WO2022171198A1 - Influenza virus inhibitor and use thereof - Google Patents

Influenza virus inhibitor and use thereof Download PDF

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WO2022171198A1
WO2022171198A1 PCT/CN2022/077312 CN2022077312W WO2022171198A1 WO 2022171198 A1 WO2022171198 A1 WO 2022171198A1 CN 2022077312 W CN2022077312 W CN 2022077312W WO 2022171198 A1 WO2022171198 A1 WO 2022171198A1
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alkylene
saturated
halogen
membered
unsaturated
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PCT/CN2022/077312
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French (fr)
Chinese (zh)
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朱晓鹤
关慧平
董利明
戴维扬
李加文
徐浩宇
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扬子江药业集团有限公司
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Priority to CN202280013478.0A priority Critical patent/CN117120441A/en
Publication of WO2022171198A1 publication Critical patent/WO2022171198A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—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 systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the present invention relates to a new class of compounds as influenza virus replication inhibitors and their use in the treatment of influenza, particularly as influenza virus cap-dependent endonuclease inhibitors.
  • Influenza (flu) is an acute respiratory infectious disease caused by influenza virus that seriously endangers human health. Influenza in humans is caused by influenza subtypes A and B, according to the type of hemagglutinin (H or HA) and neuraminidase (N) antigens, influenza virus A can be further classified, such as the subtypes that have been found to exist H1N1, H1N2, H2N2, H3N1, etc.
  • H or HA hemagglutinin
  • N neuraminidase
  • the RNA polymerase of influenza virus is responsible for the replication and transcription of viral RNA and is a heterotrimer composed of 3 subunits: polymerase acid (PA), polymerase base 1 (PB1) and polymerase base 2 (PB2).
  • the transcription of influenza virus RNA has a special "cap” mechanism.
  • the PB2 subunit is responsible for recognizing and binding the "cap structure" of the host pre-mRNA, and the PA subunit cleaves the host mRNA as a primer to initiate the transcription process. Cleaved mRNA primers are used in the PB1 subunit for viral mRNA synthesis.
  • cap-dependent endonuclease of the PA subunit is very conserved in the process of influenza mutation, it is necessary for the life process of the virus, and the binding site is specific, so this binding domain is very suitable as a target for anti-influenza drugs. for the development of new anti-influenza drugs.
  • Baloxavir a new anti-influenza agent with this mechanism of action, has been marketed, which can inhibit the synthesis of viral mRNA by inhibiting cap-dependent endonuclease, and ultimately inhibit virus proliferation.
  • cap-dependent endonuclease a new anti-influenza agent with this mechanism of action
  • the present invention provides a compound of formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkane optionally substituted by halogen base, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1a , -C 0-4 alkylene -OC(O)R 1a , -C 0-4 alkylene-SR 1a , -C 0-4 alkylene-C(O)R 1a , -C 0-4 alkylene-C(O)OR 1a , -C 0-4 alkylene-C(O)NR 1a R 1b , -C 0-4 alkylene-NR 1a R 1b , -C 0-4 alkylene-NR 1a C(O)R 1b
  • R 1a and R 1b are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ; Wherein, the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring group, aromatic heterocyclic group can be further replaced by one, two or three independent R
  • Each R 1c is independently selected from hydrogen, -C 1-6 linear or branched alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C optionally substituted by halogen C 2-6 alkynyl, halogen, cyano, -OH, -SH, -OC 1-6 alkyl, -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1- 6 alkyl), -N(C 1-6 alkyl) (C 1-6 alkyl), -C 0-4 alkylene-S(O) 2 R 1d , -C 0-4 alkylene- S(O)R 1d , -C 0-4 alkylene-S(O) 2 NR 1d R 1e , -C 0-4 alkylene-S(O)NR 1d R 1e ;
  • R 1d and R 1e are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ;
  • R 1 and R 2 , R 3 and R 4 , R 5 and R 6 are formed together with the connecting atoms, respectively Saturated or unsaturated 3- to 10-membered carbocyclic groups, saturated or unsaturated 4- to 10-membered heterocycloalkyl groups; the carbocyclic groups and heterocycloalkyl groups may be further replaced by one, two, three, four one, five, six or seven independent R 1d substitutions;
  • Each R 1d is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1e , -C 0-4 alkylene-OC(O)R 1e , -C 0-4 Alkylene-C(O)R 1e , -C 0-4 alkylene-C(O)OR 1e , -C 0-4 alkylene-C(O)NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 alkylene-NR 1e C(O)R 1f , -C 0-4 alkylene-(saturated or uns
  • R 1e and R 1f are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any Select -C 2-6 alkynyl substituted by halogen, C 1-6 alkyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0 ⁇ 4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene- (5-10-membered aromatic heterocyclic group); wherein, the alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocycloalkyl group, aryl ring group, aromatic heterocyclic group may be further composed of
  • Each R 1g is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen base, halogen, cyano, -SH, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl) base), -N(C 1-6 alkyl) (C 1-6 alkyl);
  • R 1ds Two independent R 1ds are formed together with connected atoms Saturated or unsaturated 3-10-membered carbocyclic group, saturated or unsaturated 4-10-membered heterocycloalkyl, 6-10-membered aromatic ring group, 5-10-membered aromatic heterocyclic group; wherein carbocyclic group, heterocyclic group Cycloalkyl, aryl, and aryl heterocyclyl may be further substituted with one, two, three, four or five R 1h ;
  • Each R 1h is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1i , -C 0-4 alkylene-OC(O)R 1i , -C 0-4 Alkylene-C(O)R 1i , -C 0-4 alkylene-C(O)OR 1i , -C 0-4 alkylene-C(O)NR 1i R 1j , -C 0-4 Alkylene-NR 1i R 1j , -C 0-4 Alkylene-NR 1i R 1j , -C 0-4 alkylene-NR 1i C(O)R 1j , -C 0-4 alkylene-(saturated or uns
  • R 1i and R 1j are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ;
  • A is selected from a saturated or unsaturated carbocyclic group, a saturated or unsaturated heterocycloalkane composed of 5 to 30 atoms consisting of a monocyclic, bi-fused, tri-fused, tetra-fused, penta-fused or hexa-fused ring wherein the carbocyclyl, heterocycloalkyl, aryl, and aromatic heterocyclyl may be further combined with one, two, three, four, five, six or seven R A1 substitutions;
  • Each R A1 is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR A2 , -C 0-4 alkylene-OC(O)R A2 , -C 0-4 Alkylene-C(O)R A2 , -C 0-4 alkylene-C(O)OR A2 , -C 0-4 alkylene-C(O)NR A2 R A3 , -C 0-4 Alkylene-NR A2 R A3 , -C 0-4 alkylene-NR A2 C(O)R A3 , -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group) , -
  • R A2 and R A3 are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ; Or, R A2 and R A3 together with the connecting atom form a saturated or unsaturated 4-10-membered heterocycloalkyl;
  • Each R A4 is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen group, halogen, cyano, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N(C 1-6 alkyl) (C 1-6 alkyl), -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene base-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10 membered aromatic heterocyclic group);
  • R A1s Two independent R A1s are formed together with connected atoms Saturated or unsaturated 3-10-membered carbocyclic group, saturated or unsaturated 3-10-membered heterocycloalkyl group; wherein the carbocyclic group and heterocycloalkyl group can be further replaced by one, two or three R A5 replace;
  • Each R A5 is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen base, halogen, cyano, -SH, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl) base), -N(C 1-6 alkyl) (C 1-6 alkyl), -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0- 4 -alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-( 5-10-membered aromatic heterocyclic
  • heteroatoms in the saturated or unsaturated heterocycloalkyl and aromatic heterocyclic groups are independently selected from one or more of O, S, B or N, and the unsaturated carbocyclic group does not include aromatic group, the unsaturated heterocycloalkyl group does not include an aromatic heterocyclic group.
  • Ring B is selected from saturated or unsaturated 3- to 10-membered carbocyclyl, saturated or unsaturated 4- to 10-membered heterocycloalkyl; wherein the saturated or unsaturated carbocyclyl, saturated or unsaturated heterocycle
  • the alkyl group can be further substituted with one, two, three, four or five independent R 1d ;
  • Each R 1d is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1e , -C 0-4 alkylene-OC(O)R 1e , -C 0-4 Alkylene-C(O)R 1e , -C 0-4 alkylene-C(O)OR 1e , -C 0-4 alkylene-C(O)NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 alkylene-NR 1e C(O)R 1f , -C 0-4 alkylene-(saturated or uns
  • Ring B is selected from saturated or unsaturated 3-membered carbocyclyl, saturated or unsaturated 4-membered carbocyclyl, saturated or unsaturated 5-membered carbocyclyl, saturated or unsaturated 6-membered carbocyclyl, saturated or unsaturated Unsaturated 4-membered heterocycloalkyl, saturated or unsaturated 5-membered heterocycloalkyl, saturated or unsaturated 6-membered heterocycloalkyl; wherein the heteroatom of the heterocycloalkyl is selected from N, O, S; wherein carbocyclyl, heterocycloalkyl can be further substituted with one, two, three, four or five independent R 1d .
  • the B ring is selected from wherein the B ring may be further substituted with one, two or three independent R 1d ;
  • Each R 1d is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1e , -C 0-4 alkylene-OC(O)R 1e , -C 0-4 Alkylene-C(O)R 1e , -C 0-4 alkylene-C(O)OR 1e , -C 0-4 alkylene-C(O)NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 alkylene-NR 1e C(O)R 1f , -C 0-4 alkylene-(saturated or uns
  • R 1e and R 1f are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ; Or, R 1e and R 1f together with the connecting atoms form a saturated or unsaturated 4-10-membered heterocycloalkyl;
  • Each R 1g is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen base, halogen, cyano, -SH, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl) base), -N(C 1-6 alkyl) (C 1-6 alkyl).
  • R 1d Two independent R 1d are connected to form saturated or unsaturated 3-membered carbocyclyl, saturated or unsaturated 4-membered carbocyclyl, saturated or unsaturated 5-membered carbocyclyl, saturated or unsaturated 6-membered carbocyclyl group, saturated or unsaturated 4-membered heterocycloalkyl, saturated or unsaturated 5-membered heterocycloalkyl, saturated or unsaturated 6-membered heterocycloalkyl; wherein carbocyclyl, heterocycloalkyl can be further One, two or three R 1h substitutions.
  • the B ring is selected from wherein the B ring may be further substituted with one, two or three R 1h ;
  • R 1h is selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any Select halogen-substituted -C 2-6 alkynyl, -C 0-4 alkylene-OR 1i , -C 0-4 alkylene-OC(O)R 1i , -C 0-4 alkylene- C(O)R 1i , -C 0-4 alkylene-C(O)OR 1i , -C 0-4 alkylene-C(O)NR 1i R 1j , -C 0-4 alkylene- NR 1i R 1j , -C 0-4 alkylene-NR 1i C(O)R 1j , -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -
  • R 1i and R 1j are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(3-10-membered carbocyclic group), -C 0-4 alkylene-(4-10-membered heterocycloalkyl) ), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocycloalkyl).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, methyl, halogen, cyano, -OH, -SH, -C(O)NH 2 , -NHC(O) CH 3 , -OCH 3 , And R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are not selected from hydrogen at the same time.
  • A is selected from wherein each X is independently selected from CH2 , NH, O, or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
  • A is selected from
  • A is selected from wherein X is selected from CH 2 , NH, O or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
  • A is selected from wherein X is selected from CH2 , NH, O or S; the ring selected by A may be further substituted with one, two, three or four R A1 .
  • the present invention also provides compounds represented by formula II and III, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof:
  • R D1 , R D2 and R D3 are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkene optionally substituted by halogen base, -C 2-6 alkynyl optionally substituted by halogen, C 1-6 alkyloxy, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), - C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene base-(5-10-membered aromatic heterocyclic group);
  • the A ring is selected from wherein each X is independently selected from CH2 , NH, O, or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
  • the present invention also provides the compound represented by formula IV, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt:
  • the A ring is selected from wherein each X is independently selected from CH2 , NH, O, or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
  • the compounds of formula I, II, III, IV are specifically:
  • the present invention also provides the use of any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for preventing or treating virus-infected diseases.
  • influenza virus infection is influenza virus infection.
  • the present invention also provides a pharmaceutical composition, comprising a preparation prepared from any of the above-mentioned compounds, or deuterated compounds, or stereoisomers thereof, or pharmaceutically acceptable salts thereof.
  • it also includes its pharmaceutically acceptable carrier, adjuvant and vehicle.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that the hydrogen atom in the molecule is replaced by other different atoms or groups; or the lone pair of electrons of the atoms in the molecule is replaced by other atoms or groups, for example, the lone pair of electrons on the S atom can be replaced by O atomic substitution
  • “Optionally substituted” means that “substitution” may or may not occur, that is, a hydrogen atom in a molecule or group is replaced by another same or different atom or group.
  • a-b alkyl denotes any alkyl group containing "a" to "b” carbon atoms.
  • a C 1-6 alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.
  • Alkyl refers to a saturated hydrocarbon chain having the specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) base) and hexyl. Alkyl groups can also be part of other groups such as -O(C 1-6 alkyl).
  • Carbocyclyl refers to those having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (fused, bridged) Saturated or partially saturated cyclic group.
  • the term “carbocyclyl” applies when the point of attachment is at a non-aromatic carbon atom (eg 5,6,7,8,-tetra Hydronaphthalene-5-yl).
  • the term “carbocyclyl” includes cycloalkenyl groups such as cyclohexenyl.
  • carbocyclyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl.
  • carbocyclyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below: dicyclohexyl and Dicyclohexyl.
  • the saturated or unsaturated 3-10-membered carbocyclic group of the present invention refers to a 3, 4, 5, 6, 7, 8, 9 or 10-membered saturated or unsaturated carbocyclic group, and the unsaturated 3-10-membered carbon Cyclic group, preferably 5-10-membered unsaturated carbocyclic group or 6-10-membered unsaturated carbocyclic group or 7-10-membered unsaturated carbocyclic group or 8-10-membered unsaturated carbocyclic group or 9-10-membered unsaturated carbocyclic group Saturated carbocyclyl.
  • heterocycloalkyl refers to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom , oxygen atoms, sulfur atoms, etc.
  • the bridge separating the two rings is a single bond or a chain of one or two ring atoms.
  • monocyclic saturated heterocycloalkyl are oxetanyl, azetidine, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidine base, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, Thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl.
  • bicyclic saturated heterocycloalkyl groups are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-Aza-bicyclo[3.3.1]nonyl.
  • partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.
  • the saturated or unsaturated 4-10-membered heterocycloalkyl in the present invention refers to a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered saturated or unsaturated heterocycloalkyl, preferably a 5-10-membered unsaturated heterocycle Alkyl or 6-10-membered unsaturated heterocycloalkyl or 7-10-membered unsaturated heterocycloalkyl or 8-10-membered unsaturated heterocycloalkyl or 9-10-membered unsaturated heterocycloalkyl.
  • Unsaturation described in the present invention refers to groups or molecules containing carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc.; the unsaturated carbocyclic bonds of the present invention
  • the group includes or does not include an aromatic ring group, and the unsaturated heterocyclic group includes or does not include a heteroaryl group, which can be freely selected by those skilled in the art.
  • aromatic ring group and “aromatic ring” in the present invention refer to an aromatic hydrocarbon group having a plurality of carbon atoms.
  • Aryl groups are typically monocyclic, bicyclic or tricyclic aryl groups having multiple carbon atoms.
  • aryl refers to an aromatic substituent which may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
  • aromatic heterocyclic group and “aromatic heterocyclic ring” refer to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to nitrogen atom, oxygen atom, sulfur atom and the like.
  • Aromatic monocyclic or bicyclic hydrocarbons generally containing multiple ring atoms, one or more of which are heteroatoms selected from O, N, S. There are preferably one to three heteroatoms.
  • Heterocyclic aryl groups represent: pyridyl, indolyl, quinoxolinyl, quinolyl, isoquinolyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzene Thiapyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazole base, benzothiazolyl, benzoxazolyl.
  • the present invention is compatible with R 1a , R 1b , R 1c , R1 d , R 1e , R 1f , R 1f , R 1g , R 1h , R 1i , R 1j , R A1 , R A2 , R A3 , R
  • said R 1a , R 1b , R 1c , R1 d , R 1e , R 1f , R 1f , R 1g , R 1h , R 1i , R 1j , R A1 , R A2 , R A3 , R A4 , and R A5 may not be selected from -OH, -SH, -NH 2 .
  • halogen in the present invention refers to fluorine, chlorine, bromine or iodine.
  • halogen-substituted alkyl group means that one or more hydrogen atoms in the alkyl group are substituted by halogen; for example, trifluoromethyl, difluoromethyl, monofluoromethyl and the like.
  • oxygen atom in "-C(O)R", “-S(O) 2 R” and the like described in the present invention is connected to a carbon atom or a sulfur atom by a double bond.
  • the "deuterated compound” of the present invention means that one or more hydrogen atoms in a molecule or group are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.
  • pharmaceutically acceptable means that a carrier, vehicle, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form, and is physiologically Compatible with receptors.
  • salts and “pharmaceutically acceptable salts” refer to the above-mentioned compounds or their stereoisomers, acid and/or base salts with inorganic and/or organic acids and bases, and also zwitterionic salts (internal). salts), also including quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above-mentioned compound, or a stereoisomer thereof, with a certain amount of acid or base as appropriate (for example, an equivalent amount).
  • salts may be precipitated in solution and collected by filtration, recovered after evaporation of the solvent, or obtained by lyophilization after reaction in an aqueous medium.
  • the salts described in the present invention can be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate of the compound salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • one or more compounds of the present invention may be used in combination with each other.
  • the compounds of the present invention may be used in combination with any other active agent for the preparation of medicaments or pharmaceutical compositions for modulating cellular function or treating diseases. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the measurement of LC-MS used Shimadzu LC-MS 2020 (ESI)).
  • the HPLC measurement used a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).
  • MPLC medium pressure preparative chromatography
  • the thin layer chromatography silica gel plate is made of Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications of the thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present invention can be synthesized by adopting or following methods known in the art, or can be purchased from companies such as Annagy Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and the like.
  • M2 can be split into:
  • the substrate 8-oxa-2-azaspiro[4,5]dec-3-one 1-1 (1.6 g, 10.0 mmol) was dissolved in tetrahydrofuran (40 mL), and the reaction system was fully Cool to minus 30 degrees Celsius, slowly add n-butyllithium (2.5M, 12.0mmol, 4.8mL) dropwise, keep minus 30 degrees Celsius to react for 1 hour, add allyl chloroformate 1-2 (1.5g, 12.0 mmol), kept the reaction at minus 30 degrees Celsius for 1 hour, added saturated ammonium chloride solution to quench the reaction, concentrated under reduced pressure, extracted with ethyl acetate and water, dried the organic phase with anhydrous sodium sulfate and concentrated under reduced pressure, the residue was used After purification by column chromatography, the product allyl 3-oxa-8-oxa-2-azaspiro[4.5]decane-2-carbonate 1-3 (2.4g) was obtained.
  • LC-MS m/z
  • the crude product can be directly used in the next step without purification.
  • the crude product is 3-hydroxy-8-oxa-2-azaspiro[4.5]decane. Allyl alkane-2-carboxylate 1-4.
  • Compound 1 can produce the following 6 isomers:
  • the substrate 8,8-difluoro-2-azaspiro[4,5]dec-3-one 2-5 (3.8 g, 20.1 mmol) was dissolved in tetrahydrofuran (50 mL), and the reaction system was fully cooled to At minus 30 degrees Celsius, n-butyllithium (2.5M, 24.1 mmol, 9.6 mL) was slowly added dropwise, kept at minus 30 degrees Celsius for 1 hour, and allyl chloroformate 1-2 (2.6 g, 21.4 mmol) was added dropwise to the reaction system.
  • reaction system was fully cooled to zero degrees Celsius, and tetrahydrothiopyran-4-one 3-1 (5.8 g, 50 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise, and the addition was completed at room temperature for 2 hours. TLC and LC-MS were monitored. .
  • the substrate 8-thia-2-azaspiro[4.5]decane-3-one 3-4 (1.0 g, 5.9 mmol) was dissolved in tetrahydrofuran (20 mL), and the reaction system was fully cooled to minus 30 degrees Celsius , slowly dropwise n-butyllithium (2.5M, 5.9mmol, 2.3mL), keep minus 30 degrees Celsius to react for 1 hour, add allyl chloroformate 1-2 (0.7g, 5.9mmol) dropwise to the reaction system, keep The reaction was carried out at minus 30 degrees Celsius for 1 hour, saturated ammonium chloride solution was added to quench the reaction, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 3-oxo-8 -Thia-2-azaspiro[4.5]decane-2-carboxylate allyl 3-5.
  • LC-MS m/z 256[M+H
  • the substrate 6-azaspiro[3.4]octane-7-one 4-4 (1.0 g, 13.6 mmol) was dissolved in tetrahydrofuran (20 mL), the reaction system was fully cooled to minus 30 degrees Celsius, and was slowly added dropwise.
  • Butyllithium (2.5M, 15.0mmol, 6.0mL) was kept at minus 30 degrees Celsius for 1 hour, allyl chloroformate 1-2 (1.8g, 15.0mmol) was added dropwise to the reaction system, and the reaction was kept at minus 30 degrees Celsius for 1 After 1 hour, saturated ammonium chloride solution was added to quench the reaction, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 7-oxo-6-azaspiro[ 3.4] Allyl octane-6-carboxylate 4-5.
  • LC-MS m/z 210 [M+H] +
  • the substrate 8,8-dimethyl-2-azaspiro[4,5]dec-3-one 5-4 (1.8 g, 10.0 mmol) was dissolved in tetrahydrofuran (40 mL), and the reaction system was fully cooled To minus 30 degrees Celsius, n-butyllithium (2.5M, 12.0 mmol, 4.8 mL) was slowly added dropwise, kept at minus 30 degrees Celsius for 1 hour, and allyl chloroformate 1-2 (1.5 g, 12.0 mmol), kept the reaction at minus 30 degrees Celsius for 1 hour, added saturated ammonium chloride solution to quench the reaction, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column After purification by chromatography, the product allyl 3-oxo-8,8-dimethyl-2-azaspiro[4.5]decane-2-carbonate 5-5 (2.6 g) was obtained.
  • the crude product can be directly used in the next step without purification.
  • the crude product 3-hydroxy-8,8-dimethyl-2 - Azaspiro[4.5]decane-2-carboxylate allyl 5-6.
  • the substrate 7.9-dimethyl-8-oxa-2-azaspiro[4.5]dec-3-one 6-4 (1.8g, 10.0mmol) was dissolved in tetrahydrofuran (40mL), and the reaction system was fully Cool to minus 30 degrees Celsius, slowly add n-butyllithium (2.5M, 12.0 mmol, 4.8 mL) dropwise, keep the reaction at minus 30 degrees Celsius for 1 hour, add allyl chloroformate 1-2 (1.5 g, 12.0 mmol), kept the reaction at minus 30 degrees Celsius for 1 hour, added saturated ammonium chloride solution to quench the reaction, concentrated under reduced pressure, extracted with ethyl acetate and water, dried the organic phase with anhydrous sodium sulfate and concentrated under reduced pressure, the residue was used After purification by column chromatography, the product allyl 3-oxo-7.9-dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carbonate 6-5 (2.6g) was
  • Compound 6 can produce the following 4 isomers:
  • Compound 9 can produce the following 4 isomers:
  • 10-1 is split from 1-7.
  • step 4 in Example 8 2-10 in step 4 was replaced with 10-1, and the synthesis method was the same to obtain product 10-2 (56 mg).
  • step 5 in Example 8 replace 8-5 in step 5 with 10-2, and the synthesis method is the same to obtain product 10 (24 mg).
  • step 1 in Example 9 According to the synthesis method of step 1 in Example 9, 6 in step 1 was replaced by 10, and the synthesis method was the same to obtain product 11 (18 mg).
  • step 1 in Example 9 replace 6 in step 1 with Isomer 1-2, and the synthesis method is the same to obtain product 13 (7 mg).
  • Compound 13 can produce one of the following isomers:
  • Compound 14-8 can be resolved into:
  • step 4 in embodiment 8 2-10 in step 4 is replaced with 15-1, and 8-4 is replaced with two split products of 8-4, and the synthetic method is the same to obtain product 15-2 ( 60 mg) and 16-1 (30 mg).
  • step 3 in Example 15 According to the synthesis method of step 3 in Example 15, 15-2 in step 3 was replaced with 16-1, and the synthesis method was the same to obtain product 16 (1.0 mg).
  • step 1 in Example 9 6 in step 1 was replaced by 16-1, and the synthesis method was the same to obtain product 17 (2.1 mg).
  • 18-5 (1.5 g, 13.5 mmol) was added to a dry round-bottomed flask, dissolved in THF (25 mL), n-BuLi (2.5 M, 6.5 mL) was added dropwise, and the system was cooled to -30 degrees Celsius and reacted for 1 hour.
  • 18-6 (2 g, 16.2 mmol, 1.7 mL) was added dropwise at -30 degrees Celsius to continue the reaction for 1 hour, monitored by LC-MS.
  • step 5 in Example 14 According to the synthesis method of step 5 in Example 14, 14-7 in step 5 was replaced with 18-10, the synthesis method was the same, and the product 18-11 (0.6 g, crude) was obtained as a white solid.
  • step 9 in Example 5 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 18-11, the synthesis method was the same, and the product 18-12 (55.6 mg, crude) was obtained as a white solid.
  • step 3 in Example 15 replace 15-2 in step 3 with 18-12, the synthesis method is the same, and the product 18 (8 mg) is obtained as a white solid.
  • step 1 in Example 9 replace 6 in step 1 with 18, and the synthesis method is the same to obtain product 19 (2.1 mg).
  • step 1 in Example 9 replace 6 in step 1 with Isomer 18-3, and the synthesis method is the same to obtain product 20 (2.5 mg).
  • step 1 in Example 9 replace 6 in step 1 with Isomer 18-1, and the synthesis method is the same to obtain product 21 (3 mg).
  • step 4 in Example 8 According to the synthesis method of step 4 in Example 8, 2-10 in step 4 was replaced with 18-11, and the synthesis method was the same to obtain product 22-1 (53.6 mg).
  • step 5 in Example 8 8-5 in step 5 was replaced with 22-1, and the synthesis method was the same to obtain product 22 (5 mg).
  • step 1 in Example 14 replace 14-1 in step 1 with 24-1, and the synthesis method is the same to obtain product 24-3 (3.9g) LC-MS: m/z 198 [M+H ] + .
  • step 2 in Example 14 replace 14-3 in step 2 with 24-3, and the synthetic method is the same to obtain product 24-4 (2.7 g) LC-MS: m/z 200 [M+H ] + .
  • step 3 in Example 14 replace 14-4 in step 3 with 24-4, and the synthesis method is the same to obtain product 24-5 (2.6g) LC-MS: m/z 214 [M+H ] + .
  • step 4 in Example 14 replace 14-5 in step 4 with 24-5, and the synthesis method is the same to obtain product 24-6 (4.3g) LC-MS: m/z 470 [M+H ] + .
  • step 5 in Example 14 replace 14-7 in step 5 with 24-6, and the synthesis method is the same to obtain the product 24-7 (4.3g) LC-MS: m/z 340 [M+H ] + .
  • step 9 in Example 5 replace 5-9 in step 9 with 24-7, and the synthetic method is the same to obtain the product 24-8 (54.2 mg) LC-MS: m/z 586 [M+H ] + .
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 24-8, the synthesis method was the same, and the product 24 (8 mg) was obtained as a white solid.
  • step 1 in Example 9 6 in step 1 was replaced by 24, and the synthesis method was the same to obtain product 25 (3.2 mg).
  • step 1 in Example 5 According to the synthesis method of step 1 in Example 5, 5-1 in step 1 was replaced with 29-1, and the synthesis method was the same to obtain product 29-2 (12.8 g).
  • step 2 in Example 5 According to the synthesis method of step 2 in Example 5, 5-2 in step 2 was replaced with 29-2, and the synthesis method was the same to obtain product 29-3 (13 g).
  • step 3 in Example 5 According to the synthesis method of step 3 in Example 5, 5-3 in step 3 was replaced with 29-3, and the synthesis method was the same to obtain product 29-4 (11.5 g).
  • step 4 in Example 5 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 29-5, and the synthesis method was the same to obtain product 29-6 (9.7 g).
  • step 5 in Example 5 5-5 in step 5 was replaced with 29-6, and the synthesis method was the same to obtain product 29-7 (7.9 g).
  • step 6 in Example 5 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 29-7, and the synthesis method was the same to obtain product 29-8 (5.1 g).
  • step 7 in Example 5 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 29-8, and the synthesis method was the same to obtain product 29-9 (2g).
  • step 8 in Example 5 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 29-9, and the synthesis method was the same to obtain product 29-10 (1.1 g).
  • step 9 in Example 5 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 29-10, and the synthesis method was the same to obtain product 29-11 (100 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 29-11, and the synthesis method was the same to obtain product 29 (10.8 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 30-1, and the synthesis method was the same to obtain product 30 (14.8 mg).
  • step 4 in Example 5 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 31-1, and the synthesis method was the same to obtain product 31-3 (1.5 g).
  • step 5 in Example 5 5-5 in step 5 was replaced with 31-3, and the synthesis method was the same to obtain the product 31-4 (736 mg).
  • step 6 in Example 5 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 31-4, and the synthesis method was the same to obtain product 31-5 (590 mg).
  • step 7 in Example 5 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 31-5, and the synthesis method was the same to obtain product 31-6 (1 g).
  • step 8 in Example 5 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced by 31-6, and the synthesis method was the same to obtain product 31-7 (300 mg).
  • Compound 31-7 can be resolved into:
  • step 9 in Example 5 5-9 in step 9 was replaced with 31-7, and the synthesis method was the same to obtain product 31-8 (30 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 31-8, and the synthesis method was the same to obtain product 31 (1.6 mg).
  • step 1 in Example 29-11 in step 1 was replaced with 31-8, and the synthesis method was the same to obtain product 32-1 (20 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 32-1, and the synthesis method was the same to obtain product 32 (1.6 mg).
  • Compound 32 can produce one of the following isomers:
  • step 4 in Example 5 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 33-1, and the synthesis method was the same to obtain product 33-3 (8.3 g).
  • step 5 in Example 5 5-5 in step 5 was replaced with 33-3, and the synthesis method was the same to obtain product 33-4 (7.7g).
  • step 7 in Example 5 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 33-5, and the synthesis method was the same to obtain product 33-6 (4.2 g).
  • step 8 in Example 5 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 33-6, and the synthesis method was the same to obtain product 33-7 (1.6g).
  • step 9 in Example 5 5-9 in step 9 was replaced with 33-8, and the synthesis method was the same to obtain the product 33-9 (35 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 33-9, and the synthesis method was the same to obtain product 33 (10 mg).
  • step 9 in Example 5 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 34-1, and the synthesis method was the same to obtain product 34-2 (5 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 34-2, and the synthesis method was the same to obtain product 34 (2 mg).
  • step 1 in Example 9 6 in step 1 was replaced with 33, and the synthesis method was the same to obtain product 35-1 (3.2 mg).
  • step 5 in Example 12 10-1 in step 5 was replaced with 33-8, and the synthesis method was the same to obtain product 36 (4.3 mg).
  • step 4 in Example 29-4 in step 4 was replaced with 37-4, and the synthesis method was the same to obtain product 37-5 (500 mg).
  • step 9 in Example 5 5-9 in step 9 was replaced with 34-1, and M2 was replaced with 37-7, and the synthetic method was the same to obtain product 37-8 (20 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 37-8, and the synthesis method was the same to obtain product 37 (14.7 mg).
  • step 1 in Example 37 According to the synthesis method of step 1 in Example 37, 37-1 in step 1 was replaced with 38-3, and the synthesis method was the same to obtain product 38-4 (4.2 g).
  • step 2 in Example 37 According to the synthesis method of step 2 in Example 37, 37-2 in step 2 was replaced with 38-4, and the synthesis method was the same to obtain the product 38-5 (3g).
  • step 3 in Example 37 37-3 in step 3 was replaced with 38-6, and the synthesis method was the same to obtain product 38-7 (2.2 g).
  • step 4 in Example 29-4 in step 4 was replaced with 38-7, and the synthesis method was the same to obtain product 38-8 (2g, crude).
  • step 5 in Example 37 37-5 in step 5 was replaced with 38-8, and the synthesis method was the same to obtain product 38-9 (350 mg).
  • step 9 in Example 5 5-9 in step 9 was replaced with 33-8, and M2 was replaced with 38-10, and the synthetic method was the same to obtain product 38-11 (50 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 38-10, and the synthesis method was the same to obtain product 38 (4.3 mg).
  • step 1 in Example 37 According to the synthesis method of step 1 in Example 37, 37-1 in step 1 was replaced with 39-5, and the synthesis method was the same to obtain product 39-6 (2g, crude).
  • step 1 in Example 38 38-1 in step 1 was replaced with 39-6, and the synthesis method was the same to obtain product 39-7 (1 g, crude).
  • step 4 in Example 29-4 in step 4 was replaced with 39-7, and the synthesis method was the same to obtain product 39-8 (300 mg).
  • step 2 in Example 39 39-3 in step 2 was replaced with 39-8, and the synthesis method was the same to obtain product 39-9 (48 mg).
  • step 9 in Example 5 5-9 in step 9 was replaced by 33-8, M2 was replaced by 39-10, and the synthetic method was the same to obtain product 39-11 (54.2 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 39-10, and the synthesis method was the same to obtain product 39 (3 mg).
  • step 9 in Example 5 5-9 in step 9 was replaced with 33-7, M2 was replaced with 40-2, and the synthetic method was the same to obtain product 40-3 (55.6 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 40-3, and the synthesis method was the same to obtain product 40 (4.7 mg).
  • step 1 in Example 5 According to the synthesis method of step 1 in Example 5, 5-1 in step 1 was replaced with 41-1, and the synthesis method was the same to obtain product 41-3 (12 g).
  • step 2 in Example 5 According to the synthesis method of step 2 in Example 5, 5-2 in step 2 was replaced with 41-3, and the synthesis method was the same to obtain product 41-4 (12 g).
  • step 3 in Example 5 According to the synthesis method of step 3 in Example 5, 5-3 in step 3 was replaced with 41-4, and the synthesis method was the same to obtain product 41-5 (5g).
  • step 4 in Example 29-4 in step 4 was replaced with 41-5, and the synthesis method was the same to obtain product 41-6 (3.8 g).
  • step 4 in Example 5 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 41-6, and the synthesis method was the same to obtain product 41-8 (4g).
  • step 5 in Example 5 5-5 in step 5 was replaced with 41-8, and the synthesis method was the same to obtain product 41-9 (1 g).
  • step 6 in Example 5 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 41-9, and the synthesis method was the same to obtain product 41-10 (1 g).
  • step 7 in Example 5 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 41-10, and the synthesis method was the same to obtain product 41-11 (328 mg).
  • step 8 in Example 5 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 41-11, and the synthesis method was the same to obtain product 41-12 (200 mg).
  • step 9 in Example 5 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 41-12, and the synthesis method was the same to obtain product 41-13 (30 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 41-13, and the synthesis method was the same to obtain product 41 (3.6 mg).
  • step 1 in Example 5 According to the synthesis method of step 1 in Example 5, 5-1 in step 1 was replaced with 42-1, and the synthesis method was the same to obtain product 42-2 (7.3 g).
  • step 2 in Example 5 According to the synthesis method of step 2 in Example 5, 5-2 in step 2 was replaced with 42-2, and the synthesis method was the same to obtain product 42-3 (8.7 g).
  • step 3 in Example 5 According to the synthesis method of step 3 in Example 5, 5-3 in step 3 was replaced with 42-3, and the synthesis method was the same to obtain product 42-4 (6.1 g).
  • step 4 in Example 29-4 in step 4 was replaced with 42-4, and the synthesis method was the same to obtain product 42-5 (4.3g).
  • step 4 in Example 5 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 42-5, and the synthesis method was the same to obtain product 42-6 (3.2 g).
  • step 5 in Example 5 5-5 in step 5 was replaced with 42-6, and the synthesis method was the same to obtain product 42-7 (2.3 g).
  • step 6 in Example 5 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 42-7, and the synthesis method was the same to obtain product 42-8 (1.6g).
  • step 7 in Example 5 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 42-8, and the synthesis method was the same to obtain product 42-9 (1.9 g).
  • step 8 in Example 5 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 42-9, and the synthesis method was the same to obtain product 42-10 (230 mg).
  • step 9 in Example 5 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 42-10, and the synthesis method was the same to obtain product 42-11 (30 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 42-11, and the synthesis method was the same to obtain product 42 (1.9 mg).
  • step 1 in Example 5 According to the synthesis method of step 1 in Example 5, 5-1 in step 1 was replaced with 44-1, and the synthesis method was the same to obtain product 44-2 (7.8g).
  • step 2 in Example 5 According to the synthesis method of step 2 in Example 5, 5-2 in step 2 was replaced with 44-2, and the synthesis method was the same to obtain product 44-3 (9.0 g).
  • step 3 in Example 5 According to the synthesis method of step 3 in Example 5, 5-3 in step 3 was replaced with 44-3, and the synthesis method was the same to obtain product 44-4 (8.5 g).
  • step 4 in Example 29-4 in step 4 was replaced with 44-4, and the synthesis method was the same to obtain product 44-5 (4.0 g).
  • step 4 in Example 5 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 44-5, and the synthesis method was the same to obtain product 44-6 (6g).
  • step 5 in Example 5 5-5 in step 5 was replaced with 44-6, and the synthesis method was the same to obtain product 44-7 (4.1 g).
  • step 6 in Example 5 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 44-7, and the synthesis method was the same to obtain product 44-8 (4.1 g).
  • step 7 in Example 5 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 44-8, and the synthesis method was the same to obtain product 44-9 (2.6g).
  • step 8 in Example 5 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 44-9, and the synthesis method was the same to obtain product 44-10 (1.9 g).
  • step 9 in Example 5 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 44-11, and the synthesis method was the same to obtain product 44-12 (19 mg).
  • step 6 in Example 14 According to the synthesis method of step 6 in Example 14, 14-8 in step 6 was replaced by 44-12, and the synthesis method was the same to obtain product 44 (7 mg).
  • step 4 in Example 5 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 45-1, and the synthesis method was the same to obtain product 45-3 (1.3 g).
  • step 5 in Example 5 5-5 in step 5 was replaced with 45-3, and the synthesis method was the same to obtain product 45-4 (1.3 g).
  • step 6 in Example 5 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 45-4, and the synthesis method was the same to obtain product 45-5 (1.2 g).
  • step 7 in Example 5 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 45-5, and the synthesis method was the same to obtain product 45-6 (2.3 g).
  • step 8 in Example 5 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 45-6, and the synthesis method was the same to obtain product 45-8 (400 mg).
  • step 9 in Example 5 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 45-8, and the synthesis method was the same to obtain product 45-9 (32 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 45-9, and the synthesis method was the same to obtain product 45 (5 mg).
  • step 4 in Example 5 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 46-1, and the synthesis method was the same to obtain product 46-3 (16.2 g).
  • step 5 in Example 5 5-5 in step 5 was replaced with 46-3, and the synthesis method was the same to obtain product 46-4 (6g).
  • step 6 in Example 5 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 46-4, and the synthesis method was the same to obtain product 46-5 (620 mg).
  • step 7 in Example 5 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 46-5, and the synthesis method was the same to obtain product 46-6 (970 mg).
  • step 8 in Example 5 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 46-6, and the synthesis method was the same to obtain product 46-7 (430 mg).
  • step 9 in Example 5 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 46-9, and the synthesis method was the same to obtain product 46-10 (30 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 45-9, and the synthesis method was the same to obtain product 46 (6 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 47-2, and the synthesis method was the same to obtain product 47 (10 mg).
  • step 9 in Example 5 5-9 in step 9 was replaced with 48-7, and the synthesis method was the same to obtain the product 48-9 (33 mg).
  • step 10 in Example 5 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 48-9, and the synthesis method was the same to obtain product 48 (8 mg).
  • test compounds were 1 uM in influenza A virus H1N1_WSN_1933PAN (protein series 1-196, del52-72) and 10 uM in influenza B virus Lee_1940PAN (protein series 1-198).
  • concentration of the compound was calculated to give the IC50 of the compound's inhibition of enzymatic activity.
  • Test results The IC 50 of the compounds of the present invention for inhibiting the enzymatic activity of 10 nM influenza virus A H1N1_WSN_1933 PAN and influenza virus B Lee_1940 PAN is shown in Table 1.
  • MDCK cells were seeded into microtiter plates at a certain density and cultured in a 5% CO 2 , 37° C. incubator overnight. The next day, double-diluted compound and virus were added. Cell controls (cells, no compound treatment or virus infection), virus controls (cells infected with virus, no compound treatment) and broth controls (broth only) were set up. The final concentration of DMSO in the culture medium was 0.5%, respectively. Cells were cultured in a 5% CO2 , 33-37°C incubator for 5 days. The cytotoxicity test was under the same conditions as the antiviral test, but there was no virus infection. Cell viability was detected using the cell viability assay kit CCK8.
  • the antiviral activity and cytotoxicity of the compounds were expressed by the inhibition rate (%) of the compounds against virus-induced cytopathic effects and the viability (%) of MRC5 cells at different concentrations, respectively.
  • the compound solution was administered to 3 male SD rats at corresponding doses by intravenous injection/oral gavage.
  • Rat anticoagulated whole blood was collected for 24 hours and plasma was separated;
  • the compound was administered to 6 male ICR mice by intravenous injection/oral gavage at the corresponding dose, and each route was administered for a small amount of time.
  • the mice were divided into two groups, A/B.
  • Anticoagulated whole blood was collected from mice in group A at 5min, 30min, 2h, and 8h after administration, and anticoagulated blood was collected from mice in group B at 15min, 1h, 4h, and 24h after administration.
  • Plasma concentrations of compounds were determined by standard curve calibration using LC-MS. Using Winnolin 5.2 software, the plasma concentration-time data were fitted to pharmacokinetic parameters, including elimination half-life (T 1/2 ), area under the curve (AUC last ), peak concentration (C max ), apparent Volume of distribution (Vz), total clearance (Cl), absolute bioavailability (F%), etc.

Abstract

Provided are compounds represented by formula (I), formula (II), formula (III) and formula (IV) as influenza virus replication inhibitors and the use thereof in the preparation of a medicament for preventing or treating influenza.

Description

一种流感病毒抑制剂及其用途A kind of influenza virus inhibitor and use thereof 技术领域technical field
本发明涉及一类具有作为流感病毒复制抑制剂的新化合物及其在治疗流感中的用途，具体涉及作为流感病毒帽依赖性核酸内切酶抑制剂。The present invention relates to a new class of compounds as influenza virus replication inhibitors and their use in the treatment of influenza, particularly as influenza virus cap-dependent endonuclease inhibitors.
背景技术Background technique
流行性感冒(流感)是一种由流感病毒引发的严重危害人类健康的急性呼吸道传染病。人类感染的流感是由流感亚型A和亚型B引起，根据血凝素(H或HA)和神经氨酸酶(N)抗原类型，流感病毒A可以进一步分类，例如已经发现存在的亚型H1N1、H1N2、H2N2、H3N1等。Influenza (flu) is an acute respiratory infectious disease caused by influenza virus that seriously endangers human health. Influenza in humans is caused by influenza subtypes A and B, according to the type of hemagglutinin (H or HA) and neuraminidase (N) antigens, influenza virus A can be further classified, such as the subtypes that have been found to exist H1N1, H1N2, H2N2, H3N1, etc.
流感病毒的RNA聚合酶负责病毒RNA的复制和转录，由3个亚基组成的异三聚体：聚合酶酸(PA)、聚合酶碱1(PB1)和聚合酶碱2(PB2)。流感病毒RNA的转录具有特殊的“夺帽”机制，PB2亚基负责识别和结合宿主前体mRNA的“帽子结构”，PA亚基剪切宿主mRNA作为引物，启动转录过程。剪切的mRNA引物在PB1亚基中用于病毒mRNA的合成。因为PA亚基的帽依赖型核酸内切酶在流感变异过程中非常保守，并且是病毒生命过程所必须的，且结合部位具有特异性，因此该结合域非常适合作为抗流感药物的靶位用于开发新型的抗流感药物。The RNA polymerase of influenza virus is responsible for the replication and transcription of viral RNA and is a heterotrimer composed of 3 subunits: polymerase acid (PA), polymerase base 1 (PB1) and polymerase base 2 (PB2). The transcription of influenza virus RNA has a special "cap" mechanism. The PB2 subunit is responsible for recognizing and binding the "cap structure" of the host pre-mRNA, and the PA subunit cleaves the host mRNA as a primer to initiate the transcription process. Cleaved mRNA primers are used in the PB1 subunit for viral mRNA synthesis. Because the cap-dependent endonuclease of the PA subunit is very conserved in the process of influenza mutation, it is necessary for the life process of the virus, and the binding site is specific, so this binding domain is very suitable as a target for anti-influenza drugs. for the development of new anti-influenza drugs.
具有这种作用机理的新的抗流感剂巴洛沙韦已上市，可以通过抑制帽依赖性核酸内切酶从而抑制病毒mRNA的合成，最终抑制病毒增殖。然而开发活性更高、副作用更小、使用更加方便的通过这种机理治疗流感的其它化合物仍是迫切需要的。Baloxavir, a new anti-influenza agent with this mechanism of action, has been marketed, which can inhibit the synthesis of viral mRNA by inhibiting cap-dependent endonuclease, and ultimately inhibit virus proliferation. However, there is still an urgent need to develop other compounds that are more active, have fewer side effects, and are more convenient to use to treat influenza through this mechanism.
发明内容SUMMARY OF THE INVENTION
本发明提供了一种式I所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐：The present invention provides a compound of formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022077312-appb-000001
Figure PCTCN2022077312-appb-000001
其中，in,
R 1、R 2、R 3、R 4、R 5、R 6分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1a、-C 0～4亚烷基-OC(O)R 1a、-C 0～4亚烷基-SR 1a、-C 0～4亚烷基-C(O)R 1a、-C 0～4亚烷基-C(O)OR 1a、-C 0～4亚烷基-C(O)NR 1aR 1b、-C 0～4亚烷基-NR 1aR 1b、-C 0～4亚烷基-NR 1aC(O)R 1b、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)、-C 0～4亚烷基-S(O) 2R 1a、-C 0～4亚烷基-S(O)R 1a、-C 0～4亚烷基-S(O) 2NR 1aR 1b、-C 0～4亚烷基-S(O)NR 1aR 1b；其中亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个、三个、四个或五个独立的R 1c取代；且R 1、R 2、R 3、R 4、R 5、R 6不同时选自氢； R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkane optionally substituted by halogen base, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1a , -C 0-4 alkylene -OC(O)R 1a , -C 0-4 alkylene-SR 1a , -C 0-4 alkylene-C(O)R 1a , -C 0-4 alkylene-C(O)OR 1a , -C 0-4 alkylene-C(O)NR 1a R 1b , -C 0-4 alkylene-NR 1a R 1b , -C 0-4 alkylene-NR 1a C(O)R 1b , -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl) , -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group), -C 0-4 alkylene-S (O) 2 R 1a , -C 0-4 alkylene-S(O)R 1a , -C 0-4 alkylene-S(O) 2 NR 1a R 1b , -C 0-4 alkylene -S(O)NR 1a R 1b ; wherein alkylene, carbocyclyl, heterocycloalkyl, aryl, arylheterocyclyl may be further separated by one, two, three, four or five independent and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are not simultaneously selected from hydrogen;
R 1a、R 1b分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；其中，所述的烷基、烯基、炔基、亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R 1c 取代；或者，R 1a、R 1b与相连原子一起形成饱和或不饱和的4～10元杂环烷基； R 1a and R 1b are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ; Wherein, the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring group, aromatic heterocyclic group can be further replaced by one, two or three independent R 1c substituted; or, R 1a and R 1b together with the connecting atoms form a saturated or unsaturated 4-10-membered heterocycloalkyl;
每个R 1c分别独立选自氢、任选被卤素取代的-C 1～6直链或支链烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、卤素、氰基、-OH、-SH、-OC 1～6烷基、-O(卤素取代的C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)、-C 0～4亚烷基-S(O) 2R 1d、-C 0～4亚烷基-S(O)R 1d、-C 0～4亚烷基-S(O) 2NR 1dR 1e、-C 0～4亚烷基-S(O)NR 1dR 1e； Each R 1c is independently selected from hydrogen, -C 1-6 linear or branched alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C optionally substituted by halogen C 2-6 alkynyl, halogen, cyano, -OH, -SH, -OC 1-6 alkyl, -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1- 6 alkyl), -N(C 1-6 alkyl) (C 1-6 alkyl), -C 0-4 alkylene-S(O) 2 R 1d , -C 0-4 alkylene- S(O)R 1d , -C 0-4 alkylene-S(O) 2 NR 1d R 1e , -C 0-4 alkylene-S(O)NR 1d R 1e ;
R 1d、R 1e分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)； R 1d and R 1e are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ;
或者，or,
R 1与R 2、R 3与R 4、R 5与R 6分别与相连原子一起形成
Figure PCTCN2022077312-appb-000002
饱和或不饱和的3～10元碳环基、饱和或不饱和的4～10元杂环烷基；其所述碳环基、杂环烷基可进一步被一个、两个、三个、四个、五个、六个或七个独立的R 1d取代； R 1 and R 2 , R 3 and R 4 , R 5 and R 6 are formed together with the connecting atoms, respectively
Figure PCTCN2022077312-appb-000002
Saturated or unsaturated 3- to 10-membered carbocyclic groups, saturated or unsaturated 4- to 10-membered heterocycloalkyl groups; the carbocyclic groups and heterocycloalkyl groups may be further replaced by one, two, three, four one, five, six or seven independent R 1d substitutions;
每个R 1d分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1e、-C 0～4亚烷基-OC(O)R 1e、-C 0～4亚烷基-C(O)R 1e、-C 0～4亚烷基-C(O)OR 1e、-C 0～4亚烷基-C(O)NR 1eR 1f、-C 0～4亚烷基-NR 1eR 1f、-C 0～4亚烷基-NR 1eC(O)R 1f、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；其中亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R 1g取代； Each R 1d is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1e , -C 0-4 alkylene-OC(O)R 1e , -C 0-4 Alkylene-C(O)R 1e , -C 0-4 alkylene-C(O)OR 1e , -C 0-4 alkylene-C(O)NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 alkylene-NR 1e C(O)R 1f , -C 0-4 alkylene-(saturated or unsaturated 3-10 membered carbocyclic group) , -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 Alkylene-(5-10-membered aromatic heterocyclic group); wherein alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring group, aromatic heterocyclic group can be further replaced by one, two or three independent R 1g replaced;
R 1e、R 1f分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、卤素取代的C 1～6烷基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；其中，所述的烷基、烯基、炔基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R 1g取代；或者，R 1e、R 1f与相连原子一起形成饱和或不饱和的4～10元杂环烷基； R 1e and R 1f are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any Select -C 2-6 alkynyl substituted by halogen, C 1-6 alkyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0 ~4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene- (5-10-membered aromatic heterocyclic group); wherein, the alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocycloalkyl group, aryl ring group, aromatic heterocyclic group may be further composed of one, two or Three independent R 1g substitutions; alternatively, R 1e and R 1f together with the connecting atoms form a saturated or unsaturated 4-10-membered heterocycloalkyl;
每个R 1g分别独立选自氢、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、卤素、氰基、-SH、-OH、-O(C 1～6烷基)、-O(卤素取代的C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)； Each R 1g is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen base, halogen, cyano, -SH, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl) base), -N(C 1-6 alkyl) (C 1-6 alkyl);
或者，or,
两个独立的R 1d与相连的原子一起形成
Figure PCTCN2022077312-appb-000003
饱和或不饱和的3～10元碳环基、饱和或不饱和的4～10元杂环烷基、6～10元芳环基、5～10元芳杂环基；其中碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个、三个、四个或五个R 1h取代； Two independent R 1ds are formed together with connected atoms
Figure PCTCN2022077312-appb-000003
Saturated or unsaturated 3-10-membered carbocyclic group, saturated or unsaturated 4-10-membered heterocycloalkyl, 6-10-membered aromatic ring group, 5-10-membered aromatic heterocyclic group; wherein carbocyclic group, heterocyclic group Cycloalkyl, aryl, and aryl heterocyclyl may be further substituted with one, two, three, four or five R 1h ;
每个R 1h分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1i、-C 0～4亚烷基-OC(O)R 1i、-C 0～4亚烷基-C(O)R 1i、-C 0～4亚烷基-C(O)OR 1i、-C 0～4亚烷基-C(O)NR 1iR 1j、-C 0～4亚烷基-NR 1iR 1j、-C 0～4亚烷基-NR 1iC(O)R 1j、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷 基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；或者，两个独立的R 1h与相连的原子一起形成
Figure PCTCN2022077312-appb-000004
Figure PCTCN2022077312-appb-000005
Each R 1h is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1i , -C 0-4 alkylene-OC(O)R 1i , -C 0-4 Alkylene-C(O)R 1i , -C 0-4 alkylene-C(O)OR 1i , -C 0-4 alkylene-C(O)NR 1i R 1j , -C 0-4 Alkylene-NR 1i R 1j , -C 0-4 alkylene-NR 1i C(O)R 1j , -C 0-4 alkylene-(saturated or unsaturated 3- to 10-membered carbocyclic group) , -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 Alkylene-(5-10-membered aromatic heterocyclyl); alternatively, two independent R 1h form together with the connected atoms
Figure PCTCN2022077312-appb-000004
Figure PCTCN2022077312-appb-000005
R 1i、R 1j分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、-任选被卤素取代的C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)； R 1i and R 1j are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ;
A选自5～30个原子构成的单环、双稠环、三稠环、四稠环、五稠环或六稠环的饱和或者不饱和的碳环基、饱和或不饱和的杂环烷基、芳环基或芳杂环基；其中碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个、三个、四个、五个、六个或七个R A1取代； A is selected from a saturated or unsaturated carbocyclic group, a saturated or unsaturated heterocycloalkane composed of 5 to 30 atoms consisting of a monocyclic, bi-fused, tri-fused, tetra-fused, penta-fused or hexa-fused ring wherein the carbocyclyl, heterocycloalkyl, aryl, and aromatic heterocyclyl may be further combined with one, two, three, four, five, six or seven R A1 substitutions;
每个R A1分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR A2、-C 0～4亚烷基-OC(O)R A2、-C 0～4亚烷基-C(O)R A2、-C 0～4亚烷基-C(O)OR A2、-C 0～4亚烷基-C(O)NR A2R A3、-C 0～4亚烷基-NR A2R A3、-C 0～4亚烷基-NR A2C(O)R A3、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)、-C 0～4亚烷基-S(O) 2R A2、-C 0～4亚烷基-S(O)R A2、-C 0～4亚烷基-S(O) 2NR A2R A3、-C 0～4亚烷基-S(O)NR A2R A3；其中亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R A4取代； Each R A1 is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR A2 , -C 0-4 alkylene-OC(O)R A2 , -C 0-4 Alkylene-C(O)R A2 , -C 0-4 alkylene-C(O)OR A2 , -C 0-4 alkylene-C(O)NR A2 R A3 , -C 0-4 Alkylene-NR A2 R A3 , -C 0-4 alkylene-NR A2 C(O)R A3 , -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group) , -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 Alkylene-(5-10-membered aromatic heterocyclic group), -C 0-4 alkylene-S(O) 2 R A2 , -C 0-4 alkylene-S(O)R A2 , -C 0-4 alkylene-S(O) 2 NR A2 R A3 , -C 0-4 alkylene-S(O)NR A2 R A3 ; wherein alkylene, carbocyclic, heterocycloalkyl, aryl The cyclic group and the aromatic heterocyclic group can be further substituted by one, two or three independent R A4 ;
R A2、R A3分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；或者，R A2、R A3与相连原子一起形成饱和或不饱和的4～10元杂环烷基； R A2 and R A3 are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ; Or, R A2 and R A3 together with the connecting atom form a saturated or unsaturated 4-10-membered heterocycloalkyl;
每个R A4分别独立选自氢、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、卤素、氰基、-OH、-O(C 1～6烷基)、-O(卤素取代的C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)； Each R A4 is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen group, halogen, cyano, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N(C 1-6 alkyl) (C 1-6 alkyl), -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene base-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10 membered aromatic heterocyclic group);
或者，or,
两个独立的R A1与相连的原子一起形成
Figure PCTCN2022077312-appb-000006
饱和或不饱和的3～10元碳环基、饱和或不饱和的3～10元杂环烷基；其中所述碳环基、杂环烷基可进一步被一个、两个或三个R A5取代； Two independent R A1s are formed together with connected atoms
Figure PCTCN2022077312-appb-000006
Saturated or unsaturated 3-10-membered carbocyclic group, saturated or unsaturated 3-10-membered heterocycloalkyl group; wherein the carbocyclic group and heterocycloalkyl group can be further replaced by one, two or three R A5 replace;
每个R A5分别独立选自氢、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、卤素、氰基、-SH、-OH、-O(C 1～6烷基)、-O(卤素取代的C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；或者，两个独立的R A5与相连的原子一起形成
Figure PCTCN2022077312-appb-000007
Each R A5 is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen base, halogen, cyano, -SH, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl) base), -N(C 1-6 alkyl) (C 1-6 alkyl), -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0- 4 -alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-( 5-10-membered aromatic heterocyclic group); alternatively, two independent R A5 are formed together with the connected atoms
Figure PCTCN2022077312-appb-000007
所述的饱和或不饱和杂环烷基、芳杂环基中的杂原子各自独立的选自O、S、B或N中的一种或几种，所述 不饱和碳环基不包括芳基，所述不饱和杂环烷基不包括芳杂环基。The heteroatoms in the saturated or unsaturated heterocycloalkyl and aromatic heterocyclic groups are independently selected from one or more of O, S, B or N, and the unsaturated carbocyclic group does not include aromatic group, the unsaturated heterocycloalkyl group does not include an aromatic heterocyclic group.
进一步地，further,
式I所示化合物如式Ia、式Ib、式Ic所式：The compound represented by formula I is represented by formula Ia, formula Ib, and formula Ic:
Figure PCTCN2022077312-appb-000008
Figure PCTCN2022077312-appb-000008
其中，in,
B环选自饱和或不饱和的3～10元碳环基、饱和或不饱和的4～10元杂环烷基；其中所述饱和或不饱和的碳环基、饱和或不饱和的杂环烷基可进一步被一个、两个、三个、四个或五个独立的R 1d取代； Ring B is selected from saturated or unsaturated 3- to 10-membered carbocyclyl, saturated or unsaturated 4- to 10-membered heterocycloalkyl; wherein the saturated or unsaturated carbocyclyl, saturated or unsaturated heterocycle The alkyl group can be further substituted with one, two, three, four or five independent R 1d ;
每个R 1d分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1e、-C 0～4亚烷基-OC(O)R 1e、-C 0～4亚烷基-C(O)R 1e、-C 0～4亚烷基-C(O)OR 1e、-C 0～4亚烷基-C(O)NR 1eR 1f、-C 0～4亚烷基-NR 1eR 1f、-C 0～4亚烷基-NR 1eC(O)R 1f、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；其中亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R 1g取代；两个独立的R 1d与相连的原子一起形成
Figure PCTCN2022077312-appb-000009
Figure PCTCN2022077312-appb-000010
饱和或不饱和的3～10元碳环基、饱和或不饱和的4～10元杂环烷基、6～10元芳环基、5～10元芳杂环基；其中碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个R 1h取代。 Each R 1d is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1e , -C 0-4 alkylene-OC(O)R 1e , -C 0-4 Alkylene-C(O)R 1e , -C 0-4 alkylene-C(O)OR 1e , -C 0-4 alkylene-C(O)NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 alkylene-NR 1e C(O)R 1f , -C 0-4 alkylene-(saturated or unsaturated 3-10 membered carbocyclic group) , -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 Alkylene-(5-10-membered aromatic heterocyclic group); wherein alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring group, aromatic heterocyclic group can be further replaced by one, two or three independent R 1g substitution; two independent R 1ds are formed together with the connected atom
Figure PCTCN2022077312-appb-000009
Figure PCTCN2022077312-appb-000010
Saturated or unsaturated 3-10-membered carbocyclic group, saturated or unsaturated 4-10-membered heterocycloalkyl, 6-10-membered aromatic ring group, 5-10-membered aromatic heterocyclic group; wherein carbocyclic group, heterocyclic group Cycloalkyl, aryl, and aryl heterocyclyl may be further substituted with one, two or three R 1h .
更进一步地，go a step further,
B环选自饱和或不饱和的3元碳环基、饱和或不饱和的4元碳环基、饱和或不饱和的5元碳环基、饱和或不饱和的6元碳环基、饱和或不饱和的4元杂环烷基、饱和或不饱和的5元杂环烷基、饱和或不饱和的6元杂环烷基；其中杂环烷基的杂原子选自N、O、S；其中碳环基、杂环烷基可进一步被一个、两个、三个、四个或五个独立的R 1d取代。 Ring B is selected from saturated or unsaturated 3-membered carbocyclyl, saturated or unsaturated 4-membered carbocyclyl, saturated or unsaturated 5-membered carbocyclyl, saturated or unsaturated 6-membered carbocyclyl, saturated or unsaturated Unsaturated 4-membered heterocycloalkyl, saturated or unsaturated 5-membered heterocycloalkyl, saturated or unsaturated 6-membered heterocycloalkyl; wherein the heteroatom of the heterocycloalkyl is selected from N, O, S; wherein carbocyclyl, heterocycloalkyl can be further substituted with one, two, three, four or five independent R 1d .
进一步具体地，More specifically,
所述B环选自
Figure PCTCN2022077312-appb-000011
Figure PCTCN2022077312-appb-000012
Figure PCTCN2022077312-appb-000013
Figure PCTCN2022077312-appb-000014
其中所述B环可进一步被一个、两个或三个独立的R 1d取代； The B ring is selected from
Figure PCTCN2022077312-appb-000011
Figure PCTCN2022077312-appb-000012
Figure PCTCN2022077312-appb-000013
Figure PCTCN2022077312-appb-000014
wherein the B ring may be further substituted with one, two or three independent R 1d ;
每个R 1d分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1e、-C 0～4亚烷基-OC(O)R 1e、-C 0～4亚烷基-C(O)R 1e、-C 0～4亚烷基-C(O)OR 1e、-C 0～4亚烷基-C(O)NR 1eR 1f、-C 0～4亚烷基-NR 1eR 1f、-C 0～4亚烷基-NR 1eC(O)R 1f、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；其中亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R 1g取代；或者，两个独立的R 1d与相连的原子一起形成
Figure PCTCN2022077312-appb-000015
Figure PCTCN2022077312-appb-000016
饱和或不饱和的3～10元碳环基、饱和或不饱和的4～10元杂环烷基、6～10元芳环基、5～10元芳杂环基；； Each R 1d is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1e , -C 0-4 alkylene-OC(O)R 1e , -C 0-4 Alkylene-C(O)R 1e , -C 0-4 alkylene-C(O)OR 1e , -C 0-4 alkylene-C(O)NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 alkylene-NR 1e C(O)R 1f , -C 0-4 alkylene-(saturated or unsaturated 3-10 membered carbocyclic group) , -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 Alkylene-(5-10-membered aromatic heterocyclic group); wherein alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring group, aromatic heterocyclic group can be further replaced by one, two or three independent R 1g substitution; alternatively, two separate R 1ds are formed together with the connected atom
Figure PCTCN2022077312-appb-000015
Figure PCTCN2022077312-appb-000016
Saturated or unsaturated 3- to 10-membered carbocyclic group, saturated or unsaturated 4- to 10-membered heterocycloalkyl, 6- to 10-membered aromatic ring group, 5- to 10-membered aromatic heterocyclic group;
R 1e、R 1f分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；或者，R 1e、R 1f与相连原子一起形成饱和或不饱和的4～10元杂环烷基； R 1e and R 1f are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ; Or, R 1e and R 1f together with the connecting atoms form a saturated or unsaturated 4-10-membered heterocycloalkyl;
每个R 1g分别独立选自氢、任选被卤素取代的-C 1～6烷基、-任选被卤素取代的C 2～6烯基、任选被卤素取代的-C 2～6炔基、卤素、氰基、-SH、-OH、-O(C 1～6烷基)、-O(卤素取代的C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)。 Each R 1g is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen base, halogen, cyano, -SH, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl) base), -N(C 1-6 alkyl) (C 1-6 alkyl).
进一步具体地，More specifically,
两个独立的R 1d相连形成饱和或不饱和的3元碳环基、饱和或不饱和的4元碳环基、饱和或不饱和的5元碳环基、饱和或不饱和的6元碳环基、饱和或不饱和的4元杂环烷基、饱和或不饱和的5元杂环烷基、饱和或不饱和的6元杂环烷基；其中碳环基、杂环烷基可进一步被一个、两个或三个R 1h取代。 Two independent R 1d are connected to form saturated or unsaturated 3-membered carbocyclyl, saturated or unsaturated 4-membered carbocyclyl, saturated or unsaturated 5-membered carbocyclyl, saturated or unsaturated 6-membered carbocyclyl group, saturated or unsaturated 4-membered heterocycloalkyl, saturated or unsaturated 5-membered heterocycloalkyl, saturated or unsaturated 6-membered heterocycloalkyl; wherein carbocyclyl, heterocycloalkyl can be further One, two or three R 1h substitutions.
更进一步具体地，More specifically,
所述B环选自
Figure PCTCN2022077312-appb-000017
Figure PCTCN2022077312-appb-000018
Figure PCTCN2022077312-appb-000019
其中所述B环可进一步被一个、两个或三个R 1h取代； The B ring is selected from
Figure PCTCN2022077312-appb-000017
Figure PCTCN2022077312-appb-000018
Figure PCTCN2022077312-appb-000019
wherein the B ring may be further substituted with one, two or three R 1h ;
R 1h选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯 基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1i、-C 0～4亚烷基-OC(O)R 1i、-C 0～4亚烷基-C(O)R 1i、-C 0～4亚烷基-C(O)OR 1i、-C 0～4亚烷基-C(O)NR 1iR 1j、-C 0～4亚烷基-NR 1iR 1j、-C 0～4亚烷基-NR 1iC(O)R 1j、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)； R 1h is selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any Select halogen-substituted -C 2-6 alkynyl, -C 0-4 alkylene-OR 1i , -C 0-4 alkylene-OC(O)R 1i , -C 0-4 alkylene- C(O)R 1i , -C 0-4 alkylene-C(O)OR 1i , -C 0-4 alkylene-C(O)NR 1i R 1j , -C 0-4 alkylene- NR 1i R 1j , -C 0-4 alkylene-NR 1i C(O)R 1j , -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0 ~4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene- (5-10-membered aromatic heterocyclic group);
R 1i、R 1j分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环烷基)。 R 1i and R 1j are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(3-10-membered carbocyclic group), -C 0-4 alkylene-(4-10-membered heterocycloalkyl) ), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocycloalkyl).
进一步地，further,
R 1、R 2、R 3、R 4、R 5、R 6分别独立选自氢、甲基、卤素、氰基、-OH、-SH、-C(O)NH 2、-NHC(O)CH 3、-OCH 3、
Figure PCTCN2022077312-appb-000020
且R 1、R 2、R 3、R 4、R 5、R 6不同时选自氢。 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, methyl, halogen, cyano, -OH, -SH, -C(O)NH 2 , -NHC(O) CH 3 , -OCH 3 ,
Figure PCTCN2022077312-appb-000020
And R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are not selected from hydrogen at the same time.
进一步地，further,
A选自
Figure PCTCN2022077312-appb-000021
Figure PCTCN2022077312-appb-000022
其中每个X分别独立选自CH 2、NH、O或S；所述A选自的环可进一步被一个、两个、三个、四个或五个R A1取代。 A is selected from
Figure PCTCN2022077312-appb-000021
Figure PCTCN2022077312-appb-000022
wherein each X is independently selected from CH2 , NH, O, or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
更进一步地，go a step further,
A选自
Figure PCTCN2022077312-appb-000023
Figure PCTCN2022077312-appb-000024
Figure PCTCN2022077312-appb-000025
A is selected from
Figure PCTCN2022077312-appb-000023
Figure PCTCN2022077312-appb-000024
Figure PCTCN2022077312-appb-000025
更进一步地，go a step further,
两个独立的R A1与其相连的原子一起形成饱和或不饱和的3元碳环基、饱和或不饱和的4元3元碳环基、饱和或不饱和的5元碳环基、饱和或不饱和的6元碳环基、饱和或不饱和的4元杂环烷基、饱和或不饱和的5元杂环烷基、饱和或不饱和的6元杂环烷基。 Two independent R A1 together with the atoms to which they are attached form saturated or unsaturated 3-membered carbocyclyl, saturated or unsaturated 4-membered 3-membered carbocyclyl, saturated or unsaturated 5-membered carbocyclyl, saturated or unsaturated Saturated 6-membered carbocyclyl, saturated or unsaturated 4-membered heterocycloalkyl, saturated or unsaturated 5-membered heterocycloalkyl, saturated or unsaturated 6-membered heterocycloalkyl.
进一步具体地，More specifically,
A选自
Figure PCTCN2022077312-appb-000026
其中X选自CH 2、NH、O或S；所述A选自的环可进一步被一个、两个、三个、四个或五个R A1取代。 A is selected from
Figure PCTCN2022077312-appb-000026
wherein X is selected from CH 2 , NH, O or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
更进一步地，go a step further,
A选自
Figure PCTCN2022077312-appb-000027
其中X选自CH 2、NH、O或S；所述A选自的环可进一步被一个、两个、三个或四个R A1取代。 A is selected from
Figure PCTCN2022077312-appb-000027
wherein X is selected from CH2 , NH, O or S; the ring selected by A may be further substituted with one, two, three or four R A1 .
本发明还提供了式II、III所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐：The present invention also provides compounds represented by formula II and III, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof:
Figure PCTCN2022077312-appb-000028
Figure PCTCN2022077312-appb-000028
其中，in,
R D1、R D2、R D3分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、-任选被卤素取代的C 2～6烯基、任选被卤素取代的-C 2～6炔基、C 1～6烷基氧基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)； R D1 , R D2 and R D3 are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkene optionally substituted by halogen base, -C 2-6 alkynyl optionally substituted by halogen, C 1-6 alkyloxy, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), - C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene base-(5-10-membered aromatic heterocyclic group);
所述A环选自
Figure PCTCN2022077312-appb-000029
Figure PCTCN2022077312-appb-000030
其中每个X分别独立选自CH 2、NH、O或S；所述A选自的环可进一步被一个、两个、三个、四个或五个R A1取代。 The A ring is selected from
Figure PCTCN2022077312-appb-000029
Figure PCTCN2022077312-appb-000030
wherein each X is independently selected from CH2 , NH, O, or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
本发明还提供了式Ⅳ所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐：The present invention also provides the compound represented by formula IV, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt:
Figure PCTCN2022077312-appb-000031
Figure PCTCN2022077312-appb-000031
所述A环选自
Figure PCTCN2022077312-appb-000032
Figure PCTCN2022077312-appb-000033
Figure PCTCN2022077312-appb-000034
其中每个X分别独立选自CH 2、NH、O或S；所述A选自的环可进一步被一个、两个、三个、四个或五个R A1取代。 The A ring is selected from
Figure PCTCN2022077312-appb-000032
Figure PCTCN2022077312-appb-000033
Figure PCTCN2022077312-appb-000034
wherein each X is independently selected from CH2 , NH, O, or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
在本发明的一些具体实施方案中，式I、II、III、Ⅳ所述化合物具体为：In some specific embodiments of the present invention, the compounds of formula I, II, III, IV are specifically:
Figure PCTCN2022077312-appb-000035
Figure PCTCN2022077312-appb-000035
Figure PCTCN2022077312-appb-000036
Figure PCTCN2022077312-appb-000036
Figure PCTCN2022077312-appb-000037
Figure PCTCN2022077312-appb-000037
Figure PCTCN2022077312-appb-000038
Figure PCTCN2022077312-appb-000038
本发明还提供了上述任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐在制备用于预防或治疗病毒感染疾病的药物中的用途。The present invention also provides the use of any of the above-mentioned compounds, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for preventing or treating virus-infected diseases.
进一步地，所述病毒感染为流感病毒感染。Further, the viral infection is influenza virus infection.
本发明还提供了一种药物组合物，包括上述任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐制备而成的制剂。The present invention also provides a pharmaceutical composition, comprising a preparation prepared from any of the above-mentioned compounds, or deuterated compounds, or stereoisomers thereof, or pharmaceutically acceptable salts thereof.
进一步地，还包括其药学上可接受的载体、辅料、媒介物。Further, it also includes its pharmaceutically acceptable carrier, adjuvant and vehicle.
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。The compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。Definitions of terms used in the present invention: Unless otherwise specified, the initial definitions of groups or terms provided herein apply to the group or term throughout the specification; for terms that are not specifically defined herein, the content and context of the disclosure should be used. , give their meanings that those skilled in the art can give them.
“取代”是指分子中的氢原子被其它不同的原子或基团所替换；或者是分子中原子的孤对电子被其它的原子或基团替换，例如S原子上的孤对电子可被O原子取代形成
Figure PCTCN2022077312-appb-000039
"Substitution" means that the hydrogen atom in the molecule is replaced by other different atoms or groups; or the lone pair of electrons of the atoms in the molecule is replaced by other atoms or groups, for example, the lone pair of electrons on the S atom can be replaced by O atomic substitution
Figure PCTCN2022077312-appb-000039
“任选被取代”是指“取代”可以发生或者不发生，亦即分子、基团中的氢原子被其它相同或不同的原子、基团所替换。"Optionally substituted" means that "substitution" may or may not occur, that is, a hydrogen atom in a molecule or group is replaced by another same or different atom or group.
“可进一步被取代”是指“取代”可以但不必须发生，该说明包括发生或不发生的情形。"May be further substituted" means that "substitution" may but need not occur, and the description includes instances where it occurs or not.
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀C a～b烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，C 1～6烷基是指包含1～6个碳原子的烷基。 Minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, eg, the prefix C a-b alkyl denotes any alkyl group containing "a" to "b" carbon atoms. Thus, for example, a C 1-6 alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.
“烷基”是指具有指定数目的成员原子的饱和烃链。烷基基团可以是直链或支链的。代表性的支链烷基基团具有一个、两个或三个支链。烷基基团可任选地被一个或多个如本文所定义的取代基取代。烷基包括甲基、乙基、丙基(正丙基和异丙基)、丁基(正丁基、异丁基和叔丁基)、戊基(正戊基、异戊基和新戊基)和己基。烷基基团也可以是其他基团的一部分，所述其他基团为例如-O(C 1～6烷基)。 "Alkyl" refers to a saturated hydrocarbon chain having the specified number of member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) base) and hexyl. Alkyl groups can also be part of other groups such as -O(C 1-6 alkyl).
本发明中所述的“碳环基”、“环烷基”、“环烷烃”是指具有多个碳原子且没有环杂原子且具有单个环或多个环(稠合、桥连)的饱和或部分饱和的环状基团。对于具有不含环杂原子的芳族和非芳族环的多环体系，当连接点位于非芳族碳原子时，适用术语“碳环基”(例如5,6,7,8,-四氢化萘-5-基)。术语“碳环基”包括环烯基基团，诸如环己烯基。碳环基基团的实例包括例如，金刚烷基、环丙基、环丁基、环己基、环戊基、环辛基、环戊烯基和环己烯基。包括多双环烷基环体系的碳环基基团的实例是双环己基、双环戊基、双环辛基等。下面例举并命名两种此类双环烷基多环结构：
Figure PCTCN2022077312-appb-000040
双环己基和
Figure PCTCN2022077312-appb-000041
双环己基。本发明饱和或不饱和的3-10元碳环基是指3、4、5、6、7、8、9或者10元饱和或不饱和碳环基，所述不饱和的3-10元碳环基，优选为5-10元不饱和碳环基或6-10元不饱和碳环基或7-10元不饱和碳环基或8-10元不饱和碳环基或9-10元不饱和碳环基。 In the present invention, "carbocyclyl", "cycloalkyl" and "cycloalkane" refer to those having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (fused, bridged) Saturated or partially saturated cyclic group. For polycyclic systems having aromatic and non-aromatic rings containing no ring heteroatoms, the term "carbocyclyl" applies when the point of attachment is at a non-aromatic carbon atom (eg 5,6,7,8,-tetra Hydronaphthalene-5-yl). The term "carbocyclyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of carbocyclyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of carbocyclyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below:
Figure PCTCN2022077312-appb-000040
dicyclohexyl and
Figure PCTCN2022077312-appb-000041
Dicyclohexyl. The saturated or unsaturated 3-10-membered carbocyclic group of the present invention refers to a 3, 4, 5, 6, 7, 8, 9 or 10-membered saturated or unsaturated carbocyclic group, and the unsaturated 3-10-membered carbon Cyclic group, preferably 5-10-membered unsaturated carbocyclic group or 6-10-membered unsaturated carbocyclic group or 7-10-membered unsaturated carbocyclic group or 8-10-membered unsaturated carbocyclic group or 9-10-membered unsaturated carbocyclic group Saturated carbocyclyl.
进一步的本发明中所述的“杂环烷基”、“杂环”、“杂环烷烃”是指包含至少一个杂原子的饱和环或非芳香性的不饱和环；其中杂原子指氮原子、氧原子、硫原子等。通常表示多个环原子的一价饱和或部分不饱和单环或二环环系统，其包含1、2或3个选自N、O和S的环杂原子，其余的环原子是碳。二环表示由共有两个环原子的两个环组成的，即将两个环分开的桥是单键或是一个或两个环原子的链。单环饱和杂环烷基的实例是氧杂环丁基、氮杂环丁基、吡咯烷基、2-氧代-吡咯烷-3-基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、
Figure PCTCN2022077312-appb-000042
硫代吗啉基、1，1-二氧代-硫代吗啉-4-基、氮杂环庚基、二氮杂环庚基、高哌嗪基或氧杂氮杂环庚基。二环饱和杂环烷基的实例是8-氮杂-二环[3.2.1]辛基、奎宁环基、8-氧杂-3-氮杂-二环[3.2.1]辛基、9-氮杂-二环[3.3.1]壬基。部分不饱和杂环烷基的实例是二氢呋喃基、咪唑啉基、四氢-吡啶基或二氢吡喃基。 Further in the present invention, "heterocycloalkyl", "heterocycle" and "heterocycloalkane" refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom , oxygen atoms, sulfur atoms, etc. Typically represents a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of multiple ring atoms containing 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings that share two ring atoms, i.e. the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl are oxetanyl, azetidine, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidine base, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl,
Figure PCTCN2022077312-appb-000042
Thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl groups are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-Aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.
本发明饱和或不饱和的4-10元杂环烷基是指4、5、6、7、8、9或者10元饱和或不饱和杂环烷基，优选为5-10元不饱和杂环烷基或6-10元不饱和杂环烷基或7-10元不饱和杂环烷基或8-10元不饱和杂环烷基或9-10元不饱和杂环烷基。The saturated or unsaturated 4-10-membered heterocycloalkyl in the present invention refers to a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered saturated or unsaturated heterocycloalkyl, preferably a 5-10-membered unsaturated heterocycle Alkyl or 6-10-membered unsaturated heterocycloalkyl or 7-10-membered unsaturated heterocycloalkyl or 8-10-membered unsaturated heterocycloalkyl or 9-10-membered unsaturated heterocycloalkyl.
本发明中所述的不饱和是指基团或者分子中含有碳碳双键、碳碳三键、碳氧双键、碳硫双键、碳氮三键等；本发明的不饱和的碳环基包括或不包括芳环基，不饱和的杂环基包括或不包括杂芳基，本领域的技术 人员可以自由选择。Unsaturation described in the present invention refers to groups or molecules containing carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc.; the unsaturated carbocyclic bonds of the present invention The group includes or does not include an aromatic ring group, and the unsaturated heterocyclic group includes or does not include a heteroaryl group, which can be freely selected by those skilled in the art.
本发明中所述的“芳环基”、“芳环”是指具有多个碳原子的芳烃基团。芳基通常是具有多个碳原子的单环、二环或三环芳基。此外，本文所用的术语“芳基”是指可以是单个芳环或稠合在一起的多个芳环的芳族取代基。非限制性实例包括苯基、萘基或四氢萘基。The "aromatic ring group" and "aromatic ring" in the present invention refer to an aromatic hydrocarbon group having a plurality of carbon atoms. Aryl groups are typically monocyclic, bicyclic or tricyclic aryl groups having multiple carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent which may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
本发明中所述的“芳杂环基”、“芳杂环”是指包含至少一个杂原子的芳香性不饱和环；其中杂原子指氮原子、氧原子、硫原子等。通常包含多个环原子的、其中一个或多个环原子选自O、N、S的杂原子的芳族单环或双环烃。优选地有一到三个杂原子。杂环芳基例如代表：吡啶基、吲哚基、喹噁啉基、喹啉基、异喹啉基、苯并噻吩基、苯并呋喃基、苯并噻吩基、苯并吡喃基、苯并噻吡喃基、呋喃基、吡咯基、噻唑基、噁唑基、异噁唑基、三唑基、四唑基、吡唑基、咪唑基、噻吩基、噁二唑基、苯并咪唑基、苯并噻唑基、苯并噁唑基。In the present invention, "aromatic heterocyclic group" and "aromatic heterocyclic ring" refer to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to nitrogen atom, oxygen atom, sulfur atom and the like. Aromatic monocyclic or bicyclic hydrocarbons generally containing multiple ring atoms, one or more of which are heteroatoms selected from O, N, S. There are preferably one to three heteroatoms. Heterocyclic aryl groups, for example, represent: pyridyl, indolyl, quinoxolinyl, quinolyl, isoquinolyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzene Thiapyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazole base, benzothiazolyl, benzoxazolyl.
进一步的，本发明当与R 1a、R 1b、R 1c、R1 d、R 1e、R 1f、R 1f、R 1g、R 1h、R 1i、R 1j、R A1、R A2、R A3、R A4、R A5相连的原子为O、S、或N时，所述的R 1a、R 1b、R 1c、R1 d、R 1e、R 1f、R 1f、R 1g、R 1h、R 1i、R 1j、R A1、R A2、R A3、R A4、R A5可以不选自-OH，-SH、-NH 2。 Further, the present invention is compatible with R 1a , R 1b , R 1c , R1 d , R 1e , R 1f , R 1f , R 1g , R 1h , R 1i , R 1j , R A1 , R A2 , R A3 , R When the atoms connecting A4 and R A5 are O, S, or N, said R 1a , R 1b , R 1c , R1 d , R 1e , R 1f , R 1f , R 1g , R 1h , R 1i , R 1j , R A1 , R A2 , R A3 , R A4 , and R A5 may not be selected from -OH, -SH, -NH 2 .
本发明中所述的“卤素”是指氟、氯、溴或碘。The "halogen" in the present invention refers to fluorine, chlorine, bromine or iodine.
本发明中所述的“卤素取代的烷基”是指烷基中的一个或多个氢原子被卤素取代；例如三氟甲基、二氟甲基、单氟甲基等。The "halogen-substituted alkyl group" mentioned in the present invention means that one or more hydrogen atoms in the alkyl group are substituted by halogen; for example, trifluoromethyl, difluoromethyl, monofluoromethyl and the like.
本发明中所述的“-OR”、“-NRR”等是指R基团与氧原子或氮原子以单键相连。"-OR", "-NRR" and the like mentioned in the present invention mean that the R group is connected to an oxygen atom or a nitrogen atom by a single bond.
本发明中所述的“-C(O)R”、“-S(O) 2R”等中的氧原子是与碳原子或硫原子以双键相连。 The oxygen atom in "-C(O)R", "-S(O) 2 R" and the like described in the present invention is connected to a carbon atom or a sulfur atom by a double bond.
本发明中所述的
Figure PCTCN2022077312-appb-000043
“＝O”、“＝S”是指氧原子、硫原子通过双键连接到取代位置。 described in the present invention
Figure PCTCN2022077312-appb-000043
"=O" and "=S" mean that an oxygen atom and a sulfur atom are connected to the substitution position through a double bond.
本发明基团描述中的“---”、
Figure PCTCN2022077312-appb-000044
是用来描述基团取代的位置。 "---" in the description of the group of the present invention,
Figure PCTCN2022077312-appb-000044
is used to describe the position at which a group is substituted.
本发明的“氘代化合物”是指分子或基团中的1个或多个氢原子被氘原子取代，其中氘原子的占比大于氘在自然界中的丰度。The "deuterated compound" of the present invention means that one or more hydrogen atoms in a molecule or group are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form, and is physiologically Compatible with receptors.
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。The terms "salts" and "pharmaceutically acceptable salts" refer to the above-mentioned compounds or their stereoisomers, acid and/or base salts with inorganic and/or organic acids and bases, and also zwitterionic salts (internal). salts), also including quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above-mentioned compound, or a stereoisomer thereof, with a certain amount of acid or base as appropriate (for example, an equivalent amount). These salts may be precipitated in solution and collected by filtration, recovered after evaporation of the solvent, or obtained by lyophilization after reaction in an aqueous medium. The salts described in the present invention can be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate of the compound salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
在某些实施方式中，本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用，用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物，则可将这些化合物同时、分别或有序地对受试对象进行给药。In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent for the preparation of medicaments or pharmaceutical compositions for modulating cellular function or treating diseases. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。Obviously, according to the above-mentioned content of the present invention, according to the common technical knowledge and conventional means in the field, without departing from the above-mentioned basic technical idea of the present invention, other various forms of modification, replacement or change can also be made.
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The above content of the present invention will be further described in detail below through the specific implementation in the form of examples. However, this should not be construed as limiting the scope of the above-mentioned subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.
具体实施方式Detailed ways
化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker AvanceIII 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3),氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10-6 (ppm). NMR was measured with (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) , the internal standard is tetramethylsilane (TMS).
LC-MS的测定使用岛津液质联用仪(Shimadzu LC-MS 2020(ESI))。HPLC的测定使用岛津高压液相色谱仪(Shimadzu LC-20A)。MPLC(中压制备色谱)使用Gilson GX-281反相制备色谱仪。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。The measurement of LC-MS used Shimadzu LC-MS 2020 (ESI)). The HPLC measurement used a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) used a Gilson GX-281 reverse phase preparative chromatograph. The thin layer chromatography silica gel plate is made of Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications of the thin layer chromatography separation and purification products are 0.4mm ~ 0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于安耐吉化学、成都科龙化工、韶远化学科技、百灵威科技等公司。The known starting materials of the present invention can be synthesized by adopting or following methods known in the art, or can be purchased from companies such as Annagy Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and the like.
实施例中无特殊说明，反应在氮气氛围下进行。实施例中无特殊说明，溶液是指水溶液。实施例中无特殊说明，反应的温度为室温。实施例中无特殊说明，M是摩尔每升。There is no special description in the examples, and the reaction is carried out under nitrogen atmosphere. There is no special description in the examples, and the solution refers to an aqueous solution. There is no special description in the examples, and the reaction temperature is room temperature. There is no special description in the examples, and M is moles per liter.
中间体化合物的合成Synthesis of Intermediate Compounds
Figure PCTCN2022077312-appb-000045
Figure PCTCN2022077312-appb-000045
步骤1、化合物M1-2的合成Step 1. Synthesis of compound M1-2
将3-(苄氧)-4-氧-4H-吡喃-2-羧酸M1-1(12.3g,50mmol)溶于二甲基甲酰胺(60mL)中，充分搅拌后，室温下向反应体系中加入1，8-二氮杂二环十一碳-7-烯(11.4g,75mmol),室温搅拌十分钟，向反应体系中加入碘乙烷(14.0g,90mmol),室温搅拌12小时，LC-MS监测。反应结束后用乙酸乙酯和水萃取，有机相用水和饱和食盐水各洗涤三次，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化。粗产物3-(苄氧)-4-氧-4H-吡喃-2-羧酸乙酯M1-2(13.4g)。LC-MS：m/z 275[M+H] + 3-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid M1-1 (12.3 g, 50 mmol) was dissolved in dimethylformamide (60 mL), and after stirring well, the reaction was carried out at room temperature. Add 1,8-diazabicycloundec-7-ene (11.4g, 75mmol) to the system, stir at room temperature for ten minutes, add iodoethane (14.0g, 90mmol) to the reaction system, stir at room temperature for 12 hours , LC-MS monitoring. After the reaction, it was extracted with ethyl acetate and water. The organic phase was washed three times with water and saturated brine each. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product can be directly used in the next reaction without purification. Crude product ethyl 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylate M1-2 (13.4 g). LC-MS: m/z 275 [M+H] +
步骤2、化合物M1-3的合成Step 2. Synthesis of Compound M1-3
将3-(苄氧)-4-氧-4H-吡喃-2-羧酸乙酯M1-2(13.4g,49mmol)溶于二甲基乙酰胺(130mL)中，充分搅拌后，室温下向反应体系中加入对甲苯磺酸吡啶盐(36.8g,147mmol),肼基甲酸叔丁酯(9.7g,73.5mmol),60摄氏度搅拌12小时，LC-MS监测。反应结束后用乙酸乙酯和水萃取，有机相用水和饱和食盐水各洗涤三次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化后得到产物3-(苄氧)-1-((叔丁氧羰基)氨基)-4-氧-1,4-二氢吡啶-2-羧酸乙酯M1-3(12.2g)。LC-MS：m/z 389[M+H] + 3-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylate ethyl ester M1-2 (13.4 g, 49 mmol) was dissolved in dimethylacetamide (130 mL), and after stirring well, at room temperature To the reaction system was added pyridinium p-toluenesulfonate (36.8 g, 147 mmol), tert-butylcarbazate (9.7 g, 73.5 mmol), stirred at 60 degrees Celsius for 12 hours, and monitored by LC-MS. After the reaction, it was extracted with ethyl acetate and water. The organic phase was washed three times with water and saturated brine each. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product 3-(benzyloxy) )-1-((tert-butoxycarbonyl)amino)-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester M1-3 (12.2 g). LC-MS: m/z 389 [M+H] +
步骤3、化合物M1的合成Step 3. Synthesis of Compound M1
将3-(苄氧)-1-((叔丁氧羰基)氨基)-4-氧-1,4-二氢吡啶-2-羧酸乙酯M1-3(7.8g,20mmol)溶于二氯甲烷(30mL)中，充分搅拌后，室温下向反应体系中加入三氟乙酸(30mL),室温下搅拌1小时，LC-MS监测。反应结束后减压浓缩除去二氯甲烷和三氟乙酸，加入饱和碳酸氢钠水溶液将体系PH值调至7-8，用二氯甲烷和水萃取，有机相用饱和食盐水洗涤一次，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化。粗产物1-氨基-3-(苄氧)-4-氧-1,4-二氢吡啶-2-羧酸乙酯M1(5.4g)。LC-MS：m/z 289[M+H] + Ethyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-1,4-dihydropyridine-2-carboxylate M1-3 (7.8 g, 20 mmol) was dissolved in dihydropyridine In chloromethane (30 mL), after fully stirring, trifluoroacetic acid (30 mL) was added to the reaction system at room temperature, stirred at room temperature for 1 hour, and monitored by LC-MS. After the reaction was completed, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure, and the pH value of the system was adjusted to 7-8 by adding saturated aqueous sodium bicarbonate solution, extracted with dichloromethane and water, and the organic phase was washed once with saturated brine. After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure, and the crude product could be directly used in the next reaction without purification. Crude product ethyl 1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2-carboxylate M1 (5.4 g). LC-MS: m/z 289 [M+H] +
Figure PCTCN2022077312-appb-000046
Figure PCTCN2022077312-appb-000046
步骤4、化合物M2-2的合成Step 4. Synthesis of compound M2-2
将3,4-二氟-2-甲基苯甲酸M2-1(8.6g,50mmol)、N-溴代丁二酰亚胺(8.9g,60mmol)、偶氮二异丁腈(164mg,1mmol)溶于四氯化碳(200mL)中，将反应体系用氮气置换三次，充入一个大气压力的氮气，80摄氏度下搅拌1小时，LC-MS监测。反应结束后减压浓缩，残余物用柱层析纯化后得到产物2-(溴甲基)-3,4-二氟苯甲酸M2-2(12.0g)。3,4-Difluoro-2-methylbenzoic acid M2-1 (8.6 g, 50 mmol), N-bromosuccinimide (8.9 g, 60 mmol), azobisisobutyronitrile (164 mg, 1 mmol) ) was dissolved in carbon tetrachloride (200 mL), the reaction system was replaced with nitrogen three times, filled with nitrogen at 1 atmospheric pressure, stirred at 80 degrees Celsius for 1 hour, and monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 2-(bromomethyl)-3,4-difluorobenzoic acid M2-2 (12.0 g).
步骤5、化合物M2-4的合成Step 5. Synthesis of compound M2-4
将二苯二硫醚M2-3(5.5g,25mmol)、氢氧化钠(2.9g,72mmol)、硼氢化钠(1.7g,46mmol)溶于四氢呋喃(80mL)和水(80mL)中，将反应体系用氮气置换三次，充入一个大气压力的氮气，70摄氏度下搅拌12小时，LC-MS监测。反应液直接用于下一步反应。将2-(溴甲基)-3,4-二氟苯甲酸M2-2(12.0g,48mmol)加入到上述的溶液中，室温下搅拌1小时，LC-MS监测。反应结束后向反应体系中加入1N稀盐酸，将体系PH值调至5-6，减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化后得到产物3,4-二氟-2-((苯硫)甲基)苯甲酸M2-4(12.6g)。LC-MS：m/z 281[M+H] + Diphenyl disulfide M2-3 (5.5 g, 25 mmol), sodium hydroxide (2.9 g, 72 mmol), sodium borohydride (1.7 g, 46 mmol) were dissolved in tetrahydrofuran (80 mL) and water (80 mL), and the reaction was carried out The system was replaced with nitrogen three times, filled with nitrogen at one atmosphere pressure, and stirred at 70 degrees Celsius for 12 hours, monitored by LC-MS. The reaction solution was directly used in the next reaction. 2-(Bromomethyl)-3,4-difluorobenzoic acid M2-2 (12.0 g, 48 mmol) was added to the above solution, stirred at room temperature for 1 hour, and monitored by LC-MS. After the reaction, 1N dilute hydrochloric acid was added to the reaction system, the pH value of the system was adjusted to 5-6, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was After purification by column chromatography, the product 3,4-difluoro-2-((phenylthio)methyl)benzoic acid M2-4 (12.6 g) was obtained. LC-MS: m/z 281 [M+H] +
步骤6、化合物M2-5的合成Step 6. Synthesis of compound M2-5
将3,4-二氟-2-((苯硫)甲基)苯甲酸M2-4(12.6g,45mmol)溶于多聚磷酸(300mL)中，120摄氏度下搅拌12小时，LC-MS监测。反应结束后将反应体系冷却至室温，将反应液倒入2千克的碎冰中，用乙酸乙酯和水萃取，有机相用饱和碳酸氢钠水溶液洗涤三次，有机相无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化后得到产物7,8-二氟二苯[b,e]噻庚-11(6H)-酮M2-5(10.1g)。LC-MS：m/z 263[M+H] + 3,4-Difluoro-2-((phenylthio)methyl)benzoic acid M2-4 (12.6 g, 45 mmol) was dissolved in polyphosphoric acid (300 mL), stirred at 120 degrees Celsius for 12 hours, monitored by LC-MS . After the reaction was completed, the reaction system was cooled to room temperature, the reaction solution was poured into 2 kg of crushed ice, extracted with ethyl acetate and water, the organic phase was washed three times with saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate and then reduced. It was concentrated under pressure, and the residue was purified by column chromatography to give the product 7,8-difluorodiphenyl[b,e]thihep-11(6H)-one M2-5 (10.1 g). LC-MS: m/z 263 [M+H] +
步骤7、化合物M2的合成Step 7. Synthesis of Compound M2
将7,8-二氟二苯[b,e]噻庚-11(6H)-酮M2-5(10.1g,38.5mmol)溶于甲醇(200mL)中，将体系充分冷却至零度，零度下缓慢加入硼氢化钠(2.9g,77mmol)，零度下搅拌1小时，LC-MS监测。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化后得到产物7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-醇M2(9.8g)。LC-MS：m/z 247[M+H-18] + 7,8-Difluorodiphenyl[b,e]thihept-11(6H)-one M2-5 (10.1 g, 38.5 mmol) was dissolved in methanol (200 mL), and the system was fully cooled to zero, under zero Sodium borohydride (2.9 g, 77 mmol) was slowly added, and the mixture was stirred at zero degrees for 1 hour and monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 7,8-difluoro-6,11-dihydro Diphenyl[b,e]thihept-11-ol M2 (9.8 g). LC-MS: m/z 247[M+H-18] +
M2可拆分为：M2 can be split into:
Figure PCTCN2022077312-appb-000047
Figure PCTCN2022077312-appb-000047
实施例1、4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-9'-羟基-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f] 吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮(化合物1)的合成Example 1, 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-9'-hydroxy-2,3,3a',4' ,5,6-Hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10 Synthesis of '(1'H,3'H)-diketone (Compound 1)
Figure PCTCN2022077312-appb-000048
Figure PCTCN2022077312-appb-000048
步骤1、化合物1-3的合成Step 1. Synthesis of Compounds 1-3
氮气保护下，将底物8-氧杂-2-氮杂螺[4,5]癸-3-酮1-1(1.6g,10.0mmol)，溶于四氢呋喃中(40mL)，将反应体系充分冷却至零下30摄氏度，缓慢滴加正丁基锂(2.5M，12.0mmol，4.8mL)，保持零下30摄氏度反应1小时，向反应体系中滴加氯甲酸烯丙酯1-2(1.5g,12.0mmol)，保持零下30摄氏度反应1小时，加入饱和氯化铵溶液淬灭反应，减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化后得到产物烯丙基3-氧-8-氧杂-2-氮杂螺[4.5]癸烷-2-碳酸脂1-3(2.4g)。LC-MS：m/z 240[M+H] + Under nitrogen protection, the substrate 8-oxa-2-azaspiro[4,5]dec-3-one 1-1 (1.6 g, 10.0 mmol) was dissolved in tetrahydrofuran (40 mL), and the reaction system was fully Cool to minus 30 degrees Celsius, slowly add n-butyllithium (2.5M, 12.0mmol, 4.8mL) dropwise, keep minus 30 degrees Celsius to react for 1 hour, add allyl chloroformate 1-2 (1.5g, 12.0 mmol), kept the reaction at minus 30 degrees Celsius for 1 hour, added saturated ammonium chloride solution to quench the reaction, concentrated under reduced pressure, extracted with ethyl acetate and water, dried the organic phase with anhydrous sodium sulfate and concentrated under reduced pressure, the residue was used After purification by column chromatography, the product allyl 3-oxa-8-oxa-2-azaspiro[4.5]decane-2-carbonate 1-3 (2.4g) was obtained. LC-MS: m/z 240 [M+H] +
步骤2、化合物1-4的合成Step 2. Synthesis of Compounds 1-4
将3-氧-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂1-3(2.38g,10.0mmol)溶于25mL四氢呋喃中，将反应体系充分冷却至零下78摄氏度，缓慢滴加二异丁基氢化铝(1.3M,12.0mmol,9.2mL)，保持零下78摄氏度反应1小时，加入饱和氯化铵溶液淬灭反应，减压浓缩，并用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-羟基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂1-4。LC-MS：m/z 224[M+H-18] + 3-Oxy-8-oxa-2-azaspiro[4.5]decane-2-carboxylate allyl ester 1-3 (2.38 g, 10.0 mmol) was dissolved in 25 mL of tetrahydrofuran, and the reaction system was fully cooled to At minus 78 degrees Celsius, diisobutylaluminum hydride (1.3M, 12.0 mmol, 9.2 mL) was slowly added dropwise, kept at minus 78 degrees Celsius for 1 hour, and saturated ammonium chloride solution was added to quench the reaction, concentrated under reduced pressure, and washed with ethyl acetate. Extracted with water, the organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The crude product can be directly used in the next step without purification. The crude product is 3-hydroxy-8-oxa-2-azaspiro[4.5]decane. Allyl alkane-2-carboxylate 1-4. LC-MS: m/z 224[M+H-18] +
步骤3、化合物1-5的合成Step 3. Synthesis of Compounds 1-5
将粗产物3-羟基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂1-4溶于甲醇(20mL)中，充分搅拌后，室温下向反应体系中加入一水合对甲苯磺酸(153mg,0.8mmol),室温搅拌12小时，LC-MS监测。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-甲氧基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂1-5。LC-MS：m/z 224[M+H-32] +步骤4、化合物1-6的合成 The crude product 3-hydroxy-8-oxa-2-azaspiro[4.5]decane-2-carboxylate allyl ester 1-4 was dissolved in methanol (20 mL), stirred well, and added to the reaction system at room temperature P-toluenesulfonic acid monohydrate (153 mg, 0.8 mmol) was added to the mixture, and the mixture was stirred at room temperature for 12 hours and monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The crude product can be directly used in the next step without purification. The crude product 3-methoxy-8 -oxa-2-azaspiro[4.5]decane-2-carboxylate allyl ester 1-5. LC-MS: m/z 224[M+H-32] + step 4, synthesis of compounds 1-6
将粗产物3-甲氧基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂1-5和1-氨基-3-(苄氧)-4-氧-1,4-二氢吡啶-2-羧酸乙酯M1(1.8g,6.2mmol)溶于乙腈(60mL)中，将反应体系充分冷却至零下30摄氏度，向反应体系中缓慢加入四氯化锡(2.4g,9.4mmol),零下30摄氏度搅拌1小时，LC-MS监测。反应结束后加入饱和碳酸氢钠水溶液淬灭反应，减压浓缩，用二氯甲烷和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-8-氧杂-2- 氮杂螺[4.5]癸烷-2-羧酸烯丙酯1-6。LC-MS：m/z 512[M+H] + The crude product 3-methoxy-8-oxa-2-azaspiro[4.5]decane-2-carboxylate allyl 1-5 and 1-amino-3-(benzyloxy)-4-oxo -1,4-dihydropyridine-2-carboxylate ethyl ester M1 (1.8g, 6.2mmol) was dissolved in acetonitrile (60mL), the reaction system was fully cooled to minus 30 degrees Celsius, and tetrachloride was slowly added to the reaction system Tin (2.4 g, 9.4 mmol) was stirred at minus 30 degrees Celsius for 1 hour and monitored by LC-MS. After the reaction, saturated aqueous sodium bicarbonate solution was added to quench the reaction, concentrated under reduced pressure, extracted with dichloromethane and water, the organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure, the crude product can be directly used in the next step without purification. , the crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-8-oxa-2-azaspiro[4.5] Allyl decane-2-carboxylate 1-6. LC-MS: m/z 512 [M+H] +
步骤5、化合物1-7的合成Step 5. Synthesis of Compounds 1-7
将粗产物3-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯1-6、四三苯基膦钯(285mg,0.3mmol)、吗啉(4.3g,50mmol)溶于四氢呋喃(40mL)中，将反应体系用氮气置换三次，充入一个大气压力的氮气，室温下搅拌1小时，TLC和LC-MS监测。反应结束后减压浓缩，残余物用柱层析纯化后得到产物9'-(苄氧)-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮1-7(1.5g)。LC-MS：m/z 382[M+H] + The crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-8-oxa-2-azaspiro[4.5] Allyl decane-2-carboxylate 1-6, palladium tetrakistriphenylphosphine (285 mg, 0.3 mmol), and morpholine (4.3 g, 50 mmol) were dissolved in tetrahydrofuran (40 mL), and the reaction system was replaced with nitrogen three times , charged with 1 atmosphere of nitrogen, stirred at room temperature for 1 hour, and monitored by TLC and LC-MS. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 9'-(benzyloxy)-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-Pyridine[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 1-7 (1.5g). LC-MS: m/z 382 [M+H] +
化合物1-7可拆分为：Compounds 1-7 can be resolved into:
Figure PCTCN2022077312-appb-000049
Figure PCTCN2022077312-appb-000049
步骤6、化合物1-8的合成Step 6. Synthesis of Compounds 1-8
将9'-(苄氧)-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮1-7(38.2mg,0.1mmol)和7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-醇M2(39.6mg,0.2mmol)、溶于1-丙基磷酸酐(50wt.％的乙酸乙酯溶液，400uL)中，微波110摄氏度下搅拌3小时，LC-MS监测。反应结束后减压浓缩得粗产物9'-(苄氧)-4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮1-8。LC-MS：m/z 628[M+H] + 9'-(benzyloxy)-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridine[2,1-f]pyrrole[2,1 -c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 1-7 (38.2 mg, 0.1 mmol) and 7,8-difluoro-6 ,11-dihydrodiphenyl[b,e]thihept-11-ol M2 (39.6mg, 0.2mmol), dissolved in 1-propylphosphoric anhydride (50wt.% in ethyl acetate, 400uL), microwave Stir at 110°C for 3 hours and monitor by LC-MS. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-2 ,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4] Triazine]-8',10'(1'H,3'H)-dione 1-8. LC-MS: m/z 628 [M+H] +
步骤7、化合物1的合成Step 7. Synthesis of Compound 1
将粗产物9'-(苄氧)-4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮1-8溶于甲醇(5mL)中，加入氢氧化钯碳(14mg,0.1mmol)，将反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌4小时，LC-MS监测。反应结束后用硅藻土过滤，滤液减压浓缩，用中压反相制备柱纯化得4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-9'-羟基-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮化合物1(24.2mg)。LC-MS：m/z 538[M+H] + The crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-2,3,3a', 4',5,6-Hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8' , 10'(1'H,3'H)-diketone 1-8 was dissolved in methanol (5mL), palladium hydroxide on carbon (14mg, 0.1mmol) was added, the reaction system was replaced with nitrogen three times, filled with an atmosphere Hydrogen under pressure, stirred at room temperature for 4 hours, monitored by LC-MS. After the reaction, it was filtered with celite, the filtrate was concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiheptyl- 11-yl)-9'-hydroxy-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridine[2,1-f]pyrrole[2, 1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione compound 1 (24.2 mg). LC-MS: m/z 538 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ7.58-7.45(m,2H),7.39-7.30(m,1H),7.13-7.07(m,1H),7.03(d,J＝7.8Hz,1H),6.94-6.82(m,2H),5.78-5.54(m,4H),4.15(d,J＝13.8Hz,1H),3.90(d,J＝12.0Hz,1H),3.42-3.40(m,3H),2.36(s,1H),2.07-1.94(m,1H),1.55-1.24(m,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.58-7.45 (m, 2H), 7.39-7.30 (m, 1H), 7.13-7.07 (m, 1H), 7.03 (d, J=7.8Hz, 1H) ),6.94-6.82(m,2H),5.78-5.54(m,4H),4.15(d,J=13.8Hz,1H),3.90(d,J=12.0Hz,1H),3.42-3.40(m, 3H), 2.36(s, 1H), 2.07-1.94(m, 1H), 1.55-1.24(m, 6H).
化合物1可产生以下6种异构体：Compound 1 can produce the following 6 isomers:
Figure PCTCN2022077312-appb-000050
Figure PCTCN2022077312-appb-000050
Isomer 1-1对应核磁： 1H NMR(400MHz,DMSO-d 6)δ7.58-7.45(m,2H),7.39-7.30(m,1H),7.13-7.07(m,1H),7.03(d,J＝7.8Hz,1H),6.94-6.82(m,2H),5.78-5.54(m,4H),4.15(d,J＝13.8Hz,1H),3.90(d,J＝12.0Hz,1H),3.42-3.40(m,3H),2.36(s,1H),2.07-1.94(m,1H),1.55-1.24(m,6H). Isomer 1-1 corresponds to NMR: 1 H NMR (400MHz, DMSO-d 6 )δ7.58-7.45(m, 2H), 7.39-7.30(m, 1H), 7.13-7.07(m, 1H), 7.03(d ,J=7.8Hz,1H),6.94-6.82(m,2H),5.78-5.54(m,4H),4.15(d,J=13.8Hz,1H),3.90(d,J=12.0Hz,1H) ,3.42-3.40(m,3H),2.36(s,1H),2.07-1.94(m,1H),1.55-1.24(m,6H).
Isomer 1-2对应核磁： 1H NMR(400MHz,DMSO-d 6)δ7.58-7.45(m,2H),7.39-7.30(m,1H),7.13-7.07(m,1H),7.03(d,J＝7.8Hz,1H),6.94-6.82(m,2H),5.78-5.54(m,4H),4.15(d,J＝13.8Hz,1H),3.90(d,J＝12.0Hz,1H),3.42-3.40(m,3H),2.36(s,1H),2.07-1.94(m,1H),1.55-1.24(m,6H). Isomer 1-2 corresponds to NMR: 1 H NMR (400MHz, DMSO-d 6 )δ7.58-7.45(m, 2H), 7.39-7.30(m, 1H), 7.13-7.07(m, 1H), 7.03(d ,J=7.8Hz,1H),6.94-6.82(m,2H),5.78-5.54(m,4H),4.15(d,J=13.8Hz,1H),3.90(d,J=12.0Hz,1H) ,3.42-3.40(m,3H),2.36(s,1H),2.07-1.94(m,1H),1.55-1.24(m,6H).
实施例2、4'-(7,8-二氟-6,11-二氢二苯[b，e]噻吩-11-基)-4,4-二氟-9'-羟基-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮(化合物2)的合成Example 2, 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiophen-11-yl)-4,4-difluoro-9'-hydroxy-3a', 4'-Dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8', 10' Synthesis of (1'H,3'H)-diketone (Compound 2)
Figure PCTCN2022077312-appb-000051
Figure PCTCN2022077312-appb-000051
步骤1、化合物2-3的合成Step 1. Synthesis of Compounds 2-3
氮气保护下，向250mL三口瓶中加入钠氢(1.9g,48mmol)，无水四氢呋喃(200mL),充分冷却至零摄氏度，缓慢滴加磷酰基乙酸三乙酯2-2(10.8g,48mmol)的四氢呋喃(50mL)溶液，滴加完毕保持零 摄氏度反应0.5小时，室温下反应1小时。将反应体系充分冷却至零摄氏度，缓慢滴加4,4-二氟环己酮2-1(5.4g,40mmol)的四氢呋喃(30mL)，滴加完毕室温下反应2小时，TLC和LC-MS监测。反应结束后向体系中加入饱和氯化铵水溶液(50mL)，减压浓缩，用乙酸乙酯和水萃取，有机相用饱和食盐水洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物2-(4,4-二氟环己基二烯)乙酸乙酯2-3(8.0g)。LC-MS：m/z 205[M+H] +。 Under nitrogen protection, sodium hydrogen (1.9g, 48mmol) and anhydrous tetrahydrofuran (200mL) were added to a 250mL there-necked flask, fully cooled to zero degrees Celsius, and slowly added dropwise triethyl phosphoryl acetate 2-2 (10.8g, 48mmol) The solution of tetrahydrofuran (50 mL) was added dropwise, and the reaction was kept at zero degrees Celsius for 0.5 hours, and the reaction was carried out at room temperature for 1 hour. The reaction system was fully cooled to zero degrees Celsius, and tetrahydrofuran (30 mL) of 4,4-difluorocyclohexanone 2-1 (5.4 g, 40 mmol) was slowly added dropwise. After the addition was completed, the reaction was carried out at room temperature for 2 hours. monitor. After the reaction, saturated aqueous ammonium chloride solution (50 mL) was added to the system, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure , the residue was purified by column chromatography to give the product ethyl 2-(4,4-difluorocyclohexyldiene)acetate 2-3 (8.0 g). LC-MS: m/z 205 [M+H] + .
步骤2、化合物2-4的合成Step 2. Synthesis of Compounds 2-4
向250mL反应瓶中加入2-(4,4-二氟环己基二烯)乙酸乙酯2-3(8.0g,39mmol)，碳酸钾(11g,80mmol)，二甲基亚砜(80mL)和硝基甲烷(4.9g,80mmol)，80摄氏度下搅拌反应2小时，TLC和LC-MS监测。反应结束后向体系中加入水(200mL)，用乙酸乙酯萃取，有机相用水合饱和食盐水各洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，得到粗品2-(4,4-二氟-1-(硝甲基)环己基)乙酸乙酯2-4直接用于下一步反应。LC-MS：m/z 266[M+H] + To a 250 mL reaction flask was added 2-(4,4-difluorocyclohexyldiene)ethyl acetate 2-3 (8.0 g, 39 mmol), potassium carbonate (11 g, 80 mmol), dimethyl sulfoxide (80 mL) and With nitromethane (4.9 g, 80 mmol), the reaction was stirred at 80 degrees Celsius for 2 hours, monitored by TLC and LC-MS. After the reaction, water (200 mL) was added to the system, extracted with ethyl acetate, the organic phase was washed twice with hydrated saturated brine each, and the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 2-(4, Ethyl 4-difluoro-1-(nitromethyl)cyclohexyl)acetate 2-4 was used directly in the next reaction. LC-MS: m/z 266[M+H] +
步骤3、化合物2-5的合成Step 3. Synthesis of Compounds 2-5
向250mL反应瓶中加入2-(4,4-二氟-1-(硝甲基)环己基)乙酸乙酯2-4，甲醇(80mL)，和雷尼镍，反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌反应12小时。LC-MS监测反应。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物8,8-二氟-2-氮杂螺[4.5]癸-3-酮2-5(3.8g)。LC-MS：m/z 190[M+H] + 2-(4,4-Difluoro-1-(nitromethyl)cyclohexyl)ethyl acetate 2-4, methanol (80mL), and Raney nickel were added to a 250mL reaction flask, and the reaction system was replaced with nitrogen three times, One atmosphere of hydrogen was charged and the reaction was stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 8,8-difluoro-2-azaspiro[ 4.5] Dec-3-one 2-5 (3.8 g). LC-MS: m/z 190 [M+H] +
步骤4、化合物2-6的合成Step 4. Synthesis of Compounds 2-6
将底物8,8-二氟-2-氮杂螺[4,5]癸-3-酮2-5(3.8g,20.1mmol)，溶于四氢呋喃中(50mL)，将反应体系充分冷却至零下30摄氏度，缓慢滴加正丁基锂(2.5M，24.1mmol，9.6mL)，保持零下30摄氏度反应1小时，向反应体系中滴加氯甲酸烯丙酯1-2(2.6g,21.4mmol)，保持零下30摄氏度反应1小时，加入饱和氯化铵溶液淬灭反应，减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化后得到产物烯丙基3-氧-8,8-二氟-2-氮杂螺[4.5]癸烷-2-碳酸脂2-6(4.3g)。LC-MS：m/z 274[M+H] + The substrate 8,8-difluoro-2-azaspiro[4,5]dec-3-one 2-5 (3.8 g, 20.1 mmol) was dissolved in tetrahydrofuran (50 mL), and the reaction system was fully cooled to At minus 30 degrees Celsius, n-butyllithium (2.5M, 24.1 mmol, 9.6 mL) was slowly added dropwise, kept at minus 30 degrees Celsius for 1 hour, and allyl chloroformate 1-2 (2.6 g, 21.4 mmol) was added dropwise to the reaction system. ), kept the reaction at minus 30 degrees Celsius for 1 hour, added saturated ammonium chloride solution to quench the reaction, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was subjected to a column layer After analysis and purification, the product allyl 3-oxo-8,8-difluoro-2-azaspiro[4.5]decane-2-carbonate 2-6 (4.3g) was obtained. LC-MS: m/z 274 [M+H] +
步骤5、化合物2-7的合成Step 5. Synthesis of Compounds 2-7
将3-氧-8,8-二氟-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂2-6(4.3g,15.8mmol)溶于四氢呋喃(40mL)中，将反应体系充分冷却至零下78摄氏度，缓慢滴加二异丁基氢化铝(1.3M，19.0mmol，14.6mL)，保持零下78摄氏度反应1小时，加入饱和氯化铵溶液淬灭反应，减压浓缩，并用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，直接用于下步反应，无需纯化，粗产物3-羟基-8,8-二氟-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂2-7。LC-MS：m/z 258[M+H-18] + 3-Oxo-8,8-difluoro-2-azaspiro[4.5]decane-2-carboxylate allyl ester 2-6 (4.3 g, 15.8 mmol) was dissolved in tetrahydrofuran (40 mL), and the reaction was The system was fully cooled to minus 78 degrees Celsius, and diisobutylaluminum hydride (1.3M, 19.0 mmol, 14.6 mL) was slowly added dropwise, kept at minus 78 degrees Celsius for 1 hour, and saturated ammonium chloride solution was added to quench the reaction, and concentrated under reduced pressure, And extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and used directly in the next step without purification, the crude product 3-hydroxy-8,8-difluoro-2-azaspiro[ 4.5] Allyl decane-2-carboxylate 2-7. LC-MS: m/z 258[M+H-18] +
步骤6、化合物2-8的合成Step 6. Synthesis of Compounds 2-8
将粗产物3-羟基-8,8-二氟-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂2-7溶于甲醇(32mL)中，充分搅拌后，室温下向反应体系中加入一水合对甲苯磺酸(241mg,1.3mmol),室温搅拌12小时，LC-MS监测。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-甲氧基-8,8-二氟-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂2-8。LC-MS：m/z 258[M+H-32] + The crude product 3-hydroxy-8,8-difluoro-2-azaspiro[4.5]decane-2-carboxylate allyl ester 2-7 was dissolved in methanol (32 mL), stirred well, and added to the solution at room temperature. To the reaction system was added p-toluenesulfonic acid monohydrate (241 mg, 1.3 mmol), stirred at room temperature for 12 hours, and monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The crude product can be directly used in the next step without purification. The crude product 3-methoxy-8 ,8-Difluoro-2-azaspiro[4.5]decane-2-carboxylate allyl 2-8. LC-MS: m/z 258[M+H-32] +
步骤7、化合物2-9的合成Step 7. Synthesis of Compounds 2-9
将粗产物3-甲氧基-8,8-二氟-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂2-8和1-氨基-3-(苄氧)-4-氧-1,4-二氢吡啶-2-羧酸乙酯M1(3.2g,11.1mmol)溶于乙腈(110mL)中，将反应体系充分冷却至零下30摄氏度，向反应体系中缓慢加入四氯化锡(7.5g,16.6mmol),零下30摄氏度搅拌1小时，LC-MS监测。反应结束后加 入饱和碳酸氢钠水溶液淬灭反应，减压浓缩，用二氯甲烷和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-8,8-二氟-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯2-9。LC-MS：m/z 546[M+H] + The crude product 3-methoxy-8,8-difluoro-2-azaspiro[4.5]decane-2-carboxylate allyl 2-8 and 1-amino-3-(benzyloxy)-4 -Oxy-1,4-dihydropyridine-2-carboxylic acid ethyl ester M1 (3.2 g, 11.1 mmol) was dissolved in acetonitrile (110 mL), the reaction system was fully cooled to minus 30 degrees Celsius, and the reaction system was slowly added with four Tin chloride (7.5 g, 16.6 mmol) was stirred at minus 30 degrees Celsius for 1 hour, and monitored by LC-MS. After the reaction, saturated aqueous sodium bicarbonate solution was added to quench the reaction, concentrated under reduced pressure, extracted with dichloromethane and water, the organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure, the crude product can be directly used in the next step without purification. , the crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-8,8-difluoro-2-azaspiro[ 4.5] Allyl decane-2-carboxylate 2-9. LC-MS: m/z 546[M+H] +
步骤8、化合物2-10的合成Step 8. Synthesis of Compounds 2-10
将粗产物3-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-8,8-二氟-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯2-9、四三苯基膦钯(480mg,0.4mmol)、吗啉(7.2g,83mmol)溶于四氢呋喃(66mL)中，将反应体系用氮气置换三次，充入一个大气压力的氮气，室温下搅拌1小时，TLC和LC-MS监测。反应结束后减压浓缩，残余物用柱层析纯化后得到产物9'-(苄氧基)-4,4-二氟-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮2-10(2.2g)。LC-MS：m/z 416[M+H] + The crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-8,8-difluoro-2-azaspiro[ 4.5] Decane-2-carboxylate allyl ester 2-9, tetrakistriphenylphosphine palladium (480mg, 0.4mmol), morpholine (7.2g, 83mmol) were dissolved in tetrahydrofuran (66mL), the reaction system was purged with nitrogen Replaced three times, charged with nitrogen at 1 atmosphere, stirred at room temperature for 1 hour, and monitored by TLC and LC-MS. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 9'-(benzyloxy)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2 '-Pyridin[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 2- 10 (2.2 g). LC-MS: m/z 416[M+H] +
步骤9、化合物2-11的合成Step 9. Synthesis of Compounds 2-11
将9'-(苄氧基)-4,4-二氟-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮2-10(41.5mg,0.1mmol)和7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-醇M2(39.6mg,0.2mmol)、溶于1-丙基磷酸酐(50wt.％的乙酸乙酯溶液，400uL)中，微波110摄氏度下搅拌3小时，LC-MS监测。反应结束后减压浓缩得粗产物9'-(苄氧基)-4'-(7,8-二氟-6,11-二氢二苯[b，e]噻吩-11-基)-4,4-二氟-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮2-11。LC-MS：m/z 662[M+H] + 9'-(benzyloxy)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridine[2,1-f]pyrrole[2, 1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 2-10 (41.5 mg, 0.1 mmol) and 7,8-difluoro- 6,11-Dihydrodiphenyl[b,e]thihept-11-ol M2 (39.6mg, 0.2mmol), dissolved in 1-propylphosphoric anhydride (50wt.% in ethyl acetate, 400uL), Stir at 110°C in microwave for 3 hours and monitor by LC-MS. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiophen-11-yl)-4 ,4-Difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4] Triazine]-8',10'(1'H,3'H)-dione 2-11. LC-MS: m/z 662 [M+H] +
步骤10、化合物2的合成Step 10. Synthesis of Compound 2
将粗产物9'-(苄氧基)-4'-(7,8-二氟-6,11-二氢二苯[b，e]噻吩-11-基)-4,4-二氟-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮2-11溶于甲醇(5mL)中，加入氢氧化钯碳(14mg,0.1mmol)，将反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌4小时，LC-MS监测。反应结束后用硅藻土过滤，滤液减压浓缩，用中压反相制备柱纯化得化合物4'-(7,8-二氟-6,11-二氢二苯[b，e]噻吩-11-基)-4,4-二氟-9'-羟基-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮2(24.5mg)。LC-MS：m/z 572[M+H] + The crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiophen-11-yl)-4,4-difluoro- 3a', 4'-Dihydrospiro[cyclohexane-1,2'-pyridinepara[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8' , 10'(1'H, 3'H)-diketone 2-11 was dissolved in methanol (5 mL), palladium hydroxide on carbon (14 mg, 0.1 mmol) was added, the reaction system was replaced with nitrogen three times, filled with an atmosphere Hydrogen under pressure, stirred at room temperature for 4 hours, monitored by LC-MS. After the reaction, it was filtered with celite, the filtrate was concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain the compound 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiophene- 11-yl)-4,4-difluoro-9'-hydroxy-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridine[2,1-f]pyrrole[2, 1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 2 (24.5 mg). LC-MS: m/z 572 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ7.44-7.35(m,2H),7.32-7.05(m,4H),7.05-6.96(m,1H),5.75-5.51(m,1H),5.45-5.31(m,1H),5.24-5.04(m,1H),4.38-4.25(m,1H),3.93-3.81(m,1H),3.58-3.53(m,2H),2.41-2.22(m,1H),2.04-1.84(m,4H),1.77-1.41(m,5H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.44-7.35 (m, 2H), 7.32-7.05 (m, 4H), 7.05-6.96 (m, 1H), 5.75-5.51 (m, 1H), 5.45 -5.31(m, 1H), 5.24-5.04(m, 1H), 4.38-4.25(m, 1H), 3.93-3.81(m, 1H), 3.58-3.53(m, 2H), 2.41-2.22(m, 1H), 2.04-1.84(m, 4H), 1.77-1.41(m, 5H).
实施例3、4-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-9-羟基-2',3a,3',4,5',6'-六氢螺[吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪-2,4'-噻喃]-8,10(1H,3H)-二酮(化合物3)的合成Example 3, 4-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-9-hydroxy-2',3a,3',4,5 ',6'-Hexahydrospiro[pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine-2,4'-thiopyran]-8,10( Synthesis of 1H,3H)-diketone (Compound 3)
Figure PCTCN2022077312-appb-000052
Figure PCTCN2022077312-appb-000052
步骤1、化合物3-2的合成Step 1. Synthesis of compound 3-2
氮气保护下，向250mL三口瓶中加入钠氢(2.2g,55mmol)，无水四氢呋喃(100mL),充分冷却至零摄氏度，缓慢滴加磷酰基乙酸三乙酯2-2(12.3g,55mmol)的四氢呋喃(40mL)溶液，滴加完毕保持零摄氏度反应0.5小时，室温下反应1小时。将反应体系充分冷却至零摄氏度，缓慢滴加四氢噻喃-4-酮3-1(5.8g,50mmol)的四氢呋喃(30mL)，滴加完毕室温下反应2小时，TLC和LC-MS监测。反应结束后向体系中加入饱和氯化铵水溶液(50mL)，减压浓缩，用乙酸乙酯和水萃取，有机相用饱和食盐水洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物2-四氢噻喃-4亚乙基乙酸乙酯3-2(8.6g)。LC-MS：m/z 187[M+H] +。 Under nitrogen protection, add sodium hydrogen (2.2g, 55mmol), anhydrous tetrahydrofuran (100mL) to a 250mL there-necked flask, fully cool to zero degrees Celsius, slowly add triethyl phosphoryl acetate 2-2 (12.3g, 55mmol) dropwise The solution of tetrahydrofuran (40 mL) was added dropwise, and the reaction was kept at zero degrees Celsius for 0.5 hours, and the reaction was carried out at room temperature for 1 hour. The reaction system was fully cooled to zero degrees Celsius, and tetrahydrothiopyran-4-one 3-1 (5.8 g, 50 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise, and the addition was completed at room temperature for 2 hours. TLC and LC-MS were monitored. . After the reaction, saturated aqueous ammonium chloride solution (50 mL) was added to the system, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure , the residue was purified by column chromatography to give the product ethyl 2-tetrahydrothiopyran-4 ethylidene acetate 3-2 (8.6 g). LC-MS: m/z 187 [M+H] + .
步骤2、化合物3-3的合成Step 2. Synthesis of compound 3-3
向250mL反应瓶中加入2-四氢噻喃-4亚乙基乙酸乙酯3-2(8.6g,46mmol)，碳酸钾(12.7g,92mmol)，二甲基亚砜(100mL)和硝基甲烷(5.6g,92mmol)，80摄氏度下搅拌反应2小时，TLC和LC-MS监测。反应结束后向体系中加入水(200mL)，用乙酸乙酯萃取，有机相用水合饱和食盐水各洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，得粗品2-[4-(硝基甲基)四氢噻喃-4-基]乙酸乙酯3-3直接用于下一步反应。LC-MS：m/z 248[M+H] + To a 250 mL reaction flask was added ethyl 2-tetrahydrothiopyran-4 ethylidene acetate 3-2 (8.6 g, 46 mmol), potassium carbonate (12.7 g, 92 mmol), dimethyl sulfoxide (100 mL) and nitro Methane (5.6 g, 92 mmol), the reaction was stirred at 80 degrees Celsius for 2 hours, monitored by TLC and LC-MS. After the reaction was completed, water (200 mL) was added to the system, extracted with ethyl acetate, the organic phase was washed twice with hydrated saturated brine, the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 2-[4- (Nitromethyl)tetrahydrothiopyran-4-yl]ethyl acetate 3-3 was used directly in the next reaction. LC-MS: m/z 248[M+H] +
步骤3、化合物3-4的合成Step 3. Synthesis of Compounds 3-4
向250mL反应瓶中加入2-[4-(硝基甲基)四氢噻喃-4-基]乙酸乙酯3-3，甲醇(80mL)，和雷尼镍，反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌反应12小时。LC-MS监测反应。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物8-硫杂-2-氮杂螺[4.5]癸烷-3-酮3-4(2.3g)。LC-MS：m/z 172[M+H] + 2-[4-(nitromethyl)tetrahydrothiopyran-4-yl]ethyl acetate 3-3, methanol (80 mL), and Raney nickel were added to a 250 mL reaction flask, and the reaction system was replaced with nitrogen three times, One atmosphere of hydrogen was charged and the reaction was stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 8-thia-2-azaspiro[4.5] Decan-3-one 3-4 (2.3 g). LC-MS: m/z 172 [M+H] +
步骤4、化合物3-5的合成Step 4. Synthesis of Compounds 3-5
将底物8-硫杂-2-氮杂螺[4.5]癸烷-3-酮3-4(1.0g,5.9mmol)，溶于四氢呋喃中(20mL)，将反应体系充分冷却至零下30摄氏度，缓慢滴加正丁基锂(2.5M，5.9mmol，2.3mL)，保持零下30摄氏度反应1小时，向反应体系中滴加氯甲酸烯丙酯1-2(0.7g,5.9mmol)，保持零下30摄氏度反应1小时，加入饱和 氯化铵溶液淬灭反应，减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，得粗品产物3-氧-8-硫杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯3-5。LC-MS：m/z 256[M+H] + The substrate 8-thia-2-azaspiro[4.5]decane-3-one 3-4 (1.0 g, 5.9 mmol) was dissolved in tetrahydrofuran (20 mL), and the reaction system was fully cooled to minus 30 degrees Celsius , slowly dropwise n-butyllithium (2.5M, 5.9mmol, 2.3mL), keep minus 30 degrees Celsius to react for 1 hour, add allyl chloroformate 1-2 (0.7g, 5.9mmol) dropwise to the reaction system, keep The reaction was carried out at minus 30 degrees Celsius for 1 hour, saturated ammonium chloride solution was added to quench the reaction, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 3-oxo-8 -Thia-2-azaspiro[4.5]decane-2-carboxylate allyl 3-5. LC-MS: m/z 256[M+H] +
步骤5、化合物3-6的合成Step 5. Synthesis of Compounds 3-6
将3-氧-8-硫杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯3-5溶于四氢呋喃(25mL)中，将反应体系充分冷却至零下78摄氏度，缓慢滴加二异丁基氢化铝(1.3M，7.9mmol，6.1mL)，保持零下78摄氏度反应1小时，加入饱和氯化铵溶液淬灭反应，减压浓缩，并用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-羟基-8-硫杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂3-6。LC-MS：m/z 240[M+H-18] + 3-Oxy-8-thia-2-azaspiro[4.5]decane-2-carboxylate allyl ester 3-5 was dissolved in tetrahydrofuran (25mL), the reaction system was fully cooled to minus 78 degrees Celsius, slowly Diisobutylaluminum hydride (1.3M, 7.9mmol, 6.1mL) was added dropwise, kept at minus 78 degrees Celsius for 1 hour, quenched by adding saturated ammonium chloride solution, concentrated under reduced pressure, and extracted with ethyl acetate and water, organic The phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next step without purification. The crude product was 3-hydroxy-8-thia-2-azaspiro[4.5]decane-2-carboxylate. Allyl acid 3-6. LC-MS: m/z 240[M+H-18] +
步骤6、化合物3-7的合成Step 6. Synthesis of Compounds 3-7
将粗产物3-羟基-8-硫杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂3-6溶于甲醇(20mL)中，充分搅拌后，室温下向反应体系中加入一水合对甲苯磺酸(114mg,0.6mmol),室温搅拌12小时，LC-MS监测。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-甲氧基-8-硫杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂3-7。LC-MS：m/z 240[M+H-32] + The crude product 3-hydroxy-8-thia-2-azaspiro[4.5]decane-2-carboxylate allyl ester 3-6 was dissolved in methanol (20 mL), stirred well, and added to the reaction system at room temperature P-toluenesulfonic acid monohydrate (114 mg, 0.6 mmol) was added to the mixture, and the mixture was stirred at room temperature for 12 hours and monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The crude product can be directly used in the next step without purification. The crude product 3-methoxy-8 -Thia-2-azaspiro[4.5]decane-2-carboxylate allyl ester 3-7. LC-MS: m/z 240[M+H-32] +
步骤7、化合物3-8的合成Step 7. Synthesis of Compounds 3-8
将粗产物3-甲氧基-8-硫杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯3-7和1-氨基-3-(苄氧)-4-氧-1,4-二氢吡啶-2-羧酸乙酯M1(1.6g,5.5mmol)溶于乙腈(60mL)中，将反应体系充分冷却至零下30摄氏度，向反应体系中缓慢加入四氯化锡(2.2g,8.3mmol),零下30摄氏度搅拌1小时，LC-MS监测。反应结束后加入饱和碳酸氢钠水溶液淬灭反应，减压浓缩，用二氯甲烷和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-8-硫杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯3-8。LC-MS：m/z 528[M+H] + The crude product 3-methoxy-8-thia-2-azaspiro[4.5]decane-2-carboxylate allyl ester 3-7 and 1-amino-3-(benzyloxy)-4-oxo -1,4-dihydropyridine-2-carboxylate ethyl ester M1 (1.6g, 5.5mmol) was dissolved in acetonitrile (60mL), the reaction system was fully cooled to minus 30 degrees Celsius, and tetrachloride was slowly added to the reaction system Tin (2.2 g, 8.3 mmol) was stirred at minus 30 degrees Celsius for 1 hour and monitored by LC-MS. After the reaction, saturated aqueous sodium bicarbonate solution was added to quench the reaction, concentrated under reduced pressure, extracted with dichloromethane and water, the organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure, the crude product can be directly used in the next step without purification. , the crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-8-thia-2-azaspiro[4.5] Allyl decane-2-carboxylate 3-8. LC-MS: m/z 528 [M+H] +
步骤8、化合物3-9的合成Step 8. Synthesis of Compounds 3-9
将粗产物3-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-8-硫杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯3-8、四三苯基膦钯(263mg,0.2mmol)、吗啉(4.0g,46mmol)溶于四氢呋喃(40mL)中，将反应体系用氮气置换三次，充入一个大气压力的氮气，室温下搅拌1小时，TLC和LC-MS监测。反应结束后减压浓缩，残余物用柱层析纯化后得到产物9-(苄氧)-2',3a,3',4,5',6'-六氢螺[吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪-2,4'-噻喃]-8,10(1H,3H)-二酮3-9(275mg)。LC-MS：m/z 398[M+H] + The crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-8-thia-2-azaspiro[4.5] Allyl decane-2-carboxylate 3-8, palladium tetrakistriphenylphosphine (263 mg, 0.2 mmol), and morpholine (4.0 g, 46 mmol) were dissolved in tetrahydrofuran (40 mL), and the reaction system was replaced with nitrogen three times , charged with 1 atmosphere of nitrogen, stirred at room temperature for 1 hour, and monitored by TLC and LC-MS. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 9-(benzyloxy)-2',3a,3',4,5',6'-hexahydrospiro[pyridinepara[2,1 -f]pyrrole[2,1-c][1,2,4]triazine-2,4'-thiopyran]-8,10(1H,3H)-dione 3-9 (275 mg). LC-MS: m/z 398 [M+H] +
步骤9、化合物3-10的合成Step 9. Synthesis of Compounds 3-10
将9-(苄氧)-2',3a,3',4,5',6'-六氢螺[吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪-2,4'-噻喃]-8,10(1H,3H)-二酮3-9(30.0mg,0.08mmol)和7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-醇M2(29.9mg,0.1mmol)、溶于1-丙基磷酸酐(50wt.％的乙酸乙酯溶液，300uL)中，微波110摄氏度下搅拌3小时，LC-MS监测。反应结束后用乙酸乙酯和水萃取，有机相干燥后过滤，滤液减压浓缩得粗产物9-(苄氧)-4-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-2',3a,3',4,5',6'-六氢螺[吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪-2,4'-噻喃]-8,10(1H,3H)-二酮3-10。LC-MS：m/z 644[M+H] + 9-(Benzyloxy)-2',3a,3',4,5',6'-hexahydrospiro[pyridinium[2,1-f]pyrrole[2,1-c][1,2 ,4]Triazine-2,4'-thiopyran]-8,10(1H,3H)-dione 3-9 (30.0 mg, 0.08 mmol) and 7,8-difluoro-6,11-dihydro Diphenyl[b,e]thihept-11-ol M2 (29.9mg, 0.1mmol), dissolved in 1-propylphosphoric anhydride (50wt.% in ethyl acetate, 300uL), stirred at 110°C in microwave for 3 hours, LC-MS monitoring. After the reaction, it was extracted with ethyl acetate and water, the organic phase was dried and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 9-(benzyloxy)-4-(7,8-difluoro-6,11-dihydrodiphenyl[ b,e]thihept-11-yl)-2',3a,3',4,5',6'-hexahydrospiro[pyridinium[2,1-f]pyrrole[2,1-c] [1,2,4]Triazine-2,4'-thiopyran]-8,10(1H,3H)-dione 3-10. LC-MS: m/z 644[M+H] +
步骤10、化合物3的合成Step 10. Synthesis of compound 3
将粗产物9-(苄氧)-4-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-2',3a,3',4,5',6'-六氢螺[吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪-2,4'-噻喃]-8,10(1H,3H)-二酮3-10溶于甲醇(5mL)中，加入氢氧化钯碳(14mg,0.1mmol)，将反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌1小时，LC-MS监测。反应结束后用硅藻土过滤，滤液减压浓缩，制备纯化得4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-9'-羟基-2,3,3a',4',5,6-六 氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮4-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-9-羟基-2',3a,3',4,5',6'-六氢螺[吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪-2,4'-噻喃]-8,10(1H,3H)-二酮化合物3(12mg)。LC-MS：m/z 554[M+H] + The crude product 9-(benzyloxy)-4-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-2',3a,3',4 ,5',6'-hexahydrospiro[pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine-2,4'-thiopyran]-8, 10(1H,3H)-diketone 3-10 was dissolved in methanol (5 mL), palladium hydroxide on carbon (14 mg, 0.1 mmol) was added, the reaction system was replaced with nitrogen three times, filled with hydrogen at 1 atmosphere pressure, and at room temperature Stir for 1 hour and monitor by LC-MS. After the reaction, it was filtered through celite, and the filtrate was concentrated under reduced pressure to prepare and purify 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-9 '-Hydroxy-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridine[2,1-f]pyrrole[2,1-c][1 ,2,4]Triazine]-8',10'(1'H,3'H)-dione 4-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thione Hept-11-yl)-9-hydroxy-2',3a,3',4,5',6'-hexahydrospiro[pyridinium[2,1-f]pyrrole[2,1-c][ 1,2,4]Triazine-2,4'-thiopyran]-8,10(1H,3H)-dione compound 3 (12 mg). LC-MS: m/z 554 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ7.56-7.46(m,2H),7.41-7.30(m,1H),7.15-7.04(m,1H),7.03(d,J＝7.8Hz,1H),6.92-6.85(m,2H),5.65-5.40(m,3H),4.15(d,J＝13.8Hz,1H),4.01(d,J＝12.0Hz,1H),2.84-2.62(m,2H),2.53-2.41(m,2H),2.36(m,1H),2.00(m,1H),1.78-1.41(m,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.56-7.46 (m, 2H), 7.41-7.30 (m, 1H), 7.15-7.04 (m, 1H), 7.03 (d, J=7.8Hz, 1H ),6.92-6.85(m,2H),5.65-5.40(m,3H),4.15(d,J=13.8Hz,1H),4.01(d,J=12.0Hz,1H),2.84-2.62(m, 2H), 2.53-2.41(m, 2H), 2.36(m, 1H), 2.00(m, 1H), 1.78-1.41(m, 6H).
实施例4、4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-9'-羟基-3a',4'-二氢螺[环丁烷-1,2'吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮(化合物4)的合成Example 4, 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-9'-hydroxy-3a',4'-dihydrospiro [Cyclobutane-1,2'pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'(1'H,3' Synthesis of H)-diketone (Compound 4)
Figure PCTCN2022077312-appb-000053
Figure PCTCN2022077312-appb-000053
步骤1、化合物4-2的合成Step 1. Synthesis of compound 4-2
氮气保护下，向250mL三口瓶中加入钠氢(2.2g,55mmol)，无水四氢呋喃(100mL),充分冷却至零摄氏度，缓慢滴加磷酰基乙酸三乙酯2-2(12.3g,55mmol)的四氢呋喃(40mL)溶液，滴加完毕保持零摄氏度反应0.5小时，室温下反应1小时。将反应体系充分冷却至零摄氏度，缓慢滴加环丁酮4-1(3.5g,50mmol)的四氢呋喃(30mL)，滴加完毕室温下反应2小时，TLC和LC-MS监测。反应结束后向体系中加入饱和氯化铵水溶液(50mL)，减压浓缩，用乙酸乙酯和水萃取，有机相用饱和食盐水洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物2-环丁烯基乙酸乙酯4-2(6.8g)。LC-MS：m/z 141[M+H] +。 Under nitrogen protection, add sodium hydrogen (2.2g, 55mmol), anhydrous tetrahydrofuran (100mL) to a 250mL there-necked flask, fully cool to zero degrees Celsius, slowly add triethyl phosphoryl acetate 2-2 (12.3g, 55mmol) dropwise The solution of tetrahydrofuran (40 mL) was added dropwise, and the reaction was kept at zero degrees Celsius for 0.5 hours, and the reaction was carried out at room temperature for 1 hour. The reaction system was fully cooled to zero degrees Celsius, cyclobutanone 4-1 (3.5 g, 50 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours, monitored by TLC and LC-MS. After the reaction, saturated aqueous ammonium chloride solution (50 mL) was added to the system, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure , the residue was purified by column chromatography to give the product ethyl 2-cyclobutenyl acetate 4-2 (6.8 g). LC-MS: m/z 141 [M+H] + .
步骤2、化合物4-3的合成Step 2. Synthesis of compound 4-3
向250mL反应瓶中加入2-环丁烯基乙酸乙酯4-2(6.8g,49mmol)，碳酸钾(13.4g,97mmol)，二甲基亚砜(100mL)和硝基甲烷(6.0g,97mmol)，80摄氏度下搅拌反应2小时，TLC和LC-MS监测。反应结束后向体系中加入水(200mL)，用乙酸乙酯萃取，有机相用水合饱和食盐水各洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，得到粗品2-[1-(硝基甲基)环丁基]乙酸乙酯4-3直接用于下一步反应。LC-MS：m/z 202[M+H] + To a 250 mL reaction flask was added ethyl 2-cyclobutenyl acetate 4-2 (6.8 g, 49 mmol), potassium carbonate (13.4 g, 97 mmol), dimethyl sulfoxide (100 mL) and nitromethane (6.0 g, 97 mmol), the reaction was stirred at 80 °C for 2 h, monitored by TLC and LC-MS. After the reaction, water (200 mL) was added to the system, extracted with ethyl acetate, the organic phase was washed twice with hydrated saturated brine, the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 2-[1- (Nitromethyl)cyclobutyl]ethyl acetate 4-3 was used directly in the next reaction. LC-MS: m/z 202[M+H] +
步骤3、化合物4-4的合成Step 3. Synthesis of Compounds 4-4
向250mL反应瓶中加入2-[1-(硝基甲基)环丁基]乙酸乙酯4-3，甲醇(80mL)，和雷尼镍，反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌反应12小时。LC-MS监测反应。反应结束后减 压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物6-氮杂螺[3.4]辛烷-7-酮4-4(1.7g)。LC-MS：m/z 126[M+H] + 2-[1-(Nitromethyl)cyclobutyl]ethyl acetate 4-3, methanol (80mL), and Raney nickel were added to a 250mL reaction flask, the reaction system was replaced with nitrogen three times, and charged to one atmospheric pressure hydrogen, and the reaction was stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 6-azaspiro[3.4]octane-7- Ketone 4-4 (1.7 g). LC-MS: m/z 126[M+H] +
步骤4、化合物4-5的合成Step 4. Synthesis of Compounds 4-5
将底物6-氮杂螺[3.4]辛烷-7-酮4-4(1.0g,13.6mmol)，溶于四氢呋喃中(20mL)，将反应体系充分冷却至零下30摄氏度，缓慢滴加正丁基锂(2.5M，15.0mmol，6.0mL)，保持零下30摄氏度反应1小时，向反应体系中滴加氯甲酸烯丙酯1-2(1.8g,15.0mmol)，保持零下30摄氏度反应1小时，加入饱和氯化铵溶液淬灭反应，减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，得到粗品产物7-氧-6-氮杂螺[3.4]辛烷-6-羧酸烯丙酯4-5。LC-MS：m/z 210[M+H] + The substrate 6-azaspiro[3.4]octane-7-one 4-4 (1.0 g, 13.6 mmol) was dissolved in tetrahydrofuran (20 mL), the reaction system was fully cooled to minus 30 degrees Celsius, and was slowly added dropwise. Butyllithium (2.5M, 15.0mmol, 6.0mL) was kept at minus 30 degrees Celsius for 1 hour, allyl chloroformate 1-2 (1.8g, 15.0mmol) was added dropwise to the reaction system, and the reaction was kept at minus 30 degrees Celsius for 1 After 1 hour, saturated ammonium chloride solution was added to quench the reaction, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 7-oxo-6-azaspiro[ 3.4] Allyl octane-6-carboxylate 4-5. LC-MS: m/z 210 [M+H] +
步骤5、化合物4-6的合成Step 5. Synthesis of Compounds 4-6
将7-氧-6-氮杂螺[3.4]辛烷-6-羧酸烯丙酯4-5溶于四氢呋喃(25mL)中，将反应体系充分冷却至零下78摄氏度，缓慢滴加二异丁基氢化铝(1.3M，3.3mmol，2.5mL)，保持零下78摄氏度反应1小时，加入饱和氯化铵溶液淬灭反应，减压浓缩，并用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物7-羟基-6-氮杂螺[3.4]辛烷-6-羧酸烯丙酯4-6。LC-MS：m/z194[M+H-18] + 7-Oxy-6-azaspiro[3.4]octane-6-carboxylate allyl ester 4-5 was dissolved in tetrahydrofuran (25 mL), the reaction system was fully cooled to minus 78 degrees Celsius, and diisobutyl was slowly added dropwise Aluminum hydride (1.3M, 3.3mmol, 2.5mL) was kept at minus 78 degrees Celsius for 1 hour, the reaction was quenched by adding saturated ammonium chloride solution, concentrated under reduced pressure, and extracted with ethyl acetate and water, the organic phase was washed with anhydrous sulfuric acid After drying over sodium, the mixture was concentrated under reduced pressure, and the crude product was directly used in the next reaction without purification. The crude product was 7-hydroxy-6-azaspiro[3.4]octane-6-carboxylate allyl ester 4-6. LC-MS: m/z194[M+H-18] +
步骤6、化合物4-7的合成Step 6. Synthesis of Compounds 4-7
将粗产物7-羟基-6-氮杂螺[3.4]辛烷-6-羧酸烯丙酯4-6溶于甲醇(10mL)中，充分搅拌后，室温下向反应体系中加入一水合对甲苯磺酸(38mg,0.2mmol),室温搅拌12小时，LC-MS监测。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物7-甲氧基-6-氮杂螺[3.4]辛烷-6-羧酸烯丙酯4-7。LC-MS：m/z 194[M+H-32] + The crude product 7-hydroxy-6-azaspiro[3.4]octane-6-carboxylate allyl ester 4-6 was dissolved in methanol (10 mL), and after thorough stirring, a hydrated paraben was added to the reaction system at room temperature. Toluenesulfonic acid (38 mg, 0.2 mmol) was stirred at room temperature for 12 hours and monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The crude product can be used directly in the next step without purification. The crude product 7-methoxy-6 - Azaspiro[3.4]octane-6-carboxylate allyl 4-7. LC-MS: m/z 194[M+H-32] +
步骤7、化合物4-8的合成Step 7. Synthesis of compounds 4-8
将粗产物3-甲氧基-8-硫杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯4-7和1-氨基-3-(苄氧)-4-氧-1,4-二氢吡啶-2-羧酸乙酯M1(610mg,2.1mmol)溶于乙腈(20mL)中，将反应体系充分冷却至零下30摄氏度，向反应体系中缓慢加入四氯化锡(830mg,3.2mmol),零下30摄氏度搅拌1小时，LC-MS监测。反应结束后加入饱和碳酸氢钠水溶液淬灭反应，减压浓缩，用二氯甲烷和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物7-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-6-氮杂螺[3.4]辛烷-6-羧酸烯丙酯4-8。LC-MS：m/z 482[M+H] + The crude product 3-methoxy-8-thia-2-azaspiro[4.5]decane-2-carboxylate allyl 4-7 and 1-amino-3-(benzyloxy)-4-oxo -1,4-dihydropyridine-2-carboxylate ethyl ester M1 (610mg, 2.1mmol) was dissolved in acetonitrile (20mL), the reaction system was fully cooled to minus 30 degrees Celsius, and tin tetrachloride was slowly added to the reaction system (830 mg, 3.2 mmol), stirred at minus 30 degrees Celsius for 1 hour, and monitored by LC-MS. After the reaction, saturated aqueous sodium bicarbonate solution was added to quench the reaction, concentrated under reduced pressure, extracted with dichloromethane and water, the organic phase was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product can be directly used in the next step without purification. , the crude product 7-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-6-azaspiro[3.4]octane-6- Allyl Carboxylate 4-8. LC-MS: m/z 482[M+H] +
步骤8、化合物4-9的合成Step 8. Synthesis of compounds 4-9
将粗产物7-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-6-氮杂螺[3.4]辛烷-6-羧酸烯丙酯4-8、四三苯基膦钯(89mg,0.08mmol)、吗啉(1.34g,15.4mmol)溶于四氢呋喃(10mL)中，将反应体系用氮气置换三次，充入一个大气压力的氮气，室温下搅拌1小时，TLC和LC-MS监测。反应结束后减压浓缩，残余物用柱层析纯化后得到产物9'-(苄氧)-3a',4'-二氢螺[环丁烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮4-9(106mg)。LC-MS：m/z 352[M+H] + The crude product 7-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-6-azaspiro[3.4]octane-6- Allyl carboxylate 4-8, tetrakistriphenylphosphine palladium (89 mg, 0.08 mmol), and morpholine (1.34 g, 15.4 mmol) were dissolved in tetrahydrofuran (10 mL), the reaction system was replaced with nitrogen three times, and a Atmospheric nitrogen, stirred at room temperature for 1 hour, monitored by TLC and LC-MS. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 9'-(benzyloxy)-3a',4'-dihydrospiro[cyclobutane-1,2'-pyridinepara[2,1 -f]pyrrole[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 4-9 (106 mg). LC-MS: m/z 352 [M+H] +
步骤9、化合物4-10的合成Step 9. Synthesis of Compounds 4-10
将9'-(苄氧)-3a',4'-二氢螺[环丁烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮4-9(30.0mg,0.09mmol)和7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-醇M2(33.8mg,0.1mmol)、溶于1-丙基磷酸酐(50wt.％的乙酸乙酯溶液，300uL)中，微波110摄氏度下搅拌3小时，LC-MS监测。反应结束后用乙酸乙酯和水萃取，有机相干燥后过滤，滤液减压浓缩得粗产物9'-(苄氧)-4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-3a',4'-二氢螺[环丁烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮4-10(45 mg)。LC-MS：m/z 598[M+H] + 9'-(benzyloxy)-3a',4'-dihydrospiro[cyclobutane-1,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2 ,4]Triazine]-8',10'(1'H,3'H)-dione 4-9 (30.0 mg, 0.09 mmol) and 7,8-difluoro-6,11-dihydrodiphenyl [b, e] Thiheptan-11-ol M2 (33.8 mg, 0.1 mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 300 uL), and stirred at 110 degrees Celsius in a microwave for 3 hours, LC-MS monitoring. After the reaction, it was extracted with ethyl acetate and water, the organic phase was dried and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodihydrodicarbonate) Benzene[b,e]thihept-11-yl)-3a',4'-dihydrospiro[cyclobutane-1,2'-pyridine[2,1-f]pyrrole[2,1-c ][1,2,4]triazine]-8',10'(1'H,3'H)-dione 4-10 (45 mg). LC-MS: m/z 598 [M+H] +
步骤10、化合物4的合成Step 10. Synthesis of Compound 4
将粗产物9'-(苄氧)-4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-3a',4'-二氢螺[环丁烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮4-10(45mg,0.08mmol)溶于甲醇(5mL)中，加入氢氧化钯碳(15mg,0.1mmol)，将反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌1小时，LC-MS监测。反应结束后用硅藻土过滤，滤液减压浓缩，制备纯化得4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-9'-羟基-3a',4'-二氢螺[环丁烷-1,2'吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮化合物4(14mg)。LC-MS：m/z 508[M+H] + The crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-3a',4'-diphenyl Hydrospiro[cyclobutane-1,2'-pyridine[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'(1'H , 3'H)-diketone 4-10 (45mg, 0.08mmol) was dissolved in methanol (5mL), palladium hydroxide on carbon (15mg, 0.1mmol) was added, the reaction system was replaced with nitrogen three times, charged with an atmospheric pressure hydrogen, stirred at room temperature for 1 hour, and monitored by LC-MS. After the reaction, it was filtered through celite, and the filtrate was concentrated under reduced pressure to prepare and purify 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-9 '-Hydroxy-3a',4'-dihydrospiro[cyclobutane-1,2'pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine] -8',10'(1'H,3'H)-diketone compound 4 (14 mg). LC-MS: m/z 508 [M+H] +
1H NMR(400MHz,CDCl 3)δ7.59(d,J＝7.6Hz,1H),7.11-7.06(m,3H),6.83(d,J＝7.6Hz,1H),6.63(d,J＝7.8Hz,1H),6.10(d,J＝7.6Hz,1H),5.55(d,J＝13.6Hz,1H),5.41-5.30(m,1H),5.14(s,1H),4.14(d,J＝13.6Hz,1H),4.09-4.02(m,2H),3.42(d,J＝12.2Hz,1H),2.11-2.97(m,3H),1.95-1.64(m,5H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J=7.6 Hz, 1H), 7.11-7.06 (m, 3H), 6.83 (d, J=7.6 Hz, 1H), 6.63 (d, J= 7.8Hz, 1H), 6.10(d, J=7.6Hz, 1H), 5.55(d, J=13.6Hz, 1H), 5.41-5.30(m, 1H), 5.14(s, 1H), 4.14(d, J=13.6Hz, 1H), 4.09-4.02(m, 2H), 3.42(d, J=12.2Hz, 1H), 2.11-2.97(m, 3H), 1.95-1.64(m, 5H).
实施例5、4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-9'-羟基-4,4-二甲基-3a',4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮(化合物5)的合成Example 5, 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-9'-hydroxy-4,4-dimethyl-3a ',4'-Dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8', Synthesis of 10'(1'H,3'H)-diketone (Compound 5)
Figure PCTCN2022077312-appb-000054
Figure PCTCN2022077312-appb-000054
步骤1、化合物5-2的合成Step 1. Synthesis of compound 5-2
氮气保护下，向250mL三口瓶中加入钠氢(2.4g,60mmol)，无水四氢呋喃(100mL),充分冷却至零摄氏度，缓慢滴加磷酰基乙酸三乙酯2-2(10.8g,60mmol)的四氢呋喃(50mL)溶液，滴加完毕保持零摄氏度反应0.5小时，室温下反应1小时。将反应体系充分冷却至零摄氏度，缓慢滴加4,4-二甲基环己酮5-1(6.3g,50mmol)的四氢呋喃(30mL)，滴加完毕室温下反应2小时，TLC和LC-MS监测。反应结束后向体系中加入饱和氯化铵水溶液(50mL)，减压浓缩，用乙酸乙酯和水萃取，有机相用饱和食盐水洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物2-(4,4-二甲基环己基二烯)乙酸乙酯5-2(9.4g)。LC-MS：m/z 197[M+H] +。 Under nitrogen protection, sodium hydrogen (2.4g, 60mmol) and anhydrous tetrahydrofuran (100mL) were added to a 250mL there-necked flask, fully cooled to zero degrees Celsius, and slowly added dropwise triethyl phosphoryl acetate 2-2 (10.8g, 60mmol) The solution of tetrahydrofuran (50 mL) was added dropwise, and the reaction was kept at zero degrees Celsius for 0.5 hours, and the reaction was carried out at room temperature for 1 hour. The reaction system was fully cooled to zero degrees Celsius, and tetrahydrofuran (30 mL) of 4,4-dimethylcyclohexanone 5-1 (6.3 g, 50 mmol) was slowly added dropwise. MS monitoring. After the reaction, saturated aqueous ammonium chloride solution (50 mL) was added to the system, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure , the residue was purified by column chromatography to obtain the product ethyl 2-(4,4-dimethylcyclohexyldiene)acetate 5-2 (9.4g). LC-MS: m/z 197 [M+H] + .
步骤2、化合物5-3的合成Step 2. Synthesis of compound 5-3
向250mL反应瓶中加入2-(4,4-二甲基环己基二烯)乙酸乙酯5-2(9.4g,48mmol)，碳酸钾(13.8g,100mmol)，二甲基亚砜(100mL)和硝基甲烷(6.1g,100mmol)，80摄氏度下搅拌反应2小时，TLC和LC-MS监测。反应结束后向体系中加入水(200mL)，用乙酸乙酯萃取，有机相用水合饱和食盐水各洗涤两次， 有机相用无水硫酸钠干燥后减压浓缩，得到粗品2-(4,4-二甲基-1-(硝甲基)环己基)乙酸乙酯5-3直接用于下一步反应。LC-MS：m/z 258[M+H] + Into a 250mL reaction flask was added ethyl 2-(4,4-dimethylcyclohexyldiene)acetate 5-2 (9.4g, 48mmol), potassium carbonate (13.8g, 100mmol), dimethyl sulfoxide (100mL) ) and nitromethane (6.1 g, 100 mmol), and the reaction was stirred at 80 degrees Celsius for 2 hours, monitored by TLC and LC-MS. After the reaction was completed, water (200 mL) was added to the system, extracted with ethyl acetate, the organic phase was washed twice with hydrated saturated brine each, and the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 2-(4, Ethyl 4-dimethyl-1-(nitromethyl)cyclohexyl)acetate 5-3 was used directly in the next reaction. LC-MS: m/z 258 [M+H] +
步骤3、化合物5-4的合成Step 3. Synthesis of Compounds 5-4
向250mL反应瓶中加入2-(4,4-二甲基-1-(硝甲基)环己基)乙酸乙酯5-3，甲醇(80mL)，和雷尼镍，反应体系用氢气置换三次，充入一个大气压力的氢气，室温下搅拌反应12小时。LC-MS监测反应。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物8,8-二甲基-2-氮杂螺[4.5]癸-3-酮5-4(4.4g)。LC-MS：m/z 182[M+H] + Add 2-(4,4-dimethyl-1-(nitromethyl)cyclohexyl)ethyl acetate 5-3, methanol (80mL), and Raney nickel to a 250mL reaction flask, and the reaction system was replaced with hydrogen three times , charged with 1 atmosphere of hydrogen, and the reaction was stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 8,8-dimethyl-2-azaspiro [4.5] Dec-3-one 5-4 (4.4 g). LC-MS: m/z 182[M+H] +
步骤4、化合物5-5的合成Step 4. Synthesis of Compounds 5-5
将底物8,8-二甲基-2-氮杂螺[4,5]癸-3-酮5-4(1.8g,10.0mmol)，溶于四氢呋喃中(40mL)，将反应体系充分冷却至零下30摄氏度，缓慢滴加正丁基锂(2.5M，12.0mmol，4.8mL)，保持零下30摄氏度反应1小时，向反应体系中滴加氯甲酸烯丙酯1-2(1.5g,12.0mmol)，保持零下30摄氏度反应1小时，加入饱和氯化铵溶液淬灭反应，减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化后得到产物烯丙基3-氧-8,8-二甲基-2-氮杂螺[4.5]癸烷-2-碳酸脂5-5(2.6g)。LC-MS：m/z 266[M+H] + The substrate 8,8-dimethyl-2-azaspiro[4,5]dec-3-one 5-4 (1.8 g, 10.0 mmol) was dissolved in tetrahydrofuran (40 mL), and the reaction system was fully cooled To minus 30 degrees Celsius, n-butyllithium (2.5M, 12.0 mmol, 4.8 mL) was slowly added dropwise, kept at minus 30 degrees Celsius for 1 hour, and allyl chloroformate 1-2 (1.5 g, 12.0 mmol), kept the reaction at minus 30 degrees Celsius for 1 hour, added saturated ammonium chloride solution to quench the reaction, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column After purification by chromatography, the product allyl 3-oxo-8,8-dimethyl-2-azaspiro[4.5]decane-2-carbonate 5-5 (2.6 g) was obtained. LC-MS: m/z 266[M+H] +
步骤5、化合物5-6的合成Step 5. Synthesis of Compounds 5-6
将3-氧-8,8-二甲基-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂5-5(2.6g,9.9mmol)溶于四氢呋喃(25mL)中，将反应体系充分冷却至零下78摄氏度，缓慢滴加二异丁基氢化铝(1.3M，12.0mmol，9.2mL)，保持零下78摄氏度反应1小时，加入饱和氯化铵溶液淬灭反应，减压浓缩，并用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-羟基-8,8-二甲基-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂5-6。LC-MS：m/z 250[M+H-18] + 3-Oxo-8,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylate allyl ester 5-5 (2.6 g, 9.9 mmol) was dissolved in tetrahydrofuran (25 mL) and the The reaction system was fully cooled to minus 78 degrees Celsius, and diisobutylaluminum hydride (1.3M, 12.0 mmol, 9.2 mL) was slowly added dropwise, kept at minus 78 degrees Celsius for 1 hour, saturated ammonium chloride solution was added to quench the reaction, and concentrated under reduced pressure , and extracted with ethyl acetate and water. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The crude product can be directly used in the next step without purification. The crude product 3-hydroxy-8,8-dimethyl-2 - Azaspiro[4.5]decane-2-carboxylate allyl 5-6. LC-MS: m/z 250[M+H-18] +
步骤6、化合物5-7的合成Step 6. Synthesis of Compounds 5-7
将粗产物3-羟基-8,8-二甲基-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂5-6溶于甲醇(20mL)中，充分搅拌后，室温下向反应体系中加入一水合对甲苯磺酸(153mg,0.8mmol),室温搅拌12小时，LC-MS监测。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-甲氧基-8,8-二甲基-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂5-7。LC-MS：m/z 250[M+H-32] + The crude product 3-hydroxy-8,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylate allyl ester 5-6 was dissolved in methanol (20 mL), and after stirring well, at room temperature To the reaction system was added p-toluenesulfonic acid monohydrate (153 mg, 0.8 mmol), stirred at room temperature for 12 hours, and monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The crude product can be directly used in the next step without purification. The crude product 3-methoxy-8 ,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylate allyl ester 5-7. LC-MS: m/z 250[M+H-32] +
步骤7、化合物5-8的合成Step 7. Synthesis of compounds 5-8
将粗产物3-甲氧基-8,8-二甲基-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂5-7和1-氨基-3-(苄氧)-4-氧-1,4-二氢吡啶-2-羧酸乙酯M1(1.8g,6.3mmol)溶于乙腈(60mL)中，将反应体系充分冷却至零下30摄氏度，向反应体系中缓慢加入四氯化锡(2.4g,9.4mmol),零下30摄氏度搅拌1小时，LC-MS监测。反应结束后加入饱和碳酸氢钠水溶液淬灭反应，减压浓缩，用二氯甲烷和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-8,8-二甲基-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯5-8。LC-MS：m/z 538[M+H] + The crude product 3-methoxy-8,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylate allyl 5-7 and 1-amino-3-(benzyloxy)- 4-Oxy-1,4-dihydropyridine-2-carboxylate ethyl ester M1 (1.8g, 6.3mmol) was dissolved in acetonitrile (60mL), the reaction system was fully cooled to minus 30 degrees Celsius, slowly added to the reaction system Tin tetrachloride (2.4 g, 9.4 mmol) was stirred at minus 30 degrees Celsius for 1 hour, and monitored by LC-MS. After the reaction, saturated aqueous sodium bicarbonate solution was added to quench the reaction, concentrated under reduced pressure, extracted with dichloromethane and water, the organic phase was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product can be directly used in the next step without purification. , the crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-8,8-dimethyl-2-azaspiro [4.5] Allyl decane-2-carboxylate 5-8. LC-MS: m/z 538 [M+H] +
步骤8、化合物5-9的合成Step 8. Synthesis of compounds 5-9
将粗产物3-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-8,8-二甲基-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯5-8、四三苯基膦钯(285mg,0.3mmol)、吗啉(4.3g,50mmol)溶于四氢呋喃(40mL)中，将反应体系用氮气置换三次，充入一个大气压力的氮气，室温下搅拌1小时，TLC和LC-MS监测。反应结束后减压浓缩，残余物用柱层析纯化后得到产物9'-(苄氧)-4,4-二甲基-3a',4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈 [2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮5-9(1.5g)。LC-MS：m/z 408[M+H] + The crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-8,8-dimethyl-2-azaspiro [4.5] Allyl decane-2-carboxylate 5-8, palladium tetrakistriphenylphosphine (285 mg, 0.3 mmol), and morpholine (4.3 g, 50 mmol) were dissolved in tetrahydrofuran (40 mL), and the reaction system was treated with Nitrogen was replaced three times, filled with nitrogen at 1 atmosphere pressure, stirred at room temperature for 1 hour, and monitored by TLC and LC-MS. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 9'-(benzyloxy)-4,4-dimethyl-3a',4'-dihydrospiro[cyclohexane-1,2 '-Pyridin[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 5- 9 (1.5 g). LC-MS: m/z 408 [M+H] +
步骤9、化合物5-10的合成Step 9. Synthesis of compounds 5-10
将9'-(苄氧)-4,4-二甲基-3a',4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮5-9(40.7mg,0.1mmol)和7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-醇M2(39.6mg,0.2mmol)、溶于1-丙基磷酸酐(50wt.％的乙酸乙酯溶液，400uL)中，微波110摄氏度下搅拌3小时，LC-MS监测。反应结束后减压浓缩得粗产物9'-(苄氧)-4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-4,4-二甲基-3a',4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮5-10。LC-MS：m/z 654[M+H] + 9'-(benzyloxy)-4,4-dimethyl-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridine[2,1-f]pyrrole[2, 1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 5-9 (40.7 mg, 0.1 mmol) and 7,8-difluoro- 6,11-Dihydrodiphenyl[b,e]thihept-11-ol M2 (39.6mg, 0.2mmol), dissolved in 1-propylphosphoric anhydride (50wt.% in ethyl acetate, 400uL), Stir at 110°C in microwave for 3 hours and monitor by LC-MS. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-4 ,4-Dimethyl-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4 ]triazine]-8',10'(1'H,3'H)-dione 5-10. LC-MS: m/z 654[M+H] +
步骤10、化合物5的合成Step 10. Synthesis of compound 5
将粗产物9'-(苄氧)-4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-4,4-二甲基-3a',4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮5-10溶于甲醇(5mL)中，加入氢氧化钯碳(14mg,0.1mmol)，将反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌4小时，LC-MS监测。反应结束后用硅藻土过滤，滤液减压浓缩，用中压反相制备柱纯化得4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-9'-羟基-4,4-二甲基-3a',4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮化合物5(23.1mg)。LC-MS：m/z 564[M+H] + The crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-4,4-dimethyl -3a',4'-Dihydrospiro[cyclohexane-1,2'-pyridinepara[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8 ',10'(1'H,3'H)-diketone 5-10 was dissolved in methanol (5 mL), palladium hydroxide on carbon (14 mg, 0.1 mmol) was added, the reaction system was replaced with nitrogen three times, and a Atmospheric hydrogen, stirred at room temperature for 4 hours and monitored by LC-MS. After the reaction, it was filtered with celite, the filtrate was concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiheptyl- 11-yl)-9'-hydroxy-4,4-dimethyl-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridine[2,1-f]pyrrole[2 ,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione compound 5 (23.1 mg). LC-MS: m/z 564 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ7.55-7.43(m,2H),7.41-7.30(m,1H),7.12-7.05(m,1H),7.02(d,J＝7.8Hz,1H),6.94-6.78(m,2H),5.71(d,J＝13.8Hz,1H),5.60(s,1H),5.56(d,J＝7.8Hz,1H),4.16(t,J＝14.6Hz,1H),3.78(d,J＝12.4Hz,1H),3.32-3.03(m,2H),1.92-1.80(m,1H),1.44-1.27(m,3H),1.23-1.14(m,4H),1.13-1.04(m,2H),0.86(s,3H),0.81(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.55-7.43(m, 2H), 7.41-7.30(m, 1H), 7.12-7.05(m, 1H), 7.02(d, J=7.8Hz, 1H ), 6.94-6.78(m, 2H), 5.71(d, J=13.8Hz, 1H), 5.60(s, 1H), 5.56(d, J=7.8Hz, 1H), 4.16(t, J=14.6Hz) ,1H),3.78(d,J＝12.4Hz,1H),3.32-3.03(m,2H),1.92-1.80(m,1H),1.44-1.27(m,3H),1.23-1.14(m,4H) ),1.13-1.04(m,2H),0.86(s,3H),0.81(s,3H).
实施例6、4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-9'-羟基-2,6-二甲基-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮(化合物6)的合成Example 6, 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-9'-hydroxy-2,6-dimethyl-2 ,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4] Synthesis of Triazine]-8',10'(1'H,3'H)-dione (Compound 6)
Figure PCTCN2022077312-appb-000055
Figure PCTCN2022077312-appb-000055
步骤1、化合物6-2的合成Step 1. Synthesis of compound 6-2
氮气保护下，向250mL三口瓶中加入钠氢(2.4g,60mmol)，无水四氢呋喃(100mL),充分冷却至零摄氏度，缓慢滴加磷酰基乙酸三乙酯2-2(10.8g,60mmol)的四氢呋喃(50mL)溶液，滴加完毕保持零摄氏度反应0.5小时，室温下反应1小时。将反应体系充分冷却至零摄氏度，缓慢滴加2,6-二甲基四氢吡喃酮6-1(6.4g,50mmol)的四氢呋喃(30mL)，滴加完毕室温下反应2小时，TLC和LC-MS监测。反应 结束后向体系中加入饱和氯化铵水溶液(50mL)，减压浓缩，用乙酸乙酯和水萃取，有机相用饱和食盐水洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物2-(3,5-二甲基-4-氧杂环己基二烯)乙酸乙酯6-2(9.5g)。LC-MS：m/z 199[M+H] +。 Under nitrogen protection, sodium hydrogen (2.4g, 60mmol) and anhydrous tetrahydrofuran (100mL) were added to a 250mL there-necked flask, fully cooled to zero degrees Celsius, and slowly added dropwise triethyl phosphoryl acetate 2-2 (10.8g, 60mmol) The solution of tetrahydrofuran (50 mL) was added dropwise, and the reaction was kept at zero degrees Celsius for 0.5 hours, and the reaction was carried out at room temperature for 1 hour. The reaction system was fully cooled to zero degrees Celsius, and tetrahydrofuran (30 mL) of 2,6-dimethyltetrahydropyranone 6-1 (6.4 g, 50 mmol) was slowly added dropwise, and the reaction was performed at room temperature for 2 hours after the dropwise addition. LC-MS monitoring. After the reaction, saturated aqueous ammonium chloride solution (50 mL) was added to the system, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure , the residue was purified by column chromatography to give the product ethyl 2-(3,5-dimethyl-4-oxanediene)acetate 6-2 (9.5g). LC-MS: m/z 199 [M+H] + .
步骤2、化合物6-3的合成Step 2. Synthesis of compound 6-3
向250mL反应瓶中加入2-(3,5-二甲基-4-氧杂环己基二烯)乙酸乙酯6-2(9.5g,48mmol)，碳酸钾(13.8g,100mmol)，二甲基亚砜(100mL)和硝基甲烷(6.1g,100mmol)，80摄氏度下搅拌反应2小时，TLC和LC-MS监测。反应结束后向体系中加入水(200mL)，用乙酸乙酯萃取，有机相用水合饱和食盐水各洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，得到粗品2-(3,5-二甲基-4-氧杂-1-(硝甲基)环己基)乙酸乙酯6-3直接用于下一步反应。LC-MS：m/z 260[M+H] + Into a 250 mL reaction flask was added ethyl 2-(3,5-dimethyl-4-oxanediene)acetate 6-2 (9.5 g, 48 mmol), potassium carbonate (13.8 g, 100 mmol), dimethyl acetate sulfoxide (100 mL) and nitromethane (6.1 g, 100 mmol), and the reaction was stirred at 80 degrees Celsius for 2 hours, monitored by TLC and LC-MS. After the reaction was completed, water (200 mL) was added to the system, extracted with ethyl acetate, the organic phase was washed twice with hydrated saturated brine, and the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 2-(3, Ethyl 5-dimethyl-4-oxa-1-(nitromethyl)cyclohexyl)acetate 6-3 was used directly in the next reaction. LC-MS: m/z 260 [M+H] +
步骤3、化合物6-4的合成Step 3. Synthesis of compound 6-4
向250mL反应瓶中加入2-(4,4-二甲基-1-(硝甲基)环己基)乙酸乙酯6-3，甲醇(80mL)，和雷尼镍，反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌反应12小时。LC-MS监测反应。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化得到产物7.9-二甲基-8-氧杂-2-氮杂螺[4.5]癸-3-酮6-4(4.5g)。LC-MS：m/z 184[M+H] + 2-(4,4-dimethyl-1-(nitromethyl)cyclohexyl)ethyl acetate 6-3, methanol (80mL), and Raney nickel were added to a 250mL reaction flask, and the reaction system was replaced with nitrogen three times , charged with 1 atmosphere of hydrogen, and the reaction was stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 7.9-dimethyl-8-oxa-2- Azaspiro[4.5]dec-3-one 6-4 (4.5 g). LC-MS: m/z 184[M+H] +
步骤4、化合物6-5的合成Step 4. Synthesis of Compounds 6-5
将底物7.9-二甲基-8-氧杂-2-氮杂螺[4.5]癸-3-酮6-4(1.8g,10.0mmol)，溶于四氢呋喃中(40mL)，将反应体系充分冷却至零下30摄氏度，缓慢滴加正丁基锂(2.5M,12.0mmol，4.8mL)，保持零下30摄氏度反应1小时，向反应体系中滴加氯甲酸烯丙酯1-2(1.5g,12.0mmol)，保持零下30摄氏度反应1小时，加入饱和氯化铵溶液淬灭反应，减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化后得到产物烯丙基3-氧-7.9-二甲基-8-氧杂-2-氮杂螺[4.5]癸烷-2-碳酸脂6-5(2.6g)。LC-MS：m/z 268[M+H] + The substrate 7.9-dimethyl-8-oxa-2-azaspiro[4.5]dec-3-one 6-4 (1.8g, 10.0mmol) was dissolved in tetrahydrofuran (40mL), and the reaction system was fully Cool to minus 30 degrees Celsius, slowly add n-butyllithium (2.5M, 12.0 mmol, 4.8 mL) dropwise, keep the reaction at minus 30 degrees Celsius for 1 hour, add allyl chloroformate 1-2 (1.5 g, 12.0 mmol), kept the reaction at minus 30 degrees Celsius for 1 hour, added saturated ammonium chloride solution to quench the reaction, concentrated under reduced pressure, extracted with ethyl acetate and water, dried the organic phase with anhydrous sodium sulfate and concentrated under reduced pressure, the residue was used After purification by column chromatography, the product allyl 3-oxo-7.9-dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carbonate 6-5 (2.6g) was obtained. LC-MS: m/z 268 [M+H] +
步骤5、化合物6-6的合成Step 5. Synthesis of Compounds 6-6
将3-氧-7.9-二甲基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂6-5(2.6g,9.9mmol)溶于四氢呋喃(25mL)中，将反应体系充分冷却至零下78摄氏度，缓慢滴加二异丁基氢化铝(1.3M，12.0mmol，9.2mL)，保持零下78摄氏度反应1小时，加入饱和氯化铵溶液淬灭反应，减压浓缩，并用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-羟基-7.9-二甲基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂6-6。LC-MS：m/z 252[M+H-18] + 3-Oxo-7.9-dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carboxylate allyl ester 6-5 (2.6 g, 9.9 mmol) was dissolved in tetrahydrofuran (25 mL) , the reaction system was fully cooled to minus 78 degrees Celsius, diisobutylaluminum hydride (1.3M, 12.0 mmol, 9.2 mL) was slowly added dropwise, kept at minus 78 degrees Celsius for 1 hour, and saturated ammonium chloride solution was added to quench the reaction, Concentrated under reduced pressure and extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was directly used in the next reaction without purification. The crude product 3-hydroxy-7.9-dimethyl- 8-oxa-2-azaspiro[4.5]decane-2-carboxylate allyl ester 6-6. LC-MS: m/z 252[M+H-18] +
步骤6、化合物6-7的合成Step 6. Synthesis of Compounds 6-7
将粗产物3-羟基-7.9-二甲基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂6-6溶于甲醇(20mL)中，充分搅拌后，室温下向反应体系中加入一水合对甲苯磺酸(153mg,0.8mmol),室温搅拌12小时，LC-MS监测。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-甲氧基-7.9-二甲基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂6-7。LC-MS：m/z 252[M+H-32] + The crude product 3-hydroxy-7.9-dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carboxylate allyl ester 6-6 was dissolved in methanol (20 mL) and stirred well , p-toluenesulfonic acid monohydrate (153 mg, 0.8 mmol) was added to the reaction system at room temperature, stirred at room temperature for 12 hours, and monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure. The crude product can be directly used in the next step without purification. The crude product 3-methoxy-7.9 - Dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carboxylate allyl ester 6-7. LC-MS: m/z 252[M+H-32] +
步骤7、化合物6-8的合成Step 7. Synthesis of Compounds 6-8
将粗产物3-甲氧基-7.9-二甲基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙脂6-7和1-氨基-3-(苄氧)-4-氧-1,4-二氢吡啶-2-羧酸乙酯M1(1.8g,6.3mmol)溶于乙腈(60mL)中，将反应体系充分冷却至零下30摄氏度，向反应体系中缓慢加入四氯化锡(2.4g,9.4mmol),零下30摄氏度搅拌1小时，LC-MS监测。反应结束后加入饱和碳酸氢钠水溶液淬灭反应，减压浓缩，用二氯甲烷和水萃取，有机相用无水硫酸钠干燥后减压浓 缩，粗产品可以直接用于下步反应，无需纯化，粗产物3-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-7.9-二甲基-8-氧杂-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯6-8。LC-MS：m/z 540[M+H] + The crude product 3-methoxy-7.9-dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carboxylate allyl ester 6-7 and 1-amino-3-(benzyl Oxy)-4-oxo-1,4-dihydropyridine-2-carboxylate ethyl ester M1 (1.8g, 6.3mmol) was dissolved in acetonitrile (60mL), the reaction system was fully cooled to minus 30 degrees Celsius, and the reaction system was added Tin tetrachloride (2.4 g, 9.4 mmol) was slowly added to it, and the mixture was stirred at minus 30 degrees Celsius for 1 hour, and monitored by LC-MS. After the reaction, saturated aqueous sodium bicarbonate solution was added to quench the reaction, concentrated under reduced pressure, extracted with dichloromethane and water, the organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure, the crude product can be directly used in the next step without purification. , the crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-7.9-dimethyl-8-oxa-2- Azaspiro[4.5]decane-2-carboxylate allyl 6-8. LC-MS: m/z 540 [M+H] +
步骤8、化合物6-9的合成Step 8. Synthesis of compounds 6-9
将粗产物3-((3-(苄氧)-2-(乙氧羰基)-4-氧吡啶-1(4H)-基)氨基)-8,8-二甲基-2-氮杂螺[4.5]癸烷-2-羧酸烯丙酯6-8、四三苯基膦钯(285mg,0.3mmol)、吗啉(4.3g,50mmol)溶于四氢呋喃(40mL)中，将反应体系用氮气置换三次，充入一个大气压力的氮气，室温下搅拌1小时，TLC和LC-MS监测。反应结束后减压浓缩，残余物用柱层析纯化后得到产物9'-(苄氧)-2,6-二甲基-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮6-9(1.6g)。LC-MS:m/z 410[M+H] + The crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxypyridin-1(4H)-yl)amino)-8,8-dimethyl-2-azaspiro [4.5] Allyl decane-2-carboxylate 6-8, palladium tetrakistriphenylphosphine (285 mg, 0.3 mmol), and morpholine (4.3 g, 50 mmol) were dissolved in tetrahydrofuran (40 mL), and the reaction system was used Nitrogen was replaced three times, filled with nitrogen at 1 atmosphere pressure, stirred at room temperature for 1 hour, and monitored by TLC and LC-MS. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 9'-(benzyloxy)-2,6-dimethyl-2,3,3a',4',5,6-hexahydrospiro [pyran-4,2'-pyridinepara[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'(1'H,3' H)-diketone 6-9 (1.6 g). LC-MS: m/z 410[M+H] +
化合物6-9可拆分为：Compounds 6-9 can be resolved into:
Figure PCTCN2022077312-appb-000056
Figure PCTCN2022077312-appb-000056
步骤9、化合物6-10的合成Step 9. Synthesis of compounds 6-10
将9'-(苄氧)-2,6-二甲基-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮6-9(40.9mg,0.1mmol)和7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-醇M2(39.6mg,0.2mmol)、溶于1-丙基磷酸酐(50wt.％的乙酸乙酯溶液，400uL)中，微波110摄氏度下搅拌3小时，LC-MS监测。反应结束后减压浓缩得粗产物9'-(苄氧)-4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-2,6-二甲基-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮6-10。LC-MS：m/z656[M+H] + 9'-(benzyloxy)-2,6-dimethyl-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridine[2,1- f]pyrrole[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 6-9 (40.9 mg, 0.1 mmol) and 7,8-Difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-ol M2 (39.6 mg, 0.2 mmol) in 1-propylphosphoric anhydride (50 wt.% in ethyl acetate ester solution, 400uL), stirred at 110 degrees Celsius in microwave for 3 hours, monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-2 ,6-Dimethyl-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridine[2,1-f]pyrrole[2,1-c ][1,2,4]triazine]-8',10'(1'H,3'H)-dione 6-10. LC-MS: m/z656[M+H] +
步骤10、化合物6的合成Step 10. Synthesis of compound 6
将粗产物9'-(苄氧)-4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-2,6-二甲基-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮6-10溶于甲醇(5mL)中，加入氢氧化钯碳(14mg,0.1mmol)，将反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌4小时，LC-MS监测。反应结束后用硅藻土过滤，滤液减压浓缩，用中压反相制备柱纯化得4'-(7,8-二氟-6,11-二氢二苯[b,e]噻庚-11-基)-9'-羟基-2,6-二甲基-2,3,3a',4',5,6-六氢螺[吡喃-4,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8',10'(1'H,3'H)-二酮化合物6(23.1mg)。LC-MS：m/z 566[M+H] + The crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thihept-11-yl)-2,6-dimethyl -2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2, 4] Triazine]-8',10'(1'H,3'H)-dione 6-10 was dissolved in methanol (5 mL), palladium hydroxide on carbon (14 mg, 0.1 mmol) was added, and the reaction system was treated with Nitrogen was replaced three times, filled with 1 atmosphere of hydrogen, stirred at room temperature for 4 hours, and monitored by LC-MS. After the reaction, it was filtered with celite, the filtrate was concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiheptyl- 11-yl)-9'-hydroxy-2,6-dimethyl-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinepara[2,1 -f]pyrrole[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione compound 6 (23.1 mg). LC-MS: m/z 566 [M+H] +
1H NMR(400MHz,CDCl3)δ7.61(s,1H),7.10-7.04(m,2H),6.89(s,1H),6.81(s,1H),6.62(s,1H),6.18(s,1H),5.59(s,1H),5.51(d,J＝13.6Hz,1H),5.13(s,1H),4.14(d,J＝13.6Hz,2H),3.73-3.60(m,1H),3.48-3.35(m,1H),3.36-3.25(m,1H),3.24-3.10(m,1H),2.25-2.17(m,1H),1.40-1.31(m,2H),1.22-1.16(m,3H),1.11-1.00(m,6H). 1 H NMR(400MHz, CDCl3)δ7.61(s,1H),7.10-7.04(m,2H),6.89(s,1H),6.81(s,1H),6.62(s,1H),6.18(s ,1H),5.59(s,1H),5.51(d,J=13.6Hz,1H),5.13(s,1H),4.14(d,J=13.6Hz,2H),3.73-3.60(m,1H) ,3.48-3.35(m,1H),3.36-3.25(m,1H),3.24-3.10(m,1H),2.25-2.17(m,1H),1.40-1.31(m,2H),1.22-1.16( m,3H),1.11-1.00(m,6H).
化合物6可以产生以下4个异构体：Compound 6 can produce the following 4 isomers:
Figure PCTCN2022077312-appb-000057
Figure PCTCN2022077312-appb-000057
实施例7、4'-(10,11-二氢-5H-二苯[a，d][7]环烯-5-基)-4,4-二氟-9'-羟基-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮(化合物7)的合成Example 7, 4'-(10,11-dihydro-5H-diphenyl[a,d][7]cycloalken-5-yl)-4,4-difluoro-9'-hydroxy-3a', 4'-Dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8', 10' Synthesis of (1'H,3'H)-diketone (Compound 7)
Figure PCTCN2022077312-appb-000058
Figure PCTCN2022077312-appb-000058
步骤1、化合物7-2的合成Step 1. Synthesis of compound 7-2
将二苯并[a,d]环庚烯-5-酮7-1(412mg,2mmol)溶于甲醇(10mL)中，加入二氧化铂(11.5mg,0.05mmol)，将反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌12小时，LC-MS监测。反应结束后用硅藻土过滤，滤液减压浓缩，用乙酸乙酯和水萃取，有机相无水硫酸钠干燥后减压浓缩，得到产物10,11-二氢-5H-二苯并[a,d][7]环烯-5-醇7-2。LC-MS：m/z 193[M+H-18] + Dibenzo[a,d]cyclohepten-5-one 7-1 (412 mg, 2 mmol) was dissolved in methanol (10 mL), platinum dioxide (11.5 mg, 0.05 mmol) was added, and the reaction system was replaced with nitrogen Three times, charged with 1 atmosphere of hydrogen, stirred at room temperature for 12 hours, and monitored by LC-MS. After the reaction, it was filtered with celite, the filtrate was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the product 10,11-dihydro-5H-dibenzo[a ,d][7]Cycloen-5-ol 7-2. LC-MS: m/z 193[M+H-18] +
步骤2、化合物7-3的合成Step 2. Synthesis of compound 7-3
将9'-(苄氧基)-4,4-二氟-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮2-10(41.5mg,0.1mmol)和10,11-二氢-5H-二苯并[a,d][7]环烯-5-醇7-2(31.5mg,0.2mmol)、溶于1-丙基磷酸酐(50wt.％的乙酸乙酯溶液，400uL)中，微波110摄氏度下搅拌3小时，LC-MS监测。反应结束后减压浓缩得粗产物9'-(苄氧基)-4'-(10,11-二氢-5H-二苯[a，d][7]环烯-5-基)-4,4-二氟-3a'，4'-二氢螺[1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮7-3。LC-MS：m/z 608[M+H] + 9'-(benzyloxy)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridine[2,1-f]pyrrole[2, 1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 2-10 (41.5 mg, 0.1 mmol) and 10,11-dihydro- 5H-Dibenzo[a,d][7]cycloen-5-ol 7-2 (31.5 mg, 0.2 mmol) in 1-propylphosphoric anhydride (50 wt.% in ethyl acetate, 400 uL) in the microwave at 110 °C for 3 hours, and monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude product 9'-(benzyloxy)-4'-(10,11-dihydro-5H-diphenyl[a,d][7]cycloalken-5-yl)-4 ,4-Difluoro-3a',4'-dihydrospiro[1,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine]- 8',10'(1'H,3'H)-diketone 7-3. LC-MS: m/z 608 [M+H] +
步骤3、化合物7的合成Step 3. Synthesis of Compound 7
将粗产物9'-(苄氧基)-4'-(10,11-二氢-5H-二苯[a，d][7]环烯-5-基)-4,4-二氟-3a'，4'-二氢螺[1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮7-3溶于甲醇(5mL)中，加入氢氧化钯碳碳(14mg,0.1mmol)，将反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌4小时，LC-MS监测。反应结束后用硅藻土过滤，滤液减压浓缩，用中压反相制备柱纯化得化合物4'-(10,11-二氢-5H-二苯[a，d][7]环烯-5-基)-4,4-二氟-9'-羟基-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮7(22.4mg)。LC-MS：m/z 518[M+H] +1 The crude product 9'-(benzyloxy)-4'-(10,11-dihydro-5H-diphenyl[a,d][7]cycloalken-5-yl)-4,4-difluoro- 3a', 4'-dihydrospiro[1,2'-pyridinepara[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8', 10'( 1'H, 3'H)-diketone 7-3 was dissolved in methanol (5mL), palladium hydroxide on carbon carbon (14mg, 0.1mmol) was added, the reaction system was replaced with nitrogen three times, and filled with hydrogen at an atmospheric pressure , stirred at room temperature for 4 hours, and monitored by LC-MS. After the reaction, it was filtered through celite, the filtrate was concentrated under reduced pressure, and purified by a medium-pressure reverse-phase preparative column to obtain the compound 4'-(10,11-dihydro-5H-diphenyl[a,d][7]cycloene- 5-yl)-4,4-difluoro-9'-hydroxy-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridine[2,1-f]pyrrole[2, 1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 7 (22.4 mg). LC-MS: m/z 518 [M+H] +1
1H NMR(400MHz,DMSO-d 6)δ7.45(d,J＝7.4Hz,1H),7.29(s,1H),7.22-7.10(m,4H),7.06(d,J＝7.6Hz,1H),6.89-6.81(m,1H),6.68(d,J＝7.8Hz,1H),5.61-5.51(m,1H),5.50-5.37(m,1H),5.35-5.22(m,1H),4.45-4.39(m,1H),3.86(d,J＝12.2Hz,1H),3.65-3.62(m,1H),3.27-3.24(m,1H),2.99-2.92(m,1H),2.82-2.77(m,1H),1.98-1.76(m,4H),1.71-1.26(m,6H). 1 H NMR (400MHz, DMSO-d 6 )δ7.45(d,J=7.4Hz,1H),7.29(s,1H),7.22-7.10(m,4H),7.06(d,J=7.6Hz, 1H), 6.89-6.81(m, 1H), 6.68(d, J=7.8Hz, 1H), 5.61-5.51(m, 1H), 5.50-5.37(m, 1H), 5.35-5.22(m, 1H) ,4.45-4.39(m,1H),3.86(d,J＝12.2Hz,1H),3.65-3.62(m,1H),3.27-3.24(m,1H),2.99-2.92(m,1H),2.82 -2.77(m,1H),1.98-1.76(m,4H),1.71-1.26(m,6H).
实施例8、4'-(6,11-二氢二苯[b，e]噻吩-11-基)-4,4-二氟-9'-羟基-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮(化合物8)的合成Example 8, 4'-(6,11-dihydrodiphenyl[b,e]thiophen-11-yl)-4,4-difluoro-9'-hydroxy-3a',4'-dihydrospiro[ Cyclohexane-1,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8', 10'(1'H,3' Synthesis of H)-diketone (Compound 8)
Figure PCTCN2022077312-appb-000059
Figure PCTCN2022077312-appb-000059
步骤1、化合物8-2的合成Step 1. Synthesis of compound 8-2
将二苯二硫醚M2-3(2.2g,10mmol)、氢氧化钠(1.2g,28.8mmol)、硼氢化钠(700mg,18.4mmol)溶于四氢呋喃(30mL)和水(30mL)中，将反应体系用氮气置换三次，充入一个大气压力的氮气，70摄氏度下搅拌12小时，LC-MS监测。反应液直接用于下一步反应。将2-溴甲基苯甲酸8-1(4.3g,20mmol)加入到上述的溶液中，室温下搅拌1小时，LC-MS监测。反应结束后向反应体系中加入1N稀盐酸，将体系PH值调至5-6，减压浓缩，用乙酸乙酯和水萃取，有机相用无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化后得到产物2-(苯硫)甲基苯甲酸8-2(1.9g)。LC-MS：m/z 245[M+H] + Diphenyl disulfide M2-3 (2.2 g, 10 mmol), sodium hydroxide (1.2 g, 28.8 mmol), sodium borohydride (700 mg, 18.4 mmol) were dissolved in tetrahydrofuran (30 mL) and water (30 mL), The reaction system was replaced with nitrogen three times, filled with nitrogen at 1 atmosphere pressure, stirred at 70°C for 12 hours, and monitored by LC-MS. The reaction solution was directly used in the next reaction. 2-Bromomethylbenzoic acid 8-1 (4.3 g, 20 mmol) was added to the above solution, stirred at room temperature for 1 hour, and monitored by LC-MS. After the reaction, 1N dilute hydrochloric acid was added to the reaction system, the pH value of the system was adjusted to 5-6, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was After purification by column chromatography, the product 2-(phenylthio)methylbenzoic acid 8-2 (1.9 g) was obtained. LC-MS: m/z 245 [M+H] +
步骤2、化合物8-3的合成Step 2. Synthesis of compound 8-3
将2-(苯硫)甲基苯甲酸8-2(1.9g,8.1mmol)溶于多聚磷酸(60mL)中，120摄氏度下搅拌12小时，LC-MS监测。反应结束后将反应体系冷却至室温，将反应液倒入0.5千克的碎冰中，用乙酸乙酯和水萃取，有机相用饱和碳酸氢钠水溶液洗涤三次，有机相无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化后得到产物二苯[b,e]噻庚-11(6H)-酮8-3(1.6g)。LC-MS：m/z 227[M+H] + 2-(Phenylthio)methylbenzoic acid 8-2 (1.9 g, 8.1 mmol) was dissolved in polyphosphoric acid (60 mL), stirred at 120 degrees Celsius for 12 hours, and monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, the reaction solution was poured into 0.5 kg of crushed ice, extracted with ethyl acetate and water, the organic phase was washed three times with saturated aqueous sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate and then reduced. After concentration under pressure, the residue was purified by column chromatography to give the product diphenyl[b,e]thihept-11(6H)-one 8-3 (1.6g). LC-MS: m/z 227[M+H] +
步骤3、化合物8-4的合成Step 3. Synthesis of Compounds 8-4
将二苯[b,e]噻庚-11(6H)-酮8-3(1.6g,7.3mmol)溶于甲醇(35mL)中，将体系充分冷却至零度，零度下缓慢加入硼氢化钠(557mg,14.6mmol)，零度下搅拌1小时，LC-MS监测。反应结束后减压浓缩，用乙酸乙酯和水萃取，有机相无水硫酸钠干燥后减压浓缩，残余物用柱层析纯化后得到产物6,11-二氢二苯[b,e]噻庚-11-醇8-4(1.5g)。LC-MS：m/z 211[M+H-18] + Diphenyl[b,e]thihept-11(6H)-one 8-3 (1.6g, 7.3mmol) was dissolved in methanol (35mL), the system was fully cooled to zero, and sodium borohydride ( 557 mg, 14.6 mmol), stirred at zero for 1 hour, monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 6,11-dihydrodiphenyl[b,e] Thiheptan-11-ol 8-4 (1.5 g). LC-MS: m/z 211[M+H-18] +
步骤4、化合物8-5的合成Step 4. Synthesis of Compounds 8-5
将9'-(苄氧基)-4,4-二氟-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮2-10(41.5mg,0.1mmol)和6,11-二氢二苯[b,e]噻庚-11-醇8-4(34.2mg,0.2mmol)、溶于1-丙基磷酸酐(50wt.％的乙酸乙酯溶液，400uL)中，微波110摄氏度下搅拌3小时，LC-MS监测。反应结束后减压浓缩得粗产物9'-(苄氧基)-4'-(6,11-二氢二苯[b，e]噻吩-11-基)-4,4-二氟-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮8-5。LC-MS：m/z 626[M+H] + 9'-(benzyloxy)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridine[2,1-f]pyrrole[2, 1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 2-10 (41.5 mg, 0.1 mmol) and 6,11-dihydrodione Benzene[b,e]thihept-11-ol 8-4 (34.2mg, 0.2mmol), dissolved in 1-propylphosphoric anhydride (50wt.% in ethyl acetate, 400uL), stirred at 110°C in microwave 3 hours, LC-MS monitoring. After the reaction was completed, it was concentrated under reduced pressure to obtain the crude product 9'-(benzyloxy)-4'-(6,11-dihydrodiphenyl[b,e]thiophen-11-yl)-4,4-difluoro-3a ',4'-dihydrospiro[cyclohexane-1,2'-pyridinepara[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8', 10'(1'H,3'H)-diketone 8-5. LC-MS: m/z 626[M+H] +
步骤5、化合物8的合成Step 5. Synthesis of Compound 8
将粗产物9'-(苄氧基)-4'-(6,11-二氢二苯[b，e]噻吩-11-基)-4,4-二氟-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮8-5溶于甲醇(5mL)中，加入氢氧化钯碳(14mg,0.1mmol)，将反应体系用氮气置换三次，充入一个大气压力的氢气，室温下搅拌4小时，LC-MS监测。反应结束后用硅藻土过滤，滤液减压浓缩，用中压反相制备柱纯化得4'-(6,11-二氢二苯[b，e]噻吩-11-基)-4,4-二氟-9'-羟基-3a'，4'-二氢螺[环己烷-1,2'-吡啶骈[2,1-f]吡咯骈[2,1-c][1,2,4]三嗪]-8'，10'(1'H，3'H)-二酮化合物8(24.6mg)。LC-MS：m/z 536[M+H] + The crude product 9'-(benzyloxy)-4'-(6,11-dihydrodiphenyl[b,e]thiophen-11-yl)-4,4-difluoro-3a',4'-difluoro Hydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8', 10'(1'H , 3'H)-diketone 8-5 was dissolved in methanol (5 mL), palladium hydroxide on carbon (14 mg, 0.1 mmol) was added, the reaction system was replaced with nitrogen three times, filled with hydrogen at an atmospheric pressure, and stirred at room temperature 4 hours, LC-MS monitoring. After the reaction, it was filtered with celite, the filtrate was concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain 4'-(6,11-dihydrodiphenyl[b,e]thiophen-11-yl)-4,4 -Difluoro-9'-hydroxy-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrole[2,1-c][1,2 ,4]Triazine]-8',10'(1'H,3'H)-dione compound 8 (24.6 mg). LC-MS: m/z 536 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ7.59-7.46(m,2H),7.45-7.29(m,2H),7.28-7.09(m,2H),7.08-6.77(m,3H),5.83-5.24(m,3H),3.91-3.85(m,2H),3.46-3.42(m,2H),1.98-1.74(m,4H),1.73-1.23(m,6H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.59-7.46(m, 2H), 7.45-7.29(m, 2H), 7.28-7.09(m, 2H), 7.08-6.77(m, 3H), 5.83 -5.24(m,3H),3.91-3.85(m,2H),3.46-3.42(m,2H),1.98-1.74(m,4H),1.73-1.23(m,6H).
实施例9、((4'-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-2,6-二甲基-8',10'-二氧-2,3,3a',4',5,6,8',10'-八氢-1'H,3'H-螺环[吡喃-4,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-9'-基)氧基)甲基碳酸甲酯(化合物9)的合成Example 9, ((4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-2,6-dimethyl-8',10 '-Dioxo-2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spiro[pyran-4,2'-pyrido[ Synthesis of 2,1-f]pyrrole[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl methyl carbonate (compound 9)
Figure PCTCN2022077312-appb-000060
Figure PCTCN2022077312-appb-000060
步骤1、化合物9的合成Step 1. Synthesis of compound 9
在干燥的圆底烧瓶中将6溶于DMA(2mL)中，加入KI(36.7mg,0.2mmol)，氯甲基碳酸二甲酯(55.0mg,0.4mmol,42.2μL)和碳酸铯(144.0mg,0.4mmol)升温至50摄氏度，搅拌1小时，LC-MS监测。反应结束后，溶液减压浓缩，残余杂质用中压反相制备柱纯化得((4'-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-2,6-二甲基-8',10'-二氧-2,3,3a',4',5,6,8',10'-八氢-1'H,3'H-螺环[吡喃-4,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-9'-基)氧基)甲基碳酸甲酯9(26mg)。LC-MS：m/z 654.4[M+H] + In a dry round bottom flask 6 was dissolved in DMA (2 mL), KI (36.7 mg, 0.2 mmol), chloromethyl dimethyl carbonate (55.0 mg, 0.4 mmol, 42.2 μL) and cesium carbonate (144.0 mg) were added , 0.4mmol) was warmed to 50 degrees Celsius, stirred for 1 hour, and monitored by LC-MS. After the reaction, the solution was concentrated under reduced pressure, and the residual impurities were purified with a medium-pressure reverse-phase preparative column to obtain ((4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11). - base)-2,6-dimethyl-8',10'-dioxo-2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spiro[pyran-4,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl methylcarbonate 9 (26 mg). LC-MS: m/z 654.4 [M+H] +
1H NMR(600MHz,DMSO-d 6)δ7.65(d,1H),7.55-7.49(m,1H),7.39-7.32(m,1H),7.13-7.06(m,1H),7.04(d,J＝8.0Hz,1H),6.92-6.87(m,2H),5.83(d,J＝7.8Hz,1H),5.72-5.66(m,2H),5.65-5.59(m,1H),5.54(d,J＝6.6Hz,1H),5.38(s,1H),4.16(d,J＝14.0Hz,1H),3.76(s,3H),3.57-3.42(m,3H),3.20-3.11(m,1H),2.30-2.24(m,1H),1.61(d,J＝13.4Hz,1H),1.32-1.24(m,1H),1.25-1.17(m,1H),1.05-0.86(m,8H). 1 H NMR (600MHz, DMSO-d 6 )δ7.65(d,1H), 7.55-7.49(m,1H), 7.39-7.32(m,1H), 7.13-7.06(m,1H), 7.04(d , J=8.0Hz, 1H), 6.92-6.87(m, 2H), 5.83(d, J=7.8Hz, 1H), 5.72-5.66(m, 2H), 5.65-5.59(m, 1H), 5.54( d, J=6.6Hz, 1H), 5.38(s, 1H), 4.16(d, J=14.0Hz, 1H), 3.76(s, 3H), 3.57-3.42(m, 3H), 3.20-3.11(m ,1H),2.30-2.24(m,1H),1.61(d,J=13.4Hz,1H),1.32-1.24(m,1H),1.25-1.17(m,1H),1.05-0.86(m,8H) ).
化合物9可以产生以下4个异构体：Compound 9 can produce the following 4 isomers:
Figure PCTCN2022077312-appb-000061
Figure PCTCN2022077312-appb-000061
实施例10和11、(3a'R)-4'-(6,11-二氢二苯并[b,e]噻吩-11-基)-9'羟基-2,3,3a',4',5,6-六氢化-1'H,3'H-螺环[吡喃-4,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物10)和(((3a'R)-4'-(6,11-二氢二苯并[b,e]噻吩-11-基)-8',10'-二氧-2,3,3a',4',5,6,8',10'-八氢-1'H,3'H-螺环[吡喃-4,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-9'-基)氧基)甲基碳酸甲酯(化合物11)的合成Examples 10 and 11, (3a'R)-4'-(6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9'hydroxy-2,3,3a',4' ,5,6-Hexahydro-1'H,3'H-spiro[pyran-4,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4 ]triazine]-8',10'-dione (Compound 10) and (((3a'R)-4'-(6,11-dihydrodibenzo[b,e]thiophen-11-yl) -8',10'-dioxo-2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spiro[pyran-4,2 Synthesis of '-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl carbonate (compound 11)
Figure PCTCN2022077312-appb-000062
Figure PCTCN2022077312-appb-000062
步骤1、化合物10-1的合成Step 1. Synthesis of Compound 10-1
10-1由1-7拆分得到。10-1 is split from 1-7.
步骤2、化合物10-2的合成Step 2. Synthesis of compound 10-2
按照实施例8中步骤4的合成方法，将步骤4中的2-10替换为10-1，合成方法相同，得到产物10-2(56mg)。LC-MS：m/z 592[M+H] +。 According to the synthesis method of step 4 in Example 8, 2-10 in step 4 was replaced with 10-1, and the synthesis method was the same to obtain product 10-2 (56 mg). LC-MS: m/z 592 [M+H] + .
步骤3、化合物10的合成Step 3. Synthesis of Compound 10
按照实施例8中步骤5的合成方法，将步骤5中的8-5替换为10-2，合成方法相同，得到产物10(24mg)。LC-MS：m/z 502[M+H] +。 According to the synthesis method of step 5 in Example 8, replace 8-5 in step 5 with 10-2, and the synthesis method is the same to obtain product 10 (24 mg). LC-MS: m/z 502 [M+H] + .
1H NMR(600MHz,DMSO-d 6)δ11.08(s,1H),7.56(d,J＝7.8Hz,1H),7.52(d,J＝7.6Hz,1H),7.42(d,J＝7.4Hz,1H),7.39-7.34(m,1H),7.27-7.21(m,1H),7.11-7.01(m,1H),7.00(d,J＝7.8Hz,1H),6.90-6.85(m,1H),6.85-6.79(m,1H),5.83-5.78(m,1H),5.66-5.59(m,2H),5.46(s,1H),3.93-3.87(m,2H),3.58-3.47(m,2H),3.45-3.29(m,3H),1.90-1.84(m,1H),1.53-1.46(m,1H),1.43-1.25(m,3H),1.17-1.10(m,1H). 1 H NMR (600MHz, DMSO-d 6 ) δ 11.08(s, 1H), 7.56(d, J=7.8Hz, 1H), 7.52(d, J=7.6Hz, 1H), 7.42(d, J= 7.4Hz, 1H), 7.39-7.34(m, 1H), 7.27-7.21(m, 1H), 7.11-7.01(m, 1H), 7.00(d, J=7.8Hz, 1H), 6.90-6.85(m ,1H),6.85-6.79(m,1H),5.83-5.78(m,1H),5.66-5.59(m,2H),5.46(s,1H),3.93-3.87(m,2H),3.58-3.47 (m,2H),3.45-3.29(m,3H),1.90-1.84(m,1H),1.53-1.46(m,1H),1.43-1.25(m,3H),1.17-1.10(m,1H) .
步骤4、化合物11的合成Step 4. Synthesis of Compound 11
按照实施例9中步骤1的合成方法，将步骤1中的6替换为10，合成方法相同，得到产物11(18mg)。LC-MS：m/z 590.3[M+H] +。 According to the synthesis method of step 1 in Example 9, 6 in step 1 was replaced by 10, and the synthesis method was the same to obtain product 11 (18 mg). LC-MS: m/z 590.3 [M+H] + .
1H NMR(600MHz,DMSO-d 6)δ7.64(d,J＝7.8Hz,1H),7.50-7.42(m,2H),7.41-7.35(m,1H),7.28-7.22(m,1H),7.11-7.03(m,1H),7.01(d,J＝8.0Hz,1H),6.86(d,J＝3.0Hz,2H),5.84-5.77(m,2H),5.71(d,J＝6.6Hz,1H),5.62-5.54(m,2H),5.19(s,1H),3.91(d,J＝13.2Hz,1H),3.82(d,J＝11.8Hz,1H),3.77(s,3H),3.55-3.50(m,2H),3.44-3.36(m,2H),3.35-3.28(m,1H),1.92-1.85(m,1H),1.46-1.35(m,2H),1.34-1.26(m,2H),1.15-1.08(m,1H). 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.64 (d, J=7.8 Hz, 1H), 7.50-7.42 (m, 2H), 7.41-7.35 (m, 1H), 7.28-7.22 (m, 1H) ), 7.11-7.03(m, 1H), 7.01(d, J=8.0Hz, 1H), 6.86(d, J=3.0Hz, 2H), 5.84-5.77(m, 2H), 5.71(d, J= 6.6Hz, 1H), 5.62-5.54(m, 2H), 5.19(s, 1H), 3.91(d, J=13.2Hz, 1H), 3.82(d, J=11.8Hz, 1H), 3.77(s, 3H), 3.55-3.50(m, 2H), 3.44-3.36(m, 2H), 3.35-3.28(m, 1H), 1.92-1.85(m, 1H), 1.46-1.35(m, 2H), 1.34- 1.26(m,2H),1.15-1.08(m,1H).
实施例12、6-((R)-9'-羟基-8',10'-二氧-2,3,3',3a',5,6,8',10'-八氢-1'H,4'H-螺环[吡喃-4,2'-吡啶[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-4'-基)-N-甲基-1,1a,6,10b-四氢二苯并[a,e]环丙烷[c][7]环烯-1-甲酰胺(化合物12)的合成Example 12, 6-((R)-9'-hydroxy-8',10'-dioxo-2,3,3',3a',5,6,8',10'-octahydro-1' H,4'H-Spiro[pyran-4,2'-pyridine[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-4'-yl)- Synthesis of N-methyl-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropane[c][7]cycloene-1-carboxamide (Compound 12)
Figure PCTCN2022077312-appb-000063
Figure PCTCN2022077312-appb-000063
步骤1、化合物12-2的合成Step 1. Synthesis of compound 12-2
在干燥的50mL三口烧瓶中加入CuSO 4(15.0mg,0.06mmol)，使用热风枪加热并用氮气置换瓶中空气。7-1(206mg,1mmol)和超干甲苯(5mL)加入瓶中后，加热至75摄氏度，搅拌5分钟。在搅拌下加 入12-1(284.9mg,2.5mmol)，继续在75摄氏度下搅拌反应18小时，LC-MS监测。反应结束后溶剂减压浓缩，无需纯化，产物可直接用于下步反应12-2(200mg,crude)为黄色油状物。LC-MS：m/z 293[M+H] +。 In a dry 50 mL three-neck flask, CuSO 4 (15.0 mg, 0.06 mmol) was added, heated with a heat gun and the air in the flask was replaced with nitrogen. 7-1 (206 mg, 1 mmol) and ultra-dry toluene (5 mL) were added to the bottle, heated to 75 degrees Celsius, and stirred for 5 minutes. 12-1 (284.9 mg, 2.5 mmol) was added with stirring and the reaction was continued to stir at 75 degrees Celsius for 18 hours, monitored by LC-MS. After the reaction, the solvent was concentrated under reduced pressure without purification, and the product could be directly used in the next step reaction 12-2 (200 mg, crude) as a yellow oil. LC-MS: m/z 293 [M+H] + .
步骤2、化合物12-3的合成Step 2. Synthesis of compound 12-3
将粗产物12-2(200mg,crude)溶于甲醇(2mL)中，加入氢氧化钠(273.7mg,6.8mmol)和水(2mL)，升温至50摄氏度搅拌反应18小时，LC-MS监测。反应结束后减压浓缩有机溶剂，用1M的HCl调节pH＝3，用乙酸乙酯萃取3次，收集有机相，无水硫酸钠干燥后减压浓缩，残余杂质用中压制备柱除去，得到12-3(40mg)。LC-MS：m/z 265[M+H] + The crude product 12-2 (200 mg, crude) was dissolved in methanol (2 mL), sodium hydroxide (273.7 mg, 6.8 mmol) and water (2 mL) were added, the temperature was raised to 50 degrees Celsius and the reaction was stirred for 18 hours, monitored by LC-MS. After the reaction, the organic solvent was concentrated under reduced pressure, adjusted to pH=3 with 1M HCl, extracted three times with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residual impurities were removed with a medium pressure preparative column to obtain 12-3 (40 mg). LC-MS: m/z 265 [M+H] +
步骤3、化合物12-4的合成Step 3. Synthesis of compound 12-4
在干燥的圆底烧瓶中加入12-3(40mg,0.2mmol)，用超干DMF(2mL)溶解后将体系降温至0摄氏度，加入DIPEA(117.4mg,0.9mmol,158.2μL)，搅拌5分钟后加入HATU(115.0mg,0.3mmol)继续搅拌5分钟。加入甲氨盐酸盐(30.7mg,0.5mmol)，继续在0摄氏度下搅拌反应20分钟，LC-MS监测。反应结束后溶剂减压浓缩，经MPLC纯化后的到产物12-4(40mg)为白色固体。LC-MS：m/z 278[M+H] +。 Add 12-3 (40 mg, 0.2 mmol) to a dry round-bottomed flask, dissolve with ultra-dry DMF (2 mL), cool the system to 0 degrees Celsius, add DIPEA (117.4 mg, 0.9 mmol, 158.2 μL), and stir for 5 minutes HATU (115.0 mg, 0.3 mmol) was then added and stirring was continued for 5 minutes. Methylamine hydrochloride (30.7 mg, 0.5 mmol) was added and the reaction was continued to stir at 0 degrees Celsius for 20 minutes, monitored by LC-MS. After the reaction, the solvent was concentrated under reduced pressure, and the product 12-4 (40 mg) was purified by MPLC as a white solid. LC-MS: m/z 278 [M+H] + .
步骤4、化合物12-5的合成Step 4. Synthesis of compound 12-5
在干燥的圆底烧瓶中加入12-4(40mg,0.1mmol)用甲醇(3mL)溶解后将体系降温至0摄氏度，加入NaBH 4(54.6mg,1.4mmol)，升温至50摄氏度，搅拌反应18小时，LC-MS监测。反应结束后溶剂减压浓缩，残余杂质经MPLC纯化后除去，得到产物12-5(20mg)为白色固体。LC-MS：m/z 280[M+H] +。 In a dry round-bottomed flask, add 12-4 (40 mg, 0.1 mmol) and dissolve it with methanol (3 mL), then cool the system to 0 degrees Celsius, add NaBH 4 (54.6 mg, 1.4 mmol), warm up to 50 degrees Celsius, and stir to react 18 hours, LC-MS monitoring. After the reaction, the solvent was concentrated under reduced pressure, and the residual impurities were purified by MPLC and removed to obtain the product 12-5 (20 mg) as a white solid. LC-MS: m/z 280 [M+H] + .
步骤5、化合物12的合成Step 5. Synthesis of compound 12
在干燥的圆底烧瓶中加入12-5(10mg,0.04mmol)和10-1(16.4mg,0.4mmol)用T 3P(200μL)溶解后将体系升温至110摄氏度，微波反应1小时后加入甲磺酸(7.1mg,0.1mmol,10μL)，继续微波110摄氏度反应1小时，LC-MS监测。反应结束后溶剂减压浓缩，残余杂质经Prep-HPLC纯化后除去，得到产物12(3.7mg)为白色固体。LC-MS：m/z 553.3[M+H] +。 12-5 (10 mg, 0.04 mmol) and 10-1 (16.4 mg, 0.4 mmol) were added to a dry round-bottomed flask, dissolved with T 3 P (200 μL), the temperature of the system was raised to 110 degrees Celsius, and the microwave reaction was added after 1 hour. Methanesulfonic acid (7.1 mg, 0.1 mmol, 10 μL), continued to microwave at 110 degrees Celsius for 1 hour, and monitored by LC-MS. After the reaction, the solvent was concentrated under reduced pressure, and the residual impurities were purified by Prep-HPLC and removed to obtain the product 12 (3.7 mg) as a white solid. LC-MS: m/z 553.3 [M+H] + .
实施例13、(((3a'R)-4'-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-8',10'-二氧-2,3,3a',4',5,6,8',10'-八氢-1'H,3'H-螺环[吡喃-4,2'-吡咯并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-9'-基)氧基)甲基碳酸甲酯(化合物13)的合成Example 13, (((3a'R)-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-8',10'- Dioxo-2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spiro[pyran-4,2'-pyrrolo[2, Synthesis of 1-f]pyrrole[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl methyl carbonate (Compound 13)
Figure PCTCN2022077312-appb-000064
Figure PCTCN2022077312-appb-000064
步骤1、化合物13的合成Step 1. Synthesis of compound 13
按照实施例9中步骤1的合成方法，将步骤1中的6替换为Isomer 1-2，合成方法相同，得到产物13(7mg)。LC-MS：m/z 626.3[M+H] +。 According to the synthesis method of step 1 in Example 9, replace 6 in step 1 with Isomer 1-2, and the synthesis method is the same to obtain product 13 (7 mg). LC-MS: m/z 626.3 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.64(d,J＝7.8Hz,1H),7.56-7.48(m,1H),7.40-7.28(m,1H),7.15-7.06(m,1H),7.07-7.00(m,1H),6.94-6.84(m,2H),5.82(d,J＝7.8Hz,1H),5.74-5.66(m,2H),5.62-5.57(m,1H),5.55(d, J＝6.6Hz,1H),5.37(s,1H),4.16(d,J＝13.8Hz,1H),3.81(d,J＝11.8Hz,1H),3.76(s,3H),3.52(d,J＝17.4Hz,3H),3.44-3.38(m,2H),2.04-1.94(m,1H),1.49-1.28(m,4H),1.26-1.18(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.64 (d, J=7.8Hz, 1H), 7.56-7.48 (m, 1H), 7.40-7.28 (m, 1H), 7.15-7.06 (m, 1H) ),7.07-7.00(m,1H),6.94-6.84(m,2H),5.82(d,J=7.8Hz,1H),5.74-5.66(m,2H),5.62-5.57(m,1H), 5.55(d, J＝6.6Hz, 1H), 5.37(s, 1H), 4.16(d, J＝13.8Hz, 1H), 3.81(d, J＝11.8Hz, 1H), 3.76(s, 3H), 3.52(d, J＝17.4Hz, 3H), 3.44-3.38(m, 2H), 2.04-1.94(m, 1H), 1.49-1.28(m, 4H), 1.26-1.18(m, 1H).
化合物13可以产生以下1个异构体：Compound 13 can produce one of the following isomers:
Figure PCTCN2022077312-appb-000065
Figure PCTCN2022077312-appb-000065
Isomer 13-1核磁数据：Isomer 13-1 NMR data:
1H NMR(400MHz,DMSO-d 6)δ7.65(d,J＝7.8Hz,1H),7.56-7.48(m,1H),7.40-7.28(m,1H),7.14-7.07(m,1H),7.04(d,J＝7.8Hz,1H),6.93-6.86(m,2H),5.82(d,J＝7.8Hz,1H),5.70(d,J＝6.6Hz,2H),5.63-5.57(m,1H),5.55(d,J＝6.4Hz,1H),5.37(s,1H),4.16(d,J＝13.9Hz,1H),3.81(d,J＝12.0Hz,1H),3.76(s,3H),3.52(d,J＝16.8Hz,3H),3.40(d,J＝5.4Hz,2H),2.05-1.93(m,1H),1.51-1.12(m,5H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.65(d, J=7.8Hz, 1H), 7.56-7.48(m, 1H), 7.40-7.28(m, 1H), 7.14-7.07(m, 1H) ),7.04(d,J＝7.8Hz,1H),6.93-6.86(m,2H),5.82(d,J＝7.8Hz,1H),5.70(d,J＝6.6Hz,2H),5.63-5.57 (m, 1H), 5.55 (d, J=6.4Hz, 1H), 5.37 (s, 1H), 4.16 (d, J=13.9Hz, 1H), 3.81 (d, J=12.0Hz, 1H), 3.76 (s, 3H), 3.52 (d, J=16.8Hz, 3H), 3.40 (d, J=5.4Hz, 2H), 2.05-1.93 (m, 1H), 1.51-1.12 (m, 5H).
实施例14、4'-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-9'-羟基-3a',4'-二氢-1'H,3'H-螺环[氧杂环丁烷-3,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物14)的合成Example 14, 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9'-hydroxy-3a',4'-dihydro- 1'H,3'H-Spiro[oxetane-3,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]- Synthesis of 8',10'-diketone (Compound 14)
Figure PCTCN2022077312-appb-000066
Figure PCTCN2022077312-appb-000066
步骤1、化合物14-3的合成Step 1. Synthesis of compound 14-3
在干燥的圆底烧瓶中加入14-1(1g,7.9mmol)用THF(20mL)溶解后缓慢滴加加入n-BuLi(2.5M,3.8mL)将体系降温至-30摄氏度，搅拌反应1小时后滴加加入14-2(1.1g,9.4mmol,1.0mL)，继续在-30摄氏度反应1小时，LC-MS监测。反应结束后用饱和氯化铵溶液淬灭，用乙酸乙酯萃取3次，合并有机相分别用饱和食盐水，无水硫酸钠干燥，有机相减压浓缩，得到产物14-3(1.5g,crude)为黄色油状物。LC-MS：m/z 212[M+H] +。 14-1 (1 g, 7.9 mmol) was added to a dry round-bottomed flask, dissolved in THF (20 mL), and n-BuLi (2.5 M, 3.8 mL) was slowly added dropwise to cool the system to -30 degrees Celsius, and the reaction was stirred for 1 hour. After that, 14-2 (1.1 g, 9.4 mmol, 1.0 mL) was added dropwise, and the reaction was continued at -30 degrees Celsius for 1 hour, monitored by LC-MS. After the reaction, it was quenched with saturated ammonium chloride solution, extracted 3 times with ethyl acetate, the combined organic phases were respectively dried with saturated brine and anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain product 14-3 (1.5 g, crude) is a yellow oil. LC-MS: m/z 212 [M+H] + .
步骤2、化合物14-4的合成Step 2. Synthesis of compound 14-4
在干燥的圆底烧瓶中加入14-3(1.5g,7.1mmol)用THF(20mL)溶解后滴加加入DIBAL-H(1.5M,7.1mL)将体系降温至-78摄氏度反应1小时，LC-MS监测。反应结束后，待体系恢复到室温后用饱和氯化铵溶液淬灭，用乙酸乙酯萃取3次，合并有机相，分别用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，得到产物14-4(1.2g,crude)为黄色油状物。LC-MS：m/z 214[M+H] +。 14-3 (1.5 g, 7.1 mmol) was added to a dry round-bottomed flask, dissolved in THF (20 mL), and then DIBAL-H (1.5 M, 7.1 mL) was added dropwise to cool the system to -78 degrees Celsius and react for 1 hour, LC -MS monitoring. After the reaction, after the system was returned to room temperature, it was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, the organic phases were combined, washed with saturated brine respectively, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain The product 14-4 (1.2 g, crude) was a yellow oil. LC-MS: m/z 214 [M+H] + .
步骤3、化合物14-5的合成Step 3. Synthesis of compound 14-5
在干燥的圆底烧瓶中加入14-4(1.2g,5.4mmol)用THF(15mL)溶解后，冰浴下加入NaH(155.3mg,6.5mmol)，0摄氏度反应1小时后，滴加加入碘甲烷(918.6mg,6.5mmol,402.9μL)搅拌反应15小时，LC-MS监测。反应结束后，待体系恢复到室温后用饱和氯化铵溶液淬灭，用乙酸乙酯萃取3次，合并有机相分别用饱和食盐水，无水硫酸钠干燥，有机相减压浓缩，得到产物14-5(1.1g,crude)为黄色油状物。LC-MS：m/z 228[M+H] +。 Add 14-4 (1.2 g, 5.4 mmol) to a dry round-bottomed flask, dissolve it with THF (15 mL), add NaH (155.3 mg, 6.5 mmol) under ice bath, react at 0 degrees Celsius for 1 hour, and add iodine dropwise The reaction was stirred with methane (918.6 mg, 6.5 mmol, 402.9 μL) for 15 hours, monitored by LC-MS. After the reaction was completed, after the system was returned to room temperature, it was quenched with saturated ammonium chloride solution, extracted with ethyl acetate 3 times, the combined organic phases were respectively dried with saturated brine and anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the product 14-5 (1.1 g, crude) was a yellow oil. LC-MS: m/z 228 [M+H] + .
步骤4、化合物14-7的合成Step 4. Synthesis of compound 14-7
在干燥的圆底烧瓶中加入14-5(1.1g,4.7mmol)和14-6(1.1g,3.9mmol)用甲苯(30mL)溶解后滴加加入SnCl 4(1.0g,3.9mmol,454.9μL)，体系降温至-30摄氏度反应1小时，LC-MS监测。反应结束后，待体系恢复到室温后用饱和碳酸氢钠溶液淬灭，用DCM萃取3次，合并有机相分别用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，得到产物14-7(2.4g,crude)为棕色油状物。LC-MS：m/z 484[M+H] +。 14-5 (1.1 g, 4.7 mmol) and 14-6 (1.1 g, 3.9 mmol) were added to a dry round-bottomed flask, dissolved in toluene (30 mL), and SnCl 4 (1.0 g, 3.9 mmol, 454.9 μL) was added dropwise. ), the system was cooled to -30 degrees Celsius and reacted for 1 hour, monitored by LC-MS. After the reaction was completed, after the system was returned to room temperature, it was quenched with saturated sodium bicarbonate solution, extracted three times with DCM, the combined organic phases were washed with saturated brine respectively, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the product 14- 7 (2.4 g, crude) was a brown oil. LC-MS: m/z 484 [M+H] + .
步骤5、化合物14-8的合成Step 5. Synthesis of Compound 14-8
在干燥的圆底烧瓶中加入14-7(2.4g,5.1mmol)和吗啉(4.4g,50.5mmol)用THF(20mL)溶解后加入Pd(PPh 3) 4(291.6mg,0.3mmol)，氮气保护下室温反应2小时，LC-MS监测。反应结束后过滤，滤饼用THF清洗三次，减压浓缩，得到产物14-8(1.6g,crude)为白色固体。LC-MS：m/z 354[M+H] +。 In a dry round-bottomed flask, 14-7 (2.4 g, 5.1 mmol) and morpholine (4.4 g, 50.5 mmol) were added to dissolve with THF (20 mL) and then Pd(PPh 3 ) 4 (291.6 mg, 0.3 mmol) was added, The reaction was carried out at room temperature for 2 hours under nitrogen protection, and monitored by LC-MS. After the reaction was completed, it was filtered, the filter cake was washed three times with THF, and concentrated under reduced pressure to obtain the product 14-8 (1.6 g, crude) as a white solid. LC-MS: m/z 354 [M+H] + .
化合物14-8可拆分成：Compound 14-8 can be resolved into:
Figure PCTCN2022077312-appb-000067
Figure PCTCN2022077312-appb-000067
步骤6、化合物14的合成Step 6. Synthesis of compound 14
在干燥的圆底烧瓶1中加入14-8(35mg,0.1mmol)用DMF(1mL)溶解后0摄氏度下加入NaH(5.9mg,0.3mmol)，搅拌1小时。另取一个圆底烧瓶2加入M2(39.3mg,0.2mmol)和SOCl 2(1.6g,13.8mmol,1mL)，在0摄氏度下搅拌1小时后，加入到圆底烧瓶1中，0摄氏度下继续反应1小时，LC-MS监测。反应结束后，用饱和氯化铵溶液淬灭，用乙酸乙酯萃取3次，合并有机相分别用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，残余杂质用MPLC除去后得到产物14(10mg)为白色固体。LC-MS：m/z 510.5[M+H] +。 In a dry round-bottomed flask 1, 14-8 (35 mg, 0.1 mmol) was added to dissolve in DMF (1 mL), and NaH (5.9 mg, 0.3 mmol) was added at 0°C, followed by stirring for 1 hour. Take another round-bottom flask 2 and add M2 (39.3 mg, 0.2 mmol) and SOCl 2 (1.6 g, 13.8 mmol, 1 mL), stir at 0 degrees Celsius for 1 hour, add to round-bottomed flask 1, and continue at 0 degrees Celsius The reaction was carried out for 1 hour and monitored by LC-MS. After the reaction, it was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, the combined organic phases were washed with saturated brine respectively, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the residual impurities were removed by MPLC to obtain the product 14 (10 mg) was a white solid. LC-MS: m/z 510.5 [M+H] + .
化合物14可拆分为以下4个异构体：Compound 14 can be resolved into the following 4 isomers:
Figure PCTCN2022077312-appb-000068
Figure PCTCN2022077312-appb-000068
实施例15和16、(2R,3a'R,6S)-4'-((R)-6,11-二氢二苯并[b,e]噻吩-11-基)-9'-羟基-2,6-二甲基-2,3,3a',4',5,6-六氢化-1'H,3'H-螺环[吡喃-4,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物15)和(2R,3a'R,6S)-4'-((S)-6,11-二氢二苯并[b,e]噻吩-11-基)-9'-羟基-2,6-二甲基-2,3,3a',4',5,6-六氢化-1'H,3'H-螺环[吡喃-4,2'-吡咯并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物16)的合成Examples 15 and 16, (2R,3a'R,6S)-4'-((R)-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9'-hydroxy- 2,6-Dimethyl-2,3,3a',4',5,6-hexahydro-1'H,3'H-spiro[pyran-4,2'-pyrido[2,1 -f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (Compound 15) and (2R,3a'R,6S)-4'-(( S)-6,11-Dihydrodibenzo[b,e]thiophen-11-yl)-9'-hydroxy-2,6-dimethyl-2,3,3a',4',5,6 - Hexahydro-1'H,3'H-spiro[pyran-4,2'-pyrrolo[2,1-f]pyrrole[2,1-c][1,2,4]triazine] Synthesis of -8',10'-dione (Compound 16)
Figure PCTCN2022077312-appb-000069
Figure PCTCN2022077312-appb-000069
步骤1、化合物15-1的合成Step 1. Synthesis of compound 15-1
化合物15-1由化合物6-9拆分得来。Compound 15-1 was resolved from compound 6-9.
步骤2、化合物15-2的合成Step 2. Synthesis of compound 15-2
按照实施例8中步骤4的合成方法，将步骤4中的2-10替换为15-1，8-4替换为8-4的两个拆分产物，合成方法相同，得到产物15-2(60mg)和16-1(30mg)。LC-MS：m/z 620[M+H] +。 According to the synthetic method of step 4 in embodiment 8, 2-10 in step 4 is replaced with 15-1, and 8-4 is replaced with two split products of 8-4, and the synthetic method is the same to obtain product 15-2 ( 60 mg) and 16-1 (30 mg). LC-MS: m/z 620 [M+H] + .
步骤3、化合物15的合成Step 3. Synthesis of compound 15
在干燥的圆底烧瓶中加入15-2(60mg,0.1mmol)和LiCl(41.0mg,1mmol)用DMA(1.5mL)溶解后升温至110摄氏度反应3小时。在冰浴下加入0.5M HCl(1.5mL)和丙酮(1.5mL)后，0摄氏度至室温继续反应1小时，LC-MS监测。反应结束后，有机相减压浓缩，残余杂质用prep-HPLC除去后得到产物15(1.2mg)为黄色固体。LC-MS：m/z 530.2[M+H] + In a dry round-bottomed flask, 15-2 (60 mg, 0.1 mmol) and LiCl (41.0 mg, 1 mmol) were added to dissolve with DMA (1.5 mL), and the temperature was raised to 110 degrees Celsius to react for 3 hours. After adding 0.5M HCl (1.5 mL) and acetone (1.5 mL) in an ice bath, the reaction was continued at 0°C to room temperature for 1 hour, and monitored by LC-MS. After the reaction, the organic phase was concentrated under reduced pressure, and the residual impurities were removed by prep-HPLC to obtain the product 15 (1.2 mg) as a yellow solid. LC-MS: m/z 530.2 [M+H] +
1H NMR(600MHz,DMSO-d 6)δ7.53-7.51(m,2H),7.42(d,J＝7.6Hz,1H),7.39-7.36(m,1H),7.26-7.24(m,1H),7.07-7.05(m,1H),7.01(d,J＝7.8Hz,1H),6.87(d,J＝7.8Hz,1H),6.83-6.81(m,1H),5.80(d,J＝13.2Hz,1H),5.65(dd,J＝10.8,6.4Hz,1H),5.59(d,J＝7.6Hz,1H),5.43(s,1H),3.89(d,J＝13.2Hz,1H),3.58(d,J＝13.2Hz,1H),3.45-3.43(m,1H),2.98(dd,J＝11.8,6.2Hz,1H),2.15(dd,J＝12.8,6.6Hz,1H),1.66(d,J＝13.6Hz,1H),1.27-1.22(m,2H),1.17(t,J＝11.8Hz,1H),0.97(d,J＝6.0Hz,3H),0.96-0.94(m,1H),0.92(d,J＝6.0Hz,3H),0.84(d,J＝13.2Hz,1H). 1 H NMR (600MHz, DMSO-d 6 ) δ 7.53-7.51 (m, 2H), 7.42 (d, J=7.6Hz, 1H), 7.39-7.36 (m, 1H), 7.26-7.24 (m, 1H) ),7.07-7.05(m,1H),7.01(d,J=7.8Hz,1H),6.87(d,J=7.8Hz,1H),6.83-6.81(m,1H),5.80(d,J= 13.2Hz, 1H), 5.65 (dd, J=10.8, 6.4Hz, 1H), 5.59 (d, J=7.6Hz, 1H), 5.43 (s, 1H), 3.89 (d, J=13.2Hz, 1H) ,3.58(d,J＝13.2Hz,1H),3.45-3.43(m,1H),2.98(dd,J＝11.8,6.2Hz,1H),2.15(dd,J＝12.8,6.6Hz,1H), 1.66(d,J=13.6Hz,1H),1.27-1.22(m,2H),1.17(t,J=11.8Hz,1H),0.97(d,J=6.0Hz,3H),0.96-0.94(m ,1H),0.92(d,J＝6.0Hz,3H),0.84(d,J＝13.2Hz,1H).
步骤4、化合物16的合成Step 4. Synthesis of compound 16
按照实施例15中步骤3的合成方法，将步骤3中的15-2替换为16-1，合成方法相同，得到产物16(1.0mg)。LC-MS：m/z 530.2[M+H] +。 According to the synthesis method of step 3 in Example 15, 15-2 in step 3 was replaced with 16-1, and the synthesis method was the same to obtain product 16 (1.0 mg). LC-MS: m/z 530.2 [M+H] + .
1H NMR(600MHz,DMSO-d 6)δ7.53-7.51(m,2H),7.42(d,J＝7.6Hz,1H),7.39-7.36(m,1H),7.26-7.24(m,1H),7.07-7.05(m,1H),7.01(d,J＝7.8Hz,1H),6.87(d,J＝7.8Hz,1H),6.83-6.81(m,1H),5.80(d,J＝13.2Hz,1H),5.65(dd,J＝10.8,6.4Hz,1H),5.59(d,J＝7.6Hz,1H),5.43(s,1H),3.89(d,J＝13.2Hz,1H),3.58(d,J＝13.2Hz,1H),3.45-3.43(m,1H),2.98(dd,J＝11.8,6.2Hz,1H),2.15(dd,J＝12.8,6.6Hz,1H),1.66(d,J＝13.6Hz,1H),1.27-1.22(m,2H),1.17(t,J＝11.8Hz,1H),0.97(d,J＝6.0Hz,3H),0.96-0.94(m,1H),0.92(d,J＝6.0Hz,3H),0.84(d,J＝13.2Hz,1H). 1 H NMR (600MHz, DMSO-d 6 ) δ 7.53-7.51 (m, 2H), 7.42 (d, J=7.6Hz, 1H), 7.39-7.36 (m, 1H), 7.26-7.24 (m, 1H) ),7.07-7.05(m,1H),7.01(d,J=7.8Hz,1H),6.87(d,J=7.8Hz,1H),6.83-6.81(m,1H),5.80(d,J= 13.2Hz, 1H), 5.65 (dd, J=10.8, 6.4Hz, 1H), 5.59 (d, J=7.6Hz, 1H), 5.43 (s, 1H), 3.89 (d, J=13.2Hz, 1H) ,3.58(d,J＝13.2Hz,1H),3.45-3.43(m,1H),2.98(dd,J＝11.8,6.2Hz,1H),2.15(dd,J＝12.8,6.6Hz,1H), 1.66(d,J=13.6Hz,1H),1.27-1.22(m,2H),1.17(t,J=11.8Hz,1H),0.97(d,J=6.0Hz,3H),0.96-0.94(m ,1H),0.92(d,J＝6.0Hz,3H),0.84(d,J＝13.2Hz,1H).
实施例17、(((2R,3a'R,6S)-4'-((R)-6,11-二氢二苯并[b,e]噻吩-11-基)-2,6-二甲基-8',10'-二氧基-2,3,3a',4',5,6,8',10'-八氢-1'H,3'H-螺环[吡喃-4,2'-吡咯并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-9'-基)氧基)甲基碳酸甲酯(化合物17)的合成Example 17, (((2R,3a'R,6S)-4'-((R)-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-2,6-di Methyl-8',10'-dioxy-2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spiro[pyran- 4,2'-Pyrrolo[2,1-f]pyrrole[2,1-c][1,2,4]triazin]-9'-yl)oxy)methyl carbonate (Compound 17) Synthesis
Figure PCTCN2022077312-appb-000070
Figure PCTCN2022077312-appb-000070
步骤1、化合物17的合成Step 1. Synthesis of compound 17
按照实施例9中步骤1的合成方法，将步骤1中的6替换为16-1，合成方法相同，得到产物17(2.1mg)。LC-MS：m/z 618.2[M+H] +。 According to the synthesis method of step 1 in Example 9, 6 in step 1 was replaced by 16-1, and the synthesis method was the same to obtain product 17 (2.1 mg). LC-MS: m/z 618.2 [M+H] + .
1H NMR(600MHz,DMSO-d 6)δ7.62(d,J＝7.8Hz,1H),7.48(d,J＝7.6Hz,1H),7.44(d,J＝7.6Hz,1H),7.40-7.38(m,1H),7.28-7.25(m,1H),7.09-7.06(m,1H),7.02(d,J＝8.0Hz,1H),6.86(d,J＝4.2Hz,2H),5.81(dd,J＝16.0,10.6Hz,2H),5.72(d,J＝6.6Hz,1H),5.61(dd,J＝10.0,7.2Hz,1H),5.55(d,J＝6.4Hz,1H),5.18(s,1H),3.91(d,J＝13.4Hz,1H),3.76(s,3H),3.51-3.41(m,3H),3.03-2.97(m,1H),2.16(dd,J＝13.2,7.0Hz,1H),1.59(d,J＝13.6Hz,1H),1.26-1.22(m,3H),1.15(t,J＝11.6Hz,1H),0.98(d,J＝6.0Hz,3H),0.92(d,J＝6.2Hz,3H). 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.62 (d, J=7.8 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.40 -7.38(m,1H),7.28-7.25(m,1H),7.09-7.06(m,1H),7.02(d,J=8.0Hz,1H),6.86(d,J=4.2Hz,2H), 5.81(dd,J＝16.0,10.6Hz,2H),5.72(d,J＝6.6Hz,1H),5.61(dd,J＝10.0,7.2Hz,1H),5.55(d,J＝6.4Hz,1H) ), 5.18(s, 1H), 3.91(d, J=13.4Hz, 1H), 3.76(s, 3H), 3.51-3.41(m, 3H), 3.03-2.97(m, 1H), 2.16(dd, J=13.2, 7.0Hz, 1H), 1.59 (d, J=13.6Hz, 1H), 1.26-1.22 (m, 3H), 1.15 (t, J=11.6Hz, 1H), 0.98 (d, J=6.0 Hz,3H),0.92(d,J＝6.2Hz,3H).
实施例18、4'-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-9'-羟基-3a',4'-二氢-1'H,3'H-螺环[环丙烷-1,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物18)的合成Example 18, 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9'-hydroxy-3a',4'-dihydro- 1'H,3'H-spiro[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8', Synthesis of 10'-diketone (Compound 18)
Figure PCTCN2022077312-appb-000071
Figure PCTCN2022077312-appb-000071
步骤1、化合物18-3的合成Step 1. Synthesis of compound 18-3
在干燥的圆底烧瓶中加入18-1(12.5g,71.7mmol)、18-2(11.4g,93.2mmol)和CEMTPP(32.5g,93.2mmol)用甲苯(150mL)溶解，N 2置换3次，升温至80摄氏度反应16小时，LC-MS监测。反应结束后，溶剂减压浓缩，残余杂质用柱层析法除去后得到产物18-3(7.5g)为浅黄色油状物。LC-MS：m/z 127[M+H] + Add 18-1 (12.5 g, 71.7 mmol), 18-2 (11.4 g, 93.2 mmol) and CEMTPP (32.5 g, 93.2 mmol) to a dry round-bottomed flask, dissolve with toluene (150 mL), and replace with N 3 times , the temperature was raised to 80 degrees Celsius and the reaction was carried out for 16 hours, monitored by LC-MS. After the reaction, the solvent was concentrated under reduced pressure, and the residual impurities were removed by column chromatography to obtain the product 18-3 (7.5 g) as a pale yellow oil. LC-MS: m/z 127[M+H] +
步骤2、化合物18-4的合成Step 2. Synthesis of compound 18-4
在干燥的圆底烧瓶中加入18-3(7.5g,59.5mmol)、硝基甲烷(7.3g,118.9mmol,6.4mL)和碳酸钾(16.4g,118.9mmol)用DMSO(120mL)溶解,升温至80摄氏度反应3小时，LC-MS监测。反应结束后，加入水(400mL)，用乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥后减压浓缩，无需进一步纯化，粗产物可直接用于下步反应，得到产物18-4(7.5g,crude)为棕色油状物。LC-MS：m/z 188[M+H] + In a dry round-bottomed flask, 18-3 (7.5 g, 59.5 mmol), nitromethane (7.3 g, 118.9 mmol, 6.4 mL) and potassium carbonate (16.4 g, 118.9 mmol) were added, dissolved in DMSO (120 mL), and the temperature was increased. The reaction was carried out at 80 degrees Celsius for 3 hours and monitored by LC-MS. After the reaction, water (400 mL) was added, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, without further purification, the crude product was directly used in the next step The reaction gave the product 18-4 (7.5 g, crude) as a brown oil. LC-MS: m/z 188 [M+H] +
步骤3、化合物18-5的合成Step 3. Synthesis of compound 18-5
在干燥的圆底烧瓶中加入18-4(7.5g,40.1mmol)和Raney Ni(2g,40.1mmol)用甲醇(50mL)溶解，室温反应12小时，LC-MS监测。反应结束后过滤，滤液减压蒸馏，剩余杂质用柱层析法除去，得到产物18-5(1.5g)为白色固体。LC-MS：m/z 112[M+H] + 18-4 (7.5 g, 40.1 mmol) and Raney Ni (2 g, 40.1 mmol) were added to a dry round-bottomed flask and dissolved in methanol (50 mL). The reaction was carried out at room temperature for 12 hours, and monitored by LC-MS. After the reaction was completed, it was filtered, the filtrate was distilled under reduced pressure, and the remaining impurities were removed by column chromatography to obtain the product 18-5 (1.5 g) as a white solid. LC-MS: m/z 112[M+H] +
步骤4、化合物18-7的合成Step 4. Synthesis of compound 18-7
在干燥的圆底烧瓶中加入18-5(1.5g,13.5mmol)用THF(25mL)溶解，滴加加入n-BuLi(2.5M,6.5mL)，体系降温至-30摄氏度反应1小时。在-30摄氏度下滴加加入18-6(2g,16.2mmol,1.7mL)继续反应1小时，LC-MS监测。反应结束后，待体系恢复至室温，用饱和氯化铵溶液淬灭，用乙酸乙酯萃取3次，合并有机相分别用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，得到产物可直接用于下步反应，无需进一步纯化，得到产物18-7(2.2g,crude)为浅黄色油状物。LC-MS：m/z 196[M+H] + 18-5 (1.5 g, 13.5 mmol) was added to a dry round-bottomed flask, dissolved in THF (25 mL), n-BuLi (2.5 M, 6.5 mL) was added dropwise, and the system was cooled to -30 degrees Celsius and reacted for 1 hour. 18-6 (2 g, 16.2 mmol, 1.7 mL) was added dropwise at -30 degrees Celsius to continue the reaction for 1 hour, monitored by LC-MS. After the reaction, when the system was returned to room temperature, it was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, the combined organic phases were washed with saturated brine respectively, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the product It can be directly used in the next step without further purification to obtain the product 18-7 (2.2 g, crude) as a pale yellow oil. LC-MS: m/z 196[M+H] +
步骤5、化合物18-8的合成Step 5. Synthesis of compound 18-8
在干燥的圆底烧瓶中加入18-7(2.2g,11.3mmol)用THF(25mL)溶解，滴加加入DIBAL-H(1.5M,11.3mL)，体系降温至-78摄氏度反应1小时，LC-MS监测。反应结束后，用饱和氯化铵溶液淬灭，用乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，得到产物可直接用于下步反应，无需进一步纯化，得到产物18-8(2g,crude)为浅黄色油状物。LC-MS：m/z 198[M+H] + 18-7 (2.2 g, 11.3 mmol) was added to a dry round-bottomed flask, dissolved in THF (25 mL), DIBAL-H (1.5 M, 11.3 mL) was added dropwise, and the system was cooled to -78 degrees Celsius and reacted for 1 hour, LC -MS monitoring. After the reaction, it was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the product that can be used directly in the next step. The reaction, without further purification, gave the product 18-8 (2 g, crude) as a pale yellow oil. LC-MS: m/z 198 [M+H] +
步骤6、化合物18-9的合成Step 6. Synthesis of compound 18-9
在干燥的圆底烧瓶中加入18-8(2g,9.9mmol)用甲醇(15mL)溶解，加入PTSA.H 2O(939.3mg,4.9mmol)，室温反应16小时，LC-MS监测。反应结束后，悬干溶剂，加水和乙酸乙酯萃取3次，合并有机相分别用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，得到产物可直接用于下步反应，无需进一步纯化，得到产物18-9(1.6g,crude)为浅黄色油状物。LC-MS：m/z 212[M+H] + 18-8 (2 g, 9.9 mmol) was added to a dry round-bottomed flask, dissolved in methanol (15 mL), PTSA.H 2 O (939.3 mg, 4.9 mmol) was added, and the reaction was carried out at room temperature for 16 hours, monitored by LC-MS. After the reaction, the solvent was suspended to dryness, water and ethyl acetate were added for extraction 3 times, the combined organic phases were washed with saturated brine respectively, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the product which can be directly used in the next step without further reaction. Purification gave the product 18-9 (1.6 g, crude) as a pale yellow oil. LC-MS: m/z 212[M+H] +
步骤7、化合物18-10的合成Step 7. Synthesis of compounds 18-10
在干燥的圆底烧瓶中加入18-9(1.6g,7.7mmol)和M1(1.8g,6.4mmol)用MeCN(40mL)溶解，将体系降温至-30摄氏度，滴加加入SnCl 4(1.7g,6.4mmol,747.9μL)，反应1小时，LC-MS监测。反应结束后，加入饱和碳酸氢钠溶液，用DCM萃取3次，合并有机相分别用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，得到产物可直接用于下步反应，无需进一步纯化，得到产物18-10(2.2g,crude)为棕色油状物。LC-MS：m/z 468[M+H] + 18-9 (1.6 g, 7.7 mmol) and M1 (1.8 g, 6.4 mmol) were added to a dry round-bottomed flask to dissolve with MeCN (40 mL), the system was cooled to -30 degrees Celsius, and SnCl 4 (1.7 g) was added dropwise. , 6.4 mmol, 747.9 μL), reacted for 1 hour, monitored by LC-MS. After the reaction, saturated sodium bicarbonate solution was added, extracted with DCM for 3 times, the combined organic phases were washed with saturated brine respectively, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the product that can be used in the next step without further Purification gave the product 18-10 (2.2 g, crude) as a brown oil. LC-MS: m/z 468 [M+H] +
步骤8、化合物18-11的合成Step 8. Synthesis of compounds 18-11
按照实施例14中步骤5的合成方法，将步骤5中14-7替换为18-10，合成方法相同，得到产物18-11(0.6g,crude)为白色固体。LC-MS：m/z 338[M+H] +。 According to the synthesis method of step 5 in Example 14, 14-7 in step 5 was replaced with 18-10, the synthesis method was the same, and the product 18-11 (0.6 g, crude) was obtained as a white solid. LC-MS: m/z 338 [M+H] + .
化合物18-11可拆分为：Compounds 18-11 can be resolved into:
Figure PCTCN2022077312-appb-000072
Figure PCTCN2022077312-appb-000072
步骤9、化合物18-12的合成Step 9. Synthesis of compounds 18-12
按照实施例5中步骤9的合成方法，将步骤9中5-9替换为18-11，合成方法相同，得到产物18-12(55.6mg,crude)为白色固体。LC-MS：m/z 584[M+H] +。 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 18-11, the synthesis method was the same, and the product 18-12 (55.6 mg, crude) was obtained as a white solid. LC-MS: m/z 584 [M+H] + .
步骤10、化合物18的合成Step 10. Synthesis of compound 18
按照实施例15中步骤3的合成方法，将步骤3中15-2替换为18-12，合成方法相同，得到产物18(8mg)为白色固体。LC-MS：m/z 494.2[M+H] +。 According to the synthesis method of step 3 in Example 15, replace 15-2 in step 3 with 18-12, the synthesis method is the same, and the product 18 (8 mg) is obtained as a white solid. LC-MS: m/z 494.2 [M+H] + .
1H NMR(600MHz,DMSO-d 6)δ11.29(s,1H),7.56(d,J＝7.8Hz,1H),7.54-7.49(m,1H),7.42-7.34(m,1H),7.12-7.05(m,1H),7.03(d,J＝8.0Hz,1H),6.94(d,J＝7.8Hz,1H),6.89-6.84(m,1H),5.76(s,1H),5.72-5.66(m, 2H),5.61(d,J＝7.8Hz,1H),4.14(d,J＝13.8Hz,1H),3.88(d,J＝11.6Hz,1H),3.36(d,J＝11.6Hz,1H),1.88-1.81(m,1H),1.51-1.45(m,1H),0.67-0.61(m,1H),0.55-0.49(m,1H),0.47-0.37(m,2H). 1 H NMR (600MHz, DMSO-d 6 ) δ 11.29(s, 1H), 7.56(d, J=7.8Hz, 1H), 7.54-7.49(m, 1H), 7.42-7.34(m, 1H), 7.12-7.05(m,1H),7.03(d,J=8.0Hz,1H),6.94(d,J=7.8Hz,1H),6.89-6.84(m,1H),5.76(s,1H),5.72 -5.66(m, 2H), 5.61(d, J=7.8Hz, 1H), 4.14(d, J=13.8Hz, 1H), 3.88(d, J=11.6Hz, 1H), 3.36(d, J= 11.6Hz,1H),1.88-1.81(m,1H),1.51-1.45(m,1H),0.67-0.61(m,1H),0.55-0.49(m,1H),0.47-0.37(m,2H) .
化合物18可拆分为以下4个异构体：Compound 18 can be resolved into the following 4 isomers:
Figure PCTCN2022077312-appb-000073
Figure PCTCN2022077312-appb-000073
实施例19、((4'-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-8',10'-二氧-3a',4',8',10'-四氢-1'H,3'H-螺环[环丙烷-1,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-9'-基)氧基)甲基碳酸甲酯(化合物19)的合成Example 19, ((4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-8',10'-dioxo-3a', 4',8',10'-tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1 Synthesis of ,2,4]triazine]-9'-yl)oxy)methyl methyl carbonate (compound 19)
Figure PCTCN2022077312-appb-000074
Figure PCTCN2022077312-appb-000074
步骤1、化合物19的合成Step 1. Synthesis of compound 19
按照实施例9中步骤1的合成方法，将步骤1中的6替换为18，合成方法相同，得到产物19(2.1mg)。LC-MS：m/z 582.5[M+H] +。 According to the synthesis method of step 1 in Example 9, replace 6 in step 1 with 18, and the synthesis method is the same to obtain product 19 (2.1 mg). LC-MS: m/z 582.5 [M+H] + .
1H NMR(600MHz,DMSO-d 6)δ7.67(d,J＝7.8Hz,1H),7.57-7.51(m,1H),7.42-7.34(m,1H),7.14-7.08(m,1H),7.06-7.01(m,1H),6.97-6.92(m,1H),6.91-6.87(m,1H),5.82(d,J＝7.8Hz,1H),5.72-5.62(m,3H),5.56-5.50(m,2H),4.15(d,J＝13.8Hz,1H),3.95(d,J＝11.6Hz,1H),3.74(s,3H),3.28-3.19(m,1H),1.84(dd,J＝12.8,9.7Hz,1H),1.52(dd,J＝12.8,6.8Hz,1H),0.67-0.61(m,1H),0.53-0.47(m,1H),0.44-0.36(m,2H). 1 H NMR (600MHz, DMSO-d 6 ) δ 7.67(d, J=7.8Hz, 1H), 7.57-7.51(m, 1H), 7.42-7.34(m, 1H), 7.14-7.08(m, 1H) ),7.06-7.01(m,1H),6.97-6.92(m,1H),6.91-6.87(m,1H),5.82(d,J=7.8Hz,1H),5.72-5.62(m,3H), 5.56-5.50(m, 2H), 4.15(d, J=13.8Hz, 1H), 3.95(d, J=11.6Hz, 1H), 3.74(s, 3H), 3.28-3.19(m, 1H), 1.84 (dd,J＝12.8,9.7Hz,1H),1.52(dd,J＝12.8,6.8Hz,1H),0.67-0.61(m,1H),0.53-0.47(m,1H),0.44-0.36(m , 2H).
实施例20、(((R)-4'-((S)-7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-8',10'-二氧-3a',4',8',10'-四氢-1'H,3'H-螺环[环丙烷-1,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-9'-基)氧基)甲基碳酸甲酯(化合物20)的合成Example 20, (((R)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-8',10 '-Dioxo-3a',4',8',10'-tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[ Synthesis of 2,1-c][1,2,4]triazine]-9'-yl)oxy)methylcarbonate (Compound 20)
Figure PCTCN2022077312-appb-000075
Figure PCTCN2022077312-appb-000075
步骤1、化合物20的合成Step 1. Synthesis of compound 20
按照实施例9中步骤1的合成方法，将步骤1中的6替换为Isomer 18-3，合成方法相同，得到产物20(2.5mg)。LC-MS：m/z 582.5[M+H] +。 According to the synthesis method of step 1 in Example 9, replace 6 in step 1 with Isomer 18-3, and the synthesis method is the same to obtain product 20 (2.5 mg). LC-MS: m/z 582.5 [M+H] + .
1H NMR(600MHz,DMSO-d 6)δ7.69-7.65(m,1H),7.57-7.52(m,1H),7.42-7.35(m,1H),7.13-7.08(m,1H),7.05-7.02(m,1H),6.95-6.92(m,1H),6.91-6.87(m,1H),5.84-5.80(m,1H),5.72-5.67(m,2H),5.67-5.63(m,1H),5.56-5.50(m,2H),4.15(d,J＝13.8Hz,1H),3.95(d,J＝11.6Hz,1H),3.74(s,3H),3.22(d,J＝11.6Hz,1H),1.87-1.81(m,1H),1.55-1.48(m,1H),0.64(d,J＝9.8Hz,1H),0.50(d,J＝9.5Hz,1H),0.40(d,J＝2.6Hz,2H). 1 H NMR (600MHz, DMSO-d 6 ) δ 7.69-7.65(m,1H), 7.57-7.52(m,1H), 7.42-7.35(m,1H), 7.13-7.08(m,1H), 7.05 -7.02(m,1H),6.95-6.92(m,1H),6.91-6.87(m,1H),5.84-5.80(m,1H),5.72-5.67(m,2H),5.67-5.63(m, 1H), 5.56-5.50(m, 2H), 4.15(d, J=13.8Hz, 1H), 3.95(d, J=11.6Hz, 1H), 3.74(s, 3H), 3.22(d, J=11.6 Hz,1H),1.87-1.81(m,1H),1.55-1.48(m,1H),0.64(d,J=9.8Hz,1H),0.50(d,J=9.5Hz,1H),0.40(d , J=2.6Hz, 2H).
实施例21、(((S)-4'-((S)-7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-8',10'-二氧-3a',4',8',10'-四氢-1'H,3'H-螺环[环丙烷-1,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-9'-基)氧基)甲基碳酸甲酯(化合物21)的合成Example 21, (((S)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-8',10 '-Dioxo-3a',4',8',10'-tetrahydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[ Synthesis of 2,1-c][1,2,4]triazine]-9'-yl)oxy)methylcarbonate (Compound 21)
Figure PCTCN2022077312-appb-000076
Figure PCTCN2022077312-appb-000076
步骤1、化合物21的合成Step 1. Synthesis of compound 21
按照实施例9中步骤1的合成方法，将步骤1中的6替换为Isomer 18-1，合成方法相同，得到产物21(3mg)。LC-MS：m/z 582.5[M+H] +。 According to the synthesis method of step 1 in Example 9, replace 6 in step 1 with Isomer 18-1, and the synthesis method is the same to obtain product 21 (3 mg). LC-MS: m/z 582.5 [M+H] + .
1H NMR(600MHz,DMSO-d 6)δ7.70-7.64(m,1H),7.58-7.50(m,1H),7.43-7.34(m,1H),7.14-7.08(m,1H),7.06-7.01(m,1H),6.97-6.92(m,1H),6.91-6.86(m,1H),5.83-5.80(m,1H),5.72-5.67(m,2H),5.67-5.62(m,1H),5.56-5.50(m,2H),4.15(d,J＝13.8Hz,1H),3.95(d,J＝11.6Hz,1H),3.74(s,3H),3.22(d,J＝11.6Hz,1H),1.87-1.79(m,1H),1.55-1.47(m,1H),0.67-0.62(m,1H),0.53-0.48(m,1H),0.43-0.37(m,2H). 1 H NMR (600MHz, DMSO-d 6 )δ7.70-7.64(m,1H), 7.58-7.50(m,1H), 7.43-7.34(m,1H), 7.14-7.08(m,1H), 7.06 -7.01(m,1H),6.97-6.92(m,1H),6.91-6.86(m,1H),5.83-5.80(m,1H),5.72-5.67(m,2H),5.67-5.62(m, 1H), 5.56-5.50(m, 2H), 4.15(d, J=13.8Hz, 1H), 3.95(d, J=11.6Hz, 1H), 3.74(s, 3H), 3.22(d, J=11.6 Hz,1H),1.87-1.79(m,1H),1.55-1.47(m,1H),0.67-0.62(m,1H),0.53-0.48(m,1H),0.43-0.37(m,2H).
实施例22、4'-(6,11-二氢二苯并[b,e]噻吩-11-基)-9'-羟基-3a',4'-二氢-1'H,3'H-螺环[环丙烷-1,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物22)的合成Example 22, 4'-(6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9'-hydroxy-3a',4'-dihydro-1'H,3'H - Spiro[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 22) Synthesis
Figure PCTCN2022077312-appb-000077
Figure PCTCN2022077312-appb-000077
步骤1、化合物22-1的合成Step 1. Synthesis of compound 22-1
按照实施例8中步骤4的合成方法，将步骤4中的2-10替换为18-11，合成方法相同，得到产物22-1(53.6mg)。LC-MS：m/z 548[M+H] +。 According to the synthesis method of step 4 in Example 8, 2-10 in step 4 was replaced with 18-11, and the synthesis method was the same to obtain product 22-1 (53.6 mg). LC-MS: m/z 548 [M+H] + .
步骤2、化合物22的合成Step 2. Synthesis of compound 22
按照实施例8中步骤5的合成方法，将步骤5中的8-5替换为22-1，合成方法相同，得到产物22(5mg)。LC-MS：m/z 458.2[M+H] +。 According to the synthesis method of step 5 in Example 8, 8-5 in step 5 was replaced with 22-1, and the synthesis method was the same to obtain product 22 (5 mg). LC-MS: m/z 458.2 [M+H] + .
实施例23、4'-(2-氯-5,11-二氢二苯并[6,7]噻唑[3,4-b]吡啶-5-基)-9'-羟基-3a',4'-二氢-1'H,3'H-螺环[环丙烷-1,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物23)的合成Example 23, 4'-(2-chloro-5,11-dihydrodibenzo[6,7]thiazo[3,4-b]pyridin-5-yl)-9'-hydroxy-3a',4 '-Dihydro-1'H,3'H-spiro[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine Synthesis of ]-8',10'-dione (Compound 23)
Figure PCTCN2022077312-appb-000078
Figure PCTCN2022077312-appb-000078
步骤1、化合物23-2的合成Step 1. Synthesis of compound 23-2
在干燥的圆底烧瓶中加入23-1(12.3g,100mmol)、AIBN(820.0mg,5mmol)和NBS(17.8g,100mmol)用CCl 4(200mL)溶解，氮气保护下，将体系升温至80摄氏度，反应18小时，LC-MS监测。反应结束后，待体系恢复到室温，有机溶剂减压浓缩，得到产物可直接用于下步反应，无需进一步纯化，得到产物23-2(20g,crude)。LC-MS：m/z 203[M+H] + In a dry round-bottomed flask, 23-1 (12.3 g, 100 mmol), AIBN (820.0 mg, 5 mmol) and NBS (17.8 g, 100 mmol) were added and dissolved with CCl 4 (200 mL), and the system was heated to 80 under nitrogen protection. Celsius, the reaction was carried out for 18 hours and monitored by LC-MS. After the reaction was completed, after the system was returned to room temperature, the organic solvent was concentrated under reduced pressure, and the obtained product could be directly used in the next reaction without further purification to obtain the product 23-2 (20 g, crude). LC-MS: m/z 203[M+H] +
步骤2、化合物23-4的合成Step 2. Synthesis of compound 23-4
在干燥的圆底烧瓶中加入23-2(30g,148.5mmol)、23-3(25g,148.5mmol)和碳酸钾(41g,296.0mmol)用DMF(150mL)溶解，0摄氏度下搅拌反应1小时，LC-MS监测。反应结束后，待体系恢复到室温，加入水和乙酸乙酯萃取3次，合并有机相，用无水硫酸钠干燥后，减压浓缩得到粗产物23-4(40g,crude)。LC-MS：m/z 290[M+H] + In a dry round-bottomed flask, 23-2 (30 g, 148.5 mmol), 23-3 (25 g, 148.5 mmol) and potassium carbonate (41 g, 296.0 mmol) were added and dissolved in DMF (150 mL), and the reaction was stirred at 0 degrees Celsius for 1 hour , LC-MS monitoring. After the reaction, when the system returned to room temperature, water and ethyl acetate were added for extraction 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 23-4 (40 g, crude). LC-MS: m/z 290 [M+H] +
步骤3、化合物23-5的合成Step 3. Synthesis of compound 23-5
在干燥的圆底烧瓶中加入23-4(40g,138.2mmol)和氢氧化钠(2.2g,55.3mmol)用甲醇(150mL)溶解，80摄氏度下搅拌反应18小时，LC-MS监测。反应结束后，待体系恢复到室温，0摄氏度下加入1N HCl溶液调节至pH＝3，加入乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压浓缩后用中压反相制备柱纯化得到产物23-5(35g)。LC-MS：m/z 276[M+H] + In a dry round-bottomed flask, 23-4 (40 g, 138.2 mmol) and sodium hydroxide (2.2 g, 55.3 mmol) were added and dissolved in methanol (150 mL). The reaction was stirred at 80 degrees Celsius for 18 hours, and monitored by LC-MS. After the reaction, when the system was returned to room temperature, 1N HCl solution was added at 0 degrees Celsius to adjust to pH=3, ethyl acetate was added for extraction 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification with a medium pressure reverse phase preparative column gave the product 23-5 (35 g). LC-MS: m/z 276 [M+H] +
步骤4、化合物23-6的合成Step 4. Synthesis of compound 23-6
在干燥的圆底烧瓶中加入23-5(13g,47.2mmol)，LiCl(12g,283.3mmol)，和TsOH(14.8g,283.3mmol)用DMF(150mL)溶解，120摄氏度下搅拌反应12小时，LC-MS监测。反应结束后，待体系恢复到室温，加入水和乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压浓缩后用中压反相制备柱纯化得到产物23-6(10.8g)。LC-MS：m/z 262[M+H] + In a dry round-bottomed flask, 23-5 (13 g, 47.2 mmol), LiCl (12 g, 283.3 mmol), and TsOH (14.8 g, 283.3 mmol) were added with DMF (150 mL) to dissolve, and the reaction was stirred at 120 degrees Celsius for 12 hours, LC-MS monitoring. After the reaction, when the system was returned to room temperature, water and ethyl acetate were added for extraction 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain product 23 -6 (10.8 g). LC-MS: m/z 262 [M+H] +
步骤5、化合物23-7的合成Step 5. Synthesis of compound 23-7
在干燥的圆底烧瓶中加入23-6(5.4g,20.7mmol)用PPA(100mL)溶解，120摄氏度下搅拌反应18小时，LC-MS监测。反应结束后，待体系降温到0摄氏度，加入水和乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压浓缩后用中压反相制备柱纯化得到产物23-7(2.8g)。LC-MS：m/z248[M+H] + In a dry round-bottomed flask, 23-6 (5.4 g, 20.7 mmol) was added to dissolve with PPA (100 mL), and the reaction was stirred at 120 degrees Celsius for 18 hours, and monitored by LC-MS. After the reaction was completed, after the system was cooled to 0 degrees Celsius, water and ethyl acetate were added for extraction 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain the product. 23-7 (2.8 g). LC-MS: m/z248[M+H] +
步骤6、化合物23-8的合成Step 6. Synthesis of compound 23-8
在干燥的圆底烧瓶中加入23-7(520mg,2.1mmol)，用DMF(5mL)溶解，0摄氏度下加入PCl 3(577.5mg,4.2mmol,366.9μL)，110摄氏度下搅拌反应2小时，LC-MS监测。反应结束后，待体系恢复到室温，加入冰水和乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压浓缩后用中压反相制备柱纯化得到产物23-8(130mg)。LC-MS：m/z 266[M+H] + 23-7 (520 mg, 2.1 mmol) was added to a dry round-bottomed flask, dissolved in DMF (5 mL), PCl 3 (577.5 mg, 4.2 mmol, 366.9 μL) was added at 0 degrees Celsius, and the reaction was stirred at 110 degrees Celsius for 2 hours, LC-MS monitoring. After the reaction, when the system was returned to room temperature, ice water and ethyl acetate were added for extraction 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain the product. 23-8 (130 mg). LC-MS: m/z 266[M+H] +
步骤7、化合物23-9的合成Step 7. Synthesis of compound 23-9
在干燥的圆底烧瓶中加入23-8(130mg,489.2μmol)，用甲醇(3mL)溶解，0摄氏度下加入硼氢化钠(92.5mg,2.5mmol)，110摄氏度下搅拌反应2小时，LC-MS监测。反应结束后，待体系恢复到室温，加入冰水和乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压浓缩后用中压反相制备柱纯化得到产物23-9(120mg)。LC-MS：m/z 268[M+H] + 23-8 (130 mg, 489.2 μmol) was added to a dry round-bottomed flask, dissolved in methanol (3 mL), sodium borohydride (92.5 mg, 2.5 mmol) was added at 0 degrees Celsius, and the reaction was stirred at 110 degrees Celsius for 2 hours. MS monitoring. After the reaction, when the system was returned to room temperature, ice water and ethyl acetate were added for extraction 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain the product. 23-9 (120 mg). LC-MS: m/z 268 [M+H] +
步骤8、化合物23-10的合成Step 8. Synthesis of compound 23-10
在干燥的圆底烧瓶中加入23-9(20mg,74.7μmol)，用T 3P(0.5mL)溶解，加入18-11(92.5mg,2.5mmol)，110摄氏度下搅拌反应2小时，LC-MS监测。反应结束后，待体系恢复到室温，加入冰水和乙酸乙酯萃取3次，合并有机相，用饱和食盐水洗，无水硫酸钠干燥，减压浓缩后用中压反相制备柱纯化得到产物23-10(20mg)。LC-MS：m/z 588[M+H] + In a dry round-bottomed flask, 23-9 (20 mg, 74.7 μmol) was added, dissolved with T 3 P (0.5 mL), 18-11 (92.5 mg, 2.5 mmol) was added, and the reaction was stirred at 110 degrees Celsius for 2 hours, LC- MS monitoring. After the reaction, when the system was returned to room temperature, ice water and ethyl acetate were added for extraction 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain the product. 23-10 (20 mg). LC-MS: m/z 588 [M+H] +
步骤9、化合物23的合成Step 9. Synthesis of compound 23
在干燥的圆底烧瓶中加入23-10(40mg,68.1μmol)，用DMA(1mL)溶解，加入LiCl(2.9mg,68.1μmol)，80摄氏度下搅拌反应3小时后反应结束后，将体系降温至0摄氏度，加入丙酮(1mL)和1N HCl，0摄氏度下搅拌1小时，LC-MS监测。反应结束后，减压浓缩，用中压反相制备柱纯化得到产物23(5mg)。LC-MS：m/z 493.2[M+H] + 23-10 (40 mg, 68.1 μmol) was added to a dry round-bottomed flask, dissolved in DMA (1 mL), LiCl (2.9 mg, 68.1 μmol) was added, and the reaction was stirred at 80 degrees Celsius for 3 hours. After the reaction was completed, the system was cooled down. To 0 degrees Celsius, acetone (1 mL) and 1N HCl were added, stirred at 0 degrees Celsius for 1 hour, and monitored by LC-MS. After the reaction was completed, it was concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain the product 23 (5 mg). LC-MS: m/z 493.2 [M+H] +
1H NMR(600MHz,DMSO-d 6)δ7.54(d,J＝8.4Hz,1H),7.51(d,J＝8.4Hz,1H),7.12-7.09(m,1H),7.05-7.04(m,1H),6.96-6.94(m,1H),6.89-6.85(m,1H),6.53(s,1H),5.92(d,J＝12.0Hz,1H),5.69-5.67(m,1H),5.56(d,J＝7.8Hz,1H),3.94(d,J＝12.0Hz,,1H),2.99(s,2H),1.76(t,J＝11.4Hz,1H),1.49-1.47(m,1H),0.66-0.63(m, 1H),0.53-0.41(m,4H). 1 H NMR (600MHz, DMSO-d 6 ) δ 7.54 (d, J=8.4Hz, 1H), 7.51 (d, J=8.4Hz, 1H), 7.12-7.09 (m, 1H), 7.05-7.04 ( m,1H),6.96-6.94(m,1H),6.89-6.85(m,1H),6.53(s,1H),5.92(d,J＝12.0Hz,1H),5.69-5.67(m,1H) ,5.56(d,J＝7.8Hz,1H),3.94(d,J＝12.0Hz,,1H),2.99(s,2H),1.76(t,J＝11.4Hz,1H),1.49-1.47(m ,1H),0.66-0.63(m,1H),0.53-0.41(m,4H).
实施例24、4-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-9-羟基-2,2-二甲基-2,3,3a,4-四氢-1H-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪-8,10-二酮(化合物24)的合成Example 24, 4-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9-hydroxy-2,2-dimethyl-2,3 Synthesis of ,3a,4-tetrahydro-1H-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine-8,10-dione (Compound 24)
Figure PCTCN2022077312-appb-000079
Figure PCTCN2022077312-appb-000079
步骤1、化合物24-3的合成Step 1. Synthesis of compound 24-3
按照实施例14中步骤1的合成方法，将步骤1中的14-1替换为24-1，合成方法相同，得到产物24-3(3.9g)LC-MS：m/z 198[M+H] +。 According to the synthesis method of step 1 in Example 14, replace 14-1 in step 1 with 24-1, and the synthesis method is the same to obtain product 24-3 (3.9g) LC-MS: m/z 198 [M+H ] + .
步骤2、化合物24-4的合成Step 2. Synthesis of compound 24-4
按照实施例14中步骤2的合成方法，将步骤2中的14-3替换为24-3，合成方法相同，得到产物24-4(2.7g)LC-MS：m/z 200[M+H] +。 According to the synthetic method of step 2 in Example 14, replace 14-3 in step 2 with 24-3, and the synthetic method is the same to obtain product 24-4 (2.7 g) LC-MS: m/z 200 [M+H ] + .
步骤3、化合物24-5的合成Step 3. Synthesis of compound 24-5
按照实施例14中步骤3的合成方法，将步骤3中的14-4替换为24-4，合成方法相同，得到产物24-5(2.6g)LC-MS：m/z 214[M+H] +。 According to the synthesis method of step 3 in Example 14, replace 14-4 in step 3 with 24-4, and the synthesis method is the same to obtain product 24-5 (2.6g) LC-MS: m/z 214 [M+H ] + .
步骤4、化合物24-6的合成Step 4. Synthesis of compound 24-6
按照实施例14中步骤4的合成方法，将步骤4中的14-5替换为24-5，合成方法相同，得到产物24-6(4.3g)LC-MS：m/z 470[M+H] +。 According to the synthesis method of step 4 in Example 14, replace 14-5 in step 4 with 24-5, and the synthesis method is the same to obtain product 24-6 (4.3g) LC-MS: m/z 470 [M+H ] + .
步骤5、化合物24-7的合成Step 5. Synthesis of compound 24-7
按照实施例14中步骤5的合成方法，将步骤5中的14-7替换为24-6，合成方法相同，得到产物24-7(4.3g)LC-MS：m/z 340[M+H] +。 According to the synthesis method of step 5 in Example 14, replace 14-7 in step 5 with 24-6, and the synthesis method is the same to obtain the product 24-7 (4.3g) LC-MS: m/z 340 [M+H ] + .
步骤6、化合物24-8的合成Step 6. Synthesis of compound 24-8
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为24-7，合成方法相同，得到产物24-8(54.2mg)LC-MS：m/z 586[M+H] +。 According to the synthetic method of step 9 in Example 5, replace 5-9 in step 9 with 24-7, and the synthetic method is the same to obtain the product 24-8 (54.2 mg) LC-MS: m/z 586 [M+H ] + .
步骤7、化合物24的合成Step 7. Synthesis of compound 24
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为24-8，合成方法相同，得到产物24(8mg)为白色固体。LC-MS：m/z 496.3[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 24-8, the synthesis method was the same, and the product 24 (8 mg) was obtained as a white solid. LC-MS: m/z 496.3 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.56-7.47(m,2H),7.43-7.31(m,1H),7.14-7.05(m,1H),7.03(d,J＝7.8Hz,1H),6.94-6.81(m,2H),5.74-5.56(m,4H),4.14(d,J＝13.8Hz,1H),3.58(d,J＝11.8Hz,1H),3.45(d,J＝11.8Hz,1H),1.73-1.62(m,1H),1.45-1.32(m,1H),0.98(s,3H),0.91(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.56-7.47(m, 2H), 7.43-7.31(m, 1H), 7.14-7.05(m, 1H), 7.03(d, J=7.8Hz, 1H ), 6.94-6.81(m, 2H), 5.74-5.56(m, 4H), 4.14(d, J=13.8Hz, 1H), 3.58(d, J=11.8Hz, 1H), 3.45(d, J= 11.8Hz, 1H), 1.73-1.62(m, 1H), 1.45-1.32(m, 1H), 0.98(s, 3H), 0.91(s, 3H).
实施例25、((4-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-2,2-二甲基-8,10-二氧-2,3,3a,4,8,10-六氢化-1H-吡 啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪-9-基)氧基)甲基碳酸甲酯(化合物25)的合成Example 25, ((4-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-2,2-dimethyl-8,10-di Oxy-2,3,3a,4,8,10-hexahydro-1H-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazin-9-yl) Synthesis of Oxy)methyl Methyl Carbonate (Compound 25)
Figure PCTCN2022077312-appb-000080
Figure PCTCN2022077312-appb-000080
步骤1、化合物25的合成Step 1. Synthesis of compound 25
按照实施例9中步骤1的合成方法，将步骤1中的6替换为24，合成方法相同，得到产物25(3.2mg)。LC-MS：m/z 584.5[M+H] +。 According to the synthesis method of step 1 in Example 9, 6 in step 1 was replaced by 24, and the synthesis method was the same to obtain product 25 (3.2 mg). LC-MS: m/z 584.5 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.63(d,J＝7.8Hz,1H),7.57-7.48(m,1H),7.43-7.31(m,1H),7.15-7.05(m,1H),7.04(d,J＝7.6Hz,1H),6.94-6.84(m,2H),5.82(d,J＝7.8Hz,1H),5.79-5.64(m,2H),5.65-5.54(m,1H),5.54(d,J＝6.6Hz,1H),5.37(s,1H),4.15(d,J＝13.8Hz,1H),3.75(s,3H),3.53-3.41(m,2H),1.73-1.63(m,1H),1.44-1.33(m,1H),0.96(s,3H),0.90(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.63(d, J=7.8Hz, 1H), 7.57-7.48(m, 1H), 7.43-7.31(m, 1H), 7.15-7.05(m, 1H) ), 7.04(d, J=7.6Hz, 1H), 6.94-6.84(m, 2H), 5.82(d, J=7.8Hz, 1H), 5.79-5.64(m, 2H), 5.65-5.54(m, 1H), 5.54(d, J=6.6Hz, 1H), 5.37(s, 1H), 4.15(d, J=13.8Hz, 1H), 3.75(s, 3H), 3.53-3.41(m, 2H), 1.73-1.63(m,1H),1.44-1.33(m,1H),0.96(s,3H),0.90(s,3H).
实施例26、1-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-5-羟基-1H-吡啶并[1,2-b]哒嗪-2,4,6(3H)-三酮(化合物26)的合成Example 26, 1-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-5-hydroxy-1H-pyrido[1,2-b] Synthesis of Pyridazine-2,4,6(3H)-trione (Compound 26)
Figure PCTCN2022077312-appb-000081
Figure PCTCN2022077312-appb-000081
步骤1、化合物26-3的合成Step 1. Synthesis of compound 26-3
在干燥的圆底烧瓶中加入26-1(10g,40.6mmol)用THF(150mL)溶解,0摄氏度和氮气保护下加入CDI(7.9g,48.7mmol)，将体系控制在10摄氏度反应1小时后加入26-2(13.8g,81.2mmol)和MgCl 2(9.7g,101.5mmol)，LC-MS监测。反应结束后，待体系恢复到室温，有机溶剂减压浓缩，残余杂质经用中压反相制备柱纯化得到产物26-3(5.1g)，为黄色油状物。LC-MS：m/z 317[M+H] + 26-1 (10 g, 40.6 mmol) was added to a dry round-bottomed flask, dissolved in THF (150 mL), CDI (7.9 g, 48.7 mmol) was added at 0 degrees Celsius and under nitrogen protection, and the system was controlled at 10 degrees Celsius and reacted for 1 hour. 26-2 (13.8 g, 81.2 mmol) and MgCl2 (9.7 g, 101.5 mmol) were added and monitored by LC-MS. After the reaction, when the system returned to room temperature, the organic solvent was concentrated under reduced pressure, and the residual impurities were purified by a medium-pressure reverse-phase preparative column to obtain the product 26-3 (5.1 g) as a yellow oil. LC-MS: m/z 317 [M+H] +
步骤2、化合物26-4的合成Step 2. Synthesis of compound 26-4
在干燥的圆底烧瓶中加入26-3(1.1g,3.6mmol)、NH 2NHBoc(570.9mg,4.3mmol)和PTSA.Py(2.7g, 10.8mmol)用DMA(15mL)溶解,氮气保护下升温至60摄氏度反应1小时，LC-MS监测。反应结束后，待体系恢复到室温，有机溶剂减压浓缩，残余杂质经用中压反相制备柱纯化得到产物26-4(1.2g)，为浅黄色油状物。LC-MS：m/z 431[M+H] + In a dry round-bottomed flask was added 26-3 (1.1 g, 3.6 mmol), NH 2 NHBoc (570.9 mg, 4.3 mmol) and PTSA.Py (2.7 g, 10.8 mmol) and dissolved with DMA (15 mL), under nitrogen protection The temperature was raised to 60°C for 1 hour, and the reaction was monitored by LC-MS. After the reaction, when the system was returned to room temperature, the organic solvent was concentrated under reduced pressure, and the residual impurities were purified by a medium pressure reverse-phase preparative column to obtain the product 26-4 (1.2 g), which was a pale yellow oil. LC-MS: m/z 431 [M+H] +
步骤3、化合物26-5的合成Step 3. Synthesis of compound 26-5
在干燥的圆底烧瓶中加入26-4(300mg,0.7mmol)用DCM(2mL)溶解，加入TFA(2mL)室温搅拌反应0.5小时，LC-MS监测。反应结束后，有机溶剂减压浓缩，无需进一步纯化，可直接用于下步反应，得到产物26-5(230mg,crude)，为黄色油状物。LC-MS：m/z 331[M+H] + In a dry round-bottomed flask, 26-4 (300 mg, 0.7 mmol) was added, dissolved in DCM (2 mL), TFA (2 mL) was added, and the reaction was stirred at room temperature for 0.5 h, monitored by LC-MS. After the reaction, the organic solvent was concentrated under reduced pressure, without further purification, it was directly used in the next step to obtain the product 26-5 (230 mg, crude) as a yellow oil. LC-MS: m/z 331 [M+H] +
步骤4、化合物26-6和26的合成Step 4. Synthesis of Compounds 26-6 and 26
在干燥的圆底烧瓶中加入26-5(230mg,0.7mmol)、M2(220.8mg,0.8mmol)用ClCH 2CH 2Cl(3.1mL)溶解，加入Cl 2HCCOOH(269.5mg,2.1mmol,172.4μL)，升温至85摄氏度反应1小时，LC-MS监测。反应结束后，待体系恢复到室温，有机溶剂减压浓缩，残余杂质经用中压反相制备柱纯化得到产物26-6(10mg)，LC-MS：m/z 531[M+H] +；26(6.2mg)，LC-MS：m/z 441.1[M+H] + In a dry round-bottomed flask was added 26-5 (230 mg, 0.7 mmol), M2 (220.8 mg, 0.8 mmol) was dissolved with ClCH 2 CH 2 Cl (3.1 mL), and Cl 2 HCCOOH (269.5 mg, 2.1 mmol, 172.4 mmol) was added. μL), the temperature was raised to 85°C for 1 hour and monitored by LC-MS. After the reaction, when the system was returned to room temperature, the organic solvent was concentrated under reduced pressure, and the residual impurities were purified with a medium-pressure reverse-phase preparative column to obtain the product 26-6 (10 mg), LC-MS: m/z 531 [M+H] + ; 26 (6.2 mg), LC-MS: m/z 441.1 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ12.17(s,1H),9.83(s,1H),9.47(s,1H),7.85(d,J＝5.6Hz,1H),7.35(d,J＝7.4Hz,1H),7.32-7.24(m,1H),7.19-7.13(m,1H),7.00-6.93(m,2H),6.88(d,J＝7.4Hz,1H),6.25(d,J＝5.6Hz,1H),5.50(s,1H),4.40(d,J＝14.4Hz,1H),3.92(d,J＝14.4Hz,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 12.17(s, 1H), 9.83(s, 1H), 9.47(s, 1H), 7.85(d, J=5.6Hz, 1H), 7.35(d, J=7.4Hz, 1H), 7.32-7.24(m, 1H), 7.19-7.13(m, 1H), 7.00-6.93(m, 2H), 6.88(d, J=7.4Hz, 1H), 6.25(d , J=5.6Hz, 1H), 5.50(s, 1H), 4.40(d, J=14.4Hz, 1H), 3.92(d, J=14.4Hz, 1H).
实施例27和28、1-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-5-羟基-4-甲氧基-1H-吡啶并[1,2-b]哒嗪-2,6-二酮(化合物27)和1-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-4,5-二羟基-3-甲基-1H-吡啶并[1,2-b]哒嗪-2,6-二酮(化合物28)的合成Examples 27 and 28, 1-(7,8-Difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-5-hydroxy-4-methoxy-1H-pyridine Do[1,2-b]pyridazine-2,6-dione (Compound 27) and 1-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11- yl)-4,5-dihydroxy-3-methyl-1H-pyrido[1,2-b]pyridazine-2,6-dione (Compound 28)
Figure PCTCN2022077312-appb-000082
Figure PCTCN2022077312-appb-000082
步骤1、化合物27-1和28-1的合成Step 1. Synthesis of Compounds 27-1 and 28-1
在干燥的圆底烧瓶中加入26-6(780mg,1.5mmol)用THF(1.7mL)溶解，在0摄氏度下滴加加入TBAF(1M,2.9mL)，搅拌5分钟后加入MeI(835.1mg,5.9mmol,366.3μL)，室温反应18小时，LC-MS监测。反应结束后，待体系恢复到室温，有机溶剂减压浓缩，残余杂质经用中压反相制备柱纯化得到产物27-1(40mg)，为黄色油状物，LC-MS：m/z 545[M+H] +；28-1(60mg)，为黄色油状物，LC-MS：m/z 545[M+H] + 26-6 (780 mg, 1.5 mmol) was added to a dry round-bottomed flask, dissolved in THF (1.7 mL), TBAF (1 M, 2.9 mL) was added dropwise at 0 degrees Celsius, and MeI (835.1 mg, 2.9 mL) was added after stirring for 5 minutes. 5.9 mmol, 366.3 μL), react at room temperature for 18 hours, and monitor by LC-MS. After the reaction, when the system was returned to room temperature, the organic solvent was concentrated under reduced pressure, and the residual impurities were purified by a medium-pressure reverse-phase preparative column to obtain the product 27-1 (40 mg) as a yellow oil, LC-MS: m/z 545[ M+H] + ; 28-1 (60 mg) as yellow oil, LC-MS: m/z 545 [M+H] +
步骤2、化合物27的合成Step 2. Synthesis of compound 27
在干燥的圆底烧瓶中加入27-1(40mg,0.07mmol)和Pd(OH) 2(10mg,0.07mmol)用MeOH(1mL)溶解，H 2置换3次，室温反应18小时，LC-MS监测。反应结束后，过滤，滤液减压浓缩，残余杂质经Prep-HPLC 纯化得到产物27(1.7mg)，为白色固体，LC-MS：m/z 455.2[M+H] + In a dry round-bottomed flask, 27-1 (40 mg, 0.07 mmol) and Pd(OH) 2 (10 mg, 0.07 mmol) were added, dissolved with MeOH (1 mL), replaced by H 3 times, and reacted at room temperature for 18 hours, LC-MS monitor. After the reaction was completed, filtered, the filtrate was concentrated under reduced pressure, and the residual impurities were purified by Prep-HPLC to obtain the product 27 (1.7 mg) as a white solid, LC-MS: m/z 455.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ12.49(s,1H),9.53(s,1H),7.83(d,J＝5.6Hz,1H),7.31(d,J＝7.4Hz,1H),7.28-7.15(m,2H),7.02-6.92(m,2H),6.89(d,J＝7.6Hz,1H),6.24(d,J＝5.4Hz,1H),5.49(s,1H),4.33(d,J＝14.4Hz,1H),3.88(d,J＝14.4Hz,2H),3.64(s,4H). 1 H NMR (400MHz, DMSO-d 6 ) δ 12.49 (s, 1H), 9.53 (s, 1H), 7.83 (d, J=5.6Hz, 1H), 7.31 (d, J=7.4Hz, 1H) ,7.28-7.15(m,2H),7.02-6.92(m,2H),6.89(d,J=7.6Hz,1H),6.24(d,J=5.4Hz,1H),5.49(s,1H), 4.33(d,J＝14.4Hz,1H),3.88(d,J＝14.4Hz,2H),3.64(s,4H).
步骤3、化合物28的合成Step 3. Synthesis of compound 28
在干燥的圆底烧瓶中加入28-1(60mg,0.1mmol)和Pd(OH) 2(10mg,0.07mmol)用MeOH(1mL)溶解，H 2置换3次，室温反应18小时，LC-MS监测。反应结束后，过滤，滤液减压浓缩，残余杂质经Prep-HPLC纯化得到产物28(1.4mg)，为白色固体，LC-MS：m/z 455.2[M+H] + In a dry round-bottomed flask, 28-1 (60 mg, 0.1 mmol) and Pd(OH) 2 (10 mg, 0.07 mmol) were added and dissolved with MeOH (1 mL), replaced by H 3 times, and the reaction was carried out at room temperature for 18 hours. LC-MS monitor. After the reaction, the filtrate was concentrated under reduced pressure, and the residual impurities were purified by Prep-HPLC to obtain the product 28 (1.4 mg) as a white solid, LC-MS: m/z 455.2 [M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.84(s,1H),9.59(s,1H),7.80(s,1H),7.32(d,J＝7.6Hz,1H),7.22-7.13(m,2H),7.00-6.92(m,2H),6.86(d,J＝7.6Hz,1H),6.23(d,J＝5.6Hz,1H),5.35(s,1H),4.45(d,J＝14.4Hz,1H),3.82(d,J＝14.4Hz,1H),3.45(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 9.84(s, 1H), 9.59(s, 1H), 7.80(s, 1H), 7.32(d, J=7.6Hz, 1H), 7.22-7.13( m, 2H), 7.00-6.92(m, 2H), 6.86(d, J=7.6Hz, 1H), 6.23(d, J=5.6Hz, 1H), 5.35(s, 1H), 4.45(d, J =14.4Hz,1H),3.82(d,J=14.4Hz,1H),3.45(s,3H).
实施例29、4-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-9-羟基-3a,4-二氢-1H,3H-螺环[吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪-2,3'-吡咯烷]-8,10-二酮(化合物29)的合成Example 29, 4-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9-hydroxy-3a,4-dihydro-1H,3H- Spiro[pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine-2,3'-pyrrolidine]-8,10-dione (Compound 29) synthesis
Figure PCTCN2022077312-appb-000083
Figure PCTCN2022077312-appb-000083
步骤1、化合物29-2的合成Step 1. Synthesis of compound 29-2
按照实施例5中步骤1的合成方法，将步骤1中的5-1替换为29-1，合成方法相同，得到产物29-2(12.8g)。LC-MS：m/z 256[M+H] +。 According to the synthesis method of step 1 in Example 5, 5-1 in step 1 was replaced with 29-1, and the synthesis method was the same to obtain product 29-2 (12.8 g). LC-MS: m/z 256 [M+H] + .
步骤2、化合物29-3的合成Step 2. Synthesis of compound 29-3
按照实施例5中步骤2的合成方法，将步骤2中的5-2替换为29-2，合成方法相同，得到产物29-3(13g)。LC-MS：m/z 317[M+H] +。 According to the synthesis method of step 2 in Example 5, 5-2 in step 2 was replaced with 29-2, and the synthesis method was the same to obtain product 29-3 (13 g). LC-MS: m/z 317 [M+H] + .
步骤3、化合物29-4的合成Step 3. Synthesis of compound 29-4
按照实施例5中步骤3的合成方法，将步骤3中的5-3替换为29-3，合成方法相同，得到产物29-4(11.5g)。LC-MS：m/z 287[M+H] +。 According to the synthesis method of step 3 in Example 5, 5-3 in step 3 was replaced with 29-3, and the synthesis method was the same to obtain product 29-4 (11.5 g). LC-MS: m/z 287 [M+H] + .
步骤4、化合物29-5的合成Step 4. Synthesis of compound 29-5
在干燥的圆底烧瓶中加入29-4(11.5g,40mmol)和NaOH(1.8g,44.0mmol)用EtOH(100mL)和H 2O(100mL)溶解，升温至50摄氏度，反应过夜，LC-MS监测。反应结束后，有机溶剂减压浓缩，残余杂质经中压反相制备柱纯化得到产物29-5(7.2g)，为浅黄色油状物，LC-MS：m/z 241[M+H] + Add 29-4 (11.5 g, 40 mmol) and NaOH (1.8 g, 44.0 mmol) to a dry round-bottomed flask, dissolve with EtOH (100 mL) and H 2 O (100 mL), warm up to 50 degrees Celsius, react overnight, LC- MS monitoring. After the reaction, the organic solvent was concentrated under reduced pressure, and the residual impurities were purified by a medium-pressure reverse-phase preparative column to obtain the product 29-5 (7.2 g) as a light yellow oil, LC-MS: m/z 241 [M+H] +
步骤5、化合物29-6的合成Step 5. Synthesis of compound 29-6
按照实施例5中步骤4的合成方法，将步骤4中的5-4替换为29-5，合成方法相同，得到产物29-6(9.7g)。LC-MS：m/z 325[M+H] +。 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 29-5, and the synthesis method was the same to obtain product 29-6 (9.7 g). LC-MS: m/z 325 [M+H] + .
步骤6、化合物29-7的合成Step 6. Synthesis of compound 29-7
按照实施例5中步骤5的合成方法，将步骤5中的5-5替换为29-6，合成方法相同，得到产物29-7(7.9g)。LC-MS：m/z 327[M+H] +。 According to the synthesis method of step 5 in Example 5, 5-5 in step 5 was replaced with 29-6, and the synthesis method was the same to obtain product 29-7 (7.9 g). LC-MS: m/z 327 [M+H] + .
步骤7、化合物29-8的合成Step 7. Synthesis of compound 29-8
按照实施例5中步骤6的合成方法，将步骤6中的5-6替换为29-7，合成方法相同，得到产物29-8(5.1g)。LC-MS：m/z 341[M+H] +。 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 29-7, and the synthesis method was the same to obtain product 29-8 (5.1 g). LC-MS: m/z 341 [M+H] + .
步骤8、化合物29-9的合成Step 8. Synthesis of compound 29-9
按照实施例5中步骤7的合成方法，将步骤7中的5-7替换为29-8，合成方法相同，得到产物29-9(2g)。LC-MS：m/z 597[M+H] +。 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 29-8, and the synthesis method was the same to obtain product 29-9 (2g). LC-MS: m/z 597 [M+H] + .
步骤9、化合物29-10的合成Step 9. Synthesis of Compounds 29-10
按照实施例5中步骤8的合成方法，将步骤8中的5-8替换为29-9，合成方法相同，得到产物29-10(1.1g)。LC-MS：m/z 467[M+H] +。 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 29-9, and the synthesis method was the same to obtain product 29-10 (1.1 g). LC-MS: m/z 467 [M+H] + .
步骤10、化合物29-11的合成Step 10. Synthesis of Compounds 29-11
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为29-10，合成方法相同，得到产物29-11(100mg)。LC-MS：m/z 613[M+H] +。 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 29-10, and the synthesis method was the same to obtain product 29-11 (100 mg). LC-MS: m/z 613 [M+H] + .
步骤11、化合物29的合成Step 11. Synthesis of compound 29
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为29-11，合成方法相同，得到产物29(10.8mg)。LC-MS：m/z 523.3[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 29-11, and the synthesis method was the same to obtain product 29 (10.8 mg). LC-MS: m/z 523.3 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ9.27(s,2H),7.70(ddt,J＝8.8,5.4,3.0Hz,1H),7.61–7.45(m,2H),7.36(q,J＝8.8Hz,1H),7.15–6.99(m,2H),6.95–6.80(m,1H),5.69(d,J＝16.8Hz,2H),5.60(d,J＝7.6Hz,1H),4.22–4.10(m,2H),3.17(s,2H),2.12–1.87(m,2H),1.63(s,2H),1.41–1.20(m,2H),0.97–0.80(m,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.27 (s, 2H), 7.70 (ddt, J=8.8, 5.4, 3.0 Hz, 1H), 7.61-7.45 (m, 2H), 7.36 (q, J = 8.8Hz, 1H), 7.15–6.99 (m, 2H), 6.95–6.80 (m, 1H), 5.69 (d, J=16.8Hz, 2H), 5.60 (d, J=7.6Hz, 1H), 4.22 –4.10(m, 2H), 3.17(s, 2H), 2.12 – 1.87(m, 2H), 1.63(s, 2H), 1.41 – 1.20(m, 2H), 0.97 – 0.80(m, 2H).
实施例30、1'-乙酰基-4-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-9-羟基-3a,4-二氢-1H,3H-螺环[吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪-2,3'-吡咯烷]-8,10-二酮(化合物30)的合成Example 30, 1'-acetyl-4-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9-hydroxy-3a,4-di Hydro-1H,3H-spiro[pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine-2,3'-pyrrolidine]-8,10-di Synthesis of Ketone (Compound 30)
Figure PCTCN2022077312-appb-000084
Figure PCTCN2022077312-appb-000084
步骤1、化合物30-1的合成Step 1. Synthesis of compound 30-1
在干燥的圆底烧瓶中加入29-11(11.5g,40mmol)、NaHCO 3(0.2mmol)和Ac 2O(13.3mg,0.1mmol) 用THF(1mL)和H 2O(0.5mL)溶解，室温反应1小时，LC-MS监测。反应结束后，有机溶剂减压浓缩，用乙酸乙酯萃取3次，有机相用饱和食盐水洗涤两次，无水硫酸钠干燥后减压浓缩，残余杂质经Prep-HPLC纯化得到产物30-1(20mg)，为黄色油状物，LC-MS：m/z 655[M+H] + In a dry round-bottomed flask was added 29-11 (11.5 g, 40 mmol), NaHCO 3 (0.2 mmol) and Ac 2 O (13.3 mg, 0.1 mmol) and dissolved with THF (1 mL) and H 2 O (0.5 mL), The reaction was carried out for 1 hour at room temperature and monitored by LC-MS. After the reaction, the organic solvent was concentrated under reduced pressure, extracted three times with ethyl acetate, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residual impurities were purified by Prep-HPLC to obtain the product 30-1 (20 mg) as yellow oil, LC-MS: m/z 655 [M+H] +
步骤2、化合物30的合成Step 2. Synthesis of compound 30
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为30-1，合成方法相同，得到产物30(14.8mg)。LC-MS：m/z 565.3[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 30-1, and the synthesis method was the same to obtain product 30 (14.8 mg). LC-MS: m/z 565.3 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ9.14(s,1H),7.52(t,J＝8.4Hz,1H),7.44–7.25(m,2H),7.22–7.06(m,2H),7.03(d,J＝7.6Hz,1H),6.87(t,J＝7.4Hz,1H),5.67(d,J＝5.6Hz,1H),5.61(d,J＝12.6Hz,1H),5.57(d,J＝7.6Hz,1H),4.14(d,J＝14.0Hz,1H),3.74(d,J＝11.8Hz,1H),3.62(d,J＝12.2Hz,1H),2.87(d,J＝64.2Hz,1H),2.67(q,J＝1.8Hz,1H),2.42(s,1H),2.33(p,J＝1.8Hz,2H),1.96(s,1H),1.89(d,J＝4.0Hz,1H),1.85(d,J＝5.4Hz,2H),1.51(d,J＝11.6Hz,1H),1.24(s,2H). 1 H NMR (400MHz, DMSO-d 6 )δ9.14(s,1H),7.52(t,J=8.4Hz,1H),7.44-7.25(m,2H),7.22-7.06(m,2H), 7.03(d,J＝7.6Hz,1H),6.87(t,J＝7.4Hz,1H),5.67(d,J＝5.6Hz,1H),5.61(d,J＝12.6Hz,1H),5.57( d, J=7.6Hz, 1H), 4.14 (d, J=14.0Hz, 1H), 3.74 (d, J=11.8Hz, 1H), 3.62 (d, J=12.2Hz, 1H), 2.87 (d, J=64.2Hz, 1H), 2.67(q, J=1.8Hz, 1H), 2.42(s, 1H), 2.33(p, J=1.8Hz, 2H), 1.96(s, 1H), 1.89(d, J=4.0Hz, 1H), 1.85(d, J=5.4Hz, 2H), 1.51(d, J=11.6Hz, 1H), 1.24(s, 2H).
实施例31、4'-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-9'-羟基-3a',4'-二氢-1'H,3'H-螺环[哌啶-4,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物31)的合成Example 31, 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9'-hydroxy-3a',4'-dihydro- 1'H,3'H-spiro[piperidine-4,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8', Synthesis of 10'-diketone (Compound 31)
Figure PCTCN2022077312-appb-000085
Figure PCTCN2022077312-appb-000085
步骤1、化合物31-3的合成Step 1. Synthesis of compound 31-3
按照实施例5中步骤4的合成方法，将步骤4中的5-4替换为31-1，合成方法相同，得到产物31-3(1.5g)。LC-MS：m/z 339[M+H] +。 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 31-1, and the synthesis method was the same to obtain product 31-3 (1.5 g). LC-MS: m/z 339 [M+H] + .
步骤2、化合物31-4的合成Step 2. Synthesis of compound 31-4
按照实施例5中步骤5的合成方法，将步骤5中的5-5替换为31-3，合成方法相同，得到产物31-4(736mg)。LC-MS：m/z 341[M+H] +。 According to the synthesis method of step 5 in Example 5, 5-5 in step 5 was replaced with 31-3, and the synthesis method was the same to obtain the product 31-4 (736 mg). LC-MS: m/z 341 [M+H] + .
步骤3、化合物31-5的合成Step 3. Synthesis of compound 31-5
按照实施例5中步骤6的合成方法，将步骤6中的5-6替换为31-4，合成方法相同，得到产物31-5(590mg)。LC-MS：m/z 355[M+H] +。 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 31-4, and the synthesis method was the same to obtain product 31-5 (590 mg). LC-MS: m/z 355 [M+H] + .
步骤4、化合物31-6的合成Step 4. Synthesis of compound 31-6
按照实施例5中步骤7的合成方法，将步骤7中的5-7替换为31-5，合成方法相同，得到产物31-6(1g)。LC-MS：m/z 611[M+H] +。 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 31-5, and the synthesis method was the same to obtain product 31-6 (1 g). LC-MS: m/z 611 [M+H] + .
步骤5、化合物31-7的合成Step 5. Synthesis of compound 31-7
按照实施例5中步骤8的合成方法，将步骤8中的5-8替换为31-6，合成方法相同，得到产物31-7(300mg)。LC-MS：m/z 481[M+H] +。 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced by 31-6, and the synthesis method was the same to obtain product 31-7 (300 mg). LC-MS: m/z 481 [M+H] + .
化合物31-7可拆分为：Compound 31-7 can be resolved into:
Figure PCTCN2022077312-appb-000086
Figure PCTCN2022077312-appb-000086
步骤6、化合物31-8的合成Step 6. Synthesis of compound 31-8
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为31-7，合成方法相同，得到产物31-8(30mg)。LC-MS：m/z 627[M+H] +。 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 31-7, and the synthesis method was the same to obtain product 31-8 (30 mg). LC-MS: m/z 627 [M+H] + .
步骤7、化合物31的合成Step 7. Synthesis of compound 31
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为31-8，合成方法相同，得到产物31(1.6mg)。LC-MS：m/z 537.3[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 31-8, and the synthesis method was the same to obtain product 31 (1.6 mg). LC-MS: m/z 537.3 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.66(d,J＝7.6Hz,1H),7.41(t,J＝6.8Hz,1H),7.31(q,J＝8.8Hz,1H),7.13(td,J＝7.2,6.0,2.2Hz,1H),7.06(d,J＝7.8Hz,1H),6.92–6.84(m,2H),5.78–5.67(m,1H),5.64(dd,J＝11.0,6.0Hz,1H),5.54(s,1H),4.17(d,J＝13.8Hz,1H),3.90(s,1H),3.55(d,J＝12.4Hz,1H),3.14–3.04(m,2H),2.95(d,J＝8.2Hz,2H),2.08–1.96(m,1H),1.73(d,J＝14.2Hz,1H),1.60(dd,J＝14.4,6.4Hz,2H),1.44(q,J＝12.4,10.0Hz,2H),1.28–1.15(m,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.66 (d, J=7.6 Hz, 1H), 7.41 (t, J=6.8 Hz, 1H), 7.31 (q, J=8.8 Hz, 1H), 7.13 (td, J=7.2, 6.0, 2.2Hz, 1H), 7.06 (d, J=7.8Hz, 1H), 6.92–6.84 (m, 2H), 5.78–5.67 (m, 1H), 5.64 (dd, J =11.0,6.0Hz,1H),5.54(s,1H),4.17(d,J=13.8Hz,1H),3.90(s,1H),3.55(d,J=12.4Hz,1H),3.14–3.04 (m, 2H), 2.95 (d, J=8.2Hz, 2H), 2.08–1.96 (m, 1H), 1.73 (d, J=14.2Hz, 1H), 1.60 (dd, J=14.4, 6.4Hz, 2H), 1.44(q, J=12.4, 10.0Hz, 2H), 1.28–1.15(m, 1H).
实施例32、1-乙酰基-4'-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-yl)-9'-羟基-3a',4'-二氢-1'H,3'H-螺环[哌啶-4,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物32)的合成Example 32, 1-acetyl-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-3a',4 '-Dihydro-1'H,3'H-spiro[piperidine-4,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine Synthesis of ]-8',10'-dione (Compound 32)
Figure PCTCN2022077312-appb-000087
Figure PCTCN2022077312-appb-000087
步骤1、化合物32-1的合成Step 1. Synthesis of compound 32-1
按照实施例29中步骤1的合成方法，将步骤1中的29-11替换为31-8，合成方法相同，得到产物32-1(20mg)。LC-MS：m/z 669[M+H] +。 According to the synthesis method of step 1 in Example 29, 29-11 in step 1 was replaced with 31-8, and the synthesis method was the same to obtain product 32-1 (20 mg). LC-MS: m/z 669 [M+H] + .
步骤2、化合物32的合成Step 2. Synthesis of compound 32
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为32-1，合成方法相同，得到产物32(1.6mg)。LC-MS：m/z 579.3[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 32-1, and the synthesis method was the same to obtain product 32 (1.6 mg). LC-MS: m/z 579.3 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.66(dd,J＝7.6,3.6Hz,1H),7.38(s,1H),7.33(t,J＝8.8Hz,1H),7.13(t,J＝7.0Hz,1H),7.06(d,J＝7.8Hz,1H),6.87(d,J＝7.6Hz,2H),5.70(t,J＝11.0Hz,2H),5.66–5.60(m,1H),5.52(s,1H),4.18(s,1H),4.14(s,1H),3.90(s,1H),3.87(s,1H),3.50(d,J＝12.8Hz,1H),3.38(s,0H),3.27(d,J＝7.2Hz,2H),2.02(s,0H),1.99(d,J＝6.0Hz,3H),1.96(d,J＝7.2Hz,2H),1.49–1.39(m,1H),1.35(t,J＝7.2Hz,1H),1.03(t,J＝7.2Hz,1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.66 (dd, J=7.6, 3.6 Hz, 1H), 7.38 (s, 1H), 7.33 (t, J=8.8 Hz, 1H), 7.13 (t, J＝7.0Hz, 1H), 7.06(d, J＝7.8Hz, 1H), 6.87(d, J＝7.6Hz, 2H), 5.70(t, J＝11.0Hz, 2H), 5.66–5.60(m, 1H), 5.52(s, 1H), 4.18(s, 1H), 4.14(s, 1H), 3.90(s, 1H), 3.87(s, 1H), 3.50(d, J＝12.8Hz, 1H), 3.38(s, 0H), 3.27(d, J＝7.2Hz, 2H), 2.02(s, 0H), 1.99(d, J＝6.0Hz, 3H), 1.96(d, J＝7.2Hz, 2H), 1.49–1.39(m, 1H), 1.35(t, J=7.2Hz, 1H), 1.03(t, J=7.2Hz, 1H).
化合物32可以产生以下一种异构体：Compound 32 can produce one of the following isomers:
Figure PCTCN2022077312-appb-000088
Figure PCTCN2022077312-appb-000088
实施例33、(12aR)-12-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]八氢[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物33)的合成Example 33, (12aR)-12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-7-hydroxy-3,4,12,12a - Tetrahydro-1H-[1,4]octahydro[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (Compound 33) synthesis
Figure PCTCN2022077312-appb-000089
Figure PCTCN2022077312-appb-000089
步骤1、化合物33-3的合成Step 1. Synthesis of compound 33-3
按照实施例5中步骤4的合成方法，将步骤4中的5-4替换为33-1，合成方法相同，得到产物33-3(8.3g)。LC-MS：m/z 186[M+H] +。 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 33-1, and the synthesis method was the same to obtain product 33-3 (8.3 g). LC-MS: m/z 186 [M+H] + .
步骤2、化合物33-4的合成Step 2. Synthesis of compound 33-4
按照实施例5中步骤5的合成方法，将步骤5中的5-5替换为33-3，合成方法相同，得到产物33-4(7.7g)。LC-MS：m/z 188[M+H] +。 According to the synthesis method of step 5 in Example 5, 5-5 in step 5 was replaced with 33-3, and the synthesis method was the same to obtain product 33-4 (7.7g). LC-MS: m/z 188 [M+H] + .
步骤3、化合物33-5的合成Step 3. Synthesis of compound 33-5
按照实施例5中步骤6的合成方法，将步骤6中的5-6替换为33-4，合成方法相同，得到产物33-5(590mg)。LC-MS：m/z 202[M+H] +。 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 33-4, and the synthesis method was the same to obtain product 33-5 (590 mg). LC-MS: m/z 202 [M+H] + .
步骤4、化合物33-6的合成Step 4. Synthesis of compound 33-6
按照实施例5中步骤7的合成方法，将步骤7中的5-7替换为33-5，合成方法相同，得到产物33-6(4.2g)。LC-MS：m/z 458[M+H] +。 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 33-5, and the synthesis method was the same to obtain product 33-6 (4.2 g). LC-MS: m/z 458 [M+H] + .
步骤5、化合物33-7的合成Step 5. Synthesis of compound 33-7
按照实施例5中步骤8的合成方法，将步骤8中的5-8替换为33-6，合成方法相同，得到产物33-7(1.6g)。LC-MS：m/z 328[M+H] +。 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 33-6, and the synthesis method was the same to obtain product 33-7 (1.6g). LC-MS: m/z 328 [M+H] + .
步骤6、化合物33-8的合成Step 6. Synthesis of compound 33-8
化合物33-8由33-7拆分得到Compound 33-8 was obtained from the resolution of 33-7
步骤7、化合物33-9的合成Step 7. Synthesis of compound 33-9
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为33-8，合成方法相同，得到产物33-9(35mg)。LC-MS：m/z 574[M+H] +。 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 33-8, and the synthesis method was the same to obtain the product 33-9 (35 mg). LC-MS: m/z 574 [M+H] + .
步骤8、化合物33的合成Step 8. Synthesis of compound 33
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为33-9，合成方法相同，得到产物33(10mg)。LC-MS：m/z 484.0[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 33-9, and the synthesis method was the same to obtain product 33 (10 mg). LC-MS: m/z 484.0 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.68-7.50(m,1H),7.46-7.30(m,2H),7.26-7.20(m,1H),7.18-7.12(m,1H),7.10(d,J＝8.2Hz,1H),7.02-6.76(m,1H),5.73(d,J＝25.6Hz,1H),5.60(dd,J＝29.0,7.6Hz,1H),5.52-5.35(m,1H),4.58-4.35(m,2H),4.24-4.02(m,2H),3.98(ddd,J＝9.6,6.4,3.0Hz,1H),3.74-3.56(m,2H),3.04(t,J＝12.4Hz,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.68-7.50 (m, 1H), 7.46-7.30 (m, 2H), 7.26-7.20 (m, 1H), 7.18-7.12 (m, 1H), 7.10 (d, J=8.2Hz, 1H), 7.02-6.76 (m, 1H), 5.73 (d, J=25.6Hz, 1H), 5.60 (dd, J=29.0, 7.6Hz, 1H), 5.52-5.35 ( m,1H),4.58-4.35(m,2H),4.24-4.02(m,2H),3.98(ddd,J=9.6,6.4,3.0Hz,1H),3.74-3.56(m,2H),3.04( t,J=12.4Hz,1H).
实施例34、(12aS)-12-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-7-qiangji-3,4,12,12a-四氢-1H-[1,4]恶嗪[3,4-c]吡咯并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物34)的合成Example 34, (12aS)-12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-7-qiangji-3,4,12,12a - Tetrahydro-1H-[1,4]oxazine[3,4-c]pyrrolo[2,1-f][1,2,4]triazine-6,8-dione (Compound 34) synthesis
Figure PCTCN2022077312-appb-000090
Figure PCTCN2022077312-appb-000090
步骤1、化合物34-1的合成Step 1. Synthesis of compound 34-1
化合物34-1由33-7拆分得到Compound 34-1 was separated from 33-7
步骤2、化合物34-2的合成Step 2. Synthesis of compound 34-2
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为34-1，合成方法相同，得到产物34-2(5mg)。LC-MS：m/z 574[M+H] +。 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 34-1, and the synthesis method was the same to obtain product 34-2 (5 mg). LC-MS: m/z 574 [M+H] + .
步骤3、化合物34的合成Step 3. Synthesis of compound 34
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为34-2，合成方法相同，得到产物34(2mg)。LC-MS：m/z 484.0[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 34-2, and the synthesis method was the same to obtain product 34 (2 mg). LC-MS: m/z 484.0 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.66–7.48(m,1H),7.46–7.30(m,2H),7.27–7.20(m,1H),7.18–7.12(m,1H),7.09(d,J＝8.2Hz,1H),7.00–6.77(m,1H),5.72(d,J＝25.6Hz,1H),5.59(dd,J＝29.0,7.6Hz,1H),5.52–5.35(m,1H),4.57–4.36(m,2H),4.23–4.03(m,2H),3.96(ddd,J＝9.6,6.4,3.0Hz,1H),3.73–3.57(m,2H),3.03(t,J＝12.4Hz,1H). 1 H NMR (400MHz, DMSO-d 6 )δ7.66-7.48(m,1H),7.46-7.30(m,2H),7.27-7.20(m,1H),7.18-7.12(m,1H),7.09 (d, J=8.2Hz, 1H), 7.00–6.77 (m, 1H), 5.72 (d, J=25.6Hz, 1H), 5.59 (dd, J=29.0, 7.6Hz, 1H), 5.52–5.35 ( m, 1H), 4.57–4.36 (m, 2H), 4.23–4.03 (m, 2H), 3.96 (ddd, J=9.6, 6.4, 3.0Hz, 1H), 3.73–3.57 (m, 2H), 3.03 ( t,J=12.4Hz,1H).
实施例35、(((R)-12-((S)-7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-6,8-二氧-3,4,6,8,12,12a-六氢化-1H-[1,4]恶嗪[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-7-基)氧基)甲基碳酸甲酯(化合物35)的合成Example 35, (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-6,8-di Oxy-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]tris Synthesis of oxazin-7-yl)oxy)methyl methyl carbonate (compound 35)
Figure PCTCN2022077312-appb-000091
Figure PCTCN2022077312-appb-000091
步骤1、化合物35-1的合成Step 1. Synthesis of compound 35-1
按照实施例9中步骤1的合成方法，将步骤1中的6替换为33，合成方法相同，得到产物35-1(3.2mg)。LC-MS：m/z 572.3[M+H] +。 According to the synthesis method of step 1 in Example 9, 6 in step 1 was replaced with 33, and the synthesis method was the same to obtain product 35-1 (3.2 mg). LC-MS: m/z 572.3 [M+H] + .
步骤2、化合物35的合成Step 2. Synthesis of compound 35
化合物35由35-1拆分得到。Compound 35 was resolved from 35-1.
1H NMR(400MHz,DMSO-d 6)δ7.47-7.34(m,2H),7.23(d,J＝7.8Hz,1H),7.20-7.11(m,1H),7.13-7.06(m,1H),7.05-6.97(m,1H),6.90-6.81(m,1H),5.76-5.71(m,3H),5.67(d,J＝6.6Hz,1H),5.47-5.38(m,1H),4.50-4.36(m,2H),4.10-3.96(m,2H),3.73(s,3H),3.71-3.65(m,1H),3.50-3.40(m,1H),3.34-3.23(m,1H),3.01-2.89(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.47-7.34 (m, 2H), 7.23 (d, J=7.8Hz, 1H), 7.20-7.11 (m, 1H), 7.13-7.06 (m, 1H) ),7.05-6.97(m,1H),6.90-6.81(m,1H),5.76-5.71(m,3H),5.67(d,J=6.6Hz,1H),5.47-5.38(m,1H), 4.50-4.36(m, 2H), 4.10-3.96(m, 2H), 3.73(s, 3H), 3.71-3.65(m, 1H), 3.50-3.40(m, 1H), 3.34-3.23(m, 1H ),3.01-2.89(m,1H).
实施例36、6-((R)-7-羟基-6,8-二氧-1,3,4,6,8,12a-六氢化-12H-[1,4]恶嗪[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-12-基)-N-甲基-1,1a,6,10b-四氢二苯并[a,e]环丙烷甲酰氯[c][7]环轮烯-1-甲酰胺(化合物36)的合成Example 36, 6-((R)-7-hydroxy-6,8-dioxo-1,3,4,6,8,12a-hexahydro-12H-[1,4]oxazine[3,4 -c]pyrido[2,1-f][1,2,4]triazin-12-yl)-N-methyl-1,1a,6,10b-tetrahydrodibenzo[a,e] Synthesis of Cyclopropanecarbonyl Chloride [c][7]cyclorotaxene-1-carboxamide (Compound 36)
Figure PCTCN2022077312-appb-000092
Figure PCTCN2022077312-appb-000092
步骤1、化合物36的合成Step 1. Synthesis of compound 36
按照实施例12中步骤5的合成方法，将步骤5中的10-1替换为33-8，合成方法相同，得到产物36(4.3mg)。LC-MS：m/z 499.5[M+H] +。 According to the synthesis method of step 5 in Example 12, 10-1 in step 5 was replaced with 33-8, and the synthesis method was the same to obtain product 36 (4.3 mg). LC-MS: m/z 499.5 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ8.22-8.18(m,1H),7.45-7.30(m,5H),7.26-7.22(m,,2H),7.17(d,J＝7.6Hz,1H),6.98-6.92(m,2H),5.50(d,J＝7.6Hz,1H),5.32(s,1H),4.43(dd,J＝13.4,2.4Hz,1H),4.37(dd,J＝10.0,3.2Hz,1H),3.89(dd,J＝10.8,3.2Hz,1H),3.67-3.64(m,2H),3.17-3.13(m,1H),2.97(dd,J＝9.6,4.8Hz,1H),2.85-2.78(m,1H),2.74(d,J＝4.4Hz,3H),1.76(t,J＝4.8Hz,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.22-8.18 (m, 1H), 7.45-7.30 (m, 5H), 7.26-7.22 (m,, 2H), 7.17 (d, J=7.6Hz, 1H), 6.98-6.92(m, 2H), 5.50(d, J=7.6Hz, 1H), 5.32(s, 1H), 4.43(dd, J=13.4, 2.4Hz, 1H), 4.37(dd, J =10.0,3.2Hz,1H),3.89(dd,J=10.8,3.2Hz,1H),3.67-3.64(m,2H),3.17-3.13(m,1H),2.97(dd,J=9.6,4.8 Hz, 1H), 2.85-2.78(m, 1H), 2.74(d, J=4.4Hz, 3H), 1.76(t, J=4.8Hz, 1H).
实施例37、(12aS)-12-(1-溴-3-甲基-6,12-二氢-3H-苯并[6,7]噻吩[4,3-e]吲唑-12-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]恶嗪[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物37)的合成Example 37, (12aS)-12-(1-bromo-3-methyl-6,12-dihydro-3H-benzo[6,7]thiophene[4,3-e]indazol-12-yl )-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]tris Synthesis of oxazine-6,8-dione (compound 37)
Figure PCTCN2022077312-appb-000093
Figure PCTCN2022077312-appb-000093
步骤1、化合物37-2的合成Step 1. Synthesis of compound 37-2
在干燥的圆底烧瓶中加入37-1(1.6g,8.2mmol)、NBS(1.5g,8.2mmol)和AIBN(1.3g,8.2mmol)用CCl 4(50mL)溶解后将体系升温至80摄氏度，氮气保护下反应16小时，LC-MS监测。反应结束后溶剂减压浓缩，无需进一步纯化，可直接用于下步反应，得到产物37-2(3g,crude)为白色固体。LC-MS：m/z 348[M+H] +。 In a dry round-bottomed flask, 37-1 (1.6 g, 8.2 mmol), NBS (1.5 g, 8.2 mmol) and AIBN (1.3 g, 8.2 mmol) were added and dissolved with CCl 4 (50 mL), and the system was heated to 80 degrees Celsius , and reacted under nitrogen protection for 16 hours, monitored by LC-MS. After the reaction, the solvent was concentrated under reduced pressure, and without further purification, it could be directly used in the next step to obtain the product 37-2 (3 g, crude) as a white solid. LC-MS: m/z 348 [M+H] + .
步骤2、化合物37-3的合成Step 2. Synthesis of compound 37-3
在干燥的圆底烧瓶中加入37-2(3g,8.6mmol)加入H 2O(20mL)和苯硫酚钠(0.5M,17.24mL)的THF溶液(20mL)后在15摄氏度下反应0.5小时，LC-MS监测。反应结束后，向体系中加入水(200mL)，用乙酸乙酯萃取，有机相用水合饱和食盐水各洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，残余杂质用柱层析纯化得到产物37-3(700mg)为黄色固体。LC-MS：m/z 378[M+H] +。 In a dry round-bottomed flask, 37-2 (3 g, 8.6 mmol) was added with H 2 O (20 mL) and sodium thiophenate (0.5 M, 17.24 mL) in THF solution (20 mL) and reacted at 15 degrees Celsius for 0.5 h , LC-MS monitoring. After the reaction, water (200 mL) was added to the system, extracted with ethyl acetate, the organic phase was washed twice with hydrated saturated brine each, the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure, and the residual impurities were subjected to column chromatography. Purification gave the product 37-3 (700 mg) as a yellow solid. LC-MS: m/z 378 [M+H] + .
步骤3、化合物37-4的合成Step 3. Synthesis of compound 37-4
在干燥的圆底烧瓶中加入37-3(700mg,1.9mmol)、碘甲烷(316.2mg,2.2mmol,138.7μL)和碳酸铯(1.2g,3.7mmol)用DMF溶液(10mL)溶解后在60摄氏度下反应18小时，LC-MS监测。反应结束后，向体系中加入水(100mL)，用乙酸乙酯萃取3次，有机相用饱和食盐水洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，无需进一步纯化，可直接用于下步反应，得到产物37-4(700mg,crude)为黄色油状物。LC-MS：m/z 392[M+H] +。 In a dry round-bottomed flask, 37-3 (700 mg, 1.9 mmol), iodomethane (316.2 mg, 2.2 mmol, 138.7 μL) and cesium carbonate (1.2 g, 3.7 mmol) were added and dissolved in DMF solution (10 mL) at 60 The reaction was carried out at degrees Celsius for 18 hours and monitored by LC-MS. After the reaction, water (100 mL) was added to the system, extracted three times with ethyl acetate, the organic phase was washed twice with saturated brine, and the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure. Used in the next reaction to give the product 37-4 (700 mg, crude) as a yellow oil. LC-MS: m/z 392 [M+H] + .
步骤4、化合物37-5的合成Step 4. Synthesis of compound 37-5
按照实施例29中步骤4的合成方法，将步骤4中的29-4替换为37-4，合成方法相同，得到产物37-5(500mg)。LC-MS：m/z 378[M+H] +。 According to the synthesis method of step 4 in Example 29, 29-4 in step 4 was replaced with 37-4, and the synthesis method was the same to obtain product 37-5 (500 mg). LC-MS: m/z 378 [M+H] + .
步骤5、化合物37-6的合成Step 5. Synthesis of compound 37-6
在干燥的圆底烧瓶中加入37-5(500mg,1.3mmol)用PPA溶液(15mL)溶解后在100摄氏度下反应过夜，LC-MS监测。反应结束后，向体系中加入冰水，用乙酸乙酯萃取，有机相用水合饱和食盐水各洗涤两次，有机相用无水硫酸钠干燥后减压浓缩，残余杂质用柱层析纯化得到产物37-6(220mg)为白色固体。LC-MS：m/z 360[M+H] +。 In a dry round-bottomed flask, 37-5 (500 mg, 1.3 mmol) was added to dissolve it with PPA solution (15 mL) and reacted at 100 degrees Celsius overnight, monitored by LC-MS. After the reaction, ice water was added to the system, extracted with ethyl acetate, the organic phase was washed twice with hydrated saturated brine, the organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure, and the residual impurities were purified by column chromatography to obtain The product 37-6 (220 mg) was a white solid. LC-MS: m/z 360 [M+H] + .
步骤6、化合物37-7的合成Step 6. Synthesis of compound 37-7
在干燥的圆底烧瓶中加入37-6(220mg,0.6mmol)用甲醇溶液(5mL)溶解后冰浴下加入NaBH 4(231.7mg,6.1mmol)在15摄氏度下反应18小时，LC-MS监测。反应结束后，有机相用减压浓缩，残余杂质用柱层析纯化得到产物37-7(150mg)。LC-MS：m/z 362[M+H] +。 Add 37-6 (220 mg, 0.6 mmol) to a dry round-bottomed flask, dissolve it with methanol solution (5 mL), add NaBH 4 (231.7 mg, 6.1 mmol) under ice bath, and react at 15 degrees Celsius for 18 hours, monitored by LC-MS . After the reaction, the organic phase was concentrated under reduced pressure, and the residual impurities were purified by column chromatography to obtain the product 37-7 (150 mg). LC-MS: m/z 362 [M+H] + .
步骤7、化合物37-8的合成Step 7. Synthesis of compound 37-8
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为34-1，M2替换为37-7，合成方法相同，得到产物37-8(20mg)。LC-MS：m/z 671[M+H] +。 According to the synthetic method of step 9 in Example 5, 5-9 in step 9 was replaced with 34-1, and M2 was replaced with 37-7, and the synthetic method was the same to obtain product 37-8 (20 mg). LC-MS: m/z 671 [M+H] + .
步骤8、化合物37的合成Step 8. Synthesis of compound 37
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为37-8，合成方法相同，得到产物37(14.7mg)。LC-MS：m/z 582.1[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 37-8, and the synthesis method was the same to obtain product 37 (14.7 mg). LC-MS: m/z 582.1 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.83(d,J＝8.6Hz,0.59H),7.75(d,J＝8.6Hz,0.47H),7.64(d,J＝8.6Hz,0.62H),7.58(d,J＝8.6Hz,0.51H),7.50(d,J＝7.6Hz,0.5H),7.35-7.30(m,0.53H),7.25-7.22(m,1.26H),7.17-7.08(m,1.42H),7.03(d,J＝7.6Hz,0.67H),6.94-6.92(m,1H),6.88-6.84(m,1H),5.92(d,J＝14.2Hz,0.49H),5.77(d,J＝13.8Hz,0.55H),5.62(d,J＝7.6Hz,0.57H),5.41(d,J＝7.6Hz,0.47H),4.50-4.46(m,1.06H),4.43-4.40(m,0.64H),4.34(dd,J＝9.8,3.0Hz,0.50H),4.04-3.94(m,5H),3.76-3.67(m,1H),3.63-3.60(m,1H),2.91-2.77(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.83 (d, J=8.6Hz, 0.59H), 7.75 (d, J=8.6Hz, 0.47H), 7.64 (d, J=8.6Hz, 0.62H) ),7.58(d,J＝8.6Hz,0.51H),7.50(d,J＝7.6Hz,0.5H),7.35-7.30(m,0.53H),7.25-7.22(m,1.26H),7.17- 7.08(m, 1.42H), 7.03(d, J=7.6Hz, 0.67H), 6.94-6.92(m, 1H), 6.88-6.84(m, 1H), 5.92(d, J=14.2Hz, 0.49H) ),5.77(d,J＝13.8Hz,0.55H),5.62(d,J＝7.6Hz,0.57H),5.41(d,J＝7.6Hz,0.47H),4.50-4.46(m,1.06H) ,4.43-4.40(m,0.64H),4.34(dd,J=9.8,3.0Hz,0.50H),4.04-3.94(m,5H),3.76-3.67(m,1H),3.63-3.60(m, 1H),2.91-2.77(m,1H).
实施例38、(12aR)-7-羟基-12-(3-甲基-6,12-二氢-3H-苯并[6,7]噻吩[4,3-e]吲唑-12-基)-3,4,12,12a-四氢-1H-[1,4]恶嗪[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物38)的合成Example 38, (12aR)-7-hydroxy-12-(3-methyl-6,12-dihydro-3H-benzo[6,7]thiophene[4,3-e]indazol-12-yl )-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6, Synthesis of 8-diketone (Compound 38)
Figure PCTCN2022077312-appb-000094
Figure PCTCN2022077312-appb-000094
步骤1、化合物38-3的合成Step 1. Synthesis of compound 38-3
在干燥的圆底烧瓶中加入NaH(630.9mg,15.8mmol,60％purity)的THF溶液(50mL)在冰浴和氮气保护下加入38-1(2g,10.5mmol)的THF溶液(5mL)后在0摄氏度下搅拌0.5小时，0摄氏度下缓慢滴加苯磺酰氯(2.8g,15.8mmol)后在20摄氏度下搅拌反应3小时，LC-MS监测。反应结束后，用饱和氯化铵溶液淬灭，用乙酸乙酯萃取3次，合并有机相分别用饱和食盐水洗，无水硫酸钠除水，有机相减压浓缩，无需进一步纯化，粗产物可直接用于下步反应，得到产物38-3(3.5g,crude)为黄色固体。LC-MS：m/z 331[M+H] +。 A solution of NaH (630.9 mg, 15.8 mmol, 60% purity) in THF (50 mL) was added to a dry round-bottomed flask, and a solution of 38-1 (2 g, 10.5 mmol) in THF (5 mL) was added under ice bath and nitrogen protection. Stir at 0 degrees Celsius for 0.5 hours, slowly add benzenesulfonyl chloride (2.8 g, 15.8 mmol) dropwise at 0 degrees Celsius, and stir the reaction at 20 degrees Celsius for 3 hours, monitored by LC-MS. After the reaction, it was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, the combined organic phases were washed with saturated brine respectively, the water was removed with anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the crude product was obtained without further purification. It was directly used in the next step to obtain the product 38-3 (3.5 g, crude) as a yellow solid. LC-MS: m/z 331 [M+H] + .
步骤2、化合物38-4的合成Step 2. Synthesis of compound 38-4
按照实施例37中步骤1的合成方法，将步骤1中的37-1替换为38-3，合成方法相同，得到产物38-4 (4.2g)。LC-MS：m/z 410[M+H] +。 According to the synthesis method of step 1 in Example 37, 37-1 in step 1 was replaced with 38-3, and the synthesis method was the same to obtain product 38-4 (4.2 g). LC-MS: m/z 410 [M+H] + .
步骤3、化合物38-5的合成Step 3. Synthesis of compound 38-5
按照实施例37中步骤2的合成方法，将步骤2中的37-2替换为38-4，合成方法相同，得到产物38-5(3g)。LC-MS：m/z 439[M+H] +。 According to the synthesis method of step 2 in Example 37, 37-2 in step 2 was replaced with 38-4, and the synthesis method was the same to obtain the product 38-5 (3g). LC-MS: m/z 439 [M+H] + .
步骤4、化合物38-6的合成Step 4. Synthesis of compound 38-6
在干燥的圆底烧瓶中加入38-5(6g,13.7mmol)和NaOH(2.7g,68.4mmol)用甲醇溶液(40mL)和H 2O(40mL)溶解，在90摄氏度下搅拌18小时，LC-MS监测。反应结束后有机溶剂减压浓缩，用1M的HCl溶液调节pH＝3，用乙酸乙酯萃取3次，收集有机相，用饱和食盐水洗，无水硫酸钠干燥后减压浓缩，无需进一步纯化，粗产物可直接用于下步反应，得到产物38-6(4.1g,crude)为黄色固体。LC-MS：m/z 285[M+H] +。 38-5 (6 g, 13.7 mmol) and NaOH (2.7 g, 68.4 mmol) were added to a dry round-bottomed flask, dissolved with methanol solution (40 mL) and H 2 O (40 mL), and stirred at 90 °C for 18 h, LC -MS monitoring. After the reaction, the organic solvent was concentrated under reduced pressure, adjusted to pH=3 with 1M HCl solution, extracted three times with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, without further purification, The crude product was directly used in the next step to give the product 38-6 (4.1 g, crude) as a yellow solid. LC-MS: m/z 285 [M+H] + .
步骤5、化合物38-7的合成Step 5. Synthesis of compound 38-7
按照实施例37中步骤3的合成方法，将步骤3中的37-3替换为38-6，合成方法相同，得到产物38-7(2.2g)。LC-MS：m/z 313[M+H] +。 According to the synthesis method of step 3 in Example 37, 37-3 in step 3 was replaced with 38-6, and the synthesis method was the same to obtain product 38-7 (2.2 g). LC-MS: m/z 313 [M+H] + .
步骤6、化合物38-8的合成Step 6. Synthesis of compound 38-8
按照实施例29中步骤4的合成方法，将步骤4中的29-4替换为38-7，合成方法相同，得到产物38-8(2g,crude)。LC-MS：m/z 299[M+H] +。 According to the synthesis method of step 4 in Example 29, 29-4 in step 4 was replaced with 38-7, and the synthesis method was the same to obtain product 38-8 (2g, crude). LC-MS: m/z 299 [M+H] + .
步骤7、化合物38-9的合成Step 7. Synthesis of compound 38-9
按照实施例37中步骤5的合成方法，将步骤5中的37-5替换为38-8，合成方法相同，得到产物38-9(350mg)。LC-MS：m/z 281[M+H] +。 According to the synthesis method of step 5 in Example 37, 37-5 in step 5 was replaced with 38-8, and the synthesis method was the same to obtain product 38-9 (350 mg). LC-MS: m/z 281 [M+H] + .
步骤8、化合物38-10的合成Step 8. Synthesis of compound 38-10
按照实施例37中步骤6的合成方法，将步骤6中的37-6替换为38-9，合成方法相同，得到产物38-10(220mg)。LC-MS：m/z 283[M+H] +。 According to the synthesis method of step 6 in Example 37, 37-6 in step 6 was replaced with 38-9, and the synthesis method was the same to obtain product 38-10 (220 mg). LC-MS: m/z 283 [M+H] + .
步骤9、化合物38-11的合成Step 9. Synthesis of compounds 38-11
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为33-8，M2替换为38-10，合成方法相同，得到产物38-11(50mg)。LC-MS：m/z 592[M+H] +。 According to the synthetic method of step 9 in Example 5, 5-9 in step 9 was replaced with 33-8, and M2 was replaced with 38-10, and the synthetic method was the same to obtain product 38-11 (50 mg). LC-MS: m/z 592 [M+H] + .
步骤10、化合物38的合成Step 10. Synthesis of compound 38
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为38-10，合成方法相同，得到产物38(4.3mg)。LC-MS：m/z 502.2[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 38-10, and the synthesis method was the same to obtain product 38 (4.3 mg). LC-MS: m/z 502.2 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ8.61(s,1H),7.71(d,J＝8.4Hz,1H),7.52(d,J＝8.4Hz,1H),7.31(d,J＝7.6Hz,1H),7.18(d,J＝7.6Hz,1H),7.14-7.10(m,1H),7.06(d,J＝7.6Hz,1H),6.83-6.80(m,1H),6.08(s,1H),5.65(d,J＝13.6Hz,1H),5.59(d,J＝7.6Hz,1H),4.46-4.32(m,2H),4.03(s,3H),3.98(d,J＝13.8Hz,1H),3.92(dd,J＝11.0,3.2Hz,1H),3.66(t,J＝10.6Hz,2H),3.58(d,J＝13.8Hz,2H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.61 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.31 (d, J= 7.6Hz,1H),7.18(d,J=7.6Hz,1H),7.14-7.10(m,1H),7.06(d,J=7.6Hz,1H),6.83-6.80(m,1H),6.08( s,1H),5.65(d,J=13.6Hz,1H),5.59(d,J=7.6Hz,1H),4.46-4.32(m,2H),4.03(s,3H),3.98(d,J =13.8Hz,1H),3.92(dd,J=11.0,3.2Hz,1H),3.66(t,J=10.6Hz,2H),3.58(d,J=13.8Hz,2H).
实施例39、(12aR)-12-(6,12-二氢二苯并[6,7]噻吩[3,4-g]苯并呋喃-12-基)-7-羟基-3,4,12,12a-四氢-1H-[1,4]恶嗪[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物39)的合成Example 39, (12aR)-12-(6,12-dihydrodibenzo[6,7]thiophene[3,4-g]benzofuran-12-yl)-7-hydroxy-3,4, 12,12a-Tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 39) Synthesis
Figure PCTCN2022077312-appb-000095
Figure PCTCN2022077312-appb-000095
步骤1、化合物39-3的合成Step 1. Synthesis of compound 39-3
在干燥的圆底烧瓶中加入39-1(10g,53.5mmol)、39-2(15.8g,7.66mL)和KOH(4.5g,80.2mmol)用DMSO溶液(27mL)溶解，在160摄氏度下搅拌反应0.5小时，LC-MS监测。反应结束后，用水和乙酸乙酯萃取3次，合并有机相分别用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，残余杂质用柱层析法除去，得到产物39-3(14.2g)为黄色固体。LC-MS：m/z 303[M+H] +。 In a dry round-bottomed flask, 39-1 (10 g, 53.5 mmol), 39-2 (15.8 g, 7.66 mL) and KOH (4.5 g, 80.2 mmol) were added and dissolved in DMSO solution (27 mL), and stirred at 160 degrees Celsius The reaction was carried out for 0.5 hours and monitored by LC-MS. After the reaction, extracted with water and ethyl acetate 3 times, the combined organic phases were washed with saturated brine respectively, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the residual impurities were removed by column chromatography to obtain the product 39-3 (14.2 g) is a yellow solid. LC-MS: m/z 303 [M+H] + .
步骤2、化合物39-4的合成Step 2. Synthesis of compound 39-4
在干燥的圆底烧瓶中加入39-3(14.2g,46.9mmol)和PPA(15g,93.7mmol)用甲苯溶液(120mL)溶解，在110摄氏度下搅拌1小时，LC-MS监测。反应结束后，用水和乙酸乙酯萃取3次，合并有机相分别用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，残余杂质用柱层析法除去，得到产物39-4(11.6g)。LC-MS：m/z 211[M+H] +。 39-3 (14.2 g, 46.9 mmol) and PPA (15 g, 93.7 mmol) were added to a dry round-bottomed flask and dissolved in toluene solution (120 mL), stirred at 110 degrees Celsius for 1 hour, and monitored by LC-MS. After the reaction, extracted with water and ethyl acetate 3 times, the combined organic phases were washed with saturated brine respectively, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the residual impurities were removed by column chromatography to obtain the product 39-4 (11.6 g). LC-MS: m/z 211 [M+H] + .
步骤3、化合物39-5的合成Step 3. Synthesis of compound 39-5
在干燥的圆底烧瓶中加入39-4(4.4g,20.8mmol)、草酸二乙酯(3.6g,25mmol,3.35mL)、DMAP(3.1g,25.0mmol)和Pd(PPh 3) 2Cl 2(500mg,0.7mmol)用乙醇溶液(3.7mL)溶解，在150摄氏度下搅拌18小时，LC-MS监测。反应结束后，用水和乙酸乙酯萃取3次，合并有机相，分别用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，残余杂质用柱层析法除去，得到产物39-5(3g)。LC-MS：m/z 205[M+H] +。 In a dry round bottom flask were added 39-4 (4.4 g, 20.8 mmol), diethyl oxalate (3.6 g, 25 mmol, 3.35 mL), DMAP (3.1 g, 25.0 mmol) and Pd(PPh 3 ) 2 Cl 2 (500 mg, 0.7 mmol) was dissolved in ethanol solution (3.7 mL), stirred at 150 degrees Celsius for 18 hours, and monitored by LC-MS. After the completion of the reaction, extract with water and ethyl acetate 3 times, combine the organic phases, wash with saturated brine respectively, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and remove residual impurities by column chromatography to obtain product 39-5( 3g). LC-MS: m/z 205 [M+H] + .
步骤4、化合物39-6的合成Step 4. Synthesis of compound 39-6
按照实施例37中步骤1的合成方法，将步骤1中的37-1替换为39-5，合成方法相同，得到产物39-6(2g,crude)。LC-MS：m/z 284[M+H] +。 According to the synthesis method of step 1 in Example 37, 37-1 in step 1 was replaced with 39-5, and the synthesis method was the same to obtain product 39-6 (2g, crude). LC-MS: m/z 284 [M+H] + .
步骤5、化合物39-7的合成Step 5. Synthesis of compound 39-7
按照实施例38中步骤1的合成方法，将步骤1中的38-1替换为39-6，合成方法相同，得到产物39-7(1g,crude)。LC-MS：m/z 313[M+H] +。 According to the synthesis method of step 1 in Example 38, 38-1 in step 1 was replaced with 39-6, and the synthesis method was the same to obtain product 39-7 (1 g, crude). LC-MS: m/z 313 [M+H] + .
步骤6、化合物39-8的合成Step 6. Synthesis of compound 39-8
按照实施例29中步骤4的合成方法，将步骤4中的29-4替换为39-7，合成方法相同，得到产物39-8(300mg)。LC-MS：m/z 285[M+H] +。 According to the synthesis method of step 4 in Example 29, 29-4 in step 4 was replaced with 39-7, and the synthesis method was the same to obtain product 39-8 (300 mg). LC-MS: m/z 285 [M+H] + .
步骤7、化合物39-9的合成Step 7. Synthesis of compound 39-9
按照实施例39中步骤2的合成方法，将步骤2中的39-3替换为39-8，合成方法相同，得到产物39-9(48mg)。LC-MS：m/z 267[M+H] +。 According to the synthesis method of step 2 in Example 39, 39-3 in step 2 was replaced with 39-8, and the synthesis method was the same to obtain product 39-9 (48 mg). LC-MS: m/z 267 [M+H] + .
步骤8、化合物39-10的合成Step 8. Synthesis of compounds 39-10
按照实施例37中步骤6的合成方法，将步骤6中的37-6替换为39-9，合成方法相同，得到产物39-10(23mg)。LC-MS：m/z 269[M+H] +。 According to the synthesis method of step 6 in Example 37, 37-6 in step 6 was replaced with 39-9, and the synthesis method was the same to obtain product 39-10 (23 mg). LC-MS: m/z 269 [M+H] + .
步骤9、化合物39-11的合成Step 9. Synthesis of compounds 39-11
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为33-8，M2替换为39-10，合成方法相同，得到产物39-11(54.2mg)。LC-MS：m/z 578[M+H] +。 According to the synthetic method of step 9 in Example 5, 5-9 in step 9 was replaced by 33-8, M2 was replaced by 39-10, and the synthetic method was the same to obtain product 39-11 (54.2 mg). LC-MS: m/z 578 [M+H] + .
步骤10、化合物39的合成Step 10. Synthesis of compound 39
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为39-10，合成方法相同，得到产物39(3mg)。LC-MS：m/z 488.1[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 39-10, and the synthesis method was the same to obtain product 39 (3 mg). LC-MS: m/z 488.1 [M+H] + .
实施例40、7-羟基-12-(5-(三氟甲基)-10,11-二氢-5H-二苯并[a,d][7]环-5-基)-3,4,12,12a-四氢-1H-[1,4]恶嗪[3,4-c]吡啶并[2,1-f][1,2,4]三嗪-6,8-二酮(化合物40)的合成Example 40, 7-hydroxy-12-(5-(trifluoromethyl)-10,11-dihydro-5H-dibenzo[a,d][7]cyclo-5-yl)-3,4 ,12,12a-Tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione ( Synthesis of compound 40)
Figure PCTCN2022077312-appb-000096
Figure PCTCN2022077312-appb-000096
步骤1、化合物40-1的合成Step 1. Synthesis of compound 40-1
在干燥的圆底烧瓶中加入7-1(10.4g,5mmol)用TMS-CF3(10.6g,1.2mL)溶解，0摄氏度和氮气保护下搅拌5分钟后，加入TBAF(13mg,0.05mmol)升温至40摄氏度反应3小时，LC-MS监测。反应结束后，用水和乙酸乙酯萃取3次，合并有机相，分别用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，残余杂质用柱层析法除去，得到产物40-1(5g)。LC-MS：m/z 261[M+H] +。(打谱显示261) Add 7-1 (10.4 g, 5 mmol) to a dry round-bottomed flask, dissolve it with TMS-CF3 (10.6 g, 1.2 mL), stir at 0 degrees Celsius and under nitrogen protection for 5 minutes, add TBAF (13 mg, 0.05 mmol) and warm up The reaction was carried out at 40 degrees Celsius for 3 hours and monitored by LC-MS. After the completion of the reaction, extract with water and ethyl acetate 3 times, combine the organic phases, wash with saturated brine respectively, dry over anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and remove residual impurities by column chromatography to obtain product 40-1( 5g). LC-MS: m/z 261 [M+H] + . (The score shows 261)
步骤2、化合物40-2的合成Step 2. Synthesis of compound 40-2
在干燥的圆底烧瓶中加入40-1(1g,3.6mmol)用THF(5mL)溶解，加入1N的HCl(5mL)室温反应过夜，LC-MS监测。反应结束后，有机相减压浓缩，用水和乙酸乙酯萃取3次，合并有机相，分别用饱和食盐水洗，无水硫酸钠干燥，有机相减压浓缩，残余杂质用柱层析法除去，得到产物40-2(200mg)。LC-MS：m/z 279[M+H] +。 In a dry round-bottomed flask, 40-1 (1 g, 3.6 mmol) was added to dissolve with THF (5 mL), and 1N HCl (5 mL) was added to react overnight at room temperature, and monitored by LC-MS. After the reaction, the organic phase was concentrated under reduced pressure, extracted three times with water and ethyl acetate, the organic phases were combined, washed with saturated brine respectively, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the residual impurities were removed by column chromatography. The product 40-2 was obtained (200 mg). LC-MS: m/z 279 [M+H] + .
步骤3、化合物40-3的合成Step 3. Synthesis of compound 40-3
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为33-7，M2替换为40-2，合成方法相同，得到产物40-3(55.6mg)。LC-MS：m/z 588[M+H] +。 According to the synthetic method of step 9 in Example 5, 5-9 in step 9 was replaced with 33-7, M2 was replaced with 40-2, and the synthetic method was the same to obtain product 40-3 (55.6 mg). LC-MS: m/z 588 [M+H] + .
步骤4、化合物40的合成Step 4. Synthesis of compound 40
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为40-3，合成方法相同，得到产物40(4.7mg)。LC-MS：m/z 498.4[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 40-3, and the synthesis method was the same to obtain product 40 (4.7 mg). LC-MS: m/z 498.4 [M+H] + .
实施例41、4'-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-9'-羟基-3a',4,4',5-四氢-1'H,2H,3'H-螺环[呋喃-3,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物41)的合成Example 41, 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9'-hydroxy-3a',4,4',5 -Tetrahydro-1'H,2H,3'H-spiro[furan-3,2'-pyrido[2,1-f]pyrro[2,1-c][1,2,4]triazine Synthesis of ]-8',10'-dione (Compound 41)
Figure PCTCN2022077312-appb-000097
Figure PCTCN2022077312-appb-000097
步骤1、化合物41-3的合成Step 1. Synthesis of compound 41-3
按照实施例5中步骤1的合成方法，将步骤1中的5-1替换为41-1，合成方法相同，得到产物41-3(12g)。LC-MS：m/z 157[M+H] +。 According to the synthesis method of step 1 in Example 5, 5-1 in step 1 was replaced with 41-1, and the synthesis method was the same to obtain product 41-3 (12 g). LC-MS: m/z 157 [M+H] + .
步骤2、化合物41-4的合成Step 2. Synthesis of compound 41-4
按照实施例5中步骤2的合成方法，将步骤2中的5-2替换为41-3，合成方法相同，得到产物41-4(12g)。LC-MS：m/z 218[M+H] +。 According to the synthesis method of step 2 in Example 5, 5-2 in step 2 was replaced with 41-3, and the synthesis method was the same to obtain product 41-4 (12 g). LC-MS: m/z 218 [M+H] + .
步骤3、化合物41-5的合成Step 3. Synthesis of compound 41-5
按照实施例5中步骤3的合成方法，将步骤3中的5-3替换为41-4，合成方法相同，得到产物41-5(5g)。LC-MS：m/z 188[M+H] +。 According to the synthesis method of step 3 in Example 5, 5-3 in step 3 was replaced with 41-4, and the synthesis method was the same to obtain product 41-5 (5g). LC-MS: m/z 188 [M+H] + .
步骤4、化合物41-6的合成Step 4. Synthesis of compound 41-6
按照实施例29中步骤4的合成方法，将步骤4中的29-4替换为41-5，合成方法相同，得到产物41-6(3.8g)。LC-MS：m/z 142[M+H] +。 According to the synthesis method of step 4 in Example 29, 29-4 in step 4 was replaced with 41-5, and the synthesis method was the same to obtain product 41-6 (3.8 g). LC-MS: m/z 142 [M+H] + .
步骤5、化合物41-8的合成Step 5. Synthesis of compound 41-8
按照实施例5中步骤4的合成方法，将步骤4中的5-4替换为41-6，合成方法相同，得到产物41-8(4g)。LC-MS：m/z 226[M+H] +。 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 41-6, and the synthesis method was the same to obtain product 41-8 (4g). LC-MS: m/z 226 [M+H] + .
步骤6、化合物41-9的合成Step 6. Synthesis of compound 41-9
按照实施例5中步骤5的合成方法，将步骤5中的5-5替换为41-8，合成方法相同，得到产物41-9(1g)。LC-MS：m/z 228[M+H] +。 According to the synthesis method of step 5 in Example 5, 5-5 in step 5 was replaced with 41-8, and the synthesis method was the same to obtain product 41-9 (1 g). LC-MS: m/z 228 [M+H] + .
步骤7、化合物41-10的合成Step 7. Synthesis of compounds 41-10
按照实施例5中步骤6的合成方法，将步骤6中的5-6替换为41-9，合成方法相同，得到产物41-10(1g)。LC-MS：m/z 242[M+H] +。 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 41-9, and the synthesis method was the same to obtain product 41-10 (1 g). LC-MS: m/z 242 [M+H] + .
步骤8、化合物41-11的合成Step 8. Synthesis of compounds 41-11
按照实施例5中步骤7的合成方法，将步骤7中的5-7替换为41-10，合成方法相同，得到产物41-11 (328mg)。LC-MS：m/z 498[M+H] +。 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 41-10, and the synthesis method was the same to obtain product 41-11 (328 mg). LC-MS: m/z 498 [M+H] + .
步骤9、化合物41-12的合成Step 9. Synthesis of compounds 41-12
按照实施例5中步骤8的合成方法，将步骤8中的5-8替换为41-11，合成方法相同，得到产物41-12(200mg)。LC-MS：m/z 368[M+H] +。 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 41-11, and the synthesis method was the same to obtain product 41-12 (200 mg). LC-MS: m/z 368 [M+H] + .
步骤10、化合物41-13的合成Step 10. Synthesis of Compounds 41-13
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为41-12，合成方法相同，得到产物41-13(30mg)。LC-MS：m/z 614[M+H] +。 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 41-12, and the synthesis method was the same to obtain product 41-13 (30 mg). LC-MS: m/z 614 [M+H] + .
步骤11、化合物41的合成Step 11. Synthesis of compound 41
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为41-13，合成方法相同，得到产物41(3.6mg)。LC-MS：m/z 524.3[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 41-13, and the synthesis method was the same to obtain product 41 (3.6 mg). LC-MS: m/z 524.3 [M+H] + .
实施例42、4'-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-9'-羟基-3a',4'-二氢-1'H,3'H-螺环[环戊烷-1,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物42)的合成Example 42, 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9'-hydroxy-3a',4'-dihydro- 1'H,3'H-spiro[cyclopentane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8' Synthesis of ,10'-diketone (Compound 42)
Figure PCTCN2022077312-appb-000098
Figure PCTCN2022077312-appb-000098
步骤1、化合物42-2的合成Step 1. Synthesis of compound 42-2
按照实施例5中步骤1的合成方法，将步骤1中的5-1替换为42-1，合成方法相同，得到产物42-2(7.3g)。LC-MS：m/z 155[M+H] +。 According to the synthesis method of step 1 in Example 5, 5-1 in step 1 was replaced with 42-1, and the synthesis method was the same to obtain product 42-2 (7.3 g). LC-MS: m/z 155 [M+H] + .
步骤2、化合物42-3的合成Step 2. Synthesis of compound 42-3
按照实施例5中步骤2的合成方法，将步骤2中的5-2替换为42-2，合成方法相同，得到产物42-3(8.7g)。LC-MS：m/z 216[M+H] +。 According to the synthesis method of step 2 in Example 5, 5-2 in step 2 was replaced with 42-2, and the synthesis method was the same to obtain product 42-3 (8.7 g). LC-MS: m/z 216 [M+H] + .
步骤3、化合物42-4的合成Step 3. Synthesis of compound 42-4
按照实施例5中步骤3的合成方法，将步骤3中的5-3替换为42-3，合成方法相同，得到产物42-4(6.1g)。LC-MS：m/z 186[M+H] +。 According to the synthesis method of step 3 in Example 5, 5-3 in step 3 was replaced with 42-3, and the synthesis method was the same to obtain product 42-4 (6.1 g). LC-MS: m/z 186 [M+H] + .
步骤4、化合物42-5的合成Step 4. Synthesis of compound 42-5
按照实施例29中步骤4的合成方法，将步骤4中的29-4替换为42-4，合成方法相同，得到产物42-5 (4.3g)。LC-MS：m/z 140[M+H] +。 According to the synthesis method of step 4 in Example 29, 29-4 in step 4 was replaced with 42-4, and the synthesis method was the same to obtain product 42-5 (4.3g). LC-MS: m/z 140 [M+H] + .
步骤5、化合物42-6的合成Step 5. Synthesis of compound 42-6
按照实施例5中步骤4的合成方法，将步骤4中的5-4替换为42-5，合成方法相同，得到产物42-6(3.2g)。LC-MS：m/z 224[M+H] +。 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 42-5, and the synthesis method was the same to obtain product 42-6 (3.2 g). LC-MS: m/z 224 [M+H] + .
步骤6、化合物42-7的合成Step 6. Synthesis of compound 42-7
按照实施例5中步骤5的合成方法，将步骤5中的5-5替换为42-6，合成方法相同，得到产物42-7(2.3g)。LC-MS：m/z 226[M+H] +。 According to the synthesis method of step 5 in Example 5, 5-5 in step 5 was replaced with 42-6, and the synthesis method was the same to obtain product 42-7 (2.3 g). LC-MS: m/z 226 [M+H] + .
步骤7、化合物42-8的合Step 7. Synthesis of compound 42-8
按照实施例5中步骤6的合成方法，将步骤6中的5-6替换为42-7，合成方法相同，得到产物42-8(1.6g)。LC-MS：m/z 240[M+H] +。 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 42-7, and the synthesis method was the same to obtain product 42-8 (1.6g). LC-MS: m/z 240 [M+H] + .
步骤8、化合物42-9的合成Step 8. Synthesis of compound 42-9
按照实施例5中步骤7的合成方法，将步骤7中的5-7替换为42-8，合成方法相同，得到产物42-9(1.9g)。LC-MS：m/z 496[M+H] +。 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 42-8, and the synthesis method was the same to obtain product 42-9 (1.9 g). LC-MS: m/z 496 [M+H] + .
步骤9、化合物42-10的合成Step 9. Synthesis of compound 42-10
按照实施例5中步骤8的合成方法，将步骤8中的5-8替换为42-9，合成方法相同，得到产物42-10(230mg)。LC-MS：m/z 366[M+H] +。 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 42-9, and the synthesis method was the same to obtain product 42-10 (230 mg). LC-MS: m/z 366 [M+H] + .
步骤10、化合物42-11的合成Step 10. Synthesis of compound 42-11
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为42-10，合成方法相同，得到产物42-11(30mg)。LC-MS：m/z 612[M+H] +。 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 42-10, and the synthesis method was the same to obtain product 42-11 (30 mg). LC-MS: m/z 612 [M+H] + .
步骤11、化合物42的合成Step 11. Synthesis of compound 42
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为42-11，合成方法相同，得到产物42(1.9mg)。LC-MS：m/z 522.2[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 42-11, and the synthesis method was the same to obtain product 42 (1.9 mg). LC-MS: m/z 522.2 [M+H] + .
1H NMR(600MHz,DMSO-d 6)δ9.47(s,1H),7.60-7.46(m,2H),7.36-7.31(m,1H),7.12-7.01(m,2H),6.93-6.83(m,2H),5.75-5.58(m,4H),4.22-3.84(m,3H),3.45(d,J＝12.4Hz,1H),3.19-3.06(m,1H),3.02-2.88(m,1H),2.77-2.66(m,3H),1.99-1.88(m,1H),1.87-1.78(m,1H),1.66-1.54(m,1H),1.51-1.32(m,2H),1.32-1.22(m,2H). 1 H NMR (600MHz, DMSO-d 6 )δ9.47(s,1H), 7.60-7.46(m,2H), 7.36-7.31(m,1H), 7.12-7.01(m,2H), 6.93-6.83 (m,2H),5.75-5.58(m,4H),4.22-3.84(m,3H),3.45(d,J=12.4Hz,1H),3.19-3.06(m,1H),3.02-2.88(m ,1H),2.77-2.66(m,3H),1.99-1.88(m,1H),1.87-1.78(m,1H),1.66-1.54(m,1H),1.51-1.32(m,2H),1.32 -1.22(m,2H).
实施例43、1'-(7,8-二氟-6,11-二氢苯并[c][1]苯并噻吩-11-基)-5'-羟基-螺环[环丙烷-1,3'-吡啶并[1,2-b]哒嗪]-2',4',6'-三酮(化合物43)的合成Example 43, 1'-(7,8-difluoro-6,11-dihydrobenzo[c][1]benzothiophen-11-yl)-5'-hydroxy-spiro[cyclopropane-1 Synthesis of ,3'-pyrido[1,2-b]pyridazine]-2',4',6'-trione (Compound 43)
Figure PCTCN2022077312-appb-000099
Figure PCTCN2022077312-appb-000099
步骤1、化合物43-2的合成Step 1. Synthesis of compound 43-2
在干燥的圆底烧瓶中加入43-1(20g,158.6mmol)、BnBr(32.6g,190.7mmol,22.8mL)和碳酸钾(43.8g,317.4mmol)的加入DMF溶液(200mL)溶解，在80摄氏度下搅拌2小时，LC-MS监测。反应结束后，用水和乙酸乙酯萃取3次，收集有机相，用饱和食盐水洗两次，无水硫酸钠干燥后减压浓缩，无需进一步纯化，粗产物可直接用于下步反应，得到产物43-2(34g,crude)为黄色油状物。LC-MS：m/z 217[M+H] +。 In a dry round-bottomed flask, 43-1 (20 g, 158.6 mmol), BnBr (32.6 g, 190.7 mmol, 22.8 mL) and potassium carbonate (43.8 g, 317.4 mmol) were added to dissolve in DMF solution (200 mL). Stir for 2 hours at degrees Celsius and monitor by LC-MS. After the reaction, extract with water and ethyl acetate for 3 times, collect the organic phase, wash with saturated brine twice, dry with anhydrous sodium sulfate and concentrate under reduced pressure, without further purification, the crude product can be directly used in the next step to obtain the product 43-2 (34g, crude) was a yellow oil. LC-MS: m/z 217 [M+H] + .
步骤2、化合物43-3的合成Step 2. Synthesis of compound 43-3
在干燥的圆底烧瓶中加入43-2(10g,46.3mmol)和SeO 2(10.4g,92.5mmol)加入溴化苯溶液(50mL)在160摄氏度下搅拌18小时，LC-MS监测。反应结束后，用水和乙酸乙酯萃取3次，收集有机相，用饱和食盐水洗两次，无水硫酸钠干燥后减压浓缩，残余杂质用柱层析法除去，得到产物43-3(6g)为黄色油状物。LC-MS：m/z 231[M+H] +。 In a dry round bottom flask, 43-2 (10 g, 46.3 mmol) and SeO 2 (10.4 g, 92.5 mmol) were added to brominated benzene solution (50 mL) and stirred at 160 degrees Celsius for 18 hours, monitored by LC-MS. After the reaction, extracted with water and ethyl acetate 3 times, the organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residual impurities were removed by column chromatography to obtain the product 43-3 (6 g ) as a yellow oil. LC-MS: m/z 231 [M+H] + .
步骤3、化合物43-4的合成Step 3. Synthesis of compound 43-4
在干燥的圆底烧瓶中加入43-3(2.8g,9.3mmol)用THF溶液(40mL)溶解，加入2-甲基-2-丁烯(20mL)和NaClO 2(3.2g,28.0mmol,80％purity)的NaH 2PO 4(aq)溶液(40mL)在25摄氏度下搅拌18小时，LC-MS监测。反应结束后，用水和乙酸乙酯萃取3次，收集有机相，用饱和食盐水洗两次，无水硫酸钠干燥后减压浓缩，残余杂质用柱层析法除去，得到产物43-4(2.5g)为黄色油状物。LC-MS：m/z 317[M+H] +。 In a dry round-bottomed flask, 43-3 (2.8 g, 9.3 mmol) was added to dissolve with THF solution (40 mL), 2-methyl-2-butene (20 mL) and NaClO 2 (3.2 g, 28.0 mmol, 80 mL) were added. % purity) in NaH 2 PO 4 (aq) (40 mL) was stirred at 25 °C for 18 h, monitored by LC-MS. After the completion of the reaction, extract with water and ethyl acetate three times, collect the organic phase, wash with saturated brine twice, dry over anhydrous sodium sulfate and concentrate under reduced pressure, and remove the residual impurities by column chromatography to obtain the product 43-4 (2.5 g) is a yellow oil. LC-MS: m/z 317 [M+H] + .
步骤4、化合物43-5的合成Step 4. Synthesis of compound 43-5
在干燥的圆底烧瓶中加入43-4(2.5g,7.9mmol)用甲醇溶液(15mL)溶解，加入NH 3H 2O(15mL)在25摄氏度下搅拌18小时，LC-MS监测。反应结束后，用水和乙酸乙酯萃取3次，收集有机相，用饱和食盐水洗两次，无水硫酸钠干燥后减压浓缩，残余杂质用中压反相制备柱除去，得到产物43-5(2g)为黄色油状物。LC-MS：m/z 316[M+H] +。 43-4 (2.5 g, 7.9 mmol) was added to a dry round-bottomed flask, dissolved in methanol solution (15 mL), NH 3 H 2 O (15 mL) was added and stirred at 25 degrees Celsius for 18 hours, monitored by LC-MS. After the reaction, extract with water and ethyl acetate for 3 times, collect the organic phase, wash with saturated brine twice, dry with anhydrous sodium sulfate and concentrate under reduced pressure, and remove residual impurities with a medium-pressure reverse-phase preparative column to obtain product 43-5 (2g) was a yellow oil. LC-MS: m/z 316 [M+H] + .
步骤5、化合物43-6的合成Step 5. Synthesis of compound 43-6
在干燥的圆底烧瓶中加入43-5(2g,6.3mmol)用丙酮溶液(30mL)溶解，0摄氏度下缓慢滴加琼斯试剂(6mL)，在25摄氏度下搅拌18小时，LC-MS监测。反应结束后，加入异丙醇淬灭，继续搅拌30分钟，加入饱和碳酸氢钠水将体系调节至pH＝7，过滤，滤液减压浓缩，残余杂质用中压反相制备柱除去，得到产物43-6(1.5g)为黄色油状物。LC-MS：m/z 314[M+H] +。 Add 43-5 (2 g, 6.3 mmol) to a dry round-bottomed flask and dissolve in acetone solution (30 mL), slowly add Jones reagent (6 mL) dropwise at 0 degrees Celsius, stir at 25 degrees Celsius for 18 hours, and monitor by LC-MS. After the reaction was completed, isopropanol was added to quench, and stirring was continued for 30 minutes. The system was adjusted to pH=7 by adding saturated sodium bicarbonate water, filtered, and the filtrate was concentrated under reduced pressure. The residual impurities were removed with a medium-pressure reverse-phase preparative column to obtain the product 43-6 (1.5 g) was a yellow oil. LC-MS: m/z 314 [M+H] + .
步骤6、化合物43-7的合成Step 6. Synthesis of compound 43-7
在干燥的圆底烧瓶中加入43-6(1.5g,4.8mmol)用DMF溶液(20mL)溶解，加入2,4-二硝基苯基羟胺(1.14g,5.8mmol)和碳酸钾(3.3g,24.0mmol)在30摄氏度下搅拌18小时，LC-MS监测。反应结束后，加入1M的HCl溶液将体系调节至pH＝3，乙酸乙酯萃取3次，收集有机相，用饱和食盐水洗两次，无水硫酸钠干燥后减压浓缩，残余杂质用中压反相制备柱除去，得到产物43-7(1.3g)为棕色固体。LC-MS：m/z 329[M+H] +。 In a dry round-bottomed flask, 43-6 (1.5 g, 4.8 mmol) was added and dissolved in DMF solution (20 mL), 2,4-dinitrophenylhydroxylamine (1.14 g, 5.8 mmol) and potassium carbonate (3.3 g) were added. , 24.0 mmol) was stirred at 30 °C for 18 h, monitored by LC-MS. After the reaction, 1M HCl solution was added to adjust the pH of the system to 3, extracted with ethyl acetate three times, the organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Reverse phase preparative column removal gave product 43-7 (1.3 g) as a brown solid. LC-MS: m/z 329 [M+H] + .
步骤7、化合物43-8的合成Step 7. Synthesis of compound 43-8
在干燥的圆底烧瓶中加入43-7(1.3g,4.0mmol)用DMF溶液(30mL)溶解，加入DMAP(967.5mg,7.9mmol)和DIPEA(10.2g,79.2mmol)搅拌5分钟后加入EDCI(7.6g,39.6mmol)在30摄氏度下搅拌18小时，LC-MS监测。反应结束后有机相减压浓缩，残余杂质用中压反相制备柱除去，得到产物43-8(100mg)为黄色固体。LC-MS：m/z 311[M+H] +。 43-7 (1.3 g, 4.0 mmol) was added to a dry round-bottomed flask, dissolved in DMF solution (30 mL), DMAP (967.5 mg, 7.9 mmol) and DIPEA (10.2 g, 79.2 mmol) were added, and EDCI was added after stirring for 5 minutes. (7.6 g, 39.6 mmol) was stirred at 30 degrees Celsius for 18 hours, monitored by LC-MS. After the reaction, the organic phase was concentrated under reduced pressure, and the residual impurities were removed with a medium-pressure reverse-phase preparative column to obtain the product 43-8 (100 mg) as a yellow solid. LC-MS: m/z 311 [M+H] + .
步骤8、化合物43的合成Step 8. Synthesis of compound 43
在干燥的圆底烧瓶中加入43-8(5mg,0.02mmol)和M2(8.5mg,0.03mmol)溶于1-丙基磷酸酐(50wt.％的乙酸乙酯溶液，200uL)中，110摄氏度下搅拌18小时，LC-MS监测。反应结束后有机相减压浓缩，残余杂质用中压反相制备柱除去，得到产物43(1.7mg)。LC-MS：m/z 467.2[M+H] + In a dry round bottom flask was added 43-8 (5 mg, 0.02 mmol) and M2 (8.5 mg, 0.03 mmol) dissolved in 1-propylphosphoric anhydride (50 wt.% in ethyl acetate, 200 uL) at 110 degrees Celsius The mixture was stirred for 18 hours and monitored by LC-MS. After the reaction was completed, the organic phase was concentrated under reduced pressure, and the residual impurities were removed with a medium-pressure reverse-phase preparative column to obtain the product 43 (1.7 mg). LC-MS: m/z 467.2 [M+H] +
1H NMR(600MHz,DMSO-d 6)δ11.42(s,1H),7.52-7.48(m,2H),7.37-7.33(m,1H),7.29-7.26(m,1H),7.24-7.22(m,1H),7.17-7.15(m,1H),7.01(s,1H),5.89(s,1H),4.59-4.52(m,2H),3.83(s,2H),3.06-2.95(m,2H). 1 H NMR (600MHz, DMSO-d 6 ) δ 11.42(s, 1H), 7.52-7.48(m, 2H), 7.37-7.33(m, 1H), 7.29-7.26(m, 1H), 7.24-7.22 (m,1H),7.17-7.15(m,1H),7.01(s,1H),5.89(s,1H),4.59-4.52(m,2H),3.83(s,2H),3.06-2.95(m , 2H).
实施例44、4-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-9-羟基-2',3a,3',4,5',6'-六氢-1H,3H-螺环[吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪-2,4'-噻喃]-8,10-二酮1',1'-二氧化物(化合物44)的合成Example 44, 4-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9-hydroxy-2',3a,3',4,5 ',6'-Hexahydro-1H,3H-spiro[pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine-2,4'-thiopyran] Synthesis of -8,10-dione 1',1'-dioxide (Compound 44)
Figure PCTCN2022077312-appb-000100
Figure PCTCN2022077312-appb-000100
步骤1、化合物44-2的合成Step 1. Synthesis of compound 44-2
按照实施例5中步骤1的合成方法，将步骤1中的5-1替换为44-1，合成方法相同，得到产物44-2(7.8g)。LC-MS：m/z 187[M+H] +。 According to the synthesis method of step 1 in Example 5, 5-1 in step 1 was replaced with 44-1, and the synthesis method was the same to obtain product 44-2 (7.8g). LC-MS: m/z 187 [M+H] + .
步骤2、化合物44-3的合成Step 2. Synthesis of compound 44-3
按照实施例5中步骤2的合成方法，将步骤2中的5-2替换为44-2，合成方法相同，得到产物44-3(9.0g)。LC-MS：m/z 248[M+H] +。 According to the synthesis method of step 2 in Example 5, 5-2 in step 2 was replaced with 44-2, and the synthesis method was the same to obtain product 44-3 (9.0 g). LC-MS: m/z 248 [M+H] + .
步骤3、化合物44-4的合成Step 3. Synthesis of compound 44-4
按照实施例5中步骤3的合成方法，将步骤3中的5-3替换为44-3，合成方法相同，得到产物44-4(8.5g)。LC-MS：m/z 218[M+H] +。 According to the synthesis method of step 3 in Example 5, 5-3 in step 3 was replaced with 44-3, and the synthesis method was the same to obtain product 44-4 (8.5 g). LC-MS: m/z 218 [M+H] + .
步骤4、化合物44-5的合成Step 4. Synthesis of compound 44-5
按照实施例29中步骤4的合成方法，将步骤4中的29-4替换为44-4，合成方法相同，得到产物44-5(4.0g)。LC-MS：m/z 172[M+H] +。 According to the synthesis method of step 4 in Example 29, 29-4 in step 4 was replaced with 44-4, and the synthesis method was the same to obtain product 44-5 (4.0 g). LC-MS: m/z 172 [M+H] + .
步骤5、化合物44-6的合成Step 5. Synthesis of compound 44-6
按照实施例5中步骤4的合成方法，将步骤4中的5-4替换为44-5，合成方法相同，得到产物44-6(6g)。LC-MS：m/z 256[M+H] +。 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 44-5, and the synthesis method was the same to obtain product 44-6 (6g). LC-MS: m/z 256 [M+H] + .
步骤6、化合物44-7的合成Step 6. Synthesis of compound 44-7
按照实施例5中步骤5的合成方法，将步骤5中的5-5替换为44-6，合成方法相同，得到产物44-7(4.1 g)。LC-MS：m/z 258[M+H] +。 According to the synthesis method of step 5 in Example 5, 5-5 in step 5 was replaced with 44-6, and the synthesis method was the same to obtain product 44-7 (4.1 g). LC-MS: m/z 258 [M+H] + .
步骤7、化合物44-8的合成Step 7. Synthesis of compound 44-8
按照实施例5中步骤6的合成方法，将步骤6中的5-6替换为44-7，合成方法相同，得到产物44-8(4.1g)。LC-MS：m/z 271[M+H] +。 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 44-7, and the synthesis method was the same to obtain product 44-8 (4.1 g). LC-MS: m/z 271 [M+H] + .
步骤8、化合物44-9的合成Step 8. Synthesis of compound 44-9
按照实施例5中步骤7的合成方法，将步骤7中的5-7替换为44-8，合成方法相同，得到产物44-9(2.6g)。LC-MS：m/z 528[M+H] +。 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 44-8, and the synthesis method was the same to obtain product 44-9 (2.6g). LC-MS: m/z 528 [M+H] + .
步骤9、化合物44-10的合成Step 9. Synthesis of compound 44-10
按照实施例5中步骤8的合成方法，将步骤8中的5-8替换为44-9，合成方法相同，得到产物44-10(1.9g)。LC-MS：m/z 397[M+H] +。 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 44-9, and the synthesis method was the same to obtain product 44-10 (1.9 g). LC-MS: m/z 397 [M+H] + .
步骤10、化合物44-11的合成Step 10. Synthesis of compound 44-11
在干燥的圆底烧瓶中加入44-10(500mg,1.3mmol)用DCM溶液(50mL)溶解，0摄氏度下加入m-CPBA(651.2mg,3.8mmol)，0摄氏度下搅拌3小时，LC-MS监测。反应结束后，有机相减压浓缩，残余杂质用中压反相制备柱除去，得到产物44-11(75mg)。LC-MS：m/z 314[M+H] +。 Add 44-10 (500 mg, 1.3 mmol) to a dry round-bottomed flask, dissolve it with DCM solution (50 mL), add m-CPBA (651.2 mg, 3.8 mmol) at 0 degrees Celsius, stir at 0 degrees Celsius for 3 hours, LC-MS monitor. After the reaction, the organic phase was concentrated under reduced pressure, and the residual impurities were removed with a medium-pressure reverse-phase preparative column to obtain the product 44-11 (75 mg). LC-MS: m/z 314 [M+H] + .
步骤11、化合物44-12的合成Step 11. Synthesis of compounds 44-12
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为44-11，合成方法相同，得到产物44-12(19mg)。LC-MS：m/z 430.1[M+H] +。 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 44-11, and the synthesis method was the same to obtain product 44-12 (19 mg). LC-MS: m/z 430.1 [M+H] + .
步骤11、化合物44的合成Step 11. Synthesis of compound 44
按照实施例14中步骤6的合成方法，将步骤6中的14-8替换为44-12，合成方法相同，得到产物44(7mg)。LC-MS：m/z 586[M+H] +。 According to the synthesis method of step 6 in Example 14, 14-8 in step 6 was replaced by 44-12, and the synthesis method was the same to obtain product 44 (7 mg). LC-MS: m/z 586 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.39(d,J＝7.4Hz,2H),7.32-7.11(m,5H),7.06(d,J＝12.6Hz,1H),5.38(s,1H),5.23-5.01(m,1H),4.30(dd,J＝15.0,8.0Hz,1H),3.90(d,J＝13.8Hz,1H),3.63(d,J＝12.4Hz,1H),3.43(dd,J＝12.6,8.0Hz,1H),3.25-3.04(m,4H),2.46-2.31(m,1H),2.13-1.94(m,4H),1.70-1.59(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ 7.39 (d, J=7.4Hz, 2H), 7.32-7.11 (m, 5H), 7.06 (d, J=12.6Hz, 1H), 5.38 (s, 1H), 5.23-5.01(m, 1H), 4.30(dd, J=15.0, 8.0Hz, 1H), 3.90(d, J=13.8Hz, 1H), 3.63(d, J=12.4Hz, 1H), 3.43(dd,J=12.6,8.0Hz,1H),3.25-3.04(m,4H),2.46-2.31(m,1H),2.13-1.94(m,4H),1.70-1.59(m,1H).
实施例45、4'-(7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-9'-羟基-2',3',3a',4'-四氢螺环[环丙烷-1,1'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物45)的合成Example 45, 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9'-hydroxy-2',3',3a', 4'-Tetrahydrospiro[cyclopropane-1,1'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'- Synthesis of diketone (compound 45)
Figure PCTCN2022077312-appb-000101
Figure PCTCN2022077312-appb-000101
步骤1、化合物45-3的合成Step 1. Synthesis of compound 45-3
按照实施例5中步骤4的合成方法，将步骤4中的5-4替换为45-1，合成方法相同，得到产物45-3(1.3g)。LC-MS：m/z 196[M+H] +。 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 45-1, and the synthesis method was the same to obtain product 45-3 (1.3 g). LC-MS: m/z 196 [M+H] + .
步骤2、化合物45-4的合成Step 2. Synthesis of compound 45-4
按照实施例5中步骤5的合成方法，将步骤5中的5-5替换为45-3，合成方法相同，得到产物45-4(1.3g)。LC-MS：m/z 198[M+H] +。 According to the synthesis method of step 5 in Example 5, 5-5 in step 5 was replaced with 45-3, and the synthesis method was the same to obtain product 45-4 (1.3 g). LC-MS: m/z 198 [M+H] + .
步骤3、化合物45-5的合成Step 3. Synthesis of compound 45-5
按照实施例5中步骤6的合成方法，将步骤6中的5-6替换为45-4，合成方法相同，得到产物45-5(1.2g)。LC-MS：m/z 212[M+H] +。 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 45-4, and the synthesis method was the same to obtain product 45-5 (1.2 g). LC-MS: m/z 212 [M+H] + .
步骤4、化合物45-6的合成Step 4. Synthesis of compound 45-6
按照实施例5中步骤7的合成方法，将步骤7中的5-7替换为45-5，合成方法相同，得到产物45-6(2.3g)。LC-MS：m/z 468[M+H] +。 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 45-5, and the synthesis method was the same to obtain product 45-6 (2.3 g). LC-MS: m/z 468 [M+H] + .
步骤5、化合物45-8的合成Step 5. Synthesis of compound 45-8
按照实施例5中步骤8的合成方法，将步骤8中的5-8替换为45-6，合成方法相同，得到产物45-8(400mg)。LC-MS：m/z 338[M+H] +。 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 45-6, and the synthesis method was the same to obtain product 45-8 (400 mg). LC-MS: m/z 338 [M+H] + .
步骤6、化合物45-9的合成Step 6. Synthesis of compound 45-9
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为45-8，合成方法相同，得到产物45-9(32mg)。LC-MS：m/z 584[M+H] +。 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 45-8, and the synthesis method was the same to obtain product 45-9 (32 mg). LC-MS: m/z 584 [M+H] + .
步骤7、化合物45的合成Step 7. Synthesis of compound 45
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为45-9，合成方法相同，得到产物45(5mg)。LC-MS：m/z 494.3[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 45-9, and the synthesis method was the same to obtain product 45 (5 mg). LC-MS: m/z 494.3 [M+H] + .
实施例46、1'-乙酰基-2-(7,8-二氟-6,11-二氢苯并[c][1]苯并噻吩-11-基)-10-羟基-螺环[1,2,7-三氮杂三环[7.4.0.03,7]十三-9,12-二烯烃-5,3'-氮杂环丁烷]-8,11-二酮(化合物46)的合成Example 46, 1'-acetyl-2-(7,8-difluoro-6,11-dihydrobenzo[c][1]benzothiophen-11-yl)-10-hydroxy-spiro[ 1,2,7-Triazatricyclo[7.4.0.03,7]trideca-9,12-diene-5,3'-azetidine]-8,11-dione (Compound 46) Synthesis
Figure PCTCN2022077312-appb-000102
Figure PCTCN2022077312-appb-000102
步骤1、化合物46-3的合成Step 1. Synthesis of compound 46-3
按照实施例5中步骤4的合成方法，将步骤4中的5-4替换为46-1，合成方法相同，得到产物46-3(16.2g)。LC-MS：m/z 311[M+H] +。 According to the synthesis method of step 4 in Example 5, 5-4 in step 4 was replaced with 46-1, and the synthesis method was the same to obtain product 46-3 (16.2 g). LC-MS: m/z 311 [M+H] + .
步骤2、化合物46-4的合成Step 2. Synthesis of compound 46-4
按照实施例5中步骤5的合成方法，将步骤5中的5-5替换为46-3，合成方法相同，得到产物46-4(6g)。LC-MS：m/z 313[M+H] +。 According to the synthesis method of step 5 in Example 5, 5-5 in step 5 was replaced with 46-3, and the synthesis method was the same to obtain product 46-4 (6g). LC-MS: m/z 313 [M+H] + .
步骤3、化合物46-5的合成Step 3. Synthesis of compound 46-5
按照实施例5中步骤6的合成方法，将步骤6中的5-6替换为46-4，合成方法相同，得到产物46-5(620mg)。LC-MS：m/z 327[M+H] +。 According to the synthesis method of step 6 in Example 5, 5-6 in step 6 was replaced with 46-4, and the synthesis method was the same to obtain product 46-5 (620 mg). LC-MS: m/z 327 [M+H] + .
步骤4、化合物46-6的合成Step 4. Synthesis of compound 46-6
按照实施例5中步骤7的合成方法，将步骤7中的5-7替换为46-5，合成方法相同，得到产物46-6(970mg)。LC-MS：m/z 583[M+H] +。 According to the synthesis method of step 7 in Example 5, 5-7 in step 7 was replaced with 46-5, and the synthesis method was the same to obtain product 46-6 (970 mg). LC-MS: m/z 583 [M+H] + .
步骤5、化合物46-7的合成Step 5. Synthesis of compound 46-7
按照实施例5中步骤8的合成方法，将步骤8中的5-8替换为46-6，合成方法相同，得到产物46-7(430mg)。LC-MS：m/z 453[M+H] +。 According to the synthesis method of step 8 in Example 5, 5-8 in step 8 was replaced with 46-6, and the synthesis method was the same to obtain product 46-7 (430 mg). LC-MS: m/z 453 [M+H] + .
步骤6、化合物46-8的合成Step 6. Synthesis of compound 46-8
在干燥的圆底烧瓶中加入46-7(45.2mg,99.9μmol)，用EA(2mL)溶解，加入1N HCl(2mL)，25摄氏度下搅拌反应1小时，LC-MS监测。反应结束后，加入水和DCM萃取3次，合并有机相，用食盐水洗，无水硫酸钠干燥后减压浓缩，得到粗产物46-8(35.2mg)。LC-MS：m/z 353[M+H] + In a dry round-bottomed flask, 46-7 (45.2 mg, 99.9 μmol) was added, dissolved with EA (2 mL), 1N HCl (2 mL) was added, and the reaction was stirred at 25 degrees Celsius for 1 hour, monitored by LC-MS. After the reaction, water and DCM were added for extraction 3 times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 46-8 (35.2 mg). LC-MS: m/z 353 [M+H] +
步骤7、化合物46-9的合成Step 7. Synthesis of compound 46-9
在干燥的圆底烧瓶中加入46-8(35.2mg,99.9μmol)，用水(0.5mL)和THF(0.5mL)溶解，加入NaHCO 3(16.8mg,199.8μmol)和乙酸酐(0.5mL)，25摄氏度下搅拌反应0.5小时，LC-MS监测。反应结束后，加入水和DCM萃取3次，合并有机相，用食盐水洗，无水硫酸钠干燥后减压浓缩，用中压反相制备柱纯化得到产物46-9(32mg)。LC-MS：m/z 395[M+H] + In a dry round-bottomed flask was added 46-8 (35.2 mg, 99.9 μmol), dissolved in water (0.5 mL) and THF (0.5 mL), NaHCO 3 (16.8 mg, 199.8 μmol) and acetic anhydride (0.5 mL) were added, The reaction was stirred at 25°C for 0.5 h and monitored by LC-MS. After the reaction, water and DCM were added for extraction 3 times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain the product 46-9 (32 mg). LC-MS: m/z 395 [M+H] +
步骤8、化合物46-10的合成Step 8. Synthesis of compound 46-10
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为46-9，合成方法相同，得到产物46-10(30mg)。LC-MS：m/z 641[M+H] +。 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 46-9, and the synthesis method was the same to obtain product 46-10 (30 mg). LC-MS: m/z 641 [M+H] + .
步骤9、化合物46的合成Step 9. Synthesis of compound 46
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为45-9，合成方法相同，得到产物46(6mg)。LC-MS：m/z 551[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 45-9, and the synthesis method was the same to obtain product 46 (6 mg). LC-MS: m/z 551 [M+H] + .
实施例47、(S)-4'-((S)-7,8-二氟-6,11-二氢二苯并[b,e]噻吩-11-基)-9'-羟基-1-甲基-3a',4'-二氢-1'H,3'H-螺环[哌啶-4,2'-吡啶并[2,1-f]吡咯[2,1-c][1,2,4]三嗪]-8',10'-二酮(化合物47)的合成Example 47, (S)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-9'-hydroxy-1 -Methyl-3a',4'-dihydro-1'H,3'H-spiro[piperidine-4,2'-pyrido[2,1-f]pyrrole[2,1-c][ Synthesis of 1,2,4]Triazine]-8',10'-dione (Compound 47)
Figure PCTCN2022077312-appb-000103
Figure PCTCN2022077312-appb-000103
步骤1、化合物47-1的合成Step 1. Synthesis of compound 47-1
在干燥的圆底烧瓶中加入Isomer 31-7-2(24mg,49.9μmol)和Isomer M2-2(19.8mg,74.9μmol)，用T 3P(0.2mL)溶解，加入NaHCO 3(16.8mg,199.8μmol)和乙酸酐(0.5mL)，110摄氏度下搅拌反应2小时，LC-MS监测。反应结束后，加入水和乙酸乙酯萃取3次，合并有机相，用食盐水洗，无水硫酸钠干燥后减压浓缩，得到粗产物47-1(35mg)。LC-MS：m/z 395[M+H] + In a dry round-bottomed flask was added Isomer 31-7-2 (24 mg, 49.9 μmol) and Isomer M2-2 (19.8 mg, 74.9 μmol), dissolved with T 3 P (0.2 mL), and added NaHCO 3 (16.8 mg, 199.8 μmol) and acetic anhydride (0.5 mL), and the reaction was stirred at 110 degrees Celsius for 2 hours, monitored by LC-MS. After the reaction, water and ethyl acetate were added for extraction three times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 47-1 (35 mg). LC-MS: m/z 395 [M+H] +
步骤2、化合物47-2的合成Step 2. Synthesis of compound 47-2
在干燥的圆底烧瓶中加入47-1(35mg,55.9μmol)用甲醛(1mL)和甲醇(1mL)溶解，加入NaBH 3CN(7.0mg,111.7μmol)，25摄氏度下搅拌反应0.5小时，LC-MS监测。反应结束后，加入水和DCM萃取3次，合并有机相，用食盐水洗，无水硫酸钠干燥后减压浓缩，得到粗产物47-2(28mg)。LC-MS：m/z 641[M+H] + 47-1 (35 mg, 55.9 μmol) was added to a dry round-bottomed flask, dissolved in formaldehyde (1 mL) and methanol (1 mL), NaBH 3 CN (7.0 mg, 111.7 μmol) was added, and the reaction was stirred at 25 degrees Celsius for 0.5 hours, LC -MS monitoring. After the reaction, water and DCM were added for extraction 3 times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 47-2 (28 mg). LC-MS: m/z 641 [M+H] +
步骤3、化合物47的合成Step 3. Synthesis of compound 47
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为47-2，合成方法相同，得到产物47(10mg)。LC-MS：m/z 551.3[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 47-2, and the synthesis method was the same to obtain product 47 (10 mg). LC-MS: m/z 551.3 [M+H] + .
1H NMR(600MHz,DMSO-d 6)δ9.47(s,1H),7.60-7.46(m,2H),7.36-7.31(m,1H),7.12-7.01(m,2H),6.93-6.83(m,2H),5.75-5.58(m,4H),4.22-3.84(m,3H),3.45(d,J＝12.4Hz,1H),3.19-3.06(m,1H),3.02-2.88(m,1H),2.77-2.66(m,3H),1.99-1.88(m,1H),1.87-1.78(m,1H),1.66-1.54(m,1H),1.51-1.32(m,2H),1.32-1.22(m,2H). 1 H NMR (600MHz, DMSO-d 6 )δ9.47(s,1H), 7.60-7.46(m,2H), 7.36-7.31(m,1H), 7.12-7.01(m,2H), 6.93-6.83 (m,2H),5.75-5.58(m,4H),4.22-3.84(m,3H),3.45(d,J=12.4Hz,1H),3.19-3.06(m,1H),3.02-2.88(m ,1H),2.77-2.66(m,3H),1.99-1.88(m,1H),1.87-1.78(m,1H),1.66-1.54(m,1H),1.51-1.32(m,2H),1.32 -1.22(m,2H).
实施例48、(12aS)-11-(7,8-二氟-4a,6,6a,10a,11,11a-六氢二苯[b,e]噻吩-11-基)-6-羟基-1,2,3,11,12,12a-六氢吡啶[1,2-b]吡咯[1,2-e][1,2,5]三氮杂-5,7-二酮(化合物48)的合成Example 48, (12aS)-11-(7,8-difluoro-4a,6,6a,10a,11,11a-hexahydrodiphenyl[b,e]thiophen-11-yl)-6-hydroxy- 1,2,3,11,12,12a-Hexahydropyridine[1,2-b]pyrrole[1,2-e][1,2,5]triaza-5,7-dione (Compound 48 )Synthesis
Figure PCTCN2022077312-appb-000104
Figure PCTCN2022077312-appb-000104
步骤1、化合物48-3的合成Step 1. Synthesis of compound 48-3
在干燥的圆底烧瓶中加入48-1(288mg,999μmol)和48-2(238.8mg,1.2mmol)，用甲醇(5mL)溶解，50摄氏度下搅拌反应1小时，LC-MS监测。反应结束后，加入水和乙酸乙酯萃取3次，合并有机相，用食盐水洗，无水硫酸钠干燥后减压浓缩，用中压反相制备柱纯化得到产物48-3(455mg)。LC-MS：m/z470[M+H] + 48-1 (288 mg, 999 μmol) and 48-2 (238.8 mg, 1.2 mmol) were added to a dry round-bottomed flask, dissolved in methanol (5 mL), and the reaction was stirred at 50 degrees Celsius for 1 hour, monitored by LC-MS. After the reaction, water and ethyl acetate were added for extraction 3 times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain the product 48-3 (455 mg). LC-MS: m/z470[M+H] +
步骤2、化合物48-4的合成Step 2. Synthesis of compound 48-4
在干燥的圆底烧瓶中加入48-3(455mg,969.1μmol)和NaBH 4(73.3mg,1.9mmol)，用甲醇(5mL)溶解，0摄氏度下搅拌反应0.5小时，LC-MS监测。反应结束后，加入水和乙酸乙酯萃取3次，合并有机相，用食盐水洗，无水硫酸钠干燥后减压浓缩，用中压反相制备柱纯化得到产物48-4(448mg)。LC-MS：m/z472[M+H] + 48-3 (455 mg, 969.1 μmol) and NaBH 4 (73.3 mg, 1.9 mmol) were added to a dry round-bottomed flask, dissolved in methanol (5 mL), and the reaction was stirred at 0 °C for 0.5 h, monitored by LC-MS. After the reaction, water and ethyl acetate were added for extraction 3 times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain the product 48-4 (448 mg). LC-MS: m/z472[M+H] +
步骤3、化合物48-5的合成Step 3. Synthesis of compound 48-5
在干燥的圆底烧瓶中加入48-4(448mg,950.1μmol)，用甲醇(5mL)和TFA(5mL)溶解，25摄氏度下搅拌反应0.5小时，LC-MS监测。反应结束后，加入水和乙酸乙酯萃取3次，合并有机相，用食盐水洗，无水硫酸钠干燥后减压浓缩，用中压反相制备柱纯化得到产物48-5(302mg)。LC-MS：m/z 372[M+H] + 48-4 (448 mg, 950.1 μmol) was added to a dry round-bottomed flask, dissolved with methanol (5 mL) and TFA (5 mL), and the reaction was stirred at 25°C for 0.5 h, monitored by LC-MS. After the reaction, water and ethyl acetate were added for extraction 3 times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain the product 48-5 (302 mg). LC-MS: m/z 372 [M+H] +
步骤4、化合物48-6的合成Step 4. Synthesis of compound 48-6
在干燥的圆底烧瓶中加入48-5(302mg,813.1μmol)，用甲醇(3mL)溶解，0摄氏度下搅拌反应5分钟后，缓慢滴加加入MeONa的甲醇溶液(240μL)，0摄氏度至室温下搅拌反应1小时，LC-MS监测。反应结束后，加入水和乙酸乙酯萃取3次，合并有机相，用食盐水洗，无水硫酸钠干燥后减压浓缩，用中压反相制备柱纯化得到产物48-6(230mg)。LC-MS：m/z 326[M+H] + 48-5 (302 mg, 813.1 μmol) was added to a dry round-bottomed flask, dissolved in methanol (3 mL), and the reaction was stirred at 0 degrees Celsius for 5 minutes, then slowly added dropwise MeONa methanol solution (240 μL), 0 degrees Celsius to room temperature The reaction was stirred for 1 hour under LC-MS monitoring. After the reaction, water and ethyl acetate were added for extraction 3 times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified with a medium-pressure reverse-phase preparative column to obtain the product 48-6 (230 mg). LC-MS: m/z 326[M+H] +
步骤5、化合物48-7的合成Step 5. Synthesis of compound 48-7
化合物48-7由48-6拆分得到Compound 48-7 was resolved from 48-6
步骤6、化合物48-8的合成Step 6. Synthesis of compound 48-8
按照实施例5中步骤9的合成方法，将步骤9中的5-9替换为48-7，合成方法相同，得到产物48-9(33mg)。LC-MS：m/z 576[M+H] +。 According to the synthesis method of step 9 in Example 5, 5-9 in step 9 was replaced with 48-7, and the synthesis method was the same to obtain the product 48-9 (33 mg). LC-MS: m/z 576 [M+H] + .
步骤7、化合物48的合成Step 7. Synthesis of compound 48
按照实施例5中步骤10的合成方法，将步骤10中的5-10替换为48-9，合成方法相同，得到产物48(8mg)。LC-MS：m/z 483.3[M+H] +。 According to the synthesis method of step 10 in Example 5, 5-10 in step 10 was replaced with 48-9, and the synthesis method was the same to obtain product 48 (8 mg). LC-MS: m/z 483.3 [M+H] + .
1H NMR(600MHz,DMSO-d 6)δ8.15-5.81(m,8H),5.58-4.96(m,2H),4.17-3.75(m,3H),3.58-3.07(m,2H),2.69(s,1H),2.16-1.39(m,5H). 1 H NMR (600MHz, DMSO-d 6 ) δ 8.15-5.81(m, 8H), 5.58-4.96(m, 2H), 4.17-3.75(m, 3H), 3.58-3.07(m, 2H), 2.69 (s,1H),2.16-1.39(m,5H).
试验例1、酶活性实验Test Example 1. Enzyme Activity Experiment
化合物准备Compound preparation
1)取DMSO将化合物溶解到浓度为10mM测试化合物和10mM参考化合物(Baloxavir acid),将化合物用DMSO进行3倍或4倍稀释，配置成100倍DMSO溶液，共10个计量点。取4uL 100倍稀释好的化合物到96uL 1倍缓冲液中(20mM Tris-HCl,50mM NaCl,2mM MnCl 2,10mMβ-mercaptoethanol,0.05％Tween-20,pH 8.0)中，得到4倍化合物溶液。测试化合物在酶反应液中的最高浓度分别为1uM在A型流感病毒H1N1_WSN_1933PAN(蛋白系列为1-196,del52-72)和10uM在B型流感病毒Lee_1940PAN(蛋白系列为1-198)。 1) Dissolve the compound in DMSO to a concentration of 10 mM test compound and 10 mM reference compound (Baloxavir acid), dilute the compound 3-fold or 4-fold with DMSO, and prepare a 100-fold DMSO solution, with a total of 10 measurement points. Take 4uL of 100-fold diluted compound into 96uL of 1-fold buffer (20mM Tris-HCl, 50mM NaCl, 2mM MnCl 2 , 10mM β-mercaptoethanol, 0.05% Tween-20, pH 8.0) to obtain a 4-fold compound solution. The highest concentrations of test compounds in the enzyme reaction solution were 1 uM in influenza A virus H1N1_WSN_1933PAN (protein series 1-196, del52-72) and 10 uM in influenza B virus Lee_1940PAN (protein series 1-198).
酶学实验Enzyme experiment
1)准备4倍酶溶液(终浓度为10nM A型流感病毒H1N1_WSN_1933 PAN和250nM B型流感病毒Lee_1940 PAN)和两倍底物溶液(单链DNA底物)(终浓度为0.3uM)(单链DNA底物系列为[6-FAM]AAT CGC AGG CAG CAC TC[BHQ1](生工定制合成)1) Prepare 4 times enzyme solution (final concentration of 10nM influenza A virus H1N1_WSN_1933 PAN and 250nM influenza B virus Lee_1940 PAN) and twice substrate solution (single-stranded DNA substrate) (final concentration of 0.3uM) (single-stranded The DNA substrate series is [6-FAM]AAT CGC AGG CAG CAC TC[BHQ1] (custom synthesis)
2)在384孔检测板(康宁，货号：3575)中，每孔加入5uL 4倍化合物溶液和5uL 4倍酶溶液，在空白组加入等量的1倍缓冲液替代酶溶液作为100％抑制对照(阴性对照)，加入等量的1倍缓冲液替代化合物溶液作为0％抑制对照(阳性对照)，1000rpm,25℃,离心1分钟。将384检测板放入酶标板孵育摇床中于25℃，220rpm混匀并孵育15分钟。2) In a 384-well assay plate (Corning, product number: 3575), add 5uL 4x compound solution and 5uL 4x enzyme solution to each well, and add an equal amount of 1x buffer to replace the enzyme solution in the blank group as a 100% inhibition control (negative control), add an equal amount of 1-fold buffer to replace the compound solution as a 0% inhibition control (positive control), centrifuge at 1000 rpm, 25° C. for 1 minute. Put the 384 detection plate into the ELISA plate incubation shaker at 25°C, 220rpm, mix well and incubate for 15 minutes.
3)将384检测板中加入10uL2倍底物溶液，1000rpm,25℃,离心1分钟。将384检测板放入酶标板孵育摇床中于37℃，220rpm混匀并孵育120分钟。3) Add 10uL of 2x substrate solution to the 384 detection plate, centrifuge at 1000rpm, 25°C for 1 minute. Put the 384 detection plate into the ELISA plate incubation shaker at 37°C, 220rpm, mix well and incubate for 120 minutes.
4)用Tecan Spark 20M于激发波长Ex为485nm(波宽为10nm)和发射波长Em为535nm(波宽为10nm)检测荧光，据阳性对照(最大信号对照)和阴性对照(最小信号对照)获得的读数荧光信号进行标准化，以给出不同浓度化合物的抑制率。再通过GraphPad Prism 6以log(inhibitor)vs.response-Variable slope模式拟合计算得出化合物对酶活性抑制的IC 50。拟合方程为：Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))，其中Y代表已知的百分剩余酶活性，X代表Log后的已知化合物的浓度在通过计算得出化合物对酶活性抑制的IC 50。 4) Detect fluorescence with Tecan Spark 20M at excitation wavelength Ex of 485 nm (wave width of 10 nm) and emission wavelength of Em of 535 nm (wave width of 10 nm), and obtained according to positive control (maximum signal control) and negative control (minimum signal control) The readout fluorescence signals were normalized to give the inhibition rates of different concentrations of compounds. The IC 50 of compound inhibition of enzymatic activity was then calculated by GraphPad Prism 6 with log(inhibitor) vs. response-Variable slope model fitting. The fitting equation is: Y=Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope)), where Y represents the known percent remaining enzyme activity, and X represents the known percent remaining enzyme activity after Log The concentration of the compound was calculated to give the IC50 of the compound's inhibition of enzymatic activity.
5)试验结果：本发明化合物对10nM流感病毒A H1N1_WSN_1933 PAN和流感病毒B Lee_1940 PAN均具有的酶活性抑制的IC 50，在表1中展示。 5) Test results: The IC 50 of the compounds of the present invention for inhibiting the enzymatic activity of 10 nM influenza virus A H1N1_WSN_1933 PAN and influenza virus B Lee_1940 PAN is shown in Table 1.
表1 本发明化合物对流感病毒A/WSN/33(H1N1)和流感病毒B/Lee/40的抑制活性Table 1 Inhibitory activity of the compounds of the present invention on influenza virus A/WSN/33 (H1N1) and influenza virus B/Lee/40
Figure PCTCN2022077312-appb-000105
Figure PCTCN2022077312-appb-000105
Figure PCTCN2022077312-appb-000106
Figure PCTCN2022077312-appb-000106
Figure PCTCN2022077312-appb-000107
Figure PCTCN2022077312-appb-000107
其中“+”代表≤10，“++”代表＞10且≤50，“+++”代表＞50且≤250，“++++”代表＞250；N/A表示未检测。"+" means ≤10, "++" means >10 and ≤50, "+++" means >50 and ≤250, "++++" means >250; N/A means not detected.
上述实验表明，本发明化合物对流感病毒A H1N1_WSN_1933 PAN和流感病毒B Lee_1940 PAN酶活性具有较强的抑制作用。The above experiments show that the compounds of the present invention have a strong inhibitory effect on the enzymatic activity of influenza virus A H1N1_WSN_1933 PAN and influenza virus B Lee_1940 PAN.
试验例2、细胞活性Test Example 2. Cell Activity
MDCK细胞以一定密度接种导微孔板中并于5％CO 2、37℃培养箱中培养过夜。第二天，加入倍比稀释后的化合物和病毒。设置细胞对照(细胞，无化合物处理或病毒感染)，病毒对照(细胞感染病毒，无化合物处理)和培养液对照(只有培养液)。培养液中DMSO的终浓度分别为0.5％。细胞于5％CO 2、33-37℃培养箱中培养5天。细胞毒性试验与抗病毒实验条件相同，但无病毒感染。使用细胞活力检测试剂盒CCK8检测细胞活力。化合物的抗病毒活性和细胞毒性分别由不同浓度下的化合物对病毒引起的细胞病变效应的抑制率(％)和MRC5细胞的活率(％)表示。使用GraphPad Prism对化合物的抑制率和细胞活率进行非线性拟合分析，计算化合物的半数有效浓度(EC 50)和半数细胞毒性浓度(CC 50)值。 MDCK cells were seeded into microtiter plates at a certain density and cultured in a 5% CO 2 , 37° C. incubator overnight. The next day, double-diluted compound and virus were added. Cell controls (cells, no compound treatment or virus infection), virus controls (cells infected with virus, no compound treatment) and broth controls (broth only) were set up. The final concentration of DMSO in the culture medium was 0.5%, respectively. Cells were cultured in a 5% CO2 , 33-37°C incubator for 5 days. The cytotoxicity test was under the same conditions as the antiviral test, but there was no virus infection. Cell viability was detected using the cell viability assay kit CCK8. The antiviral activity and cytotoxicity of the compounds were expressed by the inhibition rate (%) of the compounds against virus-induced cytopathic effects and the viability (%) of MRC5 cells at different concentrations, respectively. Using GraphPad Prism, non-linear fitting analysis was performed on the inhibition rate and cell viability rate of the compounds, and the half effective concentration (EC 50 ) and half cytotoxic concentration (CC 50 ) values of the compounds were calculated.
表2 部分化合物对流感病毒的体外活性EC 50及对感染病毒细胞的CC 50 Table 2 In vitro activity EC 50 of some compounds against influenza virus and CC 50 against virus-infected cells
Figure PCTCN2022077312-appb-000108
Figure PCTCN2022077312-appb-000108
Figure PCTCN2022077312-appb-000109
Figure PCTCN2022077312-appb-000109
上述实验表明，本发明化合物具有很好的抗流感病毒活性，和/或很低的细胞毒性。The above experiments show that the compounds of the present invention have good anti-influenza virus activity and/or low cytotoxicity.
试验例3、药代动力学评价Test Example 3. Pharmacokinetic Evaluation
为考察化合物大鼠药代属性，化合物溶液通过静脉注射/口服灌胃的方式以相应剂量分别给予3只雄性SD大鼠，在给药后5min,15min,30min,1h,2h,4h,8h,24h分别采集大鼠抗凝全血并分离血浆；为考察化合物的小鼠药代属性，化合物通过静脉注射/口服灌胃方式，以相应剂量分别给予6只雄性ICR小鼠，每途径给药小鼠分为A/B两组，其中A组小鼠给药后在5min,30min,2h,8h采集抗凝全血，B组小鼠在给药后在15min,1h,4h,24h采集抗凝全血，分离血浆；In order to investigate the pharmacokinetic properties of the compound in rats, the compound solution was administered to 3 male SD rats at corresponding doses by intravenous injection/oral gavage. Rat anticoagulated whole blood was collected for 24 hours and plasma was separated; in order to investigate the pharmacokinetic properties of the compound in mice, the compound was administered to 6 male ICR mice by intravenous injection/oral gavage at the corresponding dose, and each route was administered for a small amount of time. The mice were divided into two groups, A/B. Anticoagulated whole blood was collected from mice in group A at 5min, 30min, 2h, and 8h after administration, and anticoagulated blood was collected from mice in group B at 15min, 1h, 4h, and 24h after administration. whole blood, separated plasma;
使用LC-MS，通过标准曲线校正法测定化合物的血浆浓度。使用Winnolin 5.2软件，将血浆浓度-时间数据拟合为药代参数，包括消除半衰期(T 1/2)，采样终点血浆药时曲线下面积(AUC last)，峰浓度(C max)，表观分布容积(Vz)，总清除率(Cl)，绝对生物利用度(F％)等。 Plasma concentrations of compounds were determined by standard curve calibration using LC-MS. Using Winnolin 5.2 software, the plasma concentration-time data were fitted to pharmacokinetic parameters, including elimination half-life (T 1/2 ), area under the curve (AUC last ), peak concentration (C max ), apparent Volume of distribution (Vz), total clearance (Cl), absolute bioavailability (F%), etc.
表3 部分化合物在动物体内的药代动力学数据Table 3 Pharmacokinetic data of some compounds in animals
Figure PCTCN2022077312-appb-000110
Figure PCTCN2022077312-appb-000110

Claims (19)

  1. 式I所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐：The compound shown in formula I, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt:
    Figure PCTCN2022077312-appb-100001
    Figure PCTCN2022077312-appb-100001
    其中，in,
    R 1、R 2、R 3、R 4、R 5、R 6分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1a、-C 0～4亚烷基-OC(O)R 1a、-C 0～4亚烷基-SR 1a、-C 0～4亚烷基-C(O)R 1a、-C 0～4亚烷基-C(O)OR 1a、-C 0～4亚烷基-C(O)NR 1aR 1b、-C 0～4亚烷基-NR 1aR 1b、-C 0～4亚烷基-NR 1aC(O)R 1b、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)、-C 0～4亚烷基-S(O) 2R 1a、-C 0～4亚烷基-S(O)R 1a、-C 0～4亚烷基-S(O) 2NR 1aR 1b、-C 0～4亚烷基-S(O)NR 1aR 1b；其中亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个、三个、四个或五个独立的R 1c取代；且R 1、R 2、R 3、R 4、R 5、R 6不同时选自氢； R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkane optionally substituted by halogen base, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1a , -C 0-4 alkylene -OC(O)R 1a , -C 0-4 alkylene-SR 1a , -C 0-4 alkylene-C(O)R 1a , -C 0-4 alkylene-C(O)OR 1a , -C 0-4 alkylene-C(O)NR 1a R 1b , -C 0-4 alkylene-NR 1a R 1b , -C 0-4 alkylene-NR 1a C(O)R 1b , -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl) , -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group), -C 0-4 alkylene-S (O) 2 R 1a , -C 0-4 alkylene-S(O)R 1a , -C 0-4 alkylene-S(O) 2 NR 1a R 1b , -C 0-4 alkylene -S(O)NR 1a R 1b ; wherein alkylene, carbocyclyl, heterocycloalkyl, aryl, arylheterocyclyl may be further separated by one, two, three, four or five independent and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are not simultaneously selected from hydrogen;
    R 1a、R 1b分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；其中，所述的烷基、烯基、炔基、亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R 1c取代；或者，R 1a、R 1b与相连原子一起形成饱和或不饱和的4～10元杂环烷基； R 1a and R 1b are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ; Wherein, the alkyl group, alkenyl group, alkynyl group, alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring group, aromatic heterocyclic group can be further replaced by one, two or three independent R 1c substituted; or, R 1a and R 1b together with the connecting atoms form a saturated or unsaturated 4-10-membered heterocycloalkyl;
    每个R 1c分别独立选自氢、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、卤素、氰基、-OH、-SH、-OC 1～6烷基、-O(卤素取代的C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)、-C 0～4亚烷基-S(O) 2R 1d、-C 0～4亚烷基-S(O)R 1d、-C 0～4亚烷基-S(O) 2NR 1dR 1e、-C 0～4亚烷基-S(O)NR 1dR 1e； Each R 1c is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen group, halogen, cyano, -OH, -SH, -OC 1-6 alkyl, -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl), -N(C 1-6 alkyl) (C 1-6 alkyl), -C 0-4 alkylene-S(O) 2 R 1d , -C 0-4 alkylene-S(O)R 1d , -C 0-4 alkylene-S(O) 2 NR 1d R 1e , -C 0-4 alkylene-S(O)NR 1d R 1e ;
    R 1d、R 1e分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)； R 1d and R 1e are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ;
    或者，or,
    R 1与R 2、R 3与R 4、R 5与R 6分别与相连原子一起形成
    Figure PCTCN2022077312-appb-100002
    饱和或不饱和的3～10元碳环基、饱和或不饱和的4～10元杂环烷基；其所述碳环基、杂环烷基可进一步被一个、两个、三个、四个、五个、六个或七个独立的R 1d取代；     R 1 and R 2 , R 3 and R 4 , R 5 and R 6 are formed together with the connecting atoms, respectively
    Figure PCTCN2022077312-appb-100002
    Saturated or unsaturated 3- to 10-membered carbocyclic groups, saturated or unsaturated 4- to 10-membered heterocycloalkyl groups; the carbocyclic groups and heterocycloalkyl groups may be further replaced by one, two, three, four one, five, six or seven independent R 1d substitutions;
    每个R 1d分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1e、-C 0～4亚烷基-OC(O)R 1e、-C 0～4亚烷基-C(O)R 1e、-C 0～4亚烷基-C(O)OR 1e、-C 0～4亚烷基-C(O)NR 1eR 1f、-C 0～4亚烷基-NR 1eR 1f、-C 0～4亚烷基-NR 1eC(O)R 1f、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷 基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；其中亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R 1g取代； Each R 1d is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1e , -C 0-4 alkylene-OC(O)R 1e , -C 0-4 Alkylene-C(O)R 1e , -C 0-4 alkylene-C(O)OR 1e , -C 0-4 alkylene-C(O)NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 alkylene-NR 1e C(O)R 1f , -C 0-4 alkylene-(saturated or unsaturated 3-10 membered carbocyclic group) , -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 Alkylene-(5-10-membered aromatic heterocyclic group); wherein alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring group, aromatic heterocyclic group can be further replaced by one, two or three independent R 1g replaced;
    R 1e、R 1f分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；其中，所述的烷基、烯基、炔基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R 1g取代；或者，R 1e、R 1f与相连原子一起形成饱和或不饱和的4～10元杂环烷基； R 1e and R 1f are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ; wherein, the alkyl, alkenyl, alkynyl, carbocyclic, heterocycloalkyl, aryl, and aryl heterocyclic groups may be further substituted by one, two or three independent R 1g ; or, R 1e and R 1f together with the connecting atoms form a saturated or unsaturated 4-10-membered heterocycloalkyl;
    每个R 1g分别独立选自氢、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、卤素、氰基、-SH、-OH、-O(C 1～6烷基)、-O(卤素取代的C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)； Each R 1g is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen base, halogen, cyano, -SH, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl) base), -N(C 1-6 alkyl) (C 1-6 alkyl);
    或者，or,
    两个独立的R 1d与相连的原子一起形成
    Figure PCTCN2022077312-appb-100003
    饱和或不饱和的3～10元碳环基、饱和或不饱和的4～10元杂环烷基、6～10元芳环基、5～10元芳杂环基；其中碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个、三个、四个或五个R 1h取代；     Two independent R 1ds are formed together with connected atoms
    Figure PCTCN2022077312-appb-100003
    Saturated or unsaturated 3-10-membered carbocyclic group, saturated or unsaturated 4-10-membered heterocycloalkyl, 6-10-membered aromatic ring group, 5-10-membered aromatic heterocyclic group; wherein carbocyclic group, heterocyclic group Cycloalkyl, aryl, and aryl heterocyclyl may be further substituted with one, two, three, four or five R 1h ;
    每个R 1h分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1i、-C 0～4亚烷基-OC(O)R 1i、-C 0～4亚烷基-C(O)R 1i、-C 0～4亚烷基-C(O)OR 1i、-C 0～4亚烷基-C(O)NR 1iR 1j、-C 0～4亚烷基-NR 1iR 1j、-C 0～4亚烷基-NR 1iC(O)R 1j、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；或者，两个独立的R 1h与相连的原子一起形成
    Figure PCTCN2022077312-appb-100004
    Figure PCTCN2022077312-appb-100005
    Each R 1h is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1i , -C 0-4 alkylene-OC(O)R 1i , -C 0-4 Alkylene-C(O)R 1i , -C 0-4 alkylene-C(O)OR 1i , -C 0-4 alkylene-C(O)NR 1i R 1j , -C 0-4 Alkylene-NR 1i R 1j , -C 0-4 alkylene-NR 1i C(O)R 1j , -C 0-4 alkylene-(saturated or unsaturated 3- to 10-membered carbocyclic group) , -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 Alkylene-(5-10-membered aromatic heterocyclyl); alternatively, two independent R 1h form together with the connected atoms
    Figure PCTCN2022077312-appb-100004
    Figure PCTCN2022077312-appb-100005
    R 1i、R 1j分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、-任选被卤素取代的C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)； R 1i and R 1j are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ;
    A选自5～30个原子构成的单环、双稠环、三稠环、四稠环、五稠环或六稠环的饱和或者不饱和的碳环基、饱和或不饱和的杂环烷基、芳环基或芳杂环基；其中碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个、三个、四个、五个、六个或七个R A1取代； A is selected from a saturated or unsaturated carbocyclic group, a saturated or unsaturated heterocycloalkane composed of 5 to 30 atoms consisting of a monocyclic, bi-fused, tri-fused, tetra-fused, penta-fused or hexa-fused ring wherein the carbocyclyl, heterocycloalkyl, aryl, and aromatic heterocyclyl may be further combined with one, two, three, four, five, six or seven R A1 substitutions;
    每个R A1分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR A2、-C 0～4亚烷基-OC(O)R A2、-C 0～4亚烷基-C(O)R A2、-C 0～4亚烷基-C(O)OR A2、-C 0～4亚烷基-C(O)NR A2R A3、-C 0～4亚烷基-NR A2R A3、-C 0～4亚烷基-NR A2C(O)R A3、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)、-C 0～4亚烷基-S(O) 2R A2、-C 0～4亚烷基-S(O)R A2、-C 0～4亚烷基-S(O) 2NR A2R A3、-C 0～4亚烷基-S(O)NR A2R A3；其中亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R A4取代； Each R A1 is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR A2 , -C 0-4 alkylene-OC(O)R A2 , -C 0-4 Alkylene-C(O)R A2 , -C 0-4 alkylene-C(O)OR A2 , -C 0-4 alkylene-C(O)NR A2 R A3 , -C 0-4 Alkylene-NR A2 R A3 , -C 0-4 alkylene-NR A2 C(O)R A3 , -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group) , -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 Alkylene-(5-10-membered aromatic heterocyclic group), -C 0-4 alkylene-S(O) 2 R A2 , -C 0-4 alkylene-S(O)R A2 , -C 0-4 alkylene-S(O) 2 NR A2 R A3 , -C 0-4 alkylene-S(O)NR A2 R A3 ; wherein alkylene, carbocyclic, heterocycloalkyl, aryl The cyclic group and the aromatic heterocyclic group can be further substituted by one, two or three independent R A4 ;
    R A2、R A3分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6 烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；或者，R A2、R A3与相连原子一起形成饱和或不饱和的4～10元杂环烷基； R A2 and R A3 are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene-(saturated or unsaturated Saturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group) ; Or, R A2 and R A3 together with the connecting atom form a saturated or unsaturated 4-10-membered heterocycloalkyl;
    每个R A4分别独立选自氢、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、卤素、氰基、-SH、-OH、-O(C 1～6烷基)、-O(卤素取代的C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)； Each R A4 is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen base, halogen, cyano, -SH, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl) base), -N(C 1-6 alkyl) (C 1-6 alkyl), -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0- 4 -alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-( 5-10-membered aromatic heterocyclic group);
    或者，or,
    两个独立的R A1与相连的原子一起形成
    Figure PCTCN2022077312-appb-100006
    饱和或不饱和的3～10元碳环基、饱和或不饱和的3～10元杂环烷基；其中所述碳环基、杂环烷基可进一步被一个、两个或三个R A5取代；     Two independent R A1s are formed together with connected atoms
    Figure PCTCN2022077312-appb-100006
    Saturated or unsaturated 3-10-membered carbocyclic group, saturated or unsaturated 3-10-membered heterocycloalkyl group; wherein the carbocyclic group and heterocycloalkyl group can be further replaced by one, two or three R A5 replace;
    每个R A5分别独立选自氢、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、卤素、氰基、-SH、-OH、-O(C 1～6烷基)、-O(卤素取代的C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；或者，两个独立的R A5与相连的原子一起形成
    Figure PCTCN2022077312-appb-100007
    Each R A5 is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen base, halogen, cyano, -SH, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl) base), -N(C 1-6 alkyl) (C 1-6 alkyl), -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0- 4 -alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-( 5-10-membered aromatic heterocyclic group); alternatively, two independent R A5 are formed together with the connected atoms
    Figure PCTCN2022077312-appb-100007
    所述的饱和或不饱和杂环烷基、芳杂环基中的杂原子各自独立的选自O、S、B或N中的一种或几种，所述不饱和碳环基不包括芳基，所述不饱和杂环烷基不包括芳杂环基。The heteroatoms in the saturated or unsaturated heterocycloalkyl and aromatic heterocyclic groups are independently selected from one or more of O, S, B or N, and the unsaturated carbocyclic group does not include aromatic group, the unsaturated heterocycloalkyl group does not include an aromatic heterocyclic group.
  2. 根据权利要求1所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：式I所示化合物如式Ia、式Ib、式Ic所式：The compound according to claim 1 or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt, is characterized in that: the compound represented by formula I is represented by formula Ia, formula Ib, and formula Ic :
    Figure PCTCN2022077312-appb-100008
    Figure PCTCN2022077312-appb-100008
    其中，in,
    B环选自饱和或不饱和的3～10元碳环基、饱和或不饱和的4～10元杂环烷基；其中饱和或不饱和的碳环基、饱和或不饱和的杂环烷基可进一步被一个、两个、三个、四个或五个独立的R 1d取代； Ring B is selected from saturated or unsaturated 3- to 10-membered carbocyclic groups, saturated or unsaturated 4- to 10-membered heterocycloalkyl groups; wherein saturated or unsaturated carbocyclic groups, saturated or unsaturated heterocycloalkyl groups may be further substituted with one, two, three, four or five independent R 1d ;
    每个R 1d分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1e、-C 0～4亚烷基-OC(O)R 1e、-C 0～4亚烷基-C(O)R 1e、-C 0～4亚烷基-C(O)OR 1e、-C 0～4亚烷基-C(O)NR 1eR 1f、-C 0～4亚烷基-NR 1eR 1f、-C 0～4亚烷基-NR 1eC(O)R 1f、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；其中亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R 1g取代； Each R 1d is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1e , -C 0-4 alkylene-OC(O)R 1e , -C 0-4 Alkylene-C(O)R 1e , -C 0-4 alkylene-C(O)OR 1e , -C 0-4 alkylene-C(O)NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 alkylene-NR 1e C(O)R 1f , -C 0-4 alkylene-(saturated or unsaturated 3-10 membered carbocyclic group) , -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 Alkylene-(5-10-membered aromatic heterocyclic group); wherein alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring group, aromatic heterocyclic group can be further replaced by one, two or three independent R 1g replaced;
    或者，or,
    两个独立的R 1d与相连的原子一起形成
    Figure PCTCN2022077312-appb-100009
    饱和或不饱和的3～10元碳环基、饱和或不饱和的4～10元杂环烷基、6～10元芳环基、5～10元芳杂环基；其中碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个R 1h取代。     Two independent R 1ds are formed together with connected atoms
    Figure PCTCN2022077312-appb-100009
    Saturated or unsaturated 3-10-membered carbocyclic group, saturated or unsaturated 4-10-membered heterocycloalkyl, 6-10-membered aromatic ring group, 5-10-membered aromatic heterocyclic group; wherein carbocyclic group, heterocyclic group Cycloalkyl, aryl, and aryl heterocyclyl may be further substituted with one, two or three R 1h .
  3. 根据权利要求2所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：B环选自饱和的3元碳环基、饱和的4元碳环基、饱和或不饱和的5元碳环基、饱和或不饱和的6元碳环基、饱和的4元杂环烷基、饱和或不饱和的5元杂环烷基、饱和或不饱和的6元杂环烷基；其中杂环烷基的杂原子选自N、O、S；其中碳环基、杂环烷基可进一步被一个、两个、三个、四个或五个独立的R 1d取代。 The compound according to claim 2, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt, wherein the B ring is selected from the group consisting of saturated 3-membered carbocyclyl, saturated 4-membered Carbocyclyl, saturated or unsaturated 5-membered carbocyclyl, saturated or unsaturated 6-membered carbocyclyl, saturated 4-membered heterocycloalkyl, saturated or unsaturated 5-membered heterocycloalkyl, saturated or unsaturated Saturated 6-membered heterocycloalkyl; wherein the heteroatoms of the heterocycloalkyl are selected from N, O, S; wherein the carbocyclyl, the heterocycloalkyl can be further replaced by one, two, three, four or five Independent R 1d substitutions.
  4. 根据权利要求3所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：The compound according to claim 3 or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt, is characterized in that:
    所述B环选自
    Figure PCTCN2022077312-appb-100010
    Figure PCTCN2022077312-appb-100011
    Figure PCTCN2022077312-appb-100012
    其中所述B环可进一步被一个、两个或三个独立的R 1d取代；     The B ring is selected from
    Figure PCTCN2022077312-appb-100010
    Figure PCTCN2022077312-appb-100011
    Figure PCTCN2022077312-appb-100012
    wherein the B ring may be further substituted with one, two or three independent R 1d ;
    每个R 1d分别独立选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1e、-C 0～4亚烷基-OC(O)R 1e、-C 0～4亚烷基-C(O)R 1e、-C 0～4亚烷基-C(O)OR 1e、-C 0～4亚烷基-C(O)NR 1eR 1f、-C 0～4亚烷基-NR 1eR 1f、-C 0～4亚烷基-NR 1eC(O)R 1f、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；其中亚烷基、碳环基、杂环烷基、芳环基、芳杂环基可进一步被一个、两个或三个独立的R 1g取代； Each R 1d is independently selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 optionally substituted by halogen Alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-OR 1e , -C 0-4 alkylene-OC(O)R 1e , -C 0-4 Alkylene-C(O)R 1e , -C 0-4 alkylene-C(O)OR 1e , -C 0-4 alkylene-C(O)NR 1e R 1f , -C 0-4 Alkylene-NR 1e R 1f , -C 0-4 alkylene-NR 1e C(O)R 1f , -C 0-4 alkylene-(saturated or unsaturated 3-10 membered carbocyclic group) , -C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 Alkylene-(5-10-membered aromatic heterocyclic group); wherein alkylene group, carbocyclic group, heterocycloalkyl group, aromatic ring group, aromatic heterocyclic group can be further replaced by one, two or three independent R 1g replaced;
    或者，or,
    两个独立的R 1d与相连的原子一起形成
    Figure PCTCN2022077312-appb-100013
    饱和或不饱和的3～10元碳环基、饱和或不饱和的4～10元杂环烷基、6～10元芳环基、5～10元芳杂环基；     Two independent R 1ds are formed together with connected atoms
    Figure PCTCN2022077312-appb-100013
    Saturated or unsaturated 3-10-membered carbocyclic group, saturated or unsaturated 4-10-membered heterocycloalkyl, 6-10-membered aromatic ring group, 5-10-membered aromatic heterocyclic group;
    R 1e、R 1f分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6支链或直链烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)；或者， R 1e、R 1f与相连原子一起形成饱和或不饱和的4～10元杂环烷基； R 1e and R 1f are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 branched or straight-chain alkyl optionally substituted by halogen, -C 2 - optionally substituted by halogen 6 alkenyl, -C 2-6 alkynyl optionally substituted by halogen, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0-4 alkylene -(Saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocyclic group); or, R 1e and R 1f together with the connecting atoms form a saturated or unsaturated 4-10-membered heterocycloalkyl group;
    每个R 1g分别独立选自氢、任选被卤素取代的-C 1～6烷基、-任选被卤素取代的C 2～6烯基、任选被卤素取代的-C 2～6炔基、卤素、氰基、-SH、-OH、-O(C 1～6烷基)、-O(卤素取代的C 1～6烷基)、-NH 2、-NH(C 1～6烷基)、-N(C 1～6烷基)(C 1～6烷基)。 Each R 1g is independently selected from hydrogen, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, -C 2-6 alkyne optionally substituted by halogen base, halogen, cyano, -SH, -OH, -O (C 1-6 alkyl), -O (halogen-substituted C 1-6 alkyl), -NH 2 , -NH (C 1-6 alkyl) base), -N(C 1-6 alkyl) (C 1-6 alkyl).
  5. 根据权利要求3所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：The compound according to claim 3 or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt, is characterized in that:
    两个独立的R 1d相连形成饱和的3元碳环基、饱和的4元碳环基、饱和或不饱和的5元碳环基、饱和或不饱和的6元碳环基、饱和的4元杂环烷基、饱和或不饱和的5元杂环烷基、饱和或不饱和的6元杂环烷基；其中碳环基、杂环烷基可进一步被一个、两个或三个R 1h取代。 Two independent R 1ds are connected to form saturated 3-membered carbocyclyl, saturated 4-membered carbocyclyl, saturated or unsaturated 5-membered carbocyclyl, saturated or unsaturated 6-membered carbocyclyl, saturated 4-membered carbocyclyl Heterocycloalkyl, saturated or unsaturated 5-membered heterocycloalkyl, saturated or unsaturated 6-membered heterocycloalkyl; wherein carbocyclyl, heterocycloalkyl can be further replaced by one, two or three R 1h replace.
  6. 根据权利要求5所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：The compound according to claim 5 or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt, is characterized in that:
    所述B环选自
    Figure PCTCN2022077312-appb-100014
    Figure PCTCN2022077312-appb-100015
    Figure PCTCN2022077312-appb-100016
    其中所述B环可进一步被一个、两个或三个R 1h取代；     The B ring is selected from
    Figure PCTCN2022077312-appb-100014
    Figure PCTCN2022077312-appb-100015
    Figure PCTCN2022077312-appb-100016
    wherein the B ring may be further substituted with one, two or three R 1h ;
    R 1h选自氢、-OH，-SH、-NH 2、卤素、氰基、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-OR 1i、-C 0～4亚烷基-OC(O)R 1i、-C 0～4亚烷基-C(O)R 1i、-C 0～4亚烷基-C(O)OR 1i、-C 0～4亚烷基-C(O)NR 1iR 1j、-C 0～4亚烷基-NR 1iR 1j、-C 0～4亚烷基-NR 1iC(O)R 1j、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)； R 1h is selected from hydrogen, -OH, -SH, -NH 2 , halogen, cyano, -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any Select halogen-substituted -C 2-6 alkynyl, -C 0-4 alkylene-OR 1i , -C 0-4 alkylene-OC(O)R 1i , -C 0-4 alkylene- C(O)R 1i , -C 0-4 alkylene-C(O)OR 1i , -C 0-4 alkylene-C(O)NR 1i R 1j , -C 0-4 alkylene- NR 1i R 1j , -C 0-4 alkylene-NR 1i C(O)R 1j , -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), -C 0 ~4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene- (5-10-membered aromatic heterocyclic group);
    R 1i、R 1j分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、任选被卤素取代的-C 2～6烯基、任选被卤素取代的-C 2～6炔基、-C 0～4亚烷基-(3～10元碳环基)、-C 0～4亚烷基-(4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环烷基)。 R 1i and R 1j are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkenyl optionally substituted by halogen, any -C 2-6 alkynyl substituted by halogen, -C 0-4 alkylene-(3-10-membered carbocyclic group), -C 0-4 alkylene-(4-10-membered heterocycloalkyl) ), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene-(5-10-membered aromatic heterocycloalkyl).
  7. 根据权利要求1或2任一项所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：The compound according to any one of claims 1 or 2, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that:
    R 1、R 2、R 3、R 4、R 5、R 6分别独立选自氢、甲基、卤素、氰基、-OH、-SH、-C(O)NH 2、-NHC(O)CH 3、-OCH 3、
    Figure PCTCN2022077312-appb-100017
    且R 1、R 2、R 3、R 4、R 5、R 6不同时选自氢。     R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are independently selected from hydrogen, methyl, halogen, cyano, -OH, -SH, -C(O)NH 2 , -NHC(O) CH 3 , -OCH 3 ,
    Figure PCTCN2022077312-appb-100017
    And R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are not selected from hydrogen at the same time.
  8. 根据权利要求1或2任一项所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：The compound according to any one of claims 1 or 2, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that:
    A选自
    Figure PCTCN2022077312-appb-100018
    Figure PCTCN2022077312-appb-100019
    A is selected from
    Figure PCTCN2022077312-appb-100018
    Figure PCTCN2022077312-appb-100019
    其中每个X分别独立选自CH 2、NH、O或S；所述A选自的环可进一步被一个、两个、三个、四个或五个R A1取代。 wherein each X is independently selected from CH2 , NH, O, or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
  9. 根据权利要求8所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：The compound according to claim 8, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that:
    A选自
    Figure PCTCN2022077312-appb-100020
    Figure PCTCN2022077312-appb-100021
    A is selected from
    Figure PCTCN2022077312-appb-100020
    Figure PCTCN2022077312-appb-100021
  10. 根据权利要求8所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：The compound according to claim 8, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that:
    两个独立的R A1与其相连的原子一起形成饱和的3元碳环基、饱和的4元3元碳环基、饱和或不饱和的5元碳环基、饱和或不饱和的6元碳环基、饱和的4元杂环烷基、饱和或不饱和的5元杂环烷基、饱和或不饱和的6元杂环烷基。 Two independent R A1 together with the atoms to which they are attached form a saturated 3-membered carbocyclyl, a saturated 4-membered 3-membered carbocyclyl, a saturated or unsaturated 5-membered carbocyclyl, a saturated or unsaturated 6-membered carbocyclyl group, saturated 4-membered heterocycloalkyl, saturated or unsaturated 5-membered heterocycloalkyl, saturated or unsaturated 6-membered heterocycloalkyl.
  11. 根据权利要求10所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特 征在于：The compound according to claim 10, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that:
    A选自
    Figure PCTCN2022077312-appb-100022
    其中X选自CH 2、NH、O或S；所述A选自的环可进一步被一个、两个、三个、四个或五个R A1取代。     A is selected from
    Figure PCTCN2022077312-appb-100022
    wherein X is selected from CH 2 , NH, O or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
  12. 根据权利要求8所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：The compound according to claim 8, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that:
    A选自
    Figure PCTCN2022077312-appb-100023
    其中X选自CH 2、NH、O或S；所述A选自的环可进一步被一个、两个、三个或四个R A1取代。     A is selected from
    Figure PCTCN2022077312-appb-100023
    wherein X is selected from CH2 , NH, O or S; the ring selected by A may be further substituted with one, two, three or four R A1 .
  13. 式II、III所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐：The compound represented by formula II and III, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt:
    Figure PCTCN2022077312-appb-100024
    Figure PCTCN2022077312-appb-100024
    其中，in,
    R D1、R D2、R D3分别独立选自氢、-OH，-SH、-NH 2、任选被卤素取代的-C 1～6烷基、-任选被卤素取代的C 2～6烯基、任选被卤素取代的-C 2～6炔基、C 1～6烷基氧基、-C 0～4亚烷基-(饱和或不饱和的3～10元碳环基)、-C 0～4亚烷基-(饱和或不饱和的4～10元杂环烷基)、-C 0～4亚烷基-(6～10元芳环基)、-C 0～4亚烷基-(5～10元芳杂环基)； R D1 , R D2 and R D3 are independently selected from hydrogen, -OH, -SH, -NH 2 , -C 1-6 alkyl optionally substituted by halogen, -C 2-6 alkene optionally substituted by halogen base, -C 2-6 alkynyl optionally substituted by halogen, C 1-6 alkyloxy, -C 0-4 alkylene-(saturated or unsaturated 3-10-membered carbocyclic group), - C 0-4 alkylene-(saturated or unsaturated 4-10-membered heterocycloalkyl), -C 0-4 alkylene-(6-10-membered aromatic ring group), -C 0-4 alkylene base-(5-10-membered aromatic heterocyclic group);
    所述A环选自
    Figure PCTCN2022077312-appb-100025
    Figure PCTCN2022077312-appb-100026
    其中每个X分别独立选自CH 2、NH、O或S；所述A选自的环可进一步被一个、两个、三个、四个或五个R A1取代。     The A ring is selected from
    Figure PCTCN2022077312-appb-100025
    Figure PCTCN2022077312-appb-100026
    wherein each X is independently selected from CH2 , NH, O, or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
  14. 式Ⅳ所示的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐：The compound represented by formula IV, or its deuterated compound, or its stereoisomer, or its pharmaceutically acceptable salt:
    Figure PCTCN2022077312-appb-100027
    Figure PCTCN2022077312-appb-100027
    所述A环选自
    Figure PCTCN2022077312-appb-100028
    Figure PCTCN2022077312-appb-100029
    Figure PCTCN2022077312-appb-100030
    其中每个X分别独立选自CH 2、NH、O或S；所述A选自的环可进一步被一个、两个、三个、四个或五个R A1取代。     The A ring is selected from
    Figure PCTCN2022077312-appb-100028
    Figure PCTCN2022077312-appb-100029
    Figure PCTCN2022077312-appb-100030
    wherein each X is independently selected from CH2 , NH, O, or S; the ring selected by A may be further substituted with one, two, three, four or five R A1 .
  15. 根据权利要求1、2、13或14任一项所述的化合物或其氘代化合物、或其立体异构体、或其药学上可接受的盐，其特征在于：所述化合物具体为：The compound according to any one of claims 1, 2, 13 or 14, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is specifically:
    Figure PCTCN2022077312-appb-100031
    Figure PCTCN2022077312-appb-100031
    Figure PCTCN2022077312-appb-100032
    Figure PCTCN2022077312-appb-100032
    Figure PCTCN2022077312-appb-100033
    Figure PCTCN2022077312-appb-100033
    Figure PCTCN2022077312-appb-100034
    Figure PCTCN2022077312-appb-100034
  16. 权利要求1～15任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐在制备用于预防或治疗病毒感染疾病的药物中的用途。Use of the compound described in any one of claims 1 to 15, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating a virus-infected disease.
  17. 根据权利要求16所述的用途，其特征在于：所述病毒感染为流感病毒感染。The use according to claim 16, wherein the viral infection is influenza virus infection.
  18. 一种药物组合物，包括权利要求1～15任一所述的化合物、或其氘代化合物、或其立体异构体、或其药学上可接受的盐制备而成的制剂。A pharmaceutical composition, comprising a preparation prepared from the compound described in any one of claims 1 to 15, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  19. 根据权利要求18所述的药物组合物，其进一步药学上可接受的载体、辅料、媒介物。The pharmaceutical composition according to claim 18, further comprising a pharmaceutically acceptable carrier, adjuvant and vehicle.
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