WO2023030459A1 - Quinolinone amide-containing compound, preparation method therefor, pharmaceutical composition thereof, and use thereof - Google Patents

Quinolinone amide-containing compound, preparation method therefor, pharmaceutical composition thereof, and use thereof Download PDF

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WO2023030459A1
WO2023030459A1 PCT/CN2022/116584 CN2022116584W WO2023030459A1 WO 2023030459 A1 WO2023030459 A1 WO 2023030459A1 CN 2022116584 W CN2022116584 W CN 2022116584W WO 2023030459 A1 WO2023030459 A1 WO 2023030459A1
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alkyl
substituted
halogen
group
ring
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周宇
李佳
张磊砢
姜智冬
臧奕
张宇旻
郑淼
苏明波
冯勃
肖庚富
柳红
蒋华良
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中国科学院上海药物研究所
中国科学院武汉病毒研究所
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    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
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    • A61P31/14—Antivirals for RNA viruses
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/10—Spiro-condensed systems
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a class of quinolinone amide-containing compounds as coronavirus main protease inhibitors, their preparation methods, pharmaceutical compositions containing such compounds and as main proteases (also known as 3CLpro) inhibitors, especially for the treatment of viral diseases where 3CL protease exists, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc.
  • Novel coronavirus pneumonia is a highly contagious disease caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), a virus closely related to SARS virus.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus type 2
  • SARS-CoV-2 is mainly spread through small droplets expelled when an infected person breathes or coughs.
  • Infected individuals may be asymptomatic or present with common COVID-19 symptoms, including fever, cough, fatigue, shortness of breath, loss of smell, and severe cases can develop complications including pneumonia, acute respiratory distress syndrome, multi-organ failure, and death.
  • the pathogen causing this novel coronavirus pneumonia is SARS-CoV-2, which is a new type of coronavirus.
  • the diameter of coronavirus is about 80-120nm. It is composed of envelope and its coated single-stranded forward RNA. The 5' end of the RNA chain has a methylated cap structure, and the 3' end has a poly(A) tail. About 27-32kb long.
  • One-third of its genome RNA is used to encode structural proteins and auxiliary proteins, including envelope M protein (membrance, M), spike S protein (spike, S), envelope E protein (envelope, E), nucleocapsid Shell N protein (nucleocapsid, N).
  • ORF 1a encodes a polyprotein of about 450kDa, called pp1a
  • ORF 1a and ORF 1b jointly encode a polyprotein of about 750kDa, called pp1ab.
  • 3CL protease is one of the key enzymes of coronavirus, which plays an important role in regulating the process of virus replication.
  • 3CL protease (3C-like proteinase, 3CLpro), also known as the main protease (M pro ), can hydrolyze the original polyproteins of pp1a and pp1ab from at least 11 conserved cleavage sites, and help them form replicase complexes.
  • COVID-19 novel coronavirus pneumonia
  • Yang Haitao, Rao Zihe and his team announced the determined crystal structure of SARS-CoV-2 coronavirus 3CL protease-binding compound N3 on January 26, 2020, with a resolution of 1 (PDB ID 6LU7).
  • SARS-CoV-2 3CLpro The active form of SARS-CoV-2 3CLpro is a homodimer containing two monomers. Each monomer consists of three domains with a total of 306 residues. Domain I (residues 8-101) and domain II (residues 102-184) have an inverted ⁇ -sheet structure. Domain III (residues 201-303) contains five ⁇ -helices connected to domain II by a long loop region (residues 185-200).
  • 3CL protease is one of the key enzymes of coronavirus and norovirus, which plays an important role in the process of regulating virus replication, and 3CL protease has no human homologue.
  • SARS-CoV coronavirus
  • SARS-CoV-2 SARS-CoV-2
  • MERS ⁇ CoV MERS ⁇ CoV
  • peptidomimetic inhibitors mainly use electrophilic "warhead” groups (warhead groups) to covalently bind to cysteine residues of 3CL protease, thereby achieving irreversible inhibitory effects.
  • Non-peptidomimetic small molecule inhibitors mainly achieve inhibitory effects by forming hydrogen bonds, hydrophobic bonds, and van der Waals interactions with amino acid residues in the binding pocket.
  • peptidomimetic inhibitors can be divided into two steps. First, an inhibitor molecule that mimics a natural peptide substrate binds to the 3CL protease to form a non-covalent complex. Then, the "warhead” group, which is sterically close to the catalytically active residue of the target protein, is subjected to nucleophilic attack, forming a covalent bond involving cysteine. These "warhead” groups are usually Michael acceptors, aldehydes, or ketones, which can covalently bind to cysteines in the binding pocket to produce inhibitory effects.
  • Non-peptidomimetic small molecule inhibitors mainly achieve the inhibitory effect by forming hydrogen bonds, hydrophobic bonds, and van der Waals interactions with amino acid residues in the S1', S1, S2, and S4 regions of the binding pocket. These inhibitors can be obtained through high-throughput screening, screening based on existing drugs, computer molecular docking and other methods. At present, research reports on inhibitors of this type of SARS-CoV-2 3CL protease are still very limited. It is generally believed that non-covalent inhibitors have a weaker and reversible binding to amino acid residues. This reversible interaction can avoid the harm caused by off-target effects. It is less toxic than covalent inhibitors and is suitable for long-term use. Therefore, research on such small molecule non-covalent 3CL protease inhibitors is very necessary.
  • the purpose of the present invention is to provide novel 3CL protease inhibitors, and be used for the treatment of viral diseases such as SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus that exist 3CL protease.
  • the first aspect of the present invention provides a quinolinone amide compound with the structure shown in general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or their mixture:
  • X is CH or N; wherein, when X is CH, the hydrogen atom on the CH can be replaced by R 1 ;
  • Y is selected from the group consisting of -(CH 2 ) n -, -CO-, -CONH-, or -SO 2 -, wherein n is 0, 1, 2, 3 or 4;
  • the ring is selected from the group consisting of 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1 -C6 alkylsulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic group;
  • R 3 is 1, 2, 3 or 4 substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, - S(O) 2 OH, C1-C6 alkylsulfonyl, C1-C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaromatic substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon Substituted C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 3-12 membered heterocyclyl,
  • two adjacent substituents can be with the atoms in the ring are joined end to end to form a combined ring, or The two substituents on the same atom on the ring are connected end to end with The ring forms a spiro ring; and when the A ring is a piperazine ring, the R 3 is not H;
  • the ring is selected from the group consisting of 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
  • R 4 are each independently selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution means that one or more hydrogen atoms on the group are selected Replacement by substituents from the following group: halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkylsulfonyl, C6-C10 aryl , and 3-12 membered heterocyclic groups;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1-C6 alkane Sulfonyl, C1-C6 alkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkyl substituted by aryl or heteroaryl ring, C3-C8 cycloalkane, 3-8 membered heterocyclic hydrocarbon, 7- C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 substituted by 12-membered spiro heterocyclic hydrocarbon or 9-12-membered fused heterocyclic hydrocarbon Halogenated cycloalkyl, C3-C10 aryl or heteroaryl, 3-12 membered heterocyclic
  • the heteroaromatic ring, heterofused ring or heterocyclic group each independently contain 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; unless otherwise specified, the alkyl, alkoxy, alkene Base, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclyl, aryl, heteroaryl are each independently substituted by 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl , Halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 Cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkylsulfonyl, C6-C10 aryl,
  • the halogen is F, Cl, Br or I.
  • the Ring is selected from the following group: wherein m 1 , m 2 , n 1 and n 2 are selected from 0, 1, 2, 3 or 4; X 1 is selected from CH 2 , CH 2 CH 2 and O; Y is selected from CH and N.
  • the R3 is selected from substituents of the following group: hydrogen, hydroxyl, hydroxymethyl, carboxyl, C1-C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaryl Ring substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon substituted C1-C6 alkyl, Among them, two adjacent substituents can be with the atoms in the ring are joined end to end to form a combined ring, or The two substituents on the same atom on the ring are connected end to end with The ring forms a spiral ring;
  • R 5 and R 6 are selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1-C6 alkylsulfonyl , C1-C6 alkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkyl substituted by aryl or heteroaryl ring, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon, C1-C6 alkoxy , C1-C6 alkoxyl substituted by halogen, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 3-12 membered heterocyclic group.
  • each of the R4s is independently selected from the following group: substituted or unsubstituted phenyl, and the substitution refers to one or more hydrogen atoms on the group being substituted by a group selected from Base substitution: halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, cyano, nitro , amino, hydroxyl, methylol, carboxyl, mercapto, -S(O) 2 OH, C1-C6 alkylsulfonyl.
  • the R3 is selected from substituents in the following group: C1-C6 alkyl substituted by hydrogen, aryl or heteroaryl ring, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon,
  • the second aspect of the present invention provides a pharmaceutical composition, which includes: the compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R- One or more of isomers, S-isomers or mixtures thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
  • the third aspect of the present invention provides a compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or their Use of the mixture for preparing a pharmaceutical composition for treating or preventing diseases related to 3CL protease activity.
  • the disease is caused by a virus with 3CL protease, preferably, the virus is selected from the group consisting of SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus Viruses, or a combination thereof.
  • Figure 1 shows the IC 50 data of some compounds.
  • the inventor After long-term and in-depth research, the inventor has designed and synthesized a class of quinolinone amide compounds with novel structure.
  • the compound has excellent inhibitory activity against 3CL protease, so it can be used for treatment, prevention and alleviation of 3CL Protease-related diseases, especially for the treatment of viral diseases with 3CL protease, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc.
  • 3CL protease such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc.
  • the present invention provides a quinolinone amide compound with a structure shown in general formula I, and racemates, R-isomers, S-isomers, pharmaceutically acceptable salts or mixtures thereof:
  • X is CH or N; wherein, when X is CH, the hydrogen atom on the CH can be replaced by R 1 ;
  • Y is selected from the group consisting of -(CH 2 ) n -, -CO-, -CONH-, or -SO 2 -, wherein n is 0, 1, 2, 3 or 4;
  • the ring is selected from the following group: 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclyl;
  • R 3 is 1, 2, 3 or 4 substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfo on ring
  • A Acyl, C1-C6 alkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkyl substituted by aryl or heteroaryl ring, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon, C1-C6 alkoxy group, halogen substituted C1-C6 alkoxy group, C3-C8 cycloalkyl group, C3-C8 halocycloalkyl group, C6-C10 aryl group, 3-12 membered heterocyclic group, Among them, two adjacent substituents can be with the atoms in the ring are joined end to end to form a combined ring, or The two substituents on the same atom on
  • the ring is selected from the group consisting of 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
  • R 4 are each independently selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution means that one or more hydrogen atoms on the group are selected Replacement by substituents from the following group: halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclyl;
  • R and R are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C1 - C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaromatic substituted C1-C6 alkyl, C3-C8 cycloalkane, 3-8 membered heterocyclic hydrocarbon, 7-12 membered spiro heterocyclic hydrocarbon or 9-12 membered condensed heterocyclic hydrocarbon Cyclohydrocarbon substituted C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halogenated cycloalkyl, C6-C10 aryl, 3 -12 membered heterocyclyl;
  • the heteroaromatic ring, heterofused ring or heterocyclic group each independently contain 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; unless otherwise specified, the alkyl, alkoxy, alkene Base, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclyl, aryl, heteroaryl are each independently substituted by 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl , Halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 Cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered hetero
  • the halogen is F, Cl, Br or I.
  • the compounds are those shown in Table A.
  • the present invention also provides a kind of preparation method of the compound represented by general formula I, and this preparation method is carried out according to the following scheme (example):
  • Step a Compound 1 is dissolved in an organic solvent, and HATU, morpholine, and DIPEA are added at room temperature to react to obtain Compound 2;
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol Diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or mixtures thereof;
  • Step b Dissolve compound 2 in an organic solvent, add BH 3 -THF complex, heat and stir until the reaction is complete, and obtain compound 3;
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, Ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or their mixture; the heating temperature range is 50-80°C;
  • Step c Dissolve compound 3 in an organic solvent, add acid dioxane solution, heat and stir until the reaction is complete to obtain compound 4;
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether , ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof;
  • the acid is hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid;
  • Step d dissolving compound 4 in an organic solvent, adding aryl compound, trisdibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heat to reflux to obtain intermediate 5;
  • the aryl compound is selected from substituted or unsubstituted benzene, substituted or unsubstituted 5-12 membered heteroaromatic compounds; wherein, the substitution refers to one or more
  • the hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro
  • Step e dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 5 at room temperature to obtain compound 6;
  • the acid is selected from
  • X can be independently selected from C or N;
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups;
  • the condensing agent is HATU or CMPI;
  • the organic solvent is tetra
  • Step f dissolving compound 1 in an organic solvent, adding aryl compound, trisdibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heating to reflux to obtain intermediate 2;
  • the aryl compound is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution refers to one or more on the group
  • Each hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano,
  • Step g Dissolve compound 2 in an organic solvent and slowly add acid under stirring at 0°C.
  • the reaction solution is stirred and reacted at room temperature for 1 hour. After the reaction is complete, it is concentrated.
  • the residue is dissolved in 100 mL of ethyl acetate and washed with saturated sodium carbonate The solution was washed and the pH was adjusted to 8-9, followed by washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance which was Intermediate 3.
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof;
  • the acid is trifluoroacetic acid, trifluoromethanesulfonic acid or hydrochloric acid.
  • Step h dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 3 at room temperature to obtain compound 4;
  • the acid is selected from
  • X can be independently selected from C or N;
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups;
  • the condensing agent is HATU or CMPI;
  • the organic solvent is tetra
  • Step i Charge N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanine, condensing agent, glycine methyl ester hydrochloride) and DMF in a round bottom flask. Add DIPEA to it. After stirring at room temperature for 5 minutes, the mixture was diluted with water and extracted with ether. The layers were separated and the organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to give N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanylglycine methyl ester as a yellow oil on concentrate , used directly in the next step.
  • the condensing agent is HATU or CMPI.
  • Steps j and k A round bottom flask was charged with N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanylglycine methyl ester, DCM and TFA. After 30 minutes, the mixture was concentrated, then redissolved in 2M ammonia in MeOH and stirred overnight at room temperature, a white precipitate precipitated and the product formed was collected by filtration to give (3S)-3(cyclohexylmethyl)-2 , 5-piperazinedione.
  • Step 1 Charge (3S)-3-(cyclohexylmethyl)-2,5-piperazinedione, an organic solvent and lithium aluminum hydride in a round bottom flask. After heating to 70°C overnight, the mixture was cooled to room temperature and sodium sulfate decahydrate was added slowly. After stirring for 1 hour, the mixture was filtered, and the filtrate was concentrated to give (2S)-2-(cyclohexylmethyl)piperazine as a colorless oil, which was used crude for the next reaction.
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof.
  • Step m dissolving compound 5 in an organic solvent, adding aryl compound, trisdibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heating to reflux to obtain intermediate 6;
  • the aryl compound is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution refers to one or more Each hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino,
  • Step n dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 6 at room temperature to obtain compound 7;
  • the acid is selected from
  • X can be independently selected from C or N;
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups;
  • the condensing agent is HATU or CMPI;
  • the organic solvent is tetra
  • Step o dissolving compound 1 in an organic solvent, adding aryl compound, tridibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heating to reflux to obtain intermediate 2;
  • the aryl compound is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution refers to one or more on the group
  • Each hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro
  • Step p Dissolve compound 2 in an organic solvent and slowly add acid under stirring conditions at 0°C.
  • the reaction solution is stirred and reacted at room temperature for 1 hour. After the reaction is completed, it is concentrated.
  • the residue is dissolved in 100 mL of ethyl acetate and washed with saturated sodium carbonate The solution was washed and the pH was adjusted to 8-9, followed by washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance which was Intermediate 3.
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof;
  • the acid is trifluoroacetic acid, trifluoromethanesulfonic acid or hydrochloric acid.
  • Step q dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 3 at room temperature to obtain compound 4;
  • the acid is selected from
  • X can be independently selected from C or N;
  • R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups;
  • the condensing agent is HATU or CMPI;
  • the organic solvent is tetra
  • Step r Dissolve compound 4 in an appropriate amount of THF/H 2 O mixed solvent, add potassium hydroxide, stir and react under reflux for two hours, spin the solvent after the reaction is completed, adjust the pH to acidic with hydrochloric acid, and observe that there is solid precipitation , and the solid collected by suction filtration is Intermediate 5.
  • Step s Dissolving intermediate 5 in an organic solvent, adding a certain amount of base, condensing agent and amine to obtain compound 6;
  • R5 and R6 can be independently selected from the following group: hydrogen, halogen, cyano, nitro, amino , amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C1-C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaromatic substituted C1-C6 alkyl, cycloalkane or hetero Cyclohydrocarbon substituted C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halogenated cycloalkyl, C6-C10 aryl, 3 -12 membered heterocyclyl.
  • the condensing agent is HATU or CMPI;
  • the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, Dichloromethane or a mixture thereof;
  • the base is sodium acetate, NaOH, KOH, sodium ethoxide, sodium methoxide, sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine.
  • compositions and methods of administration are provided.
  • the pharmaceutical composition can be used for the treatment, prevention and alleviation of diseases related to 3CL protease, especially for the treatment of viral diseases with 3CL protease, such as SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc. caused diseases.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-3000 mg (active dose range 3-30 mg/kg) of the compound of the present invention per dose, more preferably 10-2000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 6-600 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the hydrochloride was dissolved in an appropriate amount of ethyl acetate and washed with saturated sodium carbonate solution to adjust the pH to 8-9, and extracted several times with ethyl acetate until no product remained in the aqueous phase, then the organic phases were combined and used without Dried over sodium sulfate, concentrated and spin-dried to obtain a colorless oily substance, compound 7-4 (4 g, yield 72%).
  • (2S)-2-(cyclohexylmethyl)piperazine (0.954g, 5.23mmol) and 3,4-dichlorobromobenzene (1.30g, 5.76mmol) were dissolved in 20mL of toluene, followed by Add tridibenzylideneacetone dipalladium (Pd 2 dba 3 , 193.8mg, 0.21mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (X-Phos, 238.1mg, 0.5 mmol) and cesium carbonate (3.26g, 10mmol), the reaction solution was heated to 110°C and stirred overnight.
  • SARS-CoV-2 3CLpro protein As a proteolytic enzyme, a screening system for detecting the activity of SARS-CoV-2 3CLpro protein by fluorescence method was established.
  • the SARS-CoV-2 3CLpro protein can specifically cleave substrates whose P1 position is Gln(Q), and its activity detection can use fluorescent peptides as substrates to reflect the activity of its proteolytic enzymes by detecting the generation of fluorescent signals.
  • Fluorescent quantitative PCR was used to detect the copy number contained in each milliliter of the original virus solution.
  • TB Green Premix (Takara, Cat#RR820A) was used to mix the reaction system, and the amplification reaction and reading were performed on the StepOne Plus Real-time PCR instrument (brand: ABI). Calculate the copy number per milliliter of the original virus solution. Proceed as follows:
  • Cycle parameters 95°C for 15 seconds, 54°C for 15 seconds, 72°C for 30 seconds, a total of 40 cycles.
  • the results of the virus proliferation inhibition experiment showed that multiple tested compounds could effectively inhibit the replication of the SARS-CoV-2 virus genome in the infection supernatant at a concentration of 10 ⁇ M, and the inhibition rate was greater than 90%.
  • Some compounds have completed the IC 50 data determination, as shown in Figure 1, especially the IC 50 value of compound 5 is 0.702 ⁇ M, which is basically equivalent to the activity of the reported peptidomimetic inhibitors, and as a non-covalent small molecule inhibitor , may be less toxic than covalent inhibitors and suitable for long-term use.
  • Embodiment 3 mouse pharmacokinetic experiment
  • mice Nine healthy mice were randomly divided into 3 groups with 3 mice in each group. Gavage, intraperitoneal injection and intravenous injection were given Compound 5 respectively, and dosage was 20mg/kg for intragastric injection, 10mg/kg for intraperitoneal injection, and 5mg/kg for intravenous injection, and the medicine was prepared in the form of DMSO/Tween 80/normal saline (5:5: 90, v/v/v) formulation. Fasting 12h before the test, free to drink water. Eat uniformly 2 hours after administration.
  • Oral administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration; intraperitoneal administration: 5min after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24h; intravenous Administration: 0, 5min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration;
  • the time to peak plasma concentration T max was 0.5 h, and the peak concentration C max was 865 ng/ml; the area under the drug-time curve AUC 0-t was 1350 h/ml; The elimination half-life t 1/2 is 1.13h.
  • the AUC 0-t was 1210 ng h/ml; after intraperitoneal administration of 10 mg/kg compound 5 to mice, the time to peak plasma concentration T max was 0.25 h, and the peak concentration C max was 1610 ng /ml; the area under the drug-time curve AUC 0-t was 2280 h/ml; the terminal elimination half-life t 1/2 was 0.78h.
  • the absolute bioavailability of 20 mg/kg compound 5 in mice was 28.1%.
  • the absolute bioavailability of compound 5 after intraperitoneal administration of 10 mg/kg to mice was 95.0%.

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Abstract

The present invention provides a quinolinone amide-containing compound, a preparation method therefor, a pharmaceutical composition thereof, and a use thereof. Specifically, the present invention provides a quinolinone amide compound having a structure shown in general formula I, and a racemate thereof, an R-isomer thereof, an S-isomer thereof, a pharmaceutically acceptable salt thereof, or a mixture thereof. The compound has excellent inhibitory activity against 3CL protease, and therefore can be used in treating, preventing, and alleviating diseases related to 3CL protease, especially in treating viral diseases related to 3CL protease, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc.

Description

一类含喹啉酮酰胺的化合物及其制备方法、药物组合物和用途A class of quinolinone amide-containing compounds and their preparation methods, pharmaceutical compositions and uses 技术领域technical field
本发明涉及药物化学和药物治疗学领域，具体涉及作为冠状病毒主蛋白酶抑制剂的一类含喹啉酮酰胺的化合物、其制备方法、含此类化合物的药物组合物及作为主蛋白酶(也称3CLpro)抑制剂，特别是用于治疗存在3CL蛋白酶的病毒性疾病，如由SARS-CoV-2、SARS-CoV、MERS-CoV、诺如病毒等引发的疾病。The present invention relates to the fields of medicinal chemistry and pharmacotherapeutics, in particular to a class of quinolinone amide-containing compounds as coronavirus main protease inhibitors, their preparation methods, pharmaceutical compositions containing such compounds and as main proteases (also known as 3CLpro) inhibitors, especially for the treatment of viral diseases where 3CL protease exists, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc.
背景技术Background technique
新型冠状病毒肺炎(COVID-19)是由严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)引起的高度传染性疾病，SARS-CoV-2是一种与SARS病毒密切相关的病毒。SARS-CoV-2主要通过感染者呼吸或咳嗽时排出的小液滴传播。感染者可能没有症状或出现常见的COVID-19症状，包括发烧、咳嗽，疲劳、气短、嗅觉丧失，严重者可发展为并发症，包括肺炎、急性呼吸窘迫综合征、多器官衰竭和死亡。Novel coronavirus pneumonia (COVID-19) is a highly contagious disease caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), a virus closely related to SARS virus. SARS-CoV-2 is mainly spread through small droplets expelled when an infected person breathes or coughs. Infected individuals may be asymptomatic or present with common COVID-19 symptoms, including fever, cough, fatigue, shortness of breath, loss of smell, and severe cases can develop complications including pneumonia, acute respiratory distress syndrome, multi-organ failure, and death.
造成这次新型冠状病毒肺炎(COVID-19)的病原体是SARS-CoV-2，它是一种新型的冠状病毒。冠状病毒直径约80～120nm，由包膜及其包被的单链正向RNA构成，该RNA链5′端具有甲基化的帽状结构，3′端具有poly(A)尾，基因组全长约27-32kb。其基因组三分之一的RNA用于编码结构蛋白和辅助蛋白，包括囊膜M蛋白(membrance,M)、刺突S蛋白(spike，S)、包膜E蛋白(envelope，E)、核衣壳N蛋白(nucleocapsid,N)。其余三分之二的基因组由两个开放阅读框架(open reading frames,ORFs)构成，称为ORF 1a与ORF 1b。其中ORF 1a编码约450kDa的多聚蛋白，称为pp1a，ORF 1a与ORF 1b共同编码约750kDa的多聚蛋白，称为pp1ab。这两种多聚蛋白，在病毒蛋白水解酶的作用下，释放出多种非结构蛋白(Non-structural proteins,nsps)，执行病毒的复制。The pathogen causing this novel coronavirus pneumonia (COVID-19) is SARS-CoV-2, which is a new type of coronavirus. The diameter of coronavirus is about 80-120nm. It is composed of envelope and its coated single-stranded forward RNA. The 5' end of the RNA chain has a methylated cap structure, and the 3' end has a poly(A) tail. About 27-32kb long. One-third of its genome RNA is used to encode structural proteins and auxiliary proteins, including envelope M protein (membrance, M), spike S protein (spike, S), envelope E protein (envelope, E), nucleocapsid Shell N protein (nucleocapsid, N). The remaining two-thirds of the genome consist of two open reading frames (ORFs), called ORF 1a and ORF 1b. Among them, ORF 1a encodes a polyprotein of about 450kDa, called pp1a, and ORF 1a and ORF 1b jointly encode a polyprotein of about 750kDa, called pp1ab. These two polyproteins, under the action of viral proteolytic enzymes, release a variety of non-structural proteins (Non-structural proteins, nsps) to perform virus replication.
3CL蛋白酶是冠状病毒的关键酶之一，在调节病毒复制的过程中扮演着重要的角色。3CL蛋白酶(3C-like proteinase，3CLpro)，又称为主蛋白酶(M pro)能够从至少11个保守切割位点水解pp1a、pp1ab原始多聚蛋白，帮助其形成复制酶复合体。随着新型冠状肺炎(COVID-19)的爆发，杨海涛、饶子和团队于2020年1月26日公布了测定的SARS-CoV-2冠状病毒3CL蛋白酶结合化合物N3的晶体结构，分辨率达到了
Figure PCTCN2022116584-appb-000001
Figure PCTCN2022116584-appb-000002
(PDB ID 6LU7)。SARS-CoV-2 3CLpro的活性形式为一同源二聚体，包含有两个单体。每个单体由三个结构域组成，共306个残基。结构域I(残基8-101)与结构域II(残基102-184)具有反向的β-折叠结构。结构域III(残基201-303)含有5个α-螺旋结构，通过一段长的环状区域(残基185-200)连接到结构域II。 3CL protease is one of the key enzymes of coronavirus, which plays an important role in regulating the process of virus replication. 3CL protease (3C-like proteinase, 3CLpro), also known as the main protease (M pro ), can hydrolyze the original polyproteins of pp1a and pp1ab from at least 11 conserved cleavage sites, and help them form replicase complexes. With the outbreak of novel coronavirus pneumonia (COVID-19), Yang Haitao, Rao Zihe and his team announced the determined crystal structure of SARS-CoV-2 coronavirus 3CL protease-binding compound N3 on January 26, 2020, with a resolution of 1
Figure PCTCN2022116584-appb-000001
Figure PCTCN2022116584-appb-000002
(PDB ID 6LU7). The active form of SARS-CoV-2 3CLpro is a homodimer containing two monomers. Each monomer consists of three domains with a total of 306 residues. Domain I (residues 8-101) and domain II (residues 102-184) have an inverted β-sheet structure. Domain III (residues 201-303) contains five α-helices connected to domain II by a long loop region (residues 185-200).
3CL蛋白酶是冠状病毒以及诺如病毒的关键酶之一，在调节病毒复制的过程中扮演着重要的角色，且3CL蛋白酶没有人类同源物。同时，进一步的序列比较显示三种冠状病毒SARS-CoV，SARS-CoV-2与MERS‐CoV的3CL蛋白酶表现出高度的结构相似性与保守性。这些特点使得3CL蛋白酶成为了抑制SARS-CoV-2以及其他类型病毒的一个富有吸引力的成药靶点。3CL protease is one of the key enzymes of coronavirus and norovirus, which plays an important role in the process of regulating virus replication, and 3CL protease has no human homologue. At the same time, further sequence comparisons showed that the 3CL proteases of the three coronaviruses SARS-CoV, SARS-CoV-2 and MERS‐CoV showed high structural similarity and conservation. These features make the 3CL protease an attractive druggable target for the inhibition of SARS-CoV-2 as well as other types of viruses.
科研人员针对3CL蛋白酶的抑制剂做了大量工作，这些抑制剂按结构特点划分，可以大体分为两类：拟肽类抑制剂和非拟肽类小分子抑制剂。拟肽类抑制剂主要利用亲电的“弹头”基团(warhead groups)来共价结合3CL蛋白酶的半胱氨酸残基，从而实现 不可逆的抑制效果。非拟肽类小分子抑制剂主要通过与结合口袋中的氨基酸残基形成氢键、疏水键以及范德华力相互作用来实现抑制效果。Researchers have done a lot of work on inhibitors of 3CL protease. These inhibitors can be roughly divided into two categories according to their structural characteristics: peptidomimetic inhibitors and non-peptidomimetic small molecule inhibitors. Peptidomimetic inhibitors mainly use electrophilic "warhead" groups (warhead groups) to covalently bind to cysteine residues of 3CL protease, thereby achieving irreversible inhibitory effects. Non-peptidomimetic small molecule inhibitors mainly achieve inhibitory effects by forming hydrogen bonds, hydrophobic bonds, and van der Waals interactions with amino acid residues in the binding pocket.
拟肽类抑制剂的作用过程可以分为两个步骤。首先，模仿天然肽类底物的抑制剂分子结合到3CL蛋白酶上，形成一个非共价复合物。然后，在空间上非常接近靶蛋白具有催化活性残基的“弹头”基团，受到亲核进攻，形成一个含有半胱氨酸参与的共价键。这些“弹头”基团通常为迈克尔受体、醛或者酮，能够与结合口袋中的半胱氨酸发生共价结合，从而产生抑制作用。The action process of peptidomimetic inhibitors can be divided into two steps. First, an inhibitor molecule that mimics a natural peptide substrate binds to the 3CL protease to form a non-covalent complex. Then, the "warhead" group, which is sterically close to the catalytically active residue of the target protein, is subjected to nucleophilic attack, forming a covalent bond involving cysteine. These "warhead" groups are usually Michael acceptors, aldehydes, or ketones, which can covalently bind to cysteines in the binding pocket to produce inhibitory effects.
非拟肽类小分子抑制剂主要通过与结合口袋中S1’、S1、S2和S4区域的氨基酸残基形成氢键、疏水键以及范德华力相互作用来实现抑制效果。这些抑制剂可以通过高通量筛选、基于现有药物筛选、计算机分子对接等方法来获得。目前，针对此类SARS-CoV-2 3CL蛋白酶的抑制剂研究报道还十分有限。一般认为，非共价抑制剂与氨基酸残基有着较弱的、可逆的结合，这种可逆的相互作用可以避免脱靶效应带来的危害，毒性较共价抑制剂更低，适合长期使用。因此，针对这类小分子非共价3CL蛋白酶抑制剂的研究是十分有必要的。Non-peptidomimetic small molecule inhibitors mainly achieve the inhibitory effect by forming hydrogen bonds, hydrophobic bonds, and van der Waals interactions with amino acid residues in the S1', S1, S2, and S4 regions of the binding pocket. These inhibitors can be obtained through high-throughput screening, screening based on existing drugs, computer molecular docking and other methods. At present, research reports on inhibitors of this type of SARS-CoV-2 3CL protease are still very limited. It is generally believed that non-covalent inhibitors have a weaker and reversible binding to amino acid residues. This reversible interaction can avoid the harm caused by off-target effects. It is less toxic than covalent inhibitors and is suitable for long-term use. Therefore, research on such small molecule non-covalent 3CL protease inhibitors is very necessary.
发明内容Contents of the invention
本发明的目的是提供新型的3CL蛋白酶抑制剂，并用于SARS-CoV-2、SARS-CoV、MERS-CoV、诺如病毒等存在3CL蛋白酶的病毒性疾病的治疗。The purpose of the present invention is to provide novel 3CL protease inhibitors, and be used for the treatment of viral diseases such as SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus that exist 3CL protease.
本发明的第一方面，提供了一种通式I所示结构的喹啉酮酰胺类化合物，及其外消旋体、R-异构体、S-异构体、可药用盐或它们混合物：The first aspect of the present invention provides a quinolinone amide compound with the structure shown in general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or their mixture:
Figure PCTCN2022116584-appb-000003
Figure PCTCN2022116584-appb-000003
其中，in,
X为CH或N；其中，当X为CH时，所述的CH上的氢原子可以被R 1取代； X is CH or N; wherein, when X is CH, the hydrogen atom on the CH can be replaced by R 1 ;
Y选自下组：-(CH 2) n-、-CO-、-CONH-、或-SO 2-，其中n为0、1、2、3或4； Y is selected from the group consisting of -(CH 2 ) n -, -CO-, -CONH-, or -SO 2 -, wherein n is 0, 1, 2, 3 or 4;
Figure PCTCN2022116584-appb-000004
环选自下组：4-7元杂单环、或7-20元杂多环(包括稠环、桥环或螺环)；
Figure PCTCN2022116584-appb-000004
The ring is selected from the group consisting of 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
R 1和R 2选自下组：氢、卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、-S(O) 2OH、C1-C6烷基磺酰基、C6-C10芳基、和3-12元杂环基； R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1 -C6 alkylsulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic group;
R 3为位于A环上的1、2、3或4个选自下组的取代基：氢、卤素、氰基、硝基、氨基、胺基、羟基、羟甲基、羧基、巯基、-S(O) 2OH、C1-C6烷基磺酰基、C1-C6烷基、卤素取代的C1-C6烷基、芳基或杂芳环取代的C1-C6烷基、环烷烃或杂环烃取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C3-C8环烷基、C3-C8卤 代环烷基、C6-C10芳基、3-12元杂环基、
Figure PCTCN2022116584-appb-000005
R 3 is 1, 2, 3 or 4 substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, - S(O) 2 OH, C1-C6 alkylsulfonyl, C1-C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaromatic substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon Substituted C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 3-12 membered heterocyclyl,
Figure PCTCN2022116584-appb-000005
Figure PCTCN2022116584-appb-000006
其中，两个相邻的取代基可以与
Figure PCTCN2022116584-appb-000007
环上的原子首尾相连形成并环，或
Figure PCTCN2022116584-appb-000008
环上同一原子上的两个取代基首尾相连与
Figure PCTCN2022116584-appb-000009
环形成螺环；且当A环为哌嗪环时，所述的R 3不为H；
Figure PCTCN2022116584-appb-000006
Among them, two adjacent substituents can be with
Figure PCTCN2022116584-appb-000007
the atoms in the ring are joined end to end to form a combined ring, or
Figure PCTCN2022116584-appb-000008
The two substituents on the same atom on the ring are connected end to end with
Figure PCTCN2022116584-appb-000009
The ring forms a spiro ring; and when the A ring is a piperazine ring, the R 3 is not H;
Figure PCTCN2022116584-appb-000010
环选自下组：4-7元杂单环、或7-20元杂多环(包括稠环、桥环或螺环)；
Figure PCTCN2022116584-appb-000010
The ring is selected from the group consisting of 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
R 4各自独立地选自下组：取代或未取代的苯基、取代或未取代的5-12元杂芳基；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、C1-C6烷基磺酰基、C6-C10芳基、和3-12元杂环基； R 4 are each independently selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution means that one or more hydrogen atoms on the group are selected Replacement by substituents from the following group: halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkylsulfonyl, C6-C10 aryl , and 3-12 membered heterocyclic groups;
R 5和R 6各自独立地选自下组：氢、卤素、氰基、硝基、氨基、胺基、羟基、羟甲基、羧基、巯基、-S(O) 2OH、C1-C6烷基磺酰基、C1-C6烷基、卤素取代的C1-C6烷基、芳基或杂芳环取代的C1-C6烷基、被C3-C8环烷烃、3-8元杂环烃、7-12元螺杂环烃或9-12元稠杂环烃取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C3-C8环烷基、C3-C8卤代环烷基、C3-C10芳基或杂芳基、3-12元杂环基； R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1-C6 alkane Sulfonyl, C1-C6 alkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkyl substituted by aryl or heteroaryl ring, C3-C8 cycloalkane, 3-8 membered heterocyclic hydrocarbon, 7- C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 substituted by 12-membered spiro heterocyclic hydrocarbon or 9-12-membered fused heterocyclic hydrocarbon Halogenated cycloalkyl, C3-C10 aryl or heteroaryl, 3-12 membered heterocyclic group;
其中，所述杂芳环、杂稠环或杂环基各自独立地含有1～4个选自氧、硫和氮中的杂原子；除非特别说明，所述的烷基、烷氧基、烯基、炔基、环烷烃、环烷基、杂环烃、杂环基、芳基、杂芳基各自独立地被1-3个选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、C1-C6烷基磺酰基、C6-C10芳基、和3-12元杂环基；Wherein, the heteroaromatic ring, heterofused ring or heterocyclic group each independently contain 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; unless otherwise specified, the alkyl, alkoxy, alkene Base, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclyl, aryl, heteroaryl are each independently substituted by 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl , Halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 Cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkylsulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups;
所述的卤素为F、Cl、Br或I。The halogen is F, Cl, Br or I.
在另一优选例中，所述的
Figure PCTCN2022116584-appb-000011
环选自下组：
Figure PCTCN2022116584-appb-000012
Figure PCTCN2022116584-appb-000013
其中m 1，m 2，n 1和n 2分别选自0、1、2、3或4；X 1分别选自CH 2，CH 2CH 2和O；Y分别选自CH和N。 In another preferred example, the
Figure PCTCN2022116584-appb-000011
Ring is selected from the following group:
Figure PCTCN2022116584-appb-000012
Figure PCTCN2022116584-appb-000013
wherein m 1 , m 2 , n 1 and n 2 are selected from 0, 1, 2, 3 or 4; X 1 is selected from CH 2 , CH 2 CH 2 and O; Y is selected from CH and N.
在另一优选例中，所述的R 3选自下组的取代基：氢、羟基、羟甲基、羧基、C1-C6烷基、卤素取代的C1-C6烷基、芳基或杂芳环取代的C1-C6烷基、环烷烃或杂环烃取代的C1-C6烷基、
Figure PCTCN2022116584-appb-000014
其中，两个相邻的取代基可以与
Figure PCTCN2022116584-appb-000015
环上的原子首尾相连形成并环，或
Figure PCTCN2022116584-appb-000016
环上同一原子上的两个取代基首尾 相连与
Figure PCTCN2022116584-appb-000017
环形成螺环； In another preferred example, the R3 is selected from substituents of the following group: hydrogen, hydroxyl, hydroxymethyl, carboxyl, C1-C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaryl Ring substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon substituted C1-C6 alkyl,
Figure PCTCN2022116584-appb-000014
Among them, two adjacent substituents can be with
Figure PCTCN2022116584-appb-000015
the atoms in the ring are joined end to end to form a combined ring, or
Figure PCTCN2022116584-appb-000016
The two substituents on the same atom on the ring are connected end to end with
Figure PCTCN2022116584-appb-000017
The ring forms a spiral ring;
R 5和R 6选自下组：氢、卤素、氰基、硝基、氨基、胺基、羟基、羟甲基、羧基、巯基、-S(O) 2OH、C1-C6烷基磺酰基、C1-C6烷基、卤素取代的C1-C6烷基、芳基或杂芳环取代的C1-C6烷基、环烷烃或杂环烃取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C3-C8环烷基、C3-C8卤代环烷基、C6-C10芳基、3-12元杂环基。 R 5 and R 6 are selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1-C6 alkylsulfonyl , C1-C6 alkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkyl substituted by aryl or heteroaryl ring, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon, C1-C6 alkoxy , C1-C6 alkoxyl substituted by halogen, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 3-12 membered heterocyclic group.
在另一优选例中，所述的R 4各自独立地选自下组：取代或未取代的苯基，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、-S(O) 2OH、C1-C6烷基磺酰基。 In another preferred example, each of the R4s is independently selected from the following group: substituted or unsubstituted phenyl, and the substitution refers to one or more hydrogen atoms on the group being substituted by a group selected from Base substitution: halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, cyano, nitro , amino, hydroxyl, methylol, carboxyl, mercapto, -S(O) 2 OH, C1-C6 alkylsulfonyl.
在另一优选例中，所述的
Figure PCTCN2022116584-appb-000018
选自下组：
Figure PCTCN2022116584-appb-000019
其中m 1，和n 1可分别选自0、1或2；X 1可分别选自CH 2和CH 2CH 2；Y选自N。 In another preferred example, the
Figure PCTCN2022116584-appb-000018
Select from the group:
Figure PCTCN2022116584-appb-000019
Where m 1 and n 1 can be selected from 0, 1 or 2 respectively; X 1 can be selected from CH 2 and CH 2 CH 2 respectively; Y can be selected from N.
在另一优选例中，所述的R 3选自下组的取代基：氢、芳基或杂芳环取代的C1-C6烷基、环烷烃或杂环烃取代的C1-C6烷基、
Figure PCTCN2022116584-appb-000020
Figure PCTCN2022116584-appb-000021
In another preferred example, the R3 is selected from substituents in the following group: C1-C6 alkyl substituted by hydrogen, aryl or heteroaryl ring, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon,
Figure PCTCN2022116584-appb-000020
Figure PCTCN2022116584-appb-000021
本发明的第二方面，提供了一种药物组合物，所述的药物组合物包括：如本发明第一方面所述的式I化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种，以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。The second aspect of the present invention provides a pharmaceutical composition, which includes: the compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R- One or more of isomers, S-isomers or mixtures thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
本发明的第三方面，提供了一种如本发明第一方面所述的式I化合物，其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物的用途，其用于制备治疗或预防与3CL蛋白酶活性相关的疾病的药物组合物。The third aspect of the present invention provides a compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or their Use of the mixture for preparing a pharmaceutical composition for treating or preventing diseases related to 3CL protease activity.
在另一优选例中，所述的疾病是存在3CL蛋白酶的病毒引发的疾病，较佳地，所述的病毒选自下组：SARS-CoV-2、SARS-CoV、MERS-CoV、诺如病毒，或其组合。In another preferred example, the disease is caused by a virus with 3CL protease, preferably, the virus is selected from the group consisting of SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus Viruses, or a combination thereof.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.
附图说明Description of drawings
图1显示了部分化合物的IC 50数据。 Figure 1 shows the IC 50 data of some compounds.
具体实施方式Detailed ways
本发明人经过长期而深入的研究，设计合成了一类结构新颖的喹啉酮酰胺类化合物，所述的化合物具有优异的针对3CL蛋白酶的抑制活性，因此可以用于治疗、预防以 及缓解与3CL蛋白酶相关的疾病，特别是用于治疗存在3CL蛋白酶的病毒性疾病，如由SARS-CoV-2、SARS-CoV、MERS-CoV、诺如病毒等引发的疾病。基于上述发现，发明人完成了本发明。After long-term and in-depth research, the inventor has designed and synthesized a class of quinolinone amide compounds with novel structure. The compound has excellent inhibitory activity against 3CL protease, so it can be used for treatment, prevention and alleviation of 3CL Protease-related diseases, especially for the treatment of viral diseases with 3CL protease, such as diseases caused by SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc. Based on the above findings, the inventors have accomplished the present invention.
式I化合物Compound of formula I
本发明提供了一种通式I所示结构的喹啉酮酰胺类化合物，及其外消旋体、R-异构体、S-异构体、可药用盐或它们混合物：The present invention provides a quinolinone amide compound with a structure shown in general formula I, and racemates, R-isomers, S-isomers, pharmaceutically acceptable salts or mixtures thereof:
Figure PCTCN2022116584-appb-000022
Figure PCTCN2022116584-appb-000022
其中，in,
X为CH或N；其中，当X为CH时，所述的CH上的氢原子可以被R 1取代； X is CH or N; wherein, when X is CH, the hydrogen atom on the CH can be replaced by R 1 ;
Y选自下组：-(CH 2) n-、-CO-、-CONH-、或-SO 2-，其中n为0、1、2、3或4； Y is selected from the group consisting of -(CH 2 ) n -, -CO-, -CONH-, or -SO 2 -, wherein n is 0, 1, 2, 3 or 4;
Figure PCTCN2022116584-appb-000023
环选自下组：4～7元杂单环、或7-20元杂多环(包括稠环、桥环或螺环)；
Figure PCTCN2022116584-appb-000023
The ring is selected from the following group: 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
R 1和R 2选自下组：氢、卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基、和3-12元杂环基； R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclyl;
R 3为位于A环上的1、2、3或4个选自下组的取代基：氢、卤素、氰基、硝基、氨基、胺基、羟基、羟甲基、羧基、巯基、磺酰基、C1-C6烷基、卤素取代的C1-C6烷基、芳基或杂芳环取代的C1-C6烷基、环烷烃或杂环烃取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C3-C8环烷基、C3-C8卤代环烷基、C6-C10芳基、3-12元杂环基、
Figure PCTCN2022116584-appb-000024
Figure PCTCN2022116584-appb-000025
其中，两个相邻的取代基可以与
Figure PCTCN2022116584-appb-000026
环上的原子首尾相连形成并环，或
Figure PCTCN2022116584-appb-000027
环上同一原子上的两个取代基首尾相连与
Figure PCTCN2022116584-appb-000028
环形成螺环；且当A环为哌嗪环时，所述的R 3不为H； R 3 is 1, 2, 3 or 4 substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfo on ring A Acyl, C1-C6 alkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkyl substituted by aryl or heteroaryl ring, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon, C1-C6 alkoxy group, halogen substituted C1-C6 alkoxy group, C3-C8 cycloalkyl group, C3-C8 halocycloalkyl group, C6-C10 aryl group, 3-12 membered heterocyclic group,
Figure PCTCN2022116584-appb-000024
Figure PCTCN2022116584-appb-000025
Among them, two adjacent substituents can be with
Figure PCTCN2022116584-appb-000026
the atoms in the ring are joined end to end to form a combined ring, or
Figure PCTCN2022116584-appb-000027
The two substituents on the same atom on the ring are connected end to end with
Figure PCTCN2022116584-appb-000028
The ring forms a spiro ring; and when the A ring is a piperazine ring, the R 3 is not H;
Figure PCTCN2022116584-appb-000029
环选自下组：4-7元杂单环、或7-20元杂多环(包括稠环、桥环或螺环)；
Figure PCTCN2022116584-appb-000029
The ring is selected from the group consisting of 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
R 4各自独立地选自下组：取代或未取代的苯基、取代或未取代的5-12元杂芳基；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的 C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基、和3-12元杂环基； R 4 are each independently selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution means that one or more hydrogen atoms on the group are selected Replacement by substituents from the following group: halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclyl;
R 5和R 6各自独立地选自下组：氢、卤素、氰基、硝基、氨基、胺基、羟基、羟甲基、羧基、巯基、磺酰基、C1-C6烷基、卤素取代的C1-C6烷基、芳基或杂芳环取代的C1-C6烷基、被C3-C8环烷烃、3-8元杂环烃、7-12元螺杂环烃或9-12元稠杂环烃取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C3-C8环烷基、C3-C8卤代环烷基、C6-C10芳基、3-12元杂环基； R and R are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C1 - C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaromatic substituted C1-C6 alkyl, C3-C8 cycloalkane, 3-8 membered heterocyclic hydrocarbon, 7-12 membered spiro heterocyclic hydrocarbon or 9-12 membered condensed heterocyclic hydrocarbon Cyclohydrocarbon substituted C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halogenated cycloalkyl, C6-C10 aryl, 3 -12 membered heterocyclyl;
其中，所述杂芳环、杂稠环或杂环基各自独立地含有1～4个选自氧、硫和氮中的杂原子；除非特别说明，所述的烷基、烷氧基、烯基、炔基、环烷烃、环烷基、杂环烃、杂环基、芳基、杂芳基各自独立地被1-3个选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基、和3-12元杂环基；Wherein, the heteroaromatic ring, heterofused ring or heterocyclic group each independently contain 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; unless otherwise specified, the alkyl, alkoxy, alkene Base, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclyl, aryl, heteroaryl are each independently substituted by 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl , Halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 Cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic;
所述的卤素为F、Cl、Br或I。The halogen is F, Cl, Br or I.
在再一优选例中，所述的化合物为如表A中所示的化合物。In yet another preferred example, the compounds are those shown in Table A.
Figure PCTCN2022116584-appb-000030
Figure PCTCN2022116584-appb-000030
Figure PCTCN2022116584-appb-000031
Figure PCTCN2022116584-appb-000031
Figure PCTCN2022116584-appb-000032
Figure PCTCN2022116584-appb-000032
Figure PCTCN2022116584-appb-000033
Figure PCTCN2022116584-appb-000033
Figure PCTCN2022116584-appb-000034
Figure PCTCN2022116584-appb-000034
Figure PCTCN2022116584-appb-000035
Figure PCTCN2022116584-appb-000035
Figure PCTCN2022116584-appb-000036
Figure PCTCN2022116584-appb-000036
Figure PCTCN2022116584-appb-000037
Figure PCTCN2022116584-appb-000037
Figure PCTCN2022116584-appb-000038
Figure PCTCN2022116584-appb-000038
Figure PCTCN2022116584-appb-000039
Figure PCTCN2022116584-appb-000039
式I化合物的制备The preparation of formula I compound
本发明还提供了一种通式I表示的化合物的制备方法，该制备方法按照如下方案进行(示例)：The present invention also provides a kind of preparation method of the compound represented by general formula I, and this preparation method is carried out according to the following scheme (example):
路线一：Route 1:
Figure PCTCN2022116584-appb-000040
Figure PCTCN2022116584-appb-000040
步骤a：化合物1溶于有机溶剂，室温下加入HATU、吗啉、DIPEA，反应得化合物2；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；Step a: Compound 1 is dissolved in an organic solvent, and HATU, morpholine, and DIPEA are added at room temperature to react to obtain Compound 2; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol Diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or mixtures thereof;
步骤b:化合物2溶于有机溶剂，加入BH 3-THF配合物，加热搅拌至反应完全，得化合物3；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；加热温度范围为50～80℃； Step b: Dissolve compound 2 in an organic solvent, add BH 3 -THF complex, heat and stir until the reaction is complete, and obtain compound 3; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, Ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or their mixture; the heating temperature range is 50-80°C;
步骤c:化合物3溶于有机溶剂中，加入酸的二氧六环溶液，加热搅拌至反应完全得化合物4；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述酸为盐酸、三氟乙酸、对甲苯磺酸；Step c: Dissolve compound 3 in an organic solvent, add acid dioxane solution, heat and stir until the reaction is complete to obtain compound 4; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether , ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof; the acid is hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid;
步骤d:将化合物4溶于有机溶剂中，加入芳基化合物、三二亚苄基丙酮二钯、2-二环己基磷-2,4,6-三异丙基联苯、一定量碱，加热回流，得中间体5；所述芳基化合物选自取代或未取代的苯、取代或未取代的5-12元杂芳香化合物；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基、和3-12元杂环基；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述碱为醋酸钠、NaOH、KOH、乙醇钠、甲醇钠、碳酸钠、碳酸钾、碳酸铯、三乙胺或二异丙基乙胺；加热温度范围为90～110℃；Step d: dissolving compound 4 in an organic solvent, adding aryl compound, trisdibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heat to reflux to obtain intermediate 5; the aryl compound is selected from substituted or unsubstituted benzene, substituted or unsubstituted 5-12 membered heteroaromatic compounds; wherein, the substitution refers to one or more The hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, Dichloromethane or its mixture; The alkali is sodium acetate, NaOH, KOH, sodium ethylate, sodium methylate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or diisopropylethylamine; the heating temperature range is 90～ 110°C;
步骤e:将酸溶于有机溶剂中，加入一定量碱、缩合剂，在室温条件下滴加中间体5的溶液，得化合物6；所述酸选自
Figure PCTCN2022116584-appb-000041
其中X可独立选自C或N；R 1和R 2选自下组：氢、卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基、和3-12元杂环基；所述缩合剂为HATU或CMPI；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合 物；所述碱为醋酸钠、NaOH、KOH、乙醇钠、甲醇钠、碳酸钠、碳酸钾、三乙胺或二异丙基乙胺。 Step e: dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 5 at room temperature to obtain compound 6; the acid is selected from
Figure PCTCN2022116584-appb-000041
Wherein X can be independently selected from C or N; R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups; the condensing agent is HATU or CMPI; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, Ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or mixtures thereof; the base is sodium acetate, NaOH, KOH, sodium ethoxide, sodium methoxide, sodium carbonate, potassium carbonate, tris ethylamine or diisopropylethylamine.
路线二：Route two:
Figure PCTCN2022116584-appb-000042
Figure PCTCN2022116584-appb-000042
步骤f:将化合物1溶于有机溶剂中，加入芳基化合物、三二亚苄基丙酮二钯、2-二环己基磷-2,4,6-三异丙基联苯、一定量碱，加热回流，得中间体2；所述芳基化合物选自取代或未取代的苯基、取代或未取代的5-12元杂芳基；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基、和3-12元杂环基；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述碱为醋酸钠、NaOH、KOH、乙醇钠、甲醇钠、碳酸钠、碳酸钾、碳酸铯、三乙胺或二异丙基乙胺；加热温度范围为90～110℃；Step f: dissolving compound 1 in an organic solvent, adding aryl compound, trisdibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heating to reflux to obtain intermediate 2; the aryl compound is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution refers to one or more on the group Each hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl , and 3-12 membered heterocyclic groups; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate , methylene chloride or a mixture thereof; the alkali is sodium acetate, NaOH, KOH, sodium ethylate, sodium methylate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or diisopropylethylamine; the heating temperature range is 90 ~110°C;
步骤g:将化合物2溶于有机溶剂中并在0℃搅拌条件下缓慢加入酸,反应液在室温下搅拌反应1小时待反应完毕后浓缩，剩余物溶于100mL乙酸乙酯中并用饱和碳酸钠溶液洗涤并调节PH至8-9，随后依次用饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩即得到黄色油状物即为中间体3。所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述酸为三氟乙酸、三氟甲磺酸或者盐酸。Step g: Dissolve compound 2 in an organic solvent and slowly add acid under stirring at 0°C. The reaction solution is stirred and reacted at room temperature for 1 hour. After the reaction is complete, it is concentrated. The residue is dissolved in 100 mL of ethyl acetate and washed with saturated sodium carbonate The solution was washed and the pH was adjusted to 8-9, followed by washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance which was Intermediate 3. The organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof; The acid is trifluoroacetic acid, trifluoromethanesulfonic acid or hydrochloric acid.
步骤h:将酸溶于有机溶剂中，加入一定量碱、缩合剂，在室温条件下滴加中间体3的溶液，得化合物4；所述酸选自
Figure PCTCN2022116584-appb-000043
其中X可独立选自C或N；R 1和R 2选自下组：氢、卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基、和3-12元杂环基；所述缩合剂为HATU或CMPI；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述碱为醋酸钠、NaOH、KOH、乙醇钠、甲醇钠、碳酸钠、碳酸钾、三乙胺或二异丙基乙胺。 Step h: dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 3 at room temperature to obtain compound 4; the acid is selected from
Figure PCTCN2022116584-appb-000043
Wherein X can be independently selected from C or N; R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups; the condensing agent is HATU or CMPI; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, Ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or mixtures thereof; the base is sodium acetate, NaOH, KOH, sodium ethoxide, sodium methoxide, sodium carbonate, potassium carbonate, tris ethylamine or diisopropylethylamine.
路线三：Route three:
Figure PCTCN2022116584-appb-000044
Figure PCTCN2022116584-appb-000044
步骤i:在圆底烧瓶中装入N-(叔丁氧羰基)-3-环己基-L-丙氨酸，缩合剂，甘氨酸甲酯盐酸盐)和DMF。向其中添加DIPEA。在室温下搅拌5分钟后，将混合物用水稀释，并用乙醚萃取。分离各层，并将有机相用水和盐水洗涤，硫酸镁干燥，浓缩，得到N-(叔丁氧基羰基)-3-环己基-L-丙氨酰甘氨酸甲酯，浓缩物为黄色油状物，直接用于下一步。所述缩合剂为HATU或CMPI。Step i: Charge N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanine, condensing agent, glycine methyl ester hydrochloride) and DMF in a round bottom flask. Add DIPEA to it. After stirring at room temperature for 5 minutes, the mixture was diluted with water and extracted with ether. The layers were separated and the organic phase was washed with water and brine, dried over magnesium sulfate and concentrated to give N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanylglycine methyl ester as a yellow oil on concentrate , used directly in the next step. The condensing agent is HATU or CMPI.
步骤j和k:在圆底烧瓶中装入N-(叔丁氧基羰基)-3-环己基-L-丙氨酰甘氨酸甲酯，DCM和TFA。30分钟后，将混合物浓缩，然后重新溶于2M氨的MeOH溶液中并在室温下搅拌过夜，白色沉淀物析出，过滤收集形成的产物，得到(3S)-3(环己基甲基)-2，5-哌嗪二酮。Steps j and k: A round bottom flask was charged with N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanylglycine methyl ester, DCM and TFA. After 30 minutes, the mixture was concentrated, then redissolved in 2M ammonia in MeOH and stirred overnight at room temperature, a white precipitate precipitated and the product formed was collected by filtration to give (3S)-3(cyclohexylmethyl)-2 , 5-piperazinedione.
步骤l:在圆底烧瓶中装入(3S)-3-(环己基甲基)-2,5-哌嗪二酮，有机溶剂和氢化铝锂。加热至70℃过夜后，将混合物冷却至室温，缓慢加入十水合硫酸钠。搅拌1小时后，将混合物过滤，并浓缩滤液，得到(2S)-2-(环己基甲基)哌嗪，为无色油状物，将其粗品用于下一步反应。所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物。Step 1: Charge (3S)-3-(cyclohexylmethyl)-2,5-piperazinedione, an organic solvent and lithium aluminum hydride in a round bottom flask. After heating to 70°C overnight, the mixture was cooled to room temperature and sodium sulfate decahydrate was added slowly. After stirring for 1 hour, the mixture was filtered, and the filtrate was concentrated to give (2S)-2-(cyclohexylmethyl)piperazine as a colorless oil, which was used crude for the next reaction. The organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof.
步骤m:将化合物5溶于有机溶剂中，加入芳基化合物、三二亚苄基丙酮二钯、2-二环己基磷-2,4,6-三异丙基联苯、一定量碱，加热回流，得中间体6；所述芳基化合物选自取代或未取代的苯基、取代或未取代的5-12元杂芳基；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基、和3-12元杂环基；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述碱为醋酸钠、NaOH、KOH、乙醇钠、甲醇钠、碳酸钠、碳酸钾、碳酸铯、三乙胺或二异丙基乙胺；加热温度范围为90～110℃；Step m: dissolving compound 5 in an organic solvent, adding aryl compound, trisdibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heating to reflux to obtain intermediate 6; the aryl compound is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution refers to one or more Each hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl , and 3-12 membered heterocyclic groups; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate , methylene chloride or a mixture thereof; the alkali is sodium acetate, NaOH, KOH, sodium ethylate, sodium methylate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or diisopropylethylamine; the heating temperature range is 90 ~110°C;
步骤n:将酸溶于有机溶剂中，加入一定量碱、缩合剂，在室温条件下滴加中间体6的溶液，得化合物7；所述酸选自
Figure PCTCN2022116584-appb-000045
其中X可独立选自C或N；R 1和R 2选自下组：氢、卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基、和3-12元杂环基；所 述缩合剂为HATU或CMPI；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述碱为醋酸钠、NaOH、KOH、乙醇钠、甲醇钠、碳酸钠、碳酸钾、三乙胺或二异丙基乙胺。 Step n: dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 6 at room temperature to obtain compound 7; the acid is selected from
Figure PCTCN2022116584-appb-000045
Wherein X can be independently selected from C or N; R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups; the condensing agent is HATU or CMPI; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, Ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or mixtures thereof; the base is sodium acetate, NaOH, KOH, sodium ethoxide, sodium methoxide, sodium carbonate, potassium carbonate, tris ethylamine or diisopropylethylamine.
路线四：Route 4:
Figure PCTCN2022116584-appb-000046
Figure PCTCN2022116584-appb-000046
步骤o:将化合物1溶于有机溶剂中，加入芳基化合物、三二亚苄基丙酮二钯、2-二环己基磷-2,4,6-三异丙基联苯、一定量碱，加热回流，得中间体2；所述芳基化合物选自取代或未取代的苯基、取代或未取代的5-12元杂芳基；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基、和3-12元杂环基；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述碱为醋酸钠、NaOH、KOH、乙醇钠、甲醇钠、碳酸钠、碳酸钾、碳酸铯、三乙胺或二异丙基乙胺；加热温度范围为90～110℃；Step o: dissolving compound 1 in an organic solvent, adding aryl compound, tridibenzylideneacetone dipalladium, 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl, and a certain amount of base, Heating to reflux to obtain intermediate 2; the aryl compound is selected from substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution refers to one or more on the group Each hydrogen atom is replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C6-C10 aryl , and 3-12 membered heterocyclic groups; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate , methylene chloride or a mixture thereof; the alkali is sodium acetate, NaOH, KOH, sodium ethylate, sodium methylate, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or diisopropylethylamine; the heating temperature range is 90 ~110°C;
步骤p:将化合物2溶于有机溶剂中并在0℃搅拌条件下缓慢加入酸,反应液在室温下搅拌反应1小时待反应完毕后浓缩，剩余物溶于100mL乙酸乙酯中并用饱和碳酸钠溶液洗涤并调节PH至8-9，随后依次用饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩即得到黄色油状物即为中间体3。所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述酸为三氟乙酸、三氟甲磺酸或者盐酸。Step p: Dissolve compound 2 in an organic solvent and slowly add acid under stirring conditions at 0°C. The reaction solution is stirred and reacted at room temperature for 1 hour. After the reaction is completed, it is concentrated. The residue is dissolved in 100 mL of ethyl acetate and washed with saturated sodium carbonate The solution was washed and the pH was adjusted to 8-9, followed by washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance which was Intermediate 3. The organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, dichloromethane or a mixture thereof; The acid is trifluoroacetic acid, trifluoromethanesulfonic acid or hydrochloric acid.
步骤q:将酸溶于有机溶剂中，加入一定量碱、缩合剂，在室温条件下滴加中间体3的溶液，得化合物4；所述酸选自
Figure PCTCN2022116584-appb-000047
其中X可独立选自C或N；R 1和R 2选自下组：氢、卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝 基、氨基、羟基、羟甲基、羧基、巯基、磺酰基、C6-C10芳基、和3-12元杂环基；所述缩合剂为HATU或CMPI；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述碱为醋酸钠、NaOH、KOH、乙醇钠、甲醇钠、碳酸钠、碳酸钾、三乙胺或二异丙基乙胺； Step q: dissolve the acid in an organic solvent, add a certain amount of base and condensing agent, and drop the solution of intermediate 3 at room temperature to obtain compound 4; the acid is selected from
Figure PCTCN2022116584-appb-000047
Wherein X can be independently selected from C or N; R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkane Oxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , sulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups; the condensing agent is HATU or CMPI; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, Ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, methylene chloride or a mixture thereof; the base is sodium acetate, NaOH, KOH, sodium ethoxide, sodium methoxide, sodium carbonate, potassium carbonate, tris Ethylamine or diisopropylethylamine;
步骤r:将化合物4溶于适量THF/H 2O的混合溶剂，加入氢氧化钾，回流下搅拌反应二小时，待反应完毕后旋干溶剂，使用盐酸调节PH至酸性，观察到有固体析出，抽滤收集固体即为中间体5。 Step r: Dissolve compound 4 in an appropriate amount of THF/H 2 O mixed solvent, add potassium hydroxide, stir and react under reflux for two hours, spin the solvent after the reaction is completed, adjust the pH to acidic with hydrochloric acid, and observe that there is solid precipitation , and the solid collected by suction filtration is Intermediate 5.
步骤s:将中间体5溶于有机溶剂中，加入一定量碱、缩合剂和胺，得化合物6；R 5和R 6可独自选自下组：氢、卤素、氰基、硝基、氨基、胺基、羟基、羟甲基、羧基、巯基、磺酰基、C1-C6烷基、卤素取代的C1-C6烷基、芳基或杂芳环取代的C1-C6烷基、环烷烃或杂环烃取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C3-C8环烷基、C3-C8卤代环烷基、C6-C10芳基、3-12元杂环基。所述缩合剂为HATU或CMPI；所述有机溶剂为四氢呋喃、乙醚、二甲基甲酰胺、乙二醇二甲醚、乙二醇二乙醚、二氧六环、乙醇、甲醇、乙酸乙酯、二氯甲烷或其混合物；所述碱为醋酸钠、NaOH、KOH、乙醇钠、甲醇钠、碳酸钠、碳酸钾、三乙胺或二异丙基乙胺。 Step s: Dissolving intermediate 5 in an organic solvent, adding a certain amount of base, condensing agent and amine to obtain compound 6; R5 and R6 can be independently selected from the following group: hydrogen, halogen, cyano, nitro, amino , amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, sulfonyl, C1-C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaromatic substituted C1-C6 alkyl, cycloalkane or hetero Cyclohydrocarbon substituted C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halogenated cycloalkyl, C6-C10 aryl, 3 -12 membered heterocyclyl. The condensing agent is HATU or CMPI; the organic solvent is tetrahydrofuran, ether, dimethylformamide, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, ethanol, methanol, ethyl acetate, Dichloromethane or a mixture thereof; the base is sodium acetate, NaOH, KOH, sodium ethoxide, sodium methoxide, sodium carbonate, potassium carbonate, triethylamine or diisopropylethylamine.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
由于本发明化合物具有优异的3CL蛋白酶抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与3CL蛋白酶相关的疾病，特别是用于治疗存在3CL蛋白酶的病毒性疾病，如由SARS-CoV-2、SARS-CoV、MERS-CoV、诺如病毒等引发的疾病。Since the compound of the present invention has excellent 3CL protease inhibitory activity, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the compound of the present invention as the main active ingredient The pharmaceutical composition can be used for the treatment, prevention and alleviation of diseases related to 3CL protease, especially for the treatment of viral diseases with 3CL protease, such as SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, etc. caused diseases.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-3000(活性剂量范围3-30mg/kg)mg本发明化合物/剂，更佳地，含有10-2000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. Wherein, "safe and effective dose" refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. Usually, the pharmaceutical composition contains 1-3000 mg (active dose range 3-30 mg/kg) of the compound of the present invention per dose, more preferably 10-2000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2022116584-appb-000048
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween
Figure PCTCN2022116584-appb-000048
), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某 些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选6～600mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is usually 1-2000 mg, preferably 6-600 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。本发明中用到的起始原料未经特别说明，均为商业购买。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated. The starting materials used in the present invention are purchased commercially without special description.
实施例1 4-(4-(3,4-二氯苯基)-3-甲基哌嗪-1-羰基)喹啉-2(1H)-酮(1)Example 1 4-(4-(3,4-dichlorophenyl)-3-methylpiperazine-1-carbonyl)quinolin-2(1H)-one (1)
1.1 4-(3,4-二氯苯基)-3-甲基哌嗪-1-羧酸叔丁酯1.1 tert-butyl 4-(3,4-dichlorophenyl)-3-methylpiperazine-1-carboxylate
氩气保护下，将1-Boc-3-甲基哌嗪(1g，5.37mmol)与3,4-二氯溴苯(1.33g,5.91mmol)溶于20mL甲苯中，随后加入三二亚苄基丙酮二钯(Pd 2dba 3,184.6mg,0.2mmol)，2-二环己基磷-2,4,6-三异丙基联苯(X-Phos,238.1mg,0.5mmol)和碳酸铯(3.26g,10mmol)，将反应液升温至110℃下搅拌反应过夜，待反应完毕后冷却至室温并用硅藻土过滤，滤饼用乙酸乙酯洗涤。收集滤液加50mL水稀释并用40mL乙酸乙酯萃取2次，随后合并有机相依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥并浓缩旋干得 棕黄色油状物，将油状物以石油醚/乙酸乙酯＝10:1作为洗脱剂进行柱色谱分离得无色固体(1.06g,产率60％)。 Under the protection of argon, 1-Boc-3-methylpiperazine (1g, 5.37mmol) and 3,4-dichlorobromobenzene (1.33g, 5.91mmol) were dissolved in 20mL of toluene, and then tribenzylidene was added Dipalladium acetone (Pd 2 dba 3 , 184.6mg, 0.2mmol), 2-dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl (X-Phos, 238.1mg, 0.5mmol) and cesium carbonate (3.26g, 10mmol), the temperature of the reaction solution was raised to 110°C and the reaction was stirred overnight. After the reaction was completed, it was cooled to room temperature and filtered with diatomaceous earth, and the filter cake was washed with ethyl acetate. The collected filtrate was diluted with 50 mL of water and extracted twice with 40 mL of ethyl acetate, then the combined organic phases were successively washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brownish-yellow oil, which was washed with petroleum ether/ Ethyl acetate=10:1 was used as the eluent for column chromatography to obtain a colorless solid (1.06 g, yield 60%).
1.2 1-(3,4-二氯苯基)-3-甲基哌嗪1.2 1-(3,4-dichlorophenyl)-3-methylpiperazine
将4-(3,4-二氯苯基)-3-甲基哌嗪-1-羧酸叔丁酯(1g,3.02mmol)溶于15mL二氯甲烷中并在0℃搅拌条件下缓慢加入15mL的三氟乙酸,反应液在室温下搅拌反应1小时待反应完毕后浓缩，剩余物溶于100mL乙酸乙酯中并用饱和碳酸钠溶液洗涤并调节PH至8-9，随后依次用饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩即得到黄色油状物即为1-(3,4-二氯苯基)-3-甲基哌嗪(628mg,产率90％)。Dissolve tert-butyl 4-(3,4-dichlorophenyl)-3-methylpiperazine-1-carboxylate (1g, 3.02mmol) in 15mL of dichloromethane and add slowly under stirring at 0°C 15mL of trifluoroacetic acid, the reaction solution was stirred at room temperature for 1 hour and concentrated after the reaction was completed. The residue was dissolved in 100mL of ethyl acetate and washed with saturated sodium carbonate solution to adjust the pH to 8-9, followed by saturated chlorination It was washed with sodium solution, dried over anhydrous sodium sulfate, and concentrated to obtain a yellow oily substance which was 1-(3,4-dichlorophenyl)-3-methylpiperazine (628 mg, yield 90%).
1.3终产物1的合成1.3 Synthesis of final product 1
将1-(3,4-二氯苯基)-3-甲基哌嗪(628mg,2.72mmol)溶于20ml DMF，加入2-羟基喹啉-4-甲酸(565mg,2.99mmol),2-氯-1-甲基吡啶碘化物(CMPI,800mg,3.13mmol),DIPEA(675mg,5.22mmol)，室温下搅拌反应一小时，待反应完毕后加入过量的水，用乙酸乙酯萃取三次，合并有机相，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥并浓缩旋干得棕黄色油状物，将油状物以二氯甲烷/甲醇＝20:1作为洗脱剂进行柱色谱分离得黄色固体即为化合物1(546mg,产率50％)。LRMS(ESI)m/z 417(M+)Dissolve 1-(3,4-dichlorophenyl)-3-methylpiperazine (628mg, 2.72mmol) in 20ml DMF, add 2-hydroxyquinoline-4-carboxylic acid (565mg, 2.99mmol), 2- Chloro-1-picoline iodide (CMPI, 800mg, 3.13mmol), DIPEA (675mg, 5.22mmol), stirred and reacted at room temperature for one hour, after the reaction was completed, an excess of water was added, extracted three times with ethyl acetate, combined The organic phase was washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brownish-yellow oil, which was separated by column chromatography using dichloromethane/methanol=20:1 as the eluent to obtain a yellow The solid was compound 1 (546 mg, yield 50%). LRMS(ESI)m/z 417(M+)
实施例2 4-(4-(3,4-二氯苯基)-3-乙基哌嗪-1-羰基)喹啉-2(1H)-酮的制备(2)Example 2 Preparation of 4-(4-(3,4-dichlorophenyl)-3-ethylpiperazine-1-carbonyl)quinolin-2(1H)-one (2)
将1-Boc-3-甲基哌嗪替换成3-乙基哌嗪-1-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物2。LRMS(ESI)m/z 431(M+)1-Boc-3-methylpiperazine was replaced by 3-ethylpiperazine-1-tert-butyl carboxylate, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 2. LRMS(ESI)m/z 431(M+)
实施例3 4-(4-(3,4-二氯苯基)-3-丙基哌嗪-1-羰基)喹啉-2(1H)-酮的制备(3)Example 3 Preparation of 4-(4-(3,4-dichlorophenyl)-3-propylpiperazine-1-carbonyl)quinolin-2(1H)-one (3)
将1-Boc-3-甲基哌嗪替换成3-丙基哌嗪-1-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物3。LRMS(ESI)m/z 445(M+)1-Boc-3-methylpiperazine was replaced by 3-propylpiperazine-1-tert-butyl carboxylate, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 3. LRMS(ESI)m/z 445(M+)
实施例4 4-(4-(3,4-二氯苯基)-3-丁基哌嗪-1-羰基)喹啉-2(1H)-酮的制备(4)Example 4 Preparation of 4-(4-(3,4-dichlorophenyl)-3-butylpiperazine-1-carbonyl)quinolin-2(1H)-one (4)
将1-Boc-3-甲基哌嗪替换成3-丁基哌嗪-1-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物4。LRMS(ESI)m/z 459(M+)1-Boc-3-methylpiperazine was replaced by 3-butylpiperazine-1-tert-butyl carboxylate, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 4. LRMS(ESI)m/z 459(M+)
实施例5 4-(4-(3,4-二氯苯基)-2-(吗啉代甲基)哌嗪-1-羰基)喹啉-2(1H)-酮的制备(5)Example 5 Preparation of 4-(4-(3,4-dichlorophenyl)-2-(morpholinomethyl)piperazine-1-carbonyl)quinolin-2(1H)-one (5)
5.1 2-(吗啉-4-羰基)哌嗪-1,4-二羧酸二叔丁酯5.1 Di-tert-butyl 2-(morpholine-4-carbonyl)piperazine-1,4-dicarboxylate
在1L圆底烧瓶中装入吗啉(2.9g，33.3mmol)，HATU(12.7g，33.3mmol)，1,4-双(叔丁氧羰基)哌嗪-2-羧酸(10.0g，30.3mmol)和DMF。向其中添加DIPEA(7.8g，60.6mmol)。在室温搅拌1h后，将混合物用水稀释，然后用乙醚萃取。分离有机层，用水，饱和NaHCO  3水溶液，盐水洗涤，用MgSO  4干燥，过滤并浓缩，得到2-(吗啉-4-羰基)哌嗪-1,4-二羧酸二叔丁酯(10.9g,产率90％)，为白色固体。 Morpholine (2.9g, 33.3mmol), HATU (12.7g, 33.3mmol), 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (10.0g, 30.3 mmol) and DMF. To this was added DIPEA (7.8 g, 60.6 mmol). After stirring at room temperature for 1 h, the mixture was diluted with water and extracted with ether. The organic layer was separated, washed with water, saturated aqueous NaHCO 3 , brine, dried over MgSO 4 , filtered and concentrated to give di-tert-butyl 2-(morpholine-4-carbonyl)piperazine-1,4-dicarboxylate (10.9 g, yield 90%), as a white solid.
5.2 4-(哌嗪-2-基甲基)吗啉5.2 4-(piperazin-2-ylmethyl)morpholine
在1L的圆底烧瓶中装入2-(吗啉-4-羰基)哌嗪-1,4-二羧酸二叔丁酯(10.9g，30mmol)和100mL THF，向其中加入BH 3-THF配合物(1M，120mL，120mmol)。加热至50℃保持2小时，然后冷却到0℃，用甲醇缓慢淬灭。将混合物真空浓缩，然后用200mL EtOAc稀释。向其中加入40mL 4N HCl的二氧六环溶液。将混合物在70℃搅拌2.5小时，然后过滤收集得到的白色沉淀物，为7-4的盐酸盐。将该盐酸盐溶于适量乙酸乙酯中并用饱和碳酸钠溶液洗涤并调节PH至8-9，使用乙酸乙酯萃取多次， 直至水相中不再残留产物，随后合并有机相，用无水硫酸钠干燥并浓缩旋干得无色油状物，即为化合物7-4(4g,产率72％)。 Charge 2-(morpholine-4-carbonyl)piperazine-1,4-dicarboxylate di-tert-butyl ester (10.9 g, 30 mmol) and 100 mL THF in a 1 L round bottom flask, add BH 3 -THF Complex (1M, 120 mL, 120 mmol). Heat to 50°C for 2 hours, then cool to 0°C and slowly quench with methanol. The mixture was concentrated in vacuo, then diluted with 200 mL EtOAc. To this was added 40 mL of 4N HCl in dioxane. The mixture was stirred at 70°C for 2.5 hours, then the resulting white precipitate was collected by filtration as the hydrochloride salt of 7-4. The hydrochloride was dissolved in an appropriate amount of ethyl acetate and washed with saturated sodium carbonate solution to adjust the pH to 8-9, and extracted several times with ethyl acetate until no product remained in the aqueous phase, then the organic phases were combined and used without Dried over sodium sulfate, concentrated and spin-dried to obtain a colorless oily substance, compound 7-4 (4 g, yield 72%).
5.3 4-((4-(3,4-二氯苯基)哌嗪-2-基)甲基)吗啉5.3 4-((4-(3,4-dichlorophenyl)piperazin-2-yl)methyl)morpholine
氩气保护下，将4-(哌嗪-2-基甲基)吗啉(1g,5.4mmol)与3,4-二氯溴苯(1.34g,5.94mmol)溶于20mL甲苯中，随后加入三二亚苄基丙酮二钯(Pd 2dba 3,203.0mg,0.22mmol)，2-二环己基磷-2,4,6-三异丙基联苯(X-Phos,238.1mg,0.5mmol)和碳酸铯(3.26g,10mmol)，将反应液升温至110℃下搅拌反应过夜，待反应完毕后冷却至室温并用硅藻土过滤，滤饼用乙酸乙酯洗涤。收集滤液加50mL水稀释并用40mL乙酸乙酯萃取2次，随后合并有机相依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥并浓缩旋干得棕黄色油状物，将油状物以二氯甲烷/甲醇＝20:1作为洗脱剂进行柱色谱分离得黄色油状物即为化合物7-5(1.07g,产率60％)。 Under argon protection, 4-(piperazin-2-ylmethyl)morpholine (1g, 5.4mmol) and 3,4-dichlorobromobenzene (1.34g, 5.94mmol) were dissolved in 20mL of toluene, and then added Trisdibenzylideneacetone dipalladium (Pd 2 dba 3 , 203.0mg, 0.22mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (X-Phos, 238.1mg, 0.5mmol ) and cesium carbonate (3.26g, 10mmol), the reaction solution was heated to 110°C and stirred overnight. After the reaction was completed, it was cooled to room temperature and filtered with diatomaceous earth, and the filter cake was washed with ethyl acetate. The collected filtrate was diluted with 50 mL of water and extracted twice with 40 mL of ethyl acetate, then the combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brownish-yellow oil, which was washed with dichloromethane /methanol=20:1 was used as the eluent for column chromatography to obtain a yellow oily substance which was compound 7-5 (1.07 g, yield 60%).
5.4终产物5的合成5.4 Synthesis of final product 5
将4-((4-(3,4-二氯苯基)哌嗪-2-基)甲基)吗啉(1.07g,3.24mmol)溶于20ml DMF，加入2-羟基喹啉-4-甲酸(674mg,3.56mmol),2-氯-1-甲基吡啶碘化物(CMPI,910mg,3.56mmol),DIPEA(838mg,6.48mmol)，室温下搅拌反应一小时，待反应完毕后加入过量的水，用乙酸乙酯萃取三次，合并有机相，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥并浓缩旋干得棕黄色油状物，将油状物以二氯甲烷/甲醇＝20:1作为洗脱剂进行柱色谱分离得黄色固体即为化合物JZD-07(812mg,产率50％)。 1H NMR(600MHz,CDCl3)δ12.62(s,1H),7.55(d,J＝51.0Hz,4H),7.21(s,1H),6.95(s,1H),6.69(d,J＝49.9Hz,2H),5.17(d,J＝39.8Hz,1H),3.73(m,6H),3.40(d,J＝30.8Hz,3H),3.07(dd,J＝61.9,30.7Hz,2H),2.75(d,J＝22.4Hz,1H),2.44(d,J＝114.0Hz,4H).LRMS(ESI)m/z 501(M+) Dissolve 4-((4-(3,4-dichlorophenyl)piperazin-2-yl)methyl)morpholine (1.07g, 3.24mmol) in 20ml DMF, add 2-hydroxyquinoline-4- Formic acid (674mg, 3.56mmol), 2-chloro-1-picoline iodide (CMPI, 910mg, 3.56mmol), DIPEA (838mg, 6.48mmol), stirred at room temperature for one hour, after the reaction was completed, an excess of water, extracted three times with ethyl acetate, the organic phases were combined, washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brownish-yellow oil, which was dichloromethane/methanol=20:1 The yellow solid was separated by column chromatography as eluent, which was compound JZD-07 (812 mg, yield 50%). 1 H NMR (600MHz, CDCl3) δ12.62(s,1H),7.55(d,J=51.0Hz,4H),7.21(s,1H),6.95(s,1H),6.69(d,J=49.9 Hz,2H),5.17(d,J=39.8Hz,1H),3.73(m,6H),3.40(d,J=30.8Hz,3H),3.07(dd,J=61.9,30.7Hz,2H), 2.75(d,J=22.4Hz,1H),2.44(d,J=114.0Hz,4H).LRMS(ESI)m/z 501(M+)
实施例6 4-(4-(3,4-二氯苯基)-2-(吗啉代甲基)哌嗪-1-羰基)-6-甲基喹啉-2(1H)-酮的制备(6)Example 6 4-(4-(3,4-dichlorophenyl)-2-(morpholinomethyl)piperazine-1-carbonyl)-6-methylquinolin-2(1H)-one Preparation (6)
将2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例5，得产物6。LRMS(ESI)m/z 515(M+)Replace 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, the rest of the required raw materials, reagents and The preparation method was the same as in Example 5 to obtain product 6. LRMS(ESI)m/z 515(M+)
实施例7 6-溴-4-(4-(4-(3,4-二氯苯基)-2-(吗啉代甲基)哌嗪-1-羰基)喹啉-2(1H)-酮的制备(7)Example 7 6-bromo-4-(4-(4-(3,4-dichlorophenyl)-2-(morpholinomethyl)piperazine-1-carbonyl)quinoline-2(1H)- Preparation of ketones (7)
将2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧代-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例5，得产物7。LRMS(ESI)m/z 579(M+)Replace 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-bromo-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, the remaining raw materials, reagents and The preparation method was the same as in Example 5 to obtain product 7. LRMS(ESI)m/z 579(M+)
实施例8 4-(4-(3,4-二氯苯基)-2-(吗啉代甲基)哌嗪-1-羰基)-6-羟基喹啉-2(1H)-酮制备(8)Example 8 Preparation of 4-(4-(3,4-dichlorophenyl)-2-(morpholinomethyl)piperazine-1-carbonyl)-6-hydroxyquinolin-2(1H)-one ( 8)
将2-氧-1,2-二氢喹啉-4-羧酸替换成6-羟基-2-氧代-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例5，得产物8。LRMS(ESI)m/z 517(M+)Replace 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-hydroxy-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, the rest of the required raw materials, reagents and The preparation method was the same as in Example 5 to obtain product 8. LRMS(ESI)m/z 517(M+)
实施例9 4-(4-(3,4-二氟苯基)-2-(吗啉代甲基)哌嗪-1-羰基)喹啉-2(1H)-酮(9)Example 9 4-(4-(3,4-difluorophenyl)-2-(morpholinomethyl)piperazine-1-carbonyl)quinolin-2(1H)-one (9)
将3,4-二氯溴苯替换成3,4-二氟溴苯，其余所需原料、试剂及制备方法同实施例5，得产物9。LRMS(ESI)m/z 469(M+)Replace 3,4-dichlorobromobenzene with 3,4-difluorobromobenzene, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 5 to obtain product 9. LRMS(ESI)m/z 469(M+)
实施例10 4-(4-(3,4-二氟苯基)-2-(吗啉代甲基)哌嗪-1-羰基)-6-甲基喹啉-2(1H)-酮(10)Example 10 4-(4-(3,4-difluorophenyl)-2-(morpholinomethyl)piperazine-1-carbonyl)-6-methylquinolin-2(1H)-one ( 10)
将3,4-二氯溴苯替换成3,4-二氟溴苯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸,其余所需原料、试剂及制备方法同实施例5，得产物10。LRMS(ESI)m/z 483(M+)Replace 3,4-dichlorobromobenzene with 3,4-difluorobromobenzene, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-methyl-2-oxo-1, 2-dihydroquinoline-4-carboxylic acid, the rest of the required raw materials, reagents and preparation methods are the same as in Example 5 to obtain the product 10. LRMS(ESI)m/z 483(M+)
实施例11 4-(4-(3,4-二氯苯基)-2-(吗啉代甲基)哌嗪-1-羰基)-1,8-萘啶-2(1H)-酮(11)Example 11 4-(4-(3,4-dichlorophenyl)-2-(morpholinomethyl)piperazine-1-carbonyl)-1,8-naphthyridin-2(1H)-one ( 11)
将2-氧-1,2-二氢喹啉-4-羧酸替换成2-氧-1,2-二氢-1,8-萘啶-4-羧酸,其余所需原料、试剂及制备方法同实施例5，得产物11。LRMS(ESI)m/z 502(M+)Replace 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 2-oxo-1,2-dihydro-1,8-naphthyridine-4-carboxylic acid, the remaining raw materials, reagents and The preparation method was the same as in Example 5 to obtain product 11. LRMS(ESI)m/z 502(M+)
实施例12 4-(4-(3,4-二氯苯基)-3-异丙基哌嗪-1-羰基)喹啉-2(1H)-酮(12)Example 12 4-(4-(3,4-dichlorophenyl)-3-isopropylpiperazine-1-carbonyl)quinolin-2(1H)-one (12)
将1-Boc-3-甲基哌嗪替换成3-异丙基哌嗪-1-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物12。LRMS(ESI)m/z 444(M+)1-Boc-3-methylpiperazine was replaced by 3-isopropylpiperazine-1-tert-butyl carboxylate, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 12. LRMS(ESI)m/z 444(M+)
实施例13 4-(8-(3,4-二氯苯基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)喹啉-2(1H)-酮(13)Example 13 4-(8-(3,4-dichlorophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)quinolin-2(1H)-one (13 )
将1-Boc-3-甲基哌嗪替换成3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物13。LRMS(ESI)m/z 428(M+)Replace 1-Boc-3-methylpiperazine with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 , the product 13 was obtained. LRMS(ESI)m/z 428(M+)
实施例14 4-(4-(3,4-二氯苯基)-2-(吗啉-4-羰基)哌嗪-1-羰基)喹啉-2(1H)-酮(14)Example 14 4-(4-(3,4-dichlorophenyl)-2-(morpholine-4-carbonyl)piperazine-1-carbonyl)quinolin-2(1H)-one (14)
14.1 1-(叔丁基)2-甲基4-(3,4-二氯苯基)哌嗪-1,2-二羧酸酯14.1 1-(tert-butyl) 2-methyl 4-(3,4-dichlorophenyl)piperazine-1,2-dicarboxylate
氩气保护下，将1-(叔丁基)2-甲基哌嗪-1,2-二羧酸酯(13-1)(1g，4.1mmol)与3,4-二氯溴苯(1.0g,4.5mmol)溶于20mL甲苯中，随后加入三二亚苄基丙酮二钯(Pd 2dba 3,151mg,0.16mmol)，2-二环己基磷-2,4,6-三异丙基联苯(X-Phos,190.5mg,0.4mmol)和碳酸铯(2.61g,8mmol)，将反应液升温至110℃下搅拌反应过夜，待反应完毕后冷却至室温并用硅藻土过滤，滤饼用乙酸乙酯洗涤。收集滤液加50mL水稀释并用40mL乙酸乙酯萃取2次，随后合并有机相依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥并浓缩旋干得棕黄色油状物，将油状物以石油醚/乙酸乙酯＝10:1作为洗脱剂进行柱色谱分离得无色固体即为化合物13-2(1.1g,产率68％)。 Under argon protection, 1-(tert-butyl) 2-methylpiperazine-1,2-dicarboxylate (13-1) (1g, 4.1mmol) and 3,4-dichlorobromobenzene (1.0 g, 4.5mmol) was dissolved in 20mL of toluene, followed by addition of tridibenzylideneacetone dipalladium (Pd 2 dba 3 , 151mg, 0.16mmol), 2-dicyclohexylphosphine-2,4,6-triisopropyl Biphenyl (X-Phos, 190.5mg, 0.4mmol) and cesium carbonate (2.61g, 8mmol), the temperature of the reaction solution was raised to 110°C and the reaction was stirred overnight. After the reaction was completed, it was cooled to room temperature and filtered with diatomaceous earth. The filter cake Wash with ethyl acetate. The collected filtrate was diluted with 50 mL of water and extracted twice with 40 mL of ethyl acetate, then the combined organic phases were successively washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brownish-yellow oil, which was washed with petroleum ether/ Ethyl acetate=10:1 was used as the eluent for column chromatography to obtain a colorless solid which was compound 13-2 (1.1 g, yield 68%).
14.2 4-(3,4-二氯苯基)哌嗪-2-羧酸甲酯14.2 Methyl 4-(3,4-dichlorophenyl)piperazine-2-carboxylate
将1-(叔丁基)2-甲基4-(3,4-二氯苯基)哌嗪-1,2-二羧酸酯(1.1g,2.82mmol)溶于15mL二氯甲烷中并在0℃搅拌条件下缓慢加入15mL的三氟乙酸,反应液在室温下搅拌反应1小时待反应完毕后浓缩，剩余物溶于100mL乙酸乙酯中并用饱和碳酸钠溶液洗涤并调节PH至8-9，随后依次用饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩即得到黄色油状物即为4-(3,4-二氯苯基)哌嗪-2-羧酸甲酯(734mg,产率90％)。Dissolve 1-(tert-butyl)2-methyl 4-(3,4-dichlorophenyl)piperazine-1,2-dicarboxylate (1.1 g, 2.82 mmol) in 15 mL of dichloromethane and Slowly add 15mL of trifluoroacetic acid under the condition of stirring at 0°C, and the reaction solution is stirred and reacted at room temperature for 1 hour. After the reaction is completed, it is concentrated. The residue is dissolved in 100mL of ethyl acetate and washed with saturated sodium carbonate solution, and the pH is adjusted to 8- 9, followed by washing with saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating to obtain a yellow oily substance which is methyl 4-(3,4-dichlorophenyl)piperazine-2-carboxylate (734mg, Yield 90%).
14.3 4-(3,4-二氯苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酸甲酯14.3 Methyl 4-(3,4-dichlorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)piperazine-2-carboxylate
将4-(3,4-二氯苯基)哌嗪-2-羧酸甲酯(734mg,2.54mmol)溶于20ml DMF，加入2-羟基喹啉-4-甲酸(530mg,2.8mmol),2-氯-1-甲基吡啶碘化物(CMPI,716mg,2.8mmol),DIPEA(657mg,5.08mmol)，室温下搅拌反应一小时，待反应完毕后加入过量的水，用乙酸乙酯萃取三次，合并有机相，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥并浓缩旋干得棕黄色油状物，将油状物以二氯甲烷/甲醇＝20:1作为洗脱剂进行柱色谱分离得黄色固体即为化合物13-4(1.1g,产率94％)。4-(3,4-dichlorophenyl)piperazine-2-carboxylic acid methyl ester (734mg, 2.54mmol) was dissolved in 20ml DMF, 2-hydroxyquinoline-4-carboxylic acid (530mg, 2.8mmol) was added, 2-Chloro-1-picoline iodide (CMPI, 716mg, 2.8mmol), DIPEA (657mg, 5.08mmol), stirred and reacted at room temperature for one hour, after the reaction was completed, an excess of water was added, extracted three times with ethyl acetate , the organic phases were combined, washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brownish-yellow oil, and the oil was separated by column chromatography using dichloromethane/methanol=20:1 as eluent The obtained yellow solid was compound 13-4 (1.1 g, yield 94%).
14.4 4-(3,4-二氯苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酸14.4 4-(3,4-Dichlorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)piperazine-2-carboxylic acid
将4-(3,4-二氯苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酸甲酯(1.1g,2.39mmol)溶于适量THF/H 2O的混合溶剂，加入氢氧化钾(536mg,9.56mmol)，回流下搅拌反应二小时，待反应完毕后旋干溶剂，使用盐酸调节PH至酸性，观察到有固体析出，抽滤收集固体即为化合物13-5(960mg,产率90％)。 Methyl 4-(3,4-dichlorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)piperazine-2-carboxylate (1.1g, 2.39mmol ) was dissolved in an appropriate amount of THF/H 2 O mixed solvent, potassium hydroxide (536mg, 9.56mmol) was added, and the reaction was stirred under reflux for two hours. The solid was collected by suction filtration and was compound 13-5 (960 mg, yield 90%).
14.5终产物14的合成14.5 Synthesis of the final product 14
将4-(3,4-二氯苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酸(100mg,0.224mmol)溶于10ml DMF，加入吗啉(22mg,0.25mmol),HATU(95.1mg,0.25mmol),DIPEA(58.2mg,0.45mmol)，室温下搅拌反应一小时，待反应完毕后加入过量的水，用乙酸乙酯萃取三次，合并有机相，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥并浓缩旋干得棕黄色油状物，将油状物以二氯甲烷/甲醇＝20:1作为洗脱剂进行柱色谱分离得黄色固体即为化合物14(79.6mg,产率69％)。 1H NMR(600MHz,CDCl3)δ12.55(s,1H),7.53(m,3H),7.33(t,J＝7.5Hz,1H),7.29(s,1H),6.85(d,J＝2.1Hz,1H),6.76–6.61(m,2H),5.60(d,J＝97.2Hz,1H),4.03(t,J＝10.5Hz,1H),3.80(s,6H),3.59(d,J＝12.9Hz,2H),3.50–3.41(m,2H),3.04(t,J＝12.9Hz,1H),2.09(s,2H).LRMS(ESI)m/z517(M+) Dissolve 4-(3,4-dichlorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)piperazine-2-carboxylic acid (100mg, 0.224mmol) in 10ml DMF, add morpholine (22mg, 0.25mmol), HATU (95.1mg, 0.25mmol), DIPEA (58.2mg, 0.45mmol), stir and react at room temperature for one hour, after the reaction is completed, add excess water, wash with ethyl acetate The ester was extracted three times, the organic phases were combined, washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brown-yellow oil, which was carried out with dichloromethane/methanol=20:1 as the eluent The yellow solid obtained by column chromatography was compound 14 (79.6 mg, yield 69%). 1 H NMR (600MHz, CDCl3) δ12.55(s, 1H), 7.53(m, 3H), 7.33(t, J=7.5Hz, 1H), 7.29(s, 1H), 6.85(d, J=2.1 Hz,1H),6.76–6.61(m,2H),5.60(d,J=97.2Hz,1H),4.03(t,J=10.5Hz,1H),3.80(s,6H),3.59(d,J ＝12.9Hz, 2H), 3.50–3.41(m, 2H), 3.04(t, J＝12.9Hz, 1H), 2.09(s, 2H).LRMS(ESI)m/z517(M+)
实施例15(R)-4-(4-(3,4-二氯苯基)-2-(吗啉代甲基)哌嗪-1-羰基)喹啉-2(1H)-酮(15)Example 15 (R)-4-(4-(3,4-dichlorophenyl)-2-(morpholinomethyl)piperazine-1-carbonyl)quinolin-2(1H)-one (15 )
将1,4-双(叔丁氧羰基)哌嗪-2-羧酸替换成(S)-1,4-双(叔丁氧羰基)哌嗪-2-羧酸，其余所需原料、试剂及制备方法同实施例5，得产物15。 1H NMR(600MHz,CDCl3)δ12.62(s,1H),7.55(d,J＝51.0Hz,4H),7.21(s,1H),6.95(s,1H),6.69(d,J＝49.9Hz,2H),5.17(d,J＝39.8Hz,1H),3.73(m,6H),3.40(d,J＝30.8Hz,3H),3.07(dd,J＝61.9,30.7Hz,2H),2.75(d,J＝22.4Hz,1H),2.44(d,J＝114.0Hz,4H).LRMS(ESI)m/z 501(M+) Replace 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid with (S)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid, and other required raw materials and reagents And the preparation method is the same as in Example 5 to obtain product 15. 1 H NMR (600MHz, CDCl3) δ12.62(s,1H),7.55(d,J=51.0Hz,4H),7.21(s,1H),6.95(s,1H),6.69(d,J=49.9 Hz,2H),5.17(d,J=39.8Hz,1H),3.73(m,6H),3.40(d,J=30.8Hz,3H),3.07(dd,J=61.9,30.7Hz,2H), 2.75(d,J=22.4Hz,1H),2.44(d,J=114.0Hz,4H).LRMS(ESI)m/z 501(M+)
实施例16(S)-4-(4-(3,4-二氯苯基)-2-(吗啉代甲基)哌嗪-1-羰基)喹啉-2(1H)-酮(16)Example 16 (S)-4-(4-(3,4-dichlorophenyl)-2-(morpholinomethyl)piperazine-1-carbonyl)quinolin-2(1H)-one (16 )
将1,4-双(叔丁氧羰基)哌嗪-2-羧酸替换成(R)-1,4-双(叔丁氧羰基)哌嗪-2-羧酸，其余所需原料、试剂及制备方法同实施例5，得产物16。 1H NMR(600MHz,CDCl3)δ12.62(s,1H),7.55(d,J＝51.0Hz,4H),7.21(s,1H),6.95(s,1H),6.69(d,J＝49.9Hz,2H),5.17(d,J＝39.8Hz,1H),3.73(m,6H),3.40(d,J＝30.8Hz,3H),3.07(dd,J＝61.9,30.7Hz,2H),2.75(d,J＝22.4Hz,1H),2.44(d,J＝114.0Hz,4H).LRMS(ESI)m/z 501(M+) Replace 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid with (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid, and other required raw materials and reagents And the preparation method is the same as in Example 5 to obtain product 16. 1 H NMR (600MHz, CDCl3) δ12.62(s,1H),7.55(d,J=51.0Hz,4H),7.21(s,1H),6.95(s,1H),6.69(d,J=49.9 Hz,2H),5.17(d,J=39.8Hz,1H),3.73(m,6H),3.40(d,J=30.8Hz,3H),3.07(dd,J=61.9,30.7Hz,2H), 2.75(d,J=22.4Hz,1H),2.44(d,J=114.0Hz,4H).LRMS(ESI)m/z 501(M+)
实施例17 4-(4-(3,4-二氯苯基)-2-(4-甲基哌嗪-1-羰基)哌嗪-1-羰基)喹啉-2(1H)-酮(17)Example 17 4-(4-(3,4-dichlorophenyl)-2-(4-methylpiperazine-1-carbonyl)piperazine-1-carbonyl)quinoline-2(1H)-one ( 17)
将吗啉替换成N-甲基哌嗪，其余所需原料、试剂及制备方法同实施例14，得产物17。 1H NMR(600MHz,CDCl3)δ12.36(s,1H),7.62–7.42(m,3H),7.33(t,J＝7.5Hz,1H),7.28(d,J＝4.8Hz,1H),6.88(d,J＝16.9Hz,1H),6.76–6.59(m,2H),5.62(d,J＝90.6Hz,1H),4.11–3.84(m,2H),3.71(s,3H),3.57(d,J＝12.6Hz,1H),3.41(m,2H),3.02(t,J＝11.2Hz,1H),2.52(s,3H),2.36(s,3H),2.10(s,2H).LRMS(ESI)m/z 528(M+) Replace morpholine with N-methylpiperazine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 17. 1 H NMR (600MHz, CDCl3) δ12.36(s, 1H), 7.62–7.42(m, 3H), 7.33(t, J=7.5Hz, 1H), 7.28(d, J=4.8Hz, 1H), 6.88(d,J=16.9Hz,1H),6.76–6.59(m,2H),5.62(d,J=90.6Hz,1H),4.11–3.84(m,2H),3.71(s,3H),3.57 (d,J=12.6Hz,1H),3.41(m,2H),3.02(t,J=11.2Hz,1H),2.52(s,3H),2.36(s,3H),2.10(s,2H) .LRMS (ESI) m/z 528 (M+)
实施例18 4-(4-(3,4-二氯苯基)-2-(4-甲基哌嗪-1-羰基)哌嗪-1-羰基)喹啉-2(1H)-酮(18)Example 18 4-(4-(3,4-dichlorophenyl)-2-(4-methylpiperazine-1-carbonyl)piperazine-1-carbonyl)quinoline-2(1H)-one ( 18)
将吗啉替换成3-甲基吗啉，其余所需原料、试剂及制备方法同实施例14，得产物18。 1H NMR(600MHz,CDCl3)δ12.59(s,1H),8.06–7.83(m,1H),7.56(d,J＝6.4Hz,1H),7.49(t,J＝8.4Hz,1H),7.33(t,J＝7.3Hz,1H),7.27(d,J＝3.4Hz,1H),6.90–6.57 (m,3H),5.56(dd,J＝96.0,39.0Hz,1H),4.19–3.88(m,3H),3.75(m,4H),3.61–3.37(m,4H),3.17–2.99(m,1H),2.11(s,1H),1.45–1.21(m,3H).LRMS(ESI)m/z 531(M+) Replace morpholine with 3-methylmorpholine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 18. 1 H NMR (600MHz, CDCl3) δ12.59(s, 1H), 8.06–7.83(m, 1H), 7.56(d, J=6.4Hz, 1H), 7.49(t, J=8.4Hz, 1H), 7.33(t, J=7.3Hz, 1H), 7.27(d, J=3.4Hz, 1H), 6.90–6.57 (m, 3H), 5.56(dd, J=96.0, 39.0Hz, 1H), 4.19–3.88 (m,3H),3.75(m,4H),3.61–3.37(m,4H),3.17–2.99(m,1H),2.11(s,1H),1.45–1.21(m,3H).LRMS(ESI )m/z 531(M+)
实施例19 4-(4-(3,4-二氯苯基)-2-(4-氧代哌啶-1-羰基)哌嗪-1-羰基)喹啉-2(1H)-酮(19)Example 19 4-(4-(3,4-dichlorophenyl)-2-(4-oxopiperidine-1-carbonyl)piperazine-1-carbonyl)quinoline-2(1H)-one ( 19)
将吗啉替换成4-哌啶，其余所需原料、试剂及制备方法同实施例14，得产物19。LRMS(ESI)m/z 529(M+)Replace morpholine with 4-piperidine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 19. LRMS(ESI)m/z 529(M+)
实施例20 4-(4-(3,4-二氯苯基)-2-(2-氧代-7-氮杂螺[3.5]壬烷-7-羰基)哌嗪-1-羰基)喹啉-2(1H)-酮(20)Example 20 4-(4-(3,4-dichlorophenyl)-2-(2-oxo-7-azaspiro[3.5]nonane-7-carbonyl)piperazine-1-carbonyl)quinone Lin-2(1H)-one(20)
将吗啉替换成7-氮杂螺[3.5]壬-2-酮，其余所需原料、试剂及制备方法同实施例14，得产物20。LRMS(ESI)m/z 569(M+)The morpholine was replaced by 7-azaspiro[3.5]nonan-2-one, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 14 to obtain the product 20. LRMS(ESI)m/z 569(M+)
实施例21 4-(4-(3,4-二氯苯基)-2-(2-氧代-7-氮杂螺[3.5]壬烷-7-羰基)哌嗪-1-羰基)喹啉-2(1H)-酮(21)Example 21 4-(4-(3,4-dichlorophenyl)-2-(2-oxo-7-azaspiro[3.5]nonane-7-carbonyl)piperazine-1-carbonyl)quinol Lin-2(1H)-one(21)
将吗啉替换成六氢环戊五[c]吡咯-5(1H)-酮，其余所需原料、试剂及制备方法同实施例14，得产物21。LRMS(ESI)m/z 555(M+)Replace morpholine with hexahydrocyclopenta[c]pyrrol-5(1H)-one, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 21. LRMS(ESI)m/z 555(M+)
实施例22 4-(3,4-二氯苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)-N-(4-氧代-4,5-二氢噻唑-2-基)哌嗪-2-羧酰胺(22)Example 22 4-(3,4-dichlorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)-N-(4-oxo-4,5- Dihydrothiazol-2-yl)piperazine-2-carboxamide (22)
将吗啉替换成2-氨基噻唑-4(5H)-盐酸盐，其余所需原料、试剂及制备方法同实施例14，得产物22。LRMS(ESI)m/z 544(M+)The morpholine was replaced by 2-aminothiazole-4(5H)-hydrochloride, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 14 to obtain the product 22. LRMS(ESI)m/z 544(M+)
实施例23 4-(3,4-二氯苯基)-N-(氧杂环丁-2-基甲基)-1-(2-氧-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(23)Example 23 4-(3,4-dichlorophenyl)-N-(oxetan-2-ylmethyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl ) piperazine-2-carboxamide (23)
将吗啉替换成2-氧杂环丁烷甲胺，其余所需原料、试剂及制备方法同实施例14，得产物23。LRMS(ESI)m/z 515(M+)The morpholine was replaced by 2-oxetanemethylamine, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 14 to obtain the product 23. LRMS(ESI)m/z 515(M+)
实施例24 4-(3,4-二氟苯基)-N-(氧杂环丁-2-基甲基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(24)Example 24 4-(3,4-difluorophenyl)-N-(oxetan-2-ylmethyl)-1-(2-oxo-1,2-dihydroquinoline-4- Carbonyl) piperazine-2-carboxamide (24)
将吗啉替换成2-氧杂环丁烷甲胺，3,4-二氯溴苯替换成3,4-二氟溴苯，其余所需原料、试剂及制备方法同实施例14，得产物24。LRMS(ESI)m/z 483(M+)Replace morpholine with 2-oxetanemethylamine, 3,4-dichlorobromobenzene with 3,4-difluorobromobenzene, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain the product twenty four. LRMS(ESI)m/z 483(M+)
实施例25 4-(3,4-二氯苯基)-1-(6-甲基-2-氧代-1,2-二氢喹啉-4-羰基)-N-(氧杂环丁-2-基甲基)哌嗪-2-羧酰胺(25)Example 25 4-(3,4-dichlorophenyl)-1-(6-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl)-N-(oxetane -2-ylmethyl)piperazine-2-carboxamide (25)
将吗啉替换成2-氧杂环丁烷甲胺，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例14，得产物25。LRMS(ESI)m/z 529(M+)Replace morpholine with 2-oxetanemethylamine and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-methyl-2-oxo-1,2-dihydroquinone Phenyl-4-carboxylic acid, the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain the product 25. LRMS(ESI)m/z 529(M+)
实施例26 1-(6-溴-2-氧代-1,2，二氢喹啉-4-羰基)-4-(3,4-二氯苯基)-N-(氧杂环丁-2-基甲基)哌嗪-2-羧酰胺(26)Example 26 1-(6-bromo-2-oxo-1,2,dihydroquinoline-4-carbonyl)-4-(3,4-dichlorophenyl)-N-(oxetane- 2-ylmethyl)piperazine-2-carboxamide (26)
将吗啉替换成2-氧杂环丁烷甲胺，2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例14，得产物26。LRMS (ESI)m/z 593(M+)Substitution of morpholine by 2-oxetanemethylamine and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid by 6-bromo-2-oxo-1,2-dihydroquinoline -4-carboxylic acid, the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain the product 26. LRMS (ESI)m/z 593(M+)
实施例27 4-(3,4-二氯苯基)-1-(6-羟基-2-氧代-1,2-二氢喹啉-4-羰基)-N-(氧杂环丁-2-基甲基)哌嗪-2-羧酰胺(27)Example 27 4-(3,4-dichlorophenyl)-1-(6-hydroxy-2-oxo-1,2-dihydroquinoline-4-carbonyl)-N-(oxetane- 2-ylmethyl)piperazine-2-carboxamide (27)
将吗啉替换成2-氧杂环丁烷甲胺，2-氧-1,2-二氢喹啉-4-羧酸替换成6-羟基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例14，得产物27。LRMS(ESI)m/z 531(M+)Replace morpholine with 2-oxetanemethylamine and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-hydroxy-2-oxo-1,2-dihydroquinoline -4-carboxylic acid, the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain the product 27. LRMS(ESI)m/z 531(M+)
实施例28 4-(3,4-二氯苯基)-N-(((2-甲基环戊基)甲基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(28)Example 28 4-(3,4-dichlorophenyl)-N-(((2-methylcyclopentyl)methyl)-1-(2-oxo-1,2-dihydroquinoline- 4-carbonyl)piperazine-2-carboxamide (28)
将吗啉替换成(2-甲基环戊基)甲胺，其余所需原料、试剂及制备方法同实施例14，得产物28。LRMS(ESI)m/z 557(M+)Replace morpholine with (2-methylcyclopentyl)methylamine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 28. LRMS(ESI)m/z 557(M+)
实施例29N-(环戊基甲基)-4-(3,4-二氯苯基)-1-(6-甲基-2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(29)Example 29 N-(cyclopentylmethyl)-4-(3,4-dichlorophenyl)-1-(6-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl ) piperazine-2-carboxamide (29)
将吗啉替换成(2-甲基环戊基)甲胺，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例14，得产物29。LRMS(ESI)m/z 541(M+)Replace morpholine with (2-methylcyclopentyl)methanamine, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-methyl-2-oxo-1,2-di Hydroquinoline-4-carboxylic acid, other required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 29. LRMS(ESI)m/z 541(M+)
实施例30N-(环戊基甲基)-4-(3,4-二氯苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(30)Example 30N-(cyclopentylmethyl)-4-(3,4-dichlorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)piperazine-2 - Carboxamide (30)
将吗啉替换成(2-环戊基)甲胺，其余所需原料、试剂及制备方法同实施例14，得产物30。LRMS(ESI)m/z 527(M+)The morpholine was replaced by (2-cyclopentyl)methylamine, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 14 to obtain the product 30. LRMS(ESI)m/z 527(M+)
实施例31 4-(3,4-二氯苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)-N-(3,3,3-三氟丙基)哌嗪-2-羧酰胺(31)Example 31 4-(3,4-dichlorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)-N-(3,3,3-trifluoropropane Base) piperazine-2-carboxamide (31)
将吗啉替换成3,3,3-三氟丙烷-1-胺盐酸盐，其余所需原料、试剂及制备方法同实施例14，得产物31。LRMS(ESI)m/z 541(M+)Morpholine was replaced with 3,3,3-trifluoropropane-1-amine hydrochloride, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 14 to obtain product 31. LRMS(ESI)m/z 541(M+)
实施例32 4-(3,4-二氯苯基)-1-(6-甲基-2-氧代-1,2-二氢喹啉-4-羰基)-N-(3,3,3-三氟丙基)哌嗪-2-羧酰胺(32)Example 32 4-(3,4-dichlorophenyl)-1-(6-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl)-N-(3,3, 3-trifluoropropyl)piperazine-2-carboxamide (32)
将吗啉替换成3,3,3-三氟丙烷-1-胺盐酸盐，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例14，得产物32。LRMS(ESI)m/z 555(M+)Replace morpholine with 3,3,3-trifluoropropane-1-amine hydrochloride and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-methyl-2-oxo- 1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 32. LRMS(ESI)m/z 555(M+)
实施例33 1-(6-溴-2-氧代-1,2-二氢喹啉-4-羰基)-4-(3,4-二氯苯基)-N-(3,3,3-三氟丙基)哌嗪-2-羧酰胺(33)Example 33 1-(6-bromo-2-oxo-1,2-dihydroquinoline-4-carbonyl)-4-(3,4-dichlorophenyl)-N-(3,3,3 -Trifluoropropyl)piperazine-2-carboxamide (33)
将吗啉替换成3,3,3-三氟丙烷-1-胺盐酸盐，2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例14，得产物33。LRMS(ESI)m/z 619(M+)Substitution of morpholine by 3,3,3-trifluoropropane-1-amine hydrochloride and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid by 6-bromo-2-oxo-1 , 2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain the product 33. LRMS(ESI)m/z 619(M+)
实施例34 4-(3,4-二氟苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)-N-(3,3,3-三氟丙基)哌嗪 -2-羧酰胺(34)Example 34 4-(3,4-difluorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)-N-(3,3,3-trifluoropropane Base) piperazine-2-carboxamide (34)
将吗啉替换成3,3,3-三氟丙烷-1-胺盐酸盐，3,4-二氯溴苯替换成3,4-二氟溴苯，其余所需原料、试剂及制备方法同实施例14，得产物34。LRMS(ESI)m/z 509(M+)Replace morpholine with 3,3,3-trifluoropropane-1-amine hydrochloride, 3,4-dichlorobromobenzene with 3,4-difluorobromobenzene, and other required raw materials, reagents and preparation methods As in Example 14, the product 34 was obtained. LRMS(ESI)m/z 509(M+)
实施例35 4-(4-(3,4-二氯苯基)-2-(2-氧杂-7-氮杂螺[3.5]壬烷-7-羰基)哌嗪-1-羰基)喹啉-2(1H)-酮(35)Example 35 4-(4-(3,4-dichlorophenyl)-2-(2-oxa-7-azaspiro[3.5]nonane-7-carbonyl)piperazine-1-carbonyl)quinol Lin-2(1H)-one(35)
将吗啉替换成2-氧杂-7-氮杂螺[3.5]壬烷，其余所需原料、试剂及制备方法同实施例14，得产物35。LRMS(ESI)m/z 555(M+)Morpholine was replaced by 2-oxa-7-azaspiro[3.5]nonane, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 14 to obtain product 35. LRMS(ESI)m/z 555(M+)
实施例36(S)-4-(2-(环己基甲基)-4-(3,4-二氯苯基)哌嗪-1-羰基)喹啉-2(1H)-酮(36)Example 36 (S)-4-(2-(cyclohexylmethyl)-4-(3,4-dichlorophenyl)piperazine-1-carbonyl)quinolin-2(1H)-one (36)
36.1N-(叔丁氧基羰基)-3-环己基-L-丙氨酰甘氨酸甲酯36.1 N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanylglycine methyl ester
在100mL圆底烧瓶中装入N-(叔丁氧羰基)-3-环己基-L-丙氨酸(2.00g，7.37mmol)，HATU(3.08g，8.11mmol)，甘氨酸甲酯盐酸盐(1.02g，8.11mmol)和20mL DMF。向其中添加DIPEA(2.57mL，14.7mmol)。在室温下搅拌5分钟后，将混合物用水(100mL)稀释，并用乙醚(2×200mL)萃取。分离各层，并将有机相用水(2×100mL)和盐水(50mL)洗涤，硫酸镁干燥，浓缩，得到N-(叔丁氧基羰基)-3-环己基-L-丙氨酰甘氨酸甲酯，浓缩物为黄色油状物(2.52g，产率100％)，直接用于下一步。A 100 mL round bottom flask was charged with N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanine (2.00 g, 7.37 mmol), HATU (3.08 g, 8.11 mmol), glycine methyl ester hydrochloride (1.02g, 8.11mmol) and 20mL DMF. To this was added DIPEA (2.57 mL, 14.7 mmol). After stirring at room temperature for 5 minutes, the mixture was diluted with water (100 mL) and extracted with diethyl ether (2 x 200 mL). The layers were separated and the organic phase was washed with water (2 x 100 mL) and brine (50 mL), dried over magnesium sulfate and concentrated to give N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanylglycine methyl The ester, concentrated as a yellow oil (2.52 g, 100% yield), was used directly in the next step.
36.2(3S)-3(环己基甲基)-2，5-哌嗪二酮36. 2(3S)-3(cyclohexylmethyl)-2,5-piperazinedione
在150mL圆底烧瓶中装入N-(叔丁氧基羰基)-3-环己基-L-丙氨酰甘氨酸甲酯(2.52g，7.37mmol)，10mL DCM和10mL TFA。30分钟后，将混合物浓缩，然后重新溶于2M氨的MeOH溶液(20mL)中并在室温下搅拌过夜，白色沉淀物析出，过滤收集形成的产物，得到(3S)-3(环己基甲基)-2，5-哌嗪二酮(1.30g，84％产率)。A 150 mL round bottom flask was charged with N-(tert-butoxycarbonyl)-3-cyclohexyl-L-alanylglycine methyl ester (2.52 g, 7.37 mmol), 10 mL DCM and 10 mL TFA. After 30 minutes, the mixture was concentrated, then redissolved in 2M ammonia in MeOH (20 mL) and stirred overnight at room temperature, a white precipitate precipitated, and the product formed was collected by filtration to give (3S)-3(cyclohexylmethyl )-2,5-piperazinedione (1.30 g, 84% yield).
36.3(2S)-2-(环己基甲基)哌嗪36.3(2S)-2-(cyclohexylmethyl)piperazine
在150mL圆底烧瓶中装入(3S)-3-(环己基甲基)-2,5-哌嗪二酮(1.10g，5.23mmol)，30ml THF和氢化铝锂(20.9mL，1M的THF溶液，20.9mmol)。加热至70℃过夜后，将混合物冷却至室温，缓慢加入十水合硫酸钠(10g)。搅拌1小时后，将混合物过滤，并浓缩滤液，得到(2S)-2-(环己基甲基)哌嗪(0.954g，100％收率)，为无色油状物，将其粗品用于下一步反应。A 150 mL round bottom flask was charged with (3S)-3-(cyclohexylmethyl)-2,5-piperazinedione (1.10 g, 5.23 mmol), 30 mL THF and lithium aluminum hydride (20.9 mL, 1 M in THF solution, 20.9 mmol). After heating to 70°C overnight, the mixture was cooled to room temperature and sodium sulfate decahydrate (10 g) was added slowly. After stirring for 1 hour, the mixture was filtered, and the filtrate was concentrated to give (2S)-2-(cyclohexylmethyl)piperazine (0.954 g, 100% yield) as a colorless oil, which was used crudely in the following One step reaction.
36.4(S)-3-(环己基甲基)-1-(3,4-二氯苯基)哌嗪36.4(S)-3-(cyclohexylmethyl)-1-(3,4-dichlorophenyl)piperazine
氩气保护下，将(2S)-2-(环己基甲基)哌嗪(0.954g,5.23mmol)与3,4-二氯溴苯(1.30g,5.76mmol)溶于20mL甲苯中，随后加入三二亚苄基丙酮二钯(Pd 2dba 3,193.8mg,0.21mmol)，2-二环己基磷-2,4,6-三异丙基联苯(X-Phos,238.1mg,0.5mmol)和碳酸铯(3.26g,10mmol)，将反应液升温至110℃下搅拌反应过夜，待反应完毕后冷却至室温并用硅藻土过滤，滤饼用乙酸乙酯洗涤。收集滤液加50mL水稀释并用40mL乙酸乙酯萃取2次，随后合并有机相依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥并浓缩旋干得棕黄色油状物，将油状物以二氯甲烷/甲醇＝20:1作为洗脱剂进行柱色谱分离得黄色油状物即为化合物6-6(1.03g,产率60％)。 Under argon protection, (2S)-2-(cyclohexylmethyl)piperazine (0.954g, 5.23mmol) and 3,4-dichlorobromobenzene (1.30g, 5.76mmol) were dissolved in 20mL of toluene, followed by Add tridibenzylideneacetone dipalladium (Pd 2 dba 3 , 193.8mg, 0.21mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (X-Phos, 238.1mg, 0.5 mmol) and cesium carbonate (3.26g, 10mmol), the reaction solution was heated to 110°C and stirred overnight. After the reaction was completed, it was cooled to room temperature and filtered with diatomaceous earth, and the filter cake was washed with ethyl acetate. The collected filtrate was diluted with 50 mL of water and extracted twice with 40 mL of ethyl acetate, then the combined organic phases were washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brownish-yellow oil, which was washed with dichloromethane /methanol=20:1 was used as the eluent for column chromatography to obtain a yellow oily substance which was compound 6-6 (1.03 g, yield 60%).
36.5终产物36的合成36.5 Synthesis of the final product 36
将(S)-3-(环己基甲基)-1-(3,4-二氯苯基)哌嗪(1.03g,3.15mmol)溶于20ml DMF，加入2-氧-1,2-二氢喹啉-4-羧酸(656.4mg,3.47mmol),HATU(1.32g,3.47mmol),DIPEA(815mg,6.3mmol)，室温下搅拌反应一小时，待反应完毕后加入过量的水，用乙酸乙酯萃取三次，合并有机相，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥并浓缩旋干得棕黄色油状物，将油状物以二氯甲烷/甲醇＝20:1作为洗脱剂进行柱色谱分离得黄色固体即为化合物36(785mg,产率50％)。 1H NMR(600MHz,CDCl 3)δ12.91(s,1H),7.67–7.45(m,3H),7.27(dd,J＝11.4,6.0Hz,2H),6.92(dd,J＝19.7,7.6Hz,1H),6.68(m,2H),5.21–4.74(m,1H),3.70–3.00(m,5H),2.67(dt,J＝107.3,10.9Hz,1H),1.81(m,9H),1.21–0.81(m,4H).LRMS(ESI)m/z 498(M+) Dissolve (S)-3-(cyclohexylmethyl)-1-(3,4-dichlorophenyl)piperazine (1.03g, 3.15mmol) in 20ml DMF, add 2-oxo-1,2-di Hydroquinoline-4-carboxylic acid (656.4mg, 3.47mmol), HATU (1.32g, 3.47mmol), DIPEA (815mg, 6.3mmol), stirred and reacted at room temperature for one hour, after the reaction was completed, an excess of water was added, and the Extracted three times with ethyl acetate, combined the organic phases, washed with saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, concentrated and spin-dried to obtain a brownish-yellow oil, which was eluted with dichloromethane/methanol=20:1 The compound 36 (785 mg, yield 50%) was obtained as a yellow solid by column chromatography. 1 H NMR (600MHz, CDCl 3 ) δ12.91(s, 1H), 7.67–7.45(m, 3H), 7.27(dd, J=11.4, 6.0Hz, 2H), 6.92(dd, J=19.7, 7.6 Hz,1H),6.68(m,2H),5.21–4.74(m,1H),3.70–3.00(m,5H),2.67(dt,J＝107.3,10.9Hz,1H),1.81(m,9H) ,1.21–0.81(m,4H).LRMS(ESI)m/z 498(M+)
实施例37 4-(3-苄基-4-(3,4-二氯苯基)哌嗪-1-羰基)喹啉-2(1H)-酮(37)Example 37 4-(3-benzyl-4-(3,4-dichlorophenyl)piperazine-1-carbonyl)quinolin-2(1H)-one (37)
将1-Boc-3-甲基哌嗪替换成3-苄基哌嗪-1-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物37。 1H NMR(600MHz,CDCl 3)δ13.72(s,1H),7.67(d,J＝5.7Hz,1H),7.54(t,J＝9.0Hz,1H),7.36–7.28(m,4H),7.20(t,J＝7.2Hz,1H),7.11(dd,J＝16.7,5.6Hz,1H),6.97(s,1H),6.80(d,J＝6.9Hz,2H),4.66(d,J＝12.9Hz,1H),3.97(d,J＝9.9Hz,1H),3.69(t,J＝10.3Hz,1H),3.61(d,J＝12.0Hz,1H),3.47(t,J＝11.8Hz,1H),3.34–3.26(m,1H),3.20(d,J＝10.8Hz,1H),3.00(d,J＝12.1Hz,1H),2.63(d,J＝12.5Hz,1H).LRMS(ESI)m/z 492(M+) 1-Boc-3-methylpiperazine was replaced by 3-benzylpiperazine-1-tert-butyl carboxylate, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 37. 1 H NMR (600MHz, CDCl 3 ) δ13.72(s, 1H), 7.67(d, J=5.7Hz, 1H), 7.54(t, J=9.0Hz, 1H), 7.36–7.28(m, 4H) ,7.20(t,J=7.2Hz,1H),7.11(dd,J=16.7,5.6Hz,1H),6.97(s,1H),6.80(d,J=6.9Hz,2H),4.66(d, J=12.9Hz, 1H), 3.97(d, J=9.9Hz, 1H), 3.69(t, J=10.3Hz, 1H), 3.61(d, J=12.0Hz, 1H), 3.47(t, J= 11.8Hz, 1H), 3.34–3.26(m, 1H), 3.20(d, J=10.8Hz, 1H), 3.00(d, J=12.1Hz, 1H), 2.63(d, J=12.5Hz, 1H) .LRMS (ESI) m/z 492 (M+)
实施例38 4-(3,4-二氯苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)-N-((四氢呋喃-2-基)甲基)哌嗪-2-羧酰胺(38)Example 38 4-(3,4-dichlorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)-N-((tetrahydrofuran-2-yl)methyl ) piperazine-2-carboxamide (38)
将吗啉替换成2-氧杂环戊烷甲胺，其余所需原料、试剂及制备方法同实施例14，得产物38。LRMS(ESI)m/z 529(M+)The morpholine is replaced by 2-oxolanemethylamine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain the product 38. LRMS(ESI)m/z 529(M+)
实施例39 4-(3,4-二氯苯基)-1-(6-甲基-2-氧代-1,2-二氢喹啉-4-羰基)-N-((四氢呋喃-2-基)甲基)哌嗪-2-羧酰胺(39)Example 39 4-(3,4-dichlorophenyl)-1-(6-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl)-N-((tetrahydrofuran-2 -yl)methyl)piperazine-2-carboxamide (39)
将吗啉替换成2-氧杂环戊烷甲胺，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸,其余所需原料、试剂及制备方法同实施例14，得产物39。LRMS(ESI)m/z 543(M+)Replace morpholine with 2-oxolanemethanamine and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-methyl-2-oxo-1,2-dihydroquinone Phenyl-4-carboxylic acid, other required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 39. LRMS(ESI)m/z 543(M+)
实施例40 1-(6-溴-2-氧代-1,2，-二氢喹啉-4-羰基)-4-(3,4-二氯苯基)-N-((四氢呋喃-2-基)甲基)哌嗪-2-羧酰胺(40)Example 40 1-(6-bromo-2-oxo-1,2,-dihydroquinoline-4-carbonyl)-4-(3,4-dichlorophenyl)-N-((tetrahydrofuran-2 -yl)methyl)piperazine-2-carboxamide (40)
将吗啉替换成2-氧杂环戊烷甲胺，2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧-1,2-二氢喹啉-4-羧酸,其余所需原料、试剂及制备方法同实施例14，得产物40。LRMS(ESI)m/z 607(M+)Substitution of morpholine by 2-oxolanemethanamine and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid by 6-bromo-2-oxo-1,2-dihydroquinoline -4-carboxylic acid, the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain the product 40. LRMS(ESI)m/z 607(M+)
实施例41 4-(3,4-二氟苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)-N-((四氢呋喃-2-基)甲基)哌嗪-2-羧酰胺(41)Example 41 4-(3,4-difluorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)-N-((tetrahydrofuran-2-yl)methyl ) piperazine-2-carboxamide (41)
将吗啉替换成2-氧杂环戊烷甲胺，3,4-二氯溴苯替换成3,4-二氯氟苯,其余所需原料、试剂及制备方法同实施例14，得产物41。LRMS(ESI)m/z 497(M+)Replace morpholine with 2-oxolanemethylamine, 3,4-dichlorobromobenzene with 3,4-dichlorofluorobenzene, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain the product 41. LRMS(ESI)m/z 497(M+)
实施例42N-(环己基甲基)-4-(3,4-二氯苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2- 羧酰胺(42)Example 42N-(cyclohexylmethyl)-4-(3,4-dichlorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)piperazine-2- Carboxamide (42)
将吗啉替换成环己基甲胺，其余所需原料、试剂及制备方法同实施例14，得产物42。LRMS(ESI)m/z 541(M+)Replace morpholine with cyclohexylmethylamine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 42. LRMS(ESI)m/z 541(M+)
实施例43N-(环己基甲基)-4-(3,4-二氯苯基)-1-(6-甲基-2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(43)Example 43 N-(cyclohexylmethyl)-4-(3,4-dichlorophenyl)-1-(6-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl) Piperazine-2-carboxamide (43)
将吗啉替换成环戊基乙胺，其余所需原料、试剂及制备方法同实施例14，得产物43。LRMS(ESI)m/z 555(M+)Replace morpholine with cyclopentylethylamine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 43. LRMS(ESI)m/z 555(M+)
实施例44 1-(6-溴-2-氧代-1,2-二氢喹啉-4-羰基)-N-(环己基甲基)-4-(3,4-二氯苯基)哌嗪-2-羧酰胺(44)Example 44 1-(6-bromo-2-oxo-1,2-dihydroquinoline-4-carbonyl)-N-(cyclohexylmethyl)-4-(3,4-dichlorophenyl) Piperazine-2-carboxamide (44)
将吗啉替换成环丙基乙胺，其余所需原料、试剂及制备方法同实施例14，得产物44。LRMS(ESI)m/z 619(M+)Replace morpholine with cyclopropylethylamine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 44. LRMS(ESI)m/z 619(M+)
实施例45N-(环己基甲基)-4-(3,4-二氟苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(45)Example 45 N-(cyclohexylmethyl)-4-(3,4-difluorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)piperazine-2- Carboxamide (45)
将吗啉替换成4,4,4-三氟丁烷-1-胺，其余所需原料、试剂及制备方法同实施例14，得产物45。LRMS(ESI)m/z 509(M+)The morpholine was replaced by 4,4,4-trifluorobutan-1-amine, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 14 to obtain the product 45. LRMS(ESI)m/z 509(M+)
实施例46N-(环丙基甲基)-4-(3,4-二氯苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(46)Example 46 N-(cyclopropylmethyl)-4-(3,4-dichlorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)piperazine-2 - Carboxamide (46)
将吗啉替换成环丙基甲胺，其余所需原料、试剂及制备方法同实施例14，得产物46。LRMS(ESI)m/z 499(M+)Replace morpholine with cyclopropylmethylamine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 46. LRMS(ESI)m/z 499(M+)
实施例47N-(环丙基甲基)-4-(3,4-二氯苯基)-1-(6-甲基-2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(47)Example 47 N-(cyclopropylmethyl)-4-(3,4-dichlorophenyl)-1-(6-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl ) piperazine-2-carboxamide (47)
将吗啉替换成环丙基甲胺，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸,其余所需原料、试剂及制备方法同实施例14，得产物47。LRMS(ESI)m/z 513(M+)Replace morpholine with cyclopropylmethylamine and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-methyl-2-oxo-1,2-dihydroquinoline-4- Carboxylic acid, the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 47. LRMS(ESI)m/z 513(M+)
实施例48 1-(6-溴-2-氧代-1,2-二氢喹啉-4-羰基)-N-(环丙基甲基)-4-(3,4-二氯苯基)哌嗪-2-羧酰胺(48)Example 48 1-(6-bromo-2-oxo-1,2-dihydroquinoline-4-carbonyl)-N-(cyclopropylmethyl)-4-(3,4-dichlorophenyl ) piperazine-2-carboxamide (48)
将吗啉替换成2-(四氢-2H-吡喃-4-基)乙烷-1-胺，其余所需原料、试剂及制备方法同实施例14，得产物48。LRMS(ESI)m/z 577(M+)The morpholine was replaced by 2-(tetrahydro-2H-pyran-4-yl)ethan-1-amine, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 14 to obtain the product 48. LRMS(ESI)m/z 577(M+)
实施例49N-(环丙基甲基)-4-(3,4-二氟苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(49)Example 49 N-(cyclopropylmethyl)-4-(3,4-difluorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)piperazine-2 - Carboxamide (49)
将吗啉替换成环丙基甲胺，3,4-二氯溴苯替换成3,4-二氯氟苯,其余所需原料、试剂及制备方法同实施例14，得产物48。LRMS(ESI)m/z 467(M+)Replace morpholine with cyclopropylmethylamine, and replace 3,4-dichlorobromobenzene with 3,4-dichlorofluorobenzene. The rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 48. LRMS(ESI)m/z 467(M+)
实施例50N-(环丁基甲基)-4-(3,4-二氯苯基)-1-(2-氧代-1,2-二氢二甲苯甲酸-4-甲苯基)哌嗪-2-酰胺(50)Example 50N-(cyclobutylmethyl)-4-(3,4-dichlorophenyl)-1-(2-oxo-1,2-dihydroxylene-4-methylphenyl)piperazine-2 -amide(50)
将吗啉替换成环丁基甲胺，其余所需原料、试剂及制备方法同实施例14，得产物50。LRMS(ESI)m/z 513(M+)The morpholine was replaced by cyclobutylmethylamine, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 14 to obtain the product 50. LRMS(ESI)m/z 513(M+)
实施例51N-(环丁基甲基)-4-(3,4-二氯苯基)-1-(6-甲基-2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(51)Example 51N-(cyclobutylmethyl)-4-(3,4-dichlorophenyl)-1-(6-methyl-2-oxo-1,2-dihydroquinoline-4-carbonyl)piper Oxazine-2-carboxamide (51)
将吗啉替换成2-吗啉乙胺，其余所需原料、试剂及制备方法同实施例14，得产物51。LRMS(ESI)m/z 527(M+)Replace morpholine with 2-morpholineethylamine, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 51. LRMS(ESI)m/z 527(M+)
实施例52 1-(6-溴-2-羰基-1,2-二氢喹啉-4-羰基)-N-(环丁基甲基)-4-(3,4-二氯苯基)哌嗪-2-羧酰胺(52)Example 52 1-(6-bromo-2-carbonyl-1,2-dihydroquinoline-4-carbonyl)-N-(cyclobutylmethyl)-4-(3,4-dichlorophenyl)piperazine -2-Carboxamide (52)
将吗啉替换成正丁胺，其余所需原料、试剂及制备方法同实施例14，得产物52。LRMS(ESI)m/z 591(M+)The morpholine was replaced by n-butylamine, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 14 to obtain the product 52. LRMS(ESI)m/z 591(M+)
实施例53N-(环丁基甲基)-4-(3,4-二氟苯基)-1-(2-氧代-1,2-二氢喹啉-4-羰基)哌嗪-2-羧酰胺(53)Example 53 N-(cyclobutylmethyl)-4-(3,4-difluorophenyl)-1-(2-oxo-1,2-dihydroquinoline-4-carbonyl)piperazine-2-carboxy Amide(53)
将吗啉替换成环丁基甲胺，3,4-二氯溴苯替换成3,4-二氯氟苯，其余所需原料、试剂及制备方法同实施例14，得产物53。LRMS(ESI)m/z 481(M+)Replace morpholine with cyclobutylmethylamine, and replace 3,4-dichlorobromobenzene with 3,4-dichlorofluorobenzene. The rest of the required raw materials, reagents and preparation methods are the same as in Example 14 to obtain product 53. LRMS(ESI)m/z 481(M+)
实施例54 4-(4-(3,4-二氯苯基)-2-甲基哌嗪-1-羰基)喹啉-2(1H)-酮(54)Example 54 4-(4-(3,4-dichlorophenyl)-2-methylpiperazine-1-carbonyl)quinolin-2(1H)-one (54)
将1-Boc-3-甲基哌嗪替换成2-甲基哌嗪-1-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物54。LRMS(ESI)m/z 416(M+)1-Boc-3-methylpiperazine was replaced by 2-methylpiperazine-1-tert-butyl carboxylate, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 54. LRMS(ESI)m/z 416(M+)
实施例55 4-(4-(3,4-二氯苯基)-2-异丙基哌嗪-1-羰基)喹啉-2(1H)-酮(55)Example 55 4-(4-(3,4-dichlorophenyl)-2-isopropylpiperazine-1-carbonyl)quinolin-2(1H)-one (55)
将1-Boc-3-甲基哌嗪替换成2-异丙基哌嗪-1-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物55。LRMS(ESI)m/z 444(M+)1-Boc-3-methylpiperazine was replaced by 2-isopropylpiperazine-1-tert-butyl carboxylate, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 55. LRMS(ESI)m/z 444(M+)
实施例56 4-(2-苄基-4-(3,4-二氯苯基)哌嗪-1-羰基)喹啉-2(1H)-酮(56)Example 56 4-(2-benzyl-4-(3,4-dichlorophenyl)piperazine-1-carbonyl)quinolin-2(1H)-one (56)
将1-Boc-3-甲基哌嗪替换成2-苄基哌嗪-1-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物56。LRMS(ESI)m/z 492(M+)1-Boc-3-methylpiperazine was replaced by 2-benzylpiperazine-1-tert-butyl carboxylate, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 56. LRMS(ESI)m/z 492(M+)
实施例57(S)-4-(4-(4-(3,4-二氯苯基)-2-乙基哌嗪-1-羰基)喹啉-2(1H)-酮(57)Example 57 (S)-4-(4-(4-(3,4-dichlorophenyl)-2-ethylpiperazine-1-carbonyl)quinolin-2(1H)-one (57)
将1-Boc-3-甲基哌嗪替换成(S)-2-乙基哌嗪-1-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物57。LRMS(ESI)m/z 430(M+)1-Boc-3-methylpiperazine was replaced by (S)-2-ethylpiperazine-1-tert-butyl carboxylate, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 57. LRMS(ESI)m/z 430(M+)
实施例58 4-(4-(3,4-二氯苯基)-2,2-二甲基哌嗪-1-羰基)喹啉-2(1H)-酮(58)Example 58 4-(4-(3,4-dichlorophenyl)-2,2-dimethylpiperazine-1-carbonyl)quinolin-2(1H)-one (58)
将1-Boc-3-甲基哌嗪替换成2,2-二甲基哌嗪-1-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物58。LRMS(ESI)m/z 430(M+)1-Boc-3-methylpiperazine was replaced by 2,2-dimethylpiperazine-1-tert-butyl carboxylate, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 58. LRMS(ESI)m/z 430(M+)
实施例59 4-(4-(3,4-二氯苯基)-2-甲基哌嗪-1-羰基)-6-甲基喹啉-2(1H)-酮(59)Example 59 4-(4-(3,4-dichlorophenyl)-2-methylpiperazine-1-carbonyl)-6-methylquinolin-2(1H)-one (59)
将1-Boc-3-甲基哌嗪替换成2-甲基哌嗪-1-羧酸叔丁酯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物59。LRMS(ESI)m/z 430(M+)Replace 1-Boc-3-methylpiperazine with tert-butyl 2-methylpiperazine-1-carboxylate and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-methylpiperazine Base-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain product 59. LRMS(ESI)m/z 430(M+)
实施例60 6-溴-4-(4-(3,4-二氯苯基)-2-甲基哌嗪-1-羰基)喹啉-2(1H)-酮(60)Example 60 6-bromo-4-(4-(3,4-dichlorophenyl)-2-methylpiperazine-1-carbonyl)quinolin-2(1H)-one (60)
将1-Boc-3-甲基哌嗪替换成2-甲基哌嗪-1-羧酸叔丁酯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物60。LRMS(ESI)m/z 493(M+)Replace 1-Boc-3-methylpiperazine with tert-butyl 2-methylpiperazine-1-carboxylate and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-bromo -2-Oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product 60. LRMS(ESI)m/z 493(M+)
实施例61 4-(4-(3,4-二氯苯基)-2-甲基哌嗪-1-羰基)-6-甲氧基喹啉-2(1H)-酮(61)Example 61 4-(4-(3,4-dichlorophenyl)-2-methylpiperazine-1-carbonyl)-6-methoxyquinolin-2(1H)-one (61)
将1-Boc-3-甲基哌嗪替换成2-甲基哌嗪-1-羧酸叔丁酯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲氧基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物61。LRMS(ESI)m/z 446(M+)Replace 1-Boc-3-methylpiperazine with tert-butyl 2-methylpiperazine-1-carboxylate and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-methylpiperazine Oxy-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and other required raw materials, reagents and preparation methods are the same as in Example 1 to obtain product 61. LRMS(ESI)m/z 446(M+)
实施例62 4-(4-(3,4-二氯苯基)-2-甲基哌嗪-1-羰基)-6-羟基喹啉-2(1H)-酮(62)Example 62 4-(4-(3,4-dichlorophenyl)-2-methylpiperazine-1-carbonyl)-6-hydroxyquinolin-2(1H)-one (62)
将1-Boc-3-甲基哌嗪替换成2-甲基哌嗪-1-羧酸叔丁酯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-羟基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物62。LRMS(ESI)m/z 432(M+)Replace 1-Boc-3-methylpiperazine with 2-methylpiperazine-1-carboxylate tert-butyl ester and 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-hydroxy -2-Oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain product 62. LRMS(ESI)m/z 432(M+)
实施例63 4-(4-(3,4-二氯苯基)-2-甲基哌嗪-1-羰基)-6-硝基喹啉-2(1H)-酮(63)Example 63 4-(4-(3,4-dichlorophenyl)-2-methylpiperazine-1-carbonyl)-6-nitroquinolin-2(1H)-one (63)
将1-Boc-3-甲基哌嗪替换成2-甲基哌嗪-1-羧酸叔丁酯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-硝基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物63。LRMS(ESI)m/z 461(M+)Replace 1-Boc-3-methylpiperazine with 2-methylpiperazine-1-carboxylate tert-butyl ester, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid with 6-nitro Base-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain product 63. LRMS(ESI)m/z 461(M+)
实施例64 4-(8-(3,4-二氯苯基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-6-甲基喹啉-2(1H)-酮(64)Example 64 4-(8-(3,4-dichlorophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-6-methylquinoline-2(1H )-ketone(64)
将1-Boc-3-甲基哌嗪替换成3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物64。LRMS(ESI)m/z 442(M+)Replace 1-Boc-3-methylpiperazine with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, 2-oxo-1,2-dihydroquinoline- The 4-carboxylic acid was replaced by 6-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 64. LRMS(ESI)m/z 442(M+)
实施例65 6-溴-4-(8-(3,4-二氯苯基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)喹啉-2(1H)-酮(65)Example 65 6-bromo-4-(8-(3,4-dichlorophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)quinoline-2(1H) -ketone(65)
将1-Boc-3-甲基哌嗪替换成3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物65。LRMS(ESI)m/z 505(M+)Replace 1-Boc-3-methylpiperazine with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, 2-oxo-1,2-dihydroquinoline- 4-carboxylic acid was replaced by 6-bromo-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 65. LRMS(ESI)m/z 505(M+)
实施例66 4-(8-(3,4-二氯苯基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-6-甲氧基喹啉-2(1H)-酮(66)Example 66 4-(8-(3,4-dichlorophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-6-methoxyquinoline-2( 1H)-Kone(66)
将1-Boc-3-甲基哌嗪替换成3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物66。LRMS(ESI)m/z 458(M+)Replace 1-Boc-3-methylpiperazine with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, 2-oxo-1,2-dihydroquinoline- 4-carboxylic acid was replaced by 6-bromo-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 66. LRMS(ESI)m/z 458(M+)
实施例67 4-(8-(3,4-二氯苯基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-6-硝基喹啉-2(1H)-酮(67)Example 67 4-(8-(3,4-dichlorophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-6-nitroquinoline-2(1H )-ketone(67)
将1-Boc-3-甲基哌嗪替换成3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯，2-氧-1,2-二 氢喹啉-4-羧酸替换成6-硝基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物67。LRMS(ESI)m/z 473(M+)Replace 1-Boc-3-methylpiperazine with tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate, 2-oxo-1,2-dihydroquinoline- 4-carboxylic acid was replaced by 6-nitro-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 67. LRMS(ESI)m/z 473(M+)
实施例68 4-(8-(3,4-二氟苯基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)喹啉-2(1H)-酮(68)Example 68 4-(8-(3,4-difluorophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)quinolin-2(1H)-one (68 )
将1-Boc-3-甲基哌嗪替换成3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯，3,4-二氯溴苯替换成3,4-二氟溴苯，其余所需原料、试剂及制备方法同实施例1，得产物68。LRMS(ESI)m/z 396(M+)Replace 1-Boc-3-methylpiperazine with 3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester, 3,4-dichlorobromobenzene with 3,4 -Difluorobromobenzene, all the other required raw materials, reagents and preparation methods are the same as in Example 1 to obtain product 68. LRMS(ESI)m/z 396(M+)
实施例69 4-(8-(3,4-二氟苯基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-6-甲基喹啉-2(1H)-酮(69)Example 69 4-(8-(3,4-difluorophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-6-methylquinoline-2(1H )-ketone(69)
将1-Boc-3-甲基哌嗪替换成3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯，3,4-二氯溴苯替换成3,4-二氟溴苯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸其余所需原料、试剂及制备方法同实施例1，得产物69。LRMS(ESI)m/z 410(M+)Replace 1-Boc-3-methylpiperazine with 3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester, 3,4-dichlorobromobenzene with 3,4 -Difluorobromobenzene, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid replaced by 6-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid for the rest required The raw materials, reagents and preparation method were the same as in Example 1 to obtain product 69. LRMS(ESI)m/z 410(M+)
实施例70 6-溴-4-(8-(3,4-二氟苯基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)喹啉-2(1H)-酮(70)Example 70 6-bromo-4-(8-(3,4-difluorophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)quinoline-2(1H) -ketone(70)
将1-Boc-3-甲基哌嗪替换成3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯，3,4-二氯溴苯替换成3,4-二氟溴苯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧-1,2-二氢喹啉-4-羧酸其余所需原料、试剂及制备方法同实施例1，得产物70。LRMS(ESI)m/z 474(M+)Replace 1-Boc-3-methylpiperazine with 3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester, 3,4-dichlorobromobenzene with 3,4 -Difluorobromobenzene, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid is replaced by 6-bromo-2-oxo-1,2-dihydroquinoline-4-carboxylic acid and the rest of the required raw materials , reagents and preparation method are the same as in Example 1 to obtain product 70. LRMS(ESI)m/z 474(M+)
实施例71 4-(8-(3,4-二氟苯基)-3,8-二氮杂双环[3.2.1]辛烷-3-羰基)-6-硝基喹啉-2(1H)-酮(71)Example 71 4-(8-(3,4-difluorophenyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-6-nitroquinoline-2(1H )-ketone(71)
将1-Boc-3-甲基哌嗪替换成3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯，3,4-二氯溴苯替换成3,4-二氟溴苯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-硝基-2-氧-1,2-二氢喹啉-4-羧酸其余所需原料、试剂及制备方法同实施例1，得产物71。LRMS(ESI)m/z 441(M+)Replace 1-Boc-3-methylpiperazine with 3,8-diazabicyclo[3.2.1]octane-3-carboxylate tert-butyl ester, 3,4-dichlorobromobenzene with 3,4 -Difluorobromobenzene, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid replaced by 6-nitro-2-oxo-1,2-dihydroquinoline-4-carboxylic acid for the rest required The raw materials, reagents and preparation method are the same as in Example 1 to obtain the product 71. LRMS(ESI)m/z 441(M+)
实施例72 4-(9-(3,4-二氯苯基)-3,9-二氮杂螺[5.5]十一烷-3-羰基)喹啉-2(1H)-酮(72)Example 72 4-(9-(3,4-dichlorophenyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)quinolin-2(1H)-one (72)
将1-Boc-3-甲基哌嗪替换成3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物72。LRMS(ESI)m/z 470(M+)Replace 1-Boc-3-methylpiperazine with 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, and the rest of the required raw materials, reagents and preparation methods are the same as in Example 1, The product 72 was obtained. LRMS(ESI)m/z 470(M+)
实施例73 4-(9-(3,4-二氯苯基)-2-甲基-3,9-二氮杂螺[5.5]十一烷-3-羰基)喹啉-2(1H)-酮(73)Example 73 4-(9-(3,4-dichlorophenyl)-2-methyl-3,9-diazaspiro[5.5]undecane-3-carbonyl)quinoline-2(1H) -ketone(73)
将1-Boc-3-甲基哌嗪替换成2-甲基-3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯，其余所需原料、试剂及制备方法同实施例1，得产物73。LRMS(ESI)m/z 484(M+)Replace 1-Boc-3-methylpiperazine with 2-methyl-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, and other required raw materials, reagents and preparation methods As in Example 1, the product 73 was obtained. LRMS(ESI)m/z 484(M+)
实施例74 4-(9-(3,4-二氯苯基)-3,9-二氮杂螺[5.5]十一烷-3-羰基)-6-甲基喹啉-2(1H)-酮(74)Example 74 4-(9-(3,4-dichlorophenyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-6-methylquinoline-2(1H) -ketone(74)
将1-Boc-3-甲基哌嗪替换成3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物74。LRMS(ESI)m/z 484(M+)Replace 1-Boc-3-methylpiperazine with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, 2-oxo-1,2-dihydroquinoline-4 -Carboxylic acid was replaced by 6-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 74. LRMS(ESI)m/z 484(M+)
实施例75 46-溴-4-(9-(3,4-二氯苯基)-3,9-二氮杂螺[5.5]十一烷-3-羰基)喹啉-2(1H)-酮(75)Example 75 46-bromo-4-(9-(3,4-dichlorophenyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)quinoline-2(1H)- Ketones(75)
将1-Boc-3-甲基哌嗪替换成3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物75。LRMS(ESI)m/z 548(M+)Replace 1-Boc-3-methylpiperazine with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, 2-oxo-1,2-dihydroquinoline-4 -Carboxylic acid was replaced by 6-bromo-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 75. LRMS(ESI)m/z 548(M+)
实施例76 4-(9-(3,4-二氯苯基)-3,9-二氮杂螺[5.5]十一烷-3-羰基)-6-硝基喹啉-2(1H)-酮(76)Example 76 4-(9-(3,4-dichlorophenyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-6-nitroquinoline-2(1H) -ketone(76)
将1-Boc-3-甲基哌嗪替换成3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-硝基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物76。LRMS(ESI)m/z 515(M+)Replace 1-Boc-3-methylpiperazine with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, 2-oxo-1,2-dihydroquinoline-4 -Carboxylic acid was replaced by 6-nitro-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 76. LRMS(ESI)m/z 515(M+)
实施例77 4-(9-(3,4-二氟苯基)-3,9-二氮杂螺[5.5]十一烷-3-羰基)喹啉-2(1H)-酮(77)Example 77 4-(9-(3,4-difluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)quinolin-2(1H)-one (77)
将1-Boc-3-甲基哌嗪替换成3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯，3,4-二氯溴苯替换成3,4-二氟溴苯，其余所需原料、试剂及制备方法同实施例1，得产物77。LRMS(ESI)m/z 438(M+)Replace 1-Boc-3-methylpiperazine with 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, 3,4-dichlorobromobenzene with 3,4- Difluorobromobenzene, the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product 77. LRMS(ESI)m/z 438(M+)
实施例78 4-(9-(3,4-二氟苯基)-3,9-二氮杂螺[5.5]十一烷-3-羰基)-6-甲基喹啉-2(1H)-酮(78)Example 78 4-(9-(3,4-difluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-6-methylquinoline-2(1H) -ketone(78)
将1-Boc-3-甲基哌嗪替换成3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯，3,4-二氯溴苯替换成3,4-二氟溴苯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物78。LRMS(ESI)m/z 452(M+)Replace 1-Boc-3-methylpiperazine with 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, 3,4-dichlorobromobenzene with 3,4- Difluorobromobenzene, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid replaced by 6-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, the rest as required The raw materials, reagents and preparation method were the same as in Example 1 to obtain product 78. LRMS(ESI)m/z 452(M+)
实施例79 6-溴-4-(9-(3,4-二氟苯基)-3,9-二氮杂螺[5.5]十一烷-3-羰基)喹啉-2(1H)-酮(79)Example 79 6-bromo-4-(9-(3,4-difluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)quinoline-2(1H)- Ketones(79)
将1-Boc-3-甲基哌嗪替换成3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯，3,4-二氯溴苯替换成3,4-二氟溴苯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物79。LRMS(ESI)m/z 516(M+)Replace 1-Boc-3-methylpiperazine with 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, 3,4-dichlorobromobenzene with 3,4- Difluorobromobenzene, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid is replaced by 6-bromo-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and other required raw materials , reagent and preparation method are the same as in Example 1 to obtain product 79. LRMS(ESI)m/z 516(M+)
实施例80 4-(9-(3,4-二氟苯基)-3,9-二氮杂螺[5.5]十一烷-3-羰基)-6-硝基喹啉-2(1H)-酮(80)Example 80 4-(9-(3,4-difluorophenyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-6-nitroquinoline-2(1H) -ketone(80)
将1-Boc-3-甲基哌嗪替换成3,9-二氮杂螺[5.5]十一烷-3-羧酸叔丁酯，3,4-二氯溴苯替换成3,4-二氟溴苯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-硝基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物80。LRMS(ESI)m/z 483(M+)Replace 1-Boc-3-methylpiperazine with 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, 3,4-dichlorobromobenzene with 3,4- Difluorobromobenzene, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid was replaced by 6-nitro-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, the rest required The raw materials, reagents and preparation method were the same as those in Example 1, and the product 80 was obtained. LRMS(ESI)m/z 483(M+)
实施例81 4-(5-(3,4-二氯苯基)八氢吡咯并[3,4-c]吡咯-2-羰基)喹啉-2(1H)-酮(81)Example 81 4-(5-(3,4-dichlorophenyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)quinolin-2(1H)-one (81)
将1-Boc-3-甲基哌嗪替换成叔丁基六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸盐，其余所需原料、试剂及制备方法同实施例1，得产物81。LRMS(ESI)m/z 428(M+)Replace 1-Boc-3-methylpiperazine with tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, and the rest of the required raw materials, reagents and preparation methods are the same as in the examples 1, the product 81 was obtained. LRMS(ESI)m/z 428(M+)
实施例82 4-(5-(3,4-二氯苯基)八氢吡咯并[3,4-c]吡咯-2-羰基)-6-甲基喹啉-2(1H)-酮(82)Example 82 4-(5-(3,4-dichlorophenyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-6-methylquinolin-2(1H)-one ( 82)
将1-Boc-3-甲基哌嗪替换成叔丁基六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸盐，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物82。LRMS(ESI)m/z 442(M+)Replace 1-Boc-3-methylpiperazine with tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 2-oxo-1,2-dihydroquinoline -4-carboxylic acid was replaced by 6-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 82. LRMS(ESI)m/z 442(M+)
实施例83 6-溴-4-(5-(3,4-二氯苯基)八氢吡咯并[3,4-c]吡咯-2-羰基)喹啉-2(1H)-酮(83)Example 83 6-bromo-4-(5-(3,4-dichlorophenyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)quinolin-2(1H)-one (83 )
将1-Boc-3-甲基哌嗪替换成叔丁基六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸盐，2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物83。LRMS(ESI)m/z 505(M+)Replace 1-Boc-3-methylpiperazine with tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 2-oxo-1,2-dihydroquinoline -4-carboxylic acid was replaced by 6-bromo-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 83. LRMS(ESI)m/z 505(M+)
实施例84 4-(5-(3,4-二氯苯基)八氢吡咯并[3,4-c]吡咯-2-羰基)-6-甲氧基喹啉-2(1H)-酮(84)Example 84 4-(5-(3,4-dichlorophenyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-6-methoxyquinolin-2(1H)-one (84)
将1-Boc-3-甲基哌嗪替换成叔丁基六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸盐，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲氧基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物84。LRMS(ESI)m/z 458(M+)Replace 1-Boc-3-methylpiperazine with tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 2-oxo-1,2-dihydroquinoline -4-carboxylic acid was replaced by 6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 84. LRMS(ESI)m/z 458(M+)
实施例85 4-(5-(3,4-二氯苯基)八氢吡咯并[3,4-c]吡咯-2-羰基)-6-硝基喹啉-2(1H)-酮(85)Example 85 4-(5-(3,4-dichlorophenyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-6-nitroquinoline-2(1H)-one ( 85)
将1-Boc-3-甲基哌嗪替换成叔丁基六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸盐，2-氧-1,2-二氢喹啉-4-羧酸替换成6-硝基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物85。LRMS(ESI)m/z 473(M+)Replace 1-Boc-3-methylpiperazine with tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 2-oxo-1,2-dihydroquinoline -4-carboxylic acid was replaced by 6-nitro-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, and the rest of the required raw materials, reagents and preparation methods were the same as in Example 1 to obtain product 85. LRMS(ESI)m/z 473(M+)
实施例86 4-(5-(3,4-二氟苯基)八氢吡咯并[3,4-c]吡咯-2-羰基)喹啉-2(1H)-酮(86)Example 86 4-(5-(3,4-difluorophenyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)quinolin-2(1H)-one (86)
将1-Boc-3-甲基哌嗪替换成叔丁基六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸盐，3,4-二氯溴苯替换成3,4-二氟溴苯，其余所需原料、试剂及制备方法同实施例1，得产物86。LRMS(ESI)m/z 396(M+)Replace 1-Boc-3-methylpiperazine with tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 3,4-dichlorobromobenzene with 3, 4-Difluorobromobenzene, the rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product 86. LRMS(ESI)m/z 396(M+)
实施例87 4-(5-(3,4-二氟苯基)八氢吡咯并[3,4-c]吡咯-2-羰基)-6-甲基喹啉-2(1H)-酮(87)Example 87 4-(5-(3,4-difluorophenyl) octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-6-methylquinolin-2(1H)-one ( 87)
将1-Boc-3-甲基哌嗪替换成叔丁基六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸盐，3,4-二氯溴苯替换成3,4-二氟溴苯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物87。LRMS(ESI)m/z 410(M+)Replace 1-Boc-3-methylpiperazine with tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 3,4-dichlorobromobenzene with 3, 4-Difluorobromobenzene, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid replaced by 6-methyl-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, the rest The required raw materials, reagents and preparation method are the same as in Example 1 to obtain the product 87. LRMS(ESI)m/z 410(M+)
实施例88 6-溴-4-(5-(3,4-二氟苯基)八氢吡咯并[3,4-c]吡咯-2-羰基)喹啉-2(1H)-酮(88)Example 88 6-bromo-4-(5-(3,4-difluorophenyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)quinolin-2(1H)-one (88 )
将1-Boc-3-甲基哌嗪替换成叔丁基六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸盐，3,4-二氯溴苯替换成3,4-二氟溴苯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-溴-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物88。LRMS(ESI)m/z 474(M+)Replace 1-Boc-3-methylpiperazine with tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 3,4-dichlorobromobenzene with 3, 4-difluorobromobenzene, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid was replaced by 6-bromo-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, the rest The required raw materials, reagents and preparation method are the same as in Example 1 to obtain the product 88. LRMS(ESI)m/z 474(M+)
实施例89 4-(5-(3,4-二氟苯基)八氢吡咯并[3,4-c]吡咯-2-羰基)-6-甲氧基喹啉-2(1H)-酮(89)Example 89 4-(5-(3,4-difluorophenyl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-6-methoxyquinolin-2(1H)-one (89)
将1-Boc-3-甲基哌嗪替换成叔丁基六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸盐，3,4-二氯溴苯替换成3,4-二氟溴苯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-甲氧基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物89。LRMS(ESI)m/z426(M+)Replace 1-Boc-3-methylpiperazine with tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 3,4-dichlorobromobenzene with 3, 4-Difluorobromobenzene, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid replaced by 6-methoxy-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, The rest of the required raw materials, reagents and preparation methods are the same as in Example 1 to obtain the product 89. LRMS(ESI)m/z426(M+)
实施例90 4-(5-(3,4-二氟苯基)八氢吡咯并[3,4-c]吡咯-2-羰基)-6-硝基喹啉-2(1H)-酮(90)Example 90 4-(5-(3,4-difluorophenyl) octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)-6-nitroquinoline-2(1H)-one ( 90)
将1-Boc-3-甲基哌嗪替换成叔丁基六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸盐，3,4-二氯溴苯替换成3,4-二氟溴苯，2-氧-1,2-二氢喹啉-4-羧酸替换成6-硝基-2-氧-1,2-二氢喹啉-4-羧酸，其余所需原料、试剂及制备方法同实施例1，得产物90。LRMS(ESI)m/z 441(M+)Replace 1-Boc-3-methylpiperazine with tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate, 3,4-dichlorobromobenzene with 3, 4-Difluorobromobenzene, 2-oxo-1,2-dihydroquinoline-4-carboxylic acid replaced by 6-nitro-2-oxo-1,2-dihydroquinoline-4-carboxylic acid, the rest The required raw materials, reagents and preparation method are the same as in Example 1 to obtain the product 90. LRMS(ESI)m/z 441(M+)
药理活性试验实施例Pharmacological Activity Test Example
药理实施例1.化合物对3CL蛋白酶的分子水平抑制活性测试Pharmacological Example 1. Molecular Level Inhibitory Activity Test of Compounds on 3CL Protease
实验原理：基于SARS-CoV-2 3CLpro蛋白是一种蛋白水解酶的基本特点，建立荧光法检测SARS-CoV-2 3CLpro蛋白活性的筛选体系。SARS-CoV-2 3CLpro蛋白可特异性剪切P1位为Gln(Q)的底物，其活性检测可采用荧光多肽为底物，通过检测荧光信号的生成来反映其蛋白水解酶的活性。Experimental principle: Based on the basic characteristics of SARS-CoV-2 3CLpro protein as a proteolytic enzyme, a screening system for detecting the activity of SARS-CoV-2 3CLpro protein by fluorescence method was established. The SARS-CoV-2 3CLpro protein can specifically cleave substrates whose P1 position is Gln(Q), and its activity detection can use fluorescent peptides as substrates to reflect the activity of its proteolytic enzymes by detecting the generation of fluorescent signals.
表1：部分化合物抑制率以及IC 50数据 Table 1: Inhibition rate and IC 50 data of some compounds
Compoundcompound Inhibition rate(20μM)Inhibition rate(20μM) IC 50(μM) IC50 (μM)
55 96.57±0.5896.57±0.58 0.15±0.060.15±0.06
1717 99.21±0.7299.21±0.72 0.29±0.060.29±0.06
1818 95.43±0.2195.43±0.21 0.74±0.220.74±0.22
2020 107.96±6.31107.96±6.31 0.56±0.020.56±0.02
22twenty two 115.78±0.92115.78±0.92 0.51±0.030.51±0.03
23twenty three 113.27±3.79113.27±3.79 0.13±0.020.13±0.02
3030 118.68±5.95118.68±5.95 0.14±0.050.14±0.05
3131 113.55±6.12113.55±6.12 0.18±0.000.18±0.00
3535 103.96±2.84103.96±2.84 0.69±0.200.69±0.20
3838 96.2±1.296.2±1.2 1.18±0.141.18±0.14
4242 96.7±0.896.7±0.8 1.15±0.251.15±0.25
4343 88.5±2.088.5±2.0 3.55±0.183.55±0.18
4444 95.8±1.095.8±1.0 1.90±0.321.90±0.32
4545 96.0±1.196.0±1.1 2.41±0.082.41±0.08
4646 90.3±1.890.3±1.8 1.92±0.261.92±0.26
5050 93.6±1.593.6±1.5 1.52±0.141.52±0.14
5252 94.9±1.494.9±1.4 2.51±0.182.51±0.18
5454 92.5±0.792.5±0.7 1.16±0.091.16±0.09
实验结论：上述18个化合物对SARS-CoV-2 3CLpro的活性具有良好的抑制效果。Experimental conclusion: the above 18 compounds have a good inhibitory effect on the activity of SARS-CoV-2 3CLpro.
药理实施例2.化合物对SARS-CoV-2病毒细胞水平抑制活性测试Pharmacological Example 2. The compound is tested for the inhibitory activity of SARS-CoV-2 virus cell level
采用荧光定量PCR检测原病毒液每毫升所含拷贝数。Fluorescent quantitative PCR was used to detect the copy number contained in each milliliter of the original virus solution.
采用TB Green Premix(Takara，Cat#RR820A)混好反应体系，在StepOne Plus Real-time PCR仪(品牌：ABI)进行扩增反应和读数。计算原病毒液每毫升所含拷贝数。步骤如下：TB Green Premix (Takara, Cat#RR820A) was used to mix the reaction system, and the amplification reaction and reading were performed on the StepOne Plus Real-time PCR instrument (brand: ABI). Calculate the copy number per milliliter of the original virus solution. Proceed as follows:
①首先建立标准品：将质粒pMT-RBD(质粒由中国科学院武汉病毒研究所提供)稀释成5×10 8copies/μL，5×10 7copies/μL，5×10 6copies/μL,5×10 5copies/μL，5×10 4copies/μL,5×10 3copies/μL,5×10 2copies/μL。取2μL标准品或cDNA模板用于qPCR反应。 ① First establish a standard product: Dilute the plasmid pMT-RBD (the plasmid is provided by the Wuhan Institute of Virology, Chinese Academy of Sciences) to 5×10 8 copies/μL, 5×10 7 copies/μL, 5×10 6 copies/μL, 5× 10 5 copies/μL, 5×10 4 copies/μL, 5×10 3 copies/μL, 5×10 2 copies/μL. Take 2 μL of standard or cDNA template for qPCR reaction.
②实验过程中所用引物序列如下(均为5’-3’方向表示)：②The sequences of the primers used in the experiment are as follows (both indicated in the 5'-3' direction):
RBD-qF:CAATGGTTTAACAGGCACAGGRBD-qF:CAATGGTTTAACAGGCACAGG
RBD-qR:CTCAAGTGTCTGTGGATCACGRBD-qR:CTCAAGTGTCTGTGGATCACG
③反应程序如下：③The reaction procedure is as follows:
预变性：95℃5分钟；Pre-denaturation: 95°C for 5 minutes;
循环参数：95℃15秒，54℃15秒，72℃30秒，共40个循环。Cycle parameters: 95°C for 15 seconds, 54°C for 15 seconds, 72°C for 30 seconds, a total of 40 cycles.
实验结果：Experimental results:
10μM浓度下，部分化合物对SARS-CoV-2抑制率可达到90％以上。结果如表2所示。At a concentration of 10 μM, the inhibition rate of some compounds against SARS-CoV-2 can reach more than 90%. The results are shown in Table 2.
Compoundcompound Inhibition rate(10μM)Inhibition rate(10μM)
55 96％96%
1212 95％95%
1818 89％89%
3030 99％99%
3131 96％96%
3838 97％97%
4242 100％100%
4343 98％98%
4444 99％99%
4545 100％100%
4646 96％96%
5050 96％96%
5252 96％96%
5454 94％94%
5555 97％97%
病毒增殖抑制实验的结果显示，多个受试化合物在10μM的浓度下，能够有效抑制感染上清中SARS-CoV-2病毒基因组的复制，抑制率大于90％。部分化合物完成了IC 50数据测定，如图1中所示，尤其是化合物5的IC 50值为0.702μM，与已报道的拟 肽类抑制剂活性基本相当，且作为非共价小分子抑制剂，与共价抑制剂相比，毒性可能更低，适合长期使用。 The results of the virus proliferation inhibition experiment showed that multiple tested compounds could effectively inhibit the replication of the SARS-CoV-2 virus genome in the infection supernatant at a concentration of 10 μM, and the inhibition rate was greater than 90%. Some compounds have completed the IC 50 data determination, as shown in Figure 1, especially the IC 50 value of compound 5 is 0.702μM, which is basically equivalent to the activity of the reported peptidomimetic inhibitors, and as a non-covalent small molecule inhibitor , may be less toxic than covalent inhibitors and suitable for long-term use.
实施例3.小鼠药代动力学实验Embodiment 3. mouse pharmacokinetic experiment
给药方案：Dosing regimen:
健康小鼠9只，随机分成3组，每组3只。分别灌胃、腹腔注射和静脉注射给予化合物5，给药剂量为灌胃20mg/kg，腹腔注射10mg/kg，静脉注射5mg/kg，药物以DMSO/吐温80/生理盐水(5:5:90，v/v/v)配制。试验前禁食12h，自由饮水。给药后2h统一进食。Nine healthy mice were randomly divided into 3 groups with 3 mice in each group. Gavage, intraperitoneal injection and intravenous injection were given Compound 5 respectively, and dosage was 20mg/kg for intragastric injection, 10mg/kg for intraperitoneal injection, and 5mg/kg for intravenous injection, and the medicine was prepared in the form of DMSO/Tween 80/normal saline (5:5: 90, v/v/v) formulation. Fasting 12h before the test, free to drink water. Eat uniformly 2 hours after administration.
采样时间点及样品处理：Sampling time points and sample processing:
灌胃给药：给药后0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；腹腔给药：给药后5min，0.25，0.5，1.0，2.0，4.0，6.0，8.0，24h；静脉给药：给药后0，5min，0.25，0.5，1.0，2.0，4.0，6.0，8.0和24h；Oral administration: 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration; intraperitoneal administration: 5min after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24h; intravenous Administration: 0, 5min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h after administration;
按以上设定时间点经小鼠眼球后静脉丛取血0.3mL，置肝素化试管中，11000rpm离心5min，分离血浆，于-20℃冰箱中冷冻。Take 0.3 mL of blood through the retroocular venous plexus of the mouse at the time point set above, put it in a heparinized test tube, centrifuge at 11,000 rpm for 5 min, separate the plasma, and freeze it in a -20°C refrigerator.
实验结果如下表中所示：The experimental results are shown in the table below:
Figure PCTCN2022116584-appb-000049
Figure PCTCN2022116584-appb-000049
小鼠灌胃给予20mg/kg化合物5后，血浆浓度达峰时间T max为0.5h，达峰浓度C max为865ng/ml；药时曲线下面积AUC 0-t为1350·h/ml；末端消除半衰期t 1/2为1.13h。静脉注射给予5mg/kg化合物5后，AUC 0-t为1210ng·h/ml；小鼠腹腔给予10mg/kg化合物5后，血浆浓度达峰时间T max为0.25h，达峰浓度C max为1610ng/ml；药时曲线下面积AUC 0-t为2280·h/ml；末端消除半衰期t 1/2为0.78h。经剂量标准化后，小鼠灌胃给予20mg/kg化合物5后的绝对生物利用度为28.1％。小鼠腹腔给予10mg/kg化合物5后的绝对生物利用度为95.0％。 After intragastric administration of 20 mg/kg compound 5 to mice, the time to peak plasma concentration T max was 0.5 h, and the peak concentration C max was 865 ng/ml; the area under the drug-time curve AUC 0-t was 1350 h/ml; The elimination half-life t 1/2 is 1.13h. After intravenous injection of compound 5 at 5 mg/kg, the AUC 0-t was 1210 ng h/ml; after intraperitoneal administration of 10 mg/kg compound 5 to mice, the time to peak plasma concentration T max was 0.25 h, and the peak concentration C max was 1610 ng /ml; the area under the drug-time curve AUC 0-t was 2280 h/ml; the terminal elimination half-life t 1/2 was 0.78h. After dose standardization, the absolute bioavailability of 20 mg/kg compound 5 in mice was 28.1%. The absolute bioavailability of compound 5 after intraperitoneal administration of 10 mg/kg to mice was 95.0%.
实验结论：Experimental results:
从以上实验结果可看出，在小鼠药代动力学实验中，化合物5表现出较好的绝对生物利用度，灌胃给药达到28.1％，腹腔给药达到95.0％。好于已报道的拟肽类抑制剂。From the above experimental results, it can be seen that in the mouse pharmacokinetic experiment, compound 5 showed a relatively good absolute bioavailability, which reached 28.1% by intragastric administration and 95.0% by intraperitoneal administration. Better than the reported peptidomimetic inhibitors.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

  1. 一种通式I所示结构的喹啉酮酰胺类化合物，及其外消旋体、R-异构体、S-异构体、可药用盐或它们混合物：A quinolinone amide compound with the structure shown in general formula I, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or their mixture:
    Figure PCTCN2022116584-appb-100001
    Figure PCTCN2022116584-appb-100001
    其中，in,
    X为CH或N；其中，当X为CH时，所述的CH上的氢原子可以被R 1取代； X is CH or N; wherein, when X is CH, the hydrogen atom on the CH can be replaced by R 1 ;
    Y选自下组：-(CH 2) n-、-CO-、-CONH-、或-SO 2-，其中n为0、1、2、3或4； Y is selected from the group consisting of -(CH 2 ) n -, -CO-, -CONH-, or -SO 2 -, wherein n is 0, 1, 2, 3 or 4;
    Figure PCTCN2022116584-appb-100002
    环选自下组：4-7元杂单环、或7-20元杂多环(包括稠环、桥环或螺环)；
    Figure PCTCN2022116584-appb-100002
    The ring is selected from the group consisting of 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
    R 1和R 2选自下组：氢、卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、-S(O) 2OH、C1-C6烷基磺酰基、C6-C10芳基、和3-12元杂环基； R 1 and R 2 are selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 Alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1 -C6 alkylsulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic group;
    R 3为位于A环上的1、2、3或4个选自下组的取代基：氢、卤素、氰基、硝基、氨基、胺基、羟基、羟甲基、羧基、巯基、-S(O) 2OH、C1-C6烷基磺酰基、C1-C6烷基、卤素取代的C1-C6烷基、芳基或杂芳环取代的C1-C6烷基、环烷烃或杂环烃取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C3-C8环烷基、C3-C8卤代环烷基、C6-C10芳基、3-12元杂环基、
    Figure PCTCN2022116584-appb-100003
    Figure PCTCN2022116584-appb-100004
    其中，两个相邻的取代基可以与
    Figure PCTCN2022116584-appb-100005
    环上的原子首尾相连形成并环，或
    Figure PCTCN2022116584-appb-100006
    环上同一原子上的两个取代基首尾相连与
    Figure PCTCN2022116584-appb-100007
    环形成螺环；且当A环为哌嗪环时，所述的R 3不为H；     R 3 is 1, 2, 3 or 4 substituents selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, - S(O) 2 OH, C1-C6 alkylsulfonyl, C1-C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaryl ring substituted C1-C6 alkyl, cycloalkane or heterocyclic hydrocarbon Substituted C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 3-12 membered heterocyclyl,
    Figure PCTCN2022116584-appb-100003
    Figure PCTCN2022116584-appb-100004
    Among them, two adjacent substituents can be with
    Figure PCTCN2022116584-appb-100005
    the atoms in the ring are joined end to end to form a combined ring, or
    Figure PCTCN2022116584-appb-100006
    The two substituents on the same atom on the ring are connected end to end with
    Figure PCTCN2022116584-appb-100007
    The ring forms a spiro ring; and when the A ring is a piperazine ring, the R 3 is not H;
    Figure PCTCN2022116584-appb-100008
    环选自下组：4-7元杂单环、或7-20元杂多环(包括稠环、桥环或螺环)；
    Figure PCTCN2022116584-appb-100008
    The ring is selected from the group consisting of 4-7 membered heteromonocyclic rings, or 7-20 membered heteropolycyclic rings (including fused rings, bridged rings or spiro rings);
    R 4各自独立地选自下组：取代或未取代的苯基、取代或未取代的5-12元杂芳基；其中，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、C1-C6烷基磺酰基、C6-C10芳基、和3-12元杂环基； R 4 are each independently selected from the following group: substituted or unsubstituted phenyl, substituted or unsubstituted 5-12 membered heteroaryl; wherein, the substitution means that one or more hydrogen atoms on the group are selected Replacement by substituents from the following group: halogen, C1-C6 alkyl, halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkylsulfonyl, C6-C10 aryl , and 3-12 membered heterocyclic groups;
    R 5和R 6各自独立地选自下组：氢、卤素、氰基、硝基、氨基、胺基、羟基、羟甲基、羧基、巯基、-S(O) 2OH、C1-C6烷基磺酰基、C1-C6烷基、卤素取代的C1-C6烷基、芳基或杂芳环取代的C1-C6烷基、被C3-C8环烷烃、3-8元杂环烃、7-12元螺杂环烃或9-12元稠杂环烃取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C3-C8环烷基、C3-C8卤代环烷基、C3-C10芳基或杂芳基、3-12元杂环基； R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1-C6 alkane Sulfonyl, C1-C6 alkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkyl substituted by aryl or heteroaryl ring, C3-C8 cycloalkane, 3-8 membered heterocyclic hydrocarbon, 7- C1-C6 alkyl, C1-C6 alkoxy, halogen substituted C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 substituted by 12-membered spiro heterocyclic hydrocarbon or 9-12-membered fused heterocyclic hydrocarbon Halogenated cycloalkyl, C3-C10 aryl or heteroaryl, 3-12 membered heterocyclic group;
    其中，所述杂芳环、杂稠环或杂环基各自独立地含有1～4个选自氧、硫和氮中的杂原子；除非特别说明，所述的烷基、烷氧基、烯基、炔基、环烷烃、环烷基、杂环烃、杂环基、芳基、杂芳基各自独立地被1-3个选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、C1-C6烷基磺酰基、C6-C10芳基、和3-12元杂环基；Wherein, the heteroaromatic ring, heterofused ring or heterocyclic group each independently contain 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; unless otherwise specified, the alkyl, alkoxy, alkene Base, alkynyl, cycloalkane, cycloalkyl, heterocyclic hydrocarbon, heterocyclyl, aryl, heteroaryl are each independently substituted by 1-3 substituents selected from the group consisting of halogen, C1-C6 alkyl , Halogen substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 Cycloalkyl, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, C1-C6 alkylsulfonyl, C6-C10 aryl, and 3-12 membered heterocyclic groups;
    所述的卤素为F、Cl、Br或I。The halogen is F, Cl, Br or I.
  2. 如权利要求1所述的喹啉酮酰胺类化合物，及其外消旋体、R-异构体、S-异构体、可药用盐或它们混合物，其特征在于，所述的
    Figure PCTCN2022116584-appb-100009
    环选自下组：
    Figure PCTCN2022116584-appb-100010
    Figure PCTCN2022116584-appb-100011
    其中m 1，m 2，n 1和n 2分别选自0、1、2、3或4；X 1分别选自CH 2，CH 2CH 2和O；Y分别选自CH和N。     Quinolinone amide compound as claimed in claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or their mixture, is characterized in that, described
    Figure PCTCN2022116584-appb-100009
    Ring is selected from the following group:
    Figure PCTCN2022116584-appb-100010
    Figure PCTCN2022116584-appb-100011
    wherein m 1 , m 2 , n 1 and n 2 are selected from 0, 1, 2, 3 or 4; X 1 is selected from CH 2 , CH 2 CH 2 and O; Y is selected from CH and N.
  3. 如权利要求1所述的喹啉酮酰胺类化合物，及其外消旋体、R-异构体、S-异构体、可药用盐或它们混合物，其特征在于，所述的R 3选自下组的取代基：氢、羟基、羟甲基、羧基、C1-C6烷基、卤素取代的C1-C6烷基、芳基或杂芳环取代的C1-C6烷基、环烷烃或杂环烃取代的C1-C6烷基、
    Figure PCTCN2022116584-appb-100012
    其中，两个相邻的取代基可以与
    Figure PCTCN2022116584-appb-100013
    环上的原子首尾相连形成并环，或
    Figure PCTCN2022116584-appb-100014
    环上同一原子上的两个取代基首尾相连与
    Figure PCTCN2022116584-appb-100015
    环形成螺环；     Quinolinone amide compound as claimed in claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or their mixture, it is characterized in that, described R 3 A substituent selected from the group consisting of hydrogen, hydroxyl, hydroxymethyl, carboxyl, C1-C6 alkyl, halogen substituted C1-C6 alkyl, aryl or heteroaryl ring substituted C1-C6 alkyl, cycloalkane or Heterocyclic hydrocarbon substituted C1-C6 alkyl,
    Figure PCTCN2022116584-appb-100012
    Among them, two adjacent substituents can be with
    Figure PCTCN2022116584-appb-100013
    the atoms in the ring are joined end to end to form a combined ring, or
    Figure PCTCN2022116584-appb-100014
    The two substituents on the same atom on the ring are connected end to end with
    Figure PCTCN2022116584-appb-100015
    The ring forms a spiral ring;
    R 5和R 6选自下组：氢、卤素、氰基、硝基、氨基、胺基、羟基、羟甲基、羧基、巯基、-S(O) 2OH、C1-C6烷基磺酰基、C1-C6烷基、卤素取代的C1-C6烷基、芳基或杂芳环取代的C1-C6烷基、环烷烃或杂环烃取代的C1-C6烷基、C1-C6烷氧基、卤素取代的C1-C6烷氧基、C3-C8环烷基、C3-C8卤代环烷基、C6-C10芳基、3-12元杂环基。 R 5 and R 6 are selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto, -S(O) 2 OH, C1-C6 alkylsulfonyl , C1-C6 alkyl, C1-C6 alkyl substituted by halogen, C1-C6 alkyl substituted by aryl or heteroaryl ring, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon, C1-C6 alkoxy , C1-C6 alkoxyl substituted by halogen, C3-C8 cycloalkyl, C3-C8 halocycloalkyl, C6-C10 aryl, 3-12 membered heterocyclic group.
  4. 如权利要求1所述的喹啉酮酰胺类化合物，及其外消旋体、R-异构体、S-异构体、可药用盐或它们混合物，其特征在于，所述的R 4各自独立地选自下组：取代或未取代的苯基，所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C6烷基、卤素取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷氧基羰基、卤素取代的C1-C6烷氧基、氰基、硝基、氨基、羟基、羟甲基、羧基、巯基、-S(O) 2OH、C1-C6烷基磺酰基。 Quinolinone amide compounds as claimed in claim 1, and racemates, R-isomers, S-isomers, pharmaceutically acceptable salts or mixtures thereof, wherein said R 4 Each independently selected from the following group: substituted or unsubstituted phenyl, the substitution means that one or more hydrogen atoms on the group are replaced by substituents selected from the group: halogen, C1-C6 alkyl, halogen Substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, halogen substituted C1-C6 alkoxy, cyano, nitro, amino, hydroxyl, hydroxymethyl, carboxyl, mercapto , -S(O) 2 OH, C1-C6 alkylsulfonyl.
  5. 如权利要求1所述的喹啉酮酰胺类化合物，及其外消旋体、R-异构体、S-异构 体、可药用盐或它们混合物，其特征在于，所述的
    Figure PCTCN2022116584-appb-100016
    选自下组：
    Figure PCTCN2022116584-appb-100017
    Figure PCTCN2022116584-appb-100018
    其中m 1，和n 1可分别选自0、1或2；X 1可分别选自CH 2和CH 2CH 2；Y选自N。     Quinolinone amide compound as claimed in claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or their mixture, is characterized in that, described
    Figure PCTCN2022116584-appb-100016
    Select from the group:
    Figure PCTCN2022116584-appb-100017
    Figure PCTCN2022116584-appb-100018
    Where m 1 and n 1 can be selected from 0, 1 or 2 respectively; X 1 can be selected from CH 2 and CH 2 CH 2 respectively; Y can be selected from N.
  6. 如权利要求1所述的喹啉酮酰胺类化合物，及其外消旋体、R-异构体、S-异构体、可药用盐或它们混合物，其特征在于，所述的R 3选自下组的取代基：氢、芳基或杂芳环取代的C1-C6烷基、环烷烃或杂环烃取代的C1-C6烷基、
    Figure PCTCN2022116584-appb-100019
    Figure PCTCN2022116584-appb-100020
    Quinolinone amide compound as claimed in claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or their mixture, it is characterized in that, described R 3 A substituent selected from the following group: C1-C6 alkyl substituted by hydrogen, aryl or heteroaryl ring, C1-C6 alkyl substituted by cycloalkane or heterocyclic hydrocarbon,
    Figure PCTCN2022116584-appb-100019
    Figure PCTCN2022116584-appb-100020
  7. 如权利要求1所述的喹啉酮酰胺类化合物，及其外消旋体、R-异构体、S-异构体、可药用盐或它们混合物，其特征在于，所述的化合物选自下组：Quinolinone amide compound as claimed in claim 1, and its racemate, R-isomer, S-isomer, pharmaceutically acceptable salt or their mixture, is characterized in that, described compound is selected from From the next group:
    Figure PCTCN2022116584-appb-100021
    Figure PCTCN2022116584-appb-100021
    Figure PCTCN2022116584-appb-100022
    Figure PCTCN2022116584-appb-100022
    Figure PCTCN2022116584-appb-100023
    Figure PCTCN2022116584-appb-100023
    Figure PCTCN2022116584-appb-100024
    Figure PCTCN2022116584-appb-100024
    Figure PCTCN2022116584-appb-100025
    Figure PCTCN2022116584-appb-100025
    Figure PCTCN2022116584-appb-100026
    Figure PCTCN2022116584-appb-100026
    Figure PCTCN2022116584-appb-100027
    Figure PCTCN2022116584-appb-100027
    Figure PCTCN2022116584-appb-100028
    Figure PCTCN2022116584-appb-100028
    Figure PCTCN2022116584-appb-100029
    Figure PCTCN2022116584-appb-100029
    Figure PCTCN2022116584-appb-100030
    Figure PCTCN2022116584-appb-100030
  8. 一种药物组合物，其特征在于，所述的药物组合物包括：如权利要求1所述的式I化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种，以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。A kind of pharmaceutical composition, it is characterized in that, described pharmaceutical composition comprises: formula I compound as claimed in claim 1, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer One or more of the conformers or their mixtures, and one or more of pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
  9. 如权利要求1所述的式I化合物，其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物的用途，其特征在于，用于制备治疗或预防与3CL蛋白酶活性相关的疾病的药物组合物。Formula I compound as claimed in claim 1, the purposes of its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or their mixture, it is characterized in that, for the preparation of treatment or Pharmaceutical compositions for the prevention of diseases associated with 3CL protease activity.
  10. 如权利要求8所述的用途，其特征在于，所述的疾病是存在3CL蛋白酶的病毒引发的疾病，较佳地，所述的病毒选自下组：SARS-CoV-2、SARS-CoV、MERS-CoV、诺如病毒，或其组合。The use according to claim 8, wherein the disease is a disease caused by a virus with 3CL protease, preferably, the virus is selected from the group consisting of SARS-CoV-2, SARS-CoV, MERS-CoV, Norovirus, or a combination thereof.
PCT/CN2022/116584 2021-09-02 2022-09-01 Quinolinone amide-containing compound, preparation method therefor, pharmaceutical composition thereof, and use thereof WO2023030459A1 (en)

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US12030904B2 (en) 2020-08-24 2024-07-09 Gilead Sciences, Inc. Phospholipid compounds and uses thereof
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