TWI439271B - Tetrahydroimidazo [1,5-a] pyrazine derivatives, preparation process and pharmaceutical use thereof - Google Patents

Description

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

The present invention relates to a novel tetrahydroimidazo[1,5-a]pyrene of the formula (I) Derivatives, methods for their preparation, and pharmaceutical compositions containing the same, and their use as therapeutic agents, particularly as dipeptidyl peptidase IV inhibitors.

Diabetes is a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or action. Diabetes is a very old disease caused by an increase in the concentration of glucose in the blood caused by absolute or relative lack of insulin in the human body. In turn, a large amount of sugar is excreted from the urine, and polydipsia, polyuria, polyphagia, weight loss, dizziness, Weakness and other symptoms.

Permanent or uncontrolled hyperglycemia leads to an increase in morbidity and mortality. Often, abnormalities in glucose homeostasis are directly or indirectly related to changes in lipids, lipoproteins, lipoprotein metabolism, or other metabolic and hemodynamic diseases. Patients with type 2 diabetes have a significant increase in the risk of diseases such as coronary heart disease, stroke, peripheral vascular disease, hypertension, kidney disease, neuropathy, and retinopathy. Therefore, the treatment and control of diseases such as constant blood sugar, lipid metabolism, and hypertension are extremely important for clinical treatment of diabetes.

Generally, there are two types of diabetes. People with type 1 diabetes, insulin-dependent diabetes mellitus (IDDM), produce little or no insulin on their own. Insulin is a hormone used in the body to regulate glucose utilization. People with type 2 diabetes, insulin-dependent diabetes mellitus (NIDDM), have the same or higher plasma insulin concentrations in patients with non-diabetic patients. However, such patients are resistant to insulin, which is the main insulin. Glucose and lipid metabolism in sensitive tissue cells such as muscle, liver, and 25 adipose tissue are stimulating. Even if the plasma insulin concentration is increased, it is impossible to overcome the patient's significant resistance to insulin.

Insulin resistance is mainly due to a decrease in the number of insulin receptors, as well as insulin receptor defects, which have not been understood so far. The resistance to insulin responsiveness causes insulin to fail to initiate glucose uptake, oxidation, and storage in muscle tissue, and is ineffective in inhibiting lipolysis of adipose tissue and production and secretion of hepatic glucose.

Dipeptidyl peptidase-IV (DPPIV) is a serine protease that cleaves N-terminal dipeptides in a peptide chain containing a proline residue at the secondary end, although DPPIV has no physiological effects on mammals. It is fully confirmed, but it plays an important role in neuroenzyme metabolism, T-cell initiation, cancer cell metastasis into the endothelium, and HIV virus entry into lymphoid cells (Patent Document WO98/19998).

Recently, studies have shown that DPPIV can block the secretion of glucagon-like peptide (GLP)-1, in particular, it can cleave the N-terminal histidine-alanine dipeptide in GLP-1 from the active form. GLP-1(7-36)NH ₂ degrades to inactive GLP-1(9-36)NH ₂ (Endocrinology, 1999, 140: 5356 to 5363). Due to physiological conditions, the half-life of intact GLP-1 in circulating blood is very short, and the inactive metabolites after DPPIV degrades GLP-1 can bind to GLP-1 receptor antagonistic activity GLP-1, thereby shortening the physiology of GLP-1. reaction. DPPIV inhibitors can completely protect endogenous or even exogenous GLP-1 from DPPIV loss of activity, greatly increasing the physiological activity of GLP-1 (5 to 10 times). Since GLP-1 is an important stimulator of pancreatic insulin secretion and can directly affect the distribution of glucose, DPPIV inhibitors play a very good role in the treatment of non-insulin dependent diabetes mellitus (NIDDM) (Patent Document US6110949).

At present, some DPP-IV inhibitors have been disclosed (Patent Documents US Pat. No. 5,462,928, US Pat. No. 5,543,396, WO 9515309, WO2003004498, WO2003082817, WO2004032836, WO2004085661), wherein the DPPIV inhibitor MK-0431 manufactured by Merck Company exhibits good DPPIV inhibitory activity and selectivity, It was launched in 2006.

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

It is an object of the present invention to provide a compound having a therapeutic or palliative drug which inhibits DPPIV activity and which can be used for diabetes or the like.

In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a tetrahydroimidazo[1,5-a]pyrene of the formula (I). Classes of compounds, as well as their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs.

Wherein: R ^{1 is} selected from a hydrogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, heterocycloalkyl group, aryl group, heteroaryl group is further optionally subjected to one or Substituted by a plurality of substituents selected from halogen, cyano, aryl, hydroxy or amine groups, preferably trifluoromethyl; R ^{2 is} selected from the group consisting of hydroxyl, amine, alkyl, alkoxy, cycloalkyl, Heterocycloalkyl, aryl, heteroaryl or -NR ⁴ R ⁵ wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally one or more Selected from halogen, amine, cyano, hydroxy, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, -NR ⁴ R ⁵ , -OC(O)OR ⁸ , carboxylic acid or carboxylate Substituted by a substituent; R ^{3 is} selected from a hydrogen atom or an alkyl group; and R ⁴ and R ⁵ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkane Or a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyano, aryl, cycloalkane Base, heterocycloalkyl, heteroaryl, hydroxyalkane Substituting a substituent of -SO ₂ R ⁷ , -NR ⁴ R ⁵ , a carboxylic acid or a carboxylic acid ester; or, R ⁴ and R ⁵ together form a 4 to 8 membered heterocyclic group, wherein the 4 to 8 member is heterozygous The ring contains one or more N, O, S atoms, and the 4 to 8 membered heterocyclic ring is further optionally one or more selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyano , aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -C(O)R ⁷ , = O, substituted by a substituent of a carboxylic acid or a carboxylic acid ester; R ^{6 is} selected from halogen, cyano, hydroxy, alkyl or alkoxy, wherein the alkyl or alkoxy group is unsubstituted or further passed through one or more Halogen substituted; R ⁷ is alkyl; R ⁸ is alkyl or cycloalkyl.

The pharmaceutically acceptable salt described in the present invention is a salt of the compound of the present invention and 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 their pharmaceutically acceptable salts.

Further, the present invention includes a compound represented by the following formula (IA) which is an intermediate for the synthesis of the compound of the formula (I):

Wherein: Ar is a phenyl group which is unsubstituted or further substituted with 1 to 5 R ⁶ ; R ^{1 is} selected from a hydrogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, an aryl group or a heteroaryl group. a group wherein the alkyl group, heterocycloalkyl group, aryl group, heteroaryl group is further optionally substituted with one or more substituents selected from a halogen, a cyano group, an aryl group, a hydroxyl group or an amine group, preferably three Fluoromethyl; R ^{3 is} selected from a hydrogen atom or an alkyl group; R ^{6 is} selected from halogen, cyano, hydroxy, alkyl or alkoxy, wherein the alkyl or alkoxy group is unsubstituted or further optionally Or substituted by a plurality of halogens; X is a halogen.

Further, the present invention includes a compound represented by the following formula (IB) which is an intermediate for the synthesis of the compound of the formula (I):

Wherein: R ^{1 is} selected from a hydrogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, heterocycloalkyl group, aryl group, heteroaryl group is further optionally subjected to one or Substituted by a plurality of substituents selected from halogen, cyano, aryl, hydroxy or amine groups, preferably trifluoromethyl; R ^{2 is} selected from the group consisting of hydroxyl, amine, alkyl, alkoxy, cycloalkyl, Heterocycloalkyl, aryl, heteroaryl or -NR ⁴ R ⁵ wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally one or more Selected from halogen, amine, cyano, hydroxy, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, -NR ⁴ R ⁵ , -OC(O)OR ⁸ , carboxylic acid or carboxylate Substituted by a substituent; R ^{3 is} selected from a hydrogen atom or an alkyl group; and R ⁴ and R ⁵ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein the alkane Or a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyano, aryl, cycloalkane Base, heterocycloalkyl, heteroaryl, hydroxy Substituted by a substituent of an alkyl group, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , a carboxylic acid or a carboxylic acid ester; or, R ⁴ and R ⁵ together form a 4 to 8 membered heterocyclic group, wherein the 4 to 8 members The heterocyclic ring contains one or more N, O, S atoms, and the 4 to 8 membered heterocyclic ring is further optionally optionally subjected to one or more selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyanide Base, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -C(O)R ⁷ , Substituted by a substituent of a carboxylic acid or a carboxylic acid ester; R ⁷ is an alkyl group; and R ^{8 is} selected from an alkyl group or a cycloalkyl group.

In another aspect of the invention, there is provided a process for the preparation of a compound of the formula (IA), which comprises the steps of:

In the ice bath to the raw material The anhydride is added dropwise to the 2-methylamine, and then reacted at room temperature to form a guanamine product;

After the guanamine product and the phosphorus oxychloride are mixed and stirred at room temperature, phosphorus pentoxide is added, and the mixture is heated and refluxed to form imidazo[1,5-a]pyridinium. ring;

Imidazo[1,5-a]pyridin The ring is reduced in hydrogen by hydrogenation under palladium on carbon to form R ¹ , R ³ substituted tetrahydroimidazo[1,5-a]pyrene product;

Imidazo[1,5-a]pyridyl substituted with R ¹ , R ³ The product is dissolved in a dichloromethane solvent and condensed with a carboxylic acid under the action of a condensing agent bis(2-oxo-3-oxazolidinyl)phosphinium chloride and triethylamine;

The resulting condensation product is reacted with a halogenated amber succinimide in an anhydrous ethanol solvent at room temperature to form an intermediate (IA).

In another aspect of the invention, there is provided a process for the preparation of a compound of the formula (IB), which comprises the steps of:

R ¹ substituted imidazo[1,5-a]pyridyl Hydrogenation reduction in an ethanol solvent at room temperature, followed by reaction with di(tert-butyl ester) dicarbonate in an ethanol solvent to protect the amine group to give an amine-protected R ¹ -substituted tetrahydroimidazo[ 1,5-a]pyridyl ;

The resulting amine-protected R ¹ -substituted tetrahydroimidazo[1,5-a]pyridinium The halogenated product is obtained by reacting with a halogenated amber in the ethanol solvent at room temperature;

The obtained halogenated product is reacted in a solvent of methanol with octacarbonylcobalt and chloroacetate in a carbon monoxide atmosphere to obtain an ester-substituted tetrahydroimidazo[1,5-a]pyrene. ;

The resulting ester group substituted tetrahydroimidazo[1,5-a]pyridyl Hydrolyzed to an acid under alkaline conditions;

The obtained carboxylic acid compound is reacted with a haloalkyl group in a dry ice-acetone bath to obtain an alkyl-substituted acid;

The alkyl-substituted acid can be further esterified to give a keto-substituted tetrahydroimidazo[1,5-a]pyridyl ;

Alternatively, the alkyl-substituted acid can be reacted with N-methoxymethylamine in a dichloromethane solvent under the action of a condensation reagent bis(2-oxo-3-oxazolidinyl)phosphorus chloride;

The product obtained by the condensation reaction is reacted with a Grignard reagent in a tetrahydrofuran solvent to obtain a ketone-substituted tetrahydroimidazo[1,5-a]pyridinium. ;

Keto-substituted tetrahydroimidazo[1,5-a]pyridin The amine protecting group is removed under acidic conditions to give the intermediate (IB).

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

The intermediate (IA) is reacted with chloroacetate in a carbon monoxide atmosphere in an oil bath under the action of octacarbonyl carbonyl in an oil bath, and then hydrolyzed to a carboxylic acid at room temperature under basic conditions;

The obtained carboxylic acid is subjected to condensation reaction with an amine or an alcohol at room temperature under a condensation reagent, or with a 1-halocarbonate, and then the amine group is removed under acidic conditions to obtain a compound of the formula (I). ).

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

The intermediate (IB) is condensed with a carboxylic acid under the conditions of a condensing reagent bis(2-oxo-3-oxazolidinyl)phosphinium chloride, and the obtained product is further subjected to removal of an amine protecting group under acidic conditions. Compound (I) of the formula.

Further, a process for producing the compound of the above formula (I), which further comprises an acid addition product salt of the compound of the formula (I). Wherein the salt is a salt of the above compound with an acid selected from the group consisting of 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 is 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 present invention relates to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance.

One aspect of the invention is a method for inhibiting the catalytic activity of dipeptidyl peptidase IV, characterized in that the dipeptidyl peptidase IV is contacted with a compound or salt of any one of formula (I).

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

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

"Alkyl" means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 10 carbon atoms is preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferred are lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl groups and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyano, aryl, Heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -C(O)R ⁷ , -OC(O) OR ⁸ , carboxylic acid or carboxylic acid ester.

"Cycloalkyl" means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 member fused or polycyclic fused ring ("fused" ring means each in the system The rings share an adjacent pair of carbon atoms) groups with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Examples of the cycloalkyl group are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclopentenyl group, a cyclohexane group, a cyclohexadienyl group, an adamantyl group, a cycloheptyl group, a cycloheptatrienyl group and the like. The cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyano, aryl, Heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -C(O)R ⁷ , carboxylic acid or carboxylic acid ester.

"Aryl" means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated π-electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyano, aryl, Heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -C(0)R ⁷ , carboxylic acid or carboxylic acid ester.

"Heteroaryl" refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, and heteroatoms including oxygen, sulfur and nitrogen. The ring can be a 5 or 6 member ring. Examples of heterocyclic aryl groups include furyl, thienyl, pyridyl, pyrrole, N-alkylpyrrolyl, pyrimidinyl, pyridyl Base, imidazolyl and the like. The heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyano, aryl. , heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -C(O)R ⁷ , carboxylic acid or carboxylate Acid ester.

"Heterocycloalkyl" means a monocyclic or fused ring radical having from 5 to 9 ring atoms in the ring wherein one or two ring atoms are selected from nitrogen, oxygen or S(O)n (where n is an integer) From 0 to 2), the remaining atoms are carbon. These rings may also have one or more double bonds. However, these rings do not have a fully conjugated π-electron system. Unsubstituted heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, hexahydropyridyl, hexahydropyridyl Base, morpholinyl, thiomorpholinyl, high hexahydropyridyl The heterocycloalkyl group may be substituted or unsubstituted. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyano, aryl, Heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -C(O)R ⁷ , carboxylic 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. The alkoxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyano, and aromatic. , heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -C(O)R ⁷ , carboxylic acid or Carboxylic acid ester.

"Halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

"Trifluoromethyl" means -CF ₃ .

"Amino" means -NH _2.

"Cyano" means -CN.

"Carbonyl" means C(=O).

"Carboxylic acid" means (alkyl)C(=O)OH.

"Carboxylic acid ester" means (alkyl)C(=O)O(alkyl).

"Hydroxyalkyl" means an alkyl group substituted with a hydroxy group.

"Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiological/pharmaceutically acceptable carrier. And excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical scheme: a preparation method of the compound (I) of the general formula of the present invention, comprising the following steps:

Raw material 2-Methylamine is added dropwise to the anhydride under ice bath, and then reacted at room temperature to form a guanamine product; the guanamine product and phosphorus oxychloride are mixed and stirred at room temperature, then phosphorus pentoxide is added, and the mixture is heated and refluxed to form Imidazo[1,5-a]pyridyl Ring; imidazo[1,5-a]pyridyl The ring is reduced in hydrogen under the palladium/carbon catalysis to form R ¹ -substituted tetrahydroimidazo[1,5-a]pyrene in ethanol solvent. Product; tetrahydroimidazo[1,5-a]pyrene substituted with R ¹ The product is condensed with a carboxylic acid in a dichloromethane solvent and under the action of a condensation reagent of bis(2-oxo-3-oxazolidinyl)phosphinium chloride and triethylamine; the resulting condensation product is in the chamber Reaction with halogenated amber succinimide in a solvent of anhydrous ethanol to form a compound of the formula (IA); intermediate compound (IA) in a solvent of methanol and chloroacetic acid in the oil bath under the action of octacarbonyl carbonyl The ester is reacted in a carbon monoxide atmosphere and then hydrolyzed to a carboxylic acid under acidic conditions at room temperature; the resulting carboxylic acid compound condensation reagent is subjected to a condensation reaction with an amine or an alcohol at room temperature, or with a 1-halogenation The carbonate reaction then removes the amine protecting group under acidic conditions to give the compound of formula (I).

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

Tetrahydroimidazo[1,5-a]pyrene substituted with starting material R ¹ Hydrogenation reduction in ethanol solvent at room temperature, and then reacting with di(tert-butyl ester) dicarbonate in ethanol solvent to obtain amine-protected R ¹ -substituted tetrahydroimidazo[1,5-a]pyridinium The resulting amine-protected R ¹ -substituted tetrahydroimidazo[1,5-a]pyridyl The halogenated product is obtained by reacting with a halogenated amber iodide in an ethanol solvent at room temperature; the obtained halogenated product is in a methanol solvent and under an oil bath with dicobalt octacarbonyl and chloroacetate in a carbon monoxide atmosphere. Reaction to give an ester-substituted tetrahydroimidazo[1,5-a]pyridyl The resulting ester-substituted tetrahydroimidazo[1,5-a]pyridyl Hydrolysis to an acid under basic conditions; the resulting carboxylic acid compound is reacted with a haloalkyl group in a dry ice-acetone bath to give an alkyl substituted product; the carboxyl group in the alkyl substituted product can be further esterified to give an intermediate ( IB); the obtained carboxylic acid compound can also be reacted with N-methoxymethylamine in a dichloromethane solvent under the action of a condensation reagent bis(2-oxo-3-oxazolidinyl)phosphinium chloride The product obtained by the condensation reaction is reacted with a Grignard reagent in a tetrahydrofuran solvent to obtain a ketone-substituted tetrahydroimidazo[1,5-a]pyridinium. Ketone-substituted tetrahydroimidazo[1,5-a]pyrene The amine protecting group is removed under acidic conditions to obtain the compound of the formula (IB); the intermediate compound (IB) and the carboxylic acid in the condensation reagent bis(2-oxo-3-oxazolidinyl)phosphinium hydrazine Condensation is carried out under chlorine conditions, and the obtained product is further subjected to removal of an amine protecting group under acidic conditions to give a compound of the formula (I).

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

[Embodiment]

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

Example

The structure of the compound is determined by nuclear magnetic resonance ( ¹ H NMR) or mass spectrometry (MS). ^{The 1} H NMR shift (δ) is presented in parts per million (ppm). ^{The 1} H NMR measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated methanol (CD ₃ OD), deuterated chloroform (CDCl ₃ ), and the standard of hexamethyl dimethyl hydrazine (DMSO-d6) was four. Methyl decane (TMS), chemical shifts are shown in units of 10 ^-6 (ppm); MS is measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX); IC ₅₀ values The NovoStar microplate reader (BMG, Germany) was used for the determination; the thin layer tannin was used in Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet; the column chromatography was generally carried out using Yantai Huanghai Rubber Tube 200 to 300 mesh gelatin as carrier.

Unless otherwise stated in the examples, the reactions were all carried out under a nitrogen atmosphere.

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

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

Example 1 (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid methyl ester hydrochloride

first step 2,2-Dimethyl-5-[2-(2,4,5-trifluorophenyl)-ethinyl]-[1,3]dioxane-4,6-dione

2,2-Dimethyl-[1,3]dioxane-4,6-dione (5.69 g, 39.5 mmol) was dissolved in 400 mL of dichloromethane with stirring, and 2 was added under ice-cooling. 4,5-trifluorophenylacetic acid 1a (7.15 g, 37.6 mmol) and p-dimethylaminopyridine (7.35 g, 60.2 mmol), slowly adding 250 mL of 1-(3-dimethylamino-propyl)- 3-ethyl-carbodiimide hydrochloride (8.28 g, 43.2 mmol) in methylene chloride suspension, stirred at room temperature for 36 hours, then 5% potassium hydrogen sulfate solution (250 mL×7) and saturated chlorine The reaction solution was washed with a sodium chloride solution (250 mL×2), dried over anhydrous magnesium sulfate, filtered and evaporated.

MS m/z (ESI): 315.5 (M-1).

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

2,2-Dimethyl-5-[2-(2,4,5-trifluorophenyl)-ethinyl]-[1,3]dioxane-4,6-dione 1b (15.72 g, 49.6 mmol) was dissolved in 280 mL of ethanol with stirring, and stirred in an oil bath at 70 ° C overnight. The mixture was cooled, evaporated, evaporated, evaporated,jjjjjjjjjjjjjjjjjj Liquid), yield: 88%.

MS m/z (ESI): 259 (M-1).

third step Ethyl 3-amino-4-(2,4,5-trifluorophenyl)-but-2-enoate

3-Oxo-4-(2,4,5-trifluorophenyl)-butyric acid ethyl ester 1c (24.6 g, 94.5 mmol) was dissolved in methanol (240 mL), and ammonium acetate (36.4 g, 473 mmol) was added and heated. After refluxing for 3 hours, the reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was concentrated under reduced pressure, and then 100 ml of water was added and extracted with ethyl acetate (200 mL×3). The organic phase was combined and washed with 200 mL of saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. 100 mL of n-hexane, placed in a refrigerator overnight, and suction filtered to give the title product, 3-amino-4-(2,4,5-trifluorophenyl)-but-2-enoic acid ethyl ester 1d (19.5 g, White solid), yield: 80%.

MS m/z (ESI): 260.1 [M+1]

the fourth step (R)-3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid ethyl ester

Add 3-amino-4-(2,4,5-trifluorophenyl)-butyric acid ethyl ester 1d (4.1 g, 15.8 mmol) to the autoclave, then add 70 mL of methanol, dicarbonate (third) Ester) (3.8 g, 17.4 mmol), chloro(1,5-cyclooctadiene) ruthenium (I) dimer (32 mg, 0.0632 mmol) and (R)-1-[(S)-2-(di) Phenylphosphino)ferrocenyl]-ethyl-tert-butylphosphine (68 mg, 0.126 mmol) was reacted for 24 hours at 30 ° C in 6.67 atmospheres of hydrogen. Filtration, concentration of the filtrate under reduced pressure, adding 34 mL of methanol at 50 ° C, completely dissolving, adding 12 mL of water, standing at room temperature, overnight in a refrigerator, filtering, mixing with methanol / water (v: v = 3: 2) The solid product was washed with a solvent and dried <RTI ID=0.0>(jjjjjjjjjjjjjjjjjjjjjjjjjjjjj Solid), yield: 70%.

MS m/z (ESI): 362.4 [M+1].

the fifth step (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid

(R)-3-Tertoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1) Methyl) dissolved in 100 mL of methanol and 50 mL of water in a mixed solvent, reacted at 40 to 45 ° C for 1 to 1.5 hours, concentrated under reduced pressure to remove a portion of the solvent, add a small amount of water, add 1 N hydrochloric acid to adjust the pH of the solution in an ice bath The mixture was extracted with ethyl acetate (200 mL × 3), EtOAc (EtOAc) Crystallization gave the title product (R)-3-(3,4,5-trifluorophenyl)-butyric acid 1f (9.2 g, white solid) reaction.

MS m/z (ESI): 332.3 [M-1].

References: Tetrahedron Asymmetry, 2006, 17(2), 205-209

Step 6 C-pyridyl -2-yl-methylamine

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

MS m/z (ESI): 110 [M + 1].

Seventh step 2,2,2-trifluoro-N-pyridyl -2-methyl-acetamide

C-pyridyl 2-H-methylamine 1h (10.9g, 100mmol) was added to the reaction flask, cooled to 0 ° C in an ice bath, and 20 mL of trifluoroacetic anhydride was slowly added dropwise over 1 hour, and stirred at room temperature for 2 hours. The reaction was traced to the disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 2,2,2-trifluoro-N-pyrid -2-Methyl-acetamide 1i (21.0 g, brown oil).

MS m/z (ESI): 206.1 [M+1].

Eighth step 3-trifluoromethyl-imidazo[1,5-a]pyridinium

2,2,2-trifluoro-N-pyridyl at room temperature 2-methyl-acetamide 1i (21.0 g, 100 mmol) was added to a reaction flask, 100 mL of phosphorus oxychloride was added, and the mixture was stirred at room temperature for 30 minutes, then phosphorus pentoxide (17.8 g, 125 mmol) was added and heated to reflux. After 5 hours, the reaction was traced by thin layer chromatography until the disappearance of the starting material, the solvent phosphorus trichloride was removed, the reaction system was quenched with deionized water, and the pH was adjusted to 5 to 6 with an aqueous solution of 20% sodium hydroxide. The title compound (3-trifluoromethyl-imidazole) was obtained by EtOAc (EtOAc) , 5-a]pyridyl 1j (12.0 g, yellow solid), yield: 65%.

MS m/z (ESI): 188.0 [M+1].

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.15 (s, 1H), 8.06 (d, 1H), 7.92 (s, 1H), 7.81 (d, 1H)

Step 9 3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridinium

3-trifluoromethyl-imidazo[1,5-a]pyridin 1j (12.0 g, 64.2 mmol) was dissolved in 150 mL of absolute ethanol with stirring, and 500 mg of 10% palladium/carbon was added thereto, and stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered through a EtOAc EtOAc EtOAc EtOAc (EtOAc). 1k (12.2 g, brown solid), yield: 99%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 6.84 (s, 1H), 4.10 (m, 4H), 3.26 (m, 2H), 1.81 (s, 1H)

Step 10 (R)-[3-oxo-1-(2,4,5-trifluorobenzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5 -a]pyridyl -7-yl)-propyl]-carbamic acid tert-butyl ester

3-tributyloxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid 1f (8.6 g, 45 mmol) and 9.4 mL of triethylamine were dissolved in 300 mL under stirring in a nitrogen atmosphere. After stirring at room temperature for 5 minutes in dichloromethane, 3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyr was added sequentially. 1k (15.0g, 45mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (17.1g, 67.3mmol), reacted at room temperature for 2 hours, traced by thin layer chromatography until the starting material disappeared The reaction mixture was concentrated under reduced pressure and purified to purified crystals crystals eluted 3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl)-propyl]-aminobutyl carboxylic acid tert-butyl ester 11 (20.0 g, white solid), yield: 88%.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.25 (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-imidazole [1,5-a]pyridyl -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]pyridyl -7-yl)-propyl]-aminocarboxylic acid tert-butyl ester 11 (20.0 g, 39.6 mmol) was dissolved in 300 mL of absolute ethanol with stirring, and N-brominated amber imine (14.1 g, was added at room temperature. 79.2 mmol), after stirring for 1 hour, potassium carbonate (10.9 g, 79.2 mmol) and di(tert-butyl ester) dicarbonate (8.6 g, 39.6 mmol) were added. After reacting for 1 hour, the reaction was traced by thin layer chromatography to The title material (R)-[3-oxo-1-(2, 2) was obtained after the crude material was evaporated. 4,5-trifluorobenzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin -7-yl)-propyl]-carbamic acid tert-butyl ester 1 m (20.0 g, white solid), yield: 86%.

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.063 (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)

Step 12 (R)-7-[3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8- Tetrahydroimidazo[1,5-a]pyridyl Methyl-1-carboxylate

The dicobalt octacarbonyl (4.02 g, 11.76 mmol), ethyl chloroacetate (0.71 g, 5.88 mmol), potassium carbonate (1.62 g, 11.76 mmol) and 50 mL of methanol were placed in a reaction flask, stirred for 5 minutes, and then added ( R)-[3-oxo-1-(2,4,5-trifluorobenzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[ 1,5-a]pyridyl -7-yl)-propyl]-aminocarboxylic acid tert-butyl ester 1m (2.3g, 3.92mmol), the oil bath reacted at 60 ° C, the color changed from dark brown to purple, after 2 hours, ESI traced the reaction, the raw materials disappeared, The reaction mixture was concentrated under reduced pressure and purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl Methyl 1-carboxylate 1 n (1.1 g, white solid), yield: 50%.

MS m/z (ESI): 565.0 (M+1).

References: Journal of Organometallic Chemistry, 1985, 285 (1-3), 293-303

Step 13 (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid methyl ester hydrochloride

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazo[1,5-a]pyridyl Methyl 1-carboxylate 1n (0.12 g, 2.12 mmol) was added to 5 mL of a 2.2N solution of hydrogen chloride in ethyl acetate. After reacting for 5 hours at room temperature, the reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture gave the title product (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanindole-3-trifluoromethyl-5,6,7, 8-tetrahydroimidazo[1,5-a]pyridin 1-carboxylic acid methyl ester hydrochloride 1 (0.12 g, pale yellow solid), yield: 94.3%.

MS m/z (ESI): 465.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.101-7.08 (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(2-methanesulfonyl-ethyl)-carbenamide hydrochloride

first step (R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydro Imidazo[1,5-a]pyridyl 1-carboxylic acid

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazo[1,5-a]pyridyl Methyl 1-carboxylate 1n (2.0 g, 3.5 mmol) was dissolved in 50 mL of methanol with stirring, and 30 mL of 4N sodium hydroxide solution was added thereto. After reacting for 1 hour at room temperature, the reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was adjusted to pH 3 with EtOAc (EtOAc) (EtOAc) [3-Tertidinoxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5 -a]pyridyl 1-carboxylic acid 2a (1.9 g, pale yellow solid).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.29-7.226 (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 (R)-[3-[1-(2-Methanesulfonyl-ethylaminomethylguanidine)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a Pyridine -7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (0.15 g, 0.27 mmol), 2-methanesulfonylethylamine (65.5 mg, 0.41 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.104) g, 0.41 mmol) was dissolved in 5 mL of dichloromethane under stirring, triethylamine (0.25 mL, 1.62 mmol) was added, and the reaction was allowed to stand overnight at room temperature. The reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) -dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 2b (60 mg, white solid), yield: 34 %.

MS m/z (ESI): 678.2 (M+23).

References: Journal of Organic Chemistry, 2006, 71 (3), 1220-1225

third step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(2-methanesulfonyl-ethyl)-carbenamide hydrochloride

(R)-[3-[1-(2-Methanesulfonyl-ethylaminocarbazinyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5- a]pyridyl -3-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 2b (0.06 g, 0.091 mmol) was dissolved in a small amount of acetic acid To the ethyl ester, 4 mL of a 3.1 N solution of hydrogen chloride in ethyl acetate was added, and after reacting for 4 hours at room temperature, the reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to give the title product (R)-7-[ 3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridinium 1-(2-Methanesulfonyl-ethyl)-carbenamide hydrochloride 2 (60 mg, white solid).

MS m/z (ESI): 556.3 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.44-7.35 (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-(morpholin-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (60 mg, 0.109 mmol), morpholine (19 mg, 0.218 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (53.5 mg, 0.218 mmol) dissolved under stirring Triethylamine (0.1 mL, 0.65 mmol) was added to 5 mL of dichloromethane, and the reaction was allowed to stand overnight at room temperature. The reaction was traced by thin layer chromatography until the material disappeared. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography. The residue gave the title product (R)-[3-[1-(morpholin-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a] Pyridine -7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 3a (60 mg, white solid), yield: 89 %.

MS m/z (ESI): 62.

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

MS m/z (ESI): 520.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.42-7.37 (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(cyanomethyl)-carbenamide hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), aminoacetonitrile sulfate (85 mg, 0.41 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.206 g, 0.81 mmol) Dissolve in 10 mL of dichloromethane with stirring with triethylamine (0.37 mL, 2.7 mmol), react overnight at room temperature, trace the reaction by thin layer chromatography until the disappearance of the starting material, concentrate the reaction mixture under reduced pressure, and use a gel column chromatography. The obtained residue was purified to give the title product (R)-[3-[1-(cyanomethyl-aminocarbazide)-3-trifluoromethyl-5,6-dihydro-8H-imidazole [1] , 5-a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 4a (150 mg, white solid), yield: 94.4% .

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(cyanomethyl)-carbenamide hydrochloride

(R)-[3-[1-(Cyanomethyl-aminocarbazinyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin 3-butyl-1-(oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 4a (0.3 g, 0.25 mmol) dissolved in 10 mL of dichloro To the methane, 5 mL of trifluoroacetic acid was added, and after reacting for 1 hour at room temperature, the reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to give the title product (R)-7-[3-amino-4- (2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-(Cyanomethyl)-carbamide hydrochloride 4 (130 mg, pale yellow solid).

MS m/z (ESI): 489.2 (M + 1).

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

first step

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), 1-methylhexahydropyridyl (54 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane with stirring and triethylamine (0.25 mL, 1.62 mmol), the reaction was carried out at room temperature overnight, and the reaction was traced to the disappearance of the material. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography to give the title product (R)-[3-[1 -(4-methyl-hexahydropyridyl -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl 3-butenyl-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 5a (80 mg, white solid), yield: 49 %. MS m/z (ESI): 63:21.

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

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

MS m/z (ESI): 533.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.45-7.38 (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-imidazole And [1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), thiomorpholine-1,1-dioxide hydrochloride (73 mg, 0.54 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium hydrazide Chlorine (0.138 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 8 mL of dichloromethane with stirring, and 4 mL of N,N-dimethylformamide was added and allowed to react at room temperature overnight, thin layer The reaction was traced to the disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure, and the residue obtained was purified to the title compound (R)-[3-[1-(1,1-dioxo-thio) Morpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 6a (170 mg, white solid), yield: 94% .

MS m/z (ESI): 668.1 (M + 1).

Second step (R)-3-Amino-1-[1-(1,1-dioxo-thiomorpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazole And [1,5-a]pyridyl -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]pyridyl 3-butyl-1-(oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 6a (0.15 g, 0.22 mmol) was dissolved in 4 mL of 3.1N The ethyl acetate solution of hydrogen chloride was reacted at room temperature overnight, and the reaction was traced by thin layer chromatography until the material disappeared, and the reaction mixture was 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]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 6 (140 mg, pale yellow solid).

MS m/z (ESI): 568.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.45-7.39 (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)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydro Imidazo[1,5-a]pyridyl -1-carbonyl}-hexahydropyridine-4-carboxamide hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), 4-carbamimidyl hexahydropyridine (70 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g) , 0.54 mmol) was dissolved in 8 mL of dichloromethane with stirring, triethylamine (0.25 mL, 1.62 mmol) was added, then 4 mL of N,N-dimethylformamide was added and allowed to react at room temperature overnight, thin layer chromatography The reaction was traced to the disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure. The residue obtained was purified to the titled product (R)-[3-[1-(4-aminocarbazinyl-hexahydropyridine- 1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 7a (180 mg, white solid), yield: 98 %.

MS m/z (ESI): 660.9 (M + 1).

Second step (R)-1-{7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydro Imidazo[1,5-a]pyridyl -1-carbonyl}-hexahydropyridine-4-carboxamide hydrochloride

(R)-[3-[1-(4-Aminocarboxamidine-hexahydropyridine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5 -a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 7a (0.18 g, 0.27 mmol) and 2 mL of ethyl acetate The ester was added to the reaction flask, and 6 mL of a 2.3 N solution of hydrogen chloride in ethyl acetate was added thereto. After reacting for 3.5 hours at room temperature, the reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to give the title product (R)- 1-{7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1 , 5-a]pyridyl 1-Carbocarbonyl}-hexahydropyridine-4-carboxamide hydrochloride 7 (0.12 g, white solid), yield: 74%.

MS m/z (ESI): 5621.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.42-7.31 (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(N-methyl)formamidine hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), methylamine hydrochloride (36.5 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.54 mmol) Dissolved in 8 mL of dichloromethane under stirring, added triethylamine (0.25 mL, 1.62 mmol), and reacted at room temperature overnight. The reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography to give the title product (R)-[3-(1-methylaminocarbazin-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5 -a]pyridyl -7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 8a (150 mg, white solid), yield: 98.6 %.

MS m/z (ESI): 563.9 (M + 1).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(N-methyl)formamidine hydrochloride

(R)-[3-(1-Methylaminocarbamimido-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 8a (0.15 g, 0.27 mmol) and 2 mL of ethyl acetate The ester was added to the reaction flask, and 5 mL of a 2.3 N solution of hydrogen chloride in ethyl acetate was added thereto. After reacting for 4 hours at room temperature, the reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to give the title product (R)- 7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyridyl 1-(N-methyl)formamidine hydrochloride 8 (0.135 g, white solid), yield: 90%.

MS m/z (ESI): 464.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.40-7.38 (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(N,N-dimethyl)formamidine hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), dimethylamine hydrochloride (44 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.54 mmol) Dissolved in 8 mL of dichloromethane under stirring, added triethylamine (0.25 mL, 1.62 mmol), and reacted at room temperature overnight. The reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography to give the title product (R)-[3-(1-dimethylaminocarbazin-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1, 5-a]pyridyl -7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 9a (120 mg, white solid), yield: 77 %.

MS m/z (ESI): 578.1 (M + 1).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(N,N-dimethyl)formamidine hydrochloride

(R)-[3-(1-Dimethylaminocarbazin-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin -7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 9a (0.138 g, 0.245 mmol) and 2 mL of ethyl acetate The ester was added to the reaction flask, and 4 mL of a 2.3 N solution of hydrogen chloride in ethyl acetate was added thereto. After reacting for 3 hours at room temperature, the reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to give the title product (R)- 7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyridyl 1-(N,N-Dimethyl)formamidine hydrochloride 9 (0.12 g, white solid), yield: 98%.

MS m/z (ESI): 478.2 (M + 1).

Example 10 (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid hydrochloride

first step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid hydrochloride

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (218 mg, 0.4 mmol) was added to a reaction flask, and 5 mL of a solution of hydrogen chloride in ethanol was added thereto, and the mixture was reacted at room temperature. The reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to give the title product (R). -7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5 -a]pyridyl 1-carboxylic acid hydrochloride 10 (60 mg, white solid), yield: 30.8%.

MS m/z (ESI): 4521.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.416-7.37 (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-hexahydropyridine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1, 5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one dihydrochloride

first step Hexahydropyridin-3-yl-carbamic acid tert-butyl ester

(R)-3-Aminopyridinium hydrochloride 11a (3 g, 22.1 mmol) and potassium carbonate (6.1 g, 44.2 mmol) were dissolved in 60 mL of methanol with stirring, and stirred for 30 minutes, then dicarbonate was added ( The third butyl ester) (4.8 g, 22.1 mmol) was reacted at room temperature overnight, and the reaction was traced to the disappearance of the material by thin layer chromatography, and the reaction mixture was concentrated under reduced pressure. Hexahydropyridin-3-yl-carbamic acid tert-butyl ester 11b (1.3 g, oily liquid), yield: 29%.

MS m/z (ESI): 201.0 (M + 1).

Second step (R)-(1-{7-[3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6, 7,8-tetrahydroimidazo[1,5-a]pyridyl -1-carbonyl}-hexahydropyridin-3-yl)-carbamic acid tert-butyl ester

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (0.12 g, 0.218 mmol), hexahydropyridin-3-yl-carbamic acid tert-butyl ester 11b (0.173 g, 0.545 mmol) and triethylamine (0.275 g, 2.18 mmol) Dissolved in 12 mL of dichloromethane, and added bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.545 mmol) at room temperature overnight, and concentrated the reaction mixture under reduced pressure. The obtained residue was purified by column chromatography to give the title product (R)-(1-{7-[3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butenyl] -3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-butylcarbonyl}-hexahydropyridin-3-yl)-carbamic acid tert-butyl ester 11c (0.1 g, oily liquid), yield: 63%. MS m/z (ESI): 733.1 (M + 1).

third step (R)-3-amino-1-[1-(3-amino-hexahydropyridine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1, 5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one salt diacid salt

(R)-(1-{7-[3-Tertidinoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6 ,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-K-carbonyl}-hexahydropyridin-3-yl)-carbamic acid tert-butyl ester 11c (0.1 g, 0.163 mmol) was added to 10 mL of aq. The reaction was traced by thin layer chromatography until the material disappeared, and the mixture was concentrated under reduced pressure to give the title product (R)-3-amino-1-[1-(3-amino-hexahydropyridine-1-carbonyl)-3- Trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one dihydrochloride 11 (0.09 g, white solid), yield: 98%.

MS m/z (ESI): 533.3 (M + 1).

¹ H NMR (400 MHz, CD ₃ 0D): δ 7.415-7.396 (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-(pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), pyrrolidine (38.4 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.54 mmol) with stirring Dissolve in 8 mL of dichloromethane, add triethylamine (0.25 mL, 1.62 mmol), react at room temperature overnight, trace the reaction to the disappearance of the starting material by thin layer chromatography, concentrate the reaction mixture under reduced pressure, and purify by column chromatography. The residue obtained gave the title product (R)-[3-oxo-3-[1-(pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[ 1,5-a]pyridyl -7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 12a (120 mg, white solid), yield: 74%.

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

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

MS m/z (ESI): 504.2 (M + 1).

Example 13 (R)-3-amino-1-[1-hexahydropyridyl -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one dihydrochloride

first step (R)-4-{7-[3-Tertidinoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7 , 8-tetrahydroimidazo[1,5-a]pyridin -1-carbonyl}-hexahydropyridyl 1-carboxylic acid tert-butyl ester

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), hexahydropyridyl 1-carboxylic acid tert-butyl ester (100.6 mg, 0.54 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) was dissolved in 6 mL of dichloromethane under stirring, and reacted at room temperature overnight. The reaction was traced by thin layer chromatography until the material disappeared. The reaction mixture was concentrated under reduced pressure. (R)-4-{7-[3-Tertidinoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7 , 8-tetrahydroimidazo[1,5-a]pyridin -1-carbonyl}-hexahydropyridyl 1-carboxylic acid tert-butyl ester 13a (200 mg, white solid), yield: 99%.

MS m/z (ESI): 719.0 (M+l).

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

(R)-4-{7-[3-Tertidinoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6, 7,8-tetrahydroimidazo[1,5-a]pyridyl -1-carbonyl}-hexahydropyridyl 1-carboxylic acid tert-butyl ester 13a (0.12g, 0.199mmol) was added to the reaction flask, 5mL of 2.3N hydrogen chloride in methanol was added, and the reaction was carried out at room temperature overnight, and the reaction liquid was concentrated under reduced pressure. The obtained residue was purified by chromatography to give the title product (R)-3-amino-1-[1-hexahydropyridin. -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one dihydrochloride 13 (0.10 g, white solid), yield: 94%.

MS m/z (ESI): 504.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.45-7.40 (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-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[ 1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), (R)-3-hydroxypyrrolidine (47 mg, 0.54 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 6 mL of dichloromethane under stirring, and reacted at room temperature overnight. The reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography to give the titled product (d)-[3-[(((())))))) Hydrogen-8H-imidazo[1,5-a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 14a (90 mg, white solid), yield: 53% .

MS m/z (ESI): 62.

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

(R)-[3-[1-((R)-3-Hydroxy-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5 -a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 14a (90 mg, 0.15 mmol) was added 10 mL of 2.3N hydrogen chloride The ethyl acetate solution was reacted at room temperature overnight, and the reaction was traced to the residue eluting with EtOAc (EtOAc). 1-[1-((R)-3-hydroxy-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 14 (60 mg, white solid), yield: 72%.

MS m/z (ESI): 520.3 (M + 1).

¹ H NMR (400 MHZ, CD ₃ OD): δ 7.417-7.372 (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(N-cyclopropyl)formamide hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (0.2 g, 0.36 mmol), cyclopropylamine (0.05 g, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.18 g, 0.72 mmol) Dissolved in 20 mL of dichloromethane under stirring, and added triethylamine (0.36 g, 3.6 mmol) at room temperature, and reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography. , the title product (R)-[3-[1-(cyclopropylaminocarbamimidyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a] Pyridine -7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 15a (0.1 g, oily liquid), yield : 45%.

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(N-cyclopropyl)formamide hydrochloride

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

MS m/z (ESI):495.

¹ H NMR (400 MHz, CD ₃ OD): δ T. 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)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazole And [1,5-a]pyridyl -1-carbonyl}-amino)-acetic acid methyl ester hydrochloride

first step

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol) and amino-acetic acid methyl ester hydrochloride (512 mg, 0.408 mmol) were dissolved in 8 mL of dichloromethane with stirring and triethylamine (0.25 mL, 1.62 mmol). After stirring for 5 minutes, bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.54 mmol) was added, and the reaction was carried out at room temperature for 20 hours, and the reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was concentrated under pressure and the residue obtained was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Phenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl Methyl -1-carbonyl}-amino)-acetate 16a (90 mg, pale yellow oil), yield: 53.6%.

Second step

(R)-({7-[3-Tertidinoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7 , 8-tetrahydroimidazo[1,5-a]pyridin Add 1-methylcarbonyl}-amino)-acetic acid methyl ester 16a (0.09 g, 0.145 mmol) and 2 mL of ethyl acetate to a reaction flask, and add 4 mL of a 2.3 N solution of hydrogen chloride in ethyl acetate, and react at room temperature for 3 hours. The reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to give the title product (R)-({7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl) ]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-Carbocarbonyl}-amino)-acetic acid methyl ester hydrochloride 16 (80 mg, white solid), yield: 99%.

MS m/z (ESI): 5221.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.47-7.30 (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-Ethyl-hexahydropyridyl) -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-3-amino-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), 1-hexahydropyridyl 1-yl-acetone hydrochloride (90 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane with stirring. Triethylamine (0.25 mL, 1.62 mmol) was added, and the reaction was carried out at room temperature overnight, and the reaction was traced to the disappearance of the material. The reaction mixture was concentrated under reduced pressure. Product (R)-[3-[1-(4-Ethyl-hexahydropyridyl) -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 17a (80 mg, white solid), yield: 45% .

MS m/z (ESI): 660.9 (M + 1).

Second step (R)-1-[1-(4-Ethyl-hexahydropyridyl) -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-3-amino-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

(R)-[3-[1-(4-Ethyl-hexahydropyridyl) -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 17a (0.08 g, 0.12 mmol) and 2 mL ethyl acetate After adding to the reaction flask, 2 mL of a 2.7 N solution of hydrogen chloride in ethyl acetate was added, and the reaction was carried out at room temperature overnight, and the reaction was traced by thin layer chromatography until the material disappeared, and the reaction mixture was concentrated under reduced pressure to give the title product (R)-1-[1 -(4-Ethyl-hexahydropyridyl -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl 7-yl]-3-amino-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 17 (70 mg, white solid), yield: 98%. MS m /z (ESI): 561.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ 0D): δ 7.50-7.36 (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-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1, 5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), (R)-pyrrolidin-2-ylmethanol (54.6 mg, 0.54 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 8 mL of dichloromethane under stirring, and allowed to react overnight at room temperature. The reaction was traced by thin layer chromatography until the starting material disappeared. The obtained residue was purified to silica gel column chromatography toiel -dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 18a (120 mg, colorless oil), yield: 70%.

MS m/z (ESI): 633.9 (M + 1).

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

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

MS m/z (ESI): 534.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ 0D): δ 7.39-7.35 (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)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydro Imidazo[1,5-a]pyridyl -1-carbonyl}-hexahydropyridyl 2-ketohydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (150 mg, 0.27 mmol), 2-carbonylhexahydropyridyl (60 mg, 0.6 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.54 mmol), triethylamine (0.25 mL, 1.62 mmol) and 8 mL dichloromethane 10 mL of N,N-dimethylformamide was added to the flask, and the reaction was carried out overnight at room temperature. The reaction was traced by thin layer chromatography until the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The title product (R)-[3-oxo-3-[1-(3-oxo-hexahydropyridyl) was obtained. -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl 3-butyl]-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 19a (140 mg, colorless oil), yield: 82%.

MS m/z (ESI): 632.7 (M + 1).

Second step (R)-4-{7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydro Imidazo[1,5-a]pyridyl -1-carbonyl}-hexahydropyridyl 2-ketohydrochloride

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

MS m/z (ESI): 533.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.38 (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]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (0.15 g, 0.27 mmol), thiazolidine (57 mg, 0.6 mmol), triethylamine (0.275 g, 2.72 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium The hydrazine chloride (0.138 g, 0.544 mmol) was dissolved in 10 mL of dichloromethane under stirring, and stirred at room temperature for 2 hours. The reaction was traced by thin layer chromatography until the material disappeared. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography. The residue obtained gave the title product (R)-[3-oxo-3-[1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[ 1,5-a]pyridyl 3-butyl]-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 20a (0.15 g, white solid), yield: 89%.

MS m/z (ESI): 644.1 (M+23).

Second step (R)-3-amino-1-[1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -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] Pyridine -7-yl]-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 20a (0.15 g, 0.24 mmol) was added to 5 mL of 2.2 N hydrogen chloride in acetic acid The ester solution was reacted at room temperature for 4 hours, and the reaction was traced by thin layer chromatography until the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography to give the title product (R)-3-amine. 1-[1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 20 (100 mg, pale yellow solid), yield: 75%.

MS m/z (ESI): 5221. (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.447-7.358 (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)-butanindole-3-trifluoromethyl-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl -1-(pyridin-3-yl)carbenamide dihydrochloride

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

(R)-7-[3-Tertioxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen imidazo[1,5-a]pyridyl 1-carboxylic acid 2a (0.15 g, 0.272 mmol) was dissolved in 10 mL of dichloromethane with stirring, then 3-aminopyridine (38.4 mg, 0.41 mmol), triethylamine (0.275 g, 2.72 mmol) and bis ( 2-oxo-3-oxazolidinyl)phosphinium chloride (0.138 g, 0.544 mmol), stirred at room temperature overnight, the reaction was traced by thin layer chromatography until the material disappeared, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography to give the titled product (D)-[3-oxo-3-[l-(pyridin-3-ylaminocarbamoyl)-3-trifluoromethyl-5,6- Dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 21a (0.1 g, white solid), yield: 58.8%.

MS m/z (ESI): 627.1 (M + 1).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanindole-3-trifluoromethyl-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl -1-(pyridin-3-yl)carbenamide dihydrochloride

(R)-[3-oxo-3-[1-(pyridin-3-ylaminocarbamimidyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1, 5-a]pyridyl -7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 21a (0.1 g, 0.16 mmol) was added to 10 mL of 2.2 N hydrogen chloride in acetic acid The ethyl ester solution was reacted at room temperature for 4 hours, and the reaction was traced by thin layer chromatography until the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography to give the title product (R)-7-[ 3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridinium 1-(Pyridin-3-yl)carbenamide dihydrochloride 21 (80 mg, white solid), yield: 89%.

MS m/z (ESI): 527.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 9.584 (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-methylsulfonyl-hexahydropyridyl) -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.15 g, 0.27 mmol), 1-methanesulfonyl-hexahydropyridyl (0.109 g, 0.55 mmol) and triethylamine (0.38 mL, 2.7 mmol) were dissolved in 10 mL of dichloromethane with stirring and bis(2-oxo-3-oxazolidine)phosphinium chloride (0.139 g) , 0.55 mmol), the reaction was stirred at room temperature overnight, and the reaction mixture was evaporated to dryness, and the residue was evaporated to dryness. [1-(4-Methanesulfonyl-hexahydropyridyl) -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl 3-butyl-1-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 22a (0.2 g, white solid).

MS m/z (ESI): 696.9 (M + 1).

Second step (R)-3-amino-1-[1-(4-methylsulfonyl-hexahydropyridyl) -1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

MS m/z (ESI): 597.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.46-7.34 (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid ethyl ester hydrochloride

first step (R)-7-[3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8- Tetrahydroimidazo[1,5-a]pyridyl Ethyl-1-carboxylate

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.16 g, 0.29 mmol) was dissolved in 10 mL of dichloromethane with stirring, and ethanol (0.05 mL, 0.87 mmol), triethylamine (0.202 mL, 1.45 mmol) and bis(2-oxo) were added. -3-oxazolidinyl)phosphinium chloride (0.148 g, 0.58 mmol), stirred at room temperature for 5 hours, the reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography to give the title product (R)-7-[3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl 5-,6,7,8-tetrahydroimidazo[1,5-a]pyridyl Ethyl 1-carboxylate 23a (0.1 g, colorless oily liquid).

MS m/z (ESI): 579.0 (M+l).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid ethyl ester hydrochloride

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazo[1,5-a]pyridyl Ethyl 1-carboxylate 23a (0.09g, 0.156mmol) and 2mL of ethyl acetate were added to the reaction flask, 4mL of 2.7N hydrogen chloride in ethyl acetate solution was added, and the reaction was carried out for 3 hours at room temperature, thin layer chromatography The reaction was followed until the disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure to give the title product (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl 5-,6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid ethyl ester hydrochloride 23 (80 mg, white solid), yield: 99%.

MS m/z (ESI): 479.1 (M + 1).

¹ H NMR (400 MHz, CD ₃ 0D): δ 7.50-7.45 (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-carboxamide hydrochloride

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

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.206 g, 1.08 mmol) and triethylamine (0.25 mL, 1.62 mmol) Dissolved in 10 mL of tetrahydrofuran with stirring. After stirring for 10 minutes, ammonium carbonate (78 mg, 0.81 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by chromatography to give the titled product (D)-[3-(1-aminocarbazin-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a Pyridine Benzyl 3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 24a (0.162 g, white solid).

MS m/z (ESI): 549.9 (M + 1).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-carboxamide hydrochloride

(R)-[3-(1-Aminoformamidine-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 24a (0.16 g, 0.29 mmol) and 2 mL ethyl acetate The reaction mixture was placed in a reaction flask, and 5 mL of a 2.7 N solution of hydrogen chloride in ethyl acetate was added thereto. After reacting for 3 hours at room temperature, the reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to give the title product (R)-7. -[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a Pyridine -1-carboxamide hydrochloride 24 (150 mg, white solid), yield: 95%.

MS m/z (ESI): 450.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.40-7.36 (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-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[ 1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.140 g, 0.54 mmol), triethylamine (0.4 mL, 2.6 mmol) And (R)-3-fluoropyrrolidine hydrochloride (68 mg, 0.54 mmol) was dissolved in 10 mL of dichloromethane with stirring, and the reaction was stirred at room temperature overnight, and the reaction was traced by thin layer chromatography until the material disappeared. The residue obtained was purified by silica gel column chromatography to give the title product (R)-[3-[1-((R)-3-fluoro-pyrrolidin-1-carbonyl)-3-trifluoromethyl -5,6-dihydro-8H-imidazo[1,5-a]pyridyl 3-butyl-1-(oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 25a (0.162 g, white solid).

MS m/z (ESI): 622.0 (M + 1).

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

(R)-[3-[1-((R)-3-fluoro-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5 -a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 25a (0.15 g, 0.27 mmol) and 2 mL ethyl acetate The reaction mixture was placed in a reaction flask, and 5 mL of a 2.7 N solution of hydrogen chloride in ethyl acetate was added thereto. After reacting for 3 hours at room temperature, the reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to give the title product (R)-3. -amino-1-[1-((R)-3-fluoro-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a Pyridine -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 25 (140 mg, white solid), yield: 94%.

MS m/z (ESI): 5221.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.42-7.37 (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-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[ 1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.140 g, 0.54 mmol), triethylamine (0.4 mL, 2.6 mmol) And (S)-3-fluoropyrrolidine hydrochloride (68 mg, 0.54 mmol) was dissolved in 10 mL of dichloromethane with stirring, and the reaction was stirred at room temperature overnight, and the reaction was traced by thin layer chromatography until the starting material disappeared. The residue was purified by silica gel column chromatography to give the title product (R)-[3-[1-((S)-3-fluoro-pyrrolidin-1-carbonyl)-3-trifluoromethyl -5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 26a (0.15 g, white solid), yield: 89 %.

MS m/z (ESI): 622.0 (M + 1).

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

(R)-[3-[1-((S)-3-fluoro-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5 -a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 26a (0.15 g, 0.24 mmol) and 2 mL ethyl acetate The reaction mixture was placed in a reaction flask, and 5 mL of a 2.7 N solution of hydrogen chloride in ethyl acetate was added thereto. After reacting for 3 hours at room temperature, the reaction was traced by thin layer chromatography until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to give the title product (R)-3. -amino-1-[1-((S)-3-fluoro-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a Pyridine -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 26 (140 mg, white solid), yield: 94%. MS m/z (ESI): 5221.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.42-7.37 (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-Ethyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridinium -7-yl)-3-amino-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

3-trifluoromethyl-imidazo[1,5-a]pyridin 1j (3.5 g, 18.7 mmol) was dissolved in 50 mL of ethanol, and 0.5 g of 10% palladium/carbon was added thereto with stirring, and the mixture was stirred overnight under a hydrogen atmosphere, and the reaction was completed. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with 100 mL of ethanol, and the obtained solution was gradually added dropwise with di(tributyl phthalate) (6.2 g, 28.1 mmol). After 100 mL of ethanol solution was added, stirring was continued for 30 minutes and the reaction was completed. The reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted eluted eluted eluted eluted -7-carboxylic acid tert-butyl ester 27a (3.7 g, white solid), yield: 68%.

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

The compound obtained in the above step was added to a 100 mL dry flask. 3-Trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin After the 7-carboxylic acid tert-butyl ester 27a (300 mg, 1.04 mmol) and 50 mL of ethanol were stirred and dissolved, N-bromosuccinimide (369 mg, 2.08 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and then purified, mjjjjjjjjjjj And [1,5-a]pyridyl -7-carboxylic acid tert-butyl ester 27b (220 mg, white solid), yield: 57.8%.

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

Dissolving octacarbonyl bis-cobalt (5.54 g, 16.2 mmol) and potassium carbonate (11.2 g, 81.1 mmol) in 100 mL of methanol with stirring, stirring at 60 ° C for 15 minutes, adding 1-bromo-3-trifluoromethyl-5 ,6-Dihydro-8H-imidazo[1,5-a]pyridin -7-carboxylic acid tert-butyl ester 27b (3 g, 8.11 mmol) and methyl chloroacetate (5.25 g, 48.6 mmol) were reacted for 6 hours under a carbon monoxide atmosphere, and the reaction was traced by thin layer chromatography until the starting material disappeared. The solution was cooled to room temperature, filtered with a EtOAc EtOAc EtOAc EtOAc. 8H-imidazo[1,5-a]pyridyl -1,7-dicarboxylic acid 7-tert-butyl ester-1-methyl ester 27c (1.92 g, 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]pyridyl -1,7-dicarboxylic acid 7-tert-butyl ester

3-Trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin -1,7-dicarboxylic acid 7-tert-butyl ester 1-methyl ester 27c (1.92 g, 5.5 mmol) was dissolved in 50 mL of methanol with stirring, and 30 mL of 4N sodium hydroxide solution was added thereto, and the reaction was carried out for 30 minutes at room temperature. The reaction was carried out by thin-layer chromatography, and the mixture was evaporated to dryness. The mixture was evaporated to ethyl acetate (100 mL×3). The title product 3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -1,7-Dicarboxylic acid 7-tert-butyl ester 27d (2 g, white solid) was used directly in the next step.

the fifth step 1-(Methoxy-methyl-aminomethylindenyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-carboxylic acid tert-butyl ester

3-Trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin -1,7-dicarboxylic acid 7-t-butyl ester 27d (1.84 g, 5.5 mmol), N-methoxymethylamine (0.805 g, 8.25 mmol) was dissolved in 50 mL of dichloromethane with stirring, and added triethyl Amine (3 mL, 22 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (2.1 g, 8.25 mmol) was added and allowed to react overnight at room temperature, and the reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was concentrated under reduced pressure and purified mjjjjjjjjjjjjjjj Hydrogen-8H-imidazo[1,5-a]pyridyl -7-carboxylic acid tert-butyl ester 27e (2.1 g, white solid).

MS m/z (ESI): 379.1 (M + 1).

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

1-(Methoxy-methyl-aminomethylmethyl)-3-trifluoromethyl-5,6-dihydro-8Π-imidazo[1,5-a]pyridyl -7-carboxylic acid tert-butyl ester 27e (0.3 g, 0.79 mmol) was dissolved in 20 mL of tetrahydrofuran with stirring, and methyl magnesium bromide (1.13 mL, 1.58 mmol) was added dropwise at 0 ° C, and reacted at 0 ° C for 1.5 hours. The mixture was subjected to chromatography and the residue was evaporated to dryness. EtOAc (EtOAc m. The filtrate was purified by silica gel column chromatography to give the titled product 1-ethyl-l-yl-trifluoromethyl-5,6-dihydro-8?-imidazo[1,5-a]pyridin. -7-carboxylic acid tert-butyl ester 27f (0.24 g, yellow oily liquid), yield: 90%.

MS m/z (ESI): 334.0 (M + 1).

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

1-Ethyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridinium -7-carboxylic acid tert-butyl ester 27f (0.24g, 0.72mmol) was dissolved in a small amount of ethyl acetate with stirring, added 5mL of 2.7N hydrogen chloride in ethyl acetate solution, reacted at room temperature, traced by thin layer chromatography The disappearance of the starting material and concentration of the reaction mixture under reduced pressure afforded the title product 1-(3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin. -1--yl)-ethanone 27 g was used directly in the next reaction.

Eighth step

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

1-(3-Trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin -1-yl)-ethanone 27g (192mg, 0.72mmol) and (R)-3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid 1f (0.24 g, 0.72 mmol) was dissolved in 20 mL of dichloromethane with stirring, triethylamine (0.4 mL, 2.88 mmol) was added, and after stirring, bis(2-oxo-3-oxazolidinyl)phosphinium chloride was added. (0.275 g, 1.08 mmol), the reaction was carried out at room temperature overnight, and the mixture was subjected to a thin layer chromatography to afford the disappearance of the material, and the reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography to give the title product (R)-[ 3-(1-Ethyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridinium T-butyl 3-phenyl)-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid, mp (3 g, m.

MS m/z (ESI): 449.2.

Step 9 (R)-1-(1-Ethyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridinium -7-yl)-3-amino-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

(R)-[3-(1-Ethyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin -3-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 27 h (0.3 g, 0.55 mmol) dissolved in 2 mL with stirring To the ethyl acetate, 5 mL of a 2.4 N solution of hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature. The reaction was traced by thin layer chromatography until the material disappeared. The reaction mixture was concentrated under reduced pressure. The title product (R)-1-(1-ethylmercapto-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl)-3-amino-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 27 (0.15 g, white solid), yield: 57%.

MS m/z (ESI): 548.9 (M+1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.37 (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]pyridyl -7-yl)-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

1-(Methoxy-methyl-aminoformamidine)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-carboxylic acid tert-butyl ester 27e (0.3 g, 0.79 mmol) was dissolved in 20 mL of tetrahydrofuran with stirring, and cyclopentylmagnesium bromide (0.79 mL, 1.58 mmol) was added dropwise at 0 ° C, and reacted at 0 ° C for 3 hours. TLC was used to trace the reaction to the disappearance of the starting material. Add 50 mL of saturated ammonium chloride solution and 10 mL of saturated sodium chloride solution, extract with ethyl acetate (100 ml × 3), and combine the organic phases, dried over anhydrous magnesium sulfate, filtered, reduced The filtrate was concentrated, and the obtained residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted Pyridine -7-carboxylic acid tert-butyl ester 28a (0.1 g, yellow oily liquid), yield: 30%.

MS m/z (ESI): 388.1 (M + 1).

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

1-cyclopentylcarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-carboxylic acid tert-butyl ester 28a (0.1 g, 0.258 mmol) was dissolved in a small amount of ethyl acetate with stirring, and 5 mL of 2.7 N hydrogen chloride in ethyl acetate was added thereto, and reacted at room temperature for 2 hours, a thin layer The reaction was traced to disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure to give the titled product, pentyl-(3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin. -1-yl)-methanone 28b was used directly in the next reaction.

MS m/z (ESI): 288.2 (M + 1).

third step (R)-[3-(1-cyclopentylcarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -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]pyridyl -1-yl)-methanone 28b (83 mg, 0.258 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid 1f (0.129 g, 0.388 mmol) was dissolved in 10 mL of dichloromethane under stirring, triethylamine (0.143 mL, 1.03 mmol) was added, and after stirring, bis(2-oxo-3-oxazolidinyl)phosphinium chloride was added. (0.099 g, 0.388 mmol), the reaction was carried out at room temperature overnight, and the reaction was traced to the disappearance of the material, and the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give the title product (R)-[ 3-(1-cyclopentylcarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester hydrochloride 28c (0.11 g, orange oily) , yield: 72%. 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]pyridyl -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]pyridyl -3-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 28c (0.11 g, 0.183 mmol) was dissolved in 2 mL with stirring To the ethyl acetate, 5 mL of a 2.4 N solution of hydrogen chloride in ethyl acetate was added, and the mixture was stirred at room temperature. The reaction was traced by thin layer chromatography until the material disappeared. The reaction mixture was concentrated under reduced pressure. The title product (R)-3-amino-1-(1-cyclopentylcarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -7-yl)-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 28 (80 mg, yellow solid), yield: 81%.

MS m/z (ESI): 50.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.41 (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(2-dimethylaminoethyl)-carbenamide dihydrochloride

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

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.14 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) Dissolve in 10 mL of dichloromethane with stirring, add N,N'-dimethylethane-1,2-diamine (48 mg, 0.54 mmol), stir the reaction at room temperature overnight, and trace the reaction to the starting material by thin layer chromatography. After disappearing, the reaction mixture was concentrated under reduced pressure. 3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl 3-butyl-1-(oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 29a (0.1 g, white solid).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(2-dimethylaminoethyl)-carbenamide dihydrochloride

(R)-[3-[1-(2-Dimethylamino-ethylaminocarbazinyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5 -a]pyridyl -3-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 29a (0.10 g, 0.16 mmol) was dissolved in 2 mL with stirring To the ethyl acetate, 6 mL of a 2.4 N solution of hydrogen chloride in ethyl acetate was added, and the reaction was carried out for 4 hours at room temperature. The reaction was traced by thin layer chromatography until the material disappeared. The reaction mixture was concentrated under reduced pressure. The title compound (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5 was obtained. ,6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-(2-Dimethylamino-ethyl)-carbenamide dihydrochloride 29 (80 mg, white solid), yield: 63%.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.46-7.39 (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-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazole [1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

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

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.15 g, 0.27 mmol), (S)-pyrrolidin-2-ylmethanol (54.62 mg, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) dissolved in 10 mL of dichloro To the methane, bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.14 g, 0.54 mmol) was added, and the reaction was stirred at room temperature overnight, and the reaction was traced by thin layer chromatography until the material disappeared. The reaction mixture was purified by silica gel column chromatography to give the titled product (R)-[3-[1-((S)-2-hydroxymethyl-pyrrolidin-1-carbonyl)-3- Fluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl 3-butyl-1-(oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 30a (0.2 g, white solid).

Second step (R)-3-amino-1-[1-((S)2-hydroxymethyl-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazole [1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

(R)-[3-[1-((S)-2-Hydroxymethyl-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1] , 5-a]pyridyl -7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 30a (0.16 g, 0.25 mmol) and 2 mL of dichloromethane Adding to the reaction flask, adding 5 mL of a 2.7 N solution of hydrogen chloride in methanol, and reacting at room temperature overnight, the reaction was traced by thin layer chromatography until the disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The title product (R)-3-Amino-1-[1-((S)2-hydroxymethyl-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H was obtained. -imidazo[1,5-a]pyridyl -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 30 (120 mg, white solid), yield: 84%.

¹ H NMR (400 MHz, CD ₃ 0D): δ 7.34-7.30 (m, 1H), 7.19-7.12 (m, 1H), 5.10 - 4.92 (m, 2H), 4.27 - 4.25 (m, 2H), 4. 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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(pyridin-2-yl)carbenamide dihydrochloride

first step (R)-[3-oxo-3-[1-(pyridin-2-ylaminocarbazinyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5- a]pyridyl -7-yl]-1-(2,4,5-trifluorobenzyl)-propyl]-aminomethylmercapto-tert-butyl ester

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.15 g, 0.27 mmol), 2-aminopyridine (51 g, 0.54 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 10 mL of dichloromethane with stirring and stirred for 20 min. Add bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.14 g, 0.54 mmol), stir the reaction at room temperature overnight, trace the reaction to the disappearance of the material by thin layer chromatography, and concentrate the reaction mixture under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford the title product (R)-[3-oxo-3-[1-(pyridin-2-ylaminocarbazinyl)-3-trifluoromethyl-5 ,6-Dihydro-8H-imidazo[1,5-a]pyridin -7-yl]-1-(2,4,5-trifluorobenzyl)-propyl]-aminomethylguanidinyl tributyl ester 31a (0.1 g, white solid), yield: 59%.

MS m/z (ESI): 627.1 (M + 1).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(pyridin-2-yl)carbenamide dihydrochloride

(R)-[3-oxo-3-[1-(pyridin-2-ylaminocarbazinyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5 -a]pyridyl -7-yl]-1-(2,4,5-trifluorobenzyl)-propyl]-aminocarbamimidyl tributyl ester 31a (0.10 g, 0.16 mmol) and 2 mL of dichloromethane were added to the reaction flask 5 mL of a 2.7 N solution of hydrogen chloride in methanol was added, and the reaction was carried out at room temperature overnight, and the reaction was traced to the disappearance of the material, and the mixture was concentrated under reduced pressure. R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1 , 5-a]pyridyl 1-(Pyridin-2-yl)carhamamine dihydrochloride 31 (80 mg, white solid), yield: 95.2%.

MS m/z (ESI): 527.1 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.48 (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(4-fluorophenyl)-carbenamide hydrochloride

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

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.14 g, 0.54 mmol), triethylamine (0.25 mL, 1.62 mmol) Dissolved in 10 mL of dichloromethane, 4-fluoroaniline (0.06 g, 0.54 mmol) was added in one portion, stirred overnight, and the reaction was traced by thin layer chromatography until the material disappeared. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography. The residue obtained gave the title product (R)-t-butyl-4-(1-((4-fluorophenyl)carbamidine)-3-(trifluoromethyl)-5,6-dihydroimidazole. And [1,5-a]pyridyl Benzyl -7(8H)-yl)-4-oxo-1-(2,4,5-trifluorophenyl)carbamate 32a (0.12 g, white solid), yield: 69%.

MS m/z (ESI): 643.9 (M + 1).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-(4-fluorophenyl)-carbenamide hydrochloride

(R)-Tertibutyl-4-(1-((4-fluorophenyl)carbamidine)-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5- a]pyridyl -3(8H)-yl)-4-oxo-1-(2,4,5-trifluorophenyl)carbamic acid tert-butyl ester 32a (0.12 g, 0.186 mmol) and 2 mL of ethyl acetate In a flask, 8 mL of a 2.7 N solution of hydrogen chloride in ethyl acetate was added, and the reaction was stirred overnight, and the reaction was traced by thin layer chromatography until the material disappeared, and the mixture was concentrated under reduced pressure to give the title product (R)-7-[3-amine 4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-(4-Fluorophenyl)-carbenamide hydrochloride 32 (110 mg, white solid). Yield: 100%.

MS m/z (ESI): 544.1 (M + 1).

^{1 HNMR (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -l-benzyl carboxylate hydrochloride

first step (R)-7-[3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8- Tetrahydroimidazole [1,5-a]pyridyl Benzyl-1-carboxylate

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.24 g, 0.44 mmol), 1-hydroxy-benzo-triazole (0.072 g, 0.53 mmol) and N-(3-dimethylaminopropyl)-N'-ethyl carbon Diimine hydrochloride (0.102 g, 0.53 mmol) was stirred and dissolved in 10 mL of dichloromethane, then benzyl alcohol (0.1 ml, 0.88 mmol) was added, and the reaction was stirred at room temperature overnight, and the reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was concentrated under reduced pressure and purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Phenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazole [1,5-a]pyridyl Benzyl 1-carboxylate 33a (0.056 g, white solid), yield: 20%.

MS m/z (ESI): 640.9 (M + 1).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl -1-carboxylic acid benzyl ester hydrochloride

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl Benzyl 1-benzoate 33a (0.056 g, 0.087 mmol) and 2 mL of 2.7 N hydrogen chloride in ethyl acetate were added to the reaction flask, stirred at room temperature for 2 hours, and the reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was concentrated to give the title product (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7, 8-tetrahydroimidazo[1,5-a]pyridin Benzyl -1-carboxylate hydrochloride 33 (0.043 g, white solid), yield: 86%.

MS m/z (ESI): 541.2 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): 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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid (1-ethoxyantoxy)ethyl ester hydrochloride

first step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid (1-ethoxyoxoxy) methyl ethyl ester

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.275 g, 0.5 mmol) and 4 mL of N,N-dimethylformamide were added to the reaction tube, and 1-chloroethylethyl carbonate (0.092 g, 0.6 mmol) was added sequentially with stirring. Potassium iodide (0.0415g, 0.25mmol), and potassium carbonate (0.083g, 0.6mmol), sealed in an oil bath, controlled at an external temperature of 65 ° C for 2 hours, traced by thin layer chromatography to disappear, the reaction tube After cooling to room temperature, 40 mL of water was added, and ethyl acetate (25 mL×3) was evaporated. The residue obtained was purified to give the title compound (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6, 7,8-tetrahydroimidazo[1,5-a]pyridyl Ethyl 1-(carboxyethoxycarbonyl)carboxylate 34a (0.26 g, white solid), yield: 78.1%.

MS m/z (ESI): 666.9 (M + 1)

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.08 (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 (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid (1-ethoxyantoxy)ethyl ester hydrochloride

(R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl 1-carboxylic acid (1-ethoxymethoxy)ethyl ester 34a (0.26 g, 0.39 mmol) and 5 mL of ethyl acetate were added to the reaction flask, and then 3 mL of a 6.5 N solution of hydrogen chloride in ethyl acetate was added. The reaction mixture was stirred at room temperature for 6 hours, and the reaction mixture was evaporated to dryness, and the residue was evaporated. 4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridinium 1-carboxylic acid (1-ethoxyoxoxy)ethyl ester hydrochloride 34 (0.2 g, white solid), yield: 85%.

MS m/z (ESI): 567.0 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 7.30 (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)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl 1-carboxylic acid isopropyl ester hydrochloride

first step (R)-7-(3-(Tertidinoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7 , 8-tetrahydroimidazo[1,5-a]pyridin Isopropyl 1-carboxylate

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.3 g, 0.54 mmol) was placed in a 50 mL reaction flask, 10 mL of dichloromethane was added, 2 mL of isopropanol was added, followed by 0.3 mL of triethylamine, and after 1 minute, bis(2- Oxo-3-oxazolidinyl)phosphinium chloride (0.277 g, 1.09 mmol), stirred at room temperature for 2 hours, then 10 mL of isopropanol and sodium isopropoxide (0.177 g, 2.16 mmol), room The reaction was stirred for 1.5 hours under temperature, and the reaction was traced by thin layer chromatography until the disappearance of the starting material. About 10 mL of a saturated ammonium chloride solution was added, and a white solid was precipitated, and the pad was filtered, and the filtrate was collected, and 50 mL of water was added thereto, and extracted with ethyl acetate ( 25 mL × 5), the combined organic phase was washed with EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 7-(3-(Tertidinoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8 -tetrahydroimidazo[1,5-a]pyridyl Isopropyl l-carboxylate 35a (0.185 g, white solid), yield: 57.8%.

MS m/z (ESI): 59.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.146-7.082 (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 (R)-7-(3-(Tertidinoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7 , 8-tetrahydroimidazo[1,5-a]pyridin 1-carboxylic acid isopropyl ester hydrochloride

(R)-7-(3-(Tertidinoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6, 7,8-tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid isopropyl ester 35a (0.17 g, 0.29 mmol) and 10 mL of ethyl acetate were placed in a reaction flask, and 5 mL of a 5.5 N solution of hydrogen chloride in ethyl acetate was added to the ice bath, and the ice was removed. The mixture was stirred at room temperature for 2 hours, and the reaction mixture was evaporated to dryness eluted with EtOAc (EtOAc). 3-(Tertidinoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl 1-carboxylic acid isopropyl ester hydrochloride 35 (0.15 g, white solid), yield: 97.8%.

MS m/z (ESI): 49:21.

¹ H NMR (400 MHz, DMSO): δ 7.631-7.482 (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)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl 1-carboxylic acid tert-butyl ester hydrochloride

first step (R)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl 1-carboxylic acid tert-butyl ester

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.3 g, 0.54 mmol), 10 mL of dichloromethane, 5 mL of tert-butanol was added to a 100 mL reaction flask, and 0.3 mL of triethylamine and bis(2-oxo-3-) were added in sequence with stirring. Oxazole alkyl)phosphorus chloride (0.277 g, 1.09 mmol), stirred at room temperature for 2 hours, then 10 mL of third butanol and potassium butoxide (0.24 g, 2.16 mmol) were added to continue at room temperature The reaction was stirred for 2 hours, and the reaction was traced by thin layer chromatography until the starting material disappeared. 10 mL of saturated ammonium chloride solution was added to the reaction solution, and a white solid was precipitated. The pad was filtered through a pad of 100-200 mesh, and the filtrate was collected. 50 mL of water was added and extracted with ethyl acetate (25 mL×5). The title compound (R)-7-(3-amino-4-() was obtained by the title compound (R)-7-(3-amino-4-( 2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid tert-butyl ester 36a (0.11 g, white solid), yield: 33.6%.

MS m/z (ESI): 629.2 (M+23).

¹ H NMR (400 MHz, CH ₃ 0D): δ 7.255-7.090 (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 (R)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl 1-carboxylic acid tert-butyl ester hydrochloride

(R)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazole And [1,5-a]pyridyl 1-carboxylic acid tert-butyl ester 36a (0.094 g, 0.15 mmol) and 10 mL of ethyl acetate were added to the reaction flask, and 3 mL of a 5.5 N solution of hydrogen chloride in ethyl acetate was added to the reaction flask under ice bath. After the addition was completed, the ice bath was removed, and the mixture was stirred at room temperature for 3 hours, and the mixture was subjected to a thin layer chromatography to afford the disappearance of the material. The mixture was concentrated under reduced pressure, washed with 20 mL of n-hexane and concentrated under reduced pressure to give the title product (R)-7- ( 3-amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a] Pyridine 1-carboxylic acid tert-butyl ester hydrochloride 36 (0.084 g, white solid), yield: 100%.

MS m/z (ESI): 507.0 (M + 1).

¹ H NMR (400 MHz, CH ₃ OD): δ 7.431-7.387 (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)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl 1-carboxylic acid (1-isopropoxymethyl methoxy) ethyl ester hydrochloride

first step (R)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl 1-carboxylic acid (1-isopropoxymethyl methoxy) ethyl ester

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.275 g, 0.5 mmol) and 4 mL of N,N-dimethylformamide were added to the reaction tube, stirred to dissolve, and then 1-hexyl carbonate was added to the reaction tube in turn - Isopropyl ester (0.1g, 0.6mmol), potassium iodide (0.0415g, 0.25mmol), potassium carbonate (0.083g, 0.6mmol), added, sealed, placed in an oil bath to control the external temperature of the oil bath 65 ° C, the reaction After 2 hours, the reaction was traced by thin layer chromatography until the starting material disappeared. The reaction tube was taken out from the oil bath, and after it was cooled to room temperature, 40 mL of water was added thereto, and extracted with ethyl acetate (25 mL×3), and the product was detected by thin layer chromatography, and the organic phase was collected and washed with water. (20 mL × 2), EtOAc (EtOAc m.) 4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin 1-carboxylic acid 1-(isopropoxymethyloxy)ethyl ester 37a (0.29 g, pale yellow solid), yield: 85.3%.

MS m/z (ESI): 698.0 (M + 18).

_{^{1 HNMR (400MHz, CDC1 3)}} : δ7.12 (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 (R)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl 1-carboxylic acid (isopropoxymethyl methoxy) ethyl ester hydrochloride

(R)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazole And [1,5-a]pyridyl 1-carboxylic acid (isopropoxymethyl methoxy) ethyl ester 37a (0.29 g, 0.43 mmol) and 5 mL of ethyl acetate were added to the reaction flask, and then 3 mL of 6.5 N hydrogen chloride in ethyl acetate solution was added at room temperature. The reaction was stirred for 4 hours, and the reaction was evaporated to dryness eluted with EtOAc (EtOAc). -(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid (isopropoxymethyl methoxy) ethyl ester hydrochloride 37 (0.24 g, white solid), yield: 91.2%.

MS m/z (ESI): 58.

¹ H NMR (400 MHZ, CD ₃ 0D): δ 7.38 (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid-(1-cyclohexyldecyloxy)ethyl ester hydrochloride

first step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid-(1-cyclohexyldecyloxy)ethyl ester

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (0.275 g, 0.5 mmol) and 4 mL of N,N-dimethylformamide were placed in a reaction tube, and 2a was dissolved by stirring, and 1-chloroethyl carbonate was sequentially added to the reaction tube. Cyclohexyl ester (0.124 g, 0.6 mmol), potassium iodide (0.0415 g, 0.25 mmol), potassium carbonate (0.083 g, 0.6 mmol), after completion, the tube was sealed, and the reaction was stirred at an external temperature of 65 ° C for 2 hours in an oil bath. The reaction was traced by thin layer chromatography until the starting material disappeared. The reaction tube was taken out from the oil bath. After the reaction mixture was cooled to room temperature, 40 mL of water was added thereto, and the mixture was extracted with ethyl acetate (30 mL×3), and the organic phase was combined, washed with 30 mL of water, and then washed with 30 mL of saturated brine. The organic phase was combined, dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin 1-carboxylic acid-(1-cyclohexyldecyloxy)ethyl ester 38a (0.25 g, white solid), yield: 69.4%.

MS m/z (ESI): 721.0 (M + 1).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[ 1,5-a]pyridyl 1-carboxylic acid-(1-cyclohexyldecyloxy)ethyl ester hydrochloride

(R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl 1-(1-cyclohexyldecyloxy)ethyl ester 38-(0.1 g, 0.347 mmol) and 5 mL of ethyl acetate were placed in a reaction flask, and 3 mL of a 6.5 N solution of hydrogen chloride in ethyl acetate was added with stirring. The reaction mixture was stirred at room temperature overnight, and the mixture was evaporated to dryness eluted eluted eluted eluted 4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin 1-carboxylic acid-(1-cyclohexyldecyloxy)ethyl ester hydrochloride 38 (0.22 g, white solid), yield: 96.1%.

MS m/z (ESI): 6221.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.30 (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)-butenyl]-8-methyl-3-trifluoromethyl-5,6,7,8- Tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid methyl ester hydrochloride

first step 8-methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -1,7-dicarboxylic acid-7-t-butyl ester

3-Trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin -1,7-dicarboxylic acid 7-t-butyl ester 27d (0.85 g, 2.54 mmol) was dissolved in a mixed solvent of 25 mL of anhydrous toluene and 8 mL of anhydrous tetrahydrofuran, and the reaction flask was placed in a dry ice-acetone bath to cool to -78 °C, tetramethylethylenediamine (1.32mL, 8087mmol) was added, n-butyl lithium (5.55mL, 8.87mmol) was added dropwise, and the addition was completed in five minutes. The external temperature was -78 ° C, and the reaction was carried out for 15 minutes. Methyl iodide (0.4 mL, 6.34 mmol) was added, and the mixture was reacted at -78 ° C for 10 minutes, then allowed to react to room temperature for 2 hours, and the reaction was traced by thin layer chromatography until the starting material disappeared. A saturated solution of 15 mL of ammonium chloride was added to the reaction mixture, and then 20 mL of water was added, and the pH was adjusted to 3 to 4 with 2N hydrochloric acid, and extracted with ethyl acetate (30 mL × 3), and the organic phase was combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted -a]pyridyl -1,7-dicarboxylic acid-7-t-butyl ester 39a (0,215 g, white solid), yield: 24.3%.

Second step 8-methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -1,7-dicarboxylic acid-7-t-butyl ester-1-methyl ester

8-methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -1,7-dicarboxylic acid-7-t-butyl ester 39a (0.349 g, 1 mmol) was dissolved in 15 mL of N,N-dimethylformamide, and sodium hydrogencarbonate (0.84 g, 10 mmol) was added with stirring. Methyl iodide (0.43 g, 3 mmol) was added dropwise, and the reaction was stirred at room temperature for 40 hr. 8-methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -1,7-dicarboxylic acid-7-t-butyl ester-1-methyl ester 39b (0.5 g, yellow oil), yield: 100%.

MS m/z (ESI): 364.0 (M + 1).

¹ H NMR (400 MHz, CDCl ₃ ): δ 5.85 (t, 1H), 4.24 (t, 2H), 4.04 (t, 2H), 3, 93 (s, 3H), 1.56 (d, 3H), 1.51 ( s, 9H).

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

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

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.10 (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-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8- Tetrahydroimidazo[1,5-a]pyridyl Methyl-1-carboxylate

8-methyl-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid methyl ester hydrochloride 39c crude (0.289 g, 0.96 mmol) and (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyl Acid 1f (0.353 g, 1.06 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (0.4 mL, 2.9 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride were added sequentially with stirring. (0.368 g, 1.45 mmol), the reaction mixture was stirred at room temperature overnight, and the mixture was evaporated to dryness, and the residue was evaporated. 7-[3-Tertidinoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazolium [1,5-a]pyridyl Methyl 1-carboxylate 39d (0.43 g, yellow oil), yield: 77.2%.

MS m/z (ESI): 579.1 (M + 1).

the fifth step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-8-methyl-3-trifluoromethyl-5,6,7,8- Tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid methyl ester hydrochloride

7-[3-Tertiaryoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazole And [1,5-a]pyridyl Methyl 1-benzoate 39d (0.23g, 0.4mmol) was placed in a reaction flask, 5mL of 2.3N hydrogen chloride in ethyl acetate solution was added, and the reaction was stirred at room temperature for 2 hours, and the reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was concentrated under reduced pressure to give the title compound (D)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-8-methyl-3-trifluoro Methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid-methyl ester hydrochloride 39 (0.205 g, white solid), yield: 100%.

MS m/z (ESI): 479.1 (M + 1).

_{^{1 HNMR (400MHz, CDCl 3)}} : δ 7.33 (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).

Example 40, 41 (R)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)-(S)-8-methyl-3-(trifluoromethyl)-5,6 ,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid methyl ester hydrochloride (R)-7-(3-amino-4-(2,4,5-trifluorophenyl)butanyl)-(R)-8-methyl-3- (trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid methyl ester hydrochloride

(R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-8-methyl-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazo[1,5-a]pyridyl Chiral resolution of chiral column Chiralcel AD-H by flow chromatography Phase: n-hexane: isopropanol: diethylamine = 70:30: 0.1, flow rate: 1.0 ml/min), the corresponding fractions were collected, the solvent was removed by rotary evaporation, and dried under vacuum at room temperature for 4 hours to give the title Product (R)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)-(S)-8-methyl-3-(trifluoromethyl)-5, 6,7,8-tetrahydroimidazo[1,5-a]pyridyl 1-carboxylic acid methyl ester hydrochloride 40 (57 mg, 11.9 mmol) and (R)-7-(3-amino-4-(2,4,5-trifluorophenyl)butanyl)-(R) -8-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl Methyl 1-carboxylic acid hydrochloride 41 (50 mg, 10.5 mmol).

Example 42 (R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazole And [1,5-a]pyridyl -1-(N-ethyl) formamide

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

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (180 mg, 0.33 mmol) was dissolved in 10 mL of tetrahydrofuran, ethylamine hydrochloride (269 mg, 3.3 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (168 mg, 0.66 mmol) and triethylamine (367 mg, 3.63 mmol), the reaction was stirred at room temperature for 4 hours, the reaction was traced by thin layer chromatography, the material disappeared, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified to give the titled product (R)-[3-(2-ethylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a Pyridine -7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 42a (190 mg, white solid), yield: 100%.

MS m/z (ESI): 600.1 (M+23).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazole And [1,5-a]pyridyl -1-(N-ethyl) formamide

(R)-[3-(1-ethylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -3-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 42a (190 mg, 0.33 mmol) dissolved in 10 mL of dichloro In the methane, trifluoroacetic acid (750 mg, 6.6 mmol) was further added, and the reaction was stirred at room temperature for 2 hours. The reaction was followed by thin layer chromatography, the starting material disappeared, and the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The title product (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butanyl]-3-trifluoromethyl-5,6,7,8- Tetrahydro-imidazo[1,5-a]pyridyl 1-(N-ethyl)formamide 42 (120 mg, white solid), yield: 76.4%.

MS m/z (ESI): 478.1 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 1.68-1.24 (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazole And [1,5-a]pyridyl -1-(N-butyl)formamide

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

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (180 mg, 0.33 mmol) was dissolved in 10 mL dichloromethane, butylamine hydrochloride (193 mg, 2.64 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium Chlorohydrazine (167 mg, 0.66 mmol) and triethylamine (100 mg, 0.99 mmol) were stirred at room temperature overnight, the reaction was traced by thin layer chromatography, the material disappeared, and the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography. The residue obtained gave the title product (R)-[3-(1-butylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin. -7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 43a (120 mg, white solid), yield: 60 %.

MS m/z (ESI): 606.0 (M + 1).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazole And [1,5-a]pyridyl -1-(N-butyl)formamide

(R)-[3-(1-butylcarbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -3-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 43a (120 mg, 0.198 mmol) dissolved in 10 mL of dichloro To the methane, trifluoroacetic acid (452 mg, 3.97 mmol) was further added, and the reaction was stirred at room temperature for 2 hours. The reaction was traced by thin layer chromatography, the starting material disappeared, and the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The title product (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butanyl]-3-trifluoromethyl-5,6,7,8- Tetrahydro-imidazo[1,5-a]pyridyl 1-(N-butyl)formamide 43 (70 mg, white solid), yield: 70%. MS m/z (ESI): 506.1 (M + 1).

¹ H NMR (400 MHz, CD ₃ OD): δ 0.93-0.99 (m, 3H), 1.34-1.41 (m, 2H), 1.59-1.62 (m, 2H), 2.80-2.98 (m, 3H), 3.07-3. (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)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazole And [1,5-a]pyridyl -1-(N-propyl) formamide

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

(R)-7-[3-Tertioxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8 -tetrahydroimidazole [1,5-a]pyridyl 1-carboxylic acid 2a (190 mg, 0.345 mmol) was dissolved in 10 mL of dichloromethane, propylamine (163 mg, 2.76 mmol), bis(2-oxo-3-oxazolidinyl)phosphinium chloride (176 mg, 0.69 mmol) and triethylamine (105 mg, 1.04 mmol), the reaction was stirred at room temperature overnight, the reaction was traced by thin layer chromatography, the material disappeared, and the reaction mixture was concentrated under reduced pressure. Title product (R)-[3-(1-propylcarbamimido-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin -7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 44a (70 mg, white solid), yield: 34.3 %.

MS m/z (ESI): 614.1 (M+23).

Second step (R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazole And [1,5-a]pyridyl -1-(N-propyl) formamide

(R)-[3-(1-propylcarbamyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl -3-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 44a (70 mg, 0.118 mmol) dissolved in 10 mL of dichloro In the methane, trifluoroacetic acid (270 mg, 2.37 mmol) was further added, and the reaction was stirred at room temperature for 1 hour, and the reaction was followed by thin layer chromatography, the starting material disappeared, and the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The title product (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butanyl]-3-trifluoromethyl-5,6,7,8- Tetrahydro-imidazo[1,5-a]pyridyl 1-(N-propyl)formamide 44 (25 mg, white solid), yield: 43.1%.

MS m/z (ESI): 4921.

¹ H NMR (400 MHz, CD ₃ OD): δ 0.90-1.00 (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 case: Biological evaluation Determination of DPP IV inhibitory activity

The following method was used to determine the ability of the compounds of the invention to inhibit DPPIV enzymatic activity. The inhibition rate or semi-inhibitory concentration IC _{50 of} each compound (the concentration of the compound measured when the enzyme activity is inhibited to 50%) is determined by a fixed amount of the enzyme mixed base and various concentrations of the test compound.

Determination of DPP IV inhibitory activity Materials and Method: material:

a. White 96-well plate (BMG)

b. Tris Buffer: Prepare 100 mL of 2 mM Tris buffer, dissolve 0.0242 g of Tris in approximately 90 mL of deionized water, adjust the pH to 8.00 with HCl and NaOH, and finally add deionized water to 100 mL.

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

d.DPPIV-Glo ^TM substrate (Promega Catalogno. G8350), was dissolved in deionized water to 1mM.

e.DPPIV-.Glo ^TM buffer (Promega Catalog no. G8350)

f. Luciferin detection reagent (Promega Catalog no. G8350)

g.DMSO

h. Deionized water

operating: In the following sequence of operations:

1. Thaw DPPIV-Glo. Buffer before use and equilibrate to room temperature.

2. Buffer frozen luciferin detection reagent before use.

3. Suspension DPPIV-Glo. After adding ultrapure water to the base and mixing gently, a 1 mM base was prepared.

4. Place the luciferin test reagent in a brown bottle and add DPPIV-Glo. The luciferin detection reagent should be dissolved within 1 minute.

5. Dissolve the test compound in DMSO to 50 times the final working concentration.

6. Add 50 μl of the test compound to 2 μL of each test tube, and add 2 μL of DMSO to the negative control and the blank control.

7. 46 μL of Tris buffer was added to each tube, and 48 μL of Tris buffer was added to the blank.

8. Add 2 μL of DPPIV enzyme to each tube of the negative control and test samples.

9. Vibrate and centrifuge the tube. Transfer all of the material in the tube to a 96-well plate.

10. Mix the base and DPPIV-Glo. The ratio is 1:49. Mix the vibrations to mix thoroughly. Allow to stand at room temperature for 30 to 60 minutes before use.

11. Add 50 μL of a mixture of DPPIV-Glo. and the base to each 96-well plate well and seal the plate with a sealing film.

12. Slowly mix the 96-well material with a plate shaker at 300 to 500 rpm / 30 s. Incubate for 30 minutes to 3 hours at room temperature.

13. Record the luminescence.

Inhibition rate definition: [1-(S-B)/(N-B)]*100%

S: sample

B: blank control

N: negative control

IC ₅₀ value:

After testing, the compounds of the present invention for measuring DPPIV inhibition concentration IC ₅₀ values in the range of 0.005μM to 0.216μM, compared with IC ₅₀ values of 0.023μM MK-0431, most of the compounds of the present invention have excellent DPPIV inhibitory activity .

Claims (20)

A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof: Wherein: Ar is a phenyl group which is unsubstituted or further substituted with 1 to 5 R ⁶ ; R ^{1 is} selected from a hydrogen atom, an alkyl group or an alkyl group substituted by one or more halogens; R ^{2 is} selected From hydroxy, amine, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or NR ⁴ R ⁵ , wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl Or an aryl or heteroaryl group, further optionally one or more selected from the group consisting of halogen, amine, cyano, hydroxy, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, -NR ⁴ R ^{5, -OC (O) oR 8} , carboxylic acid or carboxylic ester substituents; R ³ is selected from a hydrogen atom or an alkyl group; R ⁴ and R ⁵ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl Or a heterocycloalkyl, aryl or heteroaryl group, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further optionally optionally selected from one or more selected from the group consisting of halogen, hydroxy, and amine groups. , alkoxy, alkyl, cyano, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, hydroxyalkyl, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , carboxylic acid or carboxylic acid ester Substituted by a substituent; or, R ⁴ and R ⁵ together form 4 to An 8-membered heterocyclic group wherein the 4 to 8 membered heterocyclic ring contains one or more N, O, S atoms, and the 4 to 8 membered heterocyclic ring is further optionally one or more selected from the group consisting of halogen and hydroxy , amine, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , -C(O)NR Substituted by a substituent of ⁴ R ⁵ , -C(O)R ⁷ , =O, a carboxylic acid or a carboxylic acid ester; R ^{6 is} selected from halogen, cyano, hydroxy, alkyl or alkoxy, wherein alkyl or alkane The oxy group is unsubstituted or further substituted with one or more halogens; R ⁷ is an alkyl group; and R ^{8 is} selected from an alkyl group or a cycloalkyl group. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is trifluoromethyl. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the salt is the compound and an acid selected from the group consisting of Salt formed: malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid. The compound of claim 5 or a salt thereof, wherein the salt is a hydrochloride. A compound of the formula (IA) which is an intermediate of the compound of the formula (I) which is synthesized according to the first aspect of the patent application: Wherein: Ar is a phenyl group which is unsubstituted or further substituted with 1 to 5 R ⁶ ; R ^{1 is} selected from a hydrogen atom, an alkyl group or an alkyl group substituted by one or more halogens; R ^{3 is} selected From a hydrogen atom or an alkyl group; R ^{6 is} selected from halogen, cyano, hydroxy, alkyl or alkoxy, wherein the alkyl or alkoxy group is unsubstituted or further substituted with one or more halogens; X is a halogen. A compound of the formula (IA) according to claim 7 wherein R ¹ is a trifluoromethyl group. A compound of the formula (IB) which is an intermediate for the synthesis of a compound of the formula (I) in claim 1 of the scope of the patent application: Wherein R ^{1 is} selected from a hydrogen atom, an alkyl group or an alkyl group substituted with one or more halogens; R ^{2 is} selected from a hydroxyl group, an amine group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group. , heteroaryl or -NR ⁴ R ⁵ , wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally one or more selected from halogen, amine, Substituted by a substituent of a cyano group, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, an aryl group, a heteroaryl group, -NR ⁴ R ⁵ , -OC(O)OR ⁸ , a carboxylic acid or a carboxylic acid ester; ^{3 is} selected from a hydrogen atom or an alkyl group; and R ⁴ and R ⁵ are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, wherein an alkyl group, a cycloalkyl group, or a heterocyclic group The cycloalkyl, aryl or heteroaryl group is further optionally one or more selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyano, aryl, cycloalkyl, heterocycloalkyl, Substituted by a substituent of a heteroaryl group, a hydroxyalkyl group, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , a carboxylic acid or a carboxylic acid ester; or, R ⁴ and R ⁵ together form a 4- to 8-membered heterocyclic group, wherein The 4 to 8 member heterocyclic ring contains one or more N, O, S atoms And the 4 to 8 membered heterocyclic ring is further optionally one or more selected from the group consisting of halogen, hydroxy, amine, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, Substituted by a substituent of a carbonyl group, a hydroxyalkyl group, -SO ₂ R ⁷ , -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , -C(O)R ⁷ , a carboxylic acid or a carboxylic acid ester; R ⁷ Is an alkyl group; R ^{8 is} selected from an alkyl group or a cycloalkyl group. A compound of the formula (IB) according to claim 9 wherein R ¹ is a trifluoromethyl group. A process for the preparation of a compound of the formula (IA) according to item 7 or item 8 of the patent application, the method comprising: In the ice bath to the raw material The anhydride is added dropwise to the 2-methylamine, and then reacted at room temperature to form a guanamine product; After the guanamine product and the phosphorus oxychloride are mixed and stirred at room temperature, phosphorus pentoxide is added, and the mixture is heated and refluxed to form imidazo[1,5-a]pyridinium. ring; Imidazo[1,5-a]pyridin The ring is reduced in hydrogen by hydrogenation under palladium on carbon to form R ¹ , R ³ substituted tetrahydroimidazo[1,5-a]pyrene product; Tetrahydroimidazo[1,5-a]pyrryl substituted with R ¹ , R ³ The product is dissolved in a dichloromethane solvent and condensed with a carboxylic acid under the action of a condensing agent bis(2-oxo-3-oxazolidinyl)phosphinium chloride and triethylamine; The resulting condensation product is reacted with halo succinimide at room temperature in a solvent of absolute ethanol to form a compound of formula (IA). A process for the preparation of a compound of the formula (IB) of claim 9 or 10, which comprises: R ¹ substituted imidazo[1,5-a]pyridyl Hydrogenation reduction in an ethanol solvent at room temperature, followed by reaction with di(tert-butyl ester) dicarbonate in an ethanol solvent to protect the amine group to give an amine-protected R ¹ -substituted tetrahydroimidazo[1] , 5-a]pyridyl ; The resulting amine-protected R ¹ -substituted tetrahydroimidazo[1,5-a]pyridyl The halogenated product is obtained by reacting with a halogenated amber iodide in an ethanol solvent at room temperature; The obtained halogenated product is reacted in an oil bath with octacarbonyl dicobalt and chloroacetate under a carbon monoxide atmosphere to obtain an ester-substituted tetrahydroimidazo[1,5-a]pyridinium. ; The resulting ester-substituted tetrahydroimidazo[1,5-a]pyridyl Hydrolyzed to an acid under alkaline conditions; The obtained carboxylic acid compound is reacted with a haloalkyl group in a dry ice-acetone bath to obtain an alkyl-substituted acid; The alkyl-substituted acid can be further esterified to give a keto-substituted tetrahydroimidazo[1,5-a]pyridyl ; Alternatively, the alkyl-substituted acid is reacted with N-methoxymethylamine in a dichloromethane solvent under the action of a condensing reagent bis(2-oxo-3-oxazolidinyl)phosphinium chloride; The product obtained by the condensation reaction is reacted with a Grignard reagent in a tetrahydrofuran solvent to obtain a ketone-substituted tetrahydroimidazo[1,5-a]pyridinium. ; Keto-substituted tetrahydroimidazo[1,5-a]pyridin The amine protecting group is removed under acidic conditions to provide the compound of formula (IB). A process for the preparation of a compound of the formula (I) according to any one of claims 1 to 4, which comprises: The general formula (IA) of claim 7 of the patent application is reacted in a methanol solvent under the action of octacarbonyl hexacobalt under an oil bath and chloroacetate under a carbon monoxide atmosphere, and then at room temperature under alkaline conditions. Hydrolysis and re-acidification to a carboxylic acid; The obtained carboxylic acid is subjected to a condensation reaction with an amine or an alcohol at room temperature under a condensation reagent, or with a 1-halocarbonate, and then the amine group is removed under acidic conditions to obtain a formula (I). Compound. A process for the preparation of a compound of the formula (I) according to any one of claims 1 to 4, which comprises: The compound of the general formula (IB) of claim 9 and the carboxylic acid are condensed under the conditions of a condensing reagent bis(2-oxo-3-oxazolidinyl)phosphinium chloride, and the obtained product is further acidic. Removal of the amine protecting group under conditions affords the compound of formula (I). The preparation method of claim 13 or 14, wherein the compound of the formula (I) is reacted with an acid to form an acid addition salt selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, and methanesulfonic acid. Acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid. The preparation method of claim 15, wherein the acid is hydrochloric acid. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, And a pharmaceutically acceptable carrier or excipient. A use of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance. Use of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the catalytic activity of dipeptidyl peptidase IV. A pharmaceutical composition of claim 17 for use in the manufacture of a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance.