CN115677611A - 2H-benzo [ b ] [1,4] oxazin-3 (4H) -one derivatives - Google Patents

2H-benzo [ b ] [1,4] oxazin-3 (4H) -one derivatives Download PDF

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CN115677611A
CN115677611A CN202210627790.0A CN202210627790A CN115677611A CN 115677611 A CN115677611 A CN 115677611A CN 202210627790 A CN202210627790 A CN 202210627790A CN 115677611 A CN115677611 A CN 115677611A
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向永哲
曾善超
马云龙
秦琬茹
付海霞
王颖
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Chengdu Shuoder Pharmaceutical Co ltd
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Chengdu Easton Biopharmaceuticals Co Ltd
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Abstract

The invention relates to the field of medicinal chemistry, in particular to novel 2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone derivatives and 2H-benzo [ b ] [1,4] thiazine-3 (4H) -ketone derivatives, isomers and application of pharmaceutical compositions thereof in preparation of treatment and prevention, especially application in treatment of pain, inflammatory diseases, neurodegenerative diseases and the like.

Description

2H-benzo [ b ] [1,4] oxazin-3 (4H) -one derivatives
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to novel 2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone derivatives and 2H-benzo [ b ] [1,4] thiazine-3 (4H) -ketone derivatives, isomers and application of pharmaceutical compositions thereof in preparation of compounds, isomers and prevention, especially application in treatment of pain, inflammatory diseases, neurodegenerative diseases and the like.
Background
Pain, the fifth most common and most disturbing symptom in clinic, is an important factor affecting quality of life and disability, and is one of the most important unmet medical needs. Limited by the limited efficacy and adverse effects of existing analgesic drugs, about 75% of patients are not treated effectively by the american pain society. Under the guidance of multimodal analgesia, opioids (opioids) are widely used in moderate to severe pain, especially post-operative analgesia. But the clinical use is limited due to the obvious adverse reactions such as nausea, vomit, constipation, urine retention, respiratory depression and the like and tolerance, and the stronger addiction is limited by the use. Therefore, there is a great clinical need for novel analgesic drugs with similar analgesic activity while reducing adverse reactions.
Evidence accumulated in extensive research suggests that cannabinoid receptors (cannabinoid receptors) widely distributed in humans are involved in central and peripheral analgesia mediated by the endocannabinoid system, as well as in the regulation of anti-inflammatory activity. Cannabinoid receptors include the cannabinoid CB1 receptor (predominantly distributed centrally with low levels expressed at the terminal ends of peripheral neurons) and the cannabinoid CB2 receptor (predominantly expressed in peripheral circulating immune cells). CB1 and CB2 receptor agonists have been shown to be involved in acute and chronic pain suppression and lack typical physical dependence symptoms. The CB1 receptor is mainly distributed in the center, the mental activity of the cannabinoid is born, an agonist and an antagonist developed aiming at the CB1 receptor in the early stage are limited by the mental adverse reaction, the current research and development direction is shifted to the development of a selective CB2 receptor agonist, and the mental side effect mediated by the CB1 receptor can be avoided while the effective analgesic activity is kept. Extensive studies have proved that the CB2 receptor selective agonist has significant analgesic effect in various animal pain models such as preclinical neuropathic pain, inflammatory pain, acute pain and the like, and no CNS adverse reaction related to the CB1 receptor is observed, so that the CB2 receptor selective agonist is a potential novel analgesic drug with low toxicity and high efficiency.
Therefore, on the basis of the existing domestic and foreign researches, the invention strives to develop the CB2 receptor selective agonist with a novel structure, has good analgesic effect and small toxic and side effect, and provides a better medicament for clinical application.
Disclosure of Invention
The invention relates to a novel 2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone derivative and a 2H-benzo [ b ] [1,4] thiazin-3 (4H) -ketone derivative compound serving as a selective agonist of cannabinoid receptors, in particular to a novel 2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone derivative and a 2H-benzo [ b ] [1,4] thiazin-3 (4H) -ketone derivative compound and application thereof in medicine, particularly to a 2H-benzo [ b ] [1,4] oxazine-3 (4H) -ketone derivative shown in the following general formula (I) and an application thereof in preparing medicines for treating or preventing pain, inflammatory diseases and neurodegenerative diseases, particularly to application thereof in preparing medicines for treating or preventing pain, and more particularly in preparing medicines for treating or preventing neuropathic pain, inflammatory pain and pain, and medicines, and further particularly in preparing medicines for treating or preventing severe pain.
One object of the present invention is to provide 2H-benzo [ b ] [1,4] oxazin-3 (4H) -one derivatives and 2H-benzo [ b ] [1,4] thiazin-3 (4H) -one derivatives of the following general formula (I):
Figure BDA0003678364140000021
or stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites thereof,
wherein:
a is selected from N or C;
b is selected from N or C;
e is selected from N or C;
d is selected from O or S;
y is selected from O or S;
f is selected from substituted or unsubstituted C 2-6 Alkyl, substituted or unsubstituted C 3-6 A cycloalkyl group;
R 1 selected from substituted or unsubstituted C 5-12 An aryl group;
R 2 and R 3 Independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 5-10 Aryl, substituted or unsubstituted C 5-10 Heterocyclyl group, or R 2 And R 3 Taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-to 15-membered heterocyclyl group.
Preferably, in the compounds of the present invention represented by the general formula (I):
Figure BDA0003678364140000022
a is selected from N or C;
b is selected from N or C;
e is selected from N or C;
d is selected from O or S;
y is selected from O or S;
f is selected from substituted or unsubstituted C 2-6 Alkyl, substituted or unsubstituted C 3-6 A cycloalkyl group;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl, dibenzothienyl, oxadiazolyl and isofuranylOxazolyl, indolyl, isoindolyl, cinnolinyl, quinazolinyl, indolyl, benzothienyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, thiazolyl;
R 2 and R 3 Independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, or R 2 And R 3 Taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-to 15-membered heterocyclyl group.
More preferably, in the compounds represented by the general formula (I) of the present invention:
Figure BDA0003678364140000023
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted C 2-3 Alkyl, substituted or unsubstituted C 3-4 Cycloalkyl with deuterium atom as substituent C 1-3 Alkyl radical, C 1-3 An alkoxymethyl group, a fluorine atom or a chlorine atom;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A]Pyridyl group, dibenzothienyl group, wherein said group may be further substituted by deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy group, C 1-3 Alkoxy or adjacent 2C 1-3 The alkoxy forms a ring and is substituted by a substituent;
R 2 and R 3 Independently selected from methyl, ethyl or R 2 And R 3 Together with the nitrogen atom to which they are attached form a morpholinyl, piperazinyl, piperidinyl, azepanyl group, wherein the cyclic group formed may be further substituted by a deuterium atom, a fluorine atom, a chlorine atom, C 1-3 Alkyl or C 1-3 An alkoxymethyl group.
Further preferably, in the compounds represented by the general formula (I) of the present invention:
Figure BDA0003678364140000031
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl with deuterium atom as substituent C 1-3 An alkyl group, a fluorine atom or a chlorine atom;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl, dibenzothienyl, wherein said group may be further substituted with deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy, methoxy, or a substituent formed by ring-formation of adjacent 2 methoxy groups;
R 2 and R 3 Together with the nitrogen atom to which they are attached form a morpholino ring group, a piperazino ring group, a piperidino group, wherein the resulting ring group may be further substituted with a deuterium atom, a fluorine atom, a chlorine atom, a methyl group or a methoxymethyl group.
Even more preferably, the compound of the present invention represented by the general formula (I):
Figure BDA0003678364140000032
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl substituted with deuterium, methyl, fluorine or chlorine;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, iso-substituted or unsubstituted phenylQuinolyl, imidazo [1,5-A ]]Pyridyl group, dibenzothienyl group, wherein phenyl group can be further substituted by deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy group, methoxy group, substituent formed by ring formation of adjacent 2 methoxy groups; wherein naphthyl, quinolyl, isoquinolyl, imidazo [1, 5-A)]The pyridyl group and the dibenzothienyl group may be further substituted with a deuterium atom, a fluorine atom, a chlorine atom, a trifluoromethoxy group or a methoxy group;
R 2 and R 3 Together with the nitrogen atom to which they are attached form a morpholino ring group, a piperazino ring group, a piperidino group, wherein the resulting ring group may be further substituted with a deuterium atom, a fluorine atom, a chlorine atom, a methyl group or a methoxymethyl group.
Still more preferably, in the compounds represented by the general formula (I) of the present invention:
Figure BDA0003678364140000041
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl with deuterium atom, methyl group or fluorine atom as a substituent;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl group, dibenzothienyl group, wherein the phenyl group may be further substituted with deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy group, methoxy group, a substituent formed by ring formation of adjacent 2 methoxy groups, naphthyl group, quinolyl group, isoquinolyl group, imidazo [1,5-A ]]Pyridyl group, dibenzothienyl group may be further substituted by deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy group or methoxy group;
R 2 and R 3 Together with the nitrogen atom to which they are attached form a morpholinyl radical, wherein the morpholinyl radical may be further substituted by a deuterium atom, a fluorine atom, a methyl group, a methoxymethyl group.
Still more preferably, in the compounds represented by the general formula (I) of the present invention:
Figure BDA0003678364140000042
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is deuterium atom or methyl;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A]Pyridyl, dibenzothienyl, wherein phenyl can be further substituted by fluorine atom, chlorine atom, trifluoromethoxy, methoxyl, substituent formed by adjacent 2 methoxyl rings; wherein naphthyl, quinolyl, isoquinolyl, imidazo [1, 5-A)]The pyridyl group and the dibenzothienyl group may be further substituted by a fluorine atom, a chlorine atom, a trifluoromethoxy group or a methoxy group;
R 2 and R 3 Together with the nitrogen atom to which they are attached form a morpholinyl radical, wherein the morpholinyl radical may be further substituted by a fluorine atom, a methyl or methoxymethyl radical.
Most preferably, the compounds of the present invention represented by the general formula (I):
Figure BDA0003678364140000051
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is methyl;
R 1 is selected from substitutionOr unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl, dibenzothienyl, wherein the phenyl can be further substituted by a fluorine atom, a chlorine atom, a trifluoromethoxy and a substituent formed by ring formation of adjacent 2 methoxy groups; wherein naphthyl can be further substituted by trifluoromethoxy and methoxy, and quinolyl and isoquinolyl can be further substituted by fluorine atom or chlorine atom;
R 2 and R 3 Taken together with the nitrogen atom to which they are attached to form a morpholinyl group, wherein the morpholinyl group may be further substituted with a fluorine atom, a methyl group, or a methoxymethyl group.
In the 2H-benzo [ b ] [1,4] oxazine-3 (4H) -one derivatives and 2H-benzo [ b ] [1,4] thiazin-3 (4H) -one derivatives compounds shown in the general formula (I), preferred compounds include, but are not limited to, compounds:
Figure BDA0003678364140000052
Figure BDA0003678364140000061
Figure BDA0003678364140000071
further, in the 2H-benzo [ b ] [1,4] oxazine-3 (4H) -one derivatives and 2H-benzo [ b ] [1,4] thiazin-3 (4H) -one derivatives of the present invention represented by general formula (I), preferred compounds include, but are not limited to, compounds:
Figure BDA0003678364140000072
Figure BDA0003678364140000081
another object of the present invention is to provide a process for preparing the compound of formula (I) above, comprising the steps of:
Figure BDA0003678364140000091
and (3) carrying out substitution reaction on the compounds II and III to generate an intermediate IV, and reacting the intermediate IV with organic boric acid (V) or organic boric acid ester (VI) to prepare the compound I.
Wherein, X is Br or Cl, and Z is Br or Cl or MsO;
wherein A in the raw materials is selected from N or C; b is selected from N or C; e is selected from N or C; d is selected from O or S; y is selected from O or S; f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is deuterium atom, methyl, fluorine atom and chlorine atom; r is 1 Selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl, dibenzothienyl, oxadiazolyl, isoxazolyl, indolyl, isoindolyl, cinnolinyl, quinazolinyl, indolyl, benzothienyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, thiazolyl; wherein the phenyl group may be further substituted with a substituent formed by a deuterium atom, a fluorine atom, a chlorine atom, a trifluoromethoxy group, a methoxy group, or ring formation of 2 adjacent methoxy groups; wherein naphthyl, quinolyl, isoquinolyl, imidazo [1, 5-A)]Pyridyl and dibenzothienyl can be further substituted by deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy and methoxy; r is 2 And R 3 Together with the nitrogen atom to which they are attached form a morpholino ring group, a piperazino ring group, or a piperidino group, wherein the resulting ring group may be further substituted with a deuterium atom, a fluorine atom, a chlorine atom, a methyl group, or a methoxymethyl group.
Further, A is selected from C; b is selected from C; e is selected from C; d is selected from O or S; y is selected from O; f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl with deuterium atom, methyl group or fluorine atom as a substituent; r is 1 Selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A]Pyridinyl, dibenzothiaA thienyl group in which the phenyl group may be further substituted with a substituent formed by a deuterium atom, a fluorine atom, a chlorine atom, a trifluoromethoxy group, a methoxy group, or ring formation of adjacent 2 methoxy groups; wherein naphthyl, quinolyl, isoquinolyl, imidazo [1, 5-A)]Pyridyl and dibenzothienyl can be further substituted by deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy and methoxy; r 2 And R 3 Together with the nitrogen atom to which they are attached form a morpholinyl radical, wherein the morpholinyl radical may be further substituted by a deuterium atom, a fluorine atom, a methyl or methoxymethyl radical.
Still further, a is selected from C; b is selected from C; e is selected from C; d is selected from O or S; y is selected from O; f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is deuterium atom or methyl; r 1 Selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl group, dibenzothienyl group, wherein phenyl group may be further substituted by a fluorine atom, a chlorine atom, a trifluoromethoxy group, a methoxy group, a substituent formed by ring formation of adjacent 2 methoxy groups; wherein, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A]Pyridyl and dibenzothienyl can be further substituted by fluorine atom, chlorine atom, trifluoromethoxy and methoxy; r 2 And R 3 Taken together with the nitrogen atom to which they are attached to form a morpholinyl group, wherein the morpholinyl group may be further substituted with a fluorine atom, a methyl group, or a methoxymethyl group.
Further, A is selected from C; b is selected from C; e is selected from C; d is selected from O or S; y is selected from O; f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is methyl; r 1 Selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A]Pyridyl group, dibenzothienyl group, wherein phenyl group may be further substituted by a fluorine atom, a chlorine atom, trifluoromethoxy group, a substituent formed by ring formation of adjacent 2 methoxy groups; wherein naphthyl can be further substituted by trifluoromethoxy and methoxy, and quinolyl and isoquinolyl can be further substituted by fluorine atom and chlorine atom; r 2 And R 3 Together with the nitrogen atom to which they are attached form a morpholinyl radical, wherein the morpholinyl radical may be furtherSubstituted by fluorine atoms, methyl or methoxymethyl groups.
The invention also aims to provide application of the compound shown in the general formula (I) in preparing selective CB2 receptor agonist medicines, in particular application in preparing analgesic medicines, and more particularly application in preparing medicines suitable for moderate to severe pain. Through in vitro action tests on CB1 and CB2, the compound disclosed by the invention shows excellent CB2 selectivity and agonistic activity; through a pharmacodynamic test on the influence of the acetic acid writhing model of the mouse, the compound shows better analgesic effect; through research and test on pharmacokinetics of normal rats, the compound of the invention shows excellent pharmacokinetic characteristics.
Detailed Description
The present invention is further described in detail with reference to the following examples, which are not intended to limit the scope of the invention, and any equivalent substitutions in the field that are made in accordance with the present disclosure are included within the scope of the present invention.
The structure of the compound is determined by Mass Spectrometry (MS) or nuclear magnetic resonance ( 1 HNMR).
Nuclear magnetic resonance (A) 1 HNMR) displacement (δ) is given in units of parts per million (ppm); nuclear magnetic resonance (A) 1 HNMR) was performed by using Bruker AVANCE-400 NMR spectrometer, and the solvent was deuterated chloroform (CDCl) 3 ) Internal standard is Tetramethylsilane (TMS), and chemical shift is 10 -6 (ppm) is given as a unit.
Mass Spectrometry (MS) measurements were carried out using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: therm, model: finnigan LCQ advantage MAX).
The thin silica gel layer is prepared from HSGF254 or GF254 silica gel plate.
The column chromatography is carried out by using 200-300 mesh silica gel from Futai Huanghai silica gel as carrier.
In the case where no specific explanation is given to the present invention, all the reactions mentioned in the present invention are in N 2 Under protection or nitrogen atmosphere.
In the term of the present invention, "N 2 Protection "or" nitrogen atmosphere "means, for example, connecting a reaction flask to a 1L volume of nitrogen balloon.
In the case where the present invention is not specifically described, the solution mentioned in the reaction of the present invention is an aqueous solution.
The term "room temperature" in the present invention means a temperature between 10 ℃ and 25 ℃.
In one embodiment, the present invention relates to compounds of the 2H-benzo [ b ] [1,4] oxazin-3 (4H) -one derivative and 2H-benzo [ b ] [1,4] thiazin-3 (4H) -one derivative class having the following general formula (I):
Figure BDA0003678364140000101
or stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites thereof,
wherein: a is selected from C; b is selected from C; e is selected from C; d is selected from O or S; y is selected from O; f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is deuterium atom, methyl, fluorine atom, chlorine atom; r 1 Selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A]Pyridyl group, dibenzothienyl group, wherein phenyl group can be further substituted by deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy group, methoxy group, substituent formed by ring formation of adjacent 2 methoxy groups; wherein naphthyl, quinolyl, isoquinolyl, imidazo [1, 5-A)]Pyridyl group and dibenzothienyl group may be further substituted with deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy group or methoxy group; r is 2 And R 3 Together with the nitrogen atom to which they are attached form a morpholino ring group, a piperazino ring group, a piperidino group, wherein the resulting ring group may be further substituted with a deuterium atom, a fluorine atom, a chlorine atom, a methyl group or a methoxymethyl group.
In a preferred embodiment of the method of the present invention,
a is selected from C; b is selected from C; e is selected from C; d is selected from O or S; y is selected from O; f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl radicals substituted thereforThe radical is a deuterium atom, a methyl group or a fluorine atom; r is 1 Selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A]Pyridyl group, dibenzothienyl group, wherein the phenyl group may be further substituted by deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy group, methoxy group, or a substituent formed by ring formation of adjacent 2 methoxy groups; wherein naphthyl, quinolyl, isoquinolyl, imidazo [1, 5-A)]Pyridyl and dibenzothienyl can be further substituted by deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy and methoxy; r is 2 And R 3 Taken together with the nitrogen atom to which they are attached form a morpholinyl group wherein the morpholinyl group may be further substituted by a deuterium atom, a fluorine atom, a methyl group, a methoxymethyl group.
In a more preferred embodiment of the method of the invention,
R 1 selecting A from C; b is selected from C; e is selected from C; d is selected from O or S; y is selected from O; f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is deuterium atom or methyl; r 1 Selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl group, dibenzothienyl group, wherein phenyl group may be further substituted by a fluorine atom, a chlorine atom, a trifluoromethoxy group, a methoxy group, a substituent formed by ring formation of adjacent 2 methoxy groups; wherein, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A]Pyridyl and dibenzothienyl can be further substituted by fluorine atom, chlorine atom, trifluoromethoxy and methoxy; r 2 And R 3 Together with the nitrogen atom to which they are attached form a morpholinyl radical, wherein the morpholinyl radical may be further substituted by a fluorine atom, a methyl radical, a methoxymethyl radical.
In the most preferred embodiment of the present invention,
a is selected from C; b is selected from C; e is selected from C; d is selected from O or S; y is selected from O; f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is methyl; r is 1 Selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A]Pyridyl group, dibenzothienyl group, wherein the phenyl group may be further substituted by a fluorine atom, a chlorine atom, a trifluoromethoxy group, or adjacent 2 methoxy groupsThe naphthyl group can be further substituted by trifluoromethoxy and methoxy, and the quinolyl group and the isoquinolyl group can be further substituted by fluorine atom and chlorine atom; r 2 And R 3 Together with the nitrogen atom to which they are attached form a morpholinyl radical, wherein the morpholinyl radical may be further substituted by a fluorine atom, a methyl radical, a methoxymethyl radical.
Examples
EXAMPLE 1 preparation of Compound 1
Figure BDA0003678364140000111
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000112
the first step is as follows: preparation of 1c
6-bromo-2H-benzo [ b ] [1,4] oxazin-3 (4H) -one 1a (2.00g, 8.77mmol) was dissolved in N, N-dimethylformamide (30 ml), sodium hydride (1.05g, 26.31mmol) was added slowly in portions under an ice-water bath, and after stirring for 10 minutes under the ice-water bath, 4- (2-chloroethyl) morpholine hydrochloride 1b (1.96g, 10.52mmol) was added slowly to the reaction system. After the addition, the temperature is raised to 90 ℃ for reaction. After the reaction is completed, cooling the reaction solution to room temperature, slowly pouring the reaction solution into ice water to quench the reaction, extracting the reaction solution for 3 times by using ethyl acetate, combining organic phases, washing the organic phases by using water and saturated saline solution for 1 time respectively, drying the organic phases by using anhydrous sodium sulfate, performing suction filtration, and concentrating the filtrate to obtain a yellow oily substance. The yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1-2/1) to give compound 1c (2.20 g, off-white solid) in 73.5% yield.
MS m/z(ES):341.1[M+1]
The second step: preparation of Compound 1
Compound 1c (300mg, 0.88mmol), 1d (218mg, 1.06mmol) and CsF (267mg, 1.76mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 Adding Pd (dppf) Cl under protection 2 (65mg, 0.09mmol), after additionThe temperature is raised to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 1 (275 mg, off-white solid) with a purity of 99.25% and a yield of 74.1%.
MS m/z(ES):423.2[M+1]
1 HNMR(400MHz,CDCl3)δ7.43–7.35(m,4H),7.19(s,1H),7.10–7.05(m,2H),4.66(s, 2H),4.10(t,J＝7.1Hz,2H),3.69–3.67(m,4H),2.64(t,J＝7.1Hz,2H),2.54(m,4H).
EXAMPLE 2 preparation of Compound 2
Figure BDA0003678364140000121
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000122
the first step is the same as the first step of example 1;
the second step is that: preparation of Compound 2
Compound 1c (300mg, 0.88mmol), 2d (218mg, 1.06mmol) and CsF (267mg, 1.76mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 Adding Pd (dppf) Cl under protection 2 (65 mg,0.09 mmol), after the addition, the temperature was raised to 95 ℃ to react. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 2 (286 mg, off-white solid) with a purity of 99.25% and a yield of 77.0%.
MS m/z(ES):423.2[M+1]
1 HNMR(400MHz,CDCl3)δ7.48-7.46(m,2H),7.36(s,1H),7.22-7.20(m,3H),7.08(d, J＝8.3Hz,1H),4.65(s,2H),4.15(t,J＝6.8Hz,2H),3.70(m,4H),2.66(t,J＝6.8Hz,2H),2.57 (m,4H).
EXAMPLE 3 preparation of Compound 3
Figure BDA0003678364140000123
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000131
the first step is the same as the first step of example 1;
the second step: preparation of Compound 3
Compound 1c (300mg, 0.88mmol), 3d (202mg, 1.06mmol) and CsF (267mg, 1.76mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 Adding Pd (dppf) Cl under protection 2 (65 mg,0.09 mmol), after the addition, the temperature was raised to 95 ℃ to react. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 3 (273 mg, off-white solid) with a purity of 99.55% and a yield of 76.2%.
MS m/z(ES):407.1[M+1]
1 HNMR(400MHz,CDCl3)δ7.61(d,J＝1.8Hz,1H),7.51(d,J＝8.3Hz,1H),7.36(dd,J ＝8.3,1.8Hz,1H),7.25(d,J＝1.4Hz,1H),7.18(dd,J＝8.3,1.4Hz,1H),7.07(d,J＝8.3Hz, 1H),4.64(s,2H),4.14(t,J＝6.9Hz,2H),3.72-3.69(m,4H),2.65(t,J＝6.9Hz,2H),2.56(m, 4H).
EXAMPLE 4 preparation of Compound 4
Figure BDA0003678364140000132
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000133
the first step is the same as the first step of example 1;
the second step: preparation of Compound 4
Compound 1c (300mg, 0.88mmol), 4d (191mg, 1.06mmol) and CsF (267mg, 1.76mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 Adding Pd (dppf) Cl under protection 2 (65 mg,0.09 mmol), after the addition, the temperature was raised to 95 ℃ to react. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 4 (265 mg, off-white solid) with a purity of 99.33%, yield 76.0%.
MS m/z(ES):397.2[M+1]
1 HNMR(400MHz,CDCl3)δ7.22(s,1H),7.16(d,J＝8.2Hz,1H),7.05–7.01(m,3H), 6.94(d,J＝8.2Hz,1H),4.62(s,2H),4.31(m,4H),4.13(t,J＝6.5Hz,2H),3.71(m,4H),2.65(t, J＝6.5Hz,2H),2.56(m,4H).
EXAMPLE 5 preparation of Compound 5
Figure BDA0003678364140000141
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000142
the first step is the same as the first step of example 1;
the second step: preparation of Compound 5
Compound 1c (300mg, 0.88mmol), 5d (182mg, 1.06mmol) and CsF (267mg, 1.76mmol) are dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 Adding Pd (dppf) Cl under protection 2 (65 mg,0.09 mmol), after the addition, the temperature was raised to 95 ℃ to react. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 5 (269 mg, off-white solid) with a purity of 99.73% and a yield of 78.7%.
MS m/z(ES):389.2[M+1]
1 HNMR(400MHz,CDCl3)δ8.03(s,1H),7.94–7.86(m,3H),7.72-7.70(m,1H),7.54– 7.48(m,3H),7.37(d,J＝8.3Hz,1H),7.11(d,J＝8.3Hz,1H),4.66(s,2H),4.25(m,2H),3.76 (m,4H),2.76-2.66(m,6H).
EXAMPLE 6 preparation of Compound 6
Figure BDA0003678364140000143
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000144
the first step is the same as the first step of example 1;
the second step: preparation of Compound 6
Compound 1c (300mg, 0.88mmol), 6d (214mg, 1.06mmol) and CsF (267mg, 1.76mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 Adding Pd (dppf) Cl under protection 2 (65 mg,0.09 mmol), after the addition, the temperature was raised to 95 ℃ to react. After the reaction is finished, adding water and ethyl acetate into the reaction system, separating liquid, extracting the water phase for three times by using ethyl acetate, combining organic phases, washing by using water and saturated saline solution for 1 time respectively, drying by using anhydrous sodium sulfate, filteringThe solution was concentrated to give a brown crude which was purified on silica gel preparation plates (dichloromethane/methanol = 20/1) to give compound 6 (263 mg, white solid) in 99.82% purity and 71.4% yield.
MS m/z(ES):419.2[M+1]
1 HNMR(400MHz,CDCl3)δ8.22(d,J＝8.1Hz,1H),7.87(d,J＝8.1Hz,1H),7.71-7.69 (m,1H),7.58–7.50(m,4H),7.34(d,J＝8.3Hz,1H),7.11(d,J＝8.3Hz,1H),4.70(s,2H),4.26 (m,2H),3.80(m,4H),3.62(s,3H),2.84-2.76(m,6H).
EXAMPLE 7 preparation of Compound 7
Figure BDA0003678364140000151
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000152
first step the same as in example 1
The second step: preparation of Compound 7
Compound 1c (300mg, 0.88mmol), 7d (182mg, 1.06mmol) and CsF (267mg, 1.76mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 Adding Pd (dppf) Cl under protection 2 (65 mg,0.09 mmol), after the addition, the temperature was raised to 95 ℃ to react. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 7 (242 mg, white solid) with a purity of 99.56%, and a yield of 70.8%.
MS m/z(ES):389.2[M+1]
1 HNMR(400MHz,CDCl3)δ7.94-7.87(m,3H),7.56–7.42(m,4H),7.22(s,1H),7.17- 7.11(m,2H),4.70(s,2H),4.17(m,2H),3.69(m,4H),2.72-2.58(m,6H).
EXAMPLE 8 preparation of Compound 8
Figure BDA0003678364140000153
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000161
the first step is the same as the first step of example 1;
the second step is that: preparation of Compound 8
Compound 1c (300mg, 0.88mmol), 8d (183mg, 1.06mmol) and CsF (267mg, 1.76mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), and N was 2 Adding Pd (dppf) Cl under protection 2 (65 mg,0.09 mmol), after the addition, the temperature was raised to 95 ℃ to react. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 8 (245 mg, yellow solid) with a purity of 99.31% and a yield of 71.5%.
MS m/z(ES):390.2[M+1]
1 H NMR(400MHz,CDCl3)δ8.24(d,J＝8.6Hz,1H),8.14-8.11(m,2H),7.90–7.83(m, 2H),7.76-7.72(m,2H),7.54(t,J＝7.3Hz,1H),7.13(d,J＝8.3Hz,1H),4.68(s,2H),4.29(m, 2H),3.77(m,4H),2.78-2.68(m,6H).
EXAMPLE 9 preparation of Compound 9
Figure BDA0003678364140000162
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000163
the first step is the same as the first step of example 1;
the second step: preparation of Compound 9
Compound 1c (300mg, 0.88mmol), 9d (183mg, 1.06mmol) and CsF (267mg, 1.76mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), and N was 2 Adding Pd (dppf) Cl under protection 2 (65 mg,0.09 mmol), after the addition, the temperature was raised to 95 ℃ to react. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 9 (251 mg, yellow solid) with a purity of 97.74% and a yield of 73.2%.
MS m/z(ES):390.2[M+1]
1 HNMR(400MHz,CDCl3)δ9.29(s,1H),8.57(d,J＝5.7Hz,1H),8.07(d,J＝8.4Hz, 1H),7.95(s,1H),7.81(d,J＝8.4Hz,1H),7.70(d,J＝5.7Hz,1H),7.42(s,1H),7.37(d,J＝8.3 Hz,1H),7.13(d,J＝8.3Hz,1H),4.68(s,2H),4.19(t,J＝6.9Hz,2H),3.71–3.69(m,4H),2.69 (t,J＝6.9Hz,2H),2.58(m,4H).
EXAMPLE 10 preparation of Compound 10
Figure BDA0003678364140000171
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000172
the first step is the same as the first step of example 1;
the second step is that: preparation of Compound 10
Compound 1c (300mg, 0.88mmol), 10d (183mg, 1.06mmol) and CsF (267mg, 1.76 mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), and N was 2 Adding Pd under protection(dppf)Cl 2 (65mg, 0.09mmol) and then heated to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 10 (238 mg, off-white solid) with a purity of 97.79% and a yield of 69.4%.
MS m/z(ES):390.2[M+1]
1 H NMR(400MHz,CDCl3)δ9.33(s,1H),8.51(d,J＝5.8Hz,1H),8.02(d,J＝7.7Hz, 1H),7.71–7.64(m,3H),7.18-7.11(m,3H),4.70(s,2H),4.10(t,J＝6.9Hz,2H),3.60(m,4H), 2.62(t,J＝6.9Hz,2H),2.50(m,4H).
EXAMPLE 11 preparation of Compound 11
Figure BDA0003678364140000173
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000174
the first step is the same as the first step of example 1;
the second step is that: preparation of Compound 11
Compound 1c (300mg, 0.88mmol), 11d (183mg, 1.06mmol) and CsF (267mg, 1.76 mmol) are dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 Adding Pd (dppf) Cl under protection 2 (65mg, 0.09mmol), and after the addition, the temperature is raised to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 11 (251 mg, off-white solid) with a purity of 99.01%, yield 73.2%.
MS m/z(ES):390.2[M+1]
1 HNMR(400MHz,CDCl3)δ9.32(s,1H),8.55(d,J＝5.6Hz,1H),8.09(s,1H),7.94- 7.88(m,2H),7.70(d,J＝5.6Hz,1H),7.41(s,1H),7.35(d,J＝8.2Hz,1H),7.13(d,J＝8.2Hz, 1H),4.67(s,2H),4.19(t,J＝6.9Hz,2H),3.71–3.69(m,4H),2.69(t,J＝6.9Hz,2H),2.57(m, 4H).
EXAMPLE 12 preparation of Compound 12
Figure BDA0003678364140000181
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000182
the first step is the same as the first step of example 1;
the second step: preparation of Compound 12
Compound 1c (300mg, 0.88mmol), 12d (183mg, 1.06mmol) and CsF (267mg, 1.76 mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), and N was 2 Adding Pd (dppf) Cl under protection 2 (65mg, 0.09mmol) and then heated to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 12 (224 mg, brown solid) with a purity of 97.57% and a yield of 65.3%.
MS m/z(ES):390.2[M+1]
1 HNMR(400MHz,CDCl3)δ9.31(s,1H),8.04–7.99(m,3H),7.88(d,J＝8.3Hz,1H), 7.73–7.71(m,2H),7.62-7.59(m,1H),7.11(d,J＝8.3Hz,1H),4.67(s,2H),4.24(t,J＝6.9 Hz,2H),3.74–3.72(m,4H),2.72(t,J＝6.9Hz,2H),2.65-2.57(m,4H).
EXAMPLE 13 preparation of Compound 13
Figure BDA0003678364140000183
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000191
the first step is the same as the first step of example 1;
the second step: preparation of Compound 13
Dissolving compound 1c (300mg, 0.88mmol), 13d (183mg, 1.06mmol) and CsF (267mg, 1.76 mmol) in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), adding Pd (dppf) Cl under N2 protection 2 (65mg, 0.09mmol) and then heated to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 13 (232 mg, yellow solid) with a purity of 99.34% and a yield of 67.8%.
MS m/z(ES):390.2[M+1]
1 H NMR(400MHz,CDCl3)δ9.14(d,J＝2.0Hz,1H),8.26(s,1H),8.15(d,J＝8.5Hz, 1H),7.89(d,J＝8.5Hz,1H),7.75(t,J＝7.6Hz,1H),7.61(t,J＝7.6Hz,1H),7.41(s,1H),7.36 (d,J＝8.3Hz,1H),7.15(d,J＝8.3Hz,1H),4.68(s,2H),4.19(t,J＝7.0Hz,2H),3.71–3.69(m, 4H),2.68(t,J＝7.0Hz,2H),2.57(m,4H).
EXAMPLE 14 preparation of Compound 14
Figure BDA0003678364140000192
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000193
the first step is the same as the first step of example 1;
the second step: preparation of Compound 14
Dissolving compound 1c (300mg, 0.88mmol), 14d (202mg, 1.06mmol) and CsF (267mg, 1.76 mmol) in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), adding Pd (dppf) Cl under protection of N2 2 (65mg, 0.09mmol), and after the addition, the temperature is raised to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 14 (238 mg, pale yellow solid) with a purity of 97.11%, yield 66.4%.
MS m/z(ES):408.2[M+1]
1 HNMR(400MHz,CDCl3)δ9.54(s,1H),8.64(d,J＝5.8Hz,1H),7.74–7.69(m,2H), 7.47–7.33(m,3H),7.13(d,J＝8.3Hz,1H),4.68(s,2H),4.18(t,J＝6.9Hz,2H),3.72–3.69 (m,4H),2.68(t,J＝6.9Hz,2H),2.57(m,4H).
EXAMPLE 15 preparation of Compound 15
Figure BDA0003678364140000201
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000202
the first step is the same as the first step of example 1;
the second step: preparation of Compound 15
Dissolving compound 1c (300mg, 0.88mmol), 15d (202mg, 1.06mmol) and CsF (267mg, 1.76mmol) in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), adding Pd (dppf) Cl under protection of N2 2 (65mg， 0.09mmol)After the addition, the temperature is raised to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 15 (232 mg, yellow solid) with a purity of 98.12%, and a yield of 64.7%.
MS m/z(ES):408.2[M+1]
1 HNMR(400MHz,CDCl3)δ8.22(d,J＝8.6Hz,1H),8.10(d,J＝1.6Hz,1H),7.85–7.81 (m,2H),7.73–7.70(m,2H),7.35-7.30(m,1H),7.12(d,J＝8.3Hz,1H),4.68(s,2H),4.24(t, J＝7.0Hz,2H),3.73–3.71(m,4H),2.73(t,J＝7.0Hz,2H),2.62(m,4H).
EXAMPLE 16 preparation of Compound 16
Figure BDA0003678364140000203
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000204
the first step is the same as the first step of example 1;
the second step is that: preparation of Compound 16
Dissolving compound 1c (300mg, 0.88mmol), 16d (172mg, 1.06mmol) and CsF (267mg, 1.76 mmol) in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), adding Pd (dppf) Cl under protection of N2 2 (65mg, 0.09mmol), and after the addition, the temperature is raised to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 16 (252 mg, yellow-green solid) with a purity of 96.68% and a yield of 75.7%.
MS m/z(ES):408.2[M+1]
1 HNMR(400MHz,CDCl3)δ8.18(s,1H),8.06(s,1H),7.54(d,J＝9.3Hz,1H),7.47(s, 1H),7.24(m,1H),7.20-7.18(m,1H),7.09(d,J＝8.3Hz,1H),6.93(d,J＝9.3Hz,1H),4.65(s, 2H),4.15(t,J＝7.0Hz,2H),3.71-3.69(m,4H),2.65(t,J＝7.0Hz,2H),2.57–2.55(m,4H).
EXAMPLE 17 preparation of Compound 17
Figure BDA0003678364140000211
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000212
the first step is the same as the first step of example 1;
the second step is that: preparation of Compound 17
Compound 1c (300mg, 0.88mmol), 17d (242mg, 1.06mmol) and CsF (267mg, 1.76mmol) are dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 Adding Pd (dppf) Cl under protection 2 (65 mg,0.09 mmol), after the addition, the temperature was raised to 95 ℃ to react. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 17 (299 mg, yellow solid) with a purity of 98.54% and a yield of 76.5%.
MS m/z(ES):445.2[M+1]
1 H NMR(400MHz,CDCl 3 )δ8.22–8.16(m,2H),7.84–7.80(m,1H),7.57(t,J＝7.6Hz, 1H),7.52–7.44(m,4H),7.35-7.33(m,1H),7.14(d,J＝8.2Hz,1H),4.69(s,2H),4.14(t,J＝ 7.1Hz,2H),3.64–3.62(m,4H),2.71(t,J＝7.1Hz,2H),2.56–2.54(m,4H).
EXAMPLE 18 preparation of Compound 18
Figure BDA0003678364140000213
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000221
the first step is as follows: preparation of 18c
6-bromo-2H-benzo [ b ] [1,4] oxazin-3 (4H) -one 1a (2.00g, 8.77mmol) was dissolved in N, N-dimethylformamide (30 ml), sodium hydride (1.05g, 26.31mmol) was added slowly in portions under an ice-water bath, and after stirring for 10 minutes under the ice-water bath, 4- (2-chloroethyl) -3-methylmorpholine hydrochloride 18b (2.11 g,10.52 mmol) was added slowly to the reaction system. After the addition, the temperature is raised to 90 ℃ for reaction. After the reaction is completed, cooling the reaction solution to room temperature, slowly pouring the reaction solution into ice water to quench the reaction, extracting the reaction solution for 3 times by using ethyl acetate, combining organic phases, washing the organic phases by using water and saturated saline solution for 1 time respectively, drying the organic phases by using anhydrous sodium sulfate, performing suction filtration, and concentrating the filtrate to obtain a yellow oily substance. The yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1-2/1) to give compound 18c (2.17 g, off-white solid) in 69.5% yield.
MS m/z(ES):355.1[M+1]
The second step is that: preparation of Compound 18
Compound 18c (313mg, 0.88mmol), 2d (218mg, 1.06mmol) and CsF (267mg, 1.76 mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 Adding Pd (dppf) Cl under protection 2 (65mg, 0.09mmol), and after the addition, the temperature is raised to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 18 (279 mg, off-white solid) with a purity of 96.39%, and a yield of 72.6%.
MS m/z(ES):437.2[M+1]
1 HNMR(400MHz,CDCl3)δ8.10-8.07(m,1H),7.47-7.46(m,2H),7.36(s,1H),7.21(d, J＝8.3Hz,2H),7.07(d,J＝8.3Hz,1H),4.69–4.60(m,2H),4.19-4.02(m,2H),3.78-3.76(m, 1H),3.66–3.56(m,2H),3.20–3.15(m,1H),3.07–3.00(m,1H),2.89-2.86(m,1H),2.53- 2.49(m,3H),0.93(d,J＝6.2Hz,3H).
EXAMPLE 19 preparation of Compound 19
Figure BDA0003678364140000222
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000223
the first step is the same as that of example 18;
the second step: preparation of Compound 19
Compound 18c (313mg, 0.88mmol), 13d (183mg, 1.06mmol) and CsF (267mg, 1.76 mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), and N was 2 Adding Pd (dppf) Cl under protection 2 (65mg, 0.09mmol), and after the addition, the temperature is raised to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 19 (254 mg, yellow solid) with a purity of 96.50% and a yield of 71.5%.
MS m/z(ES):404.2[M+1]
1 HNMR(400MHz,CDCl3)δ9.14(d,J＝2.0Hz,1H),8.26(s,1H),8.15(d,J＝8.4Hz, 1H),7.88(d,J＝8.0Hz,1H),7.75(t,J＝7.6Hz,1H),7.61(t,J＝7.6Hz,1H),7.43(s,1H),7.36 (d,J＝8.3Hz,1H),7.15(d,J＝8.3Hz,1H),4.71-4.63(m,2H),4.20–4.09(m,2H),3.78(d,J ＝11.2Hz,1H),3.66-3.57(m,2H),3.22-3.17(m,1H),3.10–3.03(m,1H),2.90(d,J＝11.2 Hz,1H),2.54–2.50(m,3H),0.95(d,J＝6.2Hz,3H)
EXAMPLE 20 preparation of Compound 20
Figure BDA0003678364140000231
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000232
the first step is the same as that of example 18;
the second step: preparation of Compound 20
Compound 18c (313mg, 0.88mmol), 11d (183mg, 1.06mmol) and CsF (267mg, 1.76 mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), and N was 2 Adding Pd (dppf) Cl under protection 2 (65mg, 0.09mmol) and then heated to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 20 (265 mg, pale yellow solid) with a purity of 91.21% and a yield of 74.5%.
MS m/z(ES):404.2[M+1]
1 HNMR(400MHz,CDCl3)δ9.30(s,1H),8.55(d,J＝5.7Hz,1H),8.09(s,1H),7.94- 7.89(m,2H),7.69(d,J＝5.7Hz,1H),7.44(s,1H),7.36(d,J＝8.3Hz,1H),7.13(d,J＝8.3Hz, 1H),4.71–4.63(m,2H),4.23–4.07(m,2H),3.77(d,J＝11.2Hz,1H),3.67–3.56(m,2H), 3.21–3.16(m,1H),3.11–3.04(m,1H),2.90(d,J＝11.2Hz,1H),2.56-2.49(m,3H),0.95(d, J＝6.2Hz,3H).
EXAMPLE 21 preparation of Compound 21
Figure BDA0003678364140000241
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000242
the first step is as follows: preparation of 21c
6-bromo-2H-benzo [ b ] [1,4] oxazin-3 (4H) -one 1a (2.00g, 8.77mmol) was dissolved in N, N-dimethylformamide (30 ml), sodium hydride (1.05g, 26.31mmol) was added slowly in portions under an ice-water bath, and after stirring for 10 minutes under an ice-water bath, 4- (2-chloroethyl) -3-methoxymethylmorpholine hydrochloride 21b (2.42 g,10.52 mmol) was added slowly to the reaction system. After the addition, the temperature is raised to 90 ℃ for reaction. After the reaction is completed, the reaction solution is cooled to room temperature and then slowly poured into ice water to quench the reaction, ethyl acetate is used for extraction for 3 times, organic phases are combined and then washed by water and saturated saline solution for 1 time respectively, anhydrous sodium sulfate is used for drying, suction filtration is carried out, and filtrate is concentrated to obtain yellow oily matter. The yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1-2/1) to give compound 21c (2.29 g, off-white solid) in 67.8% yield.
MS m/z(ES):385.1[M+1]
The second step is that: preparation of Compound 21
Compound 21c (339mg, 0.88mmol), 11d (183mg, 1.06mmol) and CsF (267mg, 1.76 mmol) are dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), N 2 Adding Pd (dppf) Cl under protection 2 (65mg, 0.09mmol) and then heated to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 21 (273 mg, pale yellow solid) with a purity of 92.01%, and a yield of 71.5%.
MS m/z(ES):434.2[M+1]
1 HNMR(400MHz,CDCl3)δ9.31(s,1H),8.55(d,J＝5.7Hz,1H),8.12(s,1H),7.92(s, 2H),7.69(d,J＝5.7Hz,1H),7.47(s,1H),7.37-7.34(m,1H),7.13(d,J＝8.3Hz,1H),4.71– 4.63(m,2H),4.28-4.21(m,1H),4.14–4.08(m,1H),3.75-3.69(m,2H),3.60–3.55(m,1H), 3.44–3.28(m,3H),3.20–3.10(m,4H),2.92-2.89(m,1H),2.70–2.52(m,3H).
EXAMPLE 22 preparation of Compound 22
Figure BDA0003678364140000243
The preparation scheme is shown in the following scheme:
Figure BDA0003678364140000251
the first step is as follows: preparation of 22c
5-bromo-2-fluoronitrobenzene 22a (2.00g, 9.08mmol) was dissolved in N, N-dimethylformamide (10 mL), followed by addition of potassium carbonate (3.13g, 22.68mmol) and thioglycolic acid 22b (1.00g, 10.86 mmol) to the reaction in this order, and stirring was carried out at room temperature overnight. After the reaction was complete, water was added to dissolve the reaction system, ethyl acetate was used for 3 times, the pH of the aqueous phase was adjusted to 6 with dilute hydrochloric acid (2M), a large amount of solid was aspirated, suction filtration was performed, and the filter cake was dried to obtain compound 22c (2.60 g, yellow solid) with a yield of 98.1%.
MS m/z(ES):291.9[M+1]
The second step: preparation of 22d
Compound 22c (2.60g, 8.90mmol) was dissolved in aqueous ammonia (25 mL) and a solution of iron sulfate heptahydrate (24.75g, 89.04mmol) in water (40 mL) was slowly added dropwise with stirring at room temperature. After the reaction, suction filtration was performed, the filtrate was extracted with ethyl acetate three times, the organic phases were combined, washed with water and saturated brine 1 time each, dried over anhydrous sodium sulfate, suction filtration was performed, and the filtrate was concentrated to obtain compound 22d (1.78 g, yellow solid) with a yield of 81.9%.
MS m/z(ES):243.9[M+1]
The third step: preparation of 22f
Compound 22d (1.00g, 4.10mmol) was dissolved in N, N-dimethylformamide (15 mL), and sodium hydride (0.49g, 12.30mmol) was slowly added in portions under an ice-water bath, and after stirring for 10 minutes under the ice-water bath, 4- (2-chloroethyl) morpholine hydrochloride 22e (1.13 g, 6.07 mmol) was further slowly added to the reaction system. After the addition, the temperature is raised to 90 ℃ for reaction. After the reaction is completed, cooling the reaction solution to room temperature, slowly pouring the reaction solution into ice water to quench the reaction, extracting the reaction solution by ethyl acetate for 3 times, combining organic phases, washing the organic phases by water and saturated saline solution for 1 time respectively, drying the organic phases by anhydrous sodium sulfate, filtering the mixture by suction, and concentrating the filtrate to obtain yellow oily matters. The yellow oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1-3/1) to give compound 22f (1.05 g, yellow solid) in 72.1% yield.
MS m/z(ES):357.0[M+1]
The fourth step: preparation of Compound 22
Compound 22f (300mg, 0.84mmol), 13d (183mg, 1.06mmol) and CsF (267mg, 1.76 mmol) were dissolved in a mixed solution of 1, 4-dioxane (5 mL) and water (0.5 mL), and Pd (dppf) Cl was added under N2 protection 2 (61.4mg, 0.08mmol), and then heated to 95 ℃ for reaction. After the reaction was completed, water and ethyl acetate were added to the reaction system, liquid separation was performed, the aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, washed with water and saturated brine each for 1 time, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to obtain a brown crude product, which was purified by a silica gel preparation plate (dichloromethane/methanol = 20/1) to obtain compound 22 (211 mg, yellow solid) with a purity of 95.03%, yield 62.1%.
MS m/z(ES):406.2[M+1]
1 HNMR(400MHz,CDCl3)δ9.15(d,J＝2.0Hz,1H),8.30(s,1H),8.16(d,J＝8.5Hz,1H), 7.90(d,J＝8.1Hz,1H),7.77(t,J＝7.6Hz,1H),7.64–7.60(m,2H),7.53(d,J＝8.0Hz,1H), 7.38(d,J＝8.0Hz,1H),4.22(t,J＝6.7Hz,2H),3.66–3.64(m,4H),3.46(s,2H),2.68(t,J＝ 6.7Hz,2H),2.53(m,4H).
Evaluation of pharmacological toxicology test
The test drugs are:
the compound of example 1: example 1 preparation, provided by the synthetic research laboratory of bonded bio-pharmaceutical corporation, dongdong, white-like solid, purity: 99.25 percent;
the compound of example 2: example 2 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, off-white solid, purity: 99.25 percent;
the compound of example 3: example 3 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, off-white solid, purity: 99.55 percent;
the compound of example 4: example 4 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, off-white solid, purity: 99.33 percent;
the compound of example 5: example 5 preparation, provided by the synthetic research laboratory of bonded bio-pharmaceutical corporation, dongdong, white-like solid, purity: 99.73 percent;
the compound of example 6: example 6 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, white solid, purity: 99.82 percent;
the compound of example 7: example 7 preparation, provided by the synthetic research laboratory of bonded bio-pharmaceutical corporation, dongdong, white solid, purity: 99.56 percent;
the compound of example 8: example 8 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, yellow solid, purity: 99.31 percent;
the compound of example 9: example 9 preparation, provided by the synthetic research laboratory of bonded bio-pharmaceutical corporation, dongdong, inc, yellow solid, purity: 97.74 percent;
the compound of example 10: example 10 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, off-white solid, purity: 97.79 percent;
the compound of example 11: example 11 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, off-white solid, purity: 99.01 percent;
the compound of example 12: example 12 preparation, provided by the synthetic research laboratory of bonded bio-pharmaceutical corporation, dongdong, tan solid, purity: 97.57 percent;
the compound of example 13: example 13 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, yellow solid, purity: 99.34 percent;
the compound of example 14: example 14 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, light yellow solid, purity: 97.11 percent;
the compound of example 15: example 15 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, yellow solid, purity: 98.12 percent;
the compound of example 16: example 16 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, yellow-green solid, purity: 96.68 percent;
the compound of example 17: example 17 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, yellow solid, purity: 98.54 percent;
the compound of example 18: example 18 preparation, provided by the synthetic research laboratory of bonded bio-pharmaceutical corporation, dongdong, white-like solid, purity: 96.39 percent;
the compound of example 19: example 19 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, yellow solid, purity: 96.50 percent;
the compound of example 20: example 20 preparation, provided by the synthetic research laboratory of bonded bio-pharmaceutical corporation, dongdong, inc, as a pale yellow solid, purity: 91.21 percent;
the compound of example 21: example 21 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, light yellow solid, purity: 92.01 percent;
the compound of example 22: example 22 preparation, provided by the synthetic research laboratory of medeton biopharmaceutical corporation, yellow solid, purity: 95.03 percent.
EXPERIMENTAL EXAMPLE 1 in vitro assay of the Effect of the Compounds of the examples of formula (I) on the Activity of different receptors
1. The purpose of the test is as follows: the agonistic activity of CB1 and CB2 of compound samples of each embodiment is detected by using Flp-In-CHO-CB1 and Flp-In-CHO-CB2 cell strains and applying an established cAMP assay platform.
2, test method:
2.1 cell culture and reagent preparation
a. Cell lines: flp-In-CHO-CB1 (for detection of CB1 agonistic activity), flp-In-CHO-CB2 (for detection of CB2 agonistic activity)
b. Complete medium Ham's F12K +10% fetal bovine serum + 1. Mu.g/ml penicillin streptomycin + 800. Mu.g/ml hygromycin
c. Experimental buffer 1 × HBSS +20mM HEPES +0.1% BSA +500 μ M IBMX
2.2 assay of CB1 receptor Activity of test Compounds
2.2.1 cell culture and plating
a. Culturing Flp-In-CHO-CB1 cell line at 37 ℃ C. To 5% CO 2 In complete medium under ambient conditions;
after tryple digestion, cells were resuspended in complete medium, seeded into 384 cell culture plates at 8000 density per well.
c. Cells at 37 ℃ C. 5% CO 2 The culture was overnight (CB 2 activity assay omitted).
2.2.2 detection of agonistic Activity
a. Experimental buffer:1 × HBSS,0.1% BSA, 2mM HEPES and 500. Mu.M IBMX were prepared.
b. Compounds were diluted with buffer at an initial concentration of 80 μ M, 3-fold concentration gradient for a total of 10 concentrations.
c. The medium was removed from 384 plates and 15. Mu.l of buffer was added to each well (CB 2 activity assay omitted).
d. Mu.l of the compound was added to each well and incubated at 37 ℃ for 10 minutes.
e. Forskolin was diluted to 8 μ M (8 ×) with assay buffer (CB 2 activity assay diluted to 16 μ M).
f. 2.5 μ l of diluted 8 × forskolin was added and incubated at 37 ℃ for 30 min.
g. Eu-cAMP tracer and Ulight-anti-cAMP were thawed and diluted with cAMP detection buffer.
h. Add 10. Mu.l Eu-cAMP tracer to the experimental wells, then add 10. Mu.l Ulight-anti-cAMP to the experimental wells.
i. The reaction plate was centrifuged at 200g for 30s at room temperature and allowed to stand at 25 ℃ for 1 hour, and data were collected by Envision
2.3 data analysis
a.Z’factor＝1-3*(SDMax+SDMin)/(MeanMax-MeanMin)；
b.CVMax＝(SDMax/MeanMax)*100％；
c.CVMin＝(SDMin/MeanMin)*100％；
d.S/B＝Singal/Background；
e. Calculation of Compound EC Using GraphPad non-Linear fitting equation 50 :
Y＝Bottom+(Top-Bottom)/(1+10^((LogEC50-X)*HillSlope))
X is the log value of the concentration of the compound; y is Activation%
3. Test results
TABLE 1 Effect of the Compounds of the examples on the agonistic Activity of CB1, CB2
Figure BDA0003678364140000271
Figure BDA0003678364140000281
4. Conclusion
In the experimental examples of the invention, the agonistic action of each compound on CB1 is obviously weaker than that of each compound on CB2, and the compound has better selectivity.
Experimental example 2 test of analgesic Effect of Compounds of examples of the formula (I) on acetate writhing in mice
1. The purpose of the test is as follows: the analgesic effect of the compound samples of the examples on the acetate writhing of the mice is measured by using a test method of the acetate writhing of the mice.
2. The test method comprises the following steps:
(1) Dosage and route of administration:
the preparation is administered by intraperitoneal injection at a dose of 1mg/kg, with an administration volume of 10mL/kg and an administration concentration of 0.1mg/mL.
(2) The operation method comprises the following steps:
the test was carried out in a quiet environment at room temperature of 23-25 ℃. Mice (KM mice, SPF grade, weight 18-22 g, purchased from Woodson Biotech Co., ltd.) were numbered (10 per group) before administration and placed in correspondingly numbered cages for 15min. After the adaptation is completed, the mice are administrated by intraperitoneal injection, the administration dose is 1mg/kg, the administration volume is 10mL/kg, and the negative control group is administrated with the same volume of the solvent (DMSO) with the same concentration. 10min after administration, the mice were injected with 0.8% acetic acid solution 10ml/kg intraperitoneally, immediately placed in a mouse cage, and the writhing frequency of the mice within 15min was observed. The indexes of the twisted body are as follows: one writhing is considered to occur when the mouse develops the typical abdominal concavity accompanied by characteristic responses such as trunk twist, hip elevation, and hind limb elongation.
(3) Detection indexes and statistical methods:
the detection index is the writhing frequency within 15min after the mice are given 1mg/kg of the medicine and the acetic acid solution. The analgesic rate (%) after administration was calculated by the following formula: analgesic rate (%) = (number of writhing in negative control group-number of writhing in administration group)/number of writhing in negative control group × 100%
3. Test results
TABLE 2 analgesic Rate (%) after administration of each Compound
Figure BDA0003678364140000282
Figure BDA0003678364140000291
In the experimental example, each compound has a good inhibitory effect on acetic acid writhing of mice, and shows that each compound has a good analgesic effect. Among them, examples 5, 7, 10 and 13 showed a good analgesic effect with an inhibitory effect of 90% or more.
EXPERIMENTAL EXAMPLE 3 pharmacokinetic testing of the Compounds of each example of formula (I) after a single intravenous injection
1. The purpose of the test is as follows: pharmacokinetic parameters were examined for each compound of the experimental examples after a single intravenous administration.
2. Test method
(1) Test animals and drug administration
SD rats, SPF grade, all male, weighing 180-220g, were provided by Woodson Biotech Inc. Approximately 5mg of each compound was weighed, dissolved in 100. Mu.L of MSO, and then added to physiological saline to prepare a 0.25mg/mL solution. The administration mode is tail vein injection administration, the administration volume is 4mL/kg, the administration concentration is 0.25mg/mL, and the administration dosage is 1mg/kg.
(2) Designing a blood sampling point:
before administration, 5min, 15min, 30min, 45min, 1h, 1.5h, 2h, 4h, 6h, 8h, 24h after administration, blood was taken from jugular vein, 200. Mu.L of whole blood was taken at each time point, and placed in a container containing EDTA-K 2 The plasma is separated after 2000 g of the plasma is centrifuged at the low temperature of 4 ℃, transferred to a microcentrifuge tube and stored in a refrigerator at the temperature of 80 ℃ below zero for standby.
(3) Sample detection
By establishing a reliable LC/MS/MS analysis method, the blood concentration of each sample is detected, and the pharmacokinetic parameters of each compound are calculated.
3. Test results
Table 3 single tail vein administration of major pharmacokinetic parameters (n = 3)
Figure BDA0003678364140000292
Figure BDA0003678364140000301
T for examples 1, 2, 3, 5, 6, 7, 11, 14, and 17 1/2 Longer, indicates that the analgesic effect of each compound of the present example lasts longer; meanwhile, examples 1, 2, 7, 11, 12, 13, and 15C 5min Higher, indicates the implementationIn the examples, the compounds have better analgesic effect and lower effective dose.
It will be apparent to those skilled in the art from the foregoing that the compounds of the present embodiments exhibit analgesic effects and that various modifications and variations can be made in the compounds, compositions and methods of the present invention without departing from the spirit or scope of the invention, and therefore, the invention includes modifications and variations to the invention provided they come within the scope of the appended claims and their equivalents.

Claims (12)

1. A compound represented by the general formula (I):
Figure FDA0003678364130000011
or stereoisomers, geometric isomers, tautomers, hydrates, solvates, metabolites thereof,
wherein:
a is selected from N or C;
b is selected from N or C;
e is selected from N or C;
d is selected from O or S;
y is selected from O or S;
f is selected from substituted or unsubstituted C 2-6 Alkyl, substituted or unsubstituted C 3-6 A cycloalkyl group;
R 1 selected from substituted or unsubstituted C 5-12 An aryl group;
R 2 and R 3 Independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 5-10 Aryl, substituted or unsubstituted C 5-10 Heterocyclyl group, or R 2 And R 3 Taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-to 15-membered heterocyclyl group.
2. A compound of formula (I) according to claim 1, wherein:
Figure FDA0003678364130000012
a is selected from N or C;
b is selected from N or C;
e is selected from N or C;
d is selected from O or S;
y is selected from O or S;
f is selected from substituted or unsubstituted C 2-6 Alkyl, substituted or unsubstituted C 3-6 A cycloalkyl group;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A]Pyridyl, dibenzothienyl, oxadiazolyl, isoxazolyl, indolyl, isoindolyl, cinnolinyl, quinazolinyl, indolyl, benzothienyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, thiazolyl;
R 2 and R 3 Independently selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 3-6 Cycloalkyl, or R 2 And R 3 Taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted 3-to 15-membered heterocyclyl group.
3. A compound of formula (I) according to claim 1 or 2, wherein:
Figure FDA0003678364130000021
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted C 2-3 Alkyl, substituted or unsubstituted C 3-4 Cycloalkyl in which the substituents are deuterium atoms, C 1-3 Alkyl radical, C 1-3 An alkoxymethyl group, a fluorine atom or a chlorine atom;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl, dibenzothienyl, wherein said radicals may be further substituted by deuterium, fluorine, chlorine, trifluoromethoxy, C 1-3 Alkoxy or adjacent 2C 1-3 The alkoxy forms a ring and is substituted by a substituent;
R 2 and R 3 Independently selected from methyl, ethyl or R 2 And R 3 Together with the nitrogen atom to which they are attached form a morpholinyl, piperazinyl, piperidinyl, azepanyl group, wherein the cyclic group formed may be further substituted by a deuterium atom, a fluorine atom, a chlorine atom, C 1-3 Alkyl radical, C 1-3 An alkoxymethyl group.
4. A compound of formula (I) according to claims 1-3, wherein:
Figure FDA0003678364130000022
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl with deuterium atom as substituent, C 1-3 Alkyl, fluorine atom, chlorine atom;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl, dibenzothienyl, wherein said group may be further substituted with deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy, methoxy, or a substituent formed by ring-formation of adjacent 2 methoxy groups;
R 2 and R 3 Together with the nitrogen atom to which they are attached to form morpholinyl, piperazinyl, piperidinylWherein the cyclic group formed may be further substituted with a deuterium atom, a fluorine atom, a chlorine atom, a methyl group or a methoxymethyl group.
5. The compound of formula (I) according to claims 1-4, wherein:
Figure FDA0003678364130000031
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl having a substituent of deuterium atom, methyl group, fluorine atom or chlorine atom;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl, dibenzothienyl, wherein the phenyl group may be further substituted by deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy, methoxy, or a substituent formed by ring formation of adjacent 2 methoxy groups; wherein naphthyl, quinolyl, isoquinolyl, imidazo [1, 5-A)]The pyridyl group and the dibenzothienyl group may be further substituted with a deuterium atom, a fluorine atom, a chlorine atom, a trifluoromethoxy group or a methoxy group;
R 2 and R 3 Together with the nitrogen atom to which they are attached form a morpholino ring group, a piperazino ring group, a piperidino group, wherein the resulting ring group may be further substituted with a deuterium atom, a fluorine atom, a chlorine atom, a methyl group or a methoxymethyl group.
6. The compound of formula (I) according to claims 1-5, wherein:
Figure FDA0003678364130000032
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is a deuterium atom, methyl group or fluorine atom;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A]Pyridyl group, dibenzothienyl group, wherein the phenyl group may be further substituted by deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy group, methoxy group, or a substituent formed by ring formation of adjacent 2 methoxy groups; wherein naphthyl, quinolyl, isoquinolyl, imidazo [1, 5-A)]The pyridyl group and the dibenzothienyl group may be further substituted with a deuterium atom, a fluorine atom, a chlorine atom, a trifluoromethoxy group or a methoxy group;
R 2 and R 3 Taken together with the nitrogen atom to which they are attached form a morpholinyl group wherein the morpholinyl group may be further substituted by a deuterium atom, a fluorine atom, a methyl group or a methoxymethyl group.
7. The compound of formula (I) according to claims 1-6, wherein:
Figure FDA0003678364130000041
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is deuterium atom or methyl; r 1 Selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl and dibenzothienyl, wherein the phenyl can be further substituted by fluorine atom, chlorine atom, trifluoromethoxy, methoxyl and ring formation of adjacent 2 methoxylSubstituted by radicals; wherein naphthyl, quinolyl, isoquinolyl, imidazo [1, 5-A)]The pyridyl group and the dibenzothienyl group may be further substituted by a fluorine atom, a chlorine atom, a trifluoromethoxy group or a methoxy group;
R 2 and R 3 Together with the nitrogen atom to which they are attached form a morpholinyl radical, wherein the morpholinyl radical may be further substituted by a fluorine atom, a methyl or methoxymethyl radical.
8. The compound of formula (I) according to claims 1-7, wherein:
Figure FDA0003678364130000042
a is selected from C;
b is selected from C;
e is selected from C;
d is selected from O or S;
y is selected from O;
f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is methyl;
R 1 selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl group, dibenzothienyl group, wherein phenyl group can be further substituted by fluorine atom, chlorine atom, trifluoromethoxy group, substituent formed by ring formation of adjacent 2 methoxy groups, wherein naphthyl group can be further substituted by trifluoromethoxy group, methoxy group, quinolyl group and isoquinolyl group can be further substituted by fluorine atom or chlorine atom;
R 2 and R 3 Together with the nitrogen atom to which they are attached form a morpholinyl radical, wherein the morpholinyl radical may be further substituted by a fluorine atom, a methyl or methoxymethyl radical.
9. The compound of formula (I) according to any one of claims 1 to 8, selected from:
Figure FDA0003678364130000043
Figure FDA0003678364130000051
Figure FDA0003678364130000061
Figure FDA0003678364130000071
10. a compound of formula (I) according to any one of claims 1 to 9, selected from:
Figure FDA0003678364130000072
Figure FDA0003678364130000081
11. a process for the preparation of a compound of formula (I) as defined above, characterized in that it comprises the following steps:
Figure FDA0003678364130000082
wherein, X is Br or Cl, and Z is Br or Cl or MSO;
a is selected from N or C; b is selected from N or C; e is selected from N or C; d is selected from O or S; y is selected from O; f is selected from substituted or unsubstituted ethyl, substituted or unsubstituted C 3 Cycloalkyl, the substituent of which is deuterium atom, methyl, fluorine atom and chlorine atom; r 1 Selected from substituted or unsubstituted phenyl, naphthyl, quinolyl, isoquinolyl, imidazo [1,5-A [ ]]Pyridyl group, dibenzothienyl group, wherein the phenyl group may be further substituted with deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy group, methoxy group, a substituent formed by ring formation of adjacent 2 methoxy groups, naphthyl group, quinolyl group, isoquinolyl group, imidazo [1,5-A ]]Pyridyl group and dibenzothienyl group may be further substituted with deuterium atom, fluorine atom, chlorine atom, trifluoromethoxy group or methoxy group; r 2 And R 3 Independently selected from R 2 And R 3 Together with the nitrogen atom to which they are attached form a morpholino ring group, a piperazino ring group, or a piperidino group, wherein the resulting ring group may be further substituted with a deuterium atom, a fluorine atom, a chlorine atom, a methyl group, or a methoxymethyl group.
12. The compound of claims 1-11, wherein the use is in the manufacture of a medicament for treating or preventing pain, inflammatory diseases, neurodegenerative diseases; preferably, the use is in the manufacture of a medicament for the treatment or prevention of pain; more preferably, the use is in the manufacture of a medicament for the treatment or prevention of neuropathic pain, inflammatory pain and pain; further preferably, the use is in the manufacture of a medicament for the treatment or prevention of moderate to severe pain.
CN202210627790.0A 2021-07-22 2022-06-06 2H-benzo [ b ] [1,4] oxazin-3 (4H) -one derivatives Pending CN115677611A (en)

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