WO2018019296A1

WO2018019296A1 - Aminopyrazine compound, salt, or isomer, preparation method therefor, and application thereof

Info

Publication number: WO2018019296A1
Application number: PCT/CN2017/094936
Authority: WO
Inventors: 王颖; 蔡显荣; 鄢胜勇; 张涛; 刘强强; 马云龙; 乔惠; 付海霞
Original assignee: 成都苑东生物制药股份有限公司
Priority date: 2016-07-29
Filing date: 2017-07-28
Publication date: 2018-02-01
Also published as: CN109563055A; CN109563055B

Abstract

Disclosed is an aminopyrazine compound represented by formula (I), or a pharmaceutically acceptable salt or an isomer thereof. The aminopyrazine compound has prostaglandin I₂ (PGI₂) receptor agonist activity and is used as an IP receptor agonist for treating related diseases.

Description

Aminopyrazine compound or salt, isomer, preparation method and use thereof

Technical field

The present invention relates to the field of medicinal chemistry, and in particular to an aminopyrazine compound having a prostaglandin I ₂ (PGI ₂ ) receptor agonistic activity, or a salt thereof, an isomer thereof, a preparation method thereof, and a preparation thereof for treating pulmonary hypertension, platelet aggregation or Use in drugs such as arteriosclerosis obliterans.

Background technique

Prostaglandin I ₂ (PGI ₂ ) is a member of the family of lipids in the eicosanoid family and is an antagonist of thromboxane, and its reduced synthesis promotes thrombosis. The agonistic PGI ₂ receptor (IP receptor) not only inhibits platelet-mediated agglutination but also has a strong vasodilation effect. IP receptor agonists can treat pulmonary hypertension (PAH), PAH associated with various diseases, arteriosclerosis obliterans, coronary artery disease, myocardial infarction, transient ischemic attack, colic, stroke, ischemia Reperfusion injury, restenosis, atrial fibrillation, intermittent claudication, Raynaud's phenomenon, varicose veins, thrombosis, diabetes, diabetic nephropathy, hypertension, hyperlipidemia, cerebral infarction, rheumatoid arthritis, chronic obstructive pulmonary disease Disease (COPD), etc.

At present, PGI ₂ listed drugs have more or less problems such as short half-life, poor chemical stability and large side effects. For the problem of endogenous PGI ₂ compounds, many companies have begun to explore long half-life and good chemical stability. A non-endogenous PGI ₂ type IP receptor agonist with higher selectivity and less side effects, the structural formula is as follows: Among them, the marketed drug Selexipag jointly developed by Nippon Shinyaku and Actelion is an orally effective and highly selective. The IP receptor agonist of prostacyclin, the active metabolite of which is MRE-269; the clinical phase II compound FK-788 (developed by Astellas) and Ralinepag (developed by Arena); the compound in clinical phase QCC-374 (developed by Novartis) and Ono-1301 (developed by Ono).

In the above structure, two compounds belong to the aminopyrazine IP receptor agonist, one is Selexipag and the other is QCC-374. Patent CN1516690A discloses the compound Selexipag and its metabolically active compound MRE-269, and also provides a human platelet aggregation inhibition test to demonstrate the in vitro activity of such compounds; Patent CN103097385A discloses compound QCC-374, which is determined by using the Perkin Elmer Alpha Screen test. The cAMP accumulation in CHO cells (CHO-IP) stably expressing the IP receptor was evaluated for the activity of the compound on the IP receptor.

The inventors have found through long-term large-scale screening that the change of the long chain of the carboxylic acid of the aminopyrazine compound has a great influence on the activity, and the change The length of the chain length reduces the activity against platelet aggregation. Moreover, it was unexpectedly found in the study that the long-chain compound constructed by the ethylene glycol structure (especially the structure of two ethylene glycol-based units) can not only significantly increase the aminopyrazine compound in vitro compared with the MRE-269 compound. The anti-platelet aggregation activity also improves anti-platelet aggregation activity in vivo, lowers mean pulmonary artery pressure, and also improves the stability of the salt solution and reduces drug toxicity.

Summary of the invention

It is an object of the present invention to provide an aminopyrazine compound having the structure represented by the following formula I or a pharmaceutically acceptable salt or isomer thereof:

among them,

e is 0, 1 or 2;

R ¹ , R ² and R ³ are each independently selected from a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen-substituted C ₁ -C ₆ alkyl group, a halogen atom. Substituted C ₁ -C ₆ alkoxy, hydroxy, amine, C ₁ -C ₆ alkylamino, di(C ₁ -C ₆ alkyl)amine;

R ^{4 is} selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen-substituted C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₃ -C ₈ cycloalkyl group, a C ₁ -C ₆ alkane Acyl group

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a halogen atom-substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ - C ₆ alkyl, di(C ₁ -C ₆ alkyl)amino C ₁ -C ₆ alkyl, nitrile C ₁ -C ₆ alkyl;

Alternatively, R ⁵ and R ⁶ , R ⁷ and R ⁸ , R ⁹ and R ¹⁰ , R ¹¹ and R ¹² may each be bonded to a C ₁ -C ₆ alkyl substituted cyclopropane;

A and D are each independently selected from NR ¹⁵ , O, S, SO or SO ₂ , wherein R ¹⁵ is a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₃ -C ₈ naphthenic ring base;

G is selected from the group consisting of a hydroxyl group, a C ₁ -C ₆ alkoxy group, an amine group, a C ₁ -C ₆ alkylamino group, a C ₁ -C ₆ alkylamido group, a C ₁ -C ₆ alkylsulfonylamino group, a halogen atom Substituted C ₁ -C ₆ alkylsulfonylamino, C ₆ -C ₁₀ arylsulfonylamino, C ₁ -C ₆ alkyl substituted C ₆ -C ₁₀ arylsulfonylamino, halogen substituted C ₆ -C ₁₀ arylsulfonylamino group.

The aminopyrazine compound represented by the formula I provided by the present invention can be divided into three small formulas, which are three small formulas Ia corresponding to when e is equal to 0, 1 or 2 in the structure of the formula I. , Ib or Ic:

Wherein R ¹ , R ² , R ³ , R ⁴ , A, D, G are the same as defined in the above formula I;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^{12 are} independently selected from a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a halogen atom-substituted C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, di(C ₁ -C ₆ alkyl)amino C ₁ -C ₆ alkyl, nitrile C ₁ -C ₆ alkyl;

Alternatively, R ⁵ and R ⁶ , R ⁷ and R ⁸ , R ⁹ and R ¹⁰ , R ¹¹ and R ¹² may each be bonded to a C ₁ -C ₆ alkyl substituted cyclopropane.

Preferably, when e is 1, the aminopyrazine compound of the formula I of the present invention or a pharmaceutically acceptable salt or isomer thereof has the structure represented by the formula Ib:

among them,

R ¹ , R ² and R ³ are each independently selected from a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a halogen atom-substituted C ₁ -C ₆ alkyl group;

R ^{4 is} selected from the group consisting of a hydrogen atom, a C ₁ -C ₆ alkyl group, a halogen-substituted C ₁ -C ₆ alkyl group, a C ₂ -C ₆ alkenyl group, a C ₃ -C ₈ cycloalkyl group;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₆ alkoxy group. C ₁ -C ₆ alkyl;

Or, one or more pairs of R ⁵ and R ⁶ , R ⁷ and R ⁸ , R ⁹ and R ¹⁰ may be bonded to form a cyclopropane;

R ¹¹ and R ¹² are hydrogen;

A, D are each independently selected from O, S, SO or SO ₂ ;

Further preferably, in the aminopyrazine compound represented by the formula Ib of the present invention or a pharmaceutically acceptable salt or isomer thereof:

R ¹ , R ² , and R ³ are each independently selected from a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a methoxy group, a halogen atom, and a trifluoromethyl group;

R ^{4 is} selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl;

Alternatively, R ⁹ and R ¹⁰ may be linked to cyclopropane;

R ¹¹ and R ¹² are hydrogen;

A, D are independently selected from O or S;

G is selected from the group consisting of hydroxyl, methoxy, ethoxy, isopropoxy, butoxy, amine, methylamino, formamide, acetamido, methylsulfonyl, trifluoromethylsulfonamide , benzenesulfonylamino, p-toluenesulfonylamino, p-fluorobenzenesulfonylamino.

Still more preferably, in the aminopyrazine compound represented by the formula Ib of the present invention or a pharmaceutically acceptable salt or isomer thereof,

R ¹ , R ² and R ³ are each independently selected from a hydrogen atom, a methyl group, a methoxy group, and a halogen atom;

R ⁴ is an isopropyl group;

R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹¹ and R ¹² are hydrogen;

A, D is O;

G is selected from the group consisting of a hydroxyl group, an amine group, an acetamide group, a methylsulfonylamino group, a trifluoromethylsulfonylamino group, a benzenesulfonylamino group, a p-toluenesulfonylamino group, and a p-fluorobenzenesulfonylamino group.

Another object of the present invention is to provide an aminopyrazine compound having the structure represented by the following formula II or a pharmaceutically acceptable salt or isomer thereof:

among them,

e is 0, 1 or 2;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are each independently selected from a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group, and a C ₁ -C substituted by a halogen atom. ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino C ₁ - C ₆ alkyl, di(C ₁ -C ₆ alkyl)amino C ₁ -C ₆ alkyl, nitrile C ₁ -C ₆ alkyl;

G is selected from the group consisting of hydroxyl, C ₁ -C ₆ alkoxy, amine, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylamido, C ₁ -C ₆ alkylsulfonylamino, C ₆ -C ₁₀ arylsulfonylamino group.

The aminopyrazine compound represented by the general formula II provided by the present invention can be divided into three small general formulas, respectively corresponding to three small general formulas IIa when e is equal to 0, 1 or 2 in the structure of the general formula II. , IIb or IIc:

Wherein R ¹ , R ² , R ³ , R ⁴ , A, D, G are the same as defined in the above formula II;

Preferably, when e is 1, the aminopyrazine compound represented by the formula II of the present invention or a pharmaceutically acceptable salt or isomer thereof has a structure represented by the formula IIb:

among them,

R ¹¹ and R ¹² are hydrogen;

A, D are each independently selected from O, S, SO or SO ₂ ;

Further preferably, in the aminopyrazine compound represented by the formula IIb of the present invention or a pharmaceutically acceptable salt or isomer thereof,

Alternatively, R ⁹ and R ¹⁰ may be linked to cyclopropane;

R ¹¹ and R ¹² are hydrogen;

A, D are independently selected from O or S;

G is selected from the group consisting of hydroxyl, methoxy, ethoxy, isopropoxy, butoxy, amine, methylamino, formamide, acetamido, methylsulfonyl, and benzenesulfonyl.

Still more preferably, in the aminopyrazine compound represented by the formula IIb of the present invention or a pharmaceutically acceptable salt or isomer thereof,

R ⁴ is an isopropyl group;

R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹¹ and R ¹² are hydrogen;

A, D is O;

G is selected from the group consisting of a hydroxyl group, an amine group, an acetamide group, a methylsulfonylamino group, and a benzenesulfonylamino group.

As the aminopyrazine compound represented by the formula I or formula II of the present invention or a pharmaceutically acceptable salt or isomer thereof, preferred compounds include, but are not limited to, the following compounds:

The aminopyrazine compound provided by the present invention may be in the form of a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt thereof may be selected from the group consisting of an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt; An organic salt such as an amine salt, a diethanolamine salt, a meglumine salt, a piperazine salt or a choline salt Salt; mineral acid salts such as hydrochloride, sulfate, nitrate, phosphate, hydrofluoric acid, hydrobromide; acetate, trifluoroacetate, naphthoate, benzoate, tartaric acid Salt, lactate, citrate, fumarate, maleate, malate, oxalate, succinate, methanesulfonate, ethanesulfonate, besylate, p-toluene An acid salt such as an acid salt, a naphthalene sulfonate or a camphor sulfonate.

Further preferably, the pharmaceutically acceptable salt of the aminopyrazine compound provided by the present invention may be selected from the group consisting of:

Sodium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetate;

Sodium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetate;

(R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid sodium acetate;

(S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid sodium acetate;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid hydrochloride;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid potassium;

Sodium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetate;

(R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetate;

(S)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetate.

The aminopyrazine compound represented by the formula I or the formula II provided by the present invention may contain a plurality of asymmetric carbon atoms, and thus, the provided compound may be in the enantiomeric, diastereomeric, or rotationally different A form of a construct, atropisomer, tautomer or mixture thereof.

The isomer of the aminopyrazine compound or a pharmaceutically acceptable salt thereof provided by the present invention may be selected from the group consisting of:

(R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid;

(S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid;

(R)-2-{2-[1-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)-2-propyloxy]ethoxylate } acetic acid;

(S)-2-{2-[1-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)-2-propyloxy]ethoxylate } acetic acid;

(R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetic acid;

(S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetic acid;

The aminopyrazine compound represented by the above formula I or formula II provided by the present invention may be a prodrug having a corresponding carboxylic acid derivative, which can be converted into a corresponding carboxylic acid active metabolite in vivo, and the prodrug is prodrug Included are compounds in which the carboxylic acid group is converted to a group: ethyl carboxylate, isopropyl carboxylate, butyl carboxylate, amide, amidoamine, acylethylamine, acylacetamide, acylsulfonamide, Acetylbenzene sulfonamide.

Further preferably, the aminopyrazine compound of the formula I or formula II provided by the present invention is selected from the group consisting of the following prodrugs:

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-N-methanesulfonyl Amide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-N-benzenesulfonyl B Amide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-N-acetylacetamide ;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N -methanesulfonylacetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N - ethanesulfonyl acetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N -trifluoromethanesulfonylacetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N - phenylsulfonylacetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N - p-toluenesulfonylacetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N - p-fluorobenzenesulfonylacetamide;

(S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}-N- Methanesulfonyl acetamide;

(R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}-N- Methanesulfonyl acetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}acetamide .

It is still another object of the present invention to provide a process for the preparation of the aminopyrazines of the above formula I:

Preparation of compounds of formula Ia:

The compound of formula III and formula IV is refluxed in a solution of NaOH in methanol for 2-6 hours to form a compound of formula V, which is then heated to reflux in POCl ₃ to form a compound of formula VI, a compound of formula VI and a compound of formula VII-A at 120-200 ° C. The next reaction is 8-48h (preferably 8-20h) to synthesize a compound of formula VIII-A. The compound of formula VIII-A is reacted with a compound of formula IX-A in a solution of toluene KOH or NaH in THF to form a compound of formula XA, which is finally hydrolyzed by LiOH to A compound of formula Ia1 (wherein G = OH) is further derivatized by a compound of formula Ia1 to a compound of formula Ia, wherein G is optionally a C ₁ -C ₆ alkoxy group, an amine group, a C ₁ -C ₆ alkylamino group, C ₁ -C ₆ alkylamido, C ₁ -C ₆ alkylsulfonylamino, halogen-substituted C ₁ -C ₆ alkylsulfonylamino, C ₆ -C ₁₀ arylsulfonylamino, C ₁ - a C ₆ alkyl-substituted C ₆ -C ₁₀ arylsulfonylamino group or a halogen-substituted C ₆ -C ₁₀ arylsulfonylamino group.

Wherein, the compound of the formula VII-A can be synthesized by reacting a primary amine of the formula 1 with a halogenated hydrocarbon R ⁴ X or by reductive amination of a primary amine of the formula 1 with an alkane aldehyde (NaB(CN)H ₃ , NaB(OAc) ₃ H or PtO ₂ /H ₂ ) is synthesized.

Preparation of compounds of formula Ib:

The compound of formula III and formula IV is refluxed in a solution of NaOH in methanol for 2-6 hours to form a compound of formula V, which is then heated to reflux in POCl ₃ to form a compound of formula VI, a compound of formula VI and a compound of formula VII-B at 120-200 ° C. The next reaction is 8-48h (preferably 8-20h) to synthesize a compound of formula VIII-B. The compound of formula VIII-B is reacted with a compound of formula IX-B in a solution of toluene KOH or NaH in THF to form a compound of formula XB, a compound of formula XB in LiAlH. _The reaction of ₄ in THF solution for 2-6 hours to form the compound of formula XI-B, or directly by reacting the compound of formula VI with the compound of formula VII2-B at 120-200 ° C for 8-48 h (preferably 8-20 h) to synthesize formula XI- Compound B, then a compound of formula XI-B is reacted with a compound of formula IX-A in a solution of toluene KOH or NaH in THF to form a compound of formula XII-B, which is finally hydrolyzed by LiOH to a compound of formula Ib1 (wherein G = OH). Further derivatized by a compound of formula Ib1 to a compound of formula Ib, wherein G is optionally C ₁ -C ₆ alkoxy, amine, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylamido, C _1- C ₆ alkylsulfonylamino group, halogen-substituted C ₁ -C ₆ alkylsulfonylamino group, C ₆ -C ₁₀ arylsulfonylamino group, C ₁ -C ₆ alkyl substituted with C ₆ -C ₁₀ arylsulfonyl group or a halogen-substituted C ₆ -C ₁₀ arylsulfonyl group.

Wherein, the compound of the formula VII2-B can also be synthesized by reacting the corresponding primary amine of the formula 4-B with a halogenated hydrocarbon R ⁴ X or by reductive amination with a corresponding primary amine of the formula 4-B and an alkane aldehyde (NaB (CN) The synthesis of H ₃ , NaB(OAc) ₃ H or PtO ₂ /H ₂ ) can also be carried out by reacting a primary amine of formula VII with a reagent of carbon tetrabromide and triphenylphosphine to form the corresponding bromo compound of formula 2, formula 2 The substitute is reacted with a 2-hydroxy(amine or oxime)methyl acetate compound to form a compound of formula 3-B, which is then hydrogenated to reduce the compound of formula 3-B to form a compound of formula VII2-B.

Preparation of compounds of formula Ic:

The compound of the formula VIII-B is reacted with a compound of the formula IX-C in a solution of toluene KOH or NaH in THF to form a compound of the formula XC, which is reacted in a solution of LiAlH ₄ in THF for 2-6 hours to form a compound of the formula XI-C, Alternatively, the compound of formula XI-C can be synthesized directly by reacting a compound of formula VI with a compound of formula VII2-C at 120-200 ° C for 8-20 h.

The compound of the formula XI-C is reacted with a compound of the formula IX-B in a solution of toluene KOH or NaH in THF to form a compound of the formula XII-C. The compound of the formula XII-C is reacted in a solution of LiAlH ₄ in THF for 2-6 hours to form the formula XIII. Compound, a compound of formula XIII is reacted with a compound of formula IX-A in a solution of toluene KOH or NaH in THF to form a compound of formula XIV, which is hydrolyzed by LiOH to a compound of formula Ic1 (wherein G = OH), further by a compound of formula Ic1 Derived as a compound of formula Ic, wherein G is optionally C ₁ -C ₆ alkoxy, amine, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylamido, C ₁ -C ₆ alkane a sulfonamide group, a halogen-substituted C ₁ -C ₆ alkylsulfonylamino group, a C ₆ -C ₁₀ arylsulfonylamino group, a C ₁ -C ₆ alkyl substituted C ₆ -C ₁₀ arylsulfonylamino group Or a C ₆ -C ₁₀ arylsulfonylamino group substituted by a halogen atom.

Wherein, the compound of the formula VII2-C can also be synthesized by reacting the corresponding primary amine of the formula 4-C with the halogenated hydrocarbon R ⁴ X or by reductive amination with a corresponding primary amine of the formula 4-C and an alkane aldehyde (NaB (CN) The synthesis of H ₃ , NaB(OAc) ₃ H or PtO ₂ /H ₂ ) can also be carried out by reacting a primary amine of formula VII with a reagent of carbon tetrabromide and triphenylphosphine to form the corresponding bromo compound of formula 2, formula 2 The substitute is reacted with a 2-hydroxy(amine or oxime)methyl acetate compound to form a compound of formula 3-C, which is then hydrogenated to reduce the compound of formula 3-C to form a compound of formula VII2-C.

Still another object of the present invention is to provide a process for preparing the aminopyrazine compound represented by the above formula II:

Preparation of a compound of formula IIa:

The compound of formula III and formula IV is refluxed in a methanol solution of NaOH for 2-6 hours to form a compound of formula V, which is then heated to reflux in POCl ₃ to form a compound of formula VI, a compound of formula VI and a compound of formula VII-A' at 120-200. The compound of the formula VIII-A' is synthesized by reacting at ° C for 8-48 h (preferably 8-20 h), and the compound of the formula VIII-A' is reacted with the compound of the formula IX-A' in a solution of toluene KOH or NaH in THF to form the formula X-A'. The compound, which is finally hydrolyzed by LiOH to a compound of formula IIa1 (wherein G = OH), is further derivatized by the compound of formula IIa1 to a compound of formula IIa, wherein G is optionally C ₁ -C ₆ alkoxy, amine, C ₁ - A C ₆ alkylamino group, a C ₁ -C ₆ alkylamido group, a C ₁ -C ₆ alkylsulfonylamino group or a C ₆ -C ₁₀ arylsulfonylamino group or the like.

Wherein, the compound of the formula VII-A' can be synthesized by reacting a primary amine of the formula 1' with a halogenated hydrocarbon R ⁴ X or by reductive amination of a primary amine of the formula 1 with an alkane aldehyde (NaB(CN)H ₃ , NaB( OAc) ₃ H or PtO ₂ /H ₂ ) was synthesized.

Preparation of the compound of formula IIb:

The compound of formula III and formula IV is refluxed in a solution of NaOH in methanol for 2-6 hours to form a compound of formula V, which is then heated to reflux in POCl ₃ to form a compound of formula VI, a compound of formula VI and a compound of formula VII-B' at 120-200. The compound of the formula VIII-B' is synthesized by reacting at ° C for 8-48 h (preferably 8-20 h), and the compound of the formula VIII-B' is reacted with a compound of the formula IX-B' in a solution of toluene KOH or NaH in THF to form a compound of the formula X-B'. , the compound of formula X-B' is reacted in a solution of LiAlH ₄ in THF for 2-6 hours to form a compound of formula XI-B', or directly reacted with a compound of formula VII2-B' at 120-200 ° C for 8-48 h. (preferably 8-20h) synthesizing a compound of formula XI-B', then reacting a compound of formula XI-B' with a solution of formula IX-A' in a solution of toluene KOH or NaH in THF to form a compound of formula XII-B', and finally passing LiOH Hydrolysis to a compound of formula IIb1 (wherein G = OH), which is further derivatized by a compound of formula IIb1 to a compound of formula IIb, wherein G is optionally a C ₁ -C ₆ alkoxy group, an amine group, a C ₁ -C ₆ alkyl group An amine group, a C ₁ -C ₆ alkylamide group, a C ₁ -C ₆ alkylsulfonylamino group or a C ₆ -C ₁₀ arylsulfonylamino group or the like.

Wherein, the compound of the formula VII2-B' can also be synthesized by reacting the corresponding primary amine of the formula 4-B' with the halogenated hydrocarbon R ⁴ X or by reductive amination with the corresponding primary amine of the formula 4-B' and the alkane aldehyde ( NaB(CN)H ₃ , NaB(OAc) ₃ H or PtO ₂ /H ₂ ) is synthesized, and the corresponding formula 2' bromine can also be formed by reacting the primary amine of formula VII' with the reagent carbon tetrabromide and triphenylphosphine. Substitutes, a 2' bromo compound of the formula 2 is reacted with a methyl 2-hydroxy(amine or hydrazinyl)acetate to form a compound of the formula 3-B', and then the lithium aluminum hydride is reduced to form a compound of the formula VII2-B'.

Preparation of the compound of formula IIc:

The compound of the formula VIII-B' is reacted with a compound of the formula IX-C' in a solution of toluene KOH or NaH in THF to form a compound of the formula X-C', and the compound of the formula X-C' is reacted in a solution of LiAlH ₄ in 2-6 THF. The compound of formula XI-C' is formed in an hour, or the compound of formula XI-C' is synthesized directly by reacting a compound of formula VI with a compound of formula VII2-C' at 120-200 ° C for 8-20 h.

The compound of the formula XI-C' is reacted with a compound of the formula IX-B' in a solution of toluene KOH or NaH in THF to form a compound of the formula XII-C', and the compound of the formula XII-C' is reacted in a solution of LiAlH ₄ in THF for 2-6 hours. To form a compound of formula XIII', a compound of formula XIII' is reacted with a compound of formula IX-A' in a solution of toluene KOH or NaH in THF to form a compound of formula XIV', which is hydrolyzed by LiOH to a compound of formula IIc1 (wherein G = OH), which is subsequently further derivatized as a compound of formula IIc by a compound of formula IIc1, wherein G is optionally C ₁ -C ₆ alkoxy, amine, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkyl An amide group, a C ₁ -C ₆ alkylsulfonylamino group or a C ₆ -C ₁₀ arylsulfonylamino group or the like.

Wherein, the compound of the formula VII2-C' can also be synthesized by reacting the corresponding formula 4-C' primary amine with a halogenated hydrocarbon R ⁴ X or by reductive amination with a corresponding formula 4-C' primary amine and an alkane aldehyde ( NaB(CN)H ₃ , NaB(OAc) ₃ H or PtO ₂ /H ₂ ) is synthesized, and the corresponding formula 2' bromine can also be formed by reacting the primary amine of formula VII' with the reagent carbon tetrabromide and triphenylphosphine. Substitutes, a 2' bromo compound of the formula 2 is reacted with a methyl 2-hydroxy(amine or oxime)acetate to form a compound of formula 3-C', which is then hydrogenated to reduce the compound of formula 3-C' to form a compound of formula VII2-C'.

The substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , A, D, G and the above-mentioned preparation methods are The definitions of the compounds shown by the above formulae Ia, Ib, Ic, IIa, IIb and IIc are the same.

Still another object of the present invention is to provide an aminopyrazine compound represented by the above formula I or formula II or a pharmaceutically acceptable salt thereof, Use of an isomer for the preparation of an IP receptor agonist, in particular as a preparation for activating an IP receptor drug; more specifically, the invention provides a compound of the formula I or formula II or Use of a pharmaceutically acceptable salt or isomer for the preparation of a medicament for the treatment or prevention of pulmonary hypertension (PAH), PAH associated with various diseases, arteriosclerosis obliterans (ASO), Asthma and asthma symptoms, chronic obstructive pulmonary disease, Raynaud's phenomenon, scleroderma, CREST syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis, high arteritis, polymyositis and dermatomyositis, atrial septum Defect (ASD), ventricular septal defect (VSD), cardiac fibrosis, pulmonary fibrosis/pulmonary cirrhosis, renal fibrosis, multiple sclerosis, thrombotic disease associated with excessive platelet aggregation, coronary artery disease, myocardial infarction, transient Ischemic attack, colic, stroke, cerebral ischemia, ischemia-reperfusion injury, atrial fibrillation, clot formation, atherosclerosis, diabetes-related disorders, type 1 diabetes, type 2 diabetes, diabetes week Neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic complications, diabetic retina, glaucoma or other ocular diseases with abnormal intraocular pressure, hypertension, pre-eclampsia, inflammation; COX-1, COX-2 and non-selective COX inhibition Undesirable side effects of the agent; asthma, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, acne, sepsis, and the like.

The present invention also relates to a method of treating a subject having the above-mentioned disease, which comprises administering to a subject in need thereof an aminopyrazine compound of the above formula I or formula II or a pharmaceutically thereof thereof Acceptable salts, isomers.

The aminopyrazine compound provided by the present invention or a pharmaceutically acceptable salt or isomer thereof has the following advantages:

1 The inventors have found through extensive studies that the change of the long chain of the carboxylic pyrazine compound has a great influence on the activity, and changing the length of the long chain reduces the anti-platelet aggregation activity (see Examples 1, 32), and unexpectedly finds The long chain of carboxylic acid constructed by using the ethylene glycol structure (especially two ethylene glycol structures) provided by the present invention can significantly increase the anti-platelet aggregation activity of the aminopyrazine compound in vivo and in vitro.

2 The aminopyrazine compound of the ethylene glycol structure provided by the invention can significantly reduce the average pulmonary hypertension of the model animal, and the effect is obviously superior to the compound of Preparation Example 1 as a control;

3 Under the same dosage conditions, the ratio of acute toxicity death of mice after administration of the aminopyrazines of the present invention was significantly lower than that of the compound of Preparation Example 2 as a control, and it was found that the ethylene glycol structure provided by the present invention was greatly improved. Drug safety;

4 The sodium salt provided by the present invention can be stabilized for a long time under the condition of the aqueous solution, and the aqueous solution of the sodium salt of the compound of the preparation example 1 precipitates a white solid within 12 hours. It can be seen that the ethylene glycol structure provided by the invention effectively improves the stability of the aqueous solution.

detailed description

The present invention will be further described in detail below with reference to the embodiments of the present invention, which are only intended to illustrate the technical solutions of the present invention, and are not intended to limit the invention, any equivalent substitution in the field according to the disclosure of the present invention, All fall within the scope of protection of the present invention.

The structure of the compound is determined by nuclear magnetic resonance ( ¹ H NMR) or liquid chromatography-mass spectrometry (LC-MS).

The LC-MS is Agilent 6120; the nuclear magnetic resonance ( ¹ H NMR) is Bruker AVANCE-400, and the nuclear magnetic resonance ( ¹ H NMR) displacement (δ) is in parts per million (ppm). Given, the solvent was determined to be d ₆ -DMSO, the internal standard was tetramethylsilane (TMS), and the chemical shift was given in units of 10 ^-6 (ppm).

The term "room temperature" in the present invention means that the temperature is between 10 and 25 °C.

Example 1 Preparation of 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetic acid

Step 1: Preparation of 5,6-diphenyl-2-hydroxypyrazine

Under nitrogen protection, dibenzoyl (31.0 g, 0.10 mol), aminoacetamide (13.0 g, 0.12 mol) and NaOH (7.00 g, 0.24 mol) were sequentially added to 1 L of methanol solvent, and heated under reflux for 3-4 h. The reaction was monitored by LC-MS and the starting material was completely reacted. The reaction solution was cooled to 0-5 ° C, then 12.5 mL of 12 N HCl solution was added dropwise, and the reaction solution was stirred at room temperature for 30 min, then 10 g of sodium hydrogencarbonate and 130 mL of water were added, and the reaction mixture was filtered, and the solid was washed with a small amount of water and methanol. The residue was dried under vacuum to give 2,2 g of white solid, 5,6-diphenyl-2-hydroxypyrazine, yield: 88.7%, ESI-MS: m/z=249.2 (M+H) ⁺ .

Step 2: Preparation of 5-chloro-2,3-diphenylpyrazine

Under nitrogen protection, 5,6-diphenyl-2-hydroxypyrazine (22.6 g, 0.9 mol) was added to 200 mL of phosphorus oxychloride solvent, heated to reflux, and the reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was cooled to room temperature and then evaporated to dryness with EtOAc. EtOAc (EtOAc) The crude product of 3-diphenylpyrazine, then ethyl acetate was slurried, filtered and dried in vacuo to give 14.0 g of white solid 5-chloro-2,3-diphenylpyrazine, yield: 58.5%, ESI-MS: m/z = 267.2 (M+H) ⁺ .

Step 3: Preparation of 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethanol

5-Chloro-2,3-diphenylpyrazine (532 mg, 2.00 mmol) was added to 2-(N-isopropylamino)ethanol (618 mg, 6.00 mmol) and heated to 190. ℃ reflux for 48h, the reaction was monitored by LC-MS, starting material the reaction was completed, the reaction solution was cooled and the reaction mixture was added ice-water, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, Save The solvent was removed by pressure and purified by silica gel column chromatography. ] ethanol, yield: 79.6%, ESI-MS: m / z = 334.2 (m + H) +.

Step 4: Preparation of 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetic acid tert-butyl ester

2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino group was sequentially added to a mixture of 2.5 mL of toluene and 2.5 mL of 40% KOH under ice bath conditions. Ethyl alcohol (499mg, 1.50mmol), tetrabutylammonium hydrogen sulfate (510mg, 1.50mmol) and tert-butyl bromoacetate (438mg, 2.25mmol), stirred vigorously for 30min, naturally warmed to room temperature and reacted for 2h, into the reaction solution Ice water was added, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by silica gel column chromatography, were collected under reduced pressure, and dried in vacuo to give 487mg of a yellow oil 2-{2-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetic acid tert-butyl ester, yield: 72.7%, ESI-MS :m/z=448.2(M+H) ⁺ .

Step 5: Preparation of 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetic acid

In an ice bath, the compound 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy] was added sequentially to a 2 mL MeOH solution. Tert-butyl acetate (447 mg, 1.00 mmol) and LiOH (96.0 mg, 4.00 mmol) were reacted overnight, and methanol was evaporated under reduced pressure. 10 mL of ice water and 10 mL of ethyl acetate were added to the reaction, and pH was adjusted to 5-6 with 2N HCl. After extraction with ethyl acetate, the organic phase was washed with water and brine, dried over MgSO ₄ -[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetic acid, yield: 94.8%, ESI-MS: m/z = 392.2 ( ^{^{m + H) +; 1 H}} NMR (400MHz, d 6 -DMSO) δ12.66 (s, 1H), 8.24 (s, 1H), 7.38-7.20 (m, 10H), 4.71-4.66 (m, 1H) , 4.07 (s, 2H), 3.72-3.62 (m, 4H), 1.23 (d, J = 6.4 Hz, 6H).

Example 2 Preparation of 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethoxy}acetic acid

The synthesis method is the same as that of Example 1, except that the 2-(N-isopropylamino)ethanol in the step 3 of Example 1 is replaced with N-methylaminoethanol to obtain 2-{2- in the form of a yellow oil. [N- (5,6- diphenyl-pyrazin-2-yl) -N- methylamino] ethoxy} acetic acid; ESI-MS: m / z = 364.2 (m + H) +; 1 H NMR (400 MHz, d ₆ -DMSO) δ 12.64 (s, 1H), 8.19 (s, 1H), 7.37-7.20 (m, 10H), 4.07 (s, 2H), 3.71-3.62 (m, 4H), 3.13(s, 3H).

Example 3 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid

Step 1: Preparation of 5,6-diphenyl-2-hydroxypyrazine

Under nitrogen protection, dibenzoyl (63.0 g, 0.30 mol), aminoacetamide (39.0 g, 0.36 mol) and NaOH (29.0 g, 0.72 mol) were sequentially added to 1 L of methanol solvent and heated to reflux for 3-4 h. The reaction was monitored by LC-MS and the starting material was completely reacted. The reaction solution was cooled to 0-5 ° C, then 37.5 mL of 12 N HCl solution was added dropwise, and the reaction solution was stirred at room temperature for 30 min, then 30 g of sodium hydrogencarbonate and 380 mL of water were added, and the reaction mixture was filtered, and the solid was washed with a small amount of water and methanol. After drying in vacuo, 68.0 g of 5,6-diphenyl-2-hydroxypyrazine as a white solid, yield: 91.4%, ESI-MS: m/z=249.2 (M+H) ⁺ .

Step 2: Preparation of 5-chloro-2,3-diphenylpyrazine

5,6-diphenyl-2-hydroxypyrazine (68.0 g, 0.27 mol) was added to 200 mL of phosphorus oxychloride solvent under nitrogen atmosphere, heated to reflux, and the reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was cooled to room temperature and then evaporated to dryness with EtOAc. EtOAc (EtOAc)EtOAc. , a crude product of 3-diphenylpyrazine, then ethyl acetate was slurried, filtered and dried in vacuo to give 40.0 g of white solid 5-chloro-2,3-diphenylpyrazine, yield: 55.7%, ESI-MS : m/z = 267.2 (M+H) ⁺ .

Step 3: Preparation of 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethanol

5-Chloro-2,3-diphenylpyrazine (266 mg, 1.00 mmol) was added to 2-(N-isopropylamino)ethanol (309 mg, 3.00 mmol) and heated to 190. ℃ reflux for 48h, the reaction was monitored by LC-MS, starting material the reaction was completed, the reaction solution was cooled and the reaction mixture was added ice-water, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, Save The solvent was removed by pressure and purified by silica gel column chromatography. ] ethanol, yield: 78.7%, ESI-MS: m / z = 334.2 (m + H) +.

2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino group was sequentially added to a mixture of 2.5 mL of toluene and 2.5 mL of 40% KOH under ice bath conditions. Ethanol (333mg, 1.00mmol), tetrabutylammonium hydrogen sulfate (340mg, 1.00mmol) and tert-butyl bromoacetate (292mg, 1.50mmol), stirred vigorously for 30min, naturally warmed to room temperature and reacted for 2h, into the reaction solution Ice water was added, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by silica gel column chromatography, collecting under reduced pressure, and dried in vacuo to give 387mg of a yellow oil tert-Butyl 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetate, yield: 84.6%, ESI-MS :m/z=448.2(M+H) ⁺ .

Step 5: Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethanol

method 1:

2-{2-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetic acid tert-butyl ester (447 mg, EtOAc) 1.00 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and LiAlH ₄ (76.0 mg, 2.00 mmol) was slowly added in portions, and the mixture was reacted for 30 min, and then naturally warmed to room temperature, and then reacted for 2 hours. The reaction was monitored by LC-MS. After cooling the reaction solution to 0 ° C, the reaction solution was slowly poured into a stirred beaker of solid sodium sulfate decahydrate, stirred for 30 min, filtered, and the filtrate was removed under reduced pressure of tetrahydrofuran, extracted with ethyl acetate, and then sequentially. Washed with saturated brine, dried over sodium sulfate, filtered, evaporated, evaporated, evaporated, - diphenyl-pyrazin-2-yl) -N- isopropyl-amino) ethoxy] ethanol, yield: 95.5%, ESI-MS: m / z = 378.2 (m + H) +.

Method 2:

To a mixture of 2 mL of ethanol and 2 mL of acetone, diglycolamine (1.05 g, 10 mmol) and PtO ₂ (227 mg, 1 mmol) were added at room temperature, then a balloon filled with hydrogen was added, and the reaction gas was replaced with hydrogen gas of hydrogen balloon. The reaction was kept at 1-3 atm for 48 h, then the reaction solution was filtered through celite, washed with ethanol, and evaporated to dryness under reduced pressure to give crude 2-[2-(N-isopropylamino)ethoxy]ethanol. Without purification, the next step is directly carried out.

The compound 2-[2-(N-isopropylamino)ethoxy]ethanol (441 mg, 3.00 mmol) was added to 5-chloro-2,3-diphenylpyrazine (266 mg, 1.00 mmol), heated to 190 ° C reflux for 48 h, the reaction was monitored by LC-MS, the reaction was carried out until no starting materials, the reaction liquid was cooled and ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After washing, MgSO _{4 was} dried, filtered, evaporated, evaporated, evaporated, evaporated pyrazin-2-yl-phenyl) -N- isopropyl-amino) ethoxy] ethanol, yield: 61.0%, ESI-MS: m / z = 378.2 (m + H) +.

Step 6: 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid tert-butyl ester Preparation

The compound 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-) was sequentially added to a mixture of 2.5 mL of toluene and 2.5 mL of 40% KOH under ice bath. N-isopropylamino)ethoxy]ethanol (377 mg, 1.00 mmol), tetrabutylammonium hydrogen sulfate (340 mg, 2.00 mmol) and tert-butyl bromoacetate (292 mg, 1.50 mmol), stirring vigorously 30 min, after warming to room temperature, the reaction 2h, the reaction mixture was added to ice water, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by silica gel column chromatography It was collected under reduced pressure and dried in vacuo to give 395 g (yield: </RTI> 2-[2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino) ethoxylate as a yellow oil. ] ethoxy} acetic acid tert-butyl ester, yield: 80.4%, ESI-MS: m / z = 492.2 (m + H) +.

Step 7: Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino) ethoxylate was added sequentially to 2 mL of MeOH solution under ice bath Tert-butyl ethoxylate acetate (246 mg, 0.50 mmol) and LiOH (48.0 mg, 2.00 mmol) were reacted overnight, methanol was removed under reduced pressure, and 5 mL of ice water and 5 mL of ethyl acetate were added to the reaction mixture. HCl adjusted pH = 5-6, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by silica gel column chromatography, were collected under reduced pressure, and dried in vacuo to give 183mg Light yellow solid 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid Rate: 84.1%, ESI-MS: m/z = 436.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 12.60 (s, 1H), 8.22 (s, 1H), 7.38 - 7.20 (m, 10H), 4.71-4.64 (m, 1H), 4.01 (s, 2H), 3.68-3.58 (m, 8H), 1.23 (d, J = 6.8 Hz, 6H).

Example 4 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-methylamino)ethoxy]ethoxy}acetic acid

The synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, and the step 5 in the third embodiment, except that the 2-(N-- Replacement of isopropylamino)ethanol with N-methylaminoethanol gives 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-methyl as a yellow oil Ethylamino)ethoxy]ethoxy}acetic acid; ESI-MS: m/z = 408.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d ₆ -DMSO) δ 12.59 (s, 1H) , 8.21 (s, 1H), 7.35-7.23 (m, 10H), 3.99 (s, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.67 (t, J = 6.2 Hz, 2H), 3.57 ( s, 4H), 3.18 (s, 3H).

Example 5 N-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethyl}-N-isopropyl Preparation of glycine

Step 1: Preparation of 2,2'-oxybis(N-isopropylethylamine)

2,2'-oxydiethylamine (1.04 g, 10 mmol) and PtO ₂ (227 mg, 1 mmol) were added to a mixture of 2 mL of ethanol and 2 mL of acetone at room temperature, then a balloon filled with hydrogen and a balloon of hydrogen were added. The hydrogen is used to displace the reaction gas, and the reaction solution is kept at 1-3 atm for 48 hours. Then, the reaction solution is filtered through celite, washed with ethanol, and steamed under reduced pressure to obtain 2,2'-oxybis(N-isopropyl B). Amine) crude product, without purification, is used directly for the next reaction.

Step 2: N-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethyl}-N-isopropyl Preparation of glycine

The synthesis steps are the same as those in the third step, the second step, the second step, the second step, the second method, the second step, the second step, and the second step. -Isopropylamino)ethoxy]ethanol is replaced by 2,2'-oxybis(N-isopropylethylamine) to give N-{2-[2-(N-(5,6) as a yellow oil. -Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethyl}-N-isopropylglycine, ESI-MS: m/z = 476.2 (M+H) ⁺ .

Example 6 2-{2-[N-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethyl]-N-isopropylamine] Preparation of ethoxy}acetic acid

The synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, and the step 5 in the third embodiment, except that the 2-(N-- Replacement of isopropylamino)ethanol with N,N'-diisopropylethylenediamine to give 2-{2-[N-[2-(N-(5,6-diphenylpyrazine) as a yellow oil -2-yl)-N-isopropylamino)ethyl]-N-isopropylamine]ethoxy}acetic acid, ESI-MS: m/z=477.3 (M+H) ⁺ ; ¹ H NMR (400 MHz , d ₆ -DMSO) δ 8.22 (s, 1H), 7.37-7.21 (m, 10H), 4.03 (s, 2H), 3.80-3.67 (m, 6H), 3.21-3.14 (m, 2H), 2.85 (d, J = 6.4 Hz, 2H), 1.04 (d, J = 6.4 Hz, 12H).

Example 7 N-{2-[N-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-methylamino)ethyl]-N-methylamine] Preparation of ethyl}-N-methylglycine

The synthesis steps are the same as those in the third step, the second step, the second step, the second step, the second method, the second step, the second step, and the second step. -Isopropylamino)ethoxy]ethanol is replaced by N,N',N"-trimethyldiethylenetriamine, and the rest of the preparation method is prepared in the same manner as in the preparation steps 2 and 3 of Example 3, and finally Obtained N-{2-[N-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-methylamino)ethyl]-N-methylamine as a yellow oil] Ethyl}-N-methylglycine, ESI-MS: m/z = 434.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 8.19 (s, 1H), 7.39-7.22 ( m, 10H), 3.76 (s, 2H), 3.20 (s, 2H), 3.17 (s, 3H), 2.83 (t, J = 5.6 Hz, 2H), 2.71-2.63 (m, 4H), 2.46 (s) , 3H), 2.33 (s, 3H).

Example 8 2-{2-[2-(N-(3-methyl-5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy }Preparation of acetic acid

The synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, and the step 5 in the third embodiment, except that the aminoacetamide in the first step of the preparation of the third embodiment is replaced with 2-Aminopropanamide gives 2-{2-[2-(N-(3-methyl-5,6-diphenylpyrazin-2-yl)-N-isopropylamino) Oxy]ethoxy}acetic acid, ESI-MS: m/z = 450.3 (M + H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 7.37-7.23 (m, 10H), 4.64 - 4.60 (m, 1H), 3.66 (s, 2H), 3.50-3.34 (m, 8H), 3.52 (s, 3H), 1.22 (d, J = 6.8 Hz, 6H).

Example 9 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid

Step 1: Preparation of 5,6-diphenyl-2-hydroxypyrazine

Under nitrogen protection, dibenzoyl (63.0 g, 0.30 mol), aminoacetamide (39.0 g, 0.36 mol) and NaOH (29.0 g, 0.72 mol) were sequentially added to 1 L of methanol solvent and heated to reflux for 3-4 h. The reaction was monitored by LC-MS and the starting material was completely reacted. The reaction solution was cooled to 0-5 ° C, then 37.5 mL of 12 N HCl solution was added dropwise, and the reaction solution was stirred at room temperature for 30 min, then 30 g of sodium hydrogencarbonate and 380 mL of water were added, and the reaction mixture was filtered, and the solid was washed with a small amount of water and methanol. After drying in vacuo, 60.0 g of 5,6-diphenyl-2-hydroxypyrazine as a white solid, yield: 80.6%, ESI-MS: m/z=249.2 (M+H) ⁺ .

Step 2: Preparation of 5-chloro-2,3-diphenylpyrazine

5,6-diphenyl-2-hydroxypyrazine (68.0 g, 0.27 mol) was added to 200 mL of phosphorus oxychloride solvent under nitrogen atmosphere, heated to reflux, and the reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was cooled to room temperature and then evaporated to dryness with EtOAc. EtOAc (EtOAc)EtOAc. The crude product of 2,3-diphenylpyrazine was then beaten with ethyl acetate, filtered, and dried in vacuo to give 42.0 g of 5-chloro-2,3-diphenylpyrazine as a white solid, yield: 58.5%, ESI- MS: m/z = 267.2 (M + H) ⁺ .

Step 3: Preparation of 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethanol

5-Chloro-2,3-diphenylpyrazine (2.66 g, 10.0 mmol) was added to 2-(N-isopropylamino)ethanol (3.09 g, 30.0 mmol) under nitrogen. to 190 deg.] C under reflux for 48h, the reaction was monitored by LC-MS, starting material the reaction was complete, the reaction solution was cooled and the reaction mixture was added ice-water, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered The solvent was evaporated under reduced pressure and purified by silica gel column chromatography. Ethylamino]ethanol, yield: 81.1%, ESI-MS: m/z = 334.2 (M+H) ⁺ .

Step 4: Preparation of 2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propanoic acid tert-butyl ester

2-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]ethanol (1.66 g, 5.00 mmol) was dissolved in 2.5 mL anhydrous under ice-bath. In tetrahydrofuran, NaH (400 mg, 10.0 mmol) was slowly added in portions, stirred for 30 min, then the compound 2-bromopropionate (1.56 g, 7.50 mmol) was added, and the mixture was warmed to room temperature for 2 h, and the reaction was detected by LC-MS. The reaction of the starting material was completed, and the reaction mixture was cooled to 5 ° C, and ice water was slowly added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic mixed phase was washed with water and saturated brine, dried over MgSO ₄ , filtered and evaporated. Purified by chromatography on silica gel column, EtOAcjjjjjjjjjjjjjjjjjj ) ethoxy] propanoic acid tert-butyl ester, yield: 91.1%, ESI-MS: m / z = 462.2 (m + H) +.

Step 5: Preparation of 2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propanol

2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propanoic acid tert-butyl ester (461 mg) under ice-bath conditions , 1.00 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and LiAlH ₄ (76.0 mg, 2.00 mmol) was slowly added in portions, and the reaction was carried out for 30 min, and then naturally returned to room temperature, and then reacted for 2 hours. The reaction was monitored by LC-MS. . After cooling the reaction solution to 0 ° C, the reaction solution was slowly poured into a stirred beaker of solid sodium sulfate decahydrate, stirred for 30 min, filtered, and the filtrate was removed under reduced pressure of tetrahydrofuran, extracted with ethyl acetate, and then sequentially. Washed with saturated brine, dried over sodium sulfate, filtered, evaporated, evaporated, evaporated Kipyrazin-2-yl)-N-isopropylamino)ethoxy]propanol, yield: 92.1%, ESI-MS: m/z = 392.2 (M+H) ⁺ .

Step 6: 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid tert-butyl ester Preparation

2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropyl was added sequentially to a mixture of 2.5 mL of toluene and 2.5 mL of 40% KOH under ice bath conditions. Ethylamino)ethoxy]propanol (391 mg, 1.00 mmol), tetrabutylammonium hydrogen sulfate (340 mg, 2.00 mmol) and tert-butyl bromoacetate (292 mg, 1.50 mmol), stirred vigorously for 30 min, warmed to room temperature After the reaction was carried out for 2 h, ice water was added to the reaction mixture, and the mixture was combined with ethyl acetate. The organic phase was washed with water and saturated brine, dried over MgSO ₄ , filtered and evaporated. Collect and vacuum dry to give 400 mg of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy yl} acetate, yield: 79.2%, ESI-MS: m / z = 506.2 (m + H) +.

Step 7: Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino) ethoxylate was added sequentially to 2 mL of MeOH solution under ice bath Tert-butyl]propoxy}acetic acid tert-butyl ester (252 mg, 0.50 mmol) and LiOH (48.0 mg, 2.00 mmol) were reacted overnight, methanol was removed under reduced pressure, and 5 mL of ice water and 5 mL of ethyl acetate were added to the reaction mixture, and 2N was used. HCl adjusted pH = 5-6, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by silica gel column chromatography, were collected under reduced pressure, and dried in vacuo to give 180mg Light yellow solid 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid Rate: 80.2%, ESI-MS: m/z = 450.2 (M+H) ⁺ ;

^{_{1 H NMR (400MHz, d 6}} -DMSO) δ12.58 (s, 1H), 8.21 (s, 1H), 7.38-7.22 (m, 10H), 4.70-4.61 (m, 1H), 4.00 (s, 2H ), 3.67-3.43 (m, 7H), 1.22 (d, J = 6.4 Hz, 6H), 1.06 (d, J = 6.4 Hz, 3H).

Example 10(R)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy} Preparation of acetic acid

method 1:

Step 1: Preparation of N-(2-bromoethyl)isopropylamine

2-(N-Isopropylamino)ethanol (1.03 g, 10.0 mmol) and Ph ₃ P (7.89 g, 30.0 mmol) were dissolved in 50 mL of CH ₂ Cl ₂ under ice-bath. was slowly added NBS (5.34g, 30.0mmol), the reaction 2h, reaction was quenched with sodium bisulfite solution, quenched, _₂₂ and extracted with CH Cl, the organic phase was washed with a mixed 1N NaOH, saturated brine, dried MgSO _4, filtered, Save The solvent was removed by pressure and purified by silica gel column chromatography.

Step 2: Preparation of methyl (R)-2-[2-(N-isopropylamino)ethoxy]propanoate

N-(2-Bromoethyl)isopropylamine (1.12 g, 6.80 mmol) and (2R)-methyl lactate (10.6 g, 10.2 mmol) were dissolved in diethyl ether, and Ag ₂ O was added in five portions over one hour. 1.56g, 6.80mmol), then heated under reflux for 18h, the reaction mixture was cooled, the solvent was evaporated under reduced pressure, and purified by chromatography on silica gel column, and collected under vacuum, and dried in vacuo to give 244 mg of colorless liquid (R)-2-[2- (N- isopropyl-amino) ethoxy] propanoate, yield: 19.0%; ESI-MS: m / z = 190.2 (m + H) +.

Step 3: Preparation of (R)-2-[2-(N-isopropylamino)ethoxy]propanol

Methyl (R)-2-[2-(N-isopropylamino)ethoxy]propanoate (190 mg, 1.00 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran under ice-cooling. LiAlH ₄ (76.0 mg, 2.00 mmol) was slowly added in the batch. After reacting for 30 min, the mixture was naturally warmed to room temperature, and then reacted for 2 h. The reaction was monitored by LC-MS. After cooling the reaction solution to 0 ° C, the reaction solution was slowly poured into a stirred beaker of solid sodium sulfate decahydrate, stirred for 30 min, filtered, and the solvent was removed under reduced pressure, and then extracted with ethyl acetate. Washing, drying over sodium sulfate, filtration, de-solvent solvent, and purified by chromatography on silica gel column, and collected under vacuo, and dried in vacuo to give 148 mg of colorless liquid (R)-2-[2-(N-isopropylamino) ) ethoxy] propanol, yield: 91.9%, ESI-MS: m / z = 162.2 (m + H) +.

Step 4: Preparation of (R)-2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propanol

The compound (R)-2-[2-(N-isopropylamino)ethoxy]propanol (483 mg, 3.00 mmol) was added to 5-chloro-2,3-diphenyl under nitrogen. Pyrazine (266 mg, 1.00 mmol), heated to 190 ° C reflux for 48 h, the reaction was monitored by LC-MS, the reaction was carried out until no starting material, the reaction mixture was cooled, ice water was added to the reaction mixture, and extracted with ethyl acetate, organically mixed with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by column chromatography on silica gel, collected under reduced pressure, and dried in vacuo to give 220mg of a yellow oil (R) -2- [2- (N- (5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propanol, yield: 56.3%, ESI-MS: m/z = 392.2 (M+H ) ⁺ .

Step 5: (R)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy} Preparation of tert-butyl acetate

(R)-2-[2-(N-(5,6-diphenylpyrazin-2-yl)-) was added to a mixture of 2.5 mL of toluene and 2.5 mL of 40% KOH in an ice bath. N-isopropylamino)ethoxy]propanol (196 mg, 0.50 mmol), tetrabutylammonium hydrogen sulfate (170 mg, 1.00 mmol) and tert-butyl bromoacetate (146 mg, 0.75 mmol). After the temperature is raised to room temperature, the reaction is carried out for 2 h, and ice water is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The organic mixture is washed with water and saturated brine, dried over MgSO ₄ , filtered and evaporated. Purified, collected under reduced pressure and dried in vacuo to give </RTI></RTI></RTI><RTIID=0.0> yl) ethoxy] propoxy} acetic acid tert-butyl ester, yield: 75.2%, ESI-MS: m / z = 506.2 (m + H) +.

Step 6: (R)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy} Preparation of acetic acid

(R)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamine was added to 2 mL of MeOH solution in an ice bath Tert-butyl ethoxy]propoxy}acetate (126 mg, 0.25 mmol) and LiOH (48.0 mg, 1.00 mmol) were reacted overnight, methanol was removed under reduced pressure, and 2.5 mL of ice water and 2.5 mL were added to the reaction mixture. ethyl acetate = 5-6, extracted with ethyl acetate, the pH adjusted with 2N HCl, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by column chromatography on silica gel under reduced pressure Collected and dried in vacuo to give 90.0 mg (yield: </RTI><RTIgt;</RTI> 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino) Ethoxy]propoxy}acetic acid, yield: 80.2%, ESI-MS: m/z = 450.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d ₆ -DMSO) δ 12.58 (s, 1H) ), 8.21 (s, 1H), 7.38-7.23 (m, 10H), 4.70-4.62 (m, 1H), 4.00 (s, 2H), 3.67-3.42 (m, 7H), 1.22 (d, J = 6.4) Hz, 6H), 1.06 (d, J = 6.4 Hz, 3H).

Method 2:

10.0 g of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid was super Chiral preparation by critical fluid chromatography, instrument: SFC-80 (Thar, Waters), chiral column: chiralcel OJ (30*250 mm, 5 μm) (Daicel), column temperature: 35 ° C, mobile phase: A = CO ₂ , B = MeOH, detection wavelength: 293 nm, cycle time: 6.6 min, one of the components was collected, and methanol was removed under reduced pressure to obtain 4.5 g of (R)-2-{2-[2-(N-(5, 6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid, yield 45%, ESI-MS: m/z=450.2 (M+H) ¹ ; ¹ H NMR (400 MHz, d ₆ -DMSO) δ 12.58 (s, 1H), 8.21 (s, 1H), 7.38-7.22 (m, 10H), 4.70-4.62 (m, 1H), 4.00 (s) , 2H), 3.67-3.41 (m, 7H), 1.22 (d, J = 6.4 Hz, 6H), 1.06 (d, J = 6.4 Hz, 3H).

Example 11(S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy} Preparation of acetic acid

method 1:

The synthesis method is the same as that of the method 1 of the embodiment 10 except that the (2R)-methyl lactate in the step 2 of the method 1 of the embodiment 10 is replaced with (2S)-ethyl lactate to obtain a yellow oil (S)- 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid, ESI-MS: m /z=450.2(M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 12.58 (s, 1H), 8.21 (s, 1H), 7.39-7.22 (m, 10H), 4.70-4.61 (m, 1H), 4.00 (s, 2H), 3.67-3.42 (m, 7H), 1.22 (d, J = 6.4 Hz, 6H), 1.06 (d, J = 6.4 Hz, 3H).

Method 2:

10.0 g of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid was super Chiral preparation by critical fluid chromatography, instrument: SFC-80 (Thar, Waters), chiral column: chiralcel OJ (30*250 mm, 5 μm) (Daicel), column temperature: 35 ° C, mobile phase: A = CO ₂ , B = MeOH, detection wavelength: 293 nm, cycle time: 6.6 min, another component was collected, and methanol was removed under reduced pressure to obtain 4.5 g of (S)-2-{2-[2-(N-(5) ,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid, yield 45%, ESI-MS: m/z = 450.2 (M+H ^{^{) +; 1 H NMR (400MHz}} , d 6 -DMSO) δ12.58 (s, 1H), 8.21 (s, 1H), 7.38-7.21 (m, 10H), 4.70-4.62 (m, 1H), 4.00 ( s, 2H), 3.67-3.43 (m, 7H), 1.22 (d, J = 6.4 Hz, 6H), 1.06 (d, J = 6.4 Hz, 3H).

Example 12 2-{2-[1-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-oxy]ethoxy} Preparation of acetic acid

The synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, and the step 5 in the third embodiment, except that the 2-(N-- Replacement of isopropylamino)ethanol with 1-(N-isopropylamino)-2-propanol to give 2-{2-[1-(N-(5,6-diphenylpyrene) as a yellow oil Pyrazin-2-yl)-N-isopropylamino)propyl-2-oxy]ethoxy}acetic acid, ESI-MS: m/z = 450.2 (M+H) ⁺ ; ¹ H NMR (400 MHz , d ₆ -DMSO) δ12.57 (s, 1H), 8.27 (s, 1H), 7.36-7.22 (m, 10H), 4.64-4.57 (m, 1H), 3.92 (s, 2H), 3.82-3.78 (m, 1H), 3.53-3.51 (m, 1H), 3.45-3.42 (m, 5H), 1.25 (d, J = 6.4 Hz, 6H), 1.15 (d, J = 6.4 Hz, 3H).

Example 13(R)-2-{2-[1-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-oxy] Preparation of ethoxy}acetic acid

Step 1: Preparation of (R)-1-(N-isopropyl)amino-2-propanol

(R)-1-Amino-2-propanol (0.75 g, 10 mmol) and PtO ₂ (227 mg, 1 mmol) were added to a mixture of 2 mL of ethanol and 2 mL of acetone at room temperature, and then a balloon filled with hydrogen was added. The reaction gas was replaced with hydrogen gas of hydrogen balloon, and the reaction liquid was reacted at 1-3 atm for 48 hours. Then, the reaction solution was filtered through celite, washed with ethanol, and then evaporated to dryness to give (R)-1-isopropylamino group. Crude -2-propanol, without purification, the next step is carried out directly.

Step 2: (R)-2-{2-[1-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-yloxy] Preparation of ethoxy}acetic acid

The synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, and the step 5 in the third embodiment, except that the 2-(N-- Replacement of isopropylamino)ethanol with (R)-1-(N-isopropyl)amino-2-propanol to give (R)-2-{2-[1-(N-( 5,6-diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-oxy]ethoxy}acetic acid, ESI-MS: m/z = 450.2 (M+H ^{^{) +; 1 H NMR (400MHz}} , d 6 -DMSO) δ12.57 (s, 1H), 8.27 (s, 1H), 7.36-7.22 (m, 10H), 4.64-4.57 (m, 1H), 3.92 ( s, 2H), 3.82-3.78 (m, 1H), 3.53-3.51 (m, 1H), 3.45-3.42 (m, 5H), 1.25 (d, J = 6.4 Hz, 6H), 1.15 (d, J = 6.4 Hz, 3H).

Example 14(S)-2-{2-[1-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-yloxy] Preparation of ethoxy}acetic acid

Step 1: Preparation of (S)-1-(N-isopropyl)amino-2-propanol

(S)-1-Amino-2-propanol (0.75 g, 10 mmol) and PtO ₂ (227 mg, 1 mmol) were added to a mixture of 2 mL of ethanol and 2 mL of acetone at room temperature, and then a balloon filled with hydrogen was added. The reaction gas was replaced with hydrogen gas of hydrogen balloon, and the reaction solution was kept at 1-3 atm for 48 hours. Then, the reaction solution was filtered through celite, washed with ethanol, and then evaporated to dryness to give (S)-1-isopropylamino group. Crude -2-propanol, without purification, the next step is carried out directly.

Step 2: (S)-2-{2-[1-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-yloxy] Preparation of ethoxy}acetic acid

The synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, and the step 5 in the third embodiment, except that the 2-(N-- Replacement of isopropylamino)ethanol with (S)-1-(N-isopropyl)amino-2-propanol to give (S)-2-{2-[1-(N-( 5,6-diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-oxy]ethoxy}acetic acid, ESI-MS: m/z = 450.2 (M+H ^{^{) +; 1 H NMR (400MHz}} , d 6 -DMSO) δ12.57 (s, 1H), 8.27 (s, 1H), 7.36-7.22 (m, 10H), 4.64-4.57 (m, 1H), 3.92 ( s, 2H), 3.82-3.78 (m, 1H), 3.53-3.51 (m, 1H), 3.45-3.42 (m, 5H), 1.25 (d, J = 6.4 Hz, 6H), 1.15 (d, J = 6.4 Hz, 3H).

Example 15 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}propionic acid

The synthesis step is the same as the preparation step 1, step 2, step 3, step 4, step 5, step 6, step 7 of the third embodiment, except that the t-butyl bromoacetate in the preparation step 6 of the embodiment 3 is replaced with tert-Butyl 2-bromopropionate to give 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino) ethoxylate as a yellow oil Ethoxy]propionic acid, ESI-MS: m/z = 450.2 (M+H) ⁺ .

Example 16 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-2-fluoro Preparation of acetic acid

The synthesis step is the same as the preparation step 1, step 2, step 3, step 4, step 5, step 6, step 7 of the third embodiment, except that the t-butyl bromoacetate in the preparation step 6 of the embodiment 3 is replaced with Ethyl bromofluoroacetate afforded 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethyl oxy} -2-fluoro acetate, ESI-MS: m / z = 454.2 (m + H) +.

Example 17 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-2-methyl Preparation of oxyacetic acid

Step 1: Preparation of 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}-2-fluoroacetic acid tert-butyl ester

The synthesis step is the same as the preparation step 1, step 2, step 3, step 4, step 5, and step 6 of the third embodiment, except that the t-butyl bromoacetate in the preparation step 6 of the embodiment 3 is replaced with the bromofluoroacetic acid. Ethyl ester gave 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}-2-fluoroacetic acid tert-butyl ester, ESI-MS: m / z = 510.2 (m + H) +.

Step 2: 2-{2-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}-2-methoxyacetic acid tert-butyl ester preparation

2-{2-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}-2-fluoroacetic acid tert-butylate under ice-bath conditions The ester (509 mg, 1.00 mmol) was dissolved in 5 mL of anhydrous methanol, and MeONa (216 mg, 4.00 mmol) was added thereto, stirred for 30 min, and naturally heated to room temperature for 2 h. The reaction was confirmed by LC-MS. saturated NH ₄ Cl solution, the methanol was removed under reduced pressure, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by chromatography on a silica gel column, collected under reduced pressure, Drying in vacuo gave 400 mg of 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}-2-methoxyacetic acid as a yellow oil. tert-butyl ester, yield: 76.6%, ESI-MS: m / z = 522.2 (m + H) +.

Step 3: 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-2-yl Preparation of oxyacetic acid

2-{2-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}-2- was added sequentially to 2 mL of MeOH under ice bath Tert-butyl methoxyacetate (261 mg, 0.50 mmol) and LiOH (48.0 mg, 2.00 mmol) were reacted overnight, and methanol was removed under reduced pressure. 5 mL of ice water and 5 mL of ethyl acetate were added to the mixture, and pH was adjusted with 2N HCl. = 5-6, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by silica gel column chromatography, were collected under reduced pressure, and dried in vacuo to give 183mg of a pale yellow Solid 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-2-methoxy acetate, yield: 78.7%, ESI-MS: m / z = 466.2 (m + H) +.

Example 18 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetic acid

The synthesis step is the same as that in the preparation of the first step, the second step, the step 3, the step 4, the step 5, the method 1, the step 6, the step 7 of the third embodiment, except that the t-butyl bromoacetate in the step 4 of the preparation of the third embodiment is prepared. Replace with tert-butyl 2-bromobutyrate to give 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino) as a yellow oil. Ethoxy]butoxy}acetic acid, ESI-MS: m/z = 464.2 (M + H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 12.58 (s, 1H), 8.23 (s, 1H), 7.36-7.23 (m, 10H), 4.71-4.64 (m, 1H), 4.00 (s, 2H), 3.62-3.47 (m, 7H), 1.54-1.37 (m, 2H), 1.23 (d, J = 6.4 Hz, 6H), 0.85 (t, J = 7.4 Hz, 3H).

Example 19(R)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy} Preparation of acetic acid

10.0 g of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetic acid was super Chiral preparation by critical fluid chromatography, instrument: SFC-80 (Thar, Waters), chiral column: Daicel chiralcel OJ (30*250 mm, 5 μm), column temperature: 35 ° C, mobile phase: A = CO ₂ , B = MeOH , detection wavelength: 293 nm, cycle time: 7.2 min, one component was collected, and methanol was removed under reduced pressure to obtain 4.5 g of (R)-2-{2-[2-(N-(5,6-) Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetic acid, yield 45%; ESI-MS: m/z = 464.2 (M+H) ⁺ ^{_{1 H NMR (400MHz, d 6}} -DMSO) δ12.58 (s, 1H), 8.23 (s, 1H), 7.36-7.23 (m, 10H), 4.71-4.64 (m, 1H), 4.00 (s, 2H ), 3.62-3.47 (m, 7H), 1.54-1.37 (m, 2H), 1.23 (d, J = 6.4 Hz, 6H), 0.85 (t, J = 7.4 Hz, 3H).

Example 20(S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy} Preparation of acetic acid

10.0 g of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetic acid was super Chiral preparation by critical fluid chromatography, instrument: SFC-80 (Thar, Waters), chiral column: Daicel chiralcel OJ (30*250 mm, 5 μm), column temperature: 35 ° C, mobile phase: A = CO ₂ , B = MeOH , detection wavelength: 293 nm, cycle time: 7.2 min, another component was collected, and methanol was removed under reduced pressure to obtain 4.5 g of (S)-2-{2-[2-(N-(5,6) -diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetic acid, yield 45%; ESI-MS: m/z = 464.2 (M+H) ⁺ ¹ H NMR (400 MHz, d ₆ -DMSO) δ 12.58 (s, 1H), 8.23 (s, 1H), 7.36-7.23 (m, 10H), 4.71-4.64 (m, 1H), 4.00 (s, 2H), 3.62-3.47 (m, 7H), 1.54-1.37 (m, 2H), 1.23 (d, J = 6.4 Hz, 6H), 0.85 (t, J = 7.4 Hz, 3H).

Example 21 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]pentyloxy}acetic acid

The synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, the step 5, the step 1, the step 7 and the step 7. The only difference is that the t-butyl bromoacetate in the step 4 of the preparation of the third embodiment is prepared. Replace with tert-butyl 2-bromopentanoate to give 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino) as a yellow oil. Ethoxy]pentyloxy}acetic acid, ESI-MS: m/z = 478.2 (M + H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 8.22 (s, 1H), 7.37-7.21 ( m, 10H), 4.70-4.63 (m, 1H), 3.87 (s, 2H), 3.77-3.46 (m, 7H), 1.38-1.30 (m, 4H), 1.22 (d, J = 6.4 Hz, 6H) , 0.82 (t, J = 7.2 Hz, 3H).

Example 22 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-cyclopropylamino)ethoxy]ethoxy}acetic acid

Step 1: Preparation of N-cyclopropyl-5,6-diphenylpyrazin-2-amine

Add cyclopropylamine (0.57g, 10.0mmol) and 5-chloro-2,3-diphenylpyrazine (532mg, 2.00mmol) to the sealing tube, replace the gas in the sealing tube with nitrogen, then seal the tube and heat to 150 °C. the reaction 24h, LC-MS detection reaction, the starting material the reaction was complete, the reaction solution was cooled, added to saturated NH ₄ Cl solution, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure Purification by chromatography on silica gel column, EtOAc (EtOAc) m.jjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH /z=288.2(M+H) ⁺ .

Step 2: Preparation of 2-(N-(5,6-diphenylpyrazin-2-yl)-N-cyclopropylamino)acetic acid tert-butyl ester

N-cyclopropyl-5,6-diphenylpyrazin-2-amine (288 mg, 1.00 mmol) was dissolved in 2.5 mL of anhydrous tetrahydrofuran under ice-cooling, and NaH (80 mg, 2.00) (mmol), stirring for 30min, then add the compound t-butyl bromoacetate (290mg, 1.50mmol), naturally warmed to room temperature for 2h, LC-MS detection reaction, the reaction of the raw materials is complete, the reaction solution is cooled to 5 ° C, slowly to the reaction solution dropwise ice water, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by silica gel column chromatography, were collected under reduced pressure, and dried in vacuo to give 310mg of yellow Oil tert-butyl 2-(N-(5,6-diphenylpyrazin-2-yl)-N-cyclopropylamino)acetate, yield: 77.3%, ESI-MS: m/z = 402.2 (M+H) ⁺ .

Step 3: Preparation of 2-(N-(5,6-diphenylpyrazin-2-yl)-N-cyclopropylamino)ethanol

2-(N-(5,6-Diphenylpyrazin-2-yl)-N-cyclopropylamino)acetic acid tert-butyl ester (402 mg, 1.00 mmol) was dissolved in 10 mL under ice-bath In water tetrahydrofuran, LiAlH ₄ (76.0 mg, 2.00 mmol) was slowly added in portions, and after reacting for 30 min, it was naturally warmed to room temperature, and then reacted for 2 h. The reaction was monitored by LC-MS, and the starting material was completely reacted. After cooling the reaction solution to 0 ° C, the reaction solution was slowly poured into a stirred beaker of solid sodium sulfate decahydrate, stirred for 30 min, filtered, and the solvent was removed under reduced pressure, and then extracted with ethyl acetate. Washed, dried over sodium sulfate, filtered, evaporated, evaporated, evaporated, evaporated, - yl) -N- cyclopropylamino) ethanol, yield: 90.6%, ESI-MS: m / z = 332.4 (m + H) +.

Step 4: Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-cyclopropylamino)ethoxy]ethoxy}acetic acid

The synthesis steps are the same as those in the preparation of step 4, step 5, step 6, step 7 of the third embodiment, except that the 2-[N-(5,6-diphenylpyrene) in the preparation step 4 of the embodiment 3 is used. Substituting 2-[N-(5,6-diphenylpyrazin-2-yl)-N-cyclopropylamino]ethanol for 2-oxazino-2-yl)-N-isopropylamino]ethanol 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-cyclopropylamino)ethoxy]ethoxy}acetic acid in the form of yellow oil, ESI- MS: m/z = 434.2 (M + H) ⁺ .

Example 23 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy }Preparation of acetic acid

Step 1: Preparation of 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethanol

The synthesis steps are the same as those in the preparation of Step 3, Step 2, and Step 3 of Example 3 to obtain 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino group as a white solid. ethanol, ESI-MS: m / z = 334.2 (m + H) +.

Step 2: 2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropanoic acid tert-butyl ester preparation

The compound 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethanol (333 mg, 1.00 mmol) was dissolved in 2 mL of anhydrous tetrahydrofuran under ice bath. NaH (80 mg, 2.00 mmol) was slowly added portionwise, and the mixture was stirred for 1 h, and the reaction solution was added dropwise to 2 mL of 2-bromo-2-methylpropionic acid tert-butyl ester (334 mg, 1.50 mmol) at 0 ° C. In water tetrahydrofuran solution, the temperature is naturally raised to room temperature for 2 h, and the reaction is detected by LC-MS. The reaction of the starting material is complete. The reaction solution is cooled to 5 ° C, and ice water is slowly added dropwise to the reaction solution, and the mixture is extracted with ethyl acetate. saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by silica gel column chromatography, collecting under reduced pressure, and dried in vacuo to give 80.0mg of a yellow oil 2- [2- (N- (5,6- two tert-Butyl phenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropanoate, yield: 16.8%, ESI-MS: m/z = 476.2 (M +H) ⁺ .

Step 3: 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy }Preparation of acetic acid

The synthesis step is the same as the method 1, step 6, and step 7 of the preparation of the step 5 in the third embodiment, except that the 2-{2-[N-(5,6-two) in the method 1 of the preparation method of the third embodiment is prepared. Replacement of tert-butyl phenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetate with 2-[2-(N-(5,6-diphenylpyrazin-2-yl) tert-butyl-N-isopropylamino)ethoxy]-2-methylpropanoate gave 2-{2-[2-(N-(5,6-diphenylpyrazine) as a yellow oil -2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}acetic acid, ESI-MS: m/z=464.2 (M+H) ⁺ ; ¹ H NMR (400 MHz , d _{6 -} DMSO) δ 8.21 (s, 1H), 7.40 - 7.34 (m, 2H), 7.33 - 7.18 (m, 8H), 4.72-4.65 (m, 1H), 4.02 (s, 2H), 3.60 (t, J = 6.2 Hz, 2H), 3.53 (t, J = 6.0 Hz, 2H), 3.38 (s, 2H), 1.23 (d, J = 6.6 Hz, 6H), 1.12 (s, 6H).

Example 24 2-{1-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]cyclopropylmethoxy}acetic acid Preparation

Step 1: Preparation of 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethanol

The synthesis procedure is the same as in the preparation of Step 1, Step 2, and Step 3 of Example 3 to obtain a white solid 2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino] ethanol, ESI-MS: m / z = 334.2 (m + H) +.

Step 2: Preparation of 1-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]cyclopropylcarboxylic acid tert-butyl ester

2-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]ethanol (333 mg, 1.00 mmol) was dissolved in 2 mL of anhydrous tetrahydrofuran under ice bath. NaH (80 mg, 2.00 mmol) was slowly added portionwise, and the mixture was stirred for 1 h, and the reaction solution was added dropwise to a solution of tert-butyl 1-bromocyclopropylcarboxylate (331 mg, 1.50 mmol) at 0 ° C in 2 mL of anhydrous tetrahydrofuran. In the solution, the temperature is naturally raised to room temperature for 2 h, and the reaction is detected by LC-MS. The reaction of the starting material is complete. The reaction solution is cooled to 5 ° C, and ice water is slowly added dropwise to the reaction solution, and extracted with ethyl acetate. The organic mixed phase is water and saturated brine. After washing, MgSO _{4 was} dried, filtered, evaporated, evaporated, evaporated, evaporated, triazin-2-yl) -N- isopropyl-amino) ethoxy] cyclopropyl-carboxylic acid tert-butyl ester, yield: 31.7%, ESI-MS: m / z = 474.2 (m + H) +.

Step 3: 2-{1-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]cyclopropylmethoxy}acetic acid Preparation

The synthesis step is the same as the method 1, step 6, and step 7 of the preparation of the step 5 in the third embodiment, except that 2-{2-[N-(5,6-) in the method 1 of the preparation step 5 of the embodiment 3 is used. Tert-butyl diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetate was replaced by 1-[2-(N-(5,6-diphenylpyrazine-2-) Tert-butyl ester of -N-isopropylamino)ethoxy]cyclopropylcarboxylate afforded 2-{1-[2-(N-(5,6-diphenylpyrazine-2) as a yellow oil - yl) -N- isopropyl-amino) ethoxy] cyclopropylmethoxy} acetic acid, ESI-MS: m / z = 462.2 (m + H) +.

Example 25 2-{2-[2-(N-(5,6-Di(p-fluorophenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy} Preparation of acetic acid

The synthesis method is the same as the synthesis method of Example 3 except that the biphenylyl group in the preparation step 1 of Example 3 is replaced with 4,4'-difluorobenzyl to obtain a yellow oil-like 2-{2-[2 -(N-(5,6-bis(p-fluorophenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid, ESI-MS: m/z = 472.2(M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 12.58 (s, 1H), 8.22 (s, 1H), 7.42-7.09 (m, 8H), 4.70-4.63 (m, 1H), 4.02 (s, 2H), 3.65-3.58 (m, 7H), 1.23 (d, J = 6.4 Hz, 6H).

Example 26 2-{2-[2-(N-(5,6-bis(p-methylphenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy }Preparation of acetic acid

The synthesis method is the same as the synthesis method of Example 3 except that the dibenzoyl group in the preparation step 1 of Example 3 is replaced with 4,4'-dimethylbenzyl group to obtain a yellow oil-like 2-{2-[ 2-(N-(5,6-bis(p-methylphenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid, ESI-MS: m/ z=464.2 (M+H) ⁺ .

Example 27 2-{2-[2-(N-(5,6-Di(p-methoxyphenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy Preparation of acetic acid

The synthesis method is the same as the synthesis method of Example 3 except that the biphenylyl group in the preparation step 1 of Example 3 is replaced with 4,4'-dimethoxybenzil to obtain a yellow oil-like 2-{2- [2-(N-(5,6-Di(p-methoxyphenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid, ESI-MS: m/z = 496.2 (M+H) ⁺ .

Example 28 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethylthio]ethoxy}acetic acid

Step 1: Preparation of N-isopropyl-2-mercaptoethylamine

To a mixture of 2 mL of methanol and 2 mL of acetone was added mercaptoethylamine (0.77 g, 10 mmol) at room temperature. After stirring for 1 h, the reaction mixture was cooled to 0 ° C, and NaBCNH ₃ (1.86 g, 30 mmol) was added portionwise at room temperature, the reaction 48h, the solvent away under reduced pressure, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, rotary evaporated under reduced pressure to afford N- isopropyl-2-mercaptoethylamine crude No further purification is required, and the next reaction is carried out directly.

Step 2: Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethylthio]ethoxy}acetic acid

The synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, the step 5, the step 1, the step 7 and the step 7 in the third embodiment, except that the 2-(N) in the preparation step 3 of the embodiment 3 is used. -Isopropylamino)ethanol was replaced by N-isopropyl-2-mercaptoethylamine to give 2-{2-[2-(N-(5,6-diphenylpyrazine-2-) as a yellow oil. yl) -N- isopropyl-amino) ethylthio] ethoxy} acetic acid, ESI-MS: m / z = 452.2 (m + H) +; 1 H NMR (400MHz, d 6 -DMSO) δ12. 61 (s, 1H), 8.20 (s, 1H), 7.46-7.04 (m, 10H), 4.69-4.54 (m, 1H), 3.99 (s, 2H), 3.62 (dd, J = 13.3, 6.8 Hz, 4H), 2.79 (t, J = 6.7 Hz, 4H), 1.25 (d, J = 6.6 Hz, 6H).

Example 29 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethylsulfoxide]ethoxy}acetic acid

Compound 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethylthio]ethoxylate under ice-bath conditions The acetic acid (451 mg, 1.00 mmol) was dissolved in 5 mL of CHCl ₃ , and m-chloroperoxybenzoic acid (236 mg, 1.10 mmol, purity 80%) was added thereto, and the mixture was stirred for 2 hours, and sodium hydrogen sulfite was slowly added dropwise to the reaction solution. solution, extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by silica gel column chromatography, were collected under reduced pressure, and dried in vacuo to give 190mg of a yellow oil 2- {2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethyl sulfoxide]ethoxy}acetic acid, yield: 40.7%, ESI-MS: m/z = 468.2 (M+H) ⁺ .

Example 30 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethylsulfonyl]ethoxy}acetic acid

The preparation method was the same as that of Example 29 except that 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino group in Example 29 was used. Ethylthio]ethoxy}acetic acid is replaced by 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethyl sulfoxide Ethyl]ethoxy}acetic acid to give 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethylsulfonyl group as a yellow oil ] ethoxy} acetic acid, ESI-MS: m / z = 484.2 (m + H) +.

Example 31 2-{2-[2-(N-(5,6-Di(m-methylphenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy }Preparation of acetic acid

The synthesis method is the same as the synthesis method of Example 3 except that the dibenzoyl group in the preparation step 1 of Example 3 is replaced with 3,3'-dimethylbenzyl group to obtain a yellow oil-like 2-{2-[ 2-(N-(5,6-bis(m-methylphenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid, ESI-MS: m/ z=464.2 (M+H) ⁺ .

Example 32 2-{2-[2-(2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy)ethoxy]B Preparation of oxy}acetic acid

Step 1: Preparation of 2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetic acid tert-butyl ester

The synthesis step is the same as the preparation step 1, step 2, step 3, step 4, step 5, and step 6 of Example 3 to obtain 2-{2-[2-(N-(5,6-diphenylpyrene) in the form of a yellow oil. triazin-2-yl) -N- isopropyl-amino) ethoxy] ethoxy} acetate, ESI-MS: m / z = 448.2 (m + H) +.

Step 2: 2-{2-[2-(2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy)ethoxy]B Preparation of oxy}acetic acid

The synthesis step is the same as the method 1, step 6, and step 7 of the preparation of the step 5 in the third embodiment, except that 2-{2-[N-(5,6-) in the method 1 of the preparation step 5 of the embodiment 3 is used. Tert-butyl diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetate was replaced by 2-{2-[2-(N-(5,6-diphenylpyrazine) Tert-butyl ester of 2-yl)-N-isopropylamino)ethoxy]ethoxy}acetate afforded 2-{2-[2-(2-(N-(5,6-) diphenyl-2-yl) -N- isopropyl-amino) ethoxy) ethoxy] ethoxy} acetic acid, ESI-MS: m / z = 480.2 (m + H) +; 1 H NMR (400 MHz, d ₆ -DMSO) δ 12.6 (s, 1H), 8.22 (s, 1H), 7.35-7.22 (m, 10H), 4.71-4.64 (m, 1H), 4.00 (s, 2H) , 3.63 - 3.52 (m, 12H), 1.23 (d, J = 6.8 Hz, 6H).

Example 33 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-N-A Preparation of sulfonyl acetamide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid under nitrogen (435 mg, 1.00 mmol) and N,N'-carbonyldiimidazole (CDI) (178 mg, 1.10 mmol) were dissolved in 5 mL of dry THF. after stirring IH, dropwise DBU (0.15mL, 1.00mmol), the reaction at room temperature overnight, the reaction solution was poured into 1N HCl and extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered The solvent was removed under reduced pressure and purified by silica gel column chromatography. ) -N- isopropyl-amino) ethoxy] ethoxy} -N- mesyl acetamide, yield: 68.4%, ESI-MS: m / z = 513.2 (m + H) +.

Example 34 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-N-benzene Preparation of sulfonyl acetamide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid under nitrogen (435 mg, 1.00 mmol) and N,N'-carbonyldiimidazole (CDI) (178 mg, 1.10 mmol) were dissolved in 5 mL of anhydrous THF and heated to reflux for 1 h, then, after cooling, benzenesulfonamide (157 mg, 1.00 mmol) was added and stirred. after IH, dropwise addition of DBU (0.15mL, 1.00mmol), the reaction at room temperature overnight, the reaction solution was poured into 1N HCl and extracted with ethyl acetate, the organic mixture with water, washed with saturated brine, dried MgSO _4, filtered, The solvent was evaporated under reduced pressure and purified by silica gel column chromatography. -N- isopropyl-amino) ethoxy] ethoxy} -N- phenylsulfonyl acetamide, yield: 64.4%, ESI-MS: m / z = 575.2 (m + H) +.

Example 35 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-N-acetyl Preparation of acetamide

The preparation method is the same as the preparation method of the embodiment 34, except that the benzenesulfonamide in the example 34 is replaced with acetamide to obtain 2-{2-[2-(N-(5,6-diphenyl) in the form of a yellow oil. Pyryrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-N-acetylacetamide, yield: 65.1%, ESI-MS: m/z = 477.2 (M +H) ⁺ .

Example 36 Preparation of 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetamide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid under nitrogen (435 mg, 1.00 mmol) was dissolved in 5 mL of anhydrous THF, 0.5 mL of triethylamine was added thereto, and ethyl chloroformate (120 mg, 1.10 mmol) was added dropwise thereto under ice-cooling, stirred for 1 hour, and 0.5 mL of saturated ammonia was slowly added dropwise. After stirring for 1 h, THF was added dropwise with 0.5 mL of saturated ammonia gas, and the reaction was allowed to warm overnight. The reaction mixture was evaporated to dryness, and then water was applied, and the mixture was extracted with ethyl acetate. , dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to give a yellow oil 390mg of 2- {2- [2- (N- ( 5,6- diphenyl pyrazin-2-yl) -N- isopropyl-amino) ethoxy] ethoxy} acetamide, yield: 89.7%, ESI-MS: m / z = 435.2 (m + H) +.

Example 37 Preparation of sodium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetate

The compound 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy} under nitrogen protection Acetic acid (4.35 g, 10.0 mmol) and NaOH (420 mg, 10.5 mmol) were suspended in 50 mL of THF and heated to reflux for 4 h. After cooling, most solvent was removed under reduced pressure, filtered, washed with ethanol and dried in vacuo to give 4. {2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid sodium acetate, yield: 89.7%, ESI-MS: m/z = 436.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 8.22 (s, 1H), 7.38-7.20 (m, 10H), 4.71-4.64 (m) , 1H), 3.67-3.40 (m, 10H), 1.23 (d, J = 6.8 Hz, 6H).

Example 38 Preparation of sodium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetate

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid under nitrogen (4.49g, 10.0mmol) and NaOH (420mg, 10.5mmol) were suspended in 50mL of THF, heated under reflux for 4h, cooled the reaction solution, filtered, washed with ethanol and dried in vacuo to give 4.24g of white solid 2-{2-[2- (N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid sodium acetate, yield: 90.0%, ESI-MS: m/ z = 450.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 8.21 (s, 1H), 7.38 - 7.22 (m, 10H), 4.71-4.64 (m, 1H), 3.67- 3.57 (m, 5H), 3.49 (s, 2H), 3.43-3.34 (m, 2H), 1.22 (d, J = 6.4 Hz, 6H), 1.05 (d, J = 6.0 Hz, 3H).

Example 39(R)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy} Preparation of sodium acetate

(R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propyl under nitrogen Ethyloxyacetic acid (4.49 g, 10.0 mmol) and NaOH (420 mg, 10.5 mmol) were suspended in 50 mL of THF and heated to reflux for 4 h. The reaction mixture was cooled, filtered, washed with Et. Sodium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetate, yield: 90.4 %, ESI-MS: m/z = 450.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 8.21 (s, 1H), 7.38-7.22 (m, 10H), 4.71-4.64 (m, 1H), 3.67-3.57 (m, 5H), 3.49 (s, 2H), 3.43-3.32 (m, 2H), 1.22 (d, J = 6.4 Hz, 6H), 1.05 (d, J = 6.0) Hz, 3H).

Example 40(S)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy} Preparation of sodium acetate

(S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)propoxy]B under nitrogen protection Ethyloxyacetic acid (4.49 g, 10.0 mmol) and NaOH (420 mg, 10.5 mmol) were suspended in 50 mL of THF and heated to reflux for 4 h. The reaction mixture was cooled, filtered, washed with Et. Sodium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetate, yield: 89.4 %, ESI-MS: m/z = 450.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 8.21 (s, 1H), 7.38-7.22 (m, 10H), 4.71-4.64 (m, 1H), 3.67-3.56 (m, 5H), 3.49 (s, 2H), 3.43-3.34 (m, 2H), 1.22 (d, J = 6.4 Hz, 6H), 1.05 (d, J = 6.0) Hz, 3H).

Example 41 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid hydrochloride Preparation of salt

2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid (449 mg, 1.00 mmol) And hydrochloric acid (118.2 mg, 1.20 mmol, 37% aqueous solution) was dissolved in 10 mL of acetonitrile, heated under reflux for 2 h, and the solution was cooled to room temperature. The obtained clear solution was evaporated under reduced pressure at room temperature, and the residue was dissolved in 10 mL of hot diisopropyl ether. The reaction was stirred, and the precipitate was observed, filtered, and dried overnight in vacuo to give 340 mg of white powder 2-{2-[2 -(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid hydrochloride, yield: 70%, ESI- MS: m/z = 450.2 (M + H) ⁺ .

Example 42 Preparation of potassium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetate

2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid under nitrogen (4.49g, 10.0mmol) and KOH (798mg, 10.5mmol) were suspended in 50mL of THF and heated to reflux for 4h. After cooling, most solvent was removed under reduced pressure, filtered, washed with ethanol and dried in vacuo to give 4.30 g of white solid 2-{ 2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid potassium, yield: 88.3%, ¹ H NMR (400 MHz, d ₆ -DMSO) δ 8.21 (s, 1H), 7.38-7.22 (m, 10H), 4.71-4.64 (m, 1H), 3.67-3.32 (m, 9H), 1.22 (d, J = 6.4 Hz, 6H), 1.05 (d, J = 6.0 Hz, 3H).

Example 43 Preparation of sodium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetate

The preparation method was the same as that of Example 38 except that the 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino group in Example 38 was used. Ethoxy]ethoxy}acetic acid is replaced by 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy ] Butoxy}acetic acid to give a white solid 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy] Sodium oxy}acetate, ESI-MS: m/z = 464.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d ₆ -DMSO) δ 8.23 (s, 1H), 7.36-7.23 (m, 10H) , 4.71-4.64 (m, 1H), 3.62-3.30 (m, 9H), 1.54-1.36 (m, 2H), 1.23 (d, J = 6.4 Hz, 6H), 0.85 (t, J = 7.4 Hz, 3H ).

Example 44(R)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy} Preparation of sodium acetate

The preparation method was the same as that of Example 38 except that the 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino group in Example 38 was used. Ethyloxy]ethoxy}acetic acid is replaced by (R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino) Ethoxy]butoxy}acetic acid to give a white solid (R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropyl Amino) ethoxy]butoxy}sodium acetate, ESI-MS: m/z = 464.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 8.23 (s, 1H), 7.36-7.23 (m, 10H), 4.71-4.64 (m, 1H), 3.62-3.30 (m, 9H), 1.55-1.37 (m, 2H), 1.23 (d, J = 6.4 Hz, 6H), 0.85 ( t, J = 7.4 Hz, 3H).

Example 45(S)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy} Preparation of sodium acetate

The preparation method was the same as that of Example 38 except that the 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino group in Example 38 was used. Ethyloxy]ethoxy}acetic acid is replaced by (S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino) Ethoxy]butoxy}acetic acid to give a white solid (S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropyl Amino) ethoxy]butoxy}sodium acetate, ESI-MS: m/z = 464.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 8.23 (s, 1H), 7.36-7.23 (m, 10H), 4.71-4.65 (m, 1H), 3.62-3.30 (m, 9H), 1.54-1.36 (m, 2H), 1.23 (d, J = 6.4 Hz, 6H), 0.85 ( t, J = 7.4 Hz, 3H).

Example 46 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy Preparation of }-N-methanesulfonylacetamide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methyl under nitrogen Propoxy}acetic acid (463 mg, 1.00 mmol) and N,N'-carbonyldiimidazole (CDI) (178 mg, 1.10 mmol) were dissolved in 5 mL of dry THF and heated to reflux for 1 h. After stirring for 1 h, DBU (0.15 mL, 1.00 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was poured into 1N HCl and extracted with ethyl acetate. _4, drying, filtration, de-solvent to remove the solvent, and then purified by chromatography on silica gel column, collected under reduced pressure, and dried under vacuum to give 360 mg of a yellow solid 2-{2-[2-(N-(5,6-diphenylpyrazine) 2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N-methanesulfonylacetamide, yield: 66.5%, ESI-MS: m/z = 541.3(M+H) ⁺ ; ¹ H NMR (400MHz, d _{6 -} DMSO) δ 11.62 (s, 1H), 8.21 (s, 1H), 7.48-7.06 (m, 10H), 4.68 (dd, J = 13.1, 6.6 Hz, 1H), 4.09 (s, 2H), 3.64-3.50 (m, 4H), 3.39 (s, 2H), 3.25 (s, 3H), 1.23 (d, J = 6.7 Hz, 6H), 1.13 (s, 6H).

Example 47 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy }-N-ethanesulfonylacetamide Prepare

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methyl under nitrogen Propoxy}acetic acid (463 mg, 1.00 mmol) and N,N'-carbonyldiimidazole (CDI) (178 mg, 1.10 mmol) were dissolved in 5 mL of dry THF and heated to reflux for 1 h. After stirring for 1 h, DBU (0.15 mL, 1.00 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was poured into 1N HCl and extracted with ethyl acetate. _4, drying, filtration, de-solvent under reduced pressure, and purified by chromatography on silica gel column, collected under reduced pressure, and dried in vacuo to give 383 mg of y. 2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N-ethanesulfonylacetamide, yield: 69.0%, ESI-MS: m/z = 555.3(M+H) ⁺ ; ¹ H NMR (400 MHz, d ₆ -DMSO) δ 11.53 (s, 1H), 8.21 (s, 1H), 7.51-7.09 (m, 10H), 4.82-4.55 (m, 1H), 4.07 (s, 2H), 3.57 (dd, J = 20.2, 5.8 Hz, 4H), 3.39 (s, 2H), 3.33 (dd, J = 14.7, 7.3 Hz, 2H), 1.27-1.16 (m , 9H), 1.12 (s, 6H).

Example 48 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy Preparation of }-N-trifluoromethanesulfonylacetamide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methyl under nitrogen Propoxy}acetic acid (463 mg, 1.00 mmol) and N,N'-carbonyldiimidazole (CDI) (178 mg, 1.10 mmol) were dissolved in 5 mL of anhydrous THF and heated to reflux for 1 h. 149 mg, 1.00 mmol), after stirring for 1 h, DBU (0.15 mL, 1.00 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was poured into 1N HCl and extracted with ethyl acetate. , dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to give 428mg of yellow solid 2- {2- [2- (N- ( 5,6- diphenyl Pyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N-trifluoromethanesulfonylacetamide, yield: 72.0%, ESI-MS: m/z=595.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, δ _{6 -} DMSO) δ 8.94 (s, 1H), 8.20 (s, 1H), 7.43 - 7.15 (m, 10H), 4.77- 4.59 (m, 1H), 3.79 (s, 2H), 3.56 (dd, J = 23.7, 5.7 Hz, 4H), 3.34 (s, 2H), 1.23 (d, J = 6.6 Hz, 6H), 1.11 (s) , 6H).

Example 49 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy Preparation of }-N-benzenesulfonylacetamide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methyl under nitrogen Propoxy}acetic acid (463 mg, 1.00 mmol) and N,N'-carbonyldiimidazole (CDI) (178 mg, 1.10 mmol) were dissolved in 5 mL of anhydrous THF and heated to reflux for 1 h. After stirring for 1 h, DBU (0.15 mL, 1.00 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was poured into 1N HCl and extracted with ethyl acetate. _4, drying, filtration, de-solvent under reduced pressure, and purified by chromatography on silica gel column, collected under reduced pressure, and dried in vacuo to give 392 mg of y. 2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N-benzenesulfonylacetamide, yield: 65.0%, ESI-MS: m/z = 603.3(M+H) ⁺ ; ¹ H NMR (400MHz, d ₆ -DMSO) δ 12.06 (s, 1H), 8.19 (s, 1H), 7.96-7.90 (m, 2H), 7.74 - 7.58 (m, 3H), 7.39-7.21 (m, 10H), 4.74-4.58 (m, 1H), 4.02 (s, 2H), 3.52 (dd, J = 11.4, 5.1 Hz, 4H), 3.28 (s, 2H), 1.21. (d, J = 6.7 Hz, 6H), 1.07 (s, 6H).

Example 50 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy }-N-p-toluenesulfonylacetamide Preparation

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methyl under nitrogen Propoxy}acetic acid (463 mg, 1.00 mmol) and N,N'-carbonyldiimidazole (CDI) (178 mg, 1.10, mmol) were dissolved in 5 mL anhydrous THF and heated to reflux for 1 h. 171 mg, 1.00 mmol), after stirring for 1 h, DBU (0.15 mL, 1.00 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was poured into 1N HCl and extracted with ethyl acetate. , dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to give 400mg of yellow solid 2- {2- [2- (N- ( 5,6- diphenyl Pyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N-p-toluenesulfonylacetamide, yield: 65.0%, ESI-MS: m /z=617.3(M+H) ⁺ ; ¹ H NMR (400 MHz, δ _{6 -} DMSO) δ 11.97 (s, 1H), 8.19 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 7.38-7.33 (m, 2H), 7.31 - 7.21 (m, 8H), 4.73-4.61 (m, 1H), 4.00 (s, 2H), 3.52 (dd, J = 12.3, 5.2 Hz, 4H), 3.28 (s, 2H), 2.37 (s, 3H), 1.21 (d, J = 6.7 Hz, 6H), 1.07 (s, 6H).

Example 51 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy Preparation of }-N-p-fluorobenzenesulfonylacetamide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methyl under nitrogen Propoxy}acetic acid (463 mg, 1.00 mmol) and N,N'-carbonyldiimidazole (CDI) (178 mg, 1.10 mmol) were dissolved in 5 mL anhydrous THF and heated to reflux for 1 h. 175 mg, 1.00 mmol), after stirring for 1 h, DBU (0.15 mL, 1.00 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was poured into 1N HCl and extracted with ethyl acetate. , dried MgSO _4, filtered, the solvent under reduced pressure, and then purified by chromatography on a silica gel column, collected under reduced pressure, and dried in vacuo to give 440mg of yellow solid 2- {2- [2- (N- ( 5,6- diphenyl Pyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N-p-fluorobenzenesulfonylacetamide, yield: 71.0%, ESI-MS: m/z = 621.3 (M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 12.13 (s, 1H), 8.19 (s, 1H), 8.00-7.91 (m, 2H), 7.46- 7.18 (m, 12H), 4.75-4.59 (m, 1H), 3.95 (s, 2H), 3.53 (dd, J = 14.6, 5.5 Hz, 4H), 3.29 (s, 2H), 1.22 (t, J = 6.8 Hz, 6H), 1.07 (s, 6H).

Example 52(S)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy} Preparation of -N-methanesulfonylacetamide

The preparation method was the same as that of Example 46 except that the 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino group in Example 46 was used. ) ethoxy]-2-methylpropoxy}acetic acid is replaced by (S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N- Isopropylamino)ethoxy]propoxy}acetic acid gives the yellow solid (S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)- N-isopropylamino)ethoxy]propoxy}-N-methanesulfonylacetamide, yield: 66.5%, ESI-MS: m/z=526.2 (M+H) ⁺ ; ¹ H NMR (400MHz, d ₆ -DMSO) δ 11.61 (s, 1H), 8.22 (s, 1H), 7.44 - 7.15 (m, 10H), 4.82-4.49 (m, 1H), 4.07 (s, 2H), 3.72 -3.64 (m, 3H), 3.64 - 3.56 (m, 2H), 3.47 (d, J = 5.1 Hz, 2H), 3.24 (s, 3H), 1.24 (d, J = 6.7 Hz, 6H), 1.08 ( d, J = 6.3 Hz, 3H).

Example 53(R)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy} Preparation of -N-methanesulfonylacetamide

The preparation method was the same as that of Example 46 except that the 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino group in Example 46 was used. ) ethoxy]-2-methylpropoxy}acetic acid is replaced by (R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N- Isopropylamino)ethoxy]propoxy}acetic acid gives the yellow solid (R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)- N-isopropylamino)ethoxy]propoxy}-N-methanesulfonylacetamide, yield: 66.5%, ESI-MS: m/z=526.2 (M+H) ⁺ ; ¹ H NMR (400MHz, d ₆ -DMSO) δ 8.23 (s, 1H), 7.52-7.04 (m, 10H), 4.71-4.64 (m, 1H), 3.89 (s, 2H), 3.73-3.55 (m, 5H) , 3.50-3.39 (m, 2H), 2.98 (s, 3H), 1.24 (d, J = 6.6 Hz, 6H), 1.08 (d, J = 6.3 Hz, 3H).

Example 54 2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy }Preparation of acetamide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid under nitrogen (435 mg, 1.00 mmol) was dissolved in 5 mL of anhydrous THF, 0.5 mL of triethylamine was added, and ethyl chloroformate (120 mg, 1.10 mmol) was added dropwise in an ice bath, stirred for 1 h, and 0.5 mL of saturated ammonia THF was slowly added dropwise. After stirring for 1 h, then 0.5 mL of saturated ammonia in THF was added dropwise, and the reaction was allowed to warm overnight. The reaction mixture was evaporated to dryness, then water was evaporated and evaporated. _4, drying, filtration, de-solvent under reduced pressure, and purified by chromatography on silica gel column, collected under reduced pressure, and dried in vacuo to give 390 mg of 2-[2-[2-(N-(5,6-diphenylpyrazine) as a yellow oil. 2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}acetamide, yield: 89.7%, ESI-MS: m/z = 463.3 (M+H) ¹ ; ¹ H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 7.49-7.18 (m, 10H), 7.07 (m, 1H), 4.69 (d, J = 6.1 Hz, 1H), 3.82 (s) , 2H), 3.56 (dd, J = 20.4, 5.5 Hz, 4H), 3.36 (s, 2H), 1.23 (d, J = 6.4 Hz, 6H), 1.14 (s, 6H).

Preparation 1 Preparation of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}acetic acid (MRE-269)

Prepared according to the method disclosed in Example 42 of the patent CN1516690A to give 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyl Ethyl}acetic acid (MRE-269), ESI-MS: m/z = 420.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 12.59 (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 = 6.8 Hz, 6H).

Preparation 2 Preparation of sodium 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}acetate (MRE-269-Na)

Under a nitrogen atmosphere, MRE-269 (4.19 g, 10.0 mmol) and NaOH (420 mg, 10.5 mmol) were suspended in 50 mL of THF and heated to reflux for 4 h. After cooling, most solvent was removed under reduced pressure, filtered, and washed with ethanol. Drying under vacuum gave 4.00 g of a yellow solid, 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}acetic acid sodium, yield : 90.7%, ESI-MS: m/z = 420.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 8.14 (s, 1H), 7.38-7.21 (m, 10H), 4.82 - 4.74 (m, 1H), 3.53 - 3.33 (m, 4H), 1.69 - 1.61 (m, 6H), 1.22 (d, J = 6.8 Hz, 6H).

Preparation 3 Preparation of 2-{2-[3-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)propoxy]ethoxy}acetic acid

The synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, the step 5, the step 1, the step 7 and the step 7 in the third embodiment, except that the 2-(N) in the preparation step 3 of the embodiment 3 is used. -Isopropylamino)ethanol was replaced with N-isopropylaminopropanol to give 2-{2-[3-(N-(5,6-diphenylpyrazin-2-yl)-N- as a yellow oil. Isopropylamino)propoxy]ethoxy}acetic acid, ESI-MS: m/z = 450.2 (M + H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 12.58 (s, 1H ), 8.16 (s, 1H), 7.38-7.23 (m, 10H), 4.80-4.75 (m, 1H), 3.98 (s, 2H), 3.61-3.50 (m, 8H), 1.88-1.83 (m, 2H) ), 1.22 (d, J = 7.2 Hz, 6H).

Preparation 4 Preparation of 2-{3-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid

The synthesis steps are the same as those in the preparation of the first step, the second step, the step 3, the step 4, the step 5, the step 1, the step 7 and the step 7. The only difference is that the bromoacetic acid tert-but in the preparation step 4 of the embodiment 3. Replacement of the ester with t-butyl bromopropionate afforded 2-{3-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino) Oxy]propoxy}acetic acid, ESI-MS: m/z = 450.2 (M + H) ⁺ ; ¹ H NMR (400 MHz, d _{6 -} DMSO) δ 12.58 (s, 1H), 8.16 (s, 1H) ), 7.39-7.24 (m, 10H), 4.81-4.76 (m, 1H), 3.97 (s, 2H), 3.61-3.50 (m, 8H), 1.89-1.84 (m, 2H), 1.22 (d, J) = 7.2 Hz, 6H).

Preparation 5 2-{4-[N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino]butoxy}-N-methanesulfonylacetamide (selexipag) Preparation

Prepared according to the method disclosed in Example 84 of the patent CN1516690A to give 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyl OH}}-N-methanesulfonylacetamide (selexipag), ESI-MS: m/z = 496.2 (M+H) ⁺ ; ¹ H NMR (400 MHz, d ₆ -DMSO) δ 11.71 (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 = 5.9 Hz, 2H), 3.49-3.39 ( m, 2H), 3.26 (s, 3H), 1.65 (d, J = 5.4 Hz, 4H), 1.23 (d, J = 6.7 Hz, 6H).

Test Example 1 In vitro platelet aggregation test

1. Purpose of the test

The anti-platelet aggregation activity of the compounds of the examples of the present invention was examined for the inhibition of ADP-induced platelet aggregation in vitro.

2, test materials

2.1 Test materials

Platelet aggregation instrument (Plymouth LBY-NJ type 4); ADP (sigma); DMSO, 0.9% sodium chloride injection, sodium hydroxide, blood collection tube, and the like.

2.2 Experimental animals

SD rat, male, 180-220g, provided by Chengdu Dashuo Biotechnology Co., Ltd., production license number: SCXK (chuan) 2014-028.

2.3 Test drugs

Examples 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 31, Compounds of 32, 37, 38, 42-54; compounds of Preparations 1, 2, 3, 4, 5.

3. Test method

3.1 Preparation of test solution

The above test drugs were weighed and prepared into a stock solution with a concentration of 200 mM in DMSO, fully dissolved and mixed, and the stock solution was aspirated, and 0.9% sodium chloride injection solution was separately added to prepare a series of different concentrations of the test solution. (0.64 μM-2000 μM);

3.2 Preparation of PRP and PPP

Rats who had not taken antiplatelet function drugs such as aspirin within 2 weeks were bled with a disposable vacuum blood collection tube (3.2% sodium citrate anticoagulation, anticoagulant to blood ratio 1:9). Transfer to a centrifuge tube, centrifuge at 1000 rpm for 10 min, carefully draw the upper layer of liquid is PRP, the remaining plasma is centrifuged at 3500 rpm for 10 min, and the supernatant is taken as PPP.

3.3 Preparation of ADP solution

The ADP was weighed and dissolved in 0.9% sodium chloride injection to prepare an ADP stock solution, which was dispensed into a centrifuge tube and frozen at -20 °C. Reconstituted before use, diluted to 300 μM with 0.9% sodium chloride injection for use.

3.4 Maximum aggregation rate detection

After the platelet aggregator was turned on, the temperature was raised to 37 ° C and the test was started. Add 270 μL of PRP and 30 μL of the test solution to the sample cup with the small magnetic bar, preheat for 5 min in the constant temperature well, and add 300 μL of PPP as the zero hole in the other cup. After preheating for 5 minutes, insert the PPP square cup into the test channel, press the channel key to automatically detect the zero point. After the value is stable, press the channel key, take out the PPP square cup, insert the PRP square cup, press the channel key after the value is stable, and the instrument displays ADP, use a micro-sampler to draw ADP into the bottom of the cup, press the channel button, the instrument starts testing. The test negative control was an equal volume of 0.9% sodium chloride injection. Compound IC ₅₀ calculated based on platelet aggregation rate of platelet aggregation.

4. Test results

Table 1 Example and preparation of compounds inhibiting platelet aggregation

受试药物Test drug	IC₅₀(μM)IC ₅₀ (μM)	受试药物Test drug	IC₅₀(μM)IC ₅₀ (μM)
制备例1Preparation Example 1	3030	实施例24Example 24	1010
制备例2Preparation Example 2	3030	实施例25Example 25	1515
制备例3Preparation Example 3	8787	实施例26Example 26	1010
制备例4Preparation Example 4	>100>100	实施例27Example 27	6.26.2
制备例5Preparation Example 5	>300>300	实施例28Example 28	8.88.8
实施例1Example 1	>100>100	实施例31Example 31	1212
实施例3Example 3	2.82.8	实施例32Example 32	>100>100
实施例4Example 4	22twenty two	实施例37Example 37	2.82.8
实施例5Example 5	>100>100	实施例38Example 38	1.21.2
实施例6Example 6	>100>100	实施例42Example 42	1.31.3
实施例7Example 7	>100>100	实施例43Example 43	1.51.5
实施例8Example 8	2020	实施例44Example 44	1.21.2
实施例9Example 9	1.21.2	实施例45Example 45	1.71.7
实施例10Example 10	1.01.0	实施例46Example 46	1717
实施例11Example 11	1.31.3	实施例47Example 47	1818
实施例12Example 12	8.58.5	实施例48Example 48	2020
实施例15Example 15	>100>100	实施例49Example 49	1515
实施例16Example 16	>100>100	实施例50Example 50	2626
实施例18Example 18	1.51.5	实施例51Example 51	23twenty three
实施例19Example 19	1.31.3	实施例52Example 52	4040
实施例20Example 20	1.71.7	实施例53Example 53	4040
实施例22Example 22	2020	实施例54Example 54	2020
实施例23Example 23	1212	//	//

It can be seen from the above test results that the compound of Preparation Example 1 and the sodium salt thereof (i.e., the compound of Preparation Example 2) have an IC _{50 for} inhibiting platelet aggregation in vitro of 30 μM, and Embodiments 3, 4, 8-12, and 18 of the present invention. -20,22-28,31,37,38,42-51,54 compound of platelet aggregation was inhibited, IC ₅₀ IC ₅₀ less than compound prepared in Example 1 and sodium salt, wherein, Example 3, The compounds of Example 9, Example 10, Example 11, Example 18, Example 19, Example 20, Example 37, Example 38, Example 42, Example 43, Example 44 and Example 45 were all When the order of magnitude difference is reached, it can be seen that the anti-platelet aggregation activity of the compounds of the examples of the present invention is significantly better than the compound of Preparation Example 1.

Further, the prodrug of Preparation Example 1 (i.e., the compound of Preparation Example 5) had no anti-platelet aggregation activity in vitro, and the prodrugs provided by the present application (i.e., the compounds of Examples 46-54) exhibited very good anti-platelet aggregation in vitro. Active, and detected by LC-MS, during the test Not degraded to the corresponding carboxylic acid structure product, indicating that the prodrugs provided herein are all active.

Test Example 2 Acute toxicity test in mice

1. Purpose of the test

The acute toxic effects of the compounds of Example 37, Example 38, Example 43 and Preparation Example 2 on mice were examined.

2. Materials and methods

2.1 Test materials

1 mL syringe, alcohol, cotton, anatomical scissors, anatomical files, mouse holders, etc.

2.2 Experimental animals

Kunming mice, all female, 22-25g, provided by Chengdu Dashuo Biotechnology Co., Ltd., license number: SCXK (chuan) 2014-028.

2.3 Preparation of test samples

The compound of Example 37, Example 38, and Example 43 and the compound of Preparation Example 2 were weighed and dissolved in a 0.9% sodium chloride injection solution to prepare an initial solution having a concentration of 30 mg/mL, and then the initial solution was separately diluted. 15 mg/mL, 5 mg/mL, and 0.5 mg/mL were used as test solutions.

3. Test method

3.1 grouping and dose selection

Kunming mice were randomly divided into 17 groups of 12 animals per group. The test was to perform acute toxicity tests on four compounds, each of which corresponded to four dose groups, 5 mg/kg, 50 mg/kg, 150 mg/kg, and 300 mg/kg; the blank group did not require injection.

Table 2 test grouping and dose selection scheme

3.2 mode of administration

A single dose of the test drug of the same volume was administered to the tail vein of the mouse.

3.3 Test observation

The condition of the mice was observed multiple times within 4 hours after administration, and thereafter observed once a day for 14 days, and the toxicity and death after a single administration were observed and recorded.

4. Test results

Table 3 results of acute toxicity test in mice

1 high dose group (300 mg/kg): After injecting the compounds of Example 37, Example 38 and Example 43, three mice in each group survived, while the mice in the compound group of the injection preparation example 2 were all Die immediately after administration;

2 medium-high dose group (150 mg/kg): After injecting the compounds of Example 37, Example 38 and Example 43, the dead mice of each group were 2, 2 and 3, respectively, and the compound group of the injection preparation example 2 was Nine mice died; at this dose, some animals in each group were able to observe symptoms such as shortness of breath, nasal secretions, and convulsions;

3 medium dose group (50mg/kg): no obvious symptoms of toxicity were observed;

4 low dose group (5 mg / kg): no obvious symptoms of toxicity were observed.

5 No toxicity symptoms were observed in the blank group, which proved that the test environment and spontaneous disease had no effect on the test.

It can be seen that the toxicity of the compounds of Example 37, Example 38 and Example 43 of the present invention is significantly lower than that of the compound of Preparation Example 2, confirming that the toxicity of the drug is significantly reduced after the introduction of the compound provided by the present invention into the ethylene glycol chain.

Test Example 3 in vitro hemolysis test

1. Purpose of the test

The hemolysis of the compound of the examples of the present invention and the compound of Preparation Example 2 was examined by in vitro hemolysis test.

2, test materials

Rabbit blood, centrifuge (beckman X-30R), constant temperature incubator (Shanghai Yiheng DHP-9162), glass rod, beaker, 0.9% sodium chloride injection, test tube, test tube rack, etc.

3. Test method

3.1 Preparation of test samples

20 mg of each of the compound of Example 37, Example 38, Example 39, Example 40, Example 42, Example 43, Example 44, and Example 45 and the compound of Preparation Example 2 were weighed in a centrifuge tube, respectively. 0.9% sodium chloride injection was dissolved to prepare a solution with a concentration of 1.6 mg/ml, and further diluted into a solution having a concentration of 0.8 mg/mL, 0.4 mg/mL, 0.2 mg/mL, and 0.1 mg/mL, respectively. Sample solution.

3.2 Preparation of red blood cell suspension

Approximately 10 mL of rabbit blood was collected in a clean beaker and stirred with a glass rod for 10 min to remove fibrinogen to defibrate the blood. Add 0.9% sodium chloride injection about 10 times, shake well, centrifuge at 1000 rpm for 10 min, remove the supernatant, and precipitate the red blood cells and wash them with 0.9% sodium chloride injection three times as described above until the supernatant is not red. Thus, the obtained red blood cells were mixed with a 0.9% sodium chloride injection to prepare a 2% (v/v) red blood cell suspension, and used.

3.3 Loading and observation

Take 2.5 mL of the above-mentioned different concentrations of the test solution in a clean glass test tube, add 2.5 mL of the above 2% red cell suspension as the test tube; and add 2.5 mL of 0.9% sodium chloride injection instead of the negative control tube. The test solution; the positive control tube was added with 2.5 mL of sterile water for injection instead of the test solution. Each test tube, negative control tube and positive control tube were mixed, placed in an incubator and allowed to stand in a temperature range of 37 ± 0.5 ° C. After 3 hours, the observation result was taken out from the incubator.

4. Test results

Table 4 Hemolysis test results

As a result of the in vitro hemolytic test, it can be seen that when the concentration of the compound of Preparation Example 2 is 0.05 mg/mL, partial hemolysis is observed, and complete hemolysis is achieved when the concentration reaches 0.1 mg/mL; Example 37, Example 38, and implementation of the present invention When the concentration of the compound of Example 39, Example 40, Example 42, Example 43, Example 44 and Example 45 reached 0.2 mg/mL, partial hemolysis was observed, and complete hemolysis was achieved when the concentration reached 0.4 mg/mL. It can be seen that, in terms of hemolysis in vitro, the safety of the compound of the examples of the present invention is higher than that of the compound of Preparation Example 2, indicating that the introduction of the compound of the present invention significantly reduces the risk of hemolysis of the drug after introduction of the ethylene glycol chain.

Test Example 4 Solution Stability

The compounds of Example 37, Example 38, Example 39, Example 40, Example 41, Example 42, Example 43, Example 44, and Example 45 and the compound of Preparation Example 2 were each weighed 90 mg each. In the centrifuge tube, respectively, dissolved in 0.9% sodium chloride injection and formulated into three different concentrations of 30mg/mL, 6.0mg/mL and 1.0mg/mL as the test solution; also prepared with 5% glucose solution Three different concentrations of solution were used as the test solution. The above test solution was allowed to stand at room temperature for 12 hours, and its stability was observed.

Table 5 solution stability investigation results

As can be seen from the above test results, after the compounds of the various embodiments of the present invention are dissolved in 5% glucose or 0.9% sodium chloride injection, the solutions of different concentrations can be kept clear at room temperature for a long time, and the preparation of Example 2 is After the compound was dissolved in 5% glucose or 0.9% sodium chloride injection, the three concentrations of the solution were allowed to stand at room temperature. After 12 hours, a white solid precipitate appeared, indicating that the compound of Preparation 2 was unstable in aqueous solution, visible, The introduction of the compound provided by the present invention significantly increases the stability of the aqueous solution of the drug after introduction of the ethylene glycol chain.

Test Example 5 Efficacy test of rat pulmonary hypertension model

1. Purpose of the test

A rat pulmonary hypertension model was established to evaluate the effects of each compound on pulmonary hypertension in rats.

2, test materials

2.1 Test materials

RM6240BD multi-channel physiological signal acquisition and processing system (Chengdu Instrument Factory), monocrotaline (sigma), 0.9% sodium chloride injection, syringe, rat fixator, polyethylene hose, surgical scissors, surgical fistula, etc.

2.2 Test animals

Adult male rats weighing 250-300 g, provided by Chengdu Dashuo Biotechnology Co., Ltd., license number: SCXK (chuan) 2014-028. After 3-5 days of quarantine, the quarantine is used for testing.

2.3 Preparation of test materials

The compound of Preparation Example 1, Example 3, the compound of Example 9, the compound of Example 18, the compound of Example 23, the compound of Example 46, and the compound of Example 49 were weighed and injected with 0.9% sodium chloride, respectively. The solution was dissolved and formulated into a solution having a concentration of 1 mg/mL.

3. Test method

3.1 grouping and processing

Table 6 Grouping and treatment of pulmonary hypertension model rats

3.2 observation and measurement of pulmonary artery pressure

The state of the rats was observed daily during the test. After the animals were modeled, the pulmonary artery pressure was measured after 15 days of treatment with each test drug described in Table 6 above.

4. Test results

4.1 Rat observation

The rats in the blank control group and the test drug-administered group had normal reaction, the body hair was clean, and the food was normal. Rats in the model group were generally weak, unresponsive, and reduced in activity.

4.2 Measurement of pulmonary artery pressure

Table 7 Measurement data of pulmonary artery pressure

分组Grouping	动物数(只)Number of animals (only)	mPAPmPAP
空白对照组Blank control group	1010	20.45±1.85^* 20.45±1.85 ^*
模型组Model group	1010	41.33±2.7941.33±2.79
制备例1的化合物给药组Preparation group of compound of Preparation Example 1	1010	25.54±2.26^* 25.54±2.26 ^*
实施例3的化合物给药组Compound administration group of Example 3	1010	20.92±2.16^# 20.92±2.16 ^#
实施例9的化合物给药组Compound administration group of Example 9	1010	21.94±2.10^# 21.94±2.10 ^#
实施例18的化合物给药组Compound administration group of Example 18	1010	20.63±1.76^# 20.63±1.76 ^#
实施例23的化合物给药组Compound administration group of Example 23	1010	21.39±1.97^# 21.39±1.97 ^#
实施例46的化合物给药组Compound administration group of Example 46	1010	22.17±2.31^# 22.17±2.31 ^#
实施例49的化合物给药组Compound administration group of Example 49	1010	21.15±1.85^# 21.15±1.85 ^#

Note: * Compared with the model group, P < 0.01; # compared with the preparation example 1 group, P < 0.05.

From the mean pulmonary artery pressure in the above table, it can be seen that the pulmonary artery pressure of the model group was significantly larger than that of the blank control group, and therefore, the model was successfully established. After the successful modeling, the average pulmonary artery pressure was significantly reduced after the administration of the test drug, and Example 3, Example 9, and Example 18, The effects of the compound administration group of Example 23, Example 46 and Example 49 were significantly better than those of the compound preparation group of Preparation Example 1 (P < 0.05).

Test Example 6 Platelet aggregation test in rats

1. Purpose of the test

The effects of the compounds of the various examples provided herein on platelet aggregation in rats were investigated.

2. Materials and methods

2.1 Test materials

DMSO, 0.9% sodium chloride injection, sodium hydroxide, ADP (sigma), blood collection tube (3.2% sodium citrate anticoagulation), platelet aggregation instrument (Plymouth LBY-NJ type 4).

2.2 Experimental animals

SD rat, 180-220g, male, provided by Chengdu Dashuo Biotechnology Co., Ltd., license number: SCXK (chuan) 2014-028. After 3-5 days of quarantine, the quarantine is used for testing.

2.3 Preparation of test materials

The compounds of Preparation Example 1, Example 3, Example 9, Example 18, and Example 23 were weighed and dissolved in 0.9% sodium chloride injection solution to prepare a solution having a concentration of 2.5 mg/ml.

3. Test method

15 rats that had not taken antiplatelet function drugs such as aspirin were randomly divided into 5 groups, 3 in each group, respectively, intravenously injected 10 mg/kg. Preparation Example 1, Example 3, Example 9, Example 18 and Examples 23 compounds. 10 min after injection, use a disposable vacuum blood collection tube (3.2% sodium citrate anticoagulation, anticoagulant to blood ratio of 1:9) 4.5 mL of abdominal aorta, transfer to a centrifuge tube, centrifuge at 1000 rpm for 10 min, be careful The upper layer of liquid is taken as PRP, and the remaining plasma is centrifuged at 3500 rpm for 10 min, and the supernatant is taken as PPP.

After the platelet aggregator was turned on, the temperature was raised to 37 ° C and the test was started. Add 300 μL of PRP to the sample cup with the small magnetic bar, preheat for 5 min in the constant temperature well, and add 300 μL PPP as the zero hole in the other cup. After preheating for 5 minutes, insert the PPP square cup into the test channel, press the channel key to automatically detect the zero point. After the value is stable, press the channel key, take out the PPP square cup, insert the PRP square cup, press the channel key after the value is stable, and the instrument displays ADP, use a micro-sampler to draw ADP into the bottom of the cup, press the channel button, the instrument starts testing. The negative control was an equal volume of 0.9% sodium chloride injection. Record the aggregation rate at the final time point.

Platelet aggregation inhibition rate = (1 - aggregation rate after administration / aggregation rate of negative control group) × 100%

4. Test results

Table 7 Platelet aggregation inhibition rate data in rats

组别Group	血小板聚集抑制率Platelet aggregation inhibition rate
制备例1的化合物给药组Preparation group of compound of Preparation Example 1	32.92±6.0432.92±6.04
实施例3的化合物给药组Compound administration group of Example 3	49.53±8.40^* 49.53±8.40 ^*
实施例9的化合物给药组Compound administration group of Example 9	52.5±5.68^* 52.5±5.68 ^*
实施例18的化合物给药组Compound administration group of Example 18	56.93±11.09^* 56.93±11.09 ^*
实施例23的化合物给药组Compound administration group of Example 23	63.76±10.65^* 63.76±10.65 ^*

Note: * Compared with the preparation example 1, P < 0.05, n = 3.

From the platelet aggregation inhibition rate data in rats, it was found that the compounds of Example 3, Example 9, Example 18, and Example 23 were significantly superior to the compound of Preparation Example 1 in inhibiting platelets in rats.

It will be apparent to those skilled in the art that various modifications and changes can be made to the compounds, compositions and methods of the present invention without departing from the spirit or scope of the invention. And variations are within the scope of the claims and their equivalents.

Claims

An aminopyrazine compound having the structure of the formula I or a pharmaceutically acceptable salt or isomer thereof:

among them,

e is 0, 1 or 2;

R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen-substituted C 1 -C 6 alkyl group, a halogen atom. Substituted C 1 -C 6 alkoxy, hydroxy, amine, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amine;

R 4 is selected from a hydrogen atom, a C 1 -C 6 alkyl group, a halogen-substituted C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 cycloalkyl group, a C 1 -C 6 alkane Acyl group

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a halogen atom-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylamino C 1 - C 6 alkyl, di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl, nitrile C 1 -C 6 alkyl;

Or, R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 are each bonded to a C 1 -C 6 alkyl substituted cyclopropane;

A and D are each independently selected from NR 15 , O, S, SO or SO 2 , wherein R 15 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 naphthenic ring base;

G is selected from the group consisting of a hydroxyl group, a C 1 -C 6 alkoxy group, an amine group, a C 1 -C 6 alkylamino group, a C 1 -C 6 alkylamido group, a C 1 -C 6 alkylsulfonylamino group, a halogen atom Substituted C 1 -C 6 alkylsulfonylamino, C 6 -C 10 arylsulfonylamino, C 1 -C 6 alkyl substituted C 6 -C 10 arylsulfonylamino, halogen substituted C 6 -C 10 arylsulfonylamino group.
The aminopyrazine compound according to claim 1 or a pharmaceutically acceptable salt or isomer thereof, wherein G is selected from the group consisting of a hydroxyl group, a C 1 -C 6 alkoxy group, an amine group, and a C 1 -C 6 alkane. Amino group, C 1 -C 6 alkylamido group, C 1 -C 6 alkylsulfonylamino group, C 6 -C 10 arylsulfonylamino group.
The aminopyrazine compound according to claim 1, or a pharmaceutically acceptable salt or isomer thereof, which has a structure represented by the formula Ib:

among them,

R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom-substituted C 1 -C 6 alkyl group;

R 4 is selected from the group consisting of a hydrogen atom, a C 1 -C 6 alkyl group, a halogen-substituted C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 cycloalkyl group;

R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkoxy group. C 1 -C 6 alkyl;

Or one or more pairs of R 5 and R 6 , R 7 and R 8 , R 9 and R 10 are bonded to form a cyclopropane;

R 11 and R 12 are hydrogen;

A and D are each independently selected from O, S, SO or SO 2 ;

G is selected from the group consisting of a hydroxyl group, a C 1 -C 6 alkoxy group, an amine group, a C 1 -C 6 alkylamino group, a C 1 -C 6 alkylamido group, a C 1 -C 6 alkylsulfonylamino group, a halogen atom Substituted C 1 -C 6 alkylsulfonylamino, C 6 -C 10 arylsulfonylamino, C 1 -C 6 alkyl substituted C 6 -C 10 arylsulfonylamino, halogen substituted C 6 -C 10 arylsulfonylamino group.
The aminopyrazine compound according to claim 3, or a pharmaceutically acceptable salt or isomer thereof, which is characterized in that:

R 1 , R 2 , and R 3 are each independently selected from a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a methoxy group, a halogen atom, and a trifluoromethyl group;

R 4 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl;

R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl;

Alternatively, R 9 and R 10 are linked to form a cyclopropane;

R 11 and R 12 are hydrogen;

A, D are independently selected from O or S;

G is selected from the group consisting of hydroxyl, methoxy, ethoxy, isopropoxy, butoxy, amine, methylamino, formamide, acetamido, methylsulfonyl, trifluoromethylsulfonamide , benzenesulfonylamino, p-toluenesulfonylamino, p-fluorobenzenesulfonylamino.
The aminopyrazine compound according to claim 4, or a pharmaceutically acceptable salt or isomer thereof, which is characterized in that:

R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a methyl group, a methoxy group, and a halogen atom;

R 4 is an isopropyl group;

R 9 and R 10 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl;

R 5 , R 6 , R 7 , R 8 , R 11 and R 12 are hydrogen;

A, D is O;

G is selected from the group consisting of a hydroxyl group, an amine group, an acetamide group, a methylsulfonylamino group, a trifluoromethylsulfonylamino group, a benzenesulfonylamino group, a p-toluenesulfonylamino group, and a p-fluorobenzenesulfonylamino group.
The aminopyrazine compound according to claim 1, or a pharmaceutically acceptable salt or isomer thereof, which has a structure represented by the formula II:

among them,

e is 0, 1 or 2;

R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen-substituted C 1 -C 6 alkyl group, a halogen atom. Substituted C 1 -C 6 alkoxy, hydroxy, amine, C 1 -C 6 alkylamino, di(C 1 -C 6 alkyl)amine;

R 4 is selected from a hydrogen atom, a C 1 -C 6 alkyl group, a halogen-substituted C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 cycloalkyl group, a C 1 -C 6 alkane Acyl group

R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a halogen atom-substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylamino C 1 - C 6 alkyl, di(C 1 -C 6 alkyl)amino C 1 -C 6 alkyl, nitrile C 1 -C 6 alkyl;

Or, R 5 and R 6 , R 7 and R 8 , R 9 and R 10 , R 11 and R 12 are each bonded to a C 1 -C 6 alkyl substituted cyclopropane;

A and D are each independently selected from NR 15 , O, S, SO or SO 2 , wherein R 15 is a hydrogen atom, a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 naphthenic ring base;

G is selected from the group consisting of hydroxyl, C 1 -C 6 alkoxy, amine, C 1 -C 6 alkylamino, C 1 -C 6 alkylamido, C 1 -C 6 alkylsulfonylamino, C 6 -C 10 arylsulfonylamino group.
The aminopyrazine compound according to claim 6, or a pharmaceutically acceptable salt or isomer thereof, which has a structure represented by the formula IIb:

among them,

R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom-substituted C 1 -C 6 alkyl group;

R 4 is selected from the group consisting of a hydrogen atom, a C 1 -C 6 alkyl group, a halogen-substituted C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 8 cycloalkyl group;

R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkoxy group. C 1 -C 6 alkyl;

Or one or more pairs of R 5 and R 6 , R 7 and R 8 , R 9 and R 10 are bonded to form a cyclopropane;

R 11 and R 12 are hydrogen;

A, D are each independently selected from O, S, SO or SO 2 ;

G is selected from the group consisting of hydroxyl, C 1 -C 6 alkoxy, amine, C 1 -C 6 alkylamino, C 1 -C 6 alkylamido, C 1 -C 6 alkylsulfonylamino, C 6 -C 10 arylsulfonylamino group.
The aminopyrazine compound according to claim 7, or a pharmaceutically acceptable salt or isomer thereof, which is characterized in that:

R 1 , R 2 , and R 3 are each independently selected from a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a methoxy group, a halogen atom, and a trifluoromethyl group;

R 4 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl;

R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl;

Alternatively, R 9 and R 10 are linked to form a cyclopropane;

R 11 and R 12 are hydrogen;

A, D are independently selected from O or S;

G is selected from the group consisting of hydroxyl, methoxy, ethoxy, isopropoxy, butoxy, amine, methylamino, formamide, acetamido, methylsulfonyl, and benzenesulfonyl.
The aminopyrazine compound according to claim 8, or a pharmaceutically acceptable salt or isomer thereof, which is characterized in that:

R 1 , R 2 and R 3 are each independently selected from a hydrogen atom, a methyl group, a methoxy group, and a halogen atom;

R 4 is an isopropyl group;

R 9 and R 10 are each independently selected from the group consisting of hydrogen, methyl, ethyl, and propyl;

R 5 , R 6 , R 7 , R 8 , R 11 and R 12 are hydrogen;

A, D is O;

G is selected from the group consisting of a hydroxyl group, an amine group, an acetamide group, a methylsulfonylamino group, and a benzenesulfonylamino group.
The aminopyrazine compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or isomer thereof, wherein the compound is selected from the group consisting of:

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-methylamino)ethoxy]ethoxy}acetic acid;

2-{2-[2-(N-(3-methyl-5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid;

(R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid;

(S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid;

2-{2-[1-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-oxy]ethoxy}acetic acid;

(R)-2-{2-[1-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-oxy]ethoxy } acetic acid;

(S)-2-{2-[1-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)propyl-2-oxy]ethoxy } acetic acid;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetic acid;

(R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetic acid;

(S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetic acid;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]pentyloxy}acetic acid;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-cyclopropylamino)ethoxy]ethoxy}acetic acid;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}acetic acid;

2-{1-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]cyclopropylmethoxy}acetic acid;

2-{2-[2-(N-(5,6-bis(p-fluorophenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid;

2-{2-[2-(N-(5,6-bis(p-methylphenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid;

2-{2-[2-(N-(5,6-bis(p-methoxyphenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid ;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethylthio]ethoxy}acetic acid;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethylsulfoxide]ethoxy}acetic acid;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethylsulfonyl]ethoxy}acetic acid;

2-{2-[2-(N-(5,6-bis(m-methylphenyl)pyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid; or

2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]ethoxy}acetic acid;

2-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]ethoxy}acetic acid;

N-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethyl}-N-isopropylglycine;

2-{2-[N-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethyl]-N-isopropylamine]ethoxylate } acetic acid;

N-{2-[N-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-methylamino)ethyl]-N-methylamine]ethyl} -N-methylglycine;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}propionic acid

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-2-fluoroacetic acid

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-2-methoxyacetic acid

2-{2-[2-(2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy)ethoxy]ethoxy} Acetic acid.
The aminopyrazine compound or a pharmaceutically acceptable salt or isomer thereof according to any one of claims 1 to 10, wherein the pharmaceutically acceptable salt is selected from the group consisting of an alkali metal salt, Such as sodium or potassium salts; alkaline earth metal salts, such as calcium salts; diethylamine salts, diethanolamine salts, meglumine salts, piperazine salts, choline salts, sulfates, hydrochlorides, nitrates, phosphates, Hydrofluoride, hydrobromide, acetate, trifluoroacetate, naphthoate, benzoate, tartrate, lactate, citrate, fumarate, maleate , malate, oxalate, succinate, methanesulfonate, ethanesulfonate, besylate, p-toluenesulfonate, naphthalenesulfonate, camphorsulfonate.
The aminopyrazine compound according to claim 11, or a pharmaceutically acceptable salt or isomer thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of:

Sodium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetate;

Sodium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetate;

(R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid sodium acetate;

(S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}acetic acid sodium acetate;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid hydrochloride;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetic acid potassium;

Sodium 2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetate;

(R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetate;

(S)-2-{2-[2-(N-(5,6-Diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]butoxy}acetate.
The aminopyrazine compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or isomer thereof, wherein the aminopyrazine compound is selected from the group consisting of the following prodrugs:

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-N-methanesulfonyl Amide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-N-benzenesulfonyl B Amide

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}-N-acetylacetamide ;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]ethoxy}acetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N -methanesulfonylacetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N - ethanesulfonyl acetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N -trifluoromethanesulfonylacetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N - phenylsulfonylacetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N - p-toluenesulfonylacetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}-N - p-fluorobenzenesulfonylacetamide;

(S)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}-N- Methanesulfonyl acetamide;

(R)-2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]propoxy}-N- Methanesulfonyl acetamide;

2-{2-[2-(N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino)ethoxy]-2-methylpropoxy}acetamide .
A method of producing an aminopyrazine compound or a pharmaceutically acceptable salt or isomer thereof according to any one of claims 3 to 5, wherein the method comprises the steps of:

The following compound of formula III and formula IV is refluxed in a solution of NaOH in methanol for 2-6 hours to form a compound of formula V, and then the compound of formula V is heated to reflux in POCl 3 to form a compound of formula VI;

Synthesizing the compound of the formula VI with a compound of the formula VII-B at a temperature of from 120 to 200 ° C for 8 to 48 h, preferably 8 to 20 h, to synthesize a compound of the formula VIII-B;

The compound of the formula VIII-B is reacted with a compound of the formula IX-B in a toluene KOH aqueous solution or a NaH in THF to form a compound of the formula X-B;

The compound of the formula XB is reacted in a solution of LiAlH 4 in THF for 2-6 hours to form a compound of the following formula XI-B, or directly reacted by the compound of the formula VI with a compound of the formula VII2-B below at 120-200 ° C. Synthesis of the compound of formula XI-B at 8-48 h, preferably 8-20 h;

The compound of the formula XI-B is reacted with a compound of the formula IX-A in a solution of toluene KOH or NaH in THF to form a compound of the formula XII-B, which is hydrolyzed to a compound of the formula Ib1 by LiOH. Further derivatized by the compound of formula Ib1 to a compound of formula Ib;

Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , A, D, G and claim 3 The definitions of the compounds shown by the formula Ib in 5 are the same.
The method according to claim 14, wherein the compound of the formula VII2-B is produced by any one selected from the group consisting of the following:

The compound of the formula VII2-B is synthesized by reacting a primary amine of the formula 4-B with a halogenated hydrocarbon R 4 X as follows;

The compound of the formula VII2-B is synthesized by reductive amination (NaB(CN)H 3 , NaB(OAc) 3 H or PtO 2 /H 2 ) with a primary amine of the formula 4-B and an alkane aldehyde as follows;

The corresponding bromo compound of the formula 2 is formed by reacting a primary amine of the formula VII with a reagent, carbon tetrabromide and triphenylphosphine, which is formed by reacting a bromo compound of the formula 2 with a methyl 2-hydroxy(amine or oxime)acetate. a compound of formula 3-B, followed by lithium aluminum hydride to reduce the compound of formula 3-B to form the compound of formula VII2-B;

Wherein R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , A, D are the same as defined in claim 14.
The use of the aminopyrazine compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or isomer thereof, for the preparation of an IP receptor agonist.
The use according to claim 16, wherein the IP receptor agonist is for treating or preventing a disease selected from the group consisting of pulmonary hypertension (PAH), arteriosclerosis obliterans, asthma and asthma symptoms, chronic obstructive pulmonary disease , Raynaud's phenomenon, scleroderma, CREST syndrome, systemic lupus erythematosus, rheumatoid arthritis, high arteritis, polymyositis and dermatomyositis, atrial septal defect, ventricular septal defect, cardiac fibrosis, pulmonary fibrosis /Pulmonary fibrosis, renal fibrosis, multiple sclerosis, thrombotic diseases associated with excessive platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, colic, stroke, cerebral ischemia, ischemia-reperfusion injury , atrial fibrillation, clot formation, atherosclerosis, diabetes-related disorders, type 1 diabetes, type 2 diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic complications, diabetic retina, glaucoma or Other eye diseases, abnormal hypertension, pre-eclampsia, inflammation with abnormal intraocular pressure; Undesirable side effects of COX-1, COX-2 and non-selective COX inhibitors; asthma, psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, acne , sepsis.