroaromatic ring” or “heteroaromatic compound” are used interchangeably herein.
  • the heteroaryl group is a heteroaryl group consisting of 5-10 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S and N, that is, a heteroaryl group consisting of 5-10 atoms ⁇ heteroaryl.
  • the heteroaryl group is a heteroaryl group consisting of 5-8 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a heteroaryl group consisting of 5-8 atoms ⁇ heteroaryl.
  • the heteroaryl group is a heteroaryl group consisting of 5-6 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S and N, that is, a heteroaryl group consisting of 5-6 atoms ⁇ heteroaryl.
  • heteroaryl groups include, but are not limited to, furyl (e.g. 2-furyl, 3-furyl), imidazolyl (e.g. N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl), isoxazolyl (e.g. 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g.
  • 2-oxazolyl, 4-oxazolyl, 5 -Oxazolyl pyrrolyl (such as N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (such as 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (such as 3-pyridazinyl), thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazole Group (such as 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (such as 2-triazolyl, 5-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2 ,4-Triazolyl, 1,2,3-triazolyl), thienyl (e.g.
  • 2-thienyl, 3-thienyl pyrazolyl (e.g., 2-pyrazolyl, 3-pyrazolyl) ), isothiazolyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 -Oxadiazolyl), thiodiazolyl (such as 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl) , Pyrazinyl, 1,3,5-triazinyl, furanone; also includes the following bicyclic groups, but not limited to bicyclic groups: benzimidazolyl, benzofuranyl, benzothienyl, indole Group (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl
  • m typically describes the number of ring atoms in a molecule, and the number of ring atoms in the molecule is m.
  • piperidinyl is a 6-atom heterocyclic group
  • naphthyl is a 10-atom aryl group.
  • D refers to deuterium, i.e., 2 H.
  • halogen refers to F, Cl, Br or I.
  • alkylene refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated hydrocarbon group. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In other embodiments, the alkylene group contains 1 to 6 carbon atoms. In other embodiments, the alkylene group contains 1 to 12 carbon atoms. -4 carbon atoms. In other embodiments, the alkylene group contains 1-2 carbon atoms. Examples of such include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylene (-CH(CH 3 )CH 2 -), and the like.
  • cycloalkyl-alkylene means Cycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are connected to the rest of the molecule through an alkylene group, in which alkyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl and hetero
  • alkyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl and hetero alkyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl and hetero
  • aryl groups all have the meaning described in the present invention, such as benzyl (-CH 2 -Ph).
  • cycloalkyl-alkylene "carbocyclyl-alkylene”, “heterocyclyl-alkylene", “aryl-alkylene”, “heteroaryl-alkylene”
  • the group is optionally substituted with one or more substituents described in this invention.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergies or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, and the like.
  • pharmaceutically acceptable refers to those approved by a federal regulatory agency or a national government or listed in the US Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • influenza virus replication includes reducing the amount of virus replication (for example, reducing by at least 10%) and completely preventing virus replication (ie, reducing the amount of virus replication by 100%). In some embodiments, influenza virus replication is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.
  • the term "effective amount” refers to the amount of the compound of the present invention that causes the expected biological response.
  • the expected biological response is to inhibit influenza virus replication, reduce the amount of influenza virus or reduce or improve the severity, duration, progression or onset of influenza virus infection, prevent the spread of influenza virus infection, and prevent influenza virus infection-related symptoms. Recurrence, evolution, onset or progression, or enhancement or enhancement of the preventive or therapeutic effects of another anti-influenza infection therapy used.
  • the exact amount of compound administered to the subject will depend on the mode of administration, the type and severity of the infection, and the characteristics of the subject, such as health status, age, sex, weight, and tolerance to the drug. The skilled person will be able to determine the appropriate dosage based on these and other factors.
  • the "effective amount" of the second agent will depend on the type of drug used.
  • the appropriate dosage of the approved agent is known and the skilled person can adjust it according to the condition of the subject, the type of condition to be treated, and the amount of the compound of the present invention used. If the amount is not clearly indicated, an effective amount should be used.
  • the compound of the present invention can be administered to the subject in a dose range of about 0.01-100 mg/body weight/day for therapeutic or prophylactic treatment.
  • treatment refers to therapeutic and prophylactic treatments.
  • therapeutic treatment includes alleviating or ameliorating the progression, severity, and/or severity of influenza virus-mediated conditions due to administration of one or more therapies (e.g., one or more therapeutic agents (e.g., compounds and compositions of the invention) Or duration, or ameliorate one or more symptoms of influenza virus-mediated conditions (in particular, one or more discernible symptoms).
  • therapeutic treatment includes amelioration of influenza virus-mediated conditions At least one measurable physical parameter.
  • therapeutic treatment includes inhibiting influenza virus-mediated conditions by, for example, stabilizing discernible symptoms physically or by, for example, stabilizing physical parameters, physiologically, or both.
  • therapeutic treatment includes reducing or stabilizing influenza virus-mediated infections.
  • Antiviral drugs can be used in the community to treat people who already have influenza to reduce the severity of symptoms and reduce the number of days they are sick .
  • protecting group refers to when a substituent reacts with other functional groups, it is usually used to block or protect specific functionality.
  • amino protecting group refers to a substituent connected to an amino group to block or protect the functionality of the amino group in a compound.
  • Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, and Tosyl (Ts), tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethyleneoxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to a substituent of a hydroxyl group used to block or protect the functionality of the hydroxyl group. Suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group” refers to the substituent of the carboxyl group used to block or protect the functionality of the carboxyl group.
  • General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) Phosphonyl) ethyl, nitroethyl, etc.
  • protecting groups refer to the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • the present invention provides a class of new compounds as inhibitors of influenza virus RNA polymerase, more specifically, the present invention provides a class of new compounds as inhibitors of influenza virus cap-dependent endonuclease, such compounds and
  • the composition can be used to prevent, treat, treat or alleviate viral infections in patients.
  • the compound of the present invention not only has better pharmacological activity, but also has lower toxicity, better in vivo pharmacokinetic properties and in vivo pharmacodynamic properties, and better liver particles Body stability. Therefore, the compound provided by the present invention has better druggability than the existing similar compounds.
  • the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, or pharmaceutical compound represented by formula (I).
  • a compound which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, or pharmaceutical compound represented by formula (I).
  • Acceptable salts or their prodrugs
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , E and ring Cy have the definitions as described in the present invention, wherein the compounds of the present invention do not include the following compounds :
  • E is CR 10 , C or N, wherein said R 10 has the definition described in the present invention.
  • the ring Cy is a C 3-8 carbocyclic ring, a heterocyclic ring composed of 3-8 atoms, a C 6-10 aromatic ring, or a heteroaromatic ring composed of 5-8 atoms, wherein the C 3- 8- carbon ring, heterocyclic ring composed of 3-8 atoms, C 6-10 aromatic ring and heteroaromatic ring composed of 5-8 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R x Substitution; the heterocyclic ring composed of 3-8 atoms and the heteroaromatic ring composed of 5-8 atoms each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, the R x has the definition described in the present invention.
  • the ring Cy is a C 3-7 carbocyclic ring, a 5-atom heterocyclic ring, a 6-atom heterocyclic ring, a 7-atom heterocyclic ring, a C 6-10 aromatic ring, 5 atoms Consisting of a heteroaromatic ring, a heteroaromatic ring consisting of 6 atoms or a heteroaromatic ring consisting of 7 atoms, wherein the C 3-7 carbon ring, a 5-atom heterocyclic ring, a 6-atom heterocyclic ring, A heterocyclic ring composed of 7 atoms, a C 6-10 aromatic ring, a heteroaromatic ring composed of 5 atoms, a heteroaromatic ring composed of 6 atoms, and a heteroaromatic ring composed of 7 atoms are each independently unsubstituted or 1 , 2, 3, or 4 R x ; the 5-atom heterocyclic ring, 6-atom heterocyclic ring, 7-atom heterocyclic ring, 7-atom
  • ring Cy is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dithiocyclopentane, dioxocyclopentane, pyrrolidine, dihydropyrrole, pyrazole , Dihydropyrazole, imidazolidine, dihydroimidazole, piperidine, tetrahydropyridine, dihydropyridine, morpholine, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro- 2H-1,4-thiazine, thiomorpholine, dihydrothiazine, piperazine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, tetrahydrothiopyran , Dihydrothiopyran,
  • any two R x and the atoms connected to them form a C 3-6 carbon ring, a heterocyclic ring composed of 3-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms, wherein
  • any 2 R x and the atoms connected to them together form a C 3-6 carbon ring, a heterocyclic ring formed by 5-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms, wherein
  • any 2 R x and the atoms connected to them form cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, morpholine, thio Morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, Pyrazine, pyridazine or 1,3,5-triazine, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piper
  • each R a , R b , R c and Rd is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 heterocyclic group, C 6-10 aryl and 5-6 heteroaryl are each independently unsubstituted or Substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
  • R c , R d and the nitrogen atoms connected to them together form a heterocyclic ring composed of 3-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 3-6 atoms and
  • the heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino.
  • each R a , R b , R c and Rd are independently H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl group, heterocyclic group composed of 5-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 heterocyclic group, C 6-10 aryl and 5-6 heteroaryl are each independently unsubstituted or Substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-4 alkyl , C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino;
  • R c , R d and their connected nitrogen atoms together form a heterocyclic ring composed of 5-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 5-6 atoms and
  • the heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino.
  • each R a, R b, R c and R d are independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl , Heterocyclic group composed of 5-6 atoms, phenyl group or heteroaryl group composed of 5-6 atoms, wherein the methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl , Cyclobutyl, heterocyclic group consisting of 5-6 atoms, phenyl group and heteroaryl group consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2 or 3 substituents, the Substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl
  • R c , R d and their connected nitrogen atoms together form a heterocyclic ring composed of 5-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 5-6 atoms and
  • the heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.
  • the present invention relates to a compound of formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, or pharmaceutically acceptable salt thereof Or their prodrugs,
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , E and ring Cy have the definitions as described in the present invention.
  • the present invention relates to one of the following compounds or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs , But by no means limited to these compounds:
  • the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.
  • the pharmaceutical composition provided by the present invention further comprises one or more other therapeutic agents.
  • the other therapeutic agent is selected from an anti-influenza virus agent or a vaccine.
  • the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
  • the other therapeutic agents involved are Amantadine, Rimantadine, Oseltamivir, Zanamivir ), Peramivir, Laninamivir, Laninamivir Octanoate Hydrate, Favipiravir, Arbidol, Bavirin (Ribavirin), Staphyrin, Ingavirin (Ingavirin), Flu enzyme (Fludase), drugs with CAS number 1422050-75-6, Pimodivir (Pimodivir), Baloxavir ( Baloxavir marboxil), flu vaccine (FluMist Quadrivalent, Quadrivalent, or ) Or a combination of them.
  • the present invention provides the use of the compound or the pharmaceutical composition in the preparation of a medicine, wherein the medicine is used to prevent, treat or alleviate viral infectious diseases in patients.
  • the viral infection is an influenza virus infection.
  • influenza virus is influenza A virus.
  • the present invention provides the use of the compound or the pharmaceutical composition in the preparation of a medicine, wherein the medicine is used to inhibit the RNA polymerase of influenza virus.
  • the RNA polymerase is a cap-dependent endonuclease.
  • the present invention includes the use of the compounds of the present invention and their pharmaceutically acceptable salts for the production of pharmaceutical products to treat patients with influenza virus infectious diseases, including those described in the present invention.
  • the present invention includes a pharmaceutical composition comprising an effective therapeutic amount required for combining the compound represented by formula (I) or formula (II) with at least one pharmaceutically acceptable adjuvant.
  • the present invention also includes a method for treating or alleviating influenza virus infectious diseases in patients, or susceptible to this disease, and the method comprises treating the patients with a therapeutically effective amount of the compound represented by formula (I) or formula (II).
  • the salt is a pharmaceutically acceptable salt.
  • pharmaceutically acceptable includes that the substance or composition must be chemically or toxicologically suitable, related to the other components of the formulation and the mammal used for treatment.
  • the salt of the compound of the present invention also includes the salt of an intermediate for preparing or purifying the compound represented by formula (I) or formula (II) or the separated enantiomer of the compound represented by formula (I), but not necessarily A pharmaceutically acceptable salt.
  • compositions, formulation and administration of the compound of the present invention are provided.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I) or formula (II) or its stereoisomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable Accepted salt or solvate.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant, and optionally, other therapeutic and/or preventive components.
  • the pharmaceutical composition includes an effective amount of at least one pharmaceutically acceptable adjuvant.
  • the amount of the compound in the composition of the present invention can effectively treat or alleviate influenza virus infectious diseases in patients.
  • compositions of the present invention exist in free form, or are suitable as pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of patients.
  • the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable adjuvants, which, like those used in the present invention, include any solvents, diluents, or other liquid excipients, dispersants Or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for specific target dosage forms.
  • pharmaceutically acceptable adjuvants include any solvents, diluents, or other liquid excipients, dispersants Or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.
  • substances that can be used as pharmaceutically acceptable adjuvants include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., Tween 80, phosphate, glycine, sorbic acid or potassium sorbate), partial glyceride mixture of saturated plant fatty acids, water, salt or electrolyte (e.g.
  • protamine sulfate disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salt
  • silica gel magnesium trisilicate
  • polyvinylpyrrolidone polyacrylate
  • wax polyethylene-polyoxypropylene-block copolymer
  • methylcellulose hydroxypropylmethylcellulose, lanolin
  • sugars Such as lactose, glucose and sucrose
  • starch such as corn starch and potato starch
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate
  • powdered tragacanth malt
  • Gel talc
  • excipients e.g. cocoa butter and suppository wax
  • oils e.g.
  • magnesium hydroxide and aluminum hydroxide examples include alginic acid, pyrogen-free water, isotonic saline, Ringer's Ringer's solution, ethanol and phosphate buffers, and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) and colorants, anti-sticking agents, and coating agents according to the judgment of the formulator , Sweeteners and flavoring agents, preservatives and antioxidants may also be present in the composition.
  • non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate
  • colorants such as sodium lauryl sulfate and magnesium stearate
  • sweeteners and flavoring agents, preservatives and antioxidants may also be present in the composition.
  • the compound or composition of the present invention can be administered by any suitable means, according to the severity of the disease, oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (as by powder, ointment or drops) or Nasal sprays and the like administer the above-mentioned compounds and pharmaceutically acceptable compositions to humans or other animals.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate Esters, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cotton seed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, poly Fatty acid esters of ethylene glycol and sorbitan and mixtures thereof.
  • oral compositions may also include adjuvants such as we
  • Injectable preparations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, such as sterile injectable water or oil suspensions.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butanediol.
  • water, Ringer's solution and isotonic sodium chloride solution can be used.
  • sterile non-volatile oil is used as a solvent or suspending medium in accordance with the usual practice.
  • any odorless non-volatile oil can be used, including synthetic monoglycerides or diglycerides.
  • fatty acids such as octadecenoic acid
  • fatty acids such as octadecenoic acid
  • it can be filtered through a bacteria-retaining filter or added in the form of a sterile solid composition, and the sterilant that can be dissolved or dispersed in sterile water or other sterile injectable medium before use is sterilized for the injectable preparation.
  • composition for rectal or vaginal administration is particularly a suppository prepared by mixing the compound of the present invention and a suitable non-irritating adjuvant, such as cocoa butter, polyethylene glycol or suppository wax, which is at ambient temperature It is solid but liquid at body temperature and therefore melts and releases the active compound in the rectum or vaginal cavity.
  • a suitable non-irritating adjuvant such as cocoa butter, polyethylene glycol or suppository wax
  • Oral solid dosage forms include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert pharmaceutically acceptable adjuvant, such as sodium citrate or dicalcium phosphate and/or a) filler or bulking agent, such as starch, lactose, sucrose, glucose , Mannitol and silicic acid, b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants, such as glycerin, d) disintegrants, such as Agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates and sodium carbonate, e) solution blocker, such as paraffin, f) absorption accelerator, such as quaternary ammonium compound, g) wetting agent , Such as cetyl alcohol and glyceryl monostearate,
  • solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also have the properties of the composition, so that optionally only the active ingredient is released in a delayed manner, or preferably, in a certain part of the intestinal tract.
  • coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also have the properties of the composition, so that optionally only the active ingredient is released in a delayed manner, or preferably, in a certain part of the intestinal tract.
  • embedding compositions that can be used include polymers and waxes.
  • the active compound may also be in a micro-encapsulated form with one or more of the aforementioned adjuvants.
  • the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch.
  • inert diluent such as sucrose, lactose or starch.
  • dosage forms may also contain other substances besides inert diluents, such as tableting lubricants and other tableting adjuvants, such as magnesium stearate and microcrystalline cellulose. They may optionally contain opacifying agents and may also have the properties of the composition, so that optionally only the active ingredient is released in a delayed manner, or preferably, in a certain part of the intestinal tract.
  • embedding compositions that can be used include polymers and waxes.
  • the topical or transdermal application dosage forms of the compound of the present invention include ointments, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic preparations, ear drops, and eye drops are also considered within the scope of the present invention.
  • the present invention contemplates the use of a skin patch that has the added advantage of providing controlled delivery of the compound to the body.
  • This dosage form can be made by dissolving or dispersing the compound in an appropriate medium.
  • Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • composition of the present invention can also be administered orally, parenterally, locally, rectum, nose, oral cavity, vagina via inhalation spray, or via implanted kit.
  • parenteral as used in the present invention includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the composition is administered orally, intraperitoneally or intravenously.
  • the sterile injectable form of the composition of the present invention may be a water or oil suspension. These suspensions can be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art.
  • sterile non-volatile oil is used as a solvent or suspending medium in accordance with the usual practice.
  • any odorless non-volatile oil can be used, including synthetic monoglycerides or diglycerides.
  • natural pharmaceutically acceptable oils such as olive oil or castor oil, in particular in polyoxyethylated form, fatty acids such as octadecenoic acid and its glyceride derivatives are used in the preparation of injections.
  • oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions).
  • long-chain alcohol diluents or dispersants such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions).
  • Other commonly used surfactants such as Tweens, Spans and other emulsifiers or bioavailability enhancers commonly used in the production of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulation purposes.
  • the pharmaceutical composition of the present invention can be taken orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.
  • commonly used carriers include, but are not limited to, lactose and starch.
  • Lubricants such as magnesium stearate are usually added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient is combined with emulsifying and suspending agents. If necessary, certain sweeteners, flavor enhancers or colorants can also be added.
  • the pharmaceutical composition of the present invention may be administered in the form of suppositories for rectal use.
  • These pharmaceutical compositions can be prepared by mixing reagents and non-irritating excipients.
  • Such substances include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.
  • the pharmaceutical composition of the present invention can also be applied locally. It is easy to prepare a suitable topical formulation for each of these areas or organs.
  • Rectal suppository preparations (see above) or suitable enema preparations can be used to achieve local drip administration to the lower intestinal tract.
  • a topical skin patch can also be used.
  • the pharmaceutical composition can be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more adjuvants.
  • adjuvants suitable for topical instillation of the compound of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable adjuvants.
  • Suitable adjuvants include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical composition can be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or especially a solution in isotonic pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride.
  • the pharmaceutical composition can be formulated as an ointment, such as petrolatum.
  • the pharmaceutical composition can also be administered via nasal vaporized spray or inhalation.
  • This composition is prepared according to well-known techniques in the pharmaceutical field and prepared into salt water by using benzyl alcohol and other suitable preservatives, absorption promoters that improve bioavailability, fluorocarbons and/or other conventional solubilizers or dispersants Solution.
  • the compound used in the method of the present invention can be formulated into a unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable as a unit dose for a subject, each unit containing a predetermined amount of active substance calculated to produce the expected therapeutic effect, optionally combined with a suitable pharmaceutical carrier.
  • the unit dosage form can be used as a single daily dose or one of multiple daily doses (for example, about 1-4 times or more per day). When multiple daily doses are used, the unit dosage form for each dose may be the same or different.
  • the above-mentioned compounds and pharmaceutical compositions provided by the present invention can be used to prepare medicines for preventing, treating or alleviating viral infectious diseases in patients.
  • the viral infection is influenza virus infection.
  • the present invention also provides the use of the above-mentioned compound or its pharmaceutical composition in the preparation of influenza virus RNA polymerase inhibitor drugs, wherein the RNA polymerase inhibitor is a cap-dependent endonuclease.
  • the present invention provides a method for treating, preventing or delaying infection caused by a virus, the method comprising administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutical composition thereof to a patient in need of treatment, wherein the virus is an influenza virus.
  • the above-mentioned compound or pharmaceutical composition provided by the present invention can be co-administered with other therapies or therapeutic agents.
  • the mode of administration can be simultaneous, sequential or at certain time intervals.
  • the dosage of the compound or pharmaceutical composition required to implement the effects of treatment, prevention, or delay usually depends on the specific compound administered, the patient, the specific disease or condition and its severity, the route and frequency of administration, etc., and needs to be determined by the attending physician The specific situation is determined. For example, when the compound or pharmaceutical composition provided by the present invention is administered via an intravenous route, the administration may be performed once a week or even at longer intervals.
  • the present invention provides a novel compound that can be used as an inhibitor of influenza virus RNA polymerase.
  • the compound of the present invention is suitable for preparing medicines in various dosage forms, and can be widely used in the treatment of seasonal influenza, avian influenza, swine influenza, and influenza virus mutant strains resistant to Tamiflu.
  • the compound and pharmaceutical composition of the present invention can also be applied to veterinary treatment of pets, introduced species of animals, and mammals in farm animals. Other examples of animals include horses, dogs, and cats.
  • the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definition of the substituents is as shown in formula (I) or formula (II).
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, 1,4-dioxane, toluene, and ether are obtained by refluxing and drying with sodium metal.
  • Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are dried in advance with anhydrous sodium sulfate.
  • reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
  • the glassware is all dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
  • test conditions for proton nuclear magnetic resonance spectroscopy are: at room temperature, Bruker 400MHz or 600MHz nuclear magnetometer, with CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), Use TMS (0ppm) or chloroform (7.26ppm) as the reference standard.
  • s sensinglet, singlet
  • d doublet, doublet
  • t triplet, triplet
  • m multiplet, multiplet
  • br broadened, wide Peak
  • dd doublet of doublets, double doublet
  • dt doublet of triplets, double triplet
  • Coupling constant denoted by J, in hertz (Hz).
  • the test conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 ⁇ 30mm, 3.5 ⁇ m, 6min, flow rate 0.6mL/min, mobile phase: 5%-95 % ( The ratio of CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid)), detected by UV at 210nm/254nm, using electrospray ionization mode (ESI).
  • ESI electrospray ionization mode
  • the compound purity is characterized by: Agilent 1260 Pre-HPLC or Calesep Pump 250 Pre-HPLC (Column Model: NOVASEP, 50/80mm, DAC), at 210nm /254nm is detected by UV.
  • the LC/MS/MS system used for analysis in the bioassay test includes Agilent 1200 series vacuum degassing furnace, binary syringe pump, orifice automatic sampler, column thermostat, AB Sciex 4000 triple quadruple with electrospray ionization source (ESI) Polar mass spectrometer. Quantitative analysis is carried out in MRM mode, and the parameters of MRM conversion are shown in Table A:
  • the mobile phase gradient is shown in Table B:
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • THF tetrahydrofuran
  • NaBH 4 sodium borohydride
  • PPA Polyphosphoric acid
  • T3P 1-Propyl phosphoric anhydride (50% ethyl acetate solution);
  • R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , E and ring Cy have the definitions of the present invention
  • R j is a C 1-6 alkyl group; further, each R 1 , R 2 , R 3 and R 4 are independently H, F, Cl, Br or I, and R j is preferably methyl or ethyl.
  • the compound (1-a) is reacted with the compound (2-a) to obtain the compound (3-a) .
  • Compound (3-a) is hydrolyzed under alkaline conditions to obtain compound (4-a) ; compound (4-a) is ring-closed under the action of polyphosphoric acid (PPA) to form compound (5-a) ; compound (5-a) )
  • Intermediate (6-a) is generated under the action of sodium borohydride.
  • the compound represented by formula (9-a) is prepared by the method described in Synthesis Scheme 2. First, compound (6-a) and compound (7-a) are reacted in the presence of a condensing agent such as 1-propyl phosphoric anhydride to obtain compound (8-a) . Compound (8-a) removes the protective group Bn on the hydroxyl group to obtain the compound represented by formula (9-a) .
  • the compound represented by formula (9-a) can be separated by chiral preparation methods such as preparative chromatography to obtain corresponding stereoisomers.
  • the crude product (1-E) (1.89g, 6.23mmol) obtained in the previous step was dissolved in THF (25mL) and methanol (25mL), cooled to 0°C, sodium borohydride (565mg, 14.30mmol) was added in batches, and After completion, the reaction was continued at 0°C for 5 minutes, and then transferred to room temperature to react for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (30 mL ⁇ 3), and the organic phases were combined.
  • the compound compound (5-B) (1 g, 3.13 mmol) was added to a single-neck flask, and then PPA (15 mL) was added, and the temperature was raised to 120° C. for reaction for 2 h. After the reaction was cooled to room temperature, ice water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL ⁇ 2). The organic phases were combined, washed with saturated sodium bicarbonate solution (30 mL ⁇ 3), and anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure.
  • the inventors used some of the compounds of the present invention as examples to test the antiviral activity, cytotoxicity, pharmacokinetic properties, and stability of the compounds of the present invention in liver particles.
  • This experiment tested the ability of the compound to inhibit the cytopathic (CPE) of the virus H1N1A/Weiss/43 at the in vitro cell level.
  • CPE cytopathic
  • MDCK cells (Madin-Darby canine kidney cells, continuous canine kidney epithelial cell line, source: ATCC#CCL-34) were seeded in a 384-well plate at a density of 2000 cells/well at 37°C, 5% CO 2 Incubate overnight; the next day, change to fresh culture medium containing different concentrations of compounds, and influenza virus (A/Weiss/43(H1N1)) infects cells with a multiplicity of infection that can produce 80-95% CPE.
  • influenza virus A/Weiss/43(H1N1)
  • the highest detection concentration of the compound is 100nM, 3 times dilution, 8 concentrations, in order: 100nM, 33.33nM, 11.11nM, 3.70nM, 1.23nM, 0.41nM, 0.14nM, 0.05nM.
  • a virus control group without medicine and a cell control group without virus infection and medicine were set up.
  • no virus was added, and culture medium was used instead. Both are provided with two duplicate holes. Incubate at 37°C and 5% CO 2 for 5 days.
  • CCK-8 kit source: Shanghai Liji Biotechnology Co., Ltd. #D3100L4057
  • GraphPad Prism analyzes the data, calculates the CPE inhibition rate, and obtains the EC 50 and CC 50 values according to the fitted curve.
  • the experimental results are shown in Table 1.
  • the CPE inhibition rate (the absorbance value of the dosing hole-the absorbance value of the virus control hole) / (the absorbance value of the cell control hole-the absorbance value of the virus control hole) ⁇ 100%
  • Cell survival rate (the absorbance value of the dosing hole-the absorbance value of the medium control hole) / (the absorbance value of the cell control hole-the absorbance value of the medium control hole) ⁇ 100%
  • test results show that the compound of the present invention has good anti-influenza virus activity and at the same time has very low cytotoxicity.
  • Example B Evaluation of the pharmacokinetic properties of the compound of the present invention after intravenous injection or oral administration:
  • This experiment evaluated the pharmacokinetic study of the compound of the present invention in healthy, adult male SD rats, dogs or monkeys.
  • the compound of the present invention is administered with 5% DMSO+5% Kolliphor HS 15+90% physiological saline solution.
  • iv intravenous
  • po oral
  • animals are given a dose of 5 mg/kg.
  • Blood was taken (0.3mL) at time points of 0.083 (iv), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours for rats, and 0.083 (iv), 0.25, 0.5, 1.0, 2.0, 4.0 for dogs or monkeys , 6.0, 8.0, and 24 hours (48 hours for monkeys) to take blood (0.3 mL), and centrifuge at 3,000 or 4,000 rpm for 10 minutes.
  • the plasma solution was collected and stored at -20°C or -70°C until the aforementioned LC/MS/MS analysis.
  • test results show that the compound of the present invention has large exposure in rats, dogs or monkeys, good absorption, and good pharmacokinetic properties.
  • This experiment evaluated the pharmacokinetic study of the compound of the present invention in healthy, adult male SD rats, dogs or monkeys.
  • the compound of the present invention is administered with 10% DMSO+10% Kolliphor HS 15+80% physiological saline solution.
  • iv intravenous
  • po oral
  • animals are given a dose of 1 or 5 mg/kg.
  • Rats were taken at 0.083 (iv), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours of blood (0.3 mL), and dogs or monkeys were taken at 0.083 (iv), 0.25, 0.5, 1.0, 2.0, 4.0 , 6.0, 8.0, and 24 hours (48 hours for monkeys) to take blood (0.3 mL), and centrifuge at 3,000 or 4,000 rpm for 10 minutes.
  • the plasma solution was collected and stored at -20°C or -70°C until the aforementioned LC/MS/MS analysis.
  • Table 2 The experimental results are shown in Table 2.
  • test results show that the compound of the present invention has large exposure in rats, dogs or monkeys, good absorption, and good pharmacokinetic properties.
  • the stability of the compound of the present invention in mixed rat, dog, monkey or human liver microparticles was evaluated.
  • the concentration of the sample at different incubation times is measured, and the "Log[drug concentration]" versus "incubation” is used.
  • the rate constant is obtained by plotting with time, and the drug half-life and in vivo clearance Cl in vivo are calculated, and the drug half-life and in vivo clearance value are used to evaluate the stability of the drug in liver microsomes.
  • the specific experimental system is as follows:
  • the test results show that the compound of the present invention is stable in liver microparticles of rats, dogs and humans.

Abstract

Disclosed are a class of new compounds which act as an influenza virus replication inhibitor and a preparation method therefor, a pharmaceutical composition comprising the compound, and the use of the compound and the pharmaceutical composition thereof in the treatment of influenza, which fall within the pharmaceutical field. The compound is a compound as shown in formula (I) or a stereoisomer, tautomer, oxynitride, solvate, metabolite, or pharmaceutically acceptable salt of the compound as shown in formula (I), or a prodrug thereof. The compound not only can effectively inhibit the influenza virus, but also has lower cytotoxicity, better in vivo pharmacokinetic properties and in vivo pharmacodynamic properties, and better liver microsome stability.

Description

流感病毒复制抑制剂及其用途Influenza virus replication inhibitor and its use 发明领域Field of invention
本发明属于药物领域，具体涉及一类作为流感病毒复制抑制剂的新化合物及其制备它们的方法，包含所述化合物的药物组合物以及所述化合物及其药物组合物在治疗流感中的用途。更具体地说，本发明所述的化合物可以作为流感病毒帽依赖性核酸内切酶(cap-dependent endonuclease)的抑制剂。The invention belongs to the field of medicine, and specifically relates to a class of new compounds as inhibitors of influenza virus replication and a method for preparing them, a pharmaceutical composition containing the compound, and the use of the compound and the pharmaceutical composition in the treatment of influenza. More specifically, the compounds of the present invention can be used as inhibitors of influenza virus cap-dependent endonuclease (cap-dependent endonuclease).
背景技术Background technique
流行性感冒(以下简称流感)是一种严重危害人类健康的急性呼吸道传染病，由流感病毒引发，具有高患病率、流行广泛、传播迅速的特点。流行性感冒病毒在免疫力较弱的老人与小孩及一些免疫失调的病人会引起较严重的症状，如肺炎或是心肺衰竭等。流感病毒最早是由英国人威尔逊·史密斯(Wilson Smith)在1933年发现的，被称为H1N1。H代表血凝素；N代表神经氨酸酶。数字代表不同类型。流感病毒自发现以来已在全球范围内造成多次大流行，十年左右会产生一次爆发流行，在全球范围内造成巨大的损失。流感病毒流行每年可导致25万到50万例死亡，300万到500万重病例，全球共有约5％到15％的人被感染。每次大流行的原因，均是在人类中有新病毒株的出现。Influenza (hereinafter referred to as influenza) is an acute respiratory infectious disease that seriously harms human health. It is caused by influenza virus and has the characteristics of high prevalence, widespread epidemic, and rapid spread. Influenza virus can cause severe symptoms such as pneumonia or heart and lung failure in the elderly and children with weakened immune system and some patients with immune disorders. The flu virus was first discovered by the British Wilson Smith in 1933 and was called H1N1. H stands for hemagglutinin; N stands for neuraminidase. The numbers represent different types. Since its discovery, the influenza virus has caused multiple pandemics worldwide, and an outbreak will occur in about ten years, causing huge losses globally. The influenza virus epidemic can cause 250,000 to 500,000 deaths and 3 million to 5 million severe cases each year. A total of about 5% to 15% of people worldwide are infected. The cause of each pandemic is the emergence of new virus strains in humans.
流感病毒是正黏液病毒科(Orthomyxoviridae)的RNA病毒，属于流感病毒属。根据病毒粒子核蛋白(NP)和基质蛋白(M)的抗原特性及基因特性的不同，流感病毒主要分为A、B、C三型，也称甲、乙、丙三型。三型病毒具有相似的生化和生物学特征。病毒颗粒直径为80-120nm，并且通常近似球体，但可能出现丝状形式。病毒由三层构成，内层为病毒核衣壳，含核蛋白(NP)、P蛋白和RNA。NP是可溶性抗原(S抗原)，具有型特异性，抗原性稳定。P蛋白(P1、P2、P3)可能是RNA转录和复制所需的多聚酶。中层为病毒囊膜，由一层类脂体和一层膜蛋白(MP)构成，MP抗原性稳定，也具有型特异性。外层为两种不同糖蛋白构成的辐射状突起，即血凝素(hemagglutinin,H)和神经氨酸酶(neuraminidase,N)。H能引起红细胞凝集，是病毒吸咐于敏感细胞表面的工具，N则能水解粘液蛋白，水解细胞表面受体特异性糖蛋白末端的N-乙酰神经氨酸，是病毒复制完成后脱离细胞表面的工具。H和N均有变异特性，故只有株特异的抗原性，其抗体具有保护作用。Influenza viruses are RNA viruses of the Orthomyxoviridae family and belong to the genus Influenza viruses. According to the antigenic characteristics and genetic characteristics of virus particle nucleoprotein (NP) and matrix protein (M), influenza viruses are mainly divided into three types: A, B, and C, also known as A, B, and C three types. Type III viruses have similar biochemical and biological characteristics. Virus particles are 80-120nm in diameter, and are usually approximately spherical, but may appear in filamentous form. The virus consists of three layers, the inner layer is the viral nucleocapsid, containing nucleoprotein (NP), P protein and RNA. NP is a soluble antigen (S antigen) with type specificity and stable antigenicity. P protein (P1, P2, P3) may be a polymerase required for RNA transcription and replication. The middle layer is the viral envelope, which is composed of a layer of lipids and a layer of membrane protein (MP). MP has stable antigenicity and type specificity. The outer layer is a radial protrusion composed of two different glycoproteins, namely hemagglutinin (H) and neuraminidase (N). H can cause erythrocyte agglutination, which is a tool for viruses to absorb on the surface of sensitive cells. N can hydrolyze mucus proteins and hydrolyze the N-acetylneuraminic acid at the end of the receptor-specific glycoprotein on the cell surface. It is the virus that leaves the cell surface after the virus has replicated. Tool of. Both H and N have mutation characteristics, so there is only strain-specific antigenicity, and its antibodies have a protective effect.
A型流感病毒属有1个物种，A型流感病毒。野生水鸟是大量A型流感病毒的天然宿主。有时，病毒会传播至其它物种并且引起家禽中的毁灭性爆发或导致人类流感大流行。3种流感类型中，A型病毒是引起大部分严重疾病的，毒性最强的人病原体，可以传递至其他物种，并且产生人流感大面积流行。根据对这些病毒的抗体反应，可将A型流感病毒细分为不同血清型。以已知人类流感大流行死亡人数排序，已确认人类血清型为：H1N1(1918年引起西班牙流感)、H2N2(1957年引起亚洲流感)、H3N2(1968年引起香港流感)、H5N1(2007-08流感季的大流行威胁)、H7N7(具有罕见的动物传染病潜能)、H1N2(在人类和猪中的地方性流行)、H9N2、H7N2、H7N3和H10N7。Type A influenza virus has one species, type A influenza virus. Wild waterbirds are the natural hosts of a large number of influenza A viruses. Sometimes the virus can spread to other species and cause a devastating outbreak in poultry or lead to a human influenza pandemic. Among the three types of influenza, type A virus is the most virulent human pathogen that causes most serious diseases. It can be transmitted to other species and cause a large-scale epidemic of human influenza. Based on the antibody response to these viruses, influenza A viruses can be subdivided into different serotypes. Sorted by the number of deaths from the known human influenza pandemics, human serotypes have been confirmed as: H1N1 (causing Spanish influenza in 1918), H2N2 (causing Asian influenza in 1957), H3N2 (causing Hong Kong influenza in 1968), H5N1 (2007-08) Pandemic threat during influenza season), H7N7 (with rare potential for zoonotic disease), H1N2 (endemic in humans and pigs), H9N2, H7N2, H7N3, and H10N7.
B型流感病毒属有1个物种，B型流感病毒，其常引起流感局部流行，不引起世界性流感大爆发，仅在人和海豹中发现。这种类型的流感病毒按照比A型慢2-3倍的速率突变，因此遗传多样性低，仅有一种B型流感血清型。由于这种抗原多样性的缺乏，通常人类在早年即获得一定程度的B型流感免疫力。然而，由于B型流感病毒株的突变，使人类不可能持久免疫。但因B型流感病毒株抗原变化率低，合并其受限宿主变化(抑制跨物种抗原转变)，确保不会发生B型流感大流行。Influenza B virus has one species, influenza B virus, which often causes local influenza epidemics, does not cause a pandemic influenza outbreak, and is only found in humans and seals. This type of influenza virus mutates at a rate 2-3 times slower than type A, so its genetic diversity is low, and there is only one type B influenza serotype. Due to the lack of antigen diversity, humans usually acquire a certain degree of influenza B immunity at an early age. However, due to the mutation of the influenza B strain, it is impossible for humans to be permanently immune. However, due to the low rate of antigen change of influenza B virus strains, combined with its restricted host changes (inhibiting cross-species antigen transition), to ensure that influenza B pandemic does not occur.
C型流感病毒属有1个物种，C型流感病毒，其多以散在形式存在，主要侵袭婴幼儿，一般不引起流感流行，可感染人类和猪。Influenza C virus has one species. Influenza C virus, which mostly exists in scattered form, mainly invades infants and young children. Generally, it does not cause influenza epidemics and can infect humans and pigs.
流感病毒进入宿主细胞后，在细胞核完成复制(vRNA-cRNA-vRNA)和转录(vRNA-mRNA)过程，这两个过程都是由流感病毒编码的RNA聚合酶催化的。RNA聚合酶由PB1、PB2和PA亚基组成。PB1亚基主要参与病毒基因组的复制过程；PB2亚基主要负责与宿主pro-mRNA帽状结构结合，协助完成内切酶的剪切过程；PA亚基是流感病毒生命周期中关键蛋白，其具有内切酶活性，是合成病毒mRNA所必须的酶。另外，在宿主细胞中不存在PA亚基类似活性的酶。流感病毒mRNA的结构需要同时具备可供宿主细胞翻译体系识别的5’帽状结构和3’-poly(A)尾。其中5’帽状结构是通过RNA聚合酶PA亚基的内切酶活性从宿主细胞pro-mRNA的5’端剪切得到的10-13个核苷酸(即cap-snatching)，是流感病毒转录起始所必须的。cap-snatching是流感病毒生命周期中一个关键事件，宿主细胞中不存在类似的时间和相应的酶，因此针对cap-snatching的内切酶抑制剂可以选择性阻断流感病毒的转录过程，对宿主细胞不造成影响。After the influenza virus enters the host cell, it completes the process of replication (vRNA-cRNA-vRNA) and transcription (vRNA-mRNA) in the nucleus, both of which are catalyzed by the RNA polymerase encoded by the influenza virus. RNA polymerase is composed of PB1, PB2 and PA subunits. The PB1 subunit is mainly involved in the replication process of the viral genome; the PB2 subunit is mainly responsible for binding to the host pro-mRNA cap structure and assisting in the cleavage process of the endonuclease; the PA subunit is a key protein in the life cycle of the influenza virus, which has Endonuclease activity is an enzyme necessary for the synthesis of viral mRNA. In addition, there are no enzymes with similar activity to the PA subunit in the host cell. The structure of influenza virus mRNA needs to have both a 5'cap structure and a 3'-poly(A) tail that can be recognized by the host cell's translation system. The 5'cap structure is 10-13 nucleotides (ie cap-snatching) cut from the 5'end of the host cell pro-mRNA by the endonuclease activity of the PA subunit of RNA polymerase. It is an influenza virus Required for transcription initiation. Cap-snatching is a key event in the life cycle of influenza virus. There is no similar time and corresponding enzymes in the host cell. Therefore, endonuclease inhibitors for cap-snatching can selectively block the transcription process of influenza virus, which is harmful to the host. The cells do not affect.
接种疫苗和使用抗病毒药物是应对流感大流行的重要手段，然而由于流感病毒抗原变异能力强，在大流行前基本上不可能大规模生产疫苗。目前可用的抗病毒治疗剂M2离子通道阻断剂金刚胺和金刚乙胺，以及神经氨酸酶抑制剂奥司他韦(Oseltamivir)、扎那米韦(Zanamivir)、帕拉米韦(Peramivir)和拉尼米韦(Laninamivir)。然而，对于所有这些药物，流感病毒已经产生了抗药性。因此，对于新的抗流感治疗剂存在持续的需求。Vaccination and the use of antiviral drugs are important means to deal with the influenza pandemic. However, due to the strong antigenic variation of influenza viruses, it is basically impossible to produce vaccines on a large scale before the pandemic. Currently available antiviral therapy agents M2 ion channel blockers amantadine and rimantadine, and neuraminidase inhibitors Oseltamivir (Oseltamivir), Zanamivir (Zanamivir), Peramivir (Peramivir) And Laninamivir (Laninamivir). However, for all these drugs, the influenza virus has developed drug resistance. Therefore, there is a continuing need for new anti-influenza therapeutic agents.
具有新的作用机理的新的抗流感剂Baloxavir marboxil已上市，它是通过抑制帽依赖性核酸内切酶(cap-dependent endonuclease)从而抑制病毒mRNA的合成，最终抑制病毒增殖。通过这种作用机理治疗流感的其他化合物仍是科学家迫切需要开发的。Baloxavir marboxil, a new anti-influenza agent with a new mechanism of action, has been on the market. It inhibits the synthesis of viral mRNA by inhibiting cap-dependent endonuclease (cap-dependent endonuclease), and ultimately inhibits virus proliferation. Other compounds to treat influenza through this mechanism of action are still urgently needed by scientists.
发明内容Summary of the invention
本发明提供了一类作为流感病毒RNA聚合酶抑制剂的新化合物，更具体地说，本发明提供一类作为流感病毒的帽依赖性核酸内切酶(cap-dependent endonuclease)抑制剂的新化合物，此类化合物及其组合物可以制备用于预防、治疗或减轻患者病毒感染疾病的药物的用途。与已有的同类化合物相比，本发明的化合物不仅能很好的抑制流感病毒，还具有更低的细胞毒性，更优良的体内药代动力学性质和体内药效学性质以及较好的肝微粒体稳定性。因此，本发明提供的化合物相对于已有的同类化合物而言，具有更优良的成药性。The present invention provides a new class of compounds as inhibitors of influenza virus RNA polymerase, more specifically, the present invention provides a class of new compounds as inhibitors of influenza virus cap-dependent endonuclease (cap-dependent endonuclease) Such compounds and their compositions can be used to prepare drugs for the prevention, treatment or alleviation of viral infections in patients. Compared with existing similar compounds, the compound of the present invention can not only inhibit influenza virus very well, but also has lower cytotoxicity, better in vivo pharmacokinetic properties and in vivo pharmacodynamic properties, and better liver properties. Microsomal stability. Therefore, the compound provided by the present invention has better druggability than the existing similar compounds.
一方面，本发明涉及一种化合物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, or pharmaceutical compound represented by formula (I). Acceptable salts or their prodrugs,
Figure PCTCN2020139363-appb-000001
Figure PCTCN2020139363-appb-000001
其中：among them:
E为CR 10、C或N； E is CR 10 , C or N;
R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 3-6环烷基； R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C (=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-6 cycloalkyl;
R 8、R 9和R 10各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基； R 8 , R 9 and R 10 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C(=O)OH, -C(=O) NH 2 , -S(=O) 2 NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 heterocyclic group, C 6-10 aryl or 5-6 heteroaryl ；
或R 8、R 9和与它们相连的碳原子一起形成-C(＝O)-、-C(＝NH)-、-C(＝S)-、C 3-6碳环或5-6个原子组成的杂环； Or R 8 , R 9 and the carbon atoms connected to them together form -C(=O)-, -C(=NH)-, -C(=S)-, C 3-6 carbocyclic ring or 5-6 A heterocyclic ring composed of atoms;
环Cy为C 3-8碳环、3-8个原子组成的杂环、C 6-10芳环或5-8个原子组成的杂芳环，其中所述C 3-8碳环、3-8个原子组成的杂环、C 6-10芳环和5-8个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个R x所取代；所述3-8个原子组成的杂环和5-8个原子组成的杂芳环各自独立地含有1、2、3或4个独立选自N、O或S的杂原子； Ring Cy is a C 3-8 carbocyclic ring, a heterocyclic ring composed of 3-8 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-8 atoms, wherein the C 3-8 carbocyclic ring, 3- The 8-atom heterocyclic ring, the C 6-10 aromatic ring and the 5-8 atom heteroaromatic ring are each independently unsubstituted or substituted by 1, 2, 3, or 4 R x ; the 3- The 8-atom heterocyclic ring and the 5-8 atom heteroaromatic ring each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O or S;
各R x独立地为氘、F、Cl、Br、I、-CN、-NO 2、＝O、＝S、＝NH、-OR b、-NR cR d、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6碳环基、C 3-6碳环基-C 1-4亚烷基、3-6个原子组成的杂环基、(3-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6碳环基、C 3-6碳环基-C 1-4亚烷基、3-6个原子组成的杂环基、(3-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和 (5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或C 1-6烷氨基； Each R x is independently deuterium, F, Cl, Br, I , -CN, -NO 2, = O, = S, = NH, -OR b, -NR c R d, -C (= O) R a , -C(=O)OR b , -C(=O)NR c R d , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, 3-6 atom heterocyclic group, (3-6 atom Heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, heteroaryl composed of 5-6 atoms or (5-6 (Heteroaryl group consisting of three atoms) -C 1-4 alkylene, wherein the C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene group, 3-6 atom heterocyclic group, (3-6 atom heterocyclic group Cyclic)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, heteroaryl composed of 5-6 atoms and (5-6 (Atomic heteroaryl)-C 1-4 alkylene is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 Alkoxy or C 1-6 alkylamino;
或任意2个R x和与它们相连的原子一起形成C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环或5-6个原子组成的杂芳环，其中所述C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝N、-CN、-OH、-NH 2、-COOH、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基； Or any two R x and the atoms connected to them form a C 3-6 carbon ring, a heterocyclic ring composed of 3-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms, wherein The C 3-6 carbon ring, the heterocyclic ring composed of 3-6 atoms, the C 6-10 aromatic ring and the heteroaromatic ring composed of 5-6 atoms are each independently unsubstituted or by 1, 2 or 3 Substituents are substituted, the substituents are independently selected from deuterium, F, Cl, Br, I, =O, =S, =N, -CN, -OH, -NH 2 , -COOH, C 1-6 alkane Group, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
各R a、R b、R c和R d独立地为H、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或C 1-6烷氨基； Each R a , R b , R c and Rd are independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- Heterocyclic group composed of 6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group , C 3-6 cycloalkyl, 3-6 heterocyclic group, C 6-10 aryl and 5-6 heteroaryl are each independently unsubstituted or by 1, 2 or 3 Substituted by a substituent, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 1-6 haloalkoxy, C 1-6 alkoxy or C 1-6 alkylamino;
或R c、R d和与它们相连的氮原子一起，形成3-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述3-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基； Or R c , R d and the nitrogen atoms connected to them together form a heterocyclic ring composed of 3-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 3-6 atoms and The heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
其中，所述化合物不包括以下化合物：Wherein, the compound does not include the following compounds:
Figure PCTCN2020139363-appb-000002
Figure PCTCN2020139363-appb-000002
在一些实施方案中，环Cy为C 3-7碳环、5个原子组成的杂环、6个原子组成的杂环、7个原子组成的杂环、C 6-10芳环、5个原子组成的杂芳环、6个原子组成的杂芳环或7个原子组成的杂芳环，其中所述C 3-7碳环、5个原子组成的杂环、6个原子组成的杂环、7个原子组成的杂环、C 6-10芳环、5个原子组成的杂芳环、6个原子组成的杂芳环和7个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个R x所取代；所述5个原子组成的杂环、6个原子组成的杂环、7个原子组成的杂环、5个原子组成的杂芳环、6个原子组成的杂芳环和7个原子组成的杂芳环各自独立地含有1、2、3或4个独立选自N、O或S的杂原子。 In some embodiments, the ring Cy is a C 3-7 carbocyclic ring, a 5-atom heterocyclic ring, a 6-atom heterocyclic ring, a 7-atom heterocyclic ring, a C 6-10 aromatic ring, 5 atoms Consisting of a heteroaromatic ring, a heteroaromatic ring consisting of 6 atoms or a heteroaromatic ring consisting of 7 atoms, wherein the C 3-7 carbon ring, a 5-atom heterocyclic ring, a 6-atom heterocyclic ring, A heterocyclic ring composed of 7 atoms, a C 6-10 aromatic ring, a heteroaromatic ring composed of 5 atoms, a heteroaromatic ring composed of 6 atoms, and a heteroaromatic ring composed of 7 atoms are each independently unsubstituted or 1 , 2, 3, or 4 R x ; the 5-atom heterocyclic ring, 6-atom heterocyclic ring, 7-atom heterocyclic ring, 5-atom heteroaromatic ring, 6-atom The composed heteroaromatic ring and the 7-atom heteroaromatic ring each independently contain 1, 2, 3, or 4 heteroatoms independently selected from N, O or S.
在一些实施方案中，环Cy为环丙烷、环丁烷、环戊烷、环己烷、环庚烷、二硫环戊烷、二氧环戊烷、 吡咯烷、二氢吡咯、吡唑烷、二氢吡唑、咪唑烷、二氢咪唑、哌啶、四氢吡啶、二氢吡啶、吗啉、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪、硫代吗啉、二氢噻嗪、哌嗪、四氢呋喃、二氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、四氢噻喃、二氢噻喃、噁唑烷、二氢噁唑、噻唑烷、二氢噻唑、噻噁烷、高哌嗪、高哌啶、4H-1,4-噁嗪、4H-1,4-噻嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、异噻唑、吡嗪、哒嗪、1,3,5-三嗪或硫代二唑，其中所述环丙烷、环丁烷、环戊烷、环己烷、环庚烷、二硫环戊烷、二氧环戊烷、吡咯烷、二氢吡咯、吡唑烷、二氢吡唑、咪唑烷、二氢咪唑、哌啶、四氢吡啶、二氢吡啶、吗啉、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪、硫代吗啉、二氢噻嗪、哌嗪、四氢呋喃、二氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、四氢噻喃、二氢噻喃、噁唑烷、二氢噁唑、噻唑烷、二氢噻唑、噻噁烷、高哌嗪、高哌啶、4H-1,4-噁嗪、4H-1,4-噻嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、异噻唑、吡嗪、哒嗪、1,3,5-三嗪和硫代二唑各自独立地未被取代或被1、2、3或4个R x所取代。 In some embodiments, ring Cy is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dithiocyclopentane, dioxocyclopentane, pyrrolidine, dihydropyrrole, pyrazole , Dihydropyrazole, imidazolidine, dihydroimidazole, piperidine, tetrahydropyridine, dihydropyridine, morpholine, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro- 2H-1,4-thiazine, thiomorpholine, dihydrothiazine, piperazine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, tetrahydrothiopyran , Dihydrothiopyran, oxazolidine, dihydrooxazole, thiazolidine, dihydrothiazole, thiaoxane, homopiperazine, homopiperidine, 4H-1,4-oxazine, 4H-1,4-thiol Pyrazine, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, isothiazole, pyrazine, pyridazine, 1,3 , 5-triazine or thiodiazole, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dithiocyclopentane, dioxolane, pyrrolidine, dihydro Pyrrole, pyrazolidine, dihydropyrazole, imidazolidine, dihydroimidazole, piperidine, tetrahydropyridine, dihydropyridine, morpholine, 3,4-dihydro-2H-1,4-oxazine, 3, 4-dihydro-2H-1,4-thiazine, thiomorpholine, dihydrothiazine, piperazine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran , Tetrahydrothiopyran, dihydrothiopyran, oxazolidine, dihydrooxazole, thiazolidine, dihydrothiazole, thiaoxane, homopiperazine, homopiperidine, 4H-1,4-oxazine, 4H- 1,4-thiazine, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, isothiazole, pyrazine, pyridine The oxazine, 1,3,5-triazine and thiodiazole are each independently unsubstituted or substituted with 1, 2, 3, or 4 R x .
在一些实施方案中，各R x独立地为氘、F、Cl、Br、I、-CN、-NO 2、＝O、＝S、＝NH、-OR b、-NR cR d、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、C 3-6碳环基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-2亚烷基，其中所述C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、C 3-6碳环基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-2亚烷基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氧基或C 1-4烷氨基； In some embodiments, each R x is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , =0, =S, =NH, -OR b , -NR c R d , -C (=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-2 alkylene, heterocyclic group consisting of 5-6 atoms, (5 -6-atom heterocyclic group) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, 5-6 heteroaryl Group or (heteroaryl group consisting of 5-6 atoms)-C 1-2 alkylene group, wherein the C 1-4 haloalkyl group, C 1-4 haloalkoxy group, C 1-4 alkyl group, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group -C 1-2 alkylene group, heterocyclic group composed of 5-6 atoms, (5- 6-atom heterocyclic group)-C 1-2 alkylene group, C 6-10 aryl group, C 6-10 aryl group-C 1-2 alkylene group, 5-6 atom heteroaryl group And (heteroaryl group consisting of 5-6 atoms)-C 1-2 alkylene groups are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy Group, C 1-4 alkoxy or C 1-4 alkylamino;
或任意2个R x和与它们相连的原子一起形成C 3-6碳环、5-6个原子形成的杂环、C 6-10芳环或5-6个原子组成的杂芳环，其中所述C 3-6碳环、5-6个原子形成的杂环、C 6-10芳环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氧基或C 1-4烷氨基。 Or any 2 R x and the atoms connected to them together form a C 3-6 carbon ring, a heterocyclic ring formed by 5-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms, wherein The C 3-6 carbon ring, the heterocyclic ring formed by 5-6 atoms, the C 6-10 aromatic ring and the heteroaromatic ring composed of 5-6 atoms are each independently unsubstituted or by 1, 2 or 3 Substituents are substituted, the substituents are independently selected from deuterium, F, Cl, Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, C 1-4 alkane Group, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy or C 1-4 alkylamino.
在一些实施方案中，各R a、R b、R c和R d独立地为H、氘、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、5-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基，其中所述甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、5-6个原子组成的杂环基、苯基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基； In some embodiments, each R a, R b, R c and R d are independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl , Heterocyclic group composed of 5-6 atoms, phenyl group or heteroaryl group composed of 5-6 atoms, wherein the methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl , Cyclobutyl, heterocyclic group consisting of 5-6 atoms, phenyl group and heteroaryl group consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2 or 3 substituents, the Substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methyl Oxy;
或R c、R d和与它们相连的氮原子一起，形成5-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述5-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基。 Or R c , R d and their connected nitrogen atoms together form a heterocyclic ring composed of 5-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 5-6 atoms and The heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.
在一些实施方案中，各R x独立地为氘、F、Cl、Br、I、-CN、-NO 2、＝O、＝S、＝NH、-OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2、-NH 2、-NHCH 3、-NHCH 2CH 3、-N(CH 3) 2、-C(＝O)OH、-C(＝O)OCH 3、-C(＝O)OCH 2CH 3、-C(＝O)NH 2、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCHF 2、-OCF 3、-OCH 2CF 3、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、C 3-6碳环基-CH 2-、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、四氢呋喃基、四氢噻吩基、四氢吡喃基、苯基、苯基-CH 2-、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、***基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基、1,3,5-三嗪基或(5-6个原子组成的杂芳基)-CH 2-，其中所述-CH 2F、-CHF 2、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCHF 2、-OCH 2CF 3、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、C 3-6碳环基-CH 2-、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、四氢呋喃基、四氢噻吩基、四氢吡喃基、苯基、苯基-CH 2-、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、***基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基、1,3,5-三嗪基和(5-6个原子组成的杂芳基)-CH 2-各自未被取代或被1、2 或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、-CF 3、-OCF 3或-OCH 3； In some embodiments, each R x is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , =0, =S, =NH, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(=O)OH, -C( ＝O)OCH 3 , -C(＝O)OCH 2 CH 3 , -C(＝O)NH 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl, allyl, propenyl , Propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 carbocyclyl -CH 2 -, pyrrolidinyl, pyrazolidinyl, imidazolidinyl , Piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-CH 2 -, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl , Thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, 1,3,5- Triazine group or (heteroaryl group consisting of 5-6 atoms) -CH 2 -, wherein the -CH 2 F, -CHF 2 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -OCHF 2 , -OCH 2 CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl, allyl, propenyl, propargyl, 1-propynyl , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 carbocyclyl -CH 2 -, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, sulfur Morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-CH 2 -, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl , Imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl and (5-6 atoms (Heteroaryl group consisting of) -CH 2 -are each unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, =O, =S , =NH, -CN, -OH, -NH 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, -CF 3 , -OCF 3 or -OCH 3 ;
或任意2个R x和与它们相连的原子一起形成环丙烷、环丁烷、环戊烷、环己烷、吡咯烷、吡唑烷、咪唑烷、哌啶、哌嗪、吗啉、硫代吗啉、四氢呋喃、四氢噻吩、四氢吡喃、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、吡嗪、哒嗪或1,3,5-三嗪，其中所述环丙烷、环丁烷、环戊烷、环己烷、吡咯烷、吡唑烷、咪唑烷、哌啶、哌嗪、吗啉、硫代吗啉、四氢呋喃、四氢噻吩、四氢吡喃、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、吡嗪、哒嗪和1,3,5-三嗪各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、-CF 3、-OCF 3或-OCH 3。 Or any 2 R x and the atoms connected to them form cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, morpholine, thio Morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, Pyrazine, pyridazine or 1,3,5-triazine, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, Morpholine, thiomorpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, Oxadiazole, pyrazine, pyridazine and 1,3,5-triazine are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from deuterium, F, Cl , Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, -CF 3 , -OCF 3 or- OCH 3 .
在一些实施方案中，R 8、R 9和R 10各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氨基、C 1-4卤代烷氧基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基； In some embodiments, R 8 , R 9 and R 10 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 heterocyclic group, C 6-10 aryl or 5-6 Heteroaryl groups composed of atoms;
或R 8、R 9和与它们相连的碳原子一起形成-C(＝O)-、-C(＝NH)-、-C(＝S)-、C 3-6碳环或5-6个原子组成的杂环。 Or R 8 , R 9 and the carbon atoms connected to them together form -C(=O)-, -C(=NH)-, -C(=S)-, C 3-6 carbocyclic ring or 5-6 A heterocyclic ring composed of atoms.
在一些实施方案中，R 8、R 9和R 10各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-CHF 2、-CF 3、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCH 2CH 2CH 3、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-OCHF 2、-OCF 3、-OCH 2CF 3、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、四氢呋喃基、四氢噻吩基、四氢吡喃基、苯基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、***基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基或1,3,5-三嗪基； In some embodiments, R 8 , R 9 and R 10 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , Methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, allyl, propenyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl , Cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl , Pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridyl Azinyl or 1,3,5-triazinyl;
或R 8、R 9和与它们相连的碳原子一起形成-C(＝O)-、-C(＝NH)-、-C(＝S)-、环丙烷、环丁烷、环戊烷、环己烷、吡咯烷、吡唑烷、咪唑烷、哌啶、吗啉、硫代吗啉、四氢呋喃、四氢噻吩或四氢吡喃。 Or R 8 , R 9 and the carbon atoms connected to them together form -C(=O)-, -C(=NH)-, -C(=S)-, cyclopropane, cyclobutane, cyclopentane, Cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piperidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydrothiophene or tetrahydropyran.
在一些实施方案中，R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、-CHF 2、-CF 3、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCH 2CH 2CH 3、-OCHF 2、-OCF 3、-OCH 2CF 3、环丙基、环丁基、环戊基或环己基。 In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH , NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, allyl, propenyl, propargyl, 1-propynyl, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH 2 CH 3 , -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl or ring Hexyl.
在另外一些实施方案中，本发明所述化合物为式(II)所示化合物或式(II)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，In other embodiments, the compound of the present invention is a compound represented by formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, Pharmaceutically acceptable salts or their prodrugs,
Figure PCTCN2020139363-appb-000003
Figure PCTCN2020139363-appb-000003
其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、E和环Cy具有本发明所述的定义。 Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , E and ring Cy have the definitions described in the present invention.
另一方面，本发明提供一种药物组合物，所述药物组合物包含有效量的本发明所述化合物，任选地，进一步包含药学上可接受的辅剂。In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention, and optionally, further comprising a pharmaceutically acceptable adjuvant.
在一些实施方案中，本发明提供的药物组合物进一步包含一种或多种其他治疗剂。In some embodiments, the pharmaceutical composition provided by the present invention further comprises one or more other therapeutic agents.
在一些实施方案中，本发明所述其他治疗剂选自抗流感病毒剂或疫苗。In some embodiments, the other therapeutic agents of the present invention are selected from anti-influenza virus agents or vaccines.
在一些实施方案中，本发明所述其他治疗剂为金刚胺(Amantadine)、金刚乙胺(Rimantadine)、奥司他 韦(Oseltamivir)、扎那米韦(Zanamivir)、帕拉米韦(Peramivir)、拉尼米韦(Laninamivir)、拉尼米韦辛酸酯水合物(Laninamivir Octanoate Hydrate)、法匹拉韦(Favipiravir)、阿比多尔(Arbidol)、利巴韦林(Ribavirin)、司他弗林、英加韦林(Ingavirin)、流感酶(Fludase)、CAS号为1422050-75-6的药物、吡莫地韦(Pimodivir)、巴洛沙韦(Baloxavir marboxil)、流感疫苗(FluMist
Figure PCTCN2020139363-appb-000004
Quadrivalent、
Figure PCTCN2020139363-appb-000005
Quadrivalent、
Figure PCTCN2020139363-appb-000006
或
Figure PCTCN2020139363-appb-000007
)或它们的组合。 In some embodiments, the other therapeutic agent of the present invention is Amantadine, Rimantadine, Oseltamivir, Zanamivir, Peramivir , Laninamivir (Laninamivir), Laninamivir Octanoate Hydrate (Laninamivir Octanoate Hydrate), Favipiravir (Favipiravir), Arbidol (Arbidol), Ribavirin (Ribavirin), Sita Flynn, Ingavirin, Fludase, CAS No. 1422050-75-6, Pimodivir, Baloxavir marboxil, FluMist
Figure PCTCN2020139363-appb-000004
Quadrivalent,
Figure PCTCN2020139363-appb-000005
Quadrivalent,
Figure PCTCN2020139363-appb-000006
or
Figure PCTCN2020139363-appb-000007
) Or a combination of them.
在另外一些实施方案中，药物组合物可以是液体，固体，半固体，凝胶或喷雾剂型。In other embodiments, the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
另一方面，本发明提供了所述化合物或所述药物组合物在制备药物中的用途，其中所述药物用于预防、治疗或减轻患者病毒感染性疾病。In another aspect, the present invention provides the use of the compound or the pharmaceutical composition in the preparation of a medicine, wherein the medicine is used to prevent, treat or alleviate viral infectious diseases in patients.
在一些实施方案中，所述病毒感染为流感病毒感染。In some embodiments, the viral infection is an influenza virus infection.
另一方面，本发明提供了所述化合物或所述药物组合物在制备药物中的用途，其中所述药物用于抑制流感病毒的RNA聚合酶。In another aspect, the present invention provides the use of the compound or the pharmaceutical composition in the preparation of a medicament, wherein the medicament is used to inhibit the RNA polymerase of influenza virus.
在另外一些实施方案中，所述RNA聚合酶为帽依赖性核酸内切酶。In other embodiments, the RNA polymerase is a cap-dependent endonuclease.
除非另作说明，本发明包含所有本发明化合物的立体异构体，互变异构体，氮氧化物，溶剂化物，代谢产物，药学上可接受的盐和药学上可接受的前药。术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。Unless otherwise specified, the present invention includes all stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs of the compounds of the present invention. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal to be treated with it.
本发明化合物、包括其盐也可以以其水合物形式获得，或者包括其他用于其结晶的溶剂。本发明化合物可以固有地或通过设计形成具有可药用溶剂(包括水)的溶剂化物；因此，本发明还包括其溶剂化的和未溶剂化的形式。The compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention also includes solvated and unsolvated forms thereof.
另一方面，本发明化合物可能会包含几个不对称中心或其通常所描述的外消旋体混合物的形式。本发明还进一步包含外消旋混合物，部分外消旋混合物以及分离得到的对映体和非对映体。On the other hand, the compounds of the present invention may contain several asymmetric centers or the form of racemate mixtures as generally described. The present invention further includes racemic mixtures, partial racemic mixtures, and separated enantiomers and diastereomers.
本发明化合物可以以可能的异构体、旋转异构体、阻转异构体、互变异构体中的一种形式或其混合物的形式存在，本发明可以进一步包含本发明化合物的异构体、旋转异构体、阻转异构体、互变异构体的混合物，或者异构体、旋转异构体、阻转异构体、互变异构体的部分混合物或者已分离开的异构体、旋转异构体、阻转异构体、互变异构体。The compound of the present invention may exist in one form of possible isomers, rotamers, atropisomers, and tautomers or in the form of a mixture thereof. The present invention may further include the isomers of the compounds of the present invention. Mixtures of isomers, rotamers, atropisomers, tautomers, or partial mixtures of isomers, rotamers, atropisomers, tautomers, or separated Isomers, rotamers, atropisomers, tautomers.
另一方面，本发明所述化合物包括使用各种同位素标记的本发明所定义的化合物，例如，其中存在放射性同位素，如 3H， 14C和 18F的那些化合物，或者其中存在非放射性同位素，如 2H和 13C的化合物。 On the other hand, the compounds of the present invention include compounds defined in the present invention that are labeled with various isotopes, for example, radioactive isotopes such as 3 H, 14 C and 18 F are present, or non-radioactive isotopes are present, Such as 2 H and 13 C compounds.
另一方面，本发明涉及式(I)或式(II)所包含的化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to a method for the preparation, separation and purification of the compound contained in formula (I) or formula (II).
前面所述内容只概述了本发明的某些方面，但并不限于这些方面。这些方面及其他的方面的内容将在下面作更加具体完整的描述。The foregoing content only outlines certain aspects of the present invention, but is not limited to these aspects. The content of these and other aspects will be described in more detail and complete below.
详细说明书Detailed instructions
定义和一般术语Definitions and general terms
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在本发明保护范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the present invention will now be described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulas. The present invention intends to cover all alternatives, modifications and equivalent technical solutions, which are all included in the protection scope of the present invention. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The invention is by no means limited to the methods and materials described herein. In the case where one or more of the combined documents, patents and similar materials are different from or contradictory to this application (including but not limited to the defined terms, term application, described technology, etc.), this Application shall prevail.
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意适合的子组合提供。It should be further recognized that certain features of the present invention, for the sake of clarity, have been described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, the various features of the present invention are described in a single embodiment for the sake of brevity, but they can also be provided individually or in any suitable sub-combination.
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless otherwise specified, all scientific and technological terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated into the present invention in their entirety by reference.
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry"by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。Unless otherwise stated, the following definitions used herein shall apply. For the purpose of the present invention, the chemical elements are consistent with the CAS version of the Periodic Table of Elements, and "Handbook of Chemistry and Physics", 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the description in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 , The entire contents of which are incorporated herein by reference.
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至 少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。Unless otherwise stated or there is an obvious conflict in context, the articles "a", "an" and "said" used herein are intended to include "at least one" or "one or more." Therefore, these articles used herein refer to articles of one or more than one (ie at least one) object. For example, "a component" refers to one or more components, that is, there may be more than one component considered to be adopted or used in the embodiment of the described embodiment.
本发明所使用的术语“受试对象”是指动物。典型的所述动物是哺乳动物。受试对象也指灵长类动物(例如人)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述受试对象是灵长类动物。在另外其他实施方案中，所述受试对象是人。The term "subject" used in the present invention refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (such as humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.
本发明所使用的术语“受治疗者”和“患者”可交换地使用。术语“受治疗者”和“患者”指动物(例如，鸡、鹌鹑或火鸡等鸟类或哺乳动物)，特别是包括非灵长类动物在内的“哺乳动物”(例如，牛、猪、马、羊、兔、豚鼠、大鼠、猫、狗和小鼠)和灵长类动物(例如，猴子、黑猩猩和人类)，更特别的是人类。在一个实施方案中，受治疗者为非人类动物，例如家畜(例如，马、牛、猪或羊)或宠物(例如，狗、猫、豚鼠或兔)。在另一些实施方案中，“患者”是指人类。The terms "subject" and "patient" used in the present invention are used interchangeably. The terms "subject" and "patient" refer to animals (for example, birds or mammals such as chickens, quails, or turkeys), especially "mammals" including non-primates (for example, cattle, pigs, etc.) , Horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as a domestic animal (e.g., horse, cow, pig, or sheep) or a pet (e.g., dog, cat, guinea pig, or rabbit). In other embodiments, "patient" refers to a human being.
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "comprising" is an open-ended expression, that is, includes the content specified in the present invention, but does not exclude other aspects.
本发明还包括同位素标记的本发明化合物，其除以下事实外与本发明所述的那些化合物相同：一个或多个原子被原子质量或质量数不同于天然常见原子质量或质量数的原子代替。还可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，如 2H， 3H， 13C， 14C， 15N， 16O， 17O， 31P， 32P， 36S， 18F和 37Cl。 The present invention also includes isotopically-labeled compounds of the present invention, which are the same as those described in the present invention except for the fact that one or more atoms are replaced by an atom whose atomic mass or mass number is different from the natural common atomic mass or mass number. Exemplary isotopes that can also be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.
包含前述同位素和/或其他原子的其他同位素的本发明化合物以及所述化合物的药学上可接受的盐都包括在本发明范围内。同位素标记的本发明化合物，例如放射性同位素，如 3H和 14C掺入到本发明化合物中可用于药物和/或底物组织分布分析。由于易于制备以及检测，氚代的，即， 3H，以及碳-14，即 14C，同位素特别优选。此外，用重的同位素，如氘，即 2H取代，可提供一些源自更大的代谢稳定性的治疗上的优势，例如增加的体内半衰期或减少的剂量需求。因此，在一些情形下可能是优选的。 The compounds of the present invention containing the aforementioned isotopes and/or other isotopes of other atoms and pharmaceutically acceptable salts of the compounds are all included in the scope of the present invention. Isotope-labeled compounds of the present invention, such as radioisotopes, such as 3 H and 14 C, incorporated into the compounds of the present invention can be used for drug and/or substrate tissue distribution analysis. Due to the ease of preparation and detection, tritiated, i.e. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred. In addition, substitution with heavy isotopes, such as deuterium, or 2 H, can provide some therapeutic advantages derived from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Therefore, it may be preferable in some situations.
术语“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反异构体)、阻转异构体，等等。The term "stereoisomers" refers to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。本发明化合物可含有不对称中心或手性中心，因此以不同的立体异构形式存在。所预期的是，本发明化合物的所有立体异构形式，包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)及它们的混合物如外消旋混合物，也包含在本发明范围之内。许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀d和l或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或l表示化合物是左旋的。前缀为(+)或d的化合物是右旋的。一种具体的立体异构体是对映异构体，这种异构体的混合物称作对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或方法中没有立体选择性或立体特异性时，可出现所述外消旋混合物或外消旋体。The stereochemistry definitions and rules used in the present invention generally follow SPParker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry" of Organic Compounds", John Wiley&Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers, and therefore exist in different stereoisomeric forms. It is expected that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and their mixtures such as racemic mixtures, It is also included in the scope of the present invention. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule in terms of the chiral center (or chiral centers) in the molecule. The prefixes d and l or (+) and (–) are symbols used to specify the rotation of plane-polarized light caused by a compound, where (–) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. A specific stereoisomer is an enantiomer, and a mixture of such isomers is called an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or a racemate. When there is no stereoselectivity or stereospecificity in a chemical reaction or method, the racemic mixture or racemate may occur Spin body.
本发明化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-或(S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量，至少95％对映体过量，或至少99％对映体过量。如果可能的话，具有不饱和双键的原子上的取代基可以以顺式-(Z)-或反式-(E)-形式存在。Any asymmetric atom (for example, carbon, etc.) in the compound of the present invention may exist in a racemic or enantiomerically enriched form, for example, in (R)- or (S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. If possible, the substituents on the atoms with unsaturated double bonds may exist in the form of cis-(Z)- or trans-(E)-.
依据起始物料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物，例如外消旋体和非对应异构体混合物(这取决于不对称碳原子的数量)的形式存在。光学活性的(R)-或(S)-异构体可使用手性合成子或手性制剂制备，或使用常规技术拆分。如果化合物含有一个双键，取代基可能为E或Z构型；如果化合物中含有二取代的环烷基，环烷基的取代基可能为顺式或反式(cis-或trans-)构型。Depending on the choice of starting materials and method, the compound of the present invention can be one of the possible isomers or a mixture of them, such as racemates and diastereomer mixtures (depending on the number of asymmetric carbon atoms) The form exists. Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be in the cis or trans (cis- or trans-) configuration .
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体，对映异构体，非对映异构体，例如，通过色谱法和/或分步结晶法。Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
可以用已知的方法将任何所得终产物或中间体的外消旋体通过本领域技术人员熟悉的方法拆分成光学对映体，如，通过对获得的其非对映异构的盐进行分离。外消旋的产物也可以通过手性色谱来分离，如，使用手性吸附剂的高效液相色谱(HPLC)。特别地，对映异构体可以通过不对称合成制备，例如，可参考Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2 nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。 The racemate of any final product or intermediate obtained can be resolved into optical enantiomers by a method familiar to those skilled in the art using known methods, for example, by performing diastereomeric salts of the obtained diastereomers. Separate. The racemic product can also be separated by chiral chromatography, such as high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, enantiomers can be prepared by asymmetric synthesis, for example, refer to Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SHTables of Resolving Agents and Optical Resolutions p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007).
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversion through the recombination of some bond-forming electrons. Specific examples of keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
因此，如本发明所描述的那样，本发明的化合物可以以可能的异构体、旋转异构体、阻转异构体、互变异构体中的一种形式或其混合物的形式存在，例如为基本纯的几何(顺式或反式)异构体、非对映异构体、光学异构体(对映体)、外消旋体或其混合物形式。Therefore, as described in the present invention, the compound of the present invention may exist in one form of possible isomers, rotamers, atropisomers, and tautomers, or in the form of mixtures thereof, For example, they are substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.
术语“氮氧化物”是指当化合物含几个胺官能团时，可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例，如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是，N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514)，其中例如在惰性溶剂，例如二氯甲烷中，使胺化合物与间-氯过苯甲酸(MCPBA)反应。The term "nitrogen oxide" means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. Examples of oxidants, such as hydrogen peroxide or peracid (for example, peroxycarboxylic acid), can be used to treat the corresponding amine to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), in which, for example, in an inert solvent, such as methylene chloride, the amine compound is combined with m-chloroperbenzoic acid (MCPBA) reaction.
术语“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。The term "solvate" refers to an association formed by one or more solvent molecules with the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
术语“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。The term "metabolite" refers to the product obtained by the metabolism of a specific compound or its salt in the body. The metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by oxidizing, reducing, hydrolyzing, amidating, deamidating, esterifying, degreasing, enzymatic cleavage, etc. of the administered compound. Correspondingly, the present invention includes the metabolites of the compound, including the metabolites produced by fully contacting the compound of the present invention with a mammal for a period of time.
术语“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化 物和芳香磺酸化物。 The term "pharmaceutically acceptable salt" refers to the organic and inorganic salts of the compound of the present invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or through other methods described in books and literature such as ion exchange These salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionic acid Salt, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. The present invention also intends to contemplate any quaternary ammonium salts formed by compounds containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
术语“前药”代表一个化合物在体内转化为式(I)或式(II)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。 The term "prodrug" represents the conversion of a compound into a compound represented by formula (I) or formula (II) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the parent structure in the blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters can be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, and carbonates. , Carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters. For example, these phosphate ester compounds are obtained by phosphorylation of the parent hydroxyl group. For a complete discussion of prodrugs, please refer to the following documents: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008, 51,2328-2345.
术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。术语“任选地被……所取代”，可以与术语“未取代或被……所取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基取代。The term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula above, or the special examples, subclasses, and subclasses included in the examples. A class of compounds. The term "optionally substituted by" can be used interchangeably with the term "unsubstituted or substituted by", that is, the structure is unsubstituted or substituted by one or more substituents described in the present invention .
除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不止一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于，氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、＝O、＝S、＝NH、-OR b、-NR cR d、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、烷基、烯基、炔基、卤代烷基、烷氧基、烷氨基、卤代烷氧基、环烷基、杂环基、芳基、杂芳基、碳环基、碳环基-亚烷基、杂环基-亚烷基、芳基-亚烷基、杂芳基-亚烷基，其中，所述各R a、R b、R c和R d具有如本发明所述定义。 Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different substitutions. The substituents mentioned herein can be, but are not limited to, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C(=O)OH, -C(=O) NH 2, -S (= O) 2 NH 2, = O, = S, = NH, -OR b, -NR c R d, -C (= O) R a, -C (= O) OR b, -C(=O)NR c R d , alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylamino, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carbon cycloalkyl group, carbocyclyl - alkylene, heterocyclyl - alkylene, aryl - alkylene, aryl, heteroaryl - alkylene group, wherein each of R a, R b, R c and R d are It has the definition as described in the present invention.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless explicitly pointed out in other ways, the description methods used in the present invention are interchangeable with "each ... independently being" and "... each independently being" and "... independently being". Should be understood in a broad sense, it can mean that the specific options expressed between the same symbols in different groups do not affect each other, or it can mean the specific options expressed between the same symbols in the same group Do not affect each other.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-6烷基”特别指独立公开的C 1烷基，C 2烷基，C 3烷基，C 4烷基，C 5烷基和C 6烷基，术语“C 1-4烷基”特指独立公开的C 1烷基(甲基)、C 2烷基(乙基)、C 3烷基(即丙基，包括正丙基和异丙基)、C 4烷基(即丁基，包括正丁基、异丁基、仲丁基和叔丁基)。 In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or scope. In particular, the present invention includes each independent sub-combination of each member of these group types and ranges. For example, the term "C 1-6 alkyl" specifically refers to independently disclosed C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl. The term "C 1 -4 alkyl" specifically refers to independently disclosed C 1 alkyl (methyl), C 2 alkyl (ethyl), C 3 alkyl (ie propyl, including n-propyl and isopropyl), C 4 alkane Group (ie, butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In each part of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition of the variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the attached Alkylene group or arylene group.
本发明使用的术语“烷基”或“烷基基团”，表示含1-20个碳原子的饱和直链或支链的一价碳氢化合物原子团。在一些实施方案中，烷基基团含有1-8个碳原子，即C 1-8烷基；在一些实施方案中，烷基基团含有1-6个碳原子，即C 1-6烷基；在一些实施方案中，烷基基团含有1-4个碳原子，即C 1-4烷基；在一些实施方案中，烷基基团含有1-2个碳原子。所述烷基基团任选地被一个或多个本发明所描述的取代基所取代。 The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon radical containing 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-8 carbon atoms, that is, C 1-8 alkyl; in some embodiments, the alkyl group contains 1-6 carbon atoms, that is, C 1-6 alkane In some embodiments, the alkyl group contains 1-4 carbon atoms, ie, C 1-4 alkyl; in some embodiments, the alkyl group contains 1-2 carbon atoms. The alkyl group is optionally substituted with one or more substituents described in the present invention.
烷基基团的实例包含，但并不限于，甲基(Me，-CH 3)，乙基(Et，-CH 2CH 3)，正丙基(n-Pr，-CH 2CH 2CH 3)，异丙基(i-Pr，-CH(CH 3) 2)，正丁基(n-Bu，-CH 2CH 2CH 2CH 3)，异丁基(i-Bu，-CH 2CH(CH 3) 2)，仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu，-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)， 2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1- Butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-Methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl(-C(CH 3 ) 2 CH (CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and so on.
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个碳-碳sp 2双键，其中，所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代，其包括“cis”和“tans”的定位，或者"E"和"Z"的定位。在一些实施方案中，烯基基团包含2-8个碳原子，即C 2-8烯基；在一些实施方案中，烯基基团包含2-6个碳原子，即C 2-6烯基；在一些实施方案中，烯基基团包含2-4个碳原子，即C 2-4烯基。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)、丙烯基(-CH＝CH-CH 3)等等。 The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one carbon-carbon sp 2 double bond, wherein the alkenyl group may be optionally substituted by one or Multiple substituents described in the present invention are substituted, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In some embodiments, the alkenyl group contains 2-8 carbon atoms, ie C 2-8 alkenyl; in some embodiments, the alkenyl group contains 2-6 carbon atoms, ie C 2-6 alkenyl Group; In some embodiments, the alkenyl group contains 2-4 carbon atoms, ie C 2-4 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), propenyl (-CH=CH-CH 3 ), and the like.
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个碳-碳sp三键，其中，所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中，炔基基团包含2-8个碳原子，即C 2-8炔基；在一些实施方案中，炔基基团包含2-6个碳原子，即C 2-6炔基；在一些实施方案中，炔基基团包含2-4个碳原子，即C 2-4炔基。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基、1-己炔基、1-庚炔基、1-辛炔基，等等。 The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one carbon-carbon sp triple bond, wherein the alkynyl group may optionally be substituted by one or more One of the substituents described in this invention is substituted. In some embodiments, the alkynyl group contains 2-8 carbon atoms, ie C 2-8 alkynyl; in some embodiments, the alkynyl group contains 2-6 carbon atoms, ie C 2-6 alkynyl In some embodiments, an alkynyl group contains 2-4 carbon atoms, ie, C 2-4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH 2 C≡CH), 1-propynyl (-C≡C-CH 3 ), 1 -Butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octyne Kee, wait.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，即-O-烷基，其中烷基基团具有如本发明所述的含义。在一些实施方案中，烷氧基基团含有1-12个碳原子，即C 1-12烷氧基；在一些实施方案中，烷氧基基团含有1-6个碳原子，即C 1-6烷氧基；在一些实施方案中，烷氧基基团含有1-4个碳原子，即C 1-4烷氧基；在一些实施方案中，烷氧基基团含有1-3个碳原子，即C 1-3烷氧基。 The term "alkoxy" means that the alkyl group is connected to the rest of the molecule through an oxygen atom, that is, -O-alkyl, where the alkyl group has the meaning as described in the present invention. In some embodiments, the alkoxy group contains 1-12 carbon atoms, namely C 1-12 alkoxy; in some embodiments, the alkoxy group contains 1-6 carbon atoms, namely C 1 -6 alkoxy; in some embodiments, the alkoxy group contains 1-4 carbon atoms, ie, C 1-4 alkoxy; in some embodiments, the alkoxy group contains 1-3 Carbon atom, namely C 1-3 alkoxy.
烷氧基基团的实例包含，但并不限于，甲氧基(MeO,-OCH 3)，乙氧基(EtO,-OCH 2CH 3)，1-丙氧基(n-PrO,n-丙氧基,-OCH 2CH 2CH 3)，2-丙氧基(i-PrO,i-丙氧基,-OCH(CH 3) 2)，1-丁氧基(n-BuO,n-丁氧基,-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO,i-丁氧基,-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO,s-丁氧基,-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO,t-丁氧基,-OC(CH 3) 3)，1-戊氧基(n-戊氧基,-OCH 2CH 2CH 2CH 2CH 3)，2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)，3-戊氧基(-OCH(CH 2CH 3) 2)，2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)，3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)，3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)，2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。 Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butan Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy (-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentoxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy Group (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butoxy (-OCH 2 CH(CH 3 )CH 2 CH 3 ), etc.
术语“烷氨基”包括“N-烷氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代。在一些实施方案中，烷氨基为一个或两个C 1-6烷基连接到氮原子上的烷氨基基团，即C 1-6烷氨基。在一些实施方案中，烷氨基为一个或两个C 1-4烷基连接到氮原子上的烷氨基基团，即C 1-4烷氨基。在一些实施方案中，烷氨基为一个或两个C 1-3烷基连接到氮原子上的烷氨基基团，即C 1-3烷氨基。在一些实施方案中，烷氨基为一个或两个C 1-2烷基连接到氮原子上的烷氨基基团，即C 1-2烷氨基。合适的烷氨基基团可以是单烷氨基或二烷氨基，这样的实例包括，但并不限于，甲氨基(N-甲氨基)，乙氨基(N-乙氨基)，N,N-二甲氨基，N,N-二乙氨基，等等。 The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, the alkylamino group is an alkylamino group with one or two Ci-6 alkyl groups attached to the nitrogen atom, that is, a Ci -6 alkylamino group. In some embodiments, the alkylamino group is an alkylamino group with one or two C 1-4 alkyl groups attached to the nitrogen atom, that is, a C 1-4 alkylamino group. In some embodiments, the alkylamino group is an alkylamino group with one or two C 1-3 alkyl groups attached to the nitrogen atom, that is, a C 1-3 alkylamino group. In some embodiments, one or two alkylamino C 1-2 alkyl groups attached to the alkylamino group on the nitrogen atom, i.e., C 1-2 alkylamino. Suitable alkylamino groups can be monoalkylamino or dialkylamino. Examples of this include, but are not limited to, methylamino (N-methylamino), ethylamino (N-ethylamino), and N,N-dimethylamino. Amino, N,N-diethylamino, etc.
术语“碳环基”或“碳环”表示含有3-12个碳原子的，单价或多价的非芳香性的饱和或部分不饱和单环、双环或者三环体系。碳双环基包括螺碳双环基、稠合碳双环基和桥碳双环基。在一些实施方案中，碳原子的数量为3-12个，即C 3-12碳环基；在另一些实施方案中，碳原子的数量为3-10个，即C 3-10碳环基；在另一些实施方案中，碳原子的数量为3-8个，即C 3-8碳环基；在另一些实施方案中，碳原子的数量为3-6个，即C 3-6碳环基；在另一些实施方案中，碳原子的数量为3-7个，即C 3-7碳环基；在其它一些实施方案中，碳原子的数量为3-6个，即C 3-6碳环基。碳环基基团的实例包括，但并不限于，环丙基，环丁基，环戊基，1-环戊基-1-烯基，1-环戊基-2-烯基，1-环戊基-3-烯基，环己基，1-环己基-1-烯基，1-环己基-2-烯基，1-环己基-3-烯基，环己二烯基，环庚基，环辛基，环壬基，环癸基，环十一烷基，环十二烷基，等等。 The term "carbocyclic group" or "carbocyclic ring" means a monovalent or multivalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. Carbobicyclic groups include spirocarbonbicyclic groups, fused carbobicyclic groups, and bridged carbon bicyclic groups. In some embodiments, the number of carbon atoms is 3-12, ie C 3-12 carbocyclyl; in other embodiments, the number of carbon atoms is 3-10, ie C 3-10 carbocyclyl ; In other embodiments, the number of carbon atoms is 3-8, that is, C 3-8 carbocyclic group; in other embodiments, the number of carbon atoms is 3-6, that is, C 3-6 carbon Cyclic; in other embodiments, the number of carbon atoms is 3-7, that is, C 3-7 carbocyclyl; in other embodiments, the number of carbon atoms is 3-6, that is, C 3- 6 carbocyclic group. Examples of carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1- Cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl Cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
术语“环烷基”表示含有3-14个环原子的，单价或多价的非芳香性的饱和单环、双环或三环碳环体系。在一些实施方案中，环烷基包含3-12个碳原子，即C 3-12环烷基；在一些实施方案中，环烷基包含3-8个碳原子，即C 3-8环烷基；在一些实施方案中，环烷基包含3-6个碳原子，即C 3-6环烷基。环烷基基团的实例包括，但并不限于，环丙基、环丁基、环戊基、环己基、环庚基，等等。所述环烷基基团任选地被一个或多个本发明所描述的取代基所取代。 The term "cycloalkyl" refers to a monovalent or multivalent non-aromatic saturated monocyclic, bicyclic or tricyclic carbocyclic ring system containing 3-14 ring atoms. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms, that is, C 3-12 cycloalkyl; in some embodiments, the cycloalkyl group contains 3-8 carbon atoms, that is, C 3-8 cycloalkane. Group; In some embodiments, the cycloalkyl group contains 3-6 carbon atoms, that is, a C 3-6 cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described in the present invention.
术语“芳基”或“芳环”在此处可交换使用，表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环，双环，和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个 原子组成的环，且有一个或多个附着点与分子的其余部分相连。芳基基团的实例可以包括苯基、萘基和蒽基。所述芳基基团可以任选地被一个或多个本发明所描述的取代基所取代。The terms "aryl" or "aromatic ring" are used interchangeably herein and refer to monocyclic, bicyclic, and tricyclic rings containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms The carbocyclic ring system, in which at least one ring system is aromatic, and each ring system contains a ring composed of 3-7 atoms, and has one or more attachment points connected to the rest of the molecule. Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl group may be optionally substituted with one or more substituents described in the present invention.
术语“杂原子”是指O，S，N，P和Si，包括N，S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3，4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR，R为本发明所描述的取代基)。The term "heteroatom" refers to O, S, N, P and Si, including any oxidation state of N, S and P; primary, secondary, tertiary amine and quaternary ammonium salt forms; or on the nitrogen atom in the heterocycle The form in which hydrogen is substituted, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidinyl) NR, R are the substituents described in the present invention).
术语“杂环基”是指包含3-14个环原子的，单价或多价的单环、双环或者三环体系，其中至少有一个环原子选自杂原子，所述杂原子具有如本发明所述的含义。“杂环基”可以是完全饱和的或包含一个或多个不饱和度，但一个芳香性环都不能有。术语“杂环基”、“杂环的”和“杂环”在此处可交换使用。在一些实施方案中，杂环基为包含1，2，3或4个独立选自O，S和N的杂原子的3-10个环原子组成的杂环基，即3-10个原子组成的杂环基；在一些实施方案中，杂环基为包含1，2，3或4个独立选自O，S和N的杂原子的3-8个环原子组成的杂环基，即3-8个原子组成的杂环基；在一些实施方案中，杂环基为包含1，2，3或4个独立选自O，S和N的杂原子的5-8个环原子组成的杂环基，即5-8个原子组成的杂环基；在一些实施方案中，杂环基为包含1，2，3或4个独立选自O，S和N的杂原子的3-6个环原子组成的杂环基，即3-6个原子组成的杂环基；在一些实施方案中，杂环基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个环原子组成的杂环基，即5-6个原子组成的杂环基。The term "heterocyclic group" refers to a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 3-14 ring atoms, wherein at least one ring atom is selected from heteroatoms, and the heteroatoms have the characteristics of the present invention The meaning described. The "heterocyclic group" can be fully saturated or contain one or more degrees of unsaturation, but it cannot have an aromatic ring. The terms "heterocyclyl", "heterocyclic" and "heterocyclic" are used interchangeably herein. In some embodiments, the heterocyclic group is a heterocyclic group consisting of 3-10 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S and N, that is, a heterocyclic group consisting of 3-10 atoms In some embodiments, the heterocyclic group is a heterocyclic group consisting of 3-8 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, namely 3 -8-atom heterocyclic group; in some embodiments, the heterocyclic group is a heterocyclic group consisting of 5-8 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N Cyclic group is a heterocyclic group consisting of 5-8 atoms; in some embodiments, the heterocyclic group is 3-6 containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N A heterocyclic group composed of ring atoms, that is, a heterocyclic group composed of 3-6 atoms; in some embodiments, a heterocyclic group contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N A heterocyclic group consisting of 5-6 ring atoms, that is, a heterocyclic group consisting of 5-6 atoms.
除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。杂环基的实例包括，但不限于：环氧乙烷基，氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，二氢吡咯基(2-吡咯啉基，3-吡咯啉基)，二氢吡唑基，吡唑烷基，二氢咪唑基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，四氢吡啶基，二氢吡啶基，吗啉基，二氢噁嗪基，硫代吗啉基，二氢噻嗪基，哌嗪基，噁唑烷基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，3,4-二氢-2H-1,4-噁嗪，3,4-二氢-2H-1,4-噻嗪，4H-1,4-噁嗪，4H-1,4-噻嗪，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2020139363-appb-000008
基，二氮杂
Figure PCTCN2020139363-appb-000009
基，硫氮杂
Figure PCTCN2020139363-appb-000010
基，2-氧杂-5-氮杂双环[2.2.1]庚-5-基，等等。杂环基中-CH 2-基团被-C(＝O)-取代的实例包括，但不限于，2-氧代-1,3-二氧戊环基，2-氧代-1,3-二氧杂环戊烯基，呋喃-酮基，2-氧代吡咯烷基，氧代-1,3-噻唑烷基，2-哌啶酮基，3,5-二氧代哌啶基，嘧啶二酮基，等等。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、硫代吗啉基1,1-二氧化物，等等。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 Unless otherwise specified, the heterocyclic group may be a carbon group or a nitrogen group, and the -CH 2 -group may be optionally replaced by -C(=O)-. The sulfur atom of the ring can optionally be oxidized to S-oxide. The nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, dihydropyrrolyl (2-pyrrolinyl, 3-pyrrolinyl), dihydropyrazolyl, pyrazolidinyl, dihydroimidazolyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-di Oxycyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, tetrahydropyridyl, Dihydropyridyl, morpholinyl, dihydrooxazinyl, thiomorpholinyl, dihydrothiazinyl, piperazinyl, oxazolidinyl, dioxanyl, dithiazinyl, thiazinyl , Homopiperazinyl, Homopiperidinyl, 3,4-Dihydro-2H-1,4-oxazine, 3,4-Dihydro-2H-1,4-thiazine, 4H-1,4-oxazine Oxazine, 4H-1,4-thiazine, oxepanyl, thiepanyl, oxazepine
Figure PCTCN2020139363-appb-000008
Base, diaza
Figure PCTCN2020139363-appb-000009
Base, thiazepine
Figure PCTCN2020139363-appb-000010
Group, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, etc. Examples of the -CH 2 -group substituted by -C(=O)- in the heterocyclic group include, but are not limited to, 2-oxo-1,3-dioxolanyl, 2-oxo-1,3 -Dioxolyl, furan-keto, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxopiperidinyl , Pyrimidinedione group, and so on. Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. The heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
术语“杂芳基”表示含有5-10个环原子，或5-8个环原子，或5-6个环原子的单价或多价的的单环、双环或三环体系，其中至少一个环体系是芳香族的，且至少一个环包含一个或多个杂原子，所述杂原子具有本发明所述的定义。术语“杂芳基”、“杂芳环”或“杂芳族化合物”在此可交换使用。当杂芳基基团存在-CH 2-基团时，所述-CH 2-基团可任选的被-C(＝O)-替代。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-10个环原子组成的杂芳基，即5-10个原子组成的杂芳基。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-8个环原子组成的杂芳基，即5-8个原子组成的杂芳基。在一些实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个环原子组成的杂芳基，即5-6个原子组成的杂芳基。 The term "heteroaryl" means a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 5-10 ring atoms, or 5-8 ring atoms, or 5-6 ring atoms, in which at least one ring The system is aromatic, and at least one ring contains one or more heteroatoms, and the heteroatoms have the definition described in the present invention. The terms "heteroaryl", "heteroaromatic ring" or "heteroaromatic compound" are used interchangeably herein. When a -CH 2 -group is present in the heteroaryl group, the -CH 2 -group can be optionally replaced by -C(=O)-. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-10 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S and N, that is, a heteroaryl group consisting of 5-10 atoms的heteroaryl. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-8 ring atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N, that is, a heteroaryl group consisting of 5-8 atoms的heteroaryl. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 ring atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S and N, that is, a heteroaryl group consisting of 5-6 atoms的heteroaryl.
杂芳基基团的实例包括，但并不限于，呋喃基(如2-呋喃基，3-呋喃基)，咪唑基(如N-咪唑基，2-咪唑基，4-咪唑基，5-咪唑基)，异噁唑基(如3-异噁唑基，4-异噁唑基，5-异噁唑基)，噁唑基(如2-噁唑基，4-噁唑基，5-噁唑基)，吡咯基(如N-吡咯基，2-吡咯基，3-吡咯基)，吡啶基(如2-吡啶基，3-吡啶基，4-吡啶基)，嘧啶基(如2-嘧啶基，4-嘧啶基，5-嘧啶基)，哒嗪基(如3-哒嗪基)，噻唑基(如2-噻唑基，4-噻唑基，5-噻唑基)，四唑基(如5H-四唑基，2H-四唑基)，***基(如2-***基，5-***基，4H-1,2,4-***基，1H-1,2,4-***基，1,2,3-***基)，噻吩基(如2-噻吩基，3-噻吩基)，吡唑基(如，2-吡唑基，3-吡唑基)，异噻唑基，噁二唑基(如1,2,3-噁二唑基，1,2,5-噁二唑基，1,2,4-噁二唑基，1,3,4-噁二唑基)，硫代二唑基(如1,2,3-硫代二唑基，1,3,4-硫代二唑基，1,2,5-硫代二唑基)，吡嗪基，1,3,5-三嗪基,呋喃酮基；也包括以下的双环基团，但绝不限于双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4] ***并[4,3-b]哒嗪基、[1,2,4]***并[1,5-a]嘧啶基、[1,2,4]***并[1,5-a]吡啶基、吲哚啉基、1,2,3,4-四氢异喹啉基、苯并呋喃酮基。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。Examples of heteroaryl groups include, but are not limited to, furyl (e.g. 2-furyl, 3-furyl), imidazolyl (e.g. N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl), isoxazolyl (e.g. 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl, 5 -Oxazolyl), pyrrolyl (such as N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (such as 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (such as 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (such as 3-pyridazinyl), thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazole Group (such as 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (such as 2-triazolyl, 5-triazolyl, 4H-1,2,4-triazolyl, 1H-1,2 ,4-Triazolyl, 1,2,3-triazolyl), thienyl (e.g. 2-thienyl, 3-thienyl), pyrazolyl (e.g., 2-pyrazolyl, 3-pyrazolyl) ), isothiazolyl, oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 -Oxadiazolyl), thiodiazolyl (such as 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl) , Pyrazinyl, 1,3,5-triazinyl, furanone; also includes the following bicyclic groups, but not limited to bicyclic groups: benzimidazolyl, benzofuranyl, benzothienyl, indole Group (such as 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a] Pyrimidine, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1, 5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, benzofuran Ketone. The heteroaryl group is optionally substituted with one or more substituents described in the present invention.
术语“m个原子组成的”，其中m是整数，典型地描述分子中成环原子的数目，在所述分子中成环原子的数目是m。例如，哌啶基是6个原子组成的杂环基，而萘基是10个原子组成的芳基基团。The term "consisting of m atoms", where m is an integer, typically describes the number of ring atoms in a molecule, and the number of ring atoms in the molecule is m. For example, piperidinyl is a 6-atom heterocyclic group, and naphthyl is a 10-atom aryl group.
术语“D”是指氘代，即 2H。 The term "D" refers to deuterium, i.e., 2 H.
术语“卤素”是指F，Cl，Br或I。The term "halogen" refers to F, Cl, Br or I.
术语“亚烷基”表示从饱和烃基中去掉两个氢原子所得到的饱和的二价烃基基团。除非另外详细说明，亚烷基基团含有1-12个碳原子，另外一些实施例是，亚烷基基团含有1-6个碳原子，另外一些实施例是，亚烷基基团含有1-4个碳原子，另外一些实施例是，亚烷基基团含有1-2个碳原子。这样的实例包括亚甲基(-CH 2-)，亚乙基(-CH 2CH 2-)，亚异丙基(-CH(CH 3)CH 2-)等等。 The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated hydrocarbon group. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In other embodiments, the alkylene group contains 1 to 6 carbon atoms. In other embodiments, the alkylene group contains 1 to 12 carbon atoms. -4 carbon atoms. In other embodiments, the alkylene group contains 1-2 carbon atoms. Examples of such include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylene (-CH(CH 3 )CH 2 -), and the like.
术语“环烷基-亚烷基”、“碳环基-亚烷基”、“杂环基-亚烷基”、“芳基-亚烷基”、“杂芳基-亚烷基”表示环烷基、碳环基、杂环基、芳基和杂芳基通过-亚烷基-与分子其余部分相连，其中烷基、环烷基、碳环基、杂环基、芳基和杂芳基基团均具有如本发明所述的含义，如苄基(-CH 2-Ph)。所述“环烷基-亚烷基”、“碳环基-亚烷基”、“杂环基-亚烷基”、“芳基-亚烷基”、“杂芳基-亚烷基”基团任选地被一个或多个本发明所描述的取代基所取代。 The terms "cycloalkyl-alkylene", "carbocyclyl-alkylene", "heterocyclyl-alkylene", "aryl-alkylene" and "heteroaryl-alkylene" mean Cycloalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are connected to the rest of the molecule through an alkylene group, in which alkyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl and hetero The aryl groups all have the meaning described in the present invention, such as benzyl (-CH 2 -Ph). The "cycloalkyl-alkylene", "carbocyclyl-alkylene", "heterocyclyl-alkylene", "aryl-alkylene", "heteroaryl-alkylene" The group is optionally substituted with one or more substituents described in this invention.
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或相似不适当的反应，例如肠胃不适、眩晕等的分子实体和组合物。优选地，本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、更特别在人体中使用的。The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergies or similar inappropriate reactions, such as gastrointestinal discomfort, dizziness, and the like. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a national government or listed in the US Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
本发明所使用的术语“抑制流感病毒的复制”包括减少病毒复制的量(例如，减少至少10％)和完全阻止病毒复制(即，100％减少病毒复制的量)。在一些实施方案中，流感病毒复制被抑制至少50％、至少65％、至少75％、至少85％、至少90％或至少95％。The term "inhibition of influenza virus replication" as used in the present invention includes reducing the amount of virus replication (for example, reducing by at least 10%) and completely preventing virus replication (ie, reducing the amount of virus replication by 100%). In some embodiments, influenza virus replication is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.
术语“有效量”指本发明化合物引起预期生物反应的量。在本发明中，预期生物反应是抑制流感病毒复制，减少流感病毒的量或减轻或改善流感病毒感染的严重程度、持续时间、进展或发作，防止流感病毒感染蔓延，防止流感病毒感染相关症状的复发、演变、发作或进展，或增强或提高使用的另一种抗流感感染疗法的预防或治疗作用。向受治疗者施用的化合物的确切量将取决于施用模式、感染的类型和严重程度和受治疗者的特征，例如健康状况、年龄、性别、体重和对药物的耐受性。技术人员将能够根据这些和其它因素确定适当剂量。当与其它抗病毒剂联合施用时，例如与抗流感药物联合施用时，第二种试剂的“有效量”将取决于所用药物的类型。已知经核准试剂的适合剂量并且技术人员可根据受治疗者的病状、治疗病状的类型和使用的本发明所述化合物的量进行调节。在未明确指出量的情况下，应采取有效量。例如，可按约0.01-100mg/体重/天的剂量范围向受治疗者施用本发明所述化合物做治疗性或预防性治疗。The term "effective amount" refers to the amount of the compound of the present invention that causes the expected biological response. In the present invention, the expected biological response is to inhibit influenza virus replication, reduce the amount of influenza virus or reduce or improve the severity, duration, progression or onset of influenza virus infection, prevent the spread of influenza virus infection, and prevent influenza virus infection-related symptoms. Recurrence, evolution, onset or progression, or enhancement or enhancement of the preventive or therapeutic effects of another anti-influenza infection therapy used. The exact amount of compound administered to the subject will depend on the mode of administration, the type and severity of the infection, and the characteristics of the subject, such as health status, age, sex, weight, and tolerance to the drug. The skilled person will be able to determine the appropriate dosage based on these and other factors. When co-administered with other antiviral agents, such as anti-influenza drugs, the "effective amount" of the second agent will depend on the type of drug used. The appropriate dosage of the approved agent is known and the skilled person can adjust it according to the condition of the subject, the type of condition to be treated, and the amount of the compound of the present invention used. If the amount is not clearly indicated, an effective amount should be used. For example, the compound of the present invention can be administered to the subject in a dose range of about 0.01-100 mg/body weight/day for therapeutic or prophylactic treatment.
如本发明所使用的术语“治疗”指治疗性和预防性治疗。例如，治疗性治疗包括由于施用一种或多种疗法(例如，一种或多种治疗剂(例如本发明的化合物和组合物)减轻或改善流感病毒介导的病状的进展、严重程度和/或持续时间，或改善流感病毒介导的病状的一种或多种症状(特别地，一种或多种可辨症状)。在特定实施方案中，治疗性治疗包括改善流感病毒介导的病状的至少一个可测量物理参数。在其它实施方案中，治疗性治疗包括通过(例如)稳定可辨症状在物理上或通过(例如)稳定物理参数在生理上或二者抑制流感病毒介导的病状的进展。在其它实施方案中，治疗性治疗包括减轻或稳定流感病毒介导的感染。可在社区中使用抗病毒药物以治疗已经患流感的人以减少症状的严重程度并减少他们生病的天数。The term "treatment" as used in the present invention refers to therapeutic and prophylactic treatments. For example, therapeutic treatment includes alleviating or ameliorating the progression, severity, and/or severity of influenza virus-mediated conditions due to administration of one or more therapies (e.g., one or more therapeutic agents (e.g., compounds and compositions of the invention) Or duration, or ameliorate one or more symptoms of influenza virus-mediated conditions (in particular, one or more discernible symptoms). In certain embodiments, therapeutic treatment includes amelioration of influenza virus-mediated conditions At least one measurable physical parameter. In other embodiments, therapeutic treatment includes inhibiting influenza virus-mediated conditions by, for example, stabilizing discernible symptoms physically or by, for example, stabilizing physical parameters, physiologically, or both. In other embodiments, therapeutic treatment includes reducing or stabilizing influenza virus-mediated infections. Antiviral drugs can be used in the community to treat people who already have influenza to reduce the severity of symptoms and reduce the number of days they are sick .
术语“保护基团”或“PG”是指一个取代基与其他官能团起反应的时候，通常用来阻断或保护特殊的功能性。例如，“氨基的保护基团”是指一个取代基与氨基基团相连来阻断或保护化合物中氨基的功能性，合适的氨基保护基团包括但不限于乙酰基，三氟乙酰基，对甲苯磺酰基(Ts)，叔丁氧羰基(BOC,Boc)，苄氧羰基(CBZ,Cbz)和9-芴亚甲氧羰基(Fmoc)。相似地，“羟基保护基团”是指羟基的取代基用来阻断或保护羟基的功能性，合适的保护基团包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基用来阻断或保护羧基的功能性，一般的羧基保护基包括-CH 2CH 2SO 2Ph，氰基乙基，2-(三甲基硅烷基)乙基，2-(三甲基硅烷基)乙氧基甲基，2-(对甲苯磺酰基)乙基，2-(对硝基苯磺酰基)乙基，2-(二苯基膦基)乙基，硝基乙基，等等。对于保护基团一般的描述可参考文献：T W.Greene,Protective Groups in Organic Synthesis,John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005. The term "protecting group" or "PG" refers to when a substituent reacts with other functional groups, it is usually used to block or protect specific functionality. For example, "amino protecting group" refers to a substituent connected to an amino group to block or protect the functionality of the amino group in a compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, and Tosyl (Ts), tert-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to a substituent of a hydroxyl group used to block or protect the functionality of the hydroxyl group. Suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of the carboxyl group used to block or protect the functionality of the carboxyl group. General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane Yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) Phosphonyl) ethyl, nitroethyl, etc. For a general description of protecting groups, refer to the literature: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
本发明的化合物的描述Description of the compound of the present invention
本发明提供了一类作为流感病毒RNA聚合酶抑制剂的新化合物，更具体地说，本发明提供一类作为流感病毒的帽依赖性核酸内切酶抑制剂的新化合物，此类化合物及其组合物可以用于预防、处理、治疗或减轻患者病毒感染疾病。与已有的同类化合物相比，本发明的化合物不仅具有更好的药理活性，还具有更低的毒性，更优良的体内药代动力学性质和体内药效学性质，以及较好的肝微粒体稳定性。因此，本发明提供的化合物相对于已有的同类化合物而言，具有更优良的成药性。The present invention provides a class of new compounds as inhibitors of influenza virus RNA polymerase, more specifically, the present invention provides a class of new compounds as inhibitors of influenza virus cap-dependent endonuclease, such compounds and The composition can be used to prevent, treat, treat or alleviate viral infections in patients. Compared with existing similar compounds, the compound of the present invention not only has better pharmacological activity, but also has lower toxicity, better in vivo pharmacokinetic properties and in vivo pharmacodynamic properties, and better liver particles Body stability. Therefore, the compound provided by the present invention has better druggability than the existing similar compounds.
一方面，本发明涉及一种化合物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, or pharmaceutical compound represented by formula (I). Acceptable salts or their prodrugs,
Figure PCTCN2020139363-appb-000011
Figure PCTCN2020139363-appb-000011
其中R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、E和环Cy具有如本发明所述的定义，其中，本发明化合物不包括以下化合物： Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , E and ring Cy have the definitions as described in the present invention, wherein the compounds of the present invention do not include the following compounds :
Figure PCTCN2020139363-appb-000012
Figure PCTCN2020139363-appb-000012
在一些实施方案中，E为CR 10、C或N，其中所述R 10具有本发明所述的定义。 In some embodiments, E is CR 10 , C or N, wherein said R 10 has the definition described in the present invention.
在一些实施方案中，R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 3-6环烷基。 In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH , NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-6 cycloalkyl.
在一些实施方案中，R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4卤代烷氧基或C 3-6环烷基。 In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH , NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne Group, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 3-6 cycloalkyl.
在一些实施方案中，R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、-CHF 2、-CF 3、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCH 2CH 2CH 3、-OCHF 2、-OCF 3、-OCH 2CF 3、环丙基、环丁基、环戊基或环己基。 In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH , NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, allyl, propenyl, propargyl, 1-propynyl, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH 2 CH 3 , -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , cyclopropyl, cyclobutyl, cyclopentyl or ring Hexyl.
在一些实施方案中，R 8、R 9和R 10各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基； In some embodiments, R 8 , R 9 and R 10 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 heterocyclic group, C 6-10 aryl or 5-6 Heteroaryl groups composed of atoms;
或R 8、R 9和与它们相连的碳原子一起形成-C(＝O)-、-C(＝NH)-、-C(＝S)-、C 3-6碳环或5-6个原子组成的杂环。 Or R 8 , R 9 and the carbon atoms connected to them together form -C(=O)-, -C(=NH)-, -C(=S)-, C 3-6 carbocyclic ring or 5-6 A heterocyclic ring composed of atoms.
在一些实施方案中，R 8、R 9和R 10各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氨基、C 1-4卤代烷氧基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基； In some embodiments, R 8 , R 9 and R 10 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 heterocyclic group, C 6-10 aryl or 5-6 Heteroaryl groups composed of atoms;
或R 8、R 9和与它们相连的碳原子一起形成-C(＝O)-、-C(＝NH)-、-C(＝S)-、C 3-6碳环或5-6个原子组成的杂环。 Or R 8 , R 9 and the carbon atoms connected to them together form -C(=O)-, -C(=NH)-, -C(=S)-, C 3-6 carbocyclic ring or 5-6 A heterocyclic ring composed of atoms.
在一些实施方案中，R 8、R 9和R 10各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-CHF 2、-CF 3、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCH 2CH 2CH 3、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-OCHF 2、-OCF 3、-OCH 2CF 3、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、四氢呋喃基、四氢噻吩基、四氢吡喃基、苯基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、***基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基或1,3,5-三嗪基； In some embodiments, R 8 , R 9 and R 10 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , Methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, allyl, propenyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl , Cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl , Pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridyl Azinyl or 1,3,5-triazinyl;
或R 8、R 9和与它们相连的碳原子一起形成-C(＝O)-、-C(＝NH)-、-C(＝S)-、环丙烷、环丁烷、环戊烷、环己烷、吡咯烷、吡唑烷、咪唑烷、哌啶、吗啉、硫代吗啉、四氢呋喃、四氢噻吩或四氢吡喃。 Or R 8 , R 9 and the carbon atoms connected to them together form -C(=O)-, -C(=NH)-, -C(=S)-, cyclopropane, cyclobutane, cyclopentane, Cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piperidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydrothiophene or tetrahydropyran.
在一些实施方案中，环Cy为C 3-8碳环、3-8个原子组成的杂环、C 6-10芳环或5-8个原子组成的杂芳环，其中所述C 3-8碳环、3-8个原子组成的杂环、C 6-10芳环和5-8个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个R x所取代；所述3-8个原子组成的杂环和5-8个原子组成的杂芳环各自独立地含有1、2、3或4个独立选自N、O或S的杂原子，所述R x具有本发明所述的定义。 In some embodiments, the ring Cy is a C 3-8 carbocyclic ring, a heterocyclic ring composed of 3-8 atoms, a C 6-10 aromatic ring, or a heteroaromatic ring composed of 5-8 atoms, wherein the C 3- 8- carbon ring, heterocyclic ring composed of 3-8 atoms, C 6-10 aromatic ring and heteroaromatic ring composed of 5-8 atoms are each independently unsubstituted or replaced by 1, 2, 3 or 4 R x Substitution; the heterocyclic ring composed of 3-8 atoms and the heteroaromatic ring composed of 5-8 atoms each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, the R x has the definition described in the present invention.
在一些实施方案中，环Cy为C 3-7碳环、5个原子组成的杂环、6个原子组成的杂环、7个原子组成的杂环、C 6-10芳环、5个原子组成的杂芳环、6个原子组成的杂芳环或7个原子组成的杂芳环，其中所述C 3-7碳环、5个原子组成的杂环、6个原子组成的杂环、7个原子组成的杂环、C 6-10芳环、5个原子组成的杂芳环、6个原子组成的杂芳环和7个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个R x所取代；所述5个原子组成的杂环、6个原子组成的杂环、7个原子组成的杂环、5个原子组成的杂芳环、6个原子组成的杂芳环和7个原子组成的杂芳环各自独立地含有1、2、3或4个独立选自N、O或S的杂原子，所述R x具有本发明所述的定义。 In some embodiments, the ring Cy is a C 3-7 carbocyclic ring, a 5-atom heterocyclic ring, a 6-atom heterocyclic ring, a 7-atom heterocyclic ring, a C 6-10 aromatic ring, 5 atoms Consisting of a heteroaromatic ring, a heteroaromatic ring consisting of 6 atoms or a heteroaromatic ring consisting of 7 atoms, wherein the C 3-7 carbon ring, a 5-atom heterocyclic ring, a 6-atom heterocyclic ring, A heterocyclic ring composed of 7 atoms, a C 6-10 aromatic ring, a heteroaromatic ring composed of 5 atoms, a heteroaromatic ring composed of 6 atoms, and a heteroaromatic ring composed of 7 atoms are each independently unsubstituted or 1 , 2, 3, or 4 R x ; the 5-atom heterocyclic ring, 6-atom heterocyclic ring, 7-atom heterocyclic ring, 5-atom heteroaromatic ring, 6-atom The composed heteroaromatic ring and the 7-atom heteroaromatic ring each independently contain 1, 2, 3, or 4 heteroatoms independently selected from N, O or S, and the R x has the definition described in the present invention.
在一些实施方案中，环Cy为环丙烷、环丁烷、环戊烷、环己烷、环庚烷、二硫环戊烷、二氧环戊烷、吡咯烷、二氢吡咯、吡唑烷、二氢吡唑、咪唑烷、二氢咪唑、哌啶、四氢吡啶、二氢吡啶、吗啉、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪、硫代吗啉、二氢噻嗪、哌嗪、四氢呋喃、二氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、四氢噻喃、二氢噻喃、噁唑烷、二氢噁唑、噻唑烷、二氢噻唑、噻噁烷、高哌嗪、高哌啶、4H-1,4-噁嗪、4H-1,4-噻嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、异噻唑、吡嗪、哒嗪、1,3,5-三嗪或硫代二唑，其中所述环丙烷、环丁烷、环戊烷、环己烷、环庚烷、二硫环戊烷、二氧环戊烷、吡咯烷、二氢吡咯、吡唑烷、二氢吡唑、咪唑烷、二氢咪唑、哌啶、四氢吡啶、二氢吡啶、吗啉、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪、硫代 吗啉、二氢噻嗪、哌嗪、四氢呋喃、二氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、四氢噻喃、二氢噻喃、噁唑烷、二氢噁唑、噻唑烷、二氢噻唑、噻噁烷、高哌嗪、高哌啶、4H-1,4-噁嗪、4H-1,4-噻嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、异噻唑、吡嗪、哒嗪、1,3,5-三嗪和硫代二唑各自独立地未被取代或被1、2、3或4个R x所取代，所述R x具有本发明所述的定义。 In some embodiments, ring Cy is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dithiocyclopentane, dioxocyclopentane, pyrrolidine, dihydropyrrole, pyrazole , Dihydropyrazole, imidazolidine, dihydroimidazole, piperidine, tetrahydropyridine, dihydropyridine, morpholine, 3,4-dihydro-2H-1,4-oxazine, 3,4-dihydro- 2H-1,4-thiazine, thiomorpholine, dihydrothiazine, piperazine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, tetrahydrothiopyran , Dihydrothiopyran, oxazolidine, dihydrooxazole, thiazolidine, dihydrothiazole, thiaoxane, homopiperazine, homopiperidine, 4H-1,4-oxazine, 4H-1,4-thiol Pyrazine, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, isothiazole, pyrazine, pyridazine, 1,3 , 5-triazine or thiodiazole, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dithiocyclopentane, dioxolane, pyrrolidine, dihydro Pyrrole, pyrazolidine, dihydropyrazole, imidazolidine, dihydroimidazole, piperidine, tetrahydropyridine, dihydropyridine, morpholine, 3,4-dihydro-2H-1,4-oxazine, 3, 4-dihydro-2H-1,4-thiazine, thiomorpholine, dihydrothiazine, piperazine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran , Tetrahydrothiopyran, dihydrothiopyran, oxazolidine, dihydrooxazole, thiazolidine, dihydrothiazole, thiaoxane, homopiperazine, homopiperidine, 4H-1,4-oxazine, 4H- 1,4-thiazine, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, isothiazole, pyrazine, pyridine The oxazine, 1,3,5-triazine and thiodiazole are each independently unsubstituted or substituted with 1, 2, 3, or 4 R x , which R x has the definition described in the present invention.
在一些实施方案中，各R x独立地为氘、F、Cl、Br、I、-CN、-NO 2、＝O、＝S、＝NH、-OR b、-NR cR d、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6碳环基、C 3-6碳环基-C 1-4亚烷基、3-6个原子组成的杂环基、(3-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6碳环基、C 3-6碳环基-C 1-4亚烷基、3-6个原子组成的杂环基、(3-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或C 1-6烷氨基； In some embodiments, each R x is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , =0, =S, =NH, -OR b , -NR c R d , -C (=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, heterocyclic group consisting of 3-6 atoms, (3 -6-atom heterocyclic group) -C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-6 heteroaryl Group or (heteroaryl group consisting of 5-6 atoms)-C 1-4 alkylene, wherein the C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, C 2 -6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, heterocyclic group consisting of 3-6 atoms, (3- 6-atom heterocyclic group)-C 1-4 alkylene group, C 6-10 aryl group, C 6-10 aryl group-C 1-4 alkylene group, 5-6 atom heteroaryl group And (heteroaryl group consisting of 5-6 atoms)-C 1-4 alkylene groups are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy Group, C 1-6 alkoxy or C 1-6 alkylamino;
或任意2个R x和与它们相连的原子一起形成C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环或5-6个原子组成的杂芳环，其中所述C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或C 1-6烷氨基。 Or any two R x and the atoms connected to them form a C 3-6 carbon ring, a heterocyclic ring composed of 3-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms, wherein The C 3-6 carbon ring, the heterocyclic ring composed of 3-6 atoms, the C 6-10 aromatic ring and the heteroaromatic ring composed of 5-6 atoms are each independently unsubstituted or by 1, 2 or 3 Substituents are substituted, the substituents are independently selected from deuterium, F, Cl, Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, C 1-6 alkane Group, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or C 1-6 alkylamino.
在一些实施方案中，各R x独立地为氘、F、Cl、Br、I、-CN、-NO 2、＝O、＝S、＝NH、-OR b、-NR cR d、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、C 3-6碳环基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-2亚烷基，其中所述C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、C 3-6碳环基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-2亚烷基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氧基或C 1-4烷氨基； In some embodiments, each R x is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , =0, =S, =NH, -OR b , -NR c R d , -C (=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-2 alkylene, heterocyclic group consisting of 5-6 atoms, (5 -6-atom heterocyclic group) -C 1-2 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-2 alkylene, 5-6 heteroaryl Group or (heteroaryl group consisting of 5-6 atoms)-C 1-2 alkylene group, wherein the C 1-4 haloalkyl group, C 1-4 haloalkoxy group, C 1-4 alkyl group, C 2 -4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group -C 1-2 alkylene group, heterocyclic group composed of 5-6 atoms, (5- 6-atom heterocyclic group)-C 1-2 alkylene group, C 6-10 aryl group, C 6-10 aryl group-C 1-2 alkylene group, 5-6 atom heteroaryl group And (heteroaryl group consisting of 5-6 atoms)-C 1-2 alkylene groups are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy Group, C 1-4 alkoxy or C 1-4 alkylamino;
或任意2个R x和与它们相连的原子一起形成C 3-6碳环、5-6个原子形成的杂环、C 6-10芳环或5-6个原子组成的杂芳环，其中所述C 3-6碳环、5-6个原子形成的杂环、C 6-10芳环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝N、-CN、-OH、-NH 2、-COOH、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氧基或C 1-4烷氨基。 Or any 2 R x and the atoms connected to them together form a C 3-6 carbon ring, a heterocyclic ring formed by 5-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms, wherein The C 3-6 carbon ring, the heterocyclic ring formed by 5-6 atoms, the C 6-10 aromatic ring and the heteroaromatic ring composed of 5-6 atoms are each independently unsubstituted or by 1, 2 or 3 Substituents are substituted, the substituents are independently selected from deuterium, F, Cl, Br, I, =O, =S, =N, -CN, -OH, -NH 2 , -COOH, C 1-4 alkane Group, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy or C 1-4 alkylamino.
在一些实施方案中，各R x独立地为氘、F、Cl、Br、I、-CN、-NO 2、＝O、＝S、＝NH、-OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2、-NH 2、-NHCH 3、-NHCH 2CH 3、-N(CH 3) 2、-C(＝O)OH、-C(＝O)OCH 3、-C(＝O)OCH 2CH 3、-C(＝O)NH 2、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCHF 2、-OCF 3、-OCH 2CF 3、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、C 3-6碳环基-CH 2-、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、四氢呋喃基、四氢噻吩基、四氢吡喃基、苯基、苯基-CH 2-、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、***基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基、1,3,5-三嗪基或(5-6个原子组成的杂芳基)-CH 2-，其中所述-CH 2F、-CHF 2、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCHF 2、-OCH 2CF 3、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、C 3-6碳环基-CH 2-、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、四氢呋喃基、四氢噻吩基、四氢吡喃基、苯基、苯基-CH 2-、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、***基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基、1,3,5-三嗪基和(5-6个原子组成的杂芳基)-CH 2-各自未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、-CF 3、-OCF 3或-OCH 3； In some embodiments, each R x is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , =0, =S, =NH, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(=O)OH, -C( ＝O)OCH 3 , -C(＝O)OCH 2 CH 3 , -C(＝O)NH 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl, allyl, propenyl , Propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 carbocyclyl -CH 2 -, pyrrolidinyl, pyrazolidinyl, imidazolidinyl , Piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-CH 2 -, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl , Thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, 1,3,5- Triazine group or (heteroaryl group consisting of 5-6 atoms) -CH 2 -, wherein the -CH 2 F, -CHF 2 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -OCHF 2 , -OCH 2 CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl, allyl, propenyl, propargyl, 1-propynyl , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 carbocyclyl -CH 2 -, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, sulfur Morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-CH 2 -, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl , Imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl and (5-6 atoms Heteroaryl group) -CH 2 -are each unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, =O, =S , =NH, -CN, -OH, -NH 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, -CF 3 , -OCF 3 or -OCH 3 ;
或任意2个R x和与它们相连的原子一起形成环丙烷、环丁烷、环戊烷、环己烷、吡咯烷、吡唑烷、咪唑烷、哌啶、哌嗪、吗啉、硫代吗啉、四氢呋喃、四氢噻吩、四氢吡喃、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、吡嗪、哒嗪或1,3,5-三嗪，其中所述环丙烷、环丁烷、环戊烷、环己烷、吡咯烷、吡唑烷、咪唑烷、哌啶、哌嗪、吗啉、硫代吗啉、四氢呋喃、四氢噻吩、四氢吡喃、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、吡嗪、哒嗪和1,3,5-三嗪各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、-CF 3、-OCF 3或-OCH 3。 Or any 2 R x and the atoms connected to them form cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, morpholine, thio Morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, Pyrazine, pyridazine or 1,3,5-triazine, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, Morpholine, thiomorpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, Oxadiazole, pyrazine, pyridazine and 1,3,5-triazine are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from deuterium, F, Cl , Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, -CF 3 , -OCF 3 or- OCH 3 .
在一些实施方案中，各R a、R b、R c和R d独立地为H、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基； In some embodiments, each R a , R b , R c and Rd is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-6 heterocyclic group, C 6-10 aryl and 5-6 heteroaryl are each independently unsubstituted or Substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-6 alkyl , C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
或R c、R d和与它们相连的氮原子一起，形成3-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述3-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基。 Or R c , R d and the nitrogen atoms connected to them together form a heterocyclic ring composed of 3-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 3-6 atoms and The heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino.
在一些实施方案中，各R a、R b、R c和R d独立地为H、氘、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基，其中所述C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或C 1-4烷氨基； In some embodiments, each R a , R b , R c and Rd are independently H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Cycloalkyl group, heterocyclic group composed of 5-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl, C 3-6 cycloalkyl, 5-6 heterocyclic group, C 6-10 aryl and 5-6 heteroaryl are each independently unsubstituted or Substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-4 alkyl , C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino;
或R c、R d和与它们相连的氮原子一起，形成5-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述5-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或C 1-4烷氨基。 Or R c , R d and their connected nitrogen atoms together form a heterocyclic ring composed of 5-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 5-6 atoms and The heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino.
在一些实施方案中，各R a、R b、R c和R d独立地为H、氘、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、5-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基，其中所述甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、5-6个原子组成的杂环基、苯基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基； In some embodiments, each R a, R b, R c and R d are independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl , Heterocyclic group composed of 5-6 atoms, phenyl group or heteroaryl group composed of 5-6 atoms, wherein the methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl , Cyclobutyl, heterocyclic group consisting of 5-6 atoms, phenyl group and heteroaryl group consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2 or 3 substituents, the Substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methyl Oxy;
或R c、R d和与它们相连的氮原子一起，形成5-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述5-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基。 Or R c , R d and their connected nitrogen atoms together form a heterocyclic ring composed of 5-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 5-6 atoms and The heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.
在另一些实施方案中，本发明涉及一种式(II)所示结构的化合物或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，In other embodiments, the present invention relates to a compound of formula (II) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, or pharmaceutically acceptable salt thereof Or their prodrugs,
Figure PCTCN2020139363-appb-000013
Figure PCTCN2020139363-appb-000013
其中R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、E和环Cy具有如本发明所述的定义。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , E and ring Cy have the definitions as described in the present invention.
在另外一些实施方案，本发明涉及到以下其中之一的化合物或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，但绝不限于这些化合物：In other embodiments, the present invention relates to one of the following compounds or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs , But by no means limited to these compounds:
Figure PCTCN2020139363-appb-000014
Figure PCTCN2020139363-appb-000014
Figure PCTCN2020139363-appb-000015
Figure PCTCN2020139363-appb-000015
Figure PCTCN2020139363-appb-000016
Figure PCTCN2020139363-appb-000016
Figure PCTCN2020139363-appb-000017
Figure PCTCN2020139363-appb-000017
Figure PCTCN2020139363-appb-000018
Figure PCTCN2020139363-appb-000018
Figure PCTCN2020139363-appb-000019
Figure PCTCN2020139363-appb-000019
Figure PCTCN2020139363-appb-000020
Figure PCTCN2020139363-appb-000020
Figure PCTCN2020139363-appb-000021
Figure PCTCN2020139363-appb-000021
在本发明的一些实施方案中，所述药物组合物进一步包含药学上可接受的辅剂。In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.
在一些实施方案中，本发明提供的药物组合物进一步包含一种或多种其它治疗剂。In some embodiments, the pharmaceutical composition provided by the present invention further comprises one or more other therapeutic agents.
在另外一些实施方案中，所述其它治疗剂选自抗流感病毒剂或疫苗。In other embodiments, the other therapeutic agent is selected from an anti-influenza virus agent or a vaccine.
在另外一些实施方案中，药物组合物可以是液体，固体，半固体，凝胶或喷雾剂型。In other embodiments, the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
在另外一些实施方案，本发明所述的药物组合物，其中所涉及的其他治疗剂是金刚胺(Amantadine)、金刚乙胺(Rimantadine)、奥司他韦(Oseltamivir)、扎那米韦(Zanamivir)、帕拉米韦(Peramivir)、拉尼米韦(Laninamivir)、拉尼米韦辛酸酯水合物(Laninamivir Octanoate Hydrate)、法匹拉韦(Favipiravir)、阿比多尔(Arbidol)、利巴韦林(Ribavirin)、司他弗林、英加韦林(Ingavirin)、流感酶(Fludase)、CAS号为1422050-75-6的药物、吡莫地韦(Pimodivir)、巴洛沙韦(Baloxavir marboxil)、流感疫苗(FluMist
Figure PCTCN2020139363-appb-000022
Quadrivalent、
Figure PCTCN2020139363-appb-000023
Quadrivalent、
Figure PCTCN2020139363-appb-000024
或
Figure PCTCN2020139363-appb-000025
)或它们的组合。 In other embodiments, in the pharmaceutical composition of the present invention, the other therapeutic agents involved are Amantadine, Rimantadine, Oseltamivir, Zanamivir ), Peramivir, Laninamivir, Laninamivir Octanoate Hydrate, Favipiravir, Arbidol, Bavirin (Ribavirin), Staphyrin, Ingavirin (Ingavirin), Flu enzyme (Fludase), drugs with CAS number 1422050-75-6, Pimodivir (Pimodivir), Baloxavir ( Baloxavir marboxil), flu vaccine (FluMist
Figure PCTCN2020139363-appb-000022
Quadrivalent,
Figure PCTCN2020139363-appb-000023
Quadrivalent,
Figure PCTCN2020139363-appb-000024
or
Figure PCTCN2020139363-appb-000025
) Or a combination of them.
另一方面，本发明提供了所述化合物或所述药物组合物在制备药物中的用途，其中所述药物用于预防、治疗或减轻患者病毒感染性疾病。In another aspect, the present invention provides the use of the compound or the pharmaceutical composition in the preparation of a medicine, wherein the medicine is used to prevent, treat or alleviate viral infectious diseases in patients.
在一些实施方案中，所述病毒感染为流感病毒感染。In some embodiments, the viral infection is an influenza virus infection.
在另一些实施方案中，所述流感病毒为流感病毒A。In other embodiments, the influenza virus is influenza A virus.
在另外一些实施方案中，本发明提供了所述化合物或所述药物组合物在制备药物中的用途，其中所述药物用于抑制流感病毒的RNA聚合酶。In some other embodiments, the present invention provides the use of the compound or the pharmaceutical composition in the preparation of a medicine, wherein the medicine is used to inhibit the RNA polymerase of influenza virus.
在另外一些实施方案中，所述RNA聚合酶为帽依赖性核酸内切酶。In other embodiments, the RNA polymerase is a cap-dependent endonuclease.
本发明包含本发明化合物及其药学上可接受的盐的应用，用于生产医药产品治疗患者流感病毒感染性疾病，包括那些本发明所描述的疾病。本发明包含药物组合物，该药物组合物包括式(I)或式(II)所代表的化合物与至少一种药学上可接受的辅剂结合所需的有效治疗量。The present invention includes the use of the compounds of the present invention and their pharmaceutically acceptable salts for the production of pharmaceutical products to treat patients with influenza virus infectious diseases, including those described in the present invention. The present invention includes a pharmaceutical composition comprising an effective therapeutic amount required for combining the compound represented by formula (I) or formula (II) with at least one pharmaceutically acceptable adjuvant.
本发明同样包含治疗或减轻患者流感病毒感染性疾病，或对此病症敏感的方法，该方法包含使用式(I)或式(II)所代表化合物的治疗有效量对患者进行治疗。The present invention also includes a method for treating or alleviating influenza virus infectious diseases in patients, or susceptible to this disease, and the method comprises treating the patients with a therapeutically effective amount of the compound represented by formula (I) or formula (II).
除非其他方面表明，本发明的化合物所有的立体异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，药学上可接受的盐和药学上可接受的前药都属于本发明的范围。Unless otherwise indicated, all stereoisomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are It belongs to the scope of the present invention.
具体地说，盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学地，与组成制剂的其他组分和用于治疗的哺乳动物有关。Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically suitable, related to the other components of the formulation and the mammal used for treatment.
本发明的化合物的盐还包括用于制备或纯化式(I)或式(II)所示化合物的中间体或式(I)所示化合物分离的对映异构体的盐，但不一定是药学上可接受的盐。The salt of the compound of the present invention also includes the salt of an intermediate for preparing or purifying the compound represented by formula (I) or formula (II) or the separated enantiomer of the compound represented by formula (I), but not necessarily A pharmaceutically acceptable salt.
本发明的化合物的组合物、制剂和给药Composition, formulation and administration of the compound of the present invention
本发明提供了一种药物组合物，其包括式(I)或式(II)所示的化合物或其立体异构体、异构体的外消旋或非外消旋混合物或其药学上可接受的盐或溶剂化物。所述药物组合物进一步包含至少一种药学上可接受的辅剂，以及任选地、其它的治疗和/或预防成分。在一些实施方案，所述药物组合物包含有效量的至少一种药学上可接受的辅剂。本发明的组合物中化合物的量能有效地治疗或减轻患者流感病毒感染性疾病。The present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or formula (II) or its stereoisomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable Accepted salt or solvate. The pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant, and optionally, other therapeutic and/or preventive components. In some embodiments, the pharmaceutical composition includes an effective amount of at least one pharmaceutically acceptable adjuvant. The amount of the compound in the composition of the present invention can effectively treat or alleviate influenza virus infectious diseases in patients.
本发明的化合物存在自由形态，或合适的、作为药学上可接受的衍生物。根据本发明，药学上可接受的衍生物包括，但并不限于，药学上可接受的前药，盐，酯，酯类的盐，或能直接或间接地根据患者的需要给药的其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物或它的残留物。The compounds of the present invention exist in free form, or are suitable as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of patients. Adducts or derivatives, compounds described in other aspects of the present invention, their metabolites or their residues.
像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上可接受的辅剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。如以下文献所描述的：In Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容，表明不同的辅剂可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的辅剂与本发明的化合物不相容的范围，例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用，它们的用途也是本发明所考虑的范围。As described in the present invention, the pharmaceutically acceptable composition of the present invention further comprises pharmaceutically acceptable adjuvants, which, like those used in the present invention, include any solvents, diluents, or other liquid excipients, dispersants Or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for specific target dosage forms. As described in the following documents: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DBTroy, Lippincott, Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick, and 1999-JCB Marcel Dekker, New York, combining the contents of the literature here, shows that different adjuvants can be applied to the preparation of pharmaceutically acceptable compositions and their well-known preparation methods. Except for any conventional adjuvants that are incompatible with the compounds of the present invention, such as any adverse biological effects or interactions with any other components of the pharmaceutically acceptable composition in a harmful manner, they The use of is also the scope of the present invention.
可用作药学上可接受的辅剂的物质的一些实例包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(例如人血清白蛋白)、缓冲物质(例如吐温80、磷酸盐、甘氨酸、山梨酸或山梨酸钾)、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(例如硫酸精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠或锌盐)、硅胶、三硅酸镁、聚乙烯吡咯烷酮、聚丙烯酸酯、蜡、聚乙烯-聚氧化丙烯-嵌段共聚物、甲基纤维素、羟丙基甲基纤维素、羊毛脂、糖类(例如乳糖、葡萄糖和蔗糖)、淀粉(例如玉米淀粉和马铃薯淀粉)、纤维素及其衍生物(例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素)、粉状黄蓍胶、麦芽、凝胶、滑石、赋形剂(例如可可油和栓剂蜡)、油(例如花生油、棉花子油、红花油、芝麻油、橄榄油、玉米油和大豆油)、乙二醇(例如丙二醇或聚乙二醇)、酯(例如油酸乙酯和十二酸乙酯)、琼脂、缓冲剂(例如氢氧化镁和氢氧化铝)、褐藻酸、无热原水、等渗盐水、林格氏溶液(Ringer'ssolution)、乙醇和磷酸盐缓冲液以及其它无毒相容性滑润剂(例如硫酸月桂酯钠和硬脂酸镁)以及根据配制人的判断着色剂、防粘剂、涂层剂、甜味剂和增香剂、防腐剂和抗氧化剂也可存在于组合物中。Some examples of substances that can be used as pharmaceutically acceptable adjuvants include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., Tween 80, phosphate, glycine, sorbic acid or potassium sorbate), partial glyceride mixture of saturated plant fatty acids, water, salt or electrolyte (e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salt ), silica gel, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block copolymer, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars ( Such as lactose, glucose and sucrose), starch (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt , Gel, talc, excipients (e.g. cocoa butter and suppository wax), oils (e.g. peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), ethylene glycol (e.g. propylene glycol or Polyethylene glycol), esters (e.g. ethyl oleate and ethyl laurate), agar, buffers (e.g. magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's Ringer's solution, ethanol and phosphate buffers, and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) and colorants, anti-sticking agents, and coating agents according to the judgment of the formulator , Sweeteners and flavoring agents, preservatives and antioxidants may also be present in the composition.
本发明的化合物或组合物可以通过任何合适方式给药，可根据疾病的严重程度经口、直肠、肠胃外、脑池内、***内、腹膜内、局部(如同通过粉剂、药膏或滴剂)或喷鼻剂等向人或其它动物施用以上所述化 合物和药学上可接受的组合物。The compound or composition of the present invention can be administered by any suitable means, according to the severity of the disease, oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (as by powder, ointment or drops) or Nasal sprays and the like administer the above-mentioned compounds and pharmaceutically acceptable compositions to humans or other animals.
供口服的液体剂型包括但不限于药学上可接受的乳剂、微型乳剂、溶液、悬浮剂、糖浆和酏剂。除活性化合物外，液体剂型可能含有本领域常用的惰性稀释剂，例如水或其它溶剂、增溶剂和乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(尤其是棉花子油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和山梨聚糖的脂肪酸酯及其混合物。除惰性稀释剂外，口服组合物也可包括佐剂，例如湿润剂、乳化和悬浮剂、甜味剂、调味剂和增香剂。Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate Esters, propylene glycol, 1,3-butanediol, dimethylformamide, oils (especially cotton seed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol, poly Fatty acid esters of ethylene glycol and sorbitan and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
可根据已知技术使用适合的分散或湿润剂和悬浮剂配制可注射制剂，例如无菌可注射水或油悬浮剂。无菌可注射制剂也可能是无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液、悬浮剂或乳剂，例如1,3-丁二醇中的溶液。在可接受的辅剂中，可采用的是水、林格氏溶液和等渗氯化钠溶液。另外，按照惯例采用无菌不挥发性油作为溶剂或悬浮介质。为此，可采用任何无味的不挥发性油，包括合成的单酸甘油脂或甘油二酯。另外，脂肪酸，例如十八烯酸，用于制备注射剂。例如，可通过细菌保留过滤器过滤或通过加入呈无菌固体组合物形式，使用之前可溶于或分散于无菌水或其它无菌可注射介质中的杀菌剂为可注射制剂灭菌。Injectable preparations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, such as sterile injectable water or oil suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable adjuvants, water, Ringer's solution and isotonic sodium chloride solution can be used. In addition, sterile non-volatile oil is used as a solvent or suspending medium in accordance with the usual practice. For this purpose, any odorless non-volatile oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used in the preparation of injections. For example, it can be filtered through a bacteria-retaining filter or added in the form of a sterile solid composition, and the sterilant that can be dissolved or dispersed in sterile water or other sterile injectable medium before use is sterilized for the injectable preparation.
为延长本发明所述化合物或组合物的作用，常常希望减缓化合物由皮下或肌肉注射的吸收。这可通过使用水溶性差的晶体或无定形物质的液体悬浮液实现，因为化合物的吸收速率取决于其溶解速率，而溶解速率又取决于晶体大小和晶形。或者，通过将化合物溶解或悬浮于油媒介物中实现延迟吸收经肠胃外施用的化合物。或者，通过在生物可降解的聚合物例如聚交酯-聚羟基乙酸中形成化合物的微胶囊矩阵制成可注射的储存形式，根据化合物与聚合物之比和采用的特殊聚合物的性质，可控制化合物释放速率。其它生物可降解的聚合物的实例包括聚原酸酯和聚酸酐。也可通过将化合物截留在与身体组织相容的脂质体或微型乳剂中制备可注射的储存制剂。In order to prolong the effect of the compound or composition of the present invention, it is often desirable to slow the absorption of the compound by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of poorly water-soluble crystals or amorphous substances, because the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Or, by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid to make an injectable storage form, depending on the ratio of compound to polymer and the nature of the particular polymer used, Control the rate of compound release. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
经直肠或***施用的组合物特别是可通过混合本发明所述化合物和适合的非刺激性辅剂，例如可可油、聚乙二醇或栓剂蜡制备的栓剂，所述辅剂在环境温度下为固体但在体温下为液体并因此在直肠或***腔内融化并释放活性化合物。The composition for rectal or vaginal administration is particularly a suppository prepared by mixing the compound of the present invention and a suitable non-irritating adjuvant, such as cocoa butter, polyethylene glycol or suppository wax, which is at ambient temperature It is solid but liquid at body temperature and therefore melts and releases the active compound in the rectum or vaginal cavity.
口服固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒。在这种固体剂型中，活性化合物混有至少一种惰性的药学上可接受的辅剂，例如柠檬酸钠或磷酸二钙和/或a)填料或膨胀剂，例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸，b)粘合剂，例如羧基甲基纤维素、藻酸盐、凝胶、聚乙烯吡咯烷酮、蔗糖和***胶，c)保湿剂，例如甘油，d)崩解剂，例如琼脂--琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些硅酸盐和碳酸钠，e)溶液阻滞剂，例如石蜡，f)吸收加速剂，例如季铵化合物，g)湿润剂，例如鲸蜡醇和单硬脂酸甘油酯，h)吸收剂，例如高岭土和膨润土，和i)润滑剂，例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、硫酸月桂酯钠及其混合物。在为胶囊、片剂和丸剂的情况下，剂型也可包含缓冲剂。Oral solid dosage forms include capsules, tablets, pills, powders and granules. In this solid dosage form, the active compound is mixed with at least one inert pharmaceutically acceptable adjuvant, such as sodium citrate or dicalcium phosphate and/or a) filler or bulking agent, such as starch, lactose, sucrose, glucose , Mannitol and silicic acid, b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants, such as glycerin, d) disintegrants, such as Agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates and sodium carbonate, e) solution blocker, such as paraffin, f) absorption accelerator, such as quaternary ammonium compound, g) wetting agent , Such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sulfate Sodium and its mixtures. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.
也可使用如乳糖或奶糖以及高分子聚乙二醇等辅剂将相似类型的固体组合物用作软和硬凝胶胶囊中的填料。可用包衣和壳，例如肠溶衣和制药领域众所周知的其它包衣制备片剂、糖锭、胶囊、丸剂和颗粒的固体剂型。它们可任选含有乳浊剂并且还可具有组合物的性质，以致任选地以延迟方式仅释放活性成分，或优选地，在肠道的某一部分释放。可使用的包埋组合物的实例包括聚合物和蜡。It is also possible to use adjuvants such as lactose or toffee and macromolecular polyethylene glycols to use similar types of solid compositions as fillers in soft and hard gel capsules. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also have the properties of the composition, so that optionally only the active ingredient is released in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.
活性化合物也可呈现具有一种或多种上述辅剂的微密封形式。在这种固体剂型中，活性化合物可能混有至少一种惰性稀释剂，例如蔗糖、乳糖或淀粉。一般地，这种剂型也可能包含除惰性稀释剂外的另外的物质，例如压片润滑剂和其它压片辅剂，例如硬脂酸镁和微晶纤维素。它们可任选含有乳浊剂并且还可具有组合物的性质，以致任选地以延迟方式仅释放活性成分，或优选地，在肠道的某一部分释放。可使用的包埋组合物的实例包括聚合物和蜡。The active compound may also be in a micro-encapsulated form with one or more of the aforementioned adjuvants. In this solid dosage form, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Generally, such dosage forms may also contain other substances besides inert diluents, such as tableting lubricants and other tableting adjuvants, such as magnesium stearate and microcrystalline cellulose. They may optionally contain opacifying agents and may also have the properties of the composition, so that optionally only the active ingredient is released in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.
本发明所述化合物的局部或经皮施用剂型包括药膏、软膏、乳膏、洗剂、凝胶、粉剂、溶液、喷剂、吸入剂或贴片。在无菌条件下，活性化合物与药学上可接受的载体和任何需要的防腐剂或可能需要的缓冲剂。眼科制剂、耳滴剂和眼药水也被考虑到本发明的范围之内。另外，本发明考虑到具有提供控制化合物向身体递送的附加优点的皮肤贴片的用途。可通过将化合物溶解或分散于恰当介质中制成这种剂型。吸收促进剂也可用于提高化合物通过皮肤的流量。可通过提供速率控制膜或通过将化合物分散于聚合物基质或凝胶中控制速率。The topical or transdermal application dosage forms of the compound of the present invention include ointments, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic preparations, ear drops, and eye drops are also considered within the scope of the present invention. In addition, the present invention contemplates the use of a skin patch that has the added advantage of providing controlled delivery of the compound to the body. This dosage form can be made by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
也可经口、肠胃外，通过吸入喷剂经局部、直肠、鼻、口腔、***或通过植入药盒施用本发明所述的组合物。如本发明使用的术语“肠胃外”包括但不限于皮下、静脉内、肌肉、关节内、滑膜腔内、胸骨内、鞘内、肝内、病灶内和颅内注射或输注技术。特别地，经口、腹膜内或静脉内施用组合物。The composition of the present invention can also be administered orally, parenterally, locally, rectum, nose, oral cavity, vagina via inhalation spray, or via implanted kit. The term "parenteral" as used in the present invention includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the composition is administered orally, intraperitoneally or intravenously.
本发明所述组合物的无菌可注射形式可为水或油悬浮液。这些悬浮液可跟进本领域已知的技术使用适合的分散或湿润剂和悬浮剂制备。另外，按照惯例采用无菌不挥发性油作为溶剂或悬浮介质。为此，可采用任何无味的不挥发性油，包括合成的单酸甘油脂或甘油二酯。另外，正如尤其呈聚氧乙烯化形式的天然药学上可接受的油，例如橄榄油或蓖麻油，脂肪酸例如十八烯酸及其甘油酯衍生物用于制备注射剂。这些油溶液或悬浮液也可能含有长链醇稀释剂或分散剂，例如羧甲基纤维素或在配制药学上可接受的剂型(包括乳剂和悬浮液)中常用的类似分散剂。其它常用表面活性剂，例如Tweens、Spans和在生产药学上可接受的固体、液体或其它剂型中常用的其它乳化剂或生物利用率增强剂也可用于配制的目的。The sterile injectable form of the composition of the present invention may be a water or oil suspension. These suspensions can be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art. In addition, sterile non-volatile oil is used as a solvent or suspending medium in accordance with the usual practice. For this purpose, any odorless non-volatile oil can be used, including synthetic monoglycerides or diglycerides. In addition, just as natural pharmaceutically acceptable oils, such as olive oil or castor oil, in particular in polyoxyethylated form, fatty acids such as octadecenoic acid and its glyceride derivatives are used in the preparation of injections. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants such as Tweens, Spans and other emulsifiers or bioavailability enhancers commonly used in the production of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulation purposes.
可以任何口服可接受的剂型，包括但不限于胶囊、片剂、水悬浮液或溶液，口服本发明所述药物组合物。在为供口服片剂的情况下，常用载体包括但不限于乳糖和淀粉。通常还加入润滑剂，例如硬脂酸镁。为了以胶囊形式口服，有用的稀释剂包括乳糖和干玉米淀粉。当口服需要水悬浮液时，活性成分与乳化剂和悬浮剂结合。若需要，还可加入某些甜味剂、增味剂或着色剂。The pharmaceutical composition of the present invention can be taken orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, commonly used carriers include, but are not limited to, lactose and starch. Lubricants such as magnesium stearate are usually added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If necessary, certain sweeteners, flavor enhancers or colorants can also be added.
或者，可以供直肠使用的栓剂形式施用本发明所述的药物组合物。可通过混合试剂和非刺激性赋形剂制备这些药物组合物。这种物质包括但不限于可可油、蜂蜡和聚乙二醇。Alternatively, the pharmaceutical composition of the present invention may be administered in the form of suppositories for rectal use. These pharmaceutical compositions can be prepared by mixing reagents and non-irritating excipients. Such substances include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.
尤其是当治疗目标包括局部滴施易于接近的区域或器官，包括眼部、皮肤或低位肠道疾病时，还可局部施用本发明所述的药物组合物。易于为这些区域或器官的每一个制备适合的局部制剂。Especially when the target of treatment includes local dripping to easily accessible areas or organs, including diseases of the eyes, skin or lower intestinal tract, the pharmaceutical composition of the present invention can also be applied locally. It is easy to prepare a suitable topical formulation for each of these areas or organs.
以直肠栓剂制剂(见上文)或适合的灌肠剂制剂可实现对低位肠道的局部滴施。也可使用局部皮肤贴片。Rectal suppository preparations (see above) or suitable enema preparations can be used to achieve local drip administration to the lower intestinal tract. A topical skin patch can also be used.
对于局部滴施而言，可将药物组合物配制为含有悬浮或溶于一种或多种辅剂中的活性组分的适合药膏。适于局部滴施本发明的化合物的辅剂包括但不限于矿物油、凡士林油、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者，可将药物组合物配制为含有悬浮或溶于一种或多种药学上可接受的辅剂中的活性组分的适合洗剂或乳膏。适合的辅剂包括但不限于矿物油、山梨醇酐单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡硬脂醇、2-辛基十二醇、苯甲醇和水。For topical instillation, the pharmaceutical composition can be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more adjuvants. Adjuvants suitable for topical instillation of the compound of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable adjuvants. Suitable adjuvants include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
为了眼科使用，可用或不用防腐剂例如苯扎氯铵，将药物组合物配制为在等渗pH调节无菌盐水中的微粉化悬浮液，或特别是等渗pH调节无菌盐水中的溶液。或者，为了眼科使用，可将药物组合物配制为药膏，例如凡士林。For ophthalmic use, the pharmaceutical composition can be formulated as a micronized suspension in isotonic pH-adjusted sterile saline, or especially a solution in isotonic pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as an ointment, such as petrolatum.
也可通过鼻用气化喷雾剂或吸入施用药物组合物。根据制药领域中众所周知的技术制备这种组合物并且采用苯甲醇和其它适合的防腐剂、提高生物利用率的吸收促进剂、碳氟化合物和/或其它常规增溶剂或分散剂制备成盐水中的溶液。The pharmaceutical composition can also be administered via nasal vaporized spray or inhalation. This composition is prepared according to well-known techniques in the pharmaceutical field and prepared into salt water by using benzyl alcohol and other suitable preservatives, absorption promoters that improve bioavailability, fluorocarbons and/or other conventional solubilizers or dispersants Solution.
可将用于本发明的方法的化合物配制成单位剂型。术语“单位剂型”指适合作为受治疗者的单位剂量的物理分立单位，每单位含有经计算产生预期疗效的预定量的活性物质，任选地与适合的药物载体结合。单位剂型可作单次日剂量或多次日剂量(例如，每日约1-4次或更多次)的其中一次。当使用多次日剂量时，对于每次剂量的单位剂型可相同或不同。The compound used in the method of the present invention can be formulated into a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for a subject, each unit containing a predetermined amount of active substance calculated to produce the expected therapeutic effect, optionally combined with a suitable pharmaceutical carrier. The unit dosage form can be used as a single daily dose or one of multiple daily doses (for example, about 1-4 times or more per day). When multiple daily doses are used, the unit dosage form for each dose may be the same or different.
本发明化合物及组合物的用途Uses of the compounds and compositions of the present invention
本发明提供的上述化合物和药物组合物可制备用于预防、治疗或减轻患者病毒感染性疾病的药品，优选地，所述病毒感染为流感病毒感染。The above-mentioned compounds and pharmaceutical compositions provided by the present invention can be used to prepare medicines for preventing, treating or alleviating viral infectious diseases in patients. Preferably, the viral infection is influenza virus infection.
本发明还提供上述化合物或其药物组合物在制备流感病毒RNA聚合酶抑制剂类药物中的用途，其中，所述RNA聚合酶抑制剂为帽依赖性核酸内切酶。The present invention also provides the use of the above-mentioned compound or its pharmaceutical composition in the preparation of influenza virus RNA polymerase inhibitor drugs, wherein the RNA polymerase inhibitor is a cap-dependent endonuclease.
本发明提供一种用于治疗、预防或延缓由病毒引起的感染的方法，所述方法包括给予有治疗需要的患者治疗有效量的上述化合物或其药物组合物，其中所述病毒为流感病毒。并且，本发明提供的上述化合物或其药物组合物可以与其它疗法或治疗剂共同施用。施用方式可以为同时、顺序或以一定时间间隔进行。The present invention provides a method for treating, preventing or delaying infection caused by a virus, the method comprising administering a therapeutically effective amount of the above-mentioned compound or a pharmaceutical composition thereof to a patient in need of treatment, wherein the virus is an influenza virus. In addition, the above-mentioned compound or pharmaceutical composition provided by the present invention can be co-administered with other therapies or therapeutic agents. The mode of administration can be simultaneous, sequential or at certain time intervals.
实施治疗、预防或延缓等作用所需的化合物或药物组合物的剂量通常取决于施用的具体化合物、患者、具体疾病或病症及其严重程度、给药途径和频率等，并且需要由主治医师根据具体情况判定。例如，在通过经静脉途径施用本发明提供的化合物或药物组合物时，可以每周一次甚至以更长时间间隔进行施用。The dosage of the compound or pharmaceutical composition required to implement the effects of treatment, prevention, or delay usually depends on the specific compound administered, the patient, the specific disease or condition and its severity, the route and frequency of administration, etc., and needs to be determined by the attending physician The specific situation is determined. For example, when the compound or pharmaceutical composition provided by the present invention is administered via an intravenous route, the administration may be performed once a week or even at longer intervals.
综上所述，本发明提供了一种新型化合物，所述化合物可作为流感病毒RNA聚合酶抑制剂。本发明的化合物适合制成多种剂型的药物，可以广泛用于治疗季节性流感、禽流感、猪流感以及对达菲有耐药性的流感病毒突变株。In summary, the present invention provides a novel compound that can be used as an inhibitor of influenza virus RNA polymerase. The compound of the present invention is suitable for preparing medicines in various dosage forms, and can be widely used in the treatment of seasonal influenza, avian influenza, swine influenza, and influenza virus mutant strains resistant to Tamiflu.
本发明的化合物及药物组合物除了对人类治疗有益以外，还可应用于兽医治疗宠物、引进品种的动物和农场的动物中的哺乳动物。另外一些动物的实例包括马、狗和猫。在此，本发明的化合物包括其药学上可接受的衍生物。In addition to being beneficial to human treatment, the compound and pharmaceutical composition of the present invention can also be applied to veterinary treatment of pets, introduced species of animals, and mammals in farm animals. Other examples of animals include horses, dogs, and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
一般合成过程General synthesis process
在本说明书中，如果在化学名称和化学结构间存在任何差异，结构是占优的。In this specification, if there is any difference between the chemical name and the chemical structure, the structure is dominant.
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。To describe the present invention, examples are listed below. However, it needs to be understood that the present invention is not limited to these embodiments, but only provides methods for practicing the present invention.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)或式(II)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definition of the substituents is as shown in formula (I) or formula (II). The following reaction schemes and examples are used to further illustrate the content of the present invention.
所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described in the present invention can be used to appropriately prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. Inside. For example, the synthesis of non-exemplary compounds according to the present invention can be successfully completed by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or The reaction conditions are modified regularly. In addition, the reactions disclosed in the present invention or known reaction conditions are also recognized as applicable to the preparation of other compounds of the present invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，J&K Scientific Ltd.，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，青岛海洋化工厂，北京偶合科技有限公司，上海特伯化学科技有限公司和韶远科技(上海)有限公司购买得到。In the examples described below, all temperatures are set to degrees Celsius unless otherwise indicated. Reagents are purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, J&K Scientific Ltd., and are used without further purification unless otherwise indicated. General reagents from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., Qingdao Ocean Chemical Plant, Beijing Ouhe Technology Co., Ltd., Shanghai Tebo Chemical Technology Co., Ltd. and Shaoyuan Technology (Shanghai) Co., Ltd. purchased.
无水四氢呋喃，1,4-二氧六环，甲苯，***是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。Anhydrous tetrahydrofuran, 1,4-dioxane, toluene, and ether are obtained by refluxing and drying with sodium metal. Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are dried in advance with anhydrous sodium sulfate.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following reactions are generally carried out under a positive pressure of nitrogen or argon or a drying tube on an anhydrous solvent (unless otherwise indicated), the reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe. The glassware is all dried.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.
核磁共振氢谱的测试条件是：室温条件下，布鲁克(Bruker)400MHz或600MHz的核磁仪，以CDC1 3、DMSO-d 6、CD 3OD或丙酮-d 6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用J表示，单位为赫兹(Hz)。 The test conditions for proton nuclear magnetic resonance spectroscopy are: at room temperature, Bruker 400MHz or 600MHz nuclear magnetometer, with CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), Use TMS (0ppm) or chloroform (7.26ppm) as the reference standard. When multiple peaks appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, wide Peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet). Coupling constant, denoted by J, in hertz (Hz).
低分辨率质谱(MS)数据的测试条件是：Agilent 6120Quadrupole HPLC-MS(柱子型号：Zorbax SB-C18,2.1×30mm,3.5μm,6min,流速为0.6mL/min，流动相：5％-95％(含0.1％甲酸的CH 3CN)在(含0.1％甲酸的H 2O)中的比例)，在210nm/254nm用UV检测，用电喷雾电离模式(ESI)。 The test conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1×30mm, 3.5μm, 6min, flow rate 0.6mL/min, mobile phase: 5%-95 % ( The ratio of CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid)), detected by UV at 210nm/254nm, using electrospray ionization mode (ESI).
化合物纯度的表征方式为：Agilent 1260制备型高效液相色谱(Pre-HPLC)或Calesep Pump 250制备型高效液相色谱(Pre-HPLC)(柱子型号：NOVASEP,50/80mm,DAC)，在210nm/254nm用UV检测。The compound purity is characterized by: Agilent 1260 Pre-HPLC or Calesep Pump 250 Pre-HPLC (Column Model: NOVASEP, 50/80mm, DAC), at 210nm /254nm is detected by UV.
生物测定试验中分析用的LC/MS/MS***包括Agilent 1200系列真空脱气炉，二元注射泵，孔板自动采样器，柱恒温箱，带电喷雾电离源(ESI)的AB Sciex 4000三重四极杆质谱仪。定量分析在MRM模式下进行，MRM转换的参数如表A所示：The LC/MS/MS system used for analysis in the bioassay test includes Agilent 1200 series vacuum degassing furnace, binary syringe pump, orifice automatic sampler, column thermostat, AB Sciex 4000 triple quadruple with electrospray ionization source (ESI) Polar mass spectrometer. Quantitative analysis is carried out in MRM mode, and the parameters of MRM conversion are shown in Table A:
表ATable A
去簇电压Declustering voltage 80V/90V80V/90V
碰撞电压Impact voltage 32V/22V32V/22V
干燥器温度Dryer temperature 550℃550°C
雾化气Atomizing gas 50psi50psi
气帘器Air curtain 20psi20psi
分析使用Waters Xbridge-C18，2.1×30mm，3.5μm柱，注入5μL样品。分析条件：流动相为0.5％甲酸水溶液(A)和乙腈：异丙醇(v/v＝2:1)混合溶液(B)。流速为0.5mL/min。流动相梯度如表B所示：The analysis uses Waters Xbridge-C18, 2.1×30mm, 3.5μm column, and injects 5μL sample. Analysis conditions: the mobile phase is a 0.5% formic acid aqueous solution (A) and an acetonitrile: isopropanol (v/v=2:1) mixed solution (B). The flow rate is 0.5 mL/min. The mobile phase gradient is shown in Table B:
表BTable B
时间time 流动相B的梯度Gradient of mobile phase B
0.5min0.5min 20％20%
1.0min1.0min 90％90%
1.8min1.8min 90％90%
1.83min1.83min 20％20%
2.2min2.2min 20％20%
2.3min2.3min 90％90%
3.0min3.0min 90％90%
3.01min3.01min 20％20%
4.0min4.0min 终止termination
下面简写词的使用贯穿本发明：The following abbreviations are used throughout the present invention:
Bn：           苄基,苯甲基；      CDCl 3：        氘代氯仿；     DMF：         N,N-二甲基甲酰胺； Bn: benzyl, benzyl; CDCl 3 : deuterated chloroform; DMF: N,N-dimethylformamide;
DMSO-d 6：      氘代二甲基亚砜；   THF：          四氢呋喃；     NaBH 4：       硼氢化钠； DMSO-d 6 : deuterated dimethyl sulfoxide; THF: tetrahydrofuran; NaBH 4 : sodium borohydride;
PPA：          多聚磷酸；         T3P：          1-丙基磷酸酐(50％乙酸乙酯溶液)；PPA: Polyphosphoric acid; T3P: 1-Propyl phosphoric anhydride (50% ethyl acetate solution);
mmol,mmoL：    毫摩尔；           mL,ml：        毫升；         μL：          微升；mmol, mmoL: millimoles; mL,ml: milliliters; μL: microliters;
g：            克；               N,M,mol/L：    摩尔每升；     mass％：      质量百分比。g: Grams; N,M,mol/L: moles per liter; mass%: mass percentage.
一般合成方法General synthesis method
以下合成方案列出了制备本发明中公开化合物的实验步骤。其中，R 1、R 2、R 3、R 4、R 8、R 9、E和环Cy具有如本发明的定义，R j为C 1-6烷基；进一步地，各R 1、R 2、R 3和R 4独立地优选为H、F、Cl、Br或I，R j优选为甲基或乙基。 The following synthetic scheme lists the experimental procedures for preparing the compounds disclosed in the present invention. Wherein, R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , E and ring Cy have the definitions of the present invention, and R j is a C 1-6 alkyl group; further, each R 1 , R 2 , R 3 and R 4 are independently H, F, Cl, Br or I, and R j is preferably methyl or ethyl.
合成方案1Synthesis scheme 1
Figure PCTCN2020139363-appb-000026
Figure PCTCN2020139363-appb-000026
式 (6-a)所示中间体可以通过合成方案1中所描述的方法制备得到，其中，E 1为-CH＝、-NH-或-CHR 10-，其中R 10具有如本发明的定义。首先，化合物 (1-a)与化合物 (2-a)反应得到化合物 (3-a)。化合物 (3-a)在碱性条件下水解得到化合物 (4-a)；化合物 (4-a)在多聚磷酸(PPA)作用下关环生成化合物 (5-a)；化合物 (5-a)在硼氢化钠作用下生成中间体 (6-a)。 The intermediate represented by formula (6-a) can be prepared by the method described in Synthetic Scheme 1, wherein E 1 is -CH=, -NH- or -CHR 10 -, wherein R 10 has the definition of the present invention . First, the compound (1-a) is reacted with the compound (2-a) to obtain the compound (3-a) . Compound (3-a) is hydrolyzed under alkaline conditions to obtain compound (4-a) ; compound (4-a) is ring-closed under the action of polyphosphoric acid (PPA) to form compound (5-a) ; compound (5-a) ) Intermediate (6-a) is generated under the action of sodium borohydride.
合成方案2Synthesis scheme 2
Figure PCTCN2020139363-appb-000027
Figure PCTCN2020139363-appb-000027
式 (9-a)所示化合物以通过合成方案2中所描述的方法制备得到。首先，化合物 (6-a)与化合物 (7-a)在1-丙基磷酸酐等缩合剂存在的条件下发生反应，得到化合物 (8-a)。化合物 (8-a)脱除羟基上的保护基Bn，得到式 (9-a)所示化合物。式 (9-a)所示化合物可通过手性制备方法如制备色谱分离得到对应的立体异构体。 The compound represented by formula (9-a) is prepared by the method described in Synthesis Scheme 2. First, compound (6-a) and compound (7-a) are reacted in the presence of a condensing agent such as 1-propyl phosphoric anhydride to obtain compound (8-a) . Compound (8-a) removes the protective group Bn on the hydroxyl group to obtain the compound represented by formula (9-a) . The compound represented by formula (9-a) can be separated by chiral preparation methods such as preparative chromatography to obtain corresponding stereoisomers.
具体实施方式Detailed ways
以下实施例用于说明本发明，但不用于限制本发明的范围。The following examples are used to illustrate the present invention, but not to limit the scope of the present invention.
制备实施例Preparation examples
在以下制备实施例中，发明人以本发明的部分化合物为例，详细描述了本发明化合物的制备过程。In the following preparation examples, the inventors described the preparation process of the compounds of the present invention in detail by taking part of the compounds of the present invention as examples.
实施例1：化合物(1-1)和化合物(1-2)的合成Example 1: Synthesis of compound (1-1) and compound (1-2)
Figure PCTCN2020139363-appb-000028
Figure PCTCN2020139363-appb-000028
步骤1)化合物(1-A)的合成Step 1) Synthesis of compound (1-A)
Figure PCTCN2020139363-appb-000029
Figure PCTCN2020139363-appb-000029
标题化合物参考专利申请WO 2017221869中公开的合成方法制备得到。The title compound was prepared with reference to the synthetic method disclosed in the patent application WO 2017221869.
步骤2)化合物(1-B)的合成Step 2) Synthesis of compound (1-B)
Figure PCTCN2020139363-appb-000030
Figure PCTCN2020139363-appb-000030
将氯化亚铜(146mg,1.48mmol)和叔丁醇钠(1.76g,17.80mmol)混合于DMF(20mL)中，然后向其中加入苯并噻唑(2.00g,14.80mmol)，置于氧气氛围中，室温下搅拌过夜。停止反应，向反应液中加入水(20mL)，然后用乙酸乙酯(25mL)萃取，合并有机相，所得有机相用饱和食盐水(25mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗产物用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯(v/v)＝3/1)纯化，得到标题化合物为黄色固体(300mg,13.4％)。 1H NMR(400MHz,CDCl 3)δ(ppm)10.16(s,1H),7.43(d,J＝7.7Hz,1H),7.29(d,J＝6.7Hz,1H),7.22(d,3(d,本发明化。 Mix cuprous chloride (146mg, 1.48mmol) and sodium tert-butoxide (1.76g, 17.80mmol) in DMF (20mL), then add benzothiazole (2.00g, 14.80mmol) to it and place it in an oxygen atmosphere In, stirring at room temperature overnight. The reaction was stopped, water (20 mL) was added to the reaction solution, and then extracted with ethyl acetate (25 mL), and the organic phases were combined. The resulting organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain the title compound as a yellow solid (300 mg, 13.4%). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 10.16 (s, 1H), 7.43 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 6.7 Hz, 1H), 7.22 (d, 3 ( d, the present invention.
步骤3)化合物(1-C)的合成Step 3) Synthesis of compound (1-C)
Figure PCTCN2020139363-appb-000031
Figure PCTCN2020139363-appb-000031
将化合物(1-B)(100mg,0.66mmol)溶解于四氢呋喃(10mL)中，再向其中加入氢化钠(30mg,0.75mmol,60mass％)，置于室温下搅拌20分钟，然后取2-(溴甲基)-3,4-二氟苯甲酸乙酯(195mg,0.69mmol)加入其中，置于55℃下继续搅拌反应过夜。停止反应，减压浓缩，所得粗产物用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯(v/v)＝3/1)纯化，得到标题化合物为乳白色固体(66mg,29％)。MS(ESI,pos.ion)m/z:350.0[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)7.74(dd,J＝7.2,5.6Hz,1H),7.42(d,J＝7.7Hz,1H),7.30–7.08(m,4H),5.69(s,2H),4.44(q,J＝7.1Hz,2H),1.43(t,J＝7.1Hz,3H). Compound (1-B) (100mg, 0.66mmol) was dissolved in tetrahydrofuran (10mL), and sodium hydride (30mg, 0.75mmol, 60mass%) was added to it, stirred at room temperature for 20 minutes, and then 2-( (Bromomethyl)-3,4-difluorobenzoic acid ethyl ester (195 mg, 0.69 mmol) was added to it, and the mixture was kept at 55° C. for stirring and the reaction was continued overnight. The reaction was stopped and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=3/1) to obtain the title compound as a milky white solid (66mg, 29%) . MS(ESI,pos.ion)m/z:350.0[M+H] + ; 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.74(dd,J=7.2,5.6Hz,1H),7.42(d ,J=7.7Hz,1H), 7.30-7.08(m,4H), 5.69(s,2H), 4.44(q,J=7.1Hz,2H), 1.43(t,J=7.1Hz,3H).
步骤4)化合物(1-D)的合成Step 4) Synthesis of compound (1-D)
Figure PCTCN2020139363-appb-000032
Figure PCTCN2020139363-appb-000032
将化合物(1-C)(78mg,0.22mmol)溶解于四氢呋喃(4mL)以及甲醇(4mL)中，再将氢氧化钠(35mg,0.90mmol)的水(1mL)溶液加入其中，置于室温下搅拌过夜。停止反应，向反应液中加入水(20mL)，然后用乙酸乙酯(25mL×3)萃取，合并有机相，所得有机相用饱和食盐水(25mL×3)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得粗产物用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯(v/v)＝15/1)纯化，得到标题化合物为淡黄色固体(61mg,85％)。MS(ESI,pos.ion)m/z:320.0[M+H] +。 Compound (1-C) (78mg, 0.22mmol) was dissolved in tetrahydrofuran (4mL) and methanol (4mL), then sodium hydroxide (35mg, 0.90mmol) in water (1mL) was added to it, and left at room temperature Stir overnight. The reaction was stopped, water (20 mL) was added to the reaction solution, and then extracted with ethyl acetate (25 mL×3), the organic phases were combined, and the obtained organic phase was washed with saturated brine (25 mL×3), dried with anhydrous sodium sulfate, and filtered After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=15/1) to obtain the title compound as a pale yellow solid (61 mg, 85%). MS (ESI, pos.ion) m/z: 320.0 [M+H] + .
步骤5)化合物(1-E)的合成Step 5) Synthesis of compound (1-E)
Figure PCTCN2020139363-appb-000033
Figure PCTCN2020139363-appb-000033
将化合物(1-D)(2.03g,6.23mmol)置于多聚磷酸(30mL)中，升温至100℃，然后反应过夜。停止反应，向反应液中缓慢加入水(30mL)淬灭反应，然后用二氯甲烷(20mL×3)萃取，合并有机相，再加甲醇(20mL)完全溶解萃取液，用无水硫酸钠干燥，过滤，减压浓缩，得到粗产物为类白色固体，无需纯化直接用于下一步反应。Compound (1-D) (2.03 g, 6.23 mmol) was placed in polyphosphoric acid (30 mL), the temperature was raised to 100° C., and then the reaction was carried out overnight. Stop the reaction, slowly add water (30mL) to the reaction solution to quench the reaction, then extract with dichloromethane (20mL×3), combine the organic phases, add methanol (20mL) to completely dissolve the extract, and dry with anhydrous sodium sulfate , Filtered and concentrated under reduced pressure to obtain the crude product as off-white solid, which was directly used in the next reaction without purification.
步骤6)化合物(1-F)的合成Step 6) Synthesis of compound (1-F)
Figure PCTCN2020139363-appb-000034
Figure PCTCN2020139363-appb-000034
将上一步所得粗产物(1-E)(1.89g,6.23mmol)溶于THF(25mL)和甲醇(25mL)中，冷却至0℃，分批加入硼氢化钠(565mg,14.30mmol)，加完后在0℃继续反应5分钟，然后再转移至室温下反应1小时，加入饱和氯化铵溶液(20mL)淬灭反应，用乙酸乙酯(30mL×3)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，所得滤液减压浓缩得到标题化合物为白色固体(1.35g,71％)。MS(ESI,pos.ion)m/z:306.0[M+H] +。 The crude product (1-E) (1.89g, 6.23mmol) obtained in the previous step was dissolved in THF (25mL) and methanol (25mL), cooled to 0°C, sodium borohydride (565mg, 14.30mmol) was added in batches, and After completion, the reaction was continued at 0°C for 5 minutes, and then transferred to room temperature to react for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (30 mL×3), and the organic phases were combined. It was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to obtain the title compound as a white solid (1.35 g, 71%). MS (ESI, pos.ion) m/z: 306.0 [M+H] + .
步骤7)化合物(1-G)的合成Step 7) Synthesis of compound (1-G)
Figure PCTCN2020139363-appb-000035
Figure PCTCN2020139363-appb-000035
将化合物(1-F)(2.24g,7.34mmol)和化合物(1-A)(2.59g,8.07mmol)混合于乙酸乙酯(20mL)中，所得溶液转移至封管中，再向其中加入T 3P(12.00mL,22.00mmol,1.67mol/L)，置于110℃中加热反应过夜；停止反应，将反应液滴加至冰水(30mL)中，用乙酸乙酯(30mL×3)萃取，合并有机相，所得有机相用饱和碳酸氢钠水溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶柱层析纯化(洗脱剂为二氯甲烷/甲醇(v/v)＝25/1)，纯化后得到标题化合物为淡黄色固体(1.96g,44％)。MS(ESI,pos.ion)m/z:615.2[M+H] +。 Compound (1-F) (2.24g, 7.34mmol) and compound (1-A) (2.59g, 8.07mmol) were mixed in ethyl acetate (20mL), the resulting solution was transferred to a sealed tube, and then added to it T 3 P (12.00mL, 22.00mmol, 1.67mol/L), heated at 110℃ for reaction overnight; stop the reaction, add the reaction solution dropwise to ice water (30mL), use ethyl acetate (30mL×3) Extract and combine the organic phases. The resulting organic phase was washed with saturated aqueous sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent was dichloromethane). /Methanol (v/v)=25/1), after purification, the title compound was obtained as a pale yellow solid (1.96 g, 44%). MS (ESI, pos.ion) m/z: 615.2 [M+H] + .
步骤8)化合物(1-1)和化合物(1-2)的合成Step 8) Synthesis of compound (1-1) and compound (1-2)
Figure PCTCN2020139363-appb-000036
Figure PCTCN2020139363-appb-000036
将化合物(1-G)(1.96g,3.19mmol)溶于N,N-二甲基乙酰胺(30mL)中，加入无水氯化锂(1.35g,31.90mmol)，氮气保护下升温至100℃反应过夜，加入水(10mL)，然后用1M稀盐酸调节pH至6左右，用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经LUNA制备柱(洗脱剂乙腈/0.1％三氟乙酸水溶液(v/v)＝12/13)分离纯化，分别得到标题化合物1-1为淡黄色固体化合物(211mg,13％)，标题化合物1-2为淡黄色固体化合物(237mg,14.2％)。Compound (1-G) (1.96g, 3.19mmol) was dissolved in N,N-dimethylacetamide (30mL), anhydrous lithium chloride (1.35g, 31.90mmol) was added, and the temperature was raised to 100 under nitrogen protection React overnight at ℃, add water (10mL), then adjust the pH to about 6 with 1M dilute hydrochloric acid, extract with ethyl acetate (10mL×3), combine the organic phases, and wash the organic phase with saturated brine (20mL×3). The filtrate was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by LUNA preparation column (eluent acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) to obtain the title compound 1- 1 is a pale yellow solid compound (211 mg, 13%), and the title compound 1-2 is a pale yellow solid compound (237 mg, 14.2%).
化合物(1-1)：Compound (1-1):
HRMS(ESI,pos.ion)m/z:525.1023[M+H] +； HRMS(ESI,pos.ion)m/z:525.1023[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.43(d,J＝7.7Hz,1H),7.24(d,J＝8.2Hz,1H),7.17(s,1H),7.01–6.90(m,1H),6.77–6.60(m,2H),6.17(d,J＝14.5Hz,1H),5.76(d,J＝7.5Hz,1H),5.34(s,2H),4.70(d,J＝13.2Hz,1H),4.58(d,J＝9.1Hz,1H),3.94(d,J＝10.6Hz,1H),3.84(d,J＝11.7Hz,1H),3.67–3.57(m,1H),3.50(t,J＝11.2Hz,1H),3.13–2.97(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.43 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.17 (s, 1H), 7.01-6.90 (m, 1H), 6.77–6.60 (m, 2H), 6.17 (d, J = 14.5 Hz, 1H), 5.76 (d, J = 7.5 Hz, 1H), 5.34 (s, 2H), 4.70 (d, J = 13.2Hz, 1H), 4.58 (d, J = 9.1Hz, 1H), 3.94 (d, J = 10.6Hz, 1H), 3.84 (d, J = 11.7Hz, 1H), 3.67–3.57 (m, 1H), 3.50 (t, J = 11.2Hz, 1H), 3.13-2.97 (m, 1H).
化合物(1-2)：Compound (1-2):
HRMS(ESI,pos.ion)m/z:525.1026[M+H] +； HRMS(ESI,pos.ion)m/z:525.1026[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.58(d,J＝6.6Hz,1H),7.28(s,2H),7.04(d,J＝7.9Hz,1H),6.71–6.51(m,2H),6.20(d,J＝14.1Hz,1H),5.88(d,J＝6.7Hz,1H),5.45–5.19(m,2H),4.70(d,J＝12.1Hz,1H),4.58(d,J＝7.5Hz,1H),3.99(d,J＝9.6Hz,1H),3.84(d,J＝8.3Hz,1H),3.63–3.44(m,2H),2.99(s,1H). 1 H NMR(400MHz,DMSO-d 6 )δ(ppm): 7.58(d,J=6.6Hz,1H), 7.28(s,2H), 7.04(d,J=7.9Hz,1H), 6.71–6.51 (m, 2H), 6.20 (d, J = 14.1Hz, 1H), 5.88 (d, J = 6.7 Hz, 1H), 5.45-5.19 (m, 2H), 4.70 (d, J = 12.1Hz, 1H) ,4.58(d,J=7.5Hz,1H),3.99(d,J=9.6Hz,1H), 3.84(d,J=8.3Hz,1H),3.63-3.44(m,2H),2.99(s, 1H).
实施例2：化合物(2-1)和化合物(2-2)的合成Example 2: Synthesis of compound (2-1) and compound (2-2)
Figure PCTCN2020139363-appb-000037
Figure PCTCN2020139363-appb-000037
步骤1)化合物(2-A)的合成Step 1) Synthesis of compound (2-A)
Figure PCTCN2020139363-appb-000038
Figure PCTCN2020139363-appb-000038
分别称量2-氨基苯硫酚(1.08g,8.63mmol)和三乙胺(6.10mL,43.00mmol)混合在THF(20mL)中，再称量1,2-二溴乙烷(0.74mL,8.60mmol)加入其中，氮气保护下升温至50℃加热反应约2小时。停止反应，将反应液加入到水(30mL)中，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和食盐水(60mL×3)洗涤，无水硫酸钠干燥，减压浓缩，所得残留物经硅胶柱层析纯化(洗脱剂为石油醚/乙酸乙酯(v/v)＝10/1)，得到标题化合物为油状液体(610mg,47％)。MS(ESI,pos.ion)m/z:152.0[M+H] +。 Weigh 2-aminothiophenol (1.08g, 8.63mmol) and triethylamine (6.10mL, 43.00mmol) and mix them in THF (20mL), then weigh 1,2-dibromoethane (0.74mL, 8.60mmol) was added, and the temperature was raised to 50°C under the protection of nitrogen, and the reaction was heated for about 2 hours. The reaction was stopped, the reaction solution was added to water (30 mL), extracted with ethyl acetate (50 mL×3), the combined organic phase was washed with saturated brine (60 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1) to obtain the title compound as an oily liquid (610 mg, 47%). MS (ESI, pos.ion) m/z: 152.0 [M+H] + .
步骤2)化合物(2-B)的合成Step 2) Synthesis of compound (2-B)
Figure PCTCN2020139363-appb-000039
Figure PCTCN2020139363-appb-000039
称量化合物(2-A)(4.80g,31.70mmol)溶解于DMF(30mL)中，置于0℃下搅拌，将氢化钠(1.40g,35.00mmol)缓慢加入其中，15分钟后，加入2-(溴甲基)-3,4-二氟-苯甲酸乙酯(8.86g,31.70mmol)，继续搅拌5分钟左右，转移到室温下继续反应过夜。停止反应，将反应液加入到水(30mL)中，用乙酸乙酯(30mL×3)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残留物经硅胶柱层析纯化(洗脱剂为石油醚/乙酸乙酯(v/v)＝10/1)，得到标题化合物为白色固体(5.57g,50.2％)。MS(ESI,pos.ion)m/z:349.2[M+H] +。 Weigh compound (2-A) (4.80g, 31.70mmol) and dissolve it in DMF (30mL), place it at 0°C and stir, slowly add sodium hydride (1.40g, 35.00mmol) to it, 15 minutes later, add 2 -(Bromomethyl)-3,4-difluoro-benzoic acid ethyl ester (8.86g, 31.70mmol), continue to stir for about 5 minutes, transfer to room temperature and continue to react overnight. The reaction was stopped, the reaction solution was added to water (30 mL), extracted with ethyl acetate (30 mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and reduced pressure After concentration, the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=10/1) to obtain the title compound as a white solid (5.57 g, 50.2%). MS (ESI, pos.ion) m/z: 349.2 [M+H] + .
1H NMR(400MHz,CDCl 3)δ(ppm)7.53(ddd,J＝8.2,4.9,1.5Hz,1H),7.17(dd,J＝16.8,8.7Hz,1H),7.09(dd,J＝7.7,1.2Hz,1H),7.05–6.99(m,1H),6.90(d,J＝8.2Hz,1H),6.73(t,J＝7.4Hz,1H),4.76(s,2H),4.27–4.18(m,2H),3.37–3.27(m,2H),2.99(dd,J＝6.3,4.4Hz,2H),1.24(t,J＝7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.53 (ddd, J = 8.2, 4.9, 1.5 Hz, 1H), 7.17 (dd, J = 16.8, 8.7 Hz, 1H), 7.09 (dd, J = 7.7 ,1.2Hz,1H),7.05-6.99(m,1H),6.90(d,J=8.2Hz,1H),6.73(t,J=7.4Hz,1H),4.76(s,2H),4.27-4.18 (m, 2H), 3.37–3.27 (m, 2H), 2.99 (dd, J = 6.3, 4.4 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H).
步骤3)化合物(2-C)的合成Step 3) Synthesis of compound (2-C)
Figure PCTCN2020139363-appb-000040
Figure PCTCN2020139363-appb-000040
将化合物(2-B)(5.57g,15.90mmol)溶解于乙醇(30mL)中，再将氢氧化钠(2.55g,63.80mmol)的水(6mL)溶液加入到其中，置于室温下反应约1小时。停止反应，用1N稀盐酸调节反应液pH值至酸性，然后用乙酸乙酯(25mL×3)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤一次，无水硫酸钠干燥，减压浓缩，所得残留物经硅胶柱层析纯化(洗脱剂为石油醚/乙酸乙酯(v/v)＝1/1)，得到标题化合物为淡黄色固体(5.00g,97.6％)。MS(ESI,neg.ion)m/z:320.2[M-H] -。 Compound (2-B) (5.57g, 15.90mmol) was dissolved in ethanol (30mL), then sodium hydroxide (2.55g, 63.80mmol) in water (6mL) was added to it, and the reaction was kept at room temperature for approx. 1 hour. Stop the reaction, adjust the pH of the reaction solution to acidity with 1N dilute hydrochloric acid, then extract with ethyl acetate (25mL×3), combine the organic phases, wash the organic phase with saturated brine (30mL) once, dry with anhydrous sodium sulfate, and reduce It was concentrated under pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 1/1) to obtain the title compound as a pale yellow solid (5.00 g, 97.6%). MS (ESI, neg.ion) m/z: 320.2 [MH] - .
步骤4)化合物(2-D)的合成Step 4) Synthesis of compound (2-D)
Figure PCTCN2020139363-appb-000041
Figure PCTCN2020139363-appb-000041
将化合物(2-C)(245mg,0.76mmol)溶解于氯苯(2mL)中，再称量PPA(30.00g,257.10mmol,84mass％)加入其中，氮气保护下置于120℃中加热反应约2.5小时。停止反应，将反应液加入到冰水(15mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残留物经硅胶柱层析纯化(洗脱剂为石油醚/乙酸乙酯(v/v)＝5/1)，得到黄色固体为标题化合物(69mg,29.83％)。 1H NMR(400MHz,CDCl 3)δ(ppm)8.18(dd,J＝8.3,1.6Hz,1H),7.61–7.54(m,1H),7.37(dd,J＝7.2,1.6Hz,1H),7.21(dt,J＝17.1,8.5Hz,1H),6.86(t,J＝7.8Hz,1H),4.57(s,2H),3.96(t,J＝5.8Hz,2H),2.92(t,J＝5.9Hz,2H). Compound (2-C) (245mg, 0.76mmol) was dissolved in chlorobenzene (2mL), and then PPA (30.00g, 257.10mmol, 84mass%) was weighed into it, and heated at 120°C under the protection of nitrogen. 2.5 hours. Stop the reaction, add the reaction solution to ice water (15mL), extract with ethyl acetate (20mL×3), combine the organic phases, wash the organic phases with saturated brine (15mL), dry with anhydrous sodium sulfate, filter, and reduce It was concentrated under pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=5/1) to obtain the title compound (69 mg, 29.83%) as a yellow solid. 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 8.18 (dd, J = 8.3, 1.6 Hz, 1H), 7.61-7.54 (m, 1H), 7.37 (dd, J = 7.2, 1.6 Hz, 1H), 7.21 (dt, J = 17.1, 8.5 Hz, 1H), 6.86 (t, J = 7.8 Hz, 1H), 4.57 (s, 2H), 3.96 (t, J = 5.8 Hz, 2H), 2.92 (t, J =5.9Hz, 2H).
步骤5)化合物(2-E)的合成Step 5) Synthesis of compound (2-E)
Figure PCTCN2020139363-appb-000042
Figure PCTCN2020139363-appb-000042
将化合物(2-D)(460mg,1.52mmol)溶解于MeOH(5mL)以及THF(5mL)中，置于室温下搅拌，然后称量硼氢化钠(119mg,3.02mmol)加入其中，置于室温下搅拌反应约20分钟。停止反应。向其中加入饱和氯化铵溶液(20mL)，用乙酸乙酯(25mL×3)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压浓缩，得到标题化合物为浅黄色固体(460mg,99.34％)，无需纯化直接用于下一步反应。Compound (2-D) (460mg, 1.52mmol) was dissolved in MeOH (5mL) and THF (5mL), stirred at room temperature, and then sodium borohydride (119mg, 3.02mmol) was weighed and added to it, and left at room temperature Stir the reaction for about 20 minutes. Stop the reaction. Saturated ammonium chloride solution (20 mL) was added thereto, extracted with ethyl acetate (25 mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title The compound was a pale yellow solid (460 mg, 99.34%), which was directly used in the next reaction without purification.
步骤6)化合物(2-F)的合成Step 6) Synthesis of compound (2-F)
Figure PCTCN2020139363-appb-000043
Figure PCTCN2020139363-appb-000043
分别称量化合物(2-E)(437mg,1.43mmol)和化合物(1-A)(515mg,1.57mmol)混合于乙酸乙酯(30mL)中，再向其中加入T 3P乙酸乙酯溶液(0.94mL,1.57mmol,1.67mol/L)，置于60℃中加热反应约6小时。停止反应，向反应液中加入饱和碳酸氢钠溶液(20mL)淬灭反应，然后用乙酸乙酯(30mL×3)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，所得残留物经硅胶 柱层析(洗脱剂为二氯甲烷/甲醇(v/v)＝15/1)纯化，得到标题化合物为黄褐色固体(420mg,47.73％)。MS(ESI,pos.ion)m/z:614.9[M+H] +。 Weigh compound (2-E) (437 mg, 1.43 mmol) and compound (1-A) (515 mg, 1.57 mmol) and mix them in ethyl acetate (30 mL), and then add T 3 P ethyl acetate solution ( 0.94mL, 1.57mmol, 1.67mol/L), heated at 60°C and reacted for about 6 hours. The reaction was stopped, and saturated sodium bicarbonate solution (20mL) was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate (30mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (30mL) and anhydrous sulfuric acid The sodium was dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain the title compound as a tan solid (420 mg, 47.73) %). MS (ESI, pos.ion) m/z: 614.9 [M+H] + .
步骤7)化合物(2-1)和化合物(2-2)的合成Step 7) Synthesis of compound (2-1) and compound (2-2)
Figure PCTCN2020139363-appb-000044
Figure PCTCN2020139363-appb-000044
将化合物(2-F)(380mg,0.62mmol)和氯化锂(78mg,1.86mmol)混合于DMAc(3mL)中，氮气保护下升温至110℃反应约3小时。将反应液加入到水(10mL)中，然后用0.5M盐酸溶液调节pH值至弱酸性，搅拌10分钟，然后用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥,，过滤，滤液减压浓缩，所得残留物经LUNA制备柱(洗脱剂为乙腈/0.1％三氟乙酸水溶液(v/v)＝12/13)分离纯化，得到标题化合物(2-1)为淡黄色固体(45mg,14％)，标题化合物(2-2)为淡黄色固体(90mg,28％)。Compound (2-F) (380 mg, 0.62 mmol) and lithium chloride (78 mg, 1.86 mmol) were mixed in DMAc (3 mL), and the temperature was raised to 110° C. under nitrogen to react for about 3 hours. The reaction solution was added to water (10mL), and then adjusted to weakly acidic pH with 0.5M hydrochloric acid solution, stirred for 10 minutes, then extracted with ethyl acetate (20mL×3), combined the organic phases, and the organic phase was saturated with brine (30mL) washed, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was separated by a LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) After purification, the title compound (2-1) was obtained as a pale yellow solid (45 mg, 14%), and the title compound (2-2) was obtained as a pale yellow solid (90 mg, 28%).
MS(ESI,neg.ion)m/z:523.4[M-H] -。 MS (ESI, neg.ion) m/z: 523.4 [MH] - .
化合物(2-1)：Compound (2-1):
HRMS(ESI,pos.ion)m/z:525.1247[M+H] +； HRMS(ESI,pos.ion)m/z:525.1247[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.16(dd,J＝16.2,8.3Hz,3H),6.82(d,J＝7.5Hz,1H),6.53(t,J＝7.6Hz,1H),6.31(d,J＝7.3Hz,1H),5.90(d,J＝7.4Hz,1H),5.41(d,J＝14.9Hz,1H),5.16(s,1H),4.65(d,J＝13.1Hz,1H),4.45(t,J＝11.0Hz,2H),3.83(dd,J＝24.2,10.8Hz,2H),3.64–3.36(m,4H),3.24–3.14(m,1H),2.94(ddd,J＝13.7,12.4,9.1Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.16 (dd, J = 16.2, 8.3 Hz, 3H), 6.82 (d, J = 7.5 Hz, 1H), 6.53 (t, J = 7.6 Hz, 1H) , 6.31 (d, J = 7.3 Hz, 1H), 5.90 (d, J = 7.4 Hz, 1H), 5.41 (d, J = 14.9 Hz, 1H), 5.16 (s, 1H), 4.65 (d, J = 13.1Hz, 1H), 4.45 (t, J = 11.0 Hz, 2H), 3.83 (dd, J = 24.2, 10.8 Hz, 2H), 3.64–3.36 (m, 4H), 3.24–3.14 (m, 1H), 2.94 (ddd, J=13.7, 12.4, 9.1Hz, 2H).
化合物(2-2)：Compound (2-2):
HRMS(ESI,pos.ion)m/z:525.1395[M+H] +； HRMS(ESI,pos.ion)m/z:525.1395[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.29(d,J＝8.9Hz,1H),7.02(d,J＝7.3Hz,1H),6.98–6.91(m,1H),6.87(dd,J＝14.3,6.6Hz,1H),6.63(d,J＝7.5Hz,1H),6.59–6.52(m,1H),5.99(d,J＝7.5Hz,1H),5.16(d,J＝15.5Hz,1H),5.10(s,1H),4.77(dd,J＝9.8,2.7Hz,1H),4.65(d,J＝12.6Hz,1H),4.48(d,J＝15.6Hz,1H),3.90(dd,J＝10.9,2.5Hz,1H),3.82(dd,J＝11.8,2.6Hz,1H),3.59(dt,J＝17.5,7.3Hz,2H),3.50–3.42(m,2H),3.24–3.16(m,1H),3.08–2.95(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.29 (d, J = 8.9 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.98-6.91 (m, 1H), 6.87 (dd, J = 14.3, 6.6 Hz, 1H), 6.63 (d, J = 7.5 Hz, 1H), 6.59-6.52 (m, 1H), 5.99 (d, J = 7.5 Hz, 1H), 5.16 (d, J = 15.5 Hz, 1H), 5.10 (s, 1H), 4.77 (dd, J = 9.8, 2.7 Hz, 1H), 4.65 (d, J = 12.6 Hz, 1H), 4.48 (d, J = 15.6 Hz, 1H), 3.90 (dd, J = 10.9, 2.5 Hz, 1H), 3.82 (dd, J = 11.8, 2.6 Hz, 1H), 3.59 (dt, J = 17.5, 7.3 Hz, 2H), 3.50–3.42 (m, 2H) , 3.24–3.16(m,1H),3.08–2.95(m,2H).
实施例3：化合物(3-1)和化合物(3-2)的合成Example 3: Synthesis of compound (3-1) and compound (3-2)
Figure PCTCN2020139363-appb-000045
Figure PCTCN2020139363-appb-000045
步骤1)化合物(3-A)的合成Step 1) Synthesis of compound (3-A)
Figure PCTCN2020139363-appb-000046
Figure PCTCN2020139363-appb-000046
将2-氨基苯酚(10g,91.63mmol)和DMF(50mL)加入到单口瓶中，冷却至0℃，缓慢加入氢化钠(3.85g,96.3mmol)，0℃反应30min。滴加2-溴-2,2-二氟乙酸乙酯(12.34mL,96.24mmol)，15min后升 温至室温反应2h，再升温至90℃反应3h。加水(200mL)，用EA(250mL×2)萃取，合并有机相，有机相用饱和氯化钠溶液洗涤(100mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝3/1)纯化，得粉色固体(8.5g,50％)。 1H NMR(400MHz,CDCl 3)δ9.86(s,1H),7.23–7.13(m,3H),7.11–7.05(m,1H). Add 2-aminophenol (10g, 91.63mmol) and DMF (50mL) into a single-neck flask, cool to 0°C, slowly add sodium hydride (3.85g, 96.3mmol), and react at 0°C for 30min. Ethyl 2-bromo-2,2-difluoroacetate (12.34 mL, 96.24 mmol) was added dropwise, and after 15 minutes, the temperature was raised to room temperature for 2 hours, and then to 90° C. for 3 hours. Add water (200mL), extract with EA (250mL×2), combine the organic phases, wash the organic phase with saturated sodium chloride solution (100mL×3), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and pass the residue over silica gel Column chromatography separation (petroleum ether/ethyl acetate (v/v)=3/1) and purification gave a pink solid (8.5 g, 50%). 1 H NMR (400MHz, CDCl 3 ) δ 9.86 (s, 1H), 7.23-7.13 (m, 3H), 7.11-7.05 (m, 1H).
步骤2)化合物(3-B)的合成Step 2) Synthesis of compound (3-B)
Figure PCTCN2020139363-appb-000047
Figure PCTCN2020139363-appb-000047
将化合物(3-A)(3.8g,21mmol)和DMF(50mL)加入到单口瓶中，缓慢加入氢化钠(1.1g,28mmol)，室温反应30min，然后滴加2-(溴甲基)-3,4-二氟苯甲酸乙酯(6.3g,23mmol)，室温反应4.5h，再向反应液中加水(50mL)，用EA(100mL×2)萃取，合并有机相，有机相用饱和氯化钠溶液洗涤(50mL×3)，无水硫酸钠干燥后，过滤，滤液减压浓缩，所得残留物经硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝5/1)，得到黄色固体(1.5g,19％)。 1H NMR(400MHz,CDCl 3)δ7.76(ddd,J＝8.6,5.1,1.6Hz,1H),7.22–7.06(m,5H),5.81(s,2H),4.41(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H)。 Compound (3-A) (3.8g, 21mmol) and DMF (50mL) were added to a single-necked flask, sodium hydride (1.1g, 28mmol) was slowly added, reacted at room temperature for 30 minutes, and then 2-(bromomethyl)- Ethyl 3,4-difluorobenzoate (6.3g, 23mmol), react at room temperature for 4.5h, then add water (50mL) to the reaction solution, extract with EA (100mL×2), combine the organic phases, and use saturated chlorine for the organic phase Wash with sodium chloride solution (50mL×3), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5/1) ) To obtain a yellow solid (1.5 g, 19%). 1 H NMR (400MHz, CDCl 3 ) δ7.76 (ddd, J = 8.6, 5.1, 1.6 Hz, 1H), 7.22-7.06 (m, 5H), 5.81 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H).
步骤3)化合物(3-C)的合成Step 3) Synthesis of compound (3-C)
Figure PCTCN2020139363-appb-000048
Figure PCTCN2020139363-appb-000048
将化合物(3-B)(100mg,0.26mmol)、THF(2mL)和硼烷(0.78mL,0.78mmol)加入到单口瓶中，室温搅拌20min后升温至70℃反应3.5h，向反应液中加入甲醇(2mL)，淬灭反应，将反应液浓缩，所得残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1)纯化，得到淡黄色油状物(39mg,40.48％)。 1H NMR(600MHz,CDCl 3)δ7.65(ddd,J＝8.5,4.9,1.4Hz,1H),7.20(dd,J＝16.8,8.7Hz,1H),7.04–6.98(m,1H),6.98–6.92(m,2H),6.88–6.81(m,1H),4.78(s,2H),4.28(q,J＝7.1Hz,2H),3.33(t,J＝6.3Hz,2H),1.27(t,J＝7.1Hz,3H). Compound (3-B) (100mg, 0.26mmol), THF (2mL) and borane (0.78mL, 0.78mmol) were added to a single-neck flask, stirred at room temperature for 20 minutes, and then heated to 70°C for 3.5 hours to react, and added to the reaction solution Methanol (2mL) was added to quench the reaction, and the reaction solution was concentrated. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10/1) to obtain a pale yellow oil (39mg , 40.48%). 1 H NMR (600MHz, CDCl 3 ) δ 7.65 (ddd, J = 8.5, 4.9, 1.4 Hz, 1H), 7.20 (dd, J = 16.8, 8.7 Hz, 1H), 7.04-6.98 (m, 1H), 6.98–6.92(m,2H), 6.88–6.81(m,1H), 4.78(s,2H), 4.28(q,J=7.1Hz,2H), 3.33(t,J=6.3Hz,2H), 1.27 (t,J=7.1Hz,3H).
步骤4)化合物(3-D)的合成Step 4) Synthesis of compound (3-D)
Figure PCTCN2020139363-appb-000049
Figure PCTCN2020139363-appb-000049
将化合物(3-C)(2g,5.42mmol)、THF(20mL)、MeOH(5mL)、水(5mL)和NaOH(433mg,10.826mmol,100mass％)加入到单口瓶中，升温至50℃反应2h。将有机相浓缩后，用2M的盐酸调pH至5左右，用EA萃取(10mL×2)，合并有机相，有机相用饱和氯化钠溶液洗涤(10mL×2)，有机相无水硫酸钠干燥后，过滤，滤液浓缩，得到淡黄色固体(1.8g,97％)。MS(ESI,pos.ion)m/z:342.0[M+H] +。 Compound (3-C) (2g, 5.42mmol), THF (20mL), MeOH (5mL), water (5mL) and NaOH (433mg, 10.826mmol, 100mass%) were added to a single-necked flask, and the temperature was raised to 50°C for reaction 2h. After concentrating the organic phase, adjust the pH to about 5 with 2M hydrochloric acid, extract with EA (10mL×2), combine the organic phases, wash the organic phase with saturated sodium chloride solution (10mL×2), the organic phase is anhydrous sodium sulfate After drying, it was filtered, and the filtrate was concentrated to obtain a pale yellow solid (1.8 g, 97%). MS (ESI, pos.ion) m/z: 342.0 [M+H] + .
步骤5)化合物(3-E)的合成Step 5) Synthesis of compound (3-E)
Figure PCTCN2020139363-appb-000050
Figure PCTCN2020139363-appb-000050
将化合物(3-D)(55mg,0.16mmol)、DCM(2mL)、DMF(0.025mL)和氯化亚砜(0.025mL,0.34mmol)加入到单口瓶中，40℃反应3h。将反应液浓缩后备用。将氯化铝(64mg,0.48mmol)，DCM(2mL)加入到单口瓶中，滴加上述浓缩后的备用溶液中，室温反应过夜。向反应液中加水(10mL)，用DCM萃取(10mL×2)，有机相用无水硫酸钠干燥后，过滤，滤液减压浓缩，所得残留物经硅胶柱层析分离(石油醚/乙酸乙酯(v/v)＝10/1)纯化，得到黄色固体(7mg,13.44％)。 1H NMR(400MHz,CDCl 3)δ7.93(dd,J＝8.2,1.1Hz,1H),7.60–7.50(m,1H),7.21(dd,J＝17.4,8.4Hz,2H),6.96(t,J＝8.0Hz,1H),4.55(s,2H),3.80(t,J＝6.3Hz,2H) Compound (3-D) (55mg, 0.16mmol), DCM (2mL), DMF (0.025mL) and thionyl chloride (0.025mL, 0.34mmol) were added to a single-necked flask and reacted at 40°C for 3h. Concentrate the reaction solution for later use. Aluminum chloride (64 mg, 0.48 mmol) and DCM (2 mL) were added to a single-neck flask, and the concentrated stock solution was added dropwise, and reacted at room temperature overnight. Water (10mL) was added to the reaction solution, extracted with DCM (10mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate). Ester (v/v)=10/1) was purified to obtain a yellow solid (7 mg, 13.44%). 1 H NMR (400MHz, CDCl 3 ) δ 7.93 (dd, J = 8.2, 1.1 Hz, 1H), 7.60-7.50 (m, 1H), 7.21 (dd, J = 17.4, 8.4 Hz, 2H), 6.96 ( t,J=8.0Hz,1H),4.55(s,2H),3.80(t,J=6.3Hz,2H)
步骤6)化合物(3-F)的合成Step 6) Synthesis of compound (3-F)
Figure PCTCN2020139363-appb-000051
Figure PCTCN2020139363-appb-000051
将化合物(3-E)(20mg,0.06mmol)、DCM(1mL)和MeOH(0.2mL)加入到单口瓶中，加入硼氢化钠(5mg,0.13mmol)，室温反应30min。向反应液中加水(5mL)，用DCM萃取(5mL×2)，合并有机相，有机相用饱和氯化钠溶液洗涤(5mL×3)，无水硫酸钠干燥后，减压浓缩，得淡黄色油状物(20mg,99.35％)。Compound (3-E) (20 mg, 0.06 mmol), DCM (1 mL) and MeOH (0.2 mL) were added to a single-necked flask, sodium borohydride (5 mg, 0.13 mmol) was added, and the reaction was carried out at room temperature for 30 min. Water (5mL) was added to the reaction solution, extracted with DCM (5mL×2), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (5mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain light. Yellow oil (20 mg, 99.35%).
步骤7)化合物(3-G)的合成Step 7) Synthesis of compound (3-G)
Figure PCTCN2020139363-appb-000052
Figure PCTCN2020139363-appb-000052
将化合物(3-F)(148.5mg,0.46mmol)、化合物(1-A)(164mg,0.5mmol)、T3P(0.82mL,1.4mmol)和EA(13mL)加入到微波管中，微波110℃反应1h。向反应液中加水(20mL)，用EA萃取(10mL×2)，合并有机相，用无水硫酸钠干燥后，过滤，滤液减压浓缩，所得残留物经硅胶柱层析分离(二氯甲烷/甲醇(v/v)＝15/1)纯化，得到淡黄色固体(170mg,58.68％)。Add compound (3-F) (148.5mg, 0.46mmol), compound (1-A) (164mg, 0.5mmol), T3P (0.82mL, 1.4mmol) and EA (13mL) into the microwave tube, microwave at 110°C Reaction for 1h. Water (20mL) was added to the reaction solution, extracted with EA (10mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (dichloromethane). /Methanol (v/v)=15/1) to obtain a pale yellow solid (170 mg, 58.68%).
MS(ESI,pos.ion)m/z:635.1[M+H] +。 MS (ESI, pos.ion) m/z: 635.1 [M+H] + .
步骤8)化合物(3-1)和化合物(3-2)的合成Step 8) Synthesis of compound (3-1) and compound (3-2)
Figure PCTCN2020139363-appb-000053
Figure PCTCN2020139363-appb-000053
将化合物(3-G)(170mg,0.27mmol)、DMAc(2mL)和氯化锂(114mg,2.69mmol)加入至单口瓶中，反应混合物升温至100℃反应2h。向反应液中加水(10mL)，用2M的盐酸溶液调pH值至6左右，用EA(10mL×2)萃取，合并有机相，用饱和氯化钠溶液洗涤(10mL×3)，无水硫酸钠干燥后，过滤，滤液浓缩后，所得残留物经LUNA制备柱纯化(洗脱剂为乙腈/0.1％三氟乙酸水溶液(v/v)＝12/13)，得到标题化合物为橙色固体(化合物(8-1):40mg,27.43％；化合物(8-2):52mg,35.66％)Compound (3-G) (170 mg, 0.27 mmol), DMAc (2 mL) and lithium chloride (114 mg, 2.69 mmol) were added to a single-neck flask, and the reaction mixture was heated to 100° C. for 2 h. Add water (10mL) to the reaction solution, adjust the pH to about 6 with 2M hydrochloric acid solution, extract with EA (10mL×2), combine the organic phases, wash with saturated sodium chloride solution (10mL×3), anhydrous sulfuric acid After the sodium was dried, filtered, and the filtrate was concentrated, the residue obtained was purified by a LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) to obtain the title compound as an orange solid (compound (8-1): 40mg, 27.43%; Compound (8-2): 52mg, 35.66%)
化合物(3-1)：Compound (3-1):
HRMS(ESI,pos.ion)m/z:545.1446[M+H] +； HRMS(ESI,pos.ion)m/z:545.1446[M+H] + ;
1H NMR(400MHz,CDCl 3)δ7.15–7.05(m,1H),6.95(dt,J＝22.0,7.8Hz,3H),6.60(dd,J＝7.9,3.7Hz,1H),6.51(d,J＝7.7Hz,1H),5.81(d,J＝7.7Hz,1H),5.58(d,J＝14.4Hz,1H),5.15(s,1H),4.72(dd,J＝9.8,2.7Hz,1H),4.67(d,J＝12.1Hz,1H),4.48(d,J＝15.1Hz,1H),3.97(dd,J＝10.8,2.5Hz,1H),3.83(dd,J＝11.8,2.8Hz,1H),3.75–3.66(m,1H),3.54(t,J＝10.4Hz,1H),3.44(dt,J＝22.3,12.6Hz,2H),3.00(dd,J＝17.7,7.5Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ7.15-7.05 (m, 1H), 6.95 (dt, J = 22.0, 7.8 Hz, 3H), 6.60 (dd, J = 7.9, 3.7 Hz, 1H), 6.51 ( d,J=7.7Hz,1H), 5.81(d,J=7.7Hz,1H), 5.58(d,J=14.4Hz,1H), 5.15(s,1H), 4.72(dd,J=9.8,2.7 Hz, 1H), 4.67 (d, J = 12.1 Hz, 1H), 4.48 (d, J = 15.1 Hz, 1H), 3.97 (dd, J = 10.8, 2.5 Hz, 1H), 3.83 (dd, J = 11.8 ,2.8Hz,1H),3.75–3.66(m,1H),3.54(t,J＝10.4Hz,1H), 3.44(dt,J＝22.3,12.6Hz,2H), 3.00(dd,J＝17.7, 7.5Hz, 1H).
化合物(3-2)：Compound (3-2):
HRMS(ESI,pos.ion)m/z:545.1446[M+H] +； HRMS(ESI,pos.ion)m/z:545.1446[M+H] + ;
1H NMR(400MHz,CDCl 3)δ7.20(dd,J＝16.8,8.4Hz,1H),7.12(d,J＝3.7Hz,1H),6.97(d,J＝8.0Hz,1H),6.82(d,J＝7.7Hz,1H),6.60(t,J＝7.9Hz,1H),6.30(d,J＝7.6Hz,1H),5.84(d,J＝7.7Hz,1H),5.71(d,J＝15.1Hz,1H),5.21(s,1H),4.66(d,J＝13.4Hz,1H),4.53–4.46(m,1H),4.42(d,J＝15.1Hz,1H),3.88(d,J＝10.9Hz,1H),3.84–3.76(m,1H),3.75–3.66(m,1H),3.61–3.52(m,1H),3.44(dd,J＝26.1,13.7Hz,2H),3.02–2.92(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ 7.20 (dd, J = 16.8, 8.4 Hz, 1H), 7.12 (d, J = 3.7 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.82 (d,J=7.7Hz,1H), 6.60(t,J=7.9Hz,1H), 6.30(d,J=7.6Hz,1H), 5.84(d,J=7.7Hz,1H), 5.71(d ,J＝15.1Hz,1H),5.21(s,1H),4.66(d,J＝13.4Hz,1H),4.53-4.46(m,1H),4.42(d,J＝15.1Hz,1H),3.88 (d,J=10.9Hz,1H),3.84–3.76(m,1H),3.75–3.66(m,1H),3.61–3.52(m,1H),3.44(dd,J=26.1,13.7Hz,2H ),3.02-2.92(m,1H).
实施例4:化合物(4-1)和化合物(4-2)的合成Example 4: Synthesis of compound (4-1) and compound (4-2)
Figure PCTCN2020139363-appb-000054
Figure PCTCN2020139363-appb-000054
步骤1)化合物(4-A)的合成Step 1) Synthesis of compound (4-A)
Figure PCTCN2020139363-appb-000055
Figure PCTCN2020139363-appb-000055
将吲哚-2-酮(10.23g,76.83mmol)和LiCl(10.75g,253.60mmol)混合于THF(60mL)中，置于-78℃下搅拌，然后量取n-BuLi(61mL,150mmol,2.5mol/L)缓慢滴加到上述反应液中，并在该温度下继续搅拌反应约1小时。然后加入碘甲烷(10.10mL,161mmol)，在该温度下继续搅拌反应约20分钟，然后转移到室温下继续搅拌反应过夜。停止反应，加入饱和氯化铵溶液(20mL)，乙酸乙酯(30mL×3)萃取，合并有机相，饱和食盐水(30mL)洗涤，无水硫酸铵干燥，减压浓缩，残留物经硅胶柱层析(PE/EA(v/v)＝5/1)分离提纯，得到标题化合物为白色固体(2.38g,19.2％)。MS(ESI,pos.ion)m/z:162.2[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm)8.91(s,1H),7.21(d,J＝7.5Hz,2H),7.06(t,J＝7.4Hz,1H),6.97(d,J＝7.6Hz,1H),1.43(s,6H). Indole-2-one (10.23g, 76.83mmol) and LiCl (10.75g, 253.60mmol) were mixed in THF (60mL), placed at -78℃ and stirred, and then n-BuLi (61mL, 150mmol, 2.5mol/L) was slowly added dropwise to the above reaction solution, and the reaction was continued to be stirred at this temperature for about 1 hour. Then add methyl iodide (10.10 mL, 161 mmol), continue to stir and react at this temperature for about 20 minutes, and then transfer to room temperature to continue stirring and react overnight. Stop the reaction, add saturated ammonium chloride solution (20mL), extract with ethyl acetate (30mL×3), combine the organic phases, wash with saturated brine (30mL), dry with anhydrous ammonium sulfate, and concentrate under reduced pressure. The residue is passed through a silica gel column Separation and purification by chromatography (PE/EA(v/v)=5/1) gave the title compound as a white solid (2.38 g, 19.2%). MS(ESI,pos.ion)m/z:162.2[M+H] + ; 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.91(s,1H),7.21(d,J=7.5Hz,2H ), 7.06 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 1.43 (s, 6H).
步骤2)化合物(4-B)的合成Step 2) Synthesis of compound (4-B)
Figure PCTCN2020139363-appb-000056
Figure PCTCN2020139363-appb-000056
将化合物(4-A)(2.25g,14.00mmol)、2-溴甲基-3,4-二氟苯甲酸乙酯(4.09g,14.70mmol)和K 2CO 3(3.86g,27.9mmol)混合于DMF(30mL)中，置于室温下搅拌反应过夜。停止反应，将反应液加入到水(15mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(15mL×3)洗涤，无水硫酸 钠干燥，减压浓缩，所得残留物经硅胶柱层析(PE/EA(v/v)＝5/1)分离提纯，得到标题化合物为浅黄色固体(3.65g,72.8％)。MS(ESI,pos.ion)m/z:360.1[M+H] +。 1H NMR(600MHz,CDCl 3)δ(ppm)7.70(ddd,J＝8.6,4.9,1.4Hz,1H),7.23–7.18(m,1H),7.17–7.11(m,2H),7.02(t,J＝7.5Hz,1H),6.77(d,J＝7.8Hz,1H),5.45(s,2H),4.41(q,J＝7.1Hz,2H),1.42(t,J＝7.1Hz,3H),1.40(s,6H). The compound (4-A) (2.25g, 14.00mmol), ethyl 2-bromomethyl-3,4-difluorobenzoate (4.09g, 14.70mmol) and K 2 CO 3 (3.86g, 27.9mmol) The mixture was mixed in DMF (30 mL), and the reaction was stirred overnight at room temperature. Stop the reaction, add the reaction solution to water (15mL), extract with ethyl acetate (20mL×3), combine the organic phases, wash the organic phase with saturated brine (15mL×3), dry with anhydrous sodium sulfate, and reduce pressure After concentration, the obtained residue was separated and purified by silica gel column chromatography (PE/EA(v/v)=5/1) to obtain the title compound as a pale yellow solid (3.65 g, 72.8%). MS (ESI, pos.ion) m/z: 360.1 [M+H] + . 1 H NMR (600MHz, CDCl 3 ) δ (ppm) 7.70 (ddd, J = 8.6, 4.9, 1.4 Hz, 1H), 7.23-7.18 (m, 1H), 7.17-7.11 (m, 2H), 7.02 (t ,J=7.5Hz,1H),6.77(d,J=7.8Hz,1H),5.45(s,2H),4.41(q,J=7.1Hz,2H),1.42(t,J=7.1Hz,3H ), 1.40(s, 6H).
步骤3)化合物(4-C)的合成Step 3) Synthesis of compound (4-C)
Figure PCTCN2020139363-appb-000057
Figure PCTCN2020139363-appb-000057
将化合物(4-B)(3.24g,9.02mmol)和劳森试剂(2.26g,5.42mmol)混合于甲苯(50mL)中，氮气保护，置于100℃油浴锅中加热反应过夜。停止反应，减压浓缩，所得残留物经硅胶柱层析(PE/EA(v/v)＝4/1)法分离提纯得到黄色油状液体为标题化合物(3.24g,95.7％)。MS(ESI,pos.ion)m/z:376.1[M+H] +；1H NMR(400MHz,CDCl 3)δ(ppm)7.76(ddd,J＝8.7,5.0,1.8Hz,1H),7.35–7.30(m,1H),7.23(td,J＝7.7,1.2Hz,1H),7.20–7.11(m,2H),6.97(d,J＝7.8Hz,1H),5.98(s,2H),4.43(q,J＝7.1Hz,2H),1.51–1.39(m,9H). Compound (4-B) (3.24 g, 9.02 mmol) and Lawson's reagent (2.26 g, 5.42 mmol) were mixed in toluene (50 mL), protected by nitrogen, and heated in an oil bath at 100°C for overnight reaction. The reaction was stopped and concentrated under reduced pressure. The residue obtained was separated and purified by silica gel column chromatography (PE/EA(v/v)=4/1) to obtain a yellow oily liquid as the title compound (3.24 g, 95.7%). MS(ESI,pos.ion)m/z:376.1[M+H] + ;1H NMR(400MHz,CDCl 3 )δ(ppm)7.76(ddd,J=8.7,5.0,1.8Hz,1H),7.35– 7.30 (m, 1H), 7.23 (td, J = 7.7, 1.2 Hz, 1H), 7.20-7.11 (m, 2H), 6.97 (d, J = 7.8 Hz, 1H), 5.98 (s, 2H), 4.43 (q,J=7.1Hz,2H), 1.51-1.39(m,9H).
步骤4)化合物(4-D)的合成Step 4) Synthesis of compound (4-D)
Figure PCTCN2020139363-appb-000058
Figure PCTCN2020139363-appb-000058
将化合物(4-C)(3.24g,8.63mmol)溶解于乙醇(30mL)中，再加入氢氧化钠(690mg,17.30mmol)的水(6mL)溶液。反应混合物置于室温下进行反应约1小时。停止反应，用1M稀盐酸调节PH约为5，然后用乙酸乙酯(25mL×3)萃取，合并有机相，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压浓缩，所得残留物经硅胶柱层析(PE/EA(v/v)＝1/1)分离提纯，，得到淡黄色固体为标题化合物(2.50g,83.4％)。MS(ESI,pos.ion)m/z:346.1[M-H] -。 Compound (4-C) (3.24 g, 8.63 mmol) was dissolved in ethanol (30 mL), and a solution of sodium hydroxide (690 mg, 17.30 mmol) in water (6 mL) was added. The reaction mixture was left at room temperature and reacted for about 1 hour. Stop the reaction, adjust the pH to about 5 with 1M dilute hydrochloric acid, then extract with ethyl acetate (25mL×3), combine the organic phases, wash with saturated brine (30mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a residue After separation and purification by silica gel column chromatography (PE/EA(v/v)=1/1), a pale yellow solid was obtained as the title compound (2.50 g, 83.4%). MS (ESI, pos.ion) m/z: 346.1 [MH] - .
步骤5)化合物(4-E)的合成Step 5) Synthesis of compound (4-E)
Figure PCTCN2020139363-appb-000059
Figure PCTCN2020139363-appb-000059
将化合物(4-D)(1.38g,3.97mmol)溶于PPA(3mL,84mass％)和氯苯(3mL)中，置于140℃油浴锅中加热反应过夜。停止反应，向反应液中加入冰水(15mL)，然后用乙酸乙酯(20mL×3)萃取，合并有机相，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，减压浓缩，所得残留物经硅胶柱层析(PE/EA(v/v)＝15/1)分离提纯，得到产物为黄色固体(1.10g,84.1％)。 1H NMR(400MHz,CDCl 3)δ(ppm)7.99(d,J＝8.0Hz,1H),7.61–7.55(m,1H),7.51(d,J＝7.2Hz,1H),7.33–7.28(m,2H),5.71(s,2H),1.50(s,6H). Compound (4-D) (1.38 g, 3.97 mmol) was dissolved in PPA (3 mL, 84 mass%) and chlorobenzene (3 mL), and heated in an oil bath at 140°C for overnight reaction. The reaction was stopped, ice water (15mL) was added to the reaction solution, and then extracted with ethyl acetate (20mL×3), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue obtained The product was separated and purified by silica gel column chromatography (PE/EA(v/v)=15/1) to obtain the product as a yellow solid (1.10g, 84.1%). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.99 (d, J = 8.0 Hz, 1H), 7.61-7.55 (m, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.33-7.28 ( m, 2H), 5.71 (s, 2H), 1.50 (s, 6H).
步骤6)化合物(4-F)的合成Step 6) Synthesis of compound (4-F)
Figure PCTCN2020139363-appb-000060
Figure PCTCN2020139363-appb-000060
将化合物(4-E)(1.11g,3.37mmol)溶解于MeOH(5mL)和THF(5mL)中，置于室温下及搅拌下加入硼氢化钠(266mg,6.75mmol)。反应混合物于室温下搅拌反应约20分钟。停止反应，向其中加入饱和氯化铵溶液(20mL)，然后用乙酸乙酯(25mL×3)萃取，合并有机相，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压浓缩，得到标题化合物为浅黄色固体，直接用于下一步反应。MS(ESI,pos.ion)m/z:332.0[M+H] +。 Compound (4-E) (1.11 g, 3.37 mmol) was dissolved in MeOH (5 mL) and THF (5 mL), and sodium borohydride (266 mg, 6.75 mmol) was added while stirring at room temperature. The reaction mixture was stirred at room temperature for about 20 minutes. The reaction was stopped, saturated ammonium chloride solution (20 mL) was added, and then extracted with ethyl acetate (25 mL×3), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain The title compound was a pale yellow solid and was used directly in the next reaction. MS (ESI, pos.ion) m/z: 332.0 [M+H] + .
步骤7)化合物(4-G)的合成Step 7) Synthesis of compound (4-G)
Figure PCTCN2020139363-appb-000061
Figure PCTCN2020139363-appb-000061
将化合物(4-F)(500mg,1.51mmol)和化合物(1-A)(543mg,1.66mmol)混合于乙酸乙酯(30mL)中，再向其中加入T3P(5.42mL,9.05mmol,1.67mol/L)，置于110℃油浴锅中封管加热反应约2小时。停止反应，向反应液中加入饱和碳酸氢钠溶液(20mL)，然后用乙酸乙酯(30mL×3)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压浓缩，所得残留物通过硅胶柱层析(DCM/MeOH(v/v)＝15/1)分离提纯，得到标题化合物为黄褐色固体(371mg,38％)。MS(ESI,pos.ion)m/z:641.2[M+H] +。 Compound (4-F) (500mg, 1.51mmol) and compound (1-A) (543mg, 1.66mmol) were mixed in ethyl acetate (30mL), and then T3P (5.42mL, 9.05mmol, 1.67mol) /L), place the tube in an oil bath at 110°C and heat the reaction for about 2 hours. The reaction was stopped, saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, and then extracted with ethyl acetate (30 mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (30 mL) and dried with anhydrous sodium sulfate. It was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (DCM/MeOH(v/v)=15/1) to obtain the title compound as a yellow-brown solid (371 mg, 38%). MS (ESI, pos.ion) m/z: 641.2 [M+H] + .
步骤8)化合物(4-1)和化合物(4-2)的合成Step 8) Synthesis of compound (4-1) and compound (4-2)
Figure PCTCN2020139363-appb-000062
Figure PCTCN2020139363-appb-000062
将化合物(4-G)(344mg,0.54mmol)和氯化锂(227mg,5.37mmol)混合于DMAc(3mL)中，氮气保护，并置于110℃条件下进行搅拌反应约3小时。将反应液加水(10mL)淬灭反应，然后用0.5M HCl加入其中，使得反应呈弱酸性，搅拌10分钟，然后用乙酸乙酯(20mL×3)萃取。合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压浓缩，所得残留物经LUNA制备柱(乙腈/0.1％三氟乙酸水溶液(v/v)＝12/13)分离纯化，得到标题化合物(4-1)为淡黄色固体(48mg,16％)；化合物(4-2)为淡黄色固体(18mg,6％)。Compound (4-G) (344 mg, 0.54 mmol) and lithium chloride (227 mg, 5.37 mmol) were mixed in DMAc (3 mL), protected by nitrogen, and placed at 110° C. for a stirring reaction for about 3 hours. The reaction solution was quenched by adding water (10 mL), and then 0.5M HCl was added to it to make the reaction weakly acidic, stirred for 10 minutes, and then extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to a LUNA preparation column (acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13 ) Isolation and purification to obtain the title compound (4-1) as a pale yellow solid (48 mg, 16%); compound (4-2) as a pale yellow solid (18 mg, 6%).
化合物(4-1)：Compound (4-1):
HRMS(ESI,pos.ion)m/z:551.1561[M+H] +； HRMS(ESI,pos.ion)m/z:551.1561[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.58–7.43(m,3H),7.10(d,J＝7.6Hz,1H),6.93(t,J＝7.5Hz,1H),6.81(d,J＝7.5Hz,1H),6.62(d,J＝15.0Hz,1H),5.80(s,1H),5.73(s,1H),5.58(d,J＝14.8Hz,1H),5.44(d,J＝7.5Hz,1H),4.47(d,J＝11.1Hz,2H),3.94(d,J＝8.3Hz,1H),3.71(s,2H),3.09–3.01(m,1H),1.41(s,3H),1.27(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm) 7.58–7.43 (m, 3H), 7.10 (d, J = 7.6 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.81 ( d,J=7.5Hz,1H), 6.62(d,J=15.0Hz,1H), 5.80(s,1H), 5.73(s,1H), 5.58(d,J=14.8Hz,1H), 5.44( d, J = 7.5Hz, 1H), 4.47 (d, J = 11.1Hz, 2H), 3.94 (d, J = 8.3Hz, 1H), 3.71 (s, 2H), 3.09–3.01 (m, 1H), 1.41(s,3H), 1.27(s,3H).
化合物(4-2)：Compound (4-2):
HRMS(ESI,pos.ion)m/z:551.1553[M+H] +； HRMS(ESI,pos.ion)m/z:551.1553[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.60(d,J＝7.3Hz,1H),7.38–7.14(m,3H),6.87–6.70(m,2H),6.62(d,J＝14.8Hz,1H),5.60(d,J＝13.1Hz,1H),5.47(s,1H),5.35–5.23(m,1H),4.49(s,1H),4.28(d,J＝9.0Hz,1H),3.95–3.85(m,1H),3.71–3.59(m,2H),3.23(m,2H),1.25(d,J＝13.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.60 (d, J = 7.3Hz, 1H), 7.38-7.14 (m, 3H), 6.87-6.70 (m, 2H), 6.62 (d, J = 14.8 Hz, 1H), 5.60 (d, J = 13.1 Hz, 1H), 5.47 (s, 1H), 5.35-5.23 (m, 1H), 4.49 (s, 1H), 4.28 (d, J = 9.0 Hz, 1H ), 3.95–3.85(m,1H), 3.71–3.59(m,2H), 3.23(m,2H), 1.25(d,J=13.8Hz,6H).
实施例5：化合物(5-1)和化合物(5-2)的合成Example 5: Synthesis of compound (5-1) and compound (5-2)
Figure PCTCN2020139363-appb-000063
Figure PCTCN2020139363-appb-000063
步骤1)化合物(5-A)的合成Step 1) Synthesis of compound (5-A)
Figure PCTCN2020139363-appb-000064
Figure PCTCN2020139363-appb-000064
将化合物2H-苯并[b][1,4]噁嗪-3(4H)-酮(1.5g,10mmol)和DMF(20mL)加入到单口瓶中，冰浴下缓慢加入氢化钠(600mg,15mmol)，搅拌20min后，滴加2-(溴甲基)-3,4-二氟苯甲酸乙酯(3.4g,12mmol)，室温反应2h。向反应液中加入水(50mL)，用乙酸乙酯(50mL×2)萃取，合并有机相，有机相用用饱和氯化钠水溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗产物用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯(v/v)＝5/1)纯化，得到标题化合物为白色固体(2.64g,76％)。 1H NMR(400MHz,CDCl 3)δ7.67(ddd,J＝8.6,5.0,1.8Hz,1H),7.11(dd,J＝16.6,8.8Hz,1H),7.02–6.87(m,4H),5.68(s,2H),4.62(s,2H),4.39(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H). The compound 2H-benzo[b][1,4]oxazine-3(4H)-one (1.5g, 10mmol) and DMF (20mL) were added to the single-neck flask, and sodium hydride (600mg, 15mmol), after stirring for 20min, ethyl 2-(bromomethyl)-3,4-difluorobenzoate (3.4g, 12mmol) was added dropwise and reacted at room temperature for 2h. Water (50mL) was added to the reaction solution, extracted with ethyl acetate (50mL×2), the organic phases were combined, and the organic phase was washed with saturated sodium chloride aqueous solution (30mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=5/1) to obtain the title compound as a white solid (2.64 g, 76%). 1 H NMR (400MHz, CDCl 3 ) δ 7.67 (ddd, J = 8.6, 5.0, 1.8 Hz, 1H), 7.11 (dd, J = 16.6, 8.8 Hz, 1H), 7.02-6.87 (m, 4H), 5.68 (s, 2H), 4.62 (s, 2H), 4.39 (q, J = 7.1Hz, 2H), 1.40 (t, J = 7.1Hz, 3H).
步骤2)化合物(5-B)的合成Step 2) Synthesis of compound (5-B)
Figure PCTCN2020139363-appb-000065
Figure PCTCN2020139363-appb-000065
将化合物化合物(5-A)(2.55g,7.34mmol)加入到单口瓶中，然后加入四氢呋喃(20mL)和甲醇(10mL)，室温下滴加2M的氢氧化钠溶液(7.5mL)，室温反应1h。减压旋掉有机溶剂，残留物加水(20mL)稀释，用4M的盐酸调pH值至4左右，然后用EA(30mL×2)萃取，合并有机相，有机相用饱和氯化钠水溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为淡黄色固体(2.33g,99.4％)。MS(ESI,neg.ion)m/z:318.1[M-H] -。 Compound compound (5-A) (2.55g, 7.34mmol) was added to a single-necked flask, then tetrahydrofuran (20mL) and methanol (10mL) were added, 2M sodium hydroxide solution (7.5mL) was added dropwise at room temperature, and the reaction was carried out at room temperature. 1h. The organic solvent was spun off under reduced pressure, the residue was diluted with water (20mL), the pH was adjusted to about 4 with 4M hydrochloric acid, and then extracted with EA (30mL×2), the organic phases were combined, and the organic phase was saturated with aqueous sodium chloride solution (30mL ) Wash, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound as a pale yellow solid (2.33 g, 99.4%). MS (ESI, neg.ion) m/z: 318.1 [MH] - .
步骤3)化合物(5-C)的合成Step 3) Synthesis of compound (5-C)
Figure PCTCN2020139363-appb-000066
Figure PCTCN2020139363-appb-000066
将化合物化合物(5-B)(1g,3.13mmol)加入至单口瓶中，然后加入PPA(15mL)，升温至120℃反应2h。将反应冷却至室温后，向反应液中加冰水(50mL)，然后用乙酸乙酯(50mL×2)萃取，合并有机相，用饱和碳酸氢钠溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗产物用硅胶柱层析(洗脱剂为石油醚/乙酸乙酯(v/v)＝5/1)纯化，得到标题化合物为黄色固体(778mg,82.48％)。 1H NMR (400MHz,CDCl 3)δ8.04(dd,J＝8.1,1.5Hz,1H),7.56(ddd,J＝8.6,4.7,1.6Hz,1H),7.30–7.17(m,3H),5.22(s,2H),4.60(s,2H). The compound compound (5-B) (1 g, 3.13 mmol) was added to a single-neck flask, and then PPA (15 mL) was added, and the temperature was raised to 120° C. for reaction for 2 h. After the reaction was cooled to room temperature, ice water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with saturated sodium bicarbonate solution (30 mL×3), and anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=5/1) to obtain the title compound as a yellow solid (778mg, 82.48%). 1 H NMR (400MHz, CDCl 3 ) δ8.04 (dd, J = 8.1, 1.5 Hz, 1H), 7.56 (ddd, J = 8.6, 4.7, 1.6 Hz, 1H), 7.30-7.17 (m, 3H), 5.22(s, 2H), 4.60(s, 2H).
步骤4)化合物(5-D)的合成Step 4) Synthesis of compound (5-D)
Figure PCTCN2020139363-appb-000067
Figure PCTCN2020139363-appb-000067
将化合物化合物(5-C)(937mg,3.11mmol)加入到单口瓶中，加入THF(10mL)和MeOH(1mL)，缓慢加入硼氢化钠(180mg,4.661mmol)，室温反应15min。加入饱和氯化铵溶液(10mL)淬灭反应，然后用EA萃取(20mL×2)，合并有机相。有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为淡黄色固体(938mg,99.41％)。Compound compound (5-C) (937 mg, 3.11 mmol) was added to a single-necked flask, THF (10 mL) and MeOH (1 mL) were added, sodium borohydride (180 mg, 4.661 mmol) was slowly added, and the reaction was carried out at room temperature for 15 min. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), then extracted with EA (20 mL×2), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a pale yellow solid (938 mg, 99.41%).
步骤5)化合物(5-E)的合成Step 5) Synthesis of compound (5-E)
Figure PCTCN2020139363-appb-000068
Figure PCTCN2020139363-appb-000068
将化合物化合物(5-D)(880mg,2.90mmol)、化合物(1-A)(522mg,1.595mmol)加入到微波管中，然后加入乙酸乙酯(34mL)和1-丙基磷酸酐(5.18mL,8.7mmol)，反应混合物于微波110℃反应40min。向反应液中加水(20mL)，然后用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和碳酸氢钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗产物用硅胶柱层析(洗脱剂为二氯甲烷/甲醇(v/v)＝20/1)纯化，得到标题化合物为棕色固体(670mg,37.7％)。MS(ESI,pos.ion)m/z:613.2[M+H] +。 The compound compound (5-D) (880mg, 2.90mmol), compound (1-A) (522mg, 1.595mmol) were added to the microwave tube, and then ethyl acetate (34mL) and 1-propyl phosphoric anhydride (5.18 mL, 8.7 mmol), the reaction mixture was reacted in a microwave at 110°C for 40 min. Water (20mL) was added to the reaction solution, and then extracted with ethyl acetate (20mL×2). The organic phases were combined, washed with saturated sodium bicarbonate solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain the title compound as a brown solid (670 mg, 37.7%). MS (ESI, pos.ion) m/z: 613.2 [M+H] + .
步骤6)化合物(5-1)和化合物(5-2)的合成Step 6) Synthesis of compound (5-1) and compound (5-2)
Figure PCTCN2020139363-appb-000069
Figure PCTCN2020139363-appb-000069
将化合物(5-E)(450mg,0.7346mmol)和氯化锂(311mg,7.337mmol)加入至单口瓶中，再加入N,N-二乙基乙酰胺(5mL)，氮气保护，升温至100℃反应6h，加水(20mL)，用1M稀盐酸调节pH至6左右，用EA(20mL×3)萃取，合并有机相，有机相用饱和氯化钠溶液(20mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经LUNA制备柱纯化(洗脱剂为乙腈/0.1％三氟乙酸水溶液(v/v)＝12/13)，得到标题化合物为橙色固体(化合物(5-1)：30mg,7.8％；化合物(5-1):35mg,9.12％)。Add compound (5-E) (450mg, 0.7346mmol) and lithium chloride (311mg, 7.337mmol) into a single-neck flask, then add N,N-diethylacetamide (5mL), protect with nitrogen, and heat to 100 React at ℃ for 6h, add water (20mL), adjust the pH to about 6 with 1M dilute hydrochloric acid, extract with EA (20mL×3), combine the organic phases, wash the organic phase with saturated sodium chloride solution (20mL×3), anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) to obtain the title compound as an orange solid (compound (5-1): 30 mg, 7.8%; Compound (5-1): 35 mg, 9.12%).
化合物(5-1)：Compound (5-1):
HRMS(ESI,pos.ion)m/z:523.1414[M+H] +； HRMS(ESI,pos.ion)m/z:523.1414[M+H] + ;
1H NMR(600MHz,CDCl 3)δ7.18(d,J＝7.1Hz,1H),7.15–7.04(m,2H),6.98(dd,J＝16.2,8.1Hz,1H),6.61(s,1H),6.45(d,J＝7.5Hz,1H),6.33(d,J＝14.3Hz,1H),5.80(d,J＝7.5Hz,1H),5.23(s,1H),5.13(d,J＝14.2Hz,1H),4.75(d,J＝15.3Hz,1H),4.72–4.61(m,2H),4.38(d,J＝15.3Hz,1H),3.95(d,J＝10.6Hz,1H),3.83(d,J＝11.5Hz,1H),3.58–3.51(m,1H),3.50–3.43(m,1H),3.03–2.96(m,1H). 1 H NMR (600MHz, CDCl 3 ) δ7.18 (d, J = 7.1Hz, 1H), 7.15-7.04 (m, 2H), 6.98 (dd, J = 16.2, 8.1 Hz, 1H), 6.61 (s, 1H), 6.45 (d, J = 7.5 Hz, 1H), 6.33 (d, J = 14.3 Hz, 1H), 5.80 (d, J = 7.5 Hz, 1H), 5.23 (s, 1H), 5.13 (d, J = 14.2 Hz, 1H), 4.75 (d, J = 15.3 Hz, 1H), 4.72-4.61 (m, 2H), 4.38 (d, J = 15.3 Hz, 1H), 3.95 (d, J = 10.6 Hz, 1H), 3.83(d,J=11.5Hz,1H), 3.58–3.51(m,1H), 3.50–3.43(m,1H), 3.03–2.96(m,1H).
化合物(5-2)：Compound (5-2):
HRMS(ESI,pos.ion)m/z:523.1446[M+H] +； HRMS(ESI,pos.ion)m/z:523.1446[M+H] + ;
1H NMR(600MHz,CDCl 3)δ7.21(m,1H),7.11(dd,J＝8.0,3.7Hz,1H),7.03(d,J＝7.9Hz,1H),6.78(t,J＝7.9Hz,1H),6.74(d,J＝7.7Hz,1H),6.35(d,J＝7.7Hz,1H),6.29(d,J＝14.4Hz,1H),5.82(d,J＝7.7Hz,1H),5.31(s,1H),5.23(d,J＝14.3Hz,1H),4.69(d,J＝15.3Hz,1H),4.66(d,J＝13.5Hz,1H),4.40(dd,J＝9.8,2.7Hz,1H),4.37(d,J＝15.3Hz,1H),3.87(dd,J＝11.1,2.5Hz,1H),3.80(dd,J＝12.0,2.9Hz,1H),3.52(t,J＝10.5Hz,1H),3.45(m,1H),2.99–2.93(m,1H). 1 H NMR(600MHz, CDCl 3 )δ7.21(m,1H), 7.11(dd,J=8.0,3.7Hz,1H), 7.03(d,J=7.9Hz,1H), 6.78(t,J= 7.9Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 6.35 (d, J = 7.7 Hz, 1H), 6.29 (d, J = 14.4 Hz, 1H), 5.82 (d, J = 7.7 Hz ,1H), 5.31(s,1H), 5.23(d,J=14.3Hz,1H), 4.69(d,J=15.3Hz,1H), 4.66(d,J=13.5Hz,1H), 4.40(dd ,J=9.8,2.7Hz,1H), 4.37(d,J=15.3Hz,1H), 3.87(dd,J=11.1,2.5Hz,1H), 3.80(dd,J=12.0,2.9Hz,1H) ,3.52(t,J=10.5Hz,1H), 3.45(m,1H), 2.99–2.93(m,1H).
实施例6:化合物(6-1)和化合物(6-2)的合成Example 6: Synthesis of compound (6-1) and compound (6-2)
Figure PCTCN2020139363-appb-000070
Figure PCTCN2020139363-appb-000070
步骤1)化合物(6-A)的合成Step 1) Synthesis of compound (6-A)
Figure PCTCN2020139363-appb-000071
Figure PCTCN2020139363-appb-000071
氮气保护及-20℃下，依次将氧化吲哚(3.02g,22.53mmol)和干燥的四氢呋喃(30mL)加入反应瓶中，然后滴加二异丙胺(6.1mL,47mmol)和正丁基锂(29mL,44mmol)，在零度下反应1h，然后，零度下再加入1,2-二溴乙烷(12.69g,67.55mmol)，反应混合物转移至室温反应22h。停止反应，加入饱和食盐水溶液(50mL)淬灭反应，最后用乙酸乙酯(50mL×4)萃取，合并有机相。有机相用无水硫酸钠干燥，减压浓缩，得到标题化合物粗产品为黄色固体(3.39g,92％)。MS(ESI,pos.ion)m/z:160.1[M+H] +。 Under nitrogen protection and at -20℃, indole oxide (3.02g, 22.53mmol) and dry tetrahydrofuran (30mL) were added to the reaction flask, and then diisopropylamine (6.1mL, 47mmol) and n-butyllithium (29mL) were added dropwise. , 44mmol), react at zero for 1h, then add 1,2-dibromoethane (12.69g, 67.55mmol) at zero, and transfer the reaction mixture to room temperature for 22h. The reaction was stopped, and saturated aqueous sodium chloride solution (50 mL) was added to quench the reaction, and finally extracted with ethyl acetate (50 mL×4), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product of the title compound as a yellow solid (3.39 g, 92%). MS (ESI, pos.ion) m/z: 160.1 [M+H] + .
步骤2)化合物(6-B)的合成Step 2) Synthesis of compound (6-B)
Figure PCTCN2020139363-appb-000072
Figure PCTCN2020139363-appb-000072
将化合物(6-A)(1.45g,8.80mmol)和2-(溴甲基)-3,4-二氟苯甲酸乙酯(2.51g,8.99mmol)溶于N,N-二甲基甲酰胺(20mL)中，随后向反应液中加入氟化铯(6.02g,17.60mmol)，室温搅拌，TLC板监测反应完全后，停止反应，将反应溶液加入到水(100mL)中，用乙酸乙酯(50mL×3)萃取，合并有机相，有机相用无水硫酸钠干燥，减压浓缩，所得残留物经硅胶柱层析(PE/EA(v/v)＝10/1)纯化，得到标题化合物为黄色固体(2.98g,91％)。 1H NMR(400MHz,CDCl 3)δ(ppm)＝7.82-7.57(m,1H),7.22–7.07(m,2H),7.00(t,J＝7.5Hz,1H),6.86(dd,J＝20.9,7.5Hz,2H),5.51(s,2H),4.46–4.36(m,2H),1.80-1.70(m,2H),1.58-1.47(m,2H),1.41(t,J＝7.1Hz,3H).。 Compound (6-A) (1.45g, 8.80mmol) and ethyl 2-(bromomethyl)-3,4-difluorobenzoate (2.51g, 8.99mmol) were dissolved in N,N-dimethylform Then add cesium fluoride (6.02g, 17.60mmol) to the reaction solution and stir at room temperature. After the completion of the reaction is monitored by TLC plate, the reaction is stopped, the reaction solution is added to water (100mL), and ethyl acetate is added. Ester (50mL×3) was extracted, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (PE/EA(v/v)=10/1) to obtain The title compound was a yellow solid (2.98 g, 91%). 1 H NMR(400MHz, CDCl 3 )δ(ppm)=7.82-7.57(m,1H), 7.22-7.07(m,2H), 7.00(t,J=7.5Hz,1H), 6.86(dd,J= 20.9,7.5Hz,2H),5.51(s,2H),4.46-4.36(m,2H),1.80-1.70(m,2H),1.58-1.47(m,2H),1.41(t,J=7.1Hz ,3H)..
步骤3)化合物(6-C)的合成Step 3) Synthesis of compound (6-C)
Figure PCTCN2020139363-appb-000073
Figure PCTCN2020139363-appb-000073
将化合物(6-B)(2.98g,8.34mmol)溶于四氢呋喃(10mL)和甲醇(10mL)中，室温搅拌，将氢氧化钠(1.35g,33.40mmol)溶于水(5mL)中，加至上述反应液中，室温搅拌1h，用1M稀盐酸调节pH至6左右，分液，水相用乙酸乙酯(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为黄色固体(2.68g,97％)。MS(ESI,pos.ion)m/z:330.1[M+H] +。 Compound (6-B) (2.98g, 8.34mmol) was dissolved in tetrahydrofuran (10mL) and methanol (10mL), stirred at room temperature, sodium hydroxide (1.35g, 33.40mmol) was dissolved in water (5mL) and added Into the above reaction solution, stir at room temperature for 1 hour, adjust the pH to about 6 with 1M dilute hydrochloric acid, separate the layers, extract the aqueous phase with ethyl acetate (30mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and reduce the filtrate. It was concentrated under pressure to obtain the title compound as a yellow solid (2.68 g, 97%). MS (ESI, pos.ion) m/z: 330.1 [M+H] + .
步骤4)化合物(6-D)的合成Step 4) Synthesis of compound (6-D)
Figure PCTCN2020139363-appb-000074
Figure PCTCN2020139363-appb-000074
将化合物(6-C)(3.01g,9.11mmol)溶于多聚磷酸(10mL)中，在110度下搅拌反应1h，停止反应，冷却至室温，将反应液加入到冰水(10mL)中，乙酸乙酯(50mL×3)萃取，合并有机相，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压浓缩，所得残留物经硅胶柱层析(PE/EA(v/v)＝1/1)纯化，得到标题化合物为黄色固体(650.2mg,23％)。 1H NMR(400MHz,CDCl 3)δ(ppm):7.92(d,J＝8.1Hz,1H),7.65–7.53(m,1H),7.27–7.19(m,1H),7.17(t,J＝7.7Hz,1H),7.04(d,J＝7.2Hz,1H),5.19(d,J＝15.7Hz,2H),1.96–1.83(m,2H),1.64(dd,J＝7.9,4.2Hz,2H). Dissolve compound (6-C) (3.01g, 9.11mmol) in polyphosphoric acid (10mL), stir the reaction at 110°C for 1h, stop the reaction, cool to room temperature, add the reaction solution to ice water (10mL) , Extracted with ethyl acetate (50mL×3), combined the organic phases, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (PE/EA(v/v) = 1/1) Purification to obtain the title compound as a yellow solid (650.2 mg, 23%). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.92 (d, J = 8.1 Hz, 1H), 7.65-7.53 (m, 1H), 7.27-7.19 (m, 1H), 7.17 (t, J = 7.7Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 5.19 (d, J = 15.7 Hz, 2H), 1.96-1.83 (m, 2H), 1.64 (dd, J = 7.9, 4.2 Hz, 2H).
步骤5)化合物(6-E)的合成Step 5) Synthesis of compound (6-E)
Figure PCTCN2020139363-appb-000075
Figure PCTCN2020139363-appb-000075
将化合物(6-D)(572.2mg,1.83mmol)溶于THF(10mL)和甲醇(10mL)中，冷却至0℃，加入硼氢化钠(107.2mg,2.74mmol)，加完后0℃反应15分钟，停止反应，加入到饱和氯化铵溶液(15mL)中，随后用乙酸乙酯(15mL×3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，得到标题化合物为黄色色固体(565.1mg,92％)。MS(ESI,pos.ion)m/z:314.1[M+H] +； 1H NMR(400MHz,CDCl 3)δ(ppm):7.23(d,J＝7.7Hz,1H),7.08(dt,J＝9.2,8.0Hz,2H),7.00(dd,J＝14.7,7.1Hz,1H),6.79(d,J＝7.4Hz,1H),5.83–5.63(m,2H),5.27(d,J＝14.5Hz,1H),1.83–1.69(m,2H),1.55–1.44(m,2H). Compound (6-D) (572.2mg, 1.83mmol) was dissolved in THF (10mL) and methanol (10mL), cooled to 0°C, sodium borohydride (107.2mg, 2.74mmol) was added, and the reaction was done at 0°C. After 15 minutes, the reaction was stopped, and it was added to saturated ammonium chloride solution (15 mL), followed by extraction with ethyl acetate (15 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a yellow color. Solid (565.1 mg, 92%). MS (ESI, pos.ion) m/z: 314.1 [M+H] + ; 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.23 (d, J = 7.7 Hz, 1H), 7.08 (dt, J = 9.2, 8.0 Hz, 2H), 7.00 (dd, J = 14.7, 7.1 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 5.83-5.63 (m, 2H), 5.27 (d, J = 14.5Hz, 1H), 1.83-1.69 (m, 2H), 1.55-1.44 (m, 2H).
步骤6)化合物(6-F)的合成Step 6) Synthesis of compound (6-F)
Figure PCTCN2020139363-appb-000076
Figure PCTCN2020139363-appb-000076
将化合物(6-E)(501.2mg,1.59mmol)和化合物(1-A)(574.3mg,1.75mmol)加入到微波反应管中，加入1-丙基磷酸酐(50％的乙酸乙酯溶液，5.7mL，9.6mmol)和乙酸乙酯(5mL)，微波110℃反应2小时，停止反应，向反应体系中加入饱和碳酸氢钠溶液(10mL)，乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析(二氯甲烷/甲醇(v/v)＝15/1)纯化，得到标题化合物为白色固体(0.47g,47％)。MS(ESI,pos.ion)m/z:623.3[M+H] +。 Add compound (6-E) (501.2 mg, 1.59 mmol) and compound (1-A) (574.3 mg, 1.75 mmol) into the microwave reaction tube, add 1-propyl phosphoric anhydride (50% ethyl acetate solution) , 5.7mL, 9.6mmol) and ethyl acetate (5mL), react at 110℃ in microwave for 2 hours, stop the reaction, add saturated sodium bicarbonate solution (10mL) to the reaction system, extract with ethyl acetate (10mL×3), and combine The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=15/1) to obtain the title compound as a white solid (0.47g) ,47%). MS (ESI, pos.ion) m/z: 623.3 [M+H] + .
步骤7)化合物(6-1)和化合物(6-2)的合成Step 7) Synthesis of compound (6-1) and compound (6-2)
Figure PCTCN2020139363-appb-000077
Figure PCTCN2020139363-appb-000077
将化合物(6-F)(0.47mg,0.75mmol)溶于N,N-二甲基乙酰胺(10mL)中，加入氯化锂(0.33g,7.7mmol)，反应混合物于110℃反应5小时，停止反应，加入2M盐酸调节pH＝6-7，然后，乙酸乙酯(10mL×3)萃取，饱和氯化钠(10mL×3)洗涤，所得残留物经LUNA制备柱(洗脱剂为乙腈/0.1％三氟乙酸水溶液(v/v)＝12/13)纯化，得到标题化合物为黄色固体(化合物(6-1)：15.5mg,3.85％；化合物(6-2)：22.1mg,5.49％)。Compound (6-F) (0.47mg, 0.75mmol) was dissolved in N,N-dimethylacetamide (10mL), lithium chloride (0.33g, 7.7mmol) was added, and the reaction mixture was reacted at 110°C for 5 hours , Stop the reaction, add 2M hydrochloric acid to adjust the pH=6-7, then extract with ethyl acetate (10mL×3), wash with saturated sodium chloride (10mL×3), and pass the residue through a LUNA preparation column (eluent is acetonitrile) /0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) to obtain the title compound as a yellow solid (compound (6-1): 15.5 mg, 3.85%; compound (6-2): 22.1 mg, 5.49 %).
化合物(6-1)：Compound (6-1):
HRMS(ESI,pos.ion)m/z:533.1638[M+H] +； HRMS(ESI,pos.ion)m/z:533.1638[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):7.25-7.05(m,2H),6.77(dd,J＝8.6,5.0Hz,2H),6.72(d,J＝7.7Hz,1H),6.55(dd,J＝6.1,2.6Hz,1H),5.98(d,J＝14.6Hz,1H),5.72(d,J＝7.7Hz,1H),5.28(s,1H),5.10(dd,J＝14.7,2.6Hz,1H),4.69(d,J＝12.6Hz,1H),4.57(dt,J＝19.4,9.7Hz,1H),3.91(dd,J＝11.0,2.6Hz,1H),3.83(dd,J＝11.8,2.6Hz,1H),3.59(t,J＝10.5Hz,2H),3.48(t,J＝10.9Hz,1H),3.03(t,J＝11.0Hz,1H),1.92–1.82(m,1H),1.81-1.72(m,1H),1.68–1.58(m,1H),1.56–1.44(m,1H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.25-7.05(m,2H), 6.77(dd,J=8.6,5.0Hz,2H), 6.72(d,J=7.7Hz,1H),6.55 (dd,J=6.1,2.6Hz,1H), 5.98(d,J=14.6Hz,1H), 5.72(d,J=7.7Hz,1H), 5.28(s,1H), 5.10(dd,J= 14.7, 2.6 Hz, 1H), 4.69 (d, J = 12.6 Hz, 1H), 4.57 (dt, J = 19.4, 9.7 Hz, 1H), 3.91 (dd, J = 11.0, 2.6 Hz, 1H), 3.83 ( dd,J=11.8,2.6Hz,1H),3.59(t,J=10.5Hz,2H),3.48(t,J=10.9Hz,1H),3.03(t,J=11.0Hz,1H),1.92– 1.82 (m, 1H), 1.81-1.72 (m, 1H), 1.68-1.58 (m, 1H), 1.56-1.44 (m, 1H).
化合物(6-2)：Compound (6-2):
1H NMR(400MHz,CDCl 3)δ(ppm):7.16(d,J＝7.2Hz,1H),7.07(t,J＝7.6Hz,1H),6.97(d,J＝8.7Hz,1H),6.92(d,J＝7.1Hz,1H),6.61(d,J＝7.7Hz,2H),6.01(d,J＝14.6Hz,1H),5.85(d,J＝7.8Hz,1H),5.17(s,1H),5.08(d,J＝12.5Hz,1H),4.64(dd,J＝21.7,10.0Hz,2H),3.97(d,J＝10.0Hz,1H),3.81(d,J＝10.0Hz,2H),3.51(dt,J＝19.8,11.2Hz,3H),1.92(s,1H),1.83(s,1H),1.66(s,1H),1.57(s,1H). 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.16(d,J=7.2Hz,1H), 7.07(t,J=7.6Hz,1H), 6.97(d,J=8.7Hz,1H), 6.92 (d, J = 7.1 Hz, 1H), 6.61 (d, J = 7.7 Hz, 2H), 6.01 (d, J = 14.6 Hz, 1H), 5.85 (d, J = 7.8 Hz, 1H), 5.17 ( s, 1H), 5.08 (d, J = 12.5 Hz, 1H), 4.64 (dd, J = 21.7, 10.0 Hz, 2H), 3.97 (d, J = 10.0 Hz, 1H), 3.81 (d, J = 10.0 Hz, 2H), 3.51 (dt, J = 19.8, 11.2 Hz, 3H), 1.92 (s, 1H), 1.83 (s, 1H), 1.66 (s, 1H), 1.57 (s, 1H).
实施例7：化合物(7-1)和化合物(7-2)的合成Example 7: Synthesis of compound (7-1) and compound (7-2)
Figure PCTCN2020139363-appb-000078
Figure PCTCN2020139363-appb-000078
步骤1)化合物(7-A)的合成Step 1) Synthesis of compound (7-A)
Figure PCTCN2020139363-appb-000079
Figure PCTCN2020139363-appb-000079
将吲哚(2.01g,17mmol)装入反应瓶中，然后加入DMF(30mL)，随后，在0℃下加入氢化钠(819.2mg,20.48mmol)，将反应液室温搅拌30min，然后在0℃时滴加2-(溴甲基)-3,4-二氟苯甲酸乙酯(5.01g,18.0mmol)，室温反应5h。停止反应，加入冰水(500mL)，乙酸乙酯(50mL×3)萃取，合并有机相。合并的有机相用无水硫酸钠干燥，减压浓缩，所得残留物经硅胶柱层析(PE/EA(v/v)＝15/1)纯化，得到标题化合物为黄色液体(2.73g,50％)。MS(ESI,pos.ion)m/z:316.0[M+H] +。 Put indole (2.01g, 17mmol) into the reaction flask, then add DMF (30mL), then add sodium hydride (819.2mg, 20.48mmol) at 0°C, stir the reaction solution at room temperature for 30min, and then at 0°C At the same time, ethyl 2-(bromomethyl)-3,4-difluorobenzoate (5.01g, 18.0mmol) was added dropwise and reacted at room temperature for 5h. The reaction was stopped, ice water (500 mL) was added, ethyl acetate (50 mL×3) was extracted, and the organic phases were combined. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (PE/EA(v/v)=15/1) to obtain the title compound as a yellow liquid (2.73g, 50 %). MS (ESI, pos.ion) m/z: 316.0 [M+H] + .
步骤2)化合物(7-B)的合成Step 2) Synthesis of compound (7-B)
Figure PCTCN2020139363-appb-000080
Figure PCTCN2020139363-appb-000080
将化合物(7-A)(2.73g,8.66mmol)溶于叔丁醇(50mL)中，随后向反应液中加入NBS(1.72g,9.57mmol)室温反应2h，停止反应，将反应溶液加入到饱和碳酸氢钠溶液(50mL)中，用乙酸乙酯(50mL×5)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，得到标题化合物为黄色油状液体(2.87g,85％)。MS(ESI,pos.ion)m/z:394.1[M+H] +； Compound (7-A) (2.73g, 8.66mmol) was dissolved in tert-butanol (50mL), and then NBS (1.72g, 9.57mmol) was added to the reaction solution to react at room temperature for 2h, the reaction was stopped, and the reaction solution was added to Saturated sodium bicarbonate solution (50 mL) was extracted with ethyl acetate (50 mL×5), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a yellow oily liquid (2.87 g, 85%). MS(ESI,pos.ion)m/z:394.1[M+H] + ;
步骤3)化合物(7-C)的合成Step 3) Synthesis of compound (7-C)
Figure PCTCN2020139363-appb-000081
Figure PCTCN2020139363-appb-000081
将化合物(7-B)(2.87g,7.28mmol)溶于四氢呋喃(20mL)中，随后，将盐酸(10mL,1M)加至上述反应液中，70℃搅拌12h，然后停止反应，再将反应液用水(100mL)稀释，再用乙酸乙酯(75mL)和四氢呋喃(75mL)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶柱层析纯化(洗脱剂为石油醚/乙酸乙酯(v/v)＝5/1)，得到标题化合物为红色片状固体(1.51g,62％)。MS(ESI,pos.ion)m/z:332.1[M+H] +。 Compound (7-B) (2.87g, 7.28mmol) was dissolved in tetrahydrofuran (20mL), then hydrochloric acid (10mL, 1M) was added to the above reaction solution, stirred at 70°C for 12h, then the reaction was stopped, and the reaction The solution was diluted with water (100 mL), and then extracted with ethyl acetate (75 mL) and tetrahydrofuran (75 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography Purification (eluent: petroleum ether/ethyl acetate (v/v) = 5/1), to obtain the title compound as a red flaky solid (1.51 g, 62%). MS (ESI, pos.ion) m/z: 332.1 [M+H] + .
步骤4)化合物(7-D)的合成Step 4) Synthesis of compound (7-D)
Figure PCTCN2020139363-appb-000082
Figure PCTCN2020139363-appb-000082
将化合物(7-C)(1.51g,4.56mmol)溶于四氢呋喃(10mL)和甲醇(10mL)中，室温搅拌，将氢氧化钠(0.73g,18mmol)溶于水(5mL)中，加至上述反应液中，室温搅拌1h，用1N稀盐酸调节pH至6左右，分液，水相用乙酸乙酯(30mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为红色固体(1.37g,99％)。MS(ESI,pos.ion)m/z:304.1[M+H] +； Compound (7-C) (1.51g, 4.56mmol) was dissolved in tetrahydrofuran (10mL) and methanol (10mL), stirred at room temperature, sodium hydroxide (0.73g, 18mmol) was dissolved in water (5mL), and added to In the above reaction solution, stir at room temperature for 1 hour, adjust the pH to about 6 with 1N dilute hydrochloric acid, separate the liquids, extract the aqueous phase with ethyl acetate (30 mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and depressurize the filtrate Concentrate to obtain the title compound as a red solid (1.37 g, 99%). MS(ESI,pos.ion)m/z:304.1[M+H] + ;
步骤5)化合物(7-E)的合成Step 5) Synthesis of compound (7-E)
Figure PCTCN2020139363-appb-000083
Figure PCTCN2020139363-appb-000083
将化合物(7-D)(1.68g,5.51mmol)溶于多聚磷酸(10mL)中，在110度下搅拌反应1h，停止反应，冷却至室温，将反应液加入到冰水(10mL)中，乙酸乙酯(20mL×3)萃取，合并有机相，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，减压浓缩，残留物经硅胶柱层析分离(PE/EA(v/v)＝1/1)纯化。得到标题化合物为红色固体(0.83g,53％)。 1H NMR(400MHz,CDCl 3)δ(ppm):7.94(d,J＝8.2Hz,1H),7.55(ddd,J＝8.6,4.9,1.6Hz,1H),7.45(dd,J＝7.2,0.9Hz,1H),7.25(dd,J＝13.8,4.8Hz,1H),7.18(dd,J＝13.0,5.5Hz,1H),5.12(s,2H),3.64(s,2H). Dissolve compound (7-D) (1.68g, 5.51mmol) in polyphosphoric acid (10mL), stir the reaction at 110°C for 1h, stop the reaction, cool to room temperature, add the reaction solution to ice water (10mL) Extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (20mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is separated by silica gel column chromatography (PE/EA(v/v) = 1/1) Purification. The title compound was obtained as a red solid (0.83 g, 53%). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.94 (d, J = 8.2 Hz, 1H), 7.55 (ddd, J = 8.6, 4.9, 1.6 Hz, 1H), 7.45 (dd, J = 7.2, 0.9Hz, 1H), 7.25 (dd, J = 13.8, 4.8 Hz, 1H), 7.18 (dd, J = 13.0, 5.5 Hz, 1H), 5.12 (s, 2H), 3.64 (s, 2H).
步骤6)化合物(7-F)的合成Step 6) Synthesis of compound (7-F)
Figure PCTCN2020139363-appb-000084
Figure PCTCN2020139363-appb-000084
将化合物(7-E)(801.2mg,2.80mmol)溶于THF(10mL)和甲醇(10mL)中，冷却至-5℃，加入硼氢化钠(165.1mg,4.18mmol)，加完后0℃反应1分钟，停止反应，将反应液加入到饱和氯化铵溶液(15mL)中，随后用乙酸乙酯(15mL×3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，得到标题化合物为黄色固体(0.799g,99％)。MS(ESI,neg.ion)m/z:286.0[M-H] -。 Compound (7-E) (801.2mg, 2.80mmol) was dissolved in THF (10mL) and methanol (10mL), cooled to -5°C, sodium borohydride (165.1mg, 4.18mmol) was added, and 0°C after the addition was complete After reacting for 1 minute, the reaction was stopped. The reaction solution was added to saturated ammonium chloride solution (15mL), followed by extraction with ethyl acetate (15mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title The compound is a yellow solid (0.799 g, 99%). MS (ESI, neg.ion) m/z: 286.0 [MH] - .
步骤7)化合物(7-G)的合成Step 7) Synthesis of compound (7-G)
Figure PCTCN2020139363-appb-000085
Figure PCTCN2020139363-appb-000085
将化合物(7-F)(601.2mg,2.09mmol)和化合物(1-A)(751.1mg,2.29mmol)加入到微波反应管中，然后加入1-丙基磷酸酐(50％的乙酸乙酯溶液,7.5mL,3mmol)和乙酸乙酯(10mL)，反应混合物于110℃微波反应2小时，停止反应，向反应体系中加入饱和碳酸氢钠溶液(30mL)，乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析纯化(二氯甲烷/甲醇(v/v)＝15/1)得到标题化合物为白色固体(0.41g,32％)。Compound (7-F) (601.2mg, 2.09mmol) and compound (1-A) (751.1mg, 2.29mmol) were added to the microwave reaction tube, and then added 1-propyl phosphoric anhydride (50% ethyl acetate Solution, 7.5mL, 3mmol) and ethyl acetate (10mL). The reaction mixture was microwaved at 110°C for 2 hours. The reaction was stopped. Saturated sodium bicarbonate solution (30mL) and ethyl acetate (20mL×3) were added to the reaction system. Extract, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (dichloromethane/methanol (v/v)=15/1) to obtain the title compound as a white solid ( 0.41g, 32%).
步骤8)化合物(7-1)和化合物(7-2)的合成Step 8) Synthesis of compound (7-1) and compound (7-2)
Figure PCTCN2020139363-appb-000086
Figure PCTCN2020139363-appb-000086
在氢气氛围下，将化合物(7-G)(0.47mg,0.75mmol)溶于乙酸乙酯(10mL)中，加入Pd/C(10.2mg,0.09mmol)，然后于110℃反应23h，停止反应，将反应液用硅藻土过滤，然后，反应液减压浓缩，所得残留物经LUNA制备柱纯化(洗脱剂为乙腈/0.1％三氟乙酸水溶液(v/v)＝12/13)，分离纯化得到标题化合物为黄色固体(化合物(7-1)：15.1mg,3.78％；化合物(7-2)：14mg,3.50％)。Under a hydrogen atmosphere, compound (7-G) (0.47 mg, 0.75 mmol) was dissolved in ethyl acetate (10 mL), Pd/C (10.2 mg, 0.09 mmol) was added, and then reacted at 110°C for 23 hours to stop the reaction The reaction solution was filtered with celite, and then the reaction solution was concentrated under reduced pressure, and the residue obtained was purified by a LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13), After separation and purification, the title compound was obtained as a yellow solid (compound (7-1): 15.1 mg, 3.78%; compound (7-2): 14 mg, 3.50%).
化合物(7-1)：Compound (7-1):
HRMS(ESI,pos.ion)m/z:507.1487[M+H] +； HRMS(ESI,pos.ion)m/z:507.1487[M+H] + ;
1H NMR(400MHz,CDCl 3)δ7.26(s,2H),7.24–7.16(m,2H),7.11(d,J＝7.6Hz,1H),6.81(t,J＝7.7Hz,1H),6.69(d,J＝7.6Hz,1H),6.56(d,J＝7.8Hz,1H),5.95(d,J＝14.6Hz,1H),5.82(d,J＝7.6Hz,1H),5.23(s,1H),5.04–4.92(m,1H),4.68(d,J＝13.0Hz,1H),4.55(dd,J＝9.9,3.0Hz,1H),3.89(dd,J＝11.1,2.9Hz,1H),3.86–3.77(m,1H),3.52(s,1H),3.47(s,1H),3.08–2.94(m,2H). 1 H NMR(400MHz,CDCl 3 )δ7.26(s,2H),7.24-7.16(m,2H),7.11(d,J=7.6Hz,1H), 6.81(t,J=7.7Hz,1H) , 6.69 (d, J = 7.6 Hz, 1H), 6.56 (d, J = 7.8 Hz, 1H), 5.95 (d, J = 14.6 Hz, 1H), 5.82 (d, J = 7.6 Hz, 1H), 5.23 (s,1H),5.04–4.92(m,1H),4.68(d,J=13.0Hz,1H),4.55(dd,J=9.9,3.0Hz,1H), 3.89(dd,J=11.1,2.9 Hz, 1H), 3.86--3.77 (m, 1H), 3.52 (s, 1H), 3.47 (s, 1H), 3.08--2.94 (m, 2H).
化合物(7-2)：Compound (7-2):
HRMS(ESI,pos.ion)m/z:507.1488[M+H] +； HRMS(ESI,pos.ion)m/z:507.1488[M+H] + ;
1H NMR(400MHz,CDCl 3)δ7.46–7.32(m,1H),7.28(s,2H),7.22(d,J＝7.5Hz,1H),7.15–7.08(m,1H),7.00(d,J＝8.2Hz,1H),6.60(d,J＝7.3Hz,1H),5.99(d,J＝14.3Hz,1H),5.86(d,J＝7.3Hz,1H),5.17(s,1H), 5.01(d,J＝14.1Hz,1H),4.69(d,J＝13.2Hz,1H),4.61(d,J＝7.7Hz,1H),4.21–4.06(m,1H),3.97(d,J＝10.3Hz,1H),3.84(d,J＝12.1Hz,1H),3.73–3.45(m,2H),3.13–2.89(m,2H). 1 H NMR(400MHz, CDCl 3 )δ7.46–7.32(m,1H), 7.28(s,2H), 7.22(d,J=7.5Hz,1H), 7.15–7.08(m,1H), 7.00( d, J = 8.2 Hz, 1H), 6.60 (d, J = 7.3 Hz, 1H), 5.99 (d, J = 14.3 Hz, 1H), 5.86 (d, J = 7.3 Hz, 1H), 5.17 (s, 1H), 5.01(d,J=14.1Hz,1H), 4.69(d,J=13.2Hz,1H), 4.61(d,J=7.7Hz,1H), 4.21-4.06(m,1H), 3.97( d, J = 10.3 Hz, 1H), 3.84 (d, J = 12.1 Hz, 1H), 3.73–3.45 (m, 2H), 3.13–2.89 (m, 2H).
活性试验实施例Activity test example
在以下实施例中，发明人以本发明的部分化合物为例，检测了本发明化合物的抗病毒活性及细胞毒性、药代动力学性质以及在肝微粒中的稳定性。In the following examples, the inventors used some of the compounds of the present invention as examples to test the antiviral activity, cytotoxicity, pharmacokinetic properties, and stability of the compounds of the present invention in liver particles.
实施例A：细胞病变效应实验(CPE assay)：Example A: Cytopathic effect experiment (CPE assay):
本实验在体外细胞水平上检测了化合物抑制病毒H1N1A/Weiss/43致细胞病变(CPE)的能力。This experiment tested the ability of the compound to inhibit the cytopathic (CPE) of the virus H1N1A/Weiss/43 at the in vitro cell level.
实验步骤：MDCK细胞(Madin-Darby canine kidney cells,犬肾上皮连续细胞系，来源:ATCC#CCL-34)以2000细胞/孔的密度接种于384孔板，在37℃，5％CO 2条件下培养过夜；次日，换含有不同浓度化合物的新鲜培养液，流感病毒(A/Weiss/43(H1N1))以能产生80～95％CPE的感染复数感染细胞。化合物最高检测浓度为100nM，3倍稀释，8个浓度，依次为：100nM、33.33nM、11.11nM、3.70nM、1.23nM、0.41nM、0.14nM、0.05nM。同时设置不加药的病毒对照组和无病毒感染不加药的细胞对照组。细胞毒性实验组不加入病毒，用培养基代替。均设置两个复孔。37℃，5％CO 2条件下孵育5天。根据CCK-8试剂盒(来源：上海李记生物科技有限公司#D3100L4057)检测细胞活性，数据将被用来计算化合物的抗病毒效果和细胞毒性。GraphPad Prism分析数据，计算CPE抑制率，根据拟合曲线获得EC 50和CC 50值。实验结果见表1。 Experimental procedure: MDCK cells (Madin-Darby canine kidney cells, continuous canine kidney epithelial cell line, source: ATCC#CCL-34) were seeded in a 384-well plate at a density of 2000 cells/well at 37°C, 5% CO 2 Incubate overnight; the next day, change to fresh culture medium containing different concentrations of compounds, and influenza virus (A/Weiss/43(H1N1)) infects cells with a multiplicity of infection that can produce 80-95% CPE. The highest detection concentration of the compound is 100nM, 3 times dilution, 8 concentrations, in order: 100nM, 33.33nM, 11.11nM, 3.70nM, 1.23nM, 0.41nM, 0.14nM, 0.05nM. At the same time, a virus control group without medicine and a cell control group without virus infection and medicine were set up. In the cytotoxicity experiment group, no virus was added, and culture medium was used instead. Both are provided with two duplicate holes. Incubate at 37°C and 5% CO 2 for 5 days. According to CCK-8 kit (source: Shanghai Liji Biotechnology Co., Ltd. #D3100L4057) to detect cell activity, the data will be used to calculate the compound's antiviral effect and cytotoxicity. GraphPad Prism analyzes the data, calculates the CPE inhibition rate, and obtains the EC 50 and CC 50 values according to the fitted curve. The experimental results are shown in Table 1.
其中，CPE抑制率＝(加药孔吸光值-病毒对照孔吸光值)/(细胞对照孔吸光值-病毒对照孔吸光值)×100％Among them, the CPE inhibition rate = (the absorbance value of the dosing hole-the absorbance value of the virus control hole) / (the absorbance value of the cell control hole-the absorbance value of the virus control hole) × 100%
细胞存活率＝(加药孔吸光值-培养基对照孔吸光值)/(细胞对照孔吸光值-培养基对照孔吸光值)×100％Cell survival rate = (the absorbance value of the dosing hole-the absorbance value of the medium control hole) / (the absorbance value of the cell control hole-the absorbance value of the medium control hole) × 100%
表1，本发明化合物抗病毒活性和细胞毒性数据Table 1. Antiviral activity and cytotoxicity data of the compounds of the present invention
化合物编号Compound number EC 50(nM) EC 50 (nM) CC 50(μM) CC 50 (μM)
1-11-1 28.9828.98 >100>100
2-12-1 33.5433.54 >100>100
2-22-2 89.6789.67 47.8247.82
3-13-1 11.4311.43 28.92528.925
3-23-2 20.7920.79 29.12329.123
4-14-1 48.5448.54 10.4210.42
5-15-1 109.1109.1 >100>100
6-16-1 51.6251.62 >100>100
7-17-1 33.1933.19 >100>100
试验结果表明，本发明化合物具有很好的抗流感病毒活性，同时具有很低的细胞毒性。The test results show that the compound of the present invention has good anti-influenza virus activity and at the same time has very low cytotoxicity.
实施例B：静脉注射或口服定量本发明化合物后的药代动力学性质评价：Example B: Evaluation of the pharmacokinetic properties of the compound of the present invention after intravenous injection or oral administration:
方法一：method one:
本实验对本发明化合物在健康的、成年的雄性SD大鼠、犬或猴子体内的药代动力学研究进行了评估。本发明化合物以5％DMSO+5％Kolliphor HS 15+90％生理盐水溶液进行给药。对于静脉注射(iv)给药，动物给予1mg/kg的剂量；对于口服(po)给药，动物给予5mg/kg的剂量。大鼠在时间点为0.083(iv)、0.25、0.5、1.0、2.0、5.0、7.0和24小时取血(0.3mL)，犬或猴在0.083(iv)、0.25、0.5、1.0、2.0、4.0、6.0、8.0和24小时(猴增加48小时)取血(0.3mL)，并在3,000或4,000rpm下离心10分钟。收集血浆溶液，并于-20℃或-70℃下保存直到进行上述的LC/MS/MS分析。This experiment evaluated the pharmacokinetic study of the compound of the present invention in healthy, adult male SD rats, dogs or monkeys. The compound of the present invention is administered with 5% DMSO+5% Kolliphor HS 15+90% physiological saline solution. For intravenous (iv) administration, animals are given a dose of 1 mg/kg; for oral (po) administration, animals are given a dose of 5 mg/kg. Blood was taken (0.3mL) at time points of 0.083 (iv), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours for rats, and 0.083 (iv), 0.25, 0.5, 1.0, 2.0, 4.0 for dogs or monkeys , 6.0, 8.0, and 24 hours (48 hours for monkeys) to take blood (0.3 mL), and centrifuge at 3,000 or 4,000 rpm for 10 minutes. The plasma solution was collected and stored at -20°C or -70°C until the aforementioned LC/MS/MS analysis.
试验结果表明，本发明化合物在大鼠、犬或猴子体内的暴露量大，吸收良好，其药代动力学性质良好。The test results show that the compound of the present invention has large exposure in rats, dogs or monkeys, good absorption, and good pharmacokinetic properties.
方法二：Method Two:
本实验对本发明化合物在健康的、成年的雄性SD大鼠、犬或猴子体内的药代动力学研究进行了评估。本发明化合物以10％DMSO+10％Kolliphor HS 15+80％生理盐水溶液进行给药。对于静脉注射(iv)给药，动物给予0.2或1mg/kg的剂量；对于口服(po)给药，动物给予1或5mg/kg的剂量。大鼠在时间点为0.083(iv)、0.25、0.5、1.0、2.0、5.0、7.0和24小时取血(0.3mL)，犬或猴在0.083(iv)、0.25、0.5、1.0、 2.0、4.0、6.0、8.0和24小时(猴增加48小时)取血(0.3mL)，并在3,000或4,000rpm下离心10分钟。收集血浆溶液，并于-20℃或-70℃下保存直到进行上述的LC/MS/MS分析。实验结果见表2。This experiment evaluated the pharmacokinetic study of the compound of the present invention in healthy, adult male SD rats, dogs or monkeys. The compound of the present invention is administered with 10% DMSO+10% Kolliphor HS 15+80% physiological saline solution. For intravenous (iv) administration, animals are given a dose of 0.2 or 1 mg/kg; for oral (po) administration, animals are given a dose of 1 or 5 mg/kg. Rats were taken at 0.083 (iv), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours of blood (0.3 mL), and dogs or monkeys were taken at 0.083 (iv), 0.25, 0.5, 1.0, 2.0, 4.0 , 6.0, 8.0, and 24 hours (48 hours for monkeys) to take blood (0.3 mL), and centrifuge at 3,000 or 4,000 rpm for 10 minutes. The plasma solution was collected and stored at -20°C or -70°C until the aforementioned LC/MS/MS analysis. The experimental results are shown in Table 2.
表2：本发明部分化合物在大鼠内的药代动力学数据Table 2: Pharmacokinetic data of some compounds of the present invention in rats
Figure PCTCN2020139363-appb-000087
Figure PCTCN2020139363-appb-000087
试验结果表明，本发明化合物在大鼠、犬或猴子体内的暴露量大，吸收良好，其药代动力学性质良好。The test results show that the compound of the present invention has large exposure in rats, dogs or monkeys, good absorption, and good pharmacokinetic properties.
实施例C：肝微粒中的稳定性评价Example C: Evaluation of stability in liver microparticles
对本发明化合物在混合大鼠、犬、猴子或人肝微粒的稳定性进行了评估。将本发明化合物与混合人、大鼠、犬、猴子肝微粒体在37℃、pH＝7.4的条件下共同孵育，通过测定不同孵育时间的样品浓度，以“Log[药物浓度]”对“孵育时间”作图获得速率常数，求算出药物半衰期与体内清除率Cl in vivo，以药物半衰期与体内清除率值来评价药物在肝微粒体中的稳定性。具体实验***如下： The stability of the compound of the present invention in mixed rat, dog, monkey or human liver microparticles was evaluated. The compound of the present invention is incubated with mixed human, rat, dog, and monkey liver microsomes at 37°C and pH=7.4. The concentration of the sample at different incubation times is measured, and the "Log[drug concentration]" versus "incubation" is used. The rate constant is obtained by plotting with time, and the drug half-life and in vivo clearance Cl in vivo are calculated, and the drug half-life and in vivo clearance value are used to evaluate the stability of the drug in liver microsomes. The specific experimental system is as follows:
Figure PCTCN2020139363-appb-000088
Figure PCTCN2020139363-appb-000088
试验结果表明，本发明化合物在大鼠、犬和人的肝微粒中均稳定。The test results show that the compound of the present invention is stable in liver microparticles of rats, dogs and humans.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, descriptions with reference to the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" etc. mean specific features described in conjunction with the embodiment or example , Structures, materials or features are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine the different embodiments or examples and the features of the different embodiments or examples described in this specification without contradicting each other.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can comment on the above-mentioned embodiments within the scope of the present invention. The embodiment undergoes changes, modifications, substitutions, and modifications.

Claims (19)

  1. 一种化合物，其为式(I)所示化合物或式(I)所示化合物的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药，A compound which is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or Their prodrugs,
    Figure PCTCN2020139363-appb-100001
    Figure PCTCN2020139363-appb-100001
    其中：among them:
    E为CR 10、C或N； E is CR 10 , C or N;
    R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基或C 3-6环烷基； R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C (=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 Haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-6 cycloalkyl;
    R 8、R 9和R 10各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氨基、C 1-6卤代烷氧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基； R 8 , R 9 and R 10 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C(=O)OH, -C(=O) NH 2 , -S(=O) 2 NH 2 , C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 5-6 heterocyclic group, C 6-10 aryl or 5-6 heteroaryl ；
    或R 8、R 9和与它们相连的碳原子一起形成-C(＝O)、-C(＝NH)、-C(＝S)、C 3-6碳环或5-6个原子组成的杂环； Or R 8 , R 9 and the carbon atoms connected to them form -C(=O), -C(=NH), -C(=S), C 3-6 carbon ring or 5-6 atoms Heterocycle
    环Cy为C 3-8碳环、3-8个原子组成的杂环、C 6-10芳环或5-8个原子组成的杂芳环，其中所述C 3-8碳环、3-8个原子组成的杂环、C 6-10芳环和5-8个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个R x所取代；所述3-8个原子组成的杂环和5-8个原子组成的杂芳环各自独立地含有1、2、3或4个独立选自N、O或S的杂原子； Ring Cy is a C 3-8 carbocyclic ring, a heterocyclic ring composed of 3-8 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-8 atoms, wherein the C 3-8 carbocyclic ring, 3- The 8-atom heterocyclic ring, the C 6-10 aromatic ring and the 5-8 atom heteroaromatic ring are each independently unsubstituted or substituted by 1, 2, 3, or 4 R x ; the 3- The 8-atom heterocyclic ring and the 5-8 atom heteroaromatic ring each independently contain 1, 2, 3 or 4 heteroatoms independently selected from N, O or S;
    各R x独立地为氘、F、Cl、Br、I、-CN、-NO 2、＝O、＝S、＝NH、-OR b、-NR cR d、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6碳环基、C 3-6碳环基-C 1-4亚烷基、3-6个原子组成的杂环基、(3-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-4亚烷基，其中所述C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6碳环基、C 3-6碳环基-C 1-4亚烷基、3-6个原子组成的杂环基、(3-6个原子组成的杂环基)-C 1-4亚烷基、C 6-10芳基、C 6-10芳基-C 1-4亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-4亚烷基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或C 1-6烷氨基； Each R x is independently deuterium, F, Cl, Br, I , -CN, -NO 2, = O, = S, = NH, -OR b, -NR c R d, -C (= O) R a , -C(=O)OR b , -C(=O)NR c R d , C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene, 3-6 atom heterocyclic group, (3-6 atom Heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, heteroaryl composed of 5-6 atoms or (5-6 (Heteroaryl group consisting of three atoms) -C 1-4 alkylene, wherein the C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-4 alkylene group, 3-6 atom heterocyclic group, (3-6 atom heterocyclic group Cyclic)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, heteroaryl composed of 5-6 atoms and (5-6 (Atomic heteroaryl)-C 1-4 alkylene is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 Alkoxy or C 1-6 alkylamino;
    或任意2个R x和与它们相连的原子一起形成C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环或5-6个原子组成的杂芳环，其中所述C 3-6碳环、3-6个原子组成的杂环、C 6-10芳环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、C 1-6烷基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6烷氧基或C 1-6烷氨基； Or any two R x and the atoms connected to them form a C 3-6 carbon ring, a heterocyclic ring composed of 3-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms, wherein The C 3-6 carbon ring, the heterocyclic ring composed of 3-6 atoms, the C 6-10 aromatic ring and the heteroaromatic ring composed of 5-6 atoms are each independently unsubstituted or by 1, 2 or 3 Substituents are substituted, the substituents are independently selected from deuterium, F, Cl, Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, C 1-6 alkane Group, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkoxy or C 1-6 alkylamino;
    各R a、R b、R c和R d独立地为H、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基或5-6个原子组成的杂芳基，其中所述C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基、3-6个原子组成的杂环基、C 6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6烷氨基； Each R a , R b , R c and Rd are independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3- Heterocyclic group composed of 6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group , C 3-6 cycloalkyl, 3-6 heterocyclic group, C 6-10 aryl and 5-6 heteroaryl are each independently unsubstituted or by 1, 2 or 3 Substituted by a substituent, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 1-6 alkoxy or C 1-6 alkylamino;
    或R c、R d和与它们相连的氮原子一起，形成3-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述3-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧 基或C 1-6烷氨基； Or R c , R d and the nitrogen atoms connected to them together form a heterocyclic ring composed of 3-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 3-6 atoms and The heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
    其中，所述化合物不包括以下化合物：Wherein, the compound does not include the following compounds:
    Figure PCTCN2020139363-appb-100002
    Figure PCTCN2020139363-appb-100002
  2. 根据权利要求1所述的化合物，其中所述环Cy为C 3-7碳环、5个原子组成的杂环、6个原子组成的杂环、7个原子组成的杂环、C 6-10芳环、5个原子组成的杂芳环、6个原子组成的杂芳环或7个原子组成的杂芳环，其中所述C 3-7碳环、5个原子组成的杂环、6个原子组成的杂环、7个原子组成的杂环、C 6-10芳环、5个原子组成的杂芳环、6个原子组成的杂芳环和7个原子组成的杂芳环各自独立地未被取代或被1、2、3或4个R x所取代；所述5个原子组成的杂环、6个原子组成的杂环、7个原子组成的杂环、5个原子组成的杂芳环、6个原子组成的杂芳环和7个原子组成的杂芳环各自独立地含有1、2、3或4个独立选自N、O或S的杂原子。 The compound according to claim 1, wherein the ring Cy is a C 3-7 carbocyclic ring, a 5-atom heterocyclic ring, a 6-atom heterocyclic ring, a 7-atom heterocyclic ring, a C 6-10 Aromatic ring, 5-atom heteroaromatic ring, 6-atom heteroaromatic ring or 7-atom heteroaromatic ring, wherein the C 3-7 carbon ring, 5-atom heterocyclic ring, 6 A heterocyclic ring composed of atoms, a heterocyclic ring composed of 7 atoms, a C 6-10 aromatic ring, a heteroaromatic ring composed of 5 atoms, a heteroaromatic ring composed of 6 atoms, and a heteroaromatic ring composed of 7 atoms are each independently Unsubstituted or substituted by 1, 2, 3 or 4 R x ; said 5-atom heterocyclic ring, 6-atom heterocyclic ring, 7-atom heterocyclic ring, 5-atom heterocyclic ring The aromatic ring, the 6-atom heteroaromatic ring and the 7-atom heteroaromatic ring each independently contain 1, 2, 3, or 4 heteroatoms independently selected from N, O or S.
  3. 根据权利要求1或2所述的化合物，其中所述环Cy为环丙烷、环丁烷、环戊烷、环己烷、环庚烷、二硫环戊烷、二氧环戊烷、吡咯烷、二氢吡咯、吡唑烷、二氢吡唑、咪唑烷、二氢咪唑、哌啶、四氢吡啶、二氢吡啶、吗啉、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪、硫代吗啉、二氢噻嗪、哌嗪、四氢呋喃、二氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、四氢噻喃、二氢噻喃、噁唑烷、二氢噁唑、噻唑烷、二氢噻唑、噻噁烷、高哌嗪、高哌啶、4H-1,4-噁嗪、4H-1,4-噻嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、异噻唑、吡嗪、哒嗪、1,3,5-三嗪或硫代二唑，其中所述环丙烷、环丁烷、环戊烷、环己烷、环庚烷、二硫环戊烷、二氧环戊烷、吡咯烷、二氢吡咯、吡唑烷、二氢吡唑、咪唑烷、二氢咪唑、哌啶、四氢吡啶、二氢吡啶、吗啉、3,4-二氢-2H-1,4-噁嗪、3,4-二氢-2H-1,4-噻嗪、硫代吗啉、二氢噻嗪、哌嗪、四氢呋喃、二氢呋喃、四氢噻吩、二氢噻吩、四氢吡喃、二氢吡喃、四氢噻喃、二氢噻喃、噁唑烷、二氢噁唑、噻唑烷、二氢噻唑、噻噁烷、高哌嗪、高哌啶、4H-1,4-噁嗪、4H-1,4-噻嗪、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、异噻唑、吡嗪、哒嗪、1,3,5-三嗪和硫代二唑各自独立地未被取代或被1、2、3或4个R x所取代。 The compound according to claim 1 or 2, wherein the ring Cy is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dithiocyclopentane, dioxocyclopentane, pyrrolidine , Dihydropyrrole, Pyrazolidine, Dihydropyrazole, Imidazolidine, Dihydroimidazole, Piperidine, Tetrahydropyridine, Dihydropyridine, Morpholine, 3,4-Dihydro-2H-1,4-oxazine , 3,4-Dihydro-2H-1,4-thiazine, thiomorpholine, dihydrothiazine, piperazine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, two Hydropyran, tetrahydrothiopyran, dihydrothiopyran, oxazolidine, dihydrooxazole, thiazolidine, dihydrothiazole, thiaoxane, homopiperazine, homopiperidine, 4H-1,4-oxazine , 4H-1,4-thiazine, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, isothiazole, pyridine Oxazine, pyridazine, 1,3,5-triazine or thiodiazole, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dithiocyclopentane, dioxane Pentane, pyrrolidine, dihydropyrrole, pyrazolidine, dihydropyrazole, imidazolidine, dihydroimidazole, piperidine, tetrahydropyridine, dihydropyridine, morpholine, 3,4-dihydro-2H-1 ,4-oxazine, 3,4-dihydro-2H-1,4-thiazine, thiomorpholine, dihydrothiazine, piperazine, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, four Hydropyran, dihydropyran, tetrahydrothiopyran, dihydrothiopyran, oxazolidine, dihydrooxazole, thiazolidine, dihydrothiazole, thiaoxane, homopiperazine, homopiperidine, 4H-1 ,4-oxazine, 4H-1,4-thiazine, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole , Isothiazole, pyrazine, pyridazine, 1,3,5-triazine and thiodiazole are each independently unsubstituted or substituted with 1, 2, 3, or 4 R x .
  4. 根据权利要求1-3任意一项所述的化合物，其中所述各R x独立地为氘、F、Cl、Br、I、-CN、-NO 2、＝O、＝S、＝NH、-OR b、-NR cR d、-C(＝O)R a、-C(＝O)OR b、-C(＝O)NR cR d、C 1-4卤代烷基、C 1-4卤代烷氧基、 C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、C 3-6碳环基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基或(5-6个原子组成的杂芳基)-C 1-2亚烷基，其中所述C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6碳环基、C 3-6碳环基-C 1-2亚烷基、5-6个原子组成的杂环基、(5-6个原子组成的杂环基)-C 1-2亚烷基、C 6-10芳基、C 6-10芳基-C 1-2亚烷基、5-6个原子组成的杂芳基和(5-6个原子组成的杂芳基)-C 1-2亚烷基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氧基或C 1-4烷氨基； The compound according to any one of claims 1-3, wherein each R x is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , =O, =S, =NH,- OR b , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C 1-4 haloalkyl, C 1-4 haloalkyl Oxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl-C 1-2 alkylene, 5- 6-atom heterocyclic group, (5-6 atom heterocyclic group)-C 1-2 alkylene group, C 6-10 aryl group, C 6-10 aryl group-C 1-2 alkylene group Group, heteroaryl group consisting of 5-6 atoms or (heteroaryl group consisting of 5-6 atoms)-C 1-2 alkylene, wherein the C 1-4 haloalkyl group, C 1-4 haloalkoxy group Group, C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 3-6 carbocyclic group, C 3-6 carbocyclic group-C 1-2 alkylene group, 5-6 2-atom heterocyclic group, (5-6 atom heterocyclic group)-C 1-2 alkylene group, C 6-10 aryl group, C 6-10 aryl group-C 1-2 alkylene group , Heteroaryl groups composed of 5-6 atoms and (heteroaryl groups composed of 5-6 atoms)-C 1-2 alkylene are each independently unsubstituted or substituted by 1, 2 or 3 substituents , The substituents are independently selected from deuterium, F, Cl, Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, C 1-4 alkyl, C 1 -4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy or C 1-4 alkylamino;
    或任意2个R x和与它们相连的原子一起形成C 3-6碳环、5-6个原子形成的杂环、C 6-10芳环或5-6个原子组成的杂芳环，其中所述C 3-6碳环、5-6个原子形成的杂环、C 6-10芳环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝N、-CN、-OH、-NH 2、-COOH、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4烷氧基或C 1-4烷氨基。 Or any 2 R x and the atoms connected to them together form a C 3-6 carbon ring, a heterocyclic ring formed by 5-6 atoms, a C 6-10 aromatic ring or a heteroaromatic ring composed of 5-6 atoms, wherein The C 3-6 carbon ring, the heterocyclic ring formed by 5-6 atoms, the C 6-10 aromatic ring and the heteroaromatic ring composed of 5-6 atoms are each independently unsubstituted or by 1, 2 or 3 Substituents are substituted, the substituents are independently selected from deuterium, F, Cl, Br, I, =O, =S, =N, -CN, -OH, -NH 2 , -COOH, C 1-4 alkane Group, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy or C 1-4 alkylamino.
  5. 根据权利要求1-4任意一项所述的化合物，其中所述各R a、R b、R c和R d独立地为H、氘、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、5-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基，其中所述甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、5-6个原子组成的杂环基、苯基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基； The compound of any one of claims 1-4, wherein each of R a, R b, R c and R d are independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, Tert-butyl, cyclopropyl, cyclobutyl, heterocyclic group consisting of 5-6 atoms, phenyl group or heteroaryl group consisting of 5-6 atoms, wherein the methyl, ethyl, n-propyl, Isopropyl, tert-butyl, cyclopropyl, cyclobutyl, heterocyclic group composed of 5-6 atoms, phenyl group and heteroaryl group composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl, n-propyl , Isopropyl, trifluoromethyl or methoxy;
    或R c、R d和与它们相连的氮原子一起，形成5-6个原子组成的杂环或5-6个原子组成的杂芳环，其中所述5-6个原子组成的杂环和5-6个原子组成的杂芳环各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、-OH、-NH 2、-NO 2、甲基、乙基、正丙基、异丙基、三氟甲基或甲氧基。 Or R c , R d and their connected nitrogen atoms together form a heterocyclic ring composed of 5-6 atoms or a heteroaromatic ring composed of 5-6 atoms, wherein the heterocyclic ring composed of 5-6 atoms and The heteroaromatic ring composed of 5-6 atoms is each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , -NO 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.
  6. 根据权利要求1-5任意一项所述的化合物，其中所述各R x独立地为氘、F、Cl、Br、I、-CN、-NO 2、＝O、＝S、＝NH、-OH、-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH(CH 3) 2、-NH 2、-NHCH 3、-NHCH 2CH 3、-N(CH 3) 2、-C(＝O)OH、-C(＝O)OCH 3、-C(＝O)OCH 2CH 3、-C(＝O)NH 2、-CH 2F、-CHF 2、-CF 3、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCHF 2、-OCF 3、-OCH 2CF 3、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、C 3-6碳环基-CH 2-、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、四氢呋喃基、四氢噻吩基、四氢吡喃基、苯基、苯基-CH 2-、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、***基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基、1,3,5-三嗪基或(5-6个原子组成的杂芳基)-CH 2-，其中所述-CH 2F、-CHF 2、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCHF 2、-OCH 2CF 3、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、异丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、C 3-6碳环基-CH 2-、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、四氢呋喃基、四氢噻吩基、四氢吡喃基、苯基、苯基-CH 2-、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、***基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基、1,3,5-三嗪基和(5-6个原子组成的杂芳基)-CH 2-各自未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、-CF 3、-OCF 3或-OCH 3； The compound according to any one of claims 1-5, wherein each R x is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , =O, =S, =NH,- OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -C(=O)OH, -C(=O)OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)NH 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl , Isobutyl, allyl, propenyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 carbocyclic -CH 2 -, pyrrole Alkyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl -CH 2 -, Pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl , Pyridazinyl, 1,3,5-triazinyl or (heteroaryl group consisting of 5-6 atoms) -CH 2 -, wherein the -CH 2 F, -CHF 2 , -CH 2 CF 3 , -CHFCH 2 F, -CHFCHF 2 , -OCHF 2 , -OCH 2 CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, isobutyl, allyl, propylene Group, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 3-6 carbocyclyl -CH 2 -, pyrrolidinyl, pyrazolidinyl, imidazolidine Alkyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-CH 2 -, pyrrolyl, pyridyl, pyrimidinyl, thiazole Base, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, 1,3,5 -Triazinyl and (heteroaryl group consisting of 5-6 atoms) -CH 2 -are each unsubstituted or substituted with 1, 2 or 3 substituents independently selected from deuterium, F, Cl, Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, -CF 3 , -OCF 3 or -OCH 3 ;
    或任意2个R x和与它们相连的原子一起形成环丙烷、环丁烷、环戊烷、环己烷、吡咯烷、吡唑烷、咪唑烷、哌啶、哌嗪、吗啉、硫代吗啉、四氢呋喃、四氢噻吩、四氢吡喃、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、吡嗪、哒嗪或1,3,5-三嗪，其中所述环丙烷、环丁烷、环戊烷、环己烷、吡咯烷、吡唑烷、咪唑烷、哌啶、哌嗪、吗啉、硫代吗啉、四氢呋喃、四氢噻吩、四氢吡喃、苯、吡咯、吡啶、嘧啶、噻唑、噻吩、呋喃、吡唑、咪唑、***、四唑、噁唑、异噁唑、噁二唑、吡嗪、哒嗪和1,3,5-三嗪各自独立地未被取代或被1、2或3个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、＝S、＝NH、-CN、-OH、-NH 2、-COOH、甲基、乙基、正丙基、异丙基、-CF 3、-OCF 3或-OCH 3。 Or any 2 R x and the atoms connected to them form cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, morpholine, thio Morpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, Pyrazine, pyridazine or 1,3,5-triazine, wherein the cyclopropane, cyclobutane, cyclopentane, cyclohexane, pyrrolidine, pyrazolidine, imidazolidine, piperidine, piperazine, Morpholine, thiomorpholine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, benzene, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, Oxadiazole, pyrazine, pyridazine and 1,3,5-triazine are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from deuterium, F, Cl , Br, I, =O, =S, =NH, -CN, -OH, -NH 2 , -COOH, methyl, ethyl, n-propyl, isopropyl, -CF 3 , -OCF 3 or- OCH 3 .
  7. 根据权利要求1-6任意一项所述的化合物，其中所述R 8、R 9和R 10各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氨基、C 1-4卤代烷氧基、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、5-6个原子组成的杂环基、C 6-10 芳基或5-6个原子组成的杂芳基； The compound according to any one of claims 1-6, wherein the R 8 , R 9 and R 10 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkane Amino, C 1-4 haloalkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 aryl or heteroaryl composed of 5-6 atoms;
    或R 8、R 9和与它们相连的碳原子一起形成-C(＝O)、-C(＝NH)、-C(＝S)、C 3-6碳环或5-6个原子组成的杂环。 Or R 8 , R 9 and the carbon atoms connected to them form -C(=O), -C(=NH), -C(=S), C 3-6 carbon ring or 5-6 atoms Heterocycle.
  8. 根据权利要求1-7任意一项所述的化合物，其中所述R 8、R 9和R 10各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-CHF 2、-CF 3、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCH 2CH 2CH 3、-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-OCHF 2、-OCF 3、-OCH 2CF 3、甲基、乙基、正丙基、异丙基、叔丁基、正丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、吡咯烷基、吡唑烷基、咪唑烷基、哌啶基、吗啉基、硫代吗啉基、四氢呋喃基、四氢噻吩基、四氢吡喃基、苯基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、***基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基或1,3,5-三嗪基； The compound according to any one of claims 1-7, wherein the R 8 , R 9 and R 10 are each independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OH, SH, NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , -CHF 2 , -CF 3 , -CH 2 CF 3 , -CHFCH 2 F,- CHFCHF 2 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH 2 CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, allyl, propenyl, propargyl, 1-propynyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, Tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl , Oxadiazolyl, pyrazinyl, pyridazinyl or 1,3,5-triazinyl;
    或R 8、R 9和与它们相连的碳原子一起形成-C(＝O)、-C(＝NH)、-C(＝S)、环丙烷、环丁烷、环戊烷、环己烷、吡咯烷、吡唑烷、咪唑烷、哌啶、吗啉、硫代吗啉、四氢呋喃、四氢噻吩或四氢吡喃。 Or R 8 , R 9 and the carbon atoms connected to them form -C(=O), -C(=NH), -C(=S), cyclopropane, cyclobutane, cyclopentane, cyclohexane , Pyrrolidine, pyrazolidine, imidazolidine, piperidine, morpholine, thiomorpholine, tetrahydrofuran, tetrahydrothiophene or tetrahydropyran.
  9. 根据权利要求1-8任意一项所述的化合物，其中所述R 1、R 2、R 3、R 4、R 5、R 6和R 7各自独立地为H、氘、F、Cl、Br、I、CN、NO 2、OH、SH、NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、烯丙基、丙烯基、炔丙基、1-丙炔基、-CHF 2、-CF 3、-CH 2CF 3、-CHFCH 2F、-CHFCHF 2、-OCH 3、-OCH 2CH 3、-OCH(CH 3) 2、-OCH 2CH 2CH 3、-OCHF 2、-OCF 3、-OCH 2CF 3、环丙基、环丁基、环戊基或环己基。 The compound according to any one of claims 1-8, wherein the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently H, deuterium, F, Cl, Br , I, CN, NO 2 , OH, SH, NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , methyl, ethyl, n-propyl Base, isopropyl, n-butyl, isobutyl, tert-butyl, allyl, propenyl, propargyl, 1-propynyl, -CHF 2 , -CF 3 , -CH 2 CF 3 ,- CHFCH 2 F, -CHFCHF 2 , -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCH 2 CH 2 CH 3 , -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , cyclopropyl Group, cyclobutyl, cyclopentyl or cyclohexyl.
  10. 根据权利要求1-9任意一项所述的化合物，其中所述化合物具有如式(II)所示结构：The compound according to any one of claims 1-9, wherein the compound has a structure as shown in formula (II):
    Figure PCTCN2020139363-appb-100003
    Figure PCTCN2020139363-appb-100003
  11. 根据权利要求1-10任意一项所述的化合物，其具有以下其中之一的结构：The compound according to any one of claims 1-10, which has one of the following structures:
    Figure PCTCN2020139363-appb-100004
    Figure PCTCN2020139363-appb-100004
    Figure PCTCN2020139363-appb-100005
    Figure PCTCN2020139363-appb-100005
    Figure PCTCN2020139363-appb-100006
    Figure PCTCN2020139363-appb-100006
    Figure PCTCN2020139363-appb-100007
    Figure PCTCN2020139363-appb-100007
    Figure PCTCN2020139363-appb-100008
    Figure PCTCN2020139363-appb-100008
    Figure PCTCN2020139363-appb-100009
    Figure PCTCN2020139363-appb-100009
    Figure PCTCN2020139363-appb-100010
    Figure PCTCN2020139363-appb-100010
    Figure PCTCN2020139363-appb-100011
    Figure PCTCN2020139363-appb-100011
    Figure PCTCN2020139363-appb-100012
    Figure PCTCN2020139363-appb-100013
    或它们的立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药。
    Figure PCTCN2020139363-appb-100012
    Figure PCTCN2020139363-appb-100013
    Or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs.
  12. 一种药物组合物，其包含权利要求1-11任意一项所述的化合物，任选地进一步包含药学上可接受的辅剂。A pharmaceutical composition comprising the compound of any one of claims 1-11, optionally further comprising a pharmaceutically acceptable adjuvant.
  13. 根据权利要求12所述的药物组合物，进一步包含一种或多种其他治疗剂。The pharmaceutical composition according to claim 12, further comprising one or more other therapeutic agents.
  14. 根据权利要求13所述的药物组合物，其中所述其他治疗剂选自抗流感病毒剂或疫苗。The pharmaceutical composition according to claim 13, wherein the other therapeutic agent is selected from an anti-influenza virus agent or a vaccine.
  15. 根据权利要求13所述的药物组合物，其中所述其他治疗剂为金刚胺、金刚乙胺、奥司他韦、扎那米韦、帕拉米韦、拉尼米韦、拉尼米韦辛酸酯水合物、法匹拉韦、阿比多尔、利巴韦林、司他弗林、英加韦林、流感酶、CAS号1422050-75-6的药物、吡莫地韦、巴洛沙韦、流感疫苗或它们的组合。The pharmaceutical composition according to claim 13, wherein the other therapeutic agent is amantadine, rimantadine, oseltamivir, zanamivir, peramivir, lanimivir, lanimivir Ester hydrate, Fapilavir, Arbidol, Ribavirin, Staphyrin, Ingavirin, Influenza Enzyme, Drugs with CAS No. 1422050-75-6, Pimodivir, Barlow Savir, flu vaccine or a combination of them.
  16. 权利要求1-11任意一项所述的化合物或权利要求12-15任意一项所述的药物组合物在制备药物中的用途，其中所述药物用于预防、治疗或减轻患者病毒感染性疾病。Use of the compound according to any one of claims 1-11 or the pharmaceutical composition according to any one of claims 12-15 in the preparation of a medicine, wherein the medicine is used to prevent, treat or alleviate viral infectious diseases in patients .
  17. 根据权利要求16所述的用途，其中所述病毒感染为流感病毒感染。The use according to claim 16, wherein the viral infection is influenza virus infection.
  18. 权利要求1-11任意一项所述的化合物或权利要求12-15任意一项所述的药物组合物在制备药物中的用途，其中所述药物用于抑制流感病毒的RNA聚合酶。The use of the compound according to any one of claims 1-11 or the pharmaceutical composition according to any one of claims 12-15 in the preparation of a medicine, wherein the medicine is used to inhibit the RNA polymerase of influenza virus.
  19. 根据权利要求18所述的用途，其中所述RNA聚合酶为帽依赖性核酸内切酶。The use according to claim 18, wherein the RNA polymerase is a cap-dependent endonuclease.
PCT/CN2020/139363 2019-12-27 2020-12-25 Influenza virus replication inhibitor and use thereof WO2021129799A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911374750 2019-12-27
CN201911374750.4 2019-12-27

Publications (1)

Publication Number Publication Date
WO2021129799A1 true WO2021129799A1 (en) 2021-07-01

Family

ID=76508241

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/139363 WO2021129799A1 (en) 2019-12-27 2020-12-25 Influenza virus replication inhibitor and use thereof

Country Status (2)

Country Link
CN (1) CN113045589A (en)
WO (1) WO2021129799A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017137291A (en) * 2016-02-03 2017-08-10 塩野義製薬株式会社 Polycyclic pyridone derivative and prodrug thereof
WO2018030463A1 (en) * 2016-08-10 2018-02-15 塩野義製薬株式会社 Substituted polycyclic pyridone derivative and pharmaceutical composition containing prodrug thereof
CN107709321A (en) * 2015-04-28 2018-02-16 盐野义制药株式会社 The polycyclic Pyridione derivatives and its prodrug being substituted
CN109721615A (en) * 2017-09-18 2019-05-07 广东东阳光药业有限公司 Inhibitors of influenza viruses replication and application thereof

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ545157A (en) * 2003-08-12 2009-03-31 Achillion Pharmaceuticals Inc Isothiazoloquinolones and related compounds as anti-infective agents
RU2745071C2 (en) * 2015-12-15 2021-03-18 Сионоги Энд Ко., Лтд. Drug for influenza treatment, characterized by the fact that it combines a per-dependent endonuclease inhibitor and a drug against flu
CN110041327B (en) * 2018-01-17 2022-01-21 江西彩石医药科技有限公司 Pyridone derivative, composition thereof and application of pyridone derivative as anti-influenza virus medicament
CA3088926A1 (en) * 2018-01-17 2019-07-25 Jiangxi Caishi Pharmaceutical Technology Co., Ltd. Pyridone derivative, composition and use as antiviral drug thereof
CN110117285B (en) * 2018-02-07 2023-02-03 广东东阳光药业有限公司 Inhibitors of influenza virus replication and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107709321A (en) * 2015-04-28 2018-02-16 盐野义制药株式会社 The polycyclic Pyridione derivatives and its prodrug being substituted
JP2017137291A (en) * 2016-02-03 2017-08-10 塩野義製薬株式会社 Polycyclic pyridone derivative and prodrug thereof
WO2018030463A1 (en) * 2016-08-10 2018-02-15 塩野義製薬株式会社 Substituted polycyclic pyridone derivative and pharmaceutical composition containing prodrug thereof
CN109721615A (en) * 2017-09-18 2019-05-07 广东东阳光药业有限公司 Inhibitors of influenza viruses replication and application thereof

Also Published As

Publication number Publication date
CN113045589A (en) 2021-06-29

Similar Documents

Publication Publication Date Title
TWI785116B (en) Inhibitors of influenza virus replication and uses thereof
CN109641868B (en) Inhibitors of influenza virus replication and methods of use and uses thereof
CN109748915B (en) Inhibitors of influenza virus replication and methods of use and uses thereof
CN108218873B (en) Inhibitors of influenza virus replication and uses thereof
US10501444B2 (en) Inhibitors of influenza virus replication, application methods and uses thereof
CN111057074B (en) Inhibitors of influenza virus replication and uses thereof
KR20130128436A (en) Inhibitors of influenza viruses replication
CN108276401B (en) Inhibitors of influenza virus replication and uses thereof
CN108727369B (en) Influenza virus replication inhibitors and uses thereof
CN113286793A (en) Pyrrolopyrazine and pyridotriazine influenza virus replication inhibitors
CN110117285B (en) Inhibitors of influenza virus replication and uses thereof
US10927118B2 (en) Inhibitors of influenza virus replication and uses thereof
CN113614085B (en) Inhibitors of influenza virus replication and uses thereof
WO2021129799A1 (en) Influenza virus replication inhibitor and use thereof
TWI821343B (en) Inhibitors of influenza virus replication
CN113416198A (en) Fused polycyclic pyridone derivative and application thereof
CN114276344A (en) Pyridazinone derivative and application thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20905319

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20905319

Country of ref document: EP

Kind code of ref document: A1