WO2020177715A1 - Influenza virus replication inhibitor and use thereof - Google Patents

Influenza virus replication inhibitor and use thereof Download PDF

Info

Publication number
WO2020177715A1
WO2020177715A1 PCT/CN2020/077781 CN2020077781W WO2020177715A1 WO 2020177715 A1 WO2020177715 A1 WO 2020177715A1 CN 2020077781 W CN2020077781 W CN 2020077781W WO 2020177715 A1 WO2020177715 A1 WO 2020177715A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
atoms
alkoxy
alkylamino
Prior art date
Application number
PCT/CN2020/077781
Other languages
French (fr)
Chinese (zh)
Inventor
任青云
罗慧超
殷俊俊
吴春林
范钰新
莫玉峰
张英俊
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
Priority to CN202080018045.5A priority Critical patent/CN113614085B/en
Publication of WO2020177715A1 publication Critical patent/WO2020177715A1/en

Links

Classifications

    • 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
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a new type of compound as an inhibitor of influenza virus replication and a preparation method thereof, a pharmaceutical composition containing the compound, and the application 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 elderly and children with weakened immune systems and some patients with immune disorders.
  • the influenza 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. Each pandemic is due to the emergence of new strains of viruses in humans. Usually, these new strains are caused by the spread of existing influenza viruses from other animal species to 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 is composed 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.
  • Influenza A virus has one species, influenza A virus. Wild waterbirds are the natural hosts for a large number of influenza A viruses. Sometimes the virus spreads to other species and can 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 widespread 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 H9N2, H7N2, H7N3 and H10N7.
  • Type B influenza virus has one species, type B influenza virus, which often causes local influenza epidemics, does not cause global influenza outbreaks, and is only found in humans and seals. This type of influenza mutates at a rate 2-3 times slower than type A, so the genetic diversity is low and there is only one type B influenza serotype. Due to the lack of such antigen diversity, humans usually acquire a certain degree of influenza B immunity at an early age. However, the type B influenza mutation is enough to make it impossible for humans to be permanently immune. However, due to its low rate of antigen change, combined with its restricted host changes (inhibiting cross-species antigen transition), to ensure that influenza B pandemic will 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 epidemic 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 translation system.
  • the 5'cap structure is a 10-13 nucleotide (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 viruses. 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 viruses and affect 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 that can treat influenza through this mechanism of action are still urgently needed by scientists.
  • 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 (cap-dependent endonuclease)
  • caps-dependent endonuclease Such compounds and their compositions can be used to prepare drugs for preventing, treating or alleviating viral infections in patients.
  • the compound of the present invention can not only inhibit influenza virus well, but also has lower cytotoxicity, better in vivo pharmacokinetic properties and in vivo pharmacodynamic properties, and better liver Microsome stability. Therefore, the compound provided by the present invention has better druggability than 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, pharmaceutical Acceptable salts or their prodrugs,
  • U 1 is CR 1 or N
  • U 2 is CR 2 or N
  • U 3 is CR 3 or N
  • U 4 is CR 4 or N
  • U 5 is CR 5 or N
  • U 6 is CR 6 or N
  • U 7 is CR 7 or N
  • U 8 is CR 8 or N
  • Each Y and Z is independently C 1-6 alkyl
  • Each R Pf is independently H, deuterium, or C 1-6 alkyl
  • Each R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently C 1-6 alkyl, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl, Heterocyclic group consisting of 3-8 atoms, (heterocyclic group consisting of 3-8 atoms) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-4 alkyl, Heteroaryl group consisting of 5-10 atoms, (heteroaryl group consisting of 5-10 atoms) C 1-4 alkyl, C 1-6 alkylamino, C 1-6 alkylthio or C 1-6 alkane Group silyl group, wherein the C 1-6 alkyl group, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl group, 3-8 atoms heterocyclic group, (3 -8-atom heterocyclic group) C 1-4 alkyl, C 6-10 aryl
  • Each R Pg and R Ph is independently composed of C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 carbocyclyloxy, C 3-8 carbocyclylamino, 3-8 atoms Heterocyclyloxy, heterocyclylamino consisting of 3-8 atoms, C 6-10 aryloxy, C 6-10 arylamino, heteroaryloxy consisting of 5-10 atoms or 5- A 10-atom heteroarylamino group, wherein the C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-8 carbocyclyloxy group, C 3-8 carbocyclylamino group, 3-8 3-atom heterocyclyloxy, 3-8 heterocyclic amino, C 6-10 aryloxy, C 6-10 arylamino, 5-10 heteroaryloxy A group and a heteroarylamino group consisting of 5-10 atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br,
  • Each R a and R b are independently H, deuterium, F, Cl, Br, I , -CN, -NH 2, -OH, -SH, C 1-6 alkyl, C 2-6 alkenyl group, C 2 -6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, C 3-6 cycloalkyl, composed of 3-6 atoms heterocyclyl, C 6-10 aryl, or 5-6 atoms heteroaryl; or R a, R b and the carbon atom to which they are attached together form a C 3-6 carbocyclic ring of 3-6 atoms or Composed of heterocycles;
  • Each R c is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 A heterocyclic group consisting of atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 atoms;
  • R 11 is H, deuterium, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio Group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-4 alkyl, 3-8 heterocyclic group, ( 3-8 atoms heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl or ( Heteroaryl composed of 5-10 atoms) C 1-4 alkyl, wherein the C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkylamino, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycl
  • q 0, 1 or 2;
  • r is 1, 2, 3 or 4;
  • Each p, t or s is independently 0, 1, 2, 3 or 4;
  • the compound does not include the following compounds:
  • R 11 is H, deuterium, C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-2 alkyl group, composed of 5-6 atoms
  • the heterocyclic group (heterocyclic group composed of 5-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl, 5-6 atoms Heteroaryl group or (heteroaryl group consisting of 5-6 atoms) C 1-2 alkyl, wherein the C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C
  • R 11 is H, deuterium, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl , Tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethyl Amino, N,N-diethylamino, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl , Thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetra
  • each of R a and R b are independently H, deuterium, F, Cl, Br, I , -CN, -NH 2, -OH, -SH, methyl, ethyl, n-propyl, Isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3 to 6 atoms heterocyclyl, phenyl, or 5-6 atoms heteroaryl; or R a, R b and the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, Group, cyclohexyl or heterocyclic ring composed of 3-6 atoms;
  • Each R c is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, ring Hexyl, 3-6 heterocyclic group, phenyl or 5-6 heteroaryl.
  • Each Y and Z is independently C 1-4 alkyl
  • Each R Pf is independently H, deuterium, or C 1-6 alkyl
  • Each R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently C 1-4 alkyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-2 alkyl, Heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-2 alkyl, Heteroaryl group consisting of 5-6 atoms, (heteroaryl group consisting of 5-6 atoms) C 1-2 alkyl, C 1-4 alkylamino, C 1-4 alkylthio or C 1-4 alkane Group silyl group, wherein the C 1-4 alkyl group, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl group, heterocyclic group consisting of 3-6 atoms, (3 -6-atom heterocyclic group) C 1-2 alkyl, C 6-10
  • Each R Pg and R Ph are independently composed of C 1-4 alkoxy, C 1-4 alkylamino, C 3-6 carbocyclyloxy, C 3-6 carbocyclylamino, and 3-6 atoms Heterocyclyloxy, heterocyclylamino consisting of 3-6 atoms, C 6-10 aryloxy, C 6-10 arylamino, heteroaryloxy consisting of 5-6 atoms or 5- 6-atom heteroarylamino group, wherein the C 1-4 alkoxy group, C 1-4 alkylamino group, C 3-6 carbocyclyloxy group, C 3-6 carbocyclylamino group, 3-6 3-atom heterocyclyloxy, 3-6 heterocyclic amino, C 6-10 aryloxy, C 6-10 arylamino, 5-6 heteroaryloxy A group and a heteroarylamino group consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br,
  • P is H, deuterium
  • 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,
  • P, U 1 , U 2 , U 3 , U 4 , U 5 , U 6 , U 7 , U 8 , R 9 and R 10 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.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle, or a combination thereof.
  • 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 other therapeutic agent is Amantadine, Rimantadine, Oseltamivir, Zanamivir, Peramivir, Peramivir Nimvir (Laninamivir), Laninamivir Octanoate Hydrate, Favipiravir, Arbidol, 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 their combination.
  • the pharmaceutical composition can 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 medicament, wherein the medicament is used to prevent, treat or alleviate viral infectious diseases in patients.
  • the present invention provides a method for preventing, treating or alleviating viral infectious diseases in patients, which comprises administering to the patient an effective amount of the compound of the present invention or the pharmaceutical composition of the present invention.
  • the present invention provides the use of the compound or the pharmaceutical composition of the present invention for preventing, treating or alleviating 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 present invention provides a method for inhibiting the RNA polymerase of influenza virus, which comprises administering an effective amount of the compound or the pharmaceutical composition of the present invention to the patient.
  • the present invention provides the use of the compound or the pharmaceutical composition of the present invention 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 can form solvates with pharmaceutically acceptable solvents (including water) either inherently or by design; 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 compounds of the present invention may exist in one form of possible isomers, rotamers, atropisomers, and tautomers or in the form of mixtures 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, or 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 those in which 3 H, 14 C and 18 F are present, or non-radioactive isotopes, Such as 2 H and 13 C compounds.
  • radioactive isotopes such as those in which 3 H, 14 C and 18 F are present
  • non-radioactive isotopes such as 2 H and 13 C compounds.
  • the present invention relates to a method for the preparation, isolation and purification of the compound contained in formula (I) or formula (II).
  • 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.
  • 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 may 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
  • 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.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L or R and S are used to denote 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 the compound, where (-) or l indicates that the compound is levorotatory.
  • the prefix (+) or d indicates that the compound is 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 racemate. When there is no stereoselectivity or stereospecificity in a chemical reaction or method, the racemic mixture or racemate may occur Spin body.
  • any asymmetric atom (e.g., carbon, etc.) of the compound of the present invention can 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 in the (R)- or (S)- configuration, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • substituents on atoms with unsaturated double bonds may exist in cis-(Z)- or trans-(E)- forms.
  • the compound of the present invention can be one of the possible isomers or a mixture of them, such as racemates and diastereoisomer mixtures (depending on the number of asymmetric carbon atoms) The form exists.
  • the 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 E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be in 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 methods familiar to those skilled in the art by known methods, for example, by performing diastereomeric salts of the obtained 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, For example, it is 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.
  • the corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) to form N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • 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.
  • LWDeady Syn.Comm.1977, 7,509-514
  • 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.
  • metabolite refers to a product obtained by 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, acylating, deamidating, esterifying, degreasing, enzymatic cleavage and the like 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 to us 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 other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid 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, pic
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the quaternary ammonium salt formed by any compound containing the N group.
  • 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 include appropriate, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and 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 maternal 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, which 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 you can 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 contained in the examples.
  • substituents such as the compounds of the general formula above, or the special examples, subclasses, and subclasses contained 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).
  • the term “5-10 atom heteroaryl group” especially refers to the independently disclosed 5-atom heteroaryl group, 6-atom heteroaryl group, 7-atom heteroaryl group, and 8-atom heteroaryl group. Heteroaryl, 9-atom heteroaryl and 10-atom heteroaryl.
  • 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 refers to a saturated linear or branched monovalent hydrocarbon radical containing 1-20 carbon atoms.
  • the alkyl group contains 1-12 carbon atoms, ie C 1-12 alkyl; in some embodiments, the alkyl group contains 1-10 carbon atoms, ie C 1-10 alkane
  • 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 alkyl;
  • the alkyl group contains 1-4 carbon atoms, ie, C 1-4 alkyl; in some embodiments, the alkyl group contains 1-2 carbon atoms, ie C 1-2 alkyl.
  • the alkyl group represents a linked alkylene group.
  • 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 site of unsaturation, that is, there is a carbon-carbon sp 2 double bond, wherein the alkenyl group Groups can be optionally substituted with one or more substituents described in the present invention, 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 another embodiment, the alkenyl group contains 2-6 carbon atoms, ie C 2-6 Alkenyl; In yet another embodiment, 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 unsaturation site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted by one or more substituents described in the present invention.
  • the alkynyl group contains 2-8 carbon atoms, namely C 2-8 alkynyl; in other embodiments, the alkynyl group contains 2-6 carbon atoms, namely C 2-6 Alkynyl; In still other 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 ), etc. .
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention.
  • the alkoxy group contains 1-6 carbon atoms, namely C1-6 alkoxy; in other embodiments, the alkoxy group contains 1-4 carbon atoms, namely C C1-4 alkoxy; in still other embodiments, the alkoxy group containing 1-2 carbon atoms, i.e. C 1-2 alkoxy.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), n-propyloxy (1-propoxy, n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), isopropyloxy (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-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t- BuO,t-butoxy, -OC(CH 3 ) 3 ), 1-pentoxy (n-pentoxy, -OCH 2 CH 3
  • Carbocyclyloxy means a carbocyclyl group, a heterocyclyl group, an aryl group or a hetero
  • the aryl group is connected to the rest of the molecule through an oxygen atom
  • the "carbocyclyl”, “heterocyclic”, “aryl” and “heteroaryl” groups have the meanings described in the present invention. Examples of this include, but are not limited to,
  • alkylthio refers to a group in which a linear or branched alkyl group containing 1-10 carbon atoms is attached to a divalent sulfur atom.
  • the alkylthio group contains 1-6 carbon atoms, that is, C 1-6 alkylthio; in some embodiments, the alkylthio contains 1-4 carbon atoms, that is, C 1-4 alkylthio In some embodiments, in some embodiments, the alkylthio group contains 1-2 carbon atoms, ie, C 1-2 alkylthio. Examples of alkylthio groups include, but are not limited to, methylthio (-SCH 3 ). The alkylthio group is optionally substituted with one or more substituents described in the present invention.
  • haloalkyl means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms.
  • Such examples include, but are not limited to, monofluoromethyl (-CH 2 F), difluoromethyl (-CHF 2 ), trifluoromethyl (-CF 3 ), fluoroethyl (-CHFCH 3 ,- CH 2 CH 2 F), difluoroethyl (-CF 2 CH 3 , -CHFCH 2 F, -CH 2 CHF 2 ), perfluoroethyl, fluoropropyl (-CHFCH 2 CH 3 , -CH 2 CHFCH 3 ,-CH 2 CH 2 CH 2 F), difluoropropyl (-CF 2 CH 2 CH 3 , -CFHCFHCH 3 , -CH 2 CH 2 CHF 2 , -CH 2 CF 2 CH 3 , -CH 2 CHFCH 2 F
  • 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 carbocyclyl; in other embodiments, the number of carbon atoms is 3-6, that is, C 3-6 carbon Cyclic group; in other embodiments, the number of carbon atoms is 5-6, that is, C 5-6 carbocyclyl; in other embodiments, the number of carbon atoms is 5-8, that is, C 5- 8 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 ring system containing 3-12 carbon atoms.
  • the cycloalkyl group contains 3-12 carbon atoms, ie C 3-12 cycloalkyl; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms, ie C 3-8 ring Alkyl; In still other embodiments, cycloalkyl contains 3-6 carbon atoms, ie C 3-6 cycloalkyl.
  • 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 this invention.
  • heteroatom refers to O, S, N, P and Si, including the forms of 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).
  • heterocycle refers to a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 3-14 ring atoms, wherein One or more atoms in the ring are independently replaced by heteroatoms, and the heteroatoms have the meaning as described in the present invention.
  • the ring may be fully saturated or contain one or more degrees of unsaturation, but an aromatic ring is not allowed.
  • a “heterocyclic”, “heterocyclyl” or “heterocyclic” group is a ring system consisting of 3-8 ring atoms; in other embodiments, “heterocyclic", “heterocyclic” A “cyclic” or “heterocyclic” group is a ring system composed of 3-6 ring atoms; in some other embodiments, the "heterocyclic", “heterocyclic” or “heterocyclic” group is 5 -6 ring system consisting of ring atoms; in some other embodiments, “heterocyclic", “heterocyclyl” or “heterocyclic” group is a ring system consisting of 4 ring atoms; in some other embodiments In this, “heterocyclic", “heterocyclyl” or “heterocyclic” group is a ring system composed of 5 ring atoms; in some other embodiments, “heterocyclic”, “heterocyclyl” or “
  • a “heterocyclic”, “heterocyclyl” or “heterocyclic” group is a monocyclic ring composed of 3-8 atoms (2-6 carbon atoms and selected from N, O, P, S 1-3 heteroatoms), or 7-12 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S).
  • the "heterocyclic”, “heterocyclic” or “heterocyclic” group is optionally substituted with one or more substituents described in the present invention.
  • 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, 2-pyrrolinyl, 3-pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, disulfide ring Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Dioxanyl, Dithianyl, Thioxanyl, Homopiperazinyl, Homopiperidin
  • 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.
  • aryl or "aromatic ring” are used interchangeably herein and refer to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, in which at least one ring system is aromatic, 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.
  • the aryl group contains a carbocyclic ring system of 6-12 ring atoms, that is, a C 6-12 aryl group.
  • the aryl group contains a carbocyclic ring system of 6-10 ring atoms, that is, a C 6-10 aryl group.
  • 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.
  • heteroaryl refers to a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, wherein At least one ring system is aromatic, and at least one ring contains one or more heteroatoms.
  • the heteroaryl group is a heteroaryl group consisting of 5-10 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • the heteroaryl group is a heteroaryl group consisting of 5-8 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a 5-atom heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a 6-atom heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • 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 (such as 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (such as 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 (
  • n typically describes the number of ring atoms in a molecule, and the number of ring atoms in the molecule is n.
  • piperidinyl is a 6-atom heterocyclic group
  • naphthyl is a 10-atom aryl group.
  • unsaturated means that the group contains one or more degrees of unsaturation.
  • halogen refers to F, Cl, Br or I.
  • hydroxyl means -OH.
  • cyano means -CN.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups (-OH), and the alkyl group has the meaning described in the present invention, wherein the hydroxyalkyl group may optionally be substituted by one or Multiple substituents described in this invention are substituted.
  • the hydroxyalkyl group in the present invention refers to a C 1-6 alkyl group substituted by one or more hydroxy groups (-OH), that is, a hydroxy C 1-6 alkyl group; in some embodiments
  • the hydroxyalkyl group refers to a C 1-4 alkyl group substituted by one or more hydroxy groups (-OH), that is, a hydroxy C 1-4 alkyl group; in some embodiments, the hydroxyalkyl group It refers to a C 1-2 alkyl group substituted with one or more hydroxy groups (-OH), that is, a hydroxy C 1-2 alkyl group.
  • hydroxyalkyl groups include, but are not limited to, hydroxymethyl (e.g., -CH 2 OH), hydroxyethyl (e.g., 2-hydroxyethyl), hydroxy n-propyl (e.g., -CH 2 CH 2 CH 2 OH), etc.
  • aminoalkyl refers to an alkyl group substituted with one or more amino groups (-NH 2 ).
  • the alkyl group has the meaning described in the present invention, wherein the aminoalkyl group may optionally be substituted by one Or multiple substituents described in the present invention.
  • the aminoalkyl group of the present invention refers to a C 1-6 alkyl group substituted by one or more amino groups (-NH 2 ), that is, an amino C 1-6 alkyl group; in some In embodiments, an aminoalkyl group refers to a C 1-4 alkyl group substituted with one or more amino groups (-NH 2 ), that is, an amino C 1-4 alkyl group; in some embodiments, an aminoalkyl group The group refers to a C 1-2 alkyl group substituted with one or more amino groups (-NH 2 ), that is, an amino C 1-2 alkyl group.
  • aminoalkyl groups include, but are not limited to, aminomethyl (-CH 2 NH 2 ), dimethylaminomethyl (-CH(NH 2 ) 2 ), aminoethyl (for example, 2-aminoethyl ), amino n-propyl (for example, -CH 2 CH 2 CH 2 NH 2 ), and so on.
  • cyanoalkyl refers to an alkyl group substituted with one or more cyano groups (-CN), and the alkyl group has the meaning described in the present invention, wherein the cyanoalkyl group may optionally It is substituted by one or more substituents described in the present invention.
  • the cyanoalkyl group described in the present invention refers to a C 1-6 alkyl group substituted with one or more cyano groups (-CN), that is, a cyano C 1-6 alkyl group;
  • a cyanoalkyl group refers to a C 1-4 alkyl group substituted with one or more cyano groups (-CN), that is, a cyano C 1-4 alkyl group;
  • the cyanoalkyl group refers to a C 1-2 alkyl group substituted by one or more cyano groups (-CN), that is, a cyano C 1-2 alkyl group.
  • cyanoalkyl groups include, but are not limited to, cyanomethyl (e.g., -CH 2 CN), cyanoethyl (e.g., 2-cyanoethyl), and the like.
  • carboxyalkyl refers to an alkyl group substituted with one or more carboxyl groups (-COOH), and the alkyl group has the meaning described in the present invention, wherein the carboxyalkyl group may optionally be substituted by one or Multiple substituents described in this invention are substituted.
  • the carboxyalkyl group of the present invention refers to a C 1-6 alkyl group substituted by one or more carboxy groups (-COOH), that is, a carboxy C 1-6 alkyl group; in some embodiments
  • a carboxyalkyl group refers to a C 1-4 alkyl group substituted by one or more carboxy groups (-COOH), that is, a carboxy C 1-4 alkyl group; in some embodiments, a carboxyalkyl group It refers to a C 1-2 alkyl group substituted with one or more carboxyl groups (-COOH), that is, a carboxy C 1-2 alkyl group.
  • carboxyalkyl groups include, but are not limited to, carboxymethyl, carboxyethyl (for example, 2-carboxyethyl), carboxy n-propyl (for example, -CH 2 CH 2 CH 2 COOH), carboxyisopropyl Group (for example, -C(CH 3 ) 2 COOH) and so on.
  • 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, ie, 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.
  • an alkylamino group or two C 1-2 alkyl groups attached to the nitrogen atom of the alkylamino group i.e. C 1-2 alkylamino.
  • Suitable alkylamino groups can be monoalkylamino or dialkylamino. Examples of such include, but are not limited to, methylamino (-NHCH 3 ), ethylamino (-NHCH 2 CH 3 ), N, N -Dimethylamino, N,N-diethylamino, etc.
  • Carbocyclylamino means that the amino group is covered by one or two carbocyclyl, heterocyclyl, aryl or heteroaryl groups.
  • substituted groups include, but are not limited to, N-cyclopropylamino, N-pyrrolidinylamino, N-phenylamino, N-pyrimidinylamino, and the like.
  • cycloalkyl-alkyl refers to cycloalkyl, carbon Cyclic, heterocyclic, aryl and heteroaryl are connected to the rest of the molecule through -alkyl-, wherein the alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl groups all have As defined in the present invention, such as benzyl (-CH 2 -Ph),
  • the "cycloalkyl-alkyl”, “carbocyclyl-alkyl”, “heterocyclyl-alkyl”, “aryl-alkyl” and “heteroaryl-alkyl” groups optionally It is substituted by one or more substituents described in the present 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 upset, dizziness, and the like.
  • pharmaceutically acceptable refers to those approved by a federal regulatory agency or a national government or listed in the US Pharmacopeia or other generally recognized pharmacopoeia for use in animals, more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered.
  • These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • Water and aqueous solutions Saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, especially injectable solutions. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • 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 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 effect of another anti-influenza therapy used.
  • the exact amount of the 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, 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 both therapeutic and prophylactic treatment.
  • therapeutic treatment includes alleviating or improving 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 treatments include 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 the 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. "Carboxy 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 please 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 novel compounds as inhibitors of influenza virus RNA polymerase, more specifically, the present invention provides a class of novel 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 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, pharmaceutical Acceptable salts or their prodrugs,
  • R 9 and R 10 have the definitions described in the present invention, wherein R 9 and R 10 are not at the same time Is H, and the compound of the present invention does not include the following compounds:
  • U 1 is CR 1 or N;
  • U 2 is CR 2 or N;
  • U 3 is CR 3 or N
  • U 4 is CR 4 or N;
  • U 5 is CR 5 or N;
  • U 6 is CR 6 or N;
  • U 7 is CR 7 or N;
  • U 8 is CR 8 or N
  • Each R a and R b are independently H, deuterium, F, Cl, Br, I , -CN, -NH 2, -OH, -SH, C 1-6 alkyl, C 2-6 alkenyl group, C 2 -6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, C 3-6 cycloalkyl, composed of 3-6 atoms heterocyclyl, C 6-10 aryl, or 5-6 atoms heteroaryl; or R a, R b and the carbon atom to which they are attached together form a C 3-6 carbocyclic ring of 3-6 atoms or Composed of heterocycles;
  • Each R c is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 A heterocyclic group consisting of atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 atoms;
  • R 11 is H, deuterium, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio Group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-4 alkyl, 3-8 heterocyclic group, ( 3-8 atoms heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl or ( Heteroaryl composed of 5-10 atoms) C 1-4 alkyl, wherein the C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkylamino, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocycl
  • q 0, 1 or 2;
  • r is 1, 2, 3 or 4;
  • Each p, t, or s is independently 0, 1, 2, 3, or 4.
  • Each Y and Z is independently C 1-6 alkyl
  • Each R Pf is independently H, deuterium, or C 1-6 alkyl
  • Each R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently C 1-6 alkyl, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl, Heterocyclic group consisting of 3-8 atoms, (heterocyclic group consisting of 3-8 atoms) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-4 alkyl, Heteroaryl group consisting of 5-10 atoms, (heteroaryl group consisting of 5-10 atoms) C 1-4 alkyl, C 1-6 alkylamino, C 1-6 alkylthio or C 1-6 alkane Group silyl group, wherein the C 1-6 alkyl group, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl group, 3-8 atoms heterocyclic group, (3 -8-atom heterocyclic group) C 1-4 alkyl, C 6-10 aryl
  • Each R Pg and R Ph is independently composed of C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 carbocyclyloxy, C 3-8 carbocyclylamino, 3-8 atoms Heterocyclyloxy, heterocyclylamino consisting of 3-8 atoms, C 6-10 aryloxy, C 6-10 arylamino, heteroaryloxy consisting of 5-10 atoms or 5- A 10-atom heteroarylamino group, wherein the C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-8 carbocyclyloxy group, C 3-8 carbocyclylamino group, 3-8 3-atom heterocyclyloxy, 3-8 heterocyclic amino, C 6-10 aryloxy, C 6-10 arylamino, 5-10 heteroaryloxy A group and a heteroarylamino group consisting of 5-10 atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br,
  • R 11 is H, deuterium, C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-2 alkyl group, composed of 5-6 atoms
  • the heterocyclic group (heterocyclic group composed of 5-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl, 5-6 atoms Heteroaryl group or (heteroaryl group consisting of 5-6 atoms) C 1-2 alkyl, wherein the C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C
  • R 11 is H, deuterium, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethyl Amino, N,N-diethylamino, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholine Group, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, te
  • each of R a and R b are independently H, deuterium, F, Cl, Br, I , -CN, -NH 2, -OH, -SH, C 1-4 alkyl, C 2- 4 Alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5 to 6 atoms heterocyclyl, C 6-10 aryl, or 5-6 atoms heteroaryl; or R a, R b and the carbon atom to which they are attached together form a C 3-6 carbocyclic ring Or a heterocyclic ring composed of 5-6 atoms.
  • each R c is independently H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkane Group, heterocyclic group consisting of 5-6 atoms, C 6-10 aryl group or heteroaryl group consisting of 5-6 atoms.
  • each of R a and R b are independently H, deuterium, F, Cl, Br, I , -CN, -NH 2, -OH, -SH, methyl, ethyl, n-propyl, Isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3 to 6 atoms heterocyclyl, phenyl, or 5-6 atoms heteroaryl; or R a, R b and the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, Group, cyclohexyl or heterocyclic ring composed of 3-6 atoms.
  • each R c is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, heterocyclic group composed of 3-6 atoms, phenyl group or heteroaryl group composed of 5-6 atoms.
  • each Y and Z is independently C 1-4 alkyl.
  • each R Pf is independently H, deuterium, or C 1-6 alkyl.
  • each of R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently C 1-4 alkyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl C 1-2 alkyl, heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl, heteroaryl composed of 5-6 atoms, (heteroaryl composed of 5-6 atoms) C 1-2 alkyl, C 1-4 alkylamino, C 1-4 alkylthio Or C 1-4 alkylsilyl group, wherein the C 1-4 alkyl group, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl group, 3-6 atoms Heterocyclic group, (heterocyclic group consisting of 3-6 atoms) C 1-2 alkyl, C 6-10
  • each R Pg and R Ph is independently C 1-4 alkoxy, C 1-4 alkylamino, C 3-6 carbocyclyloxy, C 3-6 carbocyclylamino, 3 -6-atom heterocyclyloxy, 3-6 heterocyclylamino, C 6-10 aryloxy, C 6-10 arylamino, 5-6 heteroaromatic Oxy group or heteroarylamino group consisting of 5-6 atoms, wherein the C 1-4 alkoxy group, C 1-4 alkylamino group, C 3-6 carbocyclic oxy group, C 3-6 carbocyclic group Amino group, heterocyclyloxy group consisting of 3-6 atoms, heterocyclylamino group consisting of 3-6 atoms, C 6-10 aryloxy group, C 6-10 arylamino group, 5-6 atoms
  • the heteroaryloxy group composed of 5-6 atoms and the heteroarylamino group composed of 5-6 atoms are each independently unsubstituted or substituted with 1,
  • P is H, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl-methyl, cyclopentyl -Methyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 2-oxo- 1,3-dioxolanyl, 2-oxo-1,3-dioxolane, 2-oxo-1,3-dioxolane-methyl, phenyl, phenyl -Methyl, furanyl, furanone, pyrrolyl, pyridyl, pyrimidinyl,
  • each Y and Z is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl.
  • each R Pf is independently H, deuterium, methyl, ethyl, n-propyl, or isopropyl.
  • each of R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclo Pentyl, cyclohexyl, cyclohexyl-methyl, cyclopentyl-methyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorph Linyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 2-oxo-1,3-dioxolanyl, 2-oxo-1,3-dioxolyl, 2 -Oxo-1,3-dioxolanyl-methyl, phenyl, phenyl-methyl, fur
  • each R Pg and R Ph is independently methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy, methylamino, ethylamino, n-propylamino , Isopropylamino, tert-butylamino, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclopropylamino, cyclobutylamino, cyclopentylamino, 3-6 atoms Heterocyclyloxy, 3-6 heterocyclic amino, phenyloxy, phenylamino, 5-6 heteroaryloxy or 5-6 heteroaryl Group amino, wherein the methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy, methylamino, ethylamino, n-propylamino, isopropylamino
  • P is H, deuterium
  • 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,
  • the present invention relates to one of the following compounds or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs , But not limited to these compounds:
  • the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.
  • the pharmaceutical composition provided by the present invention further comprises one or more other therapeutic agents.
  • the other therapeutic agent is selected from anti-influenza virus agents or vaccines.
  • the other therapeutic agent is Amantadine, Rimantadine, Oseltamivir, Zanamivir, Peramivir, Peramivir Nimvir (Laninamivir), Laninamivir Octanoate Hydrate, Favipiravir, Arbidol, 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 their combination.
  • the pharmaceutical composition can 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 medicament, wherein the medicament is used to prevent, treat or alleviate viral infectious diseases in patients.
  • the present invention provides a method for preventing, treating or alleviating viral infectious diseases in patients, which comprises administering to the patient an effective amount of the compound of the present invention or the pharmaceutical composition of the present invention.
  • the present invention provides the use of the compound or the pharmaceutical composition of the present invention for preventing, treating or alleviating 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 present invention provides a method for inhibiting the RNA polymerase of influenza virus, which comprises administering an effective amount of the compound or the pharmaceutical composition of the present invention to the patient.
  • the present invention provides the use of the compound or the pharmaceutical composition of the present invention 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 carrier.
  • the carrier of the present invention includes, but is not limited to, excipients, diluents, adjuvants, vehicles, or any combination thereof.
  • the present invention also includes a method for treating or alleviating influenza virus infectious diseases in patients, or susceptible to this disease.
  • the method includes 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, which comprises 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 carrier, diluent, adjuvant or vehicle, and optionally, other therapeutic and/or preventive components.
  • the pharmaceutical composition includes an effective amount of at least one pharmaceutically acceptable carrier, adjuvant, vehicle, or a combination thereof.
  • the amount of the compound in the composition of the present invention can effectively treat or alleviate influenza virus infectious diseases in patients.
  • 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 invention, their metabolites or their residues.
  • the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof, which, as used in the present invention, includes any solvent, diluent, Or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for specific target dosage forms.
  • a pharmaceutically acceptable carrier includes any solvent, diluent, Or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc.
  • substances that can be used as pharmaceutically acceptable carriers 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.
  • oils e.g. peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil
  • glycols e.g. propylene glycol or poly Ethylene glycol
  • esters e.g. ethyl oleate and ethyl laurate
  • agar e.g.
  • magnesium hydroxide and aluminum hydroxide examples include alginic acid, pyrogen-free water, isotonic saline, Ringer's solution (Ringer'ssolution), ethanol and phosphate buffers, and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as colorants, anti-sticking agents, coating agents, Sweetening 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 method, according to the severity of the infection being treated, oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (as by powder, ointment or drops) ), oral or nasal spray, etc. to 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 wetting agents
  • 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, U.S.P. and isotonic sodium chloride solution can be used.
  • sterile non-volatile oil is used as a solvent or suspension medium in accordance with the usual practice.
  • any odorless nonvolatile oil can be used, including synthetic monoglycerides or diglycerides.
  • fatty acids such as octadecenoic acid, are used in the preparation of injections.
  • the sterilizing agent can be dissolved or dispersed in sterile water or other sterile injectable medium before use is sterilized for the injectable preparation.
  • the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal shape.
  • delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle.
  • An injectable storage form is made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. The release rate of the compound can be controlled according to the ratio of compound to polymer and the nature of the particular polymer used. 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.
  • composition for rectal or vaginal administration is especially a suppository prepared by mixing the compound of the present invention and a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or suppository wax.
  • a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax.
  • the carrier is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.
  • Oral solid dosage forms include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier 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, certain silicates and sodium carbonate, e) solution blockers, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) Wetting agents such as cetyl alcohol and glyceryl
  • excipients such as lactose or toffee and macromolecular polyethylene glycols
  • 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 field. 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. It is also possible to use excipients such as lactose or toffee and macromolecular polyethylene glycol to use similar types of solid compositions as fillers in soft and hard gel capsules.
  • the active compound may also be in a microencapsulated form with one or more of the aforementioned excipients.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical field.
  • 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.
  • such dosage forms may also contain other substances besides inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.
  • the dosage form may also contain buffering agents. 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.
  • buffering agents include polymers and waxes.
  • the topical or transdermal application dosage form of the compound of the present invention includes ointment, ointment, cream, lotion, gel, powder, solution, spray, inhalant or patch.
  • 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 skin patches that have 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 following techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used.
  • sterile non-volatile oil is used as a solvent or suspension medium in accordance with the usual practice. For this purpose, any odorless nonvolatile oil can be used, including synthetic monoglycerides or diglycerides.
  • oils such as olive oil or castor oil, especially in polyoxyethylated form
  • fatty acids such as octadecenoic acid and its glyceride derivatives
  • 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).
  • 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 that are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug.
  • 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 formulations (see above) or suitable enema formulations can be used to achieve local dripping to the lower intestinal tract.
  • Topical skin patches 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 carriers.
  • Carriers 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 carriers.
  • Suitable carriers 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 may 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 compound and pharmaceutical composition provided by the present invention are 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 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.
  • the virus is 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 of administration and frequency, etc., and needs to be determined by the attending physician Specific situation determination.
  • 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 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 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 singlet
  • d doublet, doublet
  • t triplet, triplet
  • m multiplet, multiplet
  • br broadened, wide Peak
  • dd doublet of doublets, doublet of doublet
  • dt doublet of triplets, doublet of doublet
  • Coupling constant expressed by J, in Hertz (Hz).
  • the test conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 ⁇ 30mm, 3.5 ⁇ m, 6min, flow rate 0.6mL/min, mobile phase: 5%- The ratio of 95% (CH 3 CN with 0.1% formic acid) in (H 2 O with 0.1% formic acid)) was detected by UV at 210 nm/254 nm, and electrospray ionization (ESI) was used.
  • 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.
  • ESI electrospray ionization source
  • the intermediate represented by formula (10) can be prepared by the method described in Synthesis Scheme 1. Among them, R 1 , R 2 , R 3 , R 4 and R 10 have the same definition as in the present invention.
  • compound (1) is reacted with 3-thiophene boronic acid under the action of Pd catalyst to obtain compound (2) .
  • Compound (2) is reacted with N-bromosuccinimide to obtain compound (3) .
  • compound (3) reacts with methyl benzoate-2-boronic acid under the action of Pd catalyst to obtain compound (4) ;
  • compound (4) is hydrolyzed under alkaline conditions to obtain compound (5) ;
  • compound (5) is polymerized Ring-closing under the action of phosphoric acid or thionyl chloride produces compound (6) ;
  • compound (6) produces intermediate (7) under the action of sodium borohydride;
  • compound (7) reacts with N-bromosuccinimide
  • the reaction obtains compound (8) ; finally, compound (8 ) reacts with compound (9) under the action of Pd catalyst to obtain intermediate (10) .
  • the intermediate represented by formula (5) can also be prepared by the method described in Synthesis Scheme 2.
  • R 1 , R 2 , R 3 and R 4 have the definitions described in the present invention.
  • compound (2) is reacted with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane under low temperature conditions to obtain compound (11) ;
  • compound ( 11) Reaction with ethyl benzoate under the action of Pd catalyst to obtain compound (12) ;
  • compound (12) is hydrolyzed under alkaline conditions to obtain intermediate (5) .
  • the intermediate represented by formula (10) can also be prepared by the method described in Synthesis Scheme 3. Among them, R 1 , R 2 , R 3 , R 4 and R 10 have the same definition as in the present invention.
  • compound (13) is reacted with compound (14) under the action of Pd catalyst to obtain compound (15) ;
  • compound (15) is reacted with N-bromosuccinimide to obtain compound (16) .
  • compound (16) is reacted with methyl benzoate-2-boronic acid under the action of Pd catalyst to obtain compound (17) ; compound (17) is hydrolyzed under alkaline conditions to obtain compound (18) ; compound (18) is polymerized Under the action of phosphoric acid, the ring is closed to form compound (19) ; under the action of sodium borohydride, compound (19) forms intermediate (10) .
  • the compound represented by formula (22) is prepared by the method described in Synthesis Scheme 4. Among them, R 1 , R 2 , R 3 , R 4 and R 10 have the definitions described in the present invention.
  • compound (10) and compound (20) are reacted in the presence of a condensing agent such as 1-propyl phosphoric anhydride to obtain compound (21) .
  • compound (21) removes the protective group Bn on the hydroxyl group to obtain the compound represented by formula (22) .
  • the compound represented by formula (22) can be separated by preparative chromatography to obtain corresponding stereoisomers.
  • the compound represented by formula (24) can be prepared by the method described in Synthesis Scheme 5. Wherein, P, R 1 , R 2 , R 3 , R 4 and R 10 have the definitions described in the present invention, wherein P is not H or deuterium.
  • compound (22) reacts with compound (23) under alkaline conditions to obtain compound (24) .
  • the compound represented by formula (24) can be separated by preparative chromatography to obtain corresponding stereoisomers.
  • the intermediate represented by formula (27) can be prepared by the method described in Synthesis Scheme 6. Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the definitions described in the present invention, and PG 1 is methyl or ethyl.
  • compound (2) and compound (25) react with Pd catalyst to obtain compound (26) ; compound (26) is hydrolyzed under alkaline conditions to obtain intermediate (27) .
  • the intermediate represented by formula (33) can be prepared by the method described in Synthesis Scheme 7. Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 10 have the same definition as in the present invention.
  • compound (28) reacts with N-bromosuccinimide to obtain compound (29) ;
  • compound (29) reacts with R 10 -H or its salt to obtain compound (30) ;
  • compound (30) is basic Under the conditions of hydrolysis, compound (31) is obtained ; compound (31) is ring-closed under the action of polyphosphoric acid or thionyl chloride to form compound (32) ; compound (32) is formed to intermediate (33) under the action of sodium borohydride.
  • the intermediate represented by formula (33) can also be prepared and synthesized by referring to the synthesis scheme 1.
  • the intermediate represented by formula (33) can also be prepared and synthesized by referring to the synthesis scheme 3.
  • the intermediate represented by formula (41) can be prepared by the method described in Synthesis Scheme 8. Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 have the same definition as in the present invention.
  • compound (34) is reacted with compound (13) under the action of Pd catalyst to obtain compound (35) ;
  • compound (35) is reacted with N-bromosuccinimide to obtain compound (36) .
  • Compound (36 ) is reacted with tert-butyl lithium at low temperature to obtain compound (37) .
  • compound (37) reacts with compound (42) under the action of Pd catalyst to obtain compound (38) ; compound (38) is hydrolyzed under alkaline conditions to obtain compound (39) ; compound (39) is closed under the action of polyphosphoric acid The ring produces compound (40) ; compound (40) produces intermediate (41) under the action of sodium borohydride.
  • the intermediate represented by formula (46) can be prepared by the method described in Synthetic Scheme 9. Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 11 have the same definition as in the present invention. Among them, compound (43) can be prepared by referring to Synthesis Scheme 7. First, compound (43) is reacted with N-bromosuccinimide to obtain compound (44) . Compound (44) is reacted with R 11 -H or its salt to obtain compound (45) . Compound (45) generates intermediate (46) under the action of sodium borohydride.
  • the intermediate represented by the formula (33) , the intermediate represented by the formula (41) and the intermediate represented by the formula (46) are used instead of the intermediate represented by the formula (10) , referring to the preparation method of the synthesis scheme 4, the formula The compound represented by (47) , the compound represented by formula (48) and the compound represented by formula (49) .
  • Methyl 2-(3-(3-fluorophenyl)thiophen-2-yl)benzoate (1.06g, 3.39mmol) was dissolved in tetrahydrofuran (10mL) and methanol (5mL), stirred at room temperature to dissolve, and the hydrogen Sodium oxide (1.36g, 34.00mmol) was dissolved in water (10mL) and added to the above reaction solution. The resulting mixture was heated to 60°C and stirred overnight.
  • reaction solution was added to water (10 mL), and then extracted with ethyl acetate (10 mL ⁇ 3).
  • Step 2) ((12aR)-7-(benzyloxy)-12-(5-fluoro-2-(2-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta [1,2-b]thiophen-8-yl)-3,4,12,12a-tetra Synthesis of Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
  • reaction solution was added to water (20 mL), and then extracted with ethyl acetate (10 mL ⁇ 3).
  • Step 2) (12aR)-7-(benzyloxy)-12-(5-fluoro-2-phenyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-3,4-4,12,12a-tetrahydro Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
  • reaction solution was added to water (10 mL), and then extracted with ethyl acetate (5 mL ⁇ 3).
  • the combined organic phase was washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Methyl 2-(3-(3-fluorophenyl)-5-methylthiophen-2-yl)benzoate (5.6g, 77mmol) was dissolved in tetrahydrofuran (10mL) and methanol (10mL) at room temperature After stirring for 10 minutes, sodium hydroxide (2.8 mg, 69 mmol) was dissolved in water (5 mL), then added to the above reaction solution, and then heated to 78° C. and stirred for 19 hours.
  • the filtrate was collected and separated, the aqueous phase was extracted with ethyl acetate (30 mL ⁇ 3), the organic phases were combined, the organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure.
  • the obtained crude product was purified by silica gel column chromatography (eluent was pure petroleum ether), and after purification, the title compound was obtained as a pale yellow solid (14.2 g, 100%).
  • the reaction solution was cooled to room temperature, ethyl acetate (80mL) and water (50mL) were added to the reaction solution, and then 1N hydrochloric acid was added to adjust the pH of the reaction solution to 6-7, and the aqueous phase was separated with ethyl acetate (50mL ⁇ 3) Extract, combine the organic phases, wash the organic phase with saturated brine (80mL), dry with anhydrous sodium sulfate, filter, and spin-dry the filtrate under reduced pressure. A yellow solid crude product was obtained, and the obtained yellow solid crude product was separated using Prep-HPLC to obtain the title compound 36-1 as an orange solid compound (0.5 g, 30%), and the title compound 36-2 as an orange solid compound (0.7 g ,40%).
  • the reaction solution was cooled to room temperature, ethyl acetate (30mL) and saturated sodium bicarbonate solution (40mL) were added to the reaction solution, when no more bubbles were generated, the liquid was separated, and the aqueous phase was separated with ethyl acetate (20mL).
  • Extract combine the organic phases, wash the organic phase with saturated brine (20 mL), dry with anhydrous sodium sulfate, filter, and spin the filtrate under reduced pressure.
  • the reaction solution was cooled to room temperature, ethyl acetate (30mL) and water (20mL) were added to the reaction solution, and then 1N hydrochloric acid was added to adjust the pH of the reaction solution to 6-7, and the liquid was separated. 20mL ⁇ 3) extract, combine the organic phases, wash the organic phase with saturated brine (30mL), dry the organic phase with anhydrous sodium sulfate, filter, and spin off the filtrate under reduced pressure.
  • the crude product obtained is separated by HPLC to obtain
  • the title compound 79-1 is an orange solid (30 mg, 35%)
  • the title compound 79-2 is an orange solid (40 mg, 46%).
  • Methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (100mg, 0.24mmol), cyclopropylboronic acid (31mg, 0.36mmol), palladium acetate (5mg, 0.02mmol), triphenylphosphine (13mg, 0.05mmol) and potassium phosphate (160mg, 0.73mmol) were added to the round bottom flask, then toluene (10mL) and water (1mL) were added, and placed under nitrogen protection The reaction was heated at 100°C for about 6 hours.
  • reaction solution was added dropwise to ice water (30 mL), and then extracted with ethyl acetate (30 mL ⁇ 3).
  • the organic phases were combined, and the organic phases were washed with saturated aqueous sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, and filtered.
  • Methyl 2-(3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (2.91g, 8.81mmol) was dissolved in DMF (10mL), and NBS (1.65g, 9.27mmol) A solution of DMF (10 mL) was added dropwise to the above reaction solution, and the resulting mixture was reacted overnight at room temperature. After the reaction was completed, saturated aqueous sodium thiosulfate solution (200 mL) was added to quench the reaction, and then extracted with ethyl acetate (100 mL ⁇ 3).
  • Methyl 2-(5-(ethoxy)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (13.73g, 33.54mmol), an ethanol solution of sodium ethoxide (25.11g , 73.80mmol, 20mass%), cuprous iodide (638mg, 3.35mmol) and copper (429mg, 6.71mmol) were added to ethanol (20mL), transferred to the sealed tube, and then placed in a 150°C oil bath under nitrogen protection The reaction was heated overnight.
  • reaction solution was added to tetrahydrofuran, and sodium hydroxide (2.68 g, 67.08 mmol) in water (10 mL) was added, and the mixture was placed at 50° C. to continue stirring and reacting for about 7 hours.
  • Step 6 (R)-12-((R)-2-ethoxy-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H- [1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 78-1) and (R) -12-((S)-2-ethoxy-4,5-difluoro-8H-bis Benzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxa Azino[3,4-c]pyrido[2,1-f][1,2,4]triazine Synthesis of -6,8-dione (Compound 78-2)
  • reaction solution After the reaction is complete, add the reaction solution to water (10mL) to quench the reaction, then use 0.5N HCl to adjust the pH of the reaction solution to be weakly acidic, stir for 10 minutes, then extract with ethyl acetate (20mL ⁇ 3) and combine The organic phase, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the reaction solution was added to water (10mL) to quench the reaction, then adjusted with 0.5N HCl to make the pH weakly acidic, stirred for 10 minutes, then extracted with ethyl acetate (20mL ⁇ 3), combined the organic phases, and saturated the organic phases Wash with brine (30 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Methyl 2-(3-(2,3-difluorophenyl)-5-(2-methoxyethyl)thiophen-2-yl)benzoate (3.52g, 9.06mmol) was dissolved in methanol (15mL ) And THF (15mL), then add sodium hydroxide (1.45g, 36.30mmol) in water (3mL) solution, place it in a 50°C oil bath and heat to react for about 1 hour.
  • reaction solution was filtered, the filter cake was washed with ethyl acetate (50 mL), the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent was petroleum ether) to obtain the title compound as a pale yellow liquid (4.06g, 80%).
  • Methyl 2-(5-(tert-butyl)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (7.50g, 19.40mmol) was dissolved in THF (15mL) and methanol ( 15mL), sodium hydroxide (3.11g, 77.60mmol) was dissolved in water (6mL), added to the above reaction solution, the resulting mixture was reacted at 50°C overnight.
  • the reaction solution was added to water (15 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the reaction solution was added to water (10mL) to quench the reaction, 0.5N HCl was added to adjust the pH value to be weakly acidic, stirred for 10 minutes, then extracted with ethyl acetate (20mL ⁇ 3), combined the organic phases, and the organic phase was saturated with salt Wash with water (30mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • Methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (8.99g, 22.00mmol), morpholine (9.57mL, 110.00mmol), iodide Cuprous (418mg, 2.20mmol), copper (698mg, 11.00mmol) and water (30mL) were added to the sealed tube, and placed in a 150°C oil bath under nitrogen and heated to react for about 7 hours.
  • Methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (10.00g, 24.44mmol), a tetrahydrofuran solution of dimethylamine (62mL, 122.20mmol, 5mol/L), cuprous iodide (458mg, 2.44mmol), copper (763mg, 12.22mmol) and DMF (30mL) were added to the sealed tube, and placed in a 150°C oil bath under nitrogen and heated to react overnight.
  • reaction was stopped, the reaction solution was added to ice water (15mL), extracted with ethyl acetate (20mL ⁇ 3), the organic phases were combined, and the organic phases were washed with saturated brine (15mL), dried with anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure to obtain the title compound (5.52 g, 100%) as a yellow solid.
  • reaction solution was added to water (15 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (11.50g, 28.10mmol), a methanol solution of sodium methoxide (6.75mL, 33.80mmol, 5mol/L), cuprous iodide (535mg, 2.81mmol), copper (360mg, 5.63mmol) and methanol (30mL) were added to the sealed tube, and placed in a 150°C oil bath under the protection of nitrogen and heated to react overnight.
  • reaction solution was added to tetrahydrofuran (20 mL), and NaOH (2.24 g, 56.00 mmol) in water (10 mL) was added, and the mixture was placed at 50° C. to continue stirring and reacting for about 7 hours.
  • pH of the reaction solution was adjusted to 5-6 with 2N hydrochloric acid, and then extracted with ethyl acetate (20mL ⁇ 3).
  • the organic phases were combined, and the organic phases were washed with saturated brine (20mL) and dried with anhydrous sodium sulfate.
  • the filtrate was filtered and the filtrate was concentrated under reduced pressure.
  • reaction solution was added to water (15 mL), extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • reaction solution was added to water (10mL) to quench the reaction, and then the pH value of the reaction solution was adjusted to weakly acidic with 0.5N HCl, stirred for 10 minutes, and then extracted with ethyl acetate (20mL ⁇ 3), and the organic phases were combined.
  • the phase was washed with saturated brine (30 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the reaction solution was added to water (10mL) to quench the reaction, then adjusted with 0.5N HCl to make the pH weakly acidic, stirred for 10 minutes, then extracted with ethyl acetate (20mL ⁇ 3), combined the organic phases, and saturated the organic phases Wash with brine (30 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • reaction solution was filtered, water (20mL) was added to the filtrate, the resulting mixture was extracted with ethyl acetate (30mL ⁇ 2), the organic phases were combined, the organic phases were washed with saturated sodium chloride solution (30mL ⁇ 3), and dried over anhydrous sodium sulfate After filtration, the filtrate was spin-dried under reduced pressure.
  • the residue was purified by silica gel column chromatography (eluent was petroleum ether). After purification, the title compound was obtained as a colorless oil (303 mg, 50%).
  • reaction solution was evaporated under reduced pressure to remove the solvent, water (20mL) was added to the residue, the pH was adjusted to about 4 with 4N hydrochloric acid solution, and then extracted with ethyl acetate (30mL ⁇ 2), the organic phases were combined, and the organic phase was saturated with chlorine. Wash with sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, and spin-dry the filtrate to obtain the title compound as a yellow solid (3.12 g, 96.8%).
  • the organic solvent was spin-dried under reduced pressure, water (20 mL) was added to the residue, the pH was adjusted to about 4 with 4N hydrochloric acid solution, and then extracted with ethyl acetate (30 mL ⁇ 2), the organic phases were combined, and the organic phase was saturated with sodium chloride The solution (30 mL) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain the title compound as a yellow solid (3.8 g, 99%).
  • the reaction was quenched by adding saturated ammonium chloride solution (10 mL), then using ethyl acetate (20 mL ⁇ 2), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Rotate to dryness under reduced pressure to obtain the title compound as a white solid (325 mg, 99.39%).

Landscapes

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

Abstract

The present invention belongs to the field of medicine, and relates to an influenza virus replication inhibitor and a use thereof, and provided thereby are a novel compound as an influenza virus replication inhibitor and a preparation method therefor, a pharmaceutical composition comprising the compound and an application of the compound and the pharmaceutical composition thereof in treating influenza. The compound according to the present invention is the compound shown in formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof.

Description

流感病毒复制抑制剂及其用途Influenza virus replication inhibitor and its use
相关申请的交叉引用Cross references to related applications
本申请要求在2019年03月05日提交的中国专利申请号201910163281.5享有优先权，该专利通过引用被全部合并于此。This application claims priority to the Chinese patent application number 201910163281.5 filed on March 5, 2019, which is incorporated herein by reference.
发明领域Invention field
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应用。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 new type of compound as an inhibitor of influenza virus replication and a preparation method thereof, a pharmaceutical composition containing the compound, and the application 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、流行广泛和传播迅速的特点。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。流感病毒最早是在1933年由英国人威尔逊·史密斯(Wilson Smith)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。每次大流行均因在人类中有新病毒株的出现。通常，这些新菌株由现有流感病毒从其他动物物种向人类的传播引起。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 elderly and children with weakened immune systems and some patients with immune disorders. The influenza 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. Each pandemic is due to the emergence of new strains of viruses in humans. Usually, these new strains are caused by the spread of existing influenza viruses from other animal species to 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。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 is composed 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.
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，病毒传播至其它物种并且可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。Influenza A virus has one species, influenza A virus. Wild waterbirds are the natural hosts for a large number of influenza A viruses. Sometimes the virus spreads to other species and can 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 widespread 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 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 flu 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，B型流感突变足以使人类不可能持久免疫。但因其抗原变化率低，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。Type B influenza virus has one species, type B influenza virus, which often causes local influenza epidemics, does not cause global influenza outbreaks, and is only found in humans and seals. This type of influenza mutates at a rate 2-3 times slower than type A, so the genetic diversity is low and there is only one type B influenza serotype. Due to the lack of such antigen diversity, humans usually acquire a certain degree of influenza B immunity at an early age. However, the type B influenza mutation is enough to make it impossible for humans to be permanently immune. However, due to its low rate of antigen change, combined with its restricted host changes (inhibiting cross-species antigen transition), to ensure that influenza B pandemic will 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 epidemic 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。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 translation system. The 5'cap structure is a 10-13 nucleotide (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 viruses. 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 viruses and affect 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, influenza viruses have 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 that can 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 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 (cap-dependent endonuclease) Such compounds and their compositions can be used to prepare drugs for preventing, treating or alleviating viral infections in patients. Compared with the existing similar compounds, the compound of the present invention can not only inhibit influenza virus well, but also has lower cytotoxicity, better in vivo pharmacokinetic properties and in vivo pharmacodynamic properties, and better liver Microsome stability. Therefore, the compound provided by the present invention has better druggability than 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, pharmaceutical Acceptable salts or their prodrugs,
Figure PCTCN2020077781-appb-000001
Figure PCTCN2020077781-appb-000001
其中：among them:
U 1为CR 1或N； U 1 is CR 1 or N;
U 2为CR 2或N； U 2 is CR 2 or N;
U 3为CR 3或N； U 3 is CR 3 or N;
U 4为CR 4或N； U 4 is CR 4 or N;
U 5为CR 5或N； U 5 is CR 5 or N;
U 6为CR 6或N； U 6 is CR 6 or N;
U 7为CR 7或N； U 7 is CR 7 or N;
U 8为CR 8或N； U 8 is CR 8 or N;
P为H、氘、C 1-6烷基、C 2-6烯基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基、-C(＝O)-R Pa、-C(＝O)-Z-R Pe、-C(＝O)-Z-O-R Pb、-C(＝O)-Z-O-Z-O-R Pb、-C(＝O)-Z-O-C(＝O)-R Pa、-C(＝O)-NR PcR Pd、-C(＝O)-O-R Pb、-S(＝O) 2-R Pi、-P(＝O)-(R Pg)(R Ph)、-C(＝O)-O-Y-O-R Pb、-Z-O-R Pb、-Z-O-Z-O-R Pb、-Y-O-C(＝O)-R Pa、-Y-C(＝O)-O-R Pb、-Y-NR Pf-(C＝O)-O-R Pb、-Y-O-C(＝O)-O-R Pb、-Z-O-C(＝O)-O-NR PcR Pd、-Y-O-C(＝O)-O-Y-O-R Pb、-Z-O-(C＝O)-O-Z-NR PcR Pd、-Z-O-C(＝O)-NR Pf-Z-O-R Pb、-Z-O-C(＝O)-NR Pf-Z-NR PcR Pd、-Z-O-C(＝O)-O-Z-O-Z-O-R Pb或-Z-O-C(＝O)-O-Z-NR Pf-(C＝O)-R Pa，其中所述C 1-6烷基、C 2-6烯基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-4烷基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基； P is H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl, 3-8 atoms Cyclic group, (heterocyclic group composed of 3-8 atoms) C 1-4 alkyl group, C 6-10 aryl group, C 6-10 aryl group C 1-4 alkyl group, heterocyclic group composed of 5-10 atoms Aryl group, (heteroaryl group consisting of 5-10 atoms) C 1-4 alkyl group, -C(=O)-R Pa , -C(=O)-ZR Pe , -C(=O)-ZOR Pb , -C(=O)-ZOZOR Pb , -C(=O)-ZOC(=O)-R Pa , -C(=O)-NR Pc R Pd , -C(=O)-OR Pb , -S(=O) 2 -R Pi , -P(=O)-(R Pg )(R Ph ), -C(=O)-OYOR Pb , -ZOR Pb , -ZOZOR Pb , -YOC(=O )-R Pa , -YC(=O)-OR Pb , -Y-NR Pf -(C=O)-OR Pb , -YOC(=O)-OR Pb , -ZOC(=O)-O-NR Pc R Pd , -YOC(=O)-OYOR Pb , -ZO-(C=O)-OZ-NR Pc R Pd , -ZOC(=O)-NR Pf -ZOR Pb , -ZOC(=O)- NR Pf -Z-NR Pc R Pd , -ZOC(=O)-OZOZOR Pb or -ZOC(=O)-OZ-NR Pf -(C=O)-R Pa , wherein the C 1-6 alkyl group , C 2-6 alkenyl, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl, 3-8 atom heterocyclic group, (3-8 atom heterocyclic group Cyclic) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl and (5-10 hetero Aryl) C 1-4 alkyl groups are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =0 , -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 Alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino;
各Y和Z独立地为C 1-6烷基； Each Y and Z is independently C 1-6 alkyl;
各R Pf独立地为H、氘或C 1-6烷基； Each R Pf is independently H, deuterium, or C 1-6 alkyl;
各R Pa、R Pb、R Pc、R Pd、R Pe和R Pi独立地为C 1-6烷基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基、C 1-6烷氨基、C 1-6烷硫基或C 1-6烷基甲硅烷基，其中所述C 1-6烷基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基、C 1-6烷氨基和C 1-6烷硫基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基； Each R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently C 1-6 alkyl, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl, Heterocyclic group consisting of 3-8 atoms, (heterocyclic group consisting of 3-8 atoms) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-4 alkyl, Heteroaryl group consisting of 5-10 atoms, (heteroaryl group consisting of 5-10 atoms) C 1-4 alkyl, C 1-6 alkylamino, C 1-6 alkylthio or C 1-6 alkane Group silyl group, wherein the C 1-6 alkyl group, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl group, 3-8 atoms heterocyclic group, (3 -8-atom heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl, (5 -10 atoms of heteroaryl) C 1-4 alkyl, C 1-6 alkylamino and C 1-6 alkylthio are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O ) NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino;
各R Pg和R Ph独立地为C 1-6烷氧基、C 1-6烷氨基、C 3-8碳环基氧基、C 3-8碳环基氨基、3-8个原子组成的杂环基氧基、3-8个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-10个原子组成的杂芳基氧基或5-10个原子组成的杂芳基氨基，其中所述C 1-6烷氧基、C 1-6烷氨基、C 3-8碳环基氧基、C 3-8碳环基氨基、3-8个原子组成的杂环基氧基、3-8个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-10个原子组成的杂芳基氧基和5-10个原子组成的杂芳基氨基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基； Each R Pg and R Ph is independently composed of C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 carbocyclyloxy, C 3-8 carbocyclylamino, 3-8 atoms Heterocyclyloxy, heterocyclylamino consisting of 3-8 atoms, C 6-10 aryloxy, C 6-10 arylamino, heteroaryloxy consisting of 5-10 atoms or 5- A 10-atom heteroarylamino group, wherein the C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-8 carbocyclyloxy group, C 3-8 carbocyclylamino group, 3-8 3-atom heterocyclyloxy, 3-8 heterocyclic amino, C 6-10 aryloxy, C 6-10 arylamino, 5-10 heteroaryloxy A group and a heteroarylamino group consisting of 5-10 atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino;
R 1、R 2、R 3和R 4各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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； R 1 , R 2 , R 3 and R 4 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, 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, wherein the C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, 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 and 5-6 heteroaryl are each independently unsubstituted or Is substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
R 5、R 6、R 7和R 8各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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； R 5 , R 6 , R 7 and R 8 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, 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, wherein the C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, 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 and 5-6 heteroaryl are each independently unsubstituted or Is substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
R 9为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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； R 9 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy Group, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 Cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 haloalkyl group, C 1-6 alkoxy group , C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 ring Alkyl groups, heterocyclic groups composed of 5-6 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group or C 1-6 alkylamino;
R 10为H、氘、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烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、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烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基或L-R 11，其中所述C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、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烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-4烷基各自独立地未被取代或被1、2、3或4个R w所取代，条件是R 9和R 10不同时为H； R 10 is H, deuterium, 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 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, -C(=O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group , C 3-6 carbocyclic group C 1-4 alkyl, 3-8 atom heterocyclic group, (3-8 atom heterocyclic group) C 1-4 alkyl, C 6-10 aromatic Group, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl, (5-10 heteroaryl) C 1-4 alkyl or LR 11 , where Said C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, -C(= O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, C 3- 6- carbocyclic C 1-4 alkyl, 3-8 heterocyclic group, (3-8 heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6 -10 aryl C 1-4 alkyl, 5-10 heteroaryl and (5-10 heteroaryl) C 1-4 alkyl are each independently unsubstituted or substituted by 1, Replaced by 2, 3 or 4 R w , provided that R 9 and R 10 are not H at the same time;
L为-(CR aR b) p-O-、-(CR aR b) t-S-、-(CR aR b) s-S(＝O)-、-(CR aR b) s-S(＝O) 2-、-(CR aR b) s-N(R c)-、-(CR aR b) s-C(＝O)N(R c)-、-(CR aR b) s-C(＝O)-、-(CR aR b) s-C(＝O)-或-(CR aR b) r-； L is -(CR a R b ) p -O-, -(CR a R b ) t -S-, -(CR a R b ) s -S(=O)-, -(CR a R b ) s -S(=O) 2 -, -(CR a R b ) s -N(R c )-, -(CR a R b ) s -C(=O)N(R c )-, -(CR a R b ) s -C(=O)-, -(CR a R b ) s -C(=O)- or -(CR a R b ) r -;
各R a和R b独立地为H、氘、F、Cl、Br、I、-CN、-NH 2、-OH、-SH、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烷氨基、C 1-6卤代烷氧基、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；或R a、R b和与它们相连的碳原子一起，形成C 3-6碳环或3-6个原子组成的杂环； Each R a and R b are independently H, deuterium, F, Cl, Br, I , -CN, -NH 2, -OH, -SH, C 1-6 alkyl, C 2-6 alkenyl group, C 2 -6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, C 3-6 cycloalkyl, composed of 3-6 atoms heterocyclyl, C 6-10 aryl, or 5-6 atoms heteroaryl; or R a, R b and the carbon atom to which they are attached together form a C 3-6 carbocyclic ring of 3-6 atoms or Composed of heterocycles;
各R c独立地为H、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、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； Each R c is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 A heterocyclic group consisting of atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 atoms;
R 11为H、氘、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、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烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)C 1-4烷基，其中所述C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、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烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-4烷基各自独立地未被取代或被1、2、3或4个R w所取代； R 11 is H, deuterium, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio Group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-4 alkyl, 3-8 heterocyclic group, ( 3-8 atoms heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl or ( Heteroaryl composed of 5-10 atoms) C 1-4 alkyl, wherein the C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkylamino, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-4 alkane Group, heterocyclic group composed of 3-8 atoms, (heterocyclic group composed of 3-8 atoms) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkane Group, heteroaryl group consisting of 5-10 atoms and (heteroaryl group consisting of 5-10 atoms) C 1-4 alkyl are each independently unsubstituted or replaced by 1, 2, 3 or 4 R w replace;
各R w独立地为氘、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷氨基、-S(＝O) q-C 1-6烷基、-S(＝O) q-C 1-6烷氨基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、羧基C 1-6烷基、氨基C 1-6烷基、氰 基C 1-6烷基、C 1-6烷基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-8个原子组成的杂芳基，其中所述C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷氨基、-S(＝O) q-C 1-6烷基、-S(＝O) q-C 1-6烷氨基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、羧基C 1-6烷基、氨基C 1-6烷基、氰基C 1-6烷基、C 1-6烷基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基和5-8个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、＝O、-OH、-NH 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 w is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -C(=O)OH, -C(=O)NH 2 , -S( ＝O) 2 NH 2 , C 1-6 alkoxy, C 1-6 alkylamino, -C(=O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy , -C(=O)-C 1-6 alkylamino, -S(=O) q -C 1-6 alkyl, -S(=O) q -C 1-6 alkylamino, C 1-6 haloalkane Group, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 heterocyclic group, C 6-10 aryl or 5-8 heteroaryl, wherein the C 1-6 alkoxy, C 1 -6 alkylamino, -C(=O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy, -C(=O)-C 1-6 alkylamino, -S (=O) q -C 1-6 alkyl, -S(=O) q -C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl , Carboxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclic ring composed of 3-8 atoms Group, C 6-10 aryl group and 5-8 atom heteroaryl group are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, =O, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
q为0、1或2；q is 0, 1 or 2;
r为1、2、3或4；r is 1, 2, 3 or 4;
各p、t或s独立地为0、1、2、3或4；Each p, t or s is independently 0, 1, 2, 3 or 4;
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 PCTCN2020077781-appb-000002
Figure PCTCN2020077781-appb-000002
在一些实施方案中，R 10为H、氘、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烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、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烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)C 1-2烷基或L-R 11，其中所述C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、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烷基、C 6-10芳基、C 6-10芳基C 1-2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烷基各自独立地未被取代或被1、2、3或4个R w所取代，条件是R 9和R 10不同时为H；其中L、R 11和R w具有本发明所描述的含义。 In some embodiments, R 10 is H, deuterium, 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 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1 -4 Alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl, 5-6 heterocyclic group, (5-6 heterocyclic group) C 1-2 alkyl , C 6-10 aryl, C 6-10 aryl, C 1-2 alkyl, 5-6 heteroaryl, (5-6 heteroaryl) C 1-2 alkyl Or LR 11 , wherein the C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio Group, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbon Cyclic group, C 3-6 carbocyclic group C 1-2 alkyl group, 5-6 atom heterocyclic group, (5-6 atom heterocyclic group) C 1-2 alkyl group, C 6- 10 aryl groups, C 6-10 aryl groups, C 1-2 alkyl groups, heteroaryl groups composed of 5-6 atoms, and (heteroaryl groups composed of 5-6 atoms) C 1-2 alkyl groups are each independently Substituted or substituted by 1, 2, 3 or 4 R w , provided that R 9 and R 10 are not H at the same time; wherein L, R 11 and R w have the meaning described in the present invention.
在另外一些实施方案中，R 10为H、氘、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、一氟甲基、二氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、三氟甲氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、-C(＝O)CH 3、-C(＝O)CH 2CH 3、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、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L-R 11，其中所述一氟甲基、二氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、-C(＝O)CH 3、-C(＝O)CH 2CH 3、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立 地未被取代或被1、2、3或4个R w所取代，条件是R 9和R 10不同时为H；其中L、R 11和R w具有本发明所描述的含义。 In other embodiments, R 10 is H, deuterium, Br, I, -CN, -NO 2 , -OH, -SH, -NH 2 , -C(=O)OH, -C(=O)NH 2. -S(=O) 2 NH 2 , monofluoromethyl, difluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methyl Oxy, ethoxy, n-propyloxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethylamino, N,N- Diethylamino, methylthio, -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazole Alkyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-methyl, pyrrolyl, pyridyl, Pyrimidyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, 1 , 3,5-triazinyl or LR 11 , wherein the monofluoromethyl, difluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl Group, methoxy, ethoxy, n-propyloxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethylamino, N,N-diethyl Amino, methylthio, -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, Imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-methyl, pyrrolyl, pyridyl, pyrimidinyl, Thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1,3, The 5-triazinyl groups are each independently unsubstituted or substituted with 1, 2, 3, or 4 R w , provided that R 9 and R 10 are not H at the same time; wherein L, R 11 and R w have the present invention The meaning of the description.
在一些实施方案中，R 11为H、氘、C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、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烷基、C 6-10芳基、C 6-10芳基C 1-2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烷基，其中所述C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、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烷基、C 6-10芳基、C 6-10芳基C 1-2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烷基各自独立地未被取代或被1、2、3或4个R w所取代；其中R w具有本发明所描述的含义。 In some embodiments, R 11 is H, deuterium, C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-2 alkyl group, composed of 5-6 atoms The heterocyclic group, (heterocyclic group composed of 5-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl, 5-6 atoms Heteroaryl group or (heteroaryl group consisting of 5-6 atoms) C 1-2 alkyl, wherein the C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic ring C 1-2 alkyl, 5-6 heterocyclic group, (5-6 heterocyclic group) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl group, heteroaryl group composed of 5-6 atoms and (heteroaryl group composed of 5-6 atoms) C 1-2 alkyl group are each independently unsubstituted or by 1, 2, 3 Or substituted by 4 R w ; wherein R w has the meaning described in the present invention.
在一些实施方案中，R 11为H、氘、一氟甲基、二氟甲基、三氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、三氟甲氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、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，其中所述一氟甲基、二氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4个R w所取代；其中R w具有本发明所描述的含义。 In some embodiments, R 11 is H, deuterium, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl , Tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethyl Amino, N,N-diethylamino, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl , Thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-methyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazole Group, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3,5-triazinyl, wherein the monofluoro Methyl, difluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propyloxy, iso Propyloxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino, methylthio, cyclopropyl, cyclobutyl, cyclopentyl , Cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl -Methyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl , Pyrazinyl, pyridazinyl and 1,3,5-triazinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w ; wherein R w has the meaning described in the present invention.
在一些实施方案中，各R w独立地为氘、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-4烷氧基、C 1-4烷氨基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1-4烷氨基、-S(＝O) q-C 1-4烷基、-S(＝O) q-C 1-4烷氨基、C 1-4卤代烷基、C 1-4卤代烷氧基、羟基C 1-4烷基、羧基C 1-4烷基、氨基C 1-4烷基、氰基C 1-4烷基、C 1-4烷基、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烷氧基、C 1-4烷氨基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1-4烷氨基、-S(＝O) q-C 1-4烷基、-S(＝O) q-C 1-4烷氨基、C 1-4卤代烷基、C 1-4卤代烷氧基、羟基C 1-4烷基、羧基C 1-4烷基、氨基C 1-4烷基、氰基C 1-4烷基、C 1-4烷基、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、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、＝O、-OH、-NH 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 w is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -C(=O)OH, -C(=O) NH 2 , -S(=O) 2 NH 2 , C 1-4 alkoxy, C 1-4 alkylamino, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkoxy, -C(=O)-C 1-4 alkylamino, -S(=O) q -C 1-4 alkyl, -S(=O) q -C 1-4 alkylamino , C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxy C 1-4 alkyl, carboxy C 1-4 alkyl, amino C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 heterocyclic group, C 6-10 aryl or 5-6 heteroaryl, wherein the C 1-4 Alkoxy, C 1-4 alkylamino, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkoxy, -C(=O)-C 1- 4 alkylamino, -S (= O) q -C 1-4 alkyl, -S (= O) q -C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxy C 1-4 alkyl, carboxy C 1-4 alkyl, amino C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 A heterocyclic group consisting of three atoms, a C 6-10 aryl group and a heteroaryl group consisting of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 substituents. Independently selected from deuterium, F, Cl, Br, I, -CN, =O, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino.
在另外一些实施方案中，各R w独立地为氘、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-SCH 3、-SCH 2CH 3、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、二氟甲基、三氟甲基、三氟乙基、三氟甲氧基、二氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、羧基甲基、羧基乙基、羧基正丙基、羧基异丙基、氨基甲基、氨基乙基、氰基甲基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、四氢噻吩基、吡咯烷基、吡唑烷基、咪唑烷基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、苯基、吡咯基、噻吩基、噻唑基、咪唑基、三唑基、呋喃基、吡啶基、嘧啶基、吡嗪基或哒嗪基，其中所述甲氧基、乙氧基、正丙基氧基、异丙基氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-SCH 3、-SCH 2CH 3、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、二氟甲基、三氟乙基、二氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、羧基甲基、羧基乙基、羧基正丙基、羧基异丙基、氨基甲基、氨基乙基、氰基甲基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、四氢噻吩基、吡咯烷基、吡唑烷基、咪唑烷基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、苯基、吡咯基、噻吩基、噻唑 基、咪唑基、三唑基、呋喃基、吡啶基、嘧啶基、吡嗪基和哒嗪基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、＝O、-OH、-NH 2、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基或甲氨基。 In other embodiments, each R w is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -C(=O)OH, -C(=O )NH 2 , -S(=O) 2 NH 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, methylamino, ethylamino, N,N-dimethylamino, N , N-Diethylamino, -C(=O)-OCH 3 , -C(=O)-OCH 2 CH 3 , -SCH 3 , -SCH 2 CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 CH 2 CH 3 , difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, hydroxymethyl, hydroxyl Ethyl, carboxymethyl, carboxyethyl, carboxyn-propyl, carboxyisopropyl, aminomethyl, aminoethyl, cyanomethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholine Group, thiomorpholinyl, piperidinyl, piperazinyl, phenyl, pyrrolyl, thienyl, thiazolyl, imidazolyl, triazolyl, furyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazine Group, wherein the methoxy, ethoxy, n-propyloxy, isopropyloxy, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino,- C(=O)-OCH 3 , -C(=O)-OCH 2 CH 3 , -SCH 3 , -SCH 2 CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 CH 2 CH 3 , difluoromethyl, trifluoroethyl, difluoromethoxy, trifluoroethoxy, hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl, carboxyn-propyl, carboxyisopropyl , Aminomethyl, aminoethyl, cyanomethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, phenyl, pyrrole Group, thienyl, thiazolyl, imidazolyl, triazolyl, furyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, =O, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl Group, methoxy, ethoxy or methylamino.
在一些实施方案中，R 9为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、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，其中所述C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、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、3或4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、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，条件是R 9和R 10不同时为H。 In some embodiments, R 9 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 haloalkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne Group, 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 haloalkyl group, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 haloalkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 3-6 cycloalkyl group, 5-6 atom heterocyclic group, C 6-10 aryl group and 5-6 atom heteroaryl group are each independently unsubstituted or by 1, 2, 3 Or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino, provided that R 9 and R 10 are not H at the same time.
在另外一些实施方案中，R 9为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、三氟甲基、三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、三氟甲氧基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、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，其中所述三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4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、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基或乙氧基，条件是R 9和R 10不同时为H。 In other embodiments, R 9 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, trifluoromethyl, trifluoromethyl Fluoroethyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino, trifluoromethoxy, trifluoroethoxy Base, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidine Alkyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furanyl , Pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3,5-triazinyl, of which The trifluoroethyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino, trifluoroethoxy, methyl , Ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidine Group, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl , Imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1,3,5-triazinyl are each independently unsubstituted or Substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl Group, isopropyl, trifluoromethyl, methoxy or ethoxy, provided that R 9 and R 10 are not H at the same time.
在一些实施方案中，R 1、R 2、R 3和R 4各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、三氟甲基、三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟甲氧基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、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，其中所述三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4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、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基或乙氧基； In some embodiments, R 1 , R 2 , R 3 and R 4 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C( =O) OH, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, methylthio, methylamino, trifluoromethoxy, trifluoroethoxy, methyl, ethyl, n-propyl Base, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, Thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazole Group, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3,5-triazinyl, wherein the trifluoroethyl, methoxy, Ethoxy, methylthio, methylamino, trifluoroethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 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 The azinyl group and the 1,3,5-triazinyl group are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I , -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy;
R 5、R 6、R 7和R 8各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、三氟甲基、三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟甲氧基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、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，其中所述三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4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、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基或乙氧基。 R 5 , R 6 , R 7 and R 8 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, three Fluoromethyl, trifluoroethyl, methoxy, ethoxy, methylthio, methylamino, trifluoromethoxy, trifluoroethoxy, methyl, ethyl, n-propyl, isopropyl, N-butyl, tert-butyl, 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, wherein the trifluoroethyl, methoxy, ethoxy, methylsulfide Group, methylamino, trifluoroethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine Group, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl , Thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1,3 , 5-triazinyl groups are each independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH , -NH 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.
在一些实施方案中，各R a和R b独立地为H、氘、F、Cl、Br、I、-CN、-NH 2、-OH、-SH、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、甲氧基、乙氧基、甲氨基、三氟甲氧基、环丙基、环丁基、环戊基、环己基、3-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基；或R a、R b和与它们相连的碳原子一起，形成环丙基、环丁基、环戊基、环己基或3-6个原子组成的杂环； In some embodiments, each of R a and R b are independently H, deuterium, F, Cl, Br, I , -CN, -NH 2, -OH, -SH, methyl, ethyl, n-propyl, Isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3 to 6 atoms heterocyclyl, phenyl, or 5-6 atoms heteroaryl; or R a, R b and the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, Group, cyclohexyl or heterocyclic ring composed of 3-6 atoms;
各R c独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、环丙基、环丁基、环戊基、环己基、3-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基。 Each R c is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, ring Hexyl, 3-6 heterocyclic group, phenyl or 5-6 heteroaryl.
在一些实施方案中，P为H、氘、C 1-4烷基、C 2-4烯基、C 3-6碳环基、C 3-6碳环基C 1-2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烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-2烷基、-C(＝O)-R Pa、-C(＝O)-Z-R Pe、-C(＝O)-Z-O-R Pb、-C(＝O)-Z-O-Z-O-R Pb、-C(＝O)-Z-O-C(＝O)-R Pa、-C(＝O)-NR PcR Pd、-C(＝O)-O-R Pb、-S(＝O) 2-R Pi、-P(＝O)-(R Pg)(R Ph)、-C(＝O)-O-Y-O-R Pb、-Z-O-R Pb、-Z-O-Z-O-R Pb、-Y-O-C(＝O)-R Pa、-Y-C(＝O)-O-R Pb、-Y-NR Pf-(C＝O)-O-R Pb、-Y-O-C(＝O)-O-R Pb、-Z-O-C(＝O)-O-NR PcR Pd、-Y-O-C(＝O)-O-Y-O-R Pb、-Z-O-(C＝O)-O-Z-NR PcR Pd、-Z-O-C(＝O)-NR Pf-Z-O-R Pb、-Z-O-C(＝O)-NR Pf-Z-NR PcR Pd、-Z-O-C(＝O)-O-Z-O-Z-O-R Pb或-Z-O-C(＝O)-O-Z-NR Pf-(C＝O)-R Pa，其中所述C 1-4烷基、C 2-4烯基、C 3-6碳环基、C 3-6碳环基C 1-2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烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-2烷基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基； In some embodiments, P is H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl, C 1-2 alkyl, 5- 6-atom heterocyclic group, (5-6 atom heterocyclic group) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-2 alkyl, 5- Heteroaryl group consisting of 10 atoms, (heteroaryl group consisting of 5-10 atoms) C 1-2 alkyl group, -C(=O)-R Pa , -C(=O)-ZR Pe , -C (=O)-ZOR Pb 、-C(=O)-ZOZOR Pb 、-C(=O)-ZOC(=O)-R Pa 、-C(=O)-NR Pc R Pd 、-C(= O)-OR Pb , -S(=O) 2 -R Pi , -P(=O)-(R Pg )(R Ph ), -C(=O)-OYOR Pb , -ZOR Pb , -ZOZOR Pb , -YOC(=O)-R Pa , -YC(=O)-OR Pb , -Y-NR Pf -(C=O)-OR Pb , -YOC(=O)-OR Pb , -ZOC(= O)-O-NR Pc R Pd , -YOC(=O)-OYOR Pb , -ZO-(C=O)-OZ-NR Pc R Pd , -ZOC(=O)-NR Pf -ZOR Pb ,- ZOC(=O)-NR Pf -Z-NR Pc R Pd , -ZOC(=O)-OZOZOR Pb or -ZOC(=O)-OZ-NR Pf -(C=O)-R Pa , wherein C 1-4 alkyl, C 2-4 alkenyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl group, heterocyclic group consisting of 5-6 atoms, (5- 6-atom heterocyclic group) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl, 5-10 heteroaryl and (5- (10-atom heteroaryl) C 1-2 alkyl is each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino;
各Y和Z独立地为C 1-4烷基； Each Y and Z is independently C 1-4 alkyl;
各R Pf独立地为H、氘或C 1-6烷基； Each R Pf is independently H, deuterium, or C 1-6 alkyl;
各R Pa、R Pb、R Pc、R Pd、R Pe和R Pi独立地为C 1-4烷基、C 3-6碳环基、C 3-6碳环基C 1-2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 1-2烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)C 1-2烷基、C 1-4烷氨基、C 1-4烷硫基或C 1-4烷基甲硅烷基，其中所述C 1-4烷基、C 3-6碳环基、C 3-6碳环基C 1-2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 1-2烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)C 1-2烷基、C 1-4烷氨基和C 1-4烷硫基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷酰基、C 1-4烷氧基酰基或C 1-4烷氨基； Each R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently C 1-4 alkyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-2 alkyl, Heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-2 alkyl, Heteroaryl group consisting of 5-6 atoms, (heteroaryl group consisting of 5-6 atoms) C 1-2 alkyl, C 1-4 alkylamino, C 1-4 alkylthio or C 1-4 alkane Group silyl group, wherein the C 1-4 alkyl group, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl group, heterocyclic group consisting of 3-6 atoms, (3 -6-atom heterocyclic group) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl, 5-6 heteroaryl, (5 -6-atom heteroaryl) C 1-2 alkyl, C 1-4 alkylamino and C 1-4 alkylthio are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O ) NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkoxy acyl or C 1-4 alkylamino;
各R Pg和R Ph独立地为C 1-4烷氧基、C 1-4烷氨基、C 3-6碳环基氧基、C 3-6碳环基氨基、3-6个原子组成的杂环基氧基、3-6个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-6个原子组成的杂芳基氧基或5-6个原子组成的杂芳基氨基，其中所述C 1-4烷氧基、C 1-4烷氨基、C 3-6碳环基氧基、C 3-6碳环基氨基、3-6个原子组成的杂环基氧基、3-6个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-6个原子组成的杂芳基氧基和5-6个原子组成的杂芳基氨基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷酰基、C 1-4烷氧基酰基或C 1-4烷氨基。 Each R Pg and R Ph are independently composed of C 1-4 alkoxy, C 1-4 alkylamino, C 3-6 carbocyclyloxy, C 3-6 carbocyclylamino, and 3-6 atoms Heterocyclyloxy, heterocyclylamino consisting of 3-6 atoms, C 6-10 aryloxy, C 6-10 arylamino, heteroaryloxy consisting of 5-6 atoms or 5- 6-atom heteroarylamino group, wherein the C 1-4 alkoxy group, C 1-4 alkylamino group, C 3-6 carbocyclyloxy group, C 3-6 carbocyclylamino group, 3-6 3-atom heterocyclyloxy, 3-6 heterocyclic amino, C 6-10 aryloxy, C 6-10 arylamino, 5-6 heteroaryloxy A group and a heteroarylamino group consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkoxy acyl or C 1-4 alkylamino.
在另外一些实施方案中，P为H、氘、
Figure PCTCN2020077781-appb-000003
In other embodiments, P is H, deuterium,
Figure PCTCN2020077781-appb-000003
Figure PCTCN2020077781-appb-000004
Figure PCTCN2020077781-appb-000004
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 PCTCN2020077781-appb-000005
Figure PCTCN2020077781-appb-000005
其中，P、U 1、U 2、U 3、U 4、U 5、U 6、U 7、U 8、R 9和R 10具有本发明所述的定义。 Among them, P, U 1 , U 2 , U 3 , U 4 , U 5 , U 6 , U 7 , U 8 , R 9 and R 10 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。In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention.
在一些实施方案中，所述药物组合物进一步包含药学上可接受的载体、辅剂、媒介物或它们的组合。In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle, or a combination thereof.
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.
在另外一些实施方案中，所述其他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，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 PCTCN2020077781-appb-000006
Quadrivalent、
Figure PCTCN2020077781-appb-000007
Quadrivalent、
Figure PCTCN2020077781-appb-000008
或
Figure PCTCN2020077781-appb-000009
)或它们的组合。 In other embodiments, the other therapeutic agent is Amantadine, Rimantadine, Oseltamivir, Zanamivir, Peramivir, Peramivir Nimvir (Laninamivir), Laninamivir Octanoate Hydrate, Favipiravir, Arbidol, Ribavirin, Staphyrin , Ingavirin (Ingavirin), flu enzyme (Fludase), drugs with CAS number 1422050-75-6, pimodivir (Pimodivir), baloxavir (Baloxavir marboxil), flu vaccine (FluMist
Figure PCTCN2020077781-appb-000006
Quadrivalent,
Figure PCTCN2020077781-appb-000007
Quadrivalent,
Figure PCTCN2020077781-appb-000008
or
Figure PCTCN2020077781-appb-000009
) Or their combination.
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 can 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 medicament, wherein the medicament is used to prevent, treat or alleviate viral infectious diseases in patients.
另一方面，本发明提供一种预防、治疗或减轻患者病毒感染性疾病的方法，包括给患者使用有效量的本发明所述化合物或本发明所述药物组合物。On the other hand, the present invention provides a method for preventing, treating or alleviating viral infectious diseases in patients, which comprises administering to the patient an effective amount of the compound of the present invention or the pharmaceutical composition of the present invention.
另一方面，本发明提供本发明所述化合物或所述药物组合物用于预防、治疗或减轻患者病毒感染性疾病的用途。In another aspect, the present invention provides the use of the compound or the pharmaceutical composition of the present invention for preventing, treating or alleviating 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.
在另外一些实施方案中，所述流感病毒为流感病毒A。In other embodiments, the influenza virus is influenza A virus.
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 medicine, wherein the medicine is used to inhibit the RNA polymerase of influenza virus.
另一方面，本发明提供一种抑制流感病毒的RNA聚合酶的方法，包括给患者使用有效量的本发明所述化合物或所述药物组合物。In another aspect, the present invention provides a method for inhibiting the RNA polymerase of influenza virus, which comprises administering an effective amount of the compound or the pharmaceutical composition of the present invention to the patient.
另一方面，本发明提供本发明所述化合物或所述药物组合物抑制流感病毒的RNA聚合酶的用途。In another aspect, the present invention provides the use of the compound or the pharmaceutical composition of the present invention to inhibit the RNA polymerase of influenza virus.
在一些实施方案中，所述RNA聚合酶为帽依赖性核酸内切酶。In some 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 can form solvates with pharmaceutically acceptable solvents (including water) either inherently or by design; 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 compounds of the present invention may exist in one form of possible isomers, rotamers, atropisomers, and tautomers or in the form of mixtures 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, or 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 those in which 3 H, 14 C and 18 F are present, or non-radioactive isotopes, 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, isolation 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. 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。Now certain embodiments of the present invention are 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 or contradictory to this application (including but not limited to 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 be referred to 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.
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 may 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, can be incorporated into the compounds of the present invention and 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表示化合物是右旋的。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为对映异构体混合物。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 denote 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 the compound, where (-) or l indicates that the compound is levorotatory. The prefix (+) or d indicates that the compound is 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 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 (e.g., carbon, etc.) of the compound of the present invention can 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 in the (R)- or (S)- configuration, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. If possible, substituents on atoms with unsaturated double bonds may exist in cis-(Z)- or trans-(E)- forms.
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 methods, the compound of the present invention can be one of the possible isomers or a mixture of them, such as racemates and diastereoisomer mixtures (depending on the number of asymmetric carbon atoms) The form exists. The 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 E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be in 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 methods familiar to those skilled in the art by known methods, for example, by performing diastereomeric salts of the obtained 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 interconversion 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, it is 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. The corresponding amine can be treated with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) 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 a product obtained by 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, acylating, deamidating, esterifying, degreasing, enzymatic cleavage and the like 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 to us 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 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, camphoric acid 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 contemplates the quaternary ammonium salt formed by any compound containing the N group. 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 include appropriate, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and 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 maternal 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, which 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, you can 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 contained 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、-SH、-CN、-OH、-NH 2、-NO 2、氧代(＝O)、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、-C(＝O)-烷基、-C(＝O)-烷氧基、-C(＝O)-烷氨基、-S(＝O) q-烷基、-S(＝O) q-烷氨基、-C(＝O)-R Pa、-C(＝O)-Z-R Pe、-C(＝O)-Z-O-R Pb、-C(＝O)-Z-O-Z-O-R Pb、-C(＝O)-Z-O-C(＝O)-R Pa、-C(＝O)-NR PcR Pd、-C(＝O)-O-R Pb、-S(＝O) 2-R Pi、-P(＝O)-(R Pg)(R Ph)、-C(＝O)-O-Y-O-R Pb、-Z-O-R Pb、-Z-O-Z-O-R Pb、-Y-O-C(＝O)-R Pa、-Y-C(＝O)-O-R Pb、-Y-NR Pf-(C＝O)-O-R Pb、-Y-O-C(＝O)-O-R Pb、-Z-O-C(＝O)-O-NR PcR Pd、-Y-O-C(＝O)-O-Y-O-R Pb、-Z-O-(C＝O)-O-Z-NR PcR Pd、-Z-O-C(＝O)-NR Pf-Z-O-R Pb、-Z-O-C(＝O)-NR Pf-Z-NR PcR Pd、-Z-O-C(＝O)-O-Z-O-Z-O-R Pb、-Z-O-C(＝O)-O-Z-NR Pf-(C＝O)-R Pa、卤代烷基、烷氧基、烷硫基、烷氨基、烷酰基、烷氧基酰基、烷基甲硅烷基、碳环基氧基、碳环基氨基、杂环基氧基、杂环基氨基、芳基氨基、芳基氧基、杂芳基氧基、杂芳基氨基、卤代烷氧基、羟基烷基、氨基烷基、羧基烷基、氰基烷基、烷基、烯基、炔基、环烷基、碳环基、杂环基、芳基、杂芳基、环烷基-烷基、碳环基-烷基、杂环基-烷基、芳基-烷基或杂芳基-烷基，其中，所述各Z、Y、q、R Pa、R Pb、R Pc、R Pd、R Pe、R Pf、R Pg、R Ph和R Pi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 described therein can be, but are not limited to, deuterium, F, Cl, Br, I, -SH, -CN, -OH, -NH 2 , -NO 2 , oxo (=O), -C (=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , -C(=O)-alkyl, -C(=O)-alkoxy, -C(= O)-alkylamino, -S(=O) q -alkyl, -S(=O) q -alkylamino, -C(=O)-R Pa , -C(=O)-ZR Pe , -C (=O)-ZOR Pb 、-C(=O)-ZOZOR Pb 、-C(=O)-ZOC(=O)-R Pa 、-C(=O)-NR Pc R Pd 、-C(= O)-OR Pb , -S(=O) 2 -R Pi , -P(=O)-(R Pg )(R Ph ), -C(=O)-OYOR Pb , -ZOR Pb , -ZOZOR Pb , -YOC(=O)-R Pa , -YC(=O)-OR Pb , -Y-NR Pf -(C=O)-OR Pb , -YOC(=O)-OR Pb , -ZOC(= O)-O-NR Pc R Pd , -YOC(=O)-OYOR Pb , -ZO-(C=O)-OZ-NR Pc R Pd , -ZOC(=O)-NR Pf -ZOR Pb ,- ZOC(=O)-NR Pf -Z-NR Pc R Pd , -ZOC(=O)-OZOZOR Pb , -ZOC(=O)-OZ-NR Pf -(C=O)-R Pa , halogenated alkyl, Alkoxy, alkylthio, alkylamino, alkanoyl, alkoxyacyl, alkylsilyl, carbocyclyloxy, carbocyclylamino, heterocyclyloxy, heterocyclylamino, arylamino , Aryloxy, heteroaryloxy, heteroarylamino, haloalkoxy, hydroxyalkyl, aminoalkyl, carboxyalkyl, cyanoalkyl, alkyl, alkenyl, alkynyl, cycloalkyl , Carbocyclyl, heterocyclyl, aryl, heteroaryl, cycloalkyl-alkyl, carbocyclyl-alkyl, heterocyclyl-alkyl, aryl-alkyl or heteroaryl-alkyl, Wherein, each of the Z, Y, q, R Pa , R Pb , R Pc , R Pd , R Pe , R Pf , R Pg , R Ph and R Pi 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 clearly indicated in other ways, the description methods used in the present invention are interchangeable with "each ... independently being" and "... 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)。术语“5-10个原子组成的杂芳基”特别指独立公开的5个原子组成的杂芳基、6个原子组成的杂芳基、7个原子组成的杂芳基、8个原子组成的杂芳基、9个原子组成的杂芳基和10个原子组成的杂芳基。 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). The term "5-10 atom heteroaryl group" especially refers to the independently disclosed 5-atom heteroaryl group, 6-atom heteroaryl group, 7-atom heteroaryl group, and 8-atom heteroaryl group. Heteroaryl, 9-atom heteroaryl and 10-atom heteroaryl.
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1-12个碳原子，即C 1-12烷基；在一些实施方案中，烷基基团含有1-10个碳原子，即C 1-10烷基；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，即C 1-2烷基。在本发明中，如果该烷基基团需要连接基团时，则该烷基基团代表连接的亚烷基基团。 The term "alkyl" or "alkyl group" used in the present invention refers to a saturated linear or branched monovalent hydrocarbon radical containing 1-20 carbon atoms. In some embodiments, the alkyl group contains 1-12 carbon atoms, ie C 1-12 alkyl; in some embodiments, the alkyl group contains 1-10 carbon atoms, ie C 1-10 alkane 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 alkyl; 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, ie C 1-2 alkyl. In the present invention, if the alkyl group requires a linking group, the alkyl group represents a linked alkylene group.
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，其中至少有一个不饱和位点，即有一个 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。在一实施方案中，烯基基团包含2-8个碳原子，即C 2-8烯基；在另一实施方案中，烯基基团包含2-6个碳原子，即C 2-6烯基；在又一实施方案中，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 site of unsaturation, that is, there is a carbon-carbon sp 2 double bond, wherein the alkenyl group Groups can be optionally substituted with one or more substituents described in the present invention, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2-8 carbon atoms, ie C 2-8 alkenyl; in another embodiment, the alkenyl group contains 2-6 carbon atoms, ie C 2-6 Alkenyl; In yet another embodiment, 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，其中至少有一个不饱和位点，即有一个碳-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；在另一些实施方案中，炔基基团包含2-6个碳原子，即C 2-6炔基；在又一些实施方案中，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)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 unsaturation site, that is, a carbon-carbon sp triple bond, wherein the alkynyl group It may be optionally substituted by one or more substituents described in the present invention. In some embodiments, the alkynyl group contains 2-8 carbon atoms, namely C 2-8 alkynyl; in other embodiments, the alkynyl group contains 2-6 carbon atoms, namely C 2-6 Alkynyl; In still other 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 ), etc. .
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，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1-6个碳原子，即C 1-6烷氧基；在另一些实施方案中，烷氧基基团含有1-4个碳原子，即C 1-4烷氧基；在又一些实施方案中，烷氧基基团含有1-2个碳原子，即C 1-2烷氧基。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)，正丙基氧基(1-丙氧基,n-PrO,n-丙氧基,-OCH 2CH 2CH 3)，异丙基氧基(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。 The term "alkoxy" means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. In some embodiments, the alkoxy group contains 1-6 carbon atoms, namely C1-6 alkoxy; in other embodiments, the alkoxy group contains 1-4 carbon atoms, namely C C1-4 alkoxy; in still other embodiments, the alkoxy group containing 1-2 carbon atoms, i.e. C 1-2 alkoxy. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), n-propyloxy (1-propoxy, n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), isopropyloxy (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-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t- BuO,t-butoxy, -OC(CH 3 ) 3 ), 1-pentoxy (n-pentoxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentoxy (-OCH (CH 3 )CH 2 CH 2 CH 3 ), 3-pentyloxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy (-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“碳环基氧基”、“杂环基氧基”、“芳基氧基”或“杂芳基氧基”表示碳环基基团、杂环基基团、芳基基团或杂芳基基团通过氧原子与分子其余部分相连，其中“碳环基”、“杂环基”、“芳基”和“杂芳基”基团具有如本发明所述的含义。这样的实例包括，但不限于，
Figure PCTCN2020077781-appb-000010
Figure PCTCN2020077781-appb-000011
The term "carbocyclyloxy", "heterocyclyloxy", "aryloxy" or "heteroaryloxy" means a carbocyclyl group, a heterocyclyl group, an aryl group or a hetero The aryl group is connected to the rest of the molecule through an oxygen atom, and the "carbocyclyl", "heterocyclic", "aryl" and "heteroaryl" groups have the meanings described in the present invention. Examples of this include, but are not limited to,
Figure PCTCN2020077781-appb-000010
Figure PCTCN2020077781-appb-000011
术语“烷硫基”是指含有1-10个碳原子的直链或支链的烷基连接到二价硫原子上的基团。在一些实施方案中，烷硫基含有1-6个碳原子，即C 1-6烷硫基；在一些实施方案中，烷硫基含有1-4个碳原子，即C 1-4烷硫基；在一些实施方案中，在一些实施方案中，烷硫基含有1-2个碳原子，即C 1-2烷硫基。烷硫基基团的实例包含，但并不限于，甲硫基(-SCH 3)。所述烷硫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 "alkylthio" refers to a group in which a linear or branched alkyl group containing 1-10 carbon atoms is attached to a divalent sulfur atom. In some embodiments, the alkylthio group contains 1-6 carbon atoms, that is, C 1-6 alkylthio; in some embodiments, the alkylthio contains 1-4 carbon atoms, that is, C 1-4 alkylthio In some embodiments, in some embodiments, the alkylthio group contains 1-2 carbon atoms, ie, C 1-2 alkylthio. Examples of alkylthio groups include, but are not limited to, methylthio (-SCH 3 ). The alkylthio group is optionally substituted with one or more substituents described in the present invention.
术语“卤代烷基”，“卤代烯基”或“卤代烷氧基”表示烷基，烯基或烷氧基基团被一个或多个卤素原子所取代。这样的实例包含，但并不限于，一氟甲基(-CH 2F)、二氟甲基(-CHF 2)、三氟甲基(-CF 3)、氟乙基(-CHFCH 3,-CH 2CH 2F)、二氟乙基(-CF 2CH 3,-CHFCH 2F,-CH 2CHF 2)、全氟乙基、氟丙基(-CHFCH 2CH 3,-CH 2CHFCH 3,-CH 2CH 2CH 2F)、二氟丙基(-CF 2CH 2CH 3,-CFHCFHCH 3,-CH 2CH 2CHF 2,-CH 2CF 2CH 3,-CH 2CHFCH 2F)、三氟乙基(-CH 2CF 3,-CHFCHF 2,-CF 2CH 2F)、三氟丙基、1,1-二氯乙基、1,2-二氯丙基、三氟甲氧基(-OCF 3)、二氟甲氧基(-OCHF 2)、2,2,2-三氟乙氧基(-OCH 2CF 3)等。 The term "haloalkyl", "haloalkenyl" or "haloalkoxy" means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms. Such examples include, but are not limited to, monofluoromethyl (-CH 2 F), difluoromethyl (-CHF 2 ), trifluoromethyl (-CF 3 ), fluoroethyl (-CHFCH 3 ,- CH 2 CH 2 F), difluoroethyl (-CF 2 CH 3 , -CHFCH 2 F, -CH 2 CHF 2 ), perfluoroethyl, fluoropropyl (-CHFCH 2 CH 3 , -CH 2 CHFCH 3 ,-CH 2 CH 2 CH 2 F), difluoropropyl (-CF 2 CH 2 CH 3 , -CFHCFHCH 3 , -CH 2 CH 2 CHF 2 , -CH 2 CF 2 CH 3 , -CH 2 CHFCH 2 F ), trifluoroethyl (-CH 2 CF 3 , -CHFCHF 2 , -CF 2 CH 2 F), trifluoropropyl, 1,1-dichloroethyl, 1,2-dichloropropyl, trifluoro Methoxy (-OCF 3 ), difluoromethoxy (-OCHF 2 ), 2,2,2-trifluoroethoxy (-OCH 2 CF 3 ), 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5-6个，即C 5-6碳环基；在其它一些实施方案中，碳原子的数量为5-8个，即C 5-8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 carbocyclyl; in other embodiments, the number of carbon atoms is 3-6, that is, C 3-6 carbon Cyclic group; in other embodiments, the number of carbon atoms is 5-6, that is, C 5-6 carbocyclyl; in other embodiments, the number of carbon atoms is 5-8, that is, C 5- 8 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3-12个碳原子的，单价或多价的非芳香性的饱和单环、双环或三环体系。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；在另一些实施方案中，环烷基包含3-8个碳原子，即C 3-8环烷基；在又一些实施方案中，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 ring system containing 3-12 carbon atoms. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms, ie C 3-12 cycloalkyl; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms, ie C 3-8 ring Alkyl; In still other embodiments, cycloalkyl contains 3-6 carbon atoms, ie C 3-6 cycloalkyl. 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 this 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 the forms of 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”、“杂环基”或“杂环的”在此处可交换使用，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，其中环上一个或多个原子独立地被杂原子所替换，所述杂原子具有如本发明所述的含义，环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。在一些实施方案中，“杂环”，“杂环基”或“杂环的”基团为3-8个环原子组成的环体系；在另一些实施方案中，“杂环”，“杂环基”或“杂环的”基团为3-6个环原子组成的环体系；在其他一些实施方案中，“杂环”，“杂环基”或“杂环的”基团为5-6个环原子组成的环体系；在其他一些实施方案中，“杂环”，“杂环基”或“杂环的”基团为4个环原子组成的环体系；在其他一些实施方案中，“杂环”，“杂环基”或“杂环的”基团为5个环原子组成的环体系；在其他一些实施方案中，“杂环”，“杂环基”或“杂环的”基团为6个环原子组成的环体系；在其他一些实施方案中，“杂环”，“杂环基”或“杂环的”基团为7个环原子组成的环体系。在一些实施方案中，“杂环”，“杂环基”或“杂环的”基团是3-8个原子组成的单环(2-6个碳原子和选自N，O，P，S的1-3个杂原子)，或7-12元的双环(4-9个碳原子和选自N，O，P，S的1-3个杂原子)。所述“杂环”，“杂环基”或“杂环的”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 "heterocycle", "heterocyclyl" or "heterocyclic" are used interchangeably herein and refer to a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 3-14 ring atoms, wherein One or more atoms in the ring are independently replaced by heteroatoms, and the heteroatoms have the meaning as described in the present invention. The ring may be fully saturated or contain one or more degrees of unsaturation, but an aromatic ring is not allowed. In some embodiments, a "heterocyclic", "heterocyclyl" or "heterocyclic" group is a ring system consisting of 3-8 ring atoms; in other embodiments, "heterocyclic", "heterocyclic" A "cyclic" or "heterocyclic" group is a ring system composed of 3-6 ring atoms; in some other embodiments, the "heterocyclic", "heterocyclic" or "heterocyclic" group is 5 -6 ring system consisting of ring atoms; in some other embodiments, "heterocyclic", "heterocyclyl" or "heterocyclic" group is a ring system consisting of 4 ring atoms; in some other embodiments In this, "heterocyclic", "heterocyclyl" or "heterocyclic" group is a ring system composed of 5 ring atoms; in some other embodiments, "heterocyclic", "heterocyclyl" or "heterocyclic" A "cyclic" group is a ring system composed of 6 ring atoms; in some other embodiments, a "heterocyclic", "heterocyclyl" or "heterocyclic" group is a ring system composed of 7 ring atoms. In some embodiments, a "heterocyclic", "heterocyclyl" or "heterocyclic" group is a monocyclic ring composed of 3-8 atoms (2-6 carbon atoms and selected from N, O, P, S 1-3 heteroatoms), or 7-12 membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S). The "heterocyclic", "heterocyclic" or "heterocyclic" group is optionally substituted with one or more substituents described in the present invention.
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，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，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，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2020077781-appb-000012
基，二氮杂
Figure PCTCN2020077781-appb-000013
基，硫氮杂
Figure PCTCN2020077781-appb-000014
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, 2-pyrrolinyl, 3-pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, disulfide ring Pentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Dioxanyl, Dithianyl, Thioxanyl, Homopiperazinyl, Homopiperidinyl, Oxepanyl, Thiepanyl, Oxazepine
Figure PCTCN2020077781-appb-000012
Diaza
Figure PCTCN2020077781-appb-000013
Thiazepine
Figure PCTCN2020077781-appb-000014
Group, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, etc. Examples of the -CH 2 -group in the heterocyclic group substituted by -C(=O)- include, but are not limited to, 2-oxo-1,3-dioxolane, 2-oxo-1,3 -Dioxolyl, furan-keto, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone, 3,5-dioxopiperidinyl , Pyrimidinedione, etc. 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“芳基”或“芳环”在此处可交换使用，表示含有6-14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。在一些实施方案中，芳基基团含有6-12个环原子的碳环体系，即C 6-12芳基。在一些实施方案中，芳基基团含有6-10个环原子的碳环体系，即C 6-10芳基。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 carbocyclic ring systems containing 6-14 ring atoms, in which at least one ring system is aromatic, 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. In some embodiments, the aryl group contains a carbocyclic ring system of 6-12 ring atoms, that is, a C 6-12 aryl group. In some embodiments, the aryl group contains a carbocyclic ring system of 6-10 ring atoms, that is, a C 6-10 aryl group. 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“杂芳基”、“杂芳环”或“杂芳族化合物”在此可交换使用，表示含有5-14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。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。在另一些实施方案中，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个原子组成的杂芳基。在另一些实施方案中，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个原子组成的杂芳基。在另一些实施方案中，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个原子组成的杂芳基。在另一些实施方案中，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个原子组成的杂芳基。在另一些实施方案中，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6个原子组成的杂芳基。 The terms "heteroaryl", "heteroaromatic ring" or "heteroaromatic compound" are used interchangeably herein and refer to a monovalent or multivalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, wherein At least one ring system is aromatic, and at least one ring contains one or more heteroatoms. When a -CH 2 -group is present in the heteroaryl group, the -CH 2 -group can be optionally replaced by -C(=O)-. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-10 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-8 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a 5-atom heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, the heteroaryl group is a 6-atom heteroaryl group containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
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)，三唑基(如2-三唑基，5-三唑基，4H-1,2,4-三唑基，1H-1,2,4-三唑基，1,2,3-三唑基)，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]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[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 (such as 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (such as 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 (such as 2-thienyl, 3-thienyl), pyrazolyl (such as 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] Pyrimidyl, 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“n个原子组成的”，其中n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n。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 n atoms", where n is an integer, typically describes the number of ring atoms in a molecule, and the number of ring atoms in the molecule is n. For example, piperidinyl is a 6-atom heterocyclic group, and naphthyl is a 10-atom aryl group.
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。The term "unsaturated" as used in the present invention means that the group contains one or more degrees of unsaturation.
术语“卤素”是指F，Cl，Br或I。The term "halogen" refers to F, Cl, Br or I.
术语“羧基”，表示-(C＝O)OH。The term "carboxy" means -(C=O)OH.
术语“羟基”，表示-OH。The term "hydroxyl" means -OH.
术语“氰基”，表示-CN。The term "cyano" means -CN.
术语“羰基”或“酰基”，表示-(C＝O)-。The term "carbonyl" or "acyl" means -(C=O)-.
术语“羟基烷基”是指被一个或多个羟基(-OH)所取代的烷基，所述烷基具有本发明所描述的含义，其中，所述羟基烷基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，本发明所述的羟基烷基基团是指被一个或多个羟基(-OH)所取代的C 1-6烷基，即羟基C 1-6烷基；在一些实施方案中，羟基烷基基团是指被一个或多个羟基(-OH)所取代的C 1-4烷基，即羟基C 1-4烷基；在一些实施方案中，羟基烷基基团是指被一个或多个羟基(-OH)所取代的C 1-2烷基，即羟基C 1-2烷基。羟基烷基基团的实例包括，但不限于，羟基甲基(例如，-CH 2OH)、羟基乙基(例如，2-羟基乙基)、羟基正丙基(例如,-CH 2CH 2CH 2OH)，等等。 The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups (-OH), and the alkyl group has the meaning described in the present invention, wherein the hydroxyalkyl group may optionally be substituted by one or Multiple substituents described in this invention are substituted. In some embodiments, the hydroxyalkyl group in the present invention refers to a C 1-6 alkyl group substituted by one or more hydroxy groups (-OH), that is, a hydroxy C 1-6 alkyl group; in some embodiments In the scheme, the hydroxyalkyl group refers to a C 1-4 alkyl group substituted by one or more hydroxy groups (-OH), that is, a hydroxy C 1-4 alkyl group; in some embodiments, the hydroxyalkyl group It refers to a C 1-2 alkyl group substituted with one or more hydroxy groups (-OH), that is, a hydroxy C 1-2 alkyl group. Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl (e.g., -CH 2 OH), hydroxyethyl (e.g., 2-hydroxyethyl), hydroxy n-propyl (e.g., -CH 2 CH 2 CH 2 OH), etc.
术语“氨基烷基”是指被一个或多个氨基(-NH 2)所取代的烷基，所述烷基具有本发明所描述的含义，其中，所述氨基烷基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，本发明所述的氨基烷基基团是指被一个或多个氨基(-NH 2)所取代的C 1-6烷基，即氨基C 1-6烷基；在一些实施方案中，氨基烷基基团是指被一个或多个氨基(-NH 2)所取代的C 1-4烷基，即氨基C 1-4烷基；在一些实施方案中，氨基烷基基团是指被一个或多个氨基(-NH 2)所取代的C 1-2烷基，即氨基C 1-2烷基。氨基烷基基 团的实例包括，但不限于，氨基甲基(-CH 2NH 2)、二甲氨基甲基(-CH(NH 2) 2)、氨基乙基(例如，2-氨基乙基)、氨基正丙基(例如,-CH 2CH 2CH 2NH 2)，等等。 The term "aminoalkyl" refers to an alkyl group substituted with one or more amino groups (-NH 2 ). The alkyl group has the meaning described in the present invention, wherein the aminoalkyl group may optionally be substituted by one Or multiple substituents described in the present invention. In some embodiments, the aminoalkyl group of the present invention refers to a C 1-6 alkyl group substituted by one or more amino groups (-NH 2 ), that is, an amino C 1-6 alkyl group; in some In embodiments, an aminoalkyl group refers to a C 1-4 alkyl group substituted with one or more amino groups (-NH 2 ), that is, an amino C 1-4 alkyl group; in some embodiments, an aminoalkyl group The group refers to a C 1-2 alkyl group substituted with one or more amino groups (-NH 2 ), that is, an amino C 1-2 alkyl group. Examples of aminoalkyl groups include, but are not limited to, aminomethyl (-CH 2 NH 2 ), dimethylaminomethyl (-CH(NH 2 ) 2 ), aminoethyl (for example, 2-aminoethyl ), amino n-propyl (for example, -CH 2 CH 2 CH 2 NH 2 ), and so on.
术语“氰基烷基”是指被一个或多个氰基(-CN)所取代的烷基，所述烷基具有本发明所描述的含义，其中，所述氰基烷基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，本发明所述的氰基烷基基团是指被一个或多个氰基(-CN)所取代的C 1-6烷基，即氰基C 1-6烷基；在一些实施方案中，氰基烷基基团是指被一个或多个氰基(-CN)所取代的C 1-4烷基，即氰基C 1-4烷基；在一些实施方案中，氰基烷基基团是指被一个或多个氰基(-CN)所取代的C 1-2烷基，即氰基C 1-2烷基。氰基烷基基团的实例包括，但不限于，氰基甲基(例如，-CH 2CN)、氰基乙基(例如，2-氰基乙基)等等。 The term "cyanoalkyl" refers to an alkyl group substituted with one or more cyano groups (-CN), and the alkyl group has the meaning described in the present invention, wherein the cyanoalkyl group may optionally It is substituted by one or more substituents described in the present invention. In some embodiments, the cyanoalkyl group described in the present invention refers to a C 1-6 alkyl group substituted with one or more cyano groups (-CN), that is, a cyano C 1-6 alkyl group; In some embodiments, a cyanoalkyl group refers to a C 1-4 alkyl group substituted with one or more cyano groups (-CN), that is, a cyano C 1-4 alkyl group; in some embodiments The cyanoalkyl group refers to a C 1-2 alkyl group substituted by one or more cyano groups (-CN), that is, a cyano C 1-2 alkyl group. Examples of cyanoalkyl groups include, but are not limited to, cyanomethyl (e.g., -CH 2 CN), cyanoethyl (e.g., 2-cyanoethyl), and the like.
术语“羧基烷基”是指被一个或多个羧基(-COOH)所取代的烷基，所述烷基具有本发明所描述的含义，其中，所述羧基烷基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，本发明所述的羧基烷基基团是指被一个或多个羧基(-COOH)所取代的C 1-6烷基，即羧基C 1-6烷基；在一些实施方案中，羧基烷基基团是指被一个或多个羧基(-COOH)所取代的C 1-4烷基，即羧基C 1-4烷基；在一些实施方案中，羧基烷基基团是指被一个或多个羧基(-COOH)所取代的C 1-2烷基，即羧基C 1-2烷基。羧基烷基基团的实例包括，但不限于，羧基甲基、羧基乙基(例如，2-羧基乙基)、羧基正丙基(例如，-CH 2CH 2CH 2COOH)、羧基异丙基(例如,-C(CH 3) 2COOH)等等。 The term "carboxyalkyl" refers to an alkyl group substituted with one or more carboxyl groups (-COOH), and the alkyl group has the meaning described in the present invention, wherein the carboxyalkyl group may optionally be substituted by one or Multiple substituents described in this invention are substituted. In some embodiments, the carboxyalkyl group of the present invention refers to a C 1-6 alkyl group substituted by one or more carboxy groups (-COOH), that is, a carboxy C 1-6 alkyl group; in some embodiments In the scheme, a carboxyalkyl group refers to a C 1-4 alkyl group substituted by one or more carboxy groups (-COOH), that is, a carboxy C 1-4 alkyl group; in some embodiments, a carboxyalkyl group It refers to a C 1-2 alkyl group substituted with one or more carboxyl groups (-COOH), that is, a carboxy C 1-2 alkyl group. Examples of carboxyalkyl groups include, but are not limited to, carboxymethyl, carboxyethyl (for example, 2-carboxyethyl), carboxy n-propyl (for example, -CH 2 CH 2 CH 2 COOH), carboxyisopropyl Group (for example, -C(CH 3 ) 2 COOH) and so on.
术语“烷氨基”包括“N-烷基氨基”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，烷氨基是一个或两个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，烷氨基是一个或两个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，烷氨基是一个或两个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。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，甲氨基(-NHCH 3)，乙氨基(-NHCH 2CH 3)，N,N-二甲基氨基，N,N-二乙基氨基，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, ie, 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, an alkylamino group or two C 1-2 alkyl groups attached to the nitrogen atom of the alkylamino group, i.e. C 1-2 alkylamino. Suitable alkylamino groups can be monoalkylamino or dialkylamino. Examples of such include, but are not limited to, methylamino (-NHCH 3 ), ethylamino (-NHCH 2 CH 3 ), N, N -Dimethylamino, N,N-diethylamino, etc.
术语“碳环基氨基”、“杂环基氨基”、“芳基氨基”或“杂芳基氨基”表示氨基基团被一个或两个碳环基、杂环基、芳基或杂芳基基团所取代，这样的实例包括，但并不限于N-环丙基氨基，N-吡咯烷基氨基，N-苯基氨基，N-嘧啶基氨基，等等。The term "carbocyclylamino", "heterocyclylamino", "arylamino" or "heteroarylamino" means that the amino group is covered by one or two carbocyclyl, heterocyclyl, aryl or heteroaryl groups. Examples of substituted groups include, but are not limited to, N-cyclopropylamino, N-pyrrolidinylamino, N-phenylamino, N-pyrimidinylamino, and the like.
术语“烷酰基”表示烷基基团通过-C(＝O)-与分子其余部分相连，即-C(＝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，烷酰基基团表示C 1-6烷基通过-C(＝O)-与分子其余部分相连，即C 1-6烷酰基；在另一些实施方案中，烷酰基基团表示C 1-4烷基通过-C(＝O)-与分子其余部分相连，即C 1-4烷酰基；在又一些实施方案中，烷酰基基团表示C 1-2烷基通过-C(＝O)-与分子其余部分相连，即C 1-2烷酰基。这个的实例包括，但并不限于，-C(＝O)CH 3，-C(＝O)CH 2CH 3，-C(＝O)CH 2CH 2CH 3，-C(＝O)-CH(CH 3) 2等等。 The term "alkanoyl" means that the alkyl group is connected to the rest of the molecule through -C(=O)-, that is, -C(=O)-alkyl, where the alkyl group has the meaning as described in the present invention. In some embodiments, the alkanoyl group means that the C 1-6 alkyl group is connected to the rest of the molecule through -C(=O)-, that is, the C 1-6 alkanoyl group; in other embodiments, the alkanoyl group It means that the C 1-4 alkyl group is connected to the rest of the molecule through -C(=O)-, that is, the C 1-4 alkanoyl group; in still other embodiments, the alkanoyl group represents the C 1-2 alkyl group through -C (=O)- is connected to the rest of the molecule, namely C 1-2 alkanoyl. Examples of this include, but are not limited to, -C(=O)CH 3 , -C(=O)CH 2 CH 3 , -C(=O)CH 2 CH 2 CH 3 , -C(=O)- CH(CH 3 ) 2 and so on.
术语“烷氧基酰基”表示烷氧基基团通过-C(＝O)-与分子其余部分相连，即-C(＝O)-烷氧基，其中烷氧基基团具有如本发明所述的含义。在一些实施方案中，烷氧基酰基基团表示C 1-6烷氧基通过-C(＝O)-与分子其余部分相连，即C 1-6烷氧基酰基；在另一些实施方案中，烷氧基酰基基团表示C 1-4烷氧基通过-C(＝O)-与分子其余部分相连，即C 1-4烷氧基酰基；在又一些实施方案中，烷氧基酰基基团表示C 1-2烷氧基通过-C(＝O)-与分子其余部分相连，即C 1-2烷氧基酰基。这个的实例包括，但并不限于，-C(＝O)O-CH 3、-C(＝O)O-CH 2CH 3、-C(＝O)O-CH(CH 3) 2。 The term "alkoxyacyl" means that the alkoxy group is connected to the rest of the molecule through -C(=O)-, that is, -C(=O)-alkoxy, wherein the alkoxy group has the same meaning as in the present invention. The meaning of the statement. In some embodiments, the alkoxy acyl group means that the C 1-6 alkoxy group is connected to the rest of the molecule through -C(=O)-, that is, the C 1-6 alkoxy acyl group; in other embodiments , The alkoxy acyl group means that the C 1-4 alkoxy group is connected to the rest of the molecule through -C(=O)-, that is, the C 1-4 alkoxy acyl group; in still other embodiments, the alkoxy acyl group The group means that the C 1-2 alkoxy group is connected to the rest of the molecule through -C(=O)-, that is, the C 1-2 alkoxy acyl group. Examples of this include, but are not limited to, -C(=O)O-CH 3 , -C(=O)O-CH 2 CH 3 , -C(=O)O-CH(CH 3 ) 2 .
术语“环烷基-烷基”、“碳环基-烷基”、“杂环基-烷基”、“芳基-烷基”和“杂芳基-烷基”表示环烷基、碳环基、杂环基、芳基和杂芳基通过-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)、
Figure PCTCN2020077781-appb-000015
所述“环烷基-烷基”、“碳环基-烷基”、“杂环基-烷基”、“芳基-烷基”、“杂芳基-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-alkyl", "carbocyclyl-alkyl", "heterocyclyl-alkyl", "aryl-alkyl" and "heteroaryl-alkyl" refer to cycloalkyl, carbon Cyclic, heterocyclic, aryl and heteroaryl are connected to the rest of the molecule through -alkyl-, wherein the alkyl, cycloalkyl, carbocyclic, heterocyclic, aryl and heteroaryl groups all have As defined in the present invention, such as benzyl (-CH 2 -Ph),
Figure PCTCN2020077781-appb-000015
The "cycloalkyl-alkyl", "carbocyclyl-alkyl", "heterocyclyl-alkyl", "aryl-alkyl" and "heteroaryl-alkyl" groups optionally It is substituted by one or more substituents described in the present 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 upset, 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 Pharmacopeia or other generally recognized pharmacopoeia for use in animals, more particularly in humans.
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液体，例如水和油类，包括石油、动物、植物或合成来源的，例如花生油、大豆油、矿物油、芝麻油等。水和水性溶液盐水溶液和水性葡萄糖与甘油溶液优选用作载体、特别是可注射溶液。适宜的药物载体描述于E.W.Martin的“Remington′s Pharmaceutical Sciences”中。The term "carrier" refers to a diluent, adjuvant, excipient or base with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water and aqueous solutions Saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, especially injectable solutions. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.
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 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 effect of another anti-influenza therapy used. The exact amount of the 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, 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 both therapeutic and prophylactic treatment. For example, therapeutic treatment includes alleviating or improving 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 treatments include 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 the 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. "Carboxy 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, please 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 novel compounds as inhibitors of influenza virus RNA polymerase, more specifically, the present invention provides a class of novel 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 the 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 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, pharmaceutical Acceptable salts or their prodrugs,
Figure PCTCN2020077781-appb-000016
Figure PCTCN2020077781-appb-000016
其中P、U 1、U 2、U 3、U 4、U 5、U 6、U 7、U 8、R 9和R 10具有如本发明所述的定义，其中，R 9和R 10不同时为H，且本发明化合物不包括以下化合物： Wherein P, U 1 , U 2 , U 3 , U 4 , U 5 , U 6 , U 7 , U 8 , R 9 and R 10 have the definitions described in the present invention, wherein R 9 and R 10 are not at the same time Is H, and the compound of the present invention does not include the following compounds:
Figure PCTCN2020077781-appb-000017
Figure PCTCN2020077781-appb-000017
在一些实施方案中，U 1为CR 1或N； In some embodiments, U 1 is CR 1 or N;
R 1为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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。 R 1 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 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 1-6 haloalkyl group, C 1-6 alkoxy group , C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 ring Alkyl groups, heterocyclic groups composed of 5-6 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group or C 1-6 alkylamino group.
在一些实施方案中，U 2为CR 2或N； In some embodiments, U 2 is CR 2 or N;
R 2为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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。 R 2 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy Group, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 Cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 haloalkyl group, C 1-6 alkoxy group , C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 ring Alkyl groups, heterocyclic groups composed of 5-6 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group or C 1-6 alkylamino group.
在一些实施方案中，U 3为CR 3或N； In some embodiments, U 3 is CR 3 or N;
R 3为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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。 R 3 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy Group, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 Cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 haloalkyl group, C 1-6 alkoxy group , C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 ring Alkyl groups, heterocyclic groups composed of 5-6 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group or C 1-6 alkylamino group.
在一些实施方案中，U 4为CR 4或N； In some embodiments, U 4 is CR 4 or N;
R 4为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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。 R 4 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy Group, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 Cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 haloalkyl group, C 1-6 alkoxy group , C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 ring Alkyl groups, heterocyclic groups composed of 5-6 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group or C 1-6 alkylamino group.
在一些实施方案中，U 5为CR 5或N； In some embodiments, U 5 is CR 5 or N;
R 5为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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。 R 5 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy Group, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 Cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 haloalkyl group, C 1-6 alkoxy group , C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 ring Alkyl groups, heterocyclic groups composed of 5-6 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group or C 1-6 alkylamino group.
在一些实施方案中，U 6为CR 6或N； In some embodiments, U 6 is CR 6 or N;
R 6为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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。 R 6 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy Group, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 Cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 haloalkyl group, C 1-6 alkoxy group , C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 ring Alkyl groups, heterocyclic groups composed of 5-6 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group or C 1-6 alkylamino group.
在一些实施方案中，U 7为CR 7或N； In some embodiments, U 7 is CR 7 or N;
R 7为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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。 R 7 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 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 1-6 haloalkyl group, C 1-6 alkoxy group , C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 ring Alkyl groups, heterocyclic groups composed of 5-6 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group or C 1-6 alkylamino group.
在一些实施方案中，U 8为CR 8或N； In some embodiments, U 8 is CR 8 or N;
R 8为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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。 R 8 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 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 1-6 haloalkyl group, C 1-6 alkoxy group , C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 ring Alkyl groups, heterocyclic groups composed of 5-6 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group or C 1-6 alkylamino group.
在一些实施方案中，R 9为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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，条件是R 9和R 10不同时为H。 In some embodiments, R 9 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne Group, 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 1-6 haloalkyl group, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl , C 3-6 cycloalkyl group, 5-6 atom heterocyclic group, C 6-10 aryl group and 5-6 atom heteroaryl group are each independently unsubstituted or by 1, 2, 3 Or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino, provided that R 9 and R 10 are not H at the same time.
在一些实施方案中，R 10为H、氘、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烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、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烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基或L-R 11，其中所述C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、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烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-4烷基各自独立地未被取代或被1、2、3或4个R w所取代，条件是R 9和R 10不同时为H； In some embodiments, R 10 is H, deuterium, 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 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1 -6 alkylthio, -C(=O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-4 alkyl group, 3-8 atom heterocyclic group, (3-8 atom heterocyclic group) C 1-4 alkyl , C 6-10 aryl, C 6-10 aryl, C 1-4 alkyl, 5-10 heteroaryl, (5-10 heteroaryl) C 1-4 alkyl Or LR 11 , wherein the C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio Group, -C(=O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbon Cyclic group, C 3-6 carbocyclic group C 1-4 alkyl group, heterocyclic group composed of 3-8 atoms, (heterocyclic group composed of 3-8 atoms) C 1-4 alkyl group, C 6- 10 aryl, C 6-10 aryl, C 1-4 alkyl, 5-10 heteroaryl and (5-10 heteroaryl) C 1-4 alkyl each independently Is substituted or substituted by 1, 2, 3 or 4 R w , provided that R 9 and R 10 are not H at the same time;
L为-(CR aR b) p-O-、-(CR aR b) t-S-、-(CR aR b) s-S(＝O)-、-(CR aR b) s-S(＝O) 2-、-(CR aR b) s-N(R c)-、-(CR aR b) s-C(＝O)N(R c)-、-(CR aR b) s-C(＝O)-、-(CR aR b) s-C(＝O)-或-(CR aR b) r-； L is -(CR a R b ) p -O-, -(CR a R b ) t -S-, -(CR a R b ) s -S(=O)-, -(CR a R b ) s -S(=O) 2 -, -(CR a R b ) s -N(R c )-, -(CR a R b ) s -C(=O)N(R c )-, -(CR a R b ) s -C(=O)-, -(CR a R b ) s -C(=O)- or -(CR a R b ) r -;
各R a和R b独立地为H、氘、F、Cl、Br、I、-CN、-NH 2、-OH、-SH、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烷氨基、C 1-6卤代烷氧基、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；或R a、R b和与它们相连的碳原子一起，形成C 3-6碳环或3-6个原子组成的杂环； Each R a and R b are independently H, deuterium, F, Cl, Br, I , -CN, -NH 2, -OH, -SH, C 1-6 alkyl, C 2-6 alkenyl group, C 2 -6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, C 3-6 cycloalkyl, composed of 3-6 atoms heterocyclyl, C 6-10 aryl, or 5-6 atoms heteroaryl; or R a, R b and the carbon atom to which they are attached together form a C 3-6 carbocyclic ring of 3-6 atoms or Composed of heterocycles;
各R c独立地为H、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、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； Each R c is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 A heterocyclic group consisting of atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 atoms;
R 11为H、氘、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、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烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)C 1-4烷基，其中所述C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、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烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-4烷基各自独立地未被取代或被1、2、3或4个R w所取代； R 11 is H, deuterium, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio Group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-4 alkyl, 3-8 heterocyclic group, ( 3-8 atoms heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl or ( Heteroaryl composed of 5-10 atoms) C 1-4 alkyl, wherein the C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkylamino, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-4 alkane Group, heterocyclic group composed of 3-8 atoms, (heterocyclic group composed of 3-8 atoms) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkane Group, heteroaryl group consisting of 5-10 atoms and (heteroaryl group consisting of 5-10 atoms) C 1-4 alkyl are each independently unsubstituted or replaced by 1, 2, 3 or 4 R w replace;
各R w独立地为氘、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷氨基、-S(＝O) q-C 1-6烷基、-S(＝O) q-C 1-6烷氨基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、羧基C 1-6烷基、氨基C 1-6烷基、氰基C 1-6烷基、C 1-6烷基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-8个原子组成的杂芳基，其中所述C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷氨基、-S(＝O) q-C 1-6烷基、-S(＝O) q-C 1-6烷氨基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、羧基C 1-6烷基、氨基C 1-6烷基、氰基C 1-6烷基、C 1-6烷基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基和5-8个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、＝O、-OH、-NH 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 w is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -C(=O)OH, -C(=O)NH 2 , -S( ＝O) 2 NH 2 , C 1-6 alkoxy, C 1-6 alkylamino, -C(=O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy , -C(=O)-C 1-6 alkylamino, -S(=O) q -C 1-6 alkyl, -S(=O) q -C 1-6 alkylamino, C 1-6 haloalkane Group, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 heterocyclic group, C 6-10 aryl or 5-8 heteroaryl, wherein the C 1-6 alkoxy, C 1 -6 alkylamino, -C(=O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy, -C(=O)-C 1-6 alkylamino, -S (=O) q -C 1-6 alkyl, -S(=O) q -C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl , Carboxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclic ring composed of 3-8 atoms Group, C 6-10 aryl group and 5-8 atom heteroaryl group are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, =O, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
q为0、1或2；q is 0, 1 or 2;
r为1、2、3或4；r is 1, 2, 3 or 4;
各p、t或s独立地为0、1、2、3或4。Each p, t, or s is independently 0, 1, 2, 3, or 4.
在一些实施方案中，P为H、氘、C 1-6烷基、C 2-6烯基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基、-C(＝O)-R Pa、-C(＝O)-Z-R Pe、-C(＝O)-Z-O-R Pb、-C(＝O)-Z-O-Z-O-R Pb、-C(＝O)-Z-O-C(＝O)-R Pa、-C(＝O)-NR PcR Pd、-C(＝O)-O-R Pb、-S(＝O) 2-R Pi、-P(＝O)-(R Pg)(R Ph)、-C(＝O)-O-Y-O-R Pb、-Z-O-R Pb、-Z-O-Z-O-R Pb、-Y-O-C(＝O)-R Pa、-Y-C(＝O)-O-R Pb、-Y-NR Pf-(C＝O)-O-R Pb、-Y-O-C(＝O)-O-R Pb、-Z-O-C(＝O)-O-NR PcR Pd、-Y-O-C(＝O)-O-Y-O-R Pb、-Z-O-(C＝O)-O-Z-NR PcR Pd、-Z-O-C(＝O)-NR Pf-Z-O-R Pb、-Z-O-C(＝O)-NR Pf-Z-NR PcR Pd、-Z-O-C(＝O)-O-Z-O-Z-O-R Pb或-Z-O-C(＝O)-O-Z-NR Pf-(C＝O)-R Pa，其中所述C 1-6烷基、C 2-6烯基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-4烷基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基； In some embodiments, P is H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 carbocyclyl, C 3-8 carbocyclyl, C 1-4 alkyl, 3- 8-atom heterocyclic group, (3-8 atom heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-4 alkyl, 5- Heteroaryl group composed of 10 atoms, (heteroaryl group composed of 5-10 atoms) C 1-4 alkyl group, -C(=O)-R Pa , -C(=O)-ZR Pe , -C (=O)-ZOR Pb 、-C(=O)-ZOZOR Pb 、-C(=O)-ZOC(=O)-R Pa 、-C(=O)-NR Pc R Pd 、-C(= O)-OR Pb , -S(=O) 2 -R Pi , -P(=O)-(R Pg )(R Ph ), -C(=O)-OYOR Pb , -ZOR Pb , -ZOZOR Pb , -YOC(=O)-R Pa , -YC(=O)-OR Pb , -Y-NR Pf -(C=O)-OR Pb , -YOC(=O)-OR Pb , -ZOC(= O)-O-NR Pc R Pd , -YOC(=O)-OYOR Pb , -ZO-(C=O)-OZ-NR Pc R Pd , -ZOC(=O)-NR Pf -ZOR Pb ,- ZOC(=O)-NR Pf -Z-NR Pc R Pd , -ZOC(=O)-OZOZOR Pb or -ZOC(=O)-OZ-NR Pf -(C=O)-R Pa , wherein C 1-6 alkyl, C 2-6 alkenyl, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl, heterocyclic group consisting of 3-8 atoms, (3- 8-atom heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-4 alkyl, 5-10 heteroaryl and (5- (10-atom heteroaryl) C 1-4 alkyl is each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino;
各Y和Z独立地为C 1-6烷基； Each Y and Z is independently C 1-6 alkyl;
各R Pf独立地为H、氘或C 1-6烷基； Each R Pf is independently H, deuterium, or C 1-6 alkyl;
各R Pa、R Pb、R Pc、R Pd、R Pe和R Pi独立地为C 1-6烷基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基、C 1-6烷氨基、C 1-6烷硫基或C 1-6烷基甲硅烷基，其中所述C 1-6烷基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基、C 1-6烷氨基和C 1-6烷硫基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基； Each R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently C 1-6 alkyl, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl, Heterocyclic group consisting of 3-8 atoms, (heterocyclic group consisting of 3-8 atoms) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-4 alkyl, Heteroaryl group consisting of 5-10 atoms, (heteroaryl group consisting of 5-10 atoms) C 1-4 alkyl, C 1-6 alkylamino, C 1-6 alkylthio or C 1-6 alkane Group silyl group, wherein the C 1-6 alkyl group, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl group, 3-8 atoms heterocyclic group, (3 -8-atom heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl, (5 -10 atoms of heteroaryl) C 1-4 alkyl, C 1-6 alkylamino and C 1-6 alkylthio are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O ) NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino;
各R Pg和R Ph独立地为C 1-6烷氧基、C 1-6烷氨基、C 3-8碳环基氧基、C 3-8碳环基氨基、3-8个原子组成的杂环基氧基、3-8个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-10个原子组成的杂芳基氧基或5-10个原子组成的杂芳基氨基，其中所述C 1-6烷氧基、C 1-6烷氨基、C 3-8碳环基氧基、C 3-8碳环基氨基、3-8个原子组成的杂环基氧基、3-8个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-10个原子组成的杂芳基氧基和5-10个原子组成的杂芳基氨基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基。 Each R Pg and R Ph is independently composed of C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 carbocyclyloxy, C 3-8 carbocyclylamino, 3-8 atoms Heterocyclyloxy, heterocyclylamino consisting of 3-8 atoms, C 6-10 aryloxy, C 6-10 arylamino, heteroaryloxy consisting of 5-10 atoms or 5- A 10-atom heteroarylamino group, wherein the C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-8 carbocyclyloxy group, C 3-8 carbocyclylamino group, 3-8 3-atom heterocyclyloxy, 3-8 heterocyclic amino, C 6-10 aryloxy, C 6-10 arylamino, 5-10 heteroaryloxy A group and a heteroarylamino group consisting of 5-10 atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino.
在一些实施方案中，R 10为H、氘、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烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、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烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)C 1-2烷基或L-R 11，其中所述C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、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烷基、C 6-10芳基、C 6-10芳基C 1-2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烷基各自独立地未被取代或被1、2、3或4个R w所取代，条件是R 9和R 10不同时为H；其中L、R 11和R w具有本发明所描述的含义。 In some embodiments, R 10 is H, deuterium, 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 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1 -4 Alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl, 5-6 heterocyclic group, (5-6 heterocyclic group) C 1-2 alkyl , C 6-10 aryl, C 6-10 aryl, C 1-2 alkyl, 5-6 heteroaryl, (5-6 heteroaryl) C 1-2 alkyl Or LR 11 , wherein the C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio Group, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbon Cyclic group, C 3-6 carbocyclic group C 1-2 alkyl group, 5-6 atom heterocyclic group, (5-6 atom heterocyclic group) C 1-2 alkyl group, C 6- 10 aryl groups, C 6-10 aryl groups, C 1-2 alkyl groups, heteroaryl groups composed of 5-6 atoms, and (heteroaryl groups composed of 5-6 atoms) C 1-2 alkyl groups are each independently Substituted or substituted by 1, 2, 3 or 4 R w , provided that R 9 and R 10 are not H at the same time; wherein L, R 11 and R w have the meaning described in the present invention.
在另一些实施方案中，R 10为H、氘、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、一氟甲基、二氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、三氟甲氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、-C(＝O)CH 3、-C(＝O)CH 2CH 3、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、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L-R 11，其中所述一氟甲基、二氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、-C(＝O)CH 3、-C(＝O)CH 2CH 3、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4个R w所取代，条件是R 9和R 10不同时为H；其中L、R 11和R w具有本发明所描述的含义。 In other embodiments, R 10 is H, deuterium, Br, I, -CN, -NO 2 , -OH, -SH, -NH 2 , -C(=O)OH, -C(=O)NH 2. -S(=O) 2 NH 2 , monofluoromethyl, difluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methyl Oxy, ethoxy, n-propyloxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethylamino, N,N- Diethylamino, methylthio, -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazole Alkyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-methyl, pyrrolyl, pyridyl, Pyrimidyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, 1 , 3,5-triazinyl or LR 11 , wherein the monofluoromethyl, difluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl Group, methoxy, ethoxy, n-propyloxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethylamino, N,N-diethyl Amino, methylthio, -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, Imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-methyl, pyrrolyl, pyridyl, pyrimidinyl, Thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1,3, The 5-triazinyl groups are each independently unsubstituted or substituted with 1, 2, 3, or 4 R w , provided that R 9 and R 10 are not H at the same time; wherein L, R 11 and R w have the present invention The meaning of the description.
在一些实施方案中，R 11为H、氘、C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、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烷基、C 6-10芳基、C 6-10芳基C 1-2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烷基，其中所述C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、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烷基、C 6-10芳基、C 6-10芳基C 1-2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烷基各自独立地未被取代或被1、2、3或4个R w所取代；其中R w具有本发明所描述的含义。 In some embodiments, R 11 is H, deuterium, C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-2 alkyl group, composed of 5-6 atoms The heterocyclic group, (heterocyclic group composed of 5-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl, 5-6 atoms Heteroaryl group or (heteroaryl group consisting of 5-6 atoms) C 1-2 alkyl, wherein the C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic ring C 1-2 alkyl, 5-6 heterocyclic group, (5-6 heterocyclic group) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl group, heteroaryl group composed of 5-6 atoms and (heteroaryl group composed of 5-6 atoms) C 1-2 alkyl group are each independently unsubstituted or by 1, 2, 3 Or substituted by 4 R w ; wherein R w has the meaning described in the present invention.
在另一些实施方案中，R 11为H、氘、一氟甲基、二氟甲基、三氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、三氟甲氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、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，其中所述一氟甲基、二氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4个R w所取代；其中R w具有本发明所描述的含义。 In other embodiments, R 11 is H, deuterium, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethyl Amino, N,N-diethylamino, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholine Group, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-methyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyridine Azolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3,5-triazinyl, wherein said one Fluoromethyl, difluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propyloxy, Isopropyloxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino, methylthio, cyclopropyl, cyclobutyl, cyclopentan Group, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, benzene Group-methyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazole Group, pyrazinyl, pyridazinyl and 1,3,5-triazinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 R w ; wherein R w has the meaning described in the present invention .
在一些实施方案中，各R w独立地为氘、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-4烷氧基、C 1-4烷氨基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1-4烷氨基、-S(＝O) q-C 1-4烷基、-S(＝O) q-C 1-4烷氨基、C 1-4卤代烷基、C 1-4卤代烷氧基、羟基C 1-4烷基、羧基C 1-4烷基、氨基C 1-4烷基、氰基C 1-4烷基、C 1-4烷基、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烷氧基、C 1-4烷氨基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1-4烷氨基、-S(＝O) q-C 1-4烷基、-S(＝O) q-C 1-4烷氨基、C 1-4卤代烷基、C 1-4卤代烷氧基、羟基C 1-4烷基、羧基C 1-4烷基、氨基C 1-4烷基、氰基C 1-4烷基、C 1-4烷基、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、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、＝O、-OH、-NH 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 w is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -C(=O)OH, -C(=O) NH 2 , -S(=O) 2 NH 2 , C 1-4 alkoxy, C 1-4 alkylamino, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkoxy, -C(=O)-C 1-4 alkylamino, -S(=O) q -C 1-4 alkyl, -S(=O) q -C 1-4 alkylamino , C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxy C 1-4 alkyl, carboxy C 1-4 alkyl, amino C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 heterocyclic group, C 6-10 aryl or 5-6 heteroaryl, wherein the C 1-4 Alkoxy, C 1-4 alkylamino, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkoxy, -C(=O)-C 1- 4 alkylamino, -S (= O) q -C 1-4 alkyl, -S (= O) q -C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxy C 1-4 alkyl, carboxy C 1-4 alkyl, amino C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 A heterocyclic group consisting of three atoms, a C 6-10 aryl group and a heteroaryl group consisting of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3, or 4 substituents. Independently selected from deuterium, F, Cl, Br, I, -CN, =O, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino.
在另一些实施方案中，各R w独立地为氘、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-C(＝O)OH、-C(＝O)NH 2、 -S(＝O) 2NH 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-SCH 3、-SCH 2CH 3、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、二氟甲基、三氟甲基、三氟乙基、三氟甲氧基、二氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、羧基甲基、羧基乙基、羧基正丙基、羧基异丙基、氨基甲基、氨基乙基、氰基甲基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、四氢噻吩基、吡咯烷基、吡唑烷基、咪唑烷基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、苯基、吡咯基、噻吩基、噻唑基、咪唑基、三唑基、呋喃基、吡啶基、嘧啶基、吡嗪基或哒嗪基，其中所述甲氧基、乙氧基、正丙基氧基、异丙基氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-SCH 3、-SCH 2CH 3、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、二氟甲基、三氟乙基、二氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、羧基甲基、羧基乙基、羧基正丙基、羧基异丙基、氨基甲基、氨基乙基、氰基甲基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、四氢噻吩基、吡咯烷基、吡唑烷基、咪唑烷基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、苯基、吡咯基、噻吩基、噻唑基、咪唑基、三唑基、呋喃基、吡啶基、嘧啶基、吡嗪基和哒嗪基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、＝O、-OH、-NH 2、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基或甲氨基。 In other embodiments, each R w is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -C(=O)OH, -C(=O )NH 2 , -S(=O) 2 NH 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, methylamino, ethylamino, N,N-dimethylamino, N , N-Diethylamino, -C(=O)-OCH 3 , -C(=O)-OCH 2 CH 3 , -SCH 3 , -SCH 2 CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 CH 2 CH 3 , difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, hydroxymethyl, hydroxyl Ethyl, carboxymethyl, carboxyethyl, carboxyn-propyl, carboxyisopropyl, aminomethyl, aminoethyl, cyanomethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholine Group, thiomorpholinyl, piperidinyl, piperazinyl, phenyl, pyrrolyl, thienyl, thiazolyl, imidazolyl, triazolyl, furyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazine Group, wherein the methoxy, ethoxy, n-propyloxy, isopropyloxy, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino,- C(=O)-OCH 3 , -C(=O)-OCH 2 CH 3 , -SCH 3 , -SCH 2 CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 CH 2 CH 3 , difluoromethyl, trifluoroethyl, difluoromethoxy, trifluoroethoxy, hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl, carboxyn-propyl, carboxyisopropyl , Aminomethyl, aminoethyl, cyanomethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, phenyl, pyrrole Group, thienyl, thiazolyl, imidazolyl, triazolyl, furyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, =O, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl Group, methoxy, ethoxy or methylamino.
在一些实施方案中，R 1、R 2、R 3和R 4各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、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，其中所述C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、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、3或4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、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, R 1 , R 2 , R 3 and R 4 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C( =O) OH, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, 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 , Wherein the C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, 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 and 5-6 heteroaryl each Independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1 -4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino.
在另一些实施方案中，R 1、R 2、R 3和R 4各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、三氟甲基、三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟甲氧基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、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，其中所述三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4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、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基或乙氧基。 In other embodiments, R 1 , R 2 , R 3 and R 4 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C (=O) OH, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, methylthio, methylamino, trifluoromethoxy, trifluoroethoxy, methyl, ethyl, normal Propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl , Thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, three Azolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3,5-triazinyl, wherein the trifluoroethyl, methoxy , Ethoxy, methylthio, methylamino, trifluoroethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrole Base, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, Pyridazinyl and 1,3,5-triazinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.
在一些实施方案中，R 5、R 6、R 7和R 8各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、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，其中所述C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、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、3或4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、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, R 5 , R 6 , R 7 and R 8 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C( =O) OH, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, 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 , Wherein the C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, 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 and 5-6 heteroaryl each Independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1 -4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino.
在另一些实施方案中，R 5、R 6、R 7和R 8各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、三氟甲基、三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟甲氧基、三氟乙氧基、甲基、 乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、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，其中所述三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4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、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基或乙氧基。 In other embodiments, R 5 , R 6 , R 7 and R 8 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C (=O) OH, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, methylthio, methylamino, trifluoromethoxy, trifluoroethoxy, methyl, ethyl, normal Propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl , Thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, three Azolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3,5-triazinyl, wherein the trifluoroethyl, methoxy , Ethoxy, methylthio, methylamino, trifluoroethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrole Base, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, Pyridazinyl and 1,3,5-triazinyl are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.
在一些实施方案中，R 9为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、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，其中所述C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、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、3或4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、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，条件是R 9和R 10不同时为H。 In some embodiments, R 9 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 haloalkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne Group, 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 haloalkyl group, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 1-4 haloalkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 3-6 cycloalkyl group, 5-6 atom heterocyclic group, C 6-10 aryl group and 5-6 atom heteroaryl group are each independently unsubstituted or by 1, 2, 3 Or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino, provided that R 9 and R 10 are not H at the same time.
在另一些实施方案中，R 9为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、三氟甲基、三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、三氟甲氧基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、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，其中所述三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4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、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基或乙氧基，条件是R 9和R 10不同时为H。 In other embodiments, R 9 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, trifluoromethyl, trifluoromethyl Fluoroethyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino, trifluoromethoxy, trifluoroethoxy Base, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidine Alkyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furanyl , Pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3,5-triazinyl, of which The trifluoroethyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino, trifluoroethoxy, methyl , Ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidine Group, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl , Imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1,3,5-triazinyl are each independently unsubstituted or Substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl Group, isopropyl, trifluoromethyl, methoxy or ethoxy, provided that R 9 and R 10 are not H at the same time.
在一些实施方案中，各R a和R b独立地为H、氘、F、Cl、Br、I、-CN、-NH 2、-OH、-SH、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烷氨基、C 1-4卤代烷氧基、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；或R a、R b和与它们相连的碳原子一起，形成C 3-6碳环或5-6个原子组成的杂环。 In some embodiments, each of R a and R b are independently H, deuterium, F, Cl, Br, I , -CN, -NH 2, -OH, -SH, C 1-4 alkyl, C 2- 4 Alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 haloalkoxy, C 3-6 cycloalkyl, 5 to 6 atoms heterocyclyl, C 6-10 aryl, or 5-6 atoms heteroaryl; or R a, R b and the carbon atom to which they are attached together form a C 3-6 carbocyclic ring Or a heterocyclic ring composed of 5-6 atoms.
在一些实施方案中，各R c独立地为H、氘、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、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, each R c is independently H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 3-6 cycloalkane Group, heterocyclic group consisting of 5-6 atoms, C 6-10 aryl group or heteroaryl group consisting of 5-6 atoms.
在一些实施方案中，各R a和R b独立地为H、氘、F、Cl、Br、I、-CN、-NH 2、-OH、-SH、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、甲氧基、乙氧基、甲氨基、三氟甲氧基、环丙基、环丁基、环戊基、环己基、3-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基；或R a、R b和与它们相连的碳原子一起，形成环丙基、环丁基、环戊基、环己基或3-6个原子组成的杂环。 In some embodiments, each of R a and R b are independently H, deuterium, F, Cl, Br, I , -CN, -NH 2, -OH, -SH, methyl, ethyl, n-propyl, Isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3 to 6 atoms heterocyclyl, phenyl, or 5-6 atoms heteroaryl; or R a, R b and the carbon atom to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, Group, cyclohexyl or heterocyclic ring composed of 3-6 atoms.
在一些实施方案中，各R c独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、环丙基、环丁基、环戊基、环己基、3-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基。 In some embodiments, each R c is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, heterocyclic group composed of 3-6 atoms, phenyl group or heteroaryl group composed of 5-6 atoms.
在一些实施方案中，P为H、氘、C 1-4烷基、C 2-4烯基、C 3-6碳环基、C 3-6碳环基C 1-2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烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-2烷基、-C(＝O)-R Pa、-C(＝O)-Z-R Pe、-C(＝O)-Z-O-R Pb、-C(＝O)-Z-O-Z-O-R Pb、-C(＝O)-Z-O-C(＝O)-R Pa、-C(＝O)-NR PcR Pd、-C(＝O)-O-R Pb、-S(＝O) 2-R Pi、-P(＝O)-(R Pg)(R Ph)、-C(＝O)-O-Y-O-R Pb、-Z-O-R Pb、-Z-O-Z-O-R Pb、-Y-O-C(＝O)-R Pa、-Y-C(＝O)-O-R Pb、-Y-NR Pf-(C＝O)-O-R Pb、-Y-O-C(＝O)-O-R Pb、-Z-O-C(＝O)-O-NR PcR Pd、-Y-O-C(＝O)-O-Y-O-R Pb、-Z-O-(C＝O)-O-Z-NR PcR Pd、-Z-O-C(＝O)-NR Pf-Z-O-R Pb、-Z-O-C(＝O)-NR Pf-Z-NR PcR Pd、-Z-O-C(＝O)-O-Z-O-Z-O-R Pb或-Z-O-C(＝O)-O-Z-NR Pf-(C＝O)-R Pa，其中所述C 1-4烷基、C 2-4烯基、C 3-6碳环基、C 3-6碳环基C 1-2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烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-2烷基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基；其中，R Pa、R Pb、R Pc、R Pd、R Pe、R Pf、R Pg、R Ph、R Pi、Y和Z分别具有本发明所述的定义。 In some embodiments, P is H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl, C 1-2 alkyl, 5- 6-atom heterocyclic group, (5-6 atom heterocyclic group) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-2 alkyl, 5- Heteroaryl group consisting of 10 atoms, (heteroaryl group consisting of 5-10 atoms) C 1-2 alkyl group, -C(=O)-R Pa , -C(=O)-ZR Pe , -C (=O)-ZOR Pb 、-C(=O)-ZOZOR Pb 、-C(=O)-ZOC(=O)-R Pa 、-C(=O)-NR Pc R Pd 、-C(= O)-OR Pb , -S(=O) 2 -R Pi , -P(=O)-(R Pg )(R Ph ), -C(=O)-OYOR Pb , -ZOR Pb , -ZOZOR Pb , -YOC(=O)-R Pa , -YC(=O)-OR Pb , -Y-NR Pf -(C=O)-OR Pb , -YOC(=O)-OR Pb , -ZOC(= O)-O-NR Pc R Pd , -YOC(=O)-OYOR Pb , -ZO-(C=O)-OZ-NR Pc R Pd , -ZOC(=O)-NR Pf -ZOR Pb ,- ZOC(=O)-NR Pf -Z-NR Pc R Pd , -ZOC(=O)-OZOZOR Pb or -ZOC(=O)-OZ-NR Pf -(C=O)-R Pa , wherein C 1-4 alkyl, C 2-4 alkenyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl group, heterocyclic group consisting of 5-6 atoms, (5- 6-atom heterocyclic group) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl, 5-10 heteroaryl and (5- (10-atom heteroaryl) C 1-2 alkyl is each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino; wherein, R Pa , R Pb , R Pc , R Pd , R Pe , R Pf , R Pg , R Ph , R Pi , Y and Z respectively have the definitions described in the present invention.
在一些实施方案中，各Y和Z独立地为C 1-4烷基。 In some embodiments, each Y and Z is independently C 1-4 alkyl.
在一些实施方案中，各R Pf独立地为H、氘或C 1-6烷基。 In some embodiments, each R Pf is independently H, deuterium, or C 1-6 alkyl.
在一些实施方案中，各R Pa、R Pb、R Pc、R Pd、R Pe和R Pi独立地为C 1-4烷基、C 3-6碳环基、C 3-6碳环基C 1-2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 1-2烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)C 1-2烷基、C 1-4烷氨基、C 1-4烷硫基或C 1-4烷基甲硅烷基，其中所述C 1-4烷基、C 3-6碳环基、C 3-6碳环基C 1-2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 1-2烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)C 1-2烷基、C 1-4烷氨基和C 1-4烷硫基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷酰基、C 1-4烷氧基酰基或C 1-4烷氨基。 In some embodiments, each of R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently C 1-4 alkyl, C 3-6 carbocyclyl, C 3-6 carbocyclyl C 1-2 alkyl, heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl, heteroaryl composed of 5-6 atoms, (heteroaryl composed of 5-6 atoms) C 1-2 alkyl, C 1-4 alkylamino, C 1-4 alkylthio Or C 1-4 alkylsilyl group, wherein the C 1-4 alkyl group, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl group, 3-6 atoms Heterocyclic group, (heterocyclic group consisting of 3-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl, 5-6 atoms Heteroaryl, (heteroaryl composed of 5-6 atoms) C 1-2 alkyl, C 1-4 alkylamino and C 1-4 alkylthio are each independently unsubstituted or by 1, 2, 3 Or substituted by 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH , -C(=O)NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkoxy acyl or C 1 -4 Alkylamino.
在一些实施方案中，各R Pg和R Ph独立地为C 1-4烷氧基、C 1-4烷氨基、C 3-6碳环基氧基、C 3-6碳环基氨基、3-6个原子组成的杂环基氧基、3-6个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-6个原子组成的杂芳基氧基或5-6个原子组成的杂芳基氨基，其中所述C 1-4烷氧基、C 1-4烷氨基、C 3-6碳环基氧基、C 3-6碳环基氨基、3-6个原子组成的杂环基氧基、3-6个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-6个原子组成的杂芳基氧基和5-6个原子组成的杂芳基氨基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷酰基、C 1-4烷氧基酰基或C 1-4烷氨基。 In some embodiments, each R Pg and R Ph is independently C 1-4 alkoxy, C 1-4 alkylamino, C 3-6 carbocyclyloxy, C 3-6 carbocyclylamino, 3 -6-atom heterocyclyloxy, 3-6 heterocyclylamino, C 6-10 aryloxy, C 6-10 arylamino, 5-6 heteroaromatic Oxy group or heteroarylamino group consisting of 5-6 atoms, wherein the C 1-4 alkoxy group, C 1-4 alkylamino group, C 3-6 carbocyclic oxy group, C 3-6 carbocyclic group Amino group, heterocyclyloxy group consisting of 3-6 atoms, heterocyclylamino group consisting of 3-6 atoms, C 6-10 aryloxy group, C 6-10 arylamino group, 5-6 atoms The heteroaryloxy group composed of 5-6 atoms and the heteroarylamino group composed of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkoxyacyl, or C 1-4 alkylamino.
在一些实施方案中，P为H、氘、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环己基-甲基、环戊基-甲基、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、2-氧代-1,3-二氧戊环基、2-氧代-1,3-二氧杂环戊烯基、2-氧代-1,3-二氧戊环基-甲基、苯基、苯基-甲基、呋喃基、呋喃酮基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、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、苯并呋喃酮基、苯并呋喃基、吲哚基、苯并噻吩基、苯并咪唑基、喹啉基、异喹啉基、嘌呤基、-C(＝O)-R Pa、-C(＝O)-Z-R Pe、-C(＝O)-Z-O-R Pb、-C(＝O)-Z-O-Z-O-R Pb、-C(＝O)-Z-O-C(＝O)-R Pa、-C(＝O)-NR PcR Pd、-C(＝O)-O-R Pb、-S(＝O) 2-R Pi、-P(＝O)-(R Pg)(R Ph)、-C(＝O)-O-Y-O-R Pb、-Z-O-R Pb、-Z-O-Z-O-R Pb、-Y-O-C(＝O)-R Pa、-Y-C(＝O)-O-R Pb、-Y-NR Pf-(C＝O)-O-R Pb、-Y-O-C(＝O)-O-R Pb、-Z-O-C(＝O)-O-NR PcR Pd、-Y-O-C(＝O)-O-Y-O-R Pb、-Z-O-(C＝O)-O-Z-NR PcR Pd、-Z-O-C(＝O)-NR Pf-Z-O-R Pb、-Z-O-C(＝O)-NR Pf-Z-NR PcR Pd、-Z-O-C(＝O)-O-Z-O-Z-O-R Pb或-Z-O-C(＝O)-O-Z-NR Pf-(C＝O)-R Pa，其中所述甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环己基-甲基、环戊基-甲基、氮杂环丁烷基、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、2-氧代-1,3-二氧戊环基、2-氧代-1,3-二氧杂环戊烯基、2-氧代-1,3-二氧戊环基-甲基、苯基、苯基-甲基、呋喃基、呋喃酮基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、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、苯并呋喃酮基、苯并呋喃基、吲哚基、苯并噻吩基、苯并咪唑基、喹啉基、异喹啉基或嘌呤基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、甲酰基、乙酰基、甲氧基酰基、乙氧基酰基或甲氨基；其中，R Pa、R Pb、R Pc、R Pd、R Pe、R Pf、R Pg、R Ph、R Pi、Y和Z分别具有本发明所述的定义。 In some embodiments, P is H, deuterium, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl-methyl, cyclopentyl -Methyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 2-oxo- 1,3-dioxolanyl, 2-oxo-1,3-dioxolane, 2-oxo-1,3-dioxolane-methyl, phenyl, phenyl -Methyl, furanyl, furanone, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isooxanyl Azolyl, oxadiazolyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, benzofuranone, benzofuranyl, indolyl, benzothienyl, benzimidazolyl , Quinolinyl, isoquinolinyl, purinyl, -C(=O)-R Pa , -C(=O)-ZR Pe , -C(=O)-ZOR Pb , -C(=O)- ZOZOR Pb , -C(=O)-ZOC(=O)-R Pa , -C(=O)-NR Pc R Pd , -C(=O)-OR Pb , -S(=O) 2 -R Pi , -P(=O)-(R Pg )(R Ph ), -C(=O)-OYOR Pb , -ZOR Pb , -ZOZOR Pb , -YOC(=O)-R Pa , -YC(= O)-OR Pb , -Y-NR Pf -(C=O)-OR Pb , -YOC(=O)-OR Pb , -ZOC(=O)-O-NR Pc R Pd , -YOC(=O )-OYOR Pb , -ZO-(C=O)-OZ-NR Pc R Pd , -ZOC(=O)-NR Pf -ZOR Pb , -ZOC(=O)-NR Pf -Z-NR Pc R Pd , -ZOC(=O)-OZOZOR Pb or -ZOC(=O)-OZ-NR Pf -(C=O)-R Pa , wherein the methyl, ethyl, n-propyl, isopropyl, ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl-methyl, cyclopentyl-methyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl , Morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 2-oxo-1,3-dioxolanyl, 2-oxo-1,3-di Oxolyl, 2-oxo-1,3-dioxolanyl-methyl, phenyl, phenyl-methyl, furanyl, furanone, pyrrolyl, pyridyl, pyrimidinyl, Thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, 1,3, 5-triazinyl, benzofuranyl, benzofuranyl, indolyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl or purinyl each Independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, formyl , Acetyl, methoxyacyl, ethoxyacyl or methylamino; wherein R Pa , R Pb , R Pc , R Pd , R Pe , R Pf , R Pg , R Ph , R Pi , Y and Z are respectively Has the definition described in the present invention.
在一些实施方案中，各Y和Z独立地为甲基、乙基、正丙基、异丙基、正丁基或叔丁基。In some embodiments, each Y and Z is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl.
在一些实施方案中，各R Pf独立地为H、氘、甲基、乙基、正丙基或异丙基。 In some embodiments, each R Pf is independently H, deuterium, methyl, ethyl, n-propyl, or isopropyl.
在一些实施方案中，各R Pa、R Pb、R Pc、R Pd、R Pe和R Pi独立地为甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环己基-甲基、环戊基-甲基、氮杂环丁烷基、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、2-氧代-1,3-二氧戊环基、2-氧代-1,3-二氧杂环戊烯基、2-氧代-1,3-二氧戊环基-甲基、苯基、苯基-甲基、呋喃基、呋喃酮基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、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、苯并呋喃酮基、苯并呋喃基、吲哚基、苯并噻吩基、苯并咪唑基、喹啉基、异喹啉基、嘌呤基、甲氨基、甲硫基或C 1-4烷基甲硅烷基，其中所述甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、环己基-甲基、环戊基-甲基、氮杂环丁烷基、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、2-氧代-1,3-二氧戊环基、2-氧代-1,3-二氧杂环戊烯基、2-氧代-1,3-二氧戊环基-甲基、苯基、苯基-甲基、呋喃基、呋喃酮基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、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、苯并呋喃酮基、苯并呋喃基、吲哚基、苯并噻吩基、苯并咪唑基、喹啉基、异喹啉基、嘌呤基、甲氨基和甲硫基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、甲酰基、乙酰基、甲氧基酰基、乙氧基酰基或甲氨基。 In some embodiments, each of R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclo Pentyl, cyclohexyl, cyclohexyl-methyl, cyclopentyl-methyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorph Linyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 2-oxo-1,3-dioxolanyl, 2-oxo-1,3-dioxolyl, 2 -Oxo-1,3-dioxolanyl-methyl, phenyl, phenyl-methyl, furanyl, furanonyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl , Pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, benzo Furanone, benzofuran, indolyl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, purinyl, methylamino, methylthio or C 1-4 alkyl silane Group, wherein the methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl-methyl, cyclopentyl-methyl, azacyclic Butyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 2-oxo- 1,3-dioxolanyl, 2-oxo-1,3-dioxolane, 2-oxo-1,3-dioxolane-methyl, phenyl, phenyl -Methyl, furanyl, furanone, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isooxanyl Azolyl, oxadiazolyl, pyrazinyl, pyridazinyl, 1,3,5-triazinyl, benzofuranone, benzofuranyl, indolyl, benzothienyl, benzimidazolyl , Quinolinyl, isoquinolinyl, purinyl, methylamino and methylthio are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F , Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , methyl, ethyl, n-propyl , Isopropyl, trifluoromethyl, methoxy, ethoxy, formyl, acetyl, methoxyacyl, ethoxyacyl or methylamino.
在一些实施方案中，各R Pg和R Ph独立为甲氧基、乙氧基、正丙基氧基、异丙基氧基、叔丁基氧基、甲氨基、乙氨基、正丙基氨基、异丙基氨基、叔丁基氨基、环丙基氧基、环丁基氧基、环戊基氧基、环丙基氨基、环丁基氨基、环戊基氨基、3-6个原子组成的杂环基氧基、3-6个原子组成的杂环基氨基、苯基氧基、苯基氨基、5-6个原子组成的杂芳基氧基或5-6个原子组成的杂芳基氨基，其中所述甲氧基、乙氧基、正丙基氧基、异丙基氧基、叔丁基氧基、甲氨基、乙氨基、正丙基氨基、异丙基氨基、叔丁基氨基、环丙基氧基、环丁基氧基、环戊基氧基、环丙基氨基、环丁基氨基、环戊基氨基、3-6个原子组成的杂环基氧基、3-6个原子组成的杂环基氨基、苯基氧基、苯基氨基、5-6个原子组成的杂芳基氧基和5-6个原子组成的杂芳基氨基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、甲氧基、乙氧基、甲酰基、乙酰基、甲氧基酰基、乙氧基酰基或甲氨基。 In some embodiments, each R Pg and R Ph is independently methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy, methylamino, ethylamino, n-propylamino , Isopropylamino, tert-butylamino, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclopropylamino, cyclobutylamino, cyclopentylamino, 3-6 atoms Heterocyclyloxy, 3-6 heterocyclic amino, phenyloxy, phenylamino, 5-6 heteroaryloxy or 5-6 heteroaryl Group amino, wherein the methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy, methylamino, ethylamino, n-propylamino, isopropylamino, tert-butyl Amino, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclopropylamino, cyclobutylamino, cyclopentylamino, heterocyclyloxy composed of 3-6 atoms, 3 -6-atom heterocyclylamino, phenyloxy, phenylamino, 5-6 heteroaryloxy and 5-6 heteroarylamino are each independently unsubstituted Or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 ,- C(=O)OH, -C(=O)NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy , Formyl, acetyl, methoxyacyl, ethoxyacyl or methylamino.
在一些实施方案中，P为H、氘、
Figure PCTCN2020077781-appb-000018
Figure PCTCN2020077781-appb-000019
In some embodiments, P is H, deuterium,
Figure PCTCN2020077781-appb-000018
Figure PCTCN2020077781-appb-000019
Figure PCTCN2020077781-appb-000020
Figure PCTCN2020077781-appb-000020
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 PCTCN2020077781-appb-000021
Figure PCTCN2020077781-appb-000021
其中P、U 1、U 2、U 3、U 4、U 5、U 6、U 7、U 8、R 9和R 10具有如本发明所述的定义。 Wherein P, U 1 , U 2 , U 3 , U 4 , U 5 , U 6 , U 7 , U 8 , R 9 and R 10 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 its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs , But not limited to these compounds:
Figure PCTCN2020077781-appb-000022
Figure PCTCN2020077781-appb-000022
Figure PCTCN2020077781-appb-000023
Figure PCTCN2020077781-appb-000023
Figure PCTCN2020077781-appb-000024
Figure PCTCN2020077781-appb-000024
Figure PCTCN2020077781-appb-000025
Figure PCTCN2020077781-appb-000025
Figure PCTCN2020077781-appb-000026
Figure PCTCN2020077781-appb-000026
Figure PCTCN2020077781-appb-000027
Figure PCTCN2020077781-appb-000027
Figure PCTCN2020077781-appb-000028
Figure PCTCN2020077781-appb-000028
Figure PCTCN2020077781-appb-000029
Figure PCTCN2020077781-appb-000029
Figure PCTCN2020077781-appb-000030
Figure PCTCN2020077781-appb-000030
Figure PCTCN2020077781-appb-000031
Figure PCTCN2020077781-appb-000031
Figure PCTCN2020077781-appb-000032
Figure PCTCN2020077781-appb-000032
Figure PCTCN2020077781-appb-000033
Figure PCTCN2020077781-appb-000033
另一方面，本发明提供了一种药物组合物，所述药物组合物包含有效量的本发明所述化合物。In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention.
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载体、辅剂、媒介物或它们的组合。In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.
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 anti-influenza virus agents or vaccines.
在另外一些实施方案，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 PCTCN2020077781-appb-000034
Quadrivalent、
Figure PCTCN2020077781-appb-000035
Quadrivalent、
Figure PCTCN2020077781-appb-000036
或
Figure PCTCN2020077781-appb-000037
)或它们的组合。 In other embodiments, the other therapeutic agent is Amantadine, Rimantadine, Oseltamivir, Zanamivir, Peramivir, Peramivir Nimvir (Laninamivir), Laninamivir Octanoate Hydrate, Favipiravir, Arbidol, Ribavirin, Staphyrin , Ingavirin (Ingavirin), flu enzyme (Fludase), drugs with CAS number 1422050-75-6, pimodivir (Pimodivir), baloxavir (Baloxavir marboxil), flu vaccine (FluMist
Figure PCTCN2020077781-appb-000034
Quadrivalent,
Figure PCTCN2020077781-appb-000035
Quadrivalent,
Figure PCTCN2020077781-appb-000036
or
Figure PCTCN2020077781-appb-000037
) Or their combination.
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 can 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 medicament, wherein the medicament is used to prevent, treat or alleviate viral infectious diseases in patients.
另一方面，本发明提供一种预防、治疗或减轻患者病毒感染性疾病的方法，包括给患者使用有效量的本发明所述化合物或本发明所述药物组合物。On the other hand, the present invention provides a method for preventing, treating or alleviating viral infectious diseases in patients, which comprises administering to the patient an effective amount of the compound of the present invention or the pharmaceutical composition of the present invention.
另一方面，本发明提供本发明所述化合物或所述药物组合物用于预防、治疗或减轻患者病毒感染性疾病的用途。In another aspect, the present invention provides the use of the compound or the pharmaceutical composition of the present invention for preventing, treating or alleviating 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.
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 medicine, wherein the medicine is used to inhibit the RNA polymerase of influenza virus.
另一方面，本发明提供一种抑制流感病毒的RNA聚合酶的方法，包括给患者使用有效量的本发明所述化合物或所述药物组合物。In another aspect, the present invention provides a method for inhibiting the RNA polymerase of influenza virus, which comprises administering an effective amount of the compound or the pharmaceutical composition of the present invention to the patient.
另一方面，本发明提供本发明所述化合物或所述药物组合物抑制流感病毒的RNA聚合酶的用途。In another aspect, the present invention provides the use of the compound or the pharmaceutical composition of the present invention to inhibit the RNA polymerase of influenza virus.
在一些实施方案中，所述RNA聚合酶为帽依赖性核酸内切酶。In some 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载体结合所需的有效治疗量。本发明所述的载体包括，但不限于，赋形剂，稀释剂，辅剂，媒介物或它们的任意组合。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 carrier. The carrier of the present invention includes, but is not limited to, excipients, diluents, adjuvants, vehicles, or any combination thereof.
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. The method includes 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载体、稀释剂、佐剂或媒介物，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载体，辅剂，媒介物或它们的组合。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, which comprises 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 carrier, diluent, adjuvant or vehicle, and optionally, other therapeutic and/or preventive components. In some embodiments, the pharmaceutical composition includes an effective amount of at least one pharmaceutically acceptable carrier, adjuvant, vehicle, or a combination thereof. 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 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 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载体，辅剂，媒介物或它们的组合，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，表明不同的载体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。除了任何常规的载体媒介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 a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof, which, as used in the present invention, includes any solvent, diluent, Or other liquid excipients, dispersing 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 carriers can be applied to the preparation of pharmaceutically acceptable compositions and their well-known preparation methods. Except for any conventional carrier media 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载体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 carriers 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 (e.g. Lactose, glucose and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth, malt, Gels, talc, excipients (e.g. cocoa butter and suppository waxes), oils (e.g. peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g. propylene glycol or poly Ethylene 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 solution (Ringer'ssolution), ethanol and phosphate buffers, and other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as colorants, anti-sticking agents, coating agents, Sweetening 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，可根据受治感染的严重程度经口、直肠、肠胃外、脑池内、阴道内、腹膜内、局部(如同通过粉剂、药膏或滴剂)、口腔作为口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 method, according to the severity of the infection being treated, oral, rectal, parenteral, intracisternal, intravaginal, intraperitoneal, topical (as by powder, ointment or drops) ), oral or nasal spray, etc. to 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。在可接受的媒介物和溶剂中，可采用的是水、林格氏溶液、U.S.P.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。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 vehicles and solvents, water, Ringer's solution, U.S.P. and isotonic sodium chloride solution can be used. In addition, sterile non-volatile oil is used as a solvent or suspension medium in accordance with the usual practice. For this purpose, any odorless nonvolatile oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used in the preparation of injections.
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。For example, it can be filtered through a bacteria-retaining filter or added in the form of a sterile solid composition, and the sterilizing agent 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。然后，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。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. Then, the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal shape. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. An injectable storage form is made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. The release rate of the compound can be controlled according to the ratio of compound to polymer and the nature of the particular polymer used. 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.
经直肠或阴道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赋形剂或载体，例如可可油、聚乙二醇或栓剂蜡制备的栓剂，所述赋形剂或载体在环境温度下为固体但在体温下为液体并因此在直肠或阴道腔内融化并释放活性化合物。The composition for rectal or vaginal administration is especially a suppository prepared by mixing the compound of the present invention and a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or suppository wax. Or the carrier is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.
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赋形剂或载体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、蔗糖和阿拉伯胶，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 excipient or carrier 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, certain silicates and sodium carbonate, e) solution blockers, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) Wetting agents 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, sulfuric acid Sodium lauryl ester and mixtures thereof. 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赋形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。也可使用乳糖或奶糖以及高分子聚乙二醇等赋形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。It is also possible to use excipients 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 field. 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. It is also possible to use excipients such as lactose or toffee and macromolecular polyethylene glycol to use similar types of solid compositions as fillers in soft and hard gel capsules.
活性化合物也可呈现具有一种或多种上述赋形剂的微密封形式。可用包衣和壳，例如肠溶衣、控释包衣和制药领域中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。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助剂，例如硬脂酸镁和微晶纤维素。在为胶囊、片剂和丸剂的情况下，剂型也可包含缓冲剂。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 microencapsulated form with one or more of the aforementioned excipients. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical field. 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 aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. 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 form of the compound of the present invention includes ointment, ointment, cream, lotion, gel, powder, solution, spray, inhalant or patch. 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 skin patches that have 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、阴道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。无菌可注射制剂也可能是于无毒的可经肠胃外接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液，例如于1,3-丁二醇中的溶液。在可接受的媒介物和溶剂中，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，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 following techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used. In addition, sterile non-volatile oil is used as a solvent or suspension medium in accordance with the usual practice. For this purpose, any odorless nonvolatile oil can be used, including synthetic monoglycerides or diglycerides. In addition, just as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially 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，所述赋形剂在室温下为固体，但在直肠温度下为液体，因此将在直肠内融化以释放药物。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 that are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. 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 formulations (see above) or suitable enema formulations can be used to achieve local dripping to the lower intestinal tract. Topical skin patches 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载体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载体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载体中的活性组分的适合洗剂或乳膏。适合的载体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 carriers. Carriers 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 carriers. Suitable carriers 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 may 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 invention
本发明提供的上述化合物和药物组合物用于制备预防、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 compound and pharmaceutical composition provided by the present invention are 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 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. The virus is influenza virus. Moreover, 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 of administration and frequency, etc., and needs to be determined by the attending physician Specific situation determination. 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 should 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 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 suitably 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-exemplified 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 to be 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，乙醚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 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 performed 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, doublet of doublet), dt (doublet of triplets, doublet of doublet). Coupling constant, expressed by J, in Hertz (Hz).
低分辨率质谱(MS)数据的测试条件是：Agilent 6120 Quadrupole 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 6120 Quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1×30mm, 3.5μm, 6min, flow rate 0.6mL/min, mobile phase: 5%- The ratio of 95% (CH 3 CN with 0.1% formic acid) in (H 2 O with 0.1% formic acid)) was detected by UV at 210 nm/254 nm, and electrospray ionization (ESI) was used.
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系统包括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. The 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：Waters Xbridge-C18, 2.1×30mm, 3.5μm column was used for analysis, and 5μL of sample was injected. Analysis conditions: the mobile phase is 0.5% formic acid aqueous solution (A) and 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:
Figure PCTCN2020077781-appb-000038
Figure PCTCN2020077781-appb-000038
Figure PCTCN2020077781-appb-000039
Figure PCTCN2020077781-appb-000039
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。The following synthetic scheme lists the experimental procedures for preparing the compounds disclosed in the present invention.
合成方案1Synthesis scheme 1
Figure PCTCN2020077781-appb-000040
Figure PCTCN2020077781-appb-000040
式 (10)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，R 1、R 2、R 3、R 4和R 10具有如本发明的定义。首先，化合物 (1)与3-噻吩硼酸在Pd催化剂作用下反应得到化合物 (2)。化合物 (2)与N-溴代丁二酰亚胺反应得到化合物 (3)。然后，化合物 (3)在Pd催化剂作用下与苯甲酸甲酯-2-硼酸反应得到化合物 (4)；化合物 (4)在碱性条件下水解得到化合物 (5)；化合物 (5)在多聚磷酸或氯化亚砜作用下关环生成化合物 (6)；化合物 (6)在硼氢化钠作用下生成中间体 (7)；接着，化合物 (7)与N-溴代丁二酰亚胺发生反应得到化合物 (8)；最后，化合物 (8)在Pd催化剂作用下与化合物 (9)反应，得到中间体 (10)。 The intermediate represented by formula (10) can be prepared by the method described in Synthesis Scheme 1. Among them, R 1 , R 2 , R 3 , R 4 and R 10 have the same definition as in the present invention. First, compound (1) is reacted with 3-thiophene boronic acid under the action of Pd catalyst to obtain compound (2) . Compound (2) is reacted with N-bromosuccinimide to obtain compound (3) . Then, compound (3) reacts with methyl benzoate-2-boronic acid under the action of Pd catalyst to obtain compound (4) ; compound (4) is hydrolyzed under alkaline conditions to obtain compound (5) ; compound (5) is polymerized Ring-closing under the action of phosphoric acid or thionyl chloride produces compound (6) ; compound (6) produces intermediate (7) under the action of sodium borohydride; next, compound (7) reacts with N-bromosuccinimide The reaction obtains compound (8) ; finally, compound (8 ) reacts with compound (9) under the action of Pd catalyst to obtain intermediate (10) .
合成方案2Synthesis scheme 2
Figure PCTCN2020077781-appb-000041
Figure PCTCN2020077781-appb-000041
式 (5)所示中间体也可以通过合成方案2中所描述的方法制备得到。其中，R 1、R 2、R 3和R 4具有本发明所述的定义。首先，化合物 (2)在低温条件下与2-异丙氧基-4,4,5,5-四甲基-1,3,2-二氧硼戊环反应得到化合物 (11)；化合物 (11)在Pd催化剂作用下与苯甲酸乙酯反应得到化合物 (12)；化合物 (12)在碱性条件下水解得到中间体 (5)。 The intermediate represented by formula (5) can also be prepared by the method described in Synthesis Scheme 2. Among them, R 1 , R 2 , R 3 and R 4 have the definitions described in the present invention. First, compound (2) is reacted with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane under low temperature conditions to obtain compound (11) ; compound ( 11) Reaction with ethyl benzoate under the action of Pd catalyst to obtain compound (12) ; compound (12) is hydrolyzed under alkaline conditions to obtain intermediate (5) .
合成方案3Synthesis scheme 3
Figure PCTCN2020077781-appb-000042
Figure PCTCN2020077781-appb-000042
式 (10)所示中间体也可以通过合成方案3中所描述的方法制备得到。其中，R 1、R 2、R 3、R 4和R 10具有如本发明的定义。首先，化合物 (13)与化合物 (14)在Pd催化剂作用下反应得到化合物 (15)；化合物 (15)与N-溴代丁二酰亚胺反应得到化合物 (16)。然后，化合物 (16)在Pd催化剂作用下与苯甲酸甲酯-2-硼酸反应得到化合物 (17)；化合物 (17)在碱性条件下水解得到化合物 (18)；化合物 (18)在多聚磷酸作用下关环生成化合物 (19)；化合物 (19)在硼氢化钠作用下生成中间体 (10)。 The intermediate represented by formula (10) can also be prepared by the method described in Synthesis Scheme 3. Among them, R 1 , R 2 , R 3 , R 4 and R 10 have the same definition as in the present invention. First, compound (13) is reacted with compound (14) under the action of Pd catalyst to obtain compound (15) ; compound (15) is reacted with N-bromosuccinimide to obtain compound (16) . Then, compound (16) is reacted with methyl benzoate-2-boronic acid under the action of Pd catalyst to obtain compound (17) ; compound (17) is hydrolyzed under alkaline conditions to obtain compound (18) ; compound (18) is polymerized Under the action of phosphoric acid, the ring is closed to form compound (19) ; under the action of sodium borohydride, compound (19) forms intermediate (10) .
合成方案4Synthesis scheme 4
Figure PCTCN2020077781-appb-000043
Figure PCTCN2020077781-appb-000043
式 (22)所示化合物以通过合成方案4中所描述的方法制备得到。其中，R 1、R 2、R 3、R 4和R 10具有本发明所述的定义。首先，化合物 (10)与化合物 (20)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 (21)。化合物 (21)脱除羟基上的保护基Bn，得到式 (22)所示化合物。式 (22)所示化合物可通过制备色谱分离得到对应的立体异构体。 The compound represented by formula (22) is prepared by the method described in Synthesis Scheme 4. Among them, R 1 , R 2 , R 3 , R 4 and R 10 have the definitions described in the present invention. First, compound (10) and compound (20) are reacted in the presence of a condensing agent such as 1-propyl phosphoric anhydride to obtain compound (21) . Compound (21) removes the protective group Bn on the hydroxyl group to obtain the compound represented by formula (22) . The compound represented by formula (22) can be separated by preparative chromatography to obtain corresponding stereoisomers.
合成方案5Synthesis scheme 5
Figure PCTCN2020077781-appb-000044
Figure PCTCN2020077781-appb-000044
式 (24)所示化合物可以通过合成方案5中所描述的方法制备得到。其中，P、R 1、R 2、R 3、R 4和R 10具有本发明所述的定义，其中，P不为H或氘。首先，化合物 (22)与化合物 (23)在碱性条件下发生反应，得到化合物 (24)。式 (24)所示化合物可通过制备色谱分离得到对应的立体异构体。 The compound represented by formula (24) can be prepared by the method described in Synthesis Scheme 5. Wherein, P, R 1 , R 2 , R 3 , R 4 and R 10 have the definitions described in the present invention, wherein P is not H or deuterium. First, compound (22) reacts with compound (23) under alkaline conditions to obtain compound (24) . The compound represented by formula (24) can be separated by preparative chromatography to obtain corresponding stereoisomers.
合成方案6Synthesis scheme 6
Figure PCTCN2020077781-appb-000045
Figure PCTCN2020077781-appb-000045
式 (27)所示中间体可以通过合成方案6中所描述的方法制备得到。其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8具有本发明所述的定义，PG 1为甲基或乙基。首先，化合物 (2)与化合物 (25)在Pd催化剂作用下与反应得到化合物 (26)；化合物 (26)在碱性条件下水解得到中间体 (27)。 The intermediate represented by formula (27) can be prepared by the method described in Synthesis Scheme 6. Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the definitions described in the present invention, and PG 1 is methyl or ethyl. First, compound (2) and compound (25) react with Pd catalyst to obtain compound (26) ; compound (26) is hydrolyzed under alkaline conditions to obtain intermediate (27) .
合成方案7Synthesis scheme 7
Figure PCTCN2020077781-appb-000046
Figure PCTCN2020077781-appb-000046
式 (33)所示中间体可以通过合成方案7中所描述的方法制备得到。其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 10具有如本发明的定义。首先，化合物 (28)与N-溴代丁二酰亚胺发生反应得到化合物 (29)；化合物 (29)与R 10-H或其盐反应得到化合物 (30)；化合物 (30)在碱性条件下水解得到化合物 (31)；化合物 (31)在多聚磷酸或氯化亚砜作用下关环生成化合物 (32)；化合物 (32)在硼氢化钠作用下生成中间体 (33)。以
Figure PCTCN2020077781-appb-000047
(42)代替合成方案1中的苯甲酸甲酯-2-硼酸，式 (33)所示中间体也可以参考合成方案1的方法制备合成。以
Figure PCTCN2020077781-appb-000048
(42)代替合成方案3中的苯甲酸甲酯-2-硼酸，式 (33)所示中间体也可以参考合成方案3的方法制备合成。 The intermediate represented by formula (33) can be prepared by the method described in Synthesis Scheme 7. Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 10 have the same definition as in the present invention. First, compound (28) reacts with N-bromosuccinimide to obtain compound (29) ; compound (29) reacts with R 10 -H or its salt to obtain compound (30) ; compound (30) is basic Under the conditions of hydrolysis, compound (31) is obtained ; compound (31) is ring-closed under the action of polyphosphoric acid or thionyl chloride to form compound (32) ; compound (32) is formed to intermediate (33) under the action of sodium borohydride. To
Figure PCTCN2020077781-appb-000047
(42) Instead of methyl benzoate-2-boronic acid in the synthesis scheme 1, the intermediate represented by formula (33) can also be prepared and synthesized by referring to the synthesis scheme 1. To
Figure PCTCN2020077781-appb-000048
(42) Instead of methyl benzoate-2-boronic acid in the synthesis scheme 3, the intermediate represented by formula (33) can also be prepared and synthesized by referring to the synthesis scheme 3.
合成方案8Synthesis scheme 8
Figure PCTCN2020077781-appb-000049
Figure PCTCN2020077781-appb-000049
式 (41)所示中间体可以通过合成方案8中所描述的方法制备得到。其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 9具有如本发明的定义。首先，化合物 (34)与化合物 (13)在Pd催化剂作用下反应得到化合物 (35)；化合物 (35)与N-溴代丁二酰亚胺反应得到化合物 (36)。化合物 (36)在低温下与叔丁基锂反应得到化合物 (37)。然后，化合物 (37)在Pd催化剂作用下与化合物 (42)反应得到化合物 (38)；化合物 (38)在碱性条件下水解得到化合物 (39)；化合物 (39)在多聚磷酸作用下关环生成化合物 (40)；化合物 (40)在硼氢化钠作用下生成中间体 (41)。 The intermediate represented by formula (41) can be prepared by the method described in Synthesis Scheme 8. Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 have the same definition as in the present invention. First, compound (34) is reacted with compound (13) under the action of Pd catalyst to obtain compound (35) ; compound (35) is reacted with N-bromosuccinimide to obtain compound (36) . Compound (36 ) is reacted with tert-butyl lithium at low temperature to obtain compound (37) . Then, compound (37) reacts with compound (42) under the action of Pd catalyst to obtain compound (38) ; compound (38) is hydrolyzed under alkaline conditions to obtain compound (39) ; compound (39) is closed under the action of polyphosphoric acid The ring produces compound (40) ; compound (40) produces intermediate (41) under the action of sodium borohydride.
合成方案9Synthesis Scheme 9
Figure PCTCN2020077781-appb-000050
Figure PCTCN2020077781-appb-000050
式 (46)所示中间体可以通过合成方案9中所描述的方法制备得到。其中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8和R 11具有如本发明的定义。其中，化合物 (43)可参考合成方案7制备得到。首先，化合物 (43)与N-溴代丁二酰亚胺反应得到化合物 (44)。化合物 (44)与R 11-H或其盐反应得到化合物 (45)。化合物 (45)在硼氢化钠作用下生成中间体 (46)。 The intermediate represented by formula (46) can be prepared by the method described in Synthetic Scheme 9. Among them, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 11 have the same definition as in the present invention. Among them, compound (43) can be prepared by referring to Synthesis Scheme 7. First, compound (43) is reacted with N-bromosuccinimide to obtain compound (44) . Compound (44) is reacted with R 11 -H or its salt to obtain compound (45) . Compound (45) generates intermediate (46) under the action of sodium borohydride.
合成方案10Synthesis scheme 10
Figure PCTCN2020077781-appb-000051
Figure PCTCN2020077781-appb-000051
分别以式 (33)所示中间体、式 (41)所示中间体和式 (46)所示中间体代替式 (10)所示中间体，参考合成方案4的制备方法，可分别得到式 (47)所示化合物、式 (48)所示化合物和式 (49)所示化合物。 The intermediate represented by the formula (33) , the intermediate represented by the formula (41) and the intermediate represented by the formula (46) are used instead of the intermediate represented by the formula (10) , referring to the preparation method of the synthesis scheme 4, the formula The compound represented by (47) , the compound represented by formula (48) and the compound represented by formula (49) .
具体实施方式detailed description
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 invention in detail by taking some compounds of the invention as examples.
实施例1(R)-12-((S)-5-氟-2-(4-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物1-1)以及(R)-12-((R)-5-氟-2-(4-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物1-2)Example 1 (R)-12-((S)-5-fluoro-2-(4-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][ 1,2,4)triazine-6,8-dione (compound 1-1) and (R)-12-((R)-5-fluoro-2-(4-fluorophenyl)-8H-two Benzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxa Azino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 1-2)
Figure PCTCN2020077781-appb-000052
Figure PCTCN2020077781-appb-000052
步骤1)(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Step 1) (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1- f][1,2,4]Triazine-6,8-dione Synthesis
Figure PCTCN2020077781-appb-000053
Figure PCTCN2020077781-appb-000053
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 patent application WO 2017221869.
步骤2)2-溴-3-(3-氟苯基)噻吩的合成Step 2) Synthesis of 2-bromo-3-(3-fluorophenyl)thiophene
将3-(3-氟苯基)噻吩(4.79g,26.90mmol)溶于DMF(70mL)中，冷却至-5℃，将NBS(4.88g,26.90mmol)溶于DMF(20mL)中，然后缓慢滴加至上述反应液中，滴加完毕后，将反应液升温至0℃反应过夜。停止反应，向反应液加入饱和硫代硫酸钠水溶液(200mL)，室温搅拌10分钟，再用乙酸乙酯(100mL×3)萃取，合并的有机相用饱和食盐水(200mL×3)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(洗脱剂为石油醚)，纯化后得到标题化合物为淡黄色液体(6.53g,95％)。Dissolve 3-(3-fluorophenyl)thiophene (4.79g, 26.90mmol) in DMF (70mL), cool to -5°C, dissolve NBS (4.88g, 26.90mmol) in DMF (20mL), and then Slowly add dropwise to the above reaction solution. After the dropwise addition is completed, the reaction solution is heated to 0°C for overnight reaction. The reaction was stopped, saturated sodium thiosulfate aqueous solution (200mL) was added to the reaction solution, stirred at room temperature for 10 minutes, and then extracted with ethyl acetate (100mL×3). The combined organic phase was washed with saturated brine (200mL×3). After drying with sodium sulfate and filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent was petroleum ether). After purification, the title compound was obtained as a pale yellow liquid (6.53 g, 95%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.44–7.39(m,1H),7.37-7.34(m,2H),7.33–7.29(m,1H),7.12–7.06(m,1H),7.05(d,J＝5.7Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.44-7.39 (m, 1H), 7.37-7.34 (m, 2H), 7.33-7.29 (m, 1H), 7.12-7.06 (m, 1H), 7.05 (d, J=5.7 Hz, 1H).
步骤3)2-(3-(3-氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 3) Synthesis of methyl 2-(3-(3-fluorophenyl)thiophen-2-yl)benzoate
将2-溴-3-(3-氟苯基)噻吩(1.36g,5.29mmol)、2-(甲氧基羰基)苯基)硼酸(1.90g,10.60mmol)、二三苯基膦二氯化钯(0.38g,0.54mmol)和碳酸钾(2.25g,16.00mmol)加至反应瓶中，向其中加入四氢呋喃(30mL)和水(3mL)，所得混合物在氮气保护下，75℃反应过夜。停止反应，将反应液冷却至室温，硅藻土过滤，滤饼用乙酸乙酯(10mL)洗涤，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)＝10/1)，纯化后得到标题化合物为淡黄色固体(1.06g,64％)。Combine 2-bromo-3-(3-fluorophenyl)thiophene (1.36g, 5.29mmol), 2-(methoxycarbonyl)phenyl)boronic acid (1.90g, 10.60mmol), ditriphenylphosphine dichloride Palladium (0.38g, 0.54mmol) and potassium carbonate (2.25g, 16.00mmol) were added to the reaction flask, tetrahydrofuran (30mL) and water (3mL) were added thereto, and the resulting mixture was reacted at 75°C overnight under nitrogen protection. The reaction was stopped, the reaction solution was cooled to room temperature, celite was filtered, the filter cake was washed with ethyl acetate (10 mL), the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate Ester (v/v) = 10/1), after purification, the title compound was obtained as a pale yellow solid (1.06 g, 64%).
MS(ESI,pos.ion)m/z:334.9[M+Na] + MS(ESI,pos.ion)m/z:334.9[M+Na] +
步骤4)2-(3-(3-氟苯基)噻吩-2-基)苯甲酸的合成Step 4) Synthesis of 2-(3-(3-fluorophenyl)thiophen-2-yl)benzoic acid
将2-(3-(3-氟苯基)噻吩-2-基)苯甲酸甲酯(1.06g,3.39mmol)溶于四氢呋喃(10mL)和甲醇(5mL)中，室温搅拌溶清，将氢氧化钠(1.36g,34.00mmol)溶于水(10mL)中，再加至上述反应液中，所得混合物加热至60℃搅拌过夜。停止反应，将反应液冷却至室温，向其中加入饱和食盐水(20mL)，用1N稀盐酸调节反应液的pH至6左右，分液，水相用乙酸乙酯(20mL×2)萃取，合并的有机相用饱和食盐水(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(洗脱剂为石油醚/乙酸乙酯(v/v)＝3/1)，纯化后得到标题化合物为白色固体(0.93g,92％)。Methyl 2-(3-(3-fluorophenyl)thiophen-2-yl)benzoate (1.06g, 3.39mmol) was dissolved in tetrahydrofuran (10mL) and methanol (5mL), stirred at room temperature to dissolve, and the hydrogen Sodium oxide (1.36g, 34.00mmol) was dissolved in water (10mL) and added to the above reaction solution. The resulting mixture was heated to 60°C and stirred overnight. The reaction was stopped, the reaction solution was cooled to room temperature, saturated brine (20mL) was added to it, the pH of the reaction solution was adjusted to about 6 with 1N dilute hydrochloric acid, the layers were separated, the aqueous phase was extracted with ethyl acetate (20mL×2) and combined The organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 3/1), after purification, the title compound was obtained as a white solid (0.93 g, 92%).
MS(ESI,pos.ion)m/z:299.1[M+H] +。 MS (ESI, pos.ion) m/z: 299.1 [M+H] + .
步骤5)5-氟-8H-二苯并[3,4:6,7]环庚并[1,2-b]噻吩-8-酮的合成Step 5) Synthesis of 5-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将2-(3-(3-氟苯基)噻吩-2-基)苯甲酸(100mg,0.34mmol)溶于无水二氯甲烷(2mL)中，加入无水DMF(0.02mL)，室温搅拌下滴加氯化亚砜(0.13mL,1.80mmol)，加完后将所得混合物升温至40℃反应3.5小时，冷却至室温，再加入无水三氯化铝(92mg,0.68mmol)，室温反应1小时。停止反应，将反应液缓慢滴加至饱和碳酸氢钠水溶液(20mL)中，用二氯甲烷(10mL×3)萃取，合并的有机相用饱和食盐水(20mL)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(洗脱剂为石油醚/乙酸乙酯(v/v)＝10/1)，纯化后得到标题化合物为白色固体(60mg,64％)。Dissolve 2-(3-(3-fluorophenyl)thiophen-2-yl)benzoic acid (100mg, 0.34mmol) in dry dichloromethane (2mL), add dry DMF (0.02mL), and stir at room temperature Thionyl chloride (0.13mL, 1.80mmol) was added dropwise. After the addition, the resulting mixture was heated to 40°C and reacted for 3.5 hours, cooled to room temperature, and then anhydrous aluminum trichloride (92mg, 0.68mmol) was added and reacted at room temperature. 1 hour. The reaction was stopped, and the reaction solution was slowly added dropwise to a saturated aqueous sodium bicarbonate solution (20 mL), extracted with dichloromethane (10 mL×3), and the combined organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The filtrate was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1). After purification, the title compound was obtained as a white solid (60 mg, 64 %).
1H NMR(400MHz,CDCl 3)δ(ppm)7.97-7.93(m,2H),7.84(d,J＝7.8Hz,1H),7.63(td,J＝7.7,1.2Hz,1H),7.53(t,J＝7.6Hz,1H),7.50-7.46(m,3H),7.21(td,J＝8.5,2.4Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.97-7.93 (m, 2H), 7.84 (d, J = 7.8 Hz, 1H), 7.63 (td, J = 7.7, 1.2 Hz, 1H), 7.53 ( t, J=7.6 Hz, 1H), 7.50-7.46 (m, 3H), 7.21 (td, J=8.5, 2.4 Hz, 1H).
步骤6)5-氟-8H-二苯并[3,4:6,7]环庚并[1,2-b]噻吩-8-醇的合成Step 6) Synthesis of 5-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将5-氟-8H-二苯并[3,4:6,7]环庚并[1,2-b]噻吩-8-酮(60mg,0.21mmol)溶于THF(2mL)和甲醇(1mL)中，冷却至0℃，加入硼氢化钠(42mg,1.09mmol)，加完后所得混合物在0℃反应5分钟，再转移至室温下反应30分钟。停止反应，向反应液中加入水(10mL)，所得混合物用二氯甲烷(10mL×3)萃取，合并的有机相用饱和食盐水(20mL)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(洗脱剂为石油醚/乙酸乙酯(v/v)＝5/1)，得到标题化合物为白色固体(53mg,88％)。Dissolve 5-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (60mg, 0.21mmol) in THF (2mL) and methanol (1mL) ), cool to 0°C, add sodium borohydride (42mg, 1.09mmol), after the addition, the resulting mixture is reacted at 0°C for 5 minutes, and then transferred to room temperature for 30 minutes. The reaction was stopped, water (10 mL) was added to the reaction solution, the resulting mixture was extracted with dichloromethane (10 mL×3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed After concentration, the resulting residue 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 (53 mg, 88%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.87–7.79(m,2H),7.55(d,J＝7.7Hz,1H),7.51–7.40(m,4H),7.32(t,J＝7.6Hz,1H),7.23(dd,J＝9.7,2.5Hz,1H),7.14(td,J＝8.6,2.5Hz,1H),5.35(s,1H)。 1 H NMR (400MHz, CDCl 3 )δ (ppm) 7.87–7.79 (m, 2H), 7.55 (d, J = 7.7 Hz, 1H), 7.51–7.40 (m, 4H), 7.32 (t, J = 7.6 Hz, 1H), 7.23 (dd, J=9.7, 2.5 Hz, 1H), 7.14 (td, J=8.6, 2.5 Hz, 1H), 5.35 (s, 1H).
步骤7)2-溴-5-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 7) Synthesis of 2-bromo-5-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将5-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(5.16g,18.4mmol)和NBS(3.68g,20.2mmol)混合于醋酸(20mL)中，氮气保护下，置于50℃油浴锅中加热反应12小时。反应完全后将反应液过滤，抽干，得到标题化合物为橙色固体(5.57g,84％)。Mix 5-fluoro-8H-dibenzo[3,4:6,7]cycloheptan[1,2-b]thiophen-8-ol (5.16g, 18.4mmol) and NBS (3.68g, 20.2mmol) In acetic acid (20 mL), under the protection of nitrogen, it was placed in an oil bath at 50°C and heated for 12 hours. After the reaction was completed, the reaction solution was filtered and drained to obtain the title compound as an orange solid (5.57 g, 84%).
1H NMR(600MHz,CDCl 3)δ(ppm)7.96–7.92(m,2H),7.71(dd,J＝7.9,0.6Hz,1H),7.63(td,J＝7.6,1.4Hz,1H),7.56–7.52(m,1H),7.44(s,1H),7.40(dd,J＝9.9,2.5Hz,1H),7.24–7.20(m,1H)。 1 H NMR(600MHz, CDCl 3 )δ(ppm) 7.96–7.92(m,2H), 7.71(dd,J=7.9,0.6Hz,1H), 7.63(td,J=7.6,1.4Hz,1H), 7.56–7.52(m, 1H), 7.44(s, 1H), 7.40(dd, J=9.9, 2.5Hz, 1H), 7.24–7.20(m, 1H).
步骤8)5-氟-2-(4-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 8) Synthesis of 5-fluoro-2-(4-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将2-溴-5-氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1g,2.76mmol)、(4-氟苯基)硼酸(503mg,5.52mmol)、碳酸钠(583mg,5.52mmol)和四三苯基磷钯(335mg,0.27mmol)混合于四氢呋喃(18mL)和水(1mL)中，氮气保护下置于70℃油浴锅中加热反应4小时。反应完全后，将反应液减压浓缩，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)＝4/1)，得到标题化合物为白色固体(978mg,93％)。Combine 2-bromo-5-fluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (1g, 2.76mmol), (4-fluorophenyl) Boric acid (503mg, 5.52mmol), sodium carbonate (583mg, 5.52mmol) and palladium tetrakistriphenylphosphorus (335mg, 0.27mmol) were mixed in tetrahydrofuran (18mL) and water (1mL), and placed in oil at 70℃ under nitrogen protection Heat the reaction in a bath for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (978 mg ,93%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.84(t,J＝9.9Hz,2H),7.71(dd,J＝8.4,5.3Hz,2H),7.61–7.54(m,2H),7.49(t,J＝7.5Hz,1H),7.34(t,J＝7.4Hz,2H),7.17(t,J＝8.6Hz,3H),5.42(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.84 (t, J = 9.9 Hz, 2H), 7.71 (dd, J = 8.4, 5.3 Hz, 2H), 7.61-7.54 (m, 2H), 7.49 ( t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.17 (t, J = 8.6 Hz, 3H), 5.42 (s, 1H).
步骤9)(12aR)-7-(苄基氧基)-12-(5-氟-2-(4-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢Step 9) (12aR)-7-(benzyloxy)-12-(5-fluoro-2-(4-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta[ 1,2-b)thiophen-8-yl)-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将5-氟-2-(4-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(500mg,1.32mmol)和(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(478mg,1.46mmol)混合于乙酸异丙酯(10mL)中，然后加入1-丙基磷酸酐(2.3mL,3.98mmol)，置于70℃油浴锅中加热反应2小时。反应完全后，将反应液加入水(10mL)中，然后用乙酸乙酯(10mL×3)萃取，合并的有机相用饱和氯化钠水溶液(10mL)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)＝20/1)，得到标题化合物为淡黄色固体(367mg,40％)。Combine 5-fluoro-2-(4-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol (500mg, 1.32mmol) and (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][ 1,2,4]Triazine-6,8-dione (478mg, 1.46mmol) was mixed in isopropyl acetate (10mL), and then 1-propyl phosphoric anhydride (2.3mL, 3.98mmol) was added and placed Heat the reaction in an oil bath at 70°C for 2 hours. After the reaction was completed, the reaction solution was added to water (10 mL), and then extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain the title compound as a pale yellow solid (367 mg, 40%).
步骤10)(R)-12-((S)-5-氟-2-(4-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢Step 10) (R)-12-((S)-5-fluoro-2-(4-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物1-1)以及(R)-12-((R)-5-氟-2-(4-氟苯-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 1-1) and (R)-12-((R)-5-fluoro-2-(4-fluorobenzene 基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并Yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H- [1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4]三嗪-6,8-二酮(化合物1-2)的合成Synthesis of [2,1-f][1,2,4]triazine-6,8-dione (Compound 1-2)
将(12aR)-7-(苄基氧基)-12-(5-氟-2-(4-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(367mg,0.53mmol)溶于N,N-二甲基乙酰胺(10mL)中，加入无水氯化锂(233mg,5.35mmol)，氮气保护下加热至100℃反应过夜。反应完全后，用2N稀盐酸调节反应液pH至6左右，然后加入水(20mL)，再用乙酸乙酯(10mL×3)萃取，合并的有机相用饱和食盐水(10mL×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(50mm×250mm×10μm)(乙腈/0.1％三氟乙酸水溶液(v/v)＝65/35)分离纯化，分别得到标题化合物1-1(93mg,29％)和标题化合物1-2(86mg,27％)。The (12aR)-7-(benzyloxy)-12-(5-fluoro-2-(4-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4]Triazine-6,8-dione (367mg, 0.53mmol) was dissolved in N,N-dimethylacetamide (10mL), anhydrous lithium chloride (233mg, 5.35mmol) was added, nitrogen Under protection, heat to 100°C and react overnight. After the reaction is complete, adjust the pH of the reaction solution to about 6 with 2N dilute hydrochloric acid, then add water (20mL), and then extract with ethyl acetate (10mL×3), and wash the combined organic phase with saturated brine (10mL×3). Dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained is separated and purified by a LUNA preparation column (50mm×250mm×10μm) (acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=65/35). The title compound 1-1 (93 mg, 29%) and the title compound 1-2 (86 mg, 27%) were obtained.
化合物1-1：Compound 1-1:
1H NMR(400MHz,CDCl 3)δ(ppm)7.77–7.69(m,3H),7.61(s,1H),7.53–7.41(m,3H),7.25(d,J＝7.7Hz,1H),7.20(t,J＝8.5Hz,3H),7.01(d,J＝7.2Hz,1H),6.40(d,J＝7.5Hz,1H),5.70(d,J＝7.4Hz,1H),5.46(s,1H),4.62(d,J＝12.9Hz,1H),4.22(d,J＝7.2Hz,1H),3.74(d,J＝9.2Hz,1H),3.42(dd,J＝11.0,3.0Hz,1H),3.34(d,J＝12.2Hz,1H),3.22(t,J＝10.5Hz,1H),2.93(t,J＝10.9Hz,1H)。 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.77–7.69(m,3H), 7.61(s,1H), 7.53–7.41(m,3H), 7.25(d,J=7.7Hz,1H), 7.20(t,J=8.5Hz,3H), 7.01(d,J=7.2Hz,1H), 6.40(d,J=7.5Hz,1H), 5.70(d,J=7.4Hz,1H), 5.46( s, 1H), 4.62 (d, J = 12.9 Hz, 1H), 4.22 (d, J = 7.2 Hz, 1H), 3.74 (d, J = 9.2 Hz, 1H), 3.42 (dd, J = 11.0, 3.0 Hz, 1H), 3.34 (d, J = 12.2 Hz, 1H), 3.22 (t, J = 10.5 Hz, 1H), 2.93 (t, J = 10.9 Hz, 1H).
化合物1-2：Compound 1-2:
1H NMR(400MHz,CDCl 3)δ(ppm)7.76(dd,J＝8.1,5.2Hz,3H),7.66(s,1H),7.55(d,J＝7.9Hz,1H),7.49(d,J＝4.4Hz,2H),7.42(d,J＝8.2Hz,1H),7.19(t,J＝8.4Hz,2H),7.00(d,J＝5.4Hz,1H),6.96(d,J＝6.9Hz,1H),6.33(d,J＝7.3Hz,1H),5.77(d,J＝7.0Hz,1H),5.46(s,1H),4.61(d,J＝12.8Hz,1H),4.23–4.18(m,1H),3.73(d,J＝11.8Hz,1H),3.47–3.41(m,1H),3.35(t,J＝11.4Hz,1H),3.24(t,J＝10.5Hz,1H),2.90(t,J＝11.3Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.76 (dd, J = 8.1, 5.2 Hz, 3H), 7.66 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 4.4 Hz, 2H), 7.42 (d, J = 8.2 Hz, 1H), 7.19 (t, J = 8.4 Hz, 2H), 7.00 (d, J = 5.4 Hz, 1H), 6.96 (d, J = 6.9Hz, 1H), 6.33 (d, J = 7.3 Hz, 1H), 5.77 (d, J = 7.0 Hz, 1H), 5.46 (s, 1H), 4.61 (d, J = 12.8 Hz, 1H), 4.23 –4.18(m,1H), 3.73(d,J=11.8Hz,1H), 3.47–3.41(m,1H), 3.35(t,J=11.4Hz,1H), 3.24(t,J=10.5Hz, 1H), 2.90 (t, J=11.3 Hz, 1H).
实施例2(R)-12-((S)-5-氟-2-(2-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物2-1)以及(R)-12-((R)-5-氟-2-(2-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物2-2)Example 2 (R)-12-((S)-5-fluoro-2-(2-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][ 1,2,4)triazine-6,8-dione (compound 2-1) and (R)-12-((R)-5-fluoro-2-(2-fluorophenyl)-8H-two Benzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxa Azino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 2-2)
Figure PCTCN2020077781-appb-000054
Figure PCTCN2020077781-appb-000054
步骤1)5-氟-2-(2-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 1) Synthesis of 5-fluoro-2-(2-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol
将2-溴-5-氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(100mg,0.27mmol)、(2-氟苯基)硼酸(50mg,0.35mmol)、碳酸钠(58mg,0.54mmol)和四三苯基磷钯(35mg,0.02mmol)混合于四氢呋喃(6mL)和水(1mL)中，氮气保护下置于70℃油浴锅中加热反应3小时，反应完全后，将反应液减压浓缩，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)＝4/1)，得到标题化合物为白色固体(106mg,100％)。Combine 2-bromo-5-fluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (100mg, 0.27mmol), (2-fluorophenyl) Boric acid (50mg, 0.35mmol), sodium carbonate (58mg, 0.54mmol) and palladium tetrakistriphenylphosphorus (35mg, 0.02mmol) were mixed in tetrahydrofuran (6mL) and water (1mL), and placed in oil at 70℃ under nitrogen protection Heat the reaction in a bath for 3 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 4/1), The title compound was obtained as a white solid (106 mg, 100%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.81(ddd,J＝24.8,14.8,7.6Hz,5H),7.61(d,J＝7.5Hz,1H),7.50(t,J＝7.3Hz,1H),7.37–7.32(m,2H),7.25(d,J＝7.9Hz,2H),7.19–7.13(m,1H),5.43(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.81 (ddd, J = 24.8, 14.8, 7.6 Hz, 5H), 7.61 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.3 Hz, 1H), 7.37–7.32(m, 2H), 7.25(d, J=7.9Hz, 2H), 7.19–7.13(m, 1H), 5.43(s, 1H).
步骤2)((12aR)-7-(苄基氧基)-12-(5-氟-2-(2-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四Step 2) ((12aR)-7-(benzyloxy)-12-(5-fluoro-2-(2-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta [1,2-b]thiophen-8-yl)-3,4,12,12a-tetra 氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将5-氟-2-(2-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1g,2.7mmol)和(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(0.96g,2.9mmol)混合于乙酸异丙酯(20mL)中，加入1-丙基磷酸酐(4.7mL,8.0mmol)，置于70℃油浴锅中加热反应2小时。反应完全后，将反应液加入水(20mL)中，然后用乙酸乙酯(10mL×3)萃取，合并的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，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)＝15/1)，得到标题化合物为淡黄色固体(911mg,50％)。Combine 5-fluoro-2-(2-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (1g, 2.7mmol) and (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][ 1,2,4] Triazine-6,8-dione (0.96g, 2.9mmol) was mixed in isopropyl acetate (20mL), added 1-propyl phosphoric anhydride (4.7mL, 8.0mmol), placed Heat the reaction in an oil bath at 70°C for 2 hours. After the reaction was complete, the reaction solution was added to water (20 mL), and then extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain the title compound as a pale yellow solid (911 mg, 50%).
MS(ESI,pos.ion)m/z:686.1[M+H] +。 MS (ESI, pos.ion) m/z: 686.1 [M+H] + .
步骤3)(R)-12-((S)-5-氟-2-(2-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢Step 3) (R)-12-((S)-5-fluoro-2-(2-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物2-1)以及(R)-12-((R)-5-氟-2-(2-氟苯-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 2-1) and (R)-12-((R)-5-fluoro-2-(2-fluorobenzene 基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并Yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H- [1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4]三嗪-6,8-二酮(化合物2-2)的合成Synthesis of [2,1-f][1,2,4]triazine-6,8-dione (Compound 2-2)
将((12aR)-7-(苄基氧基)-12-(5-氟-2-(2-氟苯基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(911mg,1.3mmol)溶于N,N-二甲基乙酰胺(10mL)中，加入无水氯化锂(580mg,13.2mmol)，氮气保护，100℃反应过夜。反应完全后，用1N稀盐酸调节pH至6左右，加入水(20mL)，然后用乙酸乙酯(10mL×3)萃取，合并的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(50mm×250mm×10μm)(乙腈/0.1％三氟乙酸水溶液(v/v)＝60/40)分离纯化，分别得到标题化合物2-1(500mg,53％)和标题化合物2-2(400mg,42％)，均为淡黄色固体。Add ((12aR)-7-(benzyloxy)-12-(5-fluoro-2-(2-fluorophenyl)-8H-dibenzo[3,4:6,7]cyclohepta[1 ,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][ 1,2,4]Triazine-6,8-dione (911mg, 1.3mmol) was dissolved in N,N-dimethylacetamide (10mL), anhydrous lithium chloride (580mg, 13.2mmol) was added, Under nitrogen protection, react overnight at 100°C. After the reaction is complete, adjust the pH to about 6 with 1N dilute hydrochloric acid, add water (20mL), and then extract with ethyl acetate (10mL×3). The combined organic phase is saturated with brine (20mL). ×3) Wash, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue is passed through a LUNA preparation column (50mm×250mm×10μm) (acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=60/40 ) Isolation and purification to obtain the title compound 2-1 (500 mg, 53%) and the title compound 2-2 (400 mg, 42%), both of which are pale yellow solids.
MS(ESI,pos.ion)m/z:596.1[M+H] +。 MS (ESI, pos.ion) m/z: 596.1 [M+H] + .
化合物2-1：Compound 2-1:
1H NMR(400MHz,CDCl 3)δ(ppm)7.85(s,1H),7.80(t,J＝7.3Hz,1H),7.74(d,J＝7.7Hz,1H),7.53–7.34 (m,5H),7.25(d,J＝8.6Hz,2H),7.19(t,J＝7.9Hz,1H),7.01(d,J＝7.6Hz,1H),6.41(d,J＝7.7Hz,1H),5.73(d,J＝7.7Hz,1H),5.46(s,1H),4.61(d,J＝12.7Hz,1H),4.26–4.19(m,1H),3.74(d,J＝12.0Hz,1H),3.43–3.38(m,1H),3.33(d,J＝10.6Hz,1H),3.21(t,J＝10.5Hz,1H),2.93(t,J＝11.1Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.85 (s, 1H), 7.80 (t, J = 7.3 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.53–7.34 (m, 5H), 7.25(d,J=8.6Hz,2H), 7.19(t,J=7.9Hz,1H), 7.01(d,J=7.6Hz,1H), 6.41(d,J=7.7Hz,1H) ,5.73(d,J=7.7Hz,1H), 5.46(s,1H), 4.61(d,J=12.7Hz,1H), 4.26–4.19(m,1H), 3.74(d,J=12.0Hz, 1H), 3.43–3.38 (m, 1H), 3.33 (d, J=10.6 Hz, 1H), 3.21 (t, J=10.5 Hz, 1H), 2.93 (t, J=11.1 Hz, 1H).
化合物2-2：Compound 2-2:
1H NMR(400MHz,CDCl 3)δ(ppm)7.90(s,1H),7.83(d,J＝6.7Hz,2H),7.61–7.35(m,6H),7.30(d,J＝7.2Hz,1H),7.04–6.93(m,2H),6.38(d,J＝7.3Hz,1H),5.92(d,J＝7.4Hz,1H),5.46(s,1H),4.61(d,J＝12.9Hz,1H),4.23(d,J＝7.0Hz,1H),3.74(d,J＝9.7Hz,1H),3.45(d,J＝8.5Hz,1H),3.35(t,J＝11.1Hz,1H),3.21(t,J＝10.4Hz,1H),2.91(t,J＝11.1Hz,1H)。 1 H NMR(400MHz, CDCl 3 )δ(ppm)7.90(s,1H), 7.83(d,J=6.7Hz,2H), 7.61–7.35(m,6H), 7.30(d,J=7.2Hz, 1H), 7.04–6.93 (m, 2H), 6.38 (d, J = 7.3 Hz, 1H), 5.92 (d, J = 7.4 Hz, 1H), 5.46 (s, 1H), 4.61 (d, J = 12.9 Hz, 1H), 4.23 (d, J = 7.0 Hz, 1H), 3.74 (d, J = 9.7 Hz, 1H), 3.45 (d, J = 8.5 Hz, 1H), 3.35 (t, J = 11.1Hz, 1H), 3.21 (t, J=10.4 Hz, 1H), 2.91 (t, J=11.1 Hz, 1H).
实施例3(R)-12-((S)-5-氟-2-苯基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物3-1)以及(R)-12-((R)-5-氟-2-苯基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物3-2)Example 3 (R)-12-((S)-5-fluoro-2-phenyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8- Yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4 ] Triazine-6,8-dione (compound 3-1) and (R)-12-((R)-5-fluoro-2-phenyl-8H-dibenzo[3,4:6,7 ]Cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyridine And [2,1-f][1,2,4]triazine-6,8-dione (compound 3-2)
Figure PCTCN2020077781-appb-000055
Figure PCTCN2020077781-appb-000055
步骤1)5-氟-2-苯基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 1) Synthesis of 5-fluoro-2-phenyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将2-溴-5-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1g,2.76mmol)、苯硼酸(438mg,3.60mmol)、碳酸钠(586mg,2.77mmol)和四三苯基磷钯(355mg,0.27mmol)混合于四氢呋喃(6mL)和水(1mL)中，氮气保护下置于70℃油浴锅中加热反应12小时。将反应液过滤，然后将滤液加入水(10mL)中，再用乙酸乙酯(5mL×3)萃取，合并的有机相用饱和氯化钠水溶液(10mL)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(洗脱剂为石油醚/乙酸乙酯(v/v)＝4/1)，得到标题化合物为白色固体(983mg,99％)。Combine 2-bromo-5-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (1g, 2.76mmol), phenylboronic acid (438mg, 3.60 mmol), sodium carbonate (586mg, 2.77mmol) and palladium tetrakistriphenylphosphorus (355mg, 0.27mmol) were mixed in tetrahydrofuran (6mL) and water (1mL), heated in an oil bath at 70℃ under nitrogen protection. 12 hours. The reaction solution was filtered, and the filtrate was added to water (10 mL), and then extracted with ethyl acetate (5 mL×3). The combined organic phases were washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=4/1) to obtain the title compound as a white solid (983 mg, 99%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.84(t,J＝9.9Hz,2H),7.75(d,J＝7.4Hz,2H),7.63(s,1H),7.59(d,J＝7.6Hz,1H),7.48(dd,J＝13.8,6.8Hz,4H),7.37(dd,J＝15.4,7.7Hz,2H),7.16(t,J＝8.4Hz,1H),5.43(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.84 (t, J = 9.9 Hz, 2H), 7.75 (d, J = 7.4 Hz, 2H), 7.63 (s, 1H), 7.59 (d, J = 7.6Hz, 1H), 7.48 (dd, J = 13.8, 6.8 Hz, 4H), 7.37 (dd, J = 15.4, 7.7 Hz, 2H), 7.16 (t, J = 8.4 Hz, 1H), 5.43 (s, 1H).
步骤2)(12aR)-7-(苄基氧基)-12-(5-氟-2-苯基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4-4,12,12a-四氢Step 2) (12aR)-7-(benzyloxy)-12-(5-fluoro-2-phenyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-3,4-4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将5-氟-2-苯基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(500mg,1.39mmol)和(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(502mg,1.53mmol)混合于乙酸乙酯(2mL)中，加入1-丙基磷酸酐(2.5mL,4.18mmol)，置于微波100℃反应30分钟，将反应液加入水(10mL)，然后用乙酸乙酯(5mL×3)萃取，合并的有机相用饱和氯化钠水溶液(10mL)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(435mg,46％)。Combine 5-fluoro-2-phenyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (500mg, 1.39mmol) and (R)-7 -(Benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4 ] Triazine-6,8-dione (502 mg, 1.53 mmol) was mixed in ethyl acetate (2 mL), 1-propyl phosphoric anhydride (2.5 mL, 4.18 mmol) was added, and the mixture was placed in a microwave at 100°C for 30 minutes. The reaction solution was added to water (10 mL), and then extracted with ethyl acetate (5 mL×3). The combined organic phase was washed with saturated aqueous sodium chloride (10 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: dichloromethane/methanol (v/v)=25/1), and after purification, the title compound was obtained as a pale yellow solid (435 mg, 46%).
MS(ESI,pos.ion)m/z:668.2[M+H] +。 MS (ESI, pos.ion) m/z: 668.2 [M+H] + .
步骤3)(R)-12-((S)-5-氟-2-苯基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁Step 3) (R)-12-((S)-5-fluoro-2-phenyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8- Group)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxa 嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物3-1)以及(R)-12-((R)-5-氟-2-苯基-8H-二苯并[3,4:6,7]Azino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 3-1) and (R)-12-((R )-5-fluoro-2-phenyl-8H-dibenzo[3,4:6,7] 环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合Cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4]triazine-6,8-dione (compound 物3-2)的合成3-2) Synthesis
将(12aR)-7-(苄基氧基)-12-(5-氟-2-苯基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4-4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.1g,1.6mmol)溶于N,N-二甲基乙酰胺(10mL)中，加入无水氯化锂(700mg,16mmol)，氮气保护，升温至100℃反应过夜，然后加入水(20mL)淬灭反应，再用1N稀盐酸调节pH至6左右，用乙酸乙酯(10mL×3)萃取，合并有机相，再用饱和食盐水(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(50mm×250mm×10μm)(乙腈/0.1％三氟乙酸水溶液(v/v)＝57/43)分离纯化，分别得到标题化合物3-1(500mg,53％)和化合物3-2(400mg,42％)，均为淡黄色固体。(12aR)-7-(benzyloxy)-12-(5-fluoro-2-phenyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene -8-yl)-3,4-4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2, 4] Triazine-6,8-dione (1.1g, 1.6mmol) was dissolved in N,N-dimethylacetamide (10mL), anhydrous lithium chloride (700mg, 16mmol) was added, nitrogen protection, heating React overnight at 100°C, then add water (20mL) to quench the reaction, then adjust the pH to about 6 with 1N diluted hydrochloric acid, extract with ethyl acetate (10mL×3), combine the organic phases, and then use saturated brine (20mL× 3) Wash, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and pass the residue through a LUNA preparation column (50mm×250mm×10μm) (acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=57/43) After separation and purification, the title compound 3-1 (500 mg, 53%) and compound 3-2 (400 mg, 42%) were obtained, both of which were pale yellow solids.
MS(ESI,pos.ion)m/z:578.2[M+H] +。 MS (ESI, pos.ion) m/z: 578.2 [M+H] + .
化合物3-1：Compound 3-1:
1H NMR(400MHz,CDCl 3)δ(ppm)7.77(d,J＝7.4Hz,2H),7.73(d,J＝7.6Hz,1H),7.69(s,1H),7.55–7.41(m,7H),7.20(d,J＝6.1Hz,1H),7.00(d,J＝7.3Hz,1H),6.43(s,1H),5.75(s,1H),5.46(s,1H),4.62(d,J＝13.2Hz,1H),4.23(d,J＝7.7Hz,1H),3.74(d,J＝9.6Hz,1H),3.37(dd,J＝30.0,10.3Hz,3H),3.25–3.17(m,1H),2.93(s,2H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.77 (d, J = 7.4 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.69 (s, 1H), 7.55-7.41 (m, 7H), 7.20 (d, J = 6.1 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 6.43 (s, 1H), 5.75 (s, 1H), 5.46 (s, 1H), 4.62 ( d, J = 13.2 Hz, 1H), 4.23 (d, J = 7.7 Hz, 1H), 3.74 (d, J = 9.6 Hz, 1H), 3.37 (dd, J = 30.0, 10.3 Hz, 3H), 3.25- 3.17 (m, 1H), 2.93 (s, 2H).
化合物3-2：Compound 3-2:
1H NMR(400MHz,CDCl 3)δ(ppm)7.79(d,J＝7.6Hz,3H),7.73(s,1H),7.57–7.39(m,7H),7.03–6.98(m,1H),6.95(t,J＝8.0Hz,1H),6.33(d,J＝7.6Hz,1H),5.76(d,J＝7.6Hz,1H),5.45(s,1H),4.60(d,J＝13.0Hz,1H),4.20(dd,J＝9.8,2.6Hz,1H),4.14(dd,J＝14.2,7.1Hz,1H),3.72(d,J＝9.7Hz,1H),3.43(dd,J＝10.8,2.4Hz,1H),3.34(t,J＝11.1Hz,1H),3.22(t,J＝10.5Hz,1H),2.90(t,J＝11.1Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.79 (d, J = 7.6 Hz, 3H), 7.73 (s, 1H), 7.57-7.39 (m, 7H), 7.03-6.98 (m, 1H), 6.95(t,J=8.0Hz,1H), 6.33(d,J=7.6Hz,1H), 5.76(d,J=7.6Hz,1H), 5.45(s,1H), 4.60(d,J=13.0 Hz, 1H), 4.20 (dd, J = 9.8, 2.6 Hz, 1H), 4.14 (dd, J = 14.2, 7.1 Hz, 1H), 3.72 (d, J = 9.7 Hz, 1H), 3.43 (dd, J = 10.8, 2.4 Hz, 1H), 3.34 (t, J = 11.1 Hz, 1H), 3.22 (t, J = 10.5 Hz, 1H), 2.90 (t, J = 11.1 Hz, 1H).
实施例4(R)-12-((S)-5-氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物4-1)以及(R)-12-((R)-5-氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物4-2)Example 4 (R)-12-((S)-5-fluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8- Yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4 ] Triazine-6,8-dione (compound 4-1) and (R)-12-((R)-5-fluoro-2-methyl-8H-dibenzo[3,4:6,7 ]Cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyridine And [2,1-f][1,2,4]triazine-6,8-dione (Compound 4-2)
Figure PCTCN2020077781-appb-000056
Figure PCTCN2020077781-appb-000056
步骤1)4-(3-氟苯基)-2-甲基噻吩的合成Step 1) Synthesis of 4-(3-fluorophenyl)-2-methylthiophene
将4-溴-2-甲基噻吩(10g,56.4mmol)、(3-氟苯基)硼酸(11.8g,84.7mmol)、醋酸钯(258mg,1.1mmol)、磷酸钾(24.7g,112.9mmol)和S-Phos(956mg,2.2mmol)混合于甲苯(100mL)和水(10mL)中，氮气保护下，升温至110℃加热反应12小时。停止反应，将反应液过滤，所得滤液减压浓缩，然后用硅胶柱层析纯化(洗脱剂为石油醚)，得到标题化合物为黄色固体(10.52g,96％)。Combine 4-bromo-2-methylthiophene (10g, 56.4mmol), (3-fluorophenyl)boronic acid (11.8g, 84.7mmol), palladium acetate (258mg, 1.1mmol), potassium phosphate (24.7g, 112.9mmol) ) And S-Phos (956mg, 2.2mmol) were mixed in toluene (100mL) and water (10mL), and heated to 110°C for 12 hours under the protection of nitrogen. The reaction was stopped, the reaction solution was filtered, and the obtained filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (eluent was petroleum ether) to obtain the title compound as a yellow solid (10.52 g, 96%).
步骤2)2-溴-3-(3-氟苯基)-5-甲基噻吩的合成Step 2) Synthesis of 2-bromo-3-(3-fluorophenyl)-5-methylthiophene
将4-(3-氟苯基)-2-甲基噻吩(11.6g,60.4mmol)溶于DMF(30mL)中，将NBS(11.5g,63.4mmol)溶解于DMF(60mL)，再滴加到上述反应液中，所得混合物室温下反应24小时。向反应液加入水(200mL)，用乙酸乙酯(100mL×3)萃取，合并的有机相用饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为黄色液体(14.2g,86.7％)。Dissolve 4-(3-fluorophenyl)-2-methylthiophene (11.6g, 60.4mmol) in DMF (30mL), dissolve NBS (11.5g, 63.4mmol) in DMF (60mL), and add dropwise Into the above reaction solution, the resulting mixture was reacted at room temperature for 24 hours. Water (200 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×3), the combined organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title The compound is a yellow liquid (14.2 g, 86.7%).
MS(ESI,pos.ion)m/z:272.1[M+H] +。 MS (ESI, pos.ion) m/z: 272.1 [M+H] + .
1H NMR(400MHz,CDCl 3)δ(ppm)7.43–7.26(m,3H),7.10–7.01(m,1H),6.72(s,1H),2.47(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.43-7.26 (m, 3H), 7.10-7.01 (m, 1H), 6.72 (s, 1H), 2.47 (s, 3H).
步骤3)2-(3-(3-氟苯基)-5-甲基噻吩-2-基)苯甲酸甲酯的合成Step 3) Synthesis of methyl 2-(3-(3-fluorophenyl)-5-methylthiophen-2-yl)benzoate
将2-溴-3-(3-氟苯基)-5-甲基噻吩(1g,3.6mmol)、碳酸钾(1.5g,11.0mmol)、双三苯基磷二氯化钯(261mg,0.3mmol)、(2-(甲氧基羰基)苯基)硼酸(995mg,5.5mmol)混合于DMF(6mL)和水(0.2mL)中，氮气保护下升温至100℃加热反应5小时。然后将反应液过滤，加入水(10mL)至滤液中，用乙酸乙酯(5mL×3)萃取，合并的有机相用饱和氯化钠水溶液(10mL)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(洗脱剂为石油醚/乙酸乙酯(v/v)＝50/1)，纯化后得到标题化合物为黄色固体(600mg,49％)。Combine 2-bromo-3-(3-fluorophenyl)-5-methylthiophene (1g, 3.6mmol), potassium carbonate (1.5g, 11.0mmol), bistriphenylphosphonium palladium dichloride (261mg, 0.3 mmol), (2-(methoxycarbonyl)phenyl)boronic acid (995mg, 5.5mmol) were mixed in DMF (6mL) and water (0.2mL), and heated to 100°C for 5 hours under nitrogen protection. Then the reaction solution was filtered, water (10mL) was added to the filtrate, extracted with ethyl acetate (5mL×3), the combined organic phase was washed with saturated aqueous sodium chloride (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v)=50/1). After purification, the title compound was obtained as a yellow solid (600 mg, 49%).
1H NMR(600MHz,CDCl 3)δ(ppm)7.79–7.73(m,1H),7.49–7.45(m,1H),7.39(ddd,J＝14.9,7.6,0.9Hz,2H),7.18–7.13(m,1H),6.93(d,J＝7.7Hz,1H),6.90–6.85(m,3H),3.61(d,J＝7.1Hz,3H),2.57(d,J＝10.8Hz,3H)。 1 H NMR(600MHz, CDCl 3 )δ(ppm) 7.79–7.73(m,1H), 7.49–7.45(m,1H), 7.39(ddd,J=14.9,7.6,0.9Hz,2H), 7.18–7.13 (m, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.90-6.85 (m, 3H), 3.61 (d, J = 7.1 Hz, 3H), 2.57 (d, J = 10.8 Hz, 3H) .
步骤4)2-(3-(3-氟苯基)-5-甲基噻吩-2-基)苯甲酸的合成Step 4) Synthesis of 2-(3-(3-fluorophenyl)-5-methylthiophen-2-yl)benzoic acid
将2-(3-(3-氟苯基)-5-甲基噻吩-2-基)苯甲酸甲酯(5.6g,77mmol)溶解于四氢呋喃(10mL)和甲醇(10mL)中，在室温下搅拌10分钟，将氢氧化钠(2.8mg,69mmol)溶于水(5mL)中，再加入到上述反应液中，然后升温至78℃下搅拌19小时。加入水(30mL)至反应液，用乙酸乙酯(3mL×3)萃取，合并的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(4.93g,92％)。Methyl 2-(3-(3-fluorophenyl)-5-methylthiophen-2-yl)benzoate (5.6g, 77mmol) was dissolved in tetrahydrofuran (10mL) and methanol (10mL) at room temperature After stirring for 10 minutes, sodium hydroxide (2.8 mg, 69 mmol) was dissolved in water (5 mL), then added to the above reaction solution, and then heated to 78° C. and stirred for 19 hours. Water (30mL) was added to the reaction solution, extracted with ethyl acetate (3mL×3), the combined organic phase was washed with saturated aqueous sodium chloride solution (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title The compound is a pale yellow solid (4.93 g, 92%).
MS(ESI,neg.ion)m/z:311.0[M-H] -。 MS (ESI, neg.ion) m/z: 311.0 [MH] - .
步骤5)5-氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 5) Synthesis of 5-fluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将2-(3-(3-氟苯基)-5-甲基噻吩-2-基)苯甲酸(4.8g,15mmol)加入至多聚磷酸(10mL)中，升温至120℃下反应3小时，然后加入冰水(20mL)至反应液中，再用二氯甲烷(10mL×3)萃取，合并的有机相用饱和食盐水(20mL)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(洗脱剂为石油醚/二氯甲烷(v/v)＝30/1)，得到标题化合物为黄色固体(500mg,53％)。2-(3-(3-Fluorophenyl)-5-methylthiophen-2-yl)benzoic acid (4.8g, 15mmol) was added to polyphosphoric acid (10mL), heated to 120°C and reacted for 3 hours, Then ice water (20 mL) was added to the reaction solution, and then extracted with dichloromethane (10 mL×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/dichloromethane (v/v)=30/1) to obtain the title compound as a yellow solid (500 mg, 53%).
MS(ESI,pos.ion)m/z:272.1[M+H] +。 MS (ESI, pos.ion) m/z: 272.1 [M+H] + .
步骤6)5-氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 6) Synthesis of 5-fluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将5-氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(4.32g,14.7mmol)混合于四氢呋喃(30mL)和甲醇(30mL)中，室温下搅拌10分钟，然后缓慢加入硼氢化钠(5.78g,147mmol)，加完后继续在室温下反应20分钟。向反应液中加入饱和氯化铵溶液(10mL)淬灭反应，用乙酸乙酯(20mL×3)萃取，合并的有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为黄色固体(2.08mg,47％)。Mix 5-fluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (4.32g, 14.7mmol) in tetrahydrofuran (30mL ) And methanol (30mL), stir at room temperature for 10 minutes, then slowly add sodium borohydride (5.78g, 147mmol), after the addition, continue to react at room temperature for 20 minutes. Saturated ammonium chloride solution (10 mL) was added to the reaction solution to quench the reaction, extracted with ethyl acetate (20 mL×3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentration under reduced pressure gave the title compound as a yellow solid (2.08 mg, 47%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.80(t,J＝10.0Hz,2H),7.53–7.40(m,3H),7.18(d,J＝9.7Hz,1H),7.15–7.07(m,2H),5.33(s,1H),2.63(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.80 (t, J = 10.0 Hz, 2H), 7.53-7.40 (m, 3H), 7.18 (d, J = 9.7 Hz, 1H), 7.15-7.07 ( m, 2H), 5.33 (s, 1H), 2.63 (s, 3H).
步骤7)(12aR)-7-(苄基氧基)-12-(5-氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4-4,12,12a-四氢Step 7) (12aR)-7-(benzyloxy)-12-(5-fluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-3,4-4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将5-氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(500mg,1.68mmol)和(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(607mg,1.85mmol)混合于乙酸异丙酯(10mL)中，加入50％的1-丙基磷酸酐乙酸乙酯溶液(3mL,5.06mmol)，升温至90℃下反应5小时。向反应液中加入水(10mL)，用乙酸乙酯(5mL×3)萃取，合并的有机相用饱和氯化钠水溶液(10mL)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)，得到标题化合物为淡黄色固体(505mg,49％)。Combine 5-fluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol (500mg, 1.68mmol) and (R)-7 -(Benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4 ] Triazine-6,8-dione (607mg, 1.85mmol) was mixed in isopropyl acetate (10mL), 50% ethyl acetate solution of 1-propyl phosphoric anhydride (3mL, 5.06mmol) was added, and the temperature was raised to React at 90°C for 5 hours. Water (10mL) was added to the reaction solution, extracted with ethyl acetate (5mL×3), the combined organic phase was washed with saturated aqueous sodium chloride (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=25/1) to obtain the title compound as a pale yellow solid (505 mg, 49%).
MS(ESI,pos.ion)m/z:606.2[M+H] +。 MS (ESI, pos.ion) m/z: 606.2 [M+H] + .
步骤8)(R)-12-((S)-5-氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁Step 8) (R)-12-((S)-5-fluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8- Group)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxa 嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物4-1)以及(R)-12-((R)-5-氟-2-甲基-8H-二苯并[3,4:6,7]Azino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 4-1) and (R)-12-((R )-5-fluoro-2-methyl-8H-dibenzo[3,4:6,7] 环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合Cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4]triazine-6,8-dione (compound 物4-2)的合成4-2) Synthesis
将(12aR)-7-(苄基氧基)-12-(5-氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4-4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(505mg,0.83mmol)溶于N,N-二甲基乙酰胺(10mL)中，加入无水氯化锂(364mg,8.32mmol)，氮气保护下升温至100℃，搅拌过夜。向反应液中加入水(20mL)，用1N稀盐酸调节pH至6左右，用乙酸乙酯(10mL×3)萃取，合并的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(50mm×250mm×10μm)(乙腈/0.1％三氟乙酸水溶液(v/v)＝45/55)分离纯化，分别得到标题化合物4-1(127mg,42％)和标题化合物4-2(143mg,42％)，均为淡黄色固体。Add (12aR)-7-(benzyloxy)-12-(5-fluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene -8-yl)-3,4-4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2, 4] Triazine-6,8-dione (505mg, 0.83mmol) was dissolved in N,N-dimethylacetamide (10mL), anhydrous lithium chloride (364mg, 8.32mmol) was added, and the temperature was raised under nitrogen protection To 100°C, stir overnight. Add water (20mL) to the reaction solution, adjust the pH to about 6 with 1N dilute hydrochloric acid, extract with ethyl acetate (10mL×3), wash the combined organic phase with saturated brine (20mL×3), anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure. The residue obtained is separated and purified by a LUNA preparation column (50mm×250mm×10μm) (acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=45/55) to obtain the title compound 4. -1 (127 mg, 42%) and the title compound 4-2 (143 mg, 42%), both are pale yellow solids.
MS(ESI,pos.ion)m/z:516.2[M+H] +。 MS (ESI, pos.ion) m/z: 516.2 [M+H] + .
化合物4-1：Compound 4-1:
1H NMR(400MHz,CDCl 3)δ(ppm)7.60(d,J＝7.7Hz,1H),7.40(m,3H),7.24–7.09(m,3H),6.96(d,J＝7.3Hz,1H),6.36(d,J＝7.5Hz,1H),5.68(d,J＝7.4Hz,1H),5.41(s,1H),4.60(d,J＝13.2Hz,1H),4.17(d,J＝9.6Hz,1H),3.73(d,J＝9.2Hz,1H),3.43–3.30(m,2H),3.23(t,J＝10.5Hz,1H),2.91(t,J＝11.1Hz,1H),2.64(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.60 (d, J = 7.7Hz, 1H), 7.40 (m, 3H), 7.24-7.09 (m, 3H), 6.96 (d, J = 7.3Hz, 1H), 6.36 (d, J = 7.5 Hz, 1H), 5.68 (d, J = 7.4 Hz, 1H), 5.41 (s, 1H), 4.60 (d, J = 13.2 Hz, 1H), 4.17 (d, J = 9.6Hz, 1H), 3.73 (d, J = 9.2 Hz, 1H), 3.43–3.30 (m, 2H), 3.23 (t, J = 10.5 Hz, 1H), 2.91 (t, J = 11.1Hz, 1H), 2.64(s, 3H).
化合物4-2：Compound 4-2:
1H NMR(400MHz,CDCl 3)δ(ppm)7.68(d,J＝7.6Hz,1H),7.53–7.41(m,3H),7.31(dd,J＝9.6,1.9Hz,1H),7.17(s,1H),6.92(dt,J＝14.1,7.8Hz,2H),6.29(d,J＝7.5Hz,1H),5.74(d,J＝7.3Hz,1H),5.41(s,1H),4.59(d,J＝13.2Hz,1H),4.20-4.09(m,1H),3.72(d,J＝9.7Hz,1H),3.45-3.30(m,2H),3.24(t,J＝10.5Hz,1H),2.89(t,J＝11.2Hz,1H),2.65(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.68 (d, J = 7.6 Hz, 1H), 7.53-7.41 (m, 3H), 7.31 (dd, J = 9.6, 1.9 Hz, 1H), 7.17 ( s, 1H), 6.92 (dt, J = 14.1, 7.8 Hz, 2H), 6.29 (d, J = 7.5 Hz, 1H), 5.74 (d, J = 7.3 Hz, 1H), 5.41 (s, 1H), 4.59 (d, J = 13.2Hz, 1H), 4.20-4.09 (m, 1H), 3.72 (d, J = 9.7 Hz, 1H), 3.45-3.30 (m, 2H), 3.24 (t, J = 10.5 Hz , 1H), 2.89 (t, J = 11.2 Hz, 1H), 2.65 (s, 3H).
实施例5(((R)-12-((S)-5-氟-2-苯基-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-6,8-二氧代-3,4,6,8,12,12a-六氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-7-基)氧基)甲基碳酸甲酯(化合物5)Example 5 (((R)-12-((S)-5-fluoro-2-phenyl-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8 -Base)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1 -f][1,2,4]triazin-7-yl)oxy)methyl methyl carbonate (compound 5)
Figure PCTCN2020077781-appb-000057
Figure PCTCN2020077781-appb-000057
将(R)-12-((S)-5-氟-2-苯基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(100mg,0.17mmol)、氯甲基碳酸二甲酯(68mg,0.51mmol)、碳酸钾(48mg,0.34mmol)以及碘化钾(28mg,0.17mmol)混合于N,N-二甲基乙酰胺(5mL)中，氮气保护下升温至60℃反应30个小时。反应完全后，将反应液加入水(20mL)中，用乙酸乙酯(10mL×3)萃取，合并的有机相用饱和氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗产物用硅胶制备板纯化(洗脱剂为二氯甲烷/甲醇(v/v)＝20/1)，纯化后得到标题化合物为淡橙色固体(68mg,59％)。(R)-12-((S)-5-fluoro-2-phenyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl) -7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]tri Oxazine-6,8-dione (100mg, 0.17mmol), chloromethyl dimethyl carbonate (68mg, 0.51mmol), potassium carbonate (48mg, 0.34mmol) and potassium iodide (28mg, 0.17mmol) mixed in N, N -In dimethylacetamide (5mL), the temperature was raised to 60°C under nitrogen protection and reacted for 30 hours. After the reaction was completed, the reaction solution was added to water (20 mL), extracted with ethyl acetate (10 mL×3), the combined organic phase was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced After pressure concentration, the obtained crude product was purified with a silica gel preparation plate (eluent: dichloromethane/methanol (v/v)=20/1). After purification, the title compound was obtained as a pale orange solid (68 mg, 59%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.80(d,J＝7.4Hz,3H),7.72(s,1H),7.56–7.41(m,7H),7.17–7.10(m,1H),6.96(t,J＝6.9Hz,1H),6.38(d,J＝7.7Hz,1H),5.91(s,2H),5.84(d,J＝7.6Hz,1H),5.51(s,1H),4.58(d,J＝13.1Hz,1H),4.14(d,J＝7.8Hz,1H),3.88(s,3H),3.68(d,J＝9.9Hz,1H),3.42(d,J＝8.8Hz,1H),3.32(t,J＝11.1Hz,1H),3.18(t,J＝10.3Hz,1H),2.85(t,J＝11.0Hz,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.80 (d, J = 7.4Hz, 3H), 7.72 (s, 1H), 7.56-7.41 (m, 7H), 7.17-7.10 (m, 1H), 6.96(t,J=6.9Hz,1H), 6.38(d,J=7.7Hz,1H), 5.91(s,2H), 5.84(d,J=7.6Hz,1H), 5.51(s,1H), 4.58(d,J＝13.1Hz,1H), 4.14(d,J＝7.8Hz,1H), 3.88(s,3H), 3.68(d,J＝9.9Hz,1H),3.42(d,J＝8.8 Hz, 1H), 3.32 (t, J = 11.1 Hz, 1H), 3.18 (t, J = 10.3 Hz, 1H), 2.85 (t, J = 11.0 Hz, 1H).
实施例6(R)-12-((R)-4,5-二氟-2-(苯氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物36-1)以及(R)-12-((S)-4,5-二氟-2-(苯氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物36-2)Example 6 (R)-12-((R)-4,5-difluoro-2-(phenoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1- f][1,2,4]triazine-6,8-dione (compound 36-1) and (R)-12-((S)-4,5-difluoro-2-(phenoxymethyl Yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H- [1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 36-2)
Figure PCTCN2020077781-appb-000058
Figure PCTCN2020077781-appb-000058
步骤1)4-(2,3-二氟苯基)-2-甲基噻吩的合成Step 1) Synthesis of 4-(2,3-difluorophenyl)-2-methylthiophene
向反应瓶中加入2,3-二氟苯硼酸(13.9g,88mmol)，醋酸钯(0.311g,1.36mmol)，S-Phos(1.12g,2.72mmol)，磷酸钾(30.3g,136mmol)，甲苯(150mL)和水(15mL)。在氮气保护下，向其中加入4-溴-2-甲 基噻吩(7.6mL,68mmol)，将反应液升温至115℃搅拌反应18小时。反应完成后，将反应液冷却至室温，过滤，滤饼用乙酸乙酯(100mL)洗涤。收集滤液，分液，水相用乙酸乙酯(30mL×3)萃取，合并有机相，有机相用饱和食盐水(80mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干。所得粗产物使用硅胶柱层析纯化(洗脱剂为纯石油醚)，纯化后得到标题化合物为淡黄色固体(14.2g,100％)。Add 2,3-difluorophenylboronic acid (13.9g, 88mmol), palladium acetate (0.311g, 1.36mmol), S-Phos (1.12g, 2.72mmol), potassium phosphate (30.3g, 136mmol) into the reaction flask, Toluene (150 mL) and water (15 mL). Under the protection of nitrogen, 4-bromo-2-methylthiophene (7.6 mL, 68 mmol) was added thereto, and the reaction solution was heated to 115°C and stirred for 18 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was collected and separated, the aqueous phase was extracted with ethyl acetate (30 mL×3), the organic phases were combined, the organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent was pure petroleum ether), and after purification, the title compound was obtained as a pale yellow solid (14.2 g, 100%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.40(s,1H),7.30(dd,J＝6.9,3.9Hz,1H),7.14--7.06(m,3H),2.56(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.40 (s, 1H), 7.30 (dd, J = 6.9, 3.9 Hz, 1H), 7.14-7.06 (m, 3H), 2.56 (s, 3H) .
步骤2)2-溴-3-(2,3-二氟苯基)-5-甲基噻吩的合成Step 2) Synthesis of 2-bromo-3-(2,3-difluorophenyl)-5-methylthiophene
向反应瓶中加入4-(2,3-二氟苯基)-2-甲基噻吩(15.0g,71.4mmol)和DMF(60mL)，将反应液冷却至-5℃，然后向其中逐滴加入NBS(13.0g,71.6mmol)的DMF(50mL)溶液，滴加完成后，反应液在-5℃搅拌反应20小时。反应完成后，向反应液中加入乙酸乙酯(150mL)和饱和硫代硫酸钠溶液(100mL)，分液，水相用乙酸乙酯(80mL×4)萃取，合并有机相，有机相依次用水(60mL×4)和饱和食盐水(80mL)洗涤，无水硫酸钠干燥。过滤，滤液减压旋干，所得粗产物使用硅胶柱层析纯化(洗脱剂为纯石油醚)，纯化后得到标题化合物为淡黄色油状物(19.0g,92％)。Add 4-(2,3-difluorophenyl)-2-methylthiophene (15.0g, 71.4mmol) and DMF (60mL) into the reaction flask, cool the reaction solution to -5°C, and then dropwise into it A solution of NBS (13.0 g, 71.6 mmol) in DMF (50 mL) was added, and after the addition was completed, the reaction solution was stirred and reacted at -5°C for 20 hours. After the reaction is complete, add ethyl acetate (150mL) and saturated sodium thiosulfate solution (100mL) to the reaction solution, separate the layers, extract the aqueous phase with ethyl acetate (80mL×4), combine the organic phases, and then use water for the organic phase. (60 mL×4) and saturated brine (80 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was spin-dried under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent was pure petroleum ether). After purification, the title compound was obtained as a pale yellow oil (19.0 g, 92%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.26-7.09(m,3H),6.72(s,1H),2.49(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.26-7.09 (m, 3H), 6.72 (s, 1H), 2.49 (s, 3H).
步骤3)2-(3-(2,3-二氟苯基)-5-甲基噻吩-2-基)苯甲酸甲酯的合成Step 3) Synthesis of methyl 2-(3-(2,3-difluorophenyl)-5-methylthiophen-2-yl)benzoate
向反应瓶中加入2-溴-3-(2,3-二氟苯基)-5-甲基噻吩(19.0g,65.7mmol)，2-(甲氧基羰基)苯硼酸(17.7g,98.3mmol)，醋酸钯(0.753g,3.29mmol)，四氟硼酸三叔丁基膦(1.33g,4.58mmol)和1,4-二氧六环(100mL)，在氮气保护下，一次性加入磷酸钾(29.4g,132mmol,95mass％)的水(25mL)溶液。反应液在室温下搅拌反应18小时。反应完成后，将反应液过滤，滤饼用乙酸乙酯(100mL)洗涤。将滤液减压旋干，得到的粗产物使用硅胶层析柱纯化(洗脱剂为PE/EA(v/v)＝10/1)，得到标题化合物为淡黄色固体(21.0g,61.0mmol,93％)。Add 2-bromo-3-(2,3-difluorophenyl)-5-methylthiophene (19.0g, 65.7mmol), 2-(methoxycarbonyl)phenylboronic acid (17.7g, 98.3 mmol), palladium acetate (0.753g, 3.29mmol), tri-tert-butylphosphine tetrafluoroborate (1.33g, 4.58mmol) and 1,4-dioxane (100mL), under the protection of nitrogen, add phosphoric acid at once A solution of potassium (29.4 g, 132 mmol, 95 mass%) in water (25 mL). The reaction solution was stirred and reacted at room temperature for 18 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was spin-dried under reduced pressure, and the obtained crude product was purified by silica gel chromatography (eluent: PE/EA(v/v)=10/1) to obtain the title compound as a pale yellow solid (21.0g, 61.0mmol, 93%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.76-7.70(m,1H),7.51-7.41(m,1H),7.40-7.34(m,2H),7.01(td,J＝9.6,1.5Hz,1H),6.86(ddd,J＝13.1,8.0,3.9Hz,2H),6.75(dd,J＝7.7,6.2Hz,1H),3.64(s,3H),2.57(s,3H). 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.76-7.70(m,1H),7.51-7.41(m,1H),7.40-7.34(m,2H),7.01(td,J=9.6,1.5Hz ,1H), 6.86(ddd,J=13.1,8.0,3.9Hz,2H), 6.75(dd,J=7.7,6.2Hz,1H), 3.64(s,3H), 2.57(s,3H).
步骤4)2-(3-(2,3-二氟苯基)-5-甲基噻吩-2-基)苯甲酸的合成Step 4) Synthesis of 2-(3-(2,3-difluorophenyl)-5-methylthiophen-2-yl)benzoic acid
向反应瓶中依次加入2-(3-(2,3-二氟苯基)-5-甲基噻吩-2-基)苯甲酸甲酯(5.0g,15mmol)，THF(40mL)，甲醇(40mL)，氢氧化钠(1.8g,44mmol)和水(10mL)，将反应液升温至50℃搅拌反应5小时。反应完成后，将反应液冷却至室温，向反应液中加入乙酸乙酯(80mL)，用1N盐酸调节反应液的pH至酸性，分液，水相用乙酸乙酯(50mL×3)萃取，合并有机相，有机相用饱和食盐水洗涤(80mL)，无水硫酸钠干燥。过滤，滤液减压旋干，得到标题化合物为淡黄色固体(4.7g,98％)。Into the reaction flask was added methyl 2-(3-(2,3-difluorophenyl)-5-methylthiophen-2-yl)benzoate (5.0g, 15mmol), THF (40mL), methanol ( 40mL), sodium hydroxide (1.8g, 44mmol) and water (10mL), the reaction solution was heated to 50°C and stirred for 5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, ethyl acetate (80 mL) was added to the reaction solution, the pH of the reaction solution was adjusted to acidity with 1N hydrochloric acid, and the layers were separated. The aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, the organic phase was washed with saturated brine (80 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was spin-dried under reduced pressure to obtain the title compound as a pale yellow solid (4.7 g, 98%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.90-7.83(m,1H),7.52(dd,J＝10.7,4.3Hz,1H),7.40(t,J＝6.8Hz,2H),7.00(td,J＝9.5,1.4Hz,1H),6.89-6.81(m,2H),6.78(t,J＝6.9Hz,1H),2.57(s,3H)。 1 H NMR (400MHz, CDCl 3 )δ (ppm) 7.90-7.83 (m, 1H), 7.52 (dd, J = 10.7, 4.3 Hz, 1H), 7.40 (t, J = 6.8 Hz, 2H), 7.00 ( td, J=9.5, 1.4 Hz, 1H), 6.89-6.81 (m, 2H), 6.78 (t, J=6.9 Hz, 1H), 2.57 (s, 3H).
步骤5)4,5-二氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 5) Synthesis of 4,5-difluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
向反应瓶中加入2-(3-(2,3-二氟苯基)-5-甲基噻吩-2-基)苯甲酸(4.7g,14mmol)，PhCl(50mL)和PPA(50mL)，将反应液升温至130℃搅拌反应24小时。反应完成后，将反应液冷却至室温，然后将反应液倒入到冰水(300g)中，加入DCM(300mL)，搅拌10分钟。分液，水相用DCM(100mL×4)萃取，合并有机相，有机相用饱和食盐水洗涤(100mL×2)，无水硫酸钠干燥。过滤，滤液减压旋干。得到的粗产物使用硅胶柱层析纯化(洗脱剂为PE/DCM(v/v)＝5/1)，纯化后得到标题化合物为黄色固体(3.7g,83％)。Add 2-(3-(2,3-difluorophenyl)-5-methylthiophen-2-yl)benzoic acid (4.7g, 14mmol), PhCl (50mL) and PPA (50mL) to the reaction flask, The reaction solution was heated to 130°C and stirred for 24 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, and then the reaction solution was poured into ice water (300 g), DCM (300 mL) was added, and the mixture was stirred for 10 minutes. The layers were separated, the aqueous phase was extracted with DCM (100 mL×4), the organic phases were combined, and the organic phase was washed with saturated brine (100 mL×2), and dried over anhydrous sodium sulfate. Filter and spin dry the filtrate under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: PE/DCM (v/v)=5/1), and after purification, the title compound was obtained as a yellow solid (3.7 g, 83%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.81(dd,J＝7.8,0.9Hz,1H),7.73(d,J＝7.8Hz,1H),7.61(ddd,J＝15.1,7.2,1.5Hz,2H),7.48(t,J＝7.6Hz,1H),7.35-7.22(m,2H),2.60(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.81 (dd, J = 7.8, 0.9 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.61 (ddd, J = 15.1, 7.2, 1.5 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.35-7.22 (m, 2H), 2.60 (s, 3H).
步骤6)2-(溴甲基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 6) Synthesis of 2-(bromomethyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
向反应瓶中加入4,5-二氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(3.80g,12.2mmol)，NBS(2.21g,12.2mmol)和四氯化碳(100mL)，将反应液加热至70℃，然后加入过氧化苯甲酰(155mg,0.6080mmol)，反应液继续在70℃搅拌1小时。反应完成后，将反应液冷却至室温，减压旋干反应溶剂，得到的粗产物使用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝5/1～2/1)，纯化后得到标题化合物为淡白色固体(3.65g,77％)。Add 4,5-difluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (3.80g, 12.2) to the reaction flask mmol), NBS (2.21g, 12.2mmol) and carbon tetrachloride (100mL), the reaction solution was heated to 70°C, then benzoyl peroxide (155mg, 0.6080mmol) was added, and the reaction solution was stirred at 70°C for 1 hour. After the reaction is completed, the reaction solution is cooled to room temperature, and the reaction solvent is spin-dried under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: PE/EA(v/v)=5/1～2/1) After purification, the title compound was obtained as a pale solid (3.65 g, 77%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.83(d,J＝7.7Hz,1H),7.77(d,J＝7.8Hz,1H),7.63(dd,J＝10.6,4.8Hz,3H),7.54(t,J＝7.5Hz,1H),7.34-7.28(m,1H),4.79(s,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.83 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 10.6, 4.8 Hz, 3H) ,7.54(t,J=7.5Hz,1H),7.34-7.28(m,1H),4.79(s,2H).
步骤7)4,5-二氟-2-(苯氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 7) Synthesis of 4,5-difluoro-2-(phenoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
向反应瓶中加入NaH(60％)(0.465g,11.6mmol)，置换空气为氮气环境，冷却至0℃，然后向其中加入苯酚(842mg,8.947mmol)的DMF(30mL,100mass％)溶液，保持室温搅拌，得到苯酚钠的DMF溶液。取另一反应瓶，向其中加入2-(溴甲基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(3.50g,8.95mmol)和DMF(30mL)，将该溶液冷却至0℃搅拌，然后向其中逐滴加入上一步配置好的苯酚钠的DMF溶液，滴加完毕后将反应在0℃搅拌30分钟。反应完成后，向反应液中缓慢加入饱和氯化铵溶液(20mL)淬灭反应。然后向反应液中加入水(100mL)和乙酸乙酯(80mL)，分液，水相用乙酸乙酯(50mL×3)萃取，合并有机相，有机相依次用水(80mL×3)和饱和食盐水洗涤(80mL)，无水硫酸钠干燥。过滤，滤液减压旋干，得到的粗产物使用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝10/1)，得到标题化合物为淡黄色固体(3.40g,94％)。Add NaH (60%) (0.465g, 11.6mmol) to the reaction flask, replace the air with a nitrogen environment, cool to 0°C, then add phenol (842mg, 8.947mmol) in DMF (30mL, 100mass%) solution to it, Keep stirring at room temperature to obtain a DMF solution of sodium phenolate. Take another reaction flask and add 2-(bromomethyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8 to it -Ketone (3.50g, 8.95mmol) and DMF (30mL), the solution was cooled to 0℃ and stirred, and then the DMF solution of sodium phenolate prepared in the previous step was added dropwise to it. After the addition, the reaction was kept at 0℃ Stir for 30 minutes. After the reaction was completed, saturated ammonium chloride solution (20 mL) was slowly added to the reaction solution to quench the reaction. Then add water (100mL) and ethyl acetate (80mL) to the reaction solution, separate the layers, extract the aqueous phase with ethyl acetate (50mL×3), combine the organic phases, and then the organic phase with water (80mL×3) and saturated salt Wash with water (80 mL) and dry with anhydrous sodium sulfate. Filtration, the filtrate was spin-dried under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (eluent: PE/EA(v/v)=10/1) to obtain the title compound as a pale yellow solid (3.40g, 94%) ).
1H NMR(400MHz,CDCl 3)δ(ppm)7.81(dd,J＝18.0,7.8Hz,2H),7.68-7.59(m,3H),7.52(t,J＝7.6Hz,1H),7.40-7.27(m,3H),7.04(t,J＝8.7Hz,3H),5.32(s,2H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.81 (dd, J = 18.0, 7.8 Hz, 2H), 7.68-7.59 (m, 3H), 7.52 (t, J = 7.6 Hz, 1H), 7.40- 7.27 (m, 3H), 7.04 (t, J=8.7 Hz, 3H), 5.32 (s, 2H).
步骤8)4,5-二氟-2-(苯氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 8) Synthesis of 4,5-difluoro-2-(phenoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol
向反应瓶中加入4,5-二氟-2-(苯氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮450mg,1.113mmol)，甲醇(5mL)和THF(20mL)，在室温下搅拌，然后分批加入硼氢化钠43mg,1.091mmol)，加入完毕后继续在室温条件下搅拌反应1小时。反应完成后，向反应液中加入饱和氯化铵溶液(5mL)淬灭反应。向反应液中加入水(80mL)和乙酸乙酯(50mL)，分液，水相用乙酸乙酯(30mL×3)萃取，合并有机相，有机相用饱和食盐水洗涤(50mL)，无水硫酸钠干燥。过滤，滤液减压旋干，得到标题化合物为白色固体(450mg 99％)。Add 4,5-difluoro-2-(phenoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one to the reaction flask 450mg, 1.113mmol), methanol (5mL) and THF (20mL), stirred at room temperature, and then added sodium borohydride (43mg, 1.091mmol) in batches. After the addition, the reaction was continued at room temperature for 1 hour. After the reaction was completed, saturated ammonium chloride solution (5 mL) was added to the reaction solution to quench the reaction. Water (80 mL) and ethyl acetate (50 mL) were added to the reaction solution, separated, the aqueous phase was extracted with ethyl acetate (30 mL×3), the organic phases were combined, and the organic phase was washed with saturated brine (50 mL), anhydrous Dry with sodium sulfate. After filtration, the filtrate was spin-dried under reduced pressure to obtain the title compound as a white solid (450 mg 99%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.80(d,J＝7.8Hz,1H),7.60-7.53(m,3H),7.48(t,J＝7.6Hz,1H),7.34(dt,J＝12.5,7.6Hz,3H),7.22(dd,J＝17.2,8.9Hz,1H),7.05(dd,J＝18.0,7.7Hz,3H),5.34(s,2H),5.30(s,1H),2.59(d,J＝2.8Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.80 (d, J = 7.8 Hz, 1H), 7.60-7.53 (m, 3H), 7.48 (t, J = 7.6 Hz, 1H), 7.34 (dt, J = 12.5, 7.6 Hz, 3H), 7.22 (dd, J = 17.2, 8.9 Hz, 1H), 7.05 (dd, J = 18.0, 7.7 Hz, 3H), 5.34 (s, 2H), 5.30 (s, 1H) ), 2.59(d,J=2.8Hz,1H).
步骤9)(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-(苯氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-Step 9) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-(phenoxymethyl)-8H-dibenzo[3,4:6,7] Cyclohepta[1,2-b]thiophene-8- 基)-3,4-4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Group)-3,4-4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]tri Synthesis of oxazine-6,8-dione
向反应瓶中加入4,5-二氟-2-(苯氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(2.98g,7.33mmol)，(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(2.00g,6.11mmol)，T 3P(25mL,42mmol,50mass％乙酸乙酯溶液)和醋酸异丙酯(20mL)，将反应液升温至90℃搅拌反应5小时。反应完成后，将反应液冷却至室温，向反应液中加入乙酸乙酯(100mL)和饱和碳酸氢钠溶液(80mL)，待不再生成气泡后，分液，水相用乙酸乙酯(60mL×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，滤液减压旋干，得到的粗产物使用硅胶柱层析(洗脱剂为DCM/MeOH(v/v)＝15/1)纯化，得到标题化合物为淡黄色固体(2.20g,50％)。 Add 4,5-difluoro-2-(phenoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol to the reaction flask (2.98g, 7.33mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4]triazine-6,8-dione (2.00g, 6.11mmol), T 3 P (25mL, 42mmol, 50mass% ethyl acetate solution) and isopropyl acetate Ester (20 mL), the reaction solution was heated to 90°C and stirred for 5 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, ethyl acetate (100mL) and saturated sodium bicarbonate solution (80mL) were added to the reaction solution, when no more bubbles were generated, the liquids were separated, and the aqueous phase was separated with ethyl acetate (60mL ×3) Extract, combine the organic phases, wash the organic phase with saturated brine (50 mL), and dry with anhydrous sodium sulfate. The filtrate was filtered and the filtrate was spin-dried under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain the title compound as a pale yellow solid (2.20g, 50%) ).
MS(ESI,pos.ion)m/z:716.4[M+H] + MS(ESI,pos.ion)m/z:716.4[M+H] +
步骤10)(R)-12-((S)-4,5-二氟-2-(苯氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四Step 10) (R)-12-((S)-4,5-difluoro-2-(phenoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b)thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetra 氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物36-1)以及(R)-12-((S)-4,5-二氟-2-(苯氧Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 36-1) And (R)-12-((S)-4,5-difluoro-2-(phenoxy 基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并Methyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4]三嗪-6,8-二酮(化合物36-2)的合成Synthesis of [2,1-f][1,2,4]triazine-6,8-dione (Compound 36-2)
向反应瓶中加入(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-(苯氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(2.2g,3.1mmol)，氯化锂(1.3g,30mmol)和DMAc(30mL)，反应液升温至100℃搅拌反应2小时。反应完成后，反应液冷却至室温，向反应液中加入乙酸乙酯(80mL)和水(50mL)，然后再加入1N盐酸调节反应液pH至6-7，分液，水相用乙酸乙酯(50mL×3)萃取，合并有机相，有机相用饱和食盐水洗涤(80mL)，无水硫酸钠干燥，过滤，滤液减压旋干。得到黄色固体粗产物，所得黄色固体粗产品使用高效液相制备色谱分离，得到标题化合物36-1为橙色固体化合物(0.5g,30％)，和标题化合物36-2为橙色固体化合物(0.7g,40％)。Add (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-(phenoxymethyl)-8H-dibenzo[3,4:6, 7] Cyclohepta[1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2 ,1-f][1,2,4]triazine-6,8-dione (2.2g, 3.1mmol), lithium chloride (1.3g, 30mmol) and DMAc (30mL), the reaction solution was heated to 100℃ The reaction was stirred for 2 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, ethyl acetate (80mL) and water (50mL) were added to the reaction solution, and then 1N hydrochloric acid was added to adjust the pH of the reaction solution to 6-7, and the aqueous phase was separated with ethyl acetate (50mL×3) Extract, combine the organic phases, wash the organic phase with saturated brine (80mL), dry with anhydrous sodium sulfate, filter, and spin-dry the filtrate under reduced pressure. A yellow solid crude product was obtained, and the obtained yellow solid crude product was separated using Prep-HPLC to obtain the title compound 36-1 as an orange solid compound (0.5 g, 30%), and the title compound 36-2 as an orange solid compound (0.7 g ,40%).
化合物36-1：Compound 36-1:
1H NMR(400MHz,CDCl 3)δ(ppm)7.68(d,J＝7.6Hz,1H),7.59(d,J＝5.5Hz,1H),7.43(t,J＝7.5Hz,1H),7.33(t,J＝7.9Hz,2H),7.28-7.23(m,3H),7.06(d,J＝8.1Hz,2H),7.02(t,J＝7.4Hz,1H),6.97(d,J＝7.5Hz,1H),6.29(d,J＝7.7Hz,1H),5.67(d,J＝7.7Hz,1H),5.39-5.32(m,3H),4.60(d,J＝12.7Hz,1H),4.18(dd,J＝9.7,3.1Hz,1H),3.74(dd,J＝11.9,2.9Hz,1H),3.35(t,J＝10.8Hz,1H),3.25(dd,J＝11.0,3.0Hz,1H),3.16(t,J＝10.5Hz,1H),2.96-2.84(m,1H)； 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.68 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 5.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.33 (t,J=7.9Hz,2H),7.28-7.23(m,3H),7.06(d,J=8.1Hz,2H),7.02(t,J=7.4Hz,1H),6.97(d,J= 7.5Hz, 1H), 6.29 (d, J = 7.7 Hz, 1H), 5.67 (d, J = 7.7 Hz, 1H), 5.39-5.32 (m, 3H), 4.60 (d, J = 12.7 Hz, 1H) ,4.18(dd,J＝9.7,3.1Hz,1H), 3.74(dd,J＝11.9,2.9Hz,1H), 3.35(t,J＝10.8Hz,1H), 3.25(dd,J＝11.0,3.0 Hz, 1H), 3.16 (t, J = 10.5 Hz, 1H), 2.96-2.84 (m, 1H);
化合物36-2：Compound 36-2:
1H NMR(400MHz,CDCl 3)δ(ppm)7.75(d,J＝7.5Hz,1H),7.62(d,J＝5.3Hz,1H),7.56(t,J＝7.5Hz,1H),7.50(t,J＝7.2Hz,1H),7.43(d,J＝7.3Hz,1H),7.32-7.28(m,2H),7.05-7.03(d,J＝7.9Hz,3H),6.99(t,J＝7.3Hz,1H),6.78(m,1H),6.31(d,J＝7.5Hz,1H),6.03(d,J＝7.5Hz,1H),5.42(s,2H),5.36(d,J＝28.6Hz,2H),4.57(d,J＝13.1Hz,1H),4.14(dd,J＝9.9,3.0Hz,1H),3.73(dd,J＝11.9,2.7Hz,1H),3.34(t,J＝11.0Hz,1H),3.22(dd,J＝11.0,2.9Hz,1H),3.10(t,J＝10.5Hz,1H),2.91-2.84(m,1H)； 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.75(d,J=7.5Hz,1H), 7.62(d,J=5.3Hz,1H), 7.56(t,J=7.5Hz,1H), 7.50 (t,J=7.2Hz,1H),7.43(d,J=7.3Hz,1H),7.32-7.28(m,2H),7.05-7.03(d,J=7.9Hz,3H),6.99(t, J = 7.3Hz, 1H), 6.78 (m, 1H), 6.31 (d, J = 7.5 Hz, 1H), 6.03 (d, J = 7.5 Hz, 1H), 5.42 (s, 2H), 5.36 (d, J = 28.6Hz, 2H), 4.57 (d, J = 13.1Hz, 1H), 4.14 (dd, J = 9.9, 3.0Hz, 1H), 3.73 (dd, J = 11.9, 2.7Hz, 1H), 3.34 ( t,J=11.0Hz,1H),3.22(dd,J=11.0,2.9Hz,1H), 3.10(t,J=10.5Hz,1H),2.91-2.84(m,1H);
实施例7(R)-12-((R)-4,5-二氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物79-1)以及(R)-12-((S)-4,5-二氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物79-2)Example 7 (R)-12-((R)-4,5-difluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1- f][1,2,4]triazine-6,8-dione (Compound 79-1) and (R)-12-((S)-4,5-difluoro-2-(methoxymethyl Yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H- [1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 79-2)
Figure PCTCN2020077781-appb-000059
Figure PCTCN2020077781-appb-000059
步骤1)4,5-二氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 1) Synthesis of 4,5-difluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
向反应瓶中加入2-(溴甲基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(500mg,1.278mmol)和DMF(10mL)，将反应液冷却至0℃，然后逐滴加入甲醇钠(0.25mL,1.25mmol,5mol/L)，反应液在0℃继续搅拌反应半小时。反应完成后，向反应液中缓慢加入水(30mL)和乙酸乙酯(25mL)，分液，水相用乙酸乙酯(25mL×3)萃取，合并有机相，有机相依次用水(30mL×4)和饱和食盐水(30mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，得到的粗产物使用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝10/1)，纯化后得到标题化合物为淡黄色固体(140mg,32％)。Add 2-(bromomethyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (500mg ,1.278mmol) and DMF (10mL), the reaction solution was cooled to 0°C, then sodium methoxide (0.25mL, 1.25mmol, 5mol/L) was added dropwise, and the reaction solution was stirred and reacted at 0°C for half an hour. After the reaction was completed, water (30mL) and ethyl acetate (25mL) were slowly added to the reaction solution, and the layers were separated. The aqueous phase was extracted with ethyl acetate (25mL×3). The organic phases were combined, and the organic phase was sequentially water (30mL×4). ) And saturated brine (30mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: PE/EA(v/v) = 10/1), after purification, the title compound was obtained as a pale yellow solid (140 mg, 32%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.81(dd,J＝16.0,7.8Hz,2H),7.63(t,J＝7.0Hz,2H),7.52(dd,J＝11.5,6.6Hz,2H),7.31(d,J＝8.7Hz,1H),4.71(s,2H),3.48(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.81 (dd, J = 16.0, 7.8 Hz, 2H), 7.63 (t, J = 7.0 Hz, 2H), 7.52 (dd, J = 11.5, 6.6 Hz, 2H), 7.31(d,J=8.7Hz,1H), 4.71(s,2H), 3.48(s,3H).
步骤2)4,5-二氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 2) Synthesis of 4,5-difluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol
向反应瓶中加入4,5-二氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(140mg,0.41mmol)，甲醇(2mL)和THF(10mL)，然后分批加入硼氢化钠(16mg,0.41mmol)，反应液在室温条件搅拌反应1小时。反应完成后，向反应液中加入饱和氯化铵溶液(5mL)淬灭反应，再加入水(50mL)和乙酸乙酯(30mL)，分液，水相用乙酸乙酯(15mL×3)萃取，合并有机相，有机相用饱和食盐水洗涤(40mL)，无水硫酸钠干燥。过滤，滤液减压旋干，得到标题化合物为白色固体(135mg,96％)。Add 4,5-difluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one to the reaction flask (140 mg, 0.41 mmol), methanol (2 mL) and THF (10 mL), then sodium borohydride (16 mg, 0.41 mmol) was added in batches, and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, saturated ammonium chloride solution (5mL) was added to the reaction solution to quench the reaction, and then water (50mL) and ethyl acetate (30mL) were added to separate the layers, and the aqueous phase was extracted with ethyl acetate (15mL×3) , Combine the organic phases, wash the organic phase with saturated brine (40 mL), and dry with anhydrous sodium sulfate. After filtration, the filtrate was spin-dried under reduced pressure to obtain the title compound as a white solid (135 mg, 96%).
步骤3)(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-Step 3) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7] Cyclohepta[1,2-b]thiophene-8- 基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine- Synthesis of 6,8-dione
取反应瓶，向其中加入4,5-二氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(190mg,7.33mmol)和(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(198mg,0.60mmol)，T 3P(4.0mL,50mass％)和醋酸异丙酯(3.0mL)，反应液升温至90℃搅拌反应24小时。反应完成后，将反应液冷却至室温，向反应液中加入乙酸乙酯(30mL)和饱和碳酸氢钠溶液(40mL)，待不再生成气泡后，分液，水相用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干，得到的粗产物使用硅胶柱层析纯化(洗脱剂为DCM/MeOH(v/v)＝15/1)，得到标题化合物为淡黄色固体(130mg,36％)。 Take the reaction flask and add 4,5-difluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8 -Alcohol (190mg, 7.33mmol) and (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyridine And [2,1-f][1,2,4]triazine-6,8-dione (198mg, 0.60mmol), T 3 P (4.0mL, 50mass%) and isopropyl acetate (3.0mL) The reaction solution was heated to 90°C and stirred for 24 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, ethyl acetate (30mL) and saturated sodium bicarbonate solution (40mL) were added to the reaction solution, when no more bubbles were generated, the liquid was separated, and the aqueous phase was separated with ethyl acetate (20mL). ×3) Extract, combine the organic phases, wash the organic phase with saturated brine (20 mL), dry with anhydrous sodium sulfate, filter, and spin the filtrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent is DCM /MeOH(v/v)=15/1), the title compound was obtained as a pale yellow solid (130mg, 36%).
MS(ESI,pos.ion)m/z:654.0[M+H] +。 MS (ESI, pos.ion) m/z: 654.0 [M+H] + .
步骤4)(R)-12-((R)-4,5-二氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四Step 4) (R)-12-((R)-4,5-difluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b)thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetra 氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物79-1)和(R)-12-((S)-4,5-二氟-2-(甲氧Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 79-1) And (R)-12-((S)-4,5-difluoro-2-(methoxy 基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]Methyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]三嗪-6,8-二酮(化合物79-2)的合成Synthesis of [1,2,4]triazine-6,8-dione (Compound 79-2)
取反应瓶，向其中加入(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(100mg,0.153mmol)，氯化锂(65mg,1.52mmol)和N,N-二甲基乙酰胺(3mL)，反应液升温至100℃搅拌反应4小时。反应完成后，反应液冷却至室温，向反应液中加入乙酸乙酯(30mL)和水(20mL)，然后加入1N盐酸调节反应液pH至6-7，分液，水相用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水洗涤(30mL)，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，所得粗产物用高效液相制备色谱分离，得到标题化合物79-1为橙色固体(30mg,35％)，和标题化合物79-2为橙色固体(40mg,46％)。Take the reaction flask and add (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-(methoxymethyl)-8H-dibenzo[3,4: 6,7]cyclohepta[1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4]triazine-6,8-dione (100mg, 0.153mmol), lithium chloride (65mg, 1.52mmol) and N,N-dimethylacetamide ( 3mL), the reaction solution was heated to 100°C and stirred for 4 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, ethyl acetate (30mL) and water (20mL) were added to the reaction solution, and then 1N hydrochloric acid was added to adjust the pH of the reaction solution to 6-7, and the liquid was separated. 20mL×3) extract, combine the organic phases, wash the organic phase with saturated brine (30mL), dry the organic phase with anhydrous sodium sulfate, filter, and spin off the filtrate under reduced pressure. The crude product obtained is separated by HPLC to obtain The title compound 79-1 is an orange solid (30 mg, 35%), and the title compound 79-2 is an orange solid (40 mg, 46%).
化合物79-1：Compound 79-1:
1H NMR(400MHz,CDCl 3)δ(ppm)7.68(d,J＝7.4Hz,1H),7.50(d,J＝5.3Hz,1H),7.47-7.40(m,1H),7.28-7.25(m,3H),6.96(d,J＝7.1Hz,1H),6.34(d,J＝7.6Hz,1H),5.67(d,J＝7.5Hz,1H),5.40(s,1H),4.75(s,2H),4.60(d,J＝12.8Hz,1H),4.21(d,J＝7.5Hz,1H),3.76-3.66(m,2H),3.52(s,3H),3.34(d,J＝8.4Hz,2H),3.21(t,J＝10.4Hz,1H),2.97-2.86(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.68 (d, J = 7.4 Hz, 1H), 7.50 (d, J = 5.3 Hz, 1H), 7.47-7.40 (m, 1H), 7.28-7.25 ( m, 3H), 6.96 (d, J = 7.1 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 5.67 (d, J = 7.5 Hz, 1H), 5.40 (s, 1H), 4.75 ( s, 2H), 4.60 (d, J = 12.8 Hz, 1H), 4.21 (d, J = 7.5 Hz, 1H), 3.76-3.66 (m, 2H), 3.52 (s, 3H), 3.34 (d, J ＝8.4Hz,2H),3.21(t,J＝10.4Hz,1H),2.97-2.86(m,1H).
化合物79-2:Compound 79-2:
1H NMR(400MHz,CDCl 3)δ(ppm)7.75(d,J＝7.2Hz,1H),7.56(m,2H),7.52-7.39(m,2H),7.04(d,J＝8.0Hz,1H),6.78(m,1H),6.34(d,J＝7.1Hz,1H),5.83(d,J＝7.1Hz,1H),5.40(s,1H),4.77(s,2H),4.58(d,J＝13.1Hz,1H),4.14(d,J＝8.0Hz,1H),3.73-3.67(m,2H),3.53(s,3H),3.40-3.29(m,2H),3.25-3.15(m,1H),2.89-2.84(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.75 (d, J = 7.2Hz, 1H), 7.56 (m, 2H), 7.52-7.39 (m, 2H), 7.04 (d, J = 8.0Hz, 1H), 6.78 (m, 1H), 6.34 (d, J = 7.1 Hz, 1H), 5.83 (d, J = 7.1 Hz, 1H), 5.40 (s, 1H), 4.77 (s, 2H), 4.58 ( d, J = 13.1Hz, 1H), 4.14 (d, J = 8.0 Hz, 1H), 3.73-3.67 (m, 2H), 3.53 (s, 3H), 3.40-3.29 (m, 2H), 3.25-3.15 (m,1H), 2.89-2.84(m,1H).
实施例8(R)-12-((R)-2-环丙基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物42-1)以及(R)-12-((S)-2-环丙基-4,5-二氟 -8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物42-2)Example 8 (R)-12-((R)-2-cyclopropyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4)triazine-6,8-dione (compound 42-1) and (R)-12-((S)-2-cyclopropyl-4,5-difluoro-8H-dibenzo [3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino [3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 42-2)
Figure PCTCN2020077781-appb-000060
Figure PCTCN2020077781-appb-000060
步骤1)2-(5-环丙基-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 1) Synthesis of methyl 2-(5-cyclopropyl-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate
将2-(5-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(100mg,0.24mmol)，环丙基硼酸(31mg,0.36mmol)，醋酸钯(5mg,0.02mmol)，三苯基膦(13mg,0.05mmol)和磷酸钾(160mg,0.73mmol)加入到圆底烧瓶中，然后加入甲苯(10mL)和水(1mL)，氮气保护下置于100℃中加热反应约6小时。停止反应，减压浓缩，所得粗产物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝10/1)，得到标题化合物为类白色固体(81mg,89.48％)。Methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (100mg, 0.24mmol), cyclopropylboronic acid (31mg, 0.36mmol), palladium acetate (5mg, 0.02mmol), triphenylphosphine (13mg, 0.05mmol) and potassium phosphate (160mg, 0.73mmol) were added to the round bottom flask, then toluene (10mL) and water (1mL) were added, and placed under nitrogen protection The reaction was heated at 100°C for about 6 hours. The reaction was stopped, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: PE/EA(v/v)=10/1) to obtain the title compound as an off-white solid (81 mg, 89.48%).
MS(ESI,pos.ion)m/z:371.0(M+H) +； MS(ESI,pos.ion)m/z:371.0(M+H) + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.74–7.68(m,1H),7.48–7.42(m,1H),7.36(d,J＝7.5Hz,2H),7.00(td,J＝9.7,1.4Hz,1H),6.90–6.82(m,2H),6.75(dd,J＝7.7,6.2Hz,1H),3.63(s,3H),2.20–2.09(m,1H),1.11–1.01(m,2H),0.87–0.78(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.74–7.68(m,1H), 7.48–7.42(m,1H), 7.36(d,J=7.5Hz,2H), 7.00(td,J=9.7 ,1.4Hz,1H),6.90–6.82(m,2H),6.75(dd,J=7.7,6.2Hz,1H),3.63(s,3H),2.20–2.09(m,1H),1.11–1.01( m, 2H), 0.87-0.78 (m, 2H).
步骤2)2-(5-环丙基-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸的合成Step 2) Synthesis of 2-(5-cyclopropyl-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid
将2-(5-环丙基-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(7.62g,20.60mmol)溶解于THF(20mL)和甲醇(20mL)中，再加入氢氧化钠(2.47g,61.80mmol)的水(2mL)溶液，氮气保护下置于50℃油浴锅中加热反应约5小时。停止反应，用2N稀盐酸调节反应液pH值至酸性，然后用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)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纯化(洗脱剂为PE/EA(v/v)＝1/1)，得到标题化合物为类白色固体(7.04g,96.0％)。Dissolve methyl 2-(5-cyclopropyl-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (7.62g, 20.60mmol) in THF (20mL) and methanol (20mL) Then add sodium hydroxide (2.47g, 61.80mmol) in water (2mL) and place it in a 50°C oil bath under the protection of nitrogen and heat for reaction for about 5 hours. Stop the reaction, adjust the pH of the reaction solution to acidity with 2N dilute hydrochloric acid, then extract with ethyl acetate (10 mL×3), combine the organic phases, wash the organic phases with saturated brine (8 mL), dry with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: PE/EA(v/v)=1/1) to obtain the title compound as an off-white solid (7.04 g, 96.0%).
MS(ESI,neg.ion)m/z:355.8(M-H) -。 MS (ESI, neg. ion) m/z: 355.8 (MH) - .
步骤3)2-环丙基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 3) Synthesis of 2-cyclopropyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将2-(5-环丙基-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸(4.23g,11.90mmol)溶解于DCM(20mL)中，再向其中加入DMF(124mg,1.69mmol)，接着缓慢加入草酰氯(1.20mL,14.00mmol)，置于室温下搅拌反应约30分钟。接着向其中加入三氯化铝(1.74g,13.00mmol)，继续在该温度下反应约30分钟。停止反应，向其中加入水(20mL)，然后用二氯甲烷(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，减压浓缩，所得粗产物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝5/1)，得到标题化合物为黄色固体(4.02g,100％)。Dissolve 2-(5-cyclopropyl-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid (4.23g, 11.90mmol) in DCM (20mL), and add DMF to it (124mg, 1.69mmol), then slowly added oxalyl chloride (1.20mL, 14.00mmol), and the reaction was stirred at room temperature for about 30 minutes. Then aluminum trichloride (1.74 g, 13.00 mmol) was added thereto, and the reaction was continued at this temperature for about 30 minutes. The reaction was stopped, water (20 mL) was added, and then extracted with dichloromethane (20 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 concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: PE/EA(v/v)=5/1) to obtain the title compound as a yellow solid (4.02 g, 100%).
步骤4)2-环丙基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 4) Synthesis of 2-cyclopropyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将2-环丙基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(4.02g,11.90mmol)溶解于THF(15mL)和甲醇(15mL)中，再向其中加入硼氢化钠(936mg,23.75mmol)，置于室温下搅拌反应约1小时。停止反应，向其中加入饱和氯化铵溶液(20mL)淬灭反应，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，无水硫酸钠干燥，过滤，减压浓缩，所得粗产物用硅胶柱层析纯化(洗 脱剂为PE/EA(v/v)＝5/1)，得到标题化合物为浅黄色固体(1.81g,44.8％)。Dissolve 2-cyclopropyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (4.02g, 11.90mmol) In THF (15 mL) and methanol (15 mL), sodium borohydride (936 mg, 23.75 mmol) was added thereto, and the reaction was stirred at room temperature for about 1 hour. The reaction was stopped, and saturated ammonium chloride solution (20 mL) was added to quench the reaction, and then extracted with ethyl acetate (25 mL×3). The organic phases were combined, washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate , Filtered and concentrated under reduced pressure, the crude product obtained was purified by silica gel column chromatography (eluent: PE/EA(v/v)=5/1) to obtain the title compound as a pale yellow solid (1.81 g, 44.8%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.76(d,J＝7.8Hz,1H),7.55(dd,J＝8.2,5.3Hz,1H),7.49(d,J＝7.7Hz,1H),7.44(t,J＝7.6Hz,1H),7.34–7.27(m,1H),7.25(d,J＝5.5Hz,1H),7.22–7.15(m,1H),5.27(s,1H),2.28–2.15(m,1H),1.17–1.07(m,2H),0.92–0.86(m,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.76(d,J=7.8Hz,1H), 7.55(dd,J=8.2,5.3Hz,1H), 7.49(d,J=7.7Hz,1H) ,7.44(t,J=7.6Hz,1H),7.34-7.27(m,1H),7.25(d,J=5.5Hz,1H),7.22-7.15(m,1H),5.27(s,1H), 2.28–2.15(m,1H), 1.17–1.07(m,2H), 0.92–0.86(m,2H).
步骤5)(12aR)-7-(苄基氧基)-12-(2-环丙基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四Step 5) (12aR)-7-(benzyloxy)-12-(2-cyclopropyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cycloheptan[1 ,2-b)thiophen-8-yl)-3,4,12,12a-tetra 氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将2-环丙基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1.66g,4.88mmol)和(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6-,8-二酮(1.68g,5.13mmol)加至1-丙基磷酸酐(50％in EA，8.76mL)和乙酸异丙酯(30mL)混合液中，氮气保护下置于90℃油浴锅中加热反应约4小时。将反应液滴加至冰水(30mL)中，然后用乙酸乙酯(30mL×3)萃取，合并有机相，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)，得到标题化合物为淡黄色固体(1.17g,37％)。Combine 2-cyclopropyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (1.66g, 4.88mmol) and (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][ 1,2,4]Triazine-6-,8-dione (1.68g, 5.13mmol) was added to the mixture of 1-propyl phosphoric anhydride (50% in EA, 8.76mL) and isopropyl acetate (30mL) Under the protection of nitrogen, it is placed in an oil bath at 90°C and heated for about 4 hours. The reaction solution was added dropwise to ice water (30 mL), and then extracted with ethyl acetate (30 mL×3). The organic phases were combined, and the organic phases were washed with saturated aqueous sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=25/1) to obtain the title compound as a pale yellow solid (1.17 g, 37%).
MS(ESI,pos.ion)m/z:650.1[M+H] +。 MS (ESI, pos.ion) m/z: 650.1 [M+H] + .
步骤6)(R)-12-((R)-2-环丙基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢Step 6) (R)-12-((R)-2-cyclopropyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物42-1)以及(R)-12-((S)-2-环丙基-4,5-二氟-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 42-1) and (R)-12-((S)-2-cyclopropyl-4,5-difluoro -8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]-8H-Dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1 ,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4] 三嗪-6,8-二酮(化合物42-2)的合成Synthesis of Triazine-6,8-Dione (Compound 42-2)
将(12aR)-7-(苄基氧基)-12-(2-环丙基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.17g,1.80mmol)溶于N,N-二甲基乙酰胺(20mL)中，向其中加入无水氯化锂(763mg,18.00mmol)，氮气保护下加热至100℃反应过夜。反应完全后，加入水(10mL)淬灭反应，用1N稀盐酸调节反应液的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(洗脱剂为乙腈/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42-1为淡黄色固体(230mg,23％)和标题化合物42-2为淡黄色固体(430mg,43％)。The (12aR)-7-(benzyloxy)-12-(2-cyclopropyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cycloheptan[1,2 -b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1, 2,4] Triazine-6,8-dione (1.17g, 1.80mmol) was dissolved in N,N-dimethylacetamide (20mL), and anhydrous lithium chloride (763mg, 18.00mmol) was added to it , Under the protection of nitrogen, heat to 100°C and react overnight. After the reaction is complete, add water (10mL) to quench the reaction, adjust the pH of the reaction solution to about 6 with 1N dilute hydrochloric acid, extract with ethyl acetate (10mL×3), combine the organic phases, and use saturated brine (20mL× 3) Wash, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained is separated and purified by LUNA preparation column (eluent is acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) The title compound 42-1 was obtained as a pale yellow solid (230 mg, 23%) and the title compound 42-2 was obtained as a pale yellow solid (430 mg, 43%), respectively.
MS(ESI,pos.ion)m/z:560.1[M+H] +； MS(ESI,pos.ion)m/z:560.1[M+H] + ;
化合物42-1：Compound 42-1:
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.59(d,J＝7.4Hz,1H),7.38(t,J＝7.2Hz,1H),7.22(dd,J＝22.4,6.1Hz,4H),6.92(d,J＝7.1Hz,1H),6.32(d,J＝7.1Hz,1H),5.66(d,J＝7.1Hz,1H),5.36(s,1H),4.58(d,J＝12.4Hz,1H),4.19(d,J＝7.5Hz,1H),3.73(d,J＝10.7Hz,1H),3.35(d,J＝8.0Hz,2H),3.23(t,J＝10.3Hz,1H),2.90(s,1H),2.19(d,J＝4.3Hz,1H),1.15(d,J＝7.1Hz,2H),0.88(s,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm) 7.59 (d, J = 7.4Hz, 1H), 7.38 (t, J = 7.2Hz, 1H), 7.22 (dd, J = 22.4, 6.1Hz, 4H), 6.92 (d, J = 7.1 Hz, 1H), 6.32 (d, J = 7.1 Hz, 1H), 5.66 (d, J = 7.1 Hz, 1H), 5.36 (s, 1H), 4.58 (d, J = 12.4 Hz, 1H), 4.19 (d, J = 7.5 Hz, 1H), 3.73 (d, J = 10.7 Hz, 1H), 3.35 (d, J = 8.0 Hz, 2H), 3.23 (t, J = 10.3Hz, 1H), 2.90 (s, 1H), 2.19 (d, J = 4.3 Hz, 1H), 1.15 (d, J = 7.1 Hz, 2H), 0.88 (s, 2H).
化合物42-2：Compound 42-2:
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.67(d,J＝7.4Hz,1H),7.50(t,J＝6.9Hz,1H),7.42(dd,J＝18.4,7.0Hz,2H),7.32(d,J＝5.5Hz,1H),7.00(d,J＝7.7Hz,1H),6.76(s,1H),6.35(d,J＝6.4Hz,1H),5.81(d,J＝6.0Hz,1H),5.37(s,1H),4.56(d,J＝13.0Hz,1H),4.12(d,J＝7.4Hz,1H),3.71(d,J＝10.7Hz,1H),3.34(t,J＝12.0Hz,2H),3.22(t,J＝10.3Hz,1H),2.85(t,J＝11.6Hz,1H),2.36–2.12(m,1H),1.16(d,J＝8.1Hz,2H),0.90(dd,J＝10.0,4.8Hz,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm) 7.67 (d, J = 7.4 Hz, 1H), 7.50 (t, J = 6.9 Hz, 1H), 7.42 (dd, J = 18.4, 7.0 Hz, 2H), 7.32 (d, J = 5.5 Hz, 1H), 7.00 (d, J = 7.7 Hz, 1H), 6.76 (s, 1H), 6.35 (d, J = 6.4 Hz, 1H), 5.81 (d, J = 6.0Hz, 1H), 5.37 (s, 1H), 4.56 (d, J = 13.0 Hz, 1H), 4.12 (d, J = 7.4 Hz, 1H), 3.71 (d, J = 10.7 Hz, 1H) , 3.34 (t, J = 12.0 Hz, 2H), 3.22 (t, J = 10.3 Hz, 1H), 2.85 (t, J = 11.6 Hz, 1H), 2.36-2.12 (m, 1H), 1.16 (d, J = 8.1 Hz, 2H), 0.90 (dd, J = 10.0, 4.8 Hz, 2H).
实施例9(R)-12-((R)-4,5-二氟-3-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物74-1)和(R)-12-((S)-4,5-二氟-3-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物74-2)Example 9 (R)-12-((R)-4,5-difluoro-3-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4)triazine-6,8-dione (compound 74-1) and (R)-12-((S)-4,5-difluoro-3-methoxy-8H-dibenzo [3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino [3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 74-2)
Figure PCTCN2020077781-appb-000061
Figure PCTCN2020077781-appb-000061
步骤1)3-溴-4-甲氧基噻吩的合成Step 1) Synthesis of 3-bromo-4-methoxythiophene
将3,4-二溴噻吩(2.57g,10.60mmol)，氧化铜(598mg,7.52mmol)和碘化钾(970mg,5.84mmol)加入至封管反应器中，然后加入甲醇钠(7mL,35mmol,5mol/L)，所得混合物置于110℃微波反应仪中反应25分钟。停止反应，加水(20mL)淬灭，然后用乙酸乙酯(15mL×3)萃取，合并有机相，有机相用饱和食盐水(16mL)洗涤，减压浓缩，所得粗产物用硅胶柱层析法纯化(洗脱剂为石油醚)，得到标题化合物为浅黄色油状液体(400mg,19.5％)。Add 3,4-dibromothiophene (2.57g, 10.60mmol), copper oxide (598mg, 7.52mmol) and potassium iodide (970mg, 5.84mmol) into the sealed tube reactor, and then add sodium methoxide (7mL, 35mmol, 5mol) /L), the resulting mixture was placed in a microwave reactor at 110°C for 25 minutes. The reaction was stopped, quenched with water (20 mL), and then extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated brine (16 mL), and concentrated under reduced pressure. The resulting crude product was subjected to silica gel column chromatography Purification (eluent is petroleum ether) to obtain the title compound as a pale yellow oily liquid (400 mg, 19.5%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.20(d,J＝3.5Hz,1H),6.25(d,J＝3.5Hz,1H),3.88(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.20 (d, J = 3.5 Hz, 1H), 6.25 (d, J = 3.5 Hz, 1H), 3.88 (s, 3H).
步骤2)3-(2,3-二氟苯基)-4-甲氧基噻吩的合成Step 2) Synthesis of 3-(2,3-difluorophenyl)-4-methoxythiophene
将3-溴-4-甲氧基噻吩(360mg,1.86mmol)，2,3-二氟苯硼酸(441mg,2.79mmol)，S-Phos(170mg,0.37mmol)，醋酸钯(42mg,0.18mmol)和磷酸钾(1.22g,5.59mmol)混合于甲苯(20mL)和水(3mL)中，氮气保护下置于110℃油浴锅中加热反应过夜。停止反应，减压浓缩，所得粗产物用硅胶柱层析纯化(洗脱剂为PE)，得到标题化合物为无色油状液体(351mg,83.22％)。Combine 3-bromo-4-methoxythiophene (360mg, 1.86mmol), 2,3-difluorophenylboronic acid (441mg, 2.79mmol), S-Phos (170mg, 0.37mmol), palladium acetate (42mg, 0.18mmol) ) And potassium phosphate (1.22g, 5.59mmol) were mixed in toluene (20mL) and water (3mL), and placed in a 110°C oil bath under the protection of nitrogen and heated to react overnight. The reaction was stopped and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (eluent is PE) to obtain the title compound as a colorless oily liquid (351 mg, 83.22%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.42(dd,J＝3.2,1.5Hz,1H),7.36(dd,J＝7.8,5.7Hz,1H),7.17–7.08(m,2H),6.38(d,J＝3.4Hz,1H),3.89(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.42 (dd, J = 3.2, 1.5 Hz, 1H), 7.36 (dd, J = 7.8, 5.7 Hz, 1H), 7.17-7.08 (m, 2H), 6.38 (d, J=3.4 Hz, 1H), 3.89 (s, 3H).
步骤3)2,5-二溴-4-(2,3-二氟苯基)-3-甲氧基噻吩的合成Step 3) Synthesis of 2,5-dibromo-4-(2,3-difluorophenyl)-3-methoxythiophene
将3-(2,3-二氟苯基)-2-甲氧基噻吩(210mg,0.92mmol)，NBS(311mg,1.75mmol)混合于冰醋酸(2mL)和THF(2mL)中，氮气保护下置于50℃油浴锅中加热反应过夜。停止反应，减压浓缩，然后加入饱和碳酸氢钠溶液(20mL)，用乙酸乙酯(15mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸干燥，过滤，减压浓缩，所得粗产物用硅胶柱层析纯化(洗脱剂为PE)，得到标题化合物为无色油状液体(353mg,99.02％)。Mix 3-(2,3-difluorophenyl)-2-methoxythiophene (210mg, 0.92mmol), NBS (311mg, 1.75mmol) in glacial acetic acid (2mL) and THF (2mL) under nitrogen protection Place it in an oil bath at 50°C and heat the reaction overnight. Stop the reaction, concentrate under reduced pressure, then add saturated sodium bicarbonate solution (20mL), extract with ethyl acetate (15mL×3), combine the organic phases, wash the organic phases with saturated brine (20mL), dry with anhydrous sulfuric acid, and filter After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent is PE) to obtain the title compound as a colorless oily liquid (353 mg, 99.02%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.25(dd,J＝12.6,4.8Hz,1H),7.22–7.13(m,1H),7.08(dd,J＝7.0,6.2Hz,1H),3.73(s,3H). 1 H NMR (400MHz, CDCl 3 )δ (ppm) 7.25 (dd, J = 12.6, 4.8 Hz, 1H), 7.22-7.13 (m, 1H), 7.08 (dd, J = 7.0, 6.2 Hz, 1H), 3.73(s,3H).
步骤4)2-溴-3-(2,3-二氟苯基)-4-甲氧基噻吩的合成Step 4) Synthesis of 2-bromo-3-(2,3-difluorophenyl)-4-methoxythiophene
将2,5-二溴-4-(2,3-二氟苯基)-3-甲氧基噻吩(5.08g,13.20mmol)溶解于THF(60mL)中，氮气保护下置于-78℃下搅拌，然后将正丁基锂(8.70mL,14.00mmol,1.6mol/L)缓慢滴加到其中，继续在该温度下搅拌反应约1小时。停止搅拌，在该温度下加入水(1mL)，搅拌约10分钟，然后升至室温，接着向其中加入饱和氯化铵溶液(5mL)，用乙酸乙酯(6mL×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，得到标题化合物为棕黄色油状液体(4.51g,112％)。Dissolve 2,5-dibromo-4-(2,3-difluorophenyl)-3-methoxythiophene (5.08g, 13.20mmol) in THF (60mL) and place at -78℃ under nitrogen Under stirring, n-butyllithium (8.70 mL, 14.00 mmol, 1.6 mol/L) was slowly added dropwise thereto, and the stirring was continued at this temperature for about 1 hour. Stop stirring, add water (1mL) at this temperature, stir for about 10 minutes, then warm to room temperature, then add saturated ammonium chloride solution (5mL) to it, extract with ethyl acetate (6mL×3), and combine the organic phases The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound as a brown oily liquid (4.51 g, 112%).
MS(ESI,pos.ion)m/z:305.9[M+1] +。 MS (ESI, pos.ion) m/z: 305.9 [M+1] + .
步骤5)2-(3-(2,3-二氟苯基)-4-甲氧基噻吩-2-基)苯甲酸甲酯的合成Step 5) Synthesis of methyl 2-(3-(2,3-difluorophenyl)-4-methoxythiophen-2-yl)benzoate
将2-溴-3-(2,3-二氟苯基)-4-甲氧基噻吩(3.65g,12.00mmol)、2-甲氧羰基苯硼酸(3.23g,17.90mmol)、二三苯基膦二氯化钯(848mg,1.19mmol)和碳酸钾(4.96g,35.90mmol)混合于四氢呋喃(10mL)以及 水(0.43mL)中，氮气保护下置于70℃油浴锅中加热反应过夜。停止反应，反应液减压浓缩，所得粗产物用硅胶柱层析纯化(洗脱剂为EA/PE(v/v)＝1/3)，得到标题化合物为类白色固体(3.25g,75.4％)。Combine 2-bromo-3-(2,3-difluorophenyl)-4-methoxythiophene (3.65g, 12.00mmol), 2-methoxycarbonylphenylboronic acid (3.23g, 17.90mmol), ditriphenyl Phosphine palladium dichloride (848mg, 1.19mmol) and potassium carbonate (4.96g, 35.90mmol) were mixed in tetrahydrofuran (10mL) and water (0.43mL), and heated in an oil bath at 70°C under nitrogen for reaction overnight. . The reaction was stopped, the reaction solution was concentrated under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (eluent: EA/PE(v/v)=1/3) to obtain the title compound as an off-white solid (3.25g, 75.4%) ).
MS(ESI,pos.ion)m/z:361.0[M+H] +。 MS (ESI, pos.ion) m/z: 361.0 [M+H] + .
步骤6)2-(3-(2,3-二氟苯基)-4-甲氧基噻吩-2-基)苯甲酸的合成Step 6) Synthesis of 2-(3-(2,3-difluorophenyl)-4-methoxythiophen-2-yl)benzoic acid
将2-(3-(2,3-二氟苯基)-4-甲氧基噻吩-2-基)苯甲酸甲酯(3.25g,9.02mmol)溶解于四氢呋喃(10mL)和甲醇(10mL)中，再将氢氧化钠(1.80g,45.00mmol)的水(5mL)溶液加入其中，置于55℃油浴锅中加热反应过夜。停止反应，用2N稀盐酸调节反应液的pH值至酸性，然后用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到标题化合物为类白色固体(2.88g,92.2％)。Dissolve methyl 2-(3-(2,3-difluorophenyl)-4-methoxythiophen-2-yl)benzoate (3.25g, 9.02mmol) in tetrahydrofuran (10mL) and methanol (10mL) Then add sodium hydroxide (1.80g, 45.00mmol) in water (5mL) to it, and place it in a 55°C oil bath to heat and react overnight. Stop the reaction, adjust the pH of the reaction solution to acidity with 2N dilute hydrochloric acid, then extract with ethyl acetate (10 mL×3), combine the organic phases, wash the organic phases with saturated brine (8 mL), dry with anhydrous sodium sulfate, and filter And concentrated under reduced pressure to obtain the title compound as an off-white solid (2.88 g, 92.2%).
MS(ESI,pos.ion)m/z:347.4[M+H] +。 MS (ESI, pos.ion) m/z: 347.4 [M+H] + .
步骤7)4,5-二氟-3-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 7) Synthesis of 4,5-difluoro-3-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将2-(3-(2,3-二氟苯基)-4-甲氧基噻吩-2-基)苯甲酸(2.31g,6.67mmol)溶解于二氯甲烷(50mL)中，再向其中加入草酰氯(0.65mL)，置于室温下搅拌约15分钟，接着向其中加入氯化铝(4.45g,33.40mmol)，在该温度下继续搅拌反应约30分钟。停止反应，向反应体系里面加入水(10mL)，用二氯甲烷(10mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL)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纯化(洗脱剂为EA/PE(v/v)＝1/5)，得到标题化合物为黄色固体(1.00g,45.7％)。Dissolve 2-(3-(2,3-difluorophenyl)-4-methoxythiophen-2-yl)benzoic acid (2.31g, 6.67mmol) in dichloromethane (50mL) and add Oxalyl chloride (0.65 mL) was added, and the mixture was stirred at room temperature for about 15 minutes, and then aluminum chloride (4.45 g, 33.40 mmol) was added thereto, and the reaction was continued to be stirred at this temperature for about 30 minutes. Stop the reaction, add water (10mL) to the reaction system, extract with dichloromethane (10mL×3), combine the organic phases, wash the organic phases with saturated brine (10mL), dry with anhydrous sodium sulfate, filter, and reduce the filtrate After concentration, the obtained crude product was purified by silica gel column chromatography (eluent: EA/PE(v/v)=1/5) to obtain the title compound as a yellow solid (1.00 g, 45.7%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.80–7.68(m,2H),7.66–7.57(m,1H),7.51(ddd,J＝14.1,9.3,4.5Hz,2H),7.35–7.23(m,1H),6.47(s,1H),3.93(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.80–7.68 (m, 2H), 7.66–7.57 (m, 1H), 7.51 (ddd, J = 14.1, 9.3, 4.5 Hz, 2H), 7.35–7.23 (m, 1H), 6.47 (s, 1H), 3.93 (s, 3H).
步骤8)4,5-二氟-3-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 8) Synthesis of 4,5-difluoro-3-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将4,5-二氟-3-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(1.00g,3.05mmol)溶解于四氢呋喃(15mL)以及甲醇(15mL,100mass％)中，再将硼氢化钠(240mg,6.09mmol)加入其中，置于室温下搅拌反应约30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，过滤，滤液减压浓缩，得到标题化合物为浅黄色固体为标题化合物(1.10g,109％)。Dissolve 4,5-difluoro-3-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (1.00g, 3.05mmol) In tetrahydrofuran (15 mL) and methanol (15 mL, 100 mass%), sodium borohydride (240 mg, 6.09 mmol) was added to it, and the reaction was stirred at room temperature for about 30 minutes. The reaction was stopped, saturated ammonium chloride solution (20mL) was added to it, extracted with ethyl acetate (25mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure to obtain the title compound as a pale yellow solid (1.10 g, 109%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.77(d,J＝7.8Hz,1H),7.56–7.48(m,2H),7.46(t,J＝7.6Hz,1H),7.32(d,J＝7.5Hz,1H),7.21(dd,J＝17.1,8.9Hz,1H),6.44(s,1H),5.32(s,1H),3.97(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.77 (d, J = 7.8 Hz, 1H), 7.56-7.48 (m, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.5Hz, 1H), 7.21 (dd, J = 17.1, 8.9Hz, 1H), 6.44 (s, 1H), 5.32 (s, 1H), 3.97 (s, 3H).
步骤9)(12aR)-7-(苄基氧基)-12-(4,5-二氟-3-甲氧基8H二苯并[3,4:6,7]环庚并[1,2-b]噻吩-8-基)-3,4,12,12aStep 9) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-3-methoxy 8H dibenzo[3,4:6,7]cycloheptano[1, 2-b)thiophen-8-yl)-3,4,12,12a 四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]]三嗪-6,8-二酮的合成Synthesis of Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]]triazine-6,8-dione
将(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(1.29g,3.94mmol)，4,5-二氟-3-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1.00g,3.03mmol)和T 3P(5.44mL,9.08mmol,1.67mol/L)混合于乙酸乙酯(3mL)中，所得混合物转移至封管中，然后超声至溶清状态，置于微波反应仪中，在110℃条件下，反应2小时。停止反应，向反应液中加入饱和碳酸氢钠溶液(20mL)，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，滤液减压浓缩，所得粗产物用硅胶柱层析纯化(洗脱剂为DCM/MeOH(v/v)＝15/1)，得到标题化合物为黄褐色固体(1.03g,53.2％)。 (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] The [1,2,4]triazine-6,8-dione (1.29g, 3.94mmol), 4,5-difluoro-3-methoxy-8H-dibenzo[3,4:6, 7] Cyclohepta[1,2-b]thiophene-8-ol (1.00g, 3.03mmol) and T 3 P (5.44mL, 9.08mmol, 1.67mol/L) were mixed in ethyl acetate (3mL) to obtain The mixture was transferred to a sealed tube, then sonicated to a clear state, placed in a microwave reactor, and reacted for 2 hours at 110°C. Stop the reaction, add saturated sodium bicarbonate solution (20mL) to the reaction solution, extract with ethyl acetate (30mL×3), combine the organic phases, wash the organic phases with saturated brine (30mL), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain the title compound as a tan solid (1.03 g, 53.2%).
MS(ESI,pos.ion)m/z:639.9[M+H] +； MS(ESI,pos.ion)m/z:639.9[M+H] + ;
步骤10)(R)-12-((R)-4,5-二氟-3-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢Step 10) (R)-12-((R)-4,5-difluoro-3-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物74-1)和(R)-12-((S)-4,5-二氟-3-甲氧基-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 74-1) and (R)-12-((S)-4,5-difluoro-3-methoxy -8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]-8H-Dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1 ,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4] 三嗪-6,8-二酮(化合物74-2)的合成Synthesis of Triazine-6,8-Dione (Compound 74-2)
将(12aR)-7-(苄基氧基)-12-(4,5-二氟-3-甲氧基-8H-二苯并[3,4:6,7]环庚并[1,2-b噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]]三嗪-6,8-二酮(1.03g,1.61mmol)溶于N,N-二甲基乙酰胺(30mL)中，加入无水氯化锂(683mg,16.10mmol)，氮气保护下升温至100℃反应过夜。反应结束后，加入水(10mL)，然后用1N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74-1为淡黄色固体(135mg,15％)和标题化合物74-2为淡黄色固体(430mg,43％)。(12aR)-7-(benzyloxy)-12-(4,5-difluoro-3-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-bthiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1, 2,4]] Triazine-6,8-dione (1.03g, 1.61mmol) was dissolved in N,N-dimethylacetamide (30mL), anhydrous lithium chloride (683mg, 16.10mmol) was added, Under the protection of nitrogen, the temperature was raised to 100°C and reacted overnight. After the reaction, add water (10mL), then adjust the pH to about 6 with 1N 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 resulting residue was separated and purified by a LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) to obtain the title compound 74 1 is a pale yellow solid (135 mg, 15%) and the title compound 74-2 is a pale yellow solid (430 mg, 43%).
MS(ESI,pos.ion)m/z:550.1[M+H] +； MS(ESI,pos.ion)m/z:550.1[M+H] + ;
化合物74-1：Compound 74-1:
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.66(d,J＝7.5Hz,1H),7.43(t,J＝7.5Hz,1H),7.29–7.18(m,3H),6.93(d,J＝7.3Hz,1H),6.48(s,1H),6.34(d,J＝7.6Hz,1H),5.75(d,J＝7.6Hz,1H),5.33(d,J＝12.2Hz,1H),4.59(d,J＝14.7Hz,1H),4.37(dd,J＝9.8,2.9Hz,1H),3.97(s,3H),3.75(d,J＝11.9Hz,1H),3.40–3.27(m,2H),3.23(t,J＝10.4Hz,1H),3.01–2.90(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.66 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.29-7.18 (m, 3H), 6.93 (d,J=7.3Hz,1H),6.48(s,1H),6.34(d,J=7.6Hz,1H), 5.75(d,J=7.6Hz,1H),5.33(d,J=12.2Hz ,1H),4.59(d,J=14.7Hz,1H), 4.37(dd,J=9.8,2.9Hz,1H), 3.97(s,3H), 3.75(d,J=11.9Hz,1H), 3.40 –3.27(m,2H), 3.23(t,J=10.4Hz,1H), 3.01–2.90(m,1H).
化合物74-2：Compound 74-2:
1H NMR(400MHz,DMSO-d 6)δ(ppm)7.74(d,J＝7.5Hz,1H),7.56(t,J＝7.2Hz,1H),7.48(t,J＝7.2Hz,1H),7.41(d,J＝7.4Hz,1H),7.04(dd,J＝16.5,8.5Hz,1H),6.81–6.68(m,1H),6.62–6.51(m,2H),6.13(d,J＝7.3Hz,1H),5.37(s,1H),4.57(d,J＝12.8Hz,1H),4.18(s,1H),4.04(s,3H),3.72(dd,J＝11.9,2.6Hz,1H),3.42–3.27(m,2H),3.21(t,J＝10.5Hz,1H),2.88(dd,J＝17.7,7.4Hz,1H). 1 H NMR(400MHz,DMSO-d 6 )δ(ppm)7.74(d,J=7.5Hz,1H), 7.56(t,J=7.2Hz,1H), 7.48(t,J=7.2Hz,1H) ,7.41(d,J=7.4Hz,1H),7.04(dd,J=16.5,8.5Hz,1H), 6.81–6.68(m,1H),6.62–6.51(m,2H),6.13(d,J =7.3Hz,1H),5.37(s,1H),4.57(d,J=12.8Hz,1H),4.18(s,1H),4.04(s,3H),3.72(dd,J=11.9,2.6Hz ,1H),3.42–3.27(m,2H),3.21(t,J=10.5Hz,1H), 2.88(dd,J=17.7,7.4Hz,1H).
实施例10(R)-12-((R)-2-乙氧基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物78-1)和(R)-12-((S)-2-乙氧基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物78-2)Example 10 (R)-12-((R)-2-ethoxy-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4)triazine-6,8-dione (compound 78-1) and (R)-12-((S)-2-ethoxy-4,5-difluoro-8H-dibenzo [3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino [3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 78-2)
Figure PCTCN2020077781-appb-000062
Figure PCTCN2020077781-appb-000062
步骤1)2-(5-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 1) Synthesis of methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate
将2-(3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(2.91g,8.81mmol)溶于DMF(10mL)中，将NBS(1.65g,9.27mmol)的DMF(10mL)溶液滴加至上述反应液中，所得混合物在室温下反应过夜。反应完全后加入饱和硫代硫酸钠水溶液(200mL)淬灭反应，然后用乙酸乙酯(100mL×3)萃取，合并有机相，有机相用饱和食盐水(200mL×3)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(洗脱剂为纯石油醚)，得到标题化合物为淡黄色液体(3.60g,100％)。Methyl 2-(3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (2.91g, 8.81mmol) was dissolved in DMF (10mL), and NBS (1.65g, 9.27mmol) A solution of DMF (10 mL) was added dropwise to the above reaction solution, and the resulting mixture was reacted overnight at room temperature. After the reaction was completed, saturated aqueous sodium thiosulfate solution (200 mL) was added to quench the reaction, and then extracted with ethyl acetate (100 mL×3). The organic phases were combined, and the organic phases were washed with saturated brine (200 mL×3), anhydrous sodium sulfate After drying, filtering, and concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography (eluent is pure petroleum ether) to obtain the title compound as a pale yellow liquid (3.60 g, 100%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.78(d,J＝7.6Hz,1H),7.49(dd,J＝7.5,6.5Hz,1H),7.44–7.39(m,1H),7.36(d,J＝7.6Hz,1H),7.17(d,J＝1.9Hz,1H),7.07–6.98(m,1H),6.92–6.82(m,1H),6.74(t,J＝7.0Hz,1H),3.67(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.78 (d, J = 7.6 Hz, 1H), 7.49 (dd, J = 7.5, 6.5 Hz, 1H), 7.44-7.39 (m, 1H), 7.36 ( d,J=7.6Hz,1H), 7.17(d,J=1.9Hz,1H), 7.07–6.98(m,1H), 6.92–6.82(m,1H), 6.74(t,J=7.0Hz,1H ), 3.67(s, 3H).
步骤2)2-(5-(乙氧基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸的合成Step 2) Synthesis of 2-(5-(ethoxy)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid
将2-(5-(乙氧基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(13.73g,33.54mmol)，乙醇钠的乙醇溶液(25.11g,73.80mmol,20mass％)，碘化亚铜(638mg,3.35mmol)和铜(429mg,6.71mmol)加入乙醇(20mL)中，转移至封管，然后氮气保护下置于150℃油浴锅中加热反应过夜。然后将反应液加入到四氢呋喃中，再加氢氧化钠(2.68g,67.08mmol)的水(10mL)溶液，置于50℃下继续搅拌反应约7小时。停止搅拌，并用2N盐酸调节反应液至pH值至5-6，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为DCM/MeOH(v/v)＝15/1)，得到标题化合物为浅黄色膏状固体(11.05g,91％)。Methyl 2-(5-(ethoxy)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (13.73g, 33.54mmol), an ethanol solution of sodium ethoxide (25.11g , 73.80mmol, 20mass%), cuprous iodide (638mg, 3.35mmol) and copper (429mg, 6.71mmol) were added to ethanol (20mL), transferred to the sealed tube, and then placed in a 150℃ oil bath under nitrogen protection The reaction was heated overnight. Then the reaction solution was added to tetrahydrofuran, and sodium hydroxide (2.68 g, 67.08 mmol) in water (10 mL) was added, and the mixture was placed at 50° C. to continue stirring and reacting for about 7 hours. Stop stirring, adjust the reaction solution to pH 5-6 with 2N hydrochloric acid, extract with ethyl acetate (20mL×3), combine the organic phases, wash the organic phases with saturated brine (20mL), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain the title compound as a pale yellow cream solid (11.05g, 91%) .
MS(ESI,neg.ion)m/z:359.2[M-H] -。 MS (ESI, neg.ion) m/z: 359.2 [MH] - .
步骤3)2-(乙氧基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 3) Synthesis of 2-(ethoxy)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将化合物2-(5-(乙氧基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸(110mg,0.31mmol)溶解于氯苯(2mL)中，置于超声仪中超声溶清，再向其中加入PPA(1.52g,13.73mmol,84mass％)，氮气保护下置于110℃油浴锅中加热反应约3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，滤液减压浓缩,所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝5/1)，得到标题化合物为黄色固体(22mg,21％)。The compound 2-(5-(ethoxy)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid (110mg, 0.31mmol) was dissolved in chlorobenzene (2mL) and placed Ultrasonic dissolve in an ultrasonic instrument, then add PPA (1.52g, 13.73mmol, 84mass%) to it, and place it in an oil bath at 110°C under the protection of nitrogen to heat and react for about 3 hours. The reaction was stopped, the reaction solution was added to ice water (15mL), extracted with ethyl acetate (20mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (15mL), dried with anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=5/1) to obtain the title compound as a yellow solid (22 mg, 21%).
MS(ESI,pos.ion)m/z:343.1[M+H] +。 MS (ESI, pos.ion) m/z: 343.1 [M+H] + .
步骤4)2-(乙氧基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 4) Synthesis of 2-(ethoxy)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将化合物2-乙氧基-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(1.71g,4.99mmol)溶解于甲醇(15mL)以及四氢呋喃(15mL)中，然后再将硼氢化钠(418mg,10.61mmol)加入其中，置于室温下搅拌反应30分钟。停止反应，将反应液加入到饱和氯化铵溶液(10mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝3/1)，得到标题化合物为浅黄色固体(1.72g,100％)。Dissolve the compound 2-ethoxy-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (1.71g, 4.99mmol) In methanol (15 mL) and tetrahydrofuran (15 mL), then sodium borohydride (418 mg, 10.61 mmol) was added to it, and the reaction was stirred at room temperature for 30 minutes. The reaction was stopped, the reaction solution was added to saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=3/1) to obtain the title compound as a pale yellow solid (1.72 g, 100%).
步骤5)(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-乙氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四Step 5) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-ethoxy-8H-dibenzo[3,4:6,7]cycloheptan[1 ,2-b)thiophen-8-yl)-3,4,12,12a-tetra 氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将2-(乙氧基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1.00g,3.03mmol)，(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.29g,3.93mmol)和T 3P(5.44mL,9.08mmol,50％w/w乙酸乙酯溶液)加入到乙酸乙酯(3mL)中，置于110℃微波中反应约2小时，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)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为DCM/MeOH(v/v)＝15/1)，得到标题化合物为白色固体(1.03g,53％)。 Add 2-(ethoxy)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (1.00g, 3.03mmol ), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f ][1,2,4]triazine-6,8-dione (1.29g, 3.93mmol) and T 3 P (5.44mL, 9.08mmol, 50% w/w ethyl acetate solution) were added to ethyl acetate (3mL), place in a microwave at 110°C for about 2 hours to stop the reaction. The reaction solution was added to water (15 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain the title compound as a white solid (1.03 g, 53%).
MS(ESI,pos.ion)m/z:639.9[M+H] +。 MS (ESI, pos.ion) m/z: 639.9 [M+H] + .
步骤6：(R)-12-((R)-2-乙氧基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-Step 6: (R)-12-((R)-2-ethoxy-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H- [1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物78-1)以及(R)-12-((S)-2-乙氧基-4,5-二氟-8H-二[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 78-1) and (R) -12-((S)-2-ethoxy-4,5-difluoro-8H-bis 苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪Benzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxa Azino[3,4-c]pyrido[2,1-f][1,2,4]triazine -6,8-二酮(化合物78-2)的合成Synthesis of -6,8-dione (Compound 78-2)
将7-(苄基氧基)-12-((8R)-4,5-二氟-2-乙氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(1.59g,2.43mmol)和氯化锂(1.05g,24.30mmol)加入到N,N-二甲基乙酰胺(30mL)中，氮气保护下升温至110℃搅拌反应过夜。反应完全后，将反应液加入到水(10mL)中淬灭反应，然后用0.5N HCl调节反应液的pH值呈弱酸性，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，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78-1为淡黄色固体(210mg,15％)和标题化合物78-2为淡黄色固体(260mg,19％)。The 7-(benzyloxy)-12-((8R)-4,5-difluoro-2-ethoxy-8H-dibenzo[3,4:6,7]cycloheptan[1,2 -b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4] Triazine-6,8-dione (1.59g, 2.43mmol) and lithium chloride (1.05g, 24.30mmol) were added to N,N-dimethylacetamide (30mL), protected by nitrogen The temperature was raised to 110°C and the reaction was stirred overnight. After the reaction is complete, add the reaction solution to water (10mL) to quench the reaction, then use 0.5N HCl to adjust the pH of the reaction solution to be weakly acidic, stir for 10 minutes, then extract with ethyl acetate (20mL×3) and combine The organic phase, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to a LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/ v)=12/13) separation and purification, the title compound 78-1 was obtained as a pale yellow solid (210 mg, 15%) and the title compound 78-2 was obtained as a pale yellow solid (260 mg, 19%).
MS(ESI,pos.ion)m/z:564.2[M+H] + MS(ESI,pos.ion)m/z:564.2[M+H] +
化合物78-1：Compound 78-1:
1H NMR(400MHz,CDCl 3)δ(ppm)10.39(s,1H),7.55(d,J＝7.6Hz,1H),7.40(t,J＝7.4Hz,1H),7.26(d,J＝6.1Hz,2H),7.18(t,J＝7.3Hz,1H),6.93(d,J＝7.4Hz,1H),6.72(d,J＝5.4Hz,1H),6.55(d,J＝7.3Hz,1H),6.11(d,J＝7.1Hz,1H),5.42(s,1H),4.60(d,J＝13.0Hz,1H),4.27(ddd,J＝15.7,13.1,5.1Hz,3H),3.76(d,J＝10.2Hz,1H),3.43(dd,J＝22.9,10.4Hz,2H),3.30(t,J＝10.5Hz,1H),2.97(t,J＝11.2Hz,1H),1.53(t,J＝6.9Hz,3H). 1 H NMR (400MHz, CDCl 3 )δ (ppm) 10.39 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 6.1Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 5.4 Hz, 1H), 6.55 (d, J = 7.3 Hz ,1H),6.11(d,J=7.1Hz,1H), 5.42(s,1H), 4.60(d,J=13.0Hz,1H), 4.27(ddd,J=15.7,13.1,5.1Hz,3H) ,3.76(d,J=10.2Hz,1H), 3.43(dd,J=22.9,10.4Hz,2H), 3.30(t,J=10.5Hz,1H), 2.97(t,J=11.2Hz,1H) ,1.53(t,J=6.9Hz,3H).
化合物78-2：Compound 78-2:
1H NMR(400MHz,CDCl 3)δ(ppm)7.64(d,J＝7.6Hz,1H),7.53(d,J＝6.8Hz,1H),7.47–7.39(m,2H),7.08–7.02(m,1H),6.77(d,J＝5.3Hz,2H),6.54(d,J＝7.4Hz,1H),6.10(d,J＝7.4Hz,1H),5.39(s,1H),4.58(d,J＝12.8Hz,1H),4.29(dd,J＝13.9,6.9Hz,2H),4.23–4.15(m,1H),3.74(d,J＝9.5Hz,1H),3.51–3.34(m,2H),3.26(t,J＝10.5Hz,1H),2.89(t,J＝11.0Hz,1H),1.55(t,J＝6.9Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.64 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 6.8 Hz, 1H), 7.47–7.39 (m, 2H), 7.08–7.02 ( m, 1H), 6.77 (d, J = 5.3 Hz, 2H), 6.54 (d, J = 7.4 Hz, 1H), 6.10 (d, J = 7.4 Hz, 1H), 5.39 (s, 1H), 4.58 ( d,J=12.8Hz,1H), 4.29(dd,J=13.9,6.9Hz,2H), 4.23–4.15(m,1H), 3.74(d,J=9.5Hz,1H), 3.51–3.34(m , 2H), 3.26 (t, J = 10.5 Hz, 1H), 2.89 (t, J = 11.0 Hz, 1H), 1.55 (t, J = 6.9 Hz, 3H).
实施例11(R)-12-((S)-4,5-二氟-2-(吗啉代甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物87-1)和(R)-12-((R)-4,5-二氟-2-(吗啉代甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物87-2)Example 11 (R)-12-((S)-4,5-difluoro-2-(morpholinomethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1- f][1,2,4]triazine-6,8-dione (compound 87-1) and (R)-12-((R)-4,5-difluoro-2-(morpholinomethyl Yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H- [1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 87-2)
Figure PCTCN2020077781-appb-000063
Figure PCTCN2020077781-appb-000063
步骤1)2-(溴甲基)-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 1) Synthesis of 2-(bromomethyl)-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将2-甲基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(1.90g,6.08mmol)，NBS(1.12g,6.29mmol)和BPO(147mg,0.61mmol)混合于四氯化碳(30mL)中，氮气保护下置于80℃油浴锅中加热反应约2小时。停止反应，过滤，滤液中加入饱和硫代硫酸钠溶液(15mL)，用二氯甲烷(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为黄色固体(2.31g,97.1％)。Add 2-methyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (1.90g, 6.08mmol), NBS (1.12g, 6.29mmol) and BPO (147mg, 0.61mmol) were mixed in carbon tetrachloride (30mL), and placed in an oil bath at 80°C under the protection of nitrogen and heated to react for about 2 hours. Stop the reaction, filter, add saturated sodium thiosulfate solution (15mL) to the filtrate, extract with dichloromethane (20mL×3), combine the organic phases, wash the organic phase with saturated brine (20mL), and dry with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow solid (2.31 g, 97.1%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.83(dd,J＝7.7,1.1Hz,1H),7.77(d,J＝8.0Hz,1H),7.67–7.59(m,3H),7.57–7.52(m,1H),7.36–7.29(m,1H),4.79(s,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.83 (dd, J = 7.7, 1.1 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.67–7.59 (m, 3H), 7.57– 7.52(m,1H),7.36-7.29(m,1H),4.79(s,2H).
步骤2)2-吗啉代甲基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 2) Synthesis of 2-morpholinomethyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将2-(溴甲基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(500mg,1.28mmol)，吗啉(222mg,2.55mmol)和碳酸钾(388mg,2.80mmol)混合于DMF(10mL)中，室温下搅拌反应约两小时。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，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为EA/PE(v/v)＝5/1)，得到标题化合物为黄色固体(505mg,99.42％)。Add 2-(bromomethyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (500mg, 1.28mmol) , Morpholine (222mg, 2.55mmol) and potassium carbonate (388mg, 2.80mmol) were mixed in DMF (10mL), and the reaction was stirred at room temperature for about two hours. Stop the reaction, add the reaction solution to water (15mL), extract with ethyl acetate (20mL×3), combine the organic phases, wash the organic phases with saturated brine (15mL×3), dry with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: EA/PE(v/v)=5/1) to obtain the title compound as a yellow solid (505 mg, 99.42%).
MS(ESI,pos.ion)m/z:398.1[M+H] +。 MS (ESI, pos.ion) m/z: 398.1 [M+H] + .
步骤3)2-吗啉代甲基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 3) Synthesis of 2-morpholinomethyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将2-吗啉代甲基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(500mg,1.26mmol)溶解于甲醇 (10mL)以及THF(10mL)中，置于室温下搅拌，然后将硼氢化钠(99mg,2.52mmol)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，过滤，滤液减压浓缩，得到标题化合物为浅黄色固体(502mg,100％)。Combine 2-morpholinomethyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (500mg, 1.26mmol) Dissolved in methanol (10 mL) and THF (10 mL), stirred at room temperature, then sodium borohydride (99 mg, 2.52 mmol) was added to it, and stirred at room temperature for about 20 minutes. The reaction was stopped, saturated ammonium chloride solution (20mL) was added to it, extracted with ethyl acetate (25mL×3), the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentration under reduced pressure gave the title compound as a pale yellow solid (502 mg, 100%).
MS(ESI,pos.ion)m/z:400.1[M+H] +。 MS (ESI, pos.ion) m/z: 400.1 [M+H] + .
步骤4)(12aR)-7-(苄氧基)-12-(4,5-二氟-2-(吗啉代甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-Step 4) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-(morpholinomethyl)-8H-dibenzo[3,4:6,7] ring Hept[1,2-b]thiophen-8-yl)-3,4,12,12a- 四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将2-吗啉代甲基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(500mg,1.25mmol)，(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(450mg,1.38mmol)混合于乙酸异丙酯(10mL)中，再向其中加入T 3P(1.65mL,2.75mmol,50％w/w乙酸乙酯溶液)，置于90℃油浴锅中加热反应约2小时。停止反应，向反应液中加入饱和碳酸氢钠溶液(20mL)，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，所得残留物用硅胶柱层析纯化(洗脱剂为DCM/MeOH(v/v)＝15/1)，得到标题化合物为黄褐色固体(180mg,21％)。 Add 2-morpholinomethyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (500mg, 1.25mmol) , (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4] Triazine-6,8-dione (450mg, 1.38mmol) was mixed in isopropyl acetate (10mL), and then T 3 P (1.65mL, 2.75mmol, 50% w /w ethyl acetate solution), placed in a 90°C oil bath and heated to react for about 2 hours. Stop the reaction, add saturated sodium bicarbonate solution (20mL) to the reaction solution, extract with ethyl acetate (30mL×3), combine the organic phases, wash the organic phases with saturated brine (30mL), dry with anhydrous sodium sulfate, and filter After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain the title compound as a yellow-brown solid (180 mg, 21%).
MS(ESI,pos.ion)m/z:709.3[M+H] +。 MS (ESI, pos.ion) m/z: 709.3 [M+H] + .
步骤5)(R)-12-((S)-4,5-二氟-2-(吗啉代甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四Step 5) (R)-12-((S)-4,5-difluoro-2-(morpholinomethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b)thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetra 氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物87-1)以及(R)-12-((R)-4,5-二氟-2-(吗啉Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 87-1) And (R)-12-((R)-4,5-difluoro-2-(morpholine 代甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并(Substituted methyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4]三嗪-6,8-二酮(化合物87-2)的合成Synthesis of [2,1-f][1,2,4]triazine-6,8-dione (Compound 87-2)
将(12aR)-7-(苄氧基)-12-(4,5-二氟-2-吗啉代甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(180mg,0.25mmol)和氯化锂(107mg,2.54mmol)混合于N,N-二甲基乙酰胺(10mL)中，氮气保护下升温至100℃条件下进行反应约2.5小时。将反应液加入到水(10mL)中淬灭反应，然后用0.5N HCl调节pH值呈弱酸性，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，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，得到标题化合物为淡黄色固体87-1(16mg,10％)和标题化合物87-2为淡黄色固体(28mg,18％)。The (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-morpholinomethyl-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4] Triazine-6,8-dione (180mg, 0.25mmol) and lithium chloride (107mg, 2.54mmol) were mixed in N,N-dimethylacetamide (10mL) and heated under nitrogen protection The reaction is carried out at 100°C for about 2.5 hours. The reaction solution was added to water (10mL) to quench the reaction, then adjusted with 0.5N HCl to make the pH weakly acidic, stirred for 10 minutes, then extracted with ethyl acetate (20mL×3), combined the organic phases, and saturated the organic phases Wash with brine (30 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is passed through a LUNA preparation column (eluent is acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) After separation and purification, the title compound 87-1 (16 mg, 10%) and the title compound 87-2 were obtained as a pale yellow solid (28 mg, 18%).
MS(ESI,pos.ion)m/z:619.2[H+1] +。 MS (ESI, pos.ion) m/z: 619.2 [H+1] + .
化合物87-1：Compound 87-1:
1H NMR(400MHz,CDCl 3)δ(ppm)7.65(d,J＝7.0Hz,1H),7.42(d,J＝5.4Hz,2H),7.25–7.18(m,2H),6.96(s,1H),6.27(d,J＝5.9Hz,1H),5.54(d,J＝6.2Hz,1H),5.43(s,1H),4.59(d,J＝12.7Hz,1H),4.13(d,J＝7.1Hz,1H),3.99(dd,J＝5.8,2.3Hz,1H),3.86–3.75(m,6H),3.36–3.14(m,3H),2.98(s,1H),2.85(d,J＝11.3Hz,1H),2.62(d,J＝15.3Hz,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.65 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 5.4 Hz, 2H), 7.25-7.18 (m, 2H), 6.96 (s, 1H), 6.27 (d, J = 5.9 Hz, 1H), 5.54 (d, J = 6.2 Hz, 1H), 5.43 (s, 1H), 4.59 (d, J = 12.7 Hz, 1H), 4.13 (d, J=7.1Hz,1H),3.99(dd,J=5.8,2.3Hz,1H), 3.86–3.75(m,6H), 3.36–3.14(m,3H), 2.98(s,1H), 2.85(d ,J=11.3Hz,1H), 2.62(d,J=15.3Hz,4H).
化合物87-2：Compound 87-2:
1H NMR(400MHz,CDCl 3)δ(ppm)7.71(d,J＝7.6Hz,1H),7.46(ddd,J＝16.1,11.7,5.4Hz,4H),7.00–6.88(m,1H),6.76(s,1H),6.23(d,J＝7.3Hz,1H),5.61(d,J＝7.3Hz,1H),5.46(s,1H),4.54(d,J＝12.9Hz,1H),4.08–3.95(m,1H),3.83(d,J＝15.9Hz,2H),3.78(dd,J＝10.3,6.0Hz,4H),3.63(d,J＝11.6Hz,1H),3.24(d,J＝7.1Hz,2H),3.20–3.12(m,1H),2.75(t,J＝11.4Hz,1H),2.68–2.50(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.71 (d, J = 7.6 Hz, 1H), 7.46 (ddd, J = 16.1, 11.7, 5.4 Hz, 4H), 7.00-6.88 (m, 1H), 6.76(s,1H), 6.23(d,J=7.3Hz,1H), 5.61(d,J=7.3Hz,1H), 5.46(s,1H), 4.54(d,J=12.9Hz,1H), 4.08–3.95 (m, 1H), 3.83 (d, J = 15.9 Hz, 2H), 3.78 (dd, J = 10.3, 6.0 Hz, 4H), 3.63 (d, J = 11.6 Hz, 1H), 3.24 (d ,J=7.1Hz,2H), 3.20–3.12(m,1H), 2.75(t,J=11.4Hz,1H), 2.68–2.50(m,4H).
实施例12(R)-12-((S)-4,5-二氟-2-(2-甲氧基乙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物88-1)和(R)-12-((R)-4,5-二氟-2-(2-甲氧基乙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物88-1)Example 12 (R)-12-((S)-4,5-difluoro-2-(2-methoxyethyl)-8H-dibenzo[3,4:6,7]cyclohepta[ 1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2, 1-f][1,2,4]triazine-6,8-dione (Compound 88-1) and (R)-12-((R)-4,5-difluoro-2-(2- Methoxyethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetra Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 88-1)
Figure PCTCN2020077781-appb-000064
Figure PCTCN2020077781-appb-000064
步骤1)2-(5-溴-4-(2,3-二氟苯基)噻吩-2-基)乙-1-醇的合成Step 1) Synthesis of 2-(5-bromo-4-(2,3-difluorophenyl)thiophen-2-yl)ethan-1-ol
将2-溴-3-(2,3-二氟苯基)噻吩(2.10g,7.63mmol)溶解于THF(30mL)中，氮气保护下冷却至-78℃下搅拌反应，然后将LDA(4.20mL,8.40mmol,2mol/L)缓慢滴加到其中，在此温度下继续搅拌30分钟。将环氧乙烷(3.05mL,9.15mmol,3mol/L)加入其中，继续搅拌反应30分钟，转移到室温下继续搅拌反应过夜。停止反应，向反应液中加入饱和氯化铵溶液(20mL)，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，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝10/1)，得到标题化合物为棕黄色油状液体(1.60g,65.7％)。Dissolve 2-bromo-3-(2,3-difluorophenyl)thiophene (2.10g, 7.63mmol) in THF (30mL), cool to -78°C under nitrogen protection and stir the reaction, then add LDA (4.20 mL, 8.40mmol, 2mol/L) was slowly added dropwise, and stirring was continued for 30 minutes at this temperature. Add ethylene oxide (3.05mL, 9.15mmol, 3mol/L) to it, continue to stir and react for 30 minutes, transfer to room temperature and continue to stir and react overnight. Stop the reaction, add saturated ammonium chloride solution (20mL) to the reaction solution, extract with ethyl acetate (20mL×3), combine the organic phases, wash the organic phases with saturated brine (30mL), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=10/1) to obtain the title compound as a brownish-yellow oily liquid (1.60g, 65.7%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.21–7.09(m,2H),7.05(dd,J＝7.4,6.1Hz,1H),6.97(s,1H),3.81(t,J＝5.9Hz,2H),2.96(t,J＝6.3Hz,2H),1.75(s,1H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.21–7.09(m,2H), 7.05(dd,J=7.4,6.1Hz,1H), 6.97(s,1H), 3.81(t,J=5.9 Hz, 2H), 2.96 (t, J = 6.3 Hz, 2H), 1.75 (s, 1H).
步骤2)2-溴-3-(2,3-二氟苯基)-5-(2-甲氧基乙基)噻吩的合成Step 2) Synthesis of 2-bromo-3-(2,3-difluorophenyl)-5-(2-methoxyethyl)thiophene
将化合物2-(5-溴-4-(2,3-二氟苯基)噻吩-2-基)乙-1-醇(4.00g,12.50mmol)溶解于THF(20mL)中，置于0℃下搅拌反应，然后将氢化钠(576mg,14.40mmol,60mass％)缓慢加入其中，在该温度下继续搅拌约30分钟。然后加入碘甲烷(1.58mL,25.10mmol)，转移到室温下继续搅拌反应过夜。停止反应，向反应液中加入饱和氯化铵溶液(20mL)，用乙酸乙酯(15mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝10/1)，得到标题化合物为浅黄色油状液体(3.96g,94.8％)。The compound 2-(5-bromo-4-(2,3-difluorophenyl)thiophen-2-yl)ethan-1-ol (4.00g, 12.50mmol) was dissolved in THF (20mL) and placed in 0 The reaction was stirred at °C, and then sodium hydride (576 mg, 14.40 mmol, 60 mass%) was slowly added to it, and stirring was continued at this temperature for about 30 minutes. Then add methyl iodide (1.58mL, 25.10mmol), transfer to room temperature and continue to stir and react overnight. Stop the reaction, add saturated ammonium chloride solution (20mL) to the reaction solution, extract with ethyl acetate (15mL×3), combine the organic phases, wash the organic phases with saturated brine (20mL), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=10/1) to obtain the title compound as a pale yellow oily liquid (3.96 g, 94.8%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.22–7.08(m,2H),7.07–7.01(m,1H),6.95(s,1H),3.55(t,J＝6.3Hz,2H),3.37(s,3H),2.95(t,J＝6.3Hz,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.22–7.08(m,2H), 7.07–7.01(m,1H), 6.95(s,1H), 3.55(t,J=6.3Hz,2H), 3.37 (s, 3H), 2.95 (t, J = 6.3 Hz, 2H).
步骤3)2-(3-(2,3-二氟苯基)-5-(2-甲氧基乙基)噻吩-2-基)苯甲酸甲酯的合成Step 3) Synthesis of methyl 2-(3-(2,3-difluorophenyl)-5-(2-methoxyethyl)thiophen-2-yl)benzoate
将2-溴-3-(2,3-二氟苯基)-5-(2-甲氧基乙基)噻吩(3.96g,11.90mmol)、2-甲氧羰基苯硼酸(3.21g,17.8mmol)、PdCl 2(PPh 3) 2(848mg,1.20mmol)和碳酸钾(4.93g,35.70mmol)混合于THF(40mL)和水(0.43mL)中，氮气保护下置于70℃油浴锅中加热反应约3小时。停止反应，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝10/1)，得到标题化合物为白色固体(3.62g,78.4％)。 Combine 2-bromo-3-(2,3-difluorophenyl)-5-(2-methoxyethyl)thiophene (3.96g, 11.90mmol), 2-methoxycarbonylphenylboronic acid (3.21g, 17.8 mmol), PdCl 2 (PPh 3 ) 2 (848mg, 1.20mmol) and potassium carbonate (4.93g, 35.70mmol) were mixed in THF (40mL) and water (0.43mL), placed in a 70℃ oil bath under nitrogen protection Heat the reaction for about 3 hours. The reaction was stopped, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=10/1) to obtain the title compound as a white solid (3.62g, 78.4%) ).
1H NMR(400MHz,CDCl 3)δ(ppm)7.75–7.69(m,1H),7.53(ddd,J＝11.3,7.4,1.2Hz,2H),7.46–7.37(m,1H),7.18–7.08(m,3H),6.95(d,J＝0.9Hz,1H),3.80(s,3H),3.62(d,J＝7.3Hz,2H),3.38(s,3H),3.06(t,J＝6.6Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.75-7.69 (m, 1H), 7.53 (ddd, J = 11.3, 7.4, 1.2 Hz, 2H), 7.46-7.37 (m, 1H), 7.18-7.08 (m,3H),6.95(d,J=0.9Hz,1H),3.80(s,3H),3.62(d,J=7.3Hz,2H),3.38(s,3H),3.06(t,J= 6.6Hz, 2H).
步骤4)2-(3-(2,3-二氟苯基)-5-(2-甲氧基乙基)噻吩-2-基)苯甲酸的合成Step 4) Synthesis of 2-(3-(2,3-difluorophenyl)-5-(2-methoxyethyl)thiophen-2-yl)benzoic acid
将2-(3-(2,3-二氟苯基)-5-(2-甲氧基乙基)噻吩-2-基)苯甲酸甲酯(3.52g,9.06mmol)溶解于甲醇(15mL)以及THF(15mL)中，再加入氢氧化钠(1.45g,36.30mmol)的水(3mL)溶液，置于50℃油浴锅中加热反应约1小时。用2N稀盐酸调节反应液pH值至酸性，然后用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为浅黄色油状液体(3.13g,92.2％)。Methyl 2-(3-(2,3-difluorophenyl)-5-(2-methoxyethyl)thiophen-2-yl)benzoate (3.52g, 9.06mmol) was dissolved in methanol (15mL ) And THF (15mL), then add sodium hydroxide (1.45g, 36.30mmol) in water (3mL) solution, place it in a 50°C oil bath and heat to react for about 1 hour. Adjust the pH of the reaction solution to acidity with 2N dilute hydrochloric acid, then extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic phases with saturated brine (8mL), dry with anhydrous sodium sulfate, filter, and reduce the filtrate Concentrate to obtain the title compound as a pale yellow oily liquid (3.13 g, 92.2%).
MS(ESI,neg.ion)m/z:373.0[M-H] -。 MS (ESI, neg.ion) m/z: 373.0 [MH] - .
步骤5)2-(2-甲氧基乙基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 5) 2-(2-Methoxyethyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one Synthesis
将2-(3-(2,3-二氟苯基)-5-(2-甲氧基乙基)噻吩-2-基)苯甲酸(3.42g,9.13mmol)溶解于二氯甲烷(10mL)中，再加入DMF(1mg)，置于室温下搅拌，然后将草酰氯(1.20mL,14.00mmol)缓慢滴加到其中，在室温下继续搅拌反应1小时。向反应液中加入氯化铝(3.65mg,0.03mmol)，在室温下继续搅拌反应约5分钟。停止反应，加入水(15mL)淬灭反应，然后用二氯甲烷(12mL×3)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝10/1)，得到标题化合物为黄色固体(3.26g,100％)。Dissolve 2-(3-(2,3-difluorophenyl)-5-(2-methoxyethyl)thiophen-2-yl)benzoic acid (3.42g, 9.13mmol) in dichloromethane (10mL ), then add DMF (1mg), stir at room temperature, then slowly add oxalyl chloride (1.20mL, 14.00mmol) dropwise to it, and continue to stir and react for 1 hour at room temperature. Aluminum chloride (3.65 mg, 0.03 mmol) was added to the reaction solution, and the reaction was continued to be stirred at room temperature for about 5 minutes. The reaction was stopped, water (15mL) was added to quench the reaction, and then extracted with dichloromethane (12mL×3), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=10/1) to obtain the title compound as a yellow solid (3.26 g, 100%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.41(d,J＝7.2Hz,1H),7.34(dd,J＝11.0,4.0Hz,1H),7.27–7.09(m,5H),3.60(t,J＝6.1Hz,2H),3.40(s,3H),3.02–2.93(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.41 (d, J = 7.2 Hz, 1H), 7.34 (dd, J = 11.0, 4.0 Hz, 1H), 7.27-7.09 (m, 5H), 3.60 ( t,J=6.1Hz,2H), 3.40(s,3H), 3.02–2.93(m,2H).
步骤6)2-(2-甲氧基乙基)-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 6) 2-(2-Methoxyethyl)-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol synthesis
将2-(2-甲氧基乙基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(3.20g,9.00mmol)溶解于甲醇(30mL)以及THF(30mL)中，置于室温下搅拌，然后向其中加入硼氢化钠(710mg,18.02mmol)，室温下搅拌反应约15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，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝5/1)，得到标题化合物为浅黄色固体(3.12g,97％)。The 2-(2-methoxyethyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-one (3.20 g, 9.00mmol) was dissolved in methanol (30mL) and THF (30mL), stirred at room temperature, then sodium borohydride (710mg, 18.02mmol) was added to it, and the reaction was stirred at room temperature for about 15 minutes to stop the reaction. Saturated ammonium chloride solution (20mL) was added thereto, extracted with ethyl acetate (25mL×3), the organic phases were combined, the organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure The obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=5/1) to obtain the title compound as a pale yellow solid (3.12 g, 97%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.50(d,J＝7.4Hz,1H),7.33(t,J＝5.9Hz,2H),7.26–7.14(m,4H),5.41(s,1H),3.59(t,J＝6.5Hz,2H),3.37(s,3H),3.00(t,J＝6.5Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.50 (d, J = 7.4 Hz, 1H), 7.33 (t, J = 5.9 Hz, 2H), 7.26-7.14 (m, 4H), 5.41 (s, 1H), 3.59 (t, J = 6.5 Hz, 2H), 3.37 (s, 3H), 3.00 (t, J = 6.5 Hz, 2H).
步骤7)(R)-12-((S)-4,5-二氟-2-(2-甲氧基乙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四Step 7) (R)-12-((S)-4,5-difluoro-2-(2-methoxyethyl)-8H-dibenzo[3,4:6,7]cyclohepta[ 1,2-b)thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetra 氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物88-1)和(R)-12-((R)-4,5-二氟-2-(2-甲氧Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 88-1) And (R)-12-((R)-4,5-difluoro-2-(2-methoxy 基乙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并Ethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4]三嗪-6,8-二酮(化合物88-2)[2,1-f][1,2,4]triazine-6,8-dione (Compound 88-2)
将化合物2-(2-甲氧基乙基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1.15g,3.21mmol)，(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.05g,3.21mmol)加入到乙酸异丙酯(10mL)中，再向其中加入T 3P(15.40mL,25.70mmol,50％w/w乙酸乙酯溶液)，置于微波中130℃下反应40分钟。停止反应，向反应液中加入饱和碳酸氢钠溶液(20mL)，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，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88-1为淡黄色固体(53mg,3％)和标题化合物88-2为淡黄色固体(37mg,2％)。 The compound 2-(2-methoxyethyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol ( 1.15g, 3.21mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[ 2,1-f][1,2,4]triazine-6,8-dione (1.05g, 3.21mmol) was added to isopropyl acetate (10mL), and then T 3 P (15.40mL , 25.70mmol, 50% w/w ethyl acetate solution), placed in a microwave at 130°C and reacted for 40 minutes. Stop the reaction, add saturated sodium bicarbonate solution (20mL) to the reaction solution, extract with ethyl acetate (30mL×3), combine the organic phases, wash the organic phases with saturated brine (30mL), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the residue obtained was separated and purified by a LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) to obtain the title compound 88-1 as a pale yellow solid ( 53 mg, 3%) and the title compound 88-2 as a pale yellow solid (37 mg, 2%).
MS(ESI,pos.ion)m/z:578.0[H+1] +。 MS (ESI, pos.ion) m/z: 578.0[H+1] + .
化合物88-1：Compound 88-1:
1H NMR(400MHz,CDCl 3)δ(ppm)7.39(d,J＝7.4Hz,2H),7.22(d,J＝6.9Hz,1H),7.13–6.90(m,5H),6.82(s,1H),5.38(s,1H),4.56(d,J＝5.7Hz,1H),4.28(s,1H),4.18–3.99(m,3H),3.59(t,J＝6.5Hz,2H),3.51(d,J＝11.6Hz,1H),3.37(s,3H),3.07(t,J＝11.2Hz,1H),2.97(t,J＝6.4Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.39 (d, J = 7.4 Hz, 2H), 7.22 (d, J = 6.9 Hz, 1H), 7.13-6.90 (m, 5H), 6.82 (s, 1H), 5.38(s,1H), 4.56(d,J=5.7Hz,1H), 4.28(s,1H), 4.18–3.99(m,3H), 3.59(t,J=6.5Hz,2H), 3.51 (d, J = 11.6Hz, 1H), 3.37 (s, 3H), 3.07 (t, J = 11.2Hz, 1H), 2.97 (t, J = 6.4Hz, 2H).
化合物88-2：Compound 88-2:
1H NMR(400MHz,CDCl 3)δ(ppm)7.55(s,1H),7.43(d,J＝7.4Hz,1H),7.28(s,1H),7.04(s,5H),6.84(s,1H),5.54(s,1H),4.59(s,1H),4.34–4.13(m,2H),4.06(d,J＝8.3Hz,2H),3.60(t,J＝6.5Hz,2H),3.54(s,1H),3.37(s,3H),3.30(d,J＝10.0Hz,1H),2.99(t,J＝6.3Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.55 (s, 1H), 7.43 (d, J = 7.4 Hz, 1H), 7.28 (s, 1H), 7.04 (s, 5H), 6.84 (s, 1H),5.54(s,1H),4.59(s,1H),4.34-4.13(m,2H),4.06(d,J=8.3Hz,2H), 3.60(t,J=6.5Hz,2H), 3.54(s,1H), 3.37(s,3H), 3.30(d,J=10.0Hz,1H), 2.99(t,J=6.3Hz,2H).
实施例13(R)-12-((R)-2-(叔丁基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物29)Example 13 (R)-12-((R)-2-(tert-butyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b]Thien-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]Triazine-6,8-dione (Compound 29)
Figure PCTCN2020077781-appb-000065
Figure PCTCN2020077781-appb-000065
步骤1)3-(2,3-二氟苯基)噻吩的合成Step 1) Synthesis of 3-(2,3-difluorophenyl)thiophene
将2,3-二氟溴苯(5.01g,26.00mmol)、3-噻吩硼酸(3.98g,31.10mmol)、双三苯基膦二氯化钯(1.85g,2.61mmol)和碳酸钠(8.33g,77.80mmol)加至反应瓶中，加入THF(100mL)和水(10mL)，氮气保护下75℃反应过夜。反应结束后，将反应液过滤，滤饼用乙酸乙酯(50mL)洗涤，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)，得到标题化合物为淡黄色液体(4.06g,80％)。Combine 2,3-difluorobromobenzene (5.01g, 26.00mmol), 3-thiopheneboronic acid (3.98g, 31.10mmol), bistriphenylphosphine palladium dichloride (1.85g, 2.61mmol) and sodium carbonate (8.33 g, 77.80mmol) was added to the reaction flask, THF (100mL) and water (10mL) were added, and reacted at 75°C overnight under nitrogen protection. After the reaction, the reaction solution was filtered, the filter cake was washed with ethyl acetate (50 mL), the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent was petroleum ether) to obtain the title compound as a pale yellow liquid (4.06g, 80%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.95–7.91(m,1H),7.71(dd,J＝5.0,3.0Hz,1H),7.55–7.51(m,2H),7.42–7.33(m,1H),7.30–7.23(m,1H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.95–7.91(m,1H), 7.71(dd,J=5.0,3.0Hz,1H), 7.55–7.51(m,2H), 7.42–7.33(m ,1H),7.30-7.23(m,1H).
步骤2)2-溴-3-(2,3-二氟苯基)噻吩的合成Step 2) Synthesis of 2-bromo-3-(2,3-difluorophenyl)thiophene
将3-(2,3-二氟苯基)噻吩(4.06g，20.70mmol)溶于DMF(80mL)，将NBS(5.53g,30.40mmol)的DMF(20mL)溶液滴加至上述反应液中，所得混合物室温反应3小时。向反应液加入饱和硫代硫酸钠水溶液(200mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，有机相用饱和食盐水(200mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经硅胶柱层析(洗脱剂为纯石油醚)纯化，得到标题化合物为淡黄色液体(5.45g,96％)。3-(2,3-Difluorophenyl)thiophene (4.06g, 20.70mmol) was dissolved in DMF (80mL), and a solution of NBS (5.53g, 30.40mmol) in DMF (20mL) was added dropwise to the above reaction solution The resulting mixture was reacted at room temperature for 3 hours. Saturated sodium thiosulfate aqueous solution (200 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×3), the organic phases were combined, and the organic phase was washed with saturated brine (200 mL×3), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent is pure petroleum ether) to obtain the title compound as a pale yellow liquid (5.45 g, 96%).
步骤3)2-溴-3-(2,3-二氟苯基)-5-叔丁基噻吩的合成Step 3) Synthesis of 2-bromo-3-(2,3-difluorophenyl)-5-tert-butylthiophene
将氯化铝(969mg,7.27mmol)的二氯甲烷(30mL)溶液置于单口瓶中，然后将2-溴-3-(2,3-二氟苯基)噻吩(1.00g,3.63mmol)和溴代叔丁烷(547mg,3.99mmol)混合于滴液漏斗中，氮气保护下，于-78℃下搅拌，缓慢滴加滴到单口瓶中，滴加完毕继续反应约1小时。停止反应，向其中加入饱和食盐水(30mL)和二氯甲烷(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，滤液减压浓缩，所得粗产物用硅胶柱层析(洗脱剂为石油醚)纯化，得到标题化合物为无色油状液体(813mg,67.5％)。Place a solution of aluminum chloride (969mg, 7.27mmol) in dichloromethane (30mL) in a single-necked flask, and then add 2-bromo-3-(2,3-difluorophenyl)thiophene (1.00g, 3.63mmol) Mix with bromo-tert-butane (547mg, 3.99mmol) in a dropping funnel, under the protection of nitrogen, stir at -78°C, slowly drip into a single-neck flask, and continue to react for about 1 hour after the addition is complete. The reaction was stopped, saturated brine (30 mL) and dichloromethane (30 mL×3) were added to extract, the organic phases were combined, the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure The obtained crude product was purified by silica gel column chromatography (eluent is petroleum ether) to obtain the title compound as a colorless oily liquid (813 mg, 67.5%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.26-7.13(m,3H),6.77(d,J＝1.4Hz,1H),1.42(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.26-7.13 (m, 3H), 6.77 (d, J = 1.4Hz, 1H), 1.42 (s, 9H).
步骤4)2-(5-(叔丁基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 4) Synthesis of methyl 2-(5-(tert-butyl)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate
将2-溴-3-(2,3-二氟苯基)-5-叔丁基噻吩(756mg,2.28mmol)、苯甲酸甲酯-2-硼酸(821mg,4.57mmol)、双三苯基膦二氯化钯(161mg，0.23mmol)和碳酸钾(946mg，6.85mmol)加至反应瓶中，加入二氧六环(20mL)和水(1mL)，氮气保护，100℃反应过夜，停止加热，反应液冷却至室温，过滤，滤饼用乙酸乙酯(50mL)洗涤，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)＝10/1)，得到标题化合物为白色固体(513mg，58％)。Combine 2-bromo-3-(2,3-difluorophenyl)-5-tert-butylthiophene (756mg, 2.28mmol), methyl benzoate-2-boronic acid (821mg, 4.57mmol), bistriphenyl Phosphine palladium dichloride (161mg, 0.23mmol) and potassium carbonate (946mg, 6.85mmol) were added to the reaction flask, and dioxane (20mL) and water (1mL) were added. Under nitrogen protection, react overnight at 100°C, stop heating The reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (50 mL), the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1), the title compound was obtained as a white solid (513 mg, 58%).
MS(ESI,pos.ion)m/z:387.45MS(ESI,pos.ion)m/z:387.45
步骤5)2-(5-(叔丁基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸的合成Step 5) Synthesis of 2-(5-(tert-butyl)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid
将2-(5-(叔丁基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(7.50g,19.40mmol)溶于THF(15mL)和甲醇(15mL)中，将氢氧化钠(3.11g,77.60mmol)溶于水(6mL)中，加至上述反应液中，所得混合物于 50℃条件下反应过夜。反应结束后，向反应液中加入饱和食盐水(50mL)，用2N稀盐酸条件pH至6左右，分液，水相用乙酸乙酯(50mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)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(6.50g,90％)。Methyl 2-(5-(tert-butyl)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (7.50g, 19.40mmol) was dissolved in THF (15mL) and methanol ( 15mL), sodium hydroxide (3.11g, 77.60mmol) was dissolved in water (6mL), added to the above reaction solution, the resulting mixture was reacted at 50°C overnight. After the reaction, add saturated brine (50mL) to the reaction solution, use 2N dilute hydrochloric acid to condition the pH to about 6, separate the liquids, extract the aqueous phase with ethyl acetate (50mL×2), combine the organic phases, and use saturated It was washed with brine (100 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 (6.50 g, 90%).
MS(ESI,pos.ion)m/z:373.10[M+H] +。 MS (ESI, pos.ion) m/z: 373.10 [M+H] + .
步骤6)2-(叔丁基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 6) Synthesis of 2-(tert-butyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将2-(5-(叔丁基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸(5.81g,15.60mmol)溶解于二氯甲烷(200mL)中，然后向其中加入DMF(114mg,1.56mmol)，氮气保护下，缓慢加入草酰氯(6.60mL,78.00mmol)，所得混合物置于45℃油浴锅中加热反应约1小时。反应液减压浓缩除去溶剂和过量的草酰氯，然后加入二氯甲烷(100mL)，置于室温下搅拌，接着向其中加入氯化铝(4.16g,31.20mmol)，置于室温下搅拌反应约30分钟。停止反应，向反应液中加入饱和氯化铵溶液(25mL)，用二氯甲烷(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，过滤，滤液减压浓缩，得到标题化合物为黄色固体(5.53g,100％)。Dissolve 2-(5-(tert-butyl)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid (5.81g, 15.60mmol) in dichloromethane (200mL), then DMF (114 mg, 1.56 mmol) was added thereto, and oxalyl chloride (6.60 mL, 78.00 mmol) was slowly added under nitrogen protection, and the resulting mixture was heated in an oil bath at 45° C. for reaction for about 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent and excess oxalyl chloride, then dichloromethane (100 mL) was added, and the mixture was stirred at room temperature. Then aluminum chloride (4.16 g, 31.20 mmol) was added to it, and the reaction was stirred at room temperature for approximately 30 minutes. Stop the reaction, add saturated ammonium chloride solution (25 mL) to the reaction solution, extract with dichloromethane (25 mL×3), combine the organic phases, wash the organic phases with saturated brine (30 mL), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure to obtain the title compound as a yellow solid (5.53 g, 100%).
步骤7)2-(叔丁基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 7) Synthesis of 2-(tert-butyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol
将2-(叔丁基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(5.53g,15.60mmol)溶解于甲醇(30mL)和四氢呋喃(30mL)中，然后再加入硼氢化钠(1.23g,31.21mmol)，置于室温下搅拌反应约20分钟。停止反应，将反应液加入到饱和氯化铵溶液(10mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析(洗脱剂为PE/EA(v/v)＝3/1)法分离提纯，得到浅黄色固体为标题化合物(5.08g,91％)。Add 2-(tert-butyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (5.53g, 15.60mmol ) Was dissolved in methanol (30 mL) and tetrahydrofuran (30 mL), then sodium borohydride (1.23 g, 31.21 mmol) was added, and the reaction was stirred at room temperature for about 20 minutes. The reaction was stopped, the reaction solution was added to saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL) and dried with anhydrous sodium sulfate. The filtrate was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (eluent: PE/EA(v/v)=3/1) to obtain a pale yellow solid as the title compound (5.08g, 91%) ).
1H NMR(400MHz,CDCl 3)δ(ppm)7.77(d,J＝7.7Hz,1H),7.53(d,J＝7.5Hz,2H),7.48–7.39(m,1H),7.31(s,1H),7.20(dd,J＝17.1,8.5Hz,1H),5.30(s,1H),1.52(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.77 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.5 Hz, 2H), 7.48-7.39 (m, 1H), 7.31 (s, 1H), 7.20 (dd, J = 17.1, 8.5 Hz, 1H), 5.30 (s, 1H), 1.52 (s, 9H).
步骤8)(12aR)-7-(苄氧基)-12-(2-(叔丁基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢Step 8) (12aR)-7-(benzyloxy)-12-(2-(tert-butyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[ 1,2-b)thiophen-8-yl)-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将2-(叔丁基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(100mg,0.28mmol)，(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(101mg,0.31mmol)混合于T 3P(0.50mL,0.84mmol,50mass％)中的乙酸异丙酯(20mL)溶液，置于90℃油浴锅中反应约8小时，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)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PE/EA(v/v)＝1/2)纯化，得到白色固体为标题化合物(93mg,50％)。 Add 2-(tert-butyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (100mg, 0.28mmol) , (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4] Triazine-6,8-dione (101mg, 0.31mmol) mixed with T 3 P (0.50mL, 0.84mmol, 50mass%) in isopropyl acetate (20mL) solution, placed The reaction was stopped in an oil bath at 90°C for about 8 hours. The reaction solution was added to water (15 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) = 1/2) to obtain the title compound (93 mg, 50%) as a white solid.
MS(ESI,pos.ion)m/z:666.0[M+H] +。 MS (ESI, pos.ion) m/z: 666.0 [M+H] + .
步骤9)(R)-12-((R)-2-(叔丁基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢Step 9) (R)-12-((R)-2-(tert-butyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b)thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物29)的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 29)
将(12aR)-7-(苄氧基)-12-(2-(叔丁基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(2.60g,3.91mmol)、氯化锂(1.59g,39.10mmol)混合于N,N-二甲基乙酰胺(30mL)中，氮气保护下，将所得混合物置于110℃条件下进行搅拌反应过夜。将反应液加入到水(10mL)中淬灭反应，加入0.5N HCl调节pH值呈弱酸性，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，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，得到标题化合物为淡黄色固体(566mg,25％)。(12aR)-7-(benzyloxy)-12-(2-(tert-butyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4]Triazine-6,8-dione (2.60g, 3.91mmol), lithium chloride (1.59g, 39.10mmol) mixed in N,N-dimethylacetamide (30mL), protected by nitrogen Next, the resulting mixture was placed at 110°C for a stirring reaction overnight. The reaction solution was added to water (10mL) to quench the reaction, 0.5N HCl was added to adjust the pH value to be weakly acidic, stirred for 10 minutes, then extracted with ethyl acetate (20mL×3), combined the organic phases, and the organic phase was saturated with salt Wash with water (30mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained is separated by LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) After purification, the title compound was obtained as a pale yellow solid (566 mg, 25%).
MS(ESI,pos.ion)m/z:576.0[M+H] +； MS(ESI,pos.ion)m/z:576.0[M+H] + ;
1H NMR(600MHz,CDCl 3-d 6)δ(ppm)7.66(d,J＝7.6Hz,1H),7.41(t,J＝7.4Hz,1H),7.33(d,J＝5.6Hz, 1H),7.25–7.18(m,2H),6.94(d,J＝7.5Hz,1H),6.37(d,J＝7.5Hz,1H),5.83(d,J＝7.5Hz,1H),5.37(s,1H),4.59(d,J＝12.8Hz,1H),4.22(dd,J＝9.5,3.1Hz,1H),3.82–3.68(m,1H),3.36(t,J＝11.0Hz,1H),3.30–3.18(m,2H),2.91(t,J＝11.0Hz,1H),1.52(s,9H). 1 H NMR(600MHz, CDCl 3 -d 6 )δ(ppm) 7.66(d,J=7.6Hz,1H), 7.41(t,J=7.4Hz,1H), 7.33(d,J=5.6Hz, 1H ), 7.25–7.18 (m, 2H), 6.94 (d, J = 7.5 Hz, 1H), 6.37 (d, J = 7.5 Hz, 1H), 5.83 (d, J = 7.5 Hz, 1H), 5.37 (s ,1H),4.59(d,J=12.8Hz,1H),4.22(dd,J=9.5,3.1Hz,1H),3.82–3.68(m,1H), 3.36(t,J=11.0Hz,1H) , 3.30-3.18 (m, 2H), 2.91 (t, J = 11.0 Hz, 1H), 1.52 (s, 9H).
实施例14(R)-12-((R)-4,5-二氟-2-吗啉代-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物32)Example 14 (R)-12-((R)-4,5-difluoro-2-morpholino-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4)triazine-6,8-dione (compound 32)
Figure PCTCN2020077781-appb-000066
Figure PCTCN2020077781-appb-000066
步骤1)2-(5-吗啉基-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸的合成Step 1) Synthesis of 2-(5-morpholino-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid
将2-(5-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(8.99g,22.00mmol)、吗啉(9.57mL,110.00mmol)、碘化亚铜(418mg,2.20mmol)、铜(698mg,11.00mmol)和水(30mL)加入至封管中，氮气下置于150℃油浴锅中加热反应约7小时。停止搅拌，并用2N盐酸调节反应液pH值至5-6，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析(洗脱剂为DCM/MeOH(v/v)＝15/1)纯化，得到标题化合物为浅黄色固体(3.51g,40％)。MS(ESI,pos.ion)m/z:402.1[M+H] +。 Methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (8.99g, 22.00mmol), morpholine (9.57mL, 110.00mmol), iodide Cuprous (418mg, 2.20mmol), copper (698mg, 11.00mmol) and water (30mL) were added to the sealed tube, and placed in a 150°C oil bath under nitrogen and heated to react for about 7 hours. Stop stirring, adjust the pH of the reaction solution to 5-6 with 2N hydrochloric acid, extract with ethyl acetate (20mL×3), combine the organic phases, wash the organic phases with saturated brine (20mL), dry with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain the title compound as a pale yellow solid (3.51 g, 40%). MS (ESI, pos.ion) m/z: 402.1 [M+H] + .
步骤2)2-吗啉基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 2) Synthesis of 2-morpholinyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将2-(5-吗啉基-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸(3.00g,7.47mmol)溶解于氯苯(10mL)中，置于超声仪中超声溶清，再向其中加入PPA(39.00g,336.3mmol,84mass％)，氮气保护，置于110℃油浴锅中加热反应过夜。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，滤液减压浓缩，得到黄色固体为标题化合物(2.87g,100％)。Dissolve 2-(5-morpholinyl-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid (3.00g, 7.47mmol) in chlorobenzene (10mL) and place in an ultrasound system Dissolve it in medium ultrasound, then add PPA (39.00g, 336.3mmol, 84mass%) to it, protected by nitrogen, and place it in an oil bath at 110°C for heating overnight. The reaction was stopped, the reaction solution was added to ice water (15mL), extracted with ethyl acetate (20mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (15mL), dried with anhydrous sodium sulfate, filtered, and the filtrate Concentration under reduced pressure gave the title compound (2.87 g, 100%) as a yellow solid.
步骤3)2-吗啉基-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 3) Synthesis of 2-morpholinyl-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将2-吗啉基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(2.87g,7.47mmol)溶解于甲醇(15mL)和四氢呋喃(15mL)中，然后再加入硼氢化钠(588mg,14.95mmol)，置于室温下搅拌反应约15分钟。停止反应,将反应液加入到饱和氯化铵溶液(10mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝3/1)，得到浅黄色固体为标题化合物(2.10g,73％)。Dissolve 2-morpholinyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (2.87g, 7.47mmol) In methanol (15mL) and tetrahydrofuran (15mL), then sodium borohydride (588mg, 14.95mmol) was added, and the reaction was stirred at room temperature for about 15 minutes. Stop the reaction, add the reaction solution to saturated ammonium chloride solution (10 mL), extract with ethyl acetate (20 mL×3), combine the organic phases, wash the organic phases with saturated brine (20 mL), and dry with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=3/1) to obtain the title compound (2.10 g, 73%) as a pale yellow solid.
1H NMR(400MHz,CDCl 3)δ(ppm)7.75(d,J＝7.7Hz,1H),7.56(dd,J＝8.3,4.9Hz,1H),7.42(dd,J＝15.1,7.7Hz,2H),7.29(t,J＝7.4Hz,1H),7.20(dd,J＝17.2,8.9Hz,1H),6.60(d,J＝5.2Hz,1H),5.28(s,1H),3.95–3.89(m,4H),3.27(dd,J＝5.8,3.3Hz,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.75 (d, J = 7.7 Hz, 1H), 7.56 (dd, J = 8.3, 4.9 Hz, 1H), 7.42 (dd, J = 15.1, 7.7 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.20 (dd, J = 17.2, 8.9 Hz, 1H), 6.60 (d, J = 5.2 Hz, 1H), 5.28 (s, 1H), 3.95- 3.89(m,4H), 3.27(dd,J=5.8,3.3Hz,4H).
步骤4)(12aR)-7-(苄氧基)-12-(4,5-二氟-2-吗啉代-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢Step 4) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-morpholino-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b)thiophen-8-yl)-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将4,5-二氟-2-吗啉-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1.48g,3.84mmol)、(R)-7-(苄氧 基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.45g,4.42mmol)、T 3P(4.60mL,7.68mmol，50％w/w乙酸乙酯溶液)和乙酸乙酯(20mL)加入至封管中，置于110℃微波中反应约40分钟。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)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为DCM/MeOH(v/v)＝1/15)纯化，得到白色固体为标题化合物(644mg,24％)。 Combine 4,5-difluoro-2-morpholine-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol (1.48g, 3.84mmol), (R )-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1, 2,4] Triazine-6,8-dione (1.45 g, 4.42 mmol), T 3 P (4.60 mL, 7.68 mmol, 50% w/w ethyl acetate solution) and ethyl acetate (20 mL) were added to Seal the tube and place it in a microwave at 110°C for about 40 minutes. Stop the reaction, add the reaction solution to 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 the filtrate It was concentrated under pressure, and the obtained residue was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=1/15) to obtain the title compound (644 mg, 24%) as a white solid.
MS(ESI,pos.ion)m/z:695.0[M+H] +。 MS (ESI, pos.ion) m/z: 695.0 [M+H] + .
步骤5)(R)-12-((R)-4,5-二氟-2-吗啉代-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-Step 5) (R)-12-((R)-4,5-difluoro-2-morpholino-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H- [1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物32)的合成Synthesis of [1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 32)
将(12aR)-7-(苄氧基)-12-(4,5-二氟-2-吗啉代-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(644mg,0.93mmol)和氯化锂(392mg,9.27mmol)混合于N,N-二甲基乙酰胺(20mL)中，氮气保护，并置于100℃条件下进行搅拌反应约12小时。将反应液加入到水(10mL)中淬灭反应，然后加入0.5N HCl调节pH值至弱酸性，搅拌10分钟，然后用乙酸乙酯(20mL×3)萃取，合并的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，得到标题化合物为淡黄色固体(116mg,21％)。Add (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-morpholino-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2 ,4] Triazine-6,8-dione (644mg, 0.93mmol) and lithium chloride (392mg, 9.27mmol) were mixed in N,N-dimethylacetamide (20mL), protected by nitrogen, and placed The stirring reaction was carried out at 100°C for about 12 hours. The reaction solution was added to water (10mL) to quench the reaction, then 0.5N HCl was added to adjust the pH to weak acidity, stirred for 10 minutes, and then extracted with ethyl acetate (20mL×3), and the combined organic phase was saturated with brine (30mL) washed, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) The title compound was obtained as a pale yellow solid (116 mg, 21%).
MS(ESI,pos.ion)m/z:605.3[M+H] + MS(ESI,pos.ion)m/z:605.3[M+H] +
1H NMR(600MHz,CDCl 3-d 6)δ(ppm)7.54(d,J＝7.7Hz,1H),7.37(t,J＝7.6Hz,1H),7.22(dd,J＝12.1,5.9Hz,2H),7.16(dd,J＝13.7,6.2Hz,1H),6.91(d,J＝7.5Hz,1H),6.60(d,J＝5.6Hz,1H),6.38(d,J＝7.7Hz,1H),5.67(d,J＝7.7Hz,1H),5.37(s,1H),4.68–4.56(m,1H),4.24(dd,J＝9.9,2.9Hz,1H),4.00–3.83(m,4H),3.75(dd,J＝11.9,2.8Hz,1H),3.53–3.45(m,1H),3.44–3.12(m,6H),3.01–2.86(m,1H). 1 H NMR (600MHz, CDCl 3 -d 6 ) δ (ppm) 7.54 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.22 (dd, J = 12.1, 5.9 Hz , 2H), 7.16 (dd, J = 13.7, 6.2 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.60 (d, J = 5.6 Hz, 1H), 6.38 (d, J = 7.7 Hz ,1H), 5.67(d,J=7.7Hz,1H),5.37(s,1H),4.68–4.56(m,1H), 4.24(dd,J=9.9,2.9Hz,1H),4.00–3.83( m, 4H), 3.75 (dd, J = 11.9, 2.8 Hz, 1H), 3.53–3.45 (m, 1H), 3.44–3.12 (m, 6H), 3.01–2.86 (m, 1H).
实施例15(R)-12-((R)-2-(二甲基氨基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶基[2,1-f][1,2,4]三嗪-6,8-二酮(化合物34)Example 15 (R)-12-((R)-2-(dimethylamino)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2 -b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyridyl[2,1-f ][1,2,4]triazine-6,8-dione (Compound 34)
Figure PCTCN2020077781-appb-000067
Figure PCTCN2020077781-appb-000067
步骤1)2-(5-(N,N-二甲基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸的合成Step 1) Synthesis of 2-(5-(N,N-dimethyl)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid
将2-(5-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(10.00g,24.44mmol)、二甲胺的四氢呋喃溶液(62mL,122.20mmol,5mol/L)、碘化亚铜(458mg,2.44mmol)、铜(763mg,12.22mmol)和DMF(30mL)加入至封管中，氮气下置于150℃油浴锅中加热反应过夜。停止搅拌，并用2N盐酸调节pH值至5-6，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析(DCM/MeOH(v/v)＝15/1)纯化，得到标题化合物为浅黄色固体(6.31g,72％)。Methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (10.00g, 24.44mmol), a tetrahydrofuran solution of dimethylamine (62mL, 122.20mmol, 5mol/L), cuprous iodide (458mg, 2.44mmol), copper (763mg, 12.22mmol) and DMF (30mL) were added to the sealed tube, and placed in a 150°C oil bath under nitrogen and heated to react overnight. Stop stirring, adjust the pH to 5-6 with 2N hydrochloric acid, extract with ethyl acetate (20mL×3), combine the organic phases, wash the organic phases with saturated brine (20mL), dry with anhydrous sodium sulfate, filter, and reduce the filtrate. It was concentrated under pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH(v/v)=15/1) to obtain the title compound as a pale yellow solid (6.31 g, 72%).
MS(ESI,pos.ion)m/z:360.2[M+H] +。 MS (ESI, pos.ion) m/z: 360.2 [M+H] + .
步骤2)2-(N,N-二甲基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 2) 2-(N,N-Dimethyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one Synthesis
将2-(5-(N,N-二甲基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸(5.81g,16.20mmol)溶解于氯苯(2mL)中，用超声仪超声溶清，再向其中加入PPA(65.00g,566.00mmol,84mass％)，氮气保护，置于110℃油浴锅中加热反应过夜。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，滤液减压浓缩，得到黄色固体为标题化合物(5.52g,100％)。Dissolve 2-(5-(N,N-dimethyl)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid (5.81g, 16.20mmol) in chlorobenzene (2mL) In the process, use an ultrasonic instrument to ultrasonically dissolve it, then add PPA (65.00 g, 566.00 mmol, 84 mass%) to it, protected by nitrogen, and place it in an oil bath at 110° C. to heat and react overnight. The reaction was stopped, the reaction solution was added to ice water (15mL), extracted with ethyl acetate (20mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (15mL), dried with anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure to obtain the title compound (5.52 g, 100%) as a yellow solid.
步骤3)2-(N,N-二甲基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 3) 2-(N,N-Dimethyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol Synthesis
将2-(N,N-二甲基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(5.52g,16.20mmol)溶解于甲醇(30mL)和四氢呋喃(30mL)中，然后再加入硼氢化钠(1.27g,32.30mmol)，置于室温下搅拌反应约20分钟。停止反应，将反应液加入到饱和氯化铵溶液(10mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝3/1)，得到浅黄色固体为标题化合物(2.00g,36％)。The 2-(N,N-dimethyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (5.52 g, 16.20mmol) was dissolved in methanol (30mL) and tetrahydrofuran (30mL), then sodium borohydride (1.27g, 32.30mmol) was added, and the reaction was stirred at room temperature for about 20 minutes. The reaction was stopped, the reaction solution was added to saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=3/1) to obtain the title compound (2.00 g, 36%) as a pale yellow solid.
1H NMR(400MHz,CDCl 3)δ(ppm)7.73(d,J＝7.8Hz,1H),7.55(dd,J＝8.2,4.4Hz,1H),7.44(d,J＝7.7Hz,1H),7.37(t,J＝7.1Hz,1H),7.28(s,1H),7.22–7.16(m,1H),6.37(d,J＝5.2Hz,1H),5.29(s,1H),3.06(s,6H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.73(d,J=7.8Hz,1H), 7.55(dd,J=8.2,4.4Hz,1H),7.44(d,J=7.7Hz,1H) ,7.37(t,J=7.1Hz,1H),7.28(s,1H),7.22-7.16(m,1H),6.37(d,J=5.2Hz,1H),5.29(s,1H),3.06( s, 6H).
步骤4)(12aR)-7-(苄氧基)-12-(2-(二甲基氨基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-Step 4) (12aR)-7-(benzyloxy)-12-(2-(dimethylamino)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta [1,2-b]thiophen-8-yl)-3,4,12,12a- 四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将4,5-二氟-2-(N,N-二甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1.89g,5.50mmol)，(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6-,8二酮(2.07g,6.33mmol)混合于T 3P(9.89mL,16.50mmol)的乙酸异丙酯(50mL)溶液中，置于90℃油浴锅中反应约3小时，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)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为DCM/MeOH(v/v)＝1/15)，得到白色固体为标题化合物(1.52g,42％)。 4,5-Difluoro-2-(N,N-dimethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (1.89 g, 5.50mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2 ,1-f][1,2,4]triazine-6-,8dione (2.07g, 6.33mmol) mixed with T 3 P (9.89mL, 16.50mmol) in isopropyl acetate (50mL) solution , Placed in a 90°C oil bath for about 3 hours to stop the reaction. The reaction solution was added to water (15 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=1/15) to obtain the title compound (1.52 g, 42%) as a white solid.
MS(ESI,pos.ion)m/z:653.3[M+H] + MS(ESI,pos.ion)m/z:653.3[M+H] +
步骤6)(R)-12-((R)-2-(二甲基氨基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四Step 6) (R)-12-((R)-2-(dimethylamino)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2 -b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetra 氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物34)的合成Synthesis of Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 34)
将(12aR)-7-(苄氧基)-12-(2-(二甲基氨基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.52g,2.33mmol)、氯化锂(987mg,23.30mmol)混合于DMAc(20mL)中，氮气保护下升温至100℃搅拌反应过夜。将反应液加入到水(10mL)中淬灭反应，然后用0.5N HCl调节pH值呈弱酸性，搅拌10分钟，然后用乙酸乙酯(20mL×3)萃取，合并的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(乙腈/0.1％三氟乙酸水溶液(v/v)＝12/13)分离纯化，得到标题化合物为淡黄色固体(490mg,37％)。MS(ESI,pos.ion)m/z:563.3[M+H] +； The (12aR)-7-(benzyloxy)-12-(2-(dimethylamino)-4,5-difluoro-8H-dibenzo[3,4:6,7]cycloheptan[1 ,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][ 1,2,4] Triazine-6,8-dione (1.52g, 2.33mmol), lithium chloride (987mg, 23.30mmol) were mixed in DMAc (20mL), heated to 100℃ under nitrogen protection, stirred overnight . The reaction solution was added to water (10mL) to quench the reaction, then adjusted with 0.5N HCl to make the pH weakly acidic, stirred for 10 minutes, and then extracted with ethyl acetate (20mL×3), and the combined organic phase was saturated with brine (30mL) washed, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by a LUNA preparation column (acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) to obtain the title compound It is a pale yellow solid (490mg, 37%). MS(ESI,pos.ion)m/z:563.3[M+H] + ;
1H NMR(600MHz,CDCl 3-d 6)δ(ppm)7.52(d,J＝7.4Hz,1H),7.35(t,J＝7.1Hz,1H),7.26–7.01(m,3H),6.87(d,J＝7.2Hz,1H),6.48(d,J＝7.1Hz,1H),6.34(d,J＝5.4Hz,1H),5.86(d,J＝6.8Hz,1H),5.36(s,1H),4.61(d,J＝12.9Hz,1H),4.29(d,J＝7.5Hz,1H),3.76(d,J＝9.6Hz,1H),3.49(d,J＝8.9Hz,1H),3.42–3.32(m,1H),3.33–3.21(m,1H),3.08(s,6H),3.00–2.87(m,1H). 1 H NMR (600MHz, CDCl 3 -d 6 ) δ (ppm) 7.52 (d, J = 7.4 Hz, 1H), 7.35 (t, J = 7.1 Hz, 1H), 7.26-7.01 (m, 3H), 6.87 (d,J=7.2Hz,1H), 6.48(d,J=7.1Hz,1H), 6.34(d,J=5.4Hz,1H), 5.86(d,J=6.8Hz,1H), 5.36(s ,1H), 4.61(d,J=12.9Hz,1H), 4.29(d,J=7.5Hz,1H), 3.76(d,J=9.6Hz,1H), 3.49(d,J=8.9Hz,1H ), 3.42–3.32(m,1H), 3.33–3.21(m,1H), 3.08(s,6H), 3.00–2.87(m,1H).
实施例16(R)-12-((R)-4,5-二氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物35)Example 16 (R)-12-((R)-4,5-difluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4)triazine-6,8-dione (compound 35)
Figure PCTCN2020077781-appb-000068
Figure PCTCN2020077781-appb-000068
步骤1)2-(5-(甲氧基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸的合成Step 1) Synthesis of 2-(5-(methoxy)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid
将2-(5-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(11.50g,28.10mmol)、甲醇钠的甲醇溶液(6.75mL,33.80mmol,5mol/L)、碘化亚铜(535mg,2.81mmol)、铜(360mg,5.63mmol)和甲醇(30mL)加入至封管中，氮气保护下置于150℃油浴锅中加热反应过夜。然后将反应液其加入到四氢呋喃(20mL)中，再加入NaOH(2.24g,56.00mmol)的水(10mL)溶液，置于50℃下继续搅拌反应约7小时。反应结束后，用2N盐酸调节反应液pH值至5～6，再用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为DCM/MeOH(v/v)＝15/1)，得到标题化合物为浅黄色膏状固体(9.71g,100％)。Methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (11.50g, 28.10mmol), a methanol solution of sodium methoxide (6.75mL, 33.80mmol, 5mol/L), cuprous iodide (535mg, 2.81mmol), copper (360mg, 5.63mmol) and methanol (30mL) were added to the sealed tube, and placed in a 150°C oil bath under the protection of nitrogen and heated to react overnight. Then the reaction solution was added to tetrahydrofuran (20 mL), and NaOH (2.24 g, 56.00 mmol) in water (10 mL) was added, and the mixture was placed at 50° C. to continue stirring and reacting for about 7 hours. After the reaction, the pH of the reaction solution was adjusted to 5-6 with 2N hydrochloric acid, and then extracted with ethyl acetate (20mL×3). The organic phases were combined, and the organic phases were washed with saturated brine (20mL) and dried with anhydrous sodium sulfate. The filtrate was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain the title compound as a pale yellow cream solid (9.71g, 100%) ).
MS(ESI,pos.ion)m/z:347.0[M+H] +。 MS (ESI, pos.ion) m/z: 347.0 [M+H] + .
步骤2)2-(甲氧基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 2) Synthesis of 2-(methoxy)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将2-(5-(甲氧基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸(285mg,0.83mmol)溶解于氯苯(2mL)中，用超声仪超声溶清，再向其中加入PPA(750mg,6.429mmol,84mass％)，氮气保护，置于120℃油浴锅中加热反应约7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，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/EA(v/v)＝5/1)纯化，得到黄色固体为标题化合物(45mg,17％)。Dissolve 2-(5-(methoxy)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid (285mg, 0.83mmol) in chlorobenzene (2mL) and use an ultrasonic instrument Dissolve it by ultrasonic, then add PPA (750 mg, 6.429 mmol, 84 mass%) to it, protected by nitrogen, and place it in an oil bath at 120° C. to heat and react for about 7 hours. The reaction was stopped, the reaction solution was added to ice water (15mL), extracted with ethyl acetate (20mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (15mL), dried with anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=5/1) to obtain the title compound (45 mg, 17%) as a yellow solid.
1H NMR(400MHz,CDCl 3)δ(ppm)7.80(d,J＝7.7Hz,1H),7.61(m,3H),7.45(t,J＝7.5Hz,1H),7.29(dd,J＝10.2,5.9Hz,1H),6.75(d,J＝6.0Hz,1H),4.01(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.80 (d, J = 7.7 Hz, 1H), 7.61 (m, 3H), 7.45 (t, J = 7.5 Hz, 1H), 7.29 (dd, J = 10.2,5.9Hz,1H), 6.75(d,J=6.0Hz,1H),4.01(s,3H).
步骤3)2-(甲氧基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 3) Synthesis of 2-(methoxy)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol
将2-(叔丁基)-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(600mg,1.83mmol)溶解于甲醇(15mL)和四氢呋喃(15mL)中，然后再加入硼氢化钠(144mg,3.66mmol)，置于室温下搅拌反应约20分钟。停止反应，将反应液加入到饱和氯化铵溶液(10mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝3/1)，得到浅黄色固体为标题化合物(598mg,99％)。Dissolve 2-(tert-butyl)-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (600mg, 1.83mmol) In methanol (15 mL) and tetrahydrofuran (15 mL), sodium borohydride (144 mg, 3.66 mmol) was added, and the reaction was stirred at room temperature for about 20 minutes. The reaction was stopped, the reaction solution was added to saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=3/1) to obtain the title compound (598 mg, 99%) as a pale yellow solid.
1H NMR(400MHz,CDCl 3)δ(ppm)7.76(d,J＝7.8Hz,1H),7.56(dd,J＝8.0,4.9Hz,1H),7.43(t,J＝8.0Hz,2H),7.29(d,J＝4.4Hz,1H),7.21(dd,J＝17.2,9.0Hz,1H),6.70(d,J＝5.2Hz,1H),5.32(d,J＝2.0Hz,1H),4.03(s,3H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.76(d,J=7.8Hz,1H), 7.56(dd,J=8.0,4.9Hz,1H), 7.43(t,J=8.0Hz,2H) ,7.29(d,J＝4.4Hz,1H), 7.21(dd,J＝17.2,9.0Hz,1H), 6.70(d,J＝5.2Hz,1H),5.32(d,J＝2.0Hz,1H) ,4.03(s,3H).
步骤4)(12aR)-7-(苄氧基)-12-(4,5-二氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢Step 4) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b)thiophen-8-yl)-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
分别称量4,5-二氟-2-甲氧基-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1.15g,3.48mmol)、(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6-,8二酮(1.31g,4.00mmol)混合于T 3P(0.50mL,0.84mmol)中的乙酸异丙酯(20mL)溶液，置于90℃油浴锅中反应约3小时，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)洗 涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为DCM/MeOH(v/v)＝1/15)，得到白色固体为标题化合物(590mg,27％)。 Weigh 4,5-difluoro-2-methoxy-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (1.15g, 3.48mmol) respectively , (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4] Triazine-6-,8 dione (1.31g, 4.00mmol) mixed with isopropyl acetate (20mL) solution in T 3 P (0.50mL, 0.84mmol), placed at 90℃ The reaction is stopped in the oil bath for about 3 hours. The reaction solution was added to water (15 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=1/15) to obtain the title compound (590 mg, 27%) as a white solid.
MS(ESI,pos.ion)m/z:640.3[M+H] +。 MS (ESI, pos.ion) m/z: 640.3 [M+H] + .
步骤6)(R)-12-((R)-4,5-二氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-Step 6) (R)-12-((R)-4,5-difluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H- [1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物35)的合成Synthesis of [1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 35)
将(12aR)-7-(苄氧基)-12-(4,5-二氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(590mg,0.92mmol)、氯化锂(391mg,9.22mmol)混合于N,N-二甲基乙酰胺(30mL)中，氮气保护加置于110℃搅拌反应过夜。将反应液加入到水(10mL)中淬灭反应，然后用0.5N HCl调节反应液的pH值呈弱酸性，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，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，得到标题化合物为淡黄色固体(63mg,12％)。The (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-methoxy-8H-dibenzo[3,4:6,7]cycloheptan[1,2- b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2 ,4] Triazine-6,8-dione (590mg, 0.92mmol), lithium chloride (391mg, 9.22mmol) were mixed in N,N-dimethylacetamide (30mL), and placed at 110 under nitrogen protection The reaction was stirred overnight at °C. The reaction solution was added to water (10mL) to quench the reaction, and then the pH value of the reaction solution was adjusted to weakly acidic with 0.5N HCl, stirred for 10 minutes, and then extracted with ethyl acetate (20mL×3), and the organic phases were combined. The phase was washed with saturated brine (30 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to a LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v) = 12 /13) Isolation and purification to obtain the title compound as a pale yellow solid (63 mg, 12%).
MS(ESI,pos.ion)m/z:550.2[M+H] +； MS(ESI,pos.ion)m/z:550.2[M+H] + ;
1H NMR(600MHz,CDCl 3-d 6)δ(ppm)7.54(d,J＝7.7Hz,1H),7.39(d,J＝7.5Hz,2H),7.27–7.17(m,2H),6.93(d,J＝7.5Hz,1H),6.71(d,J＝5.5Hz,1H),6.39(d,J＝7.6Hz,1H),5.71(d,J＝7.5Hz,1H),5.39(s,1H),4.60(d,J＝5.0Hz,1H),4.24(dd,J＝9.8,2.6Hz,1H),4.04(s,3H),3.75(d,J＝9.7Hz,1H),3.53–3.22(m,3H),2.93(t,J＝11.2Hz,1H). 1 H NMR (600MHz, CDCl 3 -d 6 ) δ (ppm) 7.54 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 7.5 Hz, 2H), 7.27-7.17 (m, 2H), 6.93 (d,J=7.5Hz,1H), 6.71(d,J=5.5Hz,1H), 6.39(d,J=7.6Hz,1H), 5.71(d,J=7.5Hz,1H), 5.39(s ,1H), 4.60(d,J=5.0Hz,1H), 4.24(dd,J=9.8,2.6Hz,1H),4.04(s,3H),3.75(d,J=9.7Hz,1H),3.53 –3.22(m,3H),2.93(t,J=11.2Hz,1H).
实施例17(R)-12-((R)-5,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基3,4,12,12a四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物82)Example 17 (R)-12-((R)-5,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1 ,2-b]thiophen-8-yl)-7-hydroxy 3,4,12,12a tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f ][1,2,4]triazine-6,8-dione (Compound 82)
Figure PCTCN2020077781-appb-000069
Figure PCTCN2020077781-appb-000069
步骤1)3-(3,5-二氟苯基)噻吩的合成Step 1) Synthesis of 3-(3,5-difluorophenyl)thiophene
将1-溴-3,5-二氟苯(15.41g,79.85mmol)、3-噻吩硼酸(15.33g,119.80mmol)、碳酸钠(25.39g,239.60mmol)和PdCl 2(PPh 3) 2(2.80g,3.99mmol)混合于THF(30mL)和水(5mL)中，氮气保护，置于70℃油浴锅中回流反应过夜。停止反应，过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/EA(v/v)＝95/5)分离提纯，得到标题化合物为浅黄色油状液体(15.00g,96％)。 Combine 1-bromo-3,5-difluorobenzene (15.41g, 79.85mmol), 3-thiopheneboronic acid (15.33g, 119.80mmol), sodium carbonate (25.39g, 239.60mmol) and PdCl 2 (PPh 3 ) 2 ( 2.80g, 3.99mmol) was mixed in THF (30mL) and water (5mL), protected by nitrogen, placed in a 70°C oil bath and refluxed overnight. The reaction was stopped, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (eluent: PE/EA(v/v)=95/5) to obtain the title compound as a pale yellow oily liquid (15.00g) ,96%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.51(dd,J＝2.8,1.2Hz,1H),7.43(dd,J＝4.9,3.0Hz,1H),7.38–7.34(m,1H),7.16–7.09(m,2H),6.76(tt,J＝8.9,2.2Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.51 (dd, J = 2.8, 1.2 Hz, 1H), 7.43 (dd, J = 4.9, 3.0 Hz, 1H), 7.38–7.34 (m, 1H), 7.16–7.09(m,2H), 6.76(tt,J=8.9,2.2Hz,1H).
步骤2)2-溴-3-(3,5-二氟苯基)噻吩的合成Step 2) Synthesis of 2-bromo-3-(3,5-difluorophenyl)thiophene
将3-(3,5-二氟苯基)噻吩(8.03g,40.90mmol)溶解于DMF(30mL)中，再将NBS(6.77g,38.00mmol)的DMF(20mL)溶液缓慢滴加到上述反应液中，并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，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝15/1)，得到标题化合物为浅黄色油状液体(11.06g,98％)。Dissolve 3-(3,5-difluorophenyl)thiophene (8.03g, 40.90mmol) in DMF (30mL), and then slowly add a solution of NBS (6.77g, 38.00mmol) in DMF (20mL) to the above In the reaction solution, the reaction mixture 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 filter. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=15/1) to obtain the title compound as a pale yellow oily liquid (11.06g, 98%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.36(d,J＝5.7Hz,1H),7.12(dd,J＝5.1,3.3Hz,2H),7.03(d,J＝5.7Hz,1H),6.84(tt,J＝8.9,2.2Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.36 (d, J = 5.7 Hz, 1H), 7.12 (dd, J = 5.1, 3.3 Hz, 2H), 7.03 (d, J = 5.7 Hz, 1H) ,6.84(tt,J=8.9,2.2Hz,1H).
步骤3)2-(3-(3,5-二氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 3) Synthesis of methyl 2-(3-(3,5-difluorophenyl)thiophen-2-yl)benzoate
将2-溴3-(3,5-二氟苯基)噻吩(11.06g,40.20mmol)、(2-(甲氧基羰基)苯基)硼酸(10.85g,60.29mmol)、PdCl 2(PPh 3) 2(1.43g,2.02mmol)、碳酸钾(16.67g,120.60mmol)混合于THF(300mL)和水(1.10mL,61.10mmol)中，氮气保护，置于70℃油浴锅中加热反应约3小时。停止反应，反应液过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/EA(v/v)＝5/1)进行分离提纯，得到标题化合物为类白色固体(8.80g,66.3％)。 Combine 2-bromo 3-(3,5-difluorophenyl)thiophene (11.06g, 40.20mmol), (2-(methoxycarbonyl)phenyl)boronic acid (10.85g, 60.29mmol), PdCl 2 (PPh 3 ) 2 (1.43g, 2.02mmol), potassium carbonate (16.67g, 120.60mmol) were mixed in THF (300mL) and water (1.10mL, 61.10mmol), protected by nitrogen, placed in a 70℃ oil bath and heated for reaction About 3 hours. The reaction was stopped, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (eluent: PE/EA(v/v)=5/1) to obtain the title compound as an off-white solid ( 8.80g, 66.3%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.84(dd,J＝7.7,1.1Hz,1H),7.45(m,4H),7.18(d,J＝5.2Hz,1H),6.76-6.68(m,2H),6.64(td,J＝6.7,3.3Hz,1H),3.63(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.84 (dd, J = 7.7, 1.1 Hz, 1H), 7.45 (m, 4H), 7.18 (d, J = 5.2 Hz, 1H), 6.76-6.68 ( m, 2H), 6.64 (td, J = 6.7, 3.3 Hz, 1H), 3.63 (s, 3H).
步骤4)2-(5-溴-3-(3,5-二氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 4) Synthesis of methyl 2-(5-bromo-3-(3,5-difluorophenyl)thiophen-2-yl)benzoate
将2-(3-(3,5-二氟苯基)噻吩-2-基)苯甲酸甲酯(8.50g,25.70mmol)的DMF(20mL)溶液置于单口瓶中，然后缓慢向其中滴加NBS(4.58g,25.70mmol)的DMF(30mL)溶液，滴加完毕后继续在室温下搅拌反应过夜。停止反应，向反应液中加水(20mL)，所得混合物用乙酸乙酯(15mL×3)萃取，合并有机相，有机相用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝10/1)，得到标题化合物为类白色固体(9.98g,95％)。Place 2-(3-(3,5-difluorophenyl)thiophen-2-yl)benzoic acid methyl ester (8.50g, 25.70mmol) in DMF (20mL) solution in a single-neck bottle, and then slowly drop it Add a solution of NBS (4.58g, 25.70mmol) in DMF (30mL), and continue to stir and react overnight at room temperature after the addition is complete. The reaction was stopped, water (20 mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (15 mL×3), the organic phases were combined, and the organic phase was washed with saturated brine (30 mL×3), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=10/1) to obtain the title compound as an off-white solid (9.98 g, 95%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.85(dd,J＝7.6,1.2Hz,1H),7.55–7.43(m,2H),7.37–7.31(m,1H),7.14(s,1H),6.64(dd,J＝7.2,1.9Hz,3H),3.67(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.85 (dd, J = 7.6, 1.2 Hz, 1H), 7.55-7.43 (m, 2H), 7.37-7.31 (m, 1H), 7.14 (s, 1H) ), 6.64(dd,J=7.2,1.9Hz,3H), 3.67(s,3H).
步骤5)2-(3-(3,5-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯的合成Step 5) Synthesis of methyl 2-(3-(3,5-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoate
将2-(5-溴-3-(3,5-二氟苯基)噻吩-2-基)苯甲酸甲酯(5.00g,12.20mmol)、四氢吡咯(2.21mL,26.90mmol)、BINAP(471mg,0.73mmol)、Pd 2(dba) 3(346mg,0.37mmol)和碳酸铯(17.50g,53.80mmol)混合于甲苯(30mL)中，氮气保护下，置于110℃油浴锅中加热反应约7小时。停止搅拌，反应液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/EA(v/v)＝10/1)分离提纯，得到标题化合物为浅黄色固体(4.00g,82％)。 Combine methyl 2-(5-bromo-3-(3,5-difluorophenyl)thiophen-2-yl)benzoate (5.00g, 12.20mmol), tetrahydropyrrole (2.21mL, 26.90mmol), BINAP (471mg, 0.73mmol), Pd 2 (dba) 3 (346mg, 0.37mmol) and cesium carbonate (17.50g, 53.80mmol) were mixed in toluene (30mL), protected by nitrogen, heated in an oil bath at 110℃ The reaction time is about 7 hours. The stirring was stopped, the reaction solution was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (eluent: PE/EA(v/v)=10/1) to obtain the title compound as a pale yellow solid (4.00g, 82 %).
1H NMR(400MHz,CDCl 3)δ(ppm)7.73–7.66(m,1H),7.47–7.41(m,1H),7.38–7.33(m,2H),6.76–6.67(m,2H),6.61(tt,J＝8.9,2.2Hz,1H),5.82(s,1H),3.64(s,3H),3.32(t,J＝6.5Hz,4H),2.07(t,J＝6.5Hz,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.73-7.66 (m, 1H), 7.47-7.41 (m, 1H), 7.38-7.33 (m, 2H), 6.76-6.67 (m, 2H), 6.61 (tt,J=8.9,2.2Hz,1H), 5.82(s,1H), 3.64(s,3H), 3.32(t,J=6.5Hz,4H), 2.07(t,J=6.5Hz,4H) .
步骤6)2-(3-(3,5-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸的合成Step 6) Synthesis of 2-(3-(3,5-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoic acid
将2-(3-(3,5-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯(2.01g,5.03mmol)溶解于THF(15mL)和甲醇(15mL)中，并置于室温下搅拌，然后加入氢氧化钠(2.01g,50.30mmol)的水(10mL)，氮气保护下，置于55℃下搅拌反应约3小时。停止反应，用2N稀盐酸调节反应液的pH值至显弱酸性，然后用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝5/1)，得到标题化合物为类白色固体(1.99g,103％)。Methyl 2-(3-(3,5-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoate (2.01g, 5.03mmol) was dissolved in THF (15mL) And methanol (15mL), and stirred at room temperature, then add sodium hydroxide (2.01g, 50.30mmol) in water (10mL), under the protection of nitrogen, place at 55°C and stir to react for about 3 hours. Stop the reaction, adjust the pH of the reaction solution with 2N dilute hydrochloric acid to show weak acidity, then extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic phases with saturated brine (8mL), and dry with anhydrous sodium sulfate After filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=5/1) to obtain the title compound as an off-white solid (1.99g, 103%) .
MS(ESI,pos.ion)m/z:386.0[M+H] + MS(ESI,pos.ion)m/z:386.0[M+H] +
步骤7)5,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 7) 5,7-Difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one synthesis
将2-(3-(3,5-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸(2.00g,5.19mmol)置于PPA(15mL,264mmol,84mass％)中，氮气保护，置于110℃油浴锅中加热反应过夜。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，滤液减压浓缩，得到黄色固体为标题化合物(1.91g,100％)。Place 2-(3-(3,5-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoic acid (2.00g, 5.19mmol) in PPA (15mL, 264mmol, 84mass%), protected by nitrogen, placed in a 110°C oil bath and heated for reaction overnight. The reaction was stopped, the reaction solution was added to ice water (15mL), extracted with ethyl acetate (20mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (15mL), dried with anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure to obtain the title compound (1.91 g, 100%) as a yellow solid.
步骤8)5,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 8) 5,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol synthesis
将5,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(1.90g,5.17mmol)溶解于甲醇(15mL)和四氢呋喃(15mL)中，然后再加入硼氢化钠(588mg,14.95mmol)，置于室温下搅拌反应约15分钟。停止反应，将反应液加入到饱和氯化铵溶液(10mL)中，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝3/1)，得到浅黄色固体为标题化合物(1.75g,92％)。Combine 5,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (1.90g , 5.17mmol) was dissolved in methanol (15mL) and tetrahydrofuran (15mL), then sodium borohydride (588mg, 14.95mmol) was added, and the reaction was stirred at room temperature for about 15 minutes. The reaction was stopped, the reaction solution was added to saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (20 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=3/1) to obtain the title compound (1.75 g, 92%) as a pale yellow solid.
1H NMR(400MHz,CDCl 3)δ(ppm)7.53(d,J＝7.6Hz,1H),7.48(d,J＝7.4Hz,1H),7.35(t,J＝7.5Hz,1H),7.29(d,J＝9.8Hz,1H),7.17(d,J＝9.8Hz,1H),6.89–6.81(m,1H),6.23(d,J＝9.2Hz,1H),6.05(s,1H),3.41(d,J＝1.5Hz,4H),2.12(dd,J＝7.9,5.1Hz,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.53 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.29 (d,J=9.8Hz,1H), 7.17(d,J=9.8Hz,1H), 6.89–6.81(m,1H), 6.23(d,J=9.2Hz,1H), 6.05(s,1H) ,3.41(d,J=1.5Hz,4H), 2.12(dd,J=7.9,5.1Hz,4H).
步骤9)(12aR)-7-(苄基氧基)-12-(5,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-Step 9) (12aR)-7-(benzyloxy)-12-(5,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7 ]Cycloheptan[1,2-b]thiophene-8- 基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine- Synthesis of 6,8-dione
将5,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(768mg,2.08mmol)、(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(748mg,2.29mmol)混合于T 3P(2.50mL,4.16mmol)的乙酸乙酯(20mL)溶液中，置于60℃油浴中反应约2小时。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)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为DCM/MeOH(v/v)＝1/15)分离提纯，得到标题化合物为黄褐色固体(590mg,42％)。 The 5,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (768mg, 2.08mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1 -f][1,2,4]triazine-6,8-dione (748mg, 2.29mmol) was mixed with T 3 P (2.50mL, 4.16mmol) in ethyl acetate (20mL) solution, placed 60 React in an oil bath at °C for about 2 hours. Stop the reaction, add the reaction solution to 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 the filtrate After pressure concentration, the residue obtained was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=1/15) to obtain the title compound as a yellow-brown solid (590mg, 42%).
MS(ESI,pos.ion)m/z:679.6[M+H] + MS(ESI,pos.ion)m/z:679.6[M+H] +
步骤10)(R)-12-((R)-5,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基3,4,12,12a四Step 10) (R)-12-((R)-5,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1 ,2-b)thiophen-8-yl)-7-hydroxy 3,4,12,12a 氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物82)的合成Synthesis of Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 82)
将(12aR)-7-(苄基氧基)-12-(5,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6-8二酮(590mg,0.87mmol)、氯化锂(368mg,8.69mmol)混合于N,N-二甲基乙酰胺(15mL)中，氮气保护，并置于100℃搅拌反应约4小时。将反应液加入到水(10mL)中淬灭反应，然后用0.5N HCl调节pH值呈弱酸性，搅拌10分钟，然后用乙酸乙酯(20mL×3)萃取，合并的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，得到标题化合物为淡黄色固体(201mg,39％)。(12aR)-7-(benzyloxy)-12-(5,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7] ring Hept[1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1- f][1,2,4]triazine-6-8 dione (590mg, 0.87mmol), lithium chloride (368mg, 8.69mmol) mixed in N,N-dimethylacetamide (15mL), nitrogen Protect, and place at 100°C and stir to react for about 4 hours. The reaction solution was added to water (10mL) to quench the reaction, then adjusted with 0.5N HCl to make the pH weakly acidic, stirred for 10 minutes, and then extracted with ethyl acetate (20mL×3), and the combined organic phases were saturated with brine (30mL) washed, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) The title compound was obtained as a pale yellow solid (201 mg, 39%).
MS(ESI,pos.ion)m/z:589.0[M+H] +； MS(ESI,pos.ion)m/z:589.0[M+H] + ;
1H NMR(600MHz,CDCl 3)δ(ppm)7.49(d,J＝7.7Hz,1H),7.41–7.33(m,1H),7.26(s,1H),7.09(t,J＝7.3Hz,1H),7.00–6.86(m,2H),6.67(d,J＝7.3Hz,1H),6.11(d,J＝7.3Hz,1H),5.98(d,J＝11.3Hz,2H),4.67(d,J＝13.0Hz,1H),4.37(d,J＝7.3Hz,1H),4.14(dd,J＝14.2,7.1Hz,1H),3.81(d,J＝9.5Hz,1H),3.57(d,J＝8.7Hz,1H),3.44(d,J＝6.9Hz,4H),3.34–3.24(m,1H),3.16–3.02(m,1H),2.16(s,4H). 1 H NMR(600MHz, CDCl 3 )δ(ppm) 7.49(d,J=7.7Hz,1H), 7.41–7.33(m,1H), 7.26(s,1H), 7.09(t,J=7.3Hz, 1H), 7.00–6.86 (m, 2H), 6.67 (d, J = 7.3 Hz, 1H), 6.11 (d, J = 7.3 Hz, 1H), 5.98 (d, J = 11.3 Hz, 2H), 4.67 ( d,J＝13.0Hz,1H), 4.37(d,J＝7.3Hz,1H), 4.14(dd,J＝14.2,7.1Hz,1H), 3.81(d,J＝9.5Hz,1H),3.57( d,J=8.7Hz,1H), 3.44(d,J=6.9Hz,4H), 3.34–3.24(m,1H), 3.16–3.02(m,1H), 2.16(s,4H).
实施例18(R)-12-((S)-4,5-二氟-2-((2-甲氧基乙氧基)甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物85)Example 18 (R)-12-((S)-4,5-difluoro-2-((2-methoxyethoxy)methyl)-8H-dibenzo[3,4:6, 7]Cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyridine And [2,1-f][1,2,4]triazine-6,8-dione (Compound 85)
Figure PCTCN2020077781-appb-000070
Figure PCTCN2020077781-appb-000070
步骤1)2-((2-甲氧基乙氧基)甲基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 1) 2-((2-Methoxyethoxy)methyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Synthesis of thiophen-8-one
将乙二醇单甲醚(10mL)置于单口瓶中，再向其中加入氢氧化钾(143mg,2.55mmol)，置于100℃油浴锅中加热反应约1小时，将上述反应液冷却至室温，向其中加入2-(溴甲基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(500mg,1.28mmol)的THF(10mL)溶液，在室温下继续反应约30分钟。反应结束后，用2N稀盐酸调节反应液的pH至酸性，然后用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝5/1)，得到标题化合物为黄色固体(490mg,99％)。Place ethylene glycol monomethyl ether (10mL) in a single-necked flask, then add potassium hydroxide (143mg, 2.55mmol) to it, and place it in an oil bath at 100°C to heat and react for about 1 hour. Cool the above reaction solution to At room temperature, add 2-(bromomethyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (500mg , 1.28mmol) in THF (10mL), continue the reaction at room temperature for about 30 minutes. After the reaction, the pH of the reaction solution was adjusted to acidity with 2N dilute hydrochloric acid, and then extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (8 mL), dried with anhydrous sodium sulfate, and filtered The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=5/1) to obtain the title compound as a yellow solid (490 mg, 99%).
MS(ESI,neg.ion)m/z:384.9[M-H] -。 MS (ESI, neg.ion) m/z: 384.9 [MH] - .
步骤2)2-((2-甲氧基乙氧基)甲基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 2) 2-((2-Methoxyethoxy)methyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b] Synthesis of thiophene-8-ol
将2-((2-甲氧基乙氧基)甲基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(500mg,1.29mmol)溶解于甲醇(10mL)和THF(10mL)中，所得混合物置于室温下搅拌，然后加入硼氢化钠(102mg,2.58mmol)，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)，所得混合物用乙酸乙酯(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，过滤，滤液减压浓缩，得到标题化合物为浅黄色固体(501mg,99％)。The 2-((2-methoxyethoxy)methyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene- 8-ketone (500mg, 1.29mmol) was dissolved in methanol (10mL) and THF (10mL), the resulting mixture was stirred at room temperature, then sodium borohydride (102mg, 2.58mmol) was added, and the reaction was stirred at room temperature for about 20 minute. The reaction was stopped, saturated ammonium chloride solution (20 mL) was added, the resulting mixture was extracted with ethyl acetate (25 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (30 mL), dried with anhydrous sodium sulfate, and filtered The filtrate was concentrated under reduced pressure to obtain the title compound as a pale yellow solid (501 mg, 99%).
步骤4)(12aR)-7-(苄氧基)-12-(4,5-二氟-2-((2-甲氧基乙氧基)甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-Step 4) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-((2-methoxyethoxy)methyl)-8H-dibenzo(3, 4:6,7]cyclohepta[1,2-b]thiophene-8- 基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine- Synthesis of 6,8-dione
将2-((2-甲氧基乙氧基)甲基)-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(500mg,1.29mmol)和(R)-7-(苄氧基)-3,4,12,12a四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(463mg,1.42mmol)混合于乙酸异丙酯(10mL)中，再向其中加入T 3P(1.70mL,2.83mmol,1.67mol/L)，置于90℃油浴锅中加热反应约2小时。停止反应，向反应液中加入饱和碳酸氢钠溶液(20mL)，所得混合物用乙酸乙酯(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，滤液减压浓缩，所得残留物经硅胶柱层析纯化(洗脱剂为DCM/MeOH(v/v)＝15/1)，得到标题化合物为黄褐色固体(280mg,31％)。 The 2-((2-methoxyethoxy)methyl)-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8 -Alcohol (500mg, 1.29mmol) and (R)-7-(benzyloxy)-3,4,12,12a tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido [2,1-f][1,2,4]triazine-6,8-dione (463mg, 1.42mmol) was mixed in isopropyl acetate (10mL), and then T 3 P (1.70mL , 2.83mmol, 1.67mol/L), placed in an oil bath at 90°C and heated to react for about 2 hours. The reaction was stopped, saturated sodium bicarbonate solution (20mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (30mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (30mL) and dried over anhydrous sodium sulfate After filtering, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain the title compound as a tan solid (280 mg, 31%).
MS(ESI,pos.ion)m/z:698.3[M+H] +。 MS (ESI, pos.ion) m/z: 698.3 [M+H] + .
步骤5)(R)-12-((S)-4,5-二氟-2-((2-甲氧基乙氧基)甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基Step 5) (R)-12-((S)-4,5-difluoro-2-((2-methoxyethoxy)methyl)-8H-dibenzo[3,4:6, 7] Cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy -3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物85)的合成-3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6, Synthesis of 8-diketone (Compound 85)
将化合物(12aR)-7-(苄氧基)-12-(4,5-二氟-2-((2-甲氧基乙氧基)甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(280mg,0.40mmol)和氯化锂(170mg,4.01mmol)混合于N,N-二甲基乙酰胺(10mL)中，氮气保护，并置于100℃条件下进行搅拌反应约2.5小时。将反应液加入到水(10mL)中淬灭反应，然后用0.5N HCl调节pH值呈弱酸性，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，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，得到标题化合物为淡黄色固体(33mg,14％)。The compound (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-((2-methoxyethoxy)methyl)-8H-dibenzo[3,4 :6,7]cyclohepta[1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyridine And [2,1-f][1,2,4]triazine-6,8-dione (280mg, 0.40mmol) and lithium chloride (170mg, 4.01mmol) mixed in N,N-dimethyl ethyl In amide (10 mL), protected by nitrogen, and placed at 100°C for stirring reaction for about 2.5 hours. The reaction solution was added to water (10mL) to quench the reaction, then adjusted with 0.5N HCl to make the pH weakly acidic, stirred for 10 minutes, then extracted with ethyl acetate (20mL×3), combined the organic phases, and saturated the organic phases Wash with brine (30 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is passed through a LUNA preparation column (eluent is acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) After separation and purification, the title compound was obtained as a pale yellow solid (33 mg, 14%).
MS(ESI,pos.ion)m/z:608.2[H+1] +； MS(ESI,pos.ion)m/z:608.2[H+1] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.67(d,J＝7.6Hz,1H),7.49(d,J＝5.5Hz,1H),7.42(t,J＝7.5Hz,1H),7.31–7.19(m,3H),6.96(d,J＝7.4Hz,1H),6.34(d,J＝7.6Hz,1H),5.70(d,J＝7.5Hz,1H),5.40(s,1H),4.87(s,2H),4.60(d,J＝12.9Hz,1H),4.21(dd,J＝9.8,2.7Hz,1H),3.83–3.71(m,3H),3.65(dd,J＝13.2,9.0Hz,2H),3.44(s,3H),3.35(dd,J＝13.4,5.8Hz,2H),3.21(t,J＝10.5Hz,1H),2.91(t,J＝11.1Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.67 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.31 –7.19(m,3H), 6.96(d,J=7.4Hz,1H), 6.34(d,J=7.6Hz,1H), 5.70(d,J=7.5Hz,1H), 5.40(s,1H) ,4.87(s,2H),4.60(d,J＝12.9Hz,1H),4.21(dd,J＝9.8,2.7Hz,1H),3.83-3.71(m,3H),3.65(dd,J＝13.2 ,9.0Hz,2H),3.44(s,3H),3.35(dd,J=13.4,5.8Hz,2H),3.21(t,J=10.5Hz,1H),2.91(t,J=11.1Hz,1H ).
实施例19(R)-12-((R)-4,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4：6,7]环庚[1,2-b]噻吩8基)-7-羟基3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物81)Example 19 (R)-12-((R)-4,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1 ,2-b]thiophene 8)-7-hydroxy 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]Triazine-6,8-dione (Compound 81)
Figure PCTCN2020077781-appb-000071
Figure PCTCN2020077781-appb-000071
步骤1)3-(2,5-二氟苯基)噻吩的合成Step 1) Synthesis of 3-(2,5-difluorophenyl)thiophene
将2,5-二氟溴苯(595mg,3.08mmol)，3-噻吩硼酸(474mg,3.7mmol)，四三苯基膦钯(179mg,0.15mmol)和碳酸钠(980mg,9.25mmol)加入到双口瓶中，向其中加入DMF(8mL)和水(0.17mL)，氮气保护，反应混合物于85℃反应过夜。反应液过滤，向滤液中加入水(20mL)，所得混合物用乙酸乙酯(30mL×2)萃取，合并有机相，有机相用饱和氯化钠溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干，所得残留物经硅胶柱层析纯化(洗脱剂为石油醚)，纯化后得到标题化合物为无色油状物(303mg,50％)。2,5-Difluorobromobenzene (595mg, 3.08mmol), 3-thiophene boronic acid (474mg, 3.7mmol), tetrakistriphenylphosphine palladium (179mg, 0.15mmol) and sodium carbonate (980mg, 9.25mmol) were added to DMF (8 mL) and water (0.17 mL) were added to the two-neck flask under nitrogen protection, and the reaction mixture was reacted at 85°C overnight. The reaction solution was filtered, water (20mL) was added to the filtrate, the resulting mixture was extracted with ethyl acetate (30mL×2), the organic phases were combined, the organic phases were washed with saturated sodium chloride solution (30mL×3), and dried over anhydrous sodium sulfate After filtration, the filtrate was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (eluent was petroleum ether). After purification, the title compound was obtained as a colorless oil (303 mg, 50%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.63(d,J＝1.4Hz,1H),7.43–7.38(m,2H),7.29–7.21(m,1H),7.13–7.04(m,1H),6.97–6.89(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.63 (d, J = 1.4Hz, 1H), 7.43-7.38 (m, 2H), 7.29-7.21 (m, 1H), 7.13-7.04 (m, 1H) ), 6.97–6.89 (m, 1H).
步骤2)2-溴-3-(2,5-二氟苯基)噻吩的合成Step 2) Synthesis of 2-bromo-3-(2,5-difluorophenyl)thiophene
于反应瓶中加入3-(2,5-二氟苯基)噻吩(200mg,1.02mmol)和DMF(1.5mL)，将NBS(195mg,1.07mmol)溶解于DMF(0.5mL)中，缓慢滴加至上述反应液，滴加完毕后，反应混合物于室温反应过夜。向反应液中加入饱和硫代硫酸钠溶液(2mL)淬灭反应，加水(10mL)，然后用乙酸乙酯(10mL×2)萃取，合并有机相，用饱和氯化钠溶液(10mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干，所得残留物经硅胶柱层析纯化(洗脱剂为石油醚)，纯化后得到标题化合物为淡黄色油状物(245mg,87.4％)。Add 3-(2,5-difluorophenyl)thiophene (200mg, 1.02mmol) and DMF (1.5mL) to the reaction flask, dissolve NBS (195mg, 1.07mmol) in DMF (0.5mL) and slowly drop Add to the above reaction solution. After the addition is complete, the reaction mixture is reacted at room temperature overnight. Add saturated sodium thiosulfate solution (2mL) to the reaction solution to quench the reaction, add water (10mL), and then extract with ethyl acetate (10mL×2), combine the organic phases, and use saturated sodium chloride solution (10mL×3) Washed, dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent is petroleum ether). After purification, the title compound was obtained as a pale yellow oil (245mg, 87.4%) .
步骤3)2-(3-(2,5-二氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 3) Synthesis of methyl 2-(3-(2,5-difluorophenyl)thiophen-2-yl)benzoate
将2-溴-3-(2,5-二氟苯基)噻吩(274mg,1mmol)、2-甲氧羰基苯硼酸(269mg,1.5mmol)、醋酸钯(23mg,0.1mmol)、S-Phos(84mg,0.2mmol)和磷酸钾(436mg,1.99mmol)，加入到双口瓶中，向其中加入甲苯(4mL)和水(0.05mL)，氮气保护下，反应混合物于100℃反应过夜。过滤，滤液旋干，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)，纯化后得到标题化合物为淡黄色油状物(263mg,79.9％)。Combine 2-bromo-3-(2,5-difluorophenyl)thiophene (274mg, 1mmol), 2-methoxycarbonylphenylboronic acid (269mg, 1.5mmol), palladium acetate (23mg, 0.1mmol), S-Phos (84mg, 0.2mmol) and potassium phosphate (436mg, 1.99mmol) were added to a two-neck flask, toluene (4mL) and water (0.05mL) were added to it, and the reaction mixture was reacted at 100°C overnight under nitrogen protection. Filter, spin-dry the filtrate, and purify the residue obtained by silica gel column chromatography (eluent is petroleum ether/ethyl acetate (v/v) = 10/1). After purification, the title compound is obtained as a pale yellow oil (263mg, 79.9%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.75(d,J＝7.4Hz,1H),7.47(dd,J＝10.6,4.4Hz,1H),7.43–7.34(m,3H),7.18(dd,J＝5.2,2.2Hz,1H),6.95(td,J＝9.1,4.6Hz,1H),6.86(ddd,J＝8.9,7.3,3.5Hz,1H),6.71(ddd,J＝8.9,5.7,3.2Hz,1H),3.61(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.75 (d, J = 7.4 Hz, 1H), 7.47 (dd, J = 10.6, 4.4 Hz, 1H), 7.43-7.34 (m, 3H), 7.18 ( dd,J=5.2,2.2Hz,1H),6.95(td,J=9.1,4.6Hz,1H), 6.86(ddd,J=8.9,7.3,3.5Hz,1H), 6.71(ddd,J=8.9, 5.7, 3.2 Hz, 1H), 3.61 (s, 3H).
步骤4)2-(5-溴-3-(2,5-二氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 4) Synthesis of methyl 2-(5-bromo-3-(2,5-difluorophenyl)thiophen-2-yl)benzoate
于反应瓶中加入2-(3-(2,5-二氟苯基)噻吩-2-基)苯甲酸甲酯(244mg,0.74mmol)和DMF(2mL)，将NBS(148mg,0.82mmol)溶解于DMF(1mL)后，缓慢滴加至上述反应液中，反应混合物于室温反应6小时。向反应液中加入饱和硫代硫酸钠溶液(2mL)淬灭反应，再加水(10mL)，然后用乙酸乙酯(20mL×2)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，滤液旋干，得到标题化合物为黄色油状物(300mg,99.27％)。Add 2-(3-(2,5-difluorophenyl)thiophen-2-yl)benzoic acid methyl ester (244mg, 0.74mmol) and DMF (2mL) into the reaction flask, add NBS (148mg, 0.82mmol) After being dissolved in DMF (1 mL), it was slowly added dropwise to the above reaction solution, and the reaction mixture was reacted at room temperature for 6 hours. Saturated sodium thiosulfate solution (2mL) was added to the reaction solution to quench the reaction, then water (10mL) was added, and then extracted with ethyl acetate (20mL×2), the organic phases were combined, and the organic phase was saturated with sodium chloride solution (20mL ×3) Wash, dry with anhydrous sodium sulfate, filter, and spin-dry the filtrate to obtain the title compound as a yellow oil (300 mg, 99.27%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.77(dd,J＝7.7,1.1Hz,1H),7.47(td,J＝7.5,1.4Hz,1H),7.40(td,J＝7.6,1.3Hz,1H),7.33(d,J＝7.6Hz,1H),7.14(d,J＝2.1Hz,1H),6.95(td,J＝9.1,4.6Hz,1H),6.90–6.83(m,1H),6.67(ddd,J＝8.8,5.7,3.1Hz,1H),3.65(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.77 (dd, J = 7.7, 1.1 Hz, 1H), 7.47 (td, J = 7.5, 1.4 Hz, 1H), 7.40 (td, J = 7.6, 1.3 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.95 (td, J = 9.1, 4.6 Hz, 1H), 6.90-6.83 (m, 1H ), 6.67 (ddd, J=8.8, 5.7, 3.1 Hz, 1H), 3.65 (s, 3H).
步骤5)2-(3-(2,5-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯的合成Step 5) Synthesis of methyl 2-(3-(2,5-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoate
将2-(5-溴-3-(2,5-二氟苯基)噻吩-2-基)苯甲酸甲酯(4g,9.78mmol)，BINAP(1.26g,1.96mmol)，Pd 2(dba) 3(913mg,0.98mmol)，碳酸铯(11.15g,34.22mmol)，四氢吡咯(1.6mL,19mmol)和甲苯(60mL)加入到双口瓶中，氮气保护下，将反应混合物于80℃反应9h。过滤，滤液减压旋干，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)，纯化后得到标题化合物为黄色固体(3.34g,85.5％)。 Methyl 2-(5-bromo-3-(2,5-difluorophenyl)thiophen-2-yl)benzoate (4g, 9.78mmol), BINAP (1.26g, 1.96mmol), Pd 2 (dba ) 3 (913mg, 0.98mmol), cesium carbonate (11.15g, 34.22mmol), tetrahydropyrrole (1.6mL, 19mmol) and toluene (60mL) were added to the two-neck flask, and the reaction mixture was kept at 80°C under nitrogen protection. Reaction 9h. After filtration, the filtrate was spin-dried under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1). After purification, the title compound was obtained as a yellow solid (3.34g) ,85.5%).
MS(ESI,pos.ion)m/z:400.0[M+H] +； MS(ESI,pos.ion)m/z:400.0[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.62(d,J＝7.7Hz,1H),7.39(t,J＝7.4Hz,1H),7.34(d,J＝6.8Hz,1H),7.27(m,1H),6.91(td,J＝9.1,4.7Hz,1H),6.83(dt,J＝12.6,4.4Hz,1H),6.77(ddd,J＝8.9,6.1,3.3Hz,1H),5.83(d,J＝1.5Hz,1H),3.63(s,3H),3.30(t,J＝6.4Hz,4H),2.04(t,J＝6.5Hz,4H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.62 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.34 (d, J = 6.8 Hz, 1H), 7.27 (m, 1H), 6.91 (td, J = 9.1, 4.7 Hz, 1H), 6.83 (dt, J = 12.6, 4.4 Hz, 1H), 6.77 (ddd, J = 8.9, 6.1, 3.3 Hz, 1H), 5.83 (d, J = 1.5 Hz, 1H), 3.63 (s, 3H), 3.30 (t, J = 6.4 Hz, 4H), 2.04 (t, J = 6.5 Hz, 4H).
步骤6)2-(3-(2,5-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸的合成Step 6) Synthesis of 2-(3-(2,5-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoic acid
将化合物2-(3-(2,5-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯(3.34g,8.36mmol)溶解于四氢呋喃(25mL)和甲醇(10mL)中，将氢氧化钠(3.34g,83.5mmol)溶解于水(10mL)后，滴加至上述溶液中，滴加完毕后，将反应混合物于60℃反应反应11h。反应液减压蒸除溶剂，向残余物中加水(20mL)，用4N的盐酸溶液调pH值至4左右，然后用乙酸乙酯(30mL×2)萃取，合并有机相，有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干，得到标题化合物为黄色固体(3.12g,96.8％)。The compound 2-(3-(2,5-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoic acid methyl ester (3.34g, 8.36mmol) was dissolved in tetrahydrofuran (25mL After dissolving sodium hydroxide (3.34g, 83.5mmol) in water (10mL) in methanol (10mL) and methanol (10mL), it was added dropwise to the above solution. After the addition, the reaction mixture was reacted at 60°C for 11h. The reaction solution was evaporated under reduced pressure to remove the solvent, water (20mL) was added to the residue, the pH was adjusted to about 4 with 4N hydrochloric acid solution, and then extracted with ethyl acetate (30mL×2), the organic phases were combined, and the organic phase was saturated with chlorine. Wash with sodium chloride solution (30 mL), dry with anhydrous sodium sulfate, filter, and spin-dry the filtrate to obtain the title compound as a yellow solid (3.12 g, 96.8%).
MS(ESI,neg.ion)m/z:384.2[M-H] -。 MS (ESI, neg.ion) m/z: 384.2 [MH] - .
步骤7)4,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 7) 4,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one synthesis
于反应瓶中加入2-(3-(2,5-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸(3.3g,8.6mmol)，氯苯(10mL)和PPA(30mL)，将反应混合物于130℃反应过夜。反应完全后，将反应液冷却至室温后，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，有机相用饱和碳酸氢钠溶液(20mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干，得到标题化合物为黄色油状物(3.08g,98％)。Add 2-(3-(2,5-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoic acid (3.3g, 8.6mmol), chlorobenzene ( 10 mL) and PPA (30 mL), and react the reaction mixture at 130°C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, ice water (50mL) was added to the reaction solution, and then extracted with ethyl acetate (50mL×2), the organic phases were combined, and the organic phase was saturated with sodium bicarbonate solution (20mL×2). 3) Wash, dry with anhydrous sodium sulfate, filter, and spin-dry the filtrate under reduced pressure to obtain the title compound as a yellow oil (3.08 g, 98%).
步骤8)4,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 8) 4,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol synthesis
于反应瓶中加入4,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4：6,7]环庚[1,2-b]噻吩-8-酮(3.08g,8.4mmol)，四氢呋喃(40mL)和甲醇(4mL)，缓慢向其中加入硼氢化钠(650mg,16.84mmol)，反应混合物于室温反应15分钟。向反应液中加入饱和氯化铵溶液(20mL)淬灭反应，然后用乙酸乙酯(50mL×2)萃取，合并有机相，有机相用饱和氯化钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干，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)，纯化后得到标题化合物为黄色固体(1.89g,61％)。Add 4,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8- into the reaction flask Ketone (3.08g, 8.4mmol), tetrahydrofuran (40mL) and methanol (4mL) were slowly added sodium borohydride (650mg, 16.84mmol), and the reaction mixture was reacted at room temperature for 15 minutes. Saturated ammonium chloride solution (20mL) was added to the reaction solution to quench the reaction, and then extracted with ethyl acetate (50mL×2), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution (50mL), anhydrous sodium sulfate Dry, filter, spin-dry the filtrate, and purify the residue obtained by silica gel column chromatography (eluent is petroleum ether/ethyl acetate (v/v) = 10/1), and after purification, the title compound is obtained as a yellow solid (1.89g) ,61%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.51(d,J＝7.6Hz,1H),7.44(d,J＝7.3Hz,1H),7.33(t,J＝7.5Hz,1H), 7.26(m,1H),7.01(tq,J＝8.7,4.4Hz,2H),6.25(d,J＝6.1Hz,1H),6.20(d,J＝9.5Hz,1H),3.46–3.30(m,4H),2.89(d,J＝9.9Hz,1H),2.13–2.05(m,4H)。 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.51(d,J=7.6Hz,1H), 7.44(d,J=7.3Hz,1H), 7.33(t,J=7.5Hz,1H), 7.26 (m, 1H), 7.01 (tq, J = 8.7, 4.4 Hz, 2H), 6.25 (d, J = 6.1 Hz, 1H), 6.20 (d, J = 9.5 Hz, 1H), 3.46–3.30 (m, 4H), 2.89 (d, J=9.9 Hz, 1H), 2.13-2.05 (m, 4H).
步骤9)(12aR)-7-(苄基氧基)-12-(4,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-Step 9) (12aR)-7-(benzyloxy)-12-(4,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7 ]Cycloheptan[1,2-b]thiophene-8- 基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8二酮的合成Yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine- Synthesis of 6,8 diketone
将4,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1.36g,3.68mmol)，(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.33g,4.06mmol)加入到微波管中，向起哄加入乙酸乙酯(50mL)和1-丙基磷酸酐(50％w/w的乙酸乙酯溶液,13.1mL,22.0mmol)，反应混合物于微波110℃反应1h。向反应液中加水(30mL)，然后用乙酸乙酯(20mL×2)萃取，合并有机相，有机相用饱和碳酸氢钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液旋干，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)＝20/1)，纯化后得到标题化合物为黄色固体(740mg，29.6％)。4,7-Difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (1.36g , 3.68mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2, 1-f][1,2,4]triazine-6,8-dione (1.33g, 4.06mmol) was added to the microwave tube, ethyl acetate (50mL) and 1-propyl phosphoric anhydride ( 50% w/w ethyl acetate solution, 13.1 mL, 22.0 mmol), the reaction mixture was reacted in a microwave at 110°C for 1 h. Water (30mL) was added to the reaction solution, then extracted with ethyl acetate (20mL×2), the organic phases were combined, and the organic phases were washed with saturated sodium bicarbonate solution (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1). After purification, the title compound was obtained as a yellow solid (740 mg, 29.6%).
MS(ESI,pos.ion)m/z:679.3[M+H] +。 MS (ESI, pos.ion) m/z: 679.3 [M+H] + .
步骤10)(R)-12-((R)-4,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四Step 10) (R)-12-((R)-4,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1 ,2-b)thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetra 氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物81)的合成Synthesis of Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 81)
于反应瓶中加入(12aR)-7-(苄基氧基)-12-(4,7-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(835mg,1.23mmol)、氯化锂(521mg,12.29mmol)和N,N-二乙基乙酰胺(10mL)，氮气保护，反应混合物于100℃反应3h。反应完全后，向反应液中加水(50mL)，用1N的稀盐酸溶液调节pH值至6左右，用二氯甲烷(30mL×3)萃取，合并有机相，有机相用饱和氯化钠溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液所得残留物经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棕色固体(233mg，32.18％)。Add (12aR)-7-(benzyloxy)-12-(4,7-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6 ,7]cyclohepta[1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[ 2,1-f][1,2,4]triazine-6,8-dione (835mg, 1.23mmol), lithium chloride (521mg, 12.29mmol) and N,N-diethylacetamide (10mL ), under nitrogen protection, the reaction mixture was reacted at 100°C for 3 hours. After the reaction is complete, add water (50mL) to the reaction solution, adjust the pH to about 6 with 1N dilute hydrochloric acid solution, extract with dichloromethane (30mL×3), combine the organic phases, and use saturated sodium chloride solution ( 30mL×3) washed, dried with anhydrous sodium sulfate, filtered, the residue obtained from the filtrate was purified by LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13), separated and purified to obtain The title compound was a brown solid (233 mg, 32.18%).
MS(ESI,pos.ion)m/z:589.2[M+H] +； MS(ESI,pos.ion)m/z:589.2[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.51(d,J＝7.7Hz,1H),7.36(t,J＝7.6Hz,1H),7.22–7.13(m,2H),7.09(t,J＝7.2Hz,1H),6.89(d,J＝7.5Hz,1H),6.67(d,J＝7.4Hz,1H),6.18(dd,J＝12.5,6.8Hz,2H),5.96(s,1H),4.65(d,J＝12.2Hz,1H),4.40(dd,J＝9.9,2.9Hz,1H),3.79(dd,J＝11.9,2.9Hz,1H),3.55(dd,J＝11.0,2.9Hz,1H),3.41(ddd,J＝20.9,9.1,2.6Hz,5H),3.24(t,J＝10.6Hz,1H),3.12–3.02(m,1H),2.12(t,J＝6.4Hz,4H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.51 (d, J = 7.7 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.22-7.13 (m, 2H), 7.09 (t, J = 7.2Hz, 1H), 6.89 (d, J = 7.5Hz, 1H), 6.67 (d, J = 7.4Hz, 1H), 6.18 (dd, J = 12.5, 6.8Hz, 2H), 5.96 (s, 1H), 4.65 (d, J = 12.2 Hz, 1H), 4.40 (dd, J = 9.9, 2.9 Hz, 1H), 3.79 (dd, J = 11.9, 2.9 Hz, 1H), 3.55 (dd, J = 11.0 ,2.9Hz,1H),3.41(ddd,J=20.9,9.1,2.6Hz,5H), 3.24(t,J=10.6Hz,1H),3.12–3.02(m,1H),2.12(t,J= 6.4Hz, 4H).
实施例20(R)-12-((R)-4-氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物92)Example 20 (R)-12-((R)-4-fluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][ 1,2,4)Triazine-6,8-dione (Compound 92)
Figure PCTCN2020077781-appb-000072
Figure PCTCN2020077781-appb-000072
步骤1)4-(2-氟苯基)-2-甲基噻吩的合成Step 1) Synthesis of 4-(2-fluorophenyl)-2-methylthiophene
将4-溴-2-甲基噻吩(7.2g,41mmol)，2-氟苯硼酸(6.8g,49mmol)，四三苯基膦钯(2.4g,2.1mmol)和碳酸钠(13g,122.65mmol)加入到双口瓶中，向其中加入DMF(100mL)和水(2.2mL)，氮气保护下，反应混合物于85℃反应过夜。过滤，向滤液中加入水(200mL)，用乙酸乙酯(200mL×2)萃取，合并有 机相，有机相用饱和氯化钠溶液(200mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干，所得残留物经硅胶柱层析纯化(洗脱剂为石油醚)，纯化后得到标题化合物为黄色油状物(7.5g,96％)。Combine 4-bromo-2-methylthiophene (7.2g, 41mmol), 2-fluorophenylboronic acid (6.8g, 49mmol), tetrakistriphenylphosphine palladium (2.4g, 2.1mmol) and sodium carbonate (13g, 122.65mmol) ) Was added to a two-neck flask, DMF (100 mL) and water (2.2 mL) were added thereto, and the reaction mixture was reacted at 85° C. overnight under the protection of nitrogen. Filter, add water (200mL) to the filtrate, extract with ethyl acetate (200mL×2), combine the organic phases, wash the organic phase with saturated sodium chloride solution (200mL×3), dry with anhydrous sodium sulfate, filter, and filtrate Rotate to dryness under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent is petroleum ether). After purification, the title compound was obtained as a yellow oil (7.5 g, 96%).
步骤2)2-溴-3-(2-氟苯基)-5-甲基噻吩的合成Step 2) Synthesis of 2-bromo-3-(2-fluorophenyl)-5-methylthiophene
于反应瓶中加入4-(2-氟苯基)-2-甲基噻吩(7.5g,39mmol)和DMF(100mL)，将NBS(7.4g,41mmol)溶解于DMF(30mL)后，缓慢滴加至上述反应液，滴加完毕后于室温反应过夜。向反应液中加入饱和硫代硫酸钠溶液(10mL)淬灭反应，加水(300mL)，然后用乙酸乙酯(200mL×2)萃取，合并有机相，有机相用饱和氯化钠溶液(20 0mL×3)洗涤，无水硫酸钠干燥，过滤，滤液旋干，所得残留物经硅胶柱层析纯化(洗脱剂为石油醚)，纯化后得到标题化合物为淡黄色油状物(9.6g,91％)。Add 4-(2-fluorophenyl)-2-methylthiophene (7.5g, 39mmol) and DMF (100mL) into the reaction flask, dissolve NBS (7.4g, 41mmol) in DMF (30mL), and slowly drop it. Add to the above reaction solution and react overnight at room temperature after the addition is complete. Add saturated sodium thiosulfate solution (10mL) to the reaction solution to quench the reaction, add water (300mL), then extract with ethyl acetate (200mL×2), combine the organic phases, and use saturated sodium chloride solution (20 0mL) ×3) Wash, dry with anhydrous sodium sulfate, filter, and spin-dry the filtrate. The residue is purified by silica gel column chromatography (eluent is petroleum ether). After purification, the title compound is obtained as a pale yellow oil (9.6g, 91 %).
步骤3)2-(3-(2-氟苯基)-5-甲基噻吩-2-基)苯甲酸甲酯的合成Step 3) Synthesis of methyl 2-(3-(2-fluorophenyl)-5-methylthiophen-2-yl)benzoate
将2-溴-3-(2-氟苯基)-5-甲基噻吩(9.3g,34mmol)、2-甲氧羰基苯硼酸(9.3g,52mmol)、双三苯基膦二氯化钯(2.4g,3.4mmol)和碳酸钾(14g,100.28mmol)，加入到双颈瓶中，向其中加入四氢呋喃(150mL)和水(1.9mL)，氮气保护，反应混合物于70℃反应过夜。过滤，滤液减压旋干，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)，纯化后得到标题化合物为黄色油状物(7.8g,70％)。Combine 2-bromo-3-(2-fluorophenyl)-5-methylthiophene (9.3g, 34mmol), 2-methoxycarbonylphenylboronic acid (9.3g, 52mmol), bistriphenylphosphine palladium dichloride (2.4g, 3.4mmol) and potassium carbonate (14g, 100.28mmol) were added to a double-necked flask, tetrahydrofuran (150mL) and water (1.9mL) were added to it, protected by nitrogen, and the reaction mixture was reacted at 70°C overnight. After filtration, the filtrate was spin-dried under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1). After purification, the title compound was obtained as a yellow oil (7.8 g, 70%).
1H NMR(600MHz,CDCl 3)δ(ppm)7.67(dd,J＝7.8,1.1Hz,1H),7.42(td,J＝7.6,1.4Hz,1H),7.36(dd,J＝7.7,1.0Hz,1H),7.32(td,J＝7.6,1.3Hz,1H),7.16(m,1H),7.01–6.96(m,2H),6.90(td,J＝7.5,1.1Hz,1H),6.86(dd,J＝2.2,1.1Hz,1H),3.60(s,3H),2.54(d,J＝1.0Hz,3H)。 1 H NMR(600MHz, CDCl 3 )δ(ppm) 7.67(dd,J=7.8,1.1Hz,1H),7.42(td,J=7.6,1.4Hz,1H),7.36(dd,J=7.7,1.0 Hz, 1H), 7.32 (td, J = 7.6, 1.3 Hz, 1H), 7.16 (m, 1H), 7.01–6.96 (m, 2H), 6.90 (td, J = 7.5, 1.1 Hz, 1H), 6.86 (dd, J=2.2, 1.1 Hz, 1H), 3.60 (s, 3H), 2.54 (d, J=1.0 Hz, 3H).
步骤4)2-(3-(2-氟苯基)-5-甲基噻吩-2-基)苯甲酸的合成Step 4) Synthesis of 2-(3-(2-fluorophenyl)-5-methylthiophen-2-yl)benzoic acid
将2-(3-(2-氟苯基)-5-甲基噻吩-2-基)苯甲酸甲酯(4g,12.25mmol)溶解于四氢呋喃(30mL)和甲醇(10mL)中，室温下滴加2N氢氧化钠溶液(12.3mL)，滴加完毕后，将反应混合物于50℃反应过夜。减压旋干有机溶剂，向残余物中加水(20mL)，用4N盐酸溶液调pH值至4左右，然后用乙酸乙酯(30mL×2)萃取，合并有机相，有机相用饱和氯化钠溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干，得到标题化合物为黄色固体(3.8g,99％)。Methyl 2-(3-(2-fluorophenyl)-5-methylthiophen-2-yl)benzoate (4g, 12.25mmol) was dissolved in tetrahydrofuran (30mL) and methanol (10mL), and dropped at room temperature 2N sodium hydroxide solution (12.3 mL) was added, and after the addition was completed, the reaction mixture was reacted at 50° C. overnight. The organic solvent was spin-dried under reduced pressure, water (20 mL) was added to the residue, the pH was adjusted to about 4 with 4N hydrochloric acid solution, and then extracted with ethyl acetate (30 mL×2), the organic phases were combined, and the organic phase was saturated with sodium chloride The solution (30 mL) was washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain the title compound as a yellow solid (3.8 g, 99%).
MS(ESI,neg.ion)m/z:311.1[M-H] -。 MS (ESI, neg.ion) m/z: 311.1 [MH] - .
步骤5)4-氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 5) Synthesis of 4-fluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
于反应瓶中加入化合物2-(3-(2-氟苯基)-5-甲基噻吩-2-基)苯甲酸(500mg,1.6mmol)和PPA(5mL)，将反应混合物于120℃反应8h。反应完全后，将反应冷却至室温后，向反应液中加冰水(10mL)，然后用乙酸乙酯(10mL×2)萃取，合并有机相，有机相用饱和碳酸氢钠溶液(10mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干，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)，纯化后得到标题化合物为黄色固体(98mg,20.81％)。The compound 2-(3-(2-fluorophenyl)-5-methylthiophen-2-yl)benzoic acid (500mg, 1.6mmol) and PPA (5mL) were added to the reaction flask, and the reaction mixture was reacted at 120°C 8h. After the reaction was completed, the reaction was cooled to room temperature, ice water (10mL) was added to the reaction solution, and then extracted with ethyl acetate (10mL×2), the organic phases were combined, and the organic phase was mixed with saturated sodium bicarbonate solution (10mL×3). ) Wash, dry with anhydrous sodium sulfate, filter, and spin off the filtrate under reduced pressure. The residue obtained is purified by silica gel column chromatography (eluent is petroleum ether/ethyl acetate (v/v) = 10/1). The title compound was obtained as a yellow solid (98 mg, 20.81%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.77(d,J＝7.4Hz,1H),7.70(d,J＝7.8Hz,1H),7.57(dd,J＝18.1,7.6Hz,2H),7.45(d,J＝7.6Hz,1H),7.43–7.37(m,1H),7.31(dd,J＝12.2,9.0Hz,2H),2.56(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.77 (d, J = 7.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.57 (dd, J = 18.1, 7.6 Hz, 2H) , 7.45 (d, J = 7.6 Hz, 1H), 7.43-7.37 (m, 1H), 7.31 (dd, J = 12.2, 9.0 Hz, 2H), 2.56 (s, 3H).
步骤6)2-(溴甲基)-4-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 6) Synthesis of 2-(bromomethyl)-4-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将4-氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(1g,3.4mmol)，NBS(679mg,3.74mmol)和过氧化苯甲酰(42mg,0.17mmol)加入到反应瓶中，向其中加入四氯化碳(20mL)，将反应混合物于78℃反应反应过夜。减压旋干有机溶剂，加入二氯甲烷(20mL)，有机相用饱和氯化钠溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干，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)，纯化后得到标题化合物为淡黄色固体(800mg,63.09％)。Combine 4-fluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (1g, 3.4mmol), NBS (679mg, 3.74 mmol) and benzoyl peroxide (42 mg, 0.17 mmol) were added to the reaction flask, carbon tetrachloride (20 mL) was added thereto, and the reaction mixture was reacted at 78° C. overnight. The organic solvent was spin-dried under reduced pressure, dichloromethane (20 mL) was added, the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The residue was subjected to silica gel column chromatography Purification (eluent: petroleum ether/ethyl acetate (v/v) = 10/1), after purification, the title compound was obtained as a pale yellow solid (800 mg, 63.09%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.79(dd,J＝7.7,1.0Hz,1H),7.76–7.71(m,1H),7.65–7.56(m,3H),7.50(td,J＝7.6,1.0Hz,1H),7.44(td,J＝8.0,5.0Hz,1H),7.34(ddd,J＝11.1,8.2,1.3Hz,1H),4.77(s,2H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.79 (dd, J = 7.7, 1.0 Hz, 1H), 7.76-7.71 (m, 1H), 7.65-7.56 (m, 3H), 7.50 (td, J =7.6, 1.0 Hz, 1H), 7.44 (td, J = 8.0, 5.0 Hz, 1H), 7.34 (ddd, J = 11.1, 8.2, 1.3 Hz, 1H), 4.77 (s, 2H).
步骤7)4-氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 7) Synthesis of 4-fluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将化合物2-(溴甲基)-4-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(576mg,1.54mmol)，加入至反应瓶中，向其中加入四氢呋喃(8mL)和甲醇钠溶液(0.34mL,1.7mmol,5mol/L)，反应混合物于室温反应1.5h。向反应液中加水(20mL)，然后用二氯甲烷(30mL×2)萃取，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，滤液减压旋干，所得残留物经硅胶柱层析纯化(洗脱剂为石油醚/二氯甲烷(v/v)＝10/1)，纯化后得到标题化合物为淡黄色固体(330mg,65.91％)。The compound 2-(bromomethyl)-4-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (576mg, 1.54mmol) was added To the reaction flask, tetrahydrofuran (8mL) and sodium methoxide solution (0.34mL, 1.7mmol, 5mol/L) were added, and the reaction mixture was reacted at room temperature for 1.5h. Water (20mL) was added to the reaction solution, and then extracted with dichloromethane (30mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was rotated under reduced pressure. After drying, the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/dichloromethane (v/v)=10/1). After purification, the title compound was obtained as a pale yellow solid (330 mg, 65.91%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.79(dd,J＝7.8,1.1Hz,1H),7.75(d,J＝7.8Hz,1H),7.63–7.55(m,2H),7.52(d,J＝6.1Hz,1H),7.48(td,J＝7.7,1.0Hz,1H),7.42(td,J＝7.9,5.0Hz,1H),7.33(ddd,J＝11.1,8.1,1.3Hz,1H),4.68(s,2H),3.45(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.79 (dd, J = 7.8, 1.1 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.63-7.55 (m, 2H), 7.52 ( d,J=6.1Hz,1H),7.48(td,J=7.7,1.0Hz,1H),7.42(td,J=7.9,5.0Hz,1H),7.33(ddd,J=11.1,8.1,1.3Hz ,1H), 4.68(s, 2H), 3.45(s, 3H).
步骤8)4-氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 8) Synthesis of 4-fluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
于反应瓶中加入4-氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(325mg,1mmol)、四氢呋喃(6mL)和甲醇(0.6mL)，向其中缓慢加入硼氢化钠(77mg,2mmol)，反应混合物于室温反应15min。加入饱和氯化铵溶液(10mL)淬灭反应，然后用乙酸乙酯(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，滤液减压旋干，得到标题化合物为白色固体(325mg,99.39％)。Add 4-fluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (325mg, 1 mmol), tetrahydrofuran (6 mL) and methanol (0.6 mL), sodium borohydride (77 mg, 2 mmol) was slowly added thereto, and the reaction mixture was reacted at room temperature for 15 min. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), then using ethyl acetate (20 mL×2), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Rotate to dryness under reduced pressure to obtain the title compound as a white solid (325 mg, 99.39%).
步骤9)(12aR)-7-(苄基氧基)-12-(4-氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-Step 9) (12aR)-7-(benzyloxy)-12-(4-fluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[ 1,2-b]thiophen-8-yl)-3,4,12,12a- 四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将4-氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(325mg,0.1mmol)，(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(359mg,1.1mmol)加入至反应瓶中，向其中加入乙酸异丙酯(13mL)和1-丙基磷酸酐(乙酸乙酯溶液)(质量分数50％,1.78mL,2.99mmol)，反应混合物于90℃反应7.5h。向反应液中加水(20mL)，然后用乙酸乙酯(20mL×2)萃取，合并有机相，有机相用饱和碳酸氢钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干，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)＝20/1)，纯化后得到标题化合物为白色固体(245mg,38.71％)。The 4-fluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (325mg, 0.1mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][ 1,2,4]Triazine-6,8-dione (359mg, 1.1mmol) was added to the reaction flask, and isopropyl acetate (13mL) and 1-propyl phosphoric anhydride (ethyl acetate solution) were added to it (Mass fraction 50%, 1.78 mL, 2.99 mmol), the reaction mixture was reacted at 90° C. for 7.5 h. 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 rotated under reduced pressure. After drying, the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1). After purification, the title compound was obtained as a white solid (245 mg, 38.71%).
MS(ESI,pos.ion)m/z:636.2[M+H] +。 MS (ESI, pos.ion) m/z: 636.2 [M+H] + .
步骤10)(R)-12-((R)-4-氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢Step 10) (R)-12-((R)-4-fluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物92)的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 92)
将(12aR)-7-(苄基氧基)-12-(4-氟-2-(甲氧基甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(245mg,0.39mmol)和氯化锂(164mg,3.87mmol)加入至单口瓶中，向其中加入N,N-二乙基乙酰胺(5mL)，氮气保护，反应混合物于100℃反应4h。向反应液中加水(20mL)，用1N的稀盐酸调节pH值至6左右，然后用乙酸乙酯(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，滤液减压旋干，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橙色固体(80mg,38.05％)。The (12aR)-7-(benzyloxy)-12-(4-fluoro-2-(methoxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4] Triazine-6,8-dione (245mg, 0.39mmol) and lithium chloride (164mg, 3.87mmol) were added to the single-neck flask, and N,N-diethylacetamide (5mL ), under nitrogen protection, the reaction mixture was reacted at 100°C for 4h. Add water (20mL) to the reaction solution, adjust the pH to about 6 with 1N dilute hydrochloric acid, then extract with ethyl acetate (20mL×3), combine the organic phases, and use saturated sodium chloride solution (20mL×3) for the organic phase Washed, dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13), separated and purified The title compound was obtained as an orange solid (80 mg, 38.05%).
MS(ESI,pos.ion)m/z:546.0[M+H] +； MS(ESI,pos.ion)m/z:546.0[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.66(d,J＝7.6Hz,1H),7.50(d,J＝5.7Hz,1H),7.45–7.37(m,2H),7.24(m,3H),6.95(d,J＝7.5Hz,1H),6.39(d,J＝7.6Hz,1H),5.79(d,J＝7.6Hz,1H),5.42(s,1H),4.73(s,2H),4.58(d,J＝12.1Hz,1H),4.23(dd,J＝9.9,3.0Hz,1H),3.72(dd,J＝11.9,2.9Hz,1H),3.50(s,3H),3.33(dd,J＝14.9,6.9Hz,2H),3.19(t,J＝10.5Hz,1H),2.96–2.83(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.66 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 5.7 Hz, 1H), 7.45-7.37 (m, 2H), 7.24 (m, 3H), 6.95(d,J=7.5Hz,1H), 6.39(d,J=7.6Hz,1H), 5.79(d,J=7.6Hz,1H), 5.42(s,1H), 4.73(s, 2H), 4.58(d,J=12.1Hz,1H), 4.23(dd,J=9.9,3.0Hz,1H), 3.72(dd,J=11.9,2.9Hz,1H), 3.50(s,3H), 3.33 (dd, J = 14.9, 6.9 Hz, 2H), 3.19 (t, J = 10.5 Hz, 1H), 2.96-2.83 (m, 1H).
实施例21(R)-12-((R)-4-氟-2-甲氧基-8H-二苯并[3,4：6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H- [1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物96)Example 21 (R)-12-((R)-4-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8 -Yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2, 4) Triazine-6,8-dione (Compound 96)
Figure PCTCN2020077781-appb-000073
Figure PCTCN2020077781-appb-000073
步骤1)2-溴-4-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 1) Synthesis of 2-bromo-4-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
于反应瓶中依次加入4-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(5g,17.84mmol)、醋酸(20mL)和NBS(3.56g,19.6mmol)，将反应混合物加热至55℃反应过夜，过滤，得到标题化合物为淡黄色固体(6g,94％)。Add 4-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (5g, 17.84mmol), acetic acid (20mL) and NBS (3.56 g, 19.6 mmol), the reaction mixture was heated to 55° C. overnight, and filtered to obtain the title compound as a pale yellow solid (6 g, 94%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.82(dd,J＝7.7,1.0Hz,1H),7.69(dd,J＝7.8,0.7Hz,1H),7.64–7.59(m,3H),7.56–7.43(m,2H),7.37(ddd,J＝11.0,8.2,1.3Hz,1H)。 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.82(dd,J=7.7,1.0Hz,1H), 7.69(dd,J=7.8,0.7Hz,1H), 7.64–7.59(m,3H), 7.56-7.43 (m, 2H), 7.37 (ddd, J=11.0, 8.2, 1.3 Hz, 1H).
步骤2)2-溴-4-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 2) Synthesis of 2-bromo-4-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
于反应瓶中加入2-溴-4-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(6g,17mmol)、四氢呋喃(30mL)和甲醇(3mL)，向其中缓慢加入硼氢化钠(6.11g,155mmol)，反应混合物于室温反应15min。向反应液中加入饱和氯化铵溶液(10mL)淬灭反应，然后用乙酸乙酯(20mL×3)萃取，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，滤液减压旋干，得到标题化合物为淡黄色固体(5.56g,92％)。Add 2-bromo-4-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (6g, 17mmol), tetrahydrofuran (30mL) to the reaction flask ) And methanol (3 mL), sodium borohydride (6.11 g, 155 mmol) was slowly added thereto, and the reaction mixture was reacted at room temperature for 15 min. Saturated ammonium chloride solution (10mL) was added to the reaction solution to quench the reaction, then extracted with ethyl acetate (20mL×3), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution (20mL) and anhydrous sodium sulfate After drying and filtering, the filtrate was spin-dried under reduced pressure to obtain the title compound as a pale yellow solid (5.56 g, 92%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.81(d,J＝8.1Hz,1H),7.64(d,J＝7.8Hz,1H),7.56(d,J＝5.1Hz,1H),7.49(d,J＝6.1Hz,2H),7.40(td,J＝8.0,5.5Hz,1H),7.33(d,J＝7.8Hz,1H),7.05(dd,J＝10.1,8.8Hz,1H),5.34(s,1H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.81 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.49 (d,J=6.1Hz,2H),7.40(td,J=8.0,5.5Hz,1H),7.33(d,J=7.8Hz,1H),7.05(dd,J=10.1,8.8Hz,1H) ,5.34(s,1H).
步骤3)4-氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 3) Synthesis of 4-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将2-溴-4-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1g,2.77mmol)、碘化钾(505mg,3.04mmol)、氧化铜(242mg,3.04mmol)、甲醇钠溶液(1mL,5.4mmol,5.4mol/L)和甲醇(10mL)加入到微波管中，将反应混合物于微波110℃反应4h。向反应液中加水(50mL)，用乙酸乙酯(100mL×2)，合并有机相，有机相用饱和氯化钠溶液(30mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干，所得残留物经硅胶柱层析纯化(洗脱剂为石油醚/二氯甲烷(v/v)＝1/1)，纯化后得到标题化合物为白色固体(600mg,69.37％)。Combine 2-bromo-4-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (1g, 2.77mmol), potassium iodide (505mg, 3.04mmol) ), copper oxide (242 mg, 3.04 mmol), sodium methoxide solution (1 mL, 5.4 mmol, 5.4 mol/L) and methanol (10 mL) were added to the microwave tube, and the reaction mixture was reacted in the microwave at 110° C. for 4 h. Add water (50mL) to the reaction solution, use ethyl acetate (100mL×2), combine the organic phases, wash the organic phase with saturated sodium chloride solution (30mL×3), dry with anhydrous sodium sulfate, filter, and spin the filtrate under reduced pressure. After drying, the obtained residue was purified by silica gel column chromatography (eluent: petroleum ether/dichloromethane (v/v) = 1/1). After purification, the title compound was obtained as a white solid (600 mg, 69.37%).
MS(ESI,pos.ion)m/z:313.1[M+H] +。 MS (ESI, pos.ion) m/z: 313.1 [M+H] + .
步骤4)(12aR)-7-(苄氧基)-12-(4-氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢Step 4) (12aR)-7-(benzyloxy)-12-(4-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将4-氟-2-甲氧基-8H-二苯并[3,4：6,7]环庚[1,2-b]噻吩-8-醇(1.4g,4.5mmol)、(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.6g,4.9mmol)、乙酸乙酯(40mL)和1-丙基磷酸酐(乙酸乙酯溶液)(质量分数50％,8mL,13.44mmol)加入至微波管中，将反应混合物于微波110℃反应2h。向反应液中加水(20mL)，然后用乙酸乙酯(20mL×2)萃取，合并有机相，有机相用饱和碳酸氢钠溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压旋干，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)＝20/1)，得到标题化合物为白色固体(790mg,28％)。The 4-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cycloheptan[1,2-b]thiophene-8-ol (1.4g, 4.5mmol), (R) -7-(Benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2 ,4] Triazine-6,8-dione (1.6g, 4.9mmol), ethyl acetate (40mL) and 1-propyl phosphoric anhydride (ethyl acetate solution) (mass fraction 50%, 8mL, 13.44mmol) It was added to a microwave tube, and the reaction mixture was reacted in a microwave at 110° C. for 2 h. 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 rotated under reduced pressure. After drying, the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=20/1) to obtain the title compound as a white solid (790 mg, 28%).
MS(ESI,pos.ion)m/z:622.2[M+H] +。 MS (ESI, pos.ion) m/z: 622.2 [M+H] + .
步骤5)(R)-12-((R)-4-氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]Step 5) (R)-12-((R)-4-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8 -Radical)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4] 噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物96)的合成Synthesis of oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 96)
将(12aR)-7-(苄氧基)-12-(4-氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(810mg,1.30mmol)和氯化锂(552mg,13.02mmol)加入至反应瓶中，向其中加入N,N-二乙基乙酰胺(15mL)，氮气保护下，反应混合物于100℃反应5h。向反应液中加水(20mL)，用1N稀盐酸调节pH值至6左右，然后用乙酸乙酯(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，滤液减压旋干，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棕色固体(113mg,16.32％)。Add (12aR)-7-(benzyloxy)-12-(4-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene -8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4] Triazine-6,8-dione (810mg, 1.30mmol) and lithium chloride (552mg, 13.02mmol) were added to the reaction flask, and N,N-diethylacetamide (15mL) was added to it under nitrogen protection The reaction mixture was reacted at 100°C for 5h. Add water (20mL) to the reaction solution, adjust the pH to about 6 with 1N dilute hydrochloric acid, then extract with ethyl acetate (20mL×3), combine the organic phases, and wash the organic phase with saturated sodium chloride solution (20mL×3) , Dried with anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue obtained was purified by LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13), separated and purified to obtain The title compound was a brown solid (113 mg, 16.32%).
MS(ESI,pos.ion)m/z:532.0[M+H] +； MS(ESI,pos.ion)m/z:532.0[M+H] + ;
1H NMR(600MHz,CDCl 3)δ(ppm)7.54(d,J＝7.7Hz,1H),7.40(ddd,J＝17.6,11.4,6.4Hz,2H),7.28–7.22(m,2H),7.17(t,J＝7.2Hz,1H),6.90(d,J＝7.5Hz,1H),6.72(d,J＝5.6Hz,1H),6.49(d,J＝7.5Hz,1H),5.95(d,J＝7.5Hz,1H),5.41(s,1H),4.59(dd,J＝13.5,1.9Hz,1H),4.29(dd,J＝10.0,3.1Hz,1H),4.03(s,3H),3.75(dd,J＝12.1,3.2Hz,1H),3.45(dd,J＝11.1,3.0Hz,1H),3.37(td,J＝11.9,2.4Hz,1H),3.24(t,J＝10.6Hz,1H),2.93(td,J＝13.5,3.4Hz,1H)。 1 H NMR (600MHz, CDCl 3 ) δ (ppm) 7.54 (d, J = 7.7 Hz, 1H), 7.40 (ddd, J = 17.6, 11.4, 6.4 Hz, 2H), 7.28-7.22 (m, 2H), 7.17(t,J=7.2Hz,1H), 6.90(d,J=7.5Hz,1H), 6.72(d,J=5.6Hz,1H), 6.49(d,J=7.5Hz,1H), 5.95( d,J=7.5Hz,1H),5.41(s,1H),4.59(dd,J=13.5,1.9Hz,1H), 4.29(dd,J=10.0,3.1Hz,1H),4.03(s,3H) ), 3.75 (dd, J = 12.1, 3.2 Hz, 1H), 3.45 (dd, J = 11.1, 3.0 Hz, 1H), 3.37 (td, J = 11.9, 2.4 Hz, 1H), 3.24 (t, J = 10.6 Hz, 1H), 2.93 (td, J=13.5, 3.4 Hz, 1H).
实施例22(R)-12-(R)-(4,5-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物31)Example 22 (R)-12-(R)-(4,5-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1 ,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1 -f][1,2,4]triazine-6,8-dione (Compound 31)
Figure PCTCN2020077781-appb-000074
Figure PCTCN2020077781-appb-000074
步骤1)2-(3-(2,3-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯的合成Step 1) Synthesis of methyl 2-(3-(2,3-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoate
于反应瓶中加入2-(5-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(5.0g,12.2mmol)、四氢吡咯(4.3g,61mmol)、BINAP(1.6g,2.4mmol)、Pd 2(dba) 3(1.4g,1.2mmol)、叔丁醇钠(2.4g,24.4mmol)和甲苯(20mL)，氮气保护，反应混合物于110℃反应3小时。过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/EtOAc(v/v)＝15/1)纯化，得标题化合物为黄色固体(2.0g,41％)。 Add 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)methyl benzoate (5.0g, 12.2mmol), tetrahydropyrrole (4.3g, 61mmol) to the reaction flask ), BINAP (1.6g, 2.4mmol), Pd 2 (dba) 3 (1.4g, 1.2mmol), sodium tert-butoxide (2.4g, 24.4mmol) and toluene (20mL), protected by nitrogen, the reaction mixture was kept at 110°C React for 3 hours. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v)=15/1) to obtain the title compound as a yellow solid (2.0 g, 41%).
MS(ESI,pos.ion)m/z:400.2[M+H] +； MS(ESI,pos.ion)m/z:400.2[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.64(d,J＝7.7Hz,1H),7.40(ddd,J＝13.0,7.6,3.8Hz,2H),7.28(s,1H),7.00(ddd,J＝9.8,8.6,1.8Hz,1H),6.90–6.77(m,2H),5.88(d,J＝1.9Hz,1H),3.65(s,3H),3.34(t,J＝6.5Hz,4H),2.07(t,J＝6.5Hz,4H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.64 (d, J = 7.7 Hz, 1H), 7.40 (ddd, J = 13.0, 7.6, 3.8 Hz, 2H), 7.28 (s, 1H), 7.00 ( ddd,J=9.8,8.6,1.8Hz,1H), 6.90–6.77(m,2H), 5.88(d,J=1.9Hz,1H), 3.65(s,3H), 3.34(t,J=6.5Hz , 4H), 2.07 (t, J=6.5 Hz, 4H).
步骤2)2-(3-(2,3-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸的合成Step 2) Synthesis of 2-(3-(2,3-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoic acid
向反应瓶中加入2-(3-(2,3-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯(3.2g,8.0mmol)、甲醇(10mL)、THF(10mL)和叔丁醇钠(3.2g,32mmol)的水(5mL)溶液，混合物于60℃搅拌反应24h。反 应结束后，加2N盐酸调pH至5左右，向反应液中加入水(10mL)，,用乙酸乙酯(10mL×2)萃取，合并有机相，有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黄色固体(2.6g,84％)。Add methyl 2-(3-(2,3-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoate (3.2g, 8.0mmol), methanol to the reaction flask (10mL), THF (10mL) and sodium tert-butoxide (3.2g, 32mmol) in water (5mL) solution, the mixture was stirred at 60°C for 24h. After the reaction, add 2N hydrochloric acid to adjust the pH to about 5, add water (10mL) to the reaction solution, extract with ethyl acetate (10mL×2), combine the organic phases, and wash the organic layer with saturated brine (20mL). It was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow solid (2.6 g, 84%).
MS(ESI,neg.ion)m/z：384.0[M-H] -。 MS (ESI, neg. ion) m/z: 384.0 [MH] - .
步骤3)4,5-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 3) 4,5-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one synthesis
于反应瓶中加入2-(3-(2,3-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸(2.5g,6.5mmol)和多聚磷酸(15mL)，反应混合物于120℃搅拌反应10h。向反应液中加入冰水(50mL)将其溶解，再用二氯甲烷(10mL×3)萃取，合并有机相，有机层用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/CH 2Cl 2(v/v)＝5/1)纯化，得标题化合物为黄色固体(1.6g,69％)。 Add 2-(3-(2,3-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoic acid (2.5g, 6.5mmol) and polyphosphoric acid in the reaction flask (15mL), the reaction mixture was stirred at 120°C for 10h. Ice water (50mL) was added to the reaction solution to dissolve it, and then extracted with dichloromethane (10mL×3), the organic phases were combined, the organic layer was washed with saturated brine (30mL), dried with anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/CH 2 Cl 2 (v/v) = 5/1) to obtain the title compound as a yellow solid (1.6 g, 69%).
步骤4)4,5-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 4) 4,5-Difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol synthesis
于反应瓶中加入4,5-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(1.6g,4.4mmol)、THF(8mL)和甲醇(8mL)，反应混合物于室温下搅拌，然后缓慢加入硼氢化钠(708mg,18mmol)，反应25分钟。向反应液加入饱和氯化铵溶液(10mL)，用乙酸乙酯(10mL)萃取，合并有机相，有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为浅黄色固体(1.3g,78％)。Add 4,5-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8- to the reaction flask Ketone (1.6g, 4.4mmol), THF (8mL) and methanol (8mL), the reaction mixture was stirred at room temperature, then sodium borohydride (708mg, 18mmol) was slowly added, and the reaction was carried out for 25 minutes. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL), the organic phases were combined, the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound was obtained as a pale yellow solid (1.3 g, 78%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.73(d,J＝7.8Hz,1H),7.58–7.52(m,1H),7.43(d,J＝7.6Hz,1H),7.36(t,J＝7.3Hz,1H),7.29–7.24(m,2H),7.19(dd,J＝17.3,8.9Hz,1H),6.24(d,J＝5.5Hz,1H),5.29(s,1H),3.41(dt,J＝9.3,6.4Hz,4H),2.11(t,J＝6.5Hz,4H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.73(d,J=7.8Hz,1H), 7.58-7.52(m,1H), 7.43(d,J=7.6Hz,1H), 7.36(t, J=7.3Hz,1H), 7.29–7.24(m,2H), 7.19(dd,J=17.3,8.9Hz,1H), 6.24(d,J=5.5Hz,1H), 5.29(s,1H), 3.41(dt,J=9.3,6.4Hz,4H), 2.11(t,J=6.5Hz,4H).
步骤5)(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-Step 5) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7 ]Cycloheptan[1,2-b]thiophene-8- 基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6-,8二酮的合成Yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine- Synthesis of 6-,8 diketone
于反应瓶中加入4,5-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1.6g,4.5mmol)、(R)-7-(苄氧基)-3,4,12,12a四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(1.6g，5.0mmol)、1-丙基磷酸酐(5.4mL,9.1mmol)和乙酸异丙酯(15mL)，反应混合物于90℃下搅拌反应2h。向反应中加水(20mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机层用饱和食盐水(20mL)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(洗脱剂为DCM/MeOH(v/v)＝15/1)纯化，得标题化合物为淡黄棕色固体(1.1g,36％)Add 4,5-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8- to the reaction flask Alcohol (1.6g, 4.5mmol), (R)-7-(benzyloxy)-3,4,12,12a tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido [2,1-f] [1,2,4]triazine-6,8-dione (1.6g, 5.0mmol), 1-propyl phosphoric anhydride (5.4mL, 9.1mmol) and isopropyl acetate (15mL), the reaction mixture was stirred at 90°C for 2h. Water (20 mL) was added to the reaction, extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue Purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1), the title compound was obtained as a pale yellow-brown solid (1.1g, 36%)
MS(ESI,pos.ion)m/z:679.4[M+H] +。 MS (ESI, pos.ion) m/z: 679.4 [M+H] + .
步骤6)(R)-12-(R)-(4,5-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四Step 6) (R)-12-(R)-(4,5-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1 ,2-b)thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetra 氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物31)的合成Synthesis of Hydrogen-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 31)
于反应瓶中加入(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6-,8二酮(1.1g,1.6mmol)、氯化锂(710mg，1.6mmol)和DMAc(10mL)，反应混合物于100℃搅拌反应16h。用1N稀盐酸调节反应液pH值至6左右，然后加水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机层用饱和食盐水(10mL×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制备柱分离纯化，得到标题化合物为淡黄色固体(228mg,24％)Add (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6 ,7]cyclohepta[1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[ 2,1-f][1,2,4]triazine-6-,8dione (1.1g, 1.6mmol), lithium chloride (710mg, 1.6mmol) and DMAc (10mL), the reaction mixture was at 100°C The reaction was stirred for 16h. Adjust the pH of the reaction solution to about 6 with 1N dilute hydrochloric acid, then add water (10mL), extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic layer with saturated brine (10mL×3), and anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by a LUNA preparation column to obtain the title compound as a pale yellow solid (228mg, 24%)
MS(ESI,pos.ion)m/z:589.3[M+H] +； MS(ESI,pos.ion)m/z:589.3[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.52(d,J＝7.7Hz,1H),7.35(t,J＝7.6Hz,1H),7.21(dd,J＝13.5,5.7Hz,2H),7.10(t,J＝7.5Hz,1H),6.87(d,J＝7.6Hz,1H),6.49(d,J＝7.6Hz,1H),6.23(d,J＝5.9Hz,1H),5.83(d,J＝7.5Hz,1H),5.35(s,1H),4.62(d,J＝13.0Hz,1H),4.30(dd,J＝9.8,2.8Hz,1H),3.77(d,J＝9.1Hz,1H),3.55–3.50(m,1H),3.43(dd,J＝27.0,9.6Hz,5H),3.23(d,J＝10.7Hz,1H),2.96(s,1H),2.15(d,J＝6.3Hz,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.52 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.21 (dd, J = 13.5, 5.7 Hz, 2H) ,7.10(t,J=7.5Hz,1H), 6.87(d,J=7.6Hz,1H), 6.49(d,J=7.6Hz,1H), 6.23(d,J=5.9Hz,1H), 5.83 (d,J=7.5Hz,1H), 5.35(s,1H), 4.62(d,J=13.0Hz,1H), 4.30(dd,J=9.8,2.8Hz,1H), 3.77(d,J= 9.1Hz, 1H), 3.55-3.50 (m, 1H), 3.43 (dd, J = 27.0, 9.6 Hz, 5H), 3.23 (d, J = 10.7 Hz, 1H), 2.96 (s, 1H), 2.15 ( d, J=6.3Hz, 4H).
实施例23(R)-12-((R)-2-苄基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,5-4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(化合物33)Example 23 (R)-12-((R)-2-benzyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene -8-yl)-7-hydroxy-3,5-4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]Triazine-6,8-dione (Compound 33)
Figure PCTCN2020077781-appb-000075
Figure PCTCN2020077781-appb-000075
步骤1)2-(5-(溴甲基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 1) Synthesis of methyl 2-(5-(bromomethyl)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate
于反应瓶中加入2-(3-(2,3-二氟苯基)-5-甲基噻吩-2-基)苯甲酸甲酯(8.9g,26mmol)，BPO(310mg,1.3mmol)，NBS(5.1g,28mmol)和四氯化碳(100mL)，氮气保护，反应混合物于75℃下搅拌反应16h。过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为石油醚/乙酸乙酯(v/v)＝10/1)纯化，得标题化合物为黄色油状液体(8.5g,78％)。Add methyl 2-(3-(2,3-difluorophenyl)-5-methylthiophen-2-yl)benzoate (8.9g, 26mmol), BPO (310mg, 1.3mmol) into the reaction flask, NBS (5.1 g, 28 mmol) and carbon tetrachloride (100 mL) were protected by nitrogen, and the reaction mixture was stirred at 75° C. for 16 h. The filtrate was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1) to obtain the title compound as a yellow oily liquid (8.5g, 78 %).
1H NMR(400MHz,CDCl 3)δ(ppm)7.76(dd,J＝5.9,2.5Hz,1H),7.47(dd,J＝10.5,4.3Hz,1H),7.39(t,J＝5.8Hz,2H),7.21(s,1H),7.05–6.97(m,1H),6.88–6.81(m,1H),6.74(t,J＝6.9Hz,1H),4.78(s,2H),3.63(d,J＝4.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.76 (dd, J = 5.9, 2.5 Hz, 1H), 7.47 (dd, J = 10.5, 4.3 Hz, 1H), 7.39 (t, J = 5.8 Hz, 2H), 7.21 (s, 1H), 7.05-6.97 (m, 1H), 6.88-6.81 (m, 1H), 6.74 (t, J = 6.9 Hz, 1H), 4.78 (s, 2H), 3.63 (d ,J=4.0Hz,3H).
步骤2)2-(5-苄基-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 2) Synthesis of methyl 2-(5-benzyl-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate
于反应瓶中加入2-(5-(溴甲基)-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(2.9g,6.9mmol)、苯硼酸(1.3g,10mmol)、醋酸钯(16mg,0.07mmol)、磷酸钾(3g,14mmol)、三苯基膦(38mg,0.14mmol)和甲苯(20mL)，氮气保护下，反应混合物于室温搅拌反应16h。过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/EtOAc(v/v)＝10/1)纯化，得标题化合物为黄色固体(2.2g,78％)。Add methyl 2-(5-(bromomethyl)-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (2.9g, 6.9mmol), phenylboronic acid (1.3 g, 10mmol), palladium acetate (16mg, 0.07mmol), potassium phosphate (3g, 14mmol), triphenylphosphine (38mg, 0.14mmol) and toluene (20mL), under nitrogen protection, the reaction mixture was stirred at room temperature for 16h. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v)=10/1) to obtain the title compound as a yellow solid (2.2 g, 78%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.73(d,J＝7.7Hz,1H),7.44(t,J＝7.4Hz,1H),7.37(d,J＝4.7Hz,6H),7.29(dd,J＝8.8,4.4Hz,1H),7.01(dd,J＝16.9,8.5Hz,1H),6.95(s,1H),6.85(dd,J＝12.6,8.1Hz,1H),6.78(t,J＝6.9Hz,1H),4.23(s,2H),3.62(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.73 (d, J = 7.7 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.37 (d, J = 4.7 Hz, 6H), 7.29 (dd, J = 8.8, 4.4 Hz, 1H), 7.01 (dd, J = 16.9, 8.5 Hz, 1H), 6.95 (s, 1H), 6.85 (dd, J = 12.6, 8.1 Hz, 1H), 6.78 ( t,J=6.9Hz,1H), 4.23(s, 2H), 3.62(s, 3H).
步骤3)2-(5-苄基-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸的合成Step 3) Synthesis of 2-(5-benzyl-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid
于反应瓶中加入2-(3-(2,3-二氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯(3.2g,8.0mmol)、甲醇(10mL)、THF(10mL)和氢氧化钠(3.2g,32mmol)的水(5mL)溶液，混合物于50℃搅拌反应2h。加2N盐酸调节反应液的pH值至5左右，向反应液中加入水(10mL)，用乙酸乙酯(10mL×2)萃取，合并有机相，有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黄色固体(2.6g,84％)。Add methyl 2-(3-(2,3-difluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoate (3.2g, 8.0mmol), methanol to the reaction flask (10mL), THF (10mL) and sodium hydroxide (3.2g, 32mmol) in water (5mL) solution, the mixture was stirred at 50°C for 2h. Add 2N hydrochloric acid to adjust the pH of the reaction solution to about 5, add water (10mL) to the reaction solution, extract with ethyl acetate (10mL×2), combine the organic phases, and wash the organic layer with saturated brine (20mL). It was dried with sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow solid (2.6 g, 84%).
MS(ESI,neg.ion)m/z：407.5[M-H] -。 MS (ESI, neg. ion) m/z: 407.5 [MH] - .
步骤4)2-苄基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 4) Synthesis of 2-benzyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
于反应瓶中加入2-(5-苄基-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸(4.1g，10mmol)和多聚磷酸(15mL)，反应混合物于120℃搅拌反应18h，向反应液中加入冰水(30mL)将其溶解，再用乙酸乙酯(20mL×2)萃取，合并有机相，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/EtOAc(v/v)＝3/1)纯化，得标题化合物为黄色固体(2g,52％)Add 2-(5-benzyl-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid (4.1g, 10mmol) and polyphosphoric acid (15mL) into the reaction flask. The reaction was stirred at 120°C for 18h. Ice water (30mL) was added to the reaction solution to dissolve it, and then extracted with ethyl acetate (20mL×2). The organic phases were combined, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed After concentration, the residue obtained was purified by silica gel column chromatography (eluent: PE/EtOAc(v/v)=3/1) to obtain the title compound as a yellow solid (2g, 52%)
1H NMR(400MHz,CDCl 3)δ(ppm)7.81(d,J＝7.7Hz,1H),7.71(d,J＝7.8Hz,1H),7.65–7.54(m,2H),7.47(t,J＝7.5Hz,1H),7.40–7.32(m,5H),7.32–7.26(m,2H),4.24(s,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.81 (d, J = 7.7 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.65-7.54 (m, 2H), 7.47 (t, J = 7.5Hz, 1H), 7.40–7.32(m,5H), 7.32–7.26(m,2H), 4.24(s,2H).
步骤5)2-苄基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 5) Synthesis of 2-benzyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
于反应瓶中加入2-苄基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(2.0g,5.1mmol)、THF(8mL)和甲醇(8mL)，反应混合物于室温下搅拌，然后缓慢加入硼氢化钠(881mg,20mmol)，反应30分钟。向反应液加入饱和氯化铵溶液(10mL)，用乙酸乙酯(10mL)萃取，合并有机相，有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为浅黄色固体(2.0g,99％)。Add 2-benzyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (2.0g, 5.1 mmol), THF (8 mL) and methanol (8 mL), the reaction mixture was stirred at room temperature, then sodium borohydride (881 mg, 20 mmol) was slowly added, and the reaction was carried out for 30 minutes. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL), the organic phases were combined, the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound was obtained as a pale yellow solid (2.0 g, 99%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.77(d,J＝7.8Hz,1H),7.55(dd,J＝8.0,5.0Hz,1H),7.50–7.40(m,2H),7.38(d,J＝4.4Hz,4H),7.29(dd,J＝13.8,7.0Hz,3H),7.20(dd,J＝17.2,8.9Hz,1H),5.28(s,1H),4.28(s,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.77 (d, J = 7.8 Hz, 1H), 7.55 (dd, J = 8.0, 5.0 Hz, 1H), 7.50-7.40 (m, 2H), 7.38 ( d,J=4.4Hz,4H),7.29(dd,J=13.8,7.0Hz,3H), 7.20(dd,J=17.2,8.9Hz,1H), 5.28(s,1H), 4.28(s,2H) ).
步骤6)(12aR)-12-(2-苄基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-(苄基氧基)-3,4,12,12a-四氢Step 6) (12aR)-12-(2-benzyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl )-7-(benzyloxy)-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮的合成Synthesis of [1,2,4]triazine-6,8-dione from -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f]
于反应瓶中加入2-苄基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(2.0g,2.1mmol)、(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(1.9g,5.6mmol)、1-丙基磷酸酐(9mL,15.3mmol,50％w/w的乙酸乙酯溶液)和乙酸异丙酯(15mL)，反应混合物于90℃下搅拌反应2h。向反应中加水(20mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机层用饱和食盐水(20mL)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(洗脱剂为DCM/MeOH(v/v)＝15/1)纯化，得标题化合物为淡黄棕色固体(1.4g,39％)。Add 2-benzyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (2.0g, 2.1 mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1- f][1,2,4]triazine-6,8-dione (1.9g, 5.6mmol), 1-propyl phosphoric anhydride (9mL, 15.3mmol, 50% w/w in ethyl acetate) And isopropyl acetate (15 mL), the reaction mixture was stirred at 90° C. for 2 h. Water (20 mL) was added to the reaction, extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue Purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1), the title compound was obtained as a pale yellow-brown solid (1.4 g, 39%).
MS(ESI,pos.ion)m/z:700.3[M+H] +。 MS (ESI, pos.ion) m/z: 700.3 [M+H] + .
步骤10)(R)-12-((R)-2-苄基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,5-4,12,12a-四氢Step 10) (R)-12-((R)-2-benzyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene -8-yl)-7-hydroxy-3,5-4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(化合物33)的合成Synthesis of [1,2,4]triazine-6,8-dione (Compound 33) of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f]
于反应瓶中加入(12aR)-12-(2-苄基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-(苄基氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.4g,2.0mmol)、氯化锂(870mg,20mmol)和DMAc(15mL)，反应混合物于100℃搅拌反应16h。用1N稀盐酸调节反应液pH值至6左右，然后加水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机层用饱和食盐水(10mL×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制备柱分离纯化，得到标题化合物为淡黄色固体(360mg,30％)Add (12aR)-12-(2-benzyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8 to the reaction flask -Yl)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4] Triazine-6,8-dione (1.4g, 2.0mmol), lithium chloride (870mg, 20mmol) and DMAc (15mL), the reaction mixture was stirred at 100°C for 16h. Adjust the pH of the reaction solution to about 6 with 1N dilute hydrochloric acid, then add water (10mL), extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic layer with saturated brine (10mL×3), and anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by a LUNA preparation column to obtain the title compound as a pale yellow solid (360mg, 30%)
MS(ESI,pos.ion)m/z:610.3[M+H] +； MS(ESI,pos.ion)m/z:610.3[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.59(d,J＝7.6Hz,1H),7.45–7.30(m,8H),7.22(dd,J＝13.0,7.0Hz,2H),6.94(d,J＝7.5Hz,1H),6.32(d,J＝7.6Hz,1H),5.69(d,J＝7.5Hz,1H),5.38(s,1H),4.59(d,J＝13.1Hz,1H),4.28(s,2H),4.20(dd,J＝9.5,2.5Hz,1H),3.74(d,J＝10.0Hz,1H),3.41–3.21(m,3H),2.90(t,J＝11.3Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.59 (d, J = 7.6 Hz, 1H), 7.45-7.30 (m, 8H), 7.22 (dd, J = 13.0, 7.0 Hz, 2H), 6.94 ( d,J=7.5Hz,1H), 6.32(d,J=7.6Hz,1H), 5.69(d,J=7.5Hz,1H), 5.38(s,1H), 4.59(d,J=13.1Hz, 1H), 4.28 (s, 2H), 4.20 (dd, J = 9.5, 2.5 Hz, 1H), 3.74 (d, J = 10.0 Hz, 1H), 3.41-3.21 (m, 3H), 2.90 (t, J = 11.3Hz, 1H).
实施例24(R)-12-((R)-4-氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物80)Example 24 (R)-12-((R)-4-fluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b]Thien-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]Triazine-6,8-dione (Compound 80)
Figure PCTCN2020077781-appb-000076
Figure PCTCN2020077781-appb-000076
步骤1)3-(2-氟苯基)噻吩的合成Step 1) Synthesis of 3-(2-fluorophenyl)thiophene
于反应瓶中加入2-氟苯基三氟甲磺酸盐(21.0g,86.0mmol)、噻吩-3-基硼酸(16.5g,129.0mmol)、磷酸钾(30.1g,172.0mmol)、醋酸钯(394mg,1.7mmol)、S-Phos(1.4g,3.4mmol)、水(15mL)和甲苯(150mL)，氮气保护，反应混合物于110℃反应13小时。反应液过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE)纯化，得标题化合物为无色透明液体(15.0g,98.2％)。Add 2-fluorophenyl triflate (21.0g, 86.0mmol), thiophen-3-ylboronic acid (16.5g, 129.0mmol), potassium phosphate (30.1g, 172.0mmol), palladium acetate in the reaction flask (394mg, 1.7mmol), S-Phos (1.4g, 3.4mmol), water (15mL) and toluene (150mL), under nitrogen protection, the reaction mixture was reacted at 110°C for 13 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: PE) to obtain the title compound as a colorless and transparent liquid (15.0 g, 98.2%).
步骤2)2-溴-3-(2-氟苯基)-噻吩的合成Step 2) Synthesis of 2-bromo-3-(2-fluorophenyl)-thiophene
于反应瓶中加入3-(2-氟苯基)噻吩(15g,84.1mmol)和DMF(60mL)，并置于0℃下搅拌，再将NBS(15.4g,85mmol)的DMF(30mL)溶液滴加到反应体系中，反应混合物在0℃搅拌反应18小时，向反应液中加入水(200mL)和饱和硫代硫酸钠溶液(5mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，有机层用饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黄色油状物(20.3g,93.9％)Add 3-(2-fluorophenyl)thiophene (15g, 84.1mmol) and DMF (60mL) into the reaction flask, and stir at 0℃, then add NBS (15.4g, 85mmol) in DMF (30mL) solution The reaction mixture was added dropwise to the reaction system, the reaction mixture was stirred at 0°C for 18 hours, water (200 mL) and saturated sodium thiosulfate solution (5 mL) were added to the reaction solution, extracted with ethyl acetate (100 mL×3), and the organic Phase, the organic layer was washed with saturated brine (100mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow oil (20.3g, 93.9%)
1H NMR(400MHz,CDCl 3)δ(ppm)7.53(td,J＝7.5,1.5Hz,1H),7.45–7.38(m,1H),7.36(d,J＝5.6Hz,1H),7.30–7.19(m,2H),7.09(dd,J＝5.6,1.5Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.53 (td, J = 7.5, 1.5 Hz, 1H), 7.45-7.38 (m, 1H), 7.36 (d, J = 5.6 Hz, 1H), 7.30- 7.19(m,2H),7.09(dd,J=5.6,1.5Hz,1H).
步骤3)2-(3-(2-氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 3) Synthesis of methyl 2-(3-(2-fluorophenyl)thiophen-2-yl)benzoate
于反应瓶中加2-溴-3-(2-氟苯基)噻吩(10.0g,38.8mmol)、(2-(甲氧基羰基)苯基)硼酸(10.5g,58.3mmol)、双三苯基磷二氯化钯(2.7g,3.8mmol)、碳酸钾(17.9g,128.3mmol)、水(3mL)和THF(100mL)，氮气保护，反应混合物于75℃下搅拌反应3h，过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/EtOAc(v/v)＝10/1)纯化，得标题化合物为黄色固体(11g,91.2％)。Add 2-bromo-3-(2-fluorophenyl)thiophene (10.0g, 38.8mmol), (2-(methoxycarbonyl)phenyl)boronic acid (10.5g, 58.3mmol), double three Phenylphosphorus palladium dichloride (2.7g, 3.8mmol), potassium carbonate (17.9g, 128.3mmol), water (3mL) and THF (100mL), protected by nitrogen, the reaction mixture was stirred at 75°C for 3h, filtered, The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v)=10/1) to obtain the title compound as a yellow solid (11 g, 91.2%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.74(d,J＝7.6Hz,1H),7.48(dd,J＝10.8,4.2Hz,1H),7.44–7.35(m,3H),7.21(ddd,J＝14.6,5.2,2.1Hz,2H),7.07–7.00(m,2H),6.95(t,J＝7.5Hz,1H),3.61(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.74 (d, J = 7.6 Hz, 1H), 7.48 (dd, J = 10.8, 4.2 Hz, 1H), 7.44-7.35 (m, 3H), 7.21 ( ddd, J=14.6, 5.2, 2.1 Hz, 2H), 7.07-7.00 (m, 2H), 6.95 (t, J=7.5 Hz, 1H), 3.61 (s, 3H).
步骤4)2-(5-溴-3-(2-氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 4) Synthesis of methyl 2-(5-bromo-3-(2-fluorophenyl)thiophen-2-yl)benzoate
于反应瓶中加入2-(3-(2-氟苯基)噻吩-2-基)苯甲酸甲酯(11.0g,35.2mmol)和DMF(60mL)，并置于室温下搅拌，再将NBS(6.4g,35.5mmol)的DMF(30mL)溶液滴加到反应体系中，反应混合物在室温搅拌反应14小时，向反应液中加入水(200mL)和饱和硫代硫酸钠溶液(5mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，有机层用饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黄色油状物(12.5g,90.7％)Add methyl 2-(3-(2-fluorophenyl)thiophen-2-yl)benzoate (11.0g, 35.2mmol) and DMF (60mL) into the reaction flask, and stir at room temperature, then add NBS (6.4g, 35.5mmol) of DMF (30mL) solution was added dropwise to the reaction system, and the reaction mixture was stirred at room temperature for 14 hours. Water (200mL) and saturated sodium thiosulfate solution (5mL) were added to the reaction solution. Extract with ethyl acetate (100mL×3), combine the organic phases, wash the organic layer with saturated brine (100mL×3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound as a yellow oil (12.5g) ,90.7%)
1H NMR(400MHz,CDCl 3)δ(ppm)7.75–7.70(m,1H),7.44(dd,J＝10.7,4.2Hz,1H),7.35(t,J＝6.8Hz,2H),7.21–7.13(m,2H),7.04–6.86(m,3H),3.62(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.75–7.70 (m, 1H), 7.44 (dd, J = 10.7, 4.2 Hz, 1H), 7.35 (t, J = 6.8 Hz, 2H), 7.21– 7.13 (m, 2H), 7.04-6.86 (m, 3H), 3.62 (s, 3H).
步骤5)2-(5-(吡咯烷-1-基)-3-(2-氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 5) Synthesis of methyl 2-(5-(pyrrolidin-1-yl)-3-(2-fluorophenyl)thiophen-2-yl)benzoate
于反应瓶中加入2-(5-溴-3-(2-氟苯基)噻吩-2-基)苯甲酸甲酯(4.0g,10.2mmol)、吡咯烷(3.6g,51.1 mmol)、三(二亚苄基丙酮)二钯(1.17g,1.0mmol)、叔丁醇钠(2.0g,20.4mmol)、BINAP(1.3g,2.0mmol)和甲苯(50mL)，氮气保护，反应混合物于110℃下搅拌反应2h。过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/EtOAc(v/v)＝15/1)纯化，得标题化合物为黄色固体(1g,25.6％)。Add 2-(5-bromo-3-(2-fluorophenyl)thiophen-2-yl)methyl benzoate (4.0g, 10.2mmol), pyrrolidine (3.6g, 51.1 mmol), three (Dibenzylideneacetone) two palladium (1.17g, 1.0mmol), sodium tert-butoxide (2.0g, 20.4mmol), BINAP (1.3g, 2.0mmol) and toluene (50mL), protected by nitrogen, the reaction mixture was heated at 110 The reaction was stirred at ℃ for 2h. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v)=15/1) to obtain the title compound as a yellow solid (1 g, 25.6%).
MS(ESI,pos.ion)m/z:382.4[M+H] +； MS(ESI,pos.ion)m/z:382.4[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.62(d,J＝7.7Hz,1H),7.39(dd,J＝8.9,3.2Hz,2H),7.27–7.23(m,1H),7.21–7.15(m,1H),7.08(td,J＝7.6,1.6Hz,1H),7.03–6.91(m,2H),5.90(d,J＝1.9Hz,1H),3.64(s,3H),3.34(t,J＝6.4Hz,4H),2.07(d,J＝3.7Hz,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.62 (d, J = 7.7 Hz, 1H), 7.39 (dd, J = 8.9, 3.2 Hz, 2H), 7.27-7.23 (m, 1H), 7.21- 7.15(m,1H), 7.08(td,J=7.6,1.6Hz,1H), 7.03–6.91(m,2H), 5.90(d,J=1.9Hz,1H), 3.64(s,3H), 3.34 (t,J=6.4Hz,4H),2.07(d,J=3.7Hz,4H).
步骤6)2-(3-(2-氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸的合成Step 6) Synthesis of 2-(3-(2-fluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoic acid
于反应瓶中加入2-(3-(2-氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯(480mg,1.2mmol)、甲醇(5mL)、THF(5mL)和氢氧化钠(508mg,12.5mmol)的水(5mL)溶液，混合物于50℃搅拌反应3h。加2N盐酸调节反应液pH值至5左右，向反应液中加入水(10mL)，用乙酸乙酯(10mL×2)萃取，合并有机相，有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黄色固体(454mg,98.2％)。Add methyl 2-(3-(2-fluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoate (480mg, 1.2mmol), methanol (5mL), A water (5 mL) solution of THF (5 mL) and sodium hydroxide (508 mg, 12.5 mmol), and the mixture was stirred at 50° C. for 3 h. Add 2N hydrochloric acid to adjust the pH of the reaction solution to about 5, add water (10mL) to the reaction solution, extract with ethyl acetate (10mL×2), combine the organic phases, and wash the organic layer with saturated brine (20mL), anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound as a yellow solid (454 mg, 98.2%).
MS(ESI,pos.ion)m/z:368.0[M+H] +。 MS (ESI, pos.ion) m/z: 368.0 [M+H] + .
步骤7)4-氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 7) Synthesis of 4-fluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
于反应瓶中加入2-(3-(2-氟苯基)-5-(吡咯烷-1-基)噻吩-2-基)苯甲酸(800mg,2.1mmol)、氯苯(10mL)和多聚磷酸(15mL)，反应混合物于120℃搅拌反应16h，向反应液中加入冰水(30mL)将其溶解，再用乙酸乙酯(20mL×2)萃取，合并有机相，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黑色粘稠液体(760mg,100％)。Add 2-(3-(2-fluorophenyl)-5-(pyrrolidin-1-yl)thiophen-2-yl)benzoic acid (800mg, 2.1mmol), chlorobenzene (10mL) and more in the reaction flask. Polyphosphoric acid (15mL), the reaction mixture was stirred at 120°C for 16h. Ice water (30mL) was added to the reaction solution to dissolve it, and then extracted with ethyl acetate (20mL×2). The organic phases were combined, and the organic layer was washed with anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound as a black viscous liquid (760 mg, 100%).
MS(ESI,pos.ion)m/z:350.3[M+H] +。 MS (ESI, pos.ion) m/z: 350.3 [M+H] + .
步骤8)4-氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 8) Synthesis of 4-fluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol
于反应瓶中加入4-氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(760mg,2.1mmol)、THF(8mL)和甲醇(8mL)，反应混合物于室温下搅拌，然后缓慢加入硼氢化钠(324mg,8.7mmol)，反应30分钟。向反应液加入饱和氯化铵溶液(10mL)，用乙酸乙酯(10mL)萃取，有机层用饱和食盐水(20mL)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(洗脱剂为石油醚/乙酸乙酯(v/v)＝10/1)，纯化得标题化合物为浅黄色固体(311mg,40.6％)。Add 4-fluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (760mg , 2.1mmol), THF (8mL) and methanol (8mL), the reaction mixture was stirred at room temperature, then sodium borohydride (324mg, 8.7mmol) was slowly added, and the reaction was carried out for 30 minutes. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL), the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1), purified to obtain the title compound as a pale yellow solid (311 mg, 40.6%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.74(d,J＝7.7Hz,1H),7.62(d,J＝7.8Hz,1H),7.44(d,J＝7.5Hz,1H),7.38–7.33(m,2H),7.25(d,J＝7.4Hz,1H),7.01(dd,J＝10.6,8.5Hz,1H),6.26(d,J＝5.6Hz,1H),5.33(s,1H),3.44–3.37(m,4H),2.11(dd,J＝6.1,3.3Hz,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.74 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.38 –7.33(m,2H),7.25(d,J=7.4Hz,1H), 7.01(dd,J=10.6,8.5Hz,1H), 6.26(d,J=5.6Hz,1H),5.33(s, 1H), 3.44–3.37 (m, 4H), 2.11 (dd, J = 6.1, 3.3 Hz, 4H).
步骤9)((12aR)-7-(苄基氧基)-12-(4-氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-Step 9) ((12aR)-7-(benzyloxy)-12-(4-fluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7] ring Hept[1,2-b]thiophen-8-yl)-3,4,12,12a- 四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
于反应瓶中加入4-氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(300mg,0.8mmol)、(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(316mg，0.9mmol)、1-丙基磷酸酐(1.4mL,2.5mmol,50％w/w的乙酸乙酯溶液)和乙酸异丙酯(15mL)，反应混合物于90℃下搅拌反应4h。向反应中加水(20mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机层用饱和食盐水(20mL)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(洗脱剂为DCM/MeOH(v/v)＝15/1)纯化，得标题化合物为黄棕色固体(164mg,29.0％)。Add 4-fluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (300mg ,0.8mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2, 1-f] [1,2,4]triazine-6,8-dione (316mg, 0.9mmol), 1-propyl phosphoric anhydride (1.4mL, 2.5mmol, 50% w/w ethyl acetate Solution) and isopropyl acetate (15mL), the reaction mixture was stirred at 90°C for 4h. Water (20 mL) was added to the reaction, extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue Purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1), the title compound was obtained as a yellow-brown solid (164 mg, 29.0%).
MS(ESI,pos.ion)m/z:661.0[M+H] +。 MS (ESI, pos.ion) m/z: 661.0 [M+H] + .
步骤10)(R)-12-((R)-4-氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢Step 10) (R)-12-((R)-4-fluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b)thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物80)的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 80)
于反应瓶中加入((12aR)-7-(苄基氧基)-12-(4-氟-2-(吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩8基)-3,4,12,12a四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(164mg，0.2mmol)、氯化锂(108mg，2.4mmol)和DMAc(5mL)，反应混合物于90℃搅拌反应2h。用1N稀盐酸将反应液调节pH至6左右，然后加水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机层用饱和食盐水(10mL×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制备柱分离纯化，得到标题化合物为淡黄色固体(47mg，33.1％)Add ((12aR)-7-(benzyloxy)-12-(4-fluoro-2-(pyrrolidin-1-yl)-8H-dibenzo[3,4:6,7 to the reaction flask ]Cyclohepta[1,2-b]thiophene 8yl)-3,4,12,12a tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f ][1,2,4]triazine-6,8-dione (164mg, 0.2mmol), lithium chloride (108mg, 2.4mmol) and DMAc (5mL), the reaction mixture was stirred at 90°C for 2h. With 1N Adjust the pH of the reaction solution to about 6 with dilute hydrochloric acid, then add water (10 mL), extract with ethyl acetate (10 mL×3), combine the organic phases, wash the organic layer with saturated brine (10 mL×3), and dry with anhydrous sodium sulfate After filtering, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by LUNA preparation column to obtain the title compound as a pale yellow solid (47mg, 33.1%)
MS(ESI,pos.ion)m/z:571.4[M+H] +； MS(ESI,pos.ion)m/z:571.4[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.52(d,J＝7.9Hz,1H),7.34(dd,J＝16.7,9.9Hz,3H),7.24(d,J＝7.6Hz,1H),7.08(t,J＝7.2Hz,1H),6.90(s,1H),6.49(d,J＝7.8Hz,1H),6.25(d,J＝5.8Hz,1H),5.77(s,1H),5.40(s,1H),4.62(d,J＝12.8Hz,1H),4.31(d,J＝7.6Hz,1H),3.74(d,J＝11.4Hz,1H),3.48(dd,J＝21.5,8.5Hz,3H),3.39(d,J＝6.3Hz,3H),3.28–3.20(m,1H),2.98–2.90(m,1H),2.13(s,4H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.52(d,J=7.9Hz,1H), 7.34(dd,J=16.7,9.9Hz,3H), 7.24(d,J=7.6Hz,1H) ,7.08(t,J=7.2Hz,1H),6.90(s,1H),6.49(d,J=7.8Hz,1H),6.25(d,J=5.8Hz,1H),5.77(s,1H) , 5.40 (s, 1H), 4.62 (d, J = 12.8 Hz, 1H), 4.31 (d, J = 7.6 Hz, 1H), 3.74 (d, J = 11.4 Hz, 1H), 3.48 (dd, J = 21.5, 8.5 Hz, 3H), 3.39 (d, J = 6.3 Hz, 3H), 3.28–3.20 (m, 1H), 2.98–2.90 (m, 1H), 2.13 (s, 4H).
实施例25(R)-12-((R)-4,5-二氟-2-((S)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物83)Example 25 (R)-12-((R)-4,5-difluoro-2-((S)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6 ,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c] Pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 83)
Figure PCTCN2020077781-appb-000077
Figure PCTCN2020077781-appb-000077
步骤1)(S)-2-(3-(2,3-二氟苯基)-5-(3-氟吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯的合成Step 1) Synthesis of methyl (S)-2-(3-(2,3-difluorophenyl)-5-(3-fluoropyrrolidin-1-yl)thiophen-2-yl)benzoate
于反应瓶中加入2-(5-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(5.0g,12.2mmol)、BINAP(1.6g,2.4mmol)、醋酸钯(279mg,1.2mmol)、碳酸铯(9.9g,30.5mmol)、(S)-3-氟吡咯烷盐酸盐(1.8g,14.6mmol)和1,4-二氧六环(20mL)，氮气保护下，反应混合物于110℃反应15小时。过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/EtOAc(v/v)＝10/1)纯化，得标题化合物为黄色固体(2.0g,39.6％)。Add methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (5.0g, 12.2mmol), BINAP (1.6g, 2.4mmol) to the reaction flask , Palladium acetate (279mg, 1.2mmol), cesium carbonate (9.9g, 30.5mmol), (S)-3-fluoropyrrolidine hydrochloride (1.8g, 14.6mmol) and 1,4-dioxane (20mL ), under the protection of nitrogen, the reaction mixture was reacted at 110°C for 15 hours. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v)=10/1) to obtain the title compound as a yellow solid (2.0 g, 39.6%).
MS(ESI,pos.ion)m/z:418.0[M+H] +； MS(ESI,pos.ion)m/z:418.0[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.66(d,J＝7.7Hz,1H),7.41(dt,J＝15.5,3.7Hz,2H),7.30(dd,J＝10.8,4.1Hz,1H),7.01(dt,J＝13.4,4.9Hz,1H),6.90–6.78(m,2H),5.94(d,J＝1.7Hz,1H),5.39(d,J＝53.4Hz,1H),3.66(s,3H),3.63–3.53(m,3H),3.46(dt,J＝8.8,4.3Hz,1H),2.46–2.14(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.66 (d, J = 7.7 Hz, 1H), 7.41 (dt, J = 15.5, 3.7 Hz, 2H), 7.30 (dd, J = 10.8, 4.1 Hz, 1H), 7.01 (dt, J = 13.4, 4.9 Hz, 1H), 6.90-6.78 (m, 2H), 5.94 (d, J = 1.7 Hz, 1H), 5.39 (d, J = 53.4 Hz, 1H), 3.66 (s, 3H), 3.63-3.53 (m, 3H), 3.46 (dt, J = 8.8, 4.3 Hz, 1H), 2.46-2.14 (m, 2H).
步骤2)(S)-2-(3-(2,3-二氟苯基)-5-(3-氟吡咯烷-1-基)噻吩-2-基)苯甲酸的合成Step 2) Synthesis of (S)-2-(3-(2,3-difluorophenyl)-5-(3-fluoropyrrolidin-1-yl)thiophen-2-yl)benzoic acid
于反应瓶中加入(S)-2-(3-(2,3-二氟苯基)-5-(3-氟吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯(2.0g,4.8mmol)、甲醇(10mL)、THF(10mL)和氢氧化钠(1.9g,48mmol)的水(5mL)溶液，混合物于60℃搅拌反应24h。加2N盐酸调节反应液的pH至5左右，向反应液中加入水(10mL)，用乙酸乙酯(10mL×2)萃取，合并有机相，有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黄色固体(1.8g,97.0％)。Add (S)-2-(3-(2,3-difluorophenyl)-5-(3-fluoropyrrolidin-1-yl)thiophen-2-yl)benzoic acid methyl ester (2.0 g, 4.8mmol), methanol (10mL), THF (10mL) and sodium hydroxide (1.9g, 48mmol) in water (5mL) solution, the mixture was stirred at 60°C for 24h. Add 2N hydrochloric acid to adjust the pH of the reaction solution to about 5. Add water (10mL) to the reaction solution, extract with ethyl acetate (10mL×2), combine the organic phases, and wash the organic layer with saturated brine (20mL), anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title compound as a yellow solid (1.8 g, 97.0%).
MS(ESI,neg.ion)m/z：402.0[M-H] -。 MS (ESI, neg. ion) m/z: 402.0 [MH] - .
步骤3)4,5-二氟-2-((S)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 3) 4,5-Difluoro-2-((S)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Synthesis of thiophen-8-one
于反应瓶中加入(S)-2-(3-(2,3-二氟苯基)-5-(3-氟吡咯烷-1-基)噻吩-2-基)苯甲酸(1.8g,4.5mmol)和多聚磷酸(15mL)，反应混合物于120℃搅拌反应13h，向反应液中加入冰水(30mL)将其溶解，再用乙酸乙酯(20mL×2)萃取，合并有机相，有机层用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黑色粘稠液体(1.7g,99％)。Add (S)-2-(3-(2,3-difluorophenyl)-5-(3-fluoropyrrolidin-1-yl)thiophen-2-yl)benzoic acid (1.8g, 4.5mmol) and polyphosphoric acid (15mL). The reaction mixture was stirred at 120°C for 13h. Ice water (30mL) was added to the reaction solution to dissolve it, and then extracted with ethyl acetate (20mL×2), and the organic phases were combined. The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a black viscous liquid (1.7 g, 99%).
MS(ESI,pos.ion)m/z:386.0[M+H] +。 MS (ESI, pos.ion) m/z: 386.0 [M+H] + .
步骤4)4,5-二氟-2-((S)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 4) 4,5-Difluoro-2-((S)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ] Synthesis of thiophen-8-ol
于反应瓶中加入4,5-二氟-2-((S)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(1.7g,4.4mmol)、THF(8mL)和甲醇(8mL)，反应混合物于室温下搅拌，然后缓慢加入硼氢化钠(342mg,18.0mmol)，反应30分钟。向反应液加入饱和氯化铵溶液(10mL)，用乙酸乙酯(10mL)萃取，合并有机相，有机层用饱和食盐水(20mL)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(洗脱剂为石油醚/乙酸乙酯(v/v)＝10/1)纯化得标题化合物为浅黄色固体(1.2g,75.0％)。Add 4,5-difluoro-2-((S)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2 -b] Thiophen-8-one (1.7 g, 4.4 mmol), THF (8 mL) and methanol (8 mL), the reaction mixture was stirred at room temperature, then sodium borohydride (342 mg, 18.0 mmol) was slowly added, and the reaction was carried out for 30 minutes. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL), the organic phases were combined, the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was 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 a pale yellow solid (1.2 g, 75.0%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.73(d,J＝6.8Hz,1H),7.54(s,1H),7.47–7.23(m,4H),7.17(d,J＝8.0Hz,1H),6.29(s,1H),5.42(d,J＝53.0Hz,1H),5.24(s,1H),3.70–3.49(m,4H),2.35(dd,J＝51.7,27.7Hz,3H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.73(d,J=6.8Hz,1H),7.54(s,1H),7.47–7.23(m,4H),7.17(d,J=8.0Hz, 1H), 6.29 (s, 1H), 5.42 (d, J = 53.0 Hz, 1H), 5.24 (s, 1H), 3.70–3.49 (m, 4H), 2.35 (dd, J = 51.7, 27.7 Hz, 3H ).
步骤5)(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-((S)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚烷[1,2-b]噻吩-8-Step 5) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-((S)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[ 3,4:6,7]cycloheptane[1,2-b]thiophene-8- 基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine- Synthesis of 6,8-dione
于反应瓶中加入4,5-二氟-2-((S)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(980mg,2.5mmol)、(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(938mg,2.7mmol)、1-丙基磷酸酐(1.5mL,2.5mmol)和乙酸异丙酯(6mL)，反应混合物于微波110℃下搅拌反应2h。向反应中加水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机层用饱和食盐水(20mL)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(洗脱剂为DCM/MeOH(v/v)＝15/1)纯化，得标题化合物为棕色固体(654mg,37.1％)Add 4,5-difluoro-2-((S)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2 -b]thiophene-8-ol (980mg, 2.5mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3 ,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (938mg, 2.7mmol), 1-propyl phosphoric anhydride (1.5mL, 2.5mmol) ) And isopropyl acetate (6 mL), the reaction mixture was stirred at 110° C. in the microwave for 2 h. Water (10 mL) was added to the reaction, extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue Purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1), the title compound was obtained as a brown solid (654mg, 37.1%)
MS(ESI,pos.ion)m/z:697.2[M+H] +。 MS (ESI, pos.ion) m/z: 697.2 [M+H] + .
步骤6)(R)-12-((R)-4,5-二氟-2-((S)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基Step 6) (R)-12-((R)-4,5-difluoro-2-((S)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6 ,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy 3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(化合物83)的合成3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6, Synthesis of 8-diketone (Compound 83)
于反应瓶中加入(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-((S)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚烷[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(654mg,0.9mmol)、氯化锂(410mg,9.3mmol)和DMAc(5mL)，反应混合物于100℃搅拌反应2h。用1N稀盐酸将反应液调节pH至6左右，然后加水(10mL)，用乙酸乙酯(10mL×3)萃取，有机层用饱和食盐水(10mL×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制备柱分离纯化，得到标题化合物为淡黄色固体(162mg,28.4％)Add (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-((S)-3-fluoropyrrolidin-1-yl)-8H-diphenyl into the reaction flask And [3,4:6,7]cycloheptane[1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3 ,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (654mg, 0.9mmol), lithium chloride (410mg, 9.3mmol) and DMAc ( 5mL), the reaction mixture was stirred at 100°C for 2h. Adjust the pH of the reaction solution to about 6 with 1N dilute hydrochloric acid, then add water (10mL), extract with ethyl acetate (10mL×3), wash the organic layer with saturated brine (10mL×3), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the residue obtained was separated and purified by LUNA preparation column to obtain the title compound as a pale yellow solid (162mg, 28.4%)
MS(ESI,pos.ion)m/z:607.1[M+H] +； MS(ESI,pos.ion)m/z:607.1[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.52(d,J＝7.7Hz,1H),7.35(t,J＝7.6Hz,1H),7.22(dd,J＝11.7,6.0Hz,3H),7.11(t,J＝7.5Hz,1H),6.90(d,J＝7.6Hz,1H),6.44(d,J＝7.7Hz,1H),6.28(d,J＝5.8Hz,1H),5.71(d,J＝7.7Hz,1H),5.37(s,1H),4.62(d,J＝12.4Hz,1H),4.28(dd,J＝9.8,2.8Hz,1H),3.79–3.73(m,2H),3.71–3.64(m,2H),3.52(dd,J＝11.6,3.5Hz,2H),3.38(t,J＝10.8Hz,2H),3.25(d,J＝10.6Hz,1H),2.95(dd,J＝17.8,7.4Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.52 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.22 (dd, J = 11.7, 6.0 Hz, 3H) ,7.11(t,J=7.5Hz,1H), 6.90(d,J=7.6Hz,1H), 6.44(d,J=7.7Hz,1H), 6.28(d,J=5.8Hz,1H), 5.71 (d,J=7.7Hz,1H),5.37(s,1H),4.62(d,J=12.4Hz,1H), 4.28(dd,J=9.8,2.8Hz,1H),3.79–3.73(m, 2H), 3.71–3.64 (m, 2H), 3.52 (dd, J = 11.6, 3.5 Hz, 2H), 3.38 (t, J = 10.8 Hz, 2H), 3.25 (d, J = 10.6 Hz, 1H), 2.95(dd,J=17.8,7.4Hz,2H).
实施例26(R)-12-((R)-3-溴-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物91-1)和(R)-12-((S)-3-溴-4,5-二氟-8H-二苯并 [3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物91-2)Example 26 (R)-12-((R)-3-bromo-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene- 8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2 ,4]triazine-6,8-dione (compound 91-1) and (R)-12-((S)-3-bromo-4,5-difluoro-8H-dibenzo[3,4 :6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4 -c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 91-2)
Figure PCTCN2020077781-appb-000078
Figure PCTCN2020077781-appb-000078
步骤1)2-(4,5-二溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 1) Synthesis of methyl 2-(4,5-dibromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate
将2-(5-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(11.75g,28.71mmol)加入反应瓶中，加入冰醋酸(50mL)和水(10mL)，氮气保护下，向其中滴加液溴(1.76mL,34.30mmol)，反应混合物在室温下反应6.5h，然后将反应升温至60℃，反应1h。停止反应，向反应液中依次加入饱和硫代硫酸钠溶液(10mL)和饱和磷酸钾溶液(20mL)，然后用乙酸乙酯(20mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为黄色固体(10.71g,77％)。Add methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (11.75g, 28.71mmol) into the reaction flask, add glacial acetic acid (50mL) and water (10 mL), under the protection of nitrogen, liquid bromine (1.76 mL, 34.30 mmol) was added dropwise thereto, and the reaction mixture was reacted at room temperature for 6.5 hours, and then the reaction was heated to 60° C. for 1 hour. The reaction was stopped, saturated sodium thiosulfate solution (10mL) and saturated potassium phosphate solution (20mL) were added to the reaction solution, and then extracted with ethyl acetate (20mL×3). The organic phases were combined and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow solid (10.71 g, 77%).
MS(ESI,pos.ion)m/z:486.8[M+H] +； MS(ESI,pos.ion)m/z:486.8[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm):7.78(d,J＝7.7Hz,1H),7.47(dd,J＝10.5,4.4Hz,1H),7.39(dd,J＝13.3,5.8Hz,1H),7.33(d,J＝7.6Hz,1H),7.14–7.04(m,1H),6.95(dd,J＝12.3,7.5Hz,1H),6.81(t,J＝6.8Hz,1H),3.75(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.78 (d, J = 7.7 Hz, 1H), 7.47 (dd, J = 10.5, 4.4 Hz, 1H), 7.39 (dd, J = 13.3, 5.8 Hz ,1H),7.33(d,J=7.6Hz,1H),7.14-7.04(m,1H),6.95(dd,J=12.3,7.5Hz,1H),6.81(t,J=6.8Hz,1H) ,3.75(s,3H).
步骤2)2-(4-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯的合成Step 2) Synthesis of methyl 2-(4-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate
将2-(4,5-二溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(10.71g,21.94mmol)溶于乙酸(20mL)和水(2mL)中，随后向反应液中加入锌粉(3.15g,48.20mmol)，加完后升温至100℃反应过夜，加入饱和磷酸钾水溶液(30mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶柱层析纯化(洗脱剂为PE/EA(v/v)＝20/1)，得到标题化合物为黄色固体(6.88g,76％)。Methyl 2-(4,5-dibromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (10.71g, 21.94mmol) was dissolved in acetic acid (20mL) and water (2mL ), then zinc powder (3.15g, 48.20mmol) was added to the reaction solution. After the addition, the temperature was raised to 100°C and reacted overnight. A saturated aqueous potassium phosphate solution (30mL) was added, extracted with ethyl acetate (20mL×3), and combined The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: PE/EA(v/v)=20/1) to obtain the title compound as a yellow solid (6.88g, 76%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.74(dd,J＝7.7,1.0Hz,1H),7.45(dd,J＝7.5,1.3Hz,1H),7.42(s,1H),7.36(td,J＝7.6,1.3Hz,1H),7.31(d,J＝7.6Hz,1H),7.07(td,J＝9.9,1.6Hz,1H),6.98–6.87(m,1H),6.81(dd,J＝7.6,6.0Hz,1H),3.69(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.74 (dd, J = 7.7, 1.0 Hz, 1H), 7.45 (dd, J = 7.5, 1.3 Hz, 1H), 7.42 (s, 1H), 7.36 ( td,J=7.6,1.3Hz,1H), 7.31(d,J=7.6Hz,1H), 7.07(td,J=9.9,1.6Hz,1H), 6.98–6.87(m,1H), 6.81(dd ,J=7.6,6.0Hz,1H), 3.69(s,3H).
步骤3)2-(4-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸的合成Step 3) Synthesis of 2-(4-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid
将2-(4-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(6.88g,16.80mmol)溶于四氢呋喃(20mL)和乙醇(20mL)中，在室温下搅拌，将氢氧化钠(2.27g,67.30mmol)溶于水(5mL)后，加至上述反应液中，反应混合物于50℃条件下搅拌2h。用1N稀盐酸调节反应液的pH至6左右，分液，水相用乙酸乙酯(30mL×3)萃取，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，得到标题化合物为白色固体(6.52g,98％)。Methyl 2-(4-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (6.88g, 16.80mmol) was dissolved in tetrahydrofuran (20mL) and ethanol (20mL), After stirring at room temperature, sodium hydroxide (2.27g, 67.30mmol) was dissolved in water (5mL), and then added to the above reaction solution. The reaction mixture was stirred at 50°C for 2h. Adjust the pH of the reaction solution to about 6 with 1N dilute hydrochloric acid, separate the layers, extract the aqueous phase with ethyl acetate (30mL×3), combine the organic phases, and wash the organic phase with saturated sodium chloride solution (20mL), anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated under reduced pressure to obtain the title compound as a white solid (6.52 g, 98%).
步骤4)3-溴-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 4) Synthesis of 3-bromo-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将2-(4-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸(4.02g,10.20mmol)加至反应瓶中，向其中加入二氯乙烷(20mL)和DMF(0.03mL)，然后缓慢滴加草酰氯(1.10mL,13.00mmol)，滴加完后在70℃反应1小时。冷却至室温，向反应液中加入三氯化铝(5.39g,40.40mmol)，室温搅拌15分钟。将反应液缓慢加至水溶液(15mL)中，用二氯甲烷(20mL×3)萃取，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，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)＝15/1)，得到标题化合物为淡黄色固体(2.21g,58％)。Add 2-(4-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoic acid (4.02g, 10.20mmol) to the reaction flask, and add dichloroethane (20mL ) And DMF (0.03mL), then slowly add oxalyl chloride (1.10mL, 13.00mmol) dropwise, and react at 70°C for 1 hour after the dropwise addition. After cooling to room temperature, aluminum trichloride (5.39 g, 40.40 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was slowly added to the aqueous solution (15 mL), extracted with dichloromethane (20 mL×3), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced It was concentrated under pressure, and the obtained residue 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 (2.21 g, 58%).
1H NMR(400MHz,CDCl 3)δ(ppm):7.73(tt,J＝11.1,5.7Hz,2H),7.67-7.59(m,1H),7.57-7.47(m,3H),7.41-7.30(m,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.73 (tt, J = 11.1, 5.7 Hz, 2H), 7.67-7.59 (m, 1H), 7.57-7.47 (m, 3H), 7.41-7.30 ( m,1H).
步骤5)3-溴-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 5) Synthesis of 3-bromo-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
将3-溴-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(500.2mg,1.32mmol)溶于THF(10mL)和甲醇(10mL)中，向其中加入硼氢化钠(78.1mg,1.98mmol)，加完后室温反应5分钟。向反应液中加入饱和氯化铵溶液(15mL)，所得混合物用乙酸乙酯(15mL×3)萃取，合并有机相，有机相用饱和氯化钠溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为黄色固体(496.2mg,98％)。Dissolve 3-bromo-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (500.2mg, 1.32mmol) in THF (10 mL) and methanol (10 mL), sodium borohydride (78.1 mg, 1.98 mmol) was added thereto, and after the addition, the reaction was carried out at room temperature for 5 minutes. Saturated ammonium chloride solution (15 mL) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (15 mL×3), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution (10 mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow solid (496.2 mg, 98%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.79(d,J＝7.9Hz,1H),7.65-7.49(m,2H),7.51-7.43(m,2H),7.34(t,J＝7.2Hz,1H),7.32-7.13(m,1H),5.31(d,J＝10.6Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.79 (d, J = 7.9 Hz, 1H), 7.65-7.49 (m, 2H), 7.51-7.43 (m, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.32-7.13 (m, 1H), 5.31 (d, J = 10.6 Hz, 1H).
步骤6)(12aR)-7-(苄氧基)-12-(3-溴-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-Step 6) (12aR)-7-(benzyloxy)-12-(3-bromo-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b)thiophen-8-yl)-3,4,12,12a-tetrahydro-1H- [1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of [1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将3-溴-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(0.5g,0.13mmol)和(R)-7-(苄氧基)-3,4,12,12a-四氢-1 H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6-,8-二酮(47.1mg,0.14mmol)加至微波管中，加入1-丙基磷酸酐(0.23mL,0.39mmol)和乙酸乙酯(3mL)，微波110℃反应2小时。将反应液滴加至饱和碳酸氢钠溶液中(30mL)，用乙酸乙酯(20mL×3)萃取，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，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)＝15/1)，得到标题化合物的粗产物，所得粗产物无需进一步纯化直接进行下一步反应。 Combine 3-bromo-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol (0.5g, 0.13mmol) and (R )-7-(benzyloxy)-3,4,12,12a-tetrahydro-1 H -[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4]Triazine-6-,8-dione (47.1mg, 0.14mmol) was added to the microwave tube, 1-propyl phosphoric anhydride (0.23mL, 0.39mmol) and ethyl acetate (3mL) were added, Microwave at 110°C for 2 hours. The reaction solution was added dropwise to saturated sodium bicarbonate solution (30 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, and the organic phases were washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate. The filtrate was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v)=15/1) to obtain the crude product of the title compound without further purification. Proceed directly to the next reaction.
步骤7)(R)-12-((R)-3-溴-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]Step 7) (R)-12-((R)-3-bromo-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene- 8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4] 噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物91-1)和(R)-12-((R)-3-溴-4,5-二氟-8H-二苯并Oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 91-1) and (R)-12-(( R)-3-Bromo-4,5-difluoro-8H-dibenzo [3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino [3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-di 酮(化合物91-2)的合成Synthesis of Ketone (Compound 91-2)
将上一步所得粗产物溶于N,N-二甲基乙酰胺(10mL)中，向其中加入氯化锂(0.57g,13.5mmol)，反应混合物在110℃下反应3小时。停止反应，加入2N盐酸调节反应液的pH为6-7，用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和氯化钠(10mL×3)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗产物用HPLC制备分离，得到标题化合物91-1为黄色固体(22.1mg,2.7％)，标题化合物91-2为浅黄色固体(20.2mg,2.5％)。The crude product obtained in the previous step was dissolved in N,N-dimethylacetamide (10 mL), lithium chloride (0.57 g, 13.5 mmol) was added thereto, and the reaction mixture was reacted at 110° C. for 3 hours. Stop the reaction, add 2N hydrochloric acid to adjust the pH of the reaction solution to 6-7, extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic phase with saturated sodium chloride (10mL×3), and wash the organic phase with anhydrous The filtrate was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was prepared and separated by HPLC to obtain the title compound 91-1 as a yellow solid (22.1 mg, 2.7%) and the title compound 91-2 as a pale yellow solid (20.2 mg, 2.5 %).
化合物91-1：Compound 91-1:
1H NMR(400MHz,CDCl 3)δ(ppm):7.68(d,J＝7.7Hz,1H),7.57(d,J＝7.1Hz,1H),7.46(t,J＝7.6Hz,1H),7.32–7.25(m,2H),7.25-7.18(m,1H),6.97(d,J＝7.6Hz,1H),6.21(d,J＝7.7Hz,1H),5.68(d,J＝7.6Hz,1H),5.39(d,J＝13.2Hz,1H),4.61(d,J＝13.0Hz,1H),4.35(dd,J＝9.9,3.1Hz,1H),3.77(dd,J＝12.0,3.0Hz,1H),3.49–3.28(m,2H),3.21(t,J＝10.5Hz,1H),2.98(dd,J＝17.8,7.6Hz,1H).。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 7.68 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 7.1 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.32–7.25(m,2H),7.25-7.18(m,1H),6.97(d,J=7.6Hz,1H), 6.21(d,J=7.7Hz,1H), 5.68(d,J=7.6Hz ,1H), 5.39(d,J=13.2Hz,1H), 4.61(d,J=13.0Hz,1H), 4.35(dd,J=9.9,3.1Hz,1H), 3.77(dd,J=12.0, 3.0Hz, 1H), 3.49–3.28 (m, 2H), 3.21 (t, J=10.5Hz, 1H), 2.98 (dd, J=17.8, 7.6Hz, 1H).
化合物91-2：Compound 91-2:
1H NMR(400MHz,CDCl 3)δ(ppm):7.73(d,J＝7.2Hz,1H),7.56(d,J＝9.7Hz,1H),7.50(t,J＝7.5Hz,1H),7.42(d,J＝7.3Hz,1H),7.28(s,2H),7.10(dd,J＝16.5,8.6Hz,1H),6.84–6.76(m,1H),6.59(d,J＝7.7Hz,1H),5.88(d,J＝7.7Hz,1H),5.40(s,1H),4.58(d,J＝11.8Hz,1H),4.20–3.97(m,1H),3.77–3.65(m,1H),3.41–3.27(m,2H),3.26–3.12(m,1H),2.93–2.77(m,1H)。 1 H NMR(400MHz, CDCl 3 )δ(ppm): 7.73(d,J=7.2Hz,1H), 7.56(d,J=9.7Hz,1H), 7.50(t,J=7.5Hz,1H), 7.42(d,J=7.3Hz,1H),7.28(s,2H),7.10(dd,J=16.5,8.6Hz,1H),6.84-6.76(m,1H),6.59(d,J=7.7Hz ,1H), 5.88(d,J=7.7Hz,1H), 5.40(s,1H), 4.58(d,J=11.8Hz,1H), 4.20–3.97(m,1H), 3.77–3.65(m, 1H), 3.41–3.27(m,2H), 3.26–3.12(m,1H), 2.93–2.77(m,1H).
实施例27(R)-12-((R)-4,5-二氟-2-(3-甲氧基丙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物86)Example 27 (R)-12-((R)-4,5-difluoro-2-(3-methoxypropyl)-8H-dibenzo[3,4:6,7]cyclohepta[ 1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2, 1-f][1,2,4]triazine-6,8-dione (Compound 86)
Figure PCTCN2020077781-appb-000079
Figure PCTCN2020077781-appb-000079
步骤1)2-(3-(2,3-二氟苯基)-5-(3-甲氧基丙-1-炔-1-基)噻吩-2-基)苯甲酸甲酯的合成Step 1) Synthesis of methyl 2-(3-(2,3-difluorophenyl)-5-(3-methoxyprop-1-yn-1-yl)thiophen-2-yl)benzoate
分别称量5-溴-2-(3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(4.72g,11.50mmol)、双三苯基膦二氯化钯(818mg,1.15mmol)、碘化亚铜(220mg,1.16mmol)、三乙胺(8.10mL,58.00mmol)混合于THF(30mL)中，氮气保护下，将3-甲氧基丙炔(1.60mL,19.00mmol)缓慢滴加到上述反应液中，置于60℃下搅拌反应过夜。停止反应，减压浓缩，所得粗产物用硅胶柱层析(洗脱剂为PE/EA(v/v)＝15/1)分离提纯，得到标题化合物为为色油状液体(3.91g,85％)。Weigh 5-bromo-2-(3-(2,3-difluorophenyl)thiophen-2-yl)methyl benzoate (4.72g, 11.50mmol), bistriphenylphosphine palladium dichloride ( 818mg, 1.15mmol), cuprous iodide (220mg, 1.16mmol), triethylamine (8.10mL, 58.00mmol) were mixed in THF (30mL), under nitrogen protection, the 3-methoxypropyne (1.60mL , 19.00mmol) was slowly added dropwise to the above reaction solution, placed at 60°C and stirred overnight. The reaction was stopped and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography (eluent: PE/EA(v/v)=15/1) to obtain the title compound as a colored oily liquid (3.91g, 85%) ).
1H NMR(400MHz,CDCl 3)δ(ppm)7.77(d,J＝7.7Hz,1H),7.49(td,J＝7.5,1.2Hz,1H),7.40(m,2H),7.32(d,J＝1.9Hz,1H),7.03(td,J＝9.5,1.4Hz,1H),6.87(m,1H),6.74(dd,J＝7.7,6.3Hz,1H),4.38(s,2H),3.64(s,3H),3.48(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.77 (d, J = 7.7 Hz, 1H), 7.49 (td, J = 7.5, 1.2 Hz, 1H), 7.40 (m, 2H), 7.32 (d, J = 1.9Hz, 1H), 7.03 (td, J = 9.5, 1.4 Hz, 1H), 6.87 (m, 1H), 6.74 (dd, J = 7.7, 6.3 Hz, 1H), 4.38 (s, 2H), 3.64(s,3H), 3.48(s,3H).
步骤2)2-(3-(2,3-二氟苯基)-5-(3-甲氧基丙基)噻吩-2-基)苯甲酸甲酯的合成Step 2) Synthesis of methyl 2-(3-(2,3-difluorophenyl)-5-(3-methoxypropyl)thiophen-2-yl)benzoate
分别将2-(3-(2,3-二氟苯基)-5-(3-甲氧基丙-1-炔-1-基)噻吩-2-基)苯甲酸甲酯(140mg,0.35mmol)、钯/碳(14mg,10mass％)混合于甲醇(10mL)和四氢呋喃(10mL)中，在室温下抽真空并置于氢气氛围中反应过夜。停止反应，过滤，滤液减压浓缩，得到标题化合物为淡黄色膏状物(135mg,95％)。Respectively, methyl 2-(3-(2,3-difluorophenyl)-5-(3-methoxyprop-1-yn-1-yl)thiophen-2-yl)benzoate (140mg, 0.35 mmol), palladium/carbon (14 mg, 10 mass%) were mixed in methanol (10 mL) and tetrahydrofuran (10 mL), evacuated at room temperature and placed in a hydrogen atmosphere to react overnight. The reaction was stopped, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a pale yellow paste (135 mg, 95%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.72(d,J＝7.9Hz,1H),7.48–7.42(m,1H),7.35(dd,J＝11.7,4.3Hz,2H),7.00(ddd,J＝15.6,9.6,1.5Hz,1H),6.92(d,J＝2.1Hz,1H),6.89–6.81(m,1H),6.75(dd,J＝7.7,6.2Hz,1H),3.62(s,3H),3.51(t,J＝6.2Hz,2H),3.39(s,3H),2.97(t,J＝7.6Hz,2H),2.06–2.00(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.72 (d, J = 7.9 Hz, 1H), 7.48-7.42 (m, 1H), 7.35 (dd, J = 11.7, 4.3 Hz, 2H), 7.00 ( ddd,J=15.6,9.6,1.5Hz,1H), 6.92(d,J=2.1Hz,1H), 6.89–6.81(m,1H), 6.75(dd,J=7.7,6.2Hz,1H),3.62 (s,3H),3.51(t,J=6.2Hz,2H), 3.39(s,3H), 2.97(t,J=7.6Hz,2H), 2.06-2.00(m,2H).
步骤3)2-(3-(2,3-二氟苯基)-5-(3-甲氧基丙基)噻吩-2-基)苯甲酸的合成Step 3) Synthesis of 2-(3-(2,3-difluorophenyl)-5-(3-methoxypropyl)thiophen-2-yl)benzoic acid
将2-(3-(2,3-二氟苯基)-5-(3-甲氧基丙基)噻吩-2-基)苯甲酸甲酯(3.51g,8.72mmol)溶解于四氢呋喃(15mL)和甲醇(15mL)中，再将氢氧化钠(1.40g,35.00mmol)的水(3mL)溶液加入其中，置于50℃油浴锅中加热反应约1小时。用2N稀盐酸调节反应液的pH至酸性，然后用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗产物通过硅胶柱层析(洗脱剂PE/EA(v/v)＝5/1)进行分离提纯，得到浅黄色油状液体为标题化合物(3.39g,100％)。Methyl 2-(3-(2,3-difluorophenyl)-5-(3-methoxypropyl)thiophen-2-yl)benzoate (3.51g, 8.72mmol) was dissolved in tetrahydrofuran (15mL ) And methanol (15 mL), and then sodium hydroxide (1.40 g, 35.00 mmol) in water (3 mL) was added to it, and placed in an oil bath at 50° C. and heated to react for about 1 hour. Adjust the pH of the reaction solution to acidity with 2N dilute hydrochloric acid, then extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic phases with saturated brine (8mL), dry with anhydrous sodium sulfate, filter, and reduce the filtrate After concentration, the obtained crude product was separated and purified by silica gel column chromatography (eluent PE/EA(v/v)=5/1) to obtain the title compound (3.39 g, 100%) as a pale yellow oily liquid.
MS(ESI,neg.ion)m/z:387.1[M-H] -。 MS (ESI, neg.ion) m/z: 387.1 [MH] - .
步骤4)4,5-二氟-2-(3-甲氧基丙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 4) 4,5-difluoro-2-(3-methoxypropyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one Synthesis
将2-(3-(2,3-二氟苯基)-5-(3-甲氧基丙基)噻吩-2-基)苯甲酸(3.39g,8.73mmol)溶解于二氯甲烷(10mL)中，再加入DMF(1mg,0.01mmol)，反应混合物置于室温下搅拌2分钟，然后将草酰氯(1.20mL,14.00mmol)缓慢滴加到其中，转移到室温下继续搅拌反应约30分钟。向其中加入氯化铝(3.49g,26.20mmol)，在室温下继续搅拌反应约10分钟。停止反应，向反应液中加水(15mL)，接着用二氯甲烷(12mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)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(洗脱剂为PE/EA(v/v)＝10/1)分离提纯，得到标题化合物为黄色固体(3.23g,100％)。Dissolve 2-(3-(2,3-difluorophenyl)-5-(3-methoxypropyl)thiophen-2-yl)benzoic acid (3.39g, 8.73mmol) in dichloromethane (10mL ), DMF (1mg, 0.01mmol) was added, the reaction mixture was stirred at room temperature for 2 minutes, then oxalyl chloride (1.20mL, 14.00mmol) was slowly added dropwise to it, and then transferred to room temperature to continue stirring for about 30 minutes . Aluminum chloride (3.49 g, 26.20 mmol) was added thereto, and the reaction was continued to be stirred at room temperature for about 10 minutes. The reaction was stopped, water (15mL) was added to the reaction solution, followed by extraction with dichloromethane (12mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed After concentration, the obtained residue was separated and purified by silica gel column chromatography (eluent: PE/EA(v/v)=10/1) to obtain the title compound as a yellow solid (3.23 g, 100%).
MS(ESI,pos.ion)m/z:371.1(M+H) +。 MS (ESI, pos.ion) m/z: 371.1 (M+H) + .
步骤5)4,5-二氟-2-(3-甲氧基丙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 5) 4,5-Difluoro-2-(3-methoxypropyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol Synthesis
将化合物4,5-二氟-2-(3-甲氧基丙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(3.23g,8.72mmol)溶解于甲醇(30mL)和THF(30mL)中，置于室温下搅拌，然后将硼氢化钠(687mg,17.40mmol)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，过滤，滤液减压浓缩，得到标题化合物为浅黄色固体为标题化合物(501mg,99％)。The compound 4,5-difluoro-2-(3-methoxypropyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one( 3.23g, 8.72mmol) was dissolved in methanol (30mL) and THF (30mL), stirred at room temperature, then sodium borohydride (687mg, 17.40mmol) was added to it, and the reaction was stirred at room temperature for about 20 minutes. The reaction was stopped, saturated ammonium chloride solution (20mL) was added to it, extracted with ethyl acetate (25mL×3), the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrated under reduced pressure to obtain the title compound as a pale yellow solid (501 mg, 99%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.78(d,J＝7.8Hz,1H),7.56(dd,J＝8.1,5.0Hz,1H),7.50(d,J＝7.6Hz,1H),7.45(dd,J＝11.0,4.2Hz,1H),7.34–7.25(m,2H),7.20(dd,J＝17.1,9.0Hz,1H),5.28(s,1H),3.52(t,J＝6.2Hz,2H),3.41(s,3H),3.02(t,J＝7.6Hz,2H),2.06(dd,J＝8.1,5.6Hz,2H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.78(d,J=7.8Hz,1H), 7.56(dd,J=8.1,5.0Hz,1H), 7.50(d,J=7.6Hz,1H) ,7.45(dd,J=11.0,4.2Hz,1H),7.34–7.25(m,2H),7.20(dd,J＝17.1,9.0Hz,1H),5.28(s,1H),3.52(t,J =6.2Hz,2H),3.41(s,3H),3.02(t,J=7.6Hz,2H),2.06(dd,J=8.1,5.6Hz,2H).
步骤6)(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-(3-甲氧基丙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-Step 6) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-(3-methoxypropyl)-8H-dibenzo[3,4:6, 7]Cycloheptan[1,2-b]thiophene-8- 基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine- Synthesis of 6,8-dione
将4,5-二氟-2-(3-甲氧基丙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(513mg,1.38mmol)，(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(450mg,1.38mmol)混合于乙酸异丙酯(10mL)中，再向其中加入T 3P乙酸乙酯溶液(2.72mL,4.54mmol,1.67mol/L)，置于90℃油浴锅中加热反应过夜。停止反应，向反应液中加入饱和碳酸氢钠溶液(20mL)，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，滤液减压浓缩，所得残留物用硅胶柱层析(洗脱剂为DCM/MeOH(v/v)＝15/1)分离提纯，得到标题化合物为黄褐色固体(496mg,53％)。 4,5-Difluoro-2-(3-methoxypropyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (513mg ,1.38mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2, 1-f][1,2,4]triazine-6,8-dione (450mg, 1.38mmol) was mixed in isopropyl acetate (10mL), and then T 3 P ethyl acetate solution (2.72 mL, 4.54mmol, 1.67mol/L), placed in a 90℃ oil bath and heated for reaction overnight. Stop the reaction, add saturated sodium bicarbonate solution (20mL) to the reaction solution, extract with ethyl acetate (30mL×3), combine the organic phases, wash the organic phases with saturated brine (30mL), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain the title compound as a yellow-brown solid (496 mg, 53%).
MS(ESI,pos.ion)m/z:682.0[M+H] + MS(ESI,pos.ion)m/z:682.0[M+H] +
步骤7)(R)-12-((R)-4,5-二氟-2-(3-甲氧基丙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-Step 7) (R)-12-((R)-4,5-difluoro-2-(3-methoxypropyl)-8H-dibenzo[3,4:6,7]cyclohepta[ 1,2-b)thiophen-8-yl)-7-hydroxy-3,4,12,12a- 四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物86)的合成Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 86) synthesis
将(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-(3-甲氧基丙基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(496mg,0.73mmol)、氯化锂(308mg,7.27mmol)混合于DMAc(20mL)中，氮气保护下，并置于100℃搅拌反应约2小时。将反应液加入到水(10mL)中淬灭反应，然后用0.5N HCl调节pH值呈弱酸性，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，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，得到标题化合物为淡黄色固体(101mg,23％)。(12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-(3-methoxypropyl)-8H-dibenzo[3,4:6,7] Cyclohepta[1,2-b]thio-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1 -f][1,2,4]triazine-6,8-dione (496mg, 0.73mmol), lithium chloride (308mg, 7.27mmol) mixed in DMAc (20mL), protected by nitrogen, and placed The reaction was stirred at 100°C for about 2 hours. The reaction solution was added to water (10mL) to quench the reaction, then adjusted with 0.5N HCl to make the pH weakly acidic, stirred for 10 minutes, then extracted with ethyl acetate (20mL×3), combined the organic phases, and saturated the organic phases Wash with brine (30 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is passed through a LUNA preparation column (eluent is acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) After separation and purification, the title compound was obtained as a pale yellow solid (101 mg, 23%).
MS(ESI,pos.ion)m/z:592.2[H+1] +。 MS (ESI, pos.ion) m/z: 592.2 [H+1] + .
1H NMR(400MHz,CDCl 3)δ(ppm)7.62(d,J＝7.5Hz,1H),7.48–7.25(m,3H),7.21(t,J＝8.7Hz,2H),6.94(d,J＝7.3Hz,1H),6.33(d,J＝7.5Hz,1H),5.68(d,J＝7.5Hz,1H),5.38(s,1H),4.59(d,J＝13.0Hz,1H),4.20(d,J＝7.2Hz,1H),3.73(d,J＝10.1Hz,1H),3.51(t,J＝5.7Hz,2H),3.46–3.27(m,5H),3.23(t,J＝10.3Hz,1H),3.05(t,J＝7.1Hz,2H),2.91(t,J＝11.2Hz,1H),2.05(dd,J＝17.1,10.7Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.62 (d, J = 7.5 Hz, 1H), 7.48-7.25 (m, 3H), 7.21 (t, J = 8.7 Hz, 2H), 6.94 (d, J = 7.3Hz, 1H), 6.33 (d, J = 7.5Hz, 1H), 5.68 (d, J = 7.5Hz, 1H), 5.38 (s, 1H), 4.59 (d, J = 13.0Hz, 1H) , 4.20 (d, J = 7.2 Hz, 1H), 3.73 (d, J = 10.1 Hz, 1H), 3.51 (t, J = 5.7 Hz, 2H), 3.46-3.27 (m, 5H), 3.23 (t, J = 10.3 Hz, 1H), 3.05 (t, J = 7.1 Hz, 2H), 2.91 (t, J = 11.2 Hz, 1H), 2.05 (dd, J = 17.1, 10.7 Hz, 2H).
实施例28(R)-12-((R)-4,5-二氟-3-异丙氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物89)Example 28 (R)-12-((R)-4,5-difluoro-3-isopropoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][ 1,2,4)Triazine-6,8-dione (Compound 89)
Figure PCTCN2020077781-appb-000080
Figure PCTCN2020077781-appb-000080
步骤1)4,5-二氟-3-异丙氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 1) Synthesis of 4,5-difluoro-3-isopropoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将4,5-二氟-3-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(50mg,0.15mmol)溶解于二氯甲烷(3mL)中，再向其中加入三溴化硼(0.07mL,0.7mmol)，置于室温下搅拌反应过夜。停止搅拌，向反应液中加入甲醇(1mL)，接着加入饱和食盐水(8mL)，所得混合物用二氯甲烷(8mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，然后将其溶解于DMF(3mL)中，再向其中加入NaH(9mg,0.22mmol,60mass％)，所得混合物置于室温下搅拌约30分钟，然后向其中加入碘代异丙烷(51mg,0.30mmol)，继续在室温下搅拌反应过夜。停止反应，用2N盐酸调节反应液pH为酸性，用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(12mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析(洗脱剂为PE/EA(v/v)＝10/1)分离提纯，得到标题化合物为浅黄色固体(6mg,11％)。Dissolve 4,5-difluoro-3-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (50mg, 0.15mmol) in In dichloromethane (3 mL), boron tribromide (0.07 mL, 0.7 mmol) was added thereto, and the reaction was stirred overnight at room temperature. Stirring was stopped, methanol (1 mL) was added to the reaction solution, followed by saturated brine (8 mL), the resulting mixture was extracted with dichloromethane (8 mL×3), the organic phases were combined, and the organic phase was washed with saturated brine (10 mL). Dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, then dissolve it in DMF (3mL), add NaH (9mg, 0.22mmol, 60mass%) to it, and stir the resulting mixture at room temperature for about 30 minutes. Then, isopropane iodide (51 mg, 0.30 mmol) was added thereto, and the reaction was stirred overnight at room temperature. Stop the reaction, adjust the pH of the reaction solution to acidity with 2N hydrochloric acid, extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic phase with saturated brine (12mL×3), dry with anhydrous sodium sulfate, filter, and filtrate It was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: PE/EA(v/v)=10/1) to obtain the title compound as a pale yellow solid (6 mg, 11%).
1H NMR(600MHz,CDCl 3)δ(ppm)7.74(dd,J＝6.8,6.3Hz,2H),7.60(t,J＝7.6Hz,1H),7.53–7.46(m,2H),7.27(d,J＝11.4Hz,1H),6.40(s,1H),4.53–4.46(m,1H),1.46(d,J＝5.9Hz,3H),1.32(d,J＝6.0Hz,3H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm) 7.74 (dd, J = 6.8, 6.3 Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.53-7.46 (m, 2H), 7.27 ( d, J = 11.4Hz, 1H), 6.40 (s, 1H), 4.53-4.46 (m, 1H), 1.46 (d, J = 5.9 Hz, 3H), 1.32 (d, J = 6.0 Hz, 3H).
步骤2)4,5-二氟-3-异丙氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 2) Synthesis of 4,5-difluoro-3-isopropoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol
将4,5-二氟-3-异丙氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(210mg,0.59mmol)溶解于四氢呋喃(15mL)和甲醇(15mL)中，再将硼氢化钠(46mg,1.18mmol)加入其中，置于室温下搅拌反应约30分钟。停止反应，向其中加入饱和氯化铵溶液(20mL)，所得混合物用乙酸乙酯(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，过滤，滤液减压浓缩，得到标题化合物为浅黄色固体(210mg,99％)。Dissolve 4,5-difluoro-3-isopropoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (210mg, 0.59mmol) In tetrahydrofuran (15 mL) and methanol (15 mL), sodium borohydride (46 mg, 1.18 mmol) was added, and the reaction was stirred at room temperature for about 30 minutes. The reaction was stopped, saturated ammonium chloride solution (20 mL) was added, the resulting mixture was extracted with ethyl acetate (25 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (30 mL), dried with anhydrous sodium sulfate, and filtered The filtrate was concentrated under reduced pressure to obtain the title compound as a pale yellow solid (210 mg, 99%).
MS(ESI,pos.ion)m/z:359.1(M+H) +； MS(ESI,pos.ion)m/z:359.1(M+H) + ;
步骤3)(R)-12-((R)-4,5-二氟-3-异丙氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢Step 3) (R)-12-((R)-4,5-difluoro-3-isopropoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物89)的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 89)
将(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.29g,3.94mmol)、4,5-二氟-3-异丙氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1.00g,3.03mmol)、T 3P乙酸乙酯溶液(5.44mL,9.08mmol,1.67mol/L)和乙酸乙酯(3mL)加入微波管中，置于超声仪中超声至溶清状态，然后130℃微波反应3小时。停止反应，向反应液中加入饱和碳酸氢钠溶液(20mL)，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，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)分离纯化分别得到标题化合物为淡黄色固体(135mg,15％)。 (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]Triazine-6,8-dione (1.29g, 3.94mmol), 4,5-difluoro-3-isopropoxy-8H-dibenzo[3,4:6, 7] Cyclohepta[1,2-b]thiophene-8-ol (1.00g, 3.03mmol), T 3 P ethyl acetate solution (5.44mL, 9.08mmol, 1.67mol/L) and ethyl acetate (3mL) Put it into a microwave tube, place it in an ultrasonic instrument and sonicate it to a clear state, and then react in a microwave at 130°C for 3 hours. The reaction was stopped, saturated sodium bicarbonate solution (20mL) was added to the reaction solution, extracted with ethyl acetate (30mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (30mL) and dried with anhydrous sodium sulfate to obtain 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 as a pale yellow solid (135 mg, 15%).
MS(ESI,pos.ion)m/z:578.0[M+H] +。 MS (ESI, pos.ion) m/z: 578.0 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.66(d,J＝7.4Hz,1H),7.45(t,J＝6.9Hz,1H),7.27–7.17(m,2H),6.92(d,J＝6.8Hz,1H),6.47(d,J＝6.1Hz,2H),6.39(s,1H),6.09(s,1H),5.35(s,1H),4.66–4.54(m,2H),4.43(d,J＝6.7Hz,2H),3.76(d,J＝10.9Hz,1H),3.39–3.30(m,1H),3.22(t,J＝10.3Hz,1H),3.10–2.91(m,1H),1.50(d,J＝6.0Hz,3H),1.37(d,J＝6.0Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.66 (d, J = 7.4 Hz, 1H), 7.45 (t, J = 6.9 Hz, 1H), 7.27-7.17 (m, 2H), 6.92 (d,J=6.8Hz,1H), 6.47(d,J=6.1Hz,2H), 6.39(s,1H), 6.09(s,1H), 5.35(s,1H), 4.66–4.54(m, 2H), 4.43 (d, J = 6.7 Hz, 2H), 3.76 (d, J = 10.9 Hz, 1H), 3.39–3.30 (m, 1H), 3.22 (t, J = 10.3 Hz, 1H), 3.10– 2.91 (m, 1H), 1.50 (d, J = 6.0 Hz, 3H), 1.37 (d, J = 6.0 Hz, 3H).
实施例29(R)-12-((R)-4,5-二氟-2-(羟甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物93)Example 29 (R)-12-((R)-4,5-difluoro-2-(hydroxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b]Thien-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]Triazine-6,8-dione (Compound 93)
Figure PCTCN2020077781-appb-000081
Figure PCTCN2020077781-appb-000081
步骤1)4,5-二氟-8-羟基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-2-甲醛的合成Step 1) Synthesis of 4,5-difluoro-8-hydroxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-2-carbaldehyde
将2-甲基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(2.20g,7.00mmol)、选择性氟试剂(3.13g,8.40mmol)和过硫酸铵(1.85g,8.05mmol)混合于乙腈(30mL)和水(30mL)中，氮气保护置于80℃油浴锅中加热反应过夜。过滤，滤液中加水(5mL)，所得混合物用乙酸乙酯(6mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析(洗脱剂为EA/PE( V/V)＝1/10)分离提纯，得到标题化合物为黄色膏状固体(416mg,18％)。 Combine 2-methyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol (2.20g, 7.00mmol), select Fluorine reagent (3.13g, 8.40mmol) and ammonium persulfate (1.85g, 8.05mmol) were mixed in acetonitrile (30mL) and water (30mL), and placed in an oil bath at 80°C under nitrogen protection and heated to react overnight. Filter, add water (5mL) to the filtrate, extract the resulting mixture with ethyl acetate (6mL×3), combine the organic phases, wash the organic phase with saturated brine (8mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (eluent: EA/PE ( V/V )=1/10) to obtain the title compound as a yellow cream solid (416 mg, 18%).
MS(ESI,pos.ion)m/z:328.90[M+H] +。 MS (ESI, pos.ion) m/z: 328.90 [M+H] + .
1H NMR(400MHz,CDCl 3)δ(ppm)7.75(d,J＝7.8Hz,1H),7.57–7.52(m,1H),7.47–7.38(m,2H),7.29(t,J＝7.6Hz,1H),7.19(dd,J＝17.2,8.8Hz,1H),6.70(d,J＝5.2Hz,1H),5.27(s,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.75 (d, J = 7.8 Hz, 1H), 7.57-7.52 (m, 1H), 7.47-7.38 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.19 (dd, J = 17.2, 8.8 Hz, 1H), 6.70 (d, J = 5.2 Hz, 1H), 5.27 (s, 1H).
步骤2)8-((R)-7-(苄氧基)-6,8-二氧代-1,3,4,6,8,12a-六氢-12H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-12-Step 2) 8-((R)-7-(benzyloxy)-6,8-dioxo-1,3,4,6,8,12a-hexahydro-12H-[1,4]oxazine And [3,4-c]pyrido[2,1-f][1,2,4]triazine-12- 基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-2-甲醛的合成Yl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-2-carbaldehyde
将4,5-二氟-8-羟基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-2-甲醛(20mg,0.95mmol)、(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6-,8二酮(21mg,1.00mmol)混合于T 3P(0.37mL,9.53mmol)的乙酸异丙酯(20mL)溶液中，封管置于120℃油浴锅中反应约5小时，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)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析(洗脱剂为MeOH/DCM(v/v)＝1/10)分离提纯，得到标题化合物为白色固体(15mg,45％)。 4,5-Difluoro-8-hydroxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-2-carbaldehyde (20mg, 0.95mmol), (R) -7-(Benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2 ,4] Triazine-6-,8 dione (21 mg, 1.00 mmol) was mixed with T 3 P (0.37 mL, 9.53 mmol) in isopropyl acetate (20 mL) solution, sealed and placed in a 120°C oil bath The reaction time is about 5 hours, and the reaction is stopped. The reaction solution was added to water (15 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (eluent: MeOH/DCM (v/v) = 1/10) to obtain the title compound as a white solid (15 mg, 45%).
MS(ESI,pos.ion)m/z:638.3[M+H] + MS(ESI,pos.ion)m/z:638.3[M+H] +
步骤3)(R)-12-((R)-4,5-二氟-2-(羟甲基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢Step 3) (R)-12-((R)-4,5-difluoro-2-(hydroxymethyl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b)thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物93)的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 93)
将8-((R)-7-(苄氧基)-6,8-二氧代-1,3,4,6,8,12a-六氢-12H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-12-基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-2-甲醛(200mg,0.31mmol)溶解于四氢呋喃(10mL)和甲醇(10mL)中，接着向其中加入硼氢化钠(24mg,0.63mmol)，置于室温下搅拌约5分钟。停止反应，接着加入饱和氯化铵溶液(10mL)，用乙酸乙酯(8mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，将浓缩残留物和氯化锂(132mg,3.13mmol)混合于DMAc(15mL)中，氮气保护，并置于100℃条件下进行搅拌反应过夜。将反应液加入到水(10mL)中淬灭反应，然后用0.5N HCl调节反应液的pH值呈弱酸性，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，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，得到标题化合物为淡黄色固体(23mg,13％)。The 8-((R)-7-(benzyloxy)-6,8-dioxo-1,3,4,6,8,12a-hexahydro-12H-[1,4]oxazino[ 3,4-c]pyrido[2,1-f][1,2,4]triazine-12-yl)-4,5-difluoro-8H-dibenzo[3,4:6,7 ]Cyclohepta[1,2-b]thiophene-2-carbaldehyde (200mg, 0.31mmol) was dissolved in tetrahydrofuran (10mL) and methanol (10mL), then sodium borohydride (24mg, 0.63mmol) was added to it, and placed Stir at room temperature for about 5 minutes. The reaction was stopped, then saturated ammonium chloride solution (10mL) was added, extracted with ethyl acetate (8mL×3), the organic phases were combined, the organic phases were washed with saturated brine (8mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was reduced Concentrate under pressure, mix the concentrated residue and lithium chloride (132 mg, 3.13 mmol) in DMAc (15 mL), protect it under nitrogen, and place it at 100°C for stirring and react overnight. The reaction solution was added to water (10mL) to quench the reaction, and then the pH value of the reaction solution was adjusted to weakly acidic with 0.5N HCl, stirred for 10 minutes, and then extracted with ethyl acetate (20mL×3), and the organic phases were combined. The phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to a LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (V/V) = 12 /13) Isolation and purification to obtain the title compound as a pale yellow solid (23 mg, 13%).
MS(ESI,pos.ion)m/z:550.0[M+H] + MS(ESI,pos.ion)m/z:550.0[M+H] +
1H NMR(600MHz,CDCl 3)δ(ppm)7.66(d,J＝2.1Hz,1H),7.53-7.39(m,2H),7.26(d,J＝15.6Hz,3H),6.96(s,1H),6.38(s,1H),5.71(s,1H),5.40(s,1H),5.00(s,2H),4.59(d,J＝11.4Hz,1H),4.22(d,J＝8.8Hz,1H),3.74(s,1H),3.35(s,2H),3.20(s,1H),2.92(s,1H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm) 7.66 (d, J = 2.1 Hz, 1H), 7.53-7.39 (m, 2H), 7.26 (d, J = 15.6 Hz, 3H), 6.96 (s, 1H), 6.38 (s, 1H), 5.71 (s, 1H), 5.40 (s, 1H), 5.00 (s, 2H), 4.59 (d, J = 11.4 Hz, 1H), 4.22 (d, J = 8.8 Hz, 1H), 3.74 (s, 1H), 3.35 (s, 2H), 3.20 (s, 1H), 2.92 (s, 1H).
实施例30(R)-12-((R)-4,5-二氟-3-(2-甲氧基乙氧基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物95)Example 30 (R)-12-((R)-4,5-difluoro-3-(2-methoxyethoxy)-8H-dibenzo[3,4:6,7]cyclohepta [1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2 ,1-f][1,2,4]triazine-6,8-dione (Compound 95)
Figure PCTCN2020077781-appb-000082
Figure PCTCN2020077781-appb-000082
步骤1)4,5-二氟-3-(2-甲氧基乙氧基基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 1) 4,5-Difluoro-3-(2-methoxyethoxy)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8 -Synthesis of ketones
将4,5-二氟-3-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(50mg,0.15mmol)溶解于二氯甲烷(3mL)中，再向其中加入三溴化硼(0.07mL,0.70mmol)，置于室温下搅拌反应过夜。停止搅拌，向反应液中加入甲醇(1mL)，接着加入饱和食盐水(8mL)，然后用二氯甲烷(8mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，然后将残留物溶解于DMF(3mL)中，再向其中加入NaH(9mg,0.22mmol,60mass％)置于室温下搅拌约30分钟，接着向其中加入甲氧基乙氧基溴(42mg,0.30mmol)，继续在室温下搅拌过夜。停止反应，用2N盐酸调节反应液pH为酸性，用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(12mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得硅胶柱层析(洗脱剂为PE/EA( V/V)＝10/1)分离提纯，得到标题化合物为浅黄色固体(13mg,23％)。 Dissolve 4,5-difluoro-3-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (50mg, 0.15mmol) in In dichloromethane (3 mL), boron tribromide (0.07 mL, 0.70 mmol) was added thereto, and the reaction was stirred overnight at room temperature. Stirring was stopped, methanol (1mL) was added to the reaction solution, followed by saturated brine (8mL), and then extracted with dichloromethane (8mL×3). The organic phases were combined, and the organic phase was washed with saturated brine (10mL). The filtrate was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (3mL), and NaH (9mg, 0.22mmol, 60mass%) was added to it and stirred at room temperature for about 30 minutes, and then added to it Methoxyethoxy bromide (42mg, 0.30mmol) was added, and stirring was continued overnight at room temperature. Stop the reaction, adjust the pH of the reaction solution to acidity with 2N hydrochloric acid, extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic phase with saturated brine (12mL×3), dry with anhydrous sodium sulfate, filter, and filtrate It was concentrated under reduced pressure, and the obtained silica gel column chromatography (eluent: PE/EA ( V/V )=10/1) was separated and purified to obtain the title compound as a pale yellow solid (13 mg, 23%).
1H NMR(600MHz,CDCl 3)δ(ppm)7.77–7.71(m,2H),7.65–7.58(m,1H),7.51(ddd,J＝14.1,7.9,4.2Hz,2H),7.25(d,J＝9.0Hz,1H),6.53(s,1H),4.24(dd,J＝9.7,5.3Hz,2H),3.84–3.75(m,2H),3.43(s,3H). 1 H NMR(600MHz, CDCl 3 )δ(ppm) 7.77–7.71(m,2H), 7.65–7.58(m,1H), 7.51(ddd,J=14.1,7.9,4.2Hz,2H), 7.25(d ,J=9.0Hz,1H),6.53(s,1H), 4.24(dd,J=9.7,5.3Hz,2H), 3.84–3.75(m,2H), 3.43(s,3H).
步骤2)4,5-二氟-3-(2-甲氧基乙氧基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 2) 4,5-Difluoro-3-(2-methoxyethoxy)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8- Synthesis of alcohol
将4,5-二氟-3-(2-甲氧基乙氧基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(123mg,0.33mmol)溶解于四氢呋喃(15mL)和甲醇(15mL)中，再将硼氢化钠(26mg,0.66mmol)加入其中，置于室温下搅拌反应约30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，有机相用用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为浅黄色固体(123mg,99％)。4,5-difluoro-3-(2-methoxyethoxy)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one( 123mg, 0.33mmol) was dissolved in tetrahydrofuran (15mL) and methanol (15mL), then sodium borohydride (26mg, 0.66mmol) was added to it, and the reaction was stirred at room temperature for about 30 minutes. The reaction was stopped, saturated ammonium chloride solution (20mL) was added to it, extracted with ethyl acetate (25mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (30mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound as a pale yellow solid (123 mg, 99%).
MS(ESI,pos.ion)m/z:375.1(M+H) +。 MS (ESI, pos.ion) m/z: 375.1 (M+H) + .
步骤3)(R)-12-((R)-4,5-二氟-3-(2-甲氧基乙氧基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基Step 3) (R)-12-((R)-4,5-difluoro-3-(2-methoxyethoxy)-8H-dibenzo[3,4:6,7]cyclohepta [1,2-b]thiophen-8-yl)-7-hydroxy -3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成-3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6, Synthesis of 8-Diketone
分别将(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(123mg,0.33mmol)、4,5-二氟-3-(2-甲氧基乙氧基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(110mg,0.34mmol)、T 3P(1.97mL,3.33mmol,1.67mol/L)、乙酸乙酯(3mL)加入至微波管中，然后130℃微波反应3小时。停止反应，向反应液中加入饱和碳酸氢钠溶液(20mL)，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，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，得到标题化合物为淡黄色固体(8mg,4％)。 (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f ][1,2,4]triazine-6,8-dione (123mg, 0.33mmol), 4,5-difluoro-3-(2-methoxyethoxy)-8H-dibenzo[ 3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (110mg, 0.34mmol), T 3 P (1.97mL, 3.33mmol, 1.67mol/L), ethyl acetate (3mL ) Was added to a microwave tube, and then reacted in a microwave at 130°C for 3 hours. Stop the reaction, add saturated sodium bicarbonate solution (20mL) to the reaction solution, extract with ethyl acetate (30mL×3), combine the organic phases, wash the organic phases with saturated brine (30mL), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the residue obtained 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 as a pale yellow solid (8mg, 4 %).
MS(ESI,pos.ion)m/z:594.2[M+H] +； MS(ESI,pos.ion)m/z:594.2[M+H] + ;
1H NMR(400MHz,DMSO-d 6)δ(ppm):7.65(d,J＝7.6Hz,1H),7.45–7.37(m,1H),7.25–7.16(m,2H),6.94(d,J＝7.3Hz,1H),6.53(s,1H),6.34(d,J＝7.6Hz,1H),5.71(d,J＝7.6Hz,1H),5.36(s,1H),4.59(d,J＝13.3Hz,1H),4.32(dtd,J＝16.2,10.3,4.2Hz,3H),3.78(ddd,J＝19.7,9.1,6.7Hz,3H),3.43(s,3H),3.40–3.30(m,2H),3.21(t,J＝10.5Hz,1H),2.97(t,J＝11.0Hz,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ (ppm): 7.65 (d, J = 7.6 Hz, 1H), 7.45-7.37 (m, 1H), 7.25-7.16 (m, 2H), 6.94 (d, J = 7.3Hz, 1H), 6.53 (s, 1H), 6.34 (d, J = 7.6 Hz, 1H), 5.71 (d, J = 7.6 Hz, 1H), 5.36 (s, 1H), 4.59 (d, J = 13.3Hz, 1H), 4.32 (dtd, J = 16.2, 10.3, 4.2 Hz, 3H), 3.78 (ddd, J = 19.7, 9.1, 6.7 Hz, 3H), 3.43 (s, 3H), 3.40–3.30 (m, 2H), 3.21 (t, J = 10.5 Hz, 1H), 2.97 (t, J = 11.0 Hz, 1H).
实施例31(R)-12-((R)-4,5-二氟-2-(甲氧基-d 3)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物99) Example 31 (R)-12-((R)-4,5-difluoro-2-(methoxy-d 3 )-8H-dibenzo[3,4:6,7]cyclohepta[1 ,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1 -f][1,2,4]triazine-6,8-dione (compound 99)
Figure PCTCN2020077781-appb-000083
Figure PCTCN2020077781-appb-000083
步骤1)4,5-二氟-2-(甲氧基-d 3)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成 Step 1) 4,5-difluoro-2-(methoxy-d 3 )-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol synthesis
将4,5-二氟-2-溴-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(500mg,1.32mmol)、碘化钾(240mg,1.45mmol)、氧化铜(115mg,1.45mmol)、CD 3ONa(2.64mL,2.64mmol,1mol/L)、氘代甲醇(5mL)加入至封管中个，然后置于110℃油浴锅中加热反应过夜。过滤，滤液中加水(5mL)，用乙酸乙酯(6mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析(洗脱剂为EA/PE( V/V)＝1/10)分离提纯，得到标题化合物为类白色固体(97mg,22％)。 1H NMR(400MHz,CDCl 3)δ(ppm)7.75(d,J＝7.8Hz,1H),7.57–7.52(m,1H),7.47–7.38(m,2H),7.29(t,J＝7.6Hz,1H),7.19(dd,J＝17.2,8.8Hz,1H),6.70(d,J＝5.2Hz,1H),5.27(s,1H). Combine 4,5-difluoro-2-bromo-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (500mg, 1.32mmol), potassium iodide (240mg, 1.45) mmol), copper oxide (115mg, 1.45mmol), CD 3 ONa (2.64mL, 2.64mmol, 1mol/L), and deuterated methanol (5mL) are added to the sealed tube, and then heated in a 110℃ oil bath React overnight. Filter, add water (5 mL) to the filtrate, extract with ethyl acetate (6 mL×3), combine the organic phases, wash the organic phase with saturated brine (8 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a residue The material was separated and purified by silica gel column chromatography (eluent: EA/PE ( V/V ) = 1/10) to obtain the title compound as an off-white solid (97 mg, 22%). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.75 (d, J = 7.8 Hz, 1H), 7.57-7.52 (m, 1H), 7.47-7.38 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.19 (dd, J = 17.2, 8.8 Hz, 1H), 6.70 (d, J = 5.2 Hz, 1H), 5.27 (s, 1H).
步骤2)(12aR)-7-(苄氧基)-12-(4,5-二氟-2-(甲氧基-d 3)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8–基)-3,4,12,12a- Step 2) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-(methoxy-d 3 )-8H-dibenzo[3,4:6,7] Cyclohepta[1,2-b]thiophen-8-yl)-3,4,12,12a- 四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将4,5-二氟-2-(甲氧基-d 3)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(168mg,0.50mmol)、(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(181mg,0.55mmol)混合于T 3P(3.02mL,5.04mmol)的乙酸异丙酯(20mL)溶液中，置于90℃油浴锅中反应约6小时，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)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物用硅胶柱层析(洗脱剂为MeOH/DCM( V/V)＝1/10)，得到标题化合物为白色固体(80mg,25％)。 4,5-Difluoro-2-(methoxy-d 3 )-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (168mg, 0.50mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1 -f][1,2,4]triazine-6,8-dione (181mg, 0.55mmol) was mixed with T 3 P (3.02mL, 5.04mmol) in isopropyl acetate (20mL) solution, placed The reaction was stopped in an oil bath at 90°C for about 6 hours. The reaction solution was added to water (15 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: MeOH/DCM ( V/V ) = 1/10) to obtain the title compound as a white solid (80 mg, 25%).
MS(ESI,pos.ion)m/z:643.1[M+H] +。 MS (ESI, pos.ion) m/z: 643.1 [M+H] + .
步骤3)(R)-12-((R)-4,5-二氟-2-(甲氧基-d 3)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢 Step 3) (R)-12-((R)-4,5-difluoro-2-(methoxy-d 3 )-8H-dibenzo[3,4:6,7]cyclohepta[1 ,2-b)thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物99)的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 99)
将(12aR)-7-(苄氧基)-12-(4,5-二氟-2-(甲氧基-d 3)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(80mg,0.12mmol)、氯化锂(52mg,1.23mmol)混合于DMAc(10mL)中，氮气保护，加热至100℃搅拌反应过夜。将反应液加入到水(10mL)中淬灭反应，然后用0.5N HCl调节反应液呈弱酸性，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，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，得到标题化合物为淡黄色固体(13mg,19％)。 (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-(methoxy-d 3 )-8H-dibenzo[3,4:6,7]cyclohepta [1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f ][1,2,4]Triazine-6,8-dione (80mg, 0.12mmol), lithium chloride (52mg, 1.23mmol) were mixed in DMAc (10mL), protected by nitrogen, heated to 100℃ and stirred for reaction overnight. The reaction solution was added to water (10mL) to quench the reaction, then the reaction solution was adjusted to be weakly acidic with 0.5N HCl, stirred for 10 minutes, and then extracted with ethyl acetate (20mL×3), the organic phases were combined, and the organic phase was saturated Wash with brine (30 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is passed through a LUNA preparation column (eluent is acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) After separation and purification, the title compound was obtained as a pale yellow solid (13 mg, 19%).
MS(ESI,pos.ion)m/z:553.7[M+H]+MS(ESI,pos.ion)m/z:553.7[M+H]+
1H NMR(600MHz,CDCl 3)δ(ppm)7.63(d,J＝7.5Hz,1H),7.51(s,2H),7.44(s,2H),7.05(s,1H),6.77(d,J＝5.0Hz,1H),6.52(s,1H),5.98(s,1H),5.39(d,J＝19.6Hz,1H),4.62(d,J＝14.6Hz,1H),4.19(d,J＝6.4Hz,1H),3.73(d,J＝11.2Hz,1H),3.46(d,J＝9.1Hz,1H),3.42-3.35(m,1H),3.27(t,J＝10.2Hz,1H),2.91-2.84(m,1H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm) 7.63 (d, J = 7.5Hz, 1H), 7.51 (s, 2H), 7.44 (s, 2H), 7.05 (s, 1H), 6.77 (d, J = 5.0Hz, 1H), 6.52 (s, 1H), 5.98 (s, 1H), 5.39 (d, J = 19.6 Hz, 1H), 4.62 (d, J = 14.6 Hz, 1H), 4.19 (d, J = 6.4Hz, 1H), 3.73 (d, J = 11.2Hz, 1H), 3.46 (d, J = 9.1Hz, 1H), 3.42-3.35 (m, 1H), 3.27 (t, J = 10.2Hz, 1H), 2.91-2.84 (m, 1H).
实施例32(R)-12-((R)-4,5-二氟-2-((R)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基3,4,12,12a四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物84)Example 32 (R)-12-((R)-4,5-difluoro-2-((R)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6 ,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy 3,4,12,12a tetrahydro-1H-[1,4]oxazino[3,4-c]pyridine And [2,1-f][1,2,4]triazine-6,8-dione (Compound 84)
Figure PCTCN2020077781-appb-000084
Figure PCTCN2020077781-appb-000084
步骤1)(R)-2-(3-(2,3-二氟苯基)-5-(3-氟吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯的合成Step 1) Synthesis of methyl (R)-2-(3-(2,3-difluorophenyl)-5-(3-fluoropyrrolidin-1-yl)thiophen-2-yl)benzoate
于反应瓶中加入2-(5-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(5.0g,12.2mmol)、BINAP(1.6g,2.4mmol)、醋酸钯(279mg,1.2mmol)、碳酸铯(9.9g,30.5mmol)、(R)-3-氟吡咯烷盐酸盐(1.8g,14.6mmol)和1,4-二氧六环(20mL)，氮气保护，反应混合物于110℃反应15小时。过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为石油醚/乙酸乙酯(v/v)＝10/1)纯化，得标题化合物为黄色固体(2.1g,42.2％)。Add methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (5.0g, 12.2mmol), BINAP (1.6g, 2.4mmol) to the reaction flask , Palladium acetate (279mg, 1.2mmol), cesium carbonate (9.9g, 30.5mmol), (R)-3-fluoropyrrolidine hydrochloride (1.8g, 14.6mmol) and 1,4-dioxane (20mL ), under nitrogen protection, the reaction mixture was reacted at 110°C for 15 hours. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1) to obtain the title compound as a yellow solid (2.1g, 42.2% ).
MS(ESI,pos.ion)m/z:418.0[M+H] +； MS(ESI,pos.ion)m/z:418.0[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.66(d,J＝7.7Hz,1H),7.46–7.26(m,3H),7.01(ddd,J＝14.8,8.8,1.6Hz,1H),6.84(ddd,J＝15.9,13.2,7.8Hz,2H),5.94(d,J＝1.8Hz,1H),5.39(d,J＝53.4Hz,1H),3.66(s,3H),3.64–3.43(m,4H),2.47–2.14(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.66 (d, J = 7.7 Hz, 1H), 7.46-7.26 (m, 3H), 7.01 (ddd, J = 14.8, 8.8, 1.6 Hz, 1H), 6.84 (ddd, J = 15.9, 13.2, 7.8 Hz, 2H), 5.94 (d, J = 1.8 Hz, 1H), 5.39 (d, J = 53.4 Hz, 1H), 3.66 (s, 3H), 3.64–3.43 (m, 4H), 2.47--2.14 (m, 2H).
步骤2)(R)-2-(3-(2,3-二氟苯基)-5-(3-氟吡咯烷-1-基)噻吩-2-基)苯甲酸的合成Step 2) Synthesis of (R)-2-(3-(2,3-difluorophenyl)-5-(3-fluoropyrrolidin-1-yl)thiophen-2-yl)benzoic acid
于反应瓶中加入(R)-2-(3-(2,3-二氟苯基)-5-(3-氟吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯(2.0g,4.8mmol)、甲醇(10mL)、THF(10mL)和氢氧化钠(1.9g,48mmol)的水(5mL)溶液，混合物于60℃搅拌反应24h。加2N盐酸调pH至5左右，向反应液中加入水(10mL)，用乙酸乙酯(10mL×2)萃取，合并有机相，有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黄色固体(1.8g,93.0％)。Add (R)-2-(3-(2,3-difluorophenyl)-5-(3-fluoropyrrolidin-1-yl)thiophen-2-yl)methyl benzoate (2.0 g, 4.8mmol), methanol (10mL), THF (10mL) and sodium hydroxide (1.9g, 48mmol) in water (5mL) solution, the mixture was stirred at 60°C for 24h. Add 2N hydrochloric acid to adjust the pH to about 5, add water (10mL) to the reaction solution, extract with ethyl acetate (10mL×2), combine the organic phases, wash the organic layer with saturated brine (20mL), and dry with anhydrous sodium sulfate After filtering, the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow solid (1.8 g, 93.0%).
MS(ESI,neg.ion)m/z：402.0[M-H] -。 MS (ESI, neg. ion) m/z: 402.0 [MH] - .
步骤3)4,5-二氟-2-((R)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 3) 4,5-difluoro-2-((R)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ]Synthesis of thiophen-8-one
于反应瓶中加入(R)-2-(3-(2,3-二氟苯基)-5-(3-氟吡咯烷-1-基)噻吩-2-基)苯甲酸(1.8g,4.5mmol)和多聚磷酸(15mL)，反应混合物于120℃搅拌反应13h，向反应液中加入冰水(30mL)将其溶解，再用乙酸乙酯(20mL×2)萃取，合并有机相，有机层用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黑色粘稠液体(1.7g,99％)。Add (R)-2-(3-(2,3-difluorophenyl)-5-(3-fluoropyrrolidin-1-yl)thiophen-2-yl)benzoic acid (1.8g, 4.5mmol) and polyphosphoric acid (15mL). The reaction mixture was stirred at 120°C for 13h. Ice water (30mL) was added to the reaction solution to dissolve it, and then extracted with ethyl acetate (20mL×2), and the organic phases were combined. The organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a black viscous liquid (1.7 g, 99%).
MS(ESI,pos.ion)m/z:385.9[M+H] +。 MS (ESI, pos.ion) m/z: 385.9 [M+H] + .
步骤4)4,5-二氟-2-((R)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 4) 4,5-Difluoro-2-((R)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ] Synthesis of thiophen-8-ol
于反应瓶中加入4,5-二氟-2-((R)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(1.7g,4.4mmol)、THF(8mL)和甲醇(8mL)，反应混合物于室温下搅拌，然后缓慢加入硼氢化钠(342mg,18.0mmol)，反应30分钟。向反应液加入饱和氯化铵溶液(10mL)，用乙酸乙酯(10mL)萃取，合并有机相，有机层用饱和食盐水(20mL)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(洗脱剂为石油醚/乙酸乙酯(v/v)＝10/1)纯化得标题化合物为浅黄色固体(818mg,48.0％)。Add 4,5-difluoro-2-((R)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2 -b] Thiophen-8-one (1.7 g, 4.4 mmol), THF (8 mL) and methanol (8 mL), the reaction mixture was stirred at room temperature, then sodium borohydride (342 mg, 18.0 mmol) was slowly added, and the reaction was carried out for 30 minutes. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL), the organic phases were combined, the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was 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 a pale yellow solid (818 mg, 48.0%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.73(d,J＝7.3Hz,1H),7.54(s,1H),7.39(dd,J＝27.7,7.3Hz,3H),7.18(dd,J＝16.8,8.4Hz,1H),6.29(d,J＝3.8Hz,1H),5.42(d,J＝53.2Hz,1H),5.26(s,1H),4.14(dd,J＝13.7,6.7Hz,2H),3.73–3.52(m,4H) . 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.73 (d, J = 7.3 Hz, 1H), 7.54 (s, 1H), 7.39 (dd, J = 27.7, 7.3 Hz, 3H), 7.18 (dd, J = 16.8, 8.4 Hz, 1H), 6.29 (d, J = 3.8 Hz, 1H), 5.42 (d, J = 53.2 Hz, 1H), 5.26 (s, 1H), 4.14 (dd, J = 13.7, 6.7 Hz,2H),3.73-3.52(m,4H) .
步骤5)(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-((R)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚烷[1,2-b]噻吩-8-Step 5) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-((R)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[ 3,4:6,7]cycloheptane[1,2-b]thiophene-8- 基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮的合成Yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine Synthesis of -6,8-dione
于反应瓶中加入4,5-二氟-2-((R)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(800mg,2.0mmol)、(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(766mg,2.2mmol)、1-丙基磷酸酐(1.2mL,2.0mmol)和乙酸异丙酯(6mL)，反应混合物于微波110℃下搅拌反应2h。向反应中加水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机层用饱和食盐水(20mL)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(洗脱剂为DCM/MeOH(v/v)＝15/1)纯化，得标题化合物为棕色固体(414mg,28.7％)Add 4,5-difluoro-2-((R)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2 -b]thiophene-8-ol (800mg, 2.0mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3 ,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (766mg, 2.2mmol), 1-propyl phosphoric anhydride (1.2mL, 2.0mmol) ) And isopropyl acetate (6 mL), the reaction mixture was stirred at 110° C. in the microwave for 2 h. Water (10 mL) was added to the reaction, extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue Purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1), the title compound was obtained as a brown solid (414 mg, 28.7%)
MS(ESI,pos.ion)m/z:697.0[M+H] +。 MS (ESI, pos.ion) m/z: 697.0 [M+H] + .
步骤6)(R)-12-((R)-4,5-二氟-2-((R)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基Step 6) (R)-12-((R)-4,5-difluoro-2-((R)-3-fluoropyrrolidin-1-yl)-8H-dibenzo[3,4:6 ,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy 3,4,12,12a四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(化合物84)的合成3,4,12,12a Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8 -Synthesis of diketone (Compound 84)
于反应瓶中加入(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-((R)-3-氟吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚烷[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(414mg,0.6mmol)、氯化锂(259mg,5.9mmol)和N,N-二甲基乙酰胺(5mL)，反应混合物于100℃搅拌反应2h。用1N稀盐酸将反应液调节pH至6左右，然后加水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机层用饱和食盐水(10mL×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制备柱分离纯化，得到标题化合物为淡黄色固体(110mg,30.5％)。Add (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-((R)-3-fluoropyrrolidin-1-yl)-8H-diphenyl into the reaction flask And [3,4:6,7]cycloheptane[1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3 ,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (414mg, 0.6mmol), lithium chloride (259mg, 5.9mmol) and N,N -Dimethylacetamide (5mL), the reaction mixture was stirred at 100°C for 2h. Adjust the pH of the reaction solution to about 6 with 1N dilute hydrochloric acid, then add water (10mL), extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic layer with saturated brine (10mL×3), and anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was separated and purified by a LUNA preparation column to obtain the title compound as a pale yellow solid (110 mg, 30.5%).
MS(ESI,pos.ion)m/z:607.0[M+H] +； MS(ESI,pos.ion)m/z:607.0[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.52(d,J＝7.7Hz,1H),7.43–7.32(m,3H),7.25–7.18(m,2H),7.11(t,J＝7.4Hz,1H),6.89(d,J＝7.3Hz,1H),6.42(d,J＝7.4Hz,1H),6.28(d,J＝5.7Hz,1H),5.68(d,J＝7.4Hz,1H),5.36(s,1H),4.61(s,1H),4.26(d,J＝7.5Hz,1H),3.75(d,J＝11.5Hz,2H),3.62(dd,J＝18.3,8.8Hz,4H),3.51(d,J＝8.6Hz,1H),3.37(t,J＝11.2Hz,1H),3.27(t,J＝10.4Hz,1H),2.94(t,J＝11.2Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.52 (d, J = 7.7 Hz, 1H), 7.43-7.32 (m, 3H), 7.25-7.18 (m, 2H), 7.11 (t, J = 7.4 Hz, 1H), 6.89 (d, J = 7.3 Hz, 1H), 6.42 (d, J = 7.4 Hz, 1H), 6.28 (d, J = 5.7 Hz, 1H), 5.68 (d, J = 7.4 Hz, 1H), 5.36 (s, 1H), 4.61 (s, 1H), 4.26 (d, J = 7.5 Hz, 1H), 3.75 (d, J = 11.5 Hz, 2H), 3.62 (dd, J = 18.3, 8.8 Hz, 4H), 3.51 (d, J = 8.6 Hz, 1H), 3.37 (t, J = 11.2 Hz, 1H), 3.27 (t, J = 10.4 Hz, 1H), 2.94 (t, J = 11.2 Hz, 1H).
实施例33((R)-12-((S)-11-氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物97)Example 33 ((R)-12-((S)-11-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene- 8-yl)7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2, 4) Triazine-6,8-dione (Compound 97)
Figure PCTCN2020077781-appb-000085
Figure PCTCN2020077781-appb-000085
步骤1)3-苯噻吩的合成Step 1) Synthesis of 3-phenylthiophene
于反应瓶中加入溴苯(20.0g,127.3mmol)、3-噻吩硼酸(24.4g,191.0mmol)、醋酸钯(583mg,2.5mmol)、磷酸钾(55.7g,254.7mmol)、S-Phos(2.1g,5.0mmol)和甲苯(200mL)，氮气保护，反应混合物于110℃反应12小时。过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE)纯化，得标题化合物为无色透明液体(20.4g,99％)。Add bromobenzene (20.0g, 127.3mmol), 3-thiopheneboronic acid (24.4g, 191.0mmol), palladium acetate (583mg, 2.5mmol), potassium phosphate (55.7g, 254.7mmol), S-Phos( 2.1g, 5.0mmol) and toluene (200mL), under nitrogen protection, the reaction mixture was reacted at 110°C for 12 hours. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE) to obtain the title compound as a colorless transparent liquid (20.4 g, 99%).
步骤2)2-溴-3-苯基噻吩的合成Step 2) Synthesis of 2-bromo-3-phenylthiophene
于反应瓶中加入3-苯噻吩(20.4g,127.0mmol)和DM F(150mL)，并置于0℃下搅拌，再将NBS(23.8g，134.0mmol)的DMF(60mL)溶液滴加到反应体系中，反应混合物在0℃下搅拌反应20小时，向反应液中加入水(200mL)和饱和硫代硫酸钠溶液(10mL)，用乙酸乙酯(100mL×3)萃取，合并有机相，有机层用饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黄色油状物(30.4g,99.9％)。Add 3-phenylthiophene (20.4g, 127.0mmol) and DM F (150mL) into the reaction flask, and stir at 0℃, and then add a solution of NBS (23.8g, 134.0mmol) in DMF (60mL) dropwise to In the reaction system, the reaction mixture was stirred and reacted at 0°C for 20 hours. Water (200 mL) and saturated sodium thiosulfate solution (10 mL) were added to the reaction solution, extracted with ethyl acetate (100 mL×3), and the organic phases were combined. The organic layer was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow oil (30.4 g, 99.9%).
步骤3)4-氟-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酸甲酯的合成Step 3) Synthesis of methyl 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
于反应瓶中加入2-溴-4-氟苯甲酸甲酯(500mg,2.1mmol)、双联频哪醇硼酸酯(860mg,3.2mmol)、醋酸钾(343mg，3.2mmol)、PdCl 2(dppf)(179mg,0.2mmol)和1,4-二氧六环(10mL)，氮气保护下，反应混合物于90℃下搅拌反应17h。过滤，滤液浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/EtOAc(v/v)＝50/1)纯化，得标题化合物为墨绿色油状液体(600mg,99.8％)。 Add methyl 2-bromo-4-fluorobenzoate (500mg, 2.1mmol), dual pinacol borate (860mg, 3.2mmol), potassium acetate (343mg, 3.2mmol), PdCl 2 ( dppf) (179mg, 0.2mmol) and 1,4-dioxane (10mL), under the protection of nitrogen, the reaction mixture was stirred at 90°C for 17h. After filtration, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v)=50/1) to obtain the title compound as a dark green oily liquid (600 mg, 99.8%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.95(dd,J＝8.6,5.3Hz,1H),7.14(dd,J＝8.6,2.5Hz,1H),7.07(ddd,J＝15.0,7.6,3.3Hz,1H),3.90(s,3H),1.41(s,12H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.95 (dd, J = 8.6, 5.3 Hz, 1H), 7.14 (dd, J = 8.6, 2.5 Hz, 1H), 7.07 (ddd, J = 15.0, 7.6 ,3.3Hz,1H),3.90(s,3H),1.41(s,12H).
步骤4)4-氟-2-(3-苯基噻吩-2-基)苯甲酸甲酯的合成Step 4) Synthesis of methyl 4-fluoro-2-(3-phenylthiophen-2-yl)benzoate
于反应瓶中加入2-溴-3-苯基噻吩(5.0g,20.9mmol)，4-氟-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酸甲酯(11.7g,41.8mmol)，碳酸钾(8.7g,62.7mmol)和双三苯基膦二氯化钯(1.46g,2.0mmol)，水(1mL)和THF(50mL)，氮气保护，反应混合物于75℃下搅拌反应18h，过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为石油醚/乙酸乙酯(v/v)＝10/1)纯化，得标题化合物为黄色固体(4.8g,73％)。Add 2-bromo-3-phenylthiophene (5.0g, 20.9mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxane into the reaction flask Boran-2-yl) methyl benzoate (11.7g, 41.8mmol), potassium carbonate (8.7g, 62.7mmol) and bistriphenylphosphine palladium dichloride (1.46g, 2.0mmol), water (1mL) And THF (50mL), under nitrogen protection, the reaction mixture was stirred at 75℃ for 18h, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 10/1) Purification to obtain the title compound as a yellow solid (4.8 g, 73%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.80(dd,J＝8.5,5.9Hz,1H),7.42(d,J＝5.2Hz,1H),7.27–7.16(m,6H),7.10(ddd,J＝16.4,8.6,2.5Hz,2H),3.56(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.80 (dd, J = 8.5, 5.9 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 7.27-7.16 (m, 6H), 7.10 ( ddd, J = 16.4, 8.6, 2.5 Hz, 2H), 3.56 (s, 3H).
步骤5)4-氟-2-(3-苯基噻吩-2-基)苯甲酸的合成Step 5) Synthesis of 4-fluoro-2-(3-phenylthiophen-2-yl)benzoic acid
于反应瓶中加入4-氟-2-(3-苯基噻吩-2-基)苯甲酸甲酯(6.5g,21mmol)、甲醇(15mL)、THF(15mL)、氢氧化钠(3.4g,83mmol)的水(10mL)溶液，混合物于50℃搅拌反应7h。加2N盐酸调节反应液pH至5左右，向反应液中加入水(20mL)，用乙酸乙酯(20mL×2)萃取，合并有机相，有机层用饱和食盐水(40mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为黄色固体(6.2g,100％)。Add methyl 4-fluoro-2-(3-phenylthiophen-2-yl)benzoate (6.5g, 21mmol), methanol (15mL), THF (15mL), sodium hydroxide (3.4g, 83mmol) in water (10mL), the mixture was stirred at 50°C for 7h. Add 2N hydrochloric acid to adjust the pH of the reaction solution to about 5. Add water (20mL) to the reaction solution, extract with ethyl acetate (20mL×2), combine the organic phases, wash the organic layer with saturated brine (40mL), and anhydrous sulfuric acid Dry with sodium, filter, and concentrate the filtrate under reduced pressure to obtain the title compound as a yellow solid (6.2 g, 100%).
MS(ESI,neg.ion)m/z:297.1[M-H] -。 MS (ESI, neg.ion) m/z: 297.1 [MH] - .
步骤6)11-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 6) Synthesis of 11-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
于反应瓶中加入4-氟-2-(3-苯基噻吩-2-基)苯甲酸(6.2g,21mmol)和多聚磷酸(20mL)，反应混合物于120℃搅拌反应2h，向反应液中加入冰水(30mL)将其溶解，再用乙酸乙酯(20mL×2)萃取，合并有机相，有机层用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为石油醚/乙酸乙酯(v/v)＝10/1)纯化，得标题化合物为黄色固体(2.5g,43％)。Add 4-fluoro-2-(3-phenylthiophen-2-yl)benzoic acid (6.2g, 21mmol) and polyphosphoric acid (20mL) into the reaction flask. The reaction mixture was stirred at 120°C for 2h. Add ice water (30mL) to dissolve it, then extract with ethyl acetate (20mL×2), combine the organic phases, wash the organic layer with saturated brine (30mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate 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 a yellow solid (2.5 g, 43%).
步骤7)2-溴-11-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 7) Synthesis of 2-bromo-11-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
于反应瓶中加入11-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(1.9g,6.8mmol)、NBS(1.4g,7.5mmol)和醋酸(20mL)，反应混合物于55℃搅拌反应16h。抽滤，滤饼用石油醚(10mL)洗涤，然后滤饼加热 至60℃真空干燥，得标题化合物为白色固体(2.1g,86％)。Add 11-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (1.9g, 6.8mmol), NBS (1.4g, 7.5mmol) and acetic acid (20mL), the reaction mixture was stirred at 55°C for 16h. After suction filtration, the filter cake was washed with petroleum ether (10 mL), and then the filter cake was heated to 60°C and dried under vacuum to obtain the title compound as a white solid (2.1 g, 86%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.98–7.90(m,2H),7.74(d,J＝7.5Hz,1H),7.68–7.63(m,1H),7.57–7.52(m,1H),7.50(s,1H),7.36(dd,J＝9.7,2.3Hz,1H),7.21(td,J＝8.7,2.4Hz,1H). 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.98–7.90(m,2H), 7.74(d,J=7.5Hz,1H), 7.68–7.63(m,1H), 7.57–7.52(m,1H) ), 7.50 (s, 1H), 7.36 (dd, J = 9.7, 2.3 Hz, 1H), 7.21 (td, J = 8.7, 2.4 Hz, 1H).
步骤8)2-溴-11-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 8) Synthesis of 2-bromo-11-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
于反应瓶中加入2-溴-11-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(2.1g,5.8mmol)、THF(8mL)和甲醇(8mL)，反应混合物于室温下搅拌，然后缓慢加入硼氢化钠(2.3g,58mmol)，反应20分钟。向反应液加入饱和氯化铵溶液(10mL)，用乙酸乙酯(10mL×2)萃取，合并有机相，有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为浅黄色固体(2.0g,95％)。Add 2-bromo-11-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (2.1g, 5.8mmol), THF to the reaction flask (8mL) and methanol (8mL), the reaction mixture was stirred at room temperature, then sodium borohydride (2.3g, 58mmol) was slowly added, and the reaction was carried out for 20 minutes. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure After concentration, the title compound was obtained as a pale yellow solid (2.0 g, 95%).
步骤9)11-氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 9) Synthesis of 11-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
于反应瓶中加入2-溴-11-氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(1.8g,5.0mmol)，碘化亚铜(910mg,5.5mmol)，氧化铜(440mg,5.5mmol)，甲醇钠(1.3mL,7.0mmol)和甲醇(20mL)，反应混合物于110℃搅拌反应12h。过滤，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为PE/CH 2Cl 2(v/v)＝3/1)纯化，得标题化合物为黄色固体(492mg,32％)。 Add 2-bromo-11-fluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (1.8g, 5.0mmol), iodine to the reaction flask Cuprous oxide (910 mg, 5.5 mmol), copper oxide (440 mg, 5.5 mmol), sodium methoxide (1.3 mL, 7.0 mmol) and methanol (20 mL), the reaction mixture was stirred at 110° C. for 12 h. The filtrate was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: PE/CH 2 Cl 2 (v/v) = 3/1) to obtain the title compound as a yellow solid (492 mg, 32%) .
步骤10)((12aR)-7-(苄氧基)-12-(11-氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢Step 10) ((12aR)-7-(benzyloxy)-12-(11-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b)thiophen-8-yl)-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
于反应瓶中加入11-氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(290mg,0.9mmol)、(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f]的[1,2,4]三嗪-6,8-二酮(341mg,1.0mmol)、1-丙基磷酸酐(1.7mL,2.7mmol)和乙酸异丙酯(15mL)，反应混合物于90℃下搅拌反应2h。向反应液中加水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机层用饱和食盐水(20mL)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(洗脱剂为DCM/MeOH(v/v)＝15/1)纯化，得标题化合物为黄棕色固体(303mg,52.5％)。Add 11-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol (290mg, 0.9mmol) to the reaction flask, (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4] Triazine-6,8-dione (341mg, 1.0mmol), 1-propyl phosphoric anhydride (1.7mL, 2.7mmol) and isopropyl acetate (15mL), the reaction mixture is at 90°C The reaction was stirred for 2h. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain the title compound as a yellow-brown solid (303 mg, 52.5%).
MS(ESI,pos.ion)m/z:622.3[M+H] +。 MS (ESI, pos.ion) m/z: 622.3 [M+H] + .
步骤11)((R)-12-((S)-11-氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)7-羟基-3,4,12,12a-四氢-1H-Step 11) ((R)-12-((S)-11-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene- 8-yl)7-hydroxy-3,4,12,12a-tetrahydro-1H- [1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物97)的合成Synthesis of [1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 97)
于反应瓶中加入((12aR)-7-(苄氧基)-12-(11-氟-2-甲氧基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(300mg，0.48mmol)、氯化锂(210mg,4.8mmol)和DMAc(5mL)，反应混合物于100℃搅拌反应1h。用1N稀盐酸将反应液调节pH至6左右，然后加水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机层用饱和食盐水(10mL×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制备柱分离纯化，得到标题化合物为橙固体(63mg,24.5％)。Add ((12aR)-7-(benzyloxy)-12-(11-fluoro-2-methoxy-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4]triazine-6,8-dione (300mg, 0.48mmol), lithium chloride (210mg, 4.8mmol) and DMAc (5mL), the reaction mixture was stirred at 100°C for 1h. The reaction mixture was stirred with 1N dilute hydrochloric acid. The pH of the reaction solution was adjusted to about 6, then water (10 mL) was added, and it was extracted with ethyl acetate (10 mL×3). The organic phases were combined. The organic layer was washed with saturated brine (10 mL×3), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by a LUNA preparation column to obtain the title compound as an orange solid (63 mg, 24.5%).
MS(ESI,pos.ion)m/z:532.1[M+H] +； MS(ESI,pos.ion)m/z:532.1[M+H] + ;
1H NMR(400MHz,CDCl 3)δ(ppm)7.69(d,J＝7.6Hz,1H),7.52(t,J＝6.8Hz,1H),7.44(q,J＝7.3Hz,2H),7.19(d,J＝8.6Hz,1H),6.96–6.90(m,1H),6.85(d,J＝6.8Hz,1H),6.60(s,1H),6.42(d,J＝7.3Hz,1H),5.74(d,J＝7.4Hz,1H),5.40(s,1H),4.59(d,J＝11.3Hz,1H),4.18(d,J＝7.6Hz,1H),4.06(s,3H),3.72(d,J＝10.3Hz,1H),3.44(d,J＝9.2Hz,1H),3.35(t,J＝11.4Hz,1H),3.26(t,J＝10.4Hz,1H),2.89(t,J＝11.2Hz,1H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.69 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 6.8 Hz, 1H), 7.44 (q, J = 7.3 Hz, 2H), 7.19 (d,J=8.6Hz,1H), 6.96–6.90(m,1H), 6.85(d,J=6.8Hz,1H), 6.60(s,1H), 6.42(d,J=7.3Hz,1H) ,5.74(d,J=7.4Hz,1H),5.40(s,1H),4.59(d,J=11.3Hz,1H), 4.18(d,J=7.6Hz,1H),4.06(s,3H) ,3.72(d,J=10.3Hz,1H),3.44(d,J=9.2Hz,1H), 3.35(t,J=11.4Hz,1H), 3.26(t,J=10.4Hz,1H), 2.89 (t,J=11.2Hz,1H).
实施例34(12aR)-12-(2-乙酰基-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物94)Example 34 (12aR)-12-(2-Acetyl-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-yl )-7-Hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4] Triazine-6,8-dione (Compound 94)
Figure PCTCN2020077781-appb-000086
Figure PCTCN2020077781-appb-000086
于反应瓶中依次加入(12aR)-7-(苯氧基)-12-(4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(300mg,0.5mmol)，二氯甲烷(10mL)，三氯化铝(131mg,0.9mml)和乙酰氯(0.1mL,1.5mml)，反应混合物于室温搅拌反应10分钟。向反应液中加水(15mL)，用二氯甲烷(10mL×3)萃取，合并有机相，有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经LUNA制备柱分离纯化，得到标题化合物为橙色固体(34mg,12.3％)。Add (12aR)-7-(phenoxy)-12-(4,5-difluoro-8H-dibenzo[3,4:6,7]cycloheptane[1,2-b ]Thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2, 4] Triazine-6,8-dione (300mg, 0.5mmol), dichloromethane (10mL), aluminum trichloride (131mg, 0.9mml) and acetyl chloride (0.1mL, 1.5mml), the reaction mixture is at room temperature The reaction was stirred for 10 minutes. Water (15 mL) was added to the reaction solution, extracted with dichloromethane (10 mL×3), and the organic phases were combined. The organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The material was separated and purified by LUNA preparation column to obtain the title compound as an orange solid (34 mg, 12.3%).
MS(ESI,pos.ion)m/z:562.0[M+H] +。 MS (ESI, pos.ion) m/z: 562.0 [M+H] + .
实施例35(R)-12-((R)-4,5-二氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶[2,1-f][1,2,4]三嗪-6,8-二酮(化合物90)Example 35 (R)-12-((R)-4,5-difluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene -8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyridine[2,1-f][1,2 ,4) Triazine-6,8-dione (Compound 90)
Figure PCTCN2020077781-appb-000087
Figure PCTCN2020077781-appb-000087
步骤1)4,5-二氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 1) Synthesis of 4,5-difluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-ol
于反应瓶中加入4,5-二氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(2.40g,7.68mmol)、THF(10mL)和甲醇(10mL)，反应混合物于室温下搅拌，然后缓慢加入硼氢化钠(290mg,7.7mmol)，室温反应2小时。向反应液加入饱和氯化铵溶液(10mL)，用乙酸乙酯(10mL×2)萃取，合并有机相，有机层用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得标题化合物为浅黄色固体(2.4g,99％)。Add 4,5-difluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (2.40g, 7.68) to the reaction flask mmol), THF (10 mL) and methanol (10 mL), the reaction mixture was stirred at room temperature, then sodium borohydride (290 mg, 7.7 mmol) was slowly added, and the reaction was carried out at room temperature for 2 hours. Saturated ammonium chloride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×2), the organic phases were combined, the organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced in pressure After concentration, the title compound was obtained as a pale yellow solid (2.4 g, 99%).
1H NMR(400MHz,CDCl 3)δ(ppm)7.77(d,J＝7.8Hz,1H),7.56(dd,J＝8.2,5.2Hz,1H),7.50(d,J＝7.6Hz,1H),7.44(t,J＝7.6Hz,1H),7.32(d,J＝7.7Hz,1H),7.27-7.22(m,1H),7.22-7.16(m,1H),5.28(s,1H),2.64(s,3H),2.52(s,1H). 1 H NMR(400MHz, CDCl 3 )δ(ppm) 7.77(d,J=7.8Hz,1H), 7.56(dd,J=8.2,5.2Hz,1H), 7.50(d,J=7.6Hz,1H) ,7.44(t,J=7.6Hz,1H),7.32(d,J=7.7Hz,1H),7.27-7.22(m,1H),7.22-7.16(m,1H),5.28(s,1H), 2.64(s,3H), 2.52(s,1H).
步骤2)(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢Step 2) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b)thiophen-8-yl)-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
于反应瓶中加入4,5-二氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(1.73g,5.50mmol)，(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.50g,4.58mmol)、1-丙基磷酸酐(9mL,15.1mmol)和乙酸异丙酯(25mL)，反应混合物于90℃下搅拌反应20h。向反应液中加水(20mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，有机层用饱和食盐水(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(洗脱剂为DCM/MeOH(v/v)＝15/1)纯化，得 标题化合物为黄棕色固体(1.85g,64.7％)Add 4,5-difluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (1.73g, 5.50) to the reaction flask mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1- f][1,2,4]triazine-6,8-dione (1.50g, 4.58mmol), 1-propyl phosphoric anhydride (9mL, 15.1mmol) and isopropyl acetate (25mL), the reaction mixture is The reaction was stirred at 90°C for 20h. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue The product was purified by silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/1) to obtain the title compound as a yellow-brown solid (1.85g, 64.7%)
MS(ESI,pos.ion)m/z:624.8[M+H] +。 MS (ESI, pos.ion) m/z: 624.8 [M+H] + .
步骤3)(R)-12-((R)-4,5-二氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢Step 3) (R)-12-((R)-4,5-difluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene -8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物90)的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 90)
于反应瓶中加入(12aR)-7-(苄基氧基)-12-(4,5-二氟-2-甲基-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(1.65g,2.65mmol)、氯化锂(1.1g,26.4mmol)和DMAc(15mL)，反应混合物于100℃搅拌反应2h。用1N稀盐酸将反应液调节pH至6左右，然后加水(30mL)，用乙酸乙酯(30mL×3)萃取，合并有机相，有机层用饱和食盐水(30mL)洗涤三次，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残留物经LUNA制备柱分离纯化，得到标题化合物为橙色固体(242mg,17.1％)Add (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-methyl-8H-dibenzo[3,4:6,7]cyclohepta[ 1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4] Triazine-6,8-dione (1.65g, 2.65mmol), lithium chloride (1.1g, 26.4mmol) and DMAc (15mL), the reaction mixture was stirred at 100°C for 2h. Adjust the pH of the reaction solution to about 6 with 1N dilute hydrochloric acid, then add water (30mL), extract with ethyl acetate (30mL×3), combine the organic phases, and wash the organic layer with saturated brine (30mL) three times, anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure. The residue obtained is separated and purified by a LUNA preparative column to obtain the title compound as an orange solid (242mg, 17.1%)
1H NMR(400MHz,CDCl 3)δ(ppm)7.61(d,J＝7.6Hz,1H),7.39(t,J＝7.5Hz,1H),7.29–7.17(m,4H),6.93(d,J＝7.5Hz,1H),6.35(d,J＝7.6Hz,1H),5.70(d,J＝7.6Hz,1H),5.38(s,1H),4.59(d,J＝13.2Hz,1H),4.21(dd,J＝9.8,2.8Hz,1H),3.76–3.71(m,1H),3.36(dd,J＝15.1,6.7Hz,2H),3.24(t,J＝10.5Hz,1H),2.92(dd,J＝17.9,7.0Hz,1H),2.64(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.61 (d, J = 7.6 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.29-7.17 (m, 4H), 6.93 (d, J = 7.5Hz, 1H), 6.35 (d, J = 7.6Hz, 1H), 5.70 (d, J = 7.6Hz, 1H), 5.38 (s, 1H), 4.59 (d, J = 13.2Hz, 1H) ,4.21(dd,J=9.8,2.8Hz,1H), 3.76–3.71(m,1H), 3.36(dd,J=15.1,6.7Hz,2H), 3.24(t,J=10.5Hz,1H), 2.92(dd,J=17.9,7.0Hz,1H), 2.64(s,3H).
实施例36(R)-12-((R)-4,5-二氟-2-((S)-3-甲基吗啉代)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物101)Example 36 (R)-12-((R)-4,5-difluoro-2-((S)-3-methylmorpholino)-8H-dibenzo[3,4:6,7 ]Cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyridine And [2,1-f][1,2,4]triazine-6,8-dione (Compound 101)
Figure PCTCN2020077781-appb-000088
Figure PCTCN2020077781-appb-000088
步骤1)2-(3-(2,3-二氟苯基)-5-((S)-3-甲基-吗啉代)代噻吩-2-基)苯甲酸的合成Step 1) Synthesis of 2-(3-(2,3-difluorophenyl)-5-((S)-3-methyl-morpholino)thiophen-2-yl)benzoic acid
将((S)-3-甲基-吗啉(2.97g,29.30mmol)、2-(3-(2,3-二氟苯基)-5-溴苯甲酸甲酯(3.00g,7.33mmol)的DME(6mL)溶液加入到磷酸钾(4.81g,22.01mmol)、甲酸钠(1.99g,29.30mmol)的水(12mL)溶液中，反应液转移至封管中，氮气鼓泡5分钟，然后向其中加入碘化亚铜(140mg,0.73mmol)、铜(233mg,3.67mmol)，置于150℃油浴锅中反应约11小时。用2N稀盐酸调节反应液的pH值至酸性，然后用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)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(洗脱剂为EA/PE(v/v)＝1/10)进行分离提纯，得到标题化合物为黄色固体(478mg,15％)。The ((S)-3-methyl-morpholine (2.97g, 29.30mmol), 2-(3-(2,3-difluorophenyl)-5-bromobenzoic acid methyl ester (3.00g, 7.33mmol) ) DME (6mL) solution was added to potassium phosphate (4.81g, 22.01mmol), sodium formate (1.99g, 29.30mmol) in water (12mL) solution, the reaction solution was transferred to the sealed tube, nitrogen bubbling for 5 minutes, then Add cuprous iodide (140mg, 0.73mmol) and copper (233mg, 3.67mmol) to it, and place it in an oil bath at 150°C for about 11 hours. Adjust the pH of the reaction solution to acidity with 2N dilute hydrochloric acid, and then use Extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic phase with saturated brine (8mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is subjected to silica gel column chromatography (eluent It was separated and purified for EA/PE (v/v)=1/10) to obtain the title compound as a yellow solid (478 mg, 15%).
MS(ESI,neg.ion)m/z:414.1[M-H] -。 MS (ESI, neg.ion) m/z: 414.1 [MH] - .
步骤2)2-(((S)-3-甲基-吗啉代))-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 2) 2-(((S)-3-Methyl-morpholino))-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b ]Synthesis of thiophen-8-one
将化合物2-(3-(2,3-二氟苯基)-5-((S)-3-甲基-吗啉代)代噻吩-2-基)苯甲酸(630mg,1.51mmol)溶解于氯苯(3mL)，然后向其中加入多聚磷酸(3mL)，反应液置于120℃油浴锅中加热反应过夜。停止反应，向反应液中加入冰水(15mL)，用乙酸乙酯(6mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)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(洗脱剂为EA/PE(v/v)＝1/10)分 离提纯，得到标题化合物为黄色固体(600mg,99％)。Dissolve compound 2-(3-(2,3-difluorophenyl)-5-((S)-3-methyl-morpholino)thiophen-2-yl)benzoic acid (630mg, 1.51mmol) In chlorobenzene (3mL), polyphosphoric acid (3mL) was added to it, and the reaction solution was heated in an oil bath at 120°C for overnight reaction. The reaction was stopped, ice water (15mL) was added to the reaction solution, extracted with ethyl acetate (6mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (8mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was reduced After pressure concentration, the obtained residue was separated and purified by silica gel column chromatography (eluent: EA/PE (v/v) = 1/10) to obtain the title compound as a yellow solid (600 mg, 99%).
MS(ESI,pos.ion)m/z:498.2[M+H] +。 MS (ESI, pos.ion) m/z: 498.2 [M+H] + .
步骤3)2-(((S)-3-甲基-吗啉代))-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 3) 2-(((S)-3-Methyl-morpholino))-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b ] Synthesis of thiophen-8-ol
将2-(((S)-3-甲基-吗啉代))-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(600mg,1.51mmol)溶解于THF(6mL)和甲醇(6mL)中，接着向其中加入硼氢化钠(118mg,3.02mmol)，置于室温下搅拌反应约15分钟。停止反应，向反应液中加入饱和氯化铵溶液(20mL)，用乙酸乙酯(6mL×3)萃取，合并有机相，有机层用饱和食盐水(8mL)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(洗脱剂为EA/PE(v/v)＝1/10)分离提纯，得到标题化合物为黄色固体(301mg,50％)。Add 2-(((S)-3-methyl-morpholino))-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene -8-ketone (600 mg, 1.51 mmol) was dissolved in THF (6 mL) and methanol (6 mL), then sodium borohydride (118 mg, 3.02 mmol) was added thereto, and the reaction was stirred at room temperature for about 15 minutes. The reaction was stopped, saturated ammonium chloride solution (20 mL) was added to the reaction solution, extracted with ethyl acetate (6 mL×3), the organic phases were combined, the organic layer was washed with saturated brine (8 mL), dried with anhydrous sodium sulfate, and filtered The filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: EA/PE(v/v)=1/10) to obtain the title compound as a yellow solid (301 mg, 50%).
MS(ESI,pos.ion)m/z:400.3[M+H] +。 MS (ESI, pos.ion) m/z: 400.3 [M+H] + .
1H NMR(400MHz,CDCl 3)δ(ppm)7.76(d,J＝7.8Hz,1H),7.63–7.51(m,1H),7.49–7.38(m,2H),7.32(d,J＝12.0Hz,1H),7.20(dd,J＝17.2,8.7Hz,1H),6.63(t,J＝5.1Hz,1H),5.32(s,1H),4.00(d,J＝11.3Hz,1H),3.93–3.86(m,1H),3.84–3.78(m,1H),3.73(dt,J＝11.2,3.2Hz,1H),3.62–3.51(m,1H),3.41–3.29(m,1H),3.26–3.13(m,1H),1.29(d,J＝6.5Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.76 (d, J = 7.8 Hz, 1H), 7.63-7.51 (m, 1H), 7.49-7.38 (m, 2H), 7.32 (d, J = 12.0 Hz, 1H), 7.20 (dd, J = 17.2, 8.7 Hz, 1H), 6.63 (t, J = 5.1 Hz, 1H), 5.32 (s, 1H), 4.00 (d, J = 11.3 Hz, 1H), 3.93–3.86 (m, 1H), 3.84–3.78 (m, 1H), 3.73 (dt, J = 11.2, 3.2 Hz, 1H), 3.62–3.51 (m, 1H), 3.41–3.29 (m, 1H), 3.26–3.13(m,1H), 1.29(d,J=6.5Hz,3H).
步骤4)(12aR)-7-(苄氧基)-12-(4,5-二氟-2-((S)-3-甲基吗啉代)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-Step 4) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-((S)-3-methylmorpholino)-8H-dibenzo[3,4 :6,7]cycloheptan[1,2-b]thiophene-8- 基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine- Synthesis of 6,8-dione
将2-(((S)-3-甲基-吗啉代))-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(388mg,0.97mmol)、(R)-7-(苄氧基)-3,4,12,12a四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6-,8二酮(349mg,1.07mmol)混合于T 3P(1.16mL,1.94mmol)的乙酸异丙酯(5mL)溶液中，置于微波反应仪中，120℃条件下反应约2小时。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)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(洗脱剂为MeOH/DCM(v/v)＝1/10)分离提纯，得到标题化合物为白色固体(116mg,17％)。 Add 2-(((S)-3-methyl-morpholino))-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene -8-alcohol (388mg, 0.97mmol), (R)-7-(benzyloxy)-3,4,12,12a tetrahydro-1H-[1,4]oxazino[3,4-c] Pyrido[2,1-f][1,2,4]triazine-6-,8dione (349mg, 1.07mmol) mixed with T 3 P (1.16mL, 1.94mmol) isopropyl acetate (5mL ) In the solution, place it in a microwave reactor and react at 120°C for about 2 hours. 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), dry with anhydrous sodium sulfate, filter, and reduce the filtrate After pressure concentration, the obtained residue was separated and purified by silica gel column chromatography (eluent: MeOH/DCM(v/v)=1/10) to obtain the title compound as a white solid (116 mg, 17%).
MS(ESI,pos.ion)m/z:709.2[M+H] +。 MS (ESI, pos.ion) m/z: 709.2 [M+H] + .
步骤5)(R)-12-((R)-4,5-二氟-2-((S)-3-甲基吗啉代)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基Step 5) (R)-12-((R)-4,5-difluoro-2-((S)-3-methylmorpholino)-8H-dibenzo[3,4:6,7 ]Cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy -3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物101)的合成-3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6, Synthesis of 8-Diketone (Compound 101)
将(12aR)-7-(苄氧基)-12-(4,5-二氟-2-((S)-3-甲基吗啉代)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(109mg,0.15mmol)、氯化锂(65mg,1.54mmol)混合于N,N-二甲基乙酰胺(6mL)中，氮气保护，置于100℃油浴锅中反应约6小时。向反应液中加入水(10mL)，然后用0.5N HCl调节反应液PH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)分离提纯，得到标题化合物为淡黄色固体(25mg,26％)。Add (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-((S)-3-methylmorpholino)-8H-dibenzo[3,4:6 ,7]cyclohepta[1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[ 2,1-f][1,2,4]triazine-6,8-dione (109mg, 0.15mmol), lithium chloride (65mg, 1.54mmol) mixed in N,N-dimethylacetamide ( 6mL), protected by nitrogen, placed in an oil bath at 100°C to react for about 6 hours. Add water (10mL) to the reaction solution, then adjust the pH of the reaction solution to weak acidity with 0.5N HCl, stir for 10 minutes, then extract with ethyl acetate (20mL×3), combine the organic phases, and use saturated brine ( 30mL) washed, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was separated and purified by a LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13). The title compound was obtained as a pale yellow solid (25 mg, 26%).
MS(ESI,pos.ion)m/z:619.1[M+H]+。MS (ESI, pos.ion) m/z: 619.1 [M+H]+.
1H NMR(600MHz,CDCl 3)δ(ppm)7.55(d,J＝7.5Hz,1H),7.45–7.32(m,2H),7.24(s,1H),7.14(s,1H),6.92(s,1H),6.58(d,J＝5.4Hz,1H),6.46(d,J＝5.7Hz,1H),5.83(s,1H),5.38(s,1H),4.61(s,1H),4.27(d,J＝8.0Hz,1H),4.02(d,J＝11.0Hz,1H),3.92(d,J＝9.4Hz,1H),3.79(t,J＝12.9Hz,3H),3.64(d,J＝6.1Hz,1H),3.40(dd,J＝22.1,10.6Hz,3H),3.28(t,J＝10.4Hz,1H),3.17(d,J＝11.8Hz,1H),2.94(t,J＝11.4Hz,1H),1.33(d,J＝6.4Hz,3H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm) 7.55 (d, J = 7.5 Hz, 1H), 7.45-7.32 (m, 2H), 7.24 (s, 1H), 7.14 (s, 1H), 6.92 ( s, 1H), 6.58 (d, J = 5.4 Hz, 1H), 6.46 (d, J = 5.7 Hz, 1H), 5.83 (s, 1H), 5.38 (s, 1H), 4.61 (s, 1H), 4.27 (d, J = 8.0 Hz, 1H), 4.02 (d, J = 11.0 Hz, 1H), 3.92 (d, J = 9.4 Hz, 1H), 3.79 (t, J = 12.9 Hz, 3H), 3.64 ( d, J = 6.1Hz, 1H), 3.40 (dd, J = 22.1, 10.6 Hz, 3H), 3.28 (t, J = 10.4 Hz, 1H), 3.17 (d, J = 11.8 Hz, 1H), 2.94 ( t,J=11.4Hz,1H),1.33(d,J=6.4Hz,3H).
实施例37(R)-12-((R)-4,5-二氟-2-硫代吗啉代-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物102)Example 37 (R)-12-((R)-4,5-difluoro-2-thiomorpholino-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b]Thien-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]Triazine-6,8-dione (Compound 102)
Figure PCTCN2020077781-appb-000089
Figure PCTCN2020077781-appb-000089
步骤1)2-(3-(2,3-二氟苯基)-5-硫代吗啉代噻吩-2-基)苯甲酸的合成Step 1) Synthesis of 2-(3-(2,3-difluorophenyl)-5-thiomorpholinothiophen-2-yl)benzoic acid
将硫代吗啉(3.33g,32.30mmol)、2-(3-(2,3-二氟苯基)-5-溴苯甲酸甲酯(3.30g,8.06mmol)的DME(6mL)溶液加入到磷酸钾(5.29g,24.20mmol)、甲酸钠(2.19g,32.20mmol)的水(12mL)溶液中，置于室温下搅拌，氮气鼓泡5分钟，然后向其中加入碘化亚铜(154mg,0.81mmol)、铜(359mg,5.65mmol)，封管置于150℃油浴锅中反应约11小时。用2N盐酸调节反应液pH至酸性，用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)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(洗脱剂为EA/PE(v/v)＝1/10)分离提纯，得到标题化合物为黄色固体(479mg,14％)。Add thiomorpholine (3.33g, 32.30mmol), 2-(3-(2,3-difluorophenyl)-5-bromobenzoic acid methyl ester (3.30g, 8.06mmol) in DME (6mL) solution To potassium phosphate (5.29g, 24.20mmol), sodium formate (2.19g, 32.20mmol) in water (12mL) solution, place at room temperature and stir, bubbling with nitrogen for 5 minutes, then add copper iodide (154mg, 0.81mmol), copper (359mg, 5.65mmol), seal the tube and place it in a 150℃ oil bath for about 11 hours. Adjust the pH of the reaction solution to acidity with 2N hydrochloric acid, extract with ethyl acetate (10mL×3), and combine the organic The organic phase was washed with saturated brine (8mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (eluent EA/PE(v/v)=1/ 10) Separation and purification to obtain the title compound as a yellow solid (479 mg, 14%).
MS(ESI,neg.ion)m/z:416.2[M-H] -。 MS (ESI, neg.ion) m/z: 416.2 [MH] - .
步骤2)2-(硫代吗啉基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 2) Synthesis of 2-(thiomorpholinyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one
将2-(3-(2,3-二氟苯基)-5-硫代吗啉代噻吩-2-基)苯甲酸(630mg,1.51mmol)溶于氯苯(3mL)，然后加入多聚磷酸(3mL)，于120℃油浴锅中加热反应过夜。停止反应，向反应液中加入冰水(15mL)，用乙酸乙酯(6mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)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(洗脱剂为EA/PE(v/v)＝1/10)分离提纯，得到标题化合物为黄色固体(600mg,99％)。Dissolve 2-(3-(2,3-difluorophenyl)-5-thiomorpholinothiophen-2-yl)benzoic acid (630mg, 1.51mmol) in chlorobenzene (3mL), then add polymer Phosphoric acid (3mL), heated in a 120°C oil bath for reaction overnight. The reaction was stopped, ice water (15mL) was added to the reaction solution, extracted with ethyl acetate (6mL×3), the organic phases were combined, and the organic phases were washed with saturated brine (8mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was reduced After pressure concentration, the obtained residue was separated and purified by silica gel column chromatography (eluent: EA/PE (v/v) = 1/10) to obtain the title compound as a yellow solid (600 mg, 99%).
MS(ESI,pos.ion)m/z:400.2[M+H] +。 MS (ESI, pos.ion) m/z: 400.2 [M+H] + .
步骤3)2-(硫代吗啉基)-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 3) Synthesis of 2-(thiomorpholinyl)-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol
将2-(硫代吗啉基)-4,5-二氟-8H二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(500mg,1.32mmol)溶解于THF(6mL)和甲醇(6mL)中，接着向其中加入硼氢化钠(95mg,2.50mmol)，置于室温下搅拌反应约15分钟。停止反应，向反应液中加入饱和氯化铵溶液(20mL)，用乙酸乙酯(6mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL)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(洗脱剂为EA/PE(v/v)＝1/10)分离提纯，得到标题化合物为浅黄色固体(301mg,50％)。Add 2-(thiomorpholinyl)-4,5-difluoro-8H dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophen-8-one (500mg, 1.32mmol ) Was dissolved in THF (6 mL) and methanol (6 mL), then sodium borohydride (95 mg, 2.50 mmol) was added thereto, and the reaction was stirred at room temperature for about 15 minutes. Stop the reaction, add saturated ammonium chloride solution (20mL) to the reaction solution, extract with ethyl acetate (6mL×3), combine the organic phases, wash the organic phases with saturated brine (8mL), dry with anhydrous sodium sulfate, and filter The filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: EA/PE(v/v)=1/10) to obtain the title compound as a pale yellow solid (301 mg, 50%).
MS(ESI,pos.ion)m/z:402.2[M+H] +。 MS (ESI, pos.ion) m/z: 402.2 [M+H] + .
1H NMR(400MHz,CDCl 3)δ(ppm)7.75(d,J＝7.8Hz,1H),7.60–7.53(m,1H),7.41(dd,J＝14.3,7.6Hz,2H),7.30(s,1H),7.20(dd,J＝17.3,8.8Hz,1H),6.58(d,J＝5.2Hz,1H),5.31(s,1H),3.77–3.58(m,4H),2.96–2.78(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ (ppm) 7.75 (d, J = 7.8 Hz, 1H), 7.60-7.53 (m, 1H), 7.41 (dd, J = 14.3, 7.6 Hz, 2H), 7.30 ( s, 1H), 7.20 (dd, J = 17.3, 8.8 Hz, 1H), 6.58 (d, J = 5.2 Hz, 1H), 5.31 (s, 1H), 3.77–3.58 (m, 4H), 2.96–2.78 (m,4H).
步骤4)(12aR)-7-(苄氧基)-12-(4,5-二氟-2-硫代吗啉代-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-Step 4) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-thiomorpholino-8H-dibenzo[3,4:6,7]cyclohepta[ 1,2-b]thiophen-8-yl)-3,4,12,12a- 四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Synthesis of Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione
将2-(硫代吗啉基)-4,5-二氟-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(220mg,0.55mmol)、(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8二酮(197mg,0.60mmol)混合于T 3P(0.50mL,0.82mmol)的乙酸异丙酯(20mL)溶液中，置于微波反应仪中在120℃下反应2小时。停止反 应，向反应液中加入水(15mL)，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，滤液减压浓缩，所得残留物经硅胶柱层析(洗脱剂为MeOH/DCM(v/v)＝1/10)分离提纯，得到标题化合物为白色固体(103mg,26％)。 Combine 2-(thiomorpholinyl)-4,5-difluoro-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b]thiophene-8-ol (220mg, 0.55 mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1- f][1,2,4]Triazine-6,8dione (197mg, 0.60mmol) was mixed with T 3 P (0.50mL, 0.82mmol) in isopropyl acetate (20mL) and placed in microwave for reaction React in the instrument at 120°C for 2 hours. Stop the reaction, add water (15mL) to the reaction solution, extract with ethyl acetate (20mL×3), combine the organic phases, wash the organic phase with saturated brine (15mL), dry with anhydrous sodium sulfate, filter, and reduce the filtrate After concentration, the obtained residue was separated and purified by silica gel column chromatography (eluent: MeOH/DCM(v/v)=1/10) to obtain the title compound as a white solid (103 mg, 26%).
MS(ESI,pos.ion)m/z:711.1[M+H] + MS(ESI,pos.ion)m/z:711.1[M+H] +
步骤5)(R)-12-((R)-4,5-二氟-2-硫代吗啉代-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢Step 5) (R)-12-((R)-4,5-difluoro-2-thiomorpholino-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b)thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro -1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物102)的合成Synthesis of -1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 102)
将化合物(12aR)-7-(苄氧基)-12-(4,5-二氟-2-硫吗啉代-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(95mg,0.13mmol)、氯化锂(56mg,1.34mmol)混合于DMAc(6mL)中，氮气保护，置于100℃油浴锅中反应约6小时。停止反应，向反应液中加入水(10mL)，然后用0.5N HCl调节反应液pH值至弱酸性，搅拌10分钟，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)分离提纯，得到标题化合物为淡黄色固体(14mg,17％)。The compound (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-thiomorpholino-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4] Triazine-6,8-dione (95mg, 0.13mmol), lithium chloride (56mg, 1.34mmol) were mixed in DMAc (6mL), protected by nitrogen, placed in a 100℃ oil bath for reaction About 6 hours. Stop the reaction, add water (10mL) to the reaction solution, then adjust the pH value of the reaction solution to weak acidity with 0.5N HCl, stir for 10 minutes, extract with ethyl acetate (20mL×3), combine the organic phases, and saturate the organic phases Wash with brine (30 mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained is passed through a LUNA preparation column (eluent is acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) After separation and purification, the title compound was obtained as a pale yellow solid (14 mg, 17%).
MS(ESI,pos.ion)m/z:621.1[M+H]+。MS (ESI, pos.ion) m/z: 621.1 [M+H]+.
1H NMR(600MHz,CDCl 3)δ(ppm)7.63(d,J＝7.6Hz,1H),7.50(d,J＝7.7Hz,1H),7.42(s,2H),7.04(d,J＝7.7Hz,1H),6.77(s,1H),6.64(t,J＝5.9Hz,2H),6.31(s,1H),5.40(s,1H),4.60(d,J＝11.9Hz,1H),4.23(d,J＝8.2Hz,1H),3.76(s,1H),3.71–3.62(m,4H),3.43(dd,J＝23.8,10.3Hz,2H),3.25(t,J＝10.3Hz,1H),2.95(d,J＝12.4Hz,1H),2.88(d,J＝4.6Hz,4H). 1 H NMR (600MHz, CDCl 3 )δ (ppm) 7.63 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.42 (s, 2H), 7.04 (d, J = 7.7Hz, 1H), 6.77 (s, 1H), 6.64 (t, J = 5.9 Hz, 2H), 6.31 (s, 1H), 5.40 (s, 1H), 4.60 (d, J = 11.9 Hz, 1H) ,4.23(d,J=8.2Hz,1H),3.76(s,1H),3.71-3.62(m,4H),3.43(dd,J=23.8,10.3Hz,2H), 3.25(t,J=10.3 Hz, 1H), 2.95 (d, J = 12.4 Hz, 1H), 2.88 (d, J = 4.6 Hz, 4H).
实施例38(R)-12-((R)-4,5-二氟-2-((S)-3-甲氧基吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物103)Example 38 (R)-12-((R)-4,5-difluoro-2-((S)-3-methoxypyrrolidin-1-yl)-8H-dibenzo[3,4 :6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4 -c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 103)
Figure PCTCN2020077781-appb-000090
Figure PCTCN2020077781-appb-000090
步骤1)(S)-2-(3-(2,3-二氟苯基)-5-(3-羟基吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯的合成Step 1) Synthesis of methyl (S)-2-(3-(2,3-difluorophenyl)-5-(3-hydroxypyrrolidin-1-yl)thiophen-2-yl)benzoate
将2-(5-溴-3-(2,3-二氟苯基)噻吩-2-基)苯甲酸甲酯(140mg,0.34mmol)、碳酸铯(491mg,1.51mmol)、(S)-吡咯烷-3-醇盐酸盐(93mg,0.75mmol)、甲苯(3mL)加入到反应瓶中，氮气保护并在室温下搅拌，约10分钟后，向其中加入BINAP(13mg,0.02mmol)和Pd 2(dba) 3(9mg,0.01mmol)，接着转移到110℃油浴锅中反应约12小时。停止反应，减压除去有机溶剂，所得残留物经硅胶柱层析(洗脱剂为石油醚/EtOAc(v/v)＝5/1)分离提纯，得到标题化合物为黄色固体(61.0mg,43％)。 The methyl 2-(5-bromo-3-(2,3-difluorophenyl)thiophen-2-yl)benzoate (140mg, 0.34mmol), cesium carbonate (491mg, 1.51mmol), (S)- Pyrrolidin-3-ol hydrochloride (93mg, 0.75mmol) and toluene (3mL) were added to the reaction flask, protected by nitrogen and stirred at room temperature, about 10 minutes later, BINAP (13mg, 0.02mmol) and Pd 2 (dba) 3 (9mg, 0.01mmol), then transferred to 110°C oil bath for about 12 hours. The reaction was stopped, the organic solvent was removed under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (eluent: petroleum ether/EtOAc (v/v) = 5/1) to obtain the title compound as a yellow solid (61.0 mg, 43 %).
MS(ESI,pos.ion)m/z:416.1[M+H] + MS(ESI,pos.ion)m/z:416.1[M+H] +
1H NMR(600MHz,CDCl 3)δ(ppm)7.64(dd,J＝7.7,0.9Hz,1H),7.40(ddd,J＝16.4,7.6,3.9Hz,2H),7.29(ddd,J＝7.6,6.2,1.4Hz,1H),7.00(td,J＝9.7,1.7Hz,1H),6.90–6.77(m,2H),5.91(d,J＝1.9Hz,1H),4.66–4.58(m,1H),3.65(s,3H),3.56(dd,J＝6.2,4.2Hz,1H),3.37(td,J＝8.8,3.5Hz,1H),3.30(d,J＝10.3Hz,1H), 2.25(ddd,J＝12.2,8.4,3.5Hz,1H),2.13–2.08(m,1H),0.93–0.86(m,2H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm) 7.64 (dd, J = 7.7, 0.9 Hz, 1H), 7.40 (ddd, J = 16.4, 7.6, 3.9 Hz, 2H), 7.29 (ddd, J = 7.6 ,6.2,1.4Hz,1H),7.00(td,J=9.7,1.7Hz,1H),6.90–6.77(m,2H),5.91(d,J=1.9Hz,1H),4.66–4.58(m, 1H), 3.65 (s, 3H), 3.56 (dd, J = 6.2, 4.2 Hz, 1H), 3.37 (td, J = 8.8, 3.5 Hz, 1H), 3.30 (d, J = 10.3 Hz, 1H), 2.25(ddd,J=12.2,8.4,3.5Hz,1H), 2.13-2.08(m,1H), 0.93-0.86(m,2H).
步骤2)(S)-2-(3-(2,3-二氟苯基)-5-(3-甲氧基吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯的合成Step 2) Synthesis of methyl (S)-2-(3-(2,3-difluorophenyl)-5-(3-methoxypyrrolidin-1-yl)thiophen-2-yl)benzoate
将(S)-2-(3-(2,3-二氟苯基)-5-(3-羟基吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯(1.14g,2.74mmol)溶解于DMF(10mL)中，然后向其中加入NaH(241mg,6.04mmol)在室温下搅拌约30分钟，接着加入碘甲烷(0.52mL,8.30mmol)反应约2小时。停止反应，用2N盐酸调节反应液pH至酸性，用乙酸乙酯(8mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL×3)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(洗脱剂为EA/PE(v/v)＝1/10)分离提纯，得到标题化合物为黄色固体(751.0mg，64％)。(S)-2-(3-(2,3-Difluorophenyl)-5-(3-hydroxypyrrolidin-1-yl)thiophen-2-yl)benzoic acid methyl ester (1.14g, 2.74mmol ) Was dissolved in DMF (10 mL), and then NaH (241 mg, 6.04 mmol) was added thereto and stirred at room temperature for about 30 minutes, and then methyl iodide (0.52 mL, 8.30 mmol) was added to react for about 2 hours. Stop the reaction, adjust the pH of the reaction solution to acidity with 2N hydrochloric acid, extract with ethyl acetate (8mL×3), combine the organic phases, wash the organic phases with saturated brine (10mL×3), dry with anhydrous sodium sulfate, filter, and filtrate Concentrated under reduced pressure, and the residue obtained was separated and purified by silica gel column chromatography (eluent: EA/PE (v/v) = 1/10) to obtain the title compound as a yellow solid (751.0 mg, 64%).
MS(ESI,pos.ion)m/z:430.0[M+H] + MS(ESI,pos.ion)m/z:430.0[M+H] +
步骤3)(S)-2-(3-(2,3-二氟苯基)-5-(3-甲氧基吡咯烷-1-基)噻吩-2-基)苯甲酸的合成Step 3) Synthesis of (S)-2-(3-(2,3-difluorophenyl)-5-(3-methoxypyrrolidin-1-yl)thiophen-2-yl)benzoic acid
将(S)-2-(3-(2,3-二氟苯基)-5-(3-甲氧基吡咯烷-1-基)噻吩-2-基)苯甲酸甲酯(930mg,2.17mmol)溶解于THF(10mL)和甲醇(10mL)中，然后向其中加入氢氧化钠(346mg,8.66mmol)的水(3mL)溶液，于55℃条件下搅拌约6小时。停止反应，用2N盐酸调节反应液PH至酸性，用乙酸乙酯(8mL×3)萃取，合并有机相，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为黄色固体(897.0mg，100％)。(S)-2-(3-(2,3-Difluorophenyl)-5-(3-methoxypyrrolidin-1-yl)thiophen-2-yl)benzoic acid methyl ester (930mg, 2.17 mmol) was dissolved in THF (10 mL) and methanol (10 mL), then a water (3 mL) solution of sodium hydroxide (346 mg, 8.66 mmol) was added thereto, and the mixture was stirred at 55°C for about 6 hours. Stop the reaction, adjust the pH of the reaction solution to acidity with 2N hydrochloric acid, extract with ethyl acetate (8mL×3), combine the organic phases, wash with saturated brine (10mL), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The title compound was a yellow solid (897.0 mg, 100%).
MS(ESI,pos.ion)m/z:416.0[M+H] +。 MS (ESI, pos.ion) m/z: 416.0 [M+H] + .
步骤4)(S)-4,5-二氟-2-(3-甲氧基吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮的合成Step 4) (S)-4,5-Difluoro-2-(3-methoxypyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2 -b] Synthesis of thiophen-8-one
将(S)-2-(3-(2,3-二氟苯基)-5-(3-甲氧基吡咯烷-1-基)噻吩-2-基)苯甲酸(951mg,2.29mmol)溶于氯苯(3mL)中，然后向其中加入PPA(5mL)，氮气保护，置于110℃油浴锅中反应约7小时。停止反应，向反应液中加入冰水(15mL)，用乙酸乙酯(8mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物为黄色固体(451.0mg,50％)。(S)-2-(3-(2,3-Difluorophenyl)-5-(3-methoxypyrrolidin-1-yl)thiophen-2-yl)benzoic acid (951mg, 2.29mmol) Dissolve in chlorobenzene (3mL), then add PPA (5mL) to it, protect it with nitrogen, and place it in an oil bath at 110°C to react for about 7 hours. Stop the reaction, add ice water (15mL) to the reaction solution, extract with ethyl acetate (8mL×3), combine the organic phases, wash the organic phases with saturated brine (10mL), dry with anhydrous sodium sulfate, filter, and reduce the filtrate It was concentrated under pressure to obtain the title compound as a yellow solid (451.0 mg, 50%).
MS(ESI,pos.ion)m/z:398.2[M+H] + MS(ESI,pos.ion)m/z:398.2[M+H] +
步骤5)((S)-4,5-二氟-2-(3-甲氧基吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇的合成Step 5) ((S)-4,5-Difluoro-2-(3-methoxypyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1, 2-b] Synthesis of thiophen-8-ol
将(S)-4,5-二氟-2-(3-甲氧基吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-酮(150mg,0.38mmol)溶解于THF(10mL)和甲醇(10mL)中，接着加入NaBH 4(44mg,1.13mmol)，在室温下搅拌约11小时。停止反应，向反应液中加入饱和氯化铵溶液(20mL)，用乙酸乙酯(8mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL×3)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(洗脱剂为EA/PE(V/V)＝1/10)分离提纯，得到标题化合物为浅黄色固体(150.0mg，100％)。 (S)-4,5-Difluoro-2-(3-methoxypyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2-b ] Thiophen-8-one (150 mg, 0.38 mmol) was dissolved in THF (10 mL) and methanol (10 mL), then NaBH 4 (44 mg, 1.13 mmol) was added, and the mixture was stirred at room temperature for about 11 hours. Stop the reaction, add saturated ammonium chloride solution (20mL) to the reaction solution, extract with ethyl acetate (8mL×3), combine the organic phases, wash the organic phase with saturated brine (10mL×3), and dry with anhydrous sodium sulfate After filtering, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (eluent: EA/PE(V/V)=1/10) to obtain the title compound as a pale yellow solid (150.0mg, 100%) ).
MS(ESI,pos.ion)m/z:400.1[M+H] +。 MS (ESI, pos.ion) m/z: 400.1 [M+H] + .
步骤6)(12aR)-7-(苄氧基)-12-(4,5-二氟-2-((S)-3-甲氧基吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-Step 6) (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-((S)-3-methoxypyrrolidin-1-yl)-8H-dibenzo [3,4:6,7]cycloheptan[1,2-b]thiophene-8- 基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮的合成Yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine- Synthesis of 6,8-dione
将((S)-4,5-二氟-2-(3-甲氧基吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-醇(160mg,0.40mmol)，(R)-7-(苄氧基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(144mg,0.44mmol)混合于乙酸异丙酯(5mL)中，然后向其中加入T 3P(0.32mL,0.52mmol)，微波110℃反应4小时。停止反应，向反应液中加入饱和碳酸氢钠溶液(20mL)，用乙酸乙酯(8mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL×3)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(洗脱剂为DCM/MeOH(v/v)＝15/1)分离提纯，得到标题化合物为黄色固体(112.0mg,39％)。 Put ((S)-4,5-difluoro-2-(3-methoxypyrrolidin-1-yl)-8H-dibenzo[3,4:6,7]cyclohepta[1,2- b]thiophene-8-alcohol (160mg, 0.40mmol), (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3, 4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (144mg, 0.44mmol) was mixed in isopropyl acetate (5mL), and then added T 3 P (0.32 mL, 0.52 mmol) was reacted in a microwave at 110°C for 4 hours. The reaction was stopped, saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, extracted with ethyl acetate (8 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: DCM/MeOH(v/v)=15/ 1) Separation and purification to obtain the title compound as a yellow solid (112.0 mg, 39%).
MS(ESI,pos.ion)m/z:709.2[M+H] + MS(ESI,pos.ion)m/z:709.2[M+H] +
步骤7)(R)-12-((S)-4,5-二氟-2-((S)-3-甲氧基吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-7-羟基Step 7) (R)-12-((S)-4,5-difluoro-2-((S)-3-methoxypyrrolidin-1-yl)-8H-dibenzo[3,4 :6,7]cyclohepta[1,2-b]thiophen-8-yl)-7-hydroxy -3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物103)的合成-3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6, Synthesis of 8-diketone (Compound 103)
将(12aR)-7-(苄氧基)-12-(4,5-二氟-2-((S)-3-甲氧基吡咯烷-1-基)-8H-二苯并[3,4:6,7]环庚[1,2-b]噻吩-8-基)-3,4,12,12a-四氢-1H-[1,4]噁嗪并[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(90mg,0.13mmol)溶解于DMAc(10mL)，接着加入氯化锂(53mg,1.27mmol)，氮气保护并置于100℃油浴锅中加热反应约2.5小时。停止反应，向反应液中加入水(10mL)，加入1N盐酸溶液调节pH至6左右，用EA(12mL×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，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，得到标题化合物为橙色固体(12.0mg,15％)。Add (12aR)-7-(benzyloxy)-12-(4,5-difluoro-2-((S)-3-methoxypyrrolidin-1-yl)-8H-dibenzo[3 ,4:6,7]cyclohepta[1,2-b]thiophen-8-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c ]Pyrido[2,1-f][1,2,4]triazine-6,8-dione (90mg, 0.13mmol) was dissolved in DMAc (10mL), followed by lithium chloride (53mg, 1.27mmol) , Nitrogen protection and placed in a 100°C oil bath for heating for about 2.5 hours. Stop the reaction, add water (10mL) to the reaction solution, add 1N hydrochloric acid solution to adjust the pH to about 6, extract with EA (12mL×3), combine the organic phases, wash the organic phases with saturated brine (15mL), anhydrous sulfuric acid The sodium was dried, filtered, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was separated and purified by a LUNA preparation column (eluent: acetonitrile/0.1% trifluoroacetic acid aqueous solution (v/v)=12/13) to obtain the title compound as orange Solid (12.0 mg, 15%).
MS(ESI,pos.ion)m/z:619.1[M+H] +。 MS (ESI, pos.ion) m/z: 619.1 [M+H] + .
1H NMR(600MHz,CDCl 3)δ(ppm)7.51(d,J＝7.6Hz,1H),7.35(t,J＝7.3Hz,1H),7.23(d,J＝7.4Hz,2H),7.10(s,1H),6.89(s,1H),6.50(s,1H),6.25(d,J＝5.7Hz,1H),5.86(s,1H),5.37(s,1H),4.63(d,J＝11.1Hz,1H),4.31(d,J＝8.5Hz,1H),4.21(s,1H),3.77(d,J＝10.9Hz,1H),3.68–3.57(m,2H),3.55(d,J＝13.1Hz,1H),3.49–3.33(m,6H),3.27(d,J＝10.3Hz,1H),2.96(s,1H),2.34–2.21(m,2H). 1 H NMR (600MHz, CDCl 3 ) δ (ppm) 7.51 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 7.23 (d, J = 7.4 Hz, 2H), 7.10 (s, 1H), 6.89 (s, 1H), 6.50 (s, 1H), 6.25 (d, J = 5.7 Hz, 1H), 5.86 (s, 1H), 5.37 (s, 1H), 4.63 (d, J = 11.1 Hz, 1H), 4.31 (d, J = 8.5 Hz, 1H), 4.21 (s, 1H), 3.77 (d, J = 10.9 Hz, 1H), 3.68-3.57 (m, 2H), 3.55 ( d, J = 13.1Hz, 1H), 3.49–3.33(m, 6H), 3.27(d, J = 10.3Hz, 1H), 2.96(s, 1H), 2.34–2.21(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。 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 are set up. No virus was added to the cytotoxicity test group, and culture medium was used instead. Both are provided with two duplicate holes. Incubate for 5 days at 37°C and 5% CO 2 . 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 analyzed the data, calculated the CPE inhibition rate, and obtained the EC 50 and CC 50 values according to the fitted curve.
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, CPE inhibition rate = (dose hole absorbance value-virus control hole absorbance value) / (cell control hole absorbance value-virus control hole absorbance value) × 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本发明部分化合物对流感病毒(A/Weiss/43(H1N1))体外实验EC 50活性数据 Table 1 EC 50 activity data of some compounds of the present invention against influenza virus (A/Weiss/43(H1N1)) in vitro
化合物编号Compound number EC 50(nM) EC 50 (nM)
化合物74-1Compound 74-1 5.065.06
化合物79-1Compound 79-1 11.6211.62
化合物91-1Compound 91-1 10.8710.87
表2本发明部分化合物对流感病毒(A/Weiss/43(H1N1))体外实验CC 50数据 Table 2 CC 50 data of some compounds of the present invention against influenza virus (A/Weiss/43(H1N1)) in vitro experiment
化合物编号Compound number CC 50(μM) CC 50 (μM) 化合物编号Compound number CC 50(μM) CC 50 (μM)
化合物31Compound 31 >100>100 化合物36-1Compound 36-1 >100>100
化合物74-1Compound 74-1 >100>100 化合物80Compound 80 >100>100
化合物82Compound 82 >100>100 化合物83Compound 83 >100>100
化合物84Compound 84 >100>100 化合物85Compound 85 >100>100
化合物92Compound 92 >100>100 化合物93Compound 93 >100>100
化合物94Compound 94 >100>100 化合物96Compound 96 >100>100
由表1和表2的数据可知，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。It can be seen from the data in Table 1 and Table 2 that the compound of the present invention has good anti-influenza virus activity and 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 invention after intravenous injection or oral administration:
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。本发明化合物以一定比例的DMSO和表面活性剂的全溶液处方(例如5％DMSO+5％Kolliphor HS 15+90％生理盐水溶液、10％DMSO+10％Kolliphor HS 15+80％生理盐水溶液、10％DMSO+10％Kolliphor HS 15+30％PEG400+50％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 formulated with a certain proportion of DMSO and a full solution of surfactant (for example, 5% DMSO + 5% Kolliphor HS 15+90% physiological saline solution, 10% DMSO + 10% Kolliphor HS 15+80% physiological saline solution, 10% DMSO + 10% Kolliphor HS 15 + 30% PEG400 + 50% physiological saline solution) for administration. 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 (0.3 mL) 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.
表3本发明部分化合物在SD大鼠体内的药代动力学数据Table 3 Pharmacokinetic data of some compounds of the present invention in SD rats
Figure PCTCN2020077781-appb-000091
Figure PCTCN2020077781-appb-000091
由表3可知，本发明化合物无论是静脉注射或者是口服给药，其在SD大鼠体内的暴露量大，吸收良好，半衰期比较长，其药代动力学性质良好。It can be seen from Table 3 that whether the compound of the present invention is administered intravenously or orally, its exposure in SD rats is large, its absorption is good, its half-life is relatively long, and its pharmacokinetic properties are good.
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。具体实验系统如下： 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, and canine liver microsomes at 37°C and pH=7.4. The concentration of samples at different incubation times is measured, and the "Log [drug concentration]" versus "incubation time" is measured. The rate constant is obtained by plotting, and the drug half-life and in vivo clearance Cl in vivo are calculated. 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 PCTCN2020077781-appb-000092
Figure PCTCN2020077781-appb-000092
表4本发明部分化合物在混合大鼠中的肝微粒体稳定性Table 4 Liver microsome stability of some compounds of the present invention in mixed rats
化合物编号Compound number 肝微粒体Liver microsomes 浓度(μM)Concentration (μM) T 1/2(min) T 1/2 (min) Cl Hep(mL/min/kg) Cl Hep (mL/min/kg) Cl in  vivo(mL/min/kg) Cl in vivo (mL/min/kg)
化合物4-1Compound 4-1 大鼠Rat 11 40.540.5 61.361.3 29.029.0
化合物3-1Compound 3-1 大鼠Rat 11 700.5700.5 3.53.5 3.33.3
化合物29Compound 29 大鼠Rat 11 160.5160.5 15.515.5 12.112.1
化合物33Compound 33 大鼠Rat 11 402.80402.80 6.176.17 5.555.55
化合物35Compound 35 大鼠Rat 11 69.4169.41 35.7835.78 21.7121.71
化合物36-1Compound 36-1 大鼠Rat 11 64.964.9 38.338.3 22.622.6
化合物42-1Compound 42-1 大鼠Rat 11 154.9154.9 16.016.0 12.412.4
化合物80Compound 80 大鼠Rat 11 80.5580.55 30.8330.83 19.7819.78
化合物81Compound 81 大鼠Rat 11 101.10101.10 24.5724.57 17.0017.00
化合物83Compound 83 大鼠Rat 11 84.084.0 29.629.6 19.319.3
表5本发明部分化合物在人中的肝微粒体稳定性Table 5 Liver microsome stability of some compounds of the present invention in humans
化合物编号Compound number 肝微粒体Liver microsomes 浓度(μM)Concentration (μM) T 1/2(min) T 1/2 (min) Cl Hep(mL/min/kg) Cl Hep (mL/min/kg) Cl in vivo(mL/min/kg) Cl in vivo (mL/min/kg)
化合物4-1Compound 4-1 人people 11 78.578.5 22.122.1 10.710.7
化合物3-1Compound 3-1 人people 11 ∞∞ // //
化合物29Compound 29 人people 11 258.5258.5 6.76.7 5.15.1
化合物35Compound 35 人people 11 530.50530.50 3.283.28 2.832.83
化合物78-1Compound 78-1 人people 11 509.70509.70 3.413.41 2.932.93
化合物80Compound 80 人people 11 246.80246.80 7.047.04 5.265.26
化合物83Compound 83 人people 11 245.3245.3 7.17.1 5.35.3
备注：∞代表无穷大。Note: ∞ stands for infinity.
表6本发明部分化合物在犬中的肝微粒体稳定性Table 6 Liver microsome stability of some compounds of the present invention in dogs
化合物编号Compound number 肝微粒体Liver microsomes 浓度(μM)Concentration (μM) T 1/2(min) T 1/2 (min) Cl Hep(mL/min/kg) Cl Hep (mL/min/kg) Cl in vivo(mL/min/kg) Cl in vivo (mL/min/kg)
化合物4-1Compound 4-1 犬dog 11 42.142.1 82.182.1 22.522.5
化合物3-1Compound 3-1 犬dog 11 ∞∞ // //
由表4-6结果可知，本发明化合物在大鼠、犬和人的肝微粒中均稳定。It can be seen from the results in Tables 4-6 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 , Structure, 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 characteristics 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 foregoing within the scope of the present invention. The embodiment undergoes changes, modifications, substitutions and modifications.

Claims (30)

  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 that is a compound represented by formula (I) or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or Their prodrugs,
    Figure PCTCN2020077781-appb-100001
    Figure PCTCN2020077781-appb-100001
    其中：among them:
    U 1为CR 1或N； U 1 is CR 1 or N;
    U 2为CR 2或N； U 2 is CR 2 or N;
    U 3为CR 3或N； U 3 is CR 3 or N;
    U 4为CR 4或N； U 4 is CR 4 or N;
    U 5为CR 5或N； U 5 is CR 5 or N;
    U 6为CR 6或N； U 6 is CR 6 or N;
    U 7为CR 7或N； U 7 is CR 7 or N;
    U 8为CR 8或N； U 8 is CR 8 or N;
    P为H、氘、C 1-6烷基、C 2-6烯基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基、-C(＝O)-R Pa、-C(＝O)-Z-R Pe、-C(＝O)-Z-O-R Pb、-C(＝O)-Z-O-Z-O-R Pb、-C(＝O)-Z-O-C(＝O)-R Pa、-C(＝O)-NR PcR Pd、-C(＝O)-O-R Pb、-S(＝O) 2-R Pi、-P(＝O)-(R Pg)(R Ph)、-C(＝O)-O-Y-O-R Pb、-Z-O-R Pb、-Z-O-Z-O-R Pb、-Y-O-C(＝O)-R Pa、-Y-C(＝O)-O-R Pb、-Y-NR Pf-(C＝O)-O-R Pb、-Y-O-C(＝O)-O-R Pb、-Z-O-C(＝O)-O-NR PcR Pd、-Y-O-C(＝O)-O-Y-O-R Pb、-Z-O-(C＝O)-O-Z-NR PcR Pd、-Z-O-C(＝O)-NR Pf-Z-O-R Pb、-Z-O-C(＝O)-NR Pf-Z-NR PcR Pd、-Z-O-C(＝O)-O-Z-O-Z-O-R Pb或-Z-O-C(＝O)-O-Z-NR Pf-(C＝O)-R Pa，其中所述C 1-6烷基、C 2-6烯基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-4烷基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基； P is H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl, 3-8 atoms Cyclic group, (heterocyclic group composed of 3-8 atoms) C 1-4 alkyl group, C 6-10 aryl group, C 6-10 aryl group C 1-4 alkyl group, heterocyclic group composed of 5-10 atoms Aryl group, (heteroaryl group consisting of 5-10 atoms) C 1-4 alkyl group, -C(=O)-R Pa , -C(=O)-ZR Pe , -C(=O)-ZOR Pb , -C(=O)-ZOZOR Pb , -C(=O)-ZOC(=O)-R Pa , -C(=O)-NR Pc R Pd , -C(=O)-OR Pb , -S(=O) 2 -R Pi , -P(=O)-(R Pg )(R Ph ), -C(=O)-OYOR Pb , -ZOR Pb , -ZOZOR Pb , -YOC(=O )-R Pa , -YC(=O)-OR Pb , -Y-NR Pf -(C=O)-OR Pb , -YOC(=O)-OR Pb , -ZOC(=O)-O-NR Pc R Pd , -YOC(=O)-OYOR Pb , -ZO-(C=O)-OZ-NR Pc R Pd , -ZOC(=O)-NR Pf -ZOR Pb , -ZOC(=O)- NR Pf -Z-NR Pc R Pd , -ZOC(=O)-OZOZOR Pb or -ZOC(=O)-OZ-NR Pf -(C=O)-R Pa , wherein the C 1-6 alkyl group , C 2-6 alkenyl, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl, 3-8 atom heterocyclic group, (3-8 atom heterocyclic group Cyclic) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl and (5-10 hetero Aryl) C 1-4 alkyl groups are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =0 , -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 Alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino;
    各Y和Z独立地为C 1-6烷基； Each Y and Z is independently C 1-6 alkyl;
    各R Pf独立地为H、氘或C 1-6烷基； Each R Pf is independently H, deuterium, or C 1-6 alkyl;
    各R Pa、R Pb、R Pc、R Pd、R Pe和R Pi独立地为C 1-6烷基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子 组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基、C 1-6烷氨基、C 1-6烷硫基或C 1-6烷基甲硅烷基，其中所述C 1-6烷基、C 3-8碳环基、C 3-8碳环基C 1-4烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基、C 1-6烷氨基和C 1-6烷硫基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基； Each R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently C 1-6 alkyl, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl, Heterocyclic group consisting of 3-8 atoms, (heterocyclic group consisting of 3-8 atoms) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-4 alkyl, Heteroaryl group consisting of 5-10 atoms, (heteroaryl group consisting of 5-10 atoms) C 1-4 alkyl, C 1-6 alkylamino, C 1-6 alkylthio or C 1-6 alkane Group silyl group, wherein the C 1-6 alkyl group, C 3-8 carbocyclic group, C 3-8 carbocyclic group C 1-4 alkyl group, 3-8 atoms heterocyclic group, (3 -8-atom heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl, (5 -10 atoms of heteroaryl) C 1-4 alkyl, C 1-6 alkylamino and C 1-6 alkylthio are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O ) NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino;
    各R Pg和R Ph独立地为C 1-6烷氧基、C 1-6烷氨基、C 3-8碳环基氧基、C 3-8碳环基氨基、3-8个原子组成的杂环基氧基、3-8个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-10个原子组成的杂芳基氧基或5-10个原子组成的杂芳基氨基，其中所述C 1-6烷氧基、C 1-6烷氨基、C 3-8碳环基氧基、C 3-8碳环基氨基、3-8个原子组成的杂环基氧基、3-8个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-10个原子组成的杂芳基氧基和5-10个原子组成的杂芳基氨基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基； Each R Pg and R Ph is independently composed of C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 carbocyclyloxy, C 3-8 carbocyclylamino, 3-8 atoms Heterocyclyloxy, heterocyclylamino consisting of 3-8 atoms, C 6-10 aryloxy, C 6-10 arylamino, heteroaryloxy consisting of 5-10 atoms or 5- A 10-atom heteroarylamino group, wherein the C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-8 carbocyclyloxy group, C 3-8 carbocyclylamino group, 3-8 3-atom heterocyclyloxy, 3-8 heterocyclic amino, C 6-10 aryloxy, C 6-10 arylamino, 5-10 heteroaryloxy A group and a heteroarylamino group consisting of 5-10 atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino;
    R 1、R 2、R 3和R 4各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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； R 1 , R 2 , R 3 and R 4 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, 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, wherein the C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, 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 and 5-6 heteroaryl are each independently unsubstituted or Is substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
    R 5、R 6、R 7和R 8各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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； R 5 , R 6 , R 7 and R 8 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, 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, wherein the C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, 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 and 5-6 heteroaryl are each independently unsubstituted or Is substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
    R 9为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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，其中所述C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷硫基、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、3或4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、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； R 9 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, C 1-6 haloalkyl, C 1-6 alkoxy Group, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 Cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 aryl group or heteroaryl group composed of 5-6 atoms, wherein the C 1-6 haloalkyl group, C 1-6 alkoxy group , C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 haloalkoxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 ring Alkyl groups, heterocyclic groups composed of 5-6 atoms, C 6-10 aryl groups and heteroaryl groups composed of 5-6 atoms are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy Group or C 1-6 alkylamino;
    R 10为H、氘、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烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、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烷基、3-8个原子组成的杂环基、(3-8个原子组 成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-4烷基或L-R 11，其中所述C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、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烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-4烷基各自独立地未被取代或被1、2、3或4个R w所取代，条件是R 9和R 10不同时为H； R 10 is H, deuterium, 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 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, -C(=O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group , C 3-6 carbocyclic group C 1-4 alkyl, 3-8 atom heterocyclic group, (3-8 atom heterocyclic group) C 1-4 alkyl, C 6-10 aromatic Group, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl, (5-10 heteroaryl) C 1-4 alkyl or LR 11 , where Said C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio, -C(= O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclyl, C 3- 6- carbocyclic C 1-4 alkyl, 3-8 heterocyclic group, (3-8 heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6 -10 aryl C 1-4 alkyl, 5-10 heteroaryl and (5-10 heteroaryl) C 1-4 alkyl are each independently unsubstituted or substituted by 1, Replaced by 2, 3 or 4 R w , provided that R 9 and R 10 are not H at the same time;
    L为-(CR aR b) p-O-、-(CR aR b) t-S-、-(CR aR b) s-S(＝O)-、-(CR aR b) s-S(＝O) 2-、-(CR aR b) s-N(R c)-、-(CR aR b) s-C(＝O)N(R c)-、-(CR aR b) s-C(＝O)-、-(CR aR b) s-C(＝O)-或-(CR aR b) r-； L is -(CR a R b ) p -O-, -(CR a R b ) t -S-, -(CR a R b ) s -S(=O)-, -(CR a R b ) s -S(=O) 2 -, -(CR a R b ) s -N(R c )-, -(CR a R b ) s -C(=O)N(R c )-, -(CR a R b ) s -C(=O)-, -(CR a R b ) s -C(=O)- or -(CR a R b ) r -;
    各R a和R b独立地为H、氘、F、Cl、Br、I、-CN、-NH 2、-OH、-SH、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烷氨基、C 1-6卤代烷氧基、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；或R a、R b和与它们相连的碳原子一起，形成C 3-6碳环或3-6个原子组成的杂环； Each R a and R b are independently H, deuterium, F, Cl, Br, I , -CN, -NH 2, -OH, -SH, C 1-6 alkyl, C 2-6 alkenyl group, C 2 -6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkoxy, C 3-6 cycloalkyl, composed of 3-6 atoms heterocyclyl, C 6-10 aryl, or 5-6 atoms heteroaryl; or R a, R b and the carbon atom to which they are attached together form a C 3-6 carbocyclic ring of 3-6 atoms or Composed of heterocycles;
    各R c独立地为H、氘、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、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； Each R c is independently H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 A heterocyclic group consisting of atoms, a C 6-10 aryl group or a heteroaryl group consisting of 5-6 atoms;
    R 11为H、氘、C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、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烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基或(5-10个原子组成的杂芳基)C 1-4烷基，其中所述C 1-6卤代烷基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 1-6烷氨基、C 1-6烷硫基、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烷基、3-8个原子组成的杂环基、(3-8个原子组成的杂环基)C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-4烷基各自独立地未被取代或被1、2、3或4个R w所取代； R 11 is H, deuterium, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 1-6 alkylthio Group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-4 alkyl, 3-8 heterocyclic group, ( 3-8 atoms heterocyclic group) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, 5-10 heteroaryl or ( Heteroaryl composed of 5-10 atoms) C 1-4 alkyl, wherein the C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkylamino, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-4 alkane Group, heterocyclic group composed of 3-8 atoms, (heterocyclic group composed of 3-8 atoms) C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkane Group, heteroaryl group consisting of 5-10 atoms and (heteroaryl group consisting of 5-10 atoms) C 1-4 alkyl are each independently unsubstituted or replaced by 1, 2, 3 or 4 R w replace;
    各R w独立地为氘、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷氨基、-S(＝O) q-C 1-6烷基、-S(＝O) q-C 1-6烷氨基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、羧基C 1-6烷基、氨基C 1-6烷基、氰基C 1-6烷基、C 1-6烷基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基或5-8个原子组成的杂芳基，其中所述C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-C 1-6烷基、-C(＝O)-C 1-6烷氧基、-C(＝O)-C 1-6烷氨基、-S(＝O) q-C 1-6烷基、-S(＝O) q-C 1-6烷氨基、C 1-6卤代烷基、C 1-6卤代烷氧基、羟基C 1-6烷基、羧基C 1-6烷基、氨基C 1-6烷基、氰基C 1-6烷基、C 1-6烷基、C 3-6环烷基、3-8个原子组成的杂环基、C 6-10芳基和5-8个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、＝O、-OH、-NH 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 w is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -C(=O)OH, -C(=O)NH 2 , -S( ＝O) 2 NH 2 , C 1-6 alkoxy, C 1-6 alkylamino, -C(=O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy , -C(=O)-C 1-6 alkylamino, -S(=O) q -C 1-6 alkyl, -S(=O) q -C 1-6 alkylamino, C 1-6 haloalkane Group, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl, carboxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 heterocyclic group, C 6-10 aryl or 5-8 heteroaryl, wherein the C 1-6 alkoxy, C 1 -6 alkylamino, -C(=O)-C 1-6 alkyl, -C(=O)-C 1-6 alkoxy, -C(=O)-C 1-6 alkylamino, -S (=O) q -C 1-6 alkyl, -S(=O) q -C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy, hydroxy C 1-6 alkyl , Carboxy C 1-6 alkyl, amino C 1-6 alkyl, cyano C 1-6 alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclic ring composed of 3-8 atoms Group, C 6-10 aryl group and 5-8 atom heteroaryl group are each independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, =O, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
    q为0、1或2；q is 0, 1 or 2;
    r为1、2、3或4；r is 1, 2, 3 or 4;
    各p、t或s独立地为0、1、2、3或4；Each p, t or s is independently 0, 1, 2, 3 or 4;
    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 PCTCN2020077781-appb-100002
    Figure PCTCN2020077781-appb-100002
  2. 根据权利要求1所述的化合物，其中所述R 10为H、氘、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烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、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烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)C 1-2烷基或L-R 11，其中所述C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、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烷基、C 6-10芳基、C 6-10芳基C 1-2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烷基各自独立地未被取代或被1、2、3或4个R w所取代，条件是R 9和R 10不同时为H。 The compound according to claim 1, wherein said R 10 is H, deuterium, 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 alkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1- 4 alkylamino, C 1-4 alkylthio, -C (= O) -C 1-4 alkyl, -C (= O) -C 1-4 alkoxy, C 2-4 alkenyl group, C 2 -4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl group, 5-6 atom heterocyclic group, (5-6 atom heterocyclic group) C 1-2 alkyl group, C 6-10 aryl group, C 6-10 aryl group, C 1-2 alkyl group, 5-6 atom heteroaryl group, (5-6 atom heteroaryl group) C 1-2 alkyl group or LR 11 , wherein the C 1-4 haloalkyl group, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 haloalkoxy group, C 1-4 alkylamino group, C 1-4 alkylthio, -C(=O)-C 1-4 alkyl, -C(=O)-C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl , C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl group, 5-6 atom heterocyclic group, (5-6 atom heterocyclic group) C 1-2 Alkyl, C 6-10 aryl, C 6-10 aryl, C 1-2 alkyl, 5-6 heteroaryl and (5-6 heteroaryl) C 1-2 Each alkyl group is independently unsubstituted or substituted with 1, 2, 3, or 4 R w , provided that R 9 and R 10 are not H at the same time.
  3. 根据权利要求1或2所述的化合物，其中所述R 10为H、氘、Br、I、-CN、-NO 2、-OH、-SH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、一氟甲基、二氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、三氟甲氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、-C(＝O)CH 3、-C(＝O)CH 2CH 3、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、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L-R 11，其中所述一氟甲基、二氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、-C(＝O)CH 3、-C(＝O)CH 2CH 3、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4个R w所取代，条件是R 9和R 10不同时为H。 The compound of claim 1 or 2, wherein the R 10 is H, deuterium, Br, I, -CN, -NO 2 , -OH, -SH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , monofluoromethyl, difluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl Group, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethyl Amino, N,N-diethylamino, methylthio, -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-methyl , Pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazine Group, pyridazinyl, 1,3,5-triazinyl or LR 11 , wherein the monofluoromethyl, difluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl , N-butyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethylamino, N,N-Diethylamino, methylthio, -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine Group, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-methyl, pyrrolyl , Pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridyl The azinyl group and the 1,3,5-triazinyl group are each independently unsubstituted or substituted with 1, 2, 3, or 4 R w , provided that R 9 and R 10 are not H at the same time.
  4. 根据权利要求1-3任意一项所述的化合物，其中所述R 11为H、氘、C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、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烷基、C 6-10芳基、C 6-10芳基C 1-2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烷基，其中所述C 1-4卤代烷基、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷氧基、C 1-4烷氨基、C 1-4烷硫基、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烷基、C 6-10芳基、C 6-10芳基C 1-2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烷基各自独立地未被取代或被1、2、3或4个R w所取代。 The compound according to any one of claims 1-3, wherein the R 11 is H, deuterium, C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 Haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1 -2 alkyl, heterocyclic group composed of 5-6 atoms, (heterocyclic group composed of 5-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1 -2 alkyl group, heteroaryl group composed of 5-6 atoms or (heteroaryl group composed of 5-6 atoms) C 1-2 alkyl group, wherein the C 1-4 haloalkyl group, C 1-4 alkane Group, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 3- 6- carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl, 5-6 heterocyclic group, (5-6 heterocyclic group) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-2 alkyl, 5-6 heteroaryl and (5-6 heteroaryl) C 1-2 alkyl are each independently Ground is unsubstituted or substituted with 1, 2, 3 or 4 R w .
  5. 根据权利要求1-4任意一项所述的化合物，其中所述R 11为H、氘、一氟甲基、二氟甲基、三氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、三氟甲氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、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，其中所述一氟甲基、二氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、正丙基氧基、异丙基氧基、二氟甲氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、甲硫基、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、苯基-甲基、吡咯基、吡啶基、嘧啶基、噻唑基、噻吩基、呋喃基、吡唑基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4个R w所取代。 The compound according to any one of claims 1-4, wherein the R 11 is H, deuterium, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, methyl, ethyl, N-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, trifluoromethoxy, difluoromethoxy, methylamino , Ethylamino, N,N-dimethylamino, N,N-diethylamino, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, Imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, phenyl-methyl, pyrrolyl, pyridyl, pyrimidinyl, Thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3, 5-triazinyl, wherein the monofluoromethyl, difluoromethyl, trifluoroethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, Ethoxy, n-propyloxy, isopropyloxy, difluoromethoxy, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino, methylthio, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, Tetrahydropyranyl, phenyl, phenyl-methyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazole , Isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1,3,5-triazinyl are each independently unsubstituted or substituted with 1, 2, 3, or 4 R w .
  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 w独立地为氘、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、C 1-4烷氧基、C 1-4烷氨基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1-4烷氨基、-S(＝O) q-C 1-4烷基、-S(＝O) q-C 1-4烷氨基、C 1-4卤代烷基、C 1-4卤代烷氧基、羟基C 1-4烷基、羧基C 1-4烷基、氨基C 1-4烷基、氰基C 1-4烷基、C 1-4烷基、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烷氧基、C 1-4烷氨基、-C(＝O)-C 1-4烷基、-C(＝O)-C 1-4烷氧基、-C(＝O)-C 1-4烷氨基、-S(＝O) q-C 1-4烷基、-S(＝O) q-C 1-4烷氨基、C 1-4卤代烷基、C 1-4卤代烷氧基、羟基C 1-4烷基、羧基C 1-4烷基、氨基C 1-4烷基、氰基C 1-4烷基、C 1-4烷基、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、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、＝O、-OH、-NH 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。 The compound according to any one of claims 1-5, wherein each R w is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -C( ＝O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , C 1-4 alkoxy, C 1-4 alkylamino, -C(=O)-C 1-4 Alkyl group, -C(=O)-C 1-4 alkoxy group, -C(=O)-C 1-4 alkylamino group, -S(=O) q -C 1-4 alkyl group, -S( =0) q -C 1-4 alkylamino, C 1-4 haloalkyl, C 1-4 haloalkoxy, hydroxy C 1-4 alkyl, carboxy C 1-4 alkyl, amino C 1-4 alkyl , Cyano C 1-4 alkyl, C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclic group composed of 5-6 atoms, C 6-10 aryl group or composed of 5-6 atoms Heteroaryl group, wherein the C 1-4 alkoxy group, C 1-4 alkylamino group, -C(=O)-C 1-4 alkyl group, -C(=O)-C 1-4 alkoxy group , -C(=O)-C 1-4 alkylamino, -S(=O) q -C 1-4 alkyl, -S(=O) q -C 1-4 alkylamino, C 1-4 haloalkane Group, C 1-4 haloalkoxy, hydroxy C 1-4 alkyl, carboxy C 1-4 alkyl, amino C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 alkyl, C 3-6 cycloalkyl, 5-6 heterocyclic group, C 6-10 aryl and 5-6 heteroaryl are each independently unsubstituted or are 1, 2, 3 or Substituted by 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, =0, -OH, -NH 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 1-6 alkoxy or C 1-6 alkylamino.
  7. 根据权利要求1-6任意一项所述的化合物，其中所述各R w独立地为氘、F、Cl、Br、I、-CN、-NO 2、-NH 2、-OH、-C(＝O)OH、-C(＝O)NH 2、-S(＝O) 2NH 2、甲氧基、乙氧基、正丙基氧基、异丙基氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-SCH 3、-SCH 2CH 3、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、二氟甲基、三氟甲基、三氟乙基、三氟甲氧基、二氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、羧基甲基、羧基乙基、羧基正丙基、羧基异丙基、氨基甲基、氨基乙基、氰基甲基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、四氢噻吩基、吡咯烷基、吡唑烷基、咪唑烷基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、苯基、吡咯基、噻吩基、噻唑基、咪唑基、三唑基、呋喃基、吡啶基、嘧啶基、吡嗪基或哒嗪基，其中所述甲氧基、乙氧基、正丙基氧基、异丙基氧基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、-C(＝O)-OCH 3、-C(＝O)-OCH 2CH 3、-SCH 3、-SCH 2CH 3、-S(＝O) 2CH 3、-S(＝O) 2CH 2CH 3、二氟甲基、三氟乙基、二氟甲氧基、三氟乙氧基、羟基甲基、羟基乙基、羧基甲基、羧基乙基、羧基正丙基、羧基异丙基、氨基甲基、氨基乙基、氰基甲基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基、环己基、四氢吡喃基、四氢呋喃基、四氢噻吩基、吡咯烷基、吡唑烷基、咪唑烷基、吗啉基、硫代吗啉基、哌啶基、 哌嗪基、苯基、吡咯基、噻吩基、噻唑基、咪唑基、三唑基、呋喃基、吡啶基、嘧啶基、吡嗪基和哒嗪基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、-CN、＝O、-OH、-NH 2、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基或甲氨基。 The compound according to any one of claims 1-6, wherein each R w is independently deuterium, F, Cl, Br, I, -CN, -NO 2 , -NH 2 , -OH, -C( =O)OH, -C(=O)NH 2 , -S(=O) 2 NH 2 , methoxy, ethoxy, n-propyloxy, isopropyloxy, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino, -C(=O)-OCH 3 , -C(=O)-OCH 2 CH 3 , -SCH 3 , -SCH 2 CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 CH 2 CH 3 , difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethyl Fluoroethoxy, hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl, carboxyn-propyl, carboxyisopropyl, aminomethyl, aminoethyl, cyanomethyl, methyl, ethyl, N-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyridine Oxazolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, phenyl, pyrrolyl, thienyl, thiazolyl, imidazolyl, triazolyl, furyl, pyridyl , Pyrimidinyl, pyrazinyl or pyridazinyl, wherein the methoxy, ethoxy, n-propyloxy, isopropyloxy, methylamino, ethylamino, N,N-dimethylamino, N,N-Diethylamino, -C(=O)-OCH 3 , -C(=O)-OCH 2 CH 3 , -SCH 3 , -SCH 2 CH 3 , -S(=O) 2 CH 3 , -S(=O) 2 CH 2 CH 3 , difluoromethyl, trifluoroethyl, difluoromethoxy, trifluoroethoxy, hydroxymethyl, hydroxyethyl, carboxymethyl, carboxyethyl , Carboxy n-propyl, carboxy isopropyl, aminomethyl, aminoethyl, cyanomethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidine Group, piperazinyl, phenyl, pyrrolyl, thienyl, thiazolyl, imidazolyl, triazolyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl are each independently unsubstituted or substituted by 1 , 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, =O, -OH, -NH 2 , methyl, ethyl, normal Propyl, isopropyl, trifluoromethyl, methoxy, ethoxy or methylamino.
  8. 根据权利要求1-7任意一项所述的化合物，其中所述R 9为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、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，其中所述C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷硫基、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、3或4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、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，条件是R 9和R 10不同时为H。 The compound according to any one of claims 1-7, wherein the R 9 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(= O) OH, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, 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, Wherein said C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkylthio, 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 and 5-6 heteroaryl are each independent Ground is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , C 1- 4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylamino, provided that R 9 and R 10 are not H at the same time.
  9. 根据权利要求1-8任意一项所述的化合物，其中所述R 9为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、三氟甲基、三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、三氟甲氧基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、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，其中所述三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、乙氨基、N,N-二甲基氨基、N,N-二乙基氨基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4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、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基或乙氧基，条件是R 9和R 10不同时为H。 The compound according to any one of claims 1-8, wherein the R 9 is H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(= O) OH, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, N,N-dimethylamino, N,N-diethylamino, Trifluoromethoxy, trifluoroethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrole Alkyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidine Group, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3,5-triazinyl, wherein the trifluoroethyl, methoxy, ethoxy, methylthio, methylamino, ethylamino, N,N-dimethylamino, N,N-diethyl Amino, trifluoroethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyridine Azolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl , Thienyl, furanyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1,3,5- The triazinyl groups are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2. Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy, provided that R 9 and R 10 are not H at the same time.
  10. 根据权利要求1-9任意一项所述的化合物，其中所述R 1、R 2、R 3和R 4各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、三氟甲基、三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟甲氧基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、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，其中所述三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4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、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基或乙氧基； The compound of any one of claims 1-9, wherein the R 1 , R 2 , R 3 and R 4 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, methylthio, methylamino, trifluoromethoxy, trifluoroethyl Oxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazole Alkyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furan Group, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3,5-triazinyl, wherein The trifluoroethyl, methoxy, ethoxy, methylthio, methylamino, trifluoroethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, 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 and 1,3,5-triazinyl are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents, which are independently Selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy;
    R 5、R 6、R 7和R 8各自独立地为H、氘、F、Cl、Br、I、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、三氟甲基、三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟甲氧基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、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，其中所述三氟乙基、甲氧基、乙氧基、甲硫基、甲氨基、三氟乙氧基、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、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、三唑基、四唑基、噁唑基、异噁唑基、噁二唑基、吡嗪基、哒嗪基和1,3,5-三嗪基各自独立地未被取代或被1、2、3或4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、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基或乙氧基。 R 5 , R 6 , R 7 and R 8 are each independently H, deuterium, F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, three Fluoromethyl, trifluoroethyl, methoxy, ethoxy, methylthio, methylamino, trifluoromethoxy, trifluoroethoxy, methyl, ethyl, n-propyl, isopropyl, N-butyl, tert-butyl, 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, wherein the trifluoroethyl, methoxy, ethoxy, methylsulfide Group, methylamino, trifluoroethoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine Group, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl , Thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1,3 , 5-triazinyl groups are each independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH , -NH 2 , methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.
  11. 根据权利要求1-10任意一项所述的化合物，其中所述各R a和R b独立地为H、氘、F、Cl、Br、I、-CN、-NH 2、-OH、-SH、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、甲氧基、乙氧基、甲氨基、三氟甲氧基、环丙基、环丁基、环戊基、环己基、3-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基；或R a、R b和与它们相连的碳原子一起，形成环丙基、环丁基、环戊基、环己基或3-6个原子组成的杂环； The compound according to any one of claims 1-10, wherein each of R a and R b is independently H, deuterium, F, Cl, Br, I, -CN, -NH 2 , -OH, -SH , Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, methoxy, ethoxy, methylamino, trifluoromethoxy, cyclopropyl, ring butyl group, a heterocyclic group cyclopentyl, cyclohexyl, 3-6 atoms, 5-6 atoms, or a phenyl group heteroaryl; or R a, R b and the carbon atom to which they are attached together, Form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or heterocyclic ring composed of 3-6 atoms;
    各R c独立地为H、氘、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、环丙基、环丁基、环戊基、环己基、3-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基。 Each R c is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, ring Hexyl, 3-6 heterocyclic group, phenyl or 5-6 heteroaryl.
  12. 根据权利要求1-11任意一项所述的化合物，其中所述P为H、氘、C 1-4烷基、C 2-4烯基、C 3-6碳环基、C 3-6碳环基C 1-2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烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-10个原子组成的杂芳基、(5-10个原子组成的杂芳基)C 1-2烷基、-C(＝O)-R Pa、-C(＝O)-Z-R Pe、-C(＝O)-Z-O-R Pb、-C(＝O)-Z-O-Z-O-R Pb、-C(＝O)-Z-O-C(＝O)-R Pa、-C(＝O)-NR PcR Pd、-C(＝O)-O-R Pb、-S(＝O) 2-R Pi、-P(＝O)-(R Pg)(R Ph)、-C(＝O)-O-Y-O-R Pb、-Z-O-R Pb、-Z-O-Z-O-R Pb、-Y-O-C(＝O)-R Pa、-Y-C(＝O)-O-R Pb、-Y-NR Pf-(C＝O)-O-R Pb、-Y-O-C(＝O)-O-R Pb、-Z-O-C(＝O)-O-NR PcR Pd、-Y-O-C(＝O)-O-Y-O-R Pb、-Z-O-(C＝O)-O-Z-NR PcR Pd、-Z-O-C(＝O)-NR Pf-Z-O-R Pb、-Z-O-C(＝O)-NR Pf-Z-NR PcR Pd、-Z-O-C(＝O)-O-Z-O-Z-O-R Pb或-Z-O-C(＝O)-O-Z-NR Pf-(C＝O)-R Pa，其中所述C 1-4烷基、C 2-4烯基、C 3-6碳环基、C 3-6碳环基C 1-2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烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-10个原子组成的杂芳基和(5-10个原子组成的杂芳基)C 1-2烷基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧基酰基或C 1-6烷氨基； The compound according to any one of claims 1-11, wherein the P is H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 carbocyclyl, C 3-6 carbon Cyclic group C 1-2 alkyl, heterocyclic group consisting of 5-6 atoms, (heterocyclic group consisting of 5-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 Aryl C 1-2 alkyl, heteroaryl composed of 5-10 atoms, (heteroaryl composed of 5-10 atoms) C 1-2 alkyl, -C(=O)-R Pa ,- C(=O)-ZR Pe , -C(=O)-ZOR Pb , -C(=O)-ZOZOR Pb , -C(=O)-ZOC(=O)-R Pa , -C(=O )-NR Pc R Pd , -C(=O)-OR Pb , -S(=O) 2 -R Pi , -P(=O)-(R Pg )(R Ph ), -C(=O) -OYOR Pb , -ZOR Pb , -ZOZOR Pb , -YOC(=O)-R Pa , -YC(=O)-OR Pb , -Y-NR Pf -(C=O)-OR Pb , -YOC( ＝O)-OR Pb , -ZOC(＝O)-O-NR Pc R Pd , -YOC(＝O)-OYOR Pb , -ZO-(C＝O)-OZ-NR Pc R Pd , -ZOC( ＝O)-NR Pf -ZOR Pb 、-ZOC(=O)-NR Pf -Z-NR Pc R Pd 、-ZOC(＝O)-OZOZOR Pb or -ZOC(＝O)-OZ-NR Pf -( C=O)-R Pa , wherein the C 1-4 alkyl group, C 2-4 alkenyl group, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl group, 5-6 A heterocyclic group consisting of three atoms, (a heterocyclic group consisting of 5-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-2 alkyl, 5-10 A heteroaryl group composed of three atoms and (heteroaryl group composed of 5-10 atoms) C 1-2 alkyl are each independently unsubstituted or substituted by 1, 2, 3, or 4 substituents. The group is independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkoxy acyl or C 1-6 alkylamino;
    各Y和Z独立地为C 1-4烷基； Each Y and Z is independently C 1-4 alkyl;
    各R Pf独立地为H、氘或C 1-6烷基； Each R Pf is independently H, deuterium, or C 1-6 alkyl;
    各R Pa、R Pb、R Pc、R Pd、R Pe和R Pi独立地为C 1-4烷基、C 3-6碳环基、C 3-6碳环基C 1-2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 1-2烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)C 1-2烷基、C 1-4烷氨基、C 1-4烷硫基或C 1-4烷基甲硅烷基，其中所述C 1-4烷基、C 3-6碳环基、C 3-6碳环基C 1-2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 1-2烷基、C 6-10芳基、C 6-10芳基C 1-2烷基、5-6个原子组成的杂芳基、(5-6个原子组成的杂芳基)C 1-2烷基、C 1-4烷氨基和C 1-4烷硫基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷酰基、C 1-4烷氧基酰基或C 1-4烷氨基； Each R Pa , R Pb , R Pc , R Pd , R Pe and R Pi is independently C 1-4 alkyl, C 3-6 carbocyclic group, C 3-6 carbocyclic group C 1-2 alkyl, Heterocyclic group composed of 3-6 atoms, (heterocyclic group composed of 3-6 atoms) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl, C 1-2 alkyl, Heteroaryl group consisting of 5-6 atoms, (heteroaryl group consisting of 5-6 atoms) C 1-2 alkyl, C 1-4 alkylamino, C 1-4 alkylthio or C 1-4 alkane Group silyl group, wherein the C 1-4 alkyl group, C 3-6 carbocyclic group, C 3-6 carbocyclic group, C 1-2 alkyl group, heterocyclic group consisting of 3-6 atoms, (3 -6-atom heterocyclic group) C 1-2 alkyl, C 6-10 aryl, C 6-10 aryl C 1-2 alkyl, 5-6 heteroaryl, (5 -6-atom heteroaryl) C 1-2 alkyl, C 1-4 alkylamino and C 1-4 alkylthio are each independently unsubstituted or substituted by 1, 2, 3 or 4 substituents Substitution, the substituents are independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O ) NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkoxy acyl or C 1-4 alkylamino;
    各R Pg和R Ph独立地为C 1-4烷氧基、C 1-4烷氨基、C 3-6碳环基氧基、C 3-6碳环基氨基、3-6个原子组成的杂环基氧基、3-6个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-6个原子组成的杂芳基氧基或5-6个原子组成的杂芳基氨基，其中所述C 1-4烷氧基、C 1-4烷氨基、C 3-6碳环基氧基、C 3-6碳环基氨基、3-6个原子组成的杂环基氧基、3-6个原子组成的杂环基氨基、C 6-10芳基氧基、C 6-10芳基氨基、5-6个原子组成的杂芳基氧基和5-6个原子组成的杂芳基氨基各自独立地未被取代或被1、2、3或4个取代基所取代，所述取代基独立地选自氘、F、Cl、Br、I、＝O、-CN、-NO 2、-OH、-NH 2、-C(＝O)OH、-C(＝O)NH 2、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷酰基、C 1-4烷氧基酰基或C 1-4烷氨基。 Each R Pg and R Ph are independently composed of C 1-4 alkoxy, C 1-4 alkylamino, C 3-6 carbocyclyloxy, C 3-6 carbocyclylamino, and 3-6 atoms Heterocyclyloxy, heterocyclylamino consisting of 3-6 atoms, C 6-10 aryloxy, C 6-10 arylamino, heteroaryloxy consisting of 5-6 atoms or 5- 6-atom heteroarylamino group, wherein the C 1-4 alkoxy group, C 1-4 alkylamino group, C 3-6 carbocyclyloxy group, C 3-6 carbocyclylamino group, 3-6 3-atom heterocyclyloxy, 3-6 heterocyclic amino, C 6-10 aryloxy, C 6-10 arylamino, 5-6 heteroaryloxy A group and a heteroarylamino group consisting of 5-6 atoms are each independently unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -NO 2 , -OH, -NH 2 , -C(=O)OH, -C(=O)NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkoxy acyl or C 1-4 alkylamino.
  13. 根据权利要求1-12任意一项所述的化合物，其中所述P为H、氘、
    Figure PCTCN2020077781-appb-100003
    Figure PCTCN2020077781-appb-100004
    The compound according to any one of claims 1-12, wherein the P is H, deuterium,
    Figure PCTCN2020077781-appb-100003
    Figure PCTCN2020077781-appb-100004
  14. 根据权利要求1-13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 1-13, wherein the compound has a structure as shown in formula (II):
    Figure PCTCN2020077781-appb-100005
    Figure PCTCN2020077781-appb-100005
  15. 根据权利要求1-14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 1-14, which has one of the following structures:
    Figure PCTCN2020077781-appb-100006
    Figure PCTCN2020077781-appb-100006
    Figure PCTCN2020077781-appb-100007
    Figure PCTCN2020077781-appb-100007
    Figure PCTCN2020077781-appb-100008
    Figure PCTCN2020077781-appb-100008
    Figure PCTCN2020077781-appb-100009
    Figure PCTCN2020077781-appb-100009
    Figure PCTCN2020077781-appb-100010
    Figure PCTCN2020077781-appb-100010
    Figure PCTCN2020077781-appb-100011
    Figure PCTCN2020077781-appb-100011
    Figure PCTCN2020077781-appb-100012
    Figure PCTCN2020077781-appb-100012
    Figure PCTCN2020077781-appb-100013
    Figure PCTCN2020077781-appb-100013
    Figure PCTCN2020077781-appb-100014
    Figure PCTCN2020077781-appb-100014
    Figure PCTCN2020077781-appb-100015
    Figure PCTCN2020077781-appb-100015
    Figure PCTCN2020077781-appb-100016
    Figure PCTCN2020077781-appb-100016
    Figure PCTCN2020077781-appb-100017
    Figure PCTCN2020077781-appb-100018
    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 PCTCN2020077781-appb-100017
    Figure PCTCN2020077781-appb-100018
    Or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or their prodrugs.
  16. 一种药物组合物，其包含权利要求1-15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载体、辅剂、媒介物或它们的组合。A pharmaceutical composition comprising the compound of any one of claims 1-15, optionally further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof.
  17. 根据权利要求16所述的药物组合物，进一步包含一种或多种其他治疗剂，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 16, further comprising one or more other therapeutic agents, wherein the other therapeutic agents are selected from anti-influenza virus agents or vaccines.
  18. 根据权利要求16所述的药物组合物，进一步包含一种或多种其他治疗剂，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、Pimodivir、Baloxavir marboxil、流感疫苗或它们的组合。The pharmaceutical composition according to claim 16, further comprising one or more other therapeutic agents, wherein the other therapeutic agents are amantadine, rimantadine, oseltamivir, zanamivir, peramivir , Lanimivir, lanimivir caprylate hydrate, fapiravir, arbidol, ribavirin, stapephrine, ingavirin, influenza enzyme, CAS number 1422050-75- 6 drugs, Pimodivir, Baloxavir marboxil, flu vaccine or their combination.
  19. 权利要求1-15任意一项所述的化合物或权利要求16-18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 of any one of claims 1-15 or the pharmaceutical composition of any one of claims 16-18 in the preparation of a medicine, wherein the medicine is used to prevent, treat or alleviate viral infectious diseases in patients .
  20. 根据权利要求19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 19, wherein the viral infection is influenza virus infection.
  21. 权利要求1-15任意一项所述的化合物或权利要求16-18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 of any one of claims 1-15 or the pharmaceutical composition of any one of claims 16-18 in the preparation of a medicine, wherein the medicine is used to inhibit the RNA polymerase of influenza virus.
  22. 根据权利要求21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 21, wherein the RNA polymerase is a cap-dependent endonuclease.
  23. 一种预防、治疗或减轻患者病毒感染性疾病的方法，包括给患者使用有效量的权利要求1-15任意一项所述的化合物或权利要求16-18任意一项所述的药物组合物。A method for preventing, treating or alleviating viral infectious diseases in patients, comprising administering an effective amount of the compound according to any one of claims 1-15 or the pharmaceutical composition according to any one of claims 16-18 to the patient.
  24. 根据权利要求23所述的方法，其中所述病毒感染为流感病毒感染。The method of claim 23, wherein the viral infection is an influenza virus infection.
  25. 一种抑制流感病毒的RNA聚合酶的方法，包括给患者使用有效量的权利要求1-15任意一项所述的化合物或权利要求16-18任意一项所述的药物组合物。A method for inhibiting the RNA polymerase of influenza virus, comprising administering to a patient an effective amount of the compound according to any one of claims 1-15 or the pharmaceutical composition according to any one of claims 16-18.
  26. 根据权利要求25所述的方法，其中所述RNA聚合酶为帽依赖性核酸内切酶。The method of claim 25, wherein the RNA polymerase is a cap-dependent endonuclease.
  27. 权利要求1-15任意一项所述的化合物或权利要求16-18任意一项所述的药物组合物用于预防、治疗或减轻患者病毒感染性疾病的用途。Use of the compound according to any one of claims 1-15 or the pharmaceutical composition according to any one of claims 16-18 for preventing, treating or alleviating viral infectious diseases in patients.
  28. 根据权利要求27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 27, wherein the viral infection is influenza virus infection.
  29. 权利要求1-15任意一项所述的化合物或权利要求16-18任意一项所述的药物组合物用于抑制流感病毒的RNA聚合酶的用途。Use of the compound of any one of claims 1-15 or the pharmaceutical composition of any one of claims 16-18 for inhibiting the RNA polymerase of influenza virus.
  30. 根据权利要求29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 29, wherein the RNA polymerase is a cap-dependent endonuclease.
PCT/CN2020/077781 2019-03-05 2020-03-04 Influenza virus replication inhibitor and use thereof WO2020177715A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080018045.5A CN113614085B (en) 2019-03-05 2020-03-04 Inhibitors of influenza virus replication and uses thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910163281.5 2019-03-05
CN201910163281 2019-03-05

Publications (1)

Publication Number Publication Date
WO2020177715A1 true WO2020177715A1 (en) 2020-09-10

Family

ID=72338359

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/077781 WO2020177715A1 (en) 2019-03-05 2020-03-04 Influenza virus replication inhibitor and use thereof

Country Status (2)

Country Link
CN (1) CN113614085B (en)
WO (1) WO2020177715A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113264917A (en) * 2021-05-28 2021-08-17 华南理工大学 Anti-hepatitis B virus compound and preparation method and application thereof
CN113620795A (en) * 2021-08-19 2021-11-09 河南师范大学 Method for synthesizing benzocycloheptenone compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103228653A (en) * 2010-09-24 2013-07-31 盐野义制药株式会社 Substituted polycyclic carbamoyl pyridone derivative prodrug
CN108697715A (en) * 2015-12-15 2018-10-23 盐野义制药株式会社 Include the treatment of influenza drug of the combination of cap dependence endonuclease enzyme inhibitor and antiviral drug
WO2019052565A1 (en) * 2017-09-18 2019-03-21 广东东阳光药业有限公司 Influenza virus replication inhibitor and use thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103228653A (en) * 2010-09-24 2013-07-31 盐野义制药株式会社 Substituted polycyclic carbamoyl pyridone derivative prodrug
CN108697715A (en) * 2015-12-15 2018-10-23 盐野义制药株式会社 Include the treatment of influenza drug of the combination of cap dependence endonuclease enzyme inhibitor and antiviral drug
WO2019052565A1 (en) * 2017-09-18 2019-03-21 广东东阳光药业有限公司 Influenza virus replication inhibitor and use thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113264917A (en) * 2021-05-28 2021-08-17 华南理工大学 Anti-hepatitis B virus compound and preparation method and application thereof
CN113620795A (en) * 2021-08-19 2021-11-09 河南师范大学 Method for synthesizing benzocycloheptenone compounds
CN113620795B (en) * 2021-08-19 2022-07-01 河南师范大学 Method for synthesizing benzocycloheptenone compounds

Also Published As

Publication number Publication date
CN113614085B (en) 2022-12-23
CN113614085A (en) 2021-11-05

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
CN107759571B (en) Inhibitors of influenza virus replication and methods of use and uses thereof
KR102057877B1 (en) Nitrogenous heterocyclic derivatives and their application in drugs
WO2018177297A1 (en) Substituted lactam compound, and preparation method therefor and use thereof
CN108276401B (en) Inhibitors of influenza virus replication and uses thereof
CN111057074B (en) Inhibitors of influenza virus replication and uses thereof
CN103153994A (en) Bicyclic heteroaryl kinase inhibitors and methods of use
US10993938B2 (en) Lactam compound, preparation method and use thereof
WO2020177715A1 (en) Influenza virus replication inhibitor and use thereof
CN110117285B (en) Inhibitors of influenza virus replication and uses thereof
CN108727369A (en) Inhibitors of influenza viruses replication and application thereof
CN110446711B (en) Inhibitors of influenza virus replication and uses thereof
WO2021227906A1 (en) Pyridine acetamide derivative serving as cdk inhibitor, and preparation method therefor and use thereof
CN112898312A (en) Fused polycyclic pyridone derivative and application thereof
CN114585616A (en) Amide derivatives and their use in medicine
WO2018171740A1 (en) Panicinotam derivative, and preparation method therefor and uses thereof
WO2021129799A1 (en) Influenza virus replication inhibitor and use thereof
WO2021143885A1 (en) Fused tetracyclic compound and application thereof in medicine
CN113416198A (en) Fused polycyclic pyridone derivative and application thereof
TW202214574A (en) Substituted (phthalazin-1-ylmethyl)ureas, substituted n-(phthalazin-1-ylmethyl)amides, and analogues thereof
EA040588B1 (en) VIRAL REPLICATION INHIBITORS

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: 20766318

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: 20766318

Country of ref document: EP

Kind code of ref document: A1