CN113150005B

CN113150005B - Quinoxaline compound, preparation method and application thereof in medicine

Info

Publication number: CN113150005B
Application number: CN202110384555.0A
Authority: CN
Inventors: 朱雄; 刘尚德; 袁铎; 谢柔洁; 李杉杉; 张玮琪
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2021-04-09
Filing date: 2021-04-09
Publication date: 2022-08-30
Anticipated expiration: 2041-04-09
Also published as: WO2022213896A1; CN113150005A

Abstract

The invention provides a quinoxaline compound, a preparation method and application thereof in medicine, in particular to the quinoxaline compound with PAR4 antagonistic activity, the preparation method thereof, a pharmaceutical composition containing the quinoxaline compound and application thereof. In particular to a compound shown in general formulas I and/or II or a tautomer or a pharmaceutically acceptable salt thereof, a preparation method thereof and application thereof in medicines for preventing and/or treating thromboembolic diseases.

Description

Quinoxaline compound, preparation method and application thereof in medicine

Technical Field

The invention relates to the technical field of medicaments, in particular to quinoxaline compounds with PAR4 antagonistic activity, a preparation method thereof, a pharmaceutical composition containing the quinoxaline compounds and application thereof.

Background

Thromboembolic diseases are one of the most causes of death in the world at present, and the existing antiplatelet medicaments have the defects of limiting the clinical safety and/or the practicability. The thrombin protease receptor-4 (PAR4), one of the three platelet G protein-coupled receptors (GPCRs) that binds thrombin (the other two being PAR1 and PAR3), mediates a relatively slow, but highly robust, sustained calcium mobilization that is critical in the diffusion phase late in platelet activation (Wong, Seiffert et al 2017). Targeted antagonism of PAR4 may be safer and more effective, blocking the sustained signal from PAR4 may prevent the growth of a deleterious stable thrombus while preserving PAR1 transient signaling to preserve initial thrombus formation (angioillo 2017). Indazoles, indoles and imidazo [2,1-b ] [1,3,4] thiadiazole PAR4 antagonists are in preclinical or clinical research phase. Among them, oral PAR4 antagonists BMS-986120 and BMS-986141, developed by Baishi Guibao corporation, were in second and third phase clinical studies, respectively. To date, no oral small molecule PAR4 antagonist has been marketed. There is a clinical need to develop a highly potent PAR4 receptor antagonist of a novel structure for prophylactic and therapeutic use in the patient population suffering from a disease associated with thrombosis, embolism, hypercoagulability or fibrotic changes. There are several PAR4 antagonist patent applications publications, e.g. CN104583218A, disclosing the use of a series of compounds of the formula as PAR4 antagonists in medicaments for inhibiting or preventing platelet aggregation.

EP1166785a1 and EP0667345 disclose various pyrazole derivatives useful as inhibitors of platelet aggregation.

PCT publications WO2013/163279, WO2013/163244, and WO2013/163241 disclose various PAR4 inhibitors useful as inhibitors of platelet aggregation.

Disclosure of Invention

The invention aims to provide a quinoxaline compound with PAR4 antagonistic activity.

The invention also aims to provide the medical application of the quinoxaline compound as a PAR4 antagonist. The compounds show remarkable antagonistic activity on PAR4 in vitro anti-platelet aggregation experiments, so that the compounds can effectively inhibit platelet aggregation, and can be used for preparing medicaments for preventing or treating various thromboembolic diseases.

The purpose of the invention can be realized by the following technical scheme:

defining:

the following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning.

The technical scheme of the invention is as follows: the alkyl group means a straight or branched saturated hydrocarbon group having 1 to 20 carbon atoms, and preferably the alkyl group is an alkyl group having 1 to 12 carbon atoms, more preferably an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, 1-heptyl, 1-octyl, 1-nonyl, and the like.

The technical scheme of the invention is as follows: the halogen is fluorine, chlorine, bromine or iodine.

The technical scheme of the invention is as follows: the haloalkyl refers to an alkyl group substituted with one or more halogens, wherein the halogens and alkyl groups are as defined above.

When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, for example, salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, formic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrocarbonic acid, carbonic acid, citric acid, ethandisulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, trifluoroacetic acid, tannic acid, tartaric acid, and p-toluenesulfonic acid.

Preferably, the neutral form of the compound is regenerated by contacting the salt or base or acid in a conventional manner and isolating the parent compound. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.

As used herein, "pharmaceutically acceptable salts" belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, for example, salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, formic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrocarbonic acid, carbonic acid, citric acid, ethandisulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, trifluoroacetic acid, tannic acid, tartaric acid, and p-toluenesulfonic acid.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention. Optically active (R) -and (S) -isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).

The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, a compound such as tritium (3H), iodine-125 (125I) or C-14(14C) may be labeled with a radioisotope. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. The term "pharmaceutically acceptable carrier" refers to any formulation vehicle or medium capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field.

The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.

The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.

A compound of formula I and/or II or a tautomer thereof or a pharmaceutically acceptable salt thereof:

wherein R is ₀ ，R ₀ ' independently from each other are H, -R ₁₂ OR-OR ₁₂ Wherein R is ₁₂ Is C _1-20 An alkyl group;

X ₁ ，X ₂ each independently is C or O; n is any one of 1 to 20Counting;

R ₁ the radicals being selected from

And: r ₃ ，R ₄ And R ₅ Each independently is H, halogen, -R ₁₂ OR-OR ₁₂ Wherein R is ₁₂ Is C _1-20 Alkyl or C _1-20 A haloalkyl group;

R ₆ ，R ₇ and R ₈ Each independently is H, halogen, -R ₁₂ 、-OR ₁₂ 、

Wherein: r ₁₂ Is C _1-20 Alkyl or C _1-20 A haloalkyl group;

R ₉ represents H, halogen, C _1-20 Alkyl radical, C _1-20 Alkoxy or C _1-20 A haloalkyl group;

R ₁₀ represents H, halogen, C _1-20 Alkyl radical, C _1-20 Alkoxy radical, C _1-20 A halogenated alkyl group,

Wherein R is ₁₁ Represents C _1-20 Alkyl radical, C _1-20 Haloalkyl or-CF ₃ ；

R ₂ The radicals are selected from

C _1-20 Alkyl or C _1-20 An alkoxy group.

Further, the definition of each group is as follows:

R ₀ ，R ₀ ' independently from each other are H, -R ₁₂ OR-OR ₁₂ Wherein R is ₁₂ Is C _1-12 Alkyl, further preferably: r ₁₂ Is C _1-6 An alkyl group;

X ₁ ，X ₂ each independently is C or O; n is any one natural number from 1 to 6;

R ₁ is selected from

R ₃ ，R ₄ And R ₅ Each independently is H, halogen, -R ₁₂ OR-OR ₁₂ Wherein R is ₁₂ Is C _1-12 Alkyl, further preferably: r ₁₂ Is C _1-6 An alkyl group;

R ₆ ，R ₇ and R ₈ Each independently is H, halogen, -R ₁₂ OR-OR ₁₂ 、

Wherein: r ₁₂ Is C _1-12 Alkyl, further preferred are: r ₁₂ Is C _1-6 An alkyl group;

wherein: r is ₁₀ Represents H, halogen, C _1-12 Alkyl, aryl, heteroaryl, and heteroaryl,

Wherein R is ₁₁ Represents C _1-12 Alkyl or-CF ₃ ；

Further preferably: r is ₁₀ Represents H, halogen, C _1-6 Alkyl, aryl, heteroaryl, and heteroaryl,

Wherein R is ₁₁ Represents C _1-6 Alkyl or-CF ₃ ；

R ₉ Represents H, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy or C _1-6 A haloalkyl group;

R ₂ the radicals are defined as follows:

C _1-12 alkyl or C _1-12 An alkoxy group; further preferably: r ₂ The radicals are defined as follows:

C _1-6 alkyl or C _1-6 An alkoxy group.

Further, the groups are defined as follows:

R ₀ ，R ₀ ' each independently is-Me;

X ₁ ，X ₂ each independently is C or O; n is 1,2 or 3;

R ₁ the radical is

R ₃ ，R ₄ And R ₅ H, Cl, -OMe, F, independently;

R ₆ ，R ₇ and R ₈ Independently represent Cl, H, F, -Me, -OMe,

Wherein: r ₉ represents-Me;

R ₁₀ represents H, -Me or

Wherein R is ₁₁ represents-Me or-CF ₃ ；

R ₂ The radicals are defined as follows:

or-OMe.

In some specific embodiments: the compound or tautomer thereof or pharmaceutically acceptable salt thereof:

wherein: x ₁ ，X ₂ Each independently is O; n is 1 or 2;

R ₁ the radical is

R ₃ And R ₄ H, Cl, -OMe, F, independently;

R ₆ and R ₇ Are respectively and independently Cl,

Wherein: r is ₉ represents-Me;

R ₁₀ represents-Me or

Wherein R is ₁₁ represents-Me;

R ₂ the radicals are defined as follows:

or-OMe.

In some more specific embodiments: the compounds of the general formula I and/or II have the following structural formula:

a process for the preparation of a compound of formula i, comprising:

the first step is as follows: carrying out a double nitration reaction on the compound Ia under an acidic condition to obtain a compound Ib;

the second step: carrying out selective nitro reduction reaction on the compound Ib to obtain a compound Ic;

the third step: performing bromination reaction on the benzene ring of the compound Ic to obtain a compound Id;

the fourth step: the double Boc protection of compound Id and the single deprotection reaction of compound Ie can yield compound If;

the fifth step: under the alkaline condition, methyl bromoacetate is used for alkylating mono-protected o-nitroaniline If to obtain a compound Ig;

and a sixth step: carrying out Boc protection removal reaction on the compound Ig to obtain a compound Ih;

the seventh step: reduction of compound Ih to initiate cyclization to produce compound Ii;

eighth step: oxidizing the compound Ii into a quinoline-2-ketone structure of the compound Ij, and then carrying out nucleophilic substitution under alkaline conditions to obtain a compound Ik;

the ninth step: the compound of formula (I) can be prepared into a compound Il by carrying out Miyaura boronization reaction on a compound Ik, and the compound Il and the compound R ₁ Carrying out Suzuki coupling preparation on the X to obtain a compound shown in the formula (I);

or: compounds Ik and R ₁ -X or R ₁ -Sn(C ₄ H ₉ ) ₃ Carrying out Suzuki coupling or Stille coupling to prepare a compound shown in the formula (I);

wherein: the definition of each group is as described above.

A process for the preparation of a compound of formula ii comprising:

the first step is as follows: carrying out double nitration reaction on the compound IIa under an acidic condition to obtain a compound IIb;

the second step: carrying out selective nitro reduction reaction on the compound IIb to obtain a compound IIc;

the third step: carrying out bromination reaction on a benzene ring of the compound IIc to obtain a compound IId;

the fourth step: the double Boc protection of the compound IId can obtain a compound IIe, and the single deprotection reaction of the compound IIe can generate a compound IIf;

the fifth step: alkylating the mono-protected o-nitroaniline IIf by methyl bromoacetate under an alkaline condition to obtain a compound IIg;

and a sixth step: carrying out Boc protection removal reaction on the compound IIg to obtain a compound IIh;

the seventh step: reduction of compound IIh initiates cyclization to produce compound IIi;

eighth step: the compound IIi is oxidized into a quinoline-2-ketone structure of the compound IIj;

the ninth step: IIj is nucleophilic substituted into a compound IIk under alkaline conditions;

the tenth step: compound IIl of formula (II) obtained by Miyaura boronation of compound IIk, said compound II and R ₁ -X for Suzuki coupling preparation; or the compound of formula (II) is directly reacted with R through the compound IIk ₁ -X or R ₁ -Sn(C ₄ H ₉ ) ₃ Carrying out Suzuki coupling or Stille coupling preparation.

Wherein: the definition of each group is as described above.

The invention has the beneficial effects that:

the invention provides bicyclic heteroaryl compounds with PAR4 antagonistic activity, which have remarkable antagonistic activity on PAR4 in an in vitro anti-platelet aggregation experiment, so that platelet aggregation is effectively inhibited, and the bicyclic heteroaryl compounds can be used for preparing medicaments for preventing or treating various thromboembolic diseases.

Detailed Description

The invention is further illustrated by the following examples, without limiting the scope of the invention:

the present invention will be described in detail with reference to examples. In the present invention, the following examples are given to better illustrate the present invention and are not intended to limit the scope of the present invention. Various changes and modifications may be made to the invention without departing from the spirit and scope of the invention.

Example 1

8- (Difluoromethoxy) -5-phenyl-2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 1)

After 60% concentrated nitric acid (60mL) and glacial acetic acid (30mL) were thoroughly mixed and stirred, the ice bath was lowered to 0 deg.C, compound 1-1(13g, 95.48mmol) was slowly added dropwise, and after the addition was complete, the reaction was allowed to warm to room temperature for 30 min. The reaction was monitored by TLC. After the raw materials are reacted, pouring the reaction liquid into ice water, stirring for 30min, then carrying out suction filtration, washing a filter cake with ice water, and drying to obtain the mono-nitrated intermediate. After drying, the intermediate is dissolved in glacial acetic acid (100mL), and a mixed solution of fuming nitric acid (20mL) and concentrated sulfuric acid (30mL) cooled by an ice bath is slowly and carefully added dropwise. After the dropwise addition, the temperature is raised to room temperature for reaction for 30min, then the reaction solution is slowly heated to 80 ℃, the reaction solution is vigorously stirred for 2h, and a tail gas absorption device is used for absorbing a large amount of nitrogen dioxide gas generated by the reaction. The reaction was monitored by TLC. And after the intermediate is reacted, cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water, stirring the reaction liquid for 30min, then performing suction filtration, washing a filter cake by the ice water, and drying the filter cake. The dried cake was recrystallized by heating with a mixed solution of DCM/diethyl ether (2/1,100mL), crystallized by cooling, and filtered to give compound 1-2(19.2g) as a pale yellow solid in 88.9% yield, Rf ═ 0.2(PE/EA ═ 3/1). ¹ H NMR(300MHz,DMSO-D6)δ7.96(s,2H),4.26(s,4H).

Compound 1-2(16g, 70.8mmol) was dissolved in glacial acetic acid (200mL) under a nitrogen atmosphere, and reduced iron powder (11.9g, 212.4mmol) was added in portions and stirred at room temperature for 30min, and then refluxing for 1.5 h. The reaction was monitored by TLC. After the raw materials are reacted, cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water, stirring the reaction liquid for 30min, filtering the product, and washing a filter cake by the ice water. The washed cake was dissolved in glacial acetic acid (200mL), refluxed for 30min, filtered while hot, the filtrate was poured into ice water, stirred for 30min and the product was filtered, washed with water and dried to give compound 1-3(12g) as a yellow solid in 86.4% yield and Rf 0.5(PE/EA 2/1). ¹ H NMR(300MHz,DMSO-D6)δ7.68(s,1H),6.94(s,1H),6.02(broad s,2H),4.42-4.26(d,4H).

To glacial acetic acid (50mL) was added liquid bromine (10.8g, 67.3mmol) and stirred at room temperature for 10 min. Compound 1-3(12g, 61.2mmol) was dissolved in glacial acetic acid (100mL), and a solution of bromine in glacial acetic acid was added dropwise at room temperature, during which a large amount of a tan solid precipitated. After the addition was complete, the mixture was stirred at room temperature for a further 30 min. The reaction was monitored by TLC. After the reaction of the raw materials, the reaction solution was poured into ice water and stirred for 30 min. Suction filtration, washing of the cake with water, drying and beating with a small amount of isopropyl ether gave compound 1-4(16g) as a pale yellow solid in 95% yield with Rf ═ 0.7(P/E ═ 2/1). ¹ H NMR(300MHz,DMSO-D6)δ7.64(s,1H),6.48(broad s,2H),4.42-4.22(d,4H).

Compound 1-4(16g, 58.2mmol) and 4-dimethylaminopyridine (0.71g, 5.8mmol) were dissolved in THF (150mL) at room temperature, di-tert-butyl dicarbonate (31.7g, 145mmol) was added, and the reaction was stirred overnight. The reaction was monitored by TLC. After the reaction is finished, the reaction liquid is concentrated, silica gel column chromatography is carried out, PE/EA (equal to 20/1-4/1) is used for leaching, crude products of the compounds 1-5 are obtained and are yellow solids, mixed solution of PE/EA (equal to 4/1) is beaten and dried, and the compounds 1-5(22.5g) are obtained and are white solids, and the yield is 81.3%. Rf is 0.5(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ7.28(s,1H),4.42-4.22(d,4H),1.42(s,18H).

At room temperature, compounds 1-5(20g, 42.1mmol) were dissolved in DCM (200mL), trifluoroacetic acid (6.23mL) was slowly added dropwise, and after the addition was complete, stirring was continued for an additional 1h at room temperature. The reaction was monitored by TLC, and the Rf values of the starting material and the product were essentially the same when PE/EA system was used as the developing solvent, DCM was used as the developing solvent. After the reaction, the reaction mixture was slowly neutralized with saturated aqueous sodium bicarbonate solution, extracted with DCM (100 mL. times.3), the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfateDrying, concentration and beating with a small amount of isopropyl ether gave compounds 1-6(15g) as pale yellow solids with a yield of 95%. Rf is 0.3 (DCM). ¹ H NMR(300MHz,DMSO-D6)δ7.26(s,1H),4.38-4.06(d,4H),1.56(s,9H).

Compounds 1-6(10g, 29.3mmol) were dissolved in DMF (100mL), cesium carbonate (28.6g, 87.9mmol) was added, cooled to 0 deg.C, stirred for 10min, methyl bromoacetate (7.5g, 58.6mmol) was slowly added dropwise, and the dark red solution became a pale yellow suspension instantaneously upon addition. The reaction solution was warmed to room temperature and stirred for 1 h. The reaction was monitored by TLC. After the reaction of the raw materials, water was added, EA (100mL × 3) was extracted, the organic phases were combined, washed three times with ice water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to silica gel column chromatography, followed by elution with PE/EA of 5/1-3/1 to obtain compounds 1-7(12g) as pale yellow solids with a yield of 91.6%. Rf is 0.3 (P/E2/1). ¹ H NMR (300MHz, DMSO-D6) indicated as a mixture of rotamers: δ 7.75-7.67(m,1H),4.62-3.97(m,6H),3.76 and 3.69(s,3H),1.55 and 1.37(s,9H).

Compound 1-7(10g, 22.4mmol) was dissolved in 1, 4-dioxane (50mL) at room temperature, and a solution of 4N hydrogen chloride in 1, 4-dioxane (50mL) was added dropwise and the reaction was stirred overnight. The reaction was monitored by TLC. After the reaction is finished, the reaction solution is concentrated, EA is added for redissolution and then concentrated to be dry, a small amount of isopropyl ether is beaten to obtain crude compounds 1-8 (8.2g) which are yellow solids, and the next reaction is directly carried out without further purification. Rf is 0.2 (P/E1/1). ¹ H NMR(300MHz,DMSO-D6)δ7.26(s,1H),4.28-4.12(d,4H),5.28(broad s,1H),4.02(d,2H),3.66(s,3H).

Dissolving the compounds 1-8(6g, 17.3mmol) in methanol (60mL), dropwise adding concentrated hydrochloric acid (2mL), adding stannous chloride dihydrate (15.6g, 69.2mmol) in batches, stirring at room temperature for 10min, heating to reflux, and stirring for 2.5h, wherein bumping of the reaction liquid is noticed. After the raw materials are reacted, cooling the reaction liquid to room temperature, adding methyl tert-butyl ether (180mL), heating to reflux and stirring for 10min, cooling to room temperature, carrying out suction filtration, washing a filter cake with a small amount of EA until no stannous chloride residue exists in the solid, and drying to obtain a crude product (2.7g) of the compound 1-9, which is an off-white solid and can be directly used for the next reaction without further purification. Rf 0.4(DCM/MeOH 20/1). ¹ H NMR(300MHz,DMSO-D6)δ7.10(s,1H),6.50(broad s,1H),4.28-4.12(d,4H),6.79(broad s,1H),3.50(d,2H).

Compounds 1-9(2g, 7.02mmol) were dissolved in methanol (20mL) at room temperature, 4.0N aqueous sodium hydroxide (5.8mL) was added, 30% aqueous hydrogen peroxide (16mL) was slowly added dropwise, the mixture was stirred at room temperature for 10min, the temperature was raised to 60 ℃ and the reaction was stirred for 20min, and the pale yellow suspension was slightly clear. Heating to 85 ℃, stirring and reacting for 1h, basically clarifying the reaction liquid, cooling to room temperature, concentrating the reaction liquid to a small volume, adding water (20mL), dropwise adding 1N hydrochloric acid to adjust the pH to be 2-3, cooling to 0 ℃ in an ice bath, stirring for 20min, carrying out suction filtration, washing a filter cake with water, washing a small amount of mixed solution of acetone/diethyl ether 1/1, and drying to obtain a compound 1-10(1.2g) which is a white solid with the yield of 60.4%. ¹ H NMR(300MHz,DMSO-D6)δ8.10(s,1H),7.02(s,1H),4.28-4.16(d,4H).

Compounds 1-10(1g, 3.53mmol) and anhydrous potassium carbonate (2.93g, 21.18mmol) were dissolved in DMF (10mL), reacted at 100 ℃ with stirring for 5min, sodium difluorochloroacetate (2.70g, 17.7mmol) was added in portions, and reacted at 100 ℃ with stirring for 20 min. The reaction was monitored by TLC. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, diluted with water, extracted with EA (20mL × 3), combined with the organic phase, washed three times with ice water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, chromatographed on silica gel, slowly passed through the column with PE/DCM ═ 10/1-2/1, and the resulting pale pink solid was slurried with a small amount of isopropyl ether to obtain compounds 1-11(600mg) as a white solid in 51% yield. Rf is 0.2(P/D is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),8.06-7.58(t,1H),7.63(s,1H),4.43-4.36(d,4H).

Compounds 1-11(200mg, 0.6mmol) and phenylboronic acid (150mg, 1.23mmol) were dissolved in toluene (21mL) and ethanol (7mL), strictly under nitrogen, and [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium dichloride (15mg, 0.02mmol) and aqueous sodium carbonate (2M, 0.47mL) were heated to 120 ℃ and reacted under reflux for 1 h. The reaction was monitored by TLC. After the compounds 1-11 react, the reaction liquid is cooled to room temperature, and EA/H is added ₂ Separating liquid from O, drying organic phase anhydrous sodium sulfate, concentrating, performing silica gel column chromatography, eluting with PE/EA (20/1-10/1) to obtain crude compound 1 (120mg), and pulping with a small amount of isopropyl ether to obtain pure product 100mg as white solid with 50.5% yield. Rf is 0.5(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),8.06-7.58(t,1H),7.48-7.34(m,6H),4.43-4.36(d,4H).ESI-MS:m/z 330.1[M+H] ⁺ .

Example 2

8-methoxy-5-phenyl-2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 2)

Intermediate 1-11(300mg, 0.9mmol) was dissolved in a mixed solution of THF (5mL) and methanol (5mL) at room temperature, and a methanol solution of sodium methoxide (4.3M, 1.2mL) was slowly added dropwise thereto, and the reaction was stirred at room temperature overnight. The reaction was monitored by TLC. After the raw materials are reacted, concentrating the reaction solution to a small volume, adding EA for dilution, quenching the reaction by 1N hydrochloric acid, separating liquid, extracting aqueous phase EA (20mL multiplied by 3), combining organic phases, washing by saturated sodium bicarbonate solution, washing by saturated saline solution, concentrating to dryness, and pulping by a small amount of isopropyl ether to obtain the compound 2-1(220mg) which is a white solid with the yield of 82.3%. Rf is 0.6(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.29(s,1H),7.43-7.34(t,1H),7.23(s,1H),4.38-4.30(d,4H),3.95(s,3H).

The title compound 2 was prepared as a white solid in 34.4% yield according to the synthesis of compound 1 in example 1 using intermediate 2-1 and phenylboronic acid. Rf is 0.6(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.29(s,1H),7.43-7.36(m,5H),7.23(s,1H),4.38-4.30(d,4H),3.98(s,3H).ESI-MS:m/z 294.1[M+H] ⁺ .

Example 3

5- (2, 4-dichlorophenyl) -8- (difluoromethoxy) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 3)

The title compound 3 was prepared as a white solid in 30% yield according to the synthesis of compound 1 in example 1 using intermediates 1-11 and 2, 4-dichlorophenylboronic acid. Rf is 0.5 (P/E5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.53(s,1H),8.04-7.72(t,1H),7.74(s,1H),7.62-7.53(m,1H),7.42(s,1H),4.44-4.38(d,4H).ESI-MS:m/z 398.0[M+H] ⁺ .

Example 4

5- (2, 4-dichlorophenyl) -8-methoxy-2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 4)

The title compound 4 was prepared as a white solid in 28% yield according to the procedure for the synthesis of compound 1 in example 1 using intermediate 2-1 and 2, 4-dichlorophenylboronic acid. Rf is 0.6(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.35(s,1H),7.72(s,1H),7.52-7.49(d,1H),7.40-7.37(d,1H),7.33(s,1H),4.39-4.31(d,4H),3.99(s,3H).ESI-MS:m/z 362.0[M+H] ⁺ .

Example 5

5- (2, 3-dichlorophenyl) -8- (difluoromethoxy) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 5)

The title compound 5 was prepared as a white solid in 44% yield according to the procedure for the synthesis of compound 1 in example 1 using intermediates 1-11 and 2, 3-dichlorophenylboronic acid. Rf is 0.5(P/E is 4/1). ¹ H NMR(300MHz,DMSO-D6)δ8.53(s,1H),8.04-7.56(t,1H),7.71(s,1H),7.56-7.36(m,3H),4.44-4.38(d,4H).ESI-MS:m/z398.0[M+H] ⁺ .

Example 6

5- (2, 3-dichlorophenyl) -8-methoxy-2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 6)

The title compound 6 was prepared as a white solid in yield according to the procedure for the synthesis of compound 1 in example 1 using intermediates 2-1 and 2, 3-dichlorophenylboronic acid55％。Rf＝0.6(P/E＝5/1)。 ¹ H NMR(300MHz,DMSO-D6)δ8.35(s,1H),7.74(s,1H),7.61-7.51(d,1H),7.40-7.37(m,2H),4.39-4.31(d,4H),3.99(s,3H).ESI-MS:m/z 362.0[M+H] ⁺ .

Example 7

8- (Difluoromethoxy) -5- (2-methoxyphenyl) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 7)

The title compound 7 was prepared as a white solid in 67% yield according to the procedure for the synthesis of compound 1 in example 1 using intermediates 1-11 and 2-methoxyphenylboronic acid. Rf is 0.3(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.53(s,1H),8.04-7.72(t,1H),7.74(s,1H),7.62-7.53(m,1H),7.42(t,1H),7.26(t,1H),4.44-4.38(d,4H),3.62(s,3H).ESI-MS:m/z 360.1[M+H] ⁺ .

Example 8

8-methoxy-5- (2-methoxyphenyl) -2, 3-dihydro- [1,4] dioxa [2,3-g ] quinoxaline (Compound 8)

The title compound 8 was prepared as a white solid in 67% yield according to the procedure for the synthesis of compound 1 in example 1 using intermediates 2-1 and 2-methoxyphenylboronic acid. Rf is 0.3(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.26(s,1H),7.36-6.92(m,6H),4.36-4.27(d,4H),3.97(s,3H),3.62(s,3H).ESI-MS:m/z 324.1[M+H] ⁺ .

Example 9

5- (4-chlorophenyl) -8- (difluoromethoxy) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 9)

According to Compound 1 of example 1The title compound 9 was prepared as a white solid in 28% yield using intermediates 1-11 and 4-chlorobenzeneboronic acid. Rf is 0.6(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),8.04-7.72(t,1H),7.74(s,1H),7.62-7.42(m,4H),4.46-4.38(d,4H).ESI-MS:m/z 364.0[M+H] ⁺ .

Example 10

5- (4-chlorophenyl) -8-methoxy-2, 3-dihydro- [1,4] dioxa [2,3-g ] quinoxaline (Compound 10)

The title compound 10 was prepared as a white solid in 66% yield according to the procedure for the synthesis of compound 1 in example 1, using intermediate 2-1 and 4-chlorobenzeneboronic acid. Rf is 0.5(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.26(s,1H),7.28-6.88(m,5H),4.36-4.27(d,4H),3.97(s,3H).ESI-MS:m/z 328.1[M+H] ⁺ .

Example 11

5- (2-chlorophenyl) -8- (difluoromethoxy) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 11)

The title compound 11 was prepared as a white solid in 30% yield according to the synthesis of compound 1 in example 1 using intermediates 1-11 and 2-chlorobenzeneboronic acid. Rf is 0.5(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.53(s,1H),8.03-7.72(t,1H),7.72(s,1H),7.68-7.55(m,4H),4.46-4.38(d,4H).ESI-MS:m/z 364.0[M+H] ⁺ .

Example 12

5- (2-chlorophenyl) -8-methoxy-2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 12)

According toThe procedure for the synthesis of compound 1 in example 1, using intermediates 2-1 and 2-chlorobenzeneboronic acid, produced the title compound 12 as a white solid in 65% yield. Rf is 0.6(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.26(s,1H),7.18-6.89(m,5H),4.36-4.27(d,4H),3.97(s,3H).ESI-MS:m/z 328.1[M+H] ⁺ .

Example 13

8- (Difluoromethoxy) -5- (2-fluorophenyl) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 13)

The title compound 13 was prepared as a white solid in 45% yield according to the procedure for the synthesis of compound 1 in example 1, using intermediates 1-11 and 2-fluorobenzeneboronic acid. Rf is 0.7(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.42(s,1H),7.87-7.46(t,1H),7.62(s,1H),7.46-7.31(m,2H),7.34-7.19(m,2H),4.45-4.32(d,4H).ESI-MS:m/z 348.1[M+H] ⁺ .

Example 14

5- (2-fluorophenyl) -8-methoxy-2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (compound 14)

The title compound 14 was prepared as a white solid in 27% yield according to the procedure for the synthesis of compound 1 in example 1, using intermediate 2-1 and 2-fluorobenzeneboronic acid. Rf is 0.4(P/E is 10/1). ¹ H NMR(300MHz,DMSO-D6)δ8.42(s,1H),7.62(s,1H),7.46-7.31(m,2H),7.34-7.19(m,2H),4.45-4.32(d,4H),2.62(s,1H).ESI-MS:m/z312.1[M+H] ⁺ .

Example 15

8- (Difluoromethoxy) -5- (pyridin-3-yl) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 15)

The title compound 15 was prepared as a white solid in 40% yield according to the procedure for the synthesis of compound 1 in example 1, using intermediates 1-11 and 3-pyridineboronic acid. Rf is 0.3(P/E is 1/1). ¹ H NMR(300MHz,DMSO-D6)δ8.88(t,1H),8.68(t,1H),8.40(s,1H),8.10(d,1H),7.86(d,1H),7.87-7.46(m,2H),4.53-4.34(d,4H).ESI-MS:m/z 331.1[M+H] ⁺ .

Example 16

8-methoxy-5- (pyridin-3-yl) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 16)

The title compound 16 was prepared as a white solid in 34% yield according to the procedure for the synthesis of compound 1 in example 1 using intermediates 2-1 and 3-pyridineboronic acid. Rf is 0.4(P/E is 1/1). ¹ H NMR(300MHz,DMSO-D6)δ8.88(t,1H),8.68(t,1H),8.40(s,1H),8.10(d,1H),7.86(d,1H),7.87-7.46(t,1H),4.53-4.34(d,4H),3.62(s,3H).ESI-MS:m/z 295.1[M+H] ⁺ .

Example 17

5- (4-chloro-6-methoxybenzo [ d ] thiazol-2-yl) -8- (difluoromethoxy) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 17)

Compound 17-1(1.00g, 5.70mmol) was dissolved in THF (10mL), and 40% sodium methoxide in methanol (2mL) was slowly added dropwise at room temperature, followed by stirring at room temperature for 2.5 h. The reaction was monitored by TLC, and after completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride (20mL) and extracted with ethyl acetate (20 mL. times.3). The organic phase was washed with saturated sodium bicarbonate (50mL), with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography was performed, eluting with PE/EA-20/1-10/1, to give compound 17-2(1.04g) as a pale yellow solid in 94% yield, Rf-0.5 (PE/EA-3/1). ¹ H NMR(300MHz,CDCl ₃ )δ8.26-8.08(m,2H),7.56(d,1H),3.84(s,3H).

Compound 17-2(1.00g, 5.33mmol) was dissolved in methanol (25mL), and zinc powder (3.5g, 53.3mmol) and ammonium chloride (5.72g, 106.6mmol) were added, followed by stirring at room temperature for 1 h. The reaction was monitored by TLC, and after completion of the reaction, the starting material was concentrated to a small volume, and extracted with water (50mL) and ethyl acetate (20 mL. times.3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Performing silica gel column chromatography, loading by a wet method, eluting by PE/EA (poly ethylene/ethyl acetate) 10/1 to obtain 500mg of a crude compound 17-3 which is an orange yellow oily substance, and standing at room temperature for 30min to obtain an orange yellow solid. Diethyl ether (5mL) was added and slurried, followed by drying to give 420mg of an orange solid in 50% yield, Rf 0.3(PE/EA 3/1). ¹ H NMR(300MHz,CDCl ₃ )δ7.26(s,1H),6.56(d,1H),6.18(d,1H),5.43-5.02(broad s,2H),3.86(s,3H).

Benzyltrimethylammonium tribromide (700mg, 1.65mmol) was dissolved in acetonitrile (2 mL). Compound 17-3(200mg, 1.27mmol) was dissolved in acetonitrile (5mL), ammonium thiocyanate (170mg, 2.41mmol) was added, stirring was carried out at room temperature for 10min, an acetonitrile solution of benzyltrimethylammonium tribromide was slowly added dropwise, the reaction solution turned into a black suspension, and after 30min, it turned into an orange-red suspension. Stirred at room temperature for 18 h. The reaction was monitored by TLC, and after completion of the reaction, saturated sodium bicarbonate (10mL) was added, and EA/THF was 1/1(10mL × 3) for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. Chromatography on silica gel with PE/EA 5/1-2/1 afforded compound 17-4(260mg) as an orange solid in 73.4% yield. Rf is 0.2(PE/EA 2/1). ¹ H NMR(300MHz,CDCl ₃ )δ7.54(s,1H),7.28(s,1H),5.66-5.28(broad s,2H),3.81(s,3H).

Compound 17-4(250mg, 1.17mmol) was dissolved in acetonitrile (8 mL). Cupric bromide (210mg, 1.40mmol) was added to acetonitrile (10mL), warmed to 40 deg.C, tert-butyl nitrite (0.2mL, 1.40mmol) was added slowly, stirred for 10min, and compound 17-4 in acetonitrile was added slowly dropwise. Stirring at 40 ℃ for 2 h. The reaction was monitored by TLC. After the reaction, the temperature was reduced to room temperature, and the reaction mixture was diluted with EA (20mL), extracted with dilute hydrochloric acid (0.5N, 30mL), washed with organic saturated sodium bicarbonate (40mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Chromatography on silica gel with elution PE/EA-10/1-5/1 gave compound 17-5(240mg) as a pale yellow solid in 74.1% yield.Rf＝0.7(PE/EA＝2/1)。 ¹ H NMR(300MHz,CDCl ₃ )δ7.58(s,1H),7.09(s,1H),3.81(s,3H).

Compounds 1-11(300mg, 0.9mmol), pinacol diboron (600mg, 2.36mmol) and anhydrous potassium acetate (300mg, 3.06mmol) were added to anhydrous 1, 4-dioxane (15mL), strictly under nitrogen protection, [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium dichloride (15mg, 0.02mmol) was refluxed at 120 ℃ for 2 h. The reaction was monitored by TLC. After the raw materials are reacted, the reaction is cooled to room temperature, and EA/H is added ₂ Separating the solution from the residue, washing the organic phase with saturated saline, drying over anhydrous sodium sulfate, and concentrating. Wet loading, flash column chromatography on silica gel, eluting with DCM/MeOH 10/1 to give crude compound 17-6 as a dark oil. Without further purification, was used for the next reaction. ESI-MS of M/z 298.1[ M + H ]] ⁺ .

Compound 17-6(120mg) and compound 17-5(100mg, 0.36mmol) were dissolved in toluene (21mL) and ethanol (7mL), strictly under nitrogen protection, and [1,1' -bis (diphenylphosphino) ferrocene was added]Palladium dichloride (15mg, 0.02mmol) and aqueous sodium carbonate (2M, 0.47mL) were heated to 120 ℃ and refluxed for 1 h. The reaction was monitored by TLC. After the compound 17-5 is reacted, cooling to room temperature, adding EA/H ₂ Separating the liquid from the residue, drying the organic phase over anhydrous sodium sulfate, concentrating, performing silica gel column chromatography, and eluting with PE/EA (20/1-10/1) to obtain crude compound 17 (60mg) as a pale yellow solid. Pulping with a small amount of isopropyl ether gave a pure product of 20mg as a white solid with a yield of 8%. Rf is 0.3(P/E is 4/1). ¹ H NMR(300MHz,DMSO-D6)δ8.79(s,1H),8.08-7.60(t,1H),7.77(s,1H),7.49(s,1H),7.31(s,1H),4.53-4.34(d,4H),3.90(s,3H).ESI-MS:m/z 474.0[M+Na] ⁺ .

Example 18

5- (4-chloro-6-methoxybenzo [ d ] thiazol-2-yl) -8-methoxy-2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 18)

The crude compound 18-1 was prepared according to the procedure for the synthesis of compound 17-6 in example 17, using intermediate 2-1, and was used directly in the next stepAnd (5) carrying out reaction. ESI-MS of M/z 262.1[ M + H ]] ⁺ .

The title compound 18 was prepared as a white solid in 16% yield according to the procedure for the synthesis of compound 17 in example 17 using intermediates 18-1 and 17-5. Rf is 0.4(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.79(s,1H),7.76(s,1H),7.49(s,1H),7.31(s,1H),4.53-4.34(d,4H),3.90(s,3H),3.64(s,3H).ESI-MS:m/z415.0[M+H] ⁺ .

Example 19

8- (Difluoromethoxy) -5- (4-fluoro-6-methoxybenzo [ d ] thiazol-2-yl) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 19)

Compound 19-1(2.0g, 12.73mmol) was dissolved in acetone (40mL), anhydrous potassium carbonate (3.51g, 25.46mmol) was added, methyl iodide (2.17g, 15.28mmol) was added dropwise at room temperature, and the red-brown suspension was stirred at room temperature overnight. TLC monitored the reaction. After the reaction of the raw materials, water is added, EA (50 mL. times.3) is extracted, an organic phase is washed with saturated common salt water, dried by anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography, and PE/EA (10/1-3/1) is used for leaching to obtain a compound 19-2(2.2g) which is a dark yellow solid with the yield of 100%. Rf is 0.5(PE/EA 2/1). ¹ H NMR(300MHz,CDCl ₃ )δ8.25-8.09(m,2H),7.06(d,1H),3.90(s,3H).

Compound 19-2(2.0g, 11.69mmol) was dissolved in methanol (50mL), and 10% palladium on carbon (0.1g, 0.05W/W) was added and reacted at room temperature under a hydrogen atmosphere overnight. TLC monitored the reaction. After the raw materials are reacted, the palladium carbon is removed by suction filtration through diatomite, the filtrate is concentrated, and after spin-drying, 1.65g of crude compound 19-3 is obtained and is light yellow oily matter, and the yield is 100%. Rf is 0.3(PE/EA 2/1). ¹ H NMR(300MHz,CDCl ₃ )δ6.98-6.64(m,3H),5.23(broad s,2H),3.68(s,3H).

Benzyltrimethylammonium tribromide (3.84g, 9.85mmol) was dissolved in acetonitrile (12 mL). Compound 19-3(1.5g, 7.57mmol) was dissolved in acetonitrile (30mL), ammonium thiocyanate (1.1g, 14.45mmol) was added, the mixture was stirred at room temperature for 10min, a solution of benzyltrimethylammonium tribromide in acetonitrile was slowly added dropwise, and the reaction solution was changedThe suspension is black, and becomes orange red suspension after 30 min. Stirred at room temperature for 18 h. The reaction was monitored by TLC, and after completion of the reaction, saturated sodium bicarbonate (10mL) was added, and EA/THF was 1/1(40mL × 3) for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Chromatography on silica gel with PE/EA 5/1-2/1 afforded compound 19-4(800mg) as an orange solid in 53.3% yield. Rf is 0.2(PE/EA 2/1). ¹ H NMR(300MHz,CDCl ₃ )δ7.23(s,1H),6.84(d,1H),6.23(broad s,2H),3.81(s,3H).

Compound 19-4(800mg, 4.04mmol) was dissolved in acetonitrile (20 mL). Cupric bromide (1.09g, 4.88mmol) was added to acetonitrile (20mL), warmed to 40 deg.C, tert-butyl nitrite (500mg, 4.85mmol) was added slowly, stirred for 10min, and compound 19-4 in acetonitrile was added slowly dropwise. Stirring at 40 ℃ for 2 h. The reaction was monitored by TLC. After the reaction, the temperature was reduced to room temperature, and the reaction mixture was diluted with EA (40mL), extracted with dilute hydrochloric acid (0.5N, 60mL), washed with saturated sodium bicarbonate (60mL) and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Chromatography on silica gel eluting with PE/EA 10/1-5/1 gave 19-5(600mg) as a pale yellow solid in 56.7% yield. Rf is 0.8(PE/EA 2/1). ¹ H NMR(300MHz,CDCl ₃ )δ7.23(s,1H),6.84(d,1H),3.81(s,3H).

The title compound 19 was prepared as a white solid in 8% yield according to the procedure for the synthesis of compound 17 in example 17, using intermediates 19-5 and 17-6. Rf is 0.4(P/E is 4/1). ¹ H NMR(300MHz,DMSO-D6)δ8.76(s,1H),7.76-7.23(m,3H),4.53-4.34(d,4H),3.89(s,3H),3.66(s,3H).ESI-MS:m/z 435.1[M+H] ⁺ .

Example 20

5- (4-fluoro-6-methoxybenzo [ d ] thiazol-2-yl) -8-methoxy-2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 20)

The title compound 20 was prepared as a white solid in 12% yield according to the method for the synthesis of compound 17 in example 17 using intermediates 19-5 and 18-1. Rf is 0.5 (P/E4/1). ¹ H NMR(300MHz,DMSO-D6)δ8.76(s,1H),7.82-7.44(m,2H),4.53-4.34(d,4H),3.89(s,3H),3.66(s,3H),3.55(s,3H).ESI-MS:m/z399.1[M+H] ⁺ .

Example 21

8- (Difluoromethoxy) -5- (4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 21)

Compound 21-1(5g, 50.9mmol) was dissolved in DCM (100 mL). N-bromosuccinimide (11g, 61.8mmol) was added to DCM (80mL), cooled to 0 deg.C, p-toluenesulfonic acid (0.9g, 5.23mmol) was added, and a solution of cyclohexanone in DCM was added dropwise. After the addition was complete, the white suspension was stirred under reflux for 4 h. The white solid gradually dissolved. TLC monitored the reaction (iodophor). After the reaction of the raw materials, water is added for liquid separation, an organic phase is washed by water, a saturated sodium bicarbonate aqueous solution and a saturated salt solution, and the mixture is concentrated and spin-dried to obtain the compound 21-2(9.6g) which is colorless oil with the yield of 100 percent. Rf 0.4(PE/EA 20/1) (iodine fumigation). ESI-MS of M/z 176.0[ M + H ]] ⁺ .

Compound 21-2(9.5g, 53.6mmol) was dissolved in ethanol (100mL), thiourea (4.76g, 62.5mmol) was added, and the mixture was stirred at reflux for 4 h. TLC monitored the reaction (iodophor). After the reaction, the reaction mixture was cooled to room temperature, and the reaction mixture was concentrated to a small volume, water (100mL) was added, an aqueous sodium hydroxide solution (1N) was added to adjust PH to 12, EA was added to extract, and the mixture was washed twice with an organic phase saturated saline solution and concentrated. Chromatography on silica gel with elution D/M-50/1-20/1 gave compound 21-3(8g) as a colorless oil in 97% yield. Rf is 0.6(D/M is 10/1). ¹ H NMR(300MHz,CD ₃ OD)δ7.66(broad s,2H),2.83-2.66(m,4H),1.96-1.74(dd,4H).

Compound 21-3(8g, 51.9mmol) was dissolved in acetonitrile (200 mL). Cupric bromide (12g, 54.4mmol) was added to acetonitrile (200mL), warmed to 40 deg.C, tert-butyl nitrite (7g, 67.9mmol) was added slowly, stirred for 10min, and a solution of compound 21-3 in acetonitrile was added slowly dropwise. Stirring at 40 ℃ for 2 h. The reaction was monitored by TLC. After the reaction was complete, the temperature was reduced to room temperature, diluted with EA (200mL), and diluted hydrochloric acid (0.5)N, 300mL), washed with organic phase saturated sodium bicarbonate (300mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Chromatography on silica gel column, eluting with PE/EA 20/1-10/1 gave compound 21-4(7g) as a colourless oil in 62.8% yield. Rf is 0.5(PE/EA 5/1). ¹ H NMR(300MHz,CD ₃ OD)δ2.83-2.66(m,4H),1.96-1.72(m,4H).

Compound 21-4(250mg, 1.15mmol) was dissolved in diethyl ether (5mL) under nitrogen and cooled to-78 ℃. N-butyllithium (2.5M in hexanes, 0.5mL) was added dropwise, stirred for 30min, held at-78 ℃. Tributyltin chloride (400mg, 1.15mmol) was added dropwise, maintaining at-78 ℃ and stirring for 40 min. Slowly warmed to room temperature, stirred for 20min, and concentrated to a small volume (bath temperature less than 25 ℃). Adding n-hexane (10mL) into the reaction product, stirring for 5min, filtering the suspension with diatomite, concentrating the filtrate, and spin-drying (the temperature of the water bath is less than 25 ℃). Compound 21-5(400mg) was obtained as a colorless oil (a small amount of n-hexane may remain). It was used in the next reaction quickly without further purification. Rf is 0.2(PE/EA 10/1). ESI-MS M/z429.2[ M + H ]] ⁺ .

At room temperature, compounds 1-11(100mg, 0.37mmol), compounds 21-5(240mg, 0.56mmol) and potassium acetate (75mg, 0.74mmol) were added to anhydrous 1, 4-dioxane (10mL) under strict nitrogen protection, tetrakis (triphenylphosphine) palladium (50mg, 0.04mmol) was added in portions, and the temperature was rapidly raised to 120 ℃ for reflux 5 h. The reaction was monitored by TLC. After the compound 16-2 is reacted, the reaction solution is cooled, EA (10mL) is diluted, the diluted solution is washed for 3 times, the washed solution is washed by saturated saline solution, dried by anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography, and PE/EA (polyethylene/EA) is 10/1-5/1 for leaching to obtain a crude compound 21 of 120mg which is a white solid. Pulping a small amount of isopropyl ether to obtain 30mg of a pure compound 21 as a white solid with the yield of 25%. Rf is 0.6(P/E is 4/1), 365nM UV lamp shines bright yellow special fluorescence. ¹ H NMR(300MHz，CDCl ₃ )δ8.61(s,1H),8.16(s,1H),8.10(s,1H),4.15-4.08(m,2H),2.92-2.89(m,4H),2.56(s,3H),1.94(m,4H),1.47-1.44(t,J＝7.1Hz,3H).ESI-MS:m/z 414.1[M+Na] ⁺ .

Example 22

8-methoxy-5- (4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 22)

The title compound 22 was prepared as a white solid in 26% yield according to the procedure for the synthesis of compound 21 in example 21, using intermediates 2-1 and 21-5. Rf is 0.5(P/E is 4/1). ¹ H NMR(300MHz,DMSO-D6)δ8.76(s,1H),7.82(s,1H),4.53-4.34(d,4H),3.89(s,3H),2.89(m,4H),1.94(m,4H).ESI-MS:m/z355.1[M+H] ⁺ .

Example 23

8- (Difluoromethoxy) -5- (4-methyl-7, 8-dihydro- [1,4] dioxine [2', 3': 3,4] benzo [1,2-d ] thiazol-2-yl) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (Compound 23)

Under a nitrogen atmosphere, compound 23-1(3.3g, 26.58mmol), anhydrous potassium carbonate (7.6g, 54.99mmol) and sodium iodide (0.4g, 2.66mmol) were dissolved in ethylene glycol (50mL), and 1, 2-dibromoethane (10g, 53.23mmol) was slowly added dropwise with stirring, and the reaction was refluxed at 130 ℃ for 5 hours. The reaction was monitored by TLC. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature and stirred overnight. The reaction mixture was filtered with celite, and a mixed solution (100mL × 3) of saturated brine (100mL) and DCM/PE/EA ═ 1/3/1 was added to the filtrate to extract, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography and PE-P/E-4/1 elution gave compound 23-2(2g) as a colorless oil in 50.1% yield. Rf is 0.8(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ7.09-6.78(m,3H),4.28-4.16(d,2H),2.79(s,3H).

Fuming nitric acid (1mL) was dissolved in acetic acid (5mL) at room temperature. Compound 23-2(1g, 6.67mmol) was dissolved in acetic acid (10mL) and a solution of nitric acid in acetic acid (5mL) was carefully and slowly added dropwise at room temperature. After completion of the dropwise addition, the reaction solution was stirred for 10min at room temperature. The reaction was monitored by TLC. A large amount of yellowish precipitate was formed during the addition. After the reaction was completed, the reaction solution was poured into ice water and stirred for 30 min. The mixture is filtered, the filter cake is washed by water and dried to obtain the compound 23-3 (1)1g) as a white solid in 84.5% yield. Rf is 0.4(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ7.86(s,1H),7.11(s,1H),4.28-4.16(d,2H),2.80(s,3H).

At room temperature, compound 23-3(1g, 5.12mmol) was dissolved in methanol (20mL), 10% palladium on carbon (0.1g, 10% w/w) was added, and the mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by TLC. After the reaction is finished, the reaction solution is filtered by suction through diatomite, and the filtrate is concentrated to be dry. To give compound 23-4(1g) as a dark red oil, redissolve with DCM (2mL), precipitate as a white solid with PE (10mL), concentrate to dryness as a pale purple solid in 100% yield. Rf is 0.2(P/E is 5/1). ESI-MS M/z165.1[ M + H ]] ⁺ .

Benzyltrimethylammonium tribromide (3.1g, 7.95mmol) was dissolved in acetonitrile (10mL) at room temperature. Compound 23-4(1g, 6.05mmol) was dissolved in acetonitrile (25mL), ammonium thiocyanate (2g, 12.18mmol) was added, stirred at room temperature for 10min, and a solution of benzyltrimethylammonium tribromide in acetonitrile (10mL) was slowly added dropwise. Stir at room temperature overnight. The reaction was monitored by TLC. After completion of the reaction, the reaction solution was poured into saturated sodium bicarbonate solution (100mL), EA (100mL × 3) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give compound 23-5(1.4g) as a pale yellow solid which was used in the next reaction without further purification. The yield was 100%. Rf is 0.2(P/E is 3/1). ¹ H NMR(300MHz,DMSO-D6)δ7.15-6.98(m,2H),4.28(d,4H),2.08(s,3H).

Compound 23-5(1.4g, 4.89mmol) was dissolved in acetonitrile (20 mL). Copper bromide (1.3g, 5.82mmol) was added to acetonitrile (30mL), stirred at 40 ℃ for 10min, tert-butyl nitrite (0.65g, 6.30mmol) was slowly added dropwise, stirred for 20min, and a solution of compound 23-5 in acetonitrile (20mL) was slowly added dropwise. Stir at 40 ℃ overnight. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted hydrochloric acid (1N, 100mL) and EA (100mL) were added to separate the reaction mixture, and the organic phase was washed with a saturated aqueous sodium bicarbonate solution (100mL), washed with a saturated common salt solution, dried over anhydrous sodium sulfate, and concentrated. Chromatography on silica gel with P/E-10/1 elution gave compound 23-6(1g) as a white solid in 71.5% yield. Rf is 0.4(P/E is 3/1). ¹ H NMR(300MHz,DMSO-D6)δ7.18(s,1H),4.33(s,4H),1.94(s,3H).

The title compound 23 was prepared as a white solid in 18% yield according to the procedure for the synthesis of compound 17 in example 17 using intermediates 23-6 and 17-6. Rf is 0.4(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.46(s,1H),7.79(s,1H),7.55-7.20(t,1H),6.89(s,1H),4.66-4.42(d,4H),4.32-4.01(d,4H),1.62(s,3H).ESI-MS:m/z 459.1[M+H] ⁺ .

Example 24

8-methoxy-5- (4-methyl-7, 8-dihydro- [1,4] dioxine [2', 3': 3,4] benzo [1,2-d ] thiazol-2-yl) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxaline (compound 24)

The title compound 24 was prepared as a white solid in 10% yield according to the procedure for the synthesis of compound 17 in example 17 using intermediates 23-6 and 18-1. Rf is 0.2(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.46(s,1H),7.79(s,1H),6.89(s,1H),4.66-4.42(d,4H),4.32-4.01(d,4H),3.62(s,3H),1.62(s,3H).ESI-MS:m/z 462.1[M+K] ⁺ .

Example 25

N- (2- ((4-chloro-2- (8- (difluoromethoxy) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxalin-5-yl) benzo [ d ] thiazol-6-yl) oxy) ethyl) methanesulfonamide (compound 25)

N-Boc ethanolamine (18.5g, 114.8, mmol) was dissolved in anhydrous THF (500mL) at room temperature, sodium bis (trimethylsilyl) amide (2M, 65mL) was slowly added dropwise, the reaction was stirred at room temperature for 10min, compound 25-1(10g, 57mmol) was added, and the reaction was stirred at room temperature for 1 h. The reaction was monitored by TLC. After the raw materials are reacted, adding EA (300mL) into the reaction liquid for dilution, quenching the reaction liquid by using a saturated ammonium chloride solution, separating the solution, washing an organic phase by using a saturated sodium bicarbonate aqueous solution, washing the organic phase by using a saturated saline solution, drying the organic phase by using anhydrous sodium sulfate, concentrating the dried organic phase, performing silica gel column chromatography, and eluting the dried organic phase by using PE/EA (10/1-5/1) to obtain a compound 25-2(16.2g) which is colorlessOil, yield 90%. Rf is 0.3 (P/E4/1). ¹ H NMR(300MHz,CDCl ₃ )δ8.11(d,1H),7.69-7.58(m,2H),6.08(broad s,1H),4.26(t,2H),3.02(t,2H),1.42(s,9H).

At room temperature, compound 25-2(10g, 31.6mmol) was dissolved in methanol (100mL), ammonium chloride solid (21g, 393mmol) was added, zinc powder (13g, 189.6mmol) was added in portions, and the reaction was stirred for 5 h. The reaction was monitored by TLC and imine intermediate was formed during the reaction. After the reaction was completed, EA (100mL) and saturated aqueous sodium bicarbonate (100mL) were added to the reaction mixture, the reaction mixture was filtered through celite, the insoluble solid was filtered off, the separated liquid was separated, the organic phase was washed with water, saturated brine was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness to give crude compound 25-3 (9.8g) as a pale yellow oil which was used in the next reaction without further treatment in 100% yield. Rf is 0.5(P/E is 2/1). ¹ H NMR(300MHz,CDCl ₃ )δ8.42(d,1H),7.55-7.43(m,2H),6.92(broad s,2H),4.12(t,2H),3.02(t,2H),1.41(s,9H).

Compound 25-4 was prepared as a pale yellow solid in 85% yield according to the procedure for synthesizing compound 17-4 in example 17, using compound 25-3 instead of compound 17-3. Rf is 0.1(P/E is 2/1). ¹ H NMR(300MHz,CDCl ₃ ) δ 7.16(s,1H),6.85(s,1H),6.60(broad s,2H),5.98(broad s,1H),4.26(t,2H),3.02(t,2H),1.42(s, 9H.) compound 25-5 was prepared as a white solid in 32% yield according to the synthetic method of compound 17-5 in example 17 using compound 25-4 instead of compound 17-4. Rf is 0.5(P/E is 2/1). ¹ H NMR(300MHz,CDCl ₃ )δ7.16(s,1H),6.85(s,1H),5.98(broad s,1H),4.26(t,2H),3.02(t,2H),1.42(s,9H).

Compound 25-6 was prepared as a white solid in 60% yield according to the procedure for the synthesis of compound 17 in example 17, using compounds 25-5 and 17-6. Rf is 0.4(P/E is 10/1). ¹ H NMR(300MHz,DMSO-D6)δ8.42(s,1H),7.92(s,1H),7.56-7.26(t,1H),7.42(s,1H),7.05(s,1H),6.52(broad s,1H),4.62-4.43(d,4H),4.12(t,2H),1.69(s,9H).

Compound 25-6(500mg, 0.86mmol) was dissolved in DCM (10mL), 2, 6-lutidine (277mg, 2.58mmol) was added, cooled to 0 ℃ in an ice bath and trimethylsilyl trifluoromethanesulfonate was slowly added dropwiseThe ester (1.15g, 5.16mmol) was slowly warmed to room temperature and stirred for 2 h. The reaction was monitored by TLC. After the reaction of the raw materials, adding saturated aqueous solution of sodium bicarbonate to quench the reaction, adding EA (20mL multiplied by 3) for extraction, combining organic phases, washing with water, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating to dryness, and pulping with a small amount of isopropyl ether to obtain a compound 25-7(300mg) which is a white solid with a yield of 75.2%. Rf is 0.3-0.1(D/M is 5/1), and tailing phenomenon is serious. ESI-MS M/z 480.1[ M + H ]] ⁺ .

Compound 25-7(100mg, 0.21mmol) was dissolved in DMF (5mL) at room temperature, diisopropylethylamine (0.32mL) and methanesulfonyl chloride (30mg, 0.25mmol) were added dropwise in this order, and the reaction was stirred for 15 min. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, EA (20mL × 3) was added for extraction, the organic phase was combined, washed three times with ice water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, subjected to silica gel column chromatography, eluted with an eluent PE/EA ═ 10/1-5/1, concentrated to dryness, slurried with a small amount of a mixed solution of isopropyl ether/dichloromethane ═ 1/1, and dried to obtain compound 25(85mg) as a white solid with a yield of 72.4%. Rf is 0.5(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.42(s,1H),7.92(s,1H),7.56-7.26(t,1H),7.42(s,1H),7.05(s,1H),6.52(broad s,1H),4.62-4.43(d,4H),4.12(t,2H),2.31(s,3H).ESI-MS:m/z 558.0[M+H] ⁺ .

Example 26

N- (2- ((4-chloro-2- (8- (difluoromethoxy) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxalin-5-yl) benzo [ d ] thiazol-6-yl) oxy) ethyl) -4-methylbenzenesulfonamide (compound 26)

Compound 25-7(100mg, 0.21mmol) was dissolved in DMF (5mL), cooled to 0 ℃ in an ice bath, diisopropylethylamine (0.32mL) was added, stirred for 10min, p-toluenesulfonic acid (60mg, 0.32mmol) was added dropwise, and the reaction was stirred at room temperature for 20 min. The reaction was monitored by TLC. After the reaction was completed, water was added to quench the reaction, EA (20 mL. times.3) was added for extraction, the organic phases were combined, washed three times with ice water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the silica gel column layerThe mixture was separated, rinsed with DCM/EA-20/1-10/1 eluent, concentrated to dryness, slurried with a small amount of isopropyl ether and dried to give compound 26(90mg) as an off-white solid in 67.5% yield. Rf is 0.2(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.64(s,1H),7.97(s,1H),7.66-6.93(m,8H),4.66-4.53(d,4H),4.24(t,2H),3.84(t,2H),2.24(s,3H).ESI-MS:m/z 634.1[M+H] ⁺ .

Example 27

N- (2- ((4-chloro-2- (8- (difluoromethoxy) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxalin-5-yl) benzo [ d ] thiazol-6-yl) oxy) ethyl) -4- (trifluoromethyl) benzenesulfonamide (compound 27)

The title compound 27 was prepared as a white solid in 85% yield according to the procedure for the synthesis of compound 26 in example 26 using compounds 25-7 and 4- (trifluoromethyl) benzenesulfonyl chloride. Rf is 0.3(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.54(s,1H),7.87(s,1H),7.76-6.98(m,8H),4.66-4.53(d,4H),4.24(t,2H),3.84(t,2H).ESI-MS:m/z 688.0[M+H] ⁺ .

Example 28

N- (2- ((4-chloro-2- (8- (difluoromethoxy) -2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxalin-5-yl) benzo [ d ] thiazol-6-yl) oxy) ethyl) benzamide (Compound 28)

Compound 25-7(150mg, 0.32mmol) was dissolved in DCM (5mL), cooled to 0 ℃ in an ice bath, diisopropylethylamine (100mg, 0.77mmol) was added, and a solution of chlorobenzene (65mg, 0.46mmol) in THF (5mL) was slowly added dropwise. The reaction was stirred at room temperature for 1 h. The reaction was monitored by TLC. After the reaction, EA (30mL) is added for dilution, 1M diluted hydrochloric acid is added for neutralization reaction, liquid separation is carried out, organic phase is washed by saturated sodium bicarbonate water solution, saturated common salt water is washed, anhydrous sodium sulfate is dried, concentration is carried out till dryness, silica gel column chromatography is carried out, elution is carried out by using eluent of P/E (4/1-2/1),after concentration to dryness, slurried with a small amount of isopropyl ether and dried, compound 28(140mg) was obtained as a white solid with a yield of 74.8%. Rf is 0.3(P/E is 1/1). ¹ H NMR(300MHz,DMSO-D6)δ8.54(s,1H),7.87(s,1H),7.76-6.98(m,9H),4.66-4.53(d,4H),4.24(t,2H),3.84(t,2H).ESI-MS:m/z 584.1[M+H] ⁺ .

Example 29

N- (2- ((4-chloro-2- (8-methoxy-2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxalin-5-yl) benzo [ d ] thiazol-6-yl) oxy) ethyl) -4-methylbenzenesulfonamide (compound 29)

Compound 29-1 was prepared as a white solid in 55% yield according to the method for synthesizing compound 25-6 in example 25 using compound 18-1 and compound 25-5. Rf is 0.4(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.42(s,1H),7.92(s,1H),7.42(s,1H),7.05(s,1H),6.52(broad s,1H),4.62-4.43(d,4H),4.12(t,2H),3.82(s,3H),1.69(s,9H).

Compound 29-2 was prepared as an off-white solid in 34% yield according to the synthesis of compound 25-7 in example 25 using compound 29-1. Rf 0.3-0.1 (D/M5/1) with severe tailing. ESI-MS of M/z 444.1[ M + H ]] ⁺ Compound 29 was prepared as a white solid in 85% yield according to the synthesis of compound 26 in example 26, using compound 29-2 and p-toluenesulfonyl chloride. Rf is 0.3 (P/E2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),7.87(s,1H),7.76-6.98(m,7H),4.66-4.53(d,4H),4.24(t,2H),3.94(s,3H),3.84(t,2H),2.43(s,3H).ESI-MS:m/z 598.1[M+H] ⁺ .

Example 30

N- (2- ((4-chloro-2- (8-methoxy-2, 3-dihydro- [1,4] dioxine [2,3-g ] quinoxalin-5-yl) benzo [ d ] thiazol-6-yl) oxy) ethyl) benzamide (Compound 30)

Compound 30 was prepared as a white solid in 92% yield according to the synthetic method for compound 28 in example 28, using compound 29-2 and chlorobenzene. Rf is 0.4(P/E is 1/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),7.87(s,1H),7.76-6.98(m,8H),4.66-4.53(d,4H),4.24(t,2H),3.94(s,3H),3.84(t,2H).ESI-MS:m/z548.1[M+H] ⁺ .

Example 31

7- (difluoromethoxy) -4-phenyl- [1,3] bisoxazole [4,5-g ] quinoxaline (Compound 31)

60% concentrated nitric acid (100mL) was cooled to 0 ℃ in an ice bath and compound 31-1(10g, 81.9mmol) was added dropwise over 0.5h, keeping the temperature below 5 ℃. After the dropwise addition, the internal temperature is kept at 0-10 ℃ and stirred for 1 h. The reaction was monitored by TLC. After the raw materials are reacted, maintaining the temperature at 0-10 ℃, slowly dripping 98% concentrated hydrochloric acid (10mL), slowly heating to room temperature after dripping is finished, stirring for reaction for 1h, then slowly heating to 80 ℃, violently stirring for reaction for 2h, preventing bumping, and absorbing a large amount of nitrogen dioxide gas generated by the reaction by using a tail gas absorption device. The reaction was monitored by TLC. And after the intermediate is reacted, cooling the reaction solution to room temperature, pouring the reaction solution into ice water, stirring the reaction solution for 30min, performing suction filtration, washing a filter cake by the ice water, and drying the filter cake. The dried cake was recrystallized by heating with a mixed solution of DCM/diethyl ether (2/1,100mL), cooled, crystallized and filtered to give compound 31-2(16g) as a pale yellow solid with a yield of 92%. Rf is 0.2(PE/EA 3/1). ¹ H NMR (300MHz, DMSO-D6) delta 8.02(s,2H),6.04(s,2H). The compound 31-3 was prepared as a yellow solid in 87% yield using compound 31-2 according to the synthetic method for compound 1-3 in example 1. Rf is 0.5(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.68(s,1H),7.96(s,1H),6.02(s,2H),5.88(broad s,2H).

Compound 31-4 was prepared as a pale yellow solid with a yield of 97% using compound 31-3 according to the synthesis method of compound 1-4 in example 1. Rf is 0.7(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.56(s,1H),6.10(s,2H).

Compound 31-5 was prepared as a white solid in 82% yield according to the synthesis of compound 1-5 in example 1 using compound 31-4. Rf is 0.5(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.54(s,1H),6.10(s,2H),1.96(s,18H).

Compound 31-6 was prepared as a pale yellow solid in 95% yield according to the synthesis method of compound 1-6 in example 1 using compound 31-5. Rf is 0.3 (DCM). ¹ H NMR(300MHz,DMSO-D6)δ8.55(s,1H),6.10(s,2H),5.54(broad s,1H),1.94(s,9H).

Compound 31-7 was prepared as a pale yellow solid with a yield of 90% according to the synthesis method of compound 1-7 in example 1 using compound 31-6. Rf is 0.3(P/E is 2/1). ¹ H NMR (300MHz, DMSO-D6) indicated as a mixture of rotamers: δ 7.75-7.67(m,1H),6.10-5.86(m,2H),4.62-3.97(m,2H),3.76 and 3.69(s,3H),1.55 and 1.37(s,9H).

Compound 31-8 was prepared as a yellow solid using compound 31-7 according to the synthesis of compound 1-8 in example 1. Rf is 0.2(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.02(s,1H),6.07(s,2H),5.28(broad s,1H),4.02(d,2H),3.56(s,3H).

Compounds 31-9 were prepared as light yellow solids in 62% yield according to the procedure for the synthesis of compounds 1-9 in example 1, using compounds 31-8. ¹ H NMR(300MHz,DMSO-D6)δ7.10(s,1H),6.50(broad s,1H),6.11(s,2H),6.03(broad s,1H),3.50(d,2H).

Compound 31-10 was prepared as a white solid in 55% yield according to the synthesis of compound 1-10 in example 1 using compound 31-9. Rf is 0.2(P/D is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.10(s,1H),7.02(s,1H),6.10(s,2H).

Compound 31-11 was prepared as a white solid with 90% yield using compound 31-10 according to the synthesis of compound 1-11 in example 1. Rf is 0.3(P/D is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),8.06-7.58(t,1H),7.52(s,1H),6.08(s,2H).

The title compound 31 was prepared as a white solid in 60% yield according to the method for synthesizing compound 1 in example 1 using compounds 31-11. Rf is 0.5(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),8.06-7.58(t,1H),7.48-7.34(m,6H),6.04(s,2H).ESI-MS:m/z 316.1[M+H] ⁺ .

Example 32

7-methoxy-4-phenyl- [1,3] bisoxazole [4,5-g ] quinoxaline (Compound 32)

Compound 32-1 was prepared as a white solid in 86% yield according to the synthesis method of compound 2-1 in example 2 using compound 31-11. Rf is 0.7(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.54(s,1H),7.48-7.34(m,6H),6.04(s,2H),3.98(s,3H).

The title compound 32 was prepared as a white solid in 53% yield according to the method for the synthesis of compound 1 in example 1, using compound 32-1 and phenylboronic acid. Rf is 0.7(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.29(s,1H),7.43-7.36(m,5H),7.23(s,1H),6.04(s,2H),3.98(s,3H).ESI-MS:m/z 280.1[M+H] ⁺ .

Example 33

4- (2, 4-dichlorophenyl) -7- (difluoromethoxy) - [1,3] bisoxazole [4,5-g ] quinoxaline (Compound 33)

The title compound 33 was prepared as a white solid in 33% yield according to the method for synthesizing compound 1 in example 1 using compound 31-11 and 2, 4-dichlorophenylboronic acid. Rf is 0.5(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.53(s,1H),8.04-7.72(t,1H),7.74(s,1H),7.62-7.53(m,1H),6.04(s,2H).ESI-MS:m/z 384.0[M+H] ⁺ .

Example 34

4- (2, 4-dichlorophenyl) -7-methoxy- [1,3] dioxazole [4,5-g ] quinoxaline (Compound 34)

The title compound 34 was prepared as a white solid in 42% yield according to the method for the synthesis of compound 1 in example 1, using compound 32-1 and 2, 4-dichlorophenylboronic acid. Rf is 0.6(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.35(s,1H),7.72(s,1H),7.52-7.49(d,1H),7.40-7.37(d,1H),7.33(s,1H),6.12(s,2H),3.99(s,3H).ESI-MS:m/z 348.0[M+H] ⁺ .

Example 35

7- (Difluoromethoxy) -4- (pyridin-3-yl) - [1,3] bisoxazole [4,5-g ] quinoxaline (Compound 35)

The title compound 35 was prepared as a white solid in 40% yield according to the method for synthesizing compound 1 in example 1 using compound 1-11 and 3-pyridineboronic acid. Rf is 0.2 (P/E2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.89(t,1H),8.68(t,1H),8.40(s,1H),8.10(d,1H),7.86(d,1H),7.87-7.46(m,2H),6.03(s,2H).ESI-MS:m/z317.1[M+H] ⁺ .

Example 36

7-methoxy-4- (2-methoxyphenyl) - [1,3] dioxazole [4,5-g ] quinoxaline (Compound 36)

The title compound 36 was prepared as a white solid in 67% yield according to the method for synthesizing compound 1 of example 1 using compound 2-1 and 2-methoxyphenylboronic acid. Rf is 0.5 (P/E5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.26(s,1H),7.36-7.62(m,6H),6.09(s,2H),3.97(s,3H),3.66(s,3H).ESI-MS:m/z 310.1[M+H] ⁺ .

Example 37

4- (4-chloro-6-methoxybenzo [ d ] thiazol-2-yl) -7- (difluoromethoxy) - [1,3] dioxazole [4,5-g ] quinoxaline (Compound 37)

The crude compound 37-1 was prepared as a dark oil using compound 31-11 according to the procedure for the synthesis of compound 17-6 in example 17 and used in the next reaction without further purification. ESI-MS M/z 284.0[ M + H ]] ⁺

The title compound 37 was prepared as a white solid in 8% yield according to the method for synthesizing compound 17 in example 17 using compounds 37-1 and 17-5. Rf is 0.3 (P/E4/1). ¹ H NMR(300MHz,DMSO-D6)δ8.79(s,1H),8.08-7.60(t,1H),7.77(s,1H),7.49(s,1H),7.31(s,1H),6.09(s,2H),3.90(s,3H).ESI-MS:m/z437.0[M+H] ⁺ .

Example 38

7-methoxy-4- (4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) - [1,3] dioxazole [4,5-g ] quinoxaline (Compound 38)

The title compound 38 was prepared as a white solid in 28% yield according to the method for synthesizing compound 21 in example 21 using compounds 21-5 and 32-1. Rf is 0.4 (P/E4/1). ¹ H NMR(300MHz,DMSO-D6)δ8.76(s,1H),7.82(s,1H),6.09(s,2H),3.89(s,3H),2.89(m,4H),1.94(m,4H).ESI-MS:m/z 341.1[M+H] ⁺ .

Example 39

N- (2- ((4-chloro-2- (7- (difluoromethoxy) - [1,3] dioxazole [4,5-g ] quinoxalin-4-yl) benzo [ d ] thiazol-6 yl) oxy) ethyl) methanesulfonamide (Compound 39)

Compound 39-1 was prepared as a white solid in 55% yield according to the procedure for the synthesis of compound 17 in example 17, using compounds 25-5 and 37-1. Rf is 0.5(P/E is 3/1). ¹ H NMR(300MHz,DMSO-D6)δ8.42(s,1H),7.92(s,1H),7.56-7.26(t,1H),7.42(s,1H),7.05(s,1H),6.52(broad s,1H),6.08(s,2H)4.12(t,2H),1.69(s,9H).

Compound 39-2 was prepared as a white solid in 34.1% yield according to the method for synthesizing compound 25-7 in example 25 using compound 39-1. Rf is 0.3-0.2(D/M is 5/1), and tailing phenomenon is serious. ESI-MS of M/z 466.0[ M + H ]] ⁺ Compound 39 was prepared as a white solid in 92% yield according to the method for synthesizing compound 25 in example 25, using compound 39-2. Rf is 0.6(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.42(s,1H),7.92(s,1H),7.56-7.22(t,1H),7.42(s,1H),7.05(s,1H),6.42(broad s,1H),6.02(s,2H),4.12(t,2H),2.31(s,3H).ESI-MS:m/z 544.0[M+H] ⁺ .

Example 40

N- (2- ((4-chloro-2- (7- (difluoromethoxy) - [1,3] bisoxazole [4,5-g ] quinoxalin-4-yl) benzo [ d ] thiazol-6 yl) oxy) ethyl) -4-methylbenzenesulfonamide (Compound 40)

The title compound 40 was prepared as a white solid in 79% yield according to the method for the synthesis of compound 26 in example 26 using compound 39-2 and p-toluenesulfonyl chloride. Rf is 0.3(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.64(s,1H),7.97(s,1H),7.66-6.93(m,8H),6.03(s,2H),4.66-4.53(d,4H),4.24(t,2H),3.84(t,2H),2.24(s,3H).ESI-MS:m/z 620.0[M+H] ⁺ .

Example 41

2- (Difluoromethoxy) -5-phenyl-8, 9-dihydro-7H- [1,4] dioxepin [2,3-g ] quinoxaline (Compound 41)

Compound 41-1(12g, 109mmol), anhydrous potassium carbonate (30.1g, 218mmol) and sodium iodide (1.63g, 10.9mmol) were dissolved in ethylene glycol (200mL) under a nitrogen atmosphere, stirred at room temperature for 10min, 1, 3-dibromopropane (44g, 218mmol) was slowly added dropwise,the temperature is increased to 130 ℃ and the reflux reaction is carried out for 5 h. The reaction was monitored by TLC, and after completion of the reaction of the starting materials, the reaction was allowed to cool to room temperature and stirred overnight. The reaction mixture was filtered with celite, and the filtrate was extracted with a mixed solution (100mL × 3) of saturated brine (100mL) and DCM/PE/EA ═ 1/3/1, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Silica gel column chromatography and PE-P/E-10/1 elution gave compound 41-2(14g) as a colorless oil in 85.5% yield. Rf is 0.7 (P/E4/1). ¹ H NMR(300MHz,DMSO-D6)δ6.88-6.54(dd,4H),4.13(t,4H),2.11(m,2H).

Compound 41-3 was prepared as a pale yellow oil in 89% yield by the double nitration reaction using compound 41-2 according to the synthesis method of compound 1-2 in example 1. Rf is 0.5(P/E is 3/1). ¹ H NMR(300MHz,DMSO-D6)δ8.56(s,2H),4.43(t,4H),2.54(m,2H).

Compound 41-4 was prepared as a yellow oil in 87% yield by reduction using compound 41-3 according to the method for synthesizing compound 1-3 in example 1. Rf is 0.6(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),7.68(s,1H),5.68(broad s,2H),4.23(m,4H),2.44-2.23(m,2H).

According to the synthesis method of the compounds 1 to 4 in example 1, the compound 41 to 5 was prepared as a yellow solid with a yield of 100% by bromination using the compound 41 to 4. Rf is 0.7(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.54(s,1H),5.52(broad s,2H),4.23(m,4H),2.44-2.23(m,2H).

Compound 41-6 was prepared as a pale yellow solid with a yield of 92% using compound 41-5 according to the synthesis method of compound 1-5 in example 1. Rf is 0.6(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.54(s,1H),4.23(m,4H),2.44-2.23(m,2H),1.69(s,18H).

Compound 41-7 was prepared as a pale yellow solid with a yield of 78% according to the synthesis method of compound 1-6 in example 1 using compound 41-6. Rf is 0.6(P/E is 2/1). ¹ H NMR(300MHz,CDCl ₃ )δ8.52(s,1H),4.23(m,4H),2.44-2.23(m,2H),1.69(s,9H).

Compounds 41-8 were prepared as pale yellow solids with 85% yield using compounds 41-7 according to the procedure for the synthesis of compounds 1-7 in example 1. Rf ═0.4(P/E＝2/1)。ESI-MS:m/z 483.1[M+Na] ⁺ .

Compounds 41-9 were prepared as yellow solids in yield according to the synthesis of compounds 1-8 in example 1 using compounds 41-8. Rf is 0.3(P/E is 1/1). ¹ H NMR(300MHz,CDCl ₃ )δ8.54(s,1H),5.84(broad s,1H),4.26(m,6H),2.44-2.23(m,4H).

Compounds 41-10 were prepared as off-white solids in 44% yield according to the procedure for the synthesis of compounds 1-9 in example 1, using compounds 41-9. Rf is 0.6(D/M is 20/1). ¹ H NMR(300MHz,DMSO-D6)δ7.10(s,1H),6.50(broad s,1H),6.11(s,2H),6.03(broad s,1H),4.23(m,4H),2.44-2.23(m,2H),3.50(d,2H).

Compounds 41-11 were prepared as white solids with 85% yield according to the synthesis of compounds 1-10 in example 1 using compounds 41-10. ¹ H NMR(300MHz,CDCl ₃ )δ8.08(s,1H),7.09(s,1H),4.26(m,4H),2.44-2.23(m,2H).

Compounds 41-12 were prepared as off-white solids in 32% yield according to the procedure for the synthesis of compounds 1-11 in example 1, using compounds 41-11. Rf is 0.3(P/D is 2/1). ¹ H NMR(300MHz,CDCl ₃ )δ8.08(s,1H),7.72-7.28(t,1H),7.09(s,1H),4.26(m,4H),2.44-2.23(m,2H).

The title compound 41 was prepared as a white solid in 28% yield according to the method for synthesizing compound 1 in example 1 using compounds 41-12 and phenylboronic acid. Rf is 0.6(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),8.06-7.58(t,1H),7.48-7.34(m,6H),4.13(dd,4H),2.23(t,2H).ESI-MS:m/z 334.1[M+H] ⁺ Example 42

7- (Difluoromethoxy) -2, 2-dimethyl-4-phenyl- [1,3] dioxane [4,5-g ] quinoxaline (Compound 42)

Compound 42-2 was prepared as a colorless oil in 85% yield according to the synthesis method of compound 1-2 in example 1 using compound 41-1 and 2, 2-dibromopropane. Rf is 0.5 (P/E4/1). ¹ H NMR(300MHz,DMSO-D6)δ6.88-6.54(dd,4H),1.74(s,6H).

Compound 42-3 was prepared as a pale yellow oil in 85% yield by the double nitration reaction using compound 42-2 according to the synthesis method of compound 1-2 in example 1. Rf is 0.4(P/E is 3/1). ¹ H NMR(300MHz,DMSO-D6)δ8.02(s,2H),1.68(s,6H).

Compound 42-4 was prepared as a yellow oil in 86% yield by reduction using compound 42-3 according to the method for synthesizing compound 1-3 in example 1. Rf is 0.3(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.68(s,1H),7.96(s,1H),5.88(broad s,2H),1.72(s,6H).

Compound 42-5 was prepared as a yellow solid in 90% yield by bromination using compound 42-4 according to the synthesis method of compound 1-4 in example 1. Rf is 0.6 (P/E2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.56(s,1H),1.78(s,6H).

Compound 42-6 was prepared as a pale yellow solid with a yield of 90% according to the synthesis method of compound 1-5 in example 1 using compound 42-5. Rf is 0.4(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.54(s,1H),1.96(s,18H),1.67(s,6H).

Compound 42-7 was prepared as a pale yellow solid in 79% yield according to the synthesis method of compound 1-6 in example 1 using compound 42-6. Rf is 0.5(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.55(s,1H),5.54(broad s,1H),1.94(s,9H),1.74(s,6H).

Compound 42-8 was prepared as a pale yellow solid with a yield of 45% using compound 42-7 according to the synthesis method of compound 1-7 in example 1. Rf is 0.6(P/E is 2/1). ¹ H NMR (300MHz, DMSO-D6) indicated as a mixture of rotamers: δ 7.75-7.67(m,1H),4.62-3.97(m,2H),3.76 and 3.69(s,3H),1.55 and 1.37(s,15H). compounds 42-9 were prepared as yellow solids using compounds 42-8 according to the synthetic method for compounds 1-8 in example 1. Rf is 0.2(P/E is 1/1). ¹ H NMR(300MHz,DMSO-D6)δ8.02(s,1H),5.28(broad s,1H),4.02(d,2H),3.56(s,3H),1.72(s,6H).

Preparation according to the Synthesis of Compounds 1-9 in example 1, Using Compounds 42-9Compound 42-10, as an off-white solid in 52% yield. Rf is 0.5(D/M is 20/1). ¹ H NMR(300MHz,DMSO-D6)δ7.10(s,1H),6.50(broad s,1H),6.03(broad s,1H),3.50(d,2H),1.72(s,6H).

Compound 42-11 was prepared as a white solid in 77% yield according to the synthesis method of compound 1-10 in example 1 using compound 42-10. ¹ H NMR (300MHz, DMSO-D6) delta 8.10(s,1H),7.02(s,1H),1.74(s,6H). Compounds 42-12 were prepared as off-white solids in 23% yield using compounds 42-11 according to the synthetic method for compounds 1-11 in example 1. Rf is 0.3(P/D is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),8.06-7.58(t,1H),7.52(s,1H),1.76(s,6H).

The title compound 42 was prepared as a white solid in 28% yield according to the method for synthesizing compound 1 in example 1 using compounds 42-12 and phenylboronic acid. Rf is 0.5(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),8.06-7.58(t,1H),7.48-7.34(m,6H),1.74(s,6H).ESI-MS:m/z 344.1[M+H] ⁺ .

Example 43

2- (Difluoromethoxy) -5-phenyl-6, 7,8, 9-tetrahydrobenzo [ g ] quinoxaline (Compound 43)

Compound 43-1(10g, 61.7mmol) was dissolved in N, N-dimethylethylamine (90mL), and sodium hydroxide (7.4g, 185mmol) was added in portions and the reaction stirred at 20-30 ℃ for 1 h. The reaction was monitored by TLC. After the reaction of the starting materials was completed, 2-bromo-2-methylpropionamide (20.7g, 185mmol) was added to the reaction mixture, and stirring was continued at 25-35 ℃ for 5 hours. The reaction was monitored by TLC. After the intermediate reaction is finished, adding sodium hydroxide (22.2g, 555mmol) into the reaction solution, heating to 50-60 ℃, and continuing stirring for reaction for 1 h. Water (90mL) was added to the system, and the reaction was stirred at reflux for 1 h. After the reaction is finished, cooling the reaction liquid to room temperature, adding water for dilution, extracting by EA (200mL multiplied by 3), combining organic phases, washing by ice water for three times, washing by saturated saline solution, drying by anhydrous sodium sulfate, concentrating to be dry, carrying out silica gel column chromatography, and eluting by PE (polyethylene) serving as an eluent to obtain a compound 43-2 ((R))2.4g) as a white solid. The yield was 24.1%. Rf is 03 (PE). ¹ H NMR(300MHz,DMSO-D6)δ7.26(d,1H),6.89(d,1H),6.73(s,1H),5.28(broad s,2H),2.78-2.56(m,6H).

At room temperature, compound 43-2(500mg, 3.1mmol) was dissolved in triethylsilane (2.5mL), and trifluoroacetic acid (5mL) was slowly added dropwise with vigorous stirring, and after completion of the addition, the reaction mixture was vigorously stirred for reaction for 2 h. After completion of the reaction, the reaction solution was concentrated to a small volume, and the residue was dissolved in EA (10mL), cooled to 0 ℃, and basified to pH 10 with 5N aqueous NaOH. Extraction with ethyl acetate (10mL × 3), combination of organic phases, water washing, brine washing, drying over anhydrous sodium sulfate, concentration to dryness, silica gel column chromatography, elution with PE/EA-20/1 as eluent, to give compound 43-3(220mg) as a brown-yellow oil. The yield was 48.2%. Rf is 0.2(P/E is 10/1). ¹ H NMR(300MHz,DMSO-D6)δ7.06(d,1H),6.89(d,1H),6.73(s,1H),5.28(broad s,2H),2.70(m,4H),1.74(m,4H).

Compound 43-3(2g, 13.6mmol) was dissolved in acetic anhydride (3mL), and a mixed solution of 60% concentrated nitric acid and acetic anhydride (1:1, 3mL) was slowly added dropwise, during which time the temperature of the reaction solution could not exceed 40 ℃. After the addition was completed, the reaction solution was stirred at room temperature for 1 hour, and the reaction was monitored by TLC. After the raw materials are reacted, pouring the reaction liquid into ice water, carrying out suction filtration, washing a filter cake by using a small amount of PE, drying, carrying out silica gel column chromatography, eluting by using P/E (3/1-2/1) as an eluent to obtain a crude product of the compound 43-4 containing the byproduct N- (1-nitro-5, 6,7, 8-tetrahydronaphthalene-2-yl) acetamide, and recrystallizing by using ethanol to obtain the compound 43-4(0.78g) which is a light yellow solid with the yield of 24.5%. Rf is 0.2(P/E is 1/1). ¹ H NMR(300MHz,DMSO-D6)δ9.78(broad s,1H),7.06(s,1H),6.73(s,1H),2.70(m,4H),2.08(s,3H),1.74(m,4H).

Compound 43-4(700mg, 2.99mmol) was dissolved in ethanol (10mL), 50% aqueous sulfuric acid (6mL) was slowly added dropwise, and after completion of the dropwise addition, the reaction solution was heated under reflux for 1 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, poured into ice water, adjusted to PH 8 with 30% aqueous ammonia, and a large amount of yellow solid was precipitated, filtered, the filter cake was washed with water, dried, and recrystallized from ethanol to obtain compound 43-5(350mg) as a yellow solid with a yield of 61%. Rf is 0.4(P/E is 2/1). ¹ H NMR(300MHz,DMSO-D6)δ7.46(s,1H),6.73(s,1H),6.05(broad s,2H),2.70(m,4H),1.74(m,4H).

According to the synthesis method of the compounds 1 to 4 in example 1, the compound 43 to 6 was prepared as a yellow solid in 100% yield by bromination using the compound 43 to 5. Rf is 0.3(P/E is 4/1). ¹ H NMR(300MHz,DMSO-D6)δ8.68(s,1H),7.96(s,1H),5.88(broad s,2H),2.70(m,4H),1.74(m,4H).

Compound 43-7 was prepared as a white solid in 92% yield according to the synthesis of compound 1-5 in example 1 using compound 43-6. Rf is 0.3(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.56(s,1H),2.70(m,4H),1.72(m,4H).

Compounds 43-8 were prepared as pale yellow solids with a 78% yield according to the procedure for the synthesis of compounds 1-6 in example 1, using compounds 43-7. Rf is 0.3(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.54(s,1H),2.72(m,4H),1.96(s,18H),1.70(m,4H).

Compounds 43-9 were prepared as yellow solids with 83% yield according to the procedure for the synthesis of compounds 1-7 in example 1 using compounds 43-8. Rf is 0.5(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.55(s,1H),5.54(broad s,1H),2.72(m,4H),1.94(s,9H),1.70(m,4H).

Compounds 43-10 were prepared as pale yellow solids with 48% yield according to the procedure for the synthesis of compounds 1-8 in example 1, using compounds 43-9. Rf is 0.4(P/E is 4/1). ESI-MS M/z 442.1[ M + H ]] ⁺ .

Compounds 43-11 were prepared as off-white solids in 33% yield according to the procedure for the synthesis of compounds 1-9 in example 1, using compounds 43-10. ¹ H NMR(300MHz,DMSO-D6)δ8.02(s,1H),5.28(broad s,1H),4.02(d,2H),3.56(s,3H),2.72(m,4H),1.70(m,4H).

Compound 43-12 was prepared as a white solid in 54% yield according to the synthesis method of compound 1-10 in example 1 using compound 43-11. Rf is 0.5(D/M is 20/1). ¹ H NMR(300MHz,DMSO-D6)δ7.10(s,1H),6.50(broad s,1H),6.03(broad s,1H),3.50(d,2H),2.72(m,4H),1.70(m,4H).

According to the synthesis of compounds 1-11 of example 1,compound 43-13 was prepared as a white solid in 65% yield using compound 43-12. Rf is 0.6(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.52(s,1H),8.06-7.58(t,1H),7.52(s,1H),2.72(m,4H),1.70(m,4H).

The title compound 43 was prepared as a white solid in 28% yield according to the method for synthesizing compound 1 in example 1 using compounds 43-13 and phenylboronic acid. Rf is 0.6(P/E is 5/1). ¹ H NMR(300MHz,DMSO-D6)δ8.42(s,1H),7.99(s,1H),7.46-7.26(m,6H),2.87-2.80(d,4H),1.88-1.79(d,4H).ESI-MS:m/z 326.1[M+H] ⁺ Example 44

Evaluation and test principle of in vitro anti-platelet aggregation activity: AYP is a specific agonist peptide of PAR4, and has sequence of AYPGKF-NH ₂ PAR4 may be selectively activated, causing platelet aggregation. The compounds of the invention antagonize platelet PAR4 and thereby inhibit platelet aggregation. The test used filtered platelets taken from mouse arterial plasma.

Platelet aggregation assay: sucking 300. mu.L of Tyrode's buffer, placing the Tyrode's buffer in a test area of a platelet aggregation instrument for fading, sucking 270. mu.L of washed platelets, placing the washed platelets in a preheating tank, adding 20. mu.L of each test sample and a positive control (the concentration of the compound is 20nM), preheating at 37 ℃ for 5min, placing the washed platelets in the test area, adding test beads and 10. mu.L of AYP, and measuring the maximum aggregation rate of the platelets within 5 min. The negative control group is physiological saline, the positive control group is BMS-986120, the positive control group is a PAR4 antagonist developed by BMS company, and the positive control group is currently in the phase II clinical research stage and is a better PAR4 antagonist. IC measured in this laboratory ₅₀ 9.7nM, which is essentially identical to the experimental data in the literature (9.5 nM). The aggregation inhibition rate of platelets was calculated by the following formula. Calculating the formula: platelet aggregation inhibition rate ═ X-Y/X]X100%, wherein X is the maximum platelet aggregation rate in the saline group and Y is the maximum platelet aggregation rate of the compound. The experimental results for some of the compounds are as follows:

the result shows that the partial compound of the invention has obvious anti-platelet aggregation activity.

Claims

1. A compound of formula I and/or II:

X ₁ ，X ₂ each independently is O; n is 1 to 3;

R ₁ the radicals being selected from

Wherein: r ₁₂ Is C _1-20 Alkyl or C _1-20 A haloalkyl group;

R ₁₀ represents H, haloElement, C _1-20 Alkyl radical, C _1-20 Alkoxy radical, C _1-20 A halogenated alkyl group,

R ₂ The radicals being selected from

C _1-20 Alkyl or C _1-20 An alkoxy group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof:

R ₀ ，R ₀ ' independently of one another are H, -R ₁₂ OR-OR ₁₂ ；

R ₁ Is selected from

R ₃ ，R ₄ And R ₅ Each independently is H, halogen, -R ₁₂ OR-OR ₁₂ ；

Wherein: r ₁₂ Is C _1-12 An alkyl group;

Wherein R is ₁₁ Represents C _1-12 Alkyl or-CF ₃ ；

Wherein R is ₁₁ Represents C _1-6 Alkyl or-CF ₃ ；

R ₂ the radicals are defined as follows:

C _1-12 alkyl or C _1-12 An alkoxy group.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein: r ₁₂ Is C _1-6 An alkyl group; r ₁₀ Represents H, halogen, C _1-6 Alkyl or

R ₂ The radicals are defined as follows:

C _1-6 alkyl or C _1-6 An alkoxy group.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

R ₀ ，R ₀ ' each independently is-Me;

X ₁ ，X ₂ each independently is O; n is 1,2 or 3;

R ₁ the radical is

R ₃ ，R ₄ And R ₅ H, Cl, -OMe, F, independently;

R ₆ ，R ₇ and R ₈ Independently represent Cl, H, F, -Me, -OMe,

Wherein: r ₉ represents-Me;

R ₁₀ represents H, -Me or

Wherein R is ₁₁ represents-Me or-CF ₃ ；

R ₂ The radicals are defined as follows:

or-OMe.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

wherein: x ₁ ，X ₂ Each independently is O; n is 1 or 2;

R ₁ the radical is

R ₃ And R ₄ H, Cl, -OMe, F, independently;

R ₆ and R ₇ Are respectively and independently Cl,

Wherein: r is ₉ represents-Me;

R ₁₀ represents-Me or

Wherein R is ₁₁ represents-Me;

R ₂ the radicals are defined as follows:

or-OMe.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof:

。

7. a process for the preparation of a compound of formula i as claimed in claim 1, which comprises:

the second step is that: carrying out selective nitro reduction reaction on the compound Ib to obtain a compound Ic;

the third step: carrying out bromination reaction on a benzene ring of the compound Ic to obtain a compound Id;

the fourth step: carrying out double Boc protection on the compound Id to obtain a compound Ie and carrying out single deprotection reaction on the compound Ie to obtain a compound If;

wherein: the radicals are as defined in claim 1.

8. A process for the preparation of a compound of formula ii as claimed in claim 1, which comprises:

the second step is that: carrying out selective nitro reduction reaction on the compound IIb to obtain a compound IIc;

the third step: performing bromination reaction on a benzene ring of the compound IIc to obtain a compound IId;

the fourth step: double Boc protection of the compound IId to obtain a compound IIe, and single deprotection reaction of the compound IIe can generate a compound IIf;

the fifth step: alkylating the mono-protected o-nitroaniline IIf by methyl bromoacetate under an alkaline condition to obtain a compound IIg; and a sixth step: carrying out Boc protection removal reaction on the compound IIg to obtain a compound IIh;

the ninth step: IIj is nucleophilic substituted into a compound IIk under the alkaline condition;

the tenth step: compound IIk is subjected to Miyaura boronization to obtain compound III, and the compound III and R are ₁ -X is subjected to a Suzuki coupling to prepare a compound of formula (II); or the compound of formula (II) is directly reacted with R through the compound IIk ₁ -X or R ₁ -Sn(C ₄ H ₉ ) ₃ Carrying out Suzuki coupling or Stille coupling preparation;

wherein: the radicals are as defined in claim 1.

9. A pharmaceutical composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 9 for the preparation of a medicament for the prophylaxis and/or treatment of thromboembolic disorders.

11. Use of a compound according to any one of claims 1 to 5 or a pharmaceutical composition according to claim 9 in the manufacture of a medicament for use in inhibiting platelet aggregation.