CN117586284A

CN117586284A - Macrocyclic compound, and preparation method and application thereof

Info

Publication number: CN117586284A
Application number: CN202311043525.9A
Authority: CN
Inventors: 吴俊军; 陆银锁; 陈度伸; 林佳盛; 邹俊龙; 黄奕强; 肖瑛; 邢伟
Original assignee: Shenzhen Salubris Pharmaceuticals Co Ltd
Current assignee: Shenzhen Salubris Pharmaceuticals Co Ltd
Priority date: 2022-08-18
Filing date: 2023-08-17
Publication date: 2024-02-23

Abstract

The invention belongs to the technical field of chemical medicaments, and relates to a compound shown in a general formula (I), or a racemate thereof, or an isomer thereof, or pharmaceutically acceptable salt thereof, and a method for treating various specific diseases or symptoms by using the compound.

Description

Macrocyclic compound, and preparation method and application thereof

Technical Field

The invention belongs to the technical field of chemical medicaments, and provides a macrocyclic compound, a preparation method and application thereof, and the macrocyclic compound is used as an inhibitor of selective Factor XIa (FXIa for short). The invention also relates to a pharmaceutical composition containing the compounds and application of the compounds in medicaments for treating diseases such as thromboembolism and the like.

Background

Cardiovascular and cerebrovascular diseases such as global cerebral vessels, cerebral infarction, myocardial infarction, coronary heart disease, arteriosclerosis and the like take 1200 tens of thousands of lives, are close to 1/4 of the total number of deaths in the world, and become the first enemy of human health. The number of people dying from cardiovascular diseases in China is more than 260 ten thousand per year, and 75% of surviving patients are disabled, wherein more than 40% of the patients are disabled seriously. The thrombus problem caused by cardiovascular and cerebrovascular diseases, diabetes and complications thereof becomes an unprecedented problem to be solved at present.

The human blood coagulation process consists of an endogenous pathway (intrinsic pathway), an exogenous pathway (extrinsic pathway) and a common pathway (annu. Rev. Med.2011. 62:4157), and is a chain reaction in which the process is continuously enhanced and amplified by sequential activation of various zymogens. The coagulation cascade is initiated by endogenous (also known as contact activation) and exogenous (also known as tissue factor) pathways to produce FXa, which in turn produces thrombin (FIIa) via a common pathway, ultimately forming fibrin.

The endogenous pathway is activated by factor XII to form XIa-VIIIa-Ca ²⁺ P L complex and activates factor X, the extrinsic coagulation pathway is released from Tissue Factor (TF) to TF-VIIa-Ca ²⁺ The process of complex formation and activation of factor X. The common pathway is the process of activating prothrombin and ultimately producing fibrin, which is the process by which factor Xa is formed, and in which FXI is essential for maintaining the endogenous pathway and plays a key role in the amplification of the coagulation cascade. In the coagulation cascade, thrombin can feedback activate FXI, which in turn causes large amounts of thrombin to be produced, thereby amplifying the coagulation cascade. Therefore, antagonists of FXI are widely developed for the treatment of various thrombosis.

Traditional anticoagulants, such as warfarin, heparin, low Molecular Weight Heparin (LMWH), and new drugs marketed in recent years, such as FXa inhibitors (rivaroxaban, apixaban, etc.) and thrombin inhibitors (dabigatran etexilate, hirudin, etc.), have good effects on reducing thrombosis, occupying the vast cardiovascular and cerebrovascular markets with their remarkable effectiveness, but their side effects are also more and more remarkable, wherein "bleeding risk" is one of the most serious problems that it is primarily in (N Engl J Med 1991;325:153-8, blood.2003; 101:4783-4788).

Inhibition of FXIa factor in a thrombotic model was found to be effective in inhibiting thrombosis, but in the case of more severe thrombosis, FXIa had very little effect (blood.2010; 116 (19): 3981-3989). Clinical statistics show that increasing the amount of FXIa increases the prevalence of VTE (Blood 2009; 114:2878-2883), whereas FXIa is severely deficient with reduced risk of DVT (Thromb Haemost 2011; 105:269273).

As an emerging target for inhibiting thrombosis, patent applications for compounds having FXIa inhibitory activity are WO9630396, WO9941276, WO2013093484, WO2004002405, WO2013056060, WO2017005725, WO2017/023992, WO2018041122, etc.

Disclosure of Invention

The invention provides a series of macrocyclic derivatives, a preparation method thereof and application thereof in medicines.

Specifically, in a first aspect, the present application provides a compound represented by general formula (I), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof:

in a second aspect, the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a third aspect, the invention also provides a pharmaceutical use of a therapeutically effective amount of a compound as described above or a pharmaceutically acceptable salt thereof, in particular, use in the manufacture of a medicament for the treatment of a condition, as an inhibitor of selective Factor XIa (FXIa) for the treatment of thromboembolic diseases.

Specifically, the invention is realized by the following technical scheme:

a compound represented by the general formula (I), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof,

wherein X is N or CH, when x=n, R ₄ Absence of;

Y ¹ 、Y ² 、Y ³ independently selected from N or CR ⁶ And at most two are simultaneously N, R ⁶ Selected from hydrogen, halogen, cyano;

Z is selected from O or-C (O) -;

ring a is selected from a substituted or unsubstituted benzene ring, a pyrazole ring, wherein the substituents are selected from halogen, cyano, alkyl, haloalkyl;

R ¹ selected from halogen, haloalkyl;

R ² selected from alkyl radicals, R ⁴ Selected from alkyl, or R ² And R is ⁴ Substituted or unsubstituted saturated or unsaturated ring with 5-6 membered, said substituents being selected from halogen, when R ² When selected from alkyl, x=n;

R ³ selected from alkyl, haloalkyl, alkoxy, - (CH) ₂ ) n-cycloalkyl, - (CH) ₂ ) n-heterocycloalkyl, n=0 or 1;

R ⁵ selected from hydrogen, halogen.

As a preferred embodiment of the present invention, the alkoxy group is selected from C _1-6 Alkoxy group, the C _1-6 The alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1, 2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, zhong Ji oxy, tert-hexoxy, neohexoxy, 2-methylpentoxy, 1, 2-dimethylbutoxy, 1-ethylbutoxy.

As a preferred embodiment of the present invention, halogen is selected from fluorine, chlorine, bromine and iodine.

As a preferred embodiment of the present invention, haloalkyl means that one hydrogen on the alkyl is replaced by halogen selected from fluorine, chlorine, bromine, iodine.

As a preferred embodiment of the present invention, the cycloalkyl group is selected from C _3-6 Naphthene of C _3-6 Is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; heterocycloalkyl means that one or more carbon atoms of the heterocycloalkyl group are replaced by heteroatoms selected from nitrogen, oxygen, sulfur, one or more heteroatoms.

As a preferred embodiment of the present invention, the compound is selected from the group consisting of a compound represented by the formula (Ia):

R ¹ selected from halogen,A haloalkyl group;

R ² is CH ₃ Or CD (compact disc) ₃ ；

R ⁵ selected from hydrogen, halogen;

R ⁷¹ 、R ⁷² 、R ⁷³ each independently selected from hydrogen, halogen, deuterium.

As a preferred embodiment of the present invention, R in the compound represented by the formula (Ia), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof ¹ Selected from chlorine, trifluoromethyl; r is R ² Is CH ₃ Or CD (compact disc) ₃ ；R ³ Selected from methyl; r is R ⁵ Selected from hydrogen and chlorine; r is R ⁷¹ 、R ⁷² 、R ⁷³ Each independently selected from hydrogen, fluorine, deuterium.

As a preferred embodiment of the present invention, the compound represented by the formula (IIa) or (IIb) or (IIc), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof:

R ¹ selected from halogen, haloalkyl;

R ⁵ selected from hydrogen, halogen;

R ⁷¹ 、R ⁷² 、R ⁷³ each independently selected from hydrogen, halogen, deuterium;

R ⁸¹ 、R ⁸² independently selected from hydrogen and halogen.

As a preferred embodiment of the present invention, R in the compound represented by the formula (IIa) or (IIb) or (IIc), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof ¹ Selected from chlorine, trifluoromethyl; r is R ³ Selected from methyl; r is R ⁵ Selected from hydrogen and chlorine; r is R ⁷¹ 、R ⁷² 、R ⁷³ Each independently selected from hydrogen, fluorine, deuterium; r is R ⁸¹ 、R ⁸² Independently selected from hydrogen and chlorine.

As a preferred embodiment of the present invention, the compound is selected from:

as a preferred embodiment of the present invention, there is provided a pharmaceutically acceptable salt of the compound, wherein the pharmaceutically acceptable salt of the compound refers to a compound, or an isomer thereof, or a racemate thereof, prepared with a pharmaceutically acceptable acid or base.

As a preferred embodiment of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the aforementioned compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

As a preferred technical scheme of the present invention, there is provided a medical use of the compound, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, in particular, a pharmaceutical use for preparing a medicament for treating FXIa-related diseases, preferably thrombosis-related diseases.

For clarity, general terms used in the description of the compounds are defined herein.

The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof. 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 salt" refers to a salt of a compound of the present invention, prepared from a compound of the present invention having a particular substituent found therein and a pharmaceutically acceptable acid or base.

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

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

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

The atoms of the compound molecule are isotopes, and the effects of prolonging half-life, reducing clearance rate, stabilizing metabolism, improving in vivo activity and the like can be achieved through isotope derivatization. And, an embodiment is included in which at least one atom is substituted with an atom having the same atomic number (proton number) and different mass numbers (proton and neutron sum). Examples of isotopes included in the compounds of the invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, each of which includes ² H、 ³ H、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ³¹ p、 ³² P、 ³⁵ S、 ¹⁸ F、 ³⁶ Cl. In particular, radioactive isotopes which emit radiation as they decay, e.g. ³ H or ¹⁴ C can be used for the local anatomic examination of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay or change with their amounts nor are radioactive, and therefore they can be safely used. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes may be converted according to general methods by substituting reagents used in the synthesis with reagents comprising the corresponding isotopes.

The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with radioisotopes, such as deuterium ² H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite 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。

Further, the compound of the present invention has one or more hydrogen atoms isotopically deuterium ² H) The compound of the invention has the effects of prolonging half-life, reducing clearance rate, stabilizing metabolism, improving in vivo activity and the like after being substituted by deuterium.

The method of preparing the isotopic derivatives generally comprises: phase transfer catalysis method. For example, preferred deuteration methods employ phase transfer catalysts (e.g., tetraalkylammonium salts, NBu ₄ HSO ₄ ). The exchange of methylene protons of diphenylmethane compounds using a phase transfer catalyst results in the introduction of higher deuterium than reduction with deuterated silanes (e.g., triethyldeuterated monosilane) in the presence of an acid (e.g., methanesulfonic acid) or with lewis acids such as aluminum trichloride using sodium deuterated borate.

The term "pharmaceutically acceptable carrier" refers to any formulation carrier or medium capable of delivering an effective amount of the active agents of the present invention, which does not interfere with the biological activity of the active agents and which does not have toxic or side effects to the host or patient, representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For further information on the carrier, reference may be made to Remington: the Science and Practice of Pharmacy,21st Ed., lippincott, williams & Wilkins (2005), the contents of which are incorporated herein by reference.

The term "excipient" generally refers to the carrier, diluent, and/or medium required to make an effective pharmaceutical composition.

For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to that amount which is required to achieve the desired effect when used in combination with another active agent in the composition. 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, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.

"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 set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.

Detailed Description

The present application is described in further detail below with reference to examples, but embodiments of the present application are not limited thereto.

Example 1

Synthesis of (5R, 9S) -9- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one

The specific synthetic route is as follows:

step A: synthesis of 1-azido-2-bromo-4-chlorobenzene

2-bromo-4-chloroaniline (8.00 g, 38.80 mmol) was dissolved in acetonitrile (200.0 ml), after nitrogen protection, stirred at 0℃for 0.5 hours, then tert-butyl nitrite (4.40 g, 42.77 mmol) was slowly added dropwise to the reaction flask, stirred at 0℃for 1 hour, and azido trimethylsilane (5.40 g, 46.50 mmol) was slowly added dropwise to the reaction flask, stirred at 25℃for 3 hours.

To the reaction solution was added water (50.0 ml), extracted with ethyl acetate (50.0 ml. Times.3), and the organic phases were combined, dried over saturated brine (25.0 ml. Times.3 times), and concentrated under reduced pressure to give 8.60 g of 1-azido-2-bromo-4-chlorobenzene as a purple black solid (yield: 67.0%).

And (B) step (B): synthesis of 1- (2-bromo-4-chlorophenyl) -4- (trimethylsilyl) -1H-1,2,3 triazole

1-azido-2-bromo-4-chlorobenzene (8.60 g, 37.00 mmol) was dissolved in toluene (100.0 ml), and then ethynyl trimethylsilane (10.90 g, 111.00 mmol) was added to a reaction flask, after which it was stirred at 110℃for 12 hours under nitrogen protection.

The reaction solution was cooled, dried by rotation, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to obtain 8.70 g of 1- (2-bromo-4-chlorophenyl) -4- (trimethylsilyl) -1H-1,2, 3-triazole as an orange-colored solid (yield: 70.7%).

Step c: synthesis of ] - (2-bromo-4-chlorophenyl) -4-chloro-1H-1, 2, 3-triazole

1- (2-bromo-4-chlorophenyl) -4- (trimethylsilyl) -1H-1,2, 3-triazole (4.30 g, 13.00 mmol) was dissolved in acetonitrile (150.0 ml), then potassium fluoride (4.50 g, 77.45 mmol) and N-chlorosuccinimide (20.83 g, 156.00 mmol) were added sequentially to the reaction flask, and after nitrogen protection, stirred at 90℃for 40 hours.

To the reaction solution was added water (50.0 ml), the mixture was filtered through celite, most of acetonitrile was removed from the filtrate by rotary evaporation, the mixture was extracted with ethyl acetate (50.0 ml×3 times), the organic phases were combined, and the organic phase was dried over saturated brine (25.0 ml×3 times), anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=3/7) to give 3.20 g of 1- (2-bromo-4-chlorophenyl) -4-monochloro-1H-1, 2, 3-triazole as a yellow solid (yield: 62.4%).

Step D: synthesis of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -3, 6-dimethoxypyridazine

1- (2-bromo-4-chlorophenyl) -4-chloro-1H-1, 2, 3-triazole (3.00 g, 7.60 mmol) was dissolved in 1, 4-dioxane (50.0 ml) and water (15.0 ml), then (3, 6-dimethoxypyridazin-4-yl) boric acid (2.10 g, 11.45 mmol), potassium carbonate (2.10 g, 15.2 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (0.55 g, 0.76 mmol) were sequentially added to the reaction flask, and after nitrogen protection, stirred at 90℃for 12 hours.

The reaction solution was filtered through celite, and the filtrate was slowly dropped into a saturated aqueous ammonium chloride solution (20.0 ml), the mixture was extracted with ethyl acetate (50.0 ml. Times.3), the organic phases were combined, and the organic phase was dried over saturated brine (25.0 ml. Times.3) and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/1) to give 1.20 g of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -3, 6-dimethoxypyridazine as a yellow solid (yield: 45.0%). LCMS: rt=1.97 min, [ m+h] ⁺ ＝352.13。

Step E: synthesis of 5- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-yl) phenyl) -6-methoxypyridazin-3 (2H) -one

4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -3, 6-dimethoxypyridazine (1.20 g, 3.40 mmol) was dissolved in tetrahydrofuran (10.0 ml) and methanol (1.0 ml), then concentrated hydrochloric acid (0.6 ml, 7.2 mmol) was added dropwise to the reaction solution, and after stirring at 45℃for 4 hours, LCMS monitored the reaction to be complete.

The reaction solution was cooled to room temperature, dried by spinning, the crude product was dissolved with 15% aqueous sodium bicarbonate (5.0 ml), the mixture was extracted with ethyl acetate (50.0 ml. Times.3), the organic phases were combined, the organic phase was dried over saturated brine (25.0 ml. Times.3), anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=7/3) to give 0.40 g of 5- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6-methoxypyridazin-3 (2H) -one as a yellow solid (yield: 35.1%). LCMS: rt=1.77 min, [ m+h ] ⁺ ＝338.09。

Step F: synthesis of (5R, 9R) -2 ¹ - (difluoromethyl) -9-hydroxy-5-methyl-2 ¹ H-3-Aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one

To (R) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridine-2 (5, 4) -pyrazole cyclononane-4, 9-dione (see, for example, patent CN201580053079, 12 g, 35.89 mmol) dry methanol (400 ml) was added, followed by cooling to-70℃and adding sodium borohydride (2.04 g, 53.84 mmol) in 4 portions. Then reacted at-70℃for 2 hours.

TLC showed no starting material remained and new spots with increased polarity were formed. The reaction solution was warmed to 0℃and saturated ammonium chloride solution (80 ml) was added thereto, then methanol was removed by concentration under reduced pressure, the resulting residue was extracted with ethyl acetate (200 ml. Times.3 times), the combined organic phases were dried over anhydrous sodium sulfate, and 10 g of an off-white solid was obtained by concentration under reduced pressure, which was resolved by a chiral liquid chromatography column (column: chiralcel OX-350X 4.6mm I.D,3 μm; mobile phase: A phase CO) ₂ Phase B EtOH (0.05% dea); gradient elution: etOH (0.05% DEA) in CO ₂ The medium volume ratio is from 5% to 40%; flow rate: 3mL/min; detecting point: a PDA; column temperature: 35 degrees; pressure: 100 Bar) gave 6.4 g of (5R, 9R) -2 as a white solid ¹ - (difluoromethyl) -9-hydroxy-5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one. (yield: 62%).

Step G: synthesis of (5R, 9R) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl 4-nitrobenzenesulfonate

Towards (5R, 9R) -2 ¹ - (difluoromethyl) -9-hydroxy-5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one (2 g, 5.95 mmol) was added dry dichloromethane (100 ml), followed by 4-nitrobenzenesulfonyl chloride (1.98 g, 8.92 mmol), triethylamine (1.81 g, 17.84 mmol), and 4-dimethylaminopyridine (726 mg, 5.95 mmol) in sequence. Then reacted at 50℃for 5 hours.

TLC showed no starting material remained and new spots with reduced polarity were formed. 100 ml of methylene chloride was added to the reaction solution, followed by washing with a saturated saline solution (80 ml. Times.3 times), followed byThe organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=2/1) to give 2.4 g of (5 r,9 r) -2 as a yellow solid ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl 4-nitrobenzenesulfonate (yield: 77%). LCMS: rt=1.89 min, [ m+h ] ⁺ ＝667.23。

Step H: synthesis of (5R, 9S) -9- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one

5- (5-chloro-2- (4-chloro-1 HH-1,2, 3-triazol-1-yl) phenyl) -6-methoxypyridazin-3 (2H) -one (37.00 mg, 0.11 mmol) was dissolved in N, N-dimethylformamide (2.0 ml), followed by potassium carbonate (28.00 mg, 0.21 mmol) and (5R, 9R) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl 4-nitrobenzenesulfonate (53.00 mg, 0.10 mmol) was added to the reaction and after stirring at 70℃for 4 hours, LCMS monitored complete reaction.

The reaction solution was cooled to room temperature, water (5.0 ml) was then added to the reaction solution, the mixture was extracted with ethyl acetate (50.0 ml. Times.3), and the organic phases were combined, dried over saturated brine (25.0 ml. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography to give 17.70 mg of (5R, 9S) -9- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one (yield: 24.6%).

LCMS：RT＝1.91 min，[M+H] ⁺ ＝656.23。 ¹ H NMR(500MHz，DMSO-d6)：δ9.38(s，1H)，8.80(s，1H)，8.68(d，J＝5.1Hz，1H)，8.11(s，0.25H)，7.96(s，0.50H)，7.90(s，1H)，7.85-7.78(m，3.25H)，7.67(m，1H)，7.40(dd，J＝5.4，1.5Hz，1H)，7.04(s，1H)，5.77(dd，J＝12.2，4.3Hz，1H)，3.29(s，3H)，2.39-2.27(m，1H)，2.04-1.84(m，3H)，1.56-1.37(m，1H)，1.35m，1H)，1.18(m，1H)，0.95(d，J＝6.7Hz，3H)。

Example 2

Synthesis of (5R, 9S) -9- (4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one

The specific synthetic route is as follows:

/>

step A: synthesis of ethyl 4, 4-trifluoro-3-22-toluenesulfonyl hydrazino) butyrate

To 4-methylbenzenesulfonyl hydrazide (9 g, 48.33 mmol) were added dry ethanol (75.0 ml) and ethyl 4, 4-trifluoro-3-oxobutanoate (9.34 g, 50.74 mmol), followed by stirring at 65 degrees for 6 hours.

TLC showed no starting material remained and new spots with reduced polarity were formed. Ethanol was removed by concentration under reduced pressure, and the resulting residue was slurried with methyl tertiary ether to give 13 g of ethyl 4, 4-trifluoro-3- (2-toluenesulfonyl) butanoate as a white solid (yield: 76%).

And (B) step (B): synthesis of 1- (2-bromo-4-chlorophenyl) -4- (trifluoromethyl) -1H-1,2, 3-triazole-5-carboxylic acid ethyl ester

Ethyl 4, 4-trifluoro-3- (2-toluenesulfonyl) butyrate (14 g, 39.74 mmol) was dissolved in dry toluene (200.0 ml) and dry dimethyl sulfoxide (40.0 ml). Subsequently, 2-bromo-4-chloroaniline (12.31 g, 59.60 mmol) and copper bromide (1.78 g, 7.95 mmol) were added to the above solution, followed by nitrogen substitution three times. Then stirred at 100 degrees for 16 hours.

TLC showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove toluene, then 200 ml of ethyl acetate was added, followed by washing with saturated brine (50 ml. Times.3 times), and the organic phase was dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to give 16 g of ethyl 1- (2-bromo-4-chlorophenyl) -4- (trifluoromethyl) -1H-1,2, 3-triazole-5-carboxylate as a reddish brown oil, which was directly used in the next reaction.

Step c: synthesis of 1- (2-bromo-4-chlorophenyl) -4-trifluoromethyl-1H-1, 2, 3-triazole-5-carboxylic acid

To ethyl 1- (2-bromo-4-chlorophenyl) -4-trifluoromethyl-1H-1, 2, 3-triazole-5-carboxylate (16 g, 40.14 mmol) was added tetrahydrofuran (72.0 ml) and water (48.0 ml) and methanol (24.0 ml), followed by addition of lithium hydroxide monohydrate (6.74 g, 160.58 mmol) and then further reaction at room temperature for 4 hours.

TLC showed the reaction was complete. The reaction solution was cooled to zero degree, 1N hydrochloric acid solution was added dropwise to the reaction solution directly to pH 4 of the reaction solution, then extracted with ethyl acetate (200 ml×3 times), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/4) to give 11 g of 1- (2-bromo-4-chlorophenyl) -4- (trifluoromethyl) -1H-1,2, 3-triazole-5-carboxylic acid (yield: 74%) as a yellow solid.

Step D: synthesis of 1- (2-bromo-4-chlorophenyl) -4- (trifluoromethyl) -1H-1,2, 3-triazole

To 1- (2-bromo-4-chlorophenyl) -4- (trifluoromethyl) -1H-1,2, 3-triazole-5-carboxylic acid (11 g, 29.69 mmol) was added dry acetonitrile (100.0 ml), triethylamine (6.01 g, 59.38 mmol), and cuprous chloride (293.91 mg, 2.97 mmol) in sequence. Then, the reaction was carried out at 65℃for 8 hours.

TLC showed the reaction was complete. To the reaction solution was poured ethyl acetate (300 ml), followed by washing with saturated brine (50 ml. Times.2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=0/1) to give 7.5 g of 1- (2-bromo-4-chlorophenyl) -4- (trifluoromethyl) -1H-1,2, 3-triazole as a yellow solid (yield: 77%).

Step E: synthesis of 4-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-ylphenyl) -3, 6-dimethoxypyridazine

1- (2-bromo-4-chlorophenyl) -4- (trifluoromethyl) -1H-1,2, 3-triazole (1.5 g, 4.59 mmol) was dissolved in dioxane (24.0 ml) and water (6.0 ml), then 3, 6-dimethoxypyridazine-4-boronic acid (930 mg, 5.05 mmol), potassium carbonate (1.90 g, 13.78 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (336 mg, 0.46 mmol) were added sequentially. Then, after three times of nitrogen substitution, the reaction was carried out at 100℃for 5 hours.

LCMS showed the reaction was complete. Silica gel powder was poured into the reaction solution, and the residue obtained after concentration was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/4) to obtain 300 mg of 4-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-ylphenyl) -3, 6-dimethoxypyridazine as a yellow solid (yield: 19%). LCMS: rt=2.04 min, [ m+h] ⁺ ＝386.12。

Step F: synthesis of 5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-ylphenyl) -6-methoxypyridazin-3 (2H) -one

4-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-ylphenyl) -3, 6-dimethoxypyridazin-3 (2H) -one (300 mg, 0.78 mmol) was dissolved in tetrahydrofuran (4.5 ml) and methanol (0.45 ml), then concentrated hydrochloric acid (0.11 ml, 1.40 mmol) was added, and then reacted at 45℃for four hours.

TLC showed no starting material remained, and two new spots with greater polarity were generated (the spot with the greatest polarity was the target product). Ethyl acetate (50 ml) was added to the reaction solution, the pH was adjusted to 9.0 with saturated sodium bicarbonate solution, the organic phase was washed with saturated brine (10 ml×1 times), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give 200 mg of 5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-ylphenyl) -6-methoxypyridazine-3 as a yellow oil (yield: 69%). LCMS: rt=1.86 min, [ m+h ] ⁺ ＝372.10。

Step G: synthesis of (5R, 9S) -9- (4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one

5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-ylphenyl) -6-methoxypyridazin-3 (2H) -one (35 mg, 94. Mu. Mol) was dissolved in dry N, N-dimethylformamide (1.0 ml), followed by the sequential addition of potassium carbonate (49.10 mg, 188. Mu. Mol) and (5R, 9R) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl 4-nitrobenzenesulfonate (26.03 mg, 188 micromolar). Then reacted at 70℃for two hours.

LCMS showed the reaction was complete. Ethyl acetate (10 ml) was added to the reaction solution, washed with saturated brine (5 ml. Times.3), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4/1), followed by further purification by preparative high performance liquid chromatography to give 25.8 mg of (5R, 9S) -9- (4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -3-methoxy-6-oxopyridazin-1 (6H) -yl) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one.

LCMS：RT＝1.97min，[M+H] ⁺ = 690.27. (yield: 39.7%). ¹ H NMR(400MHz，DMSO-d ₆ )δ9.37(s，1H)，9.29(s，1H)，8.65(d，J＝5.1Hz，1H)，7.95(t，J＝56.0Hz，1H)，7.917.84(m，4H)，7.65(s，1H)，7.417.39(m，1H)，7.11(s，1H)，5.78(dd，J＝12.2，4.3Hz，1H)，3.21(s，3H)，2.482.57(m，1H)，2.362.30(m，1H)，1.931.83(m，2H)，1.501.40(m，1H)，1.161.06(m，1H)，0.95(d，J＝6.8Hz，3H)，0.920.72(m，1H)。

Example 3

Synthesis of 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl) furo [3,2-b]Pyridin-5 (4H) -ones

The specific synthetic route is as follows:

step A: synthesis of methyl 3- (4-methoxybenzyl) amino) furan-2-carboxylate

Methyl 3-aminofuran-2-carboxylate (7 g, 49.6 mmol) was dissolved in dry methanol (140.0 ml), 4-methoxybenzaldehyde (8.10 g, 59.52 mmol) was added, acetic acid (2.98 g, 49.6 mmol) and sodium cyanoborohydride (6.23 g, 99.20 mmol) were added under an ice bath, after one hour of reaction, acetic acid (2.98 g, 49.6 mmol) and sodium cyanoborohydride (6.23 g, 99.20 mmol) were added again, and then the reaction was continued at room temperature for one hour.

TLC showed that starting material remained and new spots of reduced polarity were formed. To the reaction solution was poured 80 ml of saturated sodium chloride solution, methanol was removed by vacuum concentration, then extracted with ethyl acetate (100 ml×3 times), the organic phases were combined, then dried over anhydrous sodium sulfate, finally vacuum concentration was performed, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/9) to give 4 g of methyl 3- (4-methoxybenzyl) amino) furan-2-carboxylate as a yellow oil (yield: 30.8%).

And (B) step (B): synthesis of methyl 3- (3-methoxy-N- (4-methoxybenzyl) -3-oxopropanamido) furan-2-carboxylate

Methyl 3- (4-methoxybenzyl) amino) furan-2-carboxylate (4 g, 15.3 mmol) was dissolved in dry dichloromethane (80 ml), triethylamine (2.33 g, 23.0 mmol) was added under ice-bath, then methyl 3-chloro-3-oxopropionate (3.35 g, 24.5 mmol) was added dropwise, and then reacted for two hours at room temperature.

LCMS showed the reaction was complete. To the reaction solution was poured 100 ml of methylene chloride, followed by washing with a saturated sodium chloride solution (50 ml. Times.1), and the organic phase was dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give 5.4 g of methyl 3- (3-methoxy-N- (4-methoxybenzyl) -3-oxopropanamido) furan-2-carboxylate as a yellow solid (yield: 97.6%). LCMS: rt=1.89 min, [ m+na ]] ⁺ ＝384.13。

Step C: synthesis of 7-hydroxy-4- (4-methoxybenzyl) furo [3,2-b ] pyridin-5 (4H) -one

Methyl 3- (3-methoxy-N- (4-methoxybenzyl) -3-oxopropanamido) furan-2-carboxylate (4.2 g, 11.6 mmol) was dissolved in dry methanol (42 ml), then sodium methoxide methanol solution (4 ml,23.2 mmol, 5M) was added and then reacted at 85 degrees for two hours.

LCMS showed the reaction was complete. The reaction solution was cooled to room temperature. Sodium hydroxide (2.34 g, 58 mmol) was dissolved in water (21 ml), and then poured into the above reaction solution, and the reaction solution was heated to 120℃to react for 16 hours.

LCMS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove methanol, then cooled to zero, 1mol/L HCl solution was added dropwise, during which a solid was precipitated, and the mixture was continuously added dropwise until the pH of the aqueous phase was about 6, filtered, and the solid was washed with water, and then dried in an oven at 50℃to give 3.0 g of 7-hydroxy-4- (4-methoxybenzyl) furo [3,2-b ] pyridin-5 (4H) -one (yield: 95%). LCMS: rt=1.74 min, [ M-H ] -270.09.

Step D: synthesis of 4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrofuro [3,2-b ] pyridin-7-yl triflate

7-hydroxy-4- (4-methoxybenzyl) furo [3,2-b ] pyridin-5 (4H) -one (1.7 g, 6.27 mmol) was dissolved in dry N, N-dimethylformamide (17.0 ml). Subsequently, triethylamine (1.27 g, 12.53 mmol) and 1, 1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (2.91 g, 8.15 mmol) were added to the above solution at zero degrees. Then stirred at room temperature for 2 hours.

TLC showed no starting material remained and new spots with reduced polarity were formed. To the reaction solution was added 50 ml of ice water for quenching, the mixture was extracted with ethyl acetate (80 ml. Times.3), and the organic phases were combined, the organic phase was first dried with saturated brine (30 ml. Times.1), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=3/7) to give 2.2 g of 4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrofuro [3,2-b ] pyridin-7-yl trifluoromethanesulfonate (yield: 86.9%).

Step E: synthesis of 7-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl-4- (4-methoxybenzyl) furo [3,2-b ] pyridin-5 (4 Hr) -one 4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrofuro [3,2-b ] pyridin-7-yl triflate (720 mg, 1.79 mmol) was dissolved in dry N, N-dimethylformamide (20 ml). Subsequently, 4-chloro-1-4-chloro-2-trimethylstannylphenyl-1, 2, 3-triazole (672 g, 1.79 mmol) and triphenylarsine (54.67 mg, 0.18 mmol) were sequentially added to the above solution, bis (triphenylphosphine) palladium dichloride (125.3 mg, 0.18 mmol) was then replaced with nitrogen three times. Then stirred at 100℃for 5 hours.

LCMS showed the reaction was complete. To the reaction solution was added 80 ml of ethyl acetate, followed by washing with saturated brine (50 ml. Times.3 times), followed by drying over anhydrous sodium sulfate, and finally concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give 0.6 g of 7-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl-4- (4-methoxybenzyl) furo [3,2-b ] as a yellow oil]Pyridin-5 (4H) -one (yield: 72%). LCMS: rt=2.00 min, [ m+h] ⁺ ＝467.14。

Step F: synthesis of 7-chloro-2- (4-chloro-1, 2, 3-triazole-1-phenyl) furan

To 7-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl-4- (4-methoxybenzyl) furo [3,2-b ] pyridin-5 (4H) -one (400 mg, 0.85 mmol) was added dry 1, 2-dichloroethane (2 ml) and trifluoroacetic acid (1 ml), followed by 100 degrees microwave for 10 minutes.

LCMS showed the reaction was complete. Ethyl acetate (50 ml) was added to the reaction solution, the pH was adjusted to 10 with saturated sodium bicarbonate solution (30 ml), the organic phase was washed with saturated brine (10 ml. Times.1), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) to give 200 mg of 7-chloro-2- (4-chloro-1, 2, 3-triazole-1-phenyl) furo [3,2-b ] as a yellow solid ]Pyridin-5 (4H) -one (yield: 67%). LCMS: rt=1.77 min, [ m+h] ⁺ ＝347.03。

Step G: synthesizing 7- (5-chloro-2- (4-chloro-1H-1),2, 3-triazol-1-yl) phenyl) -4- (5 r,9 s) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl) furo [3,2-b]Pyridin-5 (4H) -ones

To 7-chloro-2- (4-chloro-1, 2, 3-triazole-1-phenyl) furan (70 mg, 0.20 mmol) was added dry tetrahydrofuran (4 ml), then 1N lithium bis- (trimethylsilyl) amide in tetrahydrofuran (0.30 ml, 0.3 mmol, 1mol/L in THF) was added dropwise at zero degree, and the reaction was continued for 30 minutes at zero degree after completion of the dropwise addition. (5R, 9R) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl 4-nitrobenzenesulfonate (105 mg, 0.20 mmol) was dissolved in 1 ml dry tetrahydrofuran, then added dropwise to the above reaction solution, and then reacted at 70℃for 3 days.

LCMS showed starting material remained, product was formed. Ethyl acetate (30 ml) was added to the reaction solution, followed by pouring an ice saturated ammonium chloride solution for washing (10 ml), saturated brine (5 ml. Times.1) was used for washing the organic phase, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) to give 43 mg of a yellow oil, which was then purified by preparative high performance liquid chromatography to give 10.4 mg of 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5 r,9 s) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl) furo [3,2-b]Pyridin-5 (4H) -one (yield: 7.4%). LCMS: rt=1.53 min, [ m+h] ⁺ ＝665.17。

Example 4

Synthesis of 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl) -2, 3-dihydrofuro [3,2-b]Pyridin-5 (4 Hr) -ones

The specific synthetic route is as follows:

step A: synthesis of 4- (4-methoxybenzyl) -7-methoxymethoxyfuro [3,2-b ] pyridin-5 (4H) -one

7-hydroxy-4- (4-methoxybenzyl) furo [3,2-b ] pyridin-5 (4H) -one (3.2 g, 11.8 mmol) was dissolved in dry N, N-dimethylformamide (40 ml) and then cooled to zero, sodium hydride (802 mg, 20.05 mmol, 60% wt) was added in three portions, then reacted for 15 minutes at zero, bromo (methoxy) methane (2.21 g, 17.69 mmol) was added, and then reacted for 1 hour at room temperature.

TLC showed some starting material remained. The reaction solution was poured into ice water (100 ml), followed by extraction with ethyl acetate (100 ml×2 times). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue obtained is purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether=4/1) to give 2.2 g of 4- (4-methoxybenzyl) -7-methoxymethoxyfuro [3,2-b ] as a colourless solid ]Pyridin-5 (4H) -one (yield: 59%). LCMS: rt=1.84 min, [ m+h] ⁺ ＝316.17。

And (B) step (B): synthesis of 4- (4-methoxybenzyl) -7-methoxymethoxy-2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) -one

4- (4-methoxybenzyl) -7-methoxymethoxyfuro [3,2-b ] pyridin-5 (4H) -one (1.1 g, 3.49 mmol) was dissolved in ethyl acetate (40 ml), then wet palladium on carbon (200 mg, 10% wt) was added, hydrogen was replaced three times, and then reacted at 10 atmospheres of hydrogen at room temperature for six days.

TLC showed that starting material remained and new spots with increased polarity were formed. Filtration through celite, washing of the filter cake with ethyl acetate (300 ml), concentration of the filtrate under reduced pressure, purification of the resulting residue by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether=1/0) gives 250 mg of 4- (4-methoxybenzyl) -7-methoxymethoxy-2, 3-dihydrofuro [3,2-b ] as a yellow oil]Pyridin-5 (4H) -one (yield: 22%).LCMS：RT＝1.80min，[M+H] ⁺ ＝318.17。

Step C: synthesis of 7-hydroxy-4- (4-methoxybenzyl) -2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) -one

4- (4-methoxybenzyl) -7-methoxymethoxy-2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) -one (200 mg, 0.63 mmol) was dissolved in methanol (5 ml), then 4-methylbenzenesulfonic acid monohydrate (156 mg, 0.82 mmol) was added, and then reacted at room temperature for two hours.

TLC showed no starting material remained and new spots with increased polarity were formed. Ethyl acetate (50 ml) was added to the reaction solution, the mixture was washed with saturated brine (10 ml. Times.2), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) to give 70 mg of 7-hydroxy-4- (4-methoxybenzyl) -2, 3-dihydrofuro [3,2-b ] as a yellow oil]Pyridin-5- (4H) -one (yield: 40%). LCMS: rt=1.66 min, [ m+h] ⁺ ＝274.20。

Step D: synthesis of 4- (4-methoxybenzyl) -5-oxo-2, 3,4, 5-tetrahydrofurano [3,2-b ] pyridin-7-yl triflate

7-hydroxy-4- (4-methoxybenzyl) -2, 3-dihydrofuro [3,2-b ] pyridin-5- (4H) -one (300 mg, 1.1 mmol) was dissolved in dry N, N-dimethylformamide (6 ml), then triethylamine (222 mg, 2.2 mmol) and 1, 1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (509 mg, 1.43 mmol) were added at zero degrees and then reacted at room temperature for two hours.

TLC showed no starting material remained and new spots with reduced polarity were formed. Ethyl acetate (50 ml) was added to the reaction solution, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give 290 mg of 4- (4-methoxybenzyl) -5-oxo-2, 3,4, 5-tetrahydrofurano [3,2-b ] pyridin-7-yl trifluoromethanesulfonate as a yellow oil (yield: 65%).

Step E: synthesis of 4-chloro-1-4-chloro-2-trimethylstannylphenyl-1, 2, 3-triazole

2-bromo-4-chlorophenyl-4-chloro-1, 2, 3-triazole (3 g, 10.24 mmol) was dissolved in dry toluene (70 ml), then after addition of hexamethylditin (6.71 g, 20.48 mmol) and tetrakis (triphenylphosphine) palladium (2.35 g, 2.05 mmol), then nitrogen was replaced three times, and then reacted at 120 degrees for 16 hours.

TLC showed some starting material remained with new spots of reduced polarity. Ethyl acetate (150 ml) was added to the reaction solution, which was washed with a saturated potassium fluoride solution (30 ml. Times.2 times), which was washed with saturated brine (20 ml. Times.1 times.), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/49) to give 2.3 g of 4-chloro-1-4-chloro-2-trimethylstannylphenyl-1, 2, 3-triazole as a white solid (yield: 59%).

Step F: synthesis of 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) -2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) -one

4- (4-methoxybenzyl) -5-oxo-2, 3,4, 5-tetrahydrofurano [3,2-b ] pyridin-7-yl triflate (270 mg, 0.66 mmol) was dissolved in dry N, N-dimethylformamide (10 ml), 4-chloro-1-4-chloro-2-trimethylstannylphenyl-1, 2, 3-triazole (251 mg, 0.66 mmol), triphenylarsine (20.4 mg, 0.066 mmol), bis (triphenylphosphine) palladium dichloride (46.75 mg, 0.066 mmol) was added sequentially under greenhouse conditions, followed by three nitrogen substitutions and then 100℃reaction for 5 hours.

LCMS showed the reaction was complete. Ethyl acetate (80 ml) was added to the reaction solution, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give 140 mg of 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) -2, 3-dihydrofuro [3,2-b ] as a yellow solid]Pyridin-5 (4H) -one (yield: 44%). LCMS: rt=1.97 min, [ m+h] ⁺ ＝469.18。

Step G: synthesis of 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) -one

To 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) -2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) -one (140 mg, 0.30 mmol) was added dry 1, 2-dichloroethane (2 ml) and trifluoroacetic acid (1 ml), followed by 100 degree microwave for 10 min.

LCMS showed the reaction was complete. To the reaction solution was added ethyl acetate (50 ml), the pH was adjusted to 10 with saturated sodium bicarbonate solution (30 ml), and the organic phase was washed with saturated brine (10 ml×1 times). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) to give 100 mg of 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 3-dihydrofuro [3,2-b ] as a yellow solid ]Pyridin-5 (4H) -one (yield: 96%). LCMS: rt=1.77 min, [ m+h] ⁺ ＝349.09。

Step H: synthesis of 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl) -2, 3-dihydrofuro [3,2-b]Pyridin-5 (4H) -ones

To 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 3-dihydrofuro [3,2-b]Pyridin-5 (4H) -one (70 mg, 0.20 mmol) dry tetrahydrofuran (4 ml) was added followed by dropwise addition of 1N lithium bis- (trimethylsilyl) amide in tetrahydrofuran (0.22 ml, 0.22 mmol, 1mol/L in THF) at zero degrees, and the reaction was continued for 30 minutes at zero degrees after completion of the dropwise addition. (5R, 9R) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl 4-nitrobenzenesulfonate (104.55 mg, 0.20 mmol) was dissolved in 1 ml dry tetrahydrofuran, then added dropwise to the above reaction solution, followed by reaction at 70℃for 3 days.

LCMS showed starting material remained, product was formed. Ethyl acetate (30 ml) was added to the reaction solution, the mixture was washed with an ice saturated ammonium chloride solution (10 ml. Times.1), the organic phase was washed with saturated brine (5 ml. Times.1), and the organic phase was dried over anhydrous sodium sulfate, followed by reduction Concentration under pressure, purification of the resulting residue by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) afforded 31 mg of a yellow solid, followed by purification by preparative high performance liquid chromatography afforded 3.4 mg of 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5 r,9 s) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl) -2, 3-dihydrofuro [3,2-b]Pyridin-5 (4H) -one (yield: 2.5%). LCMS: rt=1.89 min, [ m+h] ⁺ ＝667.23。

Example 5

Synthesis of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -1- (5R, 9S) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridine-2 (5, 4) -pyrazole cyclononanaphthalen-9-yl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione

The specific synthetic route is as follows:

step A: synthesis of 3- ((4-methoxybenzyl) amino) cyclopent-2-en-1-one

(4-methoxyphenyl) methylamine (1.4 g, 10 mmol) and cyclopentane-1, 3-dione (1.0 g, 10 mmol) were dissolved in absolute ethanol (15 ml), and the reaction solution was stirred at 80 ℃ overnight. After the reaction is completed, the reaction solution is cooled to about 5 ℃ and cooled down for crystallization for 1 hour, and then 2.0 g of light yellow solid 3- ((4-methoxybenzyl) amino) cyclopent-2-en-1-one (yield: 92.2%) is obtained by filtration and drying.

And (B) step (B): synthesis of 4-hydroxy-1- (4-methoxybenzyl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione

3- ((4-methoxybenzyl) amino) cyclopent-2-en-1-one (1.9 g, 8.75 mmol) and bis (2, 4, 6-trichlorophenyl) malonate (4 g, 8.75 mmol) were dissolved in dry toluene (50 ml) and the resulting reaction was stirred at 100 ℃ for 3 hours.

TLC monitoring showed that after the reaction was completed, it was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1), to give 1.3 g of 4-hydroxy-1- (4-methoxybenzyl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione (yield: 51%).

Step C: synthesis of 1- (4-methoxybenzyl) -2, 5-dioxo-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ b ] pyridin-4-yl triflate

4-hydroxy-1- (4-methoxybenzyl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione (1.3 g, 4.5 mmol) and N-phenylbis (trifluoromethanesulfonyl) imine (1.9 g, 5.4 mmol) were dissolved in dry dichloromethane (60 ml), then triethylamine (0.68 g, 6.75 mmol) was added and the resulting reaction was stirred at room temperature for 3 hours.

TLC monitoring showed that the reaction was completed, water was added to the reaction solution, the mixture was extracted with methylene chloride (50 ml. Times.3 times), the organic phases were combined, the organic phase was washed with saturated aqueous sodium chloride (30 ml. Times.2 times), then dried over anhydrous sodium sulfate, and finally purified by column chromatography on silica gel (eluent: n-hexane: ethyl acetate=3:1) to give 1.3 g of 1- (4-methoxybenzyl) -2, 5-dioxo-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ b ] pyridin-4-yl triflate (yield: 68.8%).

Step D: synthesis of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -1- (4-methoxybenzyl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione

1- (4-methoxybenzyl) -2, 5-dioxo-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ b ] pyridin-4-yl trifluoromethanesulfonate (1.9 g, 4.68 mmol) and 4-chloro-1- (4-chloro-2-trimethylstannyl) phenyl-1H-1, 2, 3-triazole (1.6 g, 4.25 mmol) were dissolved in dry DMF (50 ml), then triphenylarsenic (0.15 g, 0.43 mmol) and ditolylphosphine palladium dichloride (0.3 g, 0.43 mmol) were added, the resulting reaction mixture was replaced three times with nitrogen and stirred overnight at 100 ℃.

TLC monitoring showed that the reaction was completed, water was added to the reaction mixture, the mixture was extracted with ethyl acetate (200 ml x 3 times), the organic phases were combined, the organic phases were washed with saturated aqueous sodium chloride (100 ml x 2 times) and then dried over anhydrous sodium sulfate, and finally purified by column chromatography on silica gel (eluent: n-hexane: ethyl acetate=2:1) to give 1.7 g of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -1- (4-methoxybenzyl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione (yield: 83%).

Step E: synthesis of 3-chloro-4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione

4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -1- (4-methoxybenzyl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione (1.7 g, 3.53 mmol) and trifluoroacetic acid (5 ml) were dissolved in dry dichloroethane (10 ml), and the resulting reaction mixture was reacted at 100℃for 30 minutes in a microwave reactor.

TLC monitoring showed that the reaction was completed, the reaction solution was dried by spinning, the pH of the residue was adjusted to about 8 by adding water and sodium hydrogencarbonate, the mixed solution was extracted with ethyl acetate (50 ml. Times.3 times), the organic phases were combined, the organic phase was washed with saturated aqueous sodium chloride solution (100 ml. Times.2 times), then dried over anhydrous sodium sulfate, and dried by spinning to give 1.1 g of 3-chloro-4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione (yield: 86%). ¹ H NMR(400MHz，DMSO-d6)δ12.65(s，1H)，8.61(s，1H)，7.77(dd，J＝8.6，2.3Hz，1H)，7.71(d，J＝8.5Hz，1H)，7.61(d，J＝2.3Hz，1H)，6.09(s，1H)，2.85(t，J＝5.5Hz，2H)，2.31(d，J＝1.2Hz，2H)。

Step F: synthesis of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -1- (5R, 9 s) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridine-2 (5, 4) -pyrazole cyclononanaphthalen-9-yl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione

3-chloro-4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione (200 mg, 0.55 mmol) was dissolved in dry tetrahydrofuran (5 ml), then lithium bis (trimethylsilyl) amide (1 mol/l tetrahydrofuran solution, 0.82 ml, 0.82 mmol) was slowly added and the resulting reaction was stirred at room temperature for 30 minutes. (5R, 9R) -2 is then added ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl-4-nitrobenzenesulfonate (300 mg, 0.55 mmol). The reaction was warmed to 70 ℃ and stirred at this temperature for 48 hours.

After the completion of the reaction, TLC was monitored to show that it was cooled to room temperature, a saturated aqueous ammonium chloride solution (4 ml) and ethyl acetate (50 ml) were added to the reaction solution and extracted, and the obtained organic phase was washed with saturated brine (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4/1), followed by further purification by preparative high performance liquid chromatography to give 20 mg of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -1- (5 r,9 s) -21-difluoromethyl-5-methyl-4-oxo-21H-3-aza-1 (4, 2) -pyridine-2 (5, 4) -pyrazole cyclononanaphthalen-9-yl) -6, 7-dihydro-1H-cyclopentylpyridine-2, 5-dione as a white solid. LC-MS: rt=2.02 min, [ m+h] ⁺ ＝679.23。

Example 6

Synthesis of 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl) -2, 3-dihydrofuro [3,2-b ]Pyridin-5 (4H) ones

The specific synthetic route is as follows:

/>

step A: synthesis of methyl 3- (4-methoxybenzyl) amino) furan-2-carboxylate

Methyl 3-aminofuran-2-carboxylate (7 g, 49.6 mmol) was dissolved in dry methanol (140 ml), 4-methoxybenzaldehyde (8.1 g, 59.5 mmol) was added, acetic acid (3 g, 49.6 mmol) and sodium cyanoborohydride (6.2 g, 99.2 mmol) were added under an ice bath, after one hour of reaction, acetic acid (2.98 g, 49.6 mmol) and sodium cyanoborohydride (6.2 g, 99.2 mmol) were added again, and then the reaction was carried out at room temperature for one hour.

Step C: synthesis of 7-hydroxy-4- (4-methoxybenzyl) furan [3,2-b ] pyridin-5-one

Methyl 3- (3-methoxy-N- (4-methoxybenzyl) -3-oxopropanamido) furan-2-carboxylate (4.2 g, 11.6 mmol) was dissolved in dry methanol (42 ml), then sodium methoxide methanol solution (5 mol/l methanol solution, 4 ml, 23.2 mmol) was added and then reacted at 85 degrees for two hours.

LCMS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove methanol, then cooled to zero, 1mol/L HCl solution was added dropwise, during which a solid was precipitated, and the mixture was continuously added dropwise until the pH of the aqueous phase was about 6, filtered, the solid was washed with water, and then oven-dried at 50℃to give 3.0 g of 7-hydroxy-4- (4-methoxybenzyl) furan [3,2-b ] pyridin-5-one (yield: 95%). LCMS: rt=1.74 min, [ M-H ] - = 270.09.

Step D: synthesis of 4- (4-methoxybenzyl) -7-methoxymethoxyfuro [3,2-b ] pyridin-5 (4H) -one

7-hydroxy-4- (4-methoxybenzyl) furan [3,2-b ] pyridin-5-one (3.2 g, 11.8 mmol) was dissolved in dry N, N-dimethylformamide (40 ml), then cooled to zero, sodium hydride (802 mg, 20.05 mmol, 60% wt) was added in three portions, then reacted at zero for 15 minutes, bromo (methoxy) methane (2.21 g, 17.69 mmol) was added, and then reacted at room temperature for 1 hour.

TLC showed some starting material remained. The reaction solution was poured into ice water (100 ml), followed by extraction with ethyl acetate (100 ml×2 times). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue obtained is purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether=4/1) to give 2.2 g of 4- (4-methoxybenzyl) -7-methoxymethoxyfuro [3,2-b ] as a colourless solid]Pyridin-5 (4H) -one (yield: 59%). LCMS: rt=1.84 min, [ m+h] ⁺ ＝316.17。

Step E: synthesis of 4- (4-methoxybenzyl) -7-methoxymethoxy-2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) one

TLC showed that starting material remained and new spots with increased polarity were formed. Filtering with celite, washing the filter cake with ethyl acetate (300 ml), concentrating the filtrate under reduced pressureThe residue obtained was purified by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether=1/0) to give 250 mg of 4- (4-methoxybenzyl) -7-methoxymethoxy-2, 3-dihydrofuro [3,2-b ] as a yellow oil]Pyridin-5 (4H) one (yield: 22%). LCMS: rt=1.80 min, [ m+h] ⁺ ＝318.17。

Step F: synthesis of 7-hydroxy-4- (4-methoxybenzyl) -2, 3-dihydrofuran [3,2-b ] pyridin-5 (4H) -one

4- (4-methoxybenzyl) -7-methoxymethoxy-2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) one (200 mg, 0.63 mmol) was dissolved in methanol (5 ml), then 4-methylbenzenesulfonic acid monohydrate (156 mg, 0.82 mmol) was added, and then reacted at room temperature for two hours.

TLC showed no starting material remained and new spots with increased polarity were formed. Ethyl acetate (50 ml) was added to the reaction solution, the mixture was washed with saturated brine (10 ml. Times.2), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) to give 70 mg of 7-hydroxy-4- (4-methoxybenzyl) -2, 3-dihydrofuran [3,2-b ] as a yellow oil ]Pyridin-5 (4H) -one (yield: 40%). LCMS: rt=1.66 min, [ m+h] ⁺ ＝274.20。

Step G: synthesis of 4- (4-methoxybenzyl) -5-oxo-2, 3,4, 5-tetrahydrofuran [3,2-b ] pyridin-7-yl triflate

7-hydroxy-4- (4-methoxybenzyl) -2, 3-dihydrofuran [3,2-b ] pyridin-5 (4H) -one (300 mg, 1.1 mmol) was dissolved in dry N, N-dimethylformamide (6 ml), then triethylamine (222 mg, 2.2 mmol) and 1, 1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (509 mg, 1.43 mmol) were added at zero degrees and then reacted at room temperature for two hours.

TLC showed no starting material remained and new spots with reduced polarity were formed. Ethyl acetate (50 ml) was added to the reaction solution, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give 290 mg of 4- (4-methoxybenzyl) -5-oxo-2, 3,4, 5-tetrahydrofuran [3,2-b ] pyridin-7-yl trifluoromethanesulfonate as a yellow oil (yield: 65%).

Step H: synthesis of 1- (4-chloro-2-trimethylstannyl) phenyl-4-trifluoromethyl-1H-1, 2, 3-triazole

2-bromo-4-chlorophenyl-4-trifluoromethyl-1, 2, 3-triazole (7 g, 21.6 mmol) was dissolved in dry toluene (80 ml), then after hexamethylditin (14.1 g, 43.2 mmol) and tetrakis (triphenylphosphine) palladium (4.9 g, 4.32 mmol) were added, then replaced with nitrogen three times, and then reacted at 120℃for 16 hours.

TLC showed some starting material remained with new spots of reduced polarity. Ethyl acetate (150 ml) was added to the reaction solution, which was washed with saturated potassium fluoride solution (30 ml×2 times), saturated brine (20 ml×1 times), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 6 g of 1- (4-chloro-2-trimethylstannyl) phenyl-4-trifluoromethyl-1H-1, 2, 3-triazole as a white solid (yield: 67.5%), LCMS: rt=1.90 min, [ m+h] ⁺ ＝412.91。

Step I: synthesis of 7- (5-chloro-2- (4-trifluoromethyl-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) -2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) one

4- (4-methoxybenzyl) -5-oxo-2, 3,4, 5-tetrahydrofuran [3,2-b ] pyridin-7-yl trifluoromethanesulfonate (700 mg, 1.7 mmol) was dissolved in dry toluene (10 ml), 1- (4-chloro-2-trimethylstannyl) phenyl-4-trifluoromethyl-1H-1, 2, 3-triazole (852 mg, 2.07 mmol) was added sequentially under greenhouse conditions, tetrakis (triphenylphosphine) palladium (196 mg, 0.17 mmol) was then replaced three times with nitrogen, and then reacted at 100℃for 5 hours.

LCMS showed the reaction was complete. Ethyl acetate (80 ml) was added to the reaction solution, which was washed with saturated brine (30 ml×3 times), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give 580 mg of 7- (5-chloro-2- (4-trifluoromethyl-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) -2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) one as a yellow solid (yield: 68%).

Step J: synthesis of 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) one

To 7- (5-chloro-2- (4-trifluoromethyl-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) -2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) one (230 mg, 0.46 mmol) was added dry 1, 2-dichloroethane (2 ml) and trifluoroacetic acid (1 ml), followed by 100 degree microwave for 10 min.

LCMS showed the reaction was complete. To the reaction solution was added ethyl acetate (50 ml), the pH was adjusted to 10 with saturated sodium bicarbonate solution (30 ml), and the organic phase was washed with saturated brine (10 ml×1 times). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) to give 167 mg of 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -2, 3-dihydrofuro [3,2-b ] as a yellow solid ]Pyridin-5 (4H) one (yield: 95%). LCMS: rt=1.84 min, [ m+h] ⁺ ＝383.09。

Step K: synthesis of 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl) -2, 3-dihydrofuro [3,2-b]Pyridin-5 (4 Hr) ones

To 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -2, 3-dihydrofuro [3,2-b]Dry tetrahydrofuran (4 ml) was added to pyridin-5 (4H) one (100 mg, 0.26 mmol) followed by lithium bis- (trimethylsilyl) amide (1 mol/l in tetrahydrofuran, 0.29 ml, 0.29 mmol) dropwise at zero degrees, and the reaction was continued for 30 minutes at zero degrees after completion of the dropwise addition. (5R, 9R) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl-4-nitrobenzenesulfonate (136 mg, 0.26 mmol) was dissolved in 1 ml dry tetrahydrofuran, then added dropwise to the above reaction solution, and then reacted at 70℃for 3 days.

LCMSThe raw materials remained and the products were formed. Ethyl acetate (30 ml) was added to the reaction solution, the mixture was washed with a saturated ammonium chloride solution of ice (10 ml. Times.1), the organic phase was washed with saturated brine (5 ml. Times.1), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) to give 25 mg of a yellow solid, which was further purified by preparative high performance liquid chromatography to give 19 mg of a white solid, 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl) -2, 3-dihydrofuro [3,2-b]Pyridin-5 (4H) one (yield: 2.5%). LCMS: rt=1.97 min, [ m+h] ⁺ ＝701.23。 ¹ H NMR(400MHz，DMSO-d ₆ )δ9.49(s，1H)，9.21(s，1H)，8.67(d，J＝5.1Hz，1H)，8.05(d，J＝57.5Hz，1H)，7.93(s，1H)，7.81(dd，J＝9.7，1.6Hz，3H)，7.70(s，1H)，6.18(s，1H)，4.09(d，J＝8.7Hz，1H)，3.98(d，J＝9.2Hz，1H)，2.36(d，J＝24.7Hz，1H)，1.96(dd，J＝31.0，9.4Hz，1H)，1.76(s，1H)，1.60(s，1H)，1.46(s，1H)，1.23(s，1H)，1.05(d，J＝6.7Hz，3H).

Example 7

Synthesis of 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl) furan [3,2-b]Pyridin-5 (4H) ones

The specific synthetic route is as follows:

step A: synthesis of 4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrofuro [3,2-b ] pyridin-7-yl triflate

7-hydroxy-4- (4-methoxybenzyl) furan [3,2-b ] pyridin-5-one (10 g, 37 mmol) was dissolved in dry N, N-dimethylformamide (60 ml), then triethylamine (7.47 g, 74 mmol) and 1, 1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (17 g, 48 mmol) were added at zero degrees and then reacted at room temperature for two hours.

TLC showed no starting material remained and new spots with reduced polarity were formed. Ethyl acetate (500 ml) was added to the reaction solution, the mixture was washed with saturated brine (200 ml. Times.3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give 13 g of 4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrofuro [3,2-b ] as a yellow oil ]Pyridin-7-yl triflate (yield: 87%). LCMS: rt=1.97 min, [ m+h] ⁺ ＝404.64。

And (B) step (B): synthesis of 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) furo [3,2-b ] pyridin-5 (4H) one

4- (4-methoxybenzyl) -5-oxo-4, 5-dihydrofuro [3,2-b ] pyridin-7-yl trifluoromethanesulfonate (1.0 g, 2.48 mmol) was dissolved in dry N, N-dimethylformamide (10 ml), 1- (4-chloro-2-trimethylstannyl) phenyl-4-trifluoromethyl-1H-1, 2, 3-triazole (1.01 g, 2.48 mmol), triphenylarsane (153 mg, 0.5 mmol), bis (triphenylphosphine) palladium dichloride (350 mg, 0.5 mmol) was added sequentially under greenhouse conditions, followed by three nitrogen substitutions and then 100℃reaction for 5 hours.

LCMS showed the reaction was complete. Ethyl acetate (80 ml) was added to the reaction solution, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to give 570 mg of 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) furo [3,2-b ] as a yellow solid ]Pyridin-5 (4H) one (yield: 46%). LCMS: rt=2.04 min, [ m+h] ⁺ ＝501.13。

Step C: synthesis of 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-ylphenyl) furo [3,2-b ] pyridin-5 (4H) one

To 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) furo [3,2-b ] pyridine-5 (4H) (200 mg, 0.40 mmol) was added dry 1, 2-dichloroethane (2 ml) and trifluoroacetic acid (1 ml), followed by 100 degrees microwave for 10 minutes.

LCMS showed the reaction was complete. To the reaction solution was added ethyl acetate (50 ml), the pH was adjusted to 10 with saturated sodium bicarbonate solution (30 ml), and the organic phase was washed with saturated brine (10 ml×1 times). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) to give 146 mg of 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-ylphenyl) furo [3,2-b ] as a yellow solid]Pyridin-5 (4H) one (yield: 96%). LCMS: rt=1.88 min, [ m+h] ⁺ ＝381.09。

Step D: synthesis of 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl) furan [3,2-b ]Pyridin-5 (4H) ones

To 7- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-ylphenyl) furo [3,2-b]Dry tetrahydrofuran (4 ml) was added to pyridin-5 (4H) one (150 mg, 0.30 mmol) followed by dropwise addition of lithium bis- (trimethylsilyl) amide (1 mol/l in tetrahydrofuran, 0.33 ml, 0.33 mmol) at zero degrees, and the reaction was continued for 30 minutes at zero degrees after completion of the dropwise addition. (5R, 9R) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl-4-nitrobenzenesulfonate (156 mg, 0.30 mmol) was dissolved in 1 ml dry tetrahydrofuran, then added dropwise to the above reaction solution, and then reacted at 70℃for 3 days.

LCMS showed starting material remained, product was formed. Ethyl acetate (30 ml) was added to the reaction solution, which was washed with a saturated ammonium chloride solution of ice (10 ml. Times.1), the organic phase was washed with saturated brine (5 ml. Times.1), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) to give 25 mg of a yellow solid, which was further purified by preparative high performance liquid chromatography to give 27 mg of a white solid 7- (5-chloro)-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl) furan [3,2-b]Pyridin-5 (4H) one (yield: 13%). ¹ H NMR(400MHz，DMSO-d ₆ )δ9.52(s，1H)，9.23(t，J＝1.0Hz，1H)，8.65(d，J＝5.1Hz，1H)，8.197.67(m，7H)，7.497.32(m，1H)，7.02(s，1H)，6.22(s，1H)，5.62(s，1H)，2.70(d，J＝17.9Hz，1H)，2.45(s，1H)，1.84(d，J＝12.4Hz，2H)，1.671.43(m，2H)，1.16(s，1H)，1.05(d，J＝6.6Hz，3H).LCMS：RT＝2.04min，[M+H] ⁺ ＝501.13。LCMS：RT＝1.98min，[M+H] ⁺ ＝699.22。

Example 8

Synthesis of 2, 6-dichloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- ((3S, 7R) -7-methyl-11- (methyl-d 3) -8-oxo-11H-9-aza-1 (2, 3) -pyrrol-2 (1, 3) -benzocyclononan-3-yl) furan [3,2-b ] pyridin-5 (4H) -one

The specific synthetic route is as follows:

step A: synthesis of 2, 6-dichloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) -one

6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) -one (340 mg, 0.89 mmol) was dissolved in tetrahydrofuran (10 ml) and glacial acetic acid (5 ml), N-chlorobuccinimide (142 mg, 1.07 mmol) was added after cooling in an ice bath, and the reaction was allowed to warm to room temperature naturally for 18 hours.

After the reaction was completed, tap water (30 ml) was added thereto and ethyl acetate (30 ml×2 times) was extracted to obtain an organic phase, which was concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to obtain 250 mg of 2, 6-dichloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) -one as a green foam solid (yield 67%).

And (B) step (B): synthesis of 2, 6-dichloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- ((3S, 7R) -7-methyl-11- (methyl-d 3) -8-oxo-11H-9-aza-1 (2, 3) -pyrrol-2 (1, 3) -benzocyclononan-3-yl) furan [3,2-b ] pyridin-5 (4H) -one

Anhydrous tetrahydrofuran (8 ml), 2, 6-dichloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) -one (200 mg, 0.48 mmol), nitrogen substitution, ice water cooling, dropwise addition of lithium bis (trimethylsilyl) amide (1 mol/l tetrahydrofuran solution, 0.72 ml, 0.72 mmol) were added to the reaction flask at room temperature for 1 hour; (3S, 7R) -7-methyl-11- (methyl-d 3) -8-oxo-11H-9-aza-1 (2, 3) -pyrrole-2 (1, 3) -benzoylcyclononan-3-yl 4-nitrobenzenesulfonate (280 mg, 0.58 mmol) was then added and after nitrogen displacement the reaction was warmed to 70℃for 48 hours.

After the reaction, cooling to room temperature, adding saturated ammonium chloride aqueous solution (20 ml) and ethyl acetate (20 ml. Times.2) to extract an organic phase, concentrating to dryness, purifying the residue by preparative high performance liquid chromatography to obtain 31 mg of pale yellow solid 2, 6-dichloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- ((3S, 7R) -7-methyl-11- (methyl-d 3) -8-oxo-11H-9-aza-1 (2, 3) -pyrrole-2 (1, 3) -benzocyclononan-3-yl) furan [3,2-b ]Pyridin-5 (4H) -one (9% yield). LCMS: rt=2.00 min, [ m+h] ⁺ ＝700.16。

Example 9

Synthesis of 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- ((3S, 7R) -11- (difluoromethyl) -25-fluoro-7-methyl-8-oxo-11H-9-aza-1 (2, 3) -pyrrol-2 (1, 3) -benzocyclononen-3-yl) furan [3,2-b ] pyridin-5 (4H) -one

The specific synthetic route is as follows:

/>

step A: synthesis of 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) -one

7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) -one (200 mg, 0.58 mmol) was dissolved in tetrahydrofuran (2 ml) and glacial acetic acid (1 ml), N-chlorosuccinimide (93 mg, 0.70 mmol) was added after cooling in an ice bath, and the reaction was carried out at room temperature for 18 hours after natural temperature return.

After the reaction was completed, tap water (10 ml) ethyl acetate (10 ml×2 times) was added to extract an organic phase, concentrated to dryness, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to obtain a pale yellow foam solid to synthesize 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3,2-b ]]Pyridin-5 (4H) -one 140 mg (64% yield). LCMS: rt=1.84 min, [ m+h ] ⁺ ＝380.99。

And (B) step (B): synthesis of 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- ((3S, 7R) -11- (difluoromethyl) -25-fluoro-7-methyl-8-oxo-11H-9-aza-1 (2, 3) -pyrrol-2 (1, 3) -benzocyclononen-3-yl) furan [3,2-b ] pyridin-5 (4H) -one

Anhydrous tetrahydrofuran (6 ml), 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) -one (130 mg, 0.34 mmol), nitrogen substitution, ice water cooling, and dropwise addition of lithium bis (trimethylsilyl) amide (1 mol/l tetrahydrofuran solution, 0.51 ml, 0.51 mmol) were added to the reaction flask at room temperature for 1 hour; (5R, 9S) -21- (difluoromethyl) -5-methyl-4-oxo-21H-3-aza-1 (4, 2) -pyridine-2 (5, 4) -pyrazolocyclononan-9-yl-4-nitrobenzenesulfonate (218 mg, 0.42 mmol) was then added, followed by nitrogen sparge and then reaction at 70℃for 48 hours.

After the reaction was completed, the mixture was cooled to room temperature, saturated aqueous ammonium chloride (10 ml) and ethyl acetate (10 ml. Times.2) were added to extract the organic phase, and the mixture was concentrated to dryness, and the residue was purified by preparative high performance liquid chromatography to give 33 mg of 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- ((3S, 7R) -11- (difluoromethyl) -25-fluoro-7-methyl-8-oxo-11H-9-aza-1 (2, 3) -pyrrole-2 (1, 3) -benzocyclononylphenyl-3-yl) furan [3,2-b ] as a pale yellow solid ]Pyridin-5 (4H) -one (14% yield).LCMS：RT＝1.98min，[M+H] ⁺ ＝699.13。

Example 10

Synthesis of 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -5-methyl-2 ¹ - (methyl-d) ₃ ) -4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl) furan [3,2-b]Pyridin-5 (4H) ones

The specific synthetic route is as follows:

step A: synthesis of 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) one

7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) one (660 mg, 1.90 mmol) was dissolved in tetrahydrofuran (20 ml), acetic acid (6 ml) was added, and then N-chlorosuccinimide (304 mg, 2.3 mmol) was added, and the resulting reaction solution was stirred at room temperature overnight.

LC-MS monitoring shows that after the reaction, the reaction mixture is added with water, the mixture is extracted with ethyl acetate (30 ml. Times.3), the organic phases are combined, the organic phases are washed with saturated aqueous sodium chloride solution (30 ml. Times.2), then dried over anhydrous sodium sulfate, and finally purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate=1:1) to obtain 550 mg of solid 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3, 2-b) ]Pyridin-5 (4H) one (yield: 76%). LCMS: rt=1.84 min, [ m+h] ⁺ ＝380.01。

And (B) step (B): synthesis of 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -5-methyl-2 ¹ - (methyl-d) ₃ ) -4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl) furan [3,2-b]Pyridin-5 (4H) ones

6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) furo [3,2-b]Pyridin-5 (4H) one (100 mg, 0.28 mmol) was dissolved in dry tetrahydrofuranTo (5 ml) was then slowly added lithium bis (trimethylsilyl) amide (1 mol/l in tetrahydrofuran, 0.28 ml, 0.28 mmol), and the resulting reaction was stirred at room temperature for 30 minutes. (5R, 9R) -5-methyl-2 is then added ¹ - (methyl-d) ₃ ) -4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) pyrazolocyclononan-9-yl 4-nitrobenzenesulfonate (300 mg, 0.55 mmol). The reaction was warmed to 70 ℃ and stirred at this temperature for 48 hours.

After the completion of the reaction, TLC was monitored to show that it was cooled to room temperature, a saturated aqueous ammonium chloride solution (4 ml) and ethyl acetate (50 ml) were added to the reaction solution and extracted, and the obtained organic phase was washed with saturated brine (10 ml×3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4/1), followed by purification by preparative high performance liquid chromatography to give 23 mg of a white solid synthesized 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5 r,9 s) -5-methyl-2 ¹ - (methyl-d) ₃ ) -4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl) furan [3,2-b]Pyridin-5 (4H) ones. LC-MS: rt=1.91 min, [ m+h]+＝679.23。 ¹ H NMR(400MHz，DMSO-d6)δ9.35(s，1H)，8.84(d，J＝1.7Hz，1H)，8.64(dd，J＝5.1，2.9Hz，1H)，7.98(d，J＝2.5Hz，1H)，7.967.87(m，3H)，7.79(s，1H)，7.58(d，J＝5.4Hz，1H)，7.52(d，J＝1.1Hz，1H)，7.14(s，1H)，5.65(s，1H)，2.75(s，1H)，2.44(s，1H)，1.96-1.74(m，2H)，1.66(s，1H)，1.50(s，1H)，1.21(d，J＝21.7Hz，1H)，1.05(d，J＝6.7Hz，3H).

Example 11

Synthesis of 6-chloro-7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- ((5R, 9S) -5-methyl-2 ¹ -deuteromethyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononyl-9-yl) furo [3,2-b]Pyridin-5 (4H) -ones

The specific synthetic route is as follows:

step A: synthesis of 7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) furfuro [3,2-b ] pyridin-5 (4H) -one

4- (4-methoxybenzyl) -5-oxo-4, 5-dihydro [3,2-b ] pyridin-7-yl trifluoromethanesulfonate (15 g, 37.2 mmol), 1- (2-bromo-4-chlorophenyl) -4- (trifluoromethyl) -1H-1,2, 3-triazole (13.3 g, 40.9 mmol), pinacol diboronate (10.3 g, 40.9 mmol) and potassium carbonate (10.3 g, 74.4 mmol) were dissolved in 1, 4-dioxane (80 ml) and water (15 ml) and then [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (1.36 g, 1.86 mmol) was added and after nitrogen protection the reaction was stirred at 125℃for 15 min.

After the completion of the reaction, the reaction mixture was separated by adding water and ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/2) to give 5.9 g of 7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) bran [3,2-b ] as a pale yellow solid ]Pyridin-5 (4H) -one (yield: 31.7%). LCMS: rt=1.96 min, [ m+h] ⁺ ＝501.19。

And (B) step (B): synthesis of 7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) -one

7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- (4-methoxybenzyl) furo [3,2-b ] pyridin-5 (4H) -one (2.30 g, 4.60 mmol) was dissolved in 1, 2-dichloroethane (8 ml) and trifluoroacetic acid (1.05 g, 9.20 mmol) was added to the solution and the mixture was subjected to microwave reaction at 100℃for 10 minutes.

After completion of the reaction, the reaction mixture was neutralized with sodium hydrogencarbonate solution, separated with ethyl acetate, and the obtained organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a residue, which was slurried with (ethyl acetate/n-hexane=1/10) to give 1.55 g of 7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) furo [3,2-b ] as a pale solid]Pyridin-5 (4H) -one (yield: 78.7%). LCMS: rt=1.81 min, [ m+h] ⁺ ＝381.16

Step C: synthesis of 6-chloro-7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) -one

7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) furo [3,2-b ] pyridin-5 (4H) -one (350 mg, 0.921 mmol) was dissolved in tetrahydrofuran (10 ml), then N-chlorosuccinimide (135 mg, 1.01 mmol) and acetic acid (55 mg, 0.921 mmol) were added and reacted at 45℃for 6 hours.

TLC monitoring reaction completion, reaction solution adding water, ethyl acetate separating liquid, drying the obtained organic phase with anhydrous sodium sulfate, decompressing and concentrating to obtain residue, pulping by (ethyl acetate/normal hexane=1/10) to obtain 300 mg of light yellow solid 6-chloro-7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazole-1-yl) phenyl) furo [3,2-b]Pyridin-5 (4H) -one (yield: 78.7%). LCMS: rt=1.84 min, [ m+h] ⁺ ＝415.16。

Step D: synthesis of 6-chloro-7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- ((5R, 9S) -5-methyl-2 ¹ -deuteromethyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononyl-9-yl) furo [3,2-b]Pyridin-5 (4H) -ones

6-chloro-7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) furo [3,2-b]Pyridin-5 (4H) -one (100 mg, 0.242 mmol) was dissolved in anhydrous tetrahydrofuran (8 ml), then lithium bis (trimethylsilyl) amide (1 mol/l in tetrahydrofuran, 0.266 ml, 0.266 mmol) was slowly added and the resulting reaction stirred at room temperature for 30 min. (5R, 9R) -5-methyl-2 is then added ¹ -deuteromethyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl-4-nitrobenzenesulfonate (118 mg, 0.242 mmol) was reacted at 70℃for 24 hours.

After the completion of the reaction, the reaction mixture was cooled to room temperature, and a saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added thereto, followed by separation, and the obtained organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatographyThe mixture was purified by preparative high performance liquid chromatography (eluent: ethyl acetate/petroleum ether=14/1) to give 22.4 mg of 6-chloro-7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- ((5 r,9 s) -5-methyl-2 as a white solid ¹ -deuteromethyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononyl-9-yl) furo [3,2-b]Pyridin-5 (4H) -one (yield: 13.2%). LCMS: rt=1.97 min, [ m+h] ⁺ ＝700.26。 ¹ H NMR(400MHz，DMSO-d ₆ )δ9.35(d，J＝5.0Hz，2H)，8.63(t，J＝4.5Hz，1H)，8.03-7.94(m，4H)，7.79(s，1H)，7.58(d，J＝5.1Hz，1H)，7.52(s，1H)，7.18-7.04(m 1H)，5.78-5.54(m，1H)，2.81-2.65(1n，1H)，2.48-2.38(m，1H)，1.93-1.76(m，2H)，1.70-1.58(m，1H)，1.54-1.44(m，1H)，1.26-1.12(m，1H)，1.05(d，J＝6.4Hz，3H)。

Example 12

Synthesis of 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl) -2, 3-dihydrofuro [3,2-b]Pyridin-5 (4H) ones

The specific synthetic route is as follows:

step A: synthesis of 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) one

7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 3-dihydrofuro [3,2-b ] pyridin-5 (4H) one (530 mg, 1.53 mmol) was dissolved in N, N-dimethylformamide (20 ml), N-chlorosuccinimide (241 mg, 1.83 mmol) was added and reacted at room temperature for 1.5 hours.

TLC monitored half of the starting material remained, with two new spots being generated. Adding saturated saline and ethyl acetate into the reaction solution, separating, drying the obtained organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain residue, purifying by silica gel column chromatographyThe reaction was carried out (eluent: ethyl acetate/n-hexane=1/1) to give 125 mg of 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 3-dihydrofuro [3,2-b ] as a pale yellow solid]Pyridin-5 (4H) one (yield: 21.4%). LCMS: rt=1.84 min, [ m+h] ⁺ ＝383.02

And (B) step (B): synthesis of (6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2 ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl) -2, 3-dihydrofuro [3,2-b]Pyridin-5 (4H) ones

To a water bath containing 6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 3-dihydrofuro [3,2-b]Lithium bis (trimethylsilyl) amide (1 mol/l in tetrahydrofuran, 0.33 ml, 0.33 mmol) was added dropwise to a solution of pyridin-5 (4H) one (125 mg, 0.33 mmol) in tetrahydrofuran (5 ml), stirred for 30 minutes, and (5R, 9R) -2 was added again ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl 4-nitrobenzenesulfonate (170 mg, 0.33 mmol) was then reacted at 70℃for 48 hours.

LC-MS monitoring showed the reaction to end, quenching the reaction with saturated aqueous ammonium chloride, extraction with dichloromethane (20 ml. Times.2), combining the organic phases, washing the organic phase with saturated aqueous sodium chloride (30 ml. Times.2), drying over anhydrous sodium sulfate, purifying the residue by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether=4/1), finally preparing and separating 6.9 mg of a white solid (6-chloro-7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -2) ¹ -difluoromethyl-5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl) -2, 3-dihydrofuro [3,2-b]Pyridin-5 (4H) one (yield: 3.0%). LCMS: rt=1.93 min, [ m+h] ⁺ ＝701.23。

Example 13

Synthesis of 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -5-methyl-2 ¹ -methyl-d ³ -4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridine-2 (5, 4) -pyrazole ringNonnaphthalen-9-yl) -2, 3-dihydrofuran [3,2-b]Pyridin-5 (4 Hr) ones

The specific synthetic route is as follows:

step A: synthesis of 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -5-methyl-2 ¹ -methyl-d ³ -4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl) -2, 3-dihydrofuran [3,2-b ]Pyridin-5 (4 HH) ones

To a water bath containing 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 3-dihydrofuro [3,2-b ]]Lithium bis (trimethylsilyl) amide (1 mol/l in tetrahydrofuran, 0.69 ml, 0.69 mmol) was added dropwise to a solution of pyridin-5 (4H) one (220 mg, 0.63 mmol) in tetrahydrofuran (10 ml), stirred for 30 minutes, and (5 r,9 r) -5-methyl-2 was added again ¹ -methyl-d ³ -4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridine-2 (5, 4) pyrazolo cyclononanaphthalen-9-yl 4-nitrobenzenesulfonate (307 mg, 0.63 mmol) was then reacted at 70℃for 48 hours.

LC-MS monitoring showed the reaction to end, quenching the reaction with saturated aqueous ammonium chloride, extraction with dichloromethane (20 ml. Times.2), combining the organic phases, washing the organic phase with saturated aqueous sodium chloride (30 ml. Times.2), drying over anhydrous sodium sulfate, purifying the residue by column chromatography on silica gel (eluent: ethyl acetate/petroleum ether=4/1), finally preparing and separating 8.8 mg of a green solid 7- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -4- (5R, 9S) -5-methyl-2 ¹ -methyl-d ³ -4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononanaphthalen-9-yl) -2, 3-dihydrofuran [3,2-b ]Pyridin-5 (4H) one (yield: 2.2%). LCMS: rt=1.83 min, [ m+h] ⁺ ＝634.25。

Example 14

Synthesis of 7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- ((5R, 9S) -5-methyl-2 ¹ -deuteromethyl group-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononyl-9-yl) furo [3,2-b]Pyridin-5 (4H) -ones

The specific synthetic route is as follows:

step A: synthesis of 7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazole)]-yl) phenyl) -4- ((5R, 9S) -5-methyl-2 ¹ -deuteromethyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononyl-9-yl) furo [3,2-b]Pyridin-5 (4H) -ones

7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) furo [3,2-b]Pyridine-5 (4H) monoketone (120 mg, 0.316 mmol) was dissolved in anhydrous tetrahydrofuran (8 ml), then lithium bis (trimethylsilyl) amide (1 mol/l tetrahydrofuran solution, 0.347 ml, 0.347 mmol) was slowly added, and the resulting reaction solution was stirred at room temperature for 30 minutes. (5R, 9R) -5-methyl-2 is then added ¹ -deuteromethyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl-4-nitrobenzenesulfonate (154 mg, 0.316 mmol) was reacted at 70℃for 24 hours.

After the completion of the reaction, the reaction mixture was cooled to room temperature, and a saturated aqueous ammonium chloride solution (25 ml) and ethyl acetate (50 ml) were added thereto, followed by separation, and the obtained organic phase was washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=14/1) and then further purified by preparative high performance liquid chromatography to give 22.7 mg of 7- (5-chloro-2- (4- (trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -4- ((5 r,9 s) -5-methyl-2 as a white solid ¹ -deuteromethyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononyl-9-yl) furo [3,2-b]Pyridin-5 (4H) -one (yield: 10.8%). LCMS: rt=1.92 min, [ m+h] ⁺ ＝666.28。 ¹ H NMR(400MHz，DMSO-d ₆ )δ9.35(s，1H)，9.23(s，1H)，8.60(d，J＝5.1Hz，1H)，7.96(d，J＝1.8Hz，1H)，7.92(d，J＝2.3Hz，2H)，7.76(s，1H)，7.71(d，J＝2.1Hz，1H)，7.55(dd，J＝5.1，1.5Hz，1H)，7.52(s，1H)，6.96-6.82(m，1H)，6.23(s，1H)，5.77-5.55(m，1H)，2.752.62(m，1H)，2.472.40(m，1H)，1.88-1.76(m，2H)，1.681.56(m，1H)，1.541.44(m，1H)，1.26-1.14(m，1H)，1.04(d，J＝6.8Hz，3H)。

Comparative example 1

Synthesis of (5R, 9S) -9- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one

The specific synthetic route is as follows:

step A: synthesis of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine

1- (2-bromo-4-chlorophenyl) -4-chloro-1H-1, 2, 3-triazole (500 mg, 1.71 mmol) was dissolved in dioxane (12.0 ml) and water (3.0 ml), then 2, 5-dimethoxypyridine-4-boronic acid (375.0 mg, 2.05 mmol), potassium carbonate (472.0 mg, 3.41 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (125.0 mg, 0.17 mmol) were added sequentially. Then, after three times of nitrogen substitution, the reaction was carried out at 90℃for 2 hours.

TLC showed the reaction was complete. Silica gel powder was poured into the reaction solution, and the residue obtained after concentration was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=9/1) to obtain 500 mg of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine as a yellow solid (yield: 83%).

And (B) step (B): synthesis of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one

4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine (720 mg, 2.05 mmol) was dissolved in dry isopropanol (15.0 ml). Subsequently, lithium chloride (521 mg, 12.30 mmol) and 4-methylbenzenesulfonic acid monohydrate (975 mg, 5.13 mmol) were sequentially added to the above solution, followed by stirring at 80 degrees for 16 hours.

LCMS showed the reaction was complete. To the reaction solution was added 80 ml of ethyl acetate, followed by washing with saturated brine (15 ml×2 times), followed by drying over anhydrous sodium sulfate, and finally concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) to give 650 mg of 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one as a yellow solid (yield: 94%). LCMS: rt=1.75 min, [ m+h ] ⁺ ＝337.09。

Step C: (5R, 9S) -9- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one

To 4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (100 mg, 0.29 mmol) was added dry tetrahydrofuran (5 ml), then 1N solution of lithium bis- (trimethylsilyl) amine in tetrahydrofuran (0.44 ml, 0.44 mmol, 1 mol/LinTHF) was added dropwise at zero degree, and the reaction was continued for 30 minutes at zero degree after completion of the dropwise addition. (5R, 9R) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-9-yl 4-nitrobenzenesulfonate (154 mg, 0.29 mmol) was dissolved in 1 ml dry tetrahydrofuran, then added dropwise to the above reaction solution, and then reacted at 70℃for 3 days.

LCMS showed starting material remained, product was formed. Ethyl acetate (30 ml) was added to the reaction solution, followed by pouring an ice saturated ammonium chloride solution for washing (10 ml), washing the organic phase with saturated brine (5 ml. Times.1), drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, purifying the obtained residue by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=9/1) to give 86 mg of a yellow oil, and purifying by preparative high performance liquid chromatography to give 55.7 mg of (5 r,9 s) -9- (4- (5-chloro-2- (4-chloro-1H-1, 2, 3-triazol-1-yl) ) Phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one (yield: 28%). LCMS: rt=1.93 min, [ m+h] ⁺ ＝655.20。 ¹ H NMR(400MHz，DMSO-d ₆ )δ9.41(s，1H)，8.75(d，J＝5.1Hz，1H)，8.65(s，1H)，7.96(t，J＝56.0Hz，1H)，7.90(s，1H)，7.79(dd，J＝8.5，2.3Hz，1H)，7.74(d，J＝8.5Hz，1H)，7.70(d，J＝2.3Hz，1H)，7.687.63(m，2H)，7.40(d，J＝4.0Hz，1H)，6.41(s，1H)，6.03(s，1H)，3.36(s，3H)，2.682.62(m，1H)，2.302.26(m，1H)，2.082.00(m，1H)，1.791.74(m，1H)，1.541.48(m，1H)，1.351.30(m，1H)，0.88(d，J＝6.9Hz，3H)，0.420.29(m，1H)。

Comparative example 2

Synthesis of (5R, 9S) -9- (4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one

The specific synthetic route is as follows:

step A: synthesis of 4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine

1- (2-bromo-4-chlorophenyl) -4-trifluoromethyl-1H-1, 2, 3-triazole (250 mg, 766. Mu. Mol) was dissolved in dioxane (4.0 ml) and water (1.0 ml), then 2, 5-dimethoxypyridine-4-boronic acid (210 mg, 1.15. Mu. Mol), potassium carbonate (423 mg, 3.06. Mu. Mol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (56 mg, 76.6. Mu. Mol) were added sequentially. Then, after three times of nitrogen substitution, the reaction was carried out at 100℃for 5 hours.

LCMS showed the reaction was complete. Silica gel powder was poured into the reaction solution, and the residue obtained after concentration was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=9/1) to give 160 mg of 4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine as a yellow solid (yield: 64%). LCMS: rt=2.11 min, [ m+h ] ⁺ ＝385.04。

And (B) step (B): synthesis of 4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one

4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -2, 5-dimethoxypyridine (200 mg, 0.52 mmol) was dissolved in dry isopropanol (8 ml). Subsequently, lithium chloride (132 mg, 3.12 mmol) and 4-methylbenzenesulfonic acid monohydrate (248 mg, 1.30 mmol) were sequentially added to the above solution, followed by stirring at 80 degrees for 16 hours.

LCMS showed the reaction was complete. To the reaction solution was added 50 ml of ethyl acetate, followed by washing with saturated brine (10 ml×3 times), followed by drying over anhydrous sodium sulfate, and finally concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/0) to give 180 mg of 4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one as a yellow solid (yield: 93%). LCMS: rt=1.82 min, [ m+h] ⁺ ＝371.08。

Step C: synthesis of (5R, 9S) -9- (4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -yl) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one

To 4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxypyridin-2 (1H) -one (100 mg, 0.27 mmol) was added dry tetrahydrofuran (5 ml), and then a solution of 1N lithium bis- (trimethylsilyl) amine in tetrahydrofuran (0.40 ml, 0.4 mmol, 1mol/Lin THF) was added dropwise at zero degrees, and the reaction was continued for 30 minutes at zero degrees after completion of the dropwise addition. (5R, 9R) -2 ¹ - (difluoromethyl) -5-methyl-4-oxo-2 ¹ H-3-aza-1 (4, 2) -pyridine-2%5, 4) -Pyrazolecan-9-yl 4-nitrobenzenesulfonate (140 mg, 0.27 mmol) was dissolved in 1 ml of dry tetrahydrofuran, and then added dropwise to the above reaction solution, followed by reaction at 70℃for 3 days.

LCMS showed starting material remained, product was formed. Ethyl acetate (30 ml) was added to the reaction solution, followed by pouring an ice saturated ammonium chloride solution for washing (10 ml), saturated brine (5 ml. Times.1) and drying the organic phase over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying the obtained residue by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=4/1) to give 80 mg of a yellow oil, followed by purification by preparative high performance liquid chromatography to give 57.8 mg of (5R, 9S) -9- (4- (5-chloro-2- (4-trifluoromethyl) -1H-1,2, 3-triazol-1-yl) phenyl) -5-methoxy-2-oxopyridin-1 (2H) -2 ¹ - (difluoromethyl) -5-methyl-2 ¹ H-3-aza-1 (4, 2) -pyridin-2 (5, 4) -pyrazolocyclononan-4-one (yield: 31%).

LCMS：RT＝1.97min，[M+H] ⁺ ＝689.29。 ¹ H NMR(400MHz，DMSO-d ₆ )δ9.40(s，1H)，9.15(s，1H)，8.72(d，J＝5.1Hz，1H)，7.96(t，J＝56Hz，1H)，7.90(s，1H)，7.847.80(1m，2H)，7.757.73(n，1H)，7.687.60(m，2H)，7.437.40(m，1H)，6.47(s，1H)，6.02(s，1H)，3.28(s，3H)，2.672.61(m，1H)，2.322.22(m，1H)，2.092.00(m，1H)，1.781.70(m，1H)，1.561.46(1m，1H)，1.36-1.26(1m，1H)，0.88(d，J＝6.8Hz，3H)，0.10-0.27(n，1H)。

Example 15: detection of biological Activity of Compounds of the invention for inhibition of human factor XIa by absorption light

1 Experimental materials

Enzyme: human Factor XIa (ENZYME RESEARCH, cat# HFXIa 1111 a)

A substrate: s-2366 ^TM : (CHROMOPENIX, cat. No. 82109039)

Buffer solution: 145mM NaCl,5mM KCl,1mg/mL PEG 8000, 30mM HEPES, PH7.4.

2 experimental procedure

10mM test compound in 100% DMSO was diluted to 1000, 200, 40, 8, 1.6, 0.32, 0.064, 0.0128, 0.00256, 0.00128. Mu.M with 100% DMSO; 98. Mu.L (77.7 ng/mL) of FXIa enzyme solution was added to each well of a 96-well plate, and the blank wells were replaced by adding 98. Mu.L of buffer, and then 2. Mu.L of compound at different concentrations, and the blank and control wells were replaced by DMSO, mixed with a shaker, and incubated at 37℃for 20min.

Finally, 100. Mu.L of 800. Mu.M substrate was added to each well, and the absorbance was measured at 405 nm.

3 data processing

Curve fitting was performed using GraphPad Prism software to calculate IC ₅₀ The values are shown in Table I.

Table one: IC for inhibiting human FXIa by the Compounds of the invention ₅₀

Examples	hFXia IC ₅₀ (nM)
		1	0.59
2	0.48
		5	0.98
6	0.53
		7	0.92
8	0.72
		9	0.49
10	1.23
		11	0.42
12	0.44
		13	0.44
14	0.22

Conclusion: the compounds of the invention have a remarkable inhibitory activity against human FXia.

EXAMPLE 16 the Compounds of the invention have human plasma aPTT Activity

1 Experimental materials

aPTT lot 220106600, calcium chloride lot 210305600, needle wash lot 211101300: shenzhen Mairui biomedical electronics Co., ltd.

The human mixed plasma, healthy crowd, disposable vein heparin tube blood sampling uses Liuyang three power medical science and technology development limited company disposable human vein blood sample collection container batch number 211108, sodium citrate 9:1, collecting human blood, centrifuging at 3000rpm for 10min at room temperature, and collecting supernatant for use, batch number 20220606.

2 experimental procedure

10mM test compound in 100% DMSO was diluted to 0.29, 0.59, 1.17, 2.34, 4.69, 9.38, 18.75, 37.50. Mu.M with 100% DMSO; adding 99 mu L of human mixed plasma into each 1.5ml centrifuge tube, adding 1 mu L of compounds with different solubilities, adding 1 mu L of LDMSO into a blank hole, repeatedly reversing and mixing by hand, centrifuging by adopting a palm centrifuge to collect samples, incubating in a water bath of an electric heating constant temperature water bath kettle at 37 ℃ for 10min and mixing uniformly, and detecting aPTT by adopting a full-automatic coagulation analyzer according to a set program.

3 data processing

Curve fitting was performed using Graphad Prism software to calculate EC1.5 and EC 2X, see Table two.

And (II) table: the compounds of the invention have aPTT activity on human plasma

Conclusion: the compound of the invention has obvious anticoagulation activity to human plasma.

Example 17: pharmacokinetic experiments

1. Reagents and apparatus

Polyethylene glycol 400 (lot number gorkrout, saen chemical technologies (Shanghai), DMSO (lot number 20200319, guangdong photoChina, inc.) physiological saline (lot number C20052604, jiangxi Korea pharmaceutical Co., ltd.). LC-MS instrument (sammer flying multimate 3000UPLC,TSQ QUANTUM ULTRA triple quadrupole mass spectrometry, AB SCIEX 5500 QTARP).

2. Experimental animal

SD rats: male, 180-250g, purchased from Guangdong Vietnam laboratory animal technologies Co.

3. Preparation

Precisely weighing sample powder, completely dissolving in DMSO, adding PEG-400, mixing by vortex ultrasonic, adding physiological saline, mixing by vortex ultrasonic to obtain 0.5mg/mL (DMSO: PEG-400: NS=5:60:35, V/V/V), and administering by gastric lavage 10mL/kg, and administering by vein 0.5mL/kg.

4. Blood sample collection

After intravenous or intragastric administration of rats, 200 mu L of venous blood is collected in heparinized EP tubes at 5min (intragastric administration is not performed), 15min, 30min, 1h, 2h, 5h, 7h and 24h, and centrifuged at 12000rpm for 2min, and the blood plasma is frozen at-80 ℃ to be tested.

5. Biological analysis

A certain amount of test sample was precisely weighed and dissolved to 1mg/mL with DMSO to be used as a stock solution. Accurately absorbing a proper amount of compound stock solution, and adding acetonitrile to dilute the stock solution to prepare a standard series of solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, mixing uniformly by vortex, preparing into plasma samples with the plasma concentrations of 1, 3, 10, 30, 100, 300, 1000, 3000 and 5000ng/mL, carrying out double-sample analysis on each concentration, and establishing a standard curve. 20. Mu.L of plasma was taken, 200. Mu.L of acetonitrile solution of internal standard propranolol (5 ng/mL) was added, and after vortexing and mixing, the mixture was centrifuged at 4000rpm for 5min, and the supernatant was taken for LC-MS analysis. LC-MS detection conditions were as follows:

chromatographic column: watersaCQUITYTM PREMIERHSS T, 50 x 2.1mm,1.8 μm.

Mobile phase a: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: gradient elution at 0.5mL/min is shown in Table three below:

watch III

Time (min)	A(％)	B(％)
			0	95％	5％
1	10％	90％
			2.5	5％	95％
2.51	95％	5％
			3.0	95％	5％

6. Data processing

After LC-MS detection of blood concentration, the pharmacokinetic parameters of beagle dogs after administration were calculated using WinNonlin 6.1 software, non-compartmental model, and the results are shown in Table IV below.

Table four: canine pharmacokinetic parameters (iv and PO dosing) of the compounds of the invention

/>

The compound of the invention has better oral absorption, better exposure and bioavailability than the compound of the comparative example 1.

The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims

1. A compound of the general formula (I), or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that:

wherein X is N or CH, when x=n, R ₄ Absence of;

z is selected from O or-C (O) -;

R ¹ selected from halogen, haloalkyl;

R ⁵ selected from hydrogen, halogen.

2. A compound according to claim 1, or an isomer, or a racemate, or a pharmaceutically acceptable salt thereof, wherein said alkyl group is selected from C _1-6 Alkyl group of said C _1-6 The alkyl group of (a) is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1, 2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1, 2-dimethylbutyl, 1-ethylbutyl;

the alkoxy group is selected from C _1-6 Alkoxy group, the C _1-6 Alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, and n-butoxyIsobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, sec-pentoxy, 1-ethylpropoxy, 2-methylbutoxy, tert-pentoxy, 1, 2-dimethylpropoxy, isopentoxy, neopentoxy, n-hexoxy, isohexoxy, zhong Ji oxy, tert-hexoxy, neopentoxy, 2-methylpentoxy, 1, 2-dimethylbutoxy, 1-ethylbutoxy.

3. A compound according to claim 1, or an isomer, or a racemate, or a pharmaceutically acceptable salt thereof, wherein halogen is selected from fluorine, chlorine, bromine, iodine; haloalkyl means that one hydrogen on the alkyl is replaced by halogen selected from fluorine, chlorine, bromine, iodine; the cycloalkyl is selected from C _3-6 Naphthene of C _3-6 Is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; heterocycloalkyl means that one or more carbon atoms of the heterocycloalkyl group are replaced by heteroatoms selected from nitrogen, oxygen, sulfur, one or more heteroatoms.

4. The compound according to claim 1, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of a compound represented by the formula (Ia):

R ¹ selected from halogen, haloalkyl;

R ² is CH ₃ Or CD (compact disc) ₃ ；

R ⁵ selected from hydrogen, halogen;

5. The compound according to claim 4, wherein R is an isomer, a racemate or a pharmaceutically acceptable salt thereof ¹ Selected from chlorine, trifluoromethyl; r is R ² Is CH ₃ Or CD (compact disc) ₃ ；R ³ Selected from methyl; r is R ⁵ Selected from hydrogen and chlorine; r is R ⁷¹ 、R ⁷² 、R ⁷³ Each independently selected from hydrogen, fluorine, deuterium.

6. The compound according to claim 1, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of a compound represented by formula (IIa) or (IIb), or (IIc):

R ¹ Selected from halogen, haloalkyl;

R ⁵ selected from hydrogen, halogen;

R ⁸¹ 、R ⁸² independently selected from hydrogen and halogen.

7. The compound according to claim 6, wherein R is an isomer, a racemate or a pharmaceutically acceptable salt thereof ¹ Selected from chlorine, trifluoromethyl; r is R ³ Selected from methyl; r is R ⁵ Selected from hydrogen and chlorine; r is R ⁷¹ 、R ⁷² 、R ⁷³ Each independently selected from hydrogen, fluorine, deuterium; r is R ⁸¹ 、R ⁸² Independently selected from hydrogen and chlorine.

8. A compound according to claim 1 or 4 or 6, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:

9. a pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 8, or an isomer, or a racemate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The pharmaceutical use of a compound according to any one of claims 1 to 8, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, in particular for the preparation of a medicament for the treatment of FXIa-related diseases, preferably thrombosis-related diseases.