CN114907365A - Influenza virus inhibitor and application thereof - Google Patents

Influenza virus inhibitor and application thereof Download PDF

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CN114907365A
CN114907365A CN202210117938.6A CN202210117938A CN114907365A CN 114907365 A CN114907365 A CN 114907365A CN 202210117938 A CN202210117938 A CN 202210117938A CN 114907365 A CN114907365 A CN 114907365A
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alkylene
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unsaturated
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CN114907365B (en
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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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Yangtze River Pharmaceutical Group Co Ltd
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    • 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
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    • 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
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • 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
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    • 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
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    • 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
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    • 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

Abstract

The invention provides a novel compound shown as a formula I and used as an influenza virus replication inhibitor and application thereof in treating influenza, and particularly relates to an influenza virus cap-dependent endonuclease inhibitor.

Description

Influenza virus inhibitor and application thereof
Technical Field
The invention relates to a novel compound serving as an influenza virus replication inhibitor and application thereof in treating influenza, in particular to an influenza virus cap-dependent endonuclease inhibitor.
Background
Influenza (flu) is an acute respiratory infectious disease caused by influenza virus that seriously harms human health. Influenza infection in humans is caused by influenza subtypes a and B, and influenza a viruses can be further classified according to the hemagglutinin (H or HA) and neuraminidase (N) antigen types, for example, subtypes H1N1, H1N2, H2N2, H3N1, etc., which have been found to exist.
The RNA polymerase of influenza virus is responsible for the replication and transcription of viral RNA, a heterotrimer consisting of 3 subunits: polymerase Acid (PA), polymerase base 1(PB1), and polymerase base 2(PB 2). Transcription of influenza virus RNA has a special "cap-robbing" mechanism, PB2 subunit is responsible for recognizing and binding the "cap structure" of host precursor mRNA, and PA subunit cleaves host mRNA as a primer, initiating the transcription process. The spliced mRNA primers were used in the PB1 subunit for viral mRNA synthesis. Because the cap-dependent endonuclease of the PA subunit is very conserved in the influenza variation process, is necessary for the virus life process, and has specificity of a binding site, the binding domain is very suitable to be used as a target of an anti-influenza drug for developing a novel anti-influenza drug.
A new anti-influenza agent, barusavir, having such a mechanism of action is marketed, and can inhibit synthesis of viral mRNA by inhibiting cap-dependent endonuclease, and finally inhibit viral proliferation. However, there is still a pressing need to develop additional compounds that are more active, have fewer side effects, and are more convenient to use for treating influenza through this mechanism.
Disclosure of Invention
The invention provides a compound shown as a formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0003497259860000011
wherein the content of the first and second substances,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 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 (ii) a Wherein alkylene, carbocyclyl, heterocycloalkyl, aromatic, arylheterocyclyl may be further substituted with one, two, three, four or five independent R 1c Substitution; and R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 Not simultaneously selected from hydrogen;
R 1a 、R 1b are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); wherein said alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocycloalkyl, arylcyclyl, arylheterocyclyl may be further substituted with one, two or three independent R 1c Substitution; or, R 1a 、R 1b Together with the linking atoms form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group;
each R 1c Each independently selected from hydrogen, optionally halogen substituted-C 1～6 Straight or branched alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-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 Are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group);
alternatively, the first and second electrodes may be,
R 1 and R 2 、R 3 And R 4 、R 5 And R 6 Are each formed together with the linking atom
Figure BDA0003497259860000021
A saturated or unsaturated 3-to 10-membered carbocyclic group, a saturated or unsaturated 4-to 10-membered heterocycloalkyl group; wherein said carbocyclyl, heterocycloalkyl may be further substituted with one, two, three, four, five, six or seven independent R 1d Substitution;
each R 1d Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); wherein the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two or three independent R 1g Substitution;
R 1e 、R 1f are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocycloalkyl, arylcyclyl, arylheterocyclyl may be further substituted with one, two or three independent R 1g Substitution; or, R 1e 、R 1f Together with the linking atoms form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group;
each R 1g Each independently selected from hydrogen, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, halogen, cyano, -SH, -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 groups);
alternatively, the first and second electrodes may be,
two independent R 1d Together with the linking atom form
Figure BDA0003497259860000031
A saturated or unsaturated 3-to 10-membered carbocyclic group, a saturated or unsaturated 4-to 10-membered heterocycloalkyl group, a 6-to 10-membered aromatic cyclic group, a 5-to 10-membered aromatic heterocyclic group; wherein the carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two, three, four or five R 1h Substitution;
each R 1h Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally 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)And/or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); or, two independent R 1h Together with the linking atom form
Figure BDA0003497259860000032
Figure BDA0003497259860000033
R 1i 、R 1j Are each independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group);
a is selected from a monocyclic, double-condensed ring, three-condensed ring, four-condensed ring, five-condensed ring or six-condensed ring saturated or unsaturated carbocyclyl, saturated or unsaturated heterocycloalkyl, aromatic ring or aromatic heterocyclic group consisting of 5-30 atoms; wherein the carbocyclyl, heterocycloalkyl, arylcyclyl, arylheterocyclyl may be further substituted with one, two, three, four, five, six or seven R A1 Substitution;
each R A1 Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 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 (ii) a Wherein the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two or three independent R A4 Substitution;
R A2 、R A3 are each independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); or, R A2 、R A3 Together with the linking atoms form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group;
each R A4 Each independently selected from hydrogen, optionally halogen substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, 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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group))；
Alternatively, the first and second electrodes may be,
two independent R A1 Together with the linking atom form
Figure BDA0003497259860000041
A saturated or unsaturated 3-to 10-membered carbocyclic group, a saturated or unsaturated 3-to 10-membered heterocycloalkyl group; wherein said carbocyclyl, heterocycloalkyl may be further substituted with one, two or three R A5 Substitution;
each R A5 Each independently selected from hydrogen, optionally halogen substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, halogen, cyano, -SH, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); or, two independent R A5 Together with the linking atom form
Figure BDA0003497259860000042
The heteroatoms in the saturated or unsaturated heterocyclic alkyl and aromatic heterocyclic radical are respectively and independently selected from one or more of O, S, B or N, the unsaturated carbocyclyl does not comprise aryl, and the unsaturated heterocyclic alkyl does not comprise aromatic heterocyclic radical.
Further, the air conditioner is provided with a fan,
a compound of formula I is represented by formula Ia, formula Ib, formula Ic:
Figure BDA0003497259860000043
wherein, the first and the second end of the pipe are connected with each other,
the B ring is selected from saturated or unsaturated 3-to 10-membered carbocyclic group, saturated or unsaturatedUnsaturated 4-to 10-membered heterocycloalkyl; wherein said saturated or unsaturated carbocyclyl, saturated or unsaturated heterocycloalkyl may be further substituted with one, two, three, four or five independent R 1d Substitution;
each R 1d Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); wherein the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two or three independent R 1g Substitution; two independent R 1d Together with the linking atom form
Figure BDA0003497259860000044
Figure BDA0003497259860000045
A saturated or unsaturated 3-to 10-membered carbocyclic group, a saturated or unsaturated 4-to 10-membered heterocycloalkyl group, a 6-to 10-membered aromatic cyclic group, a 5-to 10-membered aromatic heterocyclic group; wherein carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two or three R 1h And (4) substitution.
Further, in the case of a liquid crystal display device,
the B ring is selected from saturated or unsaturated 3-membered carbocyclyl, saturated or unsaturated 4-membered carbocyclyl, saturated or unsaturated 5-membered carbocyclyl, saturatedAnd or unsaturated 6-membered carbocyclyl, saturated or unsaturated 4-membered heterocycloalkyl, saturated or unsaturated 5-membered heterocycloalkyl, saturated or unsaturated 6-membered heterocycloalkyl; wherein the heteroatom of the heterocycloalkyl group is selected from N, O, S; wherein carbocyclyl, heterocycloalkyl may be further substituted with one, two, three, four or five independent R 1d And (4) substitution.
In a still further particular embodiment, the first and second,
the B ring is selected from
Figure BDA0003497259860000051
Figure BDA0003497259860000052
Figure BDA0003497259860000053
Wherein the B ring may be further substituted by one, two or three independent R 1d Substitution;
each R 1d Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); wherein the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two or three independent R 1g Substitution; or, two independent R 1d Together with the linking atom form
Figure BDA0003497259860000054
Figure BDA0003497259860000055
A saturated or unsaturated 3-to 10-membered carbocyclic group, a saturated or unsaturated 4-to 10-membered heterocycloalkyl group, a 6-to 10-membered aromatic cyclic group, a 5-to 10-membered aromatic heterocyclic group; (ii) a
R 1e 、R 1f Are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); or, R 1e 、R 1f Together with the linking atoms form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group;
each R 1g Each independently selected from hydrogen, optionally halogen substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, halogen, cyano, -SH, -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 groups).
In a still further particular embodiment, the first and second,
two independent R 1d Linked to form a saturated or unsaturated 3-membered carbocyclic group, a saturated or unsaturated 4-membered carbocyclic group, a saturated or unsaturated 5-membered carbocyclic group, a saturated or unsaturated 6-membered carbocyclic group, a saturated or unsaturated 4-membered heterocycloalkyl group, a saturated or unsaturated 5-membered heterocycloalkyl group, a saturated or unsaturated 6-membered heterocycloalkyl group; wherein the carbocyclyl, heterocycloalkyl may be further substituted by one, two or three R 1h And (4) substitution.
Still more particularly, it is contemplated that the first,
the B ring is selected from
Figure BDA0003497259860000061
Figure BDA0003497259860000062
Figure BDA0003497259860000063
Wherein the B ring may be further substituted by one, two or three R 1h Substitution;
R 1h selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally 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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group);
R 1i 、R 1j are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered heteroaromatic alkyl).
Further, the air conditioner is provided with a fan,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are each independently selected from hydrogen, methyl, halogen, cyano, -OH, -SH, -C (O) NH 2 、-NHC(O)CH 3 、-OCH 3 、
Figure BDA0003497259860000064
And R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 Not simultaneously selected from hydrogen.
Further, the air conditioner is provided with a fan,
a is selected from
Figure BDA0003497259860000071
Figure BDA0003497259860000072
Figure BDA0003497259860000073
Wherein each X is independently selected from CH 2 NH, O or S; the ring from which A is selected may be further substituted by one, two, three, four or five R A1 And (4) substitution.
Further, in the present invention,
a is selected from
Figure BDA0003497259860000074
Figure BDA0003497259860000075
Further, in the present invention,
two independent R A1 Together with the atoms to which they are attached form a saturated or unsaturated 3-membered carbocyclic group, a saturated or unsaturated 4-membered 3-membered carbocyclic group, a saturated or unsaturated 5-membered carbocyclic group, a saturated or unsaturated 6-membered carbocyclic group, a saturated or unsaturated 4-membered heterocycloalkyl group, a saturated or unsaturated 5-membered heterocycloalkyl group, a saturated or unsaturated 6-membered heterocycloalkyl group.
In a still further particular embodiment, the first and second,
a is selected from
Figure BDA0003497259860000076
Wherein X is selected from CH 2 NH, O or S; the ring from which A is selected may be further substituted by one, two, three, four or five R A1 And (4) substitution.
Further, in the present invention,
a is selected from
Figure BDA0003497259860000081
Wherein X is selected from CH 2 NH, O or S; the ring from which A is selected may be further substituted by one, two, three or four R A1 And (4) substitution.
In some embodiments of the invention, the compound of formula I is specifically:
Figure BDA0003497259860000082
Figure BDA0003497259860000091
Figure BDA0003497259860000101
the invention also provides application of any one of the compounds, or the deuterated compounds, or the stereoisomers thereof, or the pharmaceutically acceptable salts thereof in preparing a medicament for preventing or treating virus infection diseases.
Further, the viral infection is an influenza viral infection.
The invention also provides a pharmaceutical composition, which comprises a preparation prepared from any one of the compounds, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
Further comprises a pharmaceutically acceptable carrier, an auxiliary material and a vector thereof.
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) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced with a different atom or group; or the lone pair of atoms in the molecule being replaced by another atom or group, e.g. the lone pair on the S atom being replaced by an O atom
Figure BDA0003497259860000102
"optionally substituted" means that "substitution" may or may not occur, i.e., replacement of a hydrogen atom in a molecule, group, etc. by another atom, group, which may be the same or different.
"can be further substituted" means that "substitution" can, but need not, occur, and that the description includes instances where it does or does not occur.
The minimum and maximum values of the content of carbon atoms in hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl means any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1～6 The alkyl group means an alkyl group having 1 to 6 carbon atoms.
"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group 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) and hexyl. The alkyl group may also be part of another group, such as-O (C) 1～6 Alkyl).
"carbocyclyl", "cycloalkane" as defined in the inventionThe group "cycloalkane" refers to a saturated or partially saturated cyclic group having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (fused, bridged). For polycyclic systems having aromatic and non-aromatic rings that do not contain ring heteroatoms, the term "carbocyclyl" (e.g., 5,6,7,8, -tetrahydronaphthalen-5-yl) applies when the point of attachment is at a non-aromatic carbon atom. 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 BDA0003497259860000111
dicyclohexyl and
Figure BDA0003497259860000112
a dicyclohexyl group. The saturated or unsaturated 3-to 10-membered carbocyclic group according to the present invention means a 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-membered saturated or unsaturated carbocyclic group, and the unsaturated 3-to 10-membered carbocyclic group is preferably a 5-to 10-membered unsaturated carbocyclic group or a 6-to 10-membered unsaturated carbocyclic group or a 7-to 10-membered unsaturated carbocyclic group or an 8-to 10-membered unsaturated carbocyclic group or a 9-to 10-membered unsaturated carbocyclic group.
Further in the present invention, "heterocycloalkyl", "heterocycle", "heterocycloalkane" means a saturated or non-aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. Generally denotes a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of a plurality of ring atoms comprising 1,2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Bicyclic means consisting of two rings sharing 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, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuryl, tetrahydro-thienyl, pyrazolidinyl, imidylOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, thienyl, piperazinyl, piperidinyl, piperazinyl, or piperazinyl,
Figure BDA0003497259860000113
Thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azepinyl, diazepanyl, homopiperazinyl or oxazepinyl. An example of a bicyclic saturated heterocycloalkyl is 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]Nonyl radical. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridinyl or dihydropyranyl.
The saturated or unsaturated 4-to 10-membered heterocycloalkyl group according to the present invention means a 4-, 5-, 6-, 7-, 8-, 9-or 10-membered saturated or unsaturated heterocycloalkyl group, preferably a 5-to 10-membered unsaturated heterocycloalkyl group or a 6-to 10-membered unsaturated heterocycloalkyl group or a 7-to 10-membered unsaturated heterocycloalkyl group or an 8-to 10-membered unsaturated heterocycloalkyl group or a 9-to 10-membered unsaturated heterocycloalkyl group.
The unsaturated refers to that a group or a molecule contains carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds and the like; the unsaturated carbocyclic group of the present invention may or may not include an aromatic ring group, and the unsaturated heterocyclic group may or may not include a heteroaryl group, which can be freely selected by those skilled in the art.
The "aromatic ring group" and "aromatic ring" as used herein refer to an aromatic hydrocarbon group having a plurality of carbon atoms. Aryl is typically a monocyclic, bicyclic or tricyclic aryl group having multiple carbon atoms. Further, the term "aryl" as used herein refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
The term "aromatic heterocyclic group" or "aromatic heterocyclic ring" as used herein means an aromatic unsaturated ring containing at least one hetero atom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. Aromatic monocyclic or bicyclic hydrocarbons which typically contain multiple ring atoms, wherein one or more ring atoms are selected from the group consisting of the heteroatoms of O, N, S. Preferably there are one to three heteroatoms. Heterocyclic aryl represents, for example: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.
Further, the invention relates to 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 When the attached atom is O, S or N, R is 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 May not be selected from-OH, -SH, -NH 2 。
The "halogen" as used herein means fluorine, chlorine, bromine or iodine.
"halogen-substituted alkyl" as used herein means an alkyl group in which one or more hydrogen atoms are substituted with halogen; such as trifluoromethyl, difluoromethyl, monofluoromethyl and the like.
As used herein, "-OR", "-NRR", etc., means that the R group is attached to an oxygen atom OR a nitrogen atom by a single bond.
The "-C (O) R", "-S (O)" mentioned in the present invention 2 The oxygen atom in R' or the like is bonded to a carbon atom or a sulfur atom with a double bond.
Described in the invention
Figure BDA0003497259860000121
"═ S" means that an oxygen atom or a sulfur atom is bonded to a substitution position via a double bond.
In the description of the groups of the invention
Figure BDA0003497259860000122
Are used to describe the position of substitution of the groups.
The term "deuterated compound" as used herein means a molecule or group wherein 1 or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic (inner) salts, and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
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 a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shifts (. delta.) are given in units of 10-6 (ppm). NMR was measured using (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetic instrument in deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS).
LC-MS was measured using Shimadzu LC-MS 2020 (ESI). HPLC was performed using Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (Medium pressure preparative chromatography) Gilson GX-281 reverse phase preparative chromatography was used. The thin layer chromatography silica gel plate is a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials for the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Enduragi chemistry, Chengdulong chemistry, Shaoshi chemistry technology, and Bailingwei technology.
In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention. In the examples, the solution means an aqueous solution unless otherwise specified. In the examples, the reaction temperature is room temperature, unless otherwise specified. In the examples, M is mole per liter, unless otherwise specified.
Synthesis of intermediate compounds
Figure BDA0003497259860000131
Step 1, Synthesis of Compound M1-2
3- (benzyloxy) -4-oxo-4H-pyran-2-carboxylic acid M1-1(12.3g, 50mmol) was dissolved in dimethylformamide (60mL), and after stirring well, 1, 8-diazabicycloundec-7-ene (11.4g,75mmol) was added to the reaction system at room temperature, stirring was carried out at room temperature for ten minutes, iodoethane (14.0g,90mmol) was added to the reaction system, stirring was carried out at room temperature for 12 hours, and LC-MS monitoring was carried out. After the reaction is finished, ethyl acetate and water are used for extraction, the organic phase is washed by water and saturated saline solution for three times respectively, the organic phase is dried by anhydrous sodium sulfate and then is decompressed and concentrated, and the crude product can be directly used for the next reaction without purification. The crude product, ethyl 3- (benzyloxy) -4-oxo-4H-pyran-2-carboxylate M1-2(13.4 g). LC-MS: m/z 275[ M + H] +
Step 2, Synthesis of Compound M1-3
3- (benzyloxy) -4-oxo-4H-pyran-2-carboxylic acid ethyl ester M1-2(13.4g, 49mmol) was dissolved in dimethylacetamide (130mL), and after stirring well, pyridinium p-toluenesulfonate (36.8g,147mmol), tert-butyl carbazinate (9.7g,73.5mmol) and stirring at 60 ℃ for 12 hours were added to the reaction system at room temperature, followed by LC-MS. After the reaction, the mixture was extracted with ethyl acetate and water, the organic phase was washed with water and saturated brine three times, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to give the product, ethyl 3- (benzyloxy) -1- ((tert-butoxycarbonyl) amino) -4-oxo-1, 4-dihydropyridine-2-carboxylate M1-3(12.2 g). LC-MS: m/z 389[ M + H ]] +
Step 3, Synthesis of Compound M1
Ethyl 3- (benzyloxy) -1- ((tert-butoxycarbonyl) amino) -4-oxo-1, 4-dihydropyridine-2-carboxylate M1-3(7.8g, 20mmol) was dissolved in dichloromethane (30mL), and after stirring well, trifluoroacetic acid (30mL) was added to the reaction system at room temperature, followed by stirring at room temperature for 1 hour and monitoring by LC-MS. After the reaction is finished, concentrating under reduced pressure to remove dichloromethane and trifluoroacetic acid, adding saturated sodium bicarbonate aqueous solution to adjust the pH value of the system to 7-8, extracting with dichloromethane and water, washing an organic phase once with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure, wherein a crude product can be directly used for the next reaction without purification. The 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 BDA0003497259860000141
Step 4, synthesis of compound M2-2
3, 4-difluoro-2-methylbenzoic acid M2-1(8.6g, 50mmol), N-bromosuccinimide (8.9g, 60mmol), azobisisobutyronitrile (164mg, 1mmol) were dissolved in carbon tetrachloride (200mL), the reaction system was replaced three times with nitrogen, and nitrogen at atmospheric pressure was introduced, stirred at 80 ℃ for 1 hour, and monitored by LC-MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give the product 2- (bromomethyl) -3, 4-difluorobenzoic acid M2-2(12.0 g).
Step 5, synthesis of compound M2-4
Diphenyl disulfide M2-3(5.5g, 25mmol), sodium hydroxide (2.87g, 72mmol), sodium borohydride (1.74g, 46mmol) were dissolved in tetrahydrofuran (80mL) and water (80mL), the reaction was replaced three times with nitrogen, charged with one atmosphere of nitrogen, stirred at 70 ℃ for 12 hours, and monitored by LC-MS. The reaction solution was used directly in the next reaction. 2- (bromomethyl) -3, 4-difluorobenzoic acid M2-2(12.0g, 48mmol) was added to the above solution and stirred at room temperature for 1 hour, monitored by LC-MS. After the reaction, 1N diluted hydrochloric acid was added to the reaction system to adjust the pH of the system to 5-6, the mixture 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 give the product, 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid M2-4(12.6 g). LC-MS: m/z 281[ M + H] +
Step 6, synthesis of compound M2-5
3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid M2-4(12.6g, 45mmol) was dissolved in polyphosphoric acid (300mL), stirred at 120 ℃ for 12 hours, and monitored by LC-MS. Cooling the reaction system to room temperature after the reaction is finished, pouring the reaction liquid into 2 kg of crushed ice, extracting with ethyl acetate and water, washing an organic phase with a saturated sodium bicarbonate aqueous solution for three times, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue with column chromatography to obtain the compoundProduct 7, 8-difluorodiphenyl [ b, e ]]Thiepin-11 (6H) -one M2-5(10.1 g). LC-MS: m/z 263[ M + H] +
Step 7, Synthesis of Compound M2
Reacting 7, 8-difluorodiphenyl [ b, e ]]Thiepin-11 (6H) -one M2-5(10.1g, 38.5mmol) was dissolved in methanol (200mL), the system was cooled well to zero, sodium borohydride (2.93g, 77mmol) was added slowly at zero, stirring at zero for 1 hour and monitored by LC-MS. Concentrating under reduced pressure after the reaction is finished, extracting with ethyl acetate and water, drying organic phase anhydrous sodium sulfate, concentrating under reduced pressure, and purifying residues by column chromatography to obtain the product 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepin-11-ol M2(9.8 g). LC-MS: m/z 247[ M + H-18] +
EXAMPLE 1 Synthesis of 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiahept-11-yl) -9' -hydroxy-2, 3,3a ',4',5, 6-hexahydro-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' (1' H,3' H) -dione (Compound 1)
Figure BDA0003497259860000151
Step 1, Synthesis of Compounds 1-3
Under the protection of nitrogen, the substrate 8-oxa-2-azaspiro [4,5 ]]Dissolving 1-1(1.55g,10.0mmol) of decan-3-one in tetrahydrofuran (40mL), fully cooling the reaction system to minus 30 ℃, slowly dropwise adding n-butyl lithium (2.5M,12.0mmol, 4.8mL), keeping the temperature at minus 30 ℃ for reaction for 1 hour, dropwise adding allyl chloroformate 1-2(1.45g,12.0mmol) into the reaction system, keeping the temperature at minus 30 ℃ for reaction for 1 hour, adding saturated ammonium chloride solution for quenching reaction, concentrating under reduced pressure, extracting with ethyl acetate and water, drying the organic phase with sodium sulfate, concentrating under reduced pressure, purifying the residue by column chromatography to obtain the product allyl 3-oxo-8-oxa-2-azaspiro [4.5 ] anhydrous]Decane-2-carbonate 1-3(2.38 g). LC-MS: m/z 240[ M + H ]] +
Step 2, Synthesis of Compounds 1 to 4
Reacting 3-oxo-8-oxa-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 1-3(2.38g,10.0mmol) was dissolved in 25mL of tetrahydrofuran, and the reaction system was sufficiently cooledCooling to minus 78 ℃, slowly dropwise adding diisobutylaluminum hydride (1.3M, 12.0mmol, 9.2mL), keeping the temperature at minus 78 ℃ for reacting for 1 hour, adding saturated ammonium chloride solution for quenching reaction, concentrating under reduced pressure, extracting with ethyl acetate and water, drying an organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and directly using a crude product for the next step without purification, wherein the crude product is 3-hydroxy-8-oxa-2-azaspiro [4.5 ]]1-4 parts of decane-2-carboxylic acid allyl ester. LC-MS: m/z 224[ M + H-18] +
Step 3, Synthesis of Compounds 1-5
The crude product 3-hydroxy-8-oxa-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 1-4 was dissolved in methanol (20mL), and after stirring sufficiently, p-toluenesulfonic acid monohydrate (153mg,0.8mmol) was added to the reaction system at room temperature, followed by stirring at room temperature for 12 hours and monitoring by LC-MS. Concentrating under reduced pressure after the reaction is finished, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and directly using the crude product in the next step without purification, wherein the crude product is 3-methoxy-8-oxa-2-azaspiro [4.5 ]]1-5 parts of decane-2-carboxylic acid allyl ester. LC-MS: m/z 224[ M + H-32] +
Step 4, Synthesis of Compounds 1-6
The crude product 3-methoxy-8-oxa-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 1-5 and ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate M1(1.8g, 6.2mmol) were dissolved in acetonitrile (60mL), the reaction was cooled sufficiently to minus 30 ℃ and tin tetrachloride (2.4g, 9.4mmol) was added slowly to the reaction, which was stirred at minus 30 ℃ for 1 hour and monitored by LC-MS. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution to quench the reaction, concentrating under reduced pressure, extracting by dichloromethane and water, drying an organic phase by anhydrous sodium sulfate and concentrating under reduced pressure, wherein a crude product can be directly used for the next reaction without purification, and the crude product is 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxypyridin-1 (4H) -yl) amino) -8-oxa-2-azaspiro [4.5]Decane-2-carboxylic acid allyl ester 1-6. LC-MS: m/z 512[ M + H] +
Step 5, Synthesis of Compounds 1 to 7
The crude product 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -8-oxa-2-azaspiro [2 ]4.5]Allyl decane-2-carboxylate 1-6, palladium tetratriphenylphosphine (285mg, 0.25mmol) and morpholine (4.3g, 50mmol) were dissolved in tetrahydrofuran (40mL), the reaction was replaced three times with nitrogen, and nitrogen at atmospheric pressure was introduced, stirred at room temperature for 1 hour, monitored by TLC and LC-MS. After the reaction is finished, the mixture is decompressed and concentrated, and the residue is purified by column chromatography to obtain the product 9'- (benzyloxy) -2,3,3a',4',5, 6-hexahydro spiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 1-7(1.5 g). LC-MS: m/z 382[ M + H ]] +
Step 6, Synthesis of Compounds 1-8
9'- (benzyloxy) -2,3,3a',4',5, 6-hexahydro spiro [ pyran-4, 2' -pyrido [2, 1-f)]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 1-7(38.2mg, 0.1mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepin-11-ol M2(39.6mg, 0.15mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% in ethyl acetate, 400uL), stirred at microwave 110 deg.C for 3 hours and monitored by LC-MS. After the reaction is finished, the crude product 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ] is obtained by decompression and concentration]Thiepin-11-yl) -2,3,3a ',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 1-8. LC-MS: m/z 628[ M + H] +
Step 7, Synthesis of Compound 1
The crude product, 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thiepin-11-yl) -2,3,3a ',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 1-8 was dissolved in methanol (5mL), palladium on carbon hydroxide (14mg, 0.1mmol) was added, the reaction system was replaced three times with nitrogen, and an atmospheric pressure of hydrogen was introduced, stirred at room temperature for 4 hours, and monitored by LC-MS. Filtering with diatomite after the reaction is finished, decompressing and concentrating the filtrate, and purifying with a medium-pressure reverse phase preparative column to obtain 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thiepin-11-yl) -9 '-hydroxy-2, 3,3a',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione compound 1(24.2 mg). LC-MS: m/z 538[ M + H] +
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).
EXAMPLE 2 Synthesis of 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ] thiophen-11-yl) -4, 4-difluoro-9 ' -hydroxy-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' (1' H,3' H) -dione (Compound 2)
Figure BDA0003497259860000171
Step 1, Synthesis of Compound 2-3
Under the protection of nitrogen, sodium hydrogen (1.92g, 48mmol) and anhydrous tetrahydrofuran (200mL) are added into a 250mL three-necked flask, the mixture is fully cooled to zero centigrade, a tetrahydrofuran (50mL) solution of triethyl phosphonoacetate 2-2(10.8g, 48mmol) is slowly added dropwise, the reaction is kept at zero centigrade for 0.5 hour after the dropwise addition, and the reaction is carried out for 1 hour at room temperature. The reaction system was cooled well to zero degrees centigrade, 4-difluorocyclohexanone 2-1(5.36g, 40mmol) in tetrahydrofuran (30mL) was slowly added dropwise, the reaction was carried out at room temperature for 2 hours after the addition was completed, and TLC and LC-MS were used for monitoring. After the reaction, a saturated aqueous ammonium chloride solution (50mL) was added to the system, and the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to give the product, ethyl 2- (4, 4-difluorocyclohexadiene) acetate 2-3(8.0 g). LC-MS: m/z 205[ M + H ]] + 。
Step 2, Synthesis of Compound 2-4
To a 250mL reaction flask was added ethyl 2- (4, 4-difluorocyclohexyldiene) acetate 2-3(8.0g,39mmol), potassium carbonate (11g, 80mmol), dimethyl sulfoxide (80mL) and nitromethane (4.9g, 80mmol), and the reaction was stirred at 80 deg.C for 2 hours, monitored by TLC and LC-MS. After the reaction, water (200mL) was added to the system, extraction was performed with ethyl acetate, the organic phase was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of 2- (4, 4-difluoro-1- (nitromethylene)Phenyl) cyclohexyl) acetic acid ethyl ester 2-4 was used directly in the next reaction. LC-MS: m/z 266[ M + H] +
Step 3, Synthesis of Compounds 2-5
To a 250mL reaction flask were added ethyl 2- (4, 4-difluoro-1- (nitromethyl) cyclohexyl) acetate 2-4, methanol (80mL), and Raney's nickel, the reaction was replaced with nitrogen three times, and hydrogen at atmospheric pressure was introduced, and the reaction was stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. Concentrating under reduced pressure after reaction, extracting with ethyl acetate and water, drying organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying residue with column chromatography to obtain product 8, 8-difluoro-2-azaspiro [4.5 ]]Decan-3-one 2-5(3.8 g). LC-MS: m/z 190[ M + H] +
Step 4, Synthesis of Compounds 2-6
The substrate 8, 8-difluoro-2-azaspiro [4,5 ]]Deca-3-one 2-5(3.8g,20.1mmol), dissolving in tetrahydrofuran (50mL), cooling the reaction system to-30 ℃, slowly adding n-butyl lithium (2.5M, 24.1mmol, 9.6mL), keeping the temperature below-30 ℃ for reaction for 1 hour, adding allyl chloroformate 1-2(2.57g,21.4mmol) into the reaction system, keeping the temperature below-30 ℃ for reaction for 1 hour, adding saturated ammonium chloride solution for quenching reaction, concentrating under reduced pressure, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, purifying the residue with column chromatography to obtain the product allyl 3-oxo-8, 8-difluoro-2-azaspiro [ 4.5.5 ]]Decane-2-carbonate 2-6(4.32 g). LC-MS: m/z 274[ M + H] +
Step 5, Synthesis of Compounds 2 to 7
Reacting 3-oxo-8, 8-difluoro-2-azaspiro [4.5 ]]Dissolving 2-6(4.32g,15.8mmol) decane-2-carboxylic acid allyl ester in 40mL tetrahydrofuran, fully cooling the reaction system to minus 78 ℃, slowly dropwise adding diisobutylaluminum hydride (1.3M, 18.96mmol, 14.6mL), keeping the temperature at minus 78 ℃ for reacting for 1 hour, adding saturated ammonium chloride solution to quench the reaction, concentrating under reduced pressure, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, directly using the organic phase in the next step without purification, and obtaining the crude product of 3-hydroxy-8, 8-difluoro-2-azaspiro [ 4.5%]2-7 parts of decane-2-carboxylic acid allyl ester. LC-MS: m/z 258[ M + H-18 ]] +
Step 6, Synthesis of Compounds 2 to 8
The crude product 3-hydroxy-8, 8-difluoro-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 2-7 was dissolved in methanol (32mL), and after stirring sufficiently, p-toluenesulfonic acid monohydrate (241mg,1.27mmol) was added to the reaction system at room temperature, followed by stirring at room temperature for 12 hours and monitoring by LC-MS. Concentrating under reduced pressure after the reaction is finished, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and directly using the crude product in the next step without purification, wherein the crude product is 3-methoxy-8, 8-difluoro-2-azaspiro [4.5 ]]2-8 parts of decane-2-carboxylic acid allyl ester. LC-MS: m/z 258[ M + H-32 ]] +
Step 7, Synthesis of Compounds 2 to 9
The crude product 3-methoxy-8, 8-difluoro-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 2-8 and ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate M1(3.2g, 11.1mmol) were dissolved in acetonitrile (110mL), the reaction was cooled well to minus 30 deg.C, tin tetrachloride (7.5g, 16.6mmol) was added slowly to the reaction, and stirring was carried out at minus 30 deg.C for 1 hour, followed by LC-MS monitoring. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution to quench the reaction, concentrating under reduced pressure, extracting by dichloromethane and water, drying an organic phase by anhydrous sodium sulfate, concentrating under reduced pressure, directly using a crude product for the next step without purification, and obtaining the crude product of 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -8, 8-difluoro-2-azaspiro [4.5]Decane-2-carboxylic acid allyl ester 2-9. LC-MS: m/z 546[ M + H] +
Step 8, Synthesis of Compounds 2-10
The crude product, 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -8, 8-difluoro-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 2-9, palladium tetratriphenylphosphine (480mg, 0.42mmol) and morpholine (7.2g, 83mmol) were dissolved in tetrahydrofuran (66mL), the reaction was replaced three times with nitrogen, and nitrogen at atmospheric pressure was introduced, stirred at room temperature for 1 hour, monitored by TLC and LC-MS. After the reaction is finished, the mixture is decompressed and concentrated, and the residue is purified by column chromatography to obtain a product 9'- (benzyloxy) -4, 4-difluoro-3 a',4 '-dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 2-10(2.17 g). LC-MS: m/z 416[ M + H ]] +
Step 9, Synthesis of Compounds 2 to 11
9'- (benzyloxy) -4, 4-difluoro-3 a',4 '-dihydrospiro [ cyclohexane-1, 2' -pyrido [2, 1-f)]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 2-10(41.5mg, 0.1mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepin-11-ol M2(39.6mg, 0.15mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% in ethyl acetate, 400uL), stirred at microwave 110 deg.C for 3 hours and monitored by LC-MS. After the reaction is finished, the crude product 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ] is obtained by decompression and concentration]Thien-11-yl) -4, 4-difluoro-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 2-11. LC-MS: m/z 662[ M + H] +
Step 10, Synthesis of Compound 2
The crude product, 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thien-11-yl) -4, 4-difluoro-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 2-11 was dissolved in methanol (5mL), palladium on carbon hydroxide (14mg, 0.1mmol) was added, the reaction system was replaced three times with nitrogen, and an atmospheric pressure of hydrogen was introduced, stirred at room temperature for 4 hours, and monitored by LC-MS. Filtering with diatomite after the reaction is finished, decompressing and concentrating the filtrate, and purifying with a medium-pressure reverse phase preparative column to obtain the compound 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thien-11-yl) -4, 4-difluoro-9 '-hydroxy-3 a',4 '-dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 2(24.5 mg). LC-MS: m/z 572[ M + H] +
1 H 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).
EXAMPLE 3 Synthesis of 4- (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ] thiahept-11-yl) -9-hydroxy-2 ',3a,3',4,5',6' -hexahydrospiro [ pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine-2, 4' -thiopyran ] -8,10(1H,3H) -dione (Compound 3)
Figure BDA0003497259860000191
Step 1, Synthesis of Compound 3-2
Under the protection of nitrogen, sodium hydrogen (2.2g, 55mmol) and anhydrous tetrahydrofuran (100mL) are added into a 250mL three-necked flask, the mixture is fully cooled to zero centigrade, a tetrahydrofuran (40mL) solution of triethyl phosphonoacetate 2-2(12.3g,55mmol) is slowly added dropwise, the reaction is kept at zero centigrade for 0.5 hour after the dropwise addition, and the reaction is carried out for 1 hour at room temperature. The reaction system was fully cooled to zero degrees centigrade, tetrahydrofuran (30mL) of tetrahydrothiopyran-4-one 3-1(5.8g,50mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours after the addition was completed, followed by TLC and LC-MS. After the reaction, a saturated aqueous ammonium chloride solution (50mL) was added to the system, and the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to give ethyl 2-tetrahydrothiopyran-4-ethylideneacetate 3-2(8.6g) as a product. LC-MS: m/z 187[ M + H ]] + 。
Step 2, Synthesis of Compound 3-3
To a 250mL reaction flask was added ethyl 2-tetrahydrothiopyran-4-ethylideneacetate 3-2(8.6g,46mmol), potassium carbonate (12.7g,92mmol), dimethyl sulfoxide (100mL) and nitromethane (5.6g,92mmol), and the reaction was stirred at 80 deg.C for 2 hours and monitored by TLC and LC-MS. After the reaction, adding water (200mL) into the system, extracting with ethyl acetate, washing the organic phase with hydrated saturated salt solution twice, drying the organic phase with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product of 2- [4- (nitromethyl) tetrahydrothiopyran-4-yl]Ethyl acetate 3-3 was used directly in the next reaction. LC-MS: m/z 248[ M + H] +
Step 3, Synthesis of Compound 3-4
To a 250mL reaction flask was added 2- [4- (nitromethyl) tetrahydrothiopyran-4-yl]3-3 parts of ethyl acetate, 80mL of methanol and 80mL of raney nickel, replacing the reaction system with nitrogen for three times, filling hydrogen at atmospheric pressure, and keeping the temperature at room temperatureThe reaction was stirred for 12 hours. The reaction was monitored by LC-MS. Concentrating under reduced pressure after reaction, extracting with ethyl acetate and water, drying organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying residue with column chromatography to obtain 8-thia-2-azaspiro [4.5 ]]Decan-3-one 3-4(2.3 g). LC-MS: m/z 172[ M + H] +
Step 4, Synthesis of Compounds 3-5
The substrate 8-thia-2-azaspiro [4.5 ]]Decane-3-one 3-4(1.0g,5.9mmol) is dissolved in tetrahydrofuran (20mL), the reaction system is fully cooled to minus 30 ℃, n-butyl lithium (2.5M, 5.9mmol, 2.3mL) is slowly dripped, the reaction is carried out for 1 hour under the minus 30 ℃, allyl chloroformate 1-2(0.7g,5.9mmol) is dripped into the reaction system, the reaction is carried out for 1 hour under the minus 30 ℃, saturated ammonium chloride solution is added for quenching reaction, decompression concentration is carried out, ethyl acetate and water are used for extraction, the organic phase is dried by sodium sulfate and decompressed and concentrated, and a crude product of 3-oxo-8-thia-2-azaspiro [4.5 anhydrous sodium sulfate ] is obtained]Decane-2-carboxylic acid allyl ester 3-5. LC-MS: m/z 256[ M + H ]] +
Step 5, Synthesis of Compounds 3-6
Reacting 3-oxo-8-thia-2-azaspiro [4.5 ]]Dissolving decane-2-allyl carboxylate 3-5 in 25mL tetrahydrofuran, fully cooling a reaction system to minus 78 ℃, slowly dropwise adding diisobutyl aluminum hydride (1.3M, 7.9mmol, 6.1mL), keeping the temperature at minus 78 ℃ for reaction for 1 hour, adding a saturated ammonium chloride solution for quenching reaction, concentrating under reduced pressure, extracting with ethyl acetate and water, drying an organic phase with anhydrous sodium sulfate and concentrating under reduced pressure, wherein a crude product can be directly used for the next reaction without purification, and the crude product is 3-hydroxy-8-thia-2-azaspiro [4.5 ]]3-6 parts of decane-2-carboxylic acid allyl ester. LC-MS: m/z 240[ M + H-18 ]] +
Step 6, Synthesis of Compounds 3-7
The crude product 3-hydroxy-8-thia-2-azaspiro [ 4.5%]Allyl decane-2-carboxylate 3-6 was dissolved in methanol (20mL), and after stirring sufficiently, p-toluenesulfonic acid monohydrate (114mg,0.6mmol) was added to the reaction system at room temperature, followed by stirring at room temperature for 12 hours and monitoring by LC-MS. Concentrating under reduced pressure after reaction, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure,the crude product can be directly used for the next reaction without purification, and the crude product is 3-methoxy-8-thia-2-azaspiro [4.5 ]]3-7 parts of decane-2-carboxylic acid allyl ester. LC-MS: m/z 240[ M + H-32 ]] +
Step 7, Synthesis of Compounds 3 to 8
The crude product 3-methoxy-8-thia-2-azaspiro [ 4.5%]Allyl decane-2-carboxylate 3-7 and ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate M1(1.6g, 5.5mmol) were dissolved in acetonitrile (60mL), the reaction was cooled sufficiently to minus 30 ℃ and tin tetrachloride (2.2g, 8.3mmol) was added slowly to the reaction, which was stirred at minus 30 ℃ for 1 hour and monitored by LC-MS. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution to quench the reaction, concentrating under reduced pressure, extracting by dichloromethane and water, drying an organic phase by anhydrous sodium sulfate, concentrating under reduced pressure, directly using a crude product for the next step without purification, and obtaining the crude product of 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxypyridine-1 (4H) -group) amino) -8-thia-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 3-8. LC-MS: m/z 528[ M + H ]] +
Step 8, Synthesis of Compounds 3 to 9
The crude product, 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -8-thia-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 3-8, palladium tetratriphenylphosphine (263mg, 0.23mmol), morpholine (4.0g, 46mmol) were dissolved in tetrahydrofuran (40mL), the reaction was replaced three times with nitrogen, and nitrogen at atmospheric pressure was introduced, stirred at room temperature for 1 hour, monitored by TLC and LC-MS. After the reaction is finished, the mixture is decompressed and concentrated, and the residue is purified by column chromatography to obtain the product 9- (benzyloxy) -2',3a,3',4,5',6' -hexahydro spiro [ pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine-2, 4' -thiopyran]-8,10(1H,3H) -dione 3-9(275 mg). LC-MS: m/z 398[ M + H] +
Step 9, Synthesis of Compounds 3 to 10
Reacting 9- (benzyloxy) -2',3a,3',4,5',6' -hexahydrospiro [ pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine-2, 4' -thiopyran]-8,10(1H,3H) -dione 3-9(30.0mg, 0.075mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thioheptan-11-ol M2(29.9mg, 0.11mmol), dissolved in 1-propylphosphoric anhydride (50 wt.% in ethyl acetate, 300uL), was microwaved 110Stirring at room temperature for 3 hours and monitoring by LC-MS. Extracting with ethyl acetate and water after reaction, drying the organic phase, filtering, and concentrating the filtrate under reduced pressure to obtain crude product 9- (benzyloxy) -4- (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepin-11-yl) -2',3a,3',4,5',6' -hexahydrospiro [ pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine-2, 4' -thiopyran]-8,10(1H,3H) -dione 3-10. LC-MS: m/z 644[ M + H ]] +
Step 10, Synthesis of Compound 3
The crude product 9- (benzyloxy) -4- (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thiepin-11-yl) -2',3a,3',4,5',6' -hexahydrospiro [ pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine-2, 4' -thiopyran]-8,10(1H,3H) -dione 3-10 was dissolved in methanol (5mL), palladium on carbon (14mg, 0.1mmol) was added, the reaction system was replaced with nitrogen three times, and an atmospheric pressure hydrogen gas was introduced, stirred at room temperature for 1 hour, and monitored by LC-MS. Filtering with diatomite after the reaction is finished, decompressing and concentrating the filtrate, and preparing and purifying to obtain the 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thiepin-11-yl) -9 '-hydroxy-2, 3,3a',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 4- (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thiepin-11-yl) -9-hydroxy-2 ',3a,3',4,5',6' -hexahydrospiro [ pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine-2, 4' -thiopyran]-8,10(1H,3H) -dione compound 3(12 mg). LC-MS: m/z 554[ M + H] +
1 H 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).
EXAMPLE 4 Synthesis of 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiahept-11-yl) -9' -hydroxy-3 a ',4' -dihydrospiro [ cyclobutane-1, 2' pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' (1' H,3' H) -dione (Compound 4)
Figure BDA0003497259860000221
Step 1, Synthesis of Compound 4-2
Under the protection of nitrogen, sodium hydrogen (2.2g, 55mmol) and anhydrous tetrahydrofuran (100mL) are added into a 250mL three-necked flask, the mixture is fully cooled to zero centigrade, a tetrahydrofuran (40mL) solution of triethyl phosphonoacetate 2-2(12.3g,55mmol) is slowly added dropwise, the reaction is kept at zero centigrade for 0.5 hour after the dropwise addition, and the reaction is carried out for 1 hour at room temperature. The reaction system was cooled sufficiently to zero degrees centigrade, cyclobutanone 4-1(3.5g, 50mmol) in tetrahydrofuran (30mL) was slowly added dropwise, the reaction was carried out at room temperature for 2 hours after the addition, and TLC and LC-MS were used for monitoring. After the reaction, a saturated aqueous ammonium chloride solution (50mL) was added to the system, and the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to give ethyl 2-cyclobutenyl acetate 4-2(6.8 g). LC-MS: m/z 141[ M + H] + 。
Step 2, Synthesis of Compound 4-3
To a 250mL reaction flask was added ethyl 2-cyclobutenyl acetate 4-2(6.8g,49mmol), potassium carbonate (13.4g, 97mmol), dimethyl sulfoxide (100mL) and nitromethane (6.0g, 97mmol), and the reaction was stirred at 80 ℃ for 2 hours, monitored by TLC and LC-MS. After the reaction, water (200mL) was added to the system, extraction was performed with ethyl acetate, the organic phase was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product of 2- [1- (nitromethyl) cyclobutyl]Ethyl acetate 4-3 was used directly in the next reaction. LC-MS: m/z 202[ M + H] +
Step 3, Synthesis of Compound 4-4
To a 250mL reaction flask was added 2- [1- (nitromethyl) cyclobutyl ] butyl]4-3 parts of ethyl acetate, 80mL of methanol and 80mL of raney nickel, and the reaction system is replaced by nitrogen three times, and hydrogen at atmospheric pressure is filled in, and the reaction is stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. Concentrating under reduced pressure after reaction, extracting with ethyl acetate and water, drying organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying residue with column chromatography to obtain 6-azaspiro [ 3.4%]Octane-7-one 4-4(1.7 g). LC-MS: m/z 126[ M + H] +
Step 4, Synthesis of Compound 4-5
The substrate 6-azaspiro [3.4 ]]Dissolving octane-7-ketone 4-4(1.0g,13.6mmol) in tetrahydrofuran (20mL), fully cooling the reaction system to minus 30 ℃, slowly dropwise adding n-butyl lithium (2.5M, 15.0mmol, 6.0mL), keeping the temperature below minus 30 ℃ for reacting for 1 hour, dropwise adding allyl chloroformate 1-2(1.8g,15.0mmol) into the reaction system, keeping the temperature below minus 30 ℃ for reacting for 1 hour, adding saturated ammonium chloride solution for quenching reaction, concentrating under reduced pressure, extracting with ethyl acetate and water, drying the organic phase with sodium sulfate, concentrating under reduced pressure to obtain a crude product of 7-oxo-6-azaspiro [3.4 anhydrous sodium sulfate ]]Octane-6-carboxylic acid allyl ester 4-5. LC-MS: m/z 210[ M + H ]] +
Step 5, Synthesis of Compounds 4-6
Reacting 7-oxo-6-azaspiro [3.4 ]]Dissolving 4-5 octane-6-allyl carboxylate in 25mL tetrahydrofuran, fully cooling a reaction system to minus 78 ℃, slowly dropwise adding diisobutyl aluminum hydride (1.3M, 3.3mmol, 2.5mL), reacting for 1 hour at minus 78 ℃, adding a saturated ammonium chloride solution to quench the reaction, concentrating under reduced pressure, extracting with ethyl acetate and water, drying an organic phase with anhydrous sodium sulfate and concentrating under reduced pressure, wherein a crude product can be directly used for the next reaction without purification, and the crude product is 7-hydroxy-6-azaspiro [3.4 ]]Octane-6-carboxylic acid allyl ester 4-6. LC-MS: m/z 194[ M + H-18] +
Step 6, Synthesis of Compounds 4-7
The crude product 7-hydroxy-6-azaspiro [3.4 ]]Octane-6-allyl carboxylate 4-6 was dissolved in methanol (10mL), and after stirring thoroughly, p-toluenesulfonic acid monohydrate (38mg,0.22mmol) was added to the reaction system at room temperature, followed by stirring at room temperature for 12 hours and monitoring by LC-MS. Concentrating under reduced pressure after the reaction is finished, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and directly using the crude product for the next step without purification, wherein the crude product is 7-methoxy-6-azaspiro [3.4 ]]Octane-6-carboxylic acid allyl ester 4-7. LC-MS: m/z 194[ M + H-32 ]] +
Step 7, Synthesis of Compounds 4 to 8
The crude product 3-methoxy-8-thia-2-azaspiro [ 4.5%]Decane-2-carboxylic acid allyl ester 4-7 and 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylic acid ethyl esterM1(610mg, 2.1mmol) was dissolved in acetonitrile (20mL), the reaction was cooled well to-30 deg.C, tin tetrachloride (830mg,3.2mmol) was added slowly to the reaction, stirred at-30 deg.C for 1 hour and monitored by LC-MS. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution to quench the reaction, concentrating under reduced pressure, extracting by dichloromethane and water, drying an organic phase by anhydrous sodium sulfate, concentrating under reduced pressure, directly using a crude product for the next step without purification, and obtaining the crude product 7- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -6-azaspiro [3.4]Octane-6-carboxylic acid allyl ester 4-8. LC-MS: m/z 482[ M + H ]] +
Step 8, Synthesis of Compounds 4-9
The crude product, 7- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -6-azaspiro [ 3.4%]4-8-octane-6-carboxylate, palladium tetratriphenylphosphine (89mg, 0.077mmol), and morpholine (1.34g, 15.4mmol) were dissolved in tetrahydrofuran (10mL), the reaction system was replaced with nitrogen three times, and nitrogen at one atmospheric pressure was introduced, and the mixture was stirred at room temperature for 1 hour, monitored by TLC and LC-MS. After the reaction is finished, the mixture is decompressed and concentrated, and the residue is purified by column chromatography to obtain a product 9'- (benzyloxy) -3a',4 '-dihydrospiro [ cyclobutane-1, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 4-9(106 mg). LC-MS: m/z 352[ M + H ]] +
Step 9, Synthesis of Compounds 4 to 10
9'- (benzyloxy) -3a',4 '-dihydrospiro [ cyclobutane-1, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 4-9(30.0mg, 0.085mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepin-11-ol M2(33.8mg, 0.13mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% in ethyl acetate, 300uL), stirred at microwave 110 deg.C for 3 hours and monitored by LC-MS. After the reaction is finished, ethyl acetate and water are used for extraction, the organic phase is dried and filtered, the filtrate is decompressed and concentrated to obtain a crude product 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thiepin-11-yl) -3a ',4' -dihydrospiro [ cyclobutane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 4-10(45 mg). LC-MS: m/z 598[ M + H] +
Step 10, Synthesis of Compound 4
The crude product, 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thiepin-11-yl) -3a ',4' -dihydrospiro [ cyclobutane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 4-10(45mg,0.075mmol) was dissolved in methanol (5mL), palladium on carbon (15mg, 0.1mmol) was added, the reaction was replaced three times with nitrogen, one atmosphere of hydrogen was charged, stirring was carried out at room temperature for 1 hour, and monitoring by LC-MS was carried out. Filtering with diatomite after the reaction is finished, decompressing and concentrating the filtrate, and preparing and purifying to obtain the 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thiepin-11-yl) -9 '-hydroxy-3 a',4 '-dihydrospiro [ cyclobutane-1, 2' pyrido [2,1-f]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione compound 4(14 mg). LC-MS: m/z 508[ M + H ]] +
1 H 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).
EXAMPLE 5 Synthesis of 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ] thiahept-11-yl) -9' -hydroxy-4, 4-dimethyl-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' (1' H,3' H) -dione (Compound 5)
Figure BDA0003497259860000241
Step 1, Synthesis of Compound 5-2
Under the protection of nitrogen, sodium hydrogen (2.4g, 60mmol) and anhydrous tetrahydrofuran (100mL) are added into a 250mL three-necked flask, the mixture is fully cooled to zero centigrade, a tetrahydrofuran (50mL) solution of triethyl phosphonoacetate 2-2(10.8g, 60mmol) is slowly added dropwise, the reaction is kept at zero centigrade for 0.5 hour after the dropwise addition, and the reaction is carried out for 1 hour at room temperature. The reaction system was cooled sufficiently to zero degrees centigrade, 4-dimethylcyclohexanone 5-1(6.3g, 50mmol) in tetrahydrofuran (30mL) was slowly added dropwise, the reaction was carried out at room temperature for 2 hours after the addition was completed, and TLC and LC-MS were used for monitoring. Adding into the system after the reaction is finishedSaturated aqueous ammonium chloride (50mL) was added, the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was washed twice with saturated brine, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to give the product ethyl 2- (4, 4-dimethylcyclohexyldiene) acetate 5-2(9.4 g). LC-MS: m/z 197[ M + H] + 。
Step 2, Synthesis of Compound 5-3
To 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 (6.1g,100mmol), and the reaction was stirred at 80 deg.C for 2 hours, monitored by TLC and LC-MS. After the reaction, water (200mL) was added to the system, extraction was performed with ethyl acetate, the organic phase was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude ethyl 2- (4, 4-dimethyl-1- (nitromethyl) cyclohexyl) acetate 5-3, which was used directly in the next reaction. LC-MS: m/z 258[ M + H ]] +
Step 3, Synthesis of Compound 5-4
To a 250mL reaction flask were added ethyl 2- (4, 4-dimethyl-1- (nitromethyl) cyclohexyl) acetate 5-3, methanol (80mL), and Raney's nickel, the reaction was replaced with nitrogen three times, and hydrogen at atmospheric pressure was introduced, and the reaction was stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. Concentrating under reduced pressure after reaction, extracting with ethyl acetate and water, drying organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying residue with column chromatography to obtain 8, 8-dimethyl-2-azaspiro [4.5 ]]Decan-3-one 5-4(4.4 g). LC-MS: m/z 182[ M + H] +
Step 4, Synthesis of Compounds 5-5
The substrate 8, 8-dimethyl-2-azaspiro [4,5 ]]Dissolving 5-4(1.81g,10.0mmol) of decan-3-one in tetrahydrofuran (40mL), fully cooling the reaction system to minus 30 ℃, slowly dropwise adding n-butyl lithium (2.5M,12.0mmol, 4.8mL), keeping the temperature below minus 30 ℃ for reacting for 1 hour, dropwise adding allyl chloroformate 1-2(1.45g,12.0mmol) into the reaction system, keeping the temperature below minus 30 ℃ for reacting for 1 hour, adding saturated ammonium chloride solution for quenching reaction, concentrating under reduced pressure, extracting with ethyl acetate and water, addingDrying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue with column chromatography to obtain allyl 3-oxo-8, 8-dimethyl-2-azaspiro [4.5 ]]Decane-2-carbonate 5-5(2.61 g). LC-MS: m/z 266[ M + H] +
Step 5, Synthesis of Compounds 5-6
3-oxo-8, 8-dimethyl-2-azaspiro [4.5 ]]5-5(2.61g,9.9mmol) of decane-2-carboxylic acid allyl ester is dissolved in 25mL tetrahydrofuran, the reaction system is fully cooled to minus 78 ℃, diisobutylaluminum hydride (1.3M, 12.0mmol, 9.2mL) is slowly added dropwise, the reaction is kept at minus 78 ℃ for 1 hour, saturated ammonium chloride solution is added to quench the reaction, the reaction is concentrated under reduced pressure and extracted by ethyl acetate and water, the organic phase is dried by anhydrous sodium sulfate and then concentrated under reduced pressure, the crude product can be directly used for the next reaction without purification, and the crude product is 3-hydroxy-8, 8-dimethyl-2-azaspiro [4.5 ]]5-6 parts of decane-2-carboxylic acid allyl ester. LC-MS: m/z 250[ M + H-18] +
Step 6, Synthesis of Compounds 5-7
The crude product 3-hydroxy-8, 8-dimethyl-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 5-6 was dissolved in methanol (20mL), and after stirring sufficiently, p-toluenesulfonic acid monohydrate (153mg,0.8mmol) was added to the reaction system at room temperature, followed by stirring at room temperature for 12 hours and monitoring by LC-MS. Concentrating under reduced pressure after the reaction is finished, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and directly using the crude product in the next step without purification, wherein the crude product is 3-methoxy-8, 8-dimethyl-2-azaspiro [4.5 ]]5-7 parts of decane-2-carboxylic acid allyl ester. LC-MS: m/z 250[ M + H-32 ]] +
Step 7, Synthesis of Compounds 5 to 8
The crude product of 3-methoxy-8, 8-dimethyl-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 5-7 and ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate M1(1.8g, 6.3mmol) were dissolved in acetonitrile (60mL), the reaction was cooled sufficiently to minus 30 ℃ and tin tetrachloride (2.4g, 9.4mmol) was added slowly to the reaction, which was stirred at minus 30 ℃ for 1 hour and monitored by LC-MS. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution to quench the reaction, concentrating under reduced pressure, extracting with dichloromethane and water, and using organic phaseThe crude product can be directly used for the next reaction without purification after being dried by anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product is 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxypyridin-1 (4H) -yl) amino) -8, 8-dimethyl-2-azaspiro [ 4.5%]5-8 parts of decane-2-carboxylic acid allyl ester. LC-MS: m/z 538[ M + H] +
Step 8, Synthesis of Compounds 5-9
The crude product, 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -8, 8-dimethyl-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 5-8, palladium tetratriphenylphosphine (285mg, 0.25mmol), morpholine (4.3g, 50mmol) were dissolved in tetrahydrofuran (40mL), the reaction was replaced three times with nitrogen, and nitrogen at atmospheric pressure was introduced, stirred at room temperature for 1 hour, monitored by TLC and LC-MS. After the reaction is finished, the mixture is decompressed and concentrated, and the residue is purified by column chromatography to obtain a product 9'- (benzyloxy) -4, 4-dimethyl-3 a',4 '-dihydrospiro [ cyclohexane-1, 2' -pyrido [2, 1-f)]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 5-9(1.53 g). LC-MS: m/z 408[ M + H] +
Step 9, Synthesis of Compounds 5-10
9'- (benzyloxy) -4, 4-dimethyl-3 a',4 '-dihydrospiro [ cyclohexane-1, 2' -pyrido [2, 1-f)]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 5-9(40.7mg, 0.1mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepin-11-ol M2(39.6mg, 0.15mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% in ethyl acetate, 400uL), stirred at microwave 110 deg.C for 3 hours and monitored by LC-MS. After the reaction is finished, the crude product 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ] is obtained by decompression and concentration]Thiepin-11-yl) -4, 4-dimethyl-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 5-10. LC-MS: m/z 654[ M + H] +
Step 10, Synthesis of Compound 5
The crude product, 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thiepin-11-yl) -4, 4-dimethyl-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 5-10 was dissolved in methanol (5mL), palladium hydroxide on carbon (14mg, 0.1mmol) was added, and the reaction system was replaced with nitrogen three timesThe mixture was stirred at room temperature for 4 hours under the introduction of atmospheric hydrogen and monitored by LC-MS. Filtering with diatomite after the reaction is finished, decompressing and concentrating the filtrate, and purifying with a medium-pressure reverse phase preparative column to obtain 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thiepin-11-yl) -9 '-hydroxy-4, 4-dimethyl-3 a',4 '-dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione compound 5(23.1 mg). LC-MS: m/z 564[ M + H] +
1 H 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).
EXAMPLE 6 Synthesis of 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiahept-11-yl) -9' -hydroxy-2, 6-dimethyl-2, 3,3a ',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' (1' H,3' H) -dione (Compound 6)
Figure BDA0003497259860000271
Step 1, Synthesis of Compound 6-2
Under the protection of nitrogen, sodium hydrogen (2.4g, 60mmol) and anhydrous tetrahydrofuran (100mL) are added into a 250mL three-necked flask, the mixture is fully cooled to zero centigrade, a tetrahydrofuran (50mL) solution of triethyl phosphonoacetate 2-2(10.8g, 60mmol) is slowly added dropwise, the reaction is kept at zero centigrade for 0.5 hour after the dropwise addition, and the reaction is carried out for 1 hour at room temperature. The reaction system was cooled sufficiently to zero degrees centigrade, 2, 6-dimethyltetrahydropyranone 6-1(6.4g, 50mmol) in tetrahydrofuran (30mL) was slowly added dropwise, and after the addition, the reaction was carried out at room temperature for 2 hours, followed by TLC and LC-MS. Adding saturated ammonium chloride aqueous solution (50mL) into the system after the reaction is finished, concentrating under reduced pressure, extracting with ethyl acetate and water, washing the organic phase with saturated saline solution twice, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue with column chromatography to obtain the product 2- (3, 5-dimethyl-4-oxo-2-methyl-4-oxo-ethyl-methyl-ethyl-acetateHeterocyclohexyldiene) Ethyl acetate 6-2(9.5 g). LC-MS: m/z 199[ M + H] + 。
Step 2, Synthesis of Compound 6-3
To a 250mL reaction flask were added ethyl 2- (3, 5-dimethyl-4-oxacyclohexadiene) acetate 6-2(9.5g,48mmol), potassium carbonate (13.8g,100mmol), dimethyl sulfoxide (100mL) and nitromethane (6.1g,100mmol), the reaction was stirred at 80 deg.C for 2 hours and monitored by TLC and LC-MS. After the reaction, water (200mL) was added to the system, extraction was performed with ethyl acetate, the organic phase was washed twice with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude ethyl 2- (3, 5-dimethyl-4-oxa-1- (nitromethyl) cyclohexyl) acetate 6-3 which was used directly in the next reaction. LC-MS: m/z 260[ M + H ]] +
Step 3, Synthesis of Compound 6-4
Ethyl 2- (4, 4-dimethyl-1- (nitromethyl) cyclohexyl) acetate 6-3, methanol (80mL), and Raney's nickel were added to a 250mL reaction flask, the reaction was replaced with nitrogen three times, and an atmospheric pressure of hydrogen was introduced, and the reaction was stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. Concentrating under reduced pressure after reaction, extracting with ethyl acetate and water, drying organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying residue with column chromatography to obtain 7.9-dimethyl-8-oxa-2-azaspiro [4.5 ]]Decan-3-one 6-4(4.5 g). LC-MS: m/z 184[ M + H ]] +
Step 4, Synthesis of Compound 6-5
The substrate 7.9-dimethyl-8-oxa-2-azaspiro [4.5 ]]Dissolving 6-4(1.83g,10.0mmol) of decan-3-one in tetrahydrofuran (40mL), fully cooling the reaction system to minus 30 ℃, slowly dropwise adding n-butyl lithium (2.5M,12.0mmol, 4.8mL), keeping the temperature at minus 30 ℃ for reaction for 1 hour, dropwise adding allyl chloroformate 1-2(1.45g,12.0mmol) into the reaction system, keeping the temperature at minus 30 ℃ for reaction for 1 hour, adding saturated ammonium chloride solution for quenching reaction, concentrating under reduced pressure, extracting with ethyl acetate and water, drying the organic phase with sodium sulfate, concentrating under reduced pressure, purifying the residue by column chromatography to obtain the product allyl 3-oxo-7.9-dimethyl-8-oxa-2-azaspiro [4.5 ] anhydrous]Decane-2-carbonate 6-5(2.64 g). LC-MS: m/z 268[ M + H] +
Step 5, Synthesis of Compound 6-6
Reacting 3-oxo-7.9-dimethyl-8-oxa-2-azaspiro [4.5 ]]Dissolving 6-5(2.64g,9.9mmol) of decane-2-carboxylic acid allyl ester in 25mL tetrahydrofuran, fully cooling the reaction system to minus 78 ℃, slowly dropwise adding diisobutylaluminum hydride (1.3M, 12.0mmol, 9.2mL), keeping the temperature below minus 78 ℃ for reacting for 1 hour, adding saturated ammonium chloride solution for quenching reaction, concentrating under reduced pressure, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, directly using the crude product in the next step without purification, and obtaining the crude product of 3-hydroxy-7.9-dimethyl-8-oxa-2-azaspiro [4.5 ]]6-allyl decane-2-carboxylate. LC-MS: m/z 252[ M + H-18] +
Step 6, Synthesis of Compounds 6-7
The crude product 3-hydroxy-7.9-dimethyl-8-oxa-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 6-6 was dissolved in methanol (20mL), and after stirring sufficiently, p-toluenesulfonic acid monohydrate (153mg,0.8mmol) was added to the reaction system at room temperature, followed by stirring at room temperature for 12 hours and monitoring by LC-MS. Concentrating under reduced pressure after the reaction is finished, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and directly using the crude product in the next step without purification, wherein the crude product is 3-methoxy-7.9-dimethyl-8-oxa-2-azaspiro [4.5 ]]6-7 parts of decane-2-carboxylic acid allyl ester. LC-MS: m/z 252[ M + H-32 ]] +
Step 7, Synthesis of Compounds 6 to 8
The crude product 3-methoxy-7.9-dimethyl-8-oxa-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 6-7 and ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate M1(1.8g, 6.3mmol) were dissolved in acetonitrile (60mL), the reaction was cooled sufficiently to minus 30 ℃ and tin tetrachloride (2.4g, 9.4mmol) was added slowly to the reaction, which was stirred at minus 30 ℃ for 1 hour and monitored by LC-MS. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution to quench the reaction, concentrating under reduced pressure, extracting with dichloromethane and water, drying an organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, directly using a crude product for the next step of reaction without purification, and obtaining the crude product 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4)-Oxopyridin-1 (4H) -yl) amino) -7.9-dimethyl-8-oxa-2-azaspiro [4.5]6-8 parts of decane-2-carboxylic acid allyl ester. LC-MS: m/z 540[ M + H ]] +
Step 8, Synthesis of Compounds 6-9
The crude product, 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -8, 8-dimethyl-2-azaspiro [4.5 ]]6-8 allyl decane-2-carboxylate, palladium tetratriphenylphosphine (285mg, 0.25mmol) and morpholine (4.3g, 50mmol) were dissolved in tetrahydrofuran (40mL), the reaction was replaced three times with nitrogen, and nitrogen at atmospheric pressure was introduced, and the mixture was stirred at room temperature for 1 hour, monitored by TLC and LC-MS. After the reaction is finished, the mixture is decompressed and concentrated, and the residue is purified by column chromatography to obtain the product 9'- (benzyloxy) -2, 6-dimethyl-2, 3,3a',4',5, 6-hexahydro spiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 6-9(1.57 g). LC-MS: m/z 410[ M + H] +
Step 9, Synthesis of Compounds 6-10
9'- (benzyloxy) -2, 6-dimethyl-2, 3,3a',4',5, 6-hexahydro spiro [ pyran-4, 2' -pyrido [2, 1-f)]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 6-9(40.9mg, 0.1mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepin-11-ol M2(39.6mg, 0.15mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% in ethyl acetate, 400uL), stirred at microwave 110 deg.C for 3 hours and monitored by LC-MS. After the reaction is finished, the crude product 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ] is obtained by decompression and concentration]Thiepin-11-yl) -2, 6-dimethyl-2, 3,3a ',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 6-10. LC-MS: m/z 656[ M + H] +
Step 10, Synthesis of Compound 6
The crude product, 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e)]Thiepin-11-yl) -2, 6-dimethyl-2, 3,3a ',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 6-10 was dissolved in methanol (5mL), palladium on carbon hydroxide (14mg, 0.1mmol) was added, the reaction system was replaced three times with nitrogen, and an atmospheric pressure of hydrogen was introduced, stirred at room temperature for 4 hours, and monitored by LC-MS. After the reaction is finished, the mixture is filtered through diatomiteFiltering, concentrating the filtrate under reduced pressure, and purifying with middle-pressure reversed-phase preparative column to obtain 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepin-11-yl) -9 '-hydroxy-2, 6-dimethyl-2, 3,3a',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione compound 6(23.1 mg). LC-MS: m/z 566[ M + H] +
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).
EXAMPLE 7 Synthesis of 4' - (10, 11-dihydro-5H-dibenz [ a, d ] [7] cycloalken-5-yl) -4, 4-difluoro-9 ' -hydroxy-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' (1' H,3' H) -dione (Compound 7)
Figure BDA0003497259860000291
Step 1, Synthesis of Compound 7-2
Dibenzo [ a, d ]]Cyclohepten-5-one 7-1(412mg, 2mmol) was dissolved in methanol (10mL), platinum dioxide (11.5mg, 0.05mmol) was added, the reaction was replaced with nitrogen three times, and an atmospheric pressure of hydrogen was introduced, stirred at room temperature for 12 hours, and monitored by LC-MS. Filtering with diatomite after the reaction is finished, concentrating the filtrate under reduced pressure, extracting with ethyl acetate and water, drying the organic phase anhydrous sodium sulfate, and concentrating under reduced pressure to obtain the product 10, 11-dihydro-5H-dibenzo [ a, d ]][7]Cycloalken-5-ol 7-2. LC-MS: m/z 193[ M + H-18 ]] +
Step 2, Synthesis of Compound 7-3
9'- (benzyloxy) -4, 4-difluoro-3 a',4 '-dihydrospiro [ cyclohexane-1, 2' -pyrido [2, 1-f)]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 2-10(41.5mg, 0.1mmol) and 10, 11-dihydro-5H-dibenzo [ a, d ]][7]Cycloalk-5-ol 7-2(31.5mg, 0.15mmol) dissolved in 1-propylphosphoric anhydride (50 wt.% in ethyl acetate, 400uL) and microwavedStirring at 110 ℃ for 3 hours and monitoring by LC-MS. After the reaction is finished, the crude product 9'- (benzyloxy) -4' - (10, 11-dihydro-5H-diphenyl [ a, d ] is obtained by decompression and concentration][7]Cyclo-5-yl) -4, 4-difluoro-3 a ',4' -dihydrospiro [1,2' -pyrido [2,1-f]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 7-3. LC-MS: m/z 608[ M + H] +
Step 3, Synthesis of Compound 7
The crude product, 9'- (benzyloxy) -4' - (10, 11-dihydro-5H-diphenyl [ a, d)][7]Cyclo-5-yl) -4, 4-difluoro-3 a ',4' -dihydrospiro [1,2' -pyrido [2,1-f]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 7-3 was dissolved in methanol (5mL), palladium hydroxide carbon (14mg, 0.1mmol) was added, the reaction system was replaced three times with nitrogen, and an atmospheric pressure of hydrogen was introduced, stirred at room temperature for 4 hours, and monitored by LC-MS. Filtering with diatomite after the reaction is finished, concentrating the filtrate under reduced pressure, and purifying with a medium-pressure reverse-phase preparation column to obtain a compound 4' - (10, 11-dihydro-5H-diphenyl [ a, d ]][7]Cyclo-5-yl) -4, 4-difluoro-9 '-hydroxy-3 a',4 '-dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ] s][1,2,4]Triazine]-8',10' (1'H,3' H) -dione 7(22.4 mg). LC-MS: m/z 518[ M + H] +1
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).
EXAMPLE 8 Synthesis of 4' - (6, 11-dihydrobenz [ b, e ] thiophen-11-yl) -4, 4-difluoro-9 ' -hydroxy-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' (1' H,3' H) -dione (Compound 8)
Figure BDA0003497259860000301
Step 1, Synthesis of Compound 8-2
Diphenyl disulfide M2-3(2.18g, 10mmol), hydrogen hydroxideSodium (1.15g, 28.8mmol), sodium borohydride (700mg, 18.4mmol) were dissolved in tetrahydrofuran (30mL) and water (30mL), the reaction was replaced three times with nitrogen, charged with nitrogen at atmospheric pressure, stirred at 70 ℃ for 12 hours, and monitored by LC-MS. The reaction solution was used directly in the next reaction. 2-Bromomethylbenzoic acid 8-1(4.3g, 20mmol) was added to the above solution, stirred at room temperature for 1 hour and monitored by LC-MS. After the reaction, 1N diluted hydrochloric acid was added to the reaction system to adjust the pH of the system to 5-6, and the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to give the product 2- (phenylthio) methylbenzoic acid 8-2(1.97 g). LC-MS: m/z 245[ M + H ]] +
Step 2, Synthesis of Compound 8-3
2- (Phenylthio) methylbenzoic acid 8-2(1.97g, 8.1mmol) was dissolved in polyphosphoric acid (60mL), stirred at 120 ℃ for 12 hours and monitored by LC-MS. Cooling the reaction system to room temperature after the reaction is finished, pouring the reaction liquid into 0.5 kg of crushed ice, extracting with ethyl acetate and water, washing an organic phase with a saturated sodium bicarbonate aqueous solution for three times, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain the product diphenyl [ b, e]Thiepin-11 (6H) -one 8-3(1.66 g). LC-MS: m/z 227[ M + H] +
Step 3, Synthesis of Compound 8-4
Diphenyl [ b, e ]]Thiepin-11 (6H) -one 8-3(1.66g, 7.3mmol) was dissolved in methanol (35mL), the system was cooled well to zero, sodium borohydride (557mg, 14.6mmol) was added slowly at zero, stirring at zero for 1 hour, monitored by LC-MS. Concentrating under reduced pressure after reaction, extracting with ethyl acetate and water, drying organic phase anhydrous sodium sulfate, concentrating under reduced pressure, and purifying residue with column chromatography to obtain 6, 11-dihydrodiphenyl [ b, e ] product]Thiepin-11-ol 8-4(1.45 g). LC-MS: m/z 211[ M + H-18 ]] +
Step 4, Synthesis of Compound 8-5
9'- (benzyloxy) -4, 4-difluoro-3 a',4 '-dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' (1'H,3' H) -dione 2-10(41.5mg, 0.1mmol) and 6, 11-dihydrodiphenyl [ b, e ] thiahept-11-ol 8-4(34.2mg,0.15mmol) were dissolved in 1-propylphosphoric anhydride (50 wt.% in ethyl acetate, 400uL), stirred at 110 ℃ for 3 hours under microwave monitoring by LC-MS. After the reaction is finished, the crude product 9' - (benzyloxy) -4' - (6, 11-dihydrodiphenyl [ b, e ] thiophene-11-yl) -4, 4-difluoro-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' (1' H,3' H) -diketone 8-5 is obtained by decompression and concentration. LC-MS: m/z 626[ M + H ] +
Step 5, Synthesis of Compound 8
The crude product 9' - (benzyloxy) -4' - (6, 11-dihydrodiphenyl [ b, e ] thiophen-11-yl) -4, 4-difluoro-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' (1' H,3' H) -dione 8-5 was dissolved in methanol (5mL), palladium on carbon hydroxide (14mg, 0.1mmol) was added, the reaction system was replaced three times with nitrogen, one atmosphere of hydrogen was charged, stirred at room temperature for 4 hours, and monitored by LC-MS. After the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by a medium-pressure reverse-phase preparative column to give 4' - (6, 11-dihydrodiphenyl [ b, e ] thiophen-11-yl) -4, 4-difluoro-9 ' -hydroxy-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ] pyrrolo [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 ] +
1 H 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).
Test example 1 enzyme Activity test
Compound preparation
1) Compounds were dissolved in DMSO at 10mM test compound and 10mM reference compound (Baloxavir acid), and compounds were diluted 3-fold or 4-fold in DMSO to make up a 100-fold DMSO solution for 10 measurement points. The 4uL of 100-fold diluted compound was taken to 96uL of 1-fold buffer (20mM Tris-HCl,50mM NaCl,2mM MnCl) 2 10mM beta-mercaptoethanol, 0.05% Tween-20, pH 8.0) to give a 4-fold solution of the compound. The highest concentrations of test compounds in the enzyme reactions were 1uM in influenza A H1N1_ WSN 1933PAN (protein series 1-196, del52-72) and del52-72, respectively10uM in type B influenza virus Lee _1940PAN (protein series 1-198).
Experiments in enzymology
1) 4-fold enzyme solution (final concentration of 10nM influenza A virus H1N1_ WSN _1933PAN and 250nM influenza B virus Lee _1940PAN) and two-fold substrate solution (single-stranded DNA substrate) (final concentration of 0.3uM) (single-stranded DNA substrate series of [6-FAM ] AAT CGC AGG CAG CAC TC [ BHQ1] (custom-made Synthesis)
2) In 384-well assay plates (corning, cat #: 3575) in this example, 5uL of 4-fold compound solution and 5uL of 4-fold enzyme solution were added to each well, and 1-fold buffer solution was added in place of the enzyme solution in an equal amount to the blank group as a 100% inhibition control (negative control), and 1-fold buffer solution was added in place of the compound solution in an equal amount to the blank group as a 0% inhibition control (positive control), and the mixture was centrifuged at 1000rpm and 25 ℃ for 1 minute. The 384 test plates were placed in an microplate incubation shaker at 25 ℃, 220rpm, mixed and incubated for 15 minutes.
3) 10uL of 2-fold substrate solution was added to 384 test plates and centrifuged at 1000rpm and 25 ℃ for 1 minute. The 384 test plates were placed in an microplate incubation shaker at 37 ℃, mixed well at 220rpm and incubated for 120 minutes.
4) Fluorescence was detected at an excitation wavelength Ex of 485nm (10 nm in width) and an emission wavelength Em of 535nm (10 nm in width) using a Tecan Spark 20M, and the read fluorescence signals obtained from the positive control (maximum signal control) and the negative control (minimum signal control) were normalized to give the inhibition of compounds at different concentrations. The IC of the compound for inhibiting enzyme activity was then calculated by GraphPad Prism 6 fitting with log (inhibition) vs. stress-Variable slope pattern 50 . The fitting equation is: y ═ Bottom +
(Top-Bottom)/(1+10^((LogIC 50 -X) HillSlope)), wherein Y represents the known percent residual enzymatic activity and X represents the concentration of the known compound after Log in the calculation to yield IC of the compound for inhibition of enzymatic activity 50 。
5) And (3) test results: IC of the compounds of the invention for inhibition of enzymatic activity of 10nM of both influenza AH1N1_ WSN _1933PAN and influenza B Lee _1940PAN 50 Shown in table 1.
And (4) conclusion: as can be seen from Table 1, the preferred compounds of the present invention have strong inhibitory effect on the enzymatic activity of influenza virus A H1N1_ WSN _1933PAN and influenza virus B Lee _1940 PAN.
TABLE 1 inhibitory Activity of the Compounds of the present invention against influenza A/WSN/33(H1N1) and influenza B/Lee/40 viruses
EXAMPLES Compounds Influenza virus A IC 50 (nM) Influenza B IC 50 (nM)
1 + +++
2 ++ +++
3 ++ ++++
4 + +++
5 ++ ++++
6 + ++++
7 + +++
8 + +++
Baloxavir acid + +++
Where "+" represents ≦ 10, "+ + +" represents > 10 and ≦ 50, "+ + + + +" represents > 50 and ≦ 250, and "+ + + + + + +" represents > 250.
The experiments show that the compound has stronger inhibition effect on the enzymatic activities of influenza virus AH1N1_ WSN _1933PAN and influenza virus B Lee _1940 PAN.

Claims (17)

1. A compound represented by formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0003497259850000011
wherein the content of the first and second substances,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 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 (ii) a Wherein alkylene, carbocyclyl, heterocycloalkyl, aromatic, arylheterocyclyl may be further substituted with one, two, three, four or five independent R 1c Substitution; and R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 Not simultaneously selected from hydrogen;
R 1a 、R 1b are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); wherein said alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocycloalkyl, arylcyclyl, arylheterocyclyl may be further substituted with one, two or three independent R 1c Substitution; or, R 1a 、R 1b Together with the linking atoms form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group;
each R 1c Each independently selected from hydrogen, optionally halogen substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-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 Are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group);
alternatively, the first and second electrodes may be,
R 1 and R 2 、R 3 And R 4 、R 5 And R 6 Are each formed together with the linking atom
Figure FDA0003497259850000012
A saturated or unsaturated 3-to 10-membered carbocyclic group, a saturated or unsaturated 4-to 10-membered heterocycloalkyl group; wherein said carbocyclyl, heterocycloalkyl may be further substituted with one, two, three, four, five, six or seven independent R 1d Substitution;
each R 1d Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); wherein the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two or three independent R 1g Substitution;
R 1e 、R 1f are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocycloalkyl, arylcyclyl, arylheterocyclyl may be further substituted with one, two or three independent R 1g Substitution; or, R 1e 、R 1f Together with the linking atoms form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group;
each R 1g Each independently selected from hydrogen, optionally halogen substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, halogen, cyano, -SH, -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 groups);
alternatively, the first and second electrodes may be,
two independent R 1d Together with the linking atom form
Figure FDA0003497259850000021
A saturated or unsaturated 3-to 10-membered carbocyclic group, a saturated or unsaturated 4-to 10-membered heterocycloalkyl group, a 6-to 10-membered aromatic cyclic group, a 5-to 10-membered aromatic heterocyclic group; wherein the carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two, three, four or five R 1h Substitution;
each R 1h Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally 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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); or, two independent R 1h Together with the linking atom form
Figure FDA0003497259850000022
Figure FDA0003497259850000023
R 1i 、R 1j Are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6 &10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group);
a is selected from a monocyclic, double-condensed ring, three-condensed ring, four-condensed ring, five-condensed ring or six-condensed ring saturated or unsaturated carbocyclyl, saturated or unsaturated heterocycloalkyl, aromatic ring or aromatic heterocyclic group consisting of 5-30 atoms; wherein the carbocyclyl, heterocycloalkyl, arylcyclyl, arylheterocyclyl may be further substituted with one, two, three, four, five, six or seven R A1 Substitution;
each R A1 Are each independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 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 (ii) a Wherein the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two or three independent R A4 Substitution;
R A2 、R A3 are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); or, R A2 、R A3 Together with the linking atoms form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group;
each R A4 Each independently selected from hydrogen, optionally halogen substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, halogen, cyano, -SH, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group);
alternatively, the first and second electrodes may be,
two independent R A1 Together with the linking atom form
Figure FDA0003497259850000031
A saturated or unsaturated 3-to 10-membered carbocyclic group, a saturated or unsaturated 3-to 10-membered heterocycloalkyl group; wherein said carbocyclyl, heterocycloalkyl may be further substituted with one, two or three R A5 Substitution;
each R A5 Each independently selected from hydrogen, optionally halogen substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, halogen, cyano, -SH, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene radical- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); or, two independent R A5 Together with the linking atom form
Figure FDA0003497259850000032
The heteroatoms in the saturated or unsaturated heterocyclic alkyl and aromatic heterocyclic radical are respectively and independently selected from one or more of O, S, B or N, the unsaturated carbocyclyl does not comprise aryl, and the unsaturated heterocyclic alkyl does not comprise aromatic heterocyclic radical.
2. The compound of claim 1, wherein: the compound shown in the formula I is shown in formula Ia, formula Ib and formula Ic:
Figure FDA0003497259850000033
Figure FDA0003497259850000041
wherein the content of the first and second substances,
the B ring is selected from saturated or unsaturated 3-10 membered carbocyclyl, saturated or unsaturated 4-10 membered heterocycloalkyl; wherein the saturated or unsaturated carbocyclyl, saturated or unsaturated heterocycloalkyl may be further substituted with one, two, three, four or five independent R 1d Substitution;
each R 1d Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); wherein the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two or three independent R 1g Substitution;
alternatively, the first and second electrodes may be,
two independent R 1d Together with the linking atom form
Figure FDA0003497259850000042
A saturated or unsaturated 3-to 10-membered carbocyclic group, a saturated or unsaturated 4-to 10-membered heterocycloalkyl group, a 6-to 10-membered aromatic cyclic group, a 5-to 10-membered aromatic heterocyclic group; wherein carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two or three R 1h And (4) substitution.
3. The compound of claim 2, wherein: ring B 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 6-membered heterocycloalkyl; wherein the heteroatom of the heterocycloalkyl group is selected from N, O, S; wherein carbocyclyl, heterocycloalkyl may be further substituted with one, two, three, four or five independent R 1d And (4) substitution.
4. A compound according to claim 3, characterized in that:
the B ring is selected from
Figure FDA0003497259850000043
Figure FDA0003497259850000044
Figure FDA0003497259850000045
Wherein the B ring may be further substituted by one, two or three independent R 1d Substitution;
each R 1d Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); wherein the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocyclic may be further substituted with one, two or three independent R 1g Substitution;
alternatively, the first and second electrodes may be,
two independent R 1d Together with the linking atom form
Figure FDA0003497259850000051
A saturated or unsaturated 3-to 10-membered carbocyclic group, a saturated or unsaturated 4-to 10-membered heterocycloalkyl group, a 6-to 10-membered aromatic cyclic group, a 5-to 10-membered aromatic heterocyclic group;
R 1e 、R 1f are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Branched or straight-chain alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionallyBy halogen substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group); or, R 1e 、R 1f Together with the linking atoms form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group;
each R 1g Each independently selected from hydrogen, optionally halogen substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, halogen, cyano, -SH, -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 groups).
5. A compound according to claim 3, characterized in that:
two independent R 1d Linked to form a saturated 3-membered carbocyclyl, a saturated 4-membered carbocyclyl, a saturated or unsaturated 5-membered carbocyclyl, a saturated or unsaturated 6-membered carbocyclyl, a saturated 4-membered heterocycloalkyl, a saturated or unsaturated 5-membered heterocycloalkyl, a saturated or unsaturated 6-membered heterocycloalkyl; wherein the carbocyclyl, heterocycloalkyl may be further substituted by one, two or three R 1h And (4) substitution.
6. The compound of claim 5, wherein:
the B ring is selected from
Figure FDA0003497259850000052
Figure FDA0003497259850000053
Figure FDA0003497259850000054
Wherein the B ring mayFurther substituted by one, two or three R 1h Substitution;
R 1h selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally 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-to 10-membered carbocyclic group), -C 0～4 Alkylene- (saturated or unsaturated 4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocyclic group);
R 1i 、R 1j are independently selected from hydrogen, -OH, -SH, -NH 2 Optionally halogen-substituted-C 1～6 Alkyl, optionally halogen-substituted-C 2～6 Alkenyl, optionally halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring group), -C 0～4 Alkylene- (5-to 10-membered heteroaromatic alkyl).
7. The compound according to any one of claims 1 or 2, characterized in that:
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 FDA0003497259850000061
And R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 Not simultaneously selected from hydrogen.
8. The compound according to any one of claims 1 or 2, characterized in that:
a is selected from
Figure FDA0003497259850000062
Figure FDA0003497259850000063
Figure FDA0003497259850000064
Wherein each X is independently selected from CH 2 NH, O or S; the ring from which A is selected may be further substituted by one, two, three, four or five R A1 And (4) substitution.
9. The compound of claim 8, wherein:
a is selected from
Figure FDA0003497259850000065
Figure FDA0003497259850000066
Figure FDA0003497259850000071
10. The compound of claim 8, wherein:
two independent R A1 Together with the atoms to which they are attached form a saturated 3-membered carbocyclic group, a saturated 4-membered 3-membered carbocyclic group, a saturated or unsaturated 5-membered carbocyclic group, a saturated or unsaturated 6-membered carbocyclic group, a saturated 4-membered heterocycloalkyl group, a saturated or unsaturated 5-membered heterocycloalkyl group, a saturated or unsaturated 6-membered heterocycloalkyl group.
11. The compound of claim 10, wherein:
a is selected from
Figure FDA0003497259850000072
Wherein X is selected from CH 2 NH, O or S; the ring from which A is selected may be further substituted by one, two, three, four or five R A1 And (4) substitution.
12. The compound of claim 8, wherein:
a is selected from
Figure FDA0003497259850000073
Wherein X is selected from CH 2 NH, O or S; the ring from which A is selected may be further substituted by one, two, three or four R A1 And (4) substitution.
13. The compound according to any one of claims 1 or 2, characterized in that: the compound is specifically:
Figure FDA0003497259850000074
Figure FDA0003497259850000081
Figure FDA0003497259850000091
14. use of the compound of any one of claims 1 to 13, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of a viral infection disease.
15. Use according to claim 14, characterized in that: the viral infection is an influenza virus infection.
16. A pharmaceutical composition comprising a preparation prepared from the compound of any one of claims 1 to 13, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
17. The pharmaceutical composition of claim 16, further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle.
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