CN114907365B - Influenza virus inhibitor and application thereof - Google Patents

Influenza virus inhibitor and application thereof Download PDF

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CN114907365B
CN114907365B CN202210117938.6A CN202210117938A CN114907365B CN 114907365 B CN114907365 B CN 114907365B CN 202210117938 A CN202210117938 A CN 202210117938A CN 114907365 B CN114907365 B CN 114907365B
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alkylene
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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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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 the novel compound shown as the formula I and used as an influenza virus cap-dependent endonuclease inhibitor.

Description

Influenza virus inhibitor and application thereof
Technical Field
The present invention relates to a novel class of compounds having utility as inhibitors of influenza virus replication and their use in the treatment of influenza, in particular as inhibitors of influenza virus cap-dependent endonucleases.
Background
Influenza (influenza) is an acute respiratory infectious disease caused by influenza virus that severely jeopardizes human health. Influenza of human infection is caused by influenza subtypes a and B, influenza virus a can be further classified according to hemagglutinin (H or HA) and neuraminidase (N) antigen types, for example, subtypes H1N1, H1N2, H2N2, H3N1, etc. that have been found to exist.
The RNA polymerase of influenza virus is responsible for replication and transcription of viral RNA, a heterotrimer consisting of 3 subunits: polymerase Acid (PA), polymerase base 1 (PB 1) and polymerase base 2 (PB 2). Transcription of influenza viral RNA has a special "cap-capturing" mechanism, with the PB2 subunit responsible for recognizing and binding to the "cap structure" of the host pre-mRNA, and the PA subunit cleaves the host mRNA as a primer, initiating the transcription process. The sheared mRNA primers were used in PB1 subunit for viral mRNA synthesis. Because the cap-dependent endonucleases of the PA subunit are very conserved during influenza variation and are necessary for the viral life process and the binding site is specific, the binding domain is very suitable as a target for anti-influenza drugs for the development of novel anti-influenza drugs.
A new anti-influenza agent, balo Sha Wei, with this mechanism of action has been marketed which can inhibit viral mRNA synthesis and ultimately viral proliferation by inhibiting cap-dependent endonucleases. However, there is still an urgent need to develop other compounds for treating influenza by this mechanism that are more active, less toxic and more convenient to use.
Disclosure of Invention
The invention provides a compound shown in a formula I, or a deuterated compound, or a stereoisomer or a pharmaceutically acceptable salt thereof:
wherein,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group), -C 0～4 alkylene-S (O) 2 R 1a 、-C 0～4 alkylene-S (O) R 1a 、-C 0～4 alkylene-S (O) 2 NR 1a R 1b 、-C 0～4 alkylene-S (O) NR 1a R 1b The method comprises the steps of carrying out a first treatment on the surface of the Wherein alkylene, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl 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 -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); wherein said alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups may be further substituted with one, two, or three independent R 1c Substitution; alternatively, R 1a 、R 1b Form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group together with the linking atom;
each R 1c Independently selected from hydrogen, optionally halogen-substituted-C 1～6 Straight or branched chainAlkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 1k 、-C 0～4 alkylene-S (O) 2 NR 1k R 1l 、-C 0～4 alkylene-S (O) NR 1k R 1l ；
R 1k 、R 1l Are independently selected from hydrogen, -OH, -SH, -NH 2 -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group);
or,
R 1 and R is R 2 、R 3 And R is R 4 、R 5 And R is R 6 Respectively with the linking atoms to formSaturated or unsaturated 3-to 10-membered carbocyclyl, saturated or unsaturated 4-to 10-membered heterocycloalkyl; wherein the carbocyclyl, heterocycloalkyl, and optionally further comprises 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, -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); wherein alkylene, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups 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 -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, halogen substituted C 1～6 Alkyl, -C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups may be further substituted with one, two, or three independent R 1g Substitution; alternatively, R 1e 、R 1f Form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group together with the linking atom;
each R 1g Independently selected from hydrogen, optionally halogen-substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 An alkyl group);
or,
two independentR of (2) 1d Together with the atoms to which they are attached formSaturated or unsaturated 3-to 10-membered carbocyclyl, saturated or unsaturated 4-to 10-membered heterocycloalkyl, 6-to 10-membered aromatic ring group, 5-to 10-membered aromatic heterocyclic group; wherein the carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups 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, -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 alkylene-OR 1i 、-C 0～4 alkylene-OC (O) R 1i 、-C 0～4 alkylene-C (O) R 1i 、-C 0～4 alkylene-C (O) OR 1i 、-C 0～4 alkylene-C (O) NR 1i R 1j 、-C 0～4 alkylene-NR 1i R 1j 、-C 0～4 alkylene-NR 1i C(O)R 1j 、-C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); alternatively, two independent R 1h Together with the atoms to which they are attached form
R 1i 、R 1j Are independently selected from hydrogen, -OH, -SH, -NH 2 -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group);
a is selected from a saturated or unsaturated carbocyclyl, saturated or unsaturated heterocycloalkyl, aryl or aromatic heterocyclic group which are formed by 5-30 atoms and are provided with a single ring, double condensed rings, three condensed rings, four condensed rings, five condensed rings or six condensed rings; wherein the carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups 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, -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group), -C 0～4 alkylene-S (O) 2 R A2 、-C 0～4 alkylene-S (O) R A2 、-C 0～4 alkylene-S (O) 2 NR A2 R A3 、-C 0～4 alkylene-S (O) NR A2 R A3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein alkylene, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups 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 -C optionally substituted by halogen 1～6 Alkyl, optionallyOptionally halogen-substituted-C 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); alternatively, R A2 、R A3 Form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group together with the linking atom;
each R A4 Independently selected from hydrogen, optionally halogen-substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group);
or,
two independent R A1 Together with the atoms to which they are attached formSaturated or unsaturated 3-to 10-membered carbocyclyl, saturated or unsaturated 3-to 10-membered heterocycloalkyl; wherein the carbocyclyl, heterocycloalkyl may be further substituted with one, two or three R A5 Substitution;
each R A5 Independently selected from hydrogen, optionally halogen-substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 group、-C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); alternatively, two independent R A5 Together with the atoms to which they are attached formThe hetero atoms in the saturated or unsaturated heterocyclic alkyl and the aromatic heterocyclic group are respectively and independently selected from one or more of O, S, B or N, the unsaturated carbocyclic group does not comprise aryl, and the unsaturated heterocyclic alkyl does not comprise aromatic heterocyclic group.
Further, the method comprises the steps of,
the compound shown in the formula I is shown in the formula Ia, the formula Ib and the formula Ic:
wherein,
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, -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 an unsaturated 3-to 10-membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); wherein alkylene, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups may be further substituted with one, two, or three independent R 1g Substitution; two independent R 1d Together with the atoms to which they are attached form Saturated or unsaturated 3-to 10-membered carbocyclyl, saturated or unsaturated 4-to 10-membered heterocycloalkyl, 6-to 10-membered aromatic ring group, 5-to 10-membered aromatic heterocyclic group; wherein the carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups may be further substituted with one, two, or three R 1h And (3) substitution.
Still further, the method further comprises the steps of,
the B ring is selected from saturated or unsaturated 3-membered carbocyclyl, saturated or unsaturated 4-membered carbocyclyl, saturated or unsaturated 5-membered carbocyclyl, saturated or unsaturated 6-membered carbocyclyl, saturated or unsaturated 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 the carbocyclyl, heterocycloalkyl, and optionally one, two, three, four, or five of the individual R' s 1d And (3) substitution.
Further specifically, the method comprises the steps of,
the B ring is selected from
Wherein the B ring may be further substituted with one, two or three independent R 1d Substitution;
each R 1d Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); wherein alkylene, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups may be further substituted with one, two, or three independent R 1g Substitution; alternatively, two independent R 1d Together with the atoms to which they are attached form Saturated or unsaturated 3-to 10-membered carbocyclyl, saturated or unsaturated 4-to 10-membered heterocycloalkyl, 6-to 10-membered aromatic ring group, 5-to 10-membered aromatic heterocyclic group; the method comprises the steps of carrying out a first treatment on the surface of the
R 1e 、R 1f Are independently selected from hydrogen, -OH, -SH, -NH 2 -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4 to ultra)10 membered heterocycloalkyl) -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); alternatively, R 1e 、R 1f Form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group together with the linking atom;
each R 1g Independently selected from hydrogen, optionally halogen-substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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).
Further specifically, the method comprises the steps of,
two independent R 1d To form a saturated or unsaturated 3-membered carbocyclyl group, a saturated or unsaturated 4-membered carbocyclyl group, a saturated or unsaturated 5-membered carbocyclyl group, a saturated or unsaturated 6-membered carbocyclyl 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 with one, two or three R 1h And (3) substitution.
Still more particularly, the method comprises the steps of,
the B ring is selected from
Wherein the B ring may be further substituted with one, two or three R' s 1h Substitution;
R 1h selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, -C optionally substituted by halogen 1～6 Alkyl, optionally taken by halogensubstituted-C 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 alkylene-OR 1i 、-C 0～4 alkylene-OC (O) R 1i 、-C 0～4 alkylene-C (O) R 1i 、-C 0～4 alkylene-C (O) OR 1i 、-C 0～4 alkylene-C (O) NR 1i R 1j 、-C 0～4 alkylene-NR 1i R 1j 、-C 0～4 alkylene-NR 1i C(O)R 1j 、-C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group);
R 1i 、R 1j are independently selected from hydrogen, -OH, -SH, -NH 2 -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 Alkylene- (3-10 membered carbocyclyl), -C 0～4 Alkylene- (4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aralkyl).
Further, the method comprises the steps of,
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 independently selected from hydrogen, methyl, halogen, cyano, -OH, -SH, -C (O) NH 2 、-NHC(O)CH 3 、-OCH 3 、And R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 Not simultaneously selected from hydrogen.
Further, the method comprises the steps of,
a is selected from
Wherein each X is independently selected from CH 2 NH, O or S; the ring selected from A may be further substituted with one, two, three, four or five R A1 And (3) substitution.
Still further, the method further comprises the steps of,
a is selected from
Still further, the method further comprises the steps of,
two independent R A1 Together with the atoms to which they are attached, form a saturated or unsaturated 3-membered carbocyclyl, a saturated or unsaturated 4-membered 3-membered carbocyclyl, a saturated or unsaturated 5-membered carbocyclyl, a saturated or unsaturated 6-membered carbocyclyl, a saturated or unsaturated 4-membered heterocycloalkyl, a saturated or unsaturated 5-membered heterocycloalkyl, a saturated or unsaturated 6-membered heterocycloalkyl.
Further specifically, the method comprises the steps of,
a is selected fromWherein X is selected from CH 2 NH, O or S; the ring selected from A may be further substituted with one, two, three, four or five R A1 And (3) substitution.
Still further, the method further comprises the steps of,
a is selected fromWherein X is selected from CH 2 NH, O or S; the ring selected from A may be further substituted with one, two, three or four R A1 Substitution of。
In some embodiments of the invention, the compounds of formula I are specifically:
the invention also provides application of the compound, or deuterated compound, or stereoisomer, or pharmaceutically acceptable salt thereof in preparing medicaments for preventing or treating viral 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 deuterated compounds, or stereoisomers, or pharmaceutically acceptable salts thereof.
Further, the composition also comprises pharmaceutically acceptable carriers, auxiliary materials and vehicles.
The compounds and derivatives provided in the present invention may be named according to IUPAC (international union of pure and applied chemistry) or CAS (chemical abstract service, columbus, OH) naming system.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"substituted" means that a hydrogen atom in the molecule is replaced with a different atom or group; or lone pair of atoms in the moleculeThe electrons being replaced by other atoms or groups, e.g. the lone pair of electrons on the S atom being replaced by an O atom
"optionally substituted" means that "substitution" may or may not occur, i.e., the hydrogen atoms in the molecule, group, are replaced by other identical or different atoms, groups.
"further substituted" means that "substitution" may, but need not, occur, and that the description includes situations that may or may not occur.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1～6 Alkyl refers to alkyl groups containing 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 other groups such as-O (C 1～6 Alkyl).
"carbocyclyl", "cycloalkyl", "cycloalkane" as used herein 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 cyclo Hexenyl groups. Examples of carbocyclyl groups including multicycloalkyl ring systems are dicyclohexyl, dicyclopentyl, bicyclooctyl, and the like. Two such bicycloalkyl polycyclic structures are exemplified and named below:dicyclohexyl and->Dicyclohexyl group. The saturated or unsaturated 3-to 10-membered carbocyclyl of the present invention means a 3, 4, 5, 6, 7, 8, 9 or 10-membered saturated or unsaturated carbocyclyl group, and the unsaturated 3-to 10-membered carbocyclyl group is preferably a 5-to 10-membered unsaturated carbocyclyl group or a 6-to 10-membered unsaturated carbocyclyl group or a 7-to 10-membered unsaturated carbocyclyl group or an 8-to 10-membered unsaturated carbocyclyl group or a 9-to 10-membered unsaturated carbocyclyl group.
Further "heterocycloalkyl", "heterocycle", "heterocycloalkane" as used herein refers to 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. Typically a monovalent saturated or partially unsaturated mono-or bicyclic ring system representing 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, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, Thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepayl, homopiperazinyl or oxaazepanyl. An example of a bicyclic saturated heterocycloalkyl group is 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]And (3) nonyl. Partially unsaturatedExamples of heterocycloalkyl are dihydrofuryl, imidazolinyl, tetrahydro-pyridyl 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 a group or a molecule containing a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-oxygen double bond, a carbon-sulfur double bond, a carbon-nitrogen triple bond and the like; the unsaturated carbocyclyl groups of the present invention may or may not include aromatic ring groups, and the unsaturated heterocyclyl groups may or may not include heteroaryl groups, as may be freely selected by those skilled in the art.
As used herein, "aromatic ring group" or "aromatic ring" refers to aromatic hydrocarbon groups having multiple carbon atoms. Aryl is typically a monocyclic, bicyclic or tricyclic aryl group having multiple carbon atoms. Furthermore, 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.
"aromatic heterocyclic group" as used herein refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. An aromatic mono-or bicyclic hydrocarbon typically comprising a plurality of ring atoms, wherein one or more of the ring atoms is selected from heteroatoms of O, N, S. Preferably one to three heteroatoms. Heteroaryl 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 is applicable 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 atom to which R is attached is O, S, or N 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 。
"halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
"halogen-substituted alkyl" as used herein means that one or more hydrogen atoms in the alkyl group are replaced with halogen; such as trifluoromethyl, difluoromethyl, monofluoromethyl and the like.
As used herein, "OR", "-NRR", etc. means that the R group is attached to the oxygen OR nitrogen atom by a single bond.
In the present invention, "-C (O) R", "-S (O) 2 The oxygen atom in R' and the like is doubly bonded to a carbon atom or a sulfur atom.
Described in the invention"=o", "=s" means that the oxygen atom, the sulfur atom is attached to the substitution position by a double bond.
In the description of the radicals according to the invention "- -",are used to describe the positions of substitution of groups.
"deuterated compound" in the present invention refers to a molecule or group in which 1 or more hydrogen atoms are replaced with deuterium atoms, wherein the ratio 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 the pharmaceutical dosage form, and physiologically compatible with the recipient.
The terms "salts" and "pharmaceutically acceptable salts" refer to the acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly in the final isolation and purification of the compounds. The compound may be obtained by mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base as appropriate (for example, equivalent). These salts may be obtained by precipitation in solution and collected by filtration, or recovered after evaporation of the solvent, or by lyophilization after reaction in an aqueous medium. The salts of the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salts of the compounds.
In certain embodiments, one or more compounds of the present invention may be used in combination with one another. The compounds of the invention may alternatively 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 a subject simultaneously, separately or sequentially.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and mass spectrometry(MS). NMR shift (. Delta.) is given in units of 10-6 (ppm). NMR was performed using a nuclear magnetic resonance apparatus (Bruker Avance III 400 and Bruker Avance 300) with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS).
LC-MS was measured using Shimadzu LC-MS 2020 (ESI). HPLC was performed using a Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (medium pressure preparative chromatography) uses Gilson GX-281 reverse phase preparative chromatograph. The specification of the thin layer chromatography separation and purification product adopted by the smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from An Naiji chemical, chengkoulochemical, shaoshan chemical technology, carbofuran technology, and the like.
The reaction was carried out under nitrogen atmosphere without specific explanation in examples. The examples are not specifically described, and the solution refers to an aqueous solution. The temperature of the reaction was room temperature, unless otherwise specified in the examples. In the examples, M is mol/liter unless otherwise specified.
Synthesis of intermediate compounds
Step 1, synthesis of Compound M1-2
3- (benzyloxy) -4-oxo-4H-pyran-2-carboxylic acid M1-1 (12.3 g,50 mmol) was dissolved in dimethylformamide (60 mL), after stirring thoroughly, 1, 8-diazabicyclo undec-7-ene (11.4 g,75 mmol) was added to the reaction system at room temperature, stirring was carried out at room temperature for ten minutes, and ethyl iodide (14.0 g,90 mmol) 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, an organic phase is washed three times by water and saturated saline water respectively, the organic phase is dried by anhydrous sodium sulfate and then is decompressed and concentrated, and a crude product can be directly obtained For the next reaction without purification. Crude 3- (benzyloxy) -4-oxo-4H-pyran-2-carboxylic acid ethyl ester 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 (13.4 g,49 mmol) was dissolved in dimethylacetamide (130 mL), after sufficient stirring, pyridine p-toluenesulfonate (36.8 g,147 mmol) and tert-butyl hydrazinoformate (9.7 g,73.5 mmol) were added to the reaction at room temperature, stirred at 60℃for 12 hours, and monitored by LC-MS. After the completion of the reaction, the organic phase was washed three times with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give ethyl 3- (benzyloxy) -1- ((t-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
3- (benzyloxy) -1- ((tert-butoxycarbonyl) amino) -4-oxo-1, 4-dihydropyridine-2-carboxylic acid ethyl ester M1-3 (7.8 g,20 mmol) was dissolved in dichloromethane (30 mL), after sufficient stirring, trifluoroacetic acid (30 mL) was added to the reaction system at room temperature, stirred at room temperature for 1 hour, and monitored by LC-MS. After the reaction 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 water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and directly using the crude product for the next reaction without purification. Crude 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylic acid ethyl ester M1 (5.4 g). LC-MS: m/z 289[ M+H ] ] +
Step 4, synthesis of Compound M2-2
3, 4-difluoro-2-methylbenzoic acid M2-1 (8.6 g,50 mmol), N-bromosuccinimide (8.9 g,60 mmol), azobisisobutyronitrile (164 mg,1 mmol) were dissolved in carbon tetrachloride (200 mL), the reaction system was replaced three times with nitrogen, nitrogen at one atmosphere pressure was charged, and stirring was performed at 80℃for 1 hour, followed by LC-MS monitoring. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give 2- (bromomethyl) -3, 4-difluorobenzoic acid M2-2 (12.0 g).
Step 5, synthesis of Compound M2-4
Diphenyldisulfide M2-3 (5.5 g,25 mmol), sodium hydroxide (2.87 g,72 mmol), sodium borohydride (1.74 g,46 mmol) were dissolved in tetrahydrofuran (80 mL) and water (80 mL), the reaction was replaced three times with nitrogen, nitrogen at one atmosphere was charged, and stirring was performed at 70℃for 12 hours, and LC-MS monitoring was performed. The reaction solution was directly used for the next reaction. 2- (bromomethyl) -3, 4-difluorobenzoic acid M2-2 (12.0 g,48 mmol) 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, the pH of the system was adjusted to 5-6, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give the product M2-4 (12.6 g) 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid. LC-MS: m/z 281[ M+H ] ] +
Step 6, synthesis of Compound M2-5
3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid M2-4 (12.6 g,45 mmol) was dissolved in polyphosphoric acid (300 mL) and stirred at 120℃for 12 hours and monitored by LC-MS. After the reaction, the reaction system is cooled to room temperature, the reaction solution is poured into 2 kg of crushed ice, extracted by ethyl acetate and water, the organic phase is washed three times by saturated sodium bicarbonate water solution, the organic phase is dried by anhydrous sodium sulfate and then is decompressed and concentrated, and the residue is purified by column chromatography to obtain the product 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
7, 8-difluorodiphenyl [ b, e ]]Thiepan-11 (6H) -one M2-5 (10.1 g,38.5 mmol) was dissolved in methanol (200 mL) and the system was cooled to zero, sodium borohydride (2.93 g,77 mmol) was added slowly at zero, stirred for 1 hour at zero, and monitored 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 pressureThe residue is purified by column chromatography to obtain the product 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepinin-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 ] thiepan-11-yl) -9' -hydroxy-2, 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 1)
Step 1, synthesis of Compounds 1-3
Under the protection of nitrogen, the substrate 8-oxa-2-azaspiro [4,5 ]]Decan-3-one 1-1 (1.55 g,10.0 mmol), dissolved in tetrahydrofuran (40 mL), cooled to-30deg.C, slowly dropped n-butyllithium (2.5M, 12.0mmol,4.8 mL), kept at-30deg.C for 1 hr, dropped allyl chloroformate 1-2 (1.45 g,12.0 mmol), kept at-30deg.C for 1 hr, quenched with saturated ammonium chloride solution, concentrated under reduced pressure, extracted with ethyl acetate and water, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by column chromatography to give allyl 3-oxo-8-oxa-2-azaspiro [ 4.5:]decane-2-carbonate 1-3 (2.38 g). LC-MS: m/z 240[ M+H ]] +
Step 2, synthesis of Compounds 1 to 4
3-oxo-8-oxa-2-azaspiro [4.5 ]]1-3 (2.38 g,10.0 mmol) of allyl decane-2-carboxylate is dissolved in 25mL of tetrahydrofuran, the reaction system is fully cooled to minus 78 ℃, diisobutyl aluminum hydride (1.3M, 12.0mmol,9.2 mL) is slowly added dropwise, the reaction is kept at minus 78 ℃ for 1 hour, saturated ammonium chloride solution is added for quenching reaction, reduced pressure concentration is carried out, ethyl acetate and water extraction are carried out, the organic phase is dried by anhydrous sodium sulfate and then reduced pressure concentration is carried out, the crude product can be directly used for the next reaction without purification, and the crude product 3-hydroxy-8-oxa-2-azaspiro [4.5 ] ]Decane-2-carboxylic acid allyl ester 1-4.LC-MS: m/z 224[ M+H-18 ]] +
Step 3, synthesis of Compounds 1 to 5
The crude product 3-hydroxy-8-oxa-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 1-4 was dissolved in methanol (20 mL), and after sufficient stirring, p-toluenesulfonic acid monohydrate (153 mg,0.8 mmol) was added to the reaction system at room temperature, and stirred at room temperature for 12 hours, followed by LC-MS monitoring. Concentrating under reduced pressure after the reaction is finished, 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 reaction without purification, wherein the crude product is 3-methoxy-8-oxa-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 1-5.LC-MS: m/z 224[ M+H-32 ]] +
Step 4, synthesis of Compounds 1 to 6
The crude product 3-methoxy-8-oxa-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 1-5 and 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylic acid ethyl ester M1 (1.8 g,6.2 mmol) were dissolved in acetonitrile (60 mL), the reaction system was cooled sufficiently to-30℃and tin tetrachloride (2.4 g,9.4 mmol) was slowly added to the reaction system, stirred for 1 hour at-30℃and monitored by LC-MS. After the reaction is finished, saturated sodium bicarbonate aqueous solution is added for quenching reaction, reduced pressure concentration is carried out, dichloromethane and water are used for extraction, the organic phase is dried by anhydrous sodium sulfate and then reduced pressure concentration is carried out, the crude product can be directly used for the next reaction without purification, and the crude product 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxypyridine-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 [4.5]Allyl decane-2-carboxylate 1-6, palladium tetraphenyl phosphine (284 mg,0.25 mmol) and morpholine (4.3 g,50 mmol) were dissolved in tetrahydrofuran (40 mL), the reaction was replaced three times with nitrogen, nitrogen at one atmosphere was charged, stirred at room temperature for 1 hour, and monitored by TLC and LC-MS. Concentrating under reduced pressure after the reaction is finished, purifying the residue by column chromatography to obtain the product 9'- (benzyloxy) -2, 3a',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ]][1,2,4]Triazines]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 to 8
9'- (benzyloxy) -2, 3a',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ]][1,2,4]Triazines]-8',10' (1 'H,3' H) -dione 1-7 (38.2 mg,0.1 mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepan-11-ol M2 (39.6 mg,0.15 mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 400 uL) and stirred for 3 hours at 110 degrees celsius with microwaves, 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 concentration ]Thiepin-11-yl) -2, 3a ',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ]][1,2,4]Triazines]-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, 3a ',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ]][1,2,4]Triazines]-8',10' (1 'H,3' H) -dione 1-8 was dissolved in methanol (5 mL), palladium on carbon hydroxide (14 mg,0.1 mmol) was added, the reaction was replaced three times with nitrogen, hydrogen at one atmosphere was charged, stirred at room temperature for 4 hours, and monitored by LC-MS. Filtering with diatomite after the reaction, concentrating the filtrate under reduced pressure, purifying with medium-pressure reverse phase preparation column to obtain 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepin-11-yl) -9 '-hydroxy-2, 3a',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ]][1,2,4]Triazines]-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-dihydrodibenzo [ 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)
Step 1, synthesis of Compounds 2-3
Sodium hydrogen (1.92 g,48 mmol) and anhydrous tetrahydrofuran (200 mL) are added into a 250mL three-necked flask under the protection of nitrogen, the mixture is fully cooled to zero ℃, a solution of triethyl phosphorylacetate 2-2 (10.8 g,48 mmol) and tetrahydrofuran (50 mL) is slowly added dropwise, the mixture is reacted for 0.5 hour at the zero ℃ after the dropwise addition, and the reaction is carried out for 1 hour at room temperature. The reaction was cooled to zero degrees centigrade, 4-difluorocyclohexanone 2-1 (5.36 g,40 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours after the dropwise addition, monitored by TLC and LC-MS. After completion of the reaction, a saturated aqueous ammonium chloride solution (50 mL) was added to the system, 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, concentrated under reduced pressure, and the residue was purified by column chromatography to give 2-3 (8.0 g) of ethyl 2- (4, 4-difluorocyclohexyldiene) acetate as a product. LC-MS: m/z 205[ M+H ]] + 。
Step 2, synthesis of Compounds 2-4
To a 250mL reaction flask was added ethyl 2-3- (4, 4-difluorocyclohexyl diene) acetate (8.0 g,39 mmol), potassium carbonate (11 g,80 mmol), dimethyl sulfoxide (80 mL) and nitromethane (4.9 g,80 mmol), and the reaction was stirred at 80℃for 2 hours, monitored by TLC and LC-MS. After the reaction, water (200 mL) was added to the system, extraction was performed with ethyl acetate, the organic phase was washed twice with aqueous saturated saline, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude 2- (4, 4-difluoro-1- (nitromethyl) cyclohexyl) ethyl acetate 2-4, which was directly used for the next reaction. LC-MS: m/z 266[ M+H ] ] +
Step 3, synthesis of Compounds 2-5
To a 250mL reaction flask, ethyl 2-4- (4, 4-difluoro-1- (nitromethyl) cyclohexyl) acetate, methanol (80 mL) and Raney nickel were added, the reaction system was replaced three times with nitrogen, hydrogen gas at one atmosphere pressure was introduced, and the reaction was stirred at room temperature for 12 hours. LC-MS monitored the reaction. Concentrating under reduced pressure after the reaction, extracting with ethyl acetate and water, and collecting the organic phase with anhydrousDrying sodium sulfate, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain 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 to 6
The substrate 8, 8-difluoro-2-azaspiro [4,5 ]]Decan-3-one 2-5 (3.8 g,20.1 mmol), dissolved in tetrahydrofuran (50 mL), cooled to-30deg.C, slowly added dropwise n-butyllithium (2.5M, 24.1mmol,9.6 mL), kept at-30deg.C for 1 hr, allyl chloroformate 1-2 (2.57 g,21.4 mmol), kept at-30deg.C for 1 hr, quenched with saturated ammonium chloride solution, concentrated under reduced pressure, extracted with ethyl acetate and water, the organic phase dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by column chromatography to give allyl 3-oxo-8, 8-difluoro-2-azaspiro [4.5 ] ]Decane-2-carbonate 2-6 (4.32 g). LC-MS: m/z 274[ M+H ]] +
Step 5, synthesis of Compounds 2 to 7
3-oxo-8, 8-difluoro-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 2-6 (4.32 g,15.8 mmol) was dissolved in 40mL tetrahydrofuran, the reaction system was cooled sufficiently to-78℃and diisobutyl aluminum hydride (1.3M, 18.96mmol,14.6 mL) was slowly added dropwise, the reaction was maintained at-78℃for 1 hour, saturated ammonium chloride solution was added to quench the reaction, the reaction was concentrated under reduced pressure, and extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and was used directly in the next reaction without purification, the crude product 3-hydroxy-8, 8-difluoro-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 2-7.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 ]]Decane-2-carboxylic acid allyl ester 2-7 was dissolved in methanol (32 mL), and after sufficient stirring, p-toluenesulfonic acid monohydrate (241 mg,1.27 mmol) was added to the reaction system at room temperature, and stirred at room temperature for 12 hours, followed by LC-MS monitoring. Concentrating under reduced pressure after the reaction is finished, 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 reaction without purifying the crude product, namely 3-methyl Oxy-8, 8-difluoro-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 2-8.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 ]]Decane-2-carboxylic acid allyl ester 2-8 and 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylic acid ethyl ester M1 (3.2 g,11.1 mmol) were dissolved in acetonitrile (110 mL), the reaction system was cooled sufficiently to-30℃and tin tetrachloride (7.5 g,16.6 mmol) was slowly added to the reaction system, stirred for 1 hour at-30℃and monitored by LC-MS. After the reaction is finished, saturated sodium bicarbonate aqueous solution is added for quenching reaction, reduced pressure concentration is carried out, dichloromethane and water are used for extraction, the organic phase is dried by anhydrous sodium sulfate and then reduced pressure concentration is carried out, the crude product can be directly used for the next reaction without purification, and the crude product 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxygen pyridine-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 to 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 tetraphenyl phosphine (480 mg,0.42 mmol) and morpholine (7.2 g,83 mmol) were dissolved in tetrahydrofuran (66 mL), the reaction was replaced three times with nitrogen, nitrogen at one atmosphere was charged, stirred at room temperature for 1 hour, and monitored by TLC and LC-MS. Concentrating under reduced pressure after the reaction is finished, and purifying the residue by column chromatography to obtain the product 9'- (benzyloxy) -4, 4-difluoro-3 a',4 '-dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ] ]Pyrrolo [2,1-c ]][1,2,4]Triazines]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 ]][1,2,4]Triazines]-8',10' (1 'H,3' H) -dione 2-10 (41.5 mg,0.1 mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiopan-11-ol M2 (39.6 mg,0.15 mmol) in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 400 uL) was stirred for 3 hours at 110℃under microwavesLC-MS monitoring. After the reaction is finished, the crude product 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ] is obtained by decompression concentration]Thiophene-11-yl) -4, 4-difluoro-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ]][1,2,4]Triazines]8',10' (1 'H,3' H) -dione 2-11.LC-MS: m/z 662[ M+H ]] +
Step 10 Synthesis of Compound 2
Crude 9'- (benzyloxy) -4' - (7, 8-difluoro-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]Triazines]-8',10' (1 'H,3' H) -dione 2-11 was dissolved in methanol (5 mL), palladium on carbon hydroxide (14 mg,0.1 mmol) was added, the reaction was replaced three times with nitrogen, hydrogen at one atmosphere was charged, stirred at room temperature for 4 hours, and monitored by LC-MS. Filtering with diatomite after the reaction, concentrating the filtrate under reduced pressure, purifying with medium-pressure reverse phase preparation column to obtain compound 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ] ]Thiophene-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]Triazines]-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 ] thiepan-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)
Step 1, synthesis of Compound 3-2
Sodium hydrogen (2.2 g,55 mmol) and anhydrous tetrahydrofuran (100 mL) are added into a 250mL three-necked flask under the protection of nitrogen, fully cooled to zero ℃, and the phosphoryl acetic acid is slowly added dropwiseA solution of triethyl2-2 (12.3 g,55 mmol) in tetrahydrofuran (40 mL) was reacted at zero℃for 0.5 hour and at room temperature for 1 hour after the completion of the dropwise addition. The reaction was cooled to zero degrees centigrade, tetrahydrofuran (30 mL) was slowly added dropwise to thiopyran-4-one 3-1 (5.8 g,50 mmol), and the reaction was carried out at room temperature for 2 hours after the addition, followed by TLC and LC-MS monitoring. After completion of the reaction, a saturated aqueous ammonium chloride solution (50 mL) was added to the system, 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, concentrated under reduced pressure, and the residue was purified by column chromatography to give 3-2 (8.6 g) of 2-tetrahydrothiopyran-4-ethylidene ethyl acetate. LC-MS: m/z 187[ M+H ] ] + 。
Step 2, synthesis of Compound 3-3
To a 250mL reaction flask was added 3-2 (8.6 g,46 mmol) of ethyl 2-tetrahydrothiopyran-4-carboxylate, potassium carbonate (12.7 g,92 mmol), dimethyl sulfoxide (100 mL) and nitromethane (5.6 g,92 mmol), and the reaction was stirred at 80℃for 2 hours, monitored by TLC and LC-MS. After the reaction, water (200 mL) was added to the reaction system, extraction was performed with ethyl acetate, the organic phase was washed twice with aqueous saturated saline, the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain crude 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
Into a 250mL reaction flask was charged 2- [4- (nitromethyl) tetrahydrothiopyran-4-yl]Ethyl acetate 3-3, methanol (80 mL), and raney nickel were replaced three times with nitrogen, and hydrogen gas at one atmosphere was introduced and the reaction was stirred at room temperature for 12 hours. LC-MS monitored the reaction. Concentrating under reduced pressure after the reaction, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain the product 8-thia-2-azaspiro [4.5 ]]Decan-3-one 3-4 (2.3 g). LC-MS: m/z 172[ M+H ]] +
Step 4, synthesis of Compounds 3-5
The substrate 8-thia-2-azaspiro [4.5 ]]Decan-3-one 3-4 (1.0 g,5.9 mmol) was dissolved in tetrahydrofuran (20 mL) and the reaction was cooled well to sub-zeroSlowly dropwise adding n-butyllithium (2.5M, 5.9mmol,2.3 mL) at 30 ℃ for 1 hour, dropwise adding allyl chloroformate 1-2 (0.7 g,5.9 mmol) into the reaction system for 1 hour at 30 ℃ and 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 to obtain a crude product of 3-oxo-8-thia-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 3-5.LC-MS: m/z 256[ M+H ]] +
Step 5, synthesis of Compounds 3-6
3-oxo-8-thia-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 3-5 is dissolved in 25mL tetrahydrofuran, the reaction system is fully cooled to minus 78 ℃, diisobutyl aluminum hydride (1.3M, 7.9mmol,6.1 mL) is slowly added dropwise, the reaction is kept at minus 78 ℃ for 1 hour, saturated ammonium chloride solution is added for quenching reaction, decompression concentration is carried out, ethyl acetate and water extraction are carried out, the organic phase is dried by anhydrous sodium sulfate and decompression concentration is carried out, the crude product can be directly used for the next reaction without purification, and the crude product 3-hydroxy-8-thia-2-azaspiro [4.5 ] ]Decane-2-carboxylic acid allyl ester 3-6.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 ]]Decane-2-carboxylic acid allyl ester 3-6 was dissolved in methanol (20 mL), and after sufficient stirring, p-toluenesulfonic acid monohydrate (114 mg,0.6 mmol) was added to the reaction system at room temperature, stirred at room temperature for 12 hours, and monitored by LC-MS. Concentrating under reduced pressure after the reaction is finished, 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 reaction without purification, wherein the crude product is 3-methoxy-8-thia-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 3-7.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 (1.6 g,5.5 mmol) were dissolved in acetonitrile (60 mL), the reaction system was cooled sufficiently to-30℃and the reaction mass was cooled toTin tetrachloride (2.2 g,8.3 mmol) was slowly added to the system and stirred for 1 hour at-30℃and monitored by LC-MS. After the reaction is finished, saturated sodium bicarbonate aqueous solution is added for quenching reaction, reduced pressure concentration is carried out, dichloromethane and water are used for extraction, the organic phase is dried by anhydrous sodium sulfate and then reduced pressure concentration is carried out, the crude product can be directly used for the next reaction without purification, and the crude product 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxypyridine-1 (4H) -yl) 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 tetraphenyl phosphine (263 mg,0.23 mmol) and morpholine (4.0 g,46 mmol) were dissolved in tetrahydrofuran (40 mL), the reaction was replaced three times with nitrogen, nitrogen at one atmosphere was charged, stirred at room temperature for 1 hour, and monitored by TLC and LC-MS. Concentrating under reduced pressure after the reaction is finished, and purifying the residue by column chromatography to obtain the product 9- (benzyloxy) -2',3a,3',4,5',6' -hexahydrospiro [ pyrido [2,1-f ]]Pyrrolo [2,1-c ]][1,2,4]Triazine-2, 4' -thiopyrans]-8,10 (1H, 3H) -dione 3-9 (275 mg). LC-MS: m/z 398[ M+H ]] +
Step 9 Synthesis of Compounds 3 to 10
9- (benzyloxy) -2',3a,3',4,5',6' -hexahydrospiro [ pyrido [2,1-f ]]Pyrrolo [2,1-c ]][1,2,4]Triazine-2, 4' -thiopyrans]-8,10 (1H, 3H) -dione 3-9 (30.0 mg,0.075 mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepan-11-ol M2 (29.9 mg,0.11 mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 300 uL) and stirred for 3 hours at 110 degrees celsius with microwaves, monitored by LC-MS. Extracting with ethyl acetate and water after the reaction, drying the organic phase, filtering, concentrating the filtrate under reduced pressure to obtain a 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 ]][1,2,4]Triazine-2, 4' -thiopyrans]-8,10 (1 h,3 h) -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 ] was taken up]Thiepin-11-yl) -2',3a,3',4,5',6' -hexahydrospiro [ pyrido [2,1-f ]]Pyrrolo [2,1-c ]][1,2,4]Triazine-2, 4' -thiopyrans]-8,10 (1H, 3H) -dione 3-10 was dissolved in methanol (5 mL), palladium on carbon hydroxide (14 mg,0.1 mmol) was added, the reaction was replaced three times with nitrogen, hydrogen at one atmosphere was charged, stirred at room temperature for 1 hour, and monitored by LC-MS. Filtering with diatomite after the reaction, concentrating the filtrate under reduced pressure to obtain 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepin-11-yl) -9 '-hydroxy-2, 3a',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ]][1,2,4]Triazines]-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 ]][1,2,4]Triazine-2, 4' -thiopyrans]-8,10 (1 h,3 h) -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, 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiepin-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)
Step 1, synthesis of Compound 4-2
Sodium hydrogen (2.2 g,55 mmol) and anhydrous tetrahydrofuran (100 mL) are added into a 250mL three-necked flask under the protection of nitrogen, the mixture is fully cooled to zero ℃, a solution of triethyl phosphorylacetate 2-2 (12.3 g,55 mmol) and tetrahydrofuran (40 mL) is slowly added dropwise, the mixture is reacted for 0.5 hour at the zero ℃ after the dropwise addition, and the reaction is carried out for 1 hour at room temperature. The reaction was cooled well to zero degrees centigrade, and cyclobutanone 4-1 (3.5 g,50 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise and reacted at room temperature for 2 hours after the addition was completed, monitored by TLC and LC-MS. After the reaction is finished, the direction isA saturated aqueous ammonium chloride solution (50 mL) was added to the reaction system, the mixture was concentrated under reduced pressure, the mixture was 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 4-2 (6.8 g) of ethyl 2-cyclobutenyl acetate. 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 (6.8 g,49 mmol), potassium carbonate (13.4 g,97 mmol), dimethyl sulfoxide (100 mL) and nitromethane (6.0 g,97 mmol), and the reaction was stirred at 80℃for 2 hours and monitored by TLC and LC-MS. After the completion of the reaction, water (200 mL) was added to the reaction system, extraction was performed with ethyl acetate, the organic phase was washed twice with aqueous saturated saline, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 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
Into a 250mL reaction flask was added 2- [1- (nitromethyl) cyclobutyl]Ethyl acetate 4-3, methanol (80 mL), and raney nickel were replaced three times with nitrogen, and hydrogen gas at one atmosphere was introduced and the reaction was stirred at room temperature for 12 hours. LC-MS monitored the reaction. Concentrating under reduced pressure after the reaction, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by 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 ]]Octane-7-ketone 4-4 (1.0 g,13.6 mmol), dissolving in tetrahydrofuran (20 mL), cooling the reaction system to minus 30 ℃, slowly dropping n-butyllithium (2.5M, 15.0mmol,6.0 mL), keeping the temperature below minus 30 ℃ for 1 hour, dropping allyl chloroformate 1-2 (1.8 g,15.0 mmol), keeping the temperature below minus 30 ℃ 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 to obtain crude product 7-oxygen -6-azaspiro [3.4 ]]Octane-6-carboxylic acid allyl ester 4-5.LC-MS: m/z 210[ M+H ]] +
Step 5, synthesis of Compounds 4-6
7-oxo-6-azaspiro [3.4 ]]The octane-6-carboxylic acid allyl ester 4-5 is dissolved in 25mL tetrahydrofuran, the reaction system is fully cooled to minus 78 ℃, diisobutyl aluminum hydride (1.3M, 3.3mmol,2.5 mL) is slowly added dropwise, the reaction is kept at minus 78 ℃ for 1 hour, saturated ammonium chloride solution is added for quenching reaction, the concentration is reduced pressure, ethyl acetate and water are used for extraction, the organic phase is dried by anhydrous sodium sulfate and then is reduced pressure and concentrated, the crude product can be directly used for the next reaction without purification, and the crude product 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 7-hydroxy-6-azaspiro [3.4 ]]Octane-6-carboxylic acid allyl ester 4-6 was dissolved in methanol (10 mL), and after stirring sufficiently, p-toluenesulfonic acid monohydrate (38 mg,0.22 mmol) was added to the reaction system at room temperature, stirred at room temperature for 12 hours, and monitored by LC-MS. Concentrating under reduced pressure after the reaction is finished, 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 reaction 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 4-8
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 ester M1 (610 mg,2.1 mmol) were dissolved in acetonitrile (20 mL), the reaction system was cooled sufficiently to-30℃and tin tetrachloride (830 mg,3.2 mmol) was slowly added to the reaction system, stirred for 1 hour at-30℃and monitored by LC-MS. After the reaction is finished, saturated sodium bicarbonate aqueous solution is added for quenching reaction, reduced pressure concentration is carried out, dichloromethane and water are used for extraction, the organic phase is dried by anhydrous sodium sulfate and then reduced pressure concentration is carried out, the crude product can be directly used for the next reaction without purification, and the crude product 7- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxypyridine-1 (4H) -yl) amino) -6-azaspiro [3.4]Octane-6-carboxylic acidAllyl acid 4-8.LC-MS: m/z 482[ M+H ]] +
Step 8, synthesis of Compounds 4-9
The crude 7- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -6-azaspiro [3.4]Allyl octane-6-carboxylate 4-8, tetraphenylphosphine palladium (89 mg,0.077 mmol), morpholine (1.34 g,15.4 mmol) were dissolved in tetrahydrofuran (10 mL), the reaction was replaced three times with nitrogen, nitrogen at one atmosphere was charged, stirred at room temperature for 1 hour, monitored by TLC and LC-MS. Concentrating under reduced pressure after the reaction is finished, and purifying the residue by column chromatography to obtain the product 9'- (benzyloxy) -3a',4 '-dihydrospiro [ cyclobutane-1, 2' -pyrido [2,1-f ] ]Pyrrolo [2,1-c ]][1,2,4]Triazines]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 ]][1,2,4]Triazines]-8',10' (1 'H,3' H) -dione 4-9 (30.0 mg,0.085 mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepan-11-ol M2 (33.8 mg,0.13 mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 300 uL) and stirred for 3 hours at 110 degrees celsius with microwaves, monitored by LC-MS. After the reaction is finished, ethyl acetate and water are used for extraction, an organic phase is dried and filtered, and a filtrate is decompressed and concentrated to obtain a crude product 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepan-11-yl) -3a ',4' -dihydrospiro [ cyclobutane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ]][1,2,4]Triazines]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 ]]Thiepan-11-yl) -3a ',4' -dihydrospiro [ cyclobutane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ]][1,2,4]Triazines]8',10' (1 'H,3' H) -dione 4-10 (45 mg,0.075 mmol) was dissolved in methanol (5 mL), palladium on carbon hydroxide (15 mg,0.1 mmol) was added, the reaction was replaced three times with nitrogen, hydrogen at one atmosphere was charged, stirred at room temperature for 1 hour, and LC-MS monitoring was performed. Filtering with diatomite after the reaction, concentrating the filtrate under reduced pressure to obtain 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 ]][1,2,4]Triazines]-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 ] thiepan-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)
Step 1, synthesis of Compound 5-2
Sodium hydrogen (2.4 g,60 mmol) and anhydrous tetrahydrofuran (100 mL) are added into a 250mL three-necked flask under the protection of nitrogen, the mixture is fully cooled to zero ℃, a solution of triethyl phosphorylacetate 2-2 (10.8 g,60 mmol) and tetrahydrofuran (50 mL) is slowly added dropwise, the mixture is reacted for 0.5 hour at the zero ℃ after the dropwise addition, and the reaction is carried out for 1 hour at room temperature. The reaction was cooled to zero degrees centigrade, 4-dimethylcyclohexanone 5-1 (6.3 g,50 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours after the dropwise addition, monitored by TLC and LC-MS. After completion of the reaction, a saturated aqueous ammonium chloride solution (50 mL) was added to the system, 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, concentrated under reduced pressure, and the residue was purified by column chromatography to give 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
Into a 250mL reaction flask was charged ethyl 2- (4, 4-dimethylcyclohexyldiene) acetate 5-2 (9.4 g,48 mmol), potassium carbonate (13.8 g100 mmol), dimethyl sulfoxide (100 mL) and nitromethane (6.1 g,100 mmol), and the reaction was stirred at 80deg.C for 2 hours, monitored by TLC and LC-MS. After the completion of the reaction, water (200 mL) was added to the system, extraction was performed with ethyl acetate, the organic phase was washed twice with aqueous saturated saline, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude ethyl 2- (4, 4-dimethyl-1- (nitromethyl) cyclohexyl) acetate 5-3, which was directly used for the next reaction. LC-MS: m/z 258[ M+H ]] +
Step 3, synthesis of Compound 5-4
To a 250mL reaction flask, ethyl 2- (4, 4-dimethyl-1- (nitromethyl) cyclohexyl) acetate 5-3, methanol (80 mL), and Raney nickel were added, the reaction system was replaced three times with nitrogen, hydrogen gas at one atmosphere pressure was introduced, and the reaction was stirred at room temperature for 12 hours. LC-MS monitored the reaction. Concentrating under reduced pressure after the reaction, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain the product 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 Compound 5-5
The substrate 8, 8-dimethyl-2-azaspiro [4,5 ]]Decan-3-one 5-4 (1.81 g,10.0 mmol), dissolved in tetrahydrofuran (40 mL), cooled to-30deg.C, slowly added dropwise n-butyllithium (2.5M, 12.0mmol,4.8 mL), kept at-30deg.C for 1 hr, allyl chloroformate 1-2 (1.45 g,12.0 mmol), kept at-30deg.C for 1 hr, quenched with saturated ammonium chloride solution, concentrated under reduced pressure, extracted with ethyl acetate and water, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by column chromatography to give 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 ]]Decane-2-carboxylic acid allyl ester 5-5 (2.61 g,9.9 mmol) was dissolved in 25mL tetrahydrofuran, the reaction was cooled sufficiently to-78℃and diisobutylaluminum hydride (1.3M, 12.0mmol,9.2 mL), maintaining the temperature below minus 78 ℃ 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 reaction without purification, wherein the crude product is 3-hydroxy-8, 8-dimethyl-2-azaspiro [4.5 ] ]Decane-2-carboxylic acid allyl ester 5-6.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 ]]Decane-2-carboxylic acid allyl ester 5-6 was dissolved in methanol (20 mL), and after sufficient stirring, p-toluenesulfonic acid monohydrate (153 mg,0.8 mmol) was added to the reaction system at room temperature, and stirred at room temperature for 12 hours, followed by LC-MS monitoring. Concentrating under reduced pressure after the reaction is finished, 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 reaction without purification, wherein the crude product is 3-methoxy-8, 8-dimethyl-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 5-7.LC-MS: m/z 250[ M+H-32 ]] +
Step 7, synthesis of Compounds 5-8
The crude product 3-methoxy-8, 8-dimethyl-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 5-7 and 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylic acid ethyl ester M1 (1.8 g,6.3 mmol) were dissolved in acetonitrile (60 mL), the reaction system was cooled sufficiently to-30℃and tin tetrachloride (2.4 g,9.4 mmol) was slowly added to the reaction system, stirred for 1 hour at-30℃and monitored by LC-MS. After the reaction is finished, saturated sodium bicarbonate aqueous solution is added for quenching reaction, reduced pressure concentration is carried out, dichloromethane and water are used for extraction, the organic phase is dried by anhydrous sodium sulfate and then reduced pressure concentration is carried out, the crude product can be directly used for the next reaction without purification, and the crude product 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxygen pyridine-1 (4H) -yl) amino) -8, 8-dimethyl-2-azaspiro [4.5 ] ]Decane-2-carboxylic acid allyl ester 5-8.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 ]]Decane-2-carboxylic acid allyl ester 5-8, tetra-triphenylphosphinePalladium (284 mg,0.25 mmol) and morpholine (4.3 g,50 mmol) were dissolved in tetrahydrofuran (40 mL), the reaction was replaced three times with nitrogen, nitrogen at one atmosphere was charged, stirred at room temperature for 1 hour, monitored by TLC and LC-MS. Concentrating under reduced pressure after the reaction is finished, and purifying the residue by column chromatography to obtain the product 9'- (benzyloxy) -4, 4-dimethyl-3 a',4 '-dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ]][1,2,4]Triazines]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 ]][1,2,4]Triazines]-8',10' (1 'H,3' H) -dione 5-9 (40.7 mg,0.1 mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepan-11-ol M2 (39.6 mg,0.15 mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 400 uL) and stirred for 3 hours at 110 degrees celsius with microwaves, 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 concentration ]Thiepin-11-yl) -4, 4-dimethyl-3 a ',4' -dihydrospiro [ cyclohexane-1, 2' -pyrido [2,1-f]Pyrrolo [2,1-c ]][1,2,4]Triazines]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 ]][1,2,4]Triazines]-8',10' (1 'H,3' H) -dione 5-10 was dissolved in methanol (5 mL), palladium on carbon hydroxide (14 mg,0.1 mmol) was added, the reaction was replaced three times with nitrogen, hydrogen at one atmosphere was charged, stirred at room temperature for 4 hours, and monitored by LC-MS. Filtering with diatomite after the reaction, concentrating the filtrate under reduced pressure, purifying with medium-pressure reverse phase preparation 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 ]][1,2,4]Triazines]-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 ] thiepan-11-yl) -9' -hydroxy-2, 6-dimethyl-2, 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)
Step 1, synthesis of Compound 6-2
Sodium hydrogen (2.4 g,60 mmol) and anhydrous tetrahydrofuran (100 mL) are added into a 250mL three-necked flask under the protection of nitrogen, the mixture is fully cooled to zero ℃, a solution of triethyl phosphorylacetate 2-2 (10.8 g,60 mmol) and tetrahydrofuran (50 mL) is slowly added dropwise, the mixture is reacted for 0.5 hour at the zero ℃ after the dropwise addition, and the reaction is carried out for 1 hour at room temperature. The reaction was cooled to zero degrees centigrade, 2, 6-dimethyltetrahydropyranone 6-1 (6.4 g,50 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours after the dropwise addition, monitored by TLC and LC-MS. After completion of the reaction, a saturated aqueous ammonium chloride solution (50 mL) was added, the mixture was concentrated under reduced pressure, the mixture was extracted with ethyl acetate and water, the organic phase was washed twice with saturated brine, the organic phase was dried over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give ethyl 2- (3, 5-dimethyl-4-oxocyclohexadiene) 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 was added ethyl 2- (3, 5-dimethyl-4-oxacyclohexadiene) acetate 6-2 (9.5 g,48 mmol), potassium carbonate (13.8 g,100 mmol), dimethyl sulfoxide (100 mL) and nitromethane (6.1 g,100 mmol), and the reaction was stirred at 80℃for 2 hours, monitored by TLC and LC-MS. After the completion of the reaction, water (200 mL) was added to the reaction system, the mixture was extracted with ethyl acetate, and the organic phase was saturated with water And brine are washed twice respectively, the organic phase is dried by anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude 2- (3, 5-dimethyl-4-oxa-1- (nitromethyl) cyclohexyl) ethyl acetate 6-3 which is directly used for the next reaction. LC-MS: m/z 260[ M+H ]] +
Step 3, synthesis of Compound 6-4
To a 250mL reaction flask, ethyl 2- (4, 4-dimethyl-1- (nitromethyl) cyclohexyl) acetate 6-3, methanol (80 mL), and Raney nickel were added, the reaction system was replaced three times with nitrogen, hydrogen gas at one atmosphere pressure was introduced, and the reaction was stirred at room temperature for 12 hours. LC-MS monitored the reaction. Concentrating under reduced pressure after the reaction, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the residue by 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 ]]Decan-3-one 6-4 (1.83 g,10.0 mmol), dissolved in tetrahydrofuran (40 mL), cooled to-30deg.C, slowly added dropwise n-butyllithium (2.5M, 12.0mmol,4.8 mL), kept at-30deg.C for 1 hr, allyl chloroformate 1-2 (1.45 g,12.0 mmol), kept at-30deg.C for 1 hr, quenched with saturated ammonium chloride solution, concentrated under reduced pressure, extracted with ethyl acetate and water, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by column chromatography to give allyl 3-oxo-7.9-dimethyl-8-oxa-2-azaspiro [4.5 ] ]Decane-2-carbonate 6-5 (2.64 g). LC-MS: m/z 268[ M+H ]] +
Step 5, synthesis of Compound 6-6
3-oxo-7.9-dimethyl-8-oxa-2-azaspiro [4.5 ]]Allyl decane-2-carboxylate 6-5 (2.64 g,9.9 mmol) was dissolved in 25mL tetrahydrofuran, the reaction system was cooled sufficiently to-78℃and diisobutylaluminum hydride (1.3M, 12.0mmol,9.2 mL) was slowly added dropwise, the reaction was kept at-78℃for 1 hour, saturated ammonium chloride solution was added to quench the reaction, the reaction was concentrated under reduced pressure, and extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfateConcentrating under reduced pressure, wherein the crude product can be directly used for the next reaction without purification, and the crude product is 3-hydroxy-7.9-dimethyl-8-oxa-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 6-6.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 ]]Decane-2-carboxylic acid allyl ester 6-6 was dissolved in methanol (20 mL), and after sufficient stirring, p-toluenesulfonic acid monohydrate (153 mg,0.8 mmol) was added to the reaction system at room temperature, and stirred at room temperature for 12 hours, followed by LC-MS monitoring. Concentrating under reduced pressure after the reaction is finished, extracting with ethyl acetate and water, drying an organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and directly using the crude product for the next reaction without purification, wherein the crude product is 3-methoxy-7.9-dimethyl-8-oxa-2-azaspiro [4.5 ] ]Decane-2-carboxylic acid allyl ester 6-7.LC-MS: m/z 252[ M+H-32 ]] +
Step 7, synthesis of Compounds 6-8
The crude product 3-methoxy-7.9-dimethyl-8-oxa-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 6-7 and 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylic acid ethyl ester M1 (1.8 g,6.3 mmol) were dissolved in acetonitrile (60 mL), the reaction system was cooled sufficiently to-30℃and tin tetrachloride (2.4 g,9.4 mmol) was slowly added to the reaction system, stirred for 1 hour at-30℃and monitored by LC-MS. After the reaction is finished, saturated sodium bicarbonate aqueous solution is added for quenching reaction, reduced pressure concentration is carried out, dichloromethane and water are used for extraction, the organic phase is dried by anhydrous sodium sulfate and then reduced pressure concentration is carried out, the crude product can be directly used for the next reaction without purification, and the crude product 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxypyridine-1 (4H) -yl) amino) -7.9-dimethyl-8-oxa-2-azaspiro [4.5 ]]Decane-2-carboxylic acid allyl ester 6-8.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 ]]Allyl decane-2-carboxylate 6-8, palladium tetraphenylphosphine (284 mg,0.25 mmol) and morpholine (4.3 g,50 mmol) were dissolved in tetrahydrofuran (40 mL), the reaction system was replaced three times with nitrogen, and a large one was charged The nitrogen gas at gas pressure was stirred at room temperature for 1 hour, monitored by TLC and LC-MS. Concentrating under reduced pressure after the reaction is finished, purifying the residue by column chromatography to obtain the product 9'- (benzyloxy) -2, 6-dimethyl-2, 3a',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ]][1,2,4]Triazines]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, 3a',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ]][1,2,4]Triazines]-8',10' (1 'H,3' H) -dione 6-9 (40.9 mg,0.1 mmol) and 7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepan-11-ol M2 (39.6 mg,0.15 mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 400 uL) and stirred for 3 hours at 110 degrees celsius with microwaves, 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 concentration]Thiepin-11-yl) -2, 6-dimethyl-2, 3a ',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ]][1,2,4]Triazines]8',10' (1 'H,3' H) -dione 6-10.LC-MS: m/z656[ 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, 3a ',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ] ]Pyrrolo [2,1-c ]][1,2,4]Triazines]-8',10' (1 'H,3' H) -dione 6-10 was dissolved in methanol (5 mL), palladium on carbon hydroxide (14 mg,0.1 mmol) was added, the reaction was replaced three times with nitrogen, hydrogen at one atmosphere was charged, stirred at room temperature for 4 hours, and monitored by LC-MS. Filtering with diatomite after the reaction, concentrating the filtrate under reduced pressure, purifying with medium-pressure reverse phase preparation column to obtain 4' - (7, 8-difluoro-6, 11-dihydrodiphenyl [ b, e ]]Thiepin-11-yl) -9 '-hydroxy-2, 6-dimethyl-2, 3a',4',5, 6-hexahydrospiro [ pyran-4, 2' -pyrido [2,1-f ]]Pyrrolo [2,1-c ]][1,2,4]Triazines]-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-diphenyl [ a, d ] [7] cycloalkenyl-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)
Step 1, synthesis of Compound 7-2
Dibenzo [ a, d]Cyclohepten-5-one 7-1 (412 mg,2 mmol) was dissolved in methanol (10 mL), platinum dioxide (11.5 mg,0.05 mmol) was added, the reaction was replaced three times with nitrogen, hydrogen at one atmosphere was charged, stirred at room temperature for 12 hours, and monitored by LC-MS. Filtering with diatomite after the reaction, concentrating the filtrate under reduced pressure, extracting with ethyl acetate and water, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain the product 10, 11-dihydro-5H-dibenzo [ a, d ] ][7]Cycloolefin-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 ]][1,2,4]Triazines]-8',10' (1 'H,3' H) -dione 2-10 (41.5 mg,0.1 mmol) and 10, 11-dihydro-5H-dibenzo [ a, d ]][7]Cycloolefin-5-ol 7-2 (31.5 mg,0.15 mmol) was dissolved in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 400 uL) and stirred for 3 hours at 110℃under microwave conditions, as monitored 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 concentration][7]Cycloolefin-5-yl) -4, 4-difluoro-3 a ',4' -dihydrospiro [1,2' -pyrido [2,1-f]Pyrrolo [2,1-c ]][1,2,4]Triazines]-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]Cycloolefin-5-yl) -4, 4-difluoro-3 a ',4' -dihydrospiro [1,2' -pioglitazoneBenzo [2,1-f]Pyrrolo [2,1-c ]][1,2,4]Triazines]-8',10' (1 'H,3' H) -dione 7-3 was dissolved in methanol (5 mL), palladium on carbon hydroxide (14 mg,0.1 mmol) was added, the reaction was replaced three times with nitrogen, hydrogen at one atmosphere was charged, stirred at room temperature for 4 hours, and monitored by LC-MS. Filtering with diatomite after the reaction, concentrating the filtrate under reduced pressure, purifying with medium-pressure reverse phase preparation column to obtain compound 4' - (10, 11-dihydro-5H-diphenyl [ a, d) ][7]Cycloolefin-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]Triazines]-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-dihydrodibenzo [ 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)
Step 1, synthesis of Compound 8-2
Diphenyldisulfide M2-3 (2.18 g,10 mmol), sodium hydroxide (1.15 g,28.8 mmol), sodium borohydride (700 mg,18.4 mmol) were dissolved in tetrahydrofuran (30 mL) and water (30 mL), the reaction system was replaced three times with nitrogen, nitrogen at one atmosphere was charged, and stirring was performed at 70℃for 12 hours, and LC-MS monitoring was performed. The reaction solution was directly used for the next reaction. 2-bromomethylbenzoic acid 8-1 (4.3 g,20 mmol) was added to the above solution, stirred at room temperature for 1 hour, and monitored by LC-MS. Adding 1N diluted hydrochloric acid into the reaction system after the reaction is finished, regulating the pH value of the system to 5-6, concentrating under reduced pressure, extracting with ethyl acetate and water, and using anhydrous sulfur as an organic phaseThe sodium acid was dried, concentrated under reduced pressure, and the residue was purified by column chromatography to give 8-2 (1.97 g) of 2- (phenylthio) methylbenzoic acid. LC-MS: m/z 245[ M+H ] ] +
Step 2, synthesis of Compound 8-3
2- (phenylthio) methylbenzoic acid 8-2 (1.97 g,8.1 mmol) was dissolved in polyphosphoric acid (60 mL), stirred at 120℃for 12 hours, and monitored by LC-MS. After the reaction, the reaction system was cooled to room temperature, the reaction solution was poured into 0.5 kg of crushed ice, extracted with ethyl acetate and water, the organic phase was washed three times with saturated aqueous sodium bicarbonate solution, 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 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
The diphenyl [ b, e ]]Thiepan-11 (6H) -one 8-3 (1.66 g,7.3 mmol) was dissolved in methanol (35 mL) and the system was cooled sufficiently to zero, sodium borohydride (557 mg,14.6 mmol) was added slowly at zero, stirred for 1 hour at zero, and monitored by LC-MS. Concentrating under reduced pressure after the reaction is finished, extracting with ethyl acetate and water, drying an organic phase anhydrous sodium sulfate, concentrating under reduced pressure, and purifying residues by column chromatography to obtain a product 6, 11-dihydrodiphenyl [ b, e ]]Thiepinin-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 (41.5 mg,0.1 mmol) and 6, 11-dihydrodibenzo [ b, e ] thiepan-11-ol 8-4 (34.2 mg,0.15 mmol) in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 400 uL) were stirred for 3 hours at 110℃and monitored by LC-MS. After the reaction, the crude product 9' - (benzyloxy) -4' - (6, 11-dihydrodibenzo [ 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 is obtained by vacuum concentration. LC-MS: m/z 626[ M+H ] +
Step 5, synthesis of Compound 8
The crude product 9' - (benzyloxy) -4' - (6, 11-dihydrodibenzo [ 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 (5 mL), palladium carbon hydroxide (14 mg,0.1 mmol) was added, the reaction system was replaced three times with nitrogen, hydrogen was charged at one atmosphere pressure, stirred at room temperature for 4 hours, and monitored by LC-MS. After the reaction, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure, and purified by a medium-pressure reverse phase column to give 4' - (6, 11-dihydrodibenzo [ 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
Preparation of Compounds
1) Compounds were dissolved in DMSO to concentrations of 10mM test compound and 10mM reference compound (Baloxavir acid), and the compounds were 3-fold or 4-fold diluted in DMSO to prepare 100-fold DMSO solutions for a total of 10 metering points. 4uL of the 100-fold diluted compound was taken in 96uL of 1-fold buffer (20 mM Tris-HCl,50mM NaCl,2mM MnCl) 2 10mM beta-mercaptoethanol, 0.05% Tween-20, pH 8.0) to give a 4-fold compound solution. The highest concentrations of test compound in the enzyme reaction solution were 1uM in influenza A virus H21N1_WSN_1933 PAN (protein series 1-196, del 52-72) and 10uM in influenza B virus Lee_1940PAN (protein series 1-198), respectively.
Enzyme experiments
1) A4-fold enzyme solution (final concentration 10nM influenza A virus H1N1_WSN_1933PAN and 250nM influenza B virus Lee_1940 PAN) and a double substrate solution (single-stranded DNA substrate) (final concentration 0.3 uM) were prepared (single-stranded DNA substrate series [6-FAM ] AAT CGC AGG CAG CAC TC [ BHQ1] (custom made Synthesis)
2) The assay plate was tested in 384 wells (corning, cat No.: 3575 5uL of 4-fold compound solution and 5uL of 4-fold enzyme solution were added per well, an equal amount of 1-fold buffer solution was added as 100% inhibition control (negative control) to the blank, an equal amount of 1-fold buffer solution was added as 0% inhibition control (positive control), 1000rpm,25℃and centrifugation was performed for 1 minute. 384 assay plates were placed in an elisa plate incubation shaker, mixed well at 25 ℃,220rpm and incubated for 15 minutes.
3) 10uL of 2-fold substrate solution was added to 384 assay plates and centrifuged at 1000rpm at 25℃for 1 min. 384 assay plates were placed in an elisa plate incubation shaker, mixed well at 37 ℃,220rpm and incubated for 120 minutes.
4) Fluorescence was detected with Tecan Spark 20M at excitation wavelength Ex of 485nm (10 nm bandwidth) and emission wavelength Em of 535nm (10 nm bandwidth), normalized to the read fluorescence signal obtained from the positive control (maximum signal control) and negative control (minimum signal control) to give inhibition of compounds at different concentrations. Then, the IC of the compound for inhibiting the enzyme activity is calculated by the GraphPad Prism 6 in log (inhibitor) vs. response-Variable slope mode fitting 50 . The fitting equation is: y=bottom+ (Top-Bottom)/(1+10 ((log ic) 50 X) HillSlope), where Y represents a known percentage of remaining enzymatic activity and X represents the IC calculated to result in inhibition of enzymatic activity by the compound at the concentration of the known compound after Log 50 。
5) Test results: IC of the present compounds for inhibition of enzymatic Activity of 10nM influenza virus A H1N1_WSN_1933PAN and influenza virus B Lee_1940PAN 50 Shown in table 1.
Conclusion: as can be seen from Table 1, the preferred compounds of the present invention have a strong inhibitory effect on the activity of influenza virus A H N1 WSN 1933PAN and influenza virus BLee 1940PAN enzymes.
TABLE 1 inhibitory Activity of the inventive Compounds against influenza A/WSN/33 (H1N 1) and influenza B/Lee/40
Example Compounds Influenza virus A IC 50 (nM) Influenza virus B IC 50 (nM)
1 + +++
2 ++ +++
3 ++ ++++
4 + +++
5 ++ ++++
6 + ++++
7 + +++
8 + +++
Baloxavir acid + +++
Wherein "+" represents 10 or less, "++" represents > 10 and 50 or less, "+++" represents > >. 50 and less than or equal to 250, 50 is less than or equal to at 250 the number of times.
The experiment shows that the compound has stronger inhibition effect on the enzyme activity of the influenza virus A H1N1 WSN 1933PAN and the influenza virus B Lee 1940 PAN.

Claims (9)

1. A compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
the compound shown in the formula I is shown in the formula Ia, the formula Ib and the formula Ic:
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 3-10 membered carbocyclyl))、-C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group), -C 0～4 alkylene-S (O) 2 R 1a 、-C 0～4 alkylene-S (O) R 1a 、-C 0～4 alkylene-S (O) 2 NR 1a R 1b 、-C 0～4 alkylene-S (O) NR 1a R 1b The method comprises the steps of carrying out a first treatment on the surface of the Wherein alkylene, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl 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 -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); wherein said alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups may be further substituted with one, two, or three independent R 1c Substitution; alternatively, R 1a 、R 1b Form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group together with the linking atom;
each R 1c Independently selected from hydrogen, optionally halogen-substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 1k 、-C 0～4 Alkylene group-S(O)R 1k 、-C 0～4 alkylene-S (O) 2 NR 1k R 1l 、-C 0～4 alkylene-S (O) NR 1k R 1l ；
R 1k 、R 1l Are independently selected from hydrogen, -OH, -SH, -NH 2 -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group);
each R 1d Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); wherein alkylene, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups 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 -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or)Unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups may be further substituted with one, two, or three independent R 1g Substitution; alternatively, R 1e 、R 1f Form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group together with the linking atom;
each R 1g Independently selected from hydrogen, optionally halogen-substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 An alkyl group);
or,
two independent R 1d Together with the atoms to which they are attached formSaturated or unsaturated 3-to 10-membered carbocyclyl, saturated or unsaturated 4-to 10-membered heterocycloalkyl, 6-to 10-membered aromatic ring group, 5-to 10-membered aromatic heterocyclic group; wherein the carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups 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, -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 alkylene-OR 1i 、-C 0～4 alkylene-OC (O) R 1i 、-C 0～4 alkylene-C (O) R 1i 、-C 0～4 alkylene-C (O) OR 1i 、-C 0～4 alkylene-C (O) NR 1i R 1j 、-C 0～4 alkylene-NR 1i R 1j 、-C 0～4 alkylene-NR 1i C(O)R 1j 、-C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); alternatively, two independent R 1h Together with the atoms to which they are attached form
R 1i 、R 1j Are independently selected from hydrogen, -OH, -SH, -NH 2 -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group);
each R A1 Are independently selected from hydrogen, -OH, -SH, -NH 2 Halogen, cyano, -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring) radical,-C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group), -C 0～4 alkylene-S (O) 2 R A2 、-C 0～4 alkylene-S (O) R A2 、-C 0～4 alkylene-S (O) 2 NR A2 R A3 、-C 0～4 alkylene-S (O) NR A2 R A3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein alkylene, carbocyclyl, heterocycloalkyl, aryl, and heteroaryl groups 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 -C optionally substituted by halogen 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 2～6 Alkynyl, -C 0～4 Alkylene- (saturated or unsaturated 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); alternatively, R A2 、R A3 Form a saturated or unsaturated 4-to 10-membered heterocycloalkyl group together with the linking atom;
each R A4 Independently selected from hydrogen, optionally halogen-substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group);
or,
two independent R A1 Together with the atoms to which they are attached formSaturation or saturationUnsaturated 3-10 membered carbocyclyl, saturated or unsaturated 3-10 membered heterocycloalkyl; wherein the carbocyclyl, heterocycloalkyl may be further substituted with one, two or three R A5 Substitution;
each R A5 Independently selected from hydrogen, optionally halogen-substituted-C 1～6 Alkyl, -C optionally substituted by halogen 2～6 Alkenyl, -C optionally substituted by halogen 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 3-10 membered carbocyclyl), -C 0～4 Alkylene- (saturated or unsaturated 4-10 membered heterocycloalkyl), -C 0～4 Alkylene- (6-10 membered aromatic ring group), -C 0～4 Alkylene- (5-10 membered aromatic heterocyclic group); alternatively, two independent R A5 Together with the atoms to which they are attached form
The hetero atoms in the saturated or unsaturated heterocyclic alkyl and the aromatic heterocyclic group are respectively and independently selected from one or more of O, S, B or N, the unsaturated carbocyclic group does not comprise aryl, and the unsaturated heterocyclic alkyl does not comprise aromatic heterocyclic group;
The B ring is selected from
Wherein the B ring may be substituted with one, two or three independent R 1d Substitution;
the A is selected from Wherein each X is independently selected from CH 2 O or S; the ring selected from A may be further substituted with one, two, three, four or five R A1 And (3) substitution.
2. A compound according to claim 1, characterized in that:
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 independently selected from hydrogen, methyl, halogen, cyano, -OH, -SH, -C (O) NH 2 、-NHC(O)CH 3 、-OCH 3 、And R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 Not simultaneously selected from hydrogen.
3. A compound according to any one of claims 1, wherein:
the R is A1 Independently selected from hydrogen, halogen, or optionally halogen substituted-C 1～6 An alkyl group.
4. A compound according to claim 1, characterized in that:
a is selected from
5. A compound according to any one of claims 1, wherein: the compound is specifically as follows:
6. use of a compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prophylaxis or treatment of a viral infection disorder.
7. Use according to claim 6, characterized in that: the viral infection is an influenza virus infection.
8. A pharmaceutical composition comprising a formulation of a compound according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
9. The pharmaceutical composition of claim 8, further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle.
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