HK1134817B - Tetrahydro-imidazo[1,5-a]pyrazine derivatives, preparation methods and medical uses thereof - Google Patents

Abstract

The present invention relates to a tetrahydroimidazo [1,5-a] pyrazine derivative represented by general formula (I), its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, particularly as a dipeptidyl peptidase IV inhibitor, wherein the definitions of each substituent in general formula (I) are the same as those in the specification.

Description

Tetrahydroimidazo [1,5-a ] pyrazine derivative, preparation method and application thereof in medicine

Technical Field

The invention relates to a novel tetrahydroimidazo [1,5-a ] pyrazine derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, in particular as a dipeptidyl peptidase IV inhibitor.

Background

Diabetes mellitus is a metabolic disease of multiple etiologies characterized by chronic hyperglycemia accompanied by disturbances in the metabolism of sugars, fats and proteins due to defective insulin secretion and/or action. Diabetes is a very ancient disease, and is a disease that the concentration of glucose in blood is increased due to the absolute or relative lack of insulin in a human body, and then a large amount of sugar is discharged from urine, and symptoms such as polydipsia, diuresis, polyphagia, emaciation, dizziness, hypodynamia and the like appear.

Persistent or uncontrolled hyperglycemia leads to increased morbidity and mortality. Abnormal glucose homeostasis is often associated, directly or indirectly, with alterations in the metabolism of lipids, lipoproteins, apoproteins or other metabolic and hemodynamic disease. Type II diabetics are at significantly increased risk for conditions such as large porous liposomes and microvascular syndromes, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy and retinopathy. Therefore, it is very important to clinically treat diabetes by controlling the treatment of diseases such as glucose homeostasis, lipid metabolism, and hypertension.

Generally, there are two types of diabetes. Type I diabetics, i.e. Insulin Dependent Diabetes Mellitus (IDDM) patients, produce little or no insulin themselves. Insulin is a hormone used in the body to regulate glucose utilization. Type II diabetics, i.e. insulin independent diabetes mellitus (NIDDM) patients, have plasma insulin levels that are the same or higher than in non-diabetic patients, however, such patients develop resistance to insulin, which stimulates glucose and lipid metabolism in the major insulin sensitive tissue cells, such as muscle, liver, 25 adipose tissues, etc. Even with elevated plasma insulin levels, the patient's significant resistance to insulin cannot be overcome.

Insulin resistance is not primarily due to a reduction in the number of insulin receptors, but insulin receptor defects, the mechanism of which has not been understood to date. The insulin-responsive resistance results in failure of insulin to activate glucose uptake, oxidation, and storage in muscle tissue, to effectively inhibit lipolysis in adipose tissue, and to regulate glucose production and secretion in the liver.

Dipeptidyl peptidase-IV (DPPIV) is a serine protease that cleaves N-terminal dipeptidases in peptide chains containing a proline residue at the secondary terminus, and although the physiological role of DPPIV in mammals has not been fully demonstrated, it plays an important role in the metabolism of neurozymes, T-cell activation, cancer cell transfer into the endothelium, and entry of HIV virus into lymphoid cells (WO 98/19998).

Recently, it has been shown that DPPIV prevents secretion of glucagon-like peptide (GLP) -1, and in particular, it cleaves N-terminal group-propanedipeptidyl peptidase from GLP-1(7-36) NH in its active form₂Degradation to inactive GLP-1(9-36) NH₂(Endocrinology, 1999, 140: 5356-5363). Under physiological conditions, the half-life of complete GLP-1 in circulating blood is very short, and inactive metabolites of the DPPIV after degrading the GLP-1 can be combined with a GLP-1 receptor to antagonize the active GLP-1, so that the physiological reaction to the GLP-1 is shortened. The DPPIV inhibitor can completely protect endogenous and even exogenous GLP-1 from being inactivated by DPPIV, greatly improves the physiological activity of GLP-1 (by 5-10 times), and plays a good role in treating non-insulin-dependent diabetes mellitus (NIDDM) because GLP-1 is an important stimulator for the secretion of pancreatic insulin and can directly influence the distribution of glucose (US 6110949).

Several DPP-IV inhibitors have been disclosed (US5462928, US5543396, WO9515309, WO2003004498, WO2003082817, WO2004032836, WO2004085661), of which the DPPIV inhibitor MK-0431 produced by Merck shows good DPPIV inhibitory activity and selectivity and has been marketed in 2006.

However, although several DPPIV inhibitors have been disclosed, there is currently no long-acting drug and there is still a need for DPPIV inhibitors with improved properties.

The object of the present invention is to provide a compound which has an inhibitory activity on DPPIV and is useful as a therapeutic or alleviative drug for diabetes or the like.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention aims to provide a tetrahydroimidazo [1,5-a ] pyrazine compound shown in a general formula (I), and tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, metabolites and metabolic precursors or prodrugs thereof.

Wherein:

R¹selected from the group consisting of hydrogen, alkyl, trifluoromethyl, cycloalkyl, aryl or heteroaryl, wherein alkyl, heterocycloalkyl, aryl, heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, aryl, hydroxy or amino, preferably trifluoromethyl;

R²selected from hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or-NR⁴R⁵Wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, cyano, hydroxy, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, -NR⁴R⁵、-OC(O)OR⁸Substituted with a substituent of a carboxylic acid or carboxylic ester;

R³selected from a hydrogen atom or an alkyl group;

R⁴and R⁵Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the aryl group or the heteroaryl group is optionally further substituted with one or more groups selected from halogen, hydroxy, amino, alkoxy, alkyl, cyanoAryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxyalkyl, -SO₂R⁷、-NR⁴R⁵Substituted with a substituent of a carboxylic acid or carboxylic ester;

or, R⁴And R⁵Together form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O, S atoms, and the 4-8 membered heterocyclic group is optionally further substituted with one or more groups selected from halogen, hydroxy, amino, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO₂R⁷、-NR⁴R⁵、-C(O)NR⁴R⁵、-C(O)R⁷O, carboxylic acid or carboxylic acid ester;

R⁶selected from halogen, cyano, hydroxy, alkyl or alkoxy, wherein alkyl or alkoxy is unsubstituted or further substituted with one or more halogens;

R⁷is an alkyl group;

R⁸is alkyl or cycloalkyl.

The pharmaceutically acceptable salts described in the present invention are salts of the compounds of the present invention with an acid selected from the group consisting of: malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, or trifluoroacetic acid.

Typical compounds of the invention include, but are not limited to:

or a pharmaceutically acceptable salt thereof.

Further, the present invention includes compounds represented by the following general formula (IA) as intermediates in the synthesis of compounds of the general formula (I):

wherein:

ar is phenyl, which phenyl is unsubstituted or further substituted by 1 to 5R⁶Substituted;

R¹selected from the group consisting of hydrogen, alkyl, trifluoromethyl, cycloalkyl, aryl or heteroaryl, wherein alkyl, heterocycloalkyl, aryl, heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, aryl, hydroxy or amino, preferably trifluoromethyl;

R³selected from a hydrogen atom or an alkyl group;

R⁶selected from halogen, cyano, hydroxy, alkyl or alkoxy, wherein alkyl or alkoxy is unsubstituted or optionally further substituted by one or more halogens;

x is halogen.

Further, the present invention includes compounds represented by the following general formula (IB) as intermediates in the synthesis of compounds of the general formula (I):

wherein:

R¹selected from the group consisting of hydrogen, alkyl, trifluoromethyl, cycloalkyl, aryl or heteroaryl, wherein alkyl, heterocycloalkyl, aryl, heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, cyano, aryl, hydroxy or amino, preferably trifluoromethyl;

R²selected from hydroxy, amino, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or-NR⁴R⁵Wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of halogen, amino, cyano, hydroxy, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, -NR⁴R⁵、-OC(O)OR⁸Substituted with a substituent of a carboxylic acid or carboxylic ester;

R³selected from a hydrogen atom or an alkyl group;

R⁴and R⁵Each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocycloalkyl group, the aryl group or the heteroaryl group is optionally further substituted with one or more groups selected from halogen, hydroxy, amino, alkoxy, alkyl, cyano, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxyalkyl, -SO₂R⁷、-NR⁴R⁵Substituted with a substituent of a carboxylic acid or carboxylic ester;

or, R⁴And R⁵Together form a 4-8 membered heterocyclic group containing one or more membersN, O, S atoms and optionally further substituted on the 4-to 8-membered heterocycle with one or more substituents selected from the group consisting of halogen, hydroxy, amino, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO₂R⁷、 -NR⁴R⁵、-C(O)NR⁴R⁵、-C(O)R⁷Substituted with a substituent of a carboxylic acid or carboxylic ester;

R⁷is an alkyl group;

R⁸selected from alkyl or cycloalkyl.

In another aspect of the present invention there is provided a process for the preparation of a compound represented by Intermediate (IA), comprising the steps of:

dropwise adding anhydride into pyrazine 2-methylamine serving as a raw material in an ice bath, and reacting at room temperature to generate an amide product;

mixing and stirring the amide product and phosphorus oxychloride at room temperature, adding phosphorus pentoxide, heating, refluxing and condensing to generate an imidazo [1,5-a ] pyrazine ring;

imidazo [1, 5-a)]The pyrazine ring is reduced to generate R in ethanol solvent under the catalysis of palladium/carbon¹，R³Substituted tetrahydroimidazo [1,5-a ]]A pyrazine product;

r is to be¹，R³Substituted imidazo [1,5-a [ ]]Dissolving a pyrazine product in a dichloromethane solvent, and carrying out condensation reaction with carboxylic acid under the action of a condensing agent bis (2-oxo-3-oxazolidinyl) phosphoryl chloride and triethylamine;

the condensation product obtained reacts with halogenated succinimide in an absolute ethyl alcohol solvent at room temperature to generate an Intermediate (IA).

In another aspect of the present invention, there is a process for the preparation of a compound represented by Intermediate (IB), comprising the steps of:

r is to be¹Substituted imidazo [1,5-a [ ]]Pyrazine is hydrogenated and reduced in ethanol solvent at room temperature, then reacts with di-tert-butyl dicarbonate in ethanol solvent to protect amino, and R protected by amino is obtained¹Substituted tetrahydroimidazo [1,5-a ]]Pyrazine;

the resulting amino protected R¹Substituted tetrahydroimidazo [1,5-a ]]Pyrazine reacts with halogenated succinimide in an ethanol solvent at room temperature to obtain a halogenated product;

reacting the obtained halogenated product with octacarbonyl cobaltic and chloroacetate in a methanol solvent in an oil bath in a carbon monoxide atmosphere to obtain ester-substituted tetrahydroimidazo [1,5-a ] pyrazine;

hydrolyzing the obtained ester-substituted tetrahydroimidazo [1,5-a ] pyrazine into acid under alkaline condition;

reacting the obtained carboxylic acid compound with halogenated alkyl in a dry ice-acetone bath to obtain alkyl substituted acid;

the acid of the alkyl substitution product can be further esterified to obtain ketone substituted tetrahydroimidazo [1,5-a ] pyrazine;

alternatively, an alkyl substituted acid may be reacted with N-methoxymethyl amine in methylene chloride solvent under the action of the condensation reagent bis (2-oxo-3-oxazolidinyl) phosphorylidene chloride;

reacting a product obtained by condensation reaction with a Grignard reagent in a tetrahydrofuran solvent to obtain ketone-substituted tetrahydroimidazo [1,5-a ] pyrazine;

removing the amino protecting group of the ketone substituted tetrahydroimidazo [1,5-a ] pyrazine under an acidic condition to obtain an Intermediate (IB).

Further, another aspect of the present invention is a process for the preparation of compound (I) of formula (la), which process comprises:

the Intermediate (IA) reacts with chloroacetate in a methanol solvent under the action of octacarbonyl cobaltic acid in an oil bath in a carbon monoxide atmosphere, and then is hydrolyzed and acidified into carboxylic acid at room temperature under the alkaline condition;

the obtained carboxylic acid is reacted with amine or alcohol under the action of a condensation reagent at room temperature, or reacted with 1-halogenated carbonate, and then the amino protecting group is removed under an acidic condition to obtain the compound (I).

Another aspect of the present invention is a process for the preparation of compound (I) of formula (la), which process comprises the steps of:

and (3) condensing the Intermediate (IB) and carboxylic acid under the condition of a condensation reagent of bis (2-oxo-3-oxazolidinyl) phosphinic chloride, and further removing amino protecting groups from the obtained product under an acidic condition to obtain the compound (I) with the general formula.

Further, the preparation method of the compound (I) also comprises the acid addition product salt of the compound (I). Wherein the salt is formed by the compound and acid selected from the following: phosphoric acid, malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid, the preferred acid being hydrochloric acid.

The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

Further, the invention also relates to the application of the compound or the pharmaceutically acceptable salt thereof in preparing medicines for treating type II diabetes, hyperglycemia, obesity or insulin resistance.

One aspect of the present invention is a method of inhibiting the catalytic activity of dipeptidyl peptidase IV, characterized in that said dipeptidyl peptidase IV is contacted with a compound or salt according to any one of the general formulae (I).

Another aspect of the present invention is the use of a compound, salt or pharmaceutical composition according to any one of the general formula (I) for the treatment of type II diabetes, hyperglycemia, obesity or insulin resistance.

Detailed description of the invention

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups having 1 to 10 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like are preferred. More preferred is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, or the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more, independently selected from halogen, hydroxy, amino, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO₂R⁷、-NR⁴R⁵、-C(O)NR⁴R⁵、-C(O)R⁷、-OC(O)OR⁸Carboxylic acid or carboxylic acid ester.

"cycloalkyl" refers to a 3 to 8 membered all carbon monocyclic, all carbon 5/6 or 6/6 membered fused or polycyclic fused ring (by "fused" ring system is meant that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system) group, wherein one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more, independently selected from halogen, hydroxy, amino, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO₂R⁷、-NR⁴R⁵、-C(O)NR⁴R⁵、-C(O)R⁷Carboxylic acid or carboxylic acid ester.

"aryl" refers to a group having at least one aromatic ring structure, i.e., an aromatic ring having a conjugated pi-electron system, including carbocyclic aryl, heteroaryl, and biaryl groups. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more, independently selected from haloElements, hydroxy, amino, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO₂R⁷、-NR⁴R⁵、-C(O)NR⁴R⁵、-C(O)R⁷Carboxylic acid or carboxylic acid ester.

"heteroaryl" refers to an aryl group having 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, the heteroatoms including oxygen, sulfur and nitrogen. The ring may be a 5-or 6-membered ring. Examples of heterocyclic aryl groups include furyl, thienyl, pyridyl, pyrrole, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, and the like. Heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more, independently selected from halogen, hydroxy, amino, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO₂R⁷、-NR⁴R⁵、-C(O)NR⁴R⁵、-C(O)R⁷Carboxylic acid or carboxylic acid ester.

"heterocycloalkyl" refers to a monocyclic or fused ring radical having 5 to 9 ring atoms in the ring, wherein one or two ring atoms are selected from nitrogen, oxygen, or a heteroatom of S (O) n (wherein n is an integer from 0 to 2), the remaining ring atoms being carbon. These rings may also have one or more double bonds. However, these rings do not have a completely conjugated pi-electron system. Unsubstituted heterocycloalkyl groups include, but are not limited to, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino, and the like, heterocycloalkyl groups can be substituted or unsubstituted. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more, independently selected from halogen, hydroxy, amino, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO₂R⁷、-NR⁴R⁵、-C(O)NR⁴R⁵、-C(O)R⁷Carboxylic acid or carboxylic acid ester.

"hydroxy" refers to an-OH group.

"alkoxy" means-O- (alkyl) and-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. Alkoxy groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more, independently selected from halogen, hydroxy, amino, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO₂R⁷、-NR⁴R⁵、-C(O)NR⁴R⁵、-C(O)R⁷Carboxylic acid or carboxylic acid ester.

"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

"trifluoromethyl" means-CF₃。

"amino" means-NH₂。

"cyano" means-CN.

"carbonyl" refers to C (═ O).

"carboxylic acid" refers to (alkyl) C (═ O) OH.

"carboxylate" refers to (alkyl) C (═ O) O (alkyl).

"hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group.

"pharmaceutical composition" means a mixture of one or more compounds described herein or physiologically/pharmaceutically acceptable salts or prodrugs thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

Synthesis of the Compounds of the invention

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

the preparation method of the compound (I) with the general formula comprises the following steps:

dripping acid anhydride into raw material pyrazine 2-methylamine in an ice bath, and reacting at room temperature to generate an amide product; mixing and stirring the amide product and phosphorus oxychloride at room temperature, adding phosphorus pentoxide, heating, refluxing and condensing to generate imidazo [1,5-a ]]A pyrazine ring; imidazo [1, 5-a)]The pyrazine ring is reduced by hydrogen to generate R in an ethanol solvent under the catalysis of palladium/carbon¹Substituted tetrahydroimidazo [1,5-a ]]A pyrazine product; r is to be¹Substituted tetrahydroimidazo [1,5-a ]]The pyrazine product is in methylene dichloride solvent and is in condensation reaction with carboxylic acid under the action of condensation reagent bis (2-oxo-3-oxazolidinyl) phosphoryl chloride and triethylamine; the obtained condensation product reacts with halogenated succinimide in an absolute ethyl alcohol solvent at room temperature to generate a compound (IA) with a general formula; reacting the intermediate compound (IA) with chloroacetate in a methanol solvent under the action of octacarbonyl cobaltic acid in an oil bath in a carbon monoxide atmosphere, and hydrolyzing the reaction product at room temperature under an acidic condition to obtain carboxylic acid; the obtained carboxylic acid compound is reacted with amine or alcohol under the action of a condensation reagent at room temperature, or reacted with 1-halogenated carbonate, and then amino protecting groups are removed under an acidic condition to obtain the compound (I).

The preparation method of the compound (I) with the general formula comprises the following steps:

mixing the raw material R¹Substituted tetrahydroimidazo [1,5-a ]]Pyrazine is hydrogenated and reduced in ethanol solvent at room temperature, and then reacts with di-tert-butyl dicarbonate in ethanol solvent to obtain amino-protected R¹Substituted tetrahydroimidazo [1,5-a ]]Pyrazine; the obtained amino acid esterR of Protect¹Substituted tetrahydroimidazo [1,5-a ]]Pyrazine reacts with halogenated succinimide in an ethanol solvent at room temperature to obtain a halogenated product; reacting the obtained halogenated product with octacarbonyl cobaltic and chloroacetate in a methanol solvent under the condition of oil bath in the atmosphere of carbon monoxide to obtain ester-substituted tetrahydroimidazo [1,5-a]Pyrazine; the obtained ester-substituted tetrahydroimidazo [1,5-a ]]Pyrazine is hydrolyzed to acid under alkaline conditions;

reacting the obtained carboxylic acid compound with halogenated alkyl in a dry ice-acetone bath to obtain an alkyl substituted product; the carboxyl in the alkyl substitution product can be further esterified to obtain an Intermediate (IB); the obtained carboxylic acid compound can also react with N-methoxy methylamine in a dichloromethane solvent under the action of a condensation reagent of bis (2-oxo-3-oxazolidinyl) phosphoryl chloride; reacting a product obtained by condensation reaction with a Grignard reagent in a tetrahydrofuran solvent to obtain ketone-substituted tetrahydroimidazo [1,5-a ] pyrazine; removing amino protecting group from ketone substituted tetrahydroimidazo [1,5-a ] pyrazine under acidic condition to obtain a compound (IB) with a general formula; and (3) condensing the intermediate general formula compound (IB) and carboxylic acid under the condition of a condensation reagent of bis (2-oxo-3-oxazolidinyl) phosphinic chloride, and further removing an amino protecting group from the obtained product under an acidic condition to obtain the general formula compound (I).

The compound (I) with the general formula is purified and then reacts in a methanol, dichloromethane or ethyl acetate solution of acid to obtain an acid addition product salt.

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

Examples

The structure of the compound is determined by nuclear magnetic resonance¹HNMR) or Mass Spectrometry (MS).¹HNMR shift (δ) is given in units of parts per million (ppm).¹HNMR was measured by Bruker AVANCE-400 NMR spectrometer using deuterated methanol (CD)₃OD), deuterated chloroform (CDCl)₃) Internal standard of hexadeuterio dimethyl sulfoxide (DMSO-d6) is Tetramethylsilane (TMS), and chemical shift is 10^-6(ppm) is given as a unit;

MS measurements were carried out using a FINNIGAN LCQad (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX;

IC₅₀the values were measured using a NovoStar microplate reader (BMG, Germany);

the thin silica gel layer is made of HSGF254 silica gel plate of yellow sea of tobacco station or GF254 silica gel plate of Qingdao;

the column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

In the examples, the reaction was carried out under a nitrogen atmosphere unless otherwise specified.

The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

Example 1

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester hydrochloride

First step of

2, 2-dimethyl-5- [2- (2, 4, 5-trifluorophenyl) -acetyl ] - [1, 3] dioxane-4, 6-dione

2, 2-dimethyl- [1, 3] dioxane-4, 6-dione (5.69g, 39.5mmol) was dissolved in 400mL of dichloromethane with stirring, and under cooling in an ice bath, a suspension of 2, 4, 5-trifluorophenylacetic acid 1a (7.15g, 37.6mmol) and p-dimethylaminopyridine (7.35g, 60.2mmol) was added dropwise slowly to the mixture, and after stirring at room temperature for 36 hours, the reaction mixture was washed with a 5% potassium hydrogensulfate solution (250 mL. times.7) and a saturated sodium chloride solution (250 mL. times.2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 2, 2-dimethyl-5- [2- (2, 4), 5-trifluorophenyl) -acetyl ] - [1, 3] dioxane-4, 6-dione 1b (11.4g, white solid), yield: 96 percent.

MS m/z(ESI)：315.5(M-1)。

Second step of

3-oxo-4- (2, 4, 5-trifluorophenyl) -butyric acid ethyl ester

2, 2-dimethyl-5- [2- (2, 4, 5-trifluorophenyl) -acetyl ] - [1, 3] dioxane-4, 6-dione 1b (15.72g, 49.6mmol) was dissolved in 280mL ethanol with stirring and stirred in an oil bath at 70 ℃ overnight. Cooled, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product, ethyl 3-oxo-4- (2, 4, 5-trifluorophenyl) -butyrate 1c (12g, yellow liquid), yield: 88 percent.

MS m/z(ESI)：259(M-1)。

The third step

3-amino-4- (2, 4, 5-trifluorophenyl) -but-2-enoic acid ethyl ester

Dissolving 3-oxo-4- (2, 4, 5-trifluorophenyl) -ethyl butyrate 1c (24.6g, 94.5mmol) in 240mL of methanol, adding ammonium acetate (36.4g, 473mmol), heating under reflux for 3 hours, following the reaction by thin layer chromatography until the starting material disappears, concentrating the reaction solution under reduced pressure, adding 100mL of water, extracting with ethyl acetate (200 mL. times.3), combining the organic phases, washing with 200mL of saturated sodium chloride solution in sequence, drying over anhydrous magnesium sulfate, filtering, adding 50mL of ethyl acetate to the pale yellow solid obtained by concentrating the filtrate under reduced pressure, dissolving at 80 ℃, adding 50mL of n-hexane, seeding, cooling to room temperature, adding 100mL of n-hexane after 0.5 hour, placing in a refrigerator overnight, suction filtering to obtain the title product ethyl 3-amino-4- (2, 4, 5-trifluorophenyl) -but-2-enoate 1d (19.5g, white solid), yield: 80 percent.

MS m/z(ESI)：260.1[M+1]

The fourth step

3-Boc-amino-4- (2, 4, 5-trifluorophenyl) -butyric acid ethyl ester

3-oxo-4- (2, 4, 5-trifluorophenyl) -butyric acid ethyl ester 1d (4.1g, 15.8mmol) was charged into an autoclave, and 70mL of methanol, di-tert-butyl dicarbonate (3.8g, 17.4mmol), chloro (1, 5-cyclooctadiene) rhodium (I) dimer (32mg, 0.0632mmol) and (R) -1- [ (S) -2- (diphenylphosphino) ferrocenyl ] -ethyl-tert-butylphosphine (68mg, 0.126mmol) were further added, and reacted at 30 ℃ under 6.67 atmospheres of hydrogen for 24 hours. Filtration and concentration of the filtrate under reduced pressure, addition of 34mL of methanol at 50 ℃, complete dissolution and addition of 12mL of water, standing to room temperature, overnight in a refrigerator, filtration, washing of the solid product with a mixed solvent of methanol/water (v: v ═ 3: 2), drying in vacuo to give the title product 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyric acid ethyl ester 1e (4g, pale yellow solid), yield: 70 percent.

MS m/z(ESI)：362.4[M+1]。

The fifth step

(R) -3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyric acid

After 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyric acid ethyl ester 1e (10g, 27.7mmol) and sodium hydroxide (3.32g, 83.1mmol) were dissolved in a mixed solvent of 100mL of methanol and 50mL of water with stirring, reacted at 40-45 ℃ for 1-1.5 hours, the solvent was partially removed by concentration under reduced pressure, a small amount of water was added, the solution was adjusted to pH 2-3 by adding 1N hydrochloric acid under ice bath, extracted with ethyl acetate (200 mL. times.3), the organic phases were combined, washed with 200mL of a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and recrystallized with ethyl acetate/N-hexane to give the title product (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyric acid 1f (9.2g, white solid) was used directly in the next reaction.

MS m/z(ESI)：332.3[M-1]。

Reference documents: tetrahedron Asymmetry, 2006, 17(2), 205-

The sixth step

C-pyrazin-2-yl-methylamines

1g (10.5g, 100mmol) of 2-cyanopyrazine was dissolved in 150mL of 1, 4-dioxane with stirring, and 1.0g of Raney nickel was added to a 250mL autoclave and reacted at 60 ℃ under 40 atm of hydrogen for 8 hours. Filtration and concentration of the filtrate under reduced pressure gave the title product C-pyrazin-2-yl-methylamine in 1h (10.7g, brown oil) yield: 98 percent.

MS m/z(ESI)：110[M+1]。

Seventh step

2, 2, 2-trifluoro-N-pyrazine-2-methyl-carboxamides

C-pyrazin-2-yl-methylamine was added to a reaction flask for 1h (10.9g, 100mmol), cooled to 0 ℃ in an ice bath, 20mL trifluoroacetic anhydride was slowly added dropwise over 1h, stirred at room temperature for 2 h, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography to give the title product 2, 2, 2-trifluoro-N-pyrazine-2-methyl-carboxamide 1i (21.0g, brown oil).

MS m/z(ESI)：206.1[M+1]。

Eighth step

3-trifluoromethyl-imidazo [1,5-a ] pyrazines

2, 2, 2-trifluoro-N-pyrazine-2-methyl-formamide 1i (21.0g, 100mmol) is added into a reaction bottle at room temperature, adding 100mL of phosphorus oxychloride, stirring at room temperature for 30 minutes, adding phosphorus pentoxide (17.8g, 125mmol), heating and refluxing for 5 hours, the thin layer chromatography followed the reaction until the starting material disappeared, removed the solvent phosphorus trichloride, the reaction system quenched with deionized water, adjusted the pH to 5-6 with 20% sodium hydroxide solution in ice bath, extracted with ethyl acetate (250mL × 4), combined the organic phases, dried with anhydrous magnesium sulfate, filtered, concentrated the filtrate under reduced pressure, purified with silica gel column chromatography to give the title product 3-trifluoromethyl-imidazo [1,5-a ] pyrazine 1j (12.0g, yellow solid), yield: 65 percent.

MS m/z(ESI)：188.0[M+1]。

¹HNMR(400MHz，CDCl₃)：δ9.15(s，1H)，8.06(d，1H)，7.92(s，1H)，7.81(d，1H)

The ninth step

3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazines

3-trifluoromethyl-imidazo [1,5-a ] pyrazine 1j (12.0g, 64.2mmol) was dissolved in 150mL of anhydrous ethanol with stirring, and 500mg of 10% palladium on carbon was added and stirred under a hydrogen atmosphere overnight. The reaction was filtered through crude silica gel, and the filtrate was concentrated under reduced pressure to give the title product 3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine 1k (12.2g, brown solid) in yield: 99 percent.

¹HNMR(400MHz，CDCl₃)：δ6.84(s，1H)，4.10(m，4H)，3.26(m，2H)，1.81(s，1H)

The tenth step

(R) - [ 3-oxo-1- (2, 4, 5-trifluorobenzyl) -3- (3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -propyl ] -carbamic acid tert-butyl ester

Under nitrogen, 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyric acid 1k (8.6g, 45mmol) and 9.4mL of triethylamine were dissolved in 300mL of dichloromethane with stirring, and after stirring at room temperature for 5 minutes, 3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine 1f (15.0g, 45mmol) and bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (17.1g, 67.3mmol) were sequentially added, followed by reaction at room temperature for 2 hours, followed by thin layer chromatography until the starting material disappeared, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [ 3-oxo-1- (2, 4, 5-trifluorobenzyl) -3- (3-trifluoromethyl-5), 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -propyl ] -carbamic acid tert-butyl ester 1l (20.0g, white solid), yield: 88 percent.

¹HNMR(400MHz，CD₃OD)：δ7.25(m，1H)，7.11(m，1H)，7.032(s，1H)，4.93(m，2H)，4.35(m，3H)，4.05(m，2H)，2.99(m，2H)，2.73(m，2H)，1.34(s，9H)

The eleventh step

(R) - [ 3-oxo-1- (2, 4, 5-trifluorobenzyl) -3- (1-bromo-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -propyl ] -carbamic acid tert-butyl ester

(R) - [ 3-oxo-1- (2, 4, 5-trifluorobenzyl) -3- (3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -propyl ] -carbamic acid tert-butyl ester 1l (20.0g, 39.6mmol) was dissolved with stirring in 300mL of anhydrous ethanol, N-bromosuccinimide (14.1g, 79.2mmol) was added at room temperature, stirring was continued for 1 hour, potassium carbonate (10.9g, 79.2mmol) and di-tert-butyl dicarbonate (8.6g, 39.6mmol) were added, after 1 hour of reaction, the reaction was followed by thin layer chromatography until the starting material disappeared, the crude silica gel was filtered, the potassium carbonate was removed, the filtrate was concentrated, the resulting residue was purified by silica gel column chromatography under reduced pressure to give the title product (R) - [ 3-oxo-1- (2, 4, 5-trifluorobenzyl) -3- (1-bromo-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -propyl ] -carbamic acid tert-butyl ester 1m (20.0g, white solid), yield: 86 percent.

¹HNMR(400MHz，CDCl₃)：δ7.063(m，1H)，6.88(m，1H)，4.72(s，1H)，4.56(s，1H)，4.13(m，3H)，3.88(m，2H)，2.94(m，2H)，2.62(m，2H)，1.36(s，9H)

The twelfth step

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester

Dicobalt octacarbonyl (4.02g, 11.76mmol), ethyl chloroacetate (0.71g, 5.88mmol), potassium carbonate (1.62g, 11.76mmol) and 50mL of methanol were placed in a reaction flask, and after stirring for 5 minutes, (R) - [ 3-oxo-1- (2, 4, 5-trifluorobenzyl) -3- (1-bromo-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -propyl ] -tert-butyl carbamate 1m (2.3g, 3.92mmol) was added and reacted at 60 ℃ in an oil bath to change the color from dark brown to purple, ESI tracing the reaction after 2 hours was completed and the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -7- [ 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester 1n (1.1g, white solid), yield: 50 percent.

MS m/z(ESI)：565.0(M+1)。

Reference documents: journal of Organometallic Chemistry, 1985, 285(1-3), 293-S303

Thirteenth step

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester hydrochloride

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester 1N (0.12g, 2.12mmol) was added to 5mL of a 2.2N solution of hydrogen chloride in ethyl acetate, and after 5 hours at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester hydrochloride 1(0.12g, light yellow solid), yield: 94.3 percent.

MS m/z(ESI)：465.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.101-7.08(m，1H)，6.906-6.864(m，1H)，5.343-4.995(m，2H)，4.221-4.093(m，5H)，3.954(s，3H)，2.978-2.937(m，2H)，2.71-2.643(m，2H)，2.061(s，2H)。

Example 2

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (2-methanesulfonyl-ethyl) -carboxamide hydrochloride

First step of

(R) -7- [ 3-tert-Butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid

(R) -7- [ 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester 1N (2.0g, 3.5mmol) was dissolved in 50mL of methanol with stirring, 30mL of 4N sodium hydroxide solution was added, after 1 hour at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, 2N hydrochloric acid was added to adjust the pH of the reaction solution to 3, the reaction solution was extracted with ethyl acetate (50 mL. times.4), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product (R) -7- [ 3-tert-butoxycarbonyl-4- (2, 4), 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (1.9g, light yellow solid).

¹HNMR(400MHz，CD₃OD)：δ7.29-7.226(m，1H)，7.121-7.082(m，1H)，5.151-5.028(m，2H)，4.409-4.064(m，5H)，2.984-2.769(m，4H)，1.417-1.255(m，9H)。

Second step of

(R) - [3- [1- (2-methanesulfonyl-ethylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.15g, 0.27mmol), 2-methanesulfonamoethylamine (65.5mg, 0.41mmol) and bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (0.104g, 0.41mmol) were dissolved in 5mL of dichloromethane with stirring, triethylamine (0.25mL, 1.62mmol) was added, the reaction was allowed to react overnight at room temperature, the reaction was followed by thin layer chromatography until the raw material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- (2-methanesulfonyl-ethylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 2b (60mg, white solid), yield: 34 percent.

MS m/z(ESI)：678.2(M+23)。

Reference documents: journal of Organic Chemistry, 2006, 71(3), 1220-

The third step

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (2-methanesulfonyl-ethyl) -carboxamide hydrochloride

(R) - [3- [1- (2-methanesulfonyl-ethylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 2b (0.06g, 0.091mmol) was dissolved in a small amount of ethyl acetate, 4mL of a 3.1N solution of hydrogen chloride in ethyl acetate was added, after 4 hours of reaction at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-Tetrahydroimidazo [1,5-a ] pyrazine-1- (2-methanesulfonyl-ethyl) -carboxamide hydrochloride 2(60mg, white solid).

MS m/z(ESI)：556.3(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.44-7.35(m，1H)，7.30-7.21(m，1H)，5.15-5.02(m，2H)，4.53-4.45(m，2H)，4.34-4.27(m，2H)，4.05-3.94(m，4H)，3.89-3.62(s，4H)，3.12-3.07(m，2H)，3.03-2.82(m，2H)。

Example 3

(R) -3-amino-1- [1- (morpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

(R) - [3- [1- (morpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (60mg, 0.109mmol), morpholine (19mg, 0.218mmol) and bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (53.5mg, 0.218mmol) were dissolved in 5mL of dichloromethane with stirring, triethylamine (0.1mL, 0.65mmol) was added, the reaction was allowed to proceed overnight at room temperature, the reaction mixture was concentrated under reduced pressure until the starting material disappeared, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- (morpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 3a (60mg, white solid), yield: 89 percent.

MS m/z(ESI)：620.0(M+1)。

Second step of

(R) -3-amino-1- [1- (morpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

(R) - [3- [1- (morpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 3a (0.07g, 0.11mmol) was dissolved in a small amount of ethyl acetate, 6mL of a 3.1N solution of hydrogen chloride in ethyl acetate was added, and after 4 hours at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product (R) -3-amino-1- [1- (morpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -but-1-one hydrochloride 3(70mg, light yellow solid).

MS m/z(ESI)：520.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.42-7.37(m，1H)，7.26-7.22(m，1H)，5.15-5.05(m，2H)，4.53-4.44(m，2H)，4.34-4.26(m，2H)，4.02-3.94(m，4H)，3.89-3.84(m，1H)，3.76-3.61(m，4H)，3.11-3.06(m，2H)，3.05-2.83(m，2H)。

Example 4

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (cyanomethyl) -carboxamide hydrochloride

First step of

(R) - [3- [1- (cyanomethyl-carbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), aminoacetonitrile sulfate (85mg, 0.41mmol), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (0.206g, 0.81mmol) and triethylamine (0.37mL, 2.7mmol) were dissolved in 10mL of dichloromethane with stirring, reacted overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- (cyanomethyl-carbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 4a (150mg, white solid), yield: 94.4 percent.

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (cyanomethyl) -carboxamide hydrochloride

(R) - [3- [1- (cyanomethyl-carbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 4a (0.3g, 0.25mmol) was dissolved in 10mL of dichloromethane, 5mL of trifluoroacetic acid was added, and after 1 hour of reaction at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-Tetrahydroimidazo [1,5-a ] pyrazine-1- (cyanomethyl) -carboxamide hydrochloride 4(130mg, light yellow solid).

MS m/z(ESI)：489.2(M+1)。

Example 5

(R) -3-amino-1- [1- (4-methyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one dihydrochloride

First step of

(R) - [3- [1- (4-methyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), 1-methylpiperazine (54mg, 0.54mmol) and bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (0.138g, 0.54mmol) were dissolved in 8mL of dichloromethane with stirring, triethylamine (0.25mL, 1.62mmol) was added, the reaction was allowed to react overnight at room temperature, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- (4-methyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 5a (80mg, white solid), yield: 49 percent.

MS m/z(ESI)：633.2(M+1)。

Second step of

(R) -3-amino-1- [1- (4-methyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one dihydrochloride

(R) - [3- [1- (4-methyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 5a (0.08g, 0.126mmol) was dissolved in 6mL of a 3.1N solution of hydrogen chloride in ethyl acetate, and after overnight reaction at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction was concentrated under reduced pressure to give the title product (R) -3-amino-1- [1- (4-methyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one dihydrochloride 5(90mg, white solid).

MS m/z(ESI)：533.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.45-7.38(m，1H)，7.27-7.23(m，1H)，5.10-5.05(m，2H)，4.35-4.28(m，2H)，4.10-4.09(m，1H)，4.00-3.95(m，2H)，3.68-3.56(m，4H)，3.35-3.24(m，4H)，3.13(m，2H)，3.00-2.88(m，5H)。

Example 6

(R) -3-amino-1- [1- (1, 1-dioxo-thiomorpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

(R) - [3- [1- (1, 1-dioxo-thiomorpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), thiomorpholine-1, 1-dioxide hydrochloride (73mg, 0.54mmol), bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (0.138g, 0.54mmol) and triethylamine (0.25mL, 1.62mmol) were dissolved with stirring in 8mL of dichloromethane, 4mL of N, N-dimethylformamide was added, the reaction was allowed to react overnight at room temperature, the thin layer chromatography followed the reaction until the raw material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- (1, 1-dioxo-thiomorpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 6a (170mg, white solid), yield: 94 percent.

MS m/z(ESI)：668.1(M+1)。

Second step of

(R) -3-amino-1- [1- (1, 1-dioxo-thiomorpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

(R) - [3- [1- (1, 1-dioxo-thiomorpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 6a (0.15g, 0.22mmol) is dissolved in 4mL of a 3.1N solution of hydrogen chloride in ethyl acetate, reacted overnight at room temperature, followed by thin layer chromatography until the starting material disappears, and the reaction solution is concentrated under reduced pressure to give the title product (R) -3-amino-1- [1- (1, 1-dioxo-thiomorpholine-4-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -but-1-one hydrochloride 6(140mg, light yellow solid).

MS m/z(ESI)：568.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.45-7.39(m，1H)，7.29-7.20(m，1H)，5.10-5.04(m，2H)，4.35-4.28(m，2H)，4.16-4.09(m，2H)，4.02-3.93(m，5H)，3.27-3.13(m，4H)，3.18-3.04(m，2H)，2.99-2.85(m，2H)。

Example 7

(R) -1- {7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperidine-4-carboxamide hydrochloride

First step of

(R) - [3- [1- (4-carbamoyl-piperidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), 4-carbamoylpiperidine (70mg, 0.54mmol) and bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (0.138g, 0.54mmol) were dissolved with stirring in 8mL of dichloromethane, triethylamine (0.25mL, 1.62mmol) was added, 4mLN, N-dimethylformamide was further added, the reaction was allowed to proceed overnight at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- (4-carbamoyl-piperidine-1- Carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 7a (180mg, white solid), yield: 98 percent.

MS m/z(ESI)：660.9(M+1)。

Second step of

(R) -1- {7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperidine-4-carboxamide hydrochloride

(R) - [3- [1- (4-carbamoyl-piperidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 7a (0.18g, 0.27mmol) and 2mL of ethyl acetate were added to a reaction flask, 6mL of a 2.3N solution of hydrogen chloride in ethyl acetate was added, after 3.5 hours at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction was concentrated under reduced pressure to give the title product (R) -1- {7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperidine-4-carboxamide hydrochloride 7(0.12g, white solid), yield: 74 percent.

MS m/z(ESI)：561.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.42-7.31(m，1H)，7.28-7.16(m，1H)，5.17-4.97(m，2H)，4.43-4.24(m，2H)，4.20-4.03(m，1H)，4.03-3.89(m，2H)，3.30-3.18(m，2H)，3.17-3.06(m，2H)，3.03-2.72(m，4H)，2.65-2.53(m，1H)，2.15-2.03(m，2H)，1.93-1.83(m，2H)，1.77-1.60(m，2H)。

Example 8

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-methylformamide hydrochloride

First step of

(R) - [3- (1-methylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), methylamine hydrochloride (36.5mg, 0.54mmol) and bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (0.138g, 0.54mmol) were dissolved in 8mL of dichloromethane with stirring, triethylamine (0.25mL, 1.62mmol) was added, the reaction was allowed to react overnight at room temperature, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- (1-methylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 8a (150mg, white solid), yield: 98.6 percent.

MS m/z(ESI)：563.9(M+1)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-methylformamide hydrochloride

(R) - [3- (1-methylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 8a (0.15g, 0.27mmol) and 2mL of ethyl acetate were added to a reaction flask, 5mL of a 2.3N solution of hydrogen chloride in ethyl acetate was added, after 4 hours at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-methylformamide hydrochloride 8(0.135g, white solid), yield: 90 percent.

MS m/z(ESI)：464.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.40-7.38(m，1H)，7.23(m，1H)，5.13-5.04(m，2H)，4.31-4.25(m，2H)，4.07(m，1H)，3.96(m，2H)，3.10(m，2H)，2.99-2.76(m，5H)。

Example 9

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-dimethylformamide hydrochloride

First step of

(R) - [3- (1-dimethylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), dimethylamine hydrochloride (44mg, 0.54mmol) and bis (2-oxo-3-oxazolidinyl) phosphinic chloride (0.138g, 0.54mmol) were dissolved in 8mL of dichloromethane with stirring, triethylamine (0.25mL, 1.62mmol) was added, the reaction was allowed to proceed overnight at room temperature, the reaction mixture was concentrated under reduced pressure until the starting material disappeared, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- (1-dimethylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 9a (120mg, white solid), yield: 77 percent.

MS m/z(ESI)：578.1(M+1)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-dimethylformamide hydrochloride

(R) - [3- (1-dimethylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 9a (0.138g, 0.245mmol) and 2mL of ethyl acetate were added to a reaction flask, 4mL of a 2.3N solution of hydrogen chloride in ethyl acetate was added, after reaction at room temperature for 3 hours, the reaction was followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-dimethylformamide hydrochloride 9(0.12g, white solid), yield: 98 percent.

MS m/z(ESI)：478.2(M+1)。

Example 10

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid hydrochloride

First step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid hydrochloride

(R) -7- [ 3-tert-butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (218mg, 0.4mmol) was added to a reaction flask, 5mL of a hydrogen chloride ethanol solution was added, reaction was performed at room temperature, thin layer chromatography followed until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate 10(60mg, white solid), yield: 30.8 percent.

MS m/z(ESI)：451.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.416-7.37(m，1H)，7.281-7.234(m，1H)，5.189-5.053(m，2H)，4.361-4.286(m，1H)，4.15-3.999(m，2H)，3.941-3.925(m，2H)，3.212-2.883(m，2H)，2.861-2.805(m，2H)。

Example 11

(R) -3-amino-1- [1- (3-amino-piperidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one dihydrochloride

First step of

Piperidin-3-yl-carbamic acid tert-butyl ester

(R) -3-Aminopiperidine hydrochloride 11a (3g, 22.1mmol) and potassium carbonate (6.1g, 44.2mmol) were dissolved in 60mL of methanol with stirring, after stirring for 30 minutes, di-tert-butyl dicarbonate (4.8g, 22.1mmol) was added, the reaction was allowed to react overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product, piperidin-3-yl-carbamic acid tert-butyl ester 11b (1.3g, oily liquid), yield: 29 percent.

MS m/z(ESI)：201.0(M+1)。

Second step of

(R) - (1- {7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperidin-3-yl) -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.12g, 0.218mmol), piperidin-3-yl-carbamic acid tert-butyl ester 11b (0.173g, 0.545mmol) and triethylamine (0.275g, 2.18mmol) were dissolved with stirring in 12mL of dichloromethane, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.138g, 0.545mmol) was added at room temperature, the reaction was overnight, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - (1- {7- [ 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperidin-3-yl) -carbamic acid tert-butyl ester 11c (0.1g, oily liquid), yield: and 63 percent.

MS m/z(ESI)：733.1(M+1)。

The third step

(R) -3-amino-1- [1- (3-amino-piperidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -but-1-one hydrochloride

(R) - (1- {7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperidin-3-yl) -carbamic acid tert-butyl ester 11c (0.1g, 0.163mmol) was added to 10mL of a 2.3N solution of hydrogen chloride in ethyl acetate, reacted overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product (R) -3-amino-1- [1- (3-amino-piperidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one dihydrochloride 11(0.09g, white solid), yield: 98 percent.

MS m/z(ESI)：533.3(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.415-7.396(m，1H)，7.26-7.2154(m，1H)，5.131-4.085(m，11H)，3.994-2.837(m，8H)，2.11-1.846(m，5H)。

Example 12

(R) -3-amino-1- [1- (pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

(R) - [ 3-oxo-3- [1- (pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), pyrrolidine (38.4mg, 0.54mmol) and bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (0.138g, 0.54mmol) were dissolved in 8mL of dichloromethane with stirring, triethylamine (0.25mL, 1.62mmol) was added, the reaction was allowed to proceed overnight at room temperature, the reaction mixture was concentrated under reduced pressure until the starting material disappeared, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [ 3-oxo-3- [1- (pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 12a (120mg, white solid), yield: 74 percent.

Second step of

(R) -3-amino-1- [1- (pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

(R) - [ 3-oxo-3- [1- (pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 12a (0.12g, 0.199mmol) and 2mL of ethyl acetate were added to a reaction flask, 4mL of a 2.3N solution of hydrogen chloride in ethyl acetate was added, after reaction at room temperature for 3 hours, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure to give the title product (R) -3-amino-1- [1- (pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride 12(0.10g, white solid), yield: 94 percent.

MS m/z(ESI)：504.2(M+1)。

Example 13

(R) -3-amino-1- [ 1-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one dihydrochloride

First step of

(R) -4- {7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperazine-1-carboxylic acid tert-butyl ester

(R) -7- [ 3-tert-butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), tert-butyl 1-carboxylate piperazine (100.6mg, 0.54mmol), bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (0.138g, 0.54mmol) and triethylamine (0.25mL, 1.62mmol) were dissolved with stirring in 6mL of dichloromethane, reacted overnight at room temperature, followed by thin layer chromatography until the raw materials disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) -4- {7- [ 3-tert-butoxycarbonylamino-4- (2), 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperazine-1-carboxylic acid tert-butyl ester 13a (200mg, white solid), yield: 99 percent.

MS m/z(ESI)：719.0(M+1)。

Second step of

(R) -3-amino-1- [ 1-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one dihydrochloride

(R) -4- {7- [ 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperazine-1-carboxylic acid tert-butyl ester 13a (0.12g, 0.199mmol) was added to a reaction flask, 5mL of a 2.3N methanol solution of hydrogen chloride was added, reaction was allowed to stand overnight at room temperature, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -3-amino-1- [ 1-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one dihydrochloride 13(0.10g, white solid), yield: 94 percent.

MS m/z(ESI)：504.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.45-7.40(m，1H)，7.26-7.23(m，1H)，5.10-5.04(m，2H)，4.71-4.46(m，2H)，4.42-4.24(m，2H)，4.18-4.06(m，2H)，4.06-3.89(m，3H)，3.78-3.55(m，4H)，3.24-3.06(m，2H)，3.06-2.80(m，2H)。

Example 14

(R) -3-amino-1- [1- ((R) -3-hydroxy-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

(R) - [3- [1- ((R) -3-hydroxy-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), (R) -3-hydroxypyrrolidine (47mg, 0.54mmol), bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (0.138g, 0.54mmol) and triethylamine (0.25mL, 1.62mmol) were dissolved with stirring in 6mL of dichloromethane, reacted overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- ((R) -3-hydroxy-pyrrolidine-1-carbonyl) -3- Trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 14a (90mg, white solid), yield: 53 percent.

MS m/z(ESI)：620.0(M+1)。

Second step of

(R) -3-amino-1- [1- ((R) -3-hydroxy-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

(R) - [3- [1- ((R) -3-hydroxy-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 14a (90mg, 0.15mmol) was added to 10mL of a 2.3N solution of hydrogen chloride in ethyl acetate, reacted overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -3-amino-1- [1- ((R) -3-hydroxy-pyrrolidine-1-carbonyl) -3-trifluoromethyl -5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride 14(60mg, white solid), yield: 72 percent.

MS m/z(ESI)：520.3(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.417-7.372(m，1H)，7.275-7.234(m，1H)，5.527-4.87(m，2H)，4.87-4.346(m，1H)，4.346-4.117(m，2H)，4.117-3.352(m，8H)，3.349-2.98(m， 2H)，2.98-2.088(m，2H)，2.088-2.029(m，2H)。

Example 15

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-cyclopropylcarboxamide hydrochloride

First step of

(R) - [3- [1- (cyclopropylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.2g, 0.36mmol), cyclopropylamine (0.05g, 0.54mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.18g, 0.72mmol) were dissolved with stirring in 20mL of dichloromethane, triethylamine (0.36g, 3.6mmol) was added at room temperature, reaction was carried out at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- (cyclopropylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 15a (0.1g, oily liquid), yield: 45 percent.

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-cyclopropylcarboxamide hydrochloride

(R) - [3- [1- (cyclopropylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 15a (0.1g, 0.16mmol) was added to 5mL of a 2.2N solution of hydrogen chloride in ethyl acetate, reacted overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, and the reaction was concentrated under reduced pressure to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-cyclopropylcarboxamide hydrochloride 15(82mg, light yellow solid), yield: 95 percent.

MS m/z(ESI)：490.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.423-7.174(m，2H)，5.284-4.872(m，2H)，4.716-2.019(m，10H)，2.019(s，2H)，1.349-1.191(m，2H)，0.907-0.596(m，2H)。

Example 16

(R) - ({7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -amino) -acetic acid methyl ester hydrochloride

First step of

(R) -7- [ 3-tert-butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol) and amino-acetic acid methyl ester hydrochloride (512mg, 0.408mmol) were dissolved with stirring in 8mL of dichloromethane, triethylamine (0.25mL, 1.62mmol) was added, after stirring for 5 minutes, bis (2-oxo-3-oxazolidinyl) phosphinic chloride (0.138g, 0.54mmol) was added, the reaction was allowed to react at room temperature for 20 hours, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - ({7- [ 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -amino) -acetic acid methyl ester 16a (90mg, light yellow oil), yield: 53.6 percent.

Second step of

(R) - ({7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -amino) -acetic acid methyl ester 16a (0.09g, 0.145mmol) and 2mL of ethyl acetate were added to a reaction flask, 4mL of a 2.3N solution of hydrogen chloride in ethyl acetate was added, after reaction at room temperature for 3 hours, the reaction was followed by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to obtain the title product (R) - ({7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -amino) -acetic acid methyl ester hydrochloride 16(80mg, white solid), yield: 99 percent.

MS m/z(ESI)：522.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.47-7.30(m，1H)，7.30-7.14(m，1H)，5.23-5.00(m，2H)，4.39-4.20(m，2H)，4.18-4.06(m，3H)，4.17-4.07(m，3H)，4.01-3.89(m，2H)，3.84-3.24(m，3H)，3.20-2.76(m，4H)。

Example 17

(R) -1- [1- (4-acetyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-amino-4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

(R) - [3- [1- (4-acetyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), 1-piperazin-1-yl-ethanone hydrochloride (90mg, 0.54mmol) and bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (0.138g, 0.54mmol) were dissolved in 8mL of dichloromethane with stirring, triethylamine (0.25mL, 1.62mmol) was added, the reaction was allowed to react overnight at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- (4-acetyl-piperazine-1-carbonyl) - 3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 17a (80mg, white solid), yield: 45 percent.

MS m/z(ESI)：660.9(M+1)。

Second step of

(R) -1- [1- (4-acetyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-amino-4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

(R) - [3- [1- (4-acetyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 17a (0.08g, 0.12mmol) and 2mL of ethyl acetate were added to a reaction flask, 2mL of a 2.7N solution of hydrogen chloride in ethyl acetate was added, the reaction was allowed to react overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure to give the title product (R) -1- [1- (4-acetyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-amino-4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride 17(70mg, white solid), yield: 98 percent.

MS m/z(ESI)：561.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.50-7.36(m，1H)，7.33-7.15(m，1H)，5.23-4.97(m，2H)，4.60-4.06(m，5H)，4.06-3.88(m，2H)，3.88-3.48(m，6H)，3.24-2.71(m，4H)，2.26-2.12(m，3H)。

Example 18

(R) -3-amino-1- [1- (2-hydroxymethyl-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

(R) - [3- [1- (2-hydroxymethyl-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), (R) -pyrrolidin-2-ylmethanol (54.6mg, 0.54mmol), bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride (0.138g, 0.54mmol) and triethylamine (0.25mL, 1.62mmol) were dissolved with stirring in 8mL of dichloromethane, reacted overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- (2-hydroxymethyl-pyrrolidine-1-carbonyl) -3- Trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 18a (120mg, colorless oil), yield: 70 percent.

MS m/z(ESI)：633.9(M+1)。

Second step of

(R) -3-amino-1- [1- (2-hydroxymethyl-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

(R) - [3- [1- (2-hydroxymethyl-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 18a (0.12g, 0.19mmol) and 2mL of ethyl acetate were added to a reaction flask, 4mL of a 2.3N solution of hydrogen chloride in ethyl acetate was added, after reaction for 3 hours at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure to give the title product (R) -3-amino-1- [1- (2-hydroxymethyl-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride 18(0.12g, white solid), yield: 88 percent.

MS m/z(ESI)：534.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.39-7.35(m，1H)，7.23-7.19(m，1H)，5.16-5.04(m，2H)， 4.33-4.26(m，2H)，4.15-4.09(m，2H)，3.98(m，1H)，3.86-3.57(m，5H)，3.04(m，2H)，2.93-2.86(m，1H)，2.82-2.72(m，1H)

Example 19

(R) -4- {7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperazin-2-one hydrochloride

First step of

(R) - [ 3-oxo-3- [1- (3-oxo-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (150mg, 0.27mmol), 2-carbonylpiperazine (60mg, 0.6mmol), bis (2-oxo-3-oxazolidinyl) phosphinic chloride (0.138g, 0.54mmol), triethylamine (0.25mL, 1.62mmol) and 8mL of dichloromethane were added to a reaction flask, 10mLN, N-dimethylformamide was added thereto, the reaction was allowed to proceed overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title product (R) - [ 3-oxo-3- [1- (3-oxo-piperazine-1-carboxylic acid -carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 19a (140mg, colorless oil), yield: 82 percent.

MS m/z(ESI)：632.7(M+1)。

Second step of

(R) -4- {7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperazin-2-one hydrochloride

(R) - [ 3-oxo-3- [1- (3-oxo-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 19a (0.14g, 0.22mmol) and 2mL of ethyl acetate were added to a reaction flask, 4mL of a 2.3N solution of hydrogen chloride in ethyl acetate was added, after overnight reaction at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction was concentrated under reduced pressure to give the title product (R) -4- {7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carbonyl } -piperazin-2-one hydrochloride 19(0.12g, white solid), yield: 93 percent.

MS m/z(ESI)：533.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.38(m，1H)，7.24-7.22(m，1H)，5.08-5.01(m，2H)，4.57(m，2H)，4.32-4.27(m，2H)，4.08(m，1H)，3.97-3.94(m，4H)，3.47(m，2H)，3.11(m，2H)，2.97-2.84(m，2H)。

Example 20

(R) -3-amino-1- [1- (thiazolidine-3-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

(R) - [ 3-oxo-3- [1- (thiazolidine-3-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.15g, 0.27mmol), thiazolidine (57mg, 0.6mmol), triethylamine (0.275g, 2.72mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.138g, 0.544mmol) were dissolved with stirring in 10mL of dichloromethane, stirred at room temperature for 2 hours, followed by thin layer chromatography until the starting material disappeared, the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [ 3-oxo-3- [1- (thiazolidine-3-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 20a (0.15g, white solid), yield: 89 percent.

MS m/z(ESI)：644.1(M+23)。

Second step of

(R) -3-amino-1- [1- (thiazolidine-3-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

(R) - [ 3-oxo-3- [1- (thiazolidine-3-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 20a (0.15g, 0.24mmol) was added to a 5mL solution of 2.2N hydrogen chloride in ethyl acetate, reacted at room temperature for 4 hours, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -3-amino-1- [1- (thiazolidine-3-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride 20(100mg, light yellow solid), yield: 75 percent.

MSm/z(ESI)：522.I(M+I)。

¹HNMR(400MHz，CD₃OD)：δ7.447-7.358(m，1H)，7.3-7.204(m，1H)，5.217-5.05(m，2H)，4.752-4.461(m，2H)，4.37-4.284(m，2H)，4.284-4.086(m，2H)，4.086-3.952(m，2H)，3.719-3.607(m，1H)，3.211-2.827(m，4H)，2.827-2.784(m，2H)。

Example 21

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (pyridin-3-yl) carboxamide dihydrochloride

First step of

(R) - [ 3-oxo-3- [1- (pyridin-3-ylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonyl-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.15g, 0.272mmol) was dissolved in 10mL of dichloromethane with stirring, 3-aminopyridine (38.4mg, 0.41mmol), triethylamine (0.275g, 2.72mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.138g, 0.544mmol) were added, stirring was continued overnight at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [ 3-oxo-3- [1- (pyridin-3-ylcarbamoyl) -3-trifluoromethyl- 5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 21a (0.1g, white solid), yield: 58.8 percent.

MSm/z(ESI)：627.1(M+1)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (pyridin-3-yl) carboxamide dihydrochloride

(R) - [ 3-oxo-3- [1- (pyridin-3-ylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 21a (0.1g, 0.16mmol) was added to 10mL of a 2.2N solution of hydrogen chloride in ethyl acetate, reacted at room temperature for 4 hours, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (pyridin-3-yl) carboxamide dihydrochloride 21(80mg, white solid), yield: 89 percent.

MSm/z(ESI)：527.2(M+I)。

¹HNMR(400MHz，CD₃OD)：δ9.584(s，1H)，8.88-8.857(m，1H)，8.63-8.601(m，1H)，8.115-8.07(m，1H)，7.438-7.215(m，2H)，5.209-5.137(m，2H)，4.87-3.937(m，5H)，3.34-2.902(m，5H)，2.061(m，2H)。

Example 22

(R) -3-amino-1- [1- (4-methanesulfonyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

(R) - [3- [1- (4-methanesulfonyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.15g, 0.27mmol), 1-methanesulfonyl-piperazine (0.109g, 0.55mmol) and triethylamine (0.38mL, 2.7mmol) were dissolved with stirring in 10mL of dichloromethane, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.139g, 0.55mmol) was added, the reaction was stirred at room temperature overnight, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- (4-methanesulfonyl-piperazine-1-carbonyl) -3-tris (4-methanesulfonyl-piperazin Fluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 22a (0.2g, white solid).

MSm/z(ESI)：696.9(M+1)。

Second step of

(R) -3-amino-1- [1- (4-methanesulfonyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

(R) - [3- [1- (4-methanesulfonyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 22a (0.19g, 0.27mmol) and 2mL of ethyl acetate were added to a reaction flask, 4mL of a 2.7N solution of hydrogen chloride in ethyl acetate was added, after reaction at room temperature for 3 hours, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure to give the title product (R) -3-amino-1- [1- (4-methanesulfonyl-piperazine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride 22(170mg, white solid), yield: 99 percent.

MS m/z(ESI)：597.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.46-7.34(m，1H)，7.33-7.20(m，1H)，5.18-5.07(s，1H)，5.06-4.97(s，1H)，4.56-4.28(m，4H)，4.17-4.07(m，1H)，4.03-3.78(m，4H)，3.73-3.17(m，3H)，3.16-2.75(m，8H)。

Example 23

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid ethyl ester hydrochloride

First step of

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid ethyl ester

(R) -7- [ 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.16g, 0.29mmol) was dissolved in 10mL of dichloromethane with stirring, ethanol (0.05mL, 0.87mmol), triethylamine (0.202mL, 1.45mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.148g, 0.58mmol) were added, and after stirring at room temperature for 5 hours, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -7- [ 3-tert-butoxycarbonylamino-4- (2, ethyl 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate 23a (0.1g, colorless oily liquid).

MS m/z(ESI)：579.0(M+1)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid ethyl ester hydrochloride

Ethyl (R) -7- [ 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate 23a (0.09g, 0.156mmol) and 2mL of ethyl acetate were added to a reaction flask, 4mL of a 2.7N solution of hydrogen chloride in ethyl acetate was added, after reaction for 3 hours at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1 ], ethyl 5-a ] pyrazine-1-carboxylate hydrochloride 23(80mg, white solid), yield: 99 percent.

MS m/z(ESI)：479.1(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.50-7.45(m，1H)，7.40-7.18(m，1H)，5.20-5.00(m，2H)，4.5-4.22(m，4H)，4.15-4.06(m，1H)，4.06-3.89(m，2H)，3.23-2.78(m，4H)，1.40-1.48(m，3H)。

Example 24

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxamide hydrochloride

First step of

(R) - [3- (1-carbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.15g, 0.27mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.206g, 1.08mmol) and triethylamine (0.25mL, 1.62mmol) were dissolved with stirring in 10mL of tetrahydrofuran, ammonium carbonate (78mg, 0.81mmol) was added after stirring for 10 minutes, the reaction was stirred overnight at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- (1-carbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 24a (0.162g, white solid).

MS m/z(ESI)：549.9(M+1)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxamide hydrochloride

(R) - [3- (1-carbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 24a (0.16g, 0.29mmol) and 2mL of ethyl acetate were added to a reaction flask, 5mL of a 2.7N solution of hydrogen chloride in ethyl acetate was added, after reaction at room temperature for 3 hours, the reaction was followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxamide hydrochloride 24(150mg, white solid), yield: 95 percent.

MS m/z(ESI)：450.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.40-7.36(m，1H)，7.28-7.22(m，1H)，5.14-5.05(m，2H)，4.34-4.27(m，2H)，4.10-4.07(m，1H)，3.99-3.94(m，1H)，3.21-3.09(m，2H)，3.02-2.85(m，1H)，2.82-2.76(m，1H)。

Example 25

(R) -3-amino-1- [1- ((R) -3-fluoro-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

(R) - [3- [1- ((R) -3-fluoro-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.15g, 0.27mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.140g, 0.54mmol), triethylamine (0.4mL, 2.6mmol) and (R) -3-fluoropyrrolidine hydrochloride (68mg, 0.54mmol) were dissolved with stirring in 10mL of dichloromethane, the reaction was stirred at room temperature overnight, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- ((R) -3-fluoro-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 25a (0.162g, white solid).

MS m/z(ESI)：622.0(M+1)。

Second step of

(R) -3-amino-1- [1- ((R) -3-fluoro-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

Adding (R) - [3- [1- ((R) -3-fluoro-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 25a (0.15g, 0.27mmol) and 2mL of ethyl acetate into a reaction bottle, adding 5mL of a 2.7N solution of hydrogen chloride in ethyl acetate, reacting at room temperature for 3 hours, followed by thin layer chromatography until the raw materials disappear, and concentrating the reaction solution under reduced pressure to obtain the title product (R) -3-amino-1- [1- ((R) -3-fluoro-pyrrolidine-1-carbonyl) -3-trifluoromethyl- 5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride 25(140mg, white solid), yield: 94 percent.

MS m/z(ESI)：522.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.42-7.37(m，1H)，7.26-7.22(m，1H)，5.47-5.29(m，1H)，5.18-5.10(m，2H)，4.56-4.48(m，1H)，4.37-4.28(m，2H)，4.16-3.89(m，5H)，3.74-3.68(m，1H)，3.16-3.11(m，2H)，3.07-2.77(m，2H)，2.39-2.03(m，2H)。

Example 26

(R) -3-amino-1- [1- ((S) -3-fluoro-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

(R) - [3- [1- ((S) -3-fluoro-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.15g, 0.27mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.140g, 0.54mmol), triethylamine (0.4mL, 2.6mmol) and (S) -3-fluoropyrrolidine hydrochloride (68mg, 0.54mmol) were dissolved with stirring in 10mL of dichloromethane, the reaction was stirred at room temperature overnight, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- ((S) -3-fluoro-pyrrolidine-1-carbonyl) - 3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 26a (0.15g, white solid), yield: 89 percent.

MS m/z(ESI)：622.0(M+1)。

Second step of

(R) -3-amino-1- [1- ((S) -3-fluoro-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

Adding (R) - [3- [1- ((S) -3-fluoro-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 26a (0.15g, 0.24mmol) and 2mL of ethyl acetate into a reaction bottle, adding 5mL of a 2.7N solution of hydrogen chloride in ethyl acetate, reacting at room temperature for 3 hours, tracking the reaction by thin layer chromatography until the raw materials disappear, and concentrating the reaction solution under reduced pressure to obtain the title product (R) -3-amino-1- [1- ((S) -3-fluoro-pyrrolidine-1-carbonyl) -3-trifluoromethyl- 5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride 26(140mg, white solid), yield: 94 percent.

MS m/z(ESI)：522.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.42-7.37(m，1H)，7.26-7.22(m，1H)，5.47-5.29(m，1H)，5.18-5.10(m，2H)，4.56-4.48(m，1H)，4.37-4.28(m，2H)，4.16-3.89(m，5H)，3.74-3.68(m，1H)，3.16-3.11(m，2H)，3.07-2.77(m，2H)，2.39-2.03(m，2H)。

Example 27

(R) -1- (1-acetyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-amino-4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester

3-trifluoromethyl-imidazo [1,5-a ] pyrazine 1j (3.5g, 18.7mmol) was dissolved in 50mL of ethanol, 0.5g of 10% palladium on carbon was added with stirring, and the mixture was stirred overnight under a hydrogen atmosphere, whereupon the reaction was completed. The reaction solution was filtered through Celite, the filtrate was concentrated under reduced pressure, the obtained residue was washed with 100mL of ethanol, and the obtained solution was gradually added dropwise with 100mL of an ethanol solution of di-tert-butyl dicarbonate (6.2g, 28.1mmol) under stirring, and after completion of the addition, the stirring was continued for 30 minutes, and the reaction was completed. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product, tert-butyl 3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylate 27a (3.7g, white solid), yield: 68 percent.

Second step of

1-bromo-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester

After the compound tert-butyl 3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylate 27a (300mg, 1.04mmol) obtained in the above step and 50mL of ethanol were added to a 100mL dry flask and dissolved with stirring, N-bromosuccinimide (369mg, 2.08mmol) was added to stir the resulting mixture at room temperature, and after completion of the reaction after 1 hour, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title product tert-butyl 1-bromo-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylate 27b (220mg, white solid) in yield: 57.8 percent.

The third step

3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylic acid 7-tert-butyl 1-methyl ester

Dicobalt octacarbonyl (5.54g, 16.2mmol) and potassium carbonate (11.2g, 81.1mmol) were dissolved in 100mL of methanol with stirring, 1-bromo-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester 27b (3g, 8.11mmol) and methyl chloroacetate (5.25g, 48.6mmol) were added at 60 ℃ for 15 minutes, reaction was carried out for 6 hours under a carbon monoxide atmosphere, the reaction solution was cooled to room temperature, filtered with silica gel, rinsed with methanol, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product 3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylic acid 7-tert-butyl ester-1-methyl ester 27c (1.92g, white solid), yield: 67%. (reference: J.organomet.chem, 1985, 293)

MS m/z(ESI)：350.5(M+1)。

The fourth step

3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylic acid 7-tert-butyl ester

Dissolving 3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylic acid 7-tert-butyl ester 1-methyl ester 27c (1.92g, 5.5mmol) in 50mL of methanol under stirring, adding 30mL of 4N sodium hydroxide solution, reacting at room temperature for 30 minutes, following the reaction by thin layer chromatography until the raw material disappears, adding 2N hydrochloric acid to adjust the pH of the reaction solution to 4-5, extracting with ethyl acetate (100 mL. times.3), combining the organic phases, drying over anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain the title product 3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylic acid 7-tert-butyl ester 27d (2g, white solid), directly used for the next reaction.

The fifth step

1- (methoxy-methyl-carbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester

7-tert-butyl 3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylate 27d (1.84g, 5.5mmol), N-methoxymethanamine (0.805g, 8.25mmol) were dissolved in 50mL of dichloromethane with stirring, triethylamine (3mL, 22mmol) was added, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (2.1g, 8.25mmol) was added, the reaction was allowed to react overnight at room temperature, the reaction solution was concentrated under reduced pressure until the raw material disappeared, the resultant residue was purified by silica gel column chromatography to give the title product 1- (methoxy-methyl-carbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester 27e (2.1g, a white solid).

MS m/z(ESI)：379.1(M+1)。

The sixth step

1-acetyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester

Dissolving tert-butyl 1- (methoxy-methyl-carbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylate 27e (0.3g, 0.79mmol) in 20mL tetrahydrofuran with stirring, adding methyl magnesium bromide (1.13mL, 1.58mmol) dropwise at 0 ℃, reacting at 0 ℃ for 1.5 hours, following the reaction by thin layer chromatography until the starting material disappears, adding 50mL of a saturated ammonium chloride solution and 10mL of a saturated sodium chloride solution, extracting with ethyl acetate (50 mL. times.3), combining the organic phases, drying over anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure, purifying the resulting residue with silica gel column chromatography to give the title product 1-acetyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester 27f (0.24g, yellow oily liquid), yield: 90 percent.

MS m/z(ESI)：334.0(M+1)。

Seventh step

1- (3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) -ethanone

1-acetyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester 27f (0.24g, 0.72mmol) was dissolved in a small amount of ethyl acetate with stirring, 5mL of a 2.7N solution of hydrogen chloride in ethyl acetate was added, the reaction was carried out at room temperature, followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product 1- (3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) -ethanone 27g, which was used directly in the next reaction.

Eighth step

(R) - [3- (1-acetyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

27g (192mg, 0.72mmol) of 1- (3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) -ethanone and 1f (0.24g, 0.72mmol) of (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyric acid (0.24g, 0.72mmol) were dissolved with stirring in 20mL of dichloromethane, triethylamine (0.4mL, 2.88mmol) was added, and after stirring, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.275g, 1.08mmol) was added, reacted overnight at room temperature, followed by thin layer chromatography until the raw material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- (1-acetyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 27H (0.3g, white solid).

MS m/z(ESI)：449.2(M+1)。

The ninth step

(R) -1- (1-acetyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-amino-4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

(R) - [3- (1-acetyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 27H (0.3g, 0.55mmol) was dissolved with stirring in 2mL of ethyl acetate, a solution of 5mL of 2.4N hydrogen chloride in ethyl acetate was added, stirring was carried out at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) -1- (1-acetyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-amino-4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride 27(0.15g, white solid), yield: 57 percent.

MS m/z(ESI)：548.9(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.37(m，1H)，7.26(m，1H)，5.09(m，1H)，5.02(d，1H)，4.87-3.92(m，5H)，3.1-2.78(m，4H)，2.57(d，2H)，2.04(d，1H)。

Example 28

(R) -3-amino-1- (1-cyclopentylcarbonyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) 4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

1-Cyclopentylcarbonyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester

1- (methoxy-methyl-carbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester 27e (0.3g, 0.79mmol) was dissolved in 20mL of tetrahydrofuran with stirring, cyclopentyl magnesium bromide (0.79mL, 1.58mmol) was added dropwise at 0 ℃, the reaction was allowed to react at 0 ℃ for 3 hours, followed by thin layer chromatography until the starting material disappeared, 50mL of a saturated ammonium chloride solution and 10mL of a saturated sodium chloride solution were added, extraction was performed with ethyl acetate (100 mL. times.3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product 1-cyclopentylcarbonyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester 28a (0.1g, yellow oily liquid), yield: 30 percent.

MS m/z(ESI)：388.1(M+1)。

Second step of

Cyclopentyl- (3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) -methanone

Dissolving 1-cyclopentylcarbonyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-7-carboxylic acid tert-butyl ester 28a (0.1g, 0.258mmol) in a small amount of ethyl acetate under stirring, adding 5mL of 2.7N ethyl acetate solution of hydrogen chloride, reacting at room temperature for 2 hours, tracking the reaction by thin layer chromatography until the raw material disappears, and concentrating the reaction solution under reduced pressure to obtain the title product cyclopentyl- (3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) -methanone 28b which is directly used for the next reaction.

MS m/z(ESI)：288.2(M+1)。

The third step

(R) - [3- (1-Cyclopentylcarbonyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester hydrochloride

Cyclopentyl- (3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazin-1-yl) -methanone 28b (83mg, 0.258mmol) and (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyric acid 1f (0.129g, 0.388mmol) were dissolved in 10mL of dichloromethane with stirring, triethylamine (0.143mL, 1.03mmol) was added, after stirring, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.099g, 0.388mmol) was added, the reaction was allowed to proceed overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- (1-cyclopentylcarbonyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester hydrochloride 28c (0.11g, orange oily liquid), yield: 72 percent.

MS m/z(ESI)：602.9(M+1)。

The fourth step

(R) -3-amino-1- (1-cyclopentylcarbonyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

(R) - [3- (1-cyclopentylcarbonyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 28c (0.11g, 0.183mmol) was dissolved with stirring in 2mL of ethyl acetate, a solution of 5mL of 2.4N hydrogen chloride in ethyl acetate was added, stirring was performed at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) -3-amino-1- (1-cyclopentylcarbonyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride 28(80mg, yellow solid), yield: 81 percent.

MS m/z(ESI)：503.2(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.41(m，1H)，7.25(m，1H)，5.10(d，1H)，4.87(s，1H)，4.37-3.91(m，6H)，3.14-2.82(m，4H)，2.03-1.72(m，8H)。

Example 29

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (2-dimethylaminoethyl) -carboxamide dihydrochloride

First step of

(R) - [3- [1- (2-dimethylamino-ethylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.15g, 0.27mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.14g, 0.54mmol) and triethylamine (0.25mL, 1.62mmol) were dissolved with stirring in 10mL of dichloromethane, N' -dimethylethane-1, 2-diamine (48mg, 0.54mmol) was added thereto, the reaction was stirred at room temperature overnight, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- (2-dimethylamino-ethylcarbamoyl) - 3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 29a (0.1g, white solid).

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (2-dimethylaminoethyl) -carboxamide dihydrochloride

(R) - [3- [1- (2-dimethylamino-ethylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 29a (0.10g, 0.16mmol) was dissolved in 2mL of ethyl acetate with stirring, a solution of 6mL of 2.4N hydrogen chloride in ethyl acetate was added, the reaction was allowed to proceed at room temperature for 4 hours, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, 5mL of ethyl acetate was added, stirring and filtration were carried out, the white solid was rinsed with ethyl acetate to obtain the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (2-dimethylamino-ethyl) -carboxamide dihydrochloride 29(80mg, white solid), yield: and 63 percent.

¹HNMR(400MHz，CD₃OD)：δ7.46-7.39(m，1H)，7.29-7.23(m，1H)，5.18-5.09(m，2H)，4.37-4.27(m，2H)，4.15-4.09(m，1H)，4.00-3.95(m，1H)，3.77-3.75(m，2H)，3.39-3.35(m，2H)，3.13-3.12(m，2H)，3.02(s，3H)，3.01(m，4H)，2.98-2.88(m，1H)。

Example 30

(R) -3-amino-1- [1- ((S) 2-hydroxymethyl-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

First step of

(R) - [3- [1- ((S) -2-hydroxymethyl-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.15g, 0.27mmol), (S) -pyrrolidin-2-ylmethanol (54.62mg, 0.54mmol) and triethylamine (0.25mL, 1.62mmol) were dissolved with stirring in 10mL of dichloromethane, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.14g, 0.54mmol) was added, the reaction was stirred at room temperature overnight, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- [1- ((S) -2-hydroxymethyl-pyrrolidine-1 -carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 30a (0.2g, white solid).

Second step of

(R) -3-amino-1- [1- ((S) 2-hydroxymethyl-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride

(R) - [3- [1- ((S) -2-hydroxymethyl-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -3-oxo-1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamic acid tert-butyl ester 30a (0.16g, 0.25mmol) and 2mL of dichloromethane were added to a reaction flask, 5mL2.7N in methanol with hydrogen chloride was added, the reaction was allowed to react overnight at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -3-amino-1- [1- ((S) 2-hydroxymethyl-pyrrolidine-1-carbonyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -4- (2, 4, 5-trifluorophenyl) -butan-1-one hydrochloride 30(120mg, white solid), yield: 84 percent.

¹HNMR(400MHz，CD₃OD)：δ7.34-7.30(m，1H)，7.19-7.12(m，1H)，5.10-4.92(m，2H)，4.27-4.25(m，2H)，4.21-4.18(m，1H)，4.06-3.98(m，2H)，3.91-3.90(m，1H)，3.84-3.80(m，1H)，3.72-3.48(m，3H)，3.03-2.99(m，2H)，2.93-2.73(m，2H)，2.01-1.85(m，4H)。

Example 31

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (pyridin-2-yl) carboxamide dihydrochloride

First step of

(R) - [ 3-oxo-3- [1- (pyridin-2-ylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamoyl tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.15g, 0.27mmol), 2-aminopyridine (51g, 0.54mmol) and triethylamine (0.25mL, 1.62mmol) were dissolved in 10mL of dichloromethane with stirring, after stirring for 20 minutes, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.14g, 0.54mmol) was added, the reaction was stirred at room temperature overnight, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) - [ 3-oxo-3- [1- (pyridin-2-ylaminoformyl) -3 -trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamoyl tert-butyl ester 31a (0.1g, white solid), yield: 59 percent.

MS m/z(ESI)：627.1(M+1)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (pyridin-2-yl) carboxamide dihydrochloride

(R) - [ 3-oxo-3- [1- (pyridin-2-ylcarbamoyl) -3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl ] -1- (2, 4, 5-trifluorobenzyl) -propyl ] -carbamoyl tert-butyl ester 31a (0.10g, 0.16mmol) and 2mL of dichloromethane were added to a reaction flask, 5mL of a 2.7N solution of hydrogen chloride in methanol was added, reaction was carried out overnight at room temperature, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (pyridin-2-yl) carboxamide dihydrochloride 31(80mg, white solid), yield: 95.2 percent.

MS m/z(ESI)：527.1(M+1)。

¹HNMR(400MHz，CD₃OD)：δ8.48(m，2H)，8.08-8.05(m，1H)，7.65-7.63(m，1H)，7.45-7.41(m，1H)，7.27-7.26(m，1H)，5.24-5.17(m，2H)，4.43-4.34(m，2H)，4.14(m，1H)，4.05(m，1H)，3.96(m，1H)，3.21-3.03(m，2H)，2.96-2.72(m，2H)。

Example 32

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (4-fluorophenyl) -carboxamide hydrochloride

First step of

(R) -tert-butyl-4- (1- ((4-fluorophenyl) carbamoyl) -3- (trifluoromethyl) -5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) -4-oxo-1- (2, 4, 5-trifluorophenyl) carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.15g, 0.27mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.14g, 0.54mmol), triethylamine (0.25mL, 1.62mmol) were dissolved with stirring in 10mL of dichloromethane, 4-fluoroaniline (0.06g, 0.54mmol) was added in one portion, stirred overnight, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) -tert-butyl-4- (1- ((4-fluorophenyl) carbamoyl) -3- (trifluoromethyl) -5, tert-butyl 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) -4-oxo-1- (2, 4, 5-trifluorophenyl) carbamate 32a (0.12g, white solid), yield: and 69 percent.

MS m/z(ESI)：643.9(M+1)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (4-fluorophenyl) -carboxamide hydrochloride

(R) -tert-butyl-4- (1- ((4-fluorophenyl) carbamoyl) -3- (trifluoromethyl) -5, 6-dihydroimidazo [1,5-a ] pyrazin-7 (8H) -yl) -4-oxo-1- (2, 4, 5-trifluorophenyl) carbamoyl tert-butyl ester 32a (0.12g, 0.186mmol) and 2mL of ethyl acetate were added to a reaction flask, 8mL of a 2.7N solution of hydrogen chloride in ethyl acetate was added thereto, the reaction was stirred overnight, followed by thin layer chromatography until the starting material disappeared, the reaction mixture was concentrated under reduced pressure to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (4-fluorophenyl) -carboxamide hydrochloride 32(110mg, white solid), yield: 100 percent.

MS m/z(ESI)：544.1(M+1)。

¹HNMR(400MHz，DMSO)：δ10.124(d，1H)，8.190(s，2H)，7.849(s，1H)，7.552(m，1H)，7.157(d，2H)，5.023(m，2H)，4.231(m，2H)，3.897(m，3H)，3.014(m，4H)，2.0(m，2H)。

Example 33

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid benzyl ester hydrochloride

First step of

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid benzyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.24g, 0.44mmol), 1-hydroxy-benzo-triazole (0.072g, 0.53mmol) and N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (0.102g, 0.53mmol) were dissolved in 10mL of dichloromethane with stirring, and benzyl alcohol (0.1mL, 0.88mmol) was added thereto, the reaction was stirred overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) -7- [ 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid benzyl ester 33a (0.056g, white solid), yield: 20 percent.

MS m/z(ESI)：640.9(M+1)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid benzyl ester hydrochloride

An ethyl acetate solution of (R) -7- [ 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid benzyl ester 33a (0.056g, 0.087mmol) and 2mL of 2.7N hydrogen chloride was added to a reaction flask, stirred at room temperature for 2 hours, followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid benzyl ester hydrochloride 33(0.043g, white solid), yield: 86 percent.

MS m/z(ESI)：541.2(M+1)。

¹HNMR(400MHz，CD₃OD)：7.526-7.498(m，2H)，7.498-7.364(m，5H)，5.415(s，2H)，5.121-5.003(m，2H)，4.498-3.820(m，5H)，3.341-2.903(m，4H)。

Example 34

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (1-ethoxyacyloxy) carboxylic acid ethyl ester hydrochloride

First step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (1-ethoxyacyloxy) carboxylic acid ethyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.275g, 0.5mmol) and 4mLN, N-dimethylformamide were added to a reaction tube, ethyl 1-chloroethylcarbonate (0.092g, 0.6mmol), potassium iodide (0.0415g, 0.25mmol) and potassium carbonate (0.083g, 0.6mmol) were sequentially added under stirring, the tube was sealed and placed in an oil bath to control the external temperature at 65 ℃ for reaction for 2 hours, thin layer chromatography followed by reaction until the raw material disappeared, the reaction tube was cooled to room temperature, 40mL of water was added, ethyl acetate (25 mL. times.3) was used to extract, the combined organic phases were washed with water (20 mL. times.2), dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -ethyl 7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (1-ethoxyacyloxy) carboxylate 34a (0.26g, white solid), yield: 78.1 percent.

MS m/z(ESI)：666.9(M+1)，689.1(M+23)。

¹HNMR(400MHz，CDCl₃)：δ7.08(m，2H)，6.90(m，1H)，5.36(m，1H)，5.15(m，1H)，5.01(m，1H)，4.27-3.94(m，6H)，3.0(m，2H)，2.68(m，1H)，1.71(d，3H)，1.61(s，2H)，1.40(s，9H)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (1-ethoxyacyloxy) carboxylic acid ethyl ester hydrochloride

Adding (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (1-ethoxyacyloxy) carboxylic acid ethyl ester 34a (0.26g, 0.39mmol) and 5mL of ethyl acetate into a reaction flask, adding 3mL of 6.5N ethyl acetate solution of hydrogen chloride, stirring at room temperature for 6 hours, carrying out thin layer chromatography until the raw materials disappear, concentrating the reaction solution under reduced pressure, purifying the obtained residue by silica gel column chromatography to obtain the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, ethyl 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1- (1-ethoxyacyloxy) carboxylate hydrochloride 34(0.2g, white solid), yield: 85 percent.

MS m/z(ESI)：567.0(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.30(m，1H)，7.15(m，1H)，6.96(m，1H)，5.06(m，2H)，4.32(t，1H)，4.24(m，3H)，4.03(m，2H)，3.60(m，1H)，2.88(d，2H)，2.67(m，2H)，1.93(s，1H)，1.65(t，3H)。

Example 35

(R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid isopropyl ester hydrochloride

First step of

(R) -7- (3- (tert-Butoxycarbonylamino) -4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid isopropyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.3g, 0.54mmol) was placed in a 50mL reaction flask, 10mL of dichloromethane was added, 2mL of isopropanol was further added, 0.3mL of triethylamine was further added, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.277g, 1.09mmol) was added after 1 minute, the reaction was stirred at room temperature for 2 hours, 10mL of isopropanol and sodium isopropoxide (0.177g, 2.16mmol) were further added, the reaction was stirred at room temperature for 1.5 hours, the reaction was followed by thin layer chromatography until the starting material disappeared, about 10mL of a saturated ammonium chloride solution was added, a white solid precipitated, filter on silica gel pad, collect the filtrate, add 50mL of water, extract with ethyl acetate (25mL × 5), combine the organic phases, wash with 30mL of saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, purify the resulting residue by silica gel column chromatography to give the title product (R) -isopropyl-7- (3- (tert-butoxycarbonylamino) -4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate 35a (0.185g, white solid), yield: 57.8 percent.

MS m/z(ESI)：593.0(M+1)。

¹HNMR(400MHz，CDCl₃)：δ7.146-7.082(m，1H)，6.929-6.883(m，1H)，5.405-5.010(m，3H)，4.219-3.937(m，5H)，3.022-2.307(m，4H)，1.484-1.242(m，15H)。

Second step of

Isopropyl (R) -7- (3- (tert-butoxycarbonylamino) -4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate hydrochloride

(R) -7- (3- (tert-butoxycarbonylamino) -4- (2, 4, 5-trifluorophenyl) butyryl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid isopropyl ester 35a (0.17g, 0.29mmol) and 10mL of ethyl acetate were put together in a reaction flask, 5mL of a 5.5N solution of hydrogen chloride in ethyl acetate was added thereto under ice bath, the ice bath was removed, stirring was carried out at room temperature for 2 hours, the reaction was followed by thin layer chromatography until the starting material disappeared, the reaction mixture was concentrated under reduced pressure, washed with N-hexane (10 mL. times.2), and the filtrate was concentrated under reduced pressure to obtain the title product (R) -7- (3- (tert-butoxycarbonylamino) -4- (2, 4, 5-trifluorophenyl) butyryl) -3- (trifluoromethyl) -5, isopropyl 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate hydrochloride 35(0.15g, white solid), yield: 97.8 percent.

MS m/z(ESI)：493.1(M+1)。

¹HNMR(400MHz，DMSO)：δ7.631-7.482(m，2H)，5.159-4.308(m，3H)，4.285-3.742(m，5H)，3.110-2.735(m，4H)，1.473-1.063(m，6H)。

Example 36

(R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid tert-butyl ester hydrochloride

First step of

(R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.3g, 0.54mmol), 10mL of dichloromethane, 5mL of tert-butanol were added to a 100mL reaction flask, 0.3mL of triethylamine and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.277g, 1.09mmol) were sequentially added under stirring, and the reaction was stirred at room temperature for 2 hours, 10mL of tert-butanol and potassium tert-butoxide (0.24g, 2.16mmol) were further added, and the reaction was continued at room temperature for 2 hours, followed by thin layer chromatography until the starting material disappeared. 10mL of a saturated ammonium chloride solution was added to the reaction solution, a white solid was precipitated, the reaction mixture was filtered through a pad of 100-mesh silica gel with 200 mesh, the filtrate was collected, 50mL of water was added, extraction was performed with ethyl acetate (25 mL. times.5), the combined organic phases were washed successively with 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title product (R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid tert-butyl ester 36a (0.11g, white solid) in yield: 33.6 percent.

MS m/z(ESI)：629.2(M+23)。

¹HNMR(400MHz，CH₃OD)：δ7.255-7.090(m，2H)，5.077-4.964(m，2H)，4.500-4.227(m，3H)，4.227-4.032(m，2H)，2.994-2.744(m，4H)，1.496-1.202(m，18H)。

Second step of

(R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid tert-butyl ester hydrochloride

Adding (R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butyryl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid tert-butyl ester 36a (0.094g, 0.15mmol) and 10mL of ethyl acetate into a reaction flask, adding 3mL of a 5.5N solution of hydrogen chloride in ethyl acetate into the reaction flask under ice bath, removing the ice bath after finishing dropwise addition, stirring at room temperature for 3 hours, tracing the reaction by thin layer chromatography until the raw materials disappear, concentrating the reaction solution under reduced pressure, adding 20mL of N-hexane for washing, and concentrating under reduced pressure to obtain the title product (R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butyryl) -3- (trifluoromethyl) -5, tert-butyl 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate hydrochloride 36(0.084g, white solid), yield: 100 percent.

MS m/z(ESI)：507.0(M+1)。

¹HNMR(400MHz，CH₃OD)：δ7.431-7.387(m，1H)，7.246-7.198(m，1H)，5.108-4.981(m，2H)，4.354-3.926(m，5H)，3.174-3.095(m，2H)，2.996-2.896(m，2H)，1.276(s，9H)。

Example 37

(R) -ethyl 7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate (isopropoxyformyloxy) hydrochloride

First step of

(R) -ethyl 7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate (isopropoxyformyloxy) ethyl ester

Adding (R) -7- [ 3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.275g, 0.5mmol) and 4mL of N, N-dimethylformamide into a reaction tube, stirring to dissolve the mixture, sequentially adding 1-chloroethyl-isopropyl carbonate (0.1g, 0.6mmol), potassium iodide (0.0415g, 0.25mmol), potassium carbonate (0.083g, 0.6mmol), sealing the reaction tube, placing the reaction tube in an oil bath, controlling the temperature outside the oil bath to 65 ℃, reacting for 2 hours, and tracking the reaction by thin layer chromatography until the raw materials disappear. The reaction tube was taken out of the oil bath, and after it was cooled to room temperature, 40mL of water was added thereto, extracted with ethyl acetate (25mL × 3), the product was not detected in the aqueous phase by thin layer chromatography, the organic phase was collected, washed with water (20mL × 2), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid (isopropoxyformyloxy) ethyl ester 37a (0.29g, pale yellow solid), yield: 85.3 percent.

MSm/z(ESI)：698.0(M+18)。

¹HNMR(400MHz，CDCl₃)：37.12(m，1H)，7.05(m，1H)，6.92(m，1H)，5.38(d，1H)，5.15(d，1H)，5.01(s，1H)，4.94(m，1H)，4.23-3.94(m，5H)，2.98(m，2H)，2.70(m，1H)，1.70(d，2H)，1.62(s，1H)，1.40(s，9H)。

Second step of

(R) -ethyl 7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate (isopropoxyformyloxy) hydrochloride

(R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butyryl) -3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid (isopropoxyformyloxy) ethyl ester 37a (0.29g, 0.43mmol) and 5mL of ethyl acetate were added to a reaction flask, 3mL of a 6.5N solution of hydrogen chloride in ethyl acetate was added thereto, the reaction was stirred at room temperature for 4 hours, followed by thin layer chromatography until the starting material disappeared, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title product (R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butyryl) -3- (trifluoromethyl) -5, ethyl 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate (isopropoxyformyloxy) hydrochloride 37(0.24g, white solid), yield: 91.2 percent.

MS m/z(ESI)：581.1(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.38(m，1H)，7.25(m，1H)，6.96(m，1H)，5.10(m，2H)，4.88(m，1H)，4.33(m，2H)，4.11(m，2H)，3.95(m，2H)，3.05(m，2H)，3.00(m，1H)，2.85(m，1H)，2.03(m，3H)，1.64(m，3H)。

Example 38

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid- (1-cyclohexylacyloxy) ethyl ester hydrochloride

First step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid- (1-cyclohexylacyloxy) ethyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (0.275g, 0.5mmol) and 4mL of N, N-dimethylformamide were put into a reaction tube, and stirred to dissolve 2a, and then 1-chloroethyl-cyclohexyl carbonate (0.124g, 0.6mmol), potassium iodide (0.0415g, 0.25mmol), potassium carbonate (0.083g, 0.6mmol) were added to the reaction tube in this order, and after completion of addition, the tube was sealed, and stirred in an oil bath at an external temperature of 65 ℃ for 2 hours, and the reaction was followed by thin layer chromatography until the starting material disappeared. The reaction tube was taken out of the oil bath, and after the reaction liquid was cooled to room temperature, 40mL of water was added thereto, extraction was performed with ethyl acetate (30mL × 3), the organic phases were combined, washed with 30mL of water and then with 30mL of saturated brine, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid- (1-cyclohexylacyloxy) ethyl ester 38a (0.25g, white solid) in yield: 69.4 percent.

MS m/z(ESI)：721.0(M+1)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid- (1-cyclohexylacyloxy) ethyl ester hydrochloride

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid- (1-cyclohexylacyloxy) ethyl ester 38a (0.25g, 0.347mmol) and 5mL of ethyl acetate were put in a reaction flask, 3mL of a 6.5N solution of hydrogen chloride in ethyl acetate was added under stirring, the reaction was stirred at room temperature overnight, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid- (1-cyclohexylacyloxy) ethyl ester hydrochloride 38(0.22g, white solid), yield: 96.1 percent.

MS m/z(ESI)：621.1(M+1)。

¹HNMR(400MHz，CD₃OD)：δ7.30(m，1H)，7.16(m，1H)，6.95(m，1H)，5.10(m，1H)，4.64(m，1H)，4.29(d，2H)，4.02(d，2H)，3.61(s，1H)，2.87(d，2H)，2.70(s，1H)，2.65(m，1H)，1.93(s，3H)，1.74(s，2H)，1.64(m，3H)，1.47(m，3H)，1.31(m，3H)。

Example 39

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -8-methyl-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester hydrochloride

First step of

8-methyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylic acid 7-tert-butyl ester

Dissolving 7-tert-butyl 3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylate 27d (0.85g, 2.54mmol) in a mixed solvent of 25mL of anhydrous toluene and 8mL of anhydrous tetrahydrofuran, placing the reaction flask in a dry ice-acetone bath, cooling to-78 ℃, adding tetramethylethylenediamine (1.32mL, 8087mmol), dropwise adding n-butyl lithium (5.55mL, 8.87mmol), dropwise adding after five minutes, keeping the external temperature at-78 ℃, reacting for 15 minutes, dropwise adding iodomethane (0.4mL, 6.34mmol), keeping the temperature at-78 ℃ for 10 minutes, then heating to room temperature, reacting for 2 hours, and tracking the reaction by thin layer chromatography until the raw materials disappear. To the reaction solution was added 15mL of a saturated solution of ammonium chloride, followed by addition of 20mL of water, pH-adjusted to 3-4 with 2N hydrochloric acid, extraction with ethyl acetate (30mL × 3), combination of organic phases, drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification of the resulting residue by silica gel column chromatography to give the title product 8-methyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylic acid-7-tert-butyl ester 39a (0.215g, white solid), yield: 24.3 percent.

Second step of

8-methyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylic acid 7-tert-butyl ester-1-methyl ester

8-methyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylic acid 7-tert-butyl ester 39a (0.349g, 1mmol) was dissolved in 15ml N, N-dimethylformamide, sodium bicarbonate (0.84g, 10mmol) was added with stirring, iodomethane (0.43g, 3mmol) was added dropwise, the reaction was stirred at room temperature for 40 hours, followed by thin layer chromatography until the starting material disappeared, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product 8-methyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylic acid-7-tert-butyl ester-1-methyl ester 39b (0.5g, yellow oil), yield: 100 percent.

MS m/z(ESI)：364.0(M+1)。

¹HNMR(400MHz，CDCl₃)：δ5.85(t，1H)，4.24(t，2H)，4.04(t，2H)，3.93(s，3H)，1.56(d，3H)，1.51(s，9H)。

The third step

8-methyl-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester hydrochloride

8-methyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazine-1, 7-dicarboxylic acid 7-tert-butyl ester-1-methyl ester 39b (0.35g, 0.96mmol) was placed in a reaction flask, 10mL of a 2.3N solution of hydrogen chloride in ethyl acetate was added, the reaction was stirred at room temperature for 2 hours, followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give the title product, 8-methyl-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester hydrochloride 39c crude product (0.4g, yellow oil).

¹HNMR(400MHz，CDCl₃)：δ7.10(m，1H)，6.91(m，1H)，5.57(m，1H)，5.45(m，2H)，4.18(m，2H)，3.97(s，3H)，3.36(t，1H)，2.98(m，2H)，2.26(m，2H)，1.60(d，3H)，1.40(s，9H)。

The fourth step

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester

Crude methyl 8-methyl-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate hydrochloride 39c (0.289g, 0.96mmol) and (R) -3-tert-butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyric acid 1f (0.353g, 1.06mmol) were dissolved in 10mL of dichloromethane, triethylamine (0.4mL, 2.9mmol) and bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (0.368g, 1.45mmol) were added successively with stirring, the reaction was stirred overnight at room temperature, followed by thin layer chromatography until the starting material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) -7- [ 3-tert-butoxycarbonylamino-4- (2), 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester 39d (0.43g, yellow oil), yield: 77.2 percent.

MS m/z(ESI)：579.1(M+1)。

The fifth step

(R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -8-methyl-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester hydrochloride

7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester 39d (0.23g, 0.4mmol) was put in a reaction flask, 5mL of a 2.3N solution of hydrogen chloride in ethyl acetate was added, the reaction was stirred at room temperature for 2 hours, followed by thin layer chromatography until the starting material disappeared, and the reaction solution was concentrated under reduced pressure to obtain the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -8-methyl-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [ 1), 5-a ] pyrazine-1-carboxylic acid methyl ester hydrochloride 39(0.205g, white solid), yield: 100 percent.

MS m/z(ESI)：479.1(M+1)。

¹HNMR(400MHz，CDCl₃)：δ7.33(m，1H)，6.93(m，1H)，5.58(m，1H)，5.02(m，1H)，4.33(m，2H)，3.86(s，3H)，3.43(t，2H)，3.06(m，2H)，2.49(m，2H)，1.57(d，3H)。

Examples 40 and 41

(R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) - (S) -8-methyl-3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester hydrochloride

(R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) - (R) -8-methyl-3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester hydrochloride

Subjecting (R) -7- [ 3-amino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -8-methyl-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid methyl ester hydrochloride 39(141mg, 29.5mmol) to chiral resolution, separating the isomers by HPLC using a chiral column (separation conditions: chiral column Chiralcel AD-H, mobile phase: n-hexane: isopropanol: diethylamine ═ 70: 30: 0.1, flow rate: 1.0ml/min), collecting the corresponding fractions thereof, removing the solvent by rotary evaporation, and drying under vacuum at room temperature for 4 hours to give the title product (R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butyryl) - (S) -8-methyl-3 Methyl- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate hydrochloride 40(57mg, 11.9mmol) and methyl (R) -7- (3-amino-4- (2, 4, 5-trifluorophenyl) butanoyl) - (R) -8-methyl-3- (trifluoromethyl) -5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylate hydrochloride 41(50mg, 10.5 mmol).

Example 42

(R) -7- [ 3-amino-4- (2, 4, 5-trifluoro-phenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo [1,5-a ] pyrazine-1-carbamoylethylamine

First step of

(R) - [3- (1-ethylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (180mg, 0.33mmol) was dissolved in 10mL of tetrahydrofuran, ethylamine hydrochloride (269mg, 3.3mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (168mg, 0.66mmol) and triethylamine (367mg, 3.63mmol) were added, the reaction was stirred at room temperature for 4 hours, the thin layer chromatography followed the reaction, the raw material disappeared, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- (1-ethylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 42a (190mg, white solid), yield: is greater than 100%.

MS m/z(ESI)：600.1(M+23)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluoro-phenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo [1,5-a ] pyrazine-1-carbamoylethylamine

(R) - [3- (1-ethylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 42a (190mg, 0.33mmol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (750mg, 6.6mmol) was added thereto, the reaction was stirred at room temperature for 2 hours, the thin layer chromatography followed the reaction, the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluoro-phenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo [1,5-a ] pyrazine-1-carbamoylethylamine 42(120mg, white solid), yield: 76.4 percent.

MS m/z(ESI)：478.1(M+1)。

¹HNMR(400MHz，CD₃OD)：δ1.68-1.24(m，3H)，2.79-3.01(m，2H)，3.10(s，2H)，3.33-3.41(m，2H)，4.24-4.30(d，2H)，5.03-5.18(m，2H)，7.14-7.23(m，1H)，7.36-7.37(d，1H)。

Example 43

(R) -7- [ 3-amino-4- (2, 4, 5-trifluoro-phenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo [1,5-a ] pyrazine-1-carbamoylbutylamine

First step of

(R) - [3- (1-butylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (180mg, 0.33mmol) was dissolved in 10mL of dichloromethane, butylamine hydrochloride (193mg, 2.64mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (167mg, 0.66mmol) and triethylamine (100mg, 0.99mmol) were added, the reaction was stirred at room temperature overnight, the reaction was followed by thin layer chromatography, the starting material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- (1-butylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 43a (120mg, white solid), yield: 60 percent.

MS m/z(ESI)：606.0(M+1)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluoro-phenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo [1,5-a ] pyrazine-1-carbamic acid butylamine

(R) - [3- (1-butylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 43a (120mg, 0.198mmol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (452mg, 3.97mmol) was added thereto, the reaction was stirred at room temperature for 2 hours, the thin layer chromatography followed the reaction, the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluoro-phenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo [1,5-a ] pyrazine-1-carbamoylbutylamine 43(70mg, white solid), yield: 70 percent.

MS m/z(ESI)：506.1(M+1)。

¹HNMR(400MHz，CD₃OD)：δ0.93-0.99(m，3H)，1.34-1.41(m，2H)，1.59-1.62(m，2H)，2.80-2.98(m，3H)，3.07-3.15(m，2H)，3.37(m，1H)，3.90-3.91(d，2H)，4.06-4.07(m，1H)，4.27-4.34(m，2H)，5.03-5.15(m，2H)，7.20-7.37(m，2H)。

Example 44

(R) -7- [ 3-amino-4- (2, 4, 5-trifluoro-phenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo [1,5-a ] pyrazine-1-carbamoylpropylamine

First step of

(R) - [3- (1-Propylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester

(R) -7- [ 3-tert-Butoxycarbonylamino-4- (2, 4, 5-trifluorophenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo [1,5-a ] pyrazine-1-carboxylic acid 2a (190mg, 0.345mmol) was dissolved in 10mL of dichloromethane, propylamine (163mg, 2.76mmol), bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride (176mg, 0.69mmol) and triethylamine (105mg, 1.04mmol) were added, the reaction was stirred at room temperature overnight, the thin layer chromatography followed reaction, the starting material disappeared, the reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography to give the title product (R) - [3- (1-propylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 44a (70mg, white solid), yield: 34.3 percent.

MS m/z(ESI)：614.1(M+23)。

Second step of

(R) -7- [ 3-amino-4- (2, 4, 5-trifluoro-phenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo [1,5-a ] pyrazine-1-carbamic acid propylamine

(R) - [3- (1-propylcarbamoyl-3-trifluoromethyl-5, 6-dihydro-8H-imidazo [1,5-a ] pyrazin-7-yl) -3-oxo-1- (2, 4, 5-trifluoro-benzyl) -propyl ] -carbamic acid tert-butyl ester 44a (70mg, 0.118mmol) was dissolved in 10mL of dichloromethane, trifluoroacetic acid (270mg, 2.37mmol) was added thereto, the reaction was stirred at room temperature for 1 hour, the thin layer chromatography followed the reaction, the starting material disappeared, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title product (R) -7- [ 3-amino-4- (2, 4, 5-trifluoro-phenyl) -butyryl ] -3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo [1,5-a ] pyrazine-1-carbamoylpropylamine 44(25mg, white solid), yield: 43.1 percent.

MS m/z(ESI)：492.1(M+1)。

¹HNMR(400MHz，CD₃OD)：δ0.90-1.00(m，3H)，1.60-1.66(m，2H)，2.75-2.84(m， 1H)，2.93-2.99(m，1H)，3.09(s，2H)，3.94-3.95(d，2H)，4.07(m，1H)，4.24-4.29(m，2H)，5.03-5.13(m，2H)，7.19-7.23(t，1H)，7.36-7.38(d，1H)。

Test example:

biological evaluation

Measurement of DPP IV inhibitory Activity

The following method was used to determine the ability of the compounds of the invention to inhibit DPPIV enzyme activity. Inhibitory Rate or half inhibitory concentration IC of Each Compound₅₀(concentration of test compound at which the enzyme activity is inhibited by 50%) was determined by mixing a fixed amount of enzyme with the substrate and varying concentrations of test compound.

Measurement of DPP IV inhibitory Activity

Materials and methods:

materials:

a. white 96-well plate (BMG)

Tris buffer: 100mL of 2mM Tris buffer was prepared, 0.0242g Tris was dissolved in about 90mL deionized water, the pH was adjusted to 8.00 with HCl and NaOH, and finally deionized water was added to 100 mL.

DPPIV enzyme (Calbiochem Catalog No.317630), dissolved in Tris buffer to 2 mM.

d.DPPIV-Glo^TMSubstrate (Promega Catalog No. G8350) was dissolved in deionized water to 1 mM.

e.DPPIV-Glo^TMBuffer (Promega Catalog No. G8350)

f. Fluorescein detection reagent (Promega Catalog No. G8350)

g.DMSO

h. Deionized water

The operation is as follows:

the method comprises the following steps:

1. thawed DPPIV-glo. buffered and equilibrated to room temperature prior to use.

2. The pre-buffer frozen fluorescein detection reagents were used.

3. Suspended DPPIV-glo.A substrate of 1mM was prepared by adding ultrapure water to the substrate and mixing the mixture gently.

4. Putting the fluorescein detection reagent into a dark brown bottle, and adding DPPIV-glo. The fluorescein detection reagent should dissolve in 1 minute.

5. The compounds tested were dissolved in DMSO to 50-fold the final working concentration.

6.2 μ L of the test compound at 50-fold concentration was added to each tube, and 2 μ L DMSO was added to the negative control blank.

7. 46 μ L Tris buffer was added to each tube and 48 μ L Tris buffer was added to the blank.

8. mu.L of DPPIV enzyme was added to each tube of the negative control and test samples.

9. Mix with shaking and centrifuge the tube. Transfer the entire contents of the tube to a 96-well plate.

10. The ratio of mixed substrate and DPPIV-Glo is 1: 49. Vibrating and mixing until fully mixed. Standing at room temperature for 30-60 min before use.

11. 50 μ L of a mixture of DPPIV-glo.and substrate was added to each well of a 96-well plate and the plate was sealed with a sealing membrane.

12. The contents of the 96 wells were mixed slowly using a plate shaker at 300-500rpm/30 s. Incubate at room temperature for 30 minutes to 3 hours.

13. Luminescence was recorded.

The inhibition rate is defined as follows: [1- (S-B)/(N-B) ]. multidot.100%

S: sample (I)

B: blank control

N: negative control

IC₅₀The value:

examples	IC50(μM)
		MK-0431	0.023
1	0.012
		2	0.008
3	0.089
		4	0.022
5	0.027
		6	0.031
7	0.025
		8	0.008
9	0.075
		10	0.021
11	0.216
		12	0.059
13	0.041
		14	0.047
15	0.025
		23	0.031
34	0.031
		36	0.221
37	0.033
		38	0.184
39	0.016
		40	0.314

41	0.005
		42	0.018
43	0.063
		44	0.052

The half-inhibitory concentration IC of the compound of the invention to DPPIV is determined by testing₅₀IC with values ranging from 0.005 μ M to 0.216 μ M with MK-0431₅₀Compared with the value of 0.023 mu M, most of the compounds of the invention have good inhibitory activity on DPPIV.

Claims (18)

1. A compound represented by the general formula (I):

wherein:

ar is phenyl which is unsubstituted or further substituted by 1 to 5R⁶Substituted;

R¹selected from hydrogen atoms, C_1-10Alkyl orC_3-8Monocyclic cycloalkyl, wherein C_1-10Alkyl or C_3-8Monocyclic cycloalkyl is optionally further substituted with one or more substituents selected from halo, cyano, hydroxy or amino;

R²selected from hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-8Monocyclic cycloalkoxy, C_3-8Monocyclic cycloalkyl or NR⁴R⁵In which C is_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-8Monocyclic cycloalkoxy or C_3-8Monocyclic cycloalkyl is optionally further substituted by one or more substituents selected from halogen, amino, cyano, hydroxy, C_1-10Alkyl radical, C_3-8Monocyclic cycloalkyl, C_1-10Alkoxy radical, C_3-8Monocyclic cycloalkoxy, -OC (O) OR⁸Or C_1-4Substituted by a substituent of an alkylcarboxyl;

R³selected from hydrogen atoms or C_1-10An alkyl group;

R⁴and R⁵Each independently selected from hydrogen atom, C_1-10Alkyl or C_3-8Monocyclic cycloalkyl, wherein C_1-10Alkyl or C_3-8Monocyclic cycloalkyl is optionally further substituted by one or more substituents selected from halogen, hydroxy, amino, C_1-10Alkoxy radical, C_3-8Monocyclic cycloalkoxy, C_1-10Alkyl, cyano, C_3-8Monocyclic cycloalkyl, C_1-10Hydroxyalkyl, -SO₂R⁷Or C_1-4Substituted by a substituent of an alkylcarboxyl;

or, R⁴And R⁵Together form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O, S atoms, and the 4-8 membered heterocyclic group is optionally further substituted with one or more groups selected from halogen, hydroxy, amino, C_1-10Alkoxy radical, C_3-8Monocyclic cycloalkoxy, C_1-10Alkyl, cyano, C_1-10Hydroxyalkyl, -SO₂R⁷、-C(O)R⁷Is ═ O or C_1-4Substituted by a substituent of an alkylcarboxyl;

R⁶selected from halogen, cyano, hydroxy, C_1-10Alkyl radical, C_1-10Alkoxy or C_3-8Monocyclic cycloalkoxy, wherein C_1-10Alkyl radical, C_1-10Alkoxy or C_3-8Monocyclic cycloalkoxy is unsubstituted or further substituted with one or more halogen;

R⁷is C_1-10An alkyl group;

R⁸is selected from C_1-10Alkyl or C_3-8A monocyclic cycloalkyl group.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is¹Is trifluoromethyl.

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

4. a compound represented by the formula or a pharmaceutically acceptable salt thereof, selected from:

5. a compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein the salt is a salt of the compound with an acid selected from the group consisting of: malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, or trifluoroacetic acid.

6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, which is the hydrochloride salt.

7. A compound of the general formula (IA):

wherein: ar, R¹And R³As defined in claim 1; x is halogen.

8. A compound represented by the general formula (IB):

wherein: r¹And R²As defined in claim 1; r³Is C_1-10An alkyl group.

9. A process for the preparation of a compound of formula (IA) according to claim 7, which process comprises:

in ice bath to the raw material R³Acid anhydride is dripped into substituted pyrazine 2-methylamine, and then the reaction is carried out at room temperature to generate an amide product;

mixing and stirring the amide product and phosphorus oxychloride at room temperature, adding phosphorus pentoxide, heating, refluxing and condensing to generate an imidazo [1,5-a ] pyrazine ring;

imidazo [1, 5-a)]The pyrazine ring is reduced to generate R in ethanol solvent under the catalysis of palladium/carbon¹，R³Substituted tetrahydroimidazo [1,5-a ]]A pyrazine product;

r is to be¹，R³Substituted tetrahydroimidazo [1,5-a ]]Dissolving a pyrazine product in a dichloromethane solvent, and carrying out condensation reaction with carboxylic acid under the action of a condensing agent bis (2-oxo-3-oxazolidinyl) phosphoryl chloride and triethylamine;

reacting the obtained condensation product with halogenated succinimide in an absolute ethyl alcohol solvent at room temperature to generate a compound shown in a general formula (IA);

wherein: ar, R¹And R³As defined in claim 1; x is halogen.

10. A process for the preparation of a compound of formula (IB) according to claim 8, which process comprises:

r is to be¹Substituted imidazo [1,5-a [ ]]Pyrazine is hydrogenated and reduced in ethanol solvent at room temperature, then reacts with di-tert-butyl dicarbonate in ethanol solvent to protect amino, and R protected by amino is obtained¹Substituted tetrahydroimidazo [1,5-a ]]Pyrazine;

the resulting amino protected R¹Substituted tetrahydroimidazo [1,5-a ]]Pyrazine reacts with halogenated succinimide in an ethanol solvent at room temperature to obtain a halogenated product;

reacting the obtained halogenated product with octacarbonyl cobaltic and chloroacetate in a methanol solvent in an oil bath in the presence of carbon monoxide to obtain ester-substituted tetrahydroimidazo [1,5-a ] pyrazine;

hydrolyzing the obtained ester-substituted tetrahydroimidazo [1,5-a ] pyrazine into acid under alkaline condition;

reacting the obtained carboxylic acid compound with halogenated alkyl in a dry ice-acetone bath to obtain alkyl substituted acid;

optionally further esterifying the alkyl-substituted acid to obtain a ketone-substituted tetrahydroimidazo [1,5-a ] pyrazine;

or, the alkyl substituted acid reacts with N-methoxy methylamine in methylene dichloride solvent under the action of a condensation reagent of bis (2-oxo-3-oxazolidinyl) phosphoryl chloride;

reacting a product obtained by condensation reaction with a Grignard reagent in a tetrahydrofuran solvent to obtain ketone-substituted tetrahydroimidazo [1,5-a ] pyrazine;

removing amino protecting groups from ketone-substituted tetrahydroimidazo [1,5-a ] pyrazine under an acidic condition to obtain a compound of a general formula (IB);

wherein: r¹、R³As defined in claim 8; r²Is selected from C_1-10Alkyl radical, C_1-10Alkoxy radical, C_3-8Monocyclic cycloalkoxy or C_3-8A monocyclic cycloalkyl group.

11. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, which comprises:

the compound of the general formula (IA) according to claim 7 is reacted in methanol solvent under the action of dicobalt octacarbonyl in an oil bath with chloroacetate under carbon monoxide atmosphere, then hydrolyzed at room temperature under basic conditions and re-acidified to carboxylic acid;

the obtained carboxylic acid is subjected to condensation reaction with amine or alcohol at room temperature under the action of a condensation reagent, or is subjected to condensation reaction with 1-halogenated carbonate, and then amino protecting groups are removed under acidic conditions to obtain a compound of a general formula (I); optionally reacting the compound of formula (I) with an acid to form a pharmaceutically acceptable salt of the compound of formula (I);

wherein: ar, R¹And R³As defined in claim 1; r²Is selected from C_1-10Alkoxy radical, C_3-8Monocyclic cycloalkoxy or NR⁴R⁵；R⁴And R⁵As defined in claim 1.

12. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, which comprises:

condensing the compound of general formula (IB) according to claim 8 with a carboxylic acid under the conditions of the condensation reagent bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride, and removing the amino protecting group of the resulting product under acidic conditions to obtain the compound of general formula (I); optionally reacting the compound of formula (I) with an acid to form a pharmaceutically acceptable salt of the compound of formula (I);

wherein: ar, R¹、R²As defined in claim 1; r³Is C_1-10An alkyl group.

13. The method according to claim 11 or 12, wherein the acid is selected from malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, or trifluoroacetic acid.

14. The method of claim 13, wherein the acid is hydrochloric acid.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

16. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of type II diabetes, hyperglycemia, obesity or insulin resistance.

17. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the catalytic activity of dipeptidyl peptidase IV.

18. Use of a pharmaceutical composition according to claim 15 for the preparation of a medicament for the treatment of type II diabetes, hyperglycemia, obesity, or insulin resistance.