Diphenylpyrazine derivatives, their preparation methods and applications

Abstract

This invention provides a compound of formula (I), its isomers, or pharmaceutically acceptable salts, with selective prostaglandin I2 receptor agonist activity, wherein each group is as defined in the specification. This compound of formula (I), its isomers, or pharmaceutically acceptable salts can be ideally converted into carboxylic acid metabolites in the lungs, exhibiting physicochemical properties more suitable for pulmonary administration. It can remain in the lungs for a longer period and slowly release effective concentrations of the carboxylic acid metabolites. Pulmonary administration of the compound of formula (I), its isomers, or pharmaceutically acceptable salts provided by this invention can significantly reduce the dosage, provide lower dosing frequency, a wider therapeutic window, reduce systemic side effects, avoid food effects, and greatly improve drug safety and patient tolerability, providing a new treatment option for patients with pulmonary hypertension.

Description

Diphenylpyrazine derivatives, preparation methods and applications thereof The present invention relates to the field of medicinal chemistry, in particular to a selective prostaglandin I 2(PGI 2) Receptor agonist diphenylpyrazine derivatives, their isomers or pharmaceutically acceptable salts, their preparation methods and uses. Specifically, a compound as shown in Formula I is provided. Formula I Pulmonary hypertension (PH) refers to a group of clinical pathophysiological syndromes characterized by a mean pulmonary artery pressure ≥25 mmHg measured by right catheter at rest at sea level. It is characterized by vascular lesions and pulmonary circulation remodeling, resulting in arterial lumen narrowing and impaired vasodilation. This leads to increased pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR), which limits the ability of the right ventricle to pump blood through the lungs, resulting in shortness of breath and ultimately right heart failure and death. PH is caused by a variety of heterogeneous diseases (etiologies) and different pathogenesis. Clinically, PH is divided into five major categories: (1) pulmonary arterial hypertension (PAH); (2) pulmonary hypertension caused by left heart disease; (3) pulmonary hypertension caused by lung disease and / or hypoxia; (4) pulmonary hypertension caused by chronic thromboembolic pulmonary hypertension (CTEPH) and / or other pulmonary artery obstructive lesions; and (5) pulmonary hypertension of unknown and / or multifactorial origin. Among PAH, idiopathic PAH (IPAH), hereditary PAH (HPAH), congenital heart disease (CHD)-related PAH, and drug- and toxin-related PAH (DPAH) are the most common. Unidentified and / or multifactorial PAH includes pulmonary hypertension associated with systemic and metabolic diseases, such as sarcoidosis-associated pulmonary hypertension (SAPH) and Gaucher disease-associated pulmonary hypertension. According to statistics, the prevalence of pulmonary hypertension (PAH) in the general population is approximately 1%, but it rises to 10% in those over 65. Although PAH is relatively rare, it has been dubbed the "cancer of the cardiovascular system." Epidemiological data show that the five-year survival rate for patients with IPAH and HPAH after conventional treatment is only 20.8%. Furthermore, due to a lack of professional disease management capabilities and effective doctor-patient communication, most PAH patients experience suboptimal disease control even after discharge. Prostaglandin I 2(PGI 2) It is an endogenous prostaglandin, mainly produced by vascular endothelial cells and is one of the metabolites of arachidonic acid (AA). PGI2 is an effective vasodilator and platelet aggregation inhibitor. Its reduced synthesis will promote thrombosis. 2 plays an important role in maintaining vascular homeostasis. It can also inhibit the differentiation, proliferation and migration of vascular smooth muscle cells. These physiological functions of 2 are achieved by activating PGI This is achieved through the IP2 receptor (IP receptor), a G-protein coupled receptor located on the surface of vascular smooth muscle cells, platelets and other cells. Downregulation of the PGI pathway is associated with the pathogenesis of various vascular diseases. IP2 receptors (IP2 receptors) not only inhibit platelet-mediated aggregation but also have a strong vasodilatory effect. IP2 receptor agonists can treat a variety of diseases, including pulmonary arterial hypertension (PAH), PAH associated with various diseases, arteriosclerosis obliterans, coronary artery disease, myocardial infarction, transient ischemic attack, hypertension, chronic obstructive pulmonary disease, and other vascular diseases. In patients with PAH, lung prostacyclin synthesis is reduced, as is IP receptor expression. Therefore, the use of prostacyclin and its analogs, as well as prostacyclin receptor agonists, to relax pulmonary vascular smooth muscle, inhibit platelet aggregation, and reduce smooth muscle cell proliferation is a viable therapeutic approach. However, currently PGI Marketed drugs in category 2 primarily include epoprostanol, iloprost, beraprost, and treprostinil. Most are expensive and have short half-lives, poor chemical stability, and significant side effects. They often require continuous intravenous or subcutaneous infusion or multiple daily inhalation administration, which carries the risks of rapid onset, overdose, or underdosage. Furthermore, inhalation administration of these drugs can lead to significant pulmonary adverse reactions such as coughing due to transient high lung drug concentrations, which can overactivate IP receptors and affect tolerability and efficacy, complicating their clinical application. Although intravenously administered prostacyclins are considered the most reliable treatment for PAH, their short half-life puts patients at risk for fatal rebound pulmonary hypertension if the intravenous infusion is suddenly interrupted. In response to the above problems, some non-endogenous PGIs with good chemical stability and higher selectivity have been developed in recent years. Two types of IP receptor agonists have been researched and developed. Among them, selexipag, jointly developed by Nippon Shinyaku and Actelion, is the first oral selective non-endogenous prostacyclin receptor agonist approved for the treatment of PAH. Selexipag is designed as a prodrug. After oral administration, it can be converted into its active metabolite MRE-269 (structural formula shown below) by the action of liver hydrolases. This hydrolysis can serve as a "sustained release mechanism," not only extending the plasma elimination half-life of MRE-269, but also reducing the peak plasma concentration (C max ) and reduce high concentrations of PGI 2Typical adverse reactions associated with agonists. However, the metabolism of selexipag and MRE-269 is easily affected by food. When taken with food, the peak plasma concentration of selexipag (C max ) decreased by 35%, and the area under the plasma concentration-time curve (AUC 0- ∞ ) decreased by 10%; while the C max and AUC 0- ∞ The time to peak (T max ) were delayed by 1.75 hours (1.0 hour vs 2.75 hours) and 1.5 hours (2.5 hours vs 4.0 hours), respectively. Due to systemic drug exposure, typical side effects of IP receptor agonists, such as headache (65.2%), diarrhea (42.4%), and nausea (33.4%), were unavoidable. The overall incidence of side effects was higher in the 24-week group than in the placebo group (91.0% vs 62.2%). Therefore, it is necessary to develop IP receptor agonist derivatives that can exert a long-lasting effect locally in the lungs, are metabolically stable, have high bioavailability, and have lower systemic reactivity. In view of the shortcomings of the prior art, the present invention aims to provide a diphenylpyrazine derivative with selective IP receptor agonist activity, a preparation method thereof and medical use thereof. In one aspect, the present invention provides a compound of formula I, an isomer or a pharmaceutically acceptable salt thereof, Formula I wherein, X is selected from O, S, NH; Y is selected from -R 1or -R 2 -Z defined group; when Y is -R 1 When R 1 Selected from C 8~C 18 Alkyl, C 6~C 18 Alkenyl, C 6~C 18 Alkynyl or C 4~C 10 Cycloalkyl, wherein C 8~C 18 Alkyl, C 6~C 18 Alkenyl, C 6~C 18 Alkynyl or C 4~C 10 The cycloalkyl group is optionally substituted with one or more substituents selected from the group consisting of cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, -NR a R b , halogen atoms, hydroxyl groups, cyano groups, mercapto groups, nitro groups or -ONO 2; When Y is -R 2 -Z, R 2 Selected from C 1~C 18 Alkylene, C 2~C 18 Alkenylene or C 3~C 10 Cycloalkylene (preferably C 3~C 8 cycloalkylene, more preferably C 3~C 6 cycloalkylene), wherein C 1~C 18 Alkylene, C 2~C 18 Alkenylene or C 3~C 10 Cycloalkylene is optionally substituted with one or more substituents selected from the group consisting of: -NR a R b , halogen atoms, hydroxyl groups or cyano groups, Z is selected from the following groups: , , , , , , , , , , , , , , , , ,or , where R j Selected from C 1~C 16 Alkyl or C 4~C 16 alkenyl, and wherein C 1~C 16 Alkyl or C 4~C 16 The alkenyl group is optionally substituted by one or more substituents selected from the group consisting of halogen atoms, hydroxyl groups, -NR a R b , cyano, nitro or -ONO 2; or R j for , wherein A is a cyclic group selected from phenyl, 6- to 10-membered heteroaryl, 8- to 12-membered fused ring aryl, 8- to 12-membered fused ring heteroaryl, or 5- to 8-membered heterocycloalkyl; wherein R a 、R b Each independently selected from H, alkyl, cycloalkyl, aryl, alkylaryl or heterocyclic group, or R a and R b Together with the nitrogen atom to which they are attached, they form a 3-8 membered heterocyclic ring; wherein R 3 、R 4 Each independently selected from H, C 1-C 6 alkyl, C 1-C 6 alkoxy or C 3-C 6 cycloalkyl, or R 3 and R 4 The carbon atoms to which they are attached form C 3-C 6 cycloalkyl ring, wherein C 1-C 6 alkyl, C 1-C 6 alkoxy or C 3-C The 6-cycloalkyl group is optionally substituted by one or more substituents selected from the following groups: alkoxy, halogen atoms, hydroxyl, amino, nitro or -ONO 2; m is an integer from 0 to 10; n is an integer from 0 to 4. In certain embodiments, X is O. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein Y is -R 1 , where R 1 C 8~C 18 Alkyl, where C 8~C 18 The alkyl group is optionally substituted by one or more substituents selected from the group consisting of halogen atoms, phenyl, substituted phenyl or -NR a R b, wherein the substituted phenyl group is an alkoxy-substituted phenyl group or a halogen-substituted phenyl group, preferably C 1-3 Alkoxy-substituted phenyl, fluorine-substituted phenyl, chlorine-substituted phenyl or bromine-substituted phenyl, more preferably methoxy-substituted phenyl or fluorine-substituted phenyl. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein Y is -R 1 , where R 1 C 8~C 16 Alkyl, preferably C 8~C 14 Alkyl, more preferably C 8~C 12 Alkyl, most preferably C 8~10 Alkyl groups, such as C 8 alkyl, C 9 alkyl or C 10 alkyl. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein Y is -R 1 , where R 1 C 6~C 18 Alkenyl, where C 6~C 18 The alkenyl group is optionally substituted with one or more substituents selected from the group consisting of halogen atoms, phenyl, substituted phenyl, or -NR a R b . According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein Y is -R 1 , where R 1 C 6~C 16 Alkenyl. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein Y is -R 2 -Z, where R 2 C 1~C 18 Alkylene, where C 1~C 18 The alkylene group is optionally substituted with one or more substituents selected from the group consisting of: -NR a R b , halogen atoms, hydroxyl groups or cyano groups. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein Y is -R 2 -Z, where R 2 C 4~C 16 Alkylene, preferably C 6~C 16 Alkylene. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein Y is -R 2 -Z, where R 2 C 2~C 18 Alkenylene, where C 2~C 18 The alkenylene group is optionally substituted with one or more substituents selected from the group consisting of: -NR a R b , halogen atoms, hydroxyl groups or cyano groups. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein Y is -R 2 -Z, where R 2 C 4~C 16 Alkenylene, preferably C 6~C 16 Alkenylene. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein Y is -R 2 -Z, and the group R in Z j Selected from C 1~C 16 Alkyl, C 4~C 16 Alkenyl, preferably C 1~C 10 Alkyl, and R j Optionally substituted by one or more substituents selected from the following groups: halogen atoms, hydroxyl groups, -NR a R b , cyano, nitro or -ONO 2. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein Y is -R 2 -Z, and the group R in Z j for The cyclic group A is selected from phenyl, 6- to 10-membered heteroaryl, 8- to 12-membered fused ring aryl, 8- to 12-membered fused ring heteroaryl or 5- to 8-membered heterocycloalkyl, and is preferably phenyl. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, wherein R a 、R b Each independently selected from H, -CH 3 or -CH 2CH 3. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof of the present invention, m is an integer from 1 to 6, preferably an integer from 4 to 6. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof of the present invention, wherein n is an integer from 0 to 2; preferably 1. According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, the compound is selected from: , , , , , , , , , , , , , , , , , , , . According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, the compound is selected from: , , , , , , , , , , , . According to the compound of formula I, its isomer or pharmaceutically acceptable salt thereof, the compound is selected from: , , , , , , . The second aspect of the present invention provides an isotope-substituted compound of the above formula I, its isomers or pharmaceutically acceptable salts, preferably a deuterium-substituted compound. The third party of the present invention provides a pharmaceutical composition comprising at least one compound of Formula I, its isomer or pharmaceutically acceptable salt, or isotope substituted product thereof, and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients include: carriers, diluents, excipients, etc. According to the pharmaceutical composition of the present invention, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg, preferably 0.001 mg-500 mg, preferably 0.001 mg-100 mg, and more preferably 0.001 mg-10 mg. The pharmaceutical composition according to the present invention, wherein, based on the total weight of the composition, the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound. The pharmaceutical composition according to the present invention, wherein, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compound. The pharmaceutical composition according to the present invention, wherein, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound. The pharmaceutical composition according to the present invention, wherein, the pharmaceutical composition contains 1%-99% of the aforementioned compound. The pharmaceutical composition according to the present invention, wherein, the pharmaceutical composition contains 2%-98% of the aforementioned compound. The remainder of the weight of the composition is contributed by pharmaceutically acceptable carriers, diluents, or excipients. According to the pharmaceutical composition of the present invention, the pharmaceutical composition may further comprise other active agents in addition to the compound of the present invention. The fourth aspect of the present invention provides a compound of formula I, an isomer or a pharmaceutically acceptable salt thereof, or an isotope-substituted product thereof, or a pharmaceutical composition thereof for use in the preparation of a pharmaceutical composition for preventing or treating a disease associated with prostaglandin I. 2 receptor-related diseases. According to the use of the present invention, the related diseases are selected from the following diseases: pulmonary hypertension (PH), arteriosclerosis obliterans, platelet formation diseases associated with excessive platelet aggregation, pulmonary fibrosis / cirrhosis, asthma and asthma symptoms, and / or chronic obstructive pulmonary disease. According to the use of the present invention, the use comprises administering to a patient an effective amount of the aforementioned compound of formula I, its isomer or pharmaceutically acceptable salt, isotope substitution, or pharmaceutical composition. According to the use of the present invention, the administration method is subcutaneous, oral, nasal, intravenous or pulmonary administration, preferably, the administration method is pulmonary administration. According to the use of the present invention, the pulmonary administration includes administration via a metered dose inhaler, a dry powder inhaler, an atomizing sprayer, or a soft mist inhaler. According to the use of the present invention, the pulmonary administration includes administration via an atomizing nebulizer. According to the use of the present invention, the pulmonary administration includes administration via a dry powder inhaler. According to the use of the present invention, the pulmonary administration includes administration via a soft mist inhaler. According to the use of the present invention, the patient is a World Health Organization (WHO) Group I PH patient, or a WHO Group II PH patient, or a WHO Group III PH patient, or a WHO Group IV PH patient, or a WHO Group V PH patient. According to the use of the present invention, the pulmonary hypertension is selected from pulmonary arterial hypertension (PAH), pulmonary hypertension caused by left heart disease, pulmonary hypertension caused by lung disease and / or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension caused by pulmonary artery obstructive lesions, and pulmonary hypertension associated with systemic or metabolic diseases. According to the use of the present invention, the PAH is selected from idiopathic pulmonary arterial hypertension (IPAH), hereditary pulmonary arterial hypertension, congenital heart disease-related pulmonary arterial hypertension, and drug- or poison-related pulmonary arterial hypertension. According to the use of the present invention, the pulmonary hypertension is chronic thromboembolic PH (CTEPH). According to the use of the present invention, the pulmonary hypertension associated with systemic or metabolic diseases is sarcoidosis-associated pulmonary hypertension (SAPH). According to the use of the present invention, the administration is to administer an effective amount of the aforementioned compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitution, or pharmaceutical composition to the patient once a day. According to the use of the present invention, an effective amount of the compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitute, or pharmaceutical composition is administered to the patient once every two days, or at a longer dosing interval. According to the use of the present invention, the administration is to administer an effective amount of the aforementioned compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitute, or pharmaceutical composition to the patient twice a day. According to the use of the present invention, after being administered to a patient via the pulmonary route, a longer elimination half-life (t 1 / 2 ), a larger area under the lung drug curve (AUC), and a larger lung-to-plasma drug concentration ratio. According to the use of the present invention, the administration is via the lungs and can be taken together with food. According to the use of the present invention, wherein, after administration via the pulmonary route, the severity of systemic adverse events can be reduced or the occurrence of systemic adverse reaction events can be reduced. The fifth aspect of the present invention provides a method for preventing or treating pulmonary hypertension, comprising administering to a patient an effective amount of the aforementioned compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitute, or pharmaceutical composition. According to the method for preventing or treating pulmonary hypertension of the present invention, the administration method is subcutaneous, oral, nasal, intravenous or pulmonary administration, preferably, the administration method is pulmonary administration. According to the method for preventing or treating pulmonary hypertension of the present invention, the pulmonary administration includes administration via a metered dose inhaler, a dry powder inhaler, an atomizing sprayer, or a soft mist inhaler. According to the method for preventing or treating pulmonary hypertension of the present invention, the pulmonary administration includes administration via an atomizing nebulizer. According to the method for preventing or treating pulmonary hypertension of the present invention, the pulmonary administration includes administration via a dry powder inhaler. According to the method for preventing or treating pulmonary hypertension of the present invention, the pulmonary administration includes administration via a soft mist inhaler. According to the method for preventing or treating pulmonary hypertension of the present invention, the patient is a World Health Organization (WHO) Group I PH patient, or a WHO Group II PH patient, or a WHO Group III PH patient, or a WHO Group IV PH patient, or a WHO Group V PH patient. According to the method for preventing or treating pulmonary hypertension of the present invention, the pulmonary hypertension is selected from pulmonary arterial hypertension (PAH), pulmonary hypertension caused by left heart disease, pulmonary hypertension caused by lung disease and / or hypoxia, chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary hypertension caused by pulmonary artery obstructive lesions, and pulmonary hypertension associated with systemic or metabolic diseases. According to the method for preventing or treating pulmonary hypertension of the present invention, the PAH is selected from idiopathic pulmonary arterial hypertension (IPAH), hereditary pulmonary arterial hypertension, congenital heart disease-related pulmonary arterial hypertension, and drug- or toxin-related pulmonary arterial hypertension. According to the method for preventing or treating pulmonary hypertension of the present invention, the pulmonary hypertension is chronic thromboembolic PH (CTEPH). According to the method for preventing or treating pulmonary hypertension of the present invention, the pulmonary hypertension associated with systemic or metabolic diseases is sarcoidosis-associated pulmonary hypertension (SAPH). According to the method for preventing or treating pulmonary hypertension of the present invention, the administration is to administer an effective amount of the aforementioned compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitution, or pharmaceutical composition to the patient once a day. According to the method for preventing or treating pulmonary hypertension of the present invention, an effective amount of the compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitute, or pharmaceutical composition is administered to the patient once every two days, or at a greater dosing interval. According to the method for preventing or treating pulmonary hypertension of the present invention, the administration is to administer an effective amount of the aforementioned compound of formula I, its isomer or pharmaceutically acceptable salt, its isotope substitute, or pharmaceutical composition to the patient twice a day. According to the method for preventing or treating pulmonary hypertension of the present invention, wherein, after being administered to a patient via the pulmonary route, a longer elimination half-life (t 1 / 2 ), a larger area under the lung drug curve (AUC), and a larger lung-to-plasma drug concentration ratio. According to the method for preventing or treating pulmonary hypertension of the present invention, the administration is via the lungs and can be taken with food. According to the method for preventing or treating pulmonary hypertension of the present invention, the severity of systemic adverse events can be reduced or the occurrence of systemic adverse reaction events can be reduced after administration via the pulmonary route. The sixth aspect of the present invention provides a method for preparing the compound of formula I, comprising the following steps: The compound of formula II is reacted with the compound of formula III to produce the compound of formula I Wherein W is -OH, -Cl or -OC(O)R c , where R c It is C 1-C 5-alkyl; wherein Y is as defined above, and P is selected from -OH, -SH or -NH 2 or P is selected from -Cl, -Br, -I. When W is -OH and P is selected from -Cl, -Br, or -I, the compound of formula (II) reacts with the compound of formula (III) in the presence of a base in an inert solvent to produce the compound of formula I, wherein X in the compound of formula I is O. Preferably, the base is an organic base or an inorganic base, wherein the organic base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropylethylamine, and / or diisopropylamine; and the inorganic base is selected from alkaline earth metal carbonates or hydroxides (such as potassium carbonate and cesium carbonate). Preferably, the inert solvent is selected from N,N'-dimethylformamide (DMF), tetrahydrofuran, benzene, toluene, dioxane, dichloromethane (DCM), acetonitrile (MeCN), and / or a polyhalogenated aliphatic hydrocarbon (such as dichloromethane). Preferably, the reaction is carried out at a temperature of -20°C to 70°C, preferably 45°C to 65°C, for 1-8 hours, preferably 3-6 hours. Preferably, when P is selected from -Cl or -Br, the reaction is carried out in the presence of an alkaline earth metal carbonate such as potassium carbonate. When W is -OH and P is selected from -OH or -NH 2, the compound represented by Formula (II) reacts with the compound represented by Formula (III) in the presence of a dehydrating agent and a catalyst in an inert solvent to produce a compound represented by Formula I, wherein X in the compound represented by Formula I is O or NH. Preferably, the dehydrating agent is selected from dicyclohexylcarbodiimide (DCC) or N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC); and the catalyst is selected from N,N-dimethylaminopyridine (DMAP), sulfuric acid, sulfonic acid, hydrofluoric acid, phosphoric acid, toluenesulfonic acid, polystyrenesulfonate, heteropolyacid, zeolite, metal oxide, graphene oxide, or a combination thereof. Preferably, the inert solvent is selected from N,N-dimethylformamide (DMF), tetrahydrofuran, benzene, toluene, dioxane, dichloromethane (DCM), acetonitrile (MeCN), and / or a polyhalogenated aliphatic hydrocarbon. Preferably, the reaction is carried out at a temperature of -20°C to 70°C for 30 minutes to 48 hours, preferably 2 hours to 24 hours. When W is -Cl and P is selected from -OH or -NH 2, the compound of formula (II) reacts with the compound of formula (III) in the presence of an organic base in an inert solvent to produce the compound of formula I, wherein X in the compound of formula I is O or NH. Preferably, the organic base is selected from DMAP, triethylamine, and / or pyridine; and the inert solvent is selected from DMF, tetrahydrofuran, benzene, toluene, dioxane, and / or a halogenated aliphatic hydrocarbon. Preferably, the reaction is carried out at a temperature of -20°C to 70°C for 30 minutes to 24 hours, preferably 2 hours to 12 hours. When W is -OC(O)R c When P is selected from -OH, the compound of formula (II) reacts with the compound of formula (III) in the presence of a catalyst in an inert solvent to produce a compound of formula I, wherein in the compound of formula I, X is O. Preferably, the catalyst is selected from N,N-dimethylaminopyridine (DMAP), an alkali metal compound catalyst, a Lewis acid catalyst, an alkaline earth metal alkoxide catalyst and / or an organic titanium catalyst. Preferably, the alkali metal compound catalyst is selected from NaOH, KOH, Li 2CO 3. Na 2CO 3. NaHCO 3. K 2CO 3. Na 2WO 4 or a combination thereof; the Lewis acid catalyst is selected from AlCl 3. ZnCl 2. SnCl 4. TiCl 4. FeCl 3. mgCl 2. Pb(OAc) 2. Zn(OAc) 2. Al 2O(OAc) 4 or a combination thereof; the alkaline earth metal alkoxide catalyst is selected from sodium methoxide, sodium ethoxide, magnesium methoxide or a combination thereof; the organic titanium catalyst is selected from butyl titanate Ti (OC 4H 9) 4. Titanocene dichloride (Cp 2TiCl 2) or a combination thereof. Preferably, the inert solvent is selected from N,N-dimethylformamide (DMF), tetrahydrofuran, benzene, toluene, dioxane, dichloromethane (DCM), acetonitrile (MeCN), and / or polyhalogenated aliphatic hydrocarbons. Preferably, the reaction is carried out at a temperature of -20°C to 70°C for 30 minutes to 24 hours, preferably 2 hours to 12 hours. When W is -OH and P is selected from -SH, the compound of formula (II) reacts with the compound of formula (III) in the presence of a dehydrating agent and a catalyst in an inert solvent to produce a compound of formula I, wherein X in the compound of formula I is S. Preferably, the dehydrating agent is selected from dicyclohexylcarbodiimide (DCC) or N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC); and the catalyst is selected from N,N-dimethylaminopyridine (DMAP), sulfuric acid, sulfonic acid, hydrofluoric acid, phosphoric acid, toluenesulfonic acid, polystyrenesulfonate, heteropolyacid, zeolite, metal oxide, graphene oxide, or a combination thereof. Preferably, the inert solvent is selected from N,N-dimethylformamide (DMF), tetrahydrofuran, benzene, toluene, dioxane, dichloromethane (DCM), acetonitrile (MeCN), and / or a polyhalogenated aliphatic hydrocarbon. Preferably, the reaction is carried out at a temperature of 0°C to 30°C for 5 minutes to 3 hours. When W is -OH and P is selected from -SH, the compound of formula (II) reacts with the compound of formula (III) in the presence of a catalyst in an inert solvent to produce a compound of formula I, wherein X is S in the compound of formula I. Preferably, the catalyst is selected from a Lewis acid (e.g., HfCl4 and / or ZrCl4). Preferably, the reaction is carried out under heating and reflux for 5 minutes to 3 hours. When W is -OH and P is selected from -SH, the compound of formula (II) reacts with the compound of formula (III) in the presence of equivalent amounts of diphenylphosphine chloride, iodine, and imidazole in a polar aprotic solvent to produce a compound of formula I, wherein in the compound of formula I, X is S. Preferably, the reaction is carried out under heating reflux for 5 minutes to 3 hours. Explanation of terms: Unless otherwise stated, the terms used in the specification and claims have the following meanings: The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing from 1 to 20 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate. The term "alkenyl" refers to a straight or branched carbon chain of 2 to 20 carbon atoms containing one or more carbon-carbon double bonds. The term "alkynyl" refers to a straight or branched carbon chain of 2 to 20 carbon atoms containing one or more carbon-carbon triple bonds. The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group having two residues derived from the same or different carbon atoms of an alkane group by removing two hydrogen atoms, preferably a straight or branched chain group containing 1 to 20 carbon atoms, more preferably a straight or branched chain group containing 1 to 10 carbon atoms. When substituted, the substituent may be substituted at any available point of attachment. The term "alkenylene" refers to a radical derived from a parent alkane by removing two hydrogen atoms from the same or different carbon atoms, preferably containing 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, and having at least one carbon-carbon double bond at any position. The term "alkynylene" refers to a radical derived from two hydrogen atoms removed from the same or different carbon atoms of a parent alkane, preferably containing 2 to 20 carbon atoms, more preferably 2 to 10 carbon atoms, and having at least one carbon-carbon triple bond at any position. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent, wherein the cycloalkyl group contains 3 to 12 carbon atoms, preferably 4 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups. The cycloalkyl group may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring that is attached to the parent group is the cycloalkyl group. The cycloalkyl group may be optionally substituted or unsubstituted. The term "aryl" or "aromatic group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings of conjugated adjacent carbon atoms) group having a conjugated π electron system, preferably a 6- to 10-membered ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indene, and indane. The aryl group may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring. The aryl group may be substituted or unsubstituted, wherein the substituted aryl group may be an alkoxy-substituted aryl group, a halogen-substituted aryl group, or the like. Non-limiting examples of the fused aryl ring include: and . The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and having 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and / or nitrogen. The heteroaryl group is preferably 5 to 12 members. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. Non-limiting examples of heteroaryl groups include: and . Heteroaryl groups can be substituted or unsubstituted. The term "heterocycle" refers to a 3-8 membered ring structure consisting of carbon atoms and heteroatoms, wherein the heteroatoms are selected from oxygen, sulfur and / or nitrogen. The term "substituted" refers to other substituents attached to the moiety at any acceptable position of the moiety. Unless otherwise specified, the moiety may be bonded via carbon, nitrogen, oxygen, sulfur or any other acceptable atom. The substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, -ONO 2. cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate. The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group. In the chemical structure of the compound of the present invention, It means that there may be multiple optionally substituted carbon units, but each carbon unit is not necessarily the same repeating unit. In the chemical structure of the compound of the present invention, the bond " " does not specify the configuration, i.e. the bond" " can be" "or" ” or both "and" " Two configurations. In the chemical structure of the compound described in the present invention, the bond " " does not specify the configuration, that is, it can be Z configuration or E configuration, or contain both configurations. Although not all of the above structural formulae are drawn in certain isomeric forms for the sake of simplicity, the present invention may include all isomers, such as stereoisomers, tautomers, rotational isomers, geometric isomers, diastereomers, racemates and enantiomers. The aforementioned compounds provided by the present invention may exist in the form of pharmaceutically acceptable salts, and the pharmaceutically acceptable salts are selected from: alkali metal salts such as sodium salts or potassium salts; alkaline earth metal salts such as calcium salts; organic base salts such as diethylamine salts, diethanolamine salts, meglumine salts, piperazine salts, and choline salts; inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, hydrofluorides, and hydrobromides; and organic acid salts such as acetates, trifluoroacetates, naphthoates, benzoates, tartrates, lactates, citrates, fumarates, maleates, malates, oxalates, succinates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, naphthalenesulfonates, and camphorsulfonates. The compound of Formula I, its isomers, or pharmaceutically acceptable salts provided herein is a prodrug form that can be converted into the corresponding carboxylic acid active metabolite (Compound R2) in vivo. The diphenylpyrazine derivatives provided herein have the following advantages: 1. The diphenylpyrazine derivatives provided by the present invention can be ideally converted into carboxylic acid active metabolites in the lungs, have physical and chemical properties that are more suitable for pulmonary administration, and have lower systemic absorption. They can stay in the local lungs for a long time and slowly release effective concentrations of carboxylic acid active metabolites. 2. Compared with the oral compound R1 (Selexipag), the diphenylpyrazine derivatives provided by the present invention can significantly reduce the mean pulmonary hypertension of experimental model animals after administration through the lungs, have the same or greater efficacy as the oral compound R1, and can show a sustained and significant antihypertensive effect for a longer period of time. 3. Under the same conditions, inhaled equimolar doses of Compound R1 are almost ineffective, as Compound R1 cannot be converted into an effective amount of active compound in the lungs under trace conditions. The diphenylpyrazine derivatives provided by the present invention are more suitable for pulmonary administration than Compound R1. 4. Compared with the oral compound R1, the diphenylpyrazine derivatives provided by the present invention can be administered through the lungs, which can greatly reduce the dosage, provide a lower dosing frequency, a wider therapeutic window, reduce systemic side effects, avoid food effects, greatly improve the safety of the drug and the patient's tolerance to the drug, and will provide a new treatment option for patients with pulmonary hypertension. The present invention will be further described in detail below with reference to the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the materials used in the following examples and comparative examples were all purchased from conventional commercial sources. The structures of the compounds were determined by nuclear magnetic resonance ( 1 H NMR) or liquid chromatography-mass spectrometry (LC-MS). The liquid chromatography-mass spectrometry (LC-MS) instrument was Agilent 1260-6120; the nuclear magnetic resonance instrument ( 1 H NMR) was performed on a Bruker Avance-400, and nuclear magnetic resonance ( 1 H NMR) shifts (δ) are given in parts per million (ppm) and are determined for the solvent d 6-DMSO or d 6-CDCl 3, the internal standard is tetramethylsilane (TMS), and the chemical shift is 10 -6 The unit is ppm. The term "room temperature" in the present invention refers to a temperature between 10-25°C. Comparative Example 1. 2-{4-[N-(5,6- diphenylpyrazine -2- base )-N- Isopropylamino ] Butoxy }-N- Methylsulfonylacetamide (selexipag , compound R1) Preparation Compound R1 was prepared according to the method disclosed in Example 84 of the specification of patent CN1516690A to obtain 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}-N-methanesulfonylacetamide (Compound R1) as a yellow solid. ESI-MS: m / z = 496.2 (M+H) + ; 1 H NMR (400 MHz, d 6-DMSO)δ11.71(s,1H),8.14(s,1H),7.41-7.15(m,10H), 4.91-4.64(m,1H), 4.05(s,2H), 3.53(t,J=5.9Hz,2H), 3.49-3.39(m,2H), 3.26(s,3H), 1.65(d,J=5.4Hz,4H), 1.23(d,J=6.7Hz,6H). Comparative Example 2. 2-{4-[N- ( 5,6- diphenylpyrazine -2- base) -N- Isopropylamino ] Butoxy } Acetic acid ( MRE-269 , compound R2 ) Compound R2 was prepared according to the method disclosed in Example 42 of the patent specification CN1516690A to obtain 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}acetic acid (Compound R2) as a yellow oil. ESI-MS: m / z=420.0 (M+H) + ; 1 H NMR (400 MH Z , d 6-DMSO) δ12 .59(s ,1H) , 8 .14(s ,1H) , 7 .38-7 .21(m ,10H) , 4 .82-4 .74(m ,1H) , 4 .00(s ,2H) , 3 .53-3 .33(m ,4H) , 1.69-1.61(m,4H), 1.22(d,J=6.8Hz,6H). Comparative Example 3. 2-(4-((5,6- diphenylpyrazine -2- base )- Isopropyl - amino ) Butoxy ) n-Butyl acetate (compound Ia-1 ) Intermediate compound R2 (499.9 mg, 1.192 mmol) was dissolved in anhydrous DMF (8 ml), and anhydrous potassium carbonate (411.1 mg, 2.974 mmol) and 1-bromobutane (270 μL, 1.971 mmol) were added. The reaction was stirred at 60°C for 3 h. Ethyl acetate was added for dilution, the organic phase was washed with water, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to obtain compound Ia-1. ESI-MS: m / z = 476.28 (M+H). + ; 1 H NMR (400 MH Z , d 6-DMSO) δ0.87 (3H, t) δ1.24 (6H, m); δ1.31 (2H, m) 1δ1.63 (6H, m) δ3.44 (2H, t) δ3.52 (2H, t) δ4.07 (4H, s×d); δ4.79 (1H, m); δ7.32 (10H, m) δ8.14 (1H, s). Comparative Example 4. 2-(4-((5,6- diphenylpyrazine -2- base )- Isopropyl - amino ) Butoxy ) n-Hexyl acetate (compound Ia-2 ) Intermediate compound R2 (500.3 mg, 1.192 mmol) was dissolved in anhydrous DMF (8 ml), and anhydrous potassium carbonate (410.6 mg, 2.971 mmol) and 1-bromohexane (290 μL, 1.757 mmol) were added. The reaction was stirred at 60°C for 3 h. Ethyl acetate was added for dilution, the organic phase was washed with water, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to obtain compound Ia-2. ESI-MS: m / z = 504.31 (M+H). + ; 1 H NMR (400 MH Z , d 6-DMSO) δ0.82 (3H, t) δ1.23 (12H, m); δ1.63 (6H, m) δ3.44 (2H, t) δ3.52 (2H, t) δ4.08 (4H, s×t); δ4.79 (1H, m); δ7.32 (10H, m) δ8.14 (1H, s). Example 1. 2-(4-((5,6- diphenylpyrazine -2- base )- Isopropyl - amino ) Butoxy ) n-Octyl acetate (compound Ia-3 ) Intermediate compound R2 (500.0 mg, 1.192 mmol) was dissolved in anhydrous DMF (8 ml), and anhydrous potassium carbonate (410.8 mg, 2.972 mmol) and 1-bromooctane (410 μL, 2.123 mmol) were added. The reaction was stirred at 60°C for 3 h. Ethyl acetate was added for dilution, the organic phase was washed with water, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to obtain compound Ia-3. ESI-MS: m / z = 532.3 (M+H). + ; 1 H NMR (400 MH Z , d 6-DMSO) δ0.82 (3H, t) δ1.23 (16H, m); δ1.63 (6H, m) δ3.44 (2H, t) δ3.52 (2H, t) δ4.08 (4H, s×t); δ4.79 (1H, m); δ7.32 (10H, m) δ8.14 (1H, s). Example 2. 2-(4-((5,6- diphenylpyrazine -2- base )- Isopropyl - amino ) Butoxy ) n-Decyl acetate (compound Ia-4 ) Intermediate compound R2 (500.0 mg, 1.192 mmol) was dissolved in anhydrous DMF (6 ml), and anhydrous potassium carbonate (410.0 mg, 2.967 mmol) and 1-bromodecane (815 μL, 3.685 mmol) were added. The reaction was stirred at 60°C for 3 h. Ethyl acetate was added for dilution, the organic phase was washed with water, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to afford compound Ia-4 (660.0 mg, 1.180 mmol) in a yield of 98.9%. ESI-MS: m / z = 560.4 (M+H). + ; HNMR (400MH Z , d 6-DMSO) δ0.84 (3H, t); δ1.23 (18H, dd) 2; δ1.62 (8H, m) δ3.44 (2H, t); δ3.53 (2H, t); δ4.07 (4H, m); δ4.79 (1H, t); δ7.27 (8H, m) δ7.37 (2H, dd); δ8.13 (1H, s). Example 3. 2-(4-((5,6- diphenylpyrazine -2- base )- Isopropyl - amino ) Butoxy ) Tetradecyl acetate (compound Ia-6 ) Intermediate compound R2 (500.6 mg, 1.193 mmol) was dissolved in anhydrous DMF (6 ml), and anhydrous potassium carbonate (411.2 mg, 2.975 mmol) and 1-bromotetradecane (650 μL, 2.344 mmol) were added. The reaction was stirred at 60°C for 3 h. Ethyl acetate was added for dilution, the organic phase was washed with water, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to afford compound Ia-6 (200.0 mg, 0.325 mmol) in a yield of 27.2%. ESI-MS: m / z = 616.5 (M+H). + ; 1 H NMR (400 MH Z , d 6-DMSO) δ0.85 (3H, t) δ1.22 (28H, m) δ1.56 (2H, m) δ1.65 (4H, m) δ3.43 (2H, t); δ 3.52 (2H, t); δ4.01 (4H, s×t); δ4.76 (1H, m); δ7.25~7.37 (10H, m) δ8.14 (1H, s). Example 4. 2-(4-((5,6- diphenylpyrazine -2- base )- Isopropyl - amino ) Butoxy ) Hexadecyl acetate (compound Ia-7 ) Intermediate compound R2 (500.1 mg, 1.192 mmol) was dissolved in anhydrous DMF (6 ml). Anhydrous potassium carbonate (409.7 mg, 2.964 mmol) and 1-bromohexadecane (590 μL, 7.932 mmol) were added. The reaction was stirred at 60°C for 3 h. The mixture was diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to obtain compound Ia-7 (600.0 mg, 0.932 mmol) in a yield of 78.2%. ESI-MS: m / z = 644.47 (M+H). + ; 1 H NMR (400 MH Z , d 6-DMSO) δ0.84 (3H, m); δ1.22 (32H, m) δ1.55~1.65 (6H, m) δ3.44 (2H, t) δ3.52 (2H, t); δ4.06 (4H, s×t); δ4.88 (1H, m) 5δ7.27~7.35 (10H, m) δ8.14 (1H, s). Example 5. 2-(4-((5,6- diphenylpyrazine -2- base )- Isopropyl - amino ) Butoxy ) Acetic acid - p-Methoxyphenoxyethyl ester (compound Ib-11 ) Intermediate compound R2 (100.2 mg, 0.239 mmol) was dissolved in anhydrous DMF (4 ml), and anhydrous potassium carbonate (82.2 mg, 0.595 mmol) and 1-(2-bromoethoxy)-4-methoxybenzene (110.0 mg, 0.476 mmol) were added. The reaction was stirred at 60°C for 3 h. Ethyl acetate was added for dilution, the organic phase was washed with water, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to afford compound Ib-11 (110.0 mg, 0.193 mmol) in an 80.7% yield. ESI-MS: m / z = 570.3 (M+H). + ; 1 H NMR (400 MH Z , d 6-DMSO) δ1.21 (6H, d) δ1.64 (4H, m) δ3.43 (2H, t) δ3.53 (2H, m) δ3.67 (3H, s); δ4.13 (4 H, s × d); δ4.38 (2H, t); δ4.76 (1H, m) δ6.84 (4H, m); δ7.27~7.36 (10H, m) δ8.14 (1H, s). Example 6. 2-(4-((5,6- diphenylpyrazine -2- base )- Isopropyl - amino ) Butoxy ) Acetic acid - Benzyloxyethyl ester (Compound Ib-12 ) Intermediate compound R2 (501.5 mg, 1.195 mmol) was dissolved in anhydrous DMF (6 ml), and anhydrous potassium carbonate (412.6 mg, 2.985 mmol) and benzyl-2-bromoethyl ether (377 μL, 1.753 mmol) were added. The reaction was stirred at 60°C for 3 h. Ethyl acetate was added for dilution, the organic phase was washed with water, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to obtain compound Ib-12 (700.0 mg, 1.265 mmol). ESI-MS: m / z = 554.3 (M+H). + ; 1 H NMR (400 MH Z , d 6-DMSO) δ1.21 (6H, d) δ1.64 (4H, m) δ3.43 (2H, t) δ3.53 (2H, t) δ3.64 (2H, t) δ4. 12(2H,d)δ4.25(2H,t)δ4.48(2H,s)δ4.76(1H,m)δ7.28(15H,m)δ8.14(1H,s). Example 7. 2-(4-((5,6- diphenylpyrazine -2- base )- Isopropyl - amino ) Butoxy ) Acetic acid - n-Hexyloxyethoxyethyl ester (compound Ic-2 ) Intermediate compound R2 (500.3 mg, 1.192 mmol) was dissolved in anhydrous DMF (6 ml), and anhydrous potassium carbonate (410.9 mg, 2.973 mmol) and 1-(2-(2-bromoethoxy)ethoxy)hexane (715.3 μL, 2.838 mmol) were added. The reaction was stirred at 60°C for 3 h. Ethyl acetate was added for dilution, the organic phase was washed with water, and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:2) to obtain compound Ic-2 (210.0 mg, 0.355 mmol) in a yield of 29.8%. (ESI-MS: m / z = 592.3 (M+H) + ; HNMR (400MH Z , d 6-DMSO) δ0.83 (3H, m); δ1.23-1.65 (18H, m) δ2.00 (1H, d) δ3.35 (2H, s) δ3.44-3 .61 (10H, t); δ4.11 (2H, s); δ4.19 (2H, m); δ7.26-7.37 (10H, m); δ8.14 (1H, s). The following compounds were synthesized using a similar procedure as above: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . Experimental Examples Experimental example 1 Study on the conversion rate of compound hydrolysis mediated by porcine esterase The diphenylpyrazine derivatives provided herein can be hydrolyzed into the corresponding active carboxylic acid metabolite, compound R2, under the action of esterases. This assay tested test compounds with varying ester side chain lengths in vitro using porcine esterase-mediated hydrolysis to assess the conversion rate of each test compound to R2. The test compounds were Ia-1, Ia-2, Ia-3, Ia-4, Ia-6, and Ia-7. Weigh 100 mg of the test compound and dissolve it in 20 ml of 20% ethanol to prepare a 5 mg / ml test compound solution. Pipette 1 ml of the test compound solution into 4 ml of PBS to prepare a 1 mg / ml test compound reaction solution. Add 20 U (80 μL) of porcine esterase, shake well, and incubate at 38°C. Samples were taken after a certain period of reaction (0, 30 min, 1 hr, and 2 hr) to measure the conversion of the test compound to compound R2. For each sample, hydrolysis was calculated from the measured reactant and product peak areas: % Hydrolysis = (Product Peak Area / (Reactant Peak Area + Product Peak Area) * 100). The results of this experiment are shown in Figure 1. These results demonstrate that the hydrolysis rate is correlated with the carbon chain length of the ester side chain. Compounds with longer side chains are hydrolyzed more slowly by esterase. Experimental example 2 use U46619 Study on the efficacy of each compound after airway aerosol administration in the rat model of acute pulmonary artery hypertension induced by 1 Experimental purpose: U46619 is a stable thromboxane A2 (TXA2) analogue that binds to the thromboxane A2 receptor and activates downstream IP 3 signal, promoting vasoconstriction and platelet aggregation. Using a U46619-induced pulmonary artery hypertension model in rats, the effects of airway aerosol administration of compound R1, along with equimolar amounts of comparison compound Ia-2 and test compounds (Ia-3 and Ia-4), on pulmonary hypertension in rats were studied, and the antihypertensive effect was compared with that of oral administration of compound R1. 2 Experimental Materials 2.1 Main instruments: MP160 16-channel physiological recorder, rat aerosol pulmonary administration device / intratracheal administration, polyethylene hose, rat laryngoscope, syringe, rat fixator, anesthetic, etc. 2.2 Main Reagents: Dimethyl sulfoxide, PBS, ethyl acetate, sodium chloride, 10% urethane, isoflurane, and heparinized saline. Modeling Reagent: U46619 (9,11-dideoxy-11A,9A-methyleneepoxyprostaglandin F2A). 2.3 Experimental Animals Thirty-nine SPF male SD rats weighing approximately 250–400 g were used. 2.4 Test Sample Preparation: Weigh the required amount of compound R1, comparative compound Ia-2, and compounds Ia-3 and Ia-4, dissolve in DMSO to prepare a stock solution (100 mg / ml), and store in a sealed container at 4°C in the dark. On the day of testing, remove the stock solution vials, equilibrate at room temperature, and then dilute the stock solution with 1x PBS to the target concentration (working solution). Modeling Preparation: Add 900 μL of methyl acetate to the original bottle of U46619, mix, and prepare a 1 mg / ml (1 μg / μL) stock solution. Aliquot 10 μL (1 μg / μL) per tube into sterile EP tubes and store at -20°C. On the day of modeling, remove the stock solution, equilibrate at room temperature, and dilute 20-fold with 0.9% sodium chloride solution (sterile) to prepare a working solution with a concentration of 50 ng / μL. 2.5 Animal Grouping and Dosing Reference was made to the literature published by Yohei Honda, et al (2020. PLOS ONE) and incorporated into the present invention. In this study, the oral gavage dose of Compound R1 (n=9) was designed to be 3.00 mg / kg. The airway aerosol doses of Compound R1 and each test compound were equimolar based on the active Compound R2. The airway aerosol doses were 5.92 μg / kg for Compound R1 (n=11), 6.00 μg / kg for Compound Ia-2 (n=5), 6.33 μg / kg for Compound Ia-3 (n=5), and 6.67 μg / kg for Compound Ia-4 (n=5). U46619 (25 μg / kg) was injected into the left jugular vein of SD rats at various time points after oral gavage and airway aerosol administration: 0.5 h (all groups except the Ia-4 airway aerosol group), 1 h, 4 h, 6 h (R1 oral gavage group only, Ia-2 airway aerosol group, and Ia-3 airway aerosol group), 16 h, and 24 h. Peak RVSP elevation was recorded and compared with the peak RVSP elevation in the model control group (U46619 alone), and the percentage of inhibition of RVSP elevation was calculated. One to four animals were used at each time point. Rats in the model control group (n=4) were administered U46619 immediately after successful catheterization. All animals underwent right ventricular systolic pressure measurement and gross respiratory status observation. Ten minutes after U46619 administration, 2–2.5 ml of whole blood was collected and anticoagulated in EP tubes containing 0.1% heparinized saline. After centrifugation, plasma was collected and stored at −70°C until further use. Whole lung tissue was collected, lung weight recorded, and photographed. The tissue was minced, mixed, and aliquoted, then stored at −20°C until further use. 2.6 Results 2.6.1 Gross Observation Results Under the experimental conditions, except for the model control group, all SD rats in the group were anesthetized with isoflurane and immediately received airway aerosol drug administration. No respiratory abnormalities were observed after drug administration. 2.6.2 Right ventricular systolic pressure (RVSP) results were based on the results of Yohei Honda et al. (2020. PLOS ONE). The effective threshold for the percentage inhibition of RVSP elevation in this model was set at approximately 35-40%. The percentage inhibition of U46619-induced RVSP elevation in each group of experimental animals at various time points is shown in Figure 2. Compound R1, administered orally at a dose of 3.00 mg / kg, reached its lowest point of blood pressure reduction 4 hours after administration. Based on the effective threshold, it is estimated that it can effectively reduce U46619-induced pulmonary artery pressure elevation in rats within 5 hours. However, airway aerosol administration of 5.92 μg / kg of Compound R1 showed no significant antihypertensive effect from 0.5 to 24 hours. In contrast, compound Ia-3, administered via airway aerosol at a dose of 6.33 μg / kg, reached its nadir blood pressure only 0.5 hours after administration, while compound R1 reached its nadir blood pressure only 4 hours after oral gavage. Furthermore, a blood pressure-lowering effect was still observed 16 hours after Ia-3 administration via airway aerosol. Compound Ia-3 not only exhibited a long-lasting antihypertensive effect but also exhibited a rapid onset, a finding that excited the inventors. Compound Ia-4, administered via airway aerosol at a dose of 6.67 μg / kg, exhibited a significant antihypertensive effect 24 hours after administration. This is presumably due to the slow conversion of Ia-4 to active compound R2 in the lungs, and the antihypertensive effect of low-dose Ia-4 administered via airway aerosol requires a certain degree of cumulative R2 conversion. Surprisingly, compound Ia-2, administered via airway aerosol at a dose of 6.00 μg / kg, showed no significant antihypertensive effect at any time point. This is presumably due to compound Ia-2's high membrane permeability, preventing it from effectively remaining in the lungs to exert its efficacy. The above results suggest that compounds Ia-3 and Ia-4 can have a significant sustained-release effect and a good antihypertensive effect at a lower dose after administration via airway aerosol. In a parallel experiment using the same rat model of acutely elevated pulmonary artery pressure, the inventors found that aerosolizing 5.00 μg / kg of Compound R2 into the airways of five rats had a significant blood pressure-lowering effect, but the effect was short-lived, lasting only 6 hours. Furthermore, as reported in prior art literature, IP receptor agonist compounds carry the risk of adverse pulmonary reactions, such as coughing, following inhalation. Experimental example 3 Aerosol administration of high doses of compounds R1 Each test compound U46619 Study on the efficacy of pulmonary artery hypertension induced by β-catenin in rats 1. Experimental Purpose: The airway aerosol dosage of each compound in this study was approximately three times that of Experimental Example 2. Using the U46619-induced model of acute pulmonary artery hypertension in rats, the authors further verified the ability of compound R1 to exert a localized hypotensive effect in the lungs after airway aerosol administration by increasing the dosage. Furthermore, they verified whether increasing the airway aerosol dosage of test compounds Ia-2 and Ia-4 could effectively convert them into active compound R2, exerting its efficacy and maintaining its desired duration of action. 2 Animal Grouping and Dosing: Model construction and dosing methods were the same as those described in Experimental Example 2. In this experiment, the dosages for each group were as follows: the oral administration dose of Compound R1 was 3 mg / kg, and the airway aerosol administration dose of Compound R1 was 16.9 μg / kg; the airway aerosol administration dose of Compound Ia-2 was 17.1 μg / kg, and the airway aerosol administration dose of Compound Ia-4 was 19 μg / kg. The airway aerosol administration dose of each compound in this experiment was approximately three times the airway aerosol administration dose in Experimental Example 2. U46619 (25 μg / kg) was injected into the left jugular vein of SD rats at various time points after administration: 1, 4, and 6 hours (R1 gavage group only), 16 hours (R1 gavage group only and Ia-4 airway aerosol group only), 24 hours (R1 gavage group only and Ia-4 airway aerosol group only), and 48 hours (Ia-4 airway aerosol group only). Peak RVSP elevation after U46619 injection was recorded and compared with the peak RVSP elevation in the model control group (U46619 injection only), and the percentage inhibition of RVSP elevation was calculated. One to two animals were used at each time point. The results of this experiment are shown in Figure 3. Even with a three-fold increase in the dose, airway aerosol administration of Compound R1 still showed no antihypertensive effect. Compound Ia-4, when administered via airway aerosol at an increased dose, exhibited a good antihypertensive effect from 1 hour to 24 hours, and was superior to oral administration of Compound R1 at all test time points, indicating that Compound Ia-4 has a sustained-release effect. In contrast, airway aerosol administration of the short-chain compound Ia-2 approached the critical effective level at 4 hours. This demonstrates that airway aerosol administration of Compound Ia-4 has a long-lasting and superior antihypertensive effect. Experimental example 4 Prodrug and active ingredient in rat plasma and lung tissue after airway aerosol administration R2 Pharmacokinetic studies of 1 Experimental purpose: After rats were given prodrug compounds (Ia-3, Ia-4) by airway aerosolization and compound R1 by oral gavage, the concentrations of prodrug compounds (Ia-3, Ia-4, R1) and active ingredient R2 in plasma and lung tissue at different time points were detected. 2 Main instruments: Xevo TQ-XS triple quadrupole mass spectrometer, ACQUITY UPLC I-Class Plus, vortex mixer, high-speed refrigerated centrifuge, medical cryogenic chamber. 3 Animal grouping, drug administration and sampling A total of 45 SPF male SD rats were grouped and dosed as shown in the following table: Three rats in each experimental group were sacrificed at 15 min, 30 min, 1 h, 4 h, and 24 h after administration, and their lung tissues were obtained. The remaining rats in each group were sacrificed at 15 min, 30 min, 1 h, and 4 h after administration, and their blood and lung tissues were obtained, with three rats at each time point. Plasma samples: Blood samples were placed in sodium heparin anticoagulant tubes, centrifuged, and plasma was collected in centrifuge tubes and frozen at -70°C. Lung samples: The rats were bled through the femoral artery, and the lungs were removed after dissection and stored at -70°C. Sample preparation method: 50 μL of sample was added to 150 μL of internal standard precipitant (50 ng / mL caffeine solution obtained by diluting with acetonitrile), vortexed for 5 min, centrifuged at 15,000 rpm for 10 min, and then 150 μL was injected to determine the drug concentration. 4 Experimental Results After inhalation, prodrug compounds Ia-3 and Ia-4 remained only in the lungs and were not detected in the blood. This result is not shown. After oral administration, compound R1 was converted to active ingredient R2, and R1 was not detected in lung tissue, as shown in Figure 4a. As shown in Figure 4b, compounds Ia-3 and Ia-4 rapidly and continuously convert to the active ingredient R2 after inhalation. Even 24 hours after inhalation, R2 levels in lung tissue remain high. Even at an inhaled dose of approximately one-eighth the oral dose of compound R1, the concentration of R2 released into the lungs was significantly higher than that observed after oral administration of compound R1. As shown in Figure 4c, after inhalation administration of Ia-3, only a trace amount of active ingredient R2 was detected in the blood, which was much lower than the concentration of R2 formed in the blood after oral administration of compound R1; after inhalation administration of Ia-4, R2 was almost undetectable in the blood, which is not shown in the figure. The experimental results show that the compound provided by the present invention can release the active ingredient R2 in the lungs for a long time after inhalation administration and maintain a high lung concentration, greatly improving the local bioavailability of R2 in the lungs and reducing potential systemic adverse reactions. In another parallel pharmacokinetic study on rats, the inventors administered an equimolar amount of compound R1 (118 μg / kg) to the rat airways via aerosol. The concentration of R1 in the rat lung tissue was significantly lower than that of the prodrug compound provided by the present invention, and R1 levels in the lung tissue were already below the detection limit half an hour after inhalation administration. This result suggests that R1's residence time in the lung tissue after inhalation administration is too short to allow the active ingredient to exert its sustained and effective pharmacological effects in the lungs, which is consistent with the results of the aforementioned efficacy studies. The above experimental results demonstrate that, compared to compound R1, the compounds provided herein are more effectively converted to active ingredient R2 in the lungs to exert their antihypertensive effects. Furthermore, compared to compounds with shorter side chains, the compounds provided herein with longer side chains exhibit a sustained and significant antihypertensive effect locally in the lungs. Compounds with medium-length side chains, on the other hand, can achieve efficacy at lower doses, achieving both rapid onset and a longer duration of action. This suggests that, in clinical practice, the compounds provided herein can reduce dosages. Furthermore, their sustained-release properties allow for less frequent dosing, making them more suitable for pulmonary administration. This reduces adverse reactions associated with systemic drug exposure, as is the case with oral administration, and avoids the interaction between oral medication and food. Furthermore, because the compounds provided herein are slowly converted to active ingredients in the lungs, the risk of pulmonary adverse reactions such as coughing caused by overactivation of IP receptors due to localized high concentrations of the active ingredient is reduced. This provides a more effective, convenient, and well-tolerated treatment option for patients with pulmonary hypertension. Although the present invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, various modifications may be made to adapt specific circumstances, materials, substances, methods, and combinations of method steps to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims. All patents, patent applications, patent application publications, journal articles, and protocols cited herein are incorporated by reference in their entirety for all purposes. Figure 1. Shows the hydrolysis conversion rates of various diphenylpyrazine derivatives (Ia-1, Ia-2, Ia-3, Ia-4, Ia-6, and Ia-7) mediated by porcine esterase at different time points. Figure 2. Shows the percentage inhibition of right ventricular systolic pressure (RVSP) elevation in a rat U46619-induced acute pulmonary artery hypertension model, compared to oral administration of 3 mg / kg of compound R1, following airway aerosol administration of 5.92 μg / kg of compound R1, 6 μg / kg of compound Ia-2, 6.33 μg / kg of compound Ia-3, and 6.67 μg / kg of compound Ia-4. Figure 3 shows the percentage inhibition of the increase in right ventricular systolic pressure (RVSP) in a rat model of acute pulmonary artery hypertension induced by U46619, following aerosol administration of a high dose of 16.9 μg / kg of Compound R1, 17.1 μg / kg of Compound Ia-2, and 19.0 μg / kg of Compound Ia-4, compared to oral administration of 3 mg / kg of Compound R1. Figure 4a shows the temporal changes in lung tissue prodrug concentrations of Compound Ia-3 and Compound Ia-4 following airway aerosol administration. Figure 4b shows the temporal changes in lung tissue active ingredient R2 concentrations of Compound Ia-3 and Compound Ia-4 following oral aerosol administration of Compound R1, compared to oral administration of Compound R1. Figure 4c shows the temporal changes in plasma active ingredient R2 concentrations of Compound Ia-3 and Compound Ia-4 following airway aerosol administration of Compound Ia-3 and Compound Ia-4, compared to oral administration of Compound R1. (After inhalation administration of Ia-4, R2 was almost undetectable in the blood, not shown in the figure)

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein, Formula I, X is selected from O; Y is selected from the group defined by -R1; R1 is selected from a straight-chain C8~C16 alkyl group, wherein the straight-chain C8~C16 alkyl group is optionally substituted by one or more substituents selected from the following groups: phenyl, substituted phenyl, -NRaRb, halogen atom; wherein the substituted phenyl is a C1-3 alkoxy-substituted phenyl, fluorine-substituted phenyl, chlorine-substituted phenyl or bromine-substituted phenyl; wherein Ra and Rb are each independently selected from H, -CH3 or -CH2CH3.

2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of: , , , , , , , , .

3. A pharmaceutical composition comprising a compound of formula I as described in claim 1 or 2, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.

4. Use of a compound of formula I or a pharmaceutically acceptable salt of claim 1 or 2, or a pharmaceutical composition of claim 3, in the preparation of a medicament for treating diseases related to prostaglandin I2 receptors, comprising administering to a patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt of claim 1 or 2, or a pharmaceutical composition of claim 3.

5. The use as described in claim 4, wherein the related disease is selected from pulmonary hypertension, arteriosclerosis obliterans, platelet-forming diseases associated with excessive platelet aggregation, pulmonary fibrosis / pulmonary induration, asthma and asthma symptoms, and / or chronic obstructive pulmonary disease.

6. The use as described in claim 5, wherein the drug is administered via the lungs.

7. The use according to claim 6, wherein administration to the lungs includes administration via a metered-dose inhaler, a dry powder inhaler, a nebulizer, or a soft fog inhaler.

8. The use as described in claim 5, wherein the related disease is pulmonary hypertension.

9. The use as described in claim 8, wherein the patient is a World Health Organization (WHO) Group I patient with pulmonary hypertension.

10. The use as described in claim 8, wherein the patient is a WHO Group II patient with pulmonary hypertension.

11. The use as described in claim 8, wherein the patient is a WHO Group III patient with pulmonary hypertension.

12. The use as described in claim 8, wherein the patient is a WHO Group IV patient with pulmonary hypertension.

13. The use as described in claim 8, wherein the patient is a WHO Group V patient with pulmonary hypertension.

14. The use according to claim 8, wherein the pulmonary hypertension is selected from pulmonary hypertension, pulmonary hypertension caused by left heart disease, pulmonary hypertension caused by lung disease and / or hypoxia, chronic thromboembolic pulmonary hypertension, pulmonary hypertension caused by pulmonary artery obstruction, and pulmonary hypertension associated with a systemic or metabolic disease.

15. The use according to claim 14, wherein the pulmonary hypertension is selected from idiopathic pulmonary hypertension, hereditary pulmonary hypertension, pulmonary hypertension associated with congenital heart disease, and pulmonary hypertension associated with drugs or toxins.

16. The use as described in claim 14, wherein the pulmonary hypertension is chronic thromboembolic pulmonary hypertension.

17. The use as described in claim 14, wherein the pulmonary hypertension associated with the systemic or metabolic disease is sarcoidosis-associated pulmonary hypertension.

18. The use according to claim 4, wherein administration is to administer the effective amount of the compound of formula I or claim 1 or 2 or a pharmaceutically acceptable salt to a patient once daily.

19. The use according to claim 4, wherein administration is to administer the effective amount of the compound of formula I or claim 1 or 2 or a pharmaceutically acceptable salt to a patient once every two days.

20. The use according to claim 4, wherein administration is to administer the effective amount of the compound of formula I or claim 1 or 2 or a pharmaceutically acceptable salt to a patient twice daily.

21. A method for preparing a compound of formula I as claimed in claim 1 or 2, comprising the following steps: The compound of formula II reacts with the compound of formula III to produce the compound of formula I, wherein... W is -OH; where Y is as defined in request item 1, and P is selected from -OH or P is selected from -Cl, -Br, -I.

22. The method according to request item 21, wherein, When P is selected from -Cl, -Br, -I, the compound of formula (II) reacts with the compound of formula (III) in the presence of a base in an inert solvent to generate the compound of formula I, wherein X is O in the compound of formula I.

23. The method according to claim 22, wherein, The base is an organic base or an inorganic base, wherein the organic base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N-diisopropylethylamine and / or diisopropylamine; the inorganic base is selected from alkaline earth metal carbonates or hydroxides; the inert solvent is selected from N,N'-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, dichloromethane, acetonitrile and / or polyhalogenated aliphatic hydrocarbons; the reaction is carried out at a temperature of -20 ℃ to 70 ℃ for 1-8 hours; when P is selected from -Cl or -Br, the reaction is carried out in the presence of alkaline earth metal carbonates such as potassium carbonate.

24. The method according to request item 21, wherein, When P is selected from -OH, the compound shown in formula (II) reacts with the compound of formula (III) in an inert solvent in the presence of a dehydrating agent and a catalyst to generate the compound of formula I, wherein X is O in the compound of formula I.

25. The method according to request item 24, wherein, The dehydrating agent is selected from dicyclohexylcarbodiimide or N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride; the catalyst is selected from N,N-dimethylaminopyridine, sulfuric acid, sulfonic acid, hydrofluoric acid, phosphoric acid, toluenesulfonic acid, polystyrene sulfonate, heteropolyacid, zeolite, metal oxide, graphene oxide, or combinations thereof; the inert solvent is selected from N,N-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, dichloromethane, acetonitrile, and / or polyhalogenated aliphatic hydrocarbons; the reaction is carried out at a temperature of -20 °C to 70 °C for 30 minutes to 48 hours.

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