CN112724156B - Polycyclic pyridone derivative, pharmaceutical composition and application thereof - Google Patents

Polycyclic pyridone derivative, pharmaceutical composition and application thereof Download PDF

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CN112724156B
CN112724156B CN202011622929.XA CN202011622929A CN112724156B CN 112724156 B CN112724156 B CN 112724156B CN 202011622929 A CN202011622929 A CN 202011622929A CN 112724156 B CN112724156 B CN 112724156B
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CN112724156A (en
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蒋宇扬
唐林
张存龙
吴伟彬
李安琪
陈大伟
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Shenzhen Berry Biomedical Technology Co ltd
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Abstract

The invention belongs to the field of medicines, and relates to a polycyclic pyridone derivative, a pharmaceutical composition and application thereof. The polycyclic pyridone derivative is a compound shown in a formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown in the formula (I). Compared with the existing similar compounds, the compound of the invention not only can well inhibit the replication of influenza virus, but also has lower cytotoxicity.
Figure DDA0002872719260000011

Description

Polycyclic pyridone derivative, pharmaceutical composition and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a polycyclic pyridone derivative, a pharmaceutical composition containing the polycyclic pyridone derivative, and applications of the polycyclic pyridone derivative and the pharmaceutical composition.
Background
Influenza is mainly caused by influenza virus infection, which can result in three to five million hospitalized cases and 29 to 65 million death cases per year on average. Influenza a viruses are often responsible for major outbreaks of influenza. However, in recent years, with the emergence of highly invasive virus strains such as H1N1, H5N1 and H7N9, and the emergence of more and more resistant virus strains, the existing anti-influenza drugs have been unable to meet the needs of people. Therefore, it is necessary to develop anti-influenza drugs having a novel mechanism of action.
The life cycle of influenza virus is a complex biological process that can be divided into the following steps: (I) binding of the virus to host cell surface receptors; (II) the virus is endocytosed into the host cell, and the viral membrane and endosomal membrane are fused; (III) viral ribonucleoproteins (vRNPs) are released into the cytoplasm and then transported into the nucleus; (IV) transcription and replication of viral RNA; (V) export of mRNA and vRNP from the nucleus, synthesis of associated proteins; (VI) the progeny virus is assembled and released from the cells by budding. Viral proteins and host cell proteins involved in the influenza virus infection cycle are important targets for the development of anti-influenza virus drugs. A number of anti-influenza drugs have been developed against these targets.
Small molecule anti-influenza virus preparations are mainly divided into five categories: (I) m2 ion channel protein inhibitors (amantadine, rimantadine, etc.); (II) Neuraminidase (NA) inhibitors (zanamivir, oseltamivir, peramivir, ranimivir, etc.); (III) Hemagglutinin (HA) inhibitors (Arbidol, nitazoxanide, etc.); (IV) inhibitors of RNA-dependent RNA polymerase (RdRp) (Favipiravir, Barosavir, etc.); (V) inhibitors of Nucleoprotein (NP) (naproxen et al). To date, only a few anti-influenza virus drugs have been approved for marketing.
Currently, the major anti-influenza drug used clinically is neuraminidase inhibitor (NAI). However, in recent years, drug-resistant influenza virus mutant strains are continuously appeared, which not only reduce the clinical curative effect of anti-influenza drugs, but also further threaten the public health safety. Therefore, the development of anti-influenza drugs with a new mechanism has important significance and wide application prospect.
Barosavir (Baloxavir marboxil), which is sold under the name Xofluza, is approved by the FDA to be marketed in 2018 and 10 months, and is the first anti-influenza drug with a new action mechanism in the last twenty years. It was developed by japan salt bisense and was first approved for marketing in japan in 2018 and 2 months. Unlike neuraminidase inhibitors, baroxavir, a novel cap-dependent endonuclease (CEN) inhibitor, which is present in the polymerase acid Protein (PA) subunit of influenza a and b viruses, prevents progeny virions from being released from infected host cells. Viral mRNA transcription depends on a unique "cap-snatching" mechanism: PB2 bound to the 5'-cap transcript in the host, and the cap-dependent endonuclease in PA endonucleases were used at a position approximately 12 nucleotides from 5' -cap, and the cleaved cap structure was used as a primer for viral mRNA transcription. Therefore, inhibition of this endonuclease can inhibit mRNA transcription and thus viral replication. In addition, compared with oseltamivir, the baloxavir has the advantages that treatment is not needed (oseltamivir is continuously treated for 5 days), only once-a-day administration is needed, the disease symptom relieving time is not inferior to that of oseltamivir, the virus titer and safety are superior to those of oseltamivir, and the like. This will break the pattern that neuraminidase inhibitor dominates the influenza market for nearly 20 years, provide a brand new therapeutic mechanism for influenza, and get the industry's extensive attention.
It is a further object in the art to optimize based on balosavir in order to obtain a more active anti-influenza drug.
Disclosure of Invention
The invention aims to provide a novel compound serving as an influenza virus RNA polymerase inhibitor, and more particularly, the invention provides a novel compound serving as a cap-dependent endonuclease inhibitor of influenza virus, and the compound and a composition thereof can be used for preventing, treating or relieving symptoms of patients infected by the influenza virus. Compared with the existing similar compounds, the compound of the invention not only can well inhibit the replication of influenza virus, but also has lower cytotoxicity, and the anti-influenza virus activity of one compound is better than that of the similar compound on the market. Therefore, compared with the existing similar compounds, the compound provided by the invention has better influenza virus activity.
In order to achieve the above object, a first aspect of the present invention provides a polycyclic pyridone derivative which is a compound represented by formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of the compound represented by formula (I), or a prodrug thereof;
Figure BDA0002872719240000031
wherein the content of the first and second substances,
p is hydrogen, benzyl, n-hexyl or P forming a prodrugRA group;
A1is CR1AR1BS or O;
A2is CR2AR2BS or O;
A3is CR3AR3BS or O;
A4each independently is CR4AR4BS or O;
and, from A1、A2、A3N number of A4And A is1Adjacent nitrogen atom and to A4The number of hetero atoms in ring-forming atoms of rings formed by adjacent carbon atoms is 1 or 2;
R1Aand R1BEach independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, or phenyl;
R2Aand R2BEach independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, or phenyl;
R3Aand R3BEach independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, or phenyl;
R4Aand R4BEach independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, or phenyl;
R3Aand R3BOptionally taken together with adjacent carbon atoms to form a carbocyclic or heterocyclic ring;
n is 1 or 2;
R1and R2Each independently is hydrogen, halogen, hydroxy, alkyl, alkoxy, or haloalkyl;
PRis at least one of the groups of formulae a) to ac) selected from:
a)-C(＝O)-PR0；
b)-C(＝O)-PR1；
c)-C(＝O)-L-PR1；
d)-C(＝O)-L-O-PR1；
e)-C(＝O)-L-O-L-O-PR1；
f)-C(＝O)-L-O-C(＝O)-O-PR1；
g)-C(＝O)-O-PR2；
h)-C(＝O)-N(-K)(PR2)；
i)-C(＝O)-O-L-O-PR2；
j)-C(PR3)2-O-PR4；
k)-C(PR3)2-O-L-O-PR4；
l)-C(PR3)2-O-C(＝O)-PR4；
m)-C(PR3)2-O-C(＝O)-O-PR4；
n)-C(PR3)2-O-C(＝O)-N(-K)-PR4；
o)-C(PR3)2-O-C(＝O)-O-L-O-PR4；
p)-C(PR3)2-O-C(＝O)-O-L-N(PR4)2；
q)-C(PR3)2-O-C(＝O)-N(-K)-L-O-PR4；
r)-C(PR3)2-O-C(＝O)-N(-K)-L-N(PR4)2；
s)-C(PR3)2-O-C(＝O)-O-L-O-L-O-PR4；
t)-C(PR3)2-O-C(＝O)-O-L-N(-K)-C(＝O)-PR4；
u)-C(PR3)2-O-P(＝O)(-PR5)2；
v)-C(PR3)2-PR6)2；
w)-C(＝N+(PR7)2)(-N(PR7)2)；
x)-C(PR3)2-C(PR3)2-C(C＝O)-O-PR2；
y)-C(PR3)2-N(-K)-C(C＝O)-O-PR2；
z)-P(＝O)(-PR8)(-PR9)；
aa)-S(＝O)2-PR10；
ab)-PR11；
ac)-C(PR3)2-C(PR3)2-O-PR2；
wherein L is a linear or branched alkylene group or a linear or branched alkenylene group;
k is hydrogen or alkyl optionally substituted by substituent group a;
PR0is alkyl optionally substituted with substituent A or alkenyl optionally substituted with substituent A;
PR1is carbocyclyl optionally substituted with substituent A, heterocyclyl optionally substituted with substituent A, alkylamino optionally substituted with substituent A, or alkylthio optionally substituted with substituent A;
PR2is alkyl optionally substituted with substituent A, carbocyclyl optionally substituted with substituent A, heterocyclyl optionally substituted with substituent A, carbocycloalkyl optionally substituted with substituent A, heterocycloalkyl optionally substituted with substituent A, or trialkylsilyl;
PR3each independently is hydrogen, alkyl;
PR4each independently is alkyl optionally substituted with substituent A, carbocyclyl optionally substituted with substituent A, heterocyclyl optionally substituted with substituent A, alkylamino optionally substituted with substituent A, carbocycloalkyl optionally substituted with substituent A, heterocycloalkyl optionally substituted with substituent A, or trialkylsilyl;
PR5each independently is OBn;
PR6is carbocyclyl optionally substituted with substituent A, or heterocyclyl optionally substituted with substituent A;
PR7each independently is alkyl optionally substituted with substituent A;
PR8is alkoxy optionally substituted with substituent a;
PR9is alkoxy optionally substituted by substituent AA group, alkylamino optionally substituted with substituent a, carbocycloxy optionally substituted with substituent a, heterocyclooxy optionally substituted with substituent a, carbocycloamino optionally substituted with substituent a, or heterocycloamino optionally substituted with substituent a;
and, PR8And PR9Optionally taken together with the adjacent phosphorus atom to form a heterocyclic ring optionally substituted with substituent A;
PR10is alkyl optionally substituted with substituent A, carbocyclyl optionally substituted with substituent A, heterocyclyl optionally substituted with substituent A, carbocycloalkyl optionally substituted with substituent A, or heterocycloalkyl optionally substituted with substituent A;
PR11is alkyl optionally substituted with substituent A, alkenyl optionally substituted with substituent A, carbocyclyl optionally substituted with substituent A, or heterocyclyl optionally substituted with substituent A;
substituent A is selected from at least one of the group consisting of: oxo, alkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl, heterocyclyl, carbocycloalkyl, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, alkoxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl, and phosphoryl.
Specifically, the polycyclic pyridone derivative is a compound shown as a formula (II) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,
Figure BDA0002872719240000061
wherein the content of the first and second substances,
p is hydrogen, benzyl, n-hexyl or P forming a prodrugRA group;
R1and R2Each independently hydrogen, halogen, hydroxy, alkylAlkoxy or haloalkyl;
PRis at least one selected from the following groups:
a)-C(＝O)-PR0；
b)-C(＝O)-PR1；
g)-C(＝O)-O-PR2；
h)-C(＝O)-N(-K)(PR2)；
i)-C(＝O)-O-L-O-PR2；
l)-C(PR3)2-O-C(＝O)-PR4；
m)-C(PR3)2-O-C(＝O)-O-PR4；
o)-C(PR3)2-O-C(＝O)-O-L-O-PR4；
v)-C(PR3)2-PR6)2；
x)-C(PR3)2-C(PR3)2-C(C＝O)-O-PR2；
y)-C(PR3)2-N(-K)-C(C＝O)-O-PR2；
z)-P(＝O)(-PR8)(-PR9)；
wherein L is a linear or branched alkylene group;
k is hydrogen or alkyl optionally substituted with substituent A;
PR0is alkyl optionally substituted with substituent A;
PR1is carbocyclyl optionally substituted with substituent A, heterocyclyl optionally substituted with substituent A;
PR2is alkyl optionally substituted with substituent A, carbocyclyl optionally substituted with substituent A, heterocyclyl optionally substituted with substituent A, carbocycloalkyl optionally substituted with substituent A, heterocycloalkyl optionally substituted with substituent A;
PR3each independently is hydrogen, alkyl;
PR4is alkyl optionally substituted by substituent A, carbocyclyl optionally substituted by substituent AA heterocyclic group;
PR6is carbocyclyl optionally substituted with substituent A, heterocyclyl optionally substituted with substituent A;
PR8is alkoxy optionally substituted with substituent a;
PR9is alkoxy optionally substituted by substituent A, alkylamino optionally substituted by substituent A, carbocyloxy optionally substituted by substituent A, heterocyclyloxy optionally substituted by substituent A, carbocyclylamino optionally substituted by substituent A, or heterocyclylamino optionally substituted by substituent A;
and, PR8And PR9Optionally taken together with the adjacent phosphorus atom to form a heterocyclic ring optionally substituted with substituent A;
the substituent A is selected from at least one of the group consisting of: oxo, alkyl, alkylamino, carbocyclyl, heterocyclyl, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylaminocarbonyloxy, alkoxy, nitro, azido, alkylsulfonyl, and trialkylsilyl.
More specifically, in the compound represented by the formula (II), R1And R2Each independently hydrogen, halogen, alkyl, alkoxy; further preferably, R1And R2Each independently hydrogen, F, Cl, Br, C1-C4Alkyl radical, C1-C4An alkoxy group;
PRis composed of
Figure BDA0002872719240000081
Said C is1-C4Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl. Said C is1-C4Alkoxy is as above C1-C4Alkoxy corresponding to alkyl.
According to the invention, in particular, the compounds of formula II are selected from:
(R) -12- (5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione (10 a);
(R) -7-hydroxy-12- (((R/S) -2-bromo-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10 b);
(R) -7-hydroxy-12- (((R/S) -3-bromo-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10 c);
(R) -7-hydroxy-12- (((R/S) -1-fluoro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10 d);
(R) -7-hydroxy-12- (((R/S) -2-fluoro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10 e);
(R) -7-hydroxy-12- (((R/S) -3-fluoro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10 f);
(R) -7-hydroxy-12- (((R/S) -1-chloro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10 g);
(R) -7-hydroxy-12- (((R/S) -2-chloro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10H);
(R) -7-hydroxy-12- (((R/S) -3-chloro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10 i);
(R) -7-hydroxy-12- (((R/S) -3-methyl-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -3,4,12,12 a-tetrahydro-1H- [ [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10 j);
(R) -7-hydroxy-12- (((R/S) -3-methoxy-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -3,4,12,12 a-tetrahydro-1H- [ [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10 k).
The invention provides a preparation method of the compound, which takes different substituted benzaldehydes as initial raw materials to obtain the compound shown in the general formula II through a plurality of reactions. The specific synthesis scheme is shown in FIG. 1.
The synthetic route shown in FIG. 1 outlines and describes the preparation of the compounds of formula II of the present invention, all starting materials are prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All of the final derivatives of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry.
In a second aspect, the present invention provides a pharmaceutical composition comprising the above-described polycyclic pyridone derivative as an active ingredient, and a pharmaceutically acceptable excipient.
The invention can contain the derivatives of the compound shown in the general formula I and pharmaceutically acceptable salts and hydrates thereof as active ingredients, and the derivatives, the pharmaceutically acceptable salts and the hydrates are mixed with pharmaceutically acceptable excipients to prepare a composition and prepare a clinically acceptable dosage form, wherein the excipients refer to diluents, auxiliary agents or carriers which can be used in the pharmaceutical field. The above dosage forms are clinically common injections, tablets, capsules and the like.
The compound or the pharmaceutically acceptable salt, hydrate and prodrug thereof can be used alone as a sole anti-influenza medicament or can be combined with the anti-influenza medicaments on the market for preventing, treating or relieving symptoms of patients infected by influenza viruses.
In a third aspect, the present invention provides the use of the polycyclic pyridone derivative and/or the pharmaceutical composition for the preparation of a medicament for treating or preventing a disease caused by a virus having a cap-dependent endonuclease. Such viruses with cap-dependent endonucleases include, but are not limited to, influenza virus.
In a fourth aspect, the invention provides the use of the polycyclic pyridone derivative and/or the pharmaceutical composition in the preparation of an influenza virus RNA polymerase inhibitor.
In a fifth aspect, the present invention provides the use of a polycyclic pyridone derivative and/or a pharmaceutical composition as described above for the preparation of a medicament for preventing, treating or alleviating symptoms in a patient after an influenza virus infection.
Through activity inhibition tests of two influenza virus strains (A/FortMonmouth/1/1947(H1N1) and A/WuhanHanFang/359/1995(H3N2)), the compound or the pharmaceutically acceptable salt, hydrate and prodrug thereof have remarkable inhibitory activity on influenza viruses, wherein the activity of a part of compounds is equivalent to that of baroxavir, and even exceeds that of baroxavir.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Drawings
The above and other objects, features and advantages of the present invention will become more apparent by describing in more detail exemplary embodiments thereof with reference to the attached drawings.
FIG. 1 is a scheme showing the synthesis scheme of the polycyclic pyridone derivatives of the present invention.
Detailed Description
Preferred embodiments of the present invention will be described in more detail below. While the following describes preferred embodiments of the present invention, it should be understood that the present invention may be practiced in various forms and should not be limited by the embodiments set forth herein.
In the following examples, methods of preparing the compounds are depicted. It is to be understood that the following methods, as well as other methods known to those of ordinary skill in the art, can be applied to the preparation of all of the compounds described herein. The examples are intended to illustrate, but not to limit, the scope of the invention.
Figure BDA0002872719240000111
Example 1: synthesis of (R) -12- (5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione (10a)
Step 1: a100 mL reaction flask was charged with 20mmol of compound 7a, 10mL of tetrahydrofuran and 2mL of anhydrous ethanol, 10mmol of sodium borohydride was slowly added under ice bath, and the mixture was stirred at room temperature for 1.5 hours. Pouring the reaction solution into ice water, decompressing and distilling off most of organic solvent, extracting the product by dichloromethane, drying the organic phase by anhydrous sodium sulfate, decompressing and distilling off the organic phase to obtain the compound 8a, and directly using the compound in the next reaction without purification.1H NMR(400MHz,DMSO-d6)δ7.68(dt,J＝7.8,1.1Hz,2H),7.39(td,J＝7.5,1.4Hz,2H),7.34(dd,J＝7.6,1.4Hz,2H),7.22(td,J＝7.4,1.4Hz,2H),7.13(s,2H),6.08(s,1H),4.99(d,J＝4.1Hz,1H).
Step 2: a100 mL reaction flask was charged with 1mmol of Compound 1, 1.2mmol of Compound 8a, and 2.5mmol of a 50 wt.% solution of 1-propylphosphoric anhydride in ethyl acetate and stirred at 50 deg.C overnight. The reaction solution was poured into an appropriate amount of ice water, the product was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified on a large silica gel plate (20 cm. times.20 cm). Compound 9a is obtained.1H NMR(400MHz,Chloroform-d)δ7.65–7.57(m,2H),7.48(dt,J＝4.9,2.9Hz,1H),7.46–7.40(m,2H),7.40–7.33(m,4H),7.31–7.25(m,2H),7.04(d,J＝6.3Hz,3H),6.56(dd,J＝7.7,1.3Hz,1H),6.25(d,J＝7.7Hz,1H),5.68–5.53(m,2H),5.41(d,J＝10.8Hz,1H),5.33(s,1H),4.58(dd,J＝13.6,2.5Hz,1H),3.90(dd,J＝9.9,3.0Hz,1H),3.61(dd,J＝11.8,3.3Hz,1H),3.51(dd,J＝10.8,3.1Hz,1H),3.18(td,J＝11.8,2.7Hz,1H),3.12–3.01(m,1H),2.76(ddd,J＝13.5,11.8,3.5Hz,1H).
And step 3: a50 mL reaction flask was charged with 0.5mmol of compound 9a, 1.5mmol of lithium chloride and 5mL of DMA, and the reaction mixture was stirred at 80 ℃ for 3 hours. While stirring in ice bath, 2mL of acetone, 9mL of 0.5M diluted hydrochloric acid and 4mL of the reaction mixture were added, and stirring in ice bath was continued for 1 hour. The product is precipitated in solid form, and is filtered to obtain solid, and the solid is dried to obtain the target compound 10a which is light pink solid. The yield was 92.3%.1H NMR(400MHz,Chloroform-d)δ7.55–7.39(m,5H),7.34(t,J＝7.5Hz,1H),7.19(t,J＝7.5Hz,1H),7.07(s,2H),6.91(d,J＝7.6Hz,1H),6.24(d,J＝7.7Hz,1H),5.58(d,J＝7.7Hz,1H),5.41(s,1H),4.57(dd,J＝13.5,2.6Hz,1H),4.03(dd,J＝10.0,3.1Hz,1H),3.70(dd,J＝12.0,3.4Hz,1H),3.61(dd,J＝11.0,3.1Hz,1H),3.40–3.23(m,2H),2.86(ddd,J＝15.1,11.8,3.5Hz,1H)；13C NMR(101MHz,Chloroform-d)δ172.23,162.04,154.02,137.85,134.51,134.40,133.08,133.05,130.89,130.73,130.69,130.38,130.33,130.18,129.55,129.34,129.29,114.79,110.93,77.28,75.72,69.51,69.04,66.54,45.59；HRMS-ESI(m/z)Calcd.For C25H22N3O4[M+H]+:428.1610,Found:428.1602.
Example 2: synthesis of (R) -7-hydroxy-12- (((R/S) -2-bromo-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10b)
Step 1: a100 mL reaction flask was charged with Compound 2(3.15g,21.0mmol), NBS (4.09g,23.0mmol), and 30mL chlorobenzene in that order. The reaction mixture was heated to 70 ℃ and AIBN (0.13g,0.80mmol) was slowly added and stirring was continued at 70 ℃ for 1 hour. And (3) cooling the reaction liquid to room temperature, and evaporating the solvent in the reaction liquid under reduced pressure to obtain a crude product of the compound 3, wherein the crude product is directly used for the next reaction without purification.
Step 2: a100 mL reaction flask was charged with the compound 3 obtained in the previous step, triphenylphosphine (5.51g, 21.0mmol) and 25mL acetone in that order, and the reaction was refluxed for 1 hour. And (4) after the reaction liquid is cooled to room temperature, carrying out suction filtration to obtain a white solid. A100 mL reaction flask was charged with the white solid obtained above, sodium methoxide (1.35g, 25.0mmol), and 30mL of methanol. The reaction mixture was stirred at room temperature for half an hour, then heated under reflux, and 11mmol 4b was added thereto and refluxed for 6 hours. And (3) cooling the reaction liquid to room temperature, pouring the reaction liquid into a large amount of ice water, extracting a product by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain a crude product. And mixing the crude product with 50mL of petroleum ether and performing ultrasonic treatment, separating out most impurities in a solid form, filtering out the solid, and evaporating the filtrate under reduced pressure to obtain a primarily purified compound 5b, wherein the compound is directly used for the next reaction without further purification.1H NMR(400MHz,Chloroform-d)δ8.01(m,1H),7.34–7.32(m,2H),7.25–7.13(m,3H),7.11(d,J＝12.0Hz,1H),6.99–6.92(m,2H),6.57(d,J＝12.0Hz,1H),3.90(s,3H).
And step 3: adding into a 100mL reaction bottle5.0mmol 5b of the compound obtained in the previous step, potassium hydroxide (0.56g,10.0mmol), 20mL of methanol and 1mL of water, and the reaction mixture was refluxed for 4 hours. And cooling the reaction liquid to room temperature, pouring the reaction liquid into a large amount of ice water, stirring continuously, adding a 4M hydrochloric acid solution for acidification, and precipitating a crude product in a solid form. And (3) performing suction filtration to obtain a solid, mixing the dried solid with 50mL of petroleum ether, performing ultrasonic treatment, dissolving most of impurities in the petroleum ether, performing suction filtration, washing the solid with the petroleum ether to obtain a primarily purified compound 6b, and directly using the primarily purified compound in the next reaction without continuous purification.1H NMR(400MHz,Chloroform-d)δ8.13-8.11(m,1H),7.38–7.34(m,2H),7.24–7.18(m,3H),7.14(d,J＝12.0Hz,1H).7.01–6.94(m,2H),6.59(d,J＝12.0Hz,1H).
And 4, step 4: a100 mL reaction flask was charged with 1.0mmol 6b of the compound obtained in the previous step, dissolved in 20mL of dichloromethane, and thionyl chloride (0.13g,1.1mmol) was slowly added thereto with stirring at room temperature, and then the reaction solution was refluxed for 1.5 hours. After the reaction mixture was cooled to room temperature, 0.17g of anhydrous aluminum chloride was slowly added thereto, and the mixture was stirred at room temperature for 3 hours. Pouring the reaction liquid into ice water, extracting a product by using dichloromethane, drying an organic phase by using anhydrous sodium sulfate, and evaporating the organic phase by reduced pressure to obtain a crude product of the compound 7b, wherein the crude product is directly used for the next reaction without purification.1H NMR(400MHz,Chloroform-d)δ8.26–8.22(m,1H),8.11(d,J＝8.5Hz,1H),7.72(d,J＝2.0Hz,1H),7.71–7.64(m,2H),7.62–7.55(m,2H),7.12(d,J＝12.1Hz,1H),6.97(d,J＝12.1Hz,1H).
And 5: the same procedure as in step 1 of example 1 gave compound 8 b.1H NMR(400MHz,Chloroform-d)δ7.69(d,J＝7.8Hz,1H),7.58(d,J＝8.3Hz,1H),7.56–7.49(m,2H),7.46(td,J＝7.5,1.5Hz,1H),7.38(dd,J＝7.7,1.4Hz,1H),7.32(dd,J＝7.4,1.3Hz,1H),7.17(d,J＝11.7Hz,1H),7.03(d,J＝11.7Hz,1H),5.37(s,1H).
Step 6: the same procedure as in step 2 of example 1 gave compound 9 b. A pair of diastereomers in a ratio of 3: 4.1H NMR(400MHz,Chloroform-d)δ7.68–7.63(m,4H),7.62–7.59(m,3H),7.55–7.52(m,3H),7.48–7.45(m,4H),7.38–7.35(m,4H),7.34–7.31(m,2H),7.16–7.02(m,4H),6.93(dd,J＝11.8,1.5Hz,2H),6.59–6.18(m,4H),5.77–5.55(m,4H),5.43(t,J＝11.4Hz,2H),5.29(d,J＝13.2Hz,2H),4.59(ddd,J＝13.5,7.1,2.5Hz,2H),3.87(ddd,J＝25.7,9.9,3.0Hz,2H),3.63(td,J＝11.5,3.3Hz,2H),3.53(ddd,J＝10.0,6.5,3.0Hz,2H),3.26–3.13(m,2H),3.07(t,J＝10.4Hz,2H),2.76(dddd,J＝25.1,13.5,11.7,3.5Hz,2H).
And 7: the same procedure as in step 3 of example 1 gave compound 10 b. The yield was 91.5%. Diastereoisomers, ratio 3: 7.1H NMR(400MHz,Chloroform-d)δ7.69–7.30(m,5H),7.21(t,J＝7.6Hz,1H),7.11(t,J＝8.9Hz,1H),7.05–6.72(m,2H),6.25(dd,J＝25.7,7.6Hz,1H),5.63(dd,J＝47.5,7.7Hz,1H),5.38(s,1H),4.57(dd,J＝13.2,8.6Hz,1H),4.01(ddd,J＝23.2,10.1,3.0Hz,1H),3.66(dtd,J＝36.2,9.3,6.7,3.2Hz,2H),3.32(dtd,J＝20.8,11.3,10.4,3.4Hz,2H),2.98–2.75(m,1H)；13C NMR(101MHz,Chloroform-d)δ172.19,162.03,154.03,137.77,136.16,133.44,132.76,132.21,132.07,131.90,131.84,131.76,131.09,130.72,130.41,130.32,129.97,129.71,129.59,129.17,128.83,123.33,114.72,111.16,110.96,75.09,74.92,69.61,69.50,69.00,66.53,45.66；HRMS-ESI(m/z)Calcd.For C25H21BrN3O4[M+H]+:506.0715,Found:506.0708.
Example 3: synthesis of (R) -7-hydroxy-12- (((R/S) -3-bromo-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10c)
The method comprises the following steps: the same procedure as in steps 1-7 of example 2 gave compound 10 c. The yield was 93.6%. Diastereoisomers in a ratio of 1: 1.1H NMR(400MHz,DMSO-d6)δ11.70(s,2H),7.99(d,J＝2.1Hz,1H),7.69(dd,J＝8.3,2.1Hz,1H),7.62(dq,J＝8.0,3.9Hz,2H),7.59–7.54(m,2H),7.54–7.47(m,4H),7.44(d,J＝8.3Hz,1H),7.38(td,J＝7.5,1.4Hz,1H),7.27–7.10(m,6H),6.35(dd,J＝15.6,7.7Hz,2H),5.85(d,J＝2.8Hz,2H),5.43(d,J＝7.7Hz,1H),5.34(d,J＝7.6Hz,1H),4.40(ddd,J＝16.2,13.4,2.5Hz,2H),3.85(dd,J＝8.4,4.6Hz,1H),3.76(dd,J＝9.5,3.5Hz,1H),3.59(ddd,J＝14.4,11.6,3.3Hz,2H),3.41(td,J＝10.0,9.0,3.6Hz,4H),3.29(dd,J＝11.3,2.7Hz,2H),2.84(ddd,J＝14.7,11.8,3.5Hz,1H),2.75(ddd,J＝15.2,11.1,3.4Hz,1H)；13C NMR(101MHz,DMSO-d6)δ171.39,161.71,153.44,138.58,135.93,135.03,133.86,133.67,133.62,133.48,133.39,132.73,132.29,132.14,131.84,131.57,131.42,131.26,131.18,130.95,130.50,129.86,129.71,129.62,129.40,122.67,122.26,116.00,115.93,110.36,110.33,72.63,72.52,69.94,69.69,68.22,65.94,45.72；HRMS-ESI(m/z)Calcd.For C25H21BrN3O4[M+H]+:506.0715,Found:506.0709.
Example 4: synthesis of (R) -7-hydroxy-12- (((R/S) -1-fluoro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10d)
The method comprises the following steps: the same procedure as in steps 1-7 of example 2 gave compound 10 d. The yield was 92.1%. Diastereoisomers in a ratio of 1: 1.1H NMR(400MHz,Chloroform-d)δ7.60–7.27(m,9H),7.18(ddt,J＝22.0,15.9,8.2Hz,6H),7.06(t,J＝9.1Hz,1H),6.90(d,J＝7.6Hz,1H),6.71(d,J＝7.6Hz,1H),6.33(d,J＝7.7Hz,1H),6.25(d,J＝7.7Hz,1H),5.66(d,J＝7.7Hz,1H),5.57(d,J＝7.7Hz,1H),5.44(s,2H),4.57(ddd,J＝13.4,6.0,2.5Hz,2H),4.04(ddd,J＝22.5,10.0,3.1Hz,2H),3.67(dtd,J＝35.1,11.5,3.3Hz,4H),3.32(dtd,J＝20.8,10.4,9.4,3.5Hz,4H),2.86(qd,J＝13.0,3.6Hz,2H)；13C NMR(101MHz,Chloroform-d)δ172.20,162.00,154.07,154.03,137.78,137.72,134.31,134.20,133.00,132.93,131.91,131.62,131.04,130.71,130.56,130.41,130.34,129.88,129.64,129.57,126.17,125.77,121.91,121.46,121.38,116.33,116.19,116.10,114.75,114.69,111.09,110.97,75.10,75.04,69.69,69.54,69.01,68.98,66.53,45.61；HRMS-ESI(m/z)Calcd.For C25H21FN3O4[M+H]+:446.1516,Found:446.1507.
Example 5: synthesis of (R) -7-hydroxy-12- (((R/S) -2-fluoro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10e)
The method comprises the following steps: the same procedure as in steps 1-7 of example 2 gave compound 10 e. The yield was 91.0%. Diastereoisomers in a ratio of 1: 1.1H NMR(400MHz,Chloroform-d)δ7.58–7.47(m,3H),7.43(td,J＝8.7,8.0,4.9Hz,3H),7.37(td,J＝7.6,1.3Hz,1H),7.23(ddd,J＝9.2,6.4,1.8Hz,2H),7.19–7.08(m,4H),7.00(dd,J＝11.8,4.7Hz,2H),6.91(dd,J＝7.2,1.9Hz,3H),6.29(d,J＝7.7Hz,1H),6.23(d,J＝7.7Hz,1H),5.69(d,J＝7.7Hz,1H),5.59(d,J＝7.7Hz,1H),5.41(s,2H),4.59(ddd,J＝13.5,5.3,2.5Hz,2H),4.03(ddd,J＝11.1,10.0,3.1Hz,2H),3.72(ddd,J＝11.5,7.7,3.4Hz,2H),3.63(ddd,J＝10.8,7.5,3.1Hz,2H),3.32(dddd,J＝23.3,11.3,9.4,2.6Hz,4H),2.87(dtd,J＝15.4,12.1,3.5Hz,2H)；13C NMR(101MHz,Chloroform-d)δ172.24,162.07,154.07,137.78,136.47,134.14,132.53,131.93,131.59,131.09,130.68,130.40,130.31,129.97,129.68,129.51,129.11,117.15,116.94,116.35,111.03,110.96,74.91,74.81,69.51,69.05,66.55,45.66,45.60；HRMS-ESI(m/z)Calcd.For C25H21FN3O4[M+H]+:446.1516,Found:446.1506.
Example 6: synthesis of (R) -7-hydroxy-12- (((R/S) -3-fluoro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10f)
The method comprises the following steps: the same procedure as in steps 1-7 of example 2 gave compound 10 f. The yield was 93.3%. Diastereoisomers in a ratio of 1: 1.1H NMR(400MHz,Chloroform-d)δ7.58–7.30(m,8H),7.19(q,J＝8.6,7.8Hz,3H),7.05(s,5H),6.90(d,J＝7.7Hz,1H),6.69(d,J＝8.6Hz,1H),6.28(dd,J＝29.0,7.7Hz,2H),5.62(dd,J＝39.0,7.7Hz,2H),5.36(d,J＝4.6Hz,2H),4.59(t,J＝14.8Hz,2H),4.03(ddd,J＝23.6,9.9,3.1Hz,2H),3.83–3.53(m,4H),3.50–3.13(m,4H),3.03–2.76(m,2H)；13C NMR(101MHz,Chloroform-d)δ172.21,162.06,161.99,154.05,137.79,134.43,134.25,132.86,132.78,132.41,132.29,132.03,130.89,130.76,130.31,130.19,129.87,129.69,129.58,129.46,129.21,117.45,116.94,116.71,111.04,110.95,75.03,69.70,69.49,69.03,68.93,66.55,45.69,45.65.；HRMS-ESI(m/z)Calcd.For C25H21FN3O4[M+H]+:446.1516,Found:446.1506.
Example 7: synthesis of (R) -7-hydroxy-12- (((R/S) -1-chloro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10g)
The method comprises the following steps: the same procedures in steps 1 to 7 of example 2 gave 10g of a compound.1H NMR(400MHz,Chloroform-d)δ7.56–7.33(m,12H),7.25–7.16(m,3H),7.10(t,J＝7.8Hz,1H),6.90(d,J＝7.6Hz,1H),6.83(d,J＝7.6Hz,1H),6.33(d,J＝7.6Hz,1H),6.26(d,J＝7.7Hz,1H),5.68(d,J＝7.7Hz,1H),5.59(d,J＝7.7Hz,1H),5.40(s,2H),4.57(ddd,J＝13.3,7.1,2.5Hz,2H),4.08(dd,J＝9.9,3.1Hz,1H),4.01(dd,J＝10.0,3.1Hz,1H),3.78–3.58(m,4H),3.41–3.23(m,4H),2.86(dddd,J＝15.3,13.4,11.8,3.5Hz,2H)；13C NMR(101MHz,Chloroform-d)δ172.21,161.94,154.11,154.05,137.76,135.76,135.61,133.90,133.32,131.87,131.61,130.90,130.83,130.77,130.47,130.15,130.11,129.97,129.92,129.78,129.70,129.64,129.23,128.89,126.42,126.05,114.70,111.13,111.01,77.28,75.39,75.25,69.79,69.59,69.00,68.98,66.54,45.62,45.59；HRMS-ESI(m/z)Calcd.For C25H21ClN3O4[M+H]+:462.1221,Found:462.1211.
Example 8: synthesis of (R) -7-hydroxy-12- (((R/S) -2-chloro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10H)
The method comprises the following steps: the same procedure as in steps 1-7 of example 2 gave compound 10 h. The yield was 92.5%. Diastereoisomers in a ratio of 1: 1.1H NMR(400MHz,Chloroform-d)δ7.57–7.30(m,11H),7.24–7.07(m,4H),6.98(dd,J＝11.8,5.5Hz,2H),6.87(dd,J＝16.6,7.9Hz,2H),6.29(d,J＝7.7Hz,1H),6.22(d,J＝7.7Hz,1H),5.68(d,J＝7.7Hz,1H),5.57(d,J＝7.6Hz,1H),5.39(s,2H),4.57(ddd,J＝13.7,7.1,2.4Hz,2H),4.01(ddd,J＝19.2,9.9,3.1Hz,2H),3.71(td,J＝11.3,3.4Hz,2H),3.61(ddd,J＝10.0,6.5,3.1Hz,2H),3.42–3.22(m,4H),2.95–2.76(m,2H)；13C NMR(101MHz,Chloroform-d)δ172.19,162.02,154.02,137.79,135.89,135.25,134.19,132.89,132.07,131.90,131.73,131.69,131.09,130.70,130.48,130.41,130.33,129.94,129.78,129.71,129.58,129.27,129.14,128.91,114.75,111.14,110.96,77.28,75.00,74.86,69.59,69.51,68.99,66.52,45.67,45.62；HRMS-ESI(m/z)Calcd.For C25H21ClN3O4[M+H]+:462.1221,Found:462.1208.
Example 9: synthesis of (R) -7-hydroxy-12- (((R/S) -3-chloro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10i)
The method comprises the following steps: the same procedure as in steps 1-7 of example 2 gave compound 10 i. The yield was 90.7%. Diastereoisomers in a ratio of 1: 1.1H NMR(400MHz,Chloroform-d)δ7.56–7.29(m,11H),7.22(td,J＝7.5,1.4Hz,1H),7.13–6.99(m,4H),6.97(d,J＝2.1Hz,1H),6.94–6.88(m,1H),6.31(d,J＝7.7Hz,1H),6.24(d,J＝7.7Hz,1H),5.69(d,J＝7.7Hz,1H),5.58(d,J＝7.7Hz,1H),5.36(d,J＝2.8Hz,2H),4.60(ddd,J＝19.8,13.3,2.5Hz,2H),4.03(ddd,J＝23.8,9.9,3.1Hz,2H),3.73(ddd,J＝16.3,12.0,3.4Hz,2H),3.62(ddd,J＝10.9,9.3,3.1Hz,2H),3.42–3.23(m,4H),2.94(ddd,J＝13.4,11.7,3.5Hz,1H),2.84(ddd,J＝13.4,11.8,3.5Hz,1H)；13C NMR(101MHz,Chloroform-d)δ172.22,162.05,154.10,137.81,137.75,135.55,134.40,132.99,132.90,132.64,132.49,132.12,131.27,131.09,130.97,130.80,130.34,130.29,130.01,129.86,129.65,129.59,129.53,129.45,129.36,129.23,114.67,114.64,110.95,77.25,75.08,74.92,69.68,69.48,69.04,68.95,66.56,66.51,45.68,45.63,29.71；HRMS-ESI(m/z)Calcd.For C25H21ClN3O4[M+H]+:462.1221,Found:462.1211.
Example 10: synthesis of (R) -7-hydroxy-12- (((R/S) -3-methyl-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -3,4,12,12 a-tetrahydro-1H- [ [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10j)
The method comprises the following steps: the same procedure as in steps 1 to 7 of example 2 gave compound 10 j. The yield was 85.3%. Diastereoisomers in a ratio of 1: 1.1H NMR(400MHz,Chloroform-d)δ7.53–7.38(m,6H),7.35–7.27(m,3H),7.23(d,J＝1.8Hz,1H),7.16(ddd,J＝12.8,7.6,1.5Hz,2H),7.07–6.98(m,4H),6.88(d,J＝7.6Hz,1H),6.72(d,J＝1.7Hz,1H),6.25(dd,J＝7.6,4.9Hz,2H),5.67–5.46(m,2H),5.35(s,2H),4.58(ddd,J＝13.5,7.6,2.5Hz,2H),4.05(ddd,J＝16.5,9.9,3.1Hz,2H),3.70(dt,J＝11.9,4.2Hz,2H),3.65–3.54(m,2H),3.50–3.13(m,4H),2.86(ddt,J＝12.3,8.7,2.8Hz,2H),2.41(s,3H),2.20(s,3H)；13C NMR(101MHz,Chloroform-d)δ172.20,162.01,153.97,140.05,139.67,138.03,137.90,134.58,132.94,132.87,131.92,131.30,130.89,130.82,130.80,130.67,130.63,130.34,130.26,130.21,130.16,130.10,130.06,129.78,129.44,129.33,129.27,129.25,129.07,114.87,114.83,110.91,110.76,75.80,69.48,69.04,66.52,45.57,21.13,20.96；HRMS-ESI(m/z)Calcd.For C26H24N3O4[M+H]+:442.1767,Found:442.1758.
Example 11: synthesis of (R) -7-hydroxy-12- (((R/S) -3-methoxy-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -3,4,12,12 a-tetrahydro-1H- [ [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10k)
The method comprises the following steps: the same procedure as in steps 1-7 of example 2 gave compound 10 k. The yield was 94.9%. Diastereoisomers in a ratio of 1: 1.1H NMR(400MHz,Chloroform-d)δ7.70–7.31(m,6H),7.08–6.84(m,3H),6.43(s,1H),6.31(d,J＝7.7Hz,1H),5.65(d,J＝7.7Hz,1H),5.34(s,1H),4.58(d,J＝12.9Hz,1H),4.03(dd,J＝9.8,3.0Hz,1H),3.85(d,J＝6.3Hz,1H),3.66(s,3H),3.32(dt,J＝21.7,11.1Hz,2H),2.86(t,J＝12.5Hz,1H)；13C NMR(101MHz,Chloroform-d)δ172.15,160.93,153.97,138.04,132.37,131.76,130.74,130.37,129.91,129.31,128.91,128.46,115.61,115.34,110.92,75.85,69.44,69.03,66.54,55.61,45.58,29.71；HRMS-ESI(m/z)Calcd.For C26H24N3O5[M+H]+:458.1716,Found:458.1707.
Biological Activity Studies of Compounds
In the following examples, some of the compounds of the present invention were used as examples to examine the antiviral activity and cytotoxicity of the compounds of the present invention.
Antiviral Activity and cytotoxicity assays
Example A: cytopathic effect experiment (CPE assay):
the ability of the compounds to inhibit the Cytopathic (CPE) effects of the viruses HlNl A/FortMonmouth/1/1947 and H3N 2A/WuhanHanFang/95/359 was tested at the cellular level in vitro.
The experimental steps are as follows:
(1) MDCK cells with 2.5 × 104Density per well was seeded into 96-well plates.
(2) After 24h, the cells were washed once with PBS and infected with 100-half of the tissue cells (50% tissue culture infectious diseases, TCID)50) The virus-infected solution (serum-free MEM medium) of (a) infected MDCK cells. Influenza virus: A/FortMonmouth/1/1947(H1N1), A/WuhanHanFang/359/1995(H3N 2).
(3) After 2h of infection at 37 ℃ the unadsorbed virus was removed and a compound-containing virus maintenance solution (MEM medium supplemented with 2. mu.g/mL of TPCK-treated pancreatin and 0.08% BSA) was added. The highest concentration of compound detected was 200nM, 3-fold dilution, 8 concentrations, in order: 100nM, 66.67nM, 22.22nM, 7.41nM, 2.47nM, 0.82nM, 0.27nM, 0.09 nM. And a virus control group without medicine and a cell control group without medicine and virus infection are arranged at the same time. The cytotoxicity test group did not add virus and was replaced with medium. Two complex holes are arranged.
(4) Incubation is continued in the incubator at 37 ℃ for about 2 days, and the CPE result of the compound group is read when the cytopathic effect (CPE) degree of the virus control group is 75-100%.
(5) By Reed&The Muench method calculates the half effective Inhibitory Concentration (IC) of the drug50) And according to TC50/IC50The ratio was used to calculate the therapeutic Index (Selective Index, SI).
The antiviral activity test and the cytotoxicity test show that the compound has good antiviral activity, and particularly, the inhibitory activity of part of the compound on influenza virus (A/FortMonmouth/1/1947) and influenza virus (A/WuhanhanHanFang/359/1995) is equivalent to that of baroxavir; at the same time, the compounds of the invention have very low cytotoxicity, TC50Is far less than the cytotoxicity of the baroxavir.
TABLE 1 in vitro assay TC for influenza Virus (A/FortMonmouth/1/1947, A/WuhanHanFang/359/1995) with the compounds of the invention50And IC50Activity data
Figure BDA0002872719240000231
Figure BDA0002872719240000241
Note: TC (tungsten carbide)50: half toxic concentration of drug; IC (integrated circuit)50: the half inhibitory concentration of the drug on the virus.
As shown in Table 1, the compound of the present invention has excellent anti-influenza virus activity and low cytotoxicity.
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.

Claims (8)

1. A polycyclic pyridone derivative is a compound shown as a formula (II) or a stereoisomer, a tautomer and a pharmaceutically acceptable salt thereof,
Figure DEST_PATH_IMAGE001
the compound represented by the formula (II) is selected from:
(R) -12- (5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazine [3,4-c ] pyrido [2,1-f ] [1,2,4] triazine-6, 8-dione (10 a);
(R) -7-hydroxy-12- (((R/S) -1-fluoro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10 d);
(R) -7-hydroxy-12- (((R/S) -2-fluoro-5H-dibenzo [ a, d ] [7] -5-cyclopentenyl) -7-hydroxy-3, 4,12,12 a-tetrahydro-1H- [1,4] oxazinyl [3,4-c ] pyridinyl [2,1-f ] [1,2,4] triazine-6, 8-dione (10 e).
2. The prodrug of a polycyclic pyridone derivative according to claim 1, wherein P is P forming a prodrugRBase, PRIs composed of
Figure DEST_PATH_IMAGE003
。
3. A pharmaceutical composition comprising the polypyridone derivative of claim 1 or the prodrug of the polypyridone derivative of claim 2 as an active ingredient, and a pharmaceutically acceptable excipient.
4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition further comprises an additional anti-influenza drug.
5. Use of a polycyclic pyridone derivative of claim 1, a prodrug of a polycyclic pyridone derivative of claim 2, or a pharmaceutical composition of any one of claims 3 to 4 for the preparation of an influenza virus RNA polymerase inhibitor.
6. Use of the polycyclic pyridone derivative of claim 1, the prodrug of the polycyclic pyridone derivative of claim 2, or the pharmaceutical composition of any one of claims 3 to 4 for the preparation of a medicament for treating or preventing a disease caused by a virus having a cap-dependent endonuclease.
7. The use of claim 6, wherein the virus having a cap-dependent endonuclease is an influenza virus.
8. Use of a polycyclic pyridone derivative of claim 1, a prodrug of a polycyclic pyridone derivative of claim 2, or a pharmaceutical composition of any one of claims 3 to 4 in the manufacture of a medicament for preventing, treating, or alleviating a symptom in a patient after an influenza virus infection.
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