TW201211043A - Tetrahydro-imidazo[1,5-a]pyrazine derivatives salts, preparation process and pharmaceutical use thereof - Google Patents

Abstract

The present invention relates to (R)-7-[3-Amino-4-(2, 4, 5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo[1, 5-a]pyrazine-1-carboxylic acid pharmaceutical salts, methods for their preparation, pharmaceutical compositions containing the same and their use as a therapeutic agent, especially as a dipeptidyl peptidase IV inhibitor.

Description

201211043 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a + base + (2,4, decyl)-3-trifluoromethyl-5,6,7,8-tetrazole A pharmaceutically acceptable salt of formic acid, a process for the preparation thereof, and a use thereof as a therapeutic pharmaceutically acceptable salt PP IV) inhibitor. The heart is particularly 疋 as a dipeptidyl peptidase [previous technique] ^ disease is a non-f ancient metabolic disease, sugar, due to the absolute or relative lack of sputum in the human body and the increase in blood class 'and then a large amount of sugar from the urine Discharged from the second:; metabolism of protein and protein, physiological manifestations of polydipsia, polyuria, polyphagia, sputum weight loss, dizziness, fatigue and other symptoms. < Permanent or uncontrolled hyperglycemia leads to an increase in mortality (4). Usually the blood sugar quenching (glucosehomeos = indirectly with), the wax protein 'lipoprotein metabolism changes :::: " shot and hemodynamic disease. Type 11 diabetes patients suffering from cerebral liposomes and microvascular syndrome, The incidence of diseases such as coronary heart disease, stroke, peripheral vascular disease, hyper-blood, kidney disease, neuropathy and retinopathy is significantly increased. Therefore, treatment of diseases such as blood sugar constant I fat and blood house (4) is clinically It is important to treat urinary tract disease. Generally speaking, there are two types of diabetes. People with type J diabetes, namely, TB-dependent diabetes mellitus (10) M), the patient's own insulin is rarely 94968 3 201211043 or no. Insulin is a kind of pedestrian in the body that regulates glucose utilization, ie insulin-independent diabetes _), :; Γ = 血 的 的 的 的 血 血 血 血 血 ^ ^ ^ 此类 此类 此类 此类 此类 此类 此类 此类 此类 此类 此类 此类 此类 此类 此类 此类 此类 此类 此类 此类This islet sin! In the main, island ί sensitive tissue cells, such as muscle, liver, 25 months of fat tissue ♦ = « then; and lipid metabolism play a stimulating effect. Even the eucalyptus The increase in the concentration of Tengdao can't overcome the patient's significant resistance to insulin. The resistance of Tengumycin is mainly due to the decrease in the number of receptors in the island, or due to defects in insulin receptor function, so far This mechanism is still unrecognizable. The resistance of the gonadotropin response causes Tengdaosu to fail to initiate glucose uptake, oxidation, and storage in muscle tissue, while not effectively inhibiting lipolysis of adipose tissue, and regulating liver glucose. Produced and secreted.

Dipeptidyl peptidase-IV (DPP IV) is a serine protease that cleaves the N-terminal dipeptide in the peptide chain containing a proline residue at the secondary end, although DPP IV is present in mammals. Physiological effects have not been fully confirmed, but they play an important role in neuroenzyme metabolism, T-cell initiation, adhesion of cancer cells to endothelial tissue, and the entry of HIV into lymphoid cells (W098/19998). . Recently, studies have shown that DPP IV can block the secretion of glucagon-like peptide (GLP)-1, in particular, it can cleave (the N-terminal histidine-alanine dipeptide in JLP-1, making it Degradation of active form of GLP-1 (7-36) NH2 to inactive GLP-1 (9-36) NH2 (Endocrinol〇gy, 1999, 4 94968 201211043

140: 5356~5363). Due to physiological conditions, the half-life of intact glp-1 in circulating blood is very short' DPP IV inactive metabolites after GLP-1 degradation can bind to GLP-1 receptor and inhibit GLP-1, thereby shortening GLP-1 Physiological response. DPP IV inhibitors completely protect endogenous or even exogenous GLP-1 from DPP IV loss, which greatly increases the physiological activity of glp-i (5 to 10 fold) due to glp-i on pancreatic insulin Secretion is an important stimulator and directly affects glucose utilization, so DPP IV inhibitors are ideal for the treatment of non-insulin dependent diabetes mellitus (NIDDM) (US6110949). However, although several DPP IV inhibitors have been disclosed, there are currently no long-acting drugs, and DPP IV inhibitors with improved properties are still needed. It is an object of the present invention to provide a compound having a therapeutic or palliative drug which inhibits Dpp" activity and which can be used for diabetes or the like. Application filed by the applicant of the present application on November π, 2008

PCT/CN2008/001936 describes a new class of tetrahydroimidazo[l,5-a]pyridinium derivatives, and their use as 1) inhibitors, wherein the disclosed examples are (7)- 7-[3, yl, 4_(2,4,5_triphenyl)butanyl]-3-tri-I-methyl-5, 6, 7' 8, four odors also tl,5_a]0 哄+ The form of formate hydrochloride, which has been shown to have a significant inhibitory effect on (iv), has thus been accepted as a reference for the present invention. Another object of the present invention is to provide pharmaceutically acceptable salt forms and filament forms of the compounds of formula (1), thereby improving their solubility, bioavailability, hypoglycemic activity and pharmacokinetic properties. 94968 5 201211043 f invention content]

1 cal salt), a preparation method thereof, and the pharmaceutically acceptable salt amine: i -5, a mono-base enzyme, the salt form has excellent therapeutic properties for diabetes, and activity in animals and Bioavailability (phaIHiaceutlcalsalt), its preparation method comprises a pharmaceutical composition and its use as a therapeutic agent, in particular as a secondary IV inhibitor. The salt-forming form has excellent pain-relieving properties, and the solubility is remarkably improved, and the kinetics are good and the toxicity is low, and it is suitable for preparing a preparation for treating diabetes.

The present invention provides a pharmaceutically acceptable salt of a compound of formula (I). The "pharmaceutically acceptable salt" as used in the present invention means a pharmaceutically non-toxic acid plus X-forming salt and a base-addition salt. The acid addition salt is the compound of the formula (1) and Suitable inorganic or organic acid salts include 'hydrochlorides, discates, hydrogen phosphates, sulfates, hydrogen sulfates, sulfites, acetates, oxalates, malonates, valerates , glutamate, oleate, palmitate, stearate, laurate, borate, p- sulfonate, citrate, malate, tartrate, benzoate , bis-naphthoate, salicylate, vanillate, mandelate, chlorate gluconate, lactobionate, lauryl sulfonate, etc., especially phosphate. The salt formed is a salt of a compound of the formula (I) with a suitable inorganic or organic base, and includes a salt such as a sodium salt, a salt, such as an alkali metal, an amine or a quaternary compound. Salt, potassium salt, dance salt, Zhen salt, amine salt 'tetramethyl quaternary salt, tetraethyl quaternary ' salt, gallstone, especially gallstone Amine salts, including salts with amines (ΝΗ3), primary amines, secondary amines or tertiary amines such as methylamine salt, dimethylamine salt, diammonium salt, triethylamine salt, ethylamine salt, ethanolamine salt Amino acid salts and arginine salts, particularly ethanolamine salts. Typical pharmaceutically acceptable salts of the compounds of formula (I) according to the invention include, but are not limited to: Example number structure name 1 fV (")-7 -[ 3-Amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoro-indenyl-5, 6, 7, 8-tetrahydroimidazo[1, 5-a]pyridin-1-indole hydrochloride 2 F H2P04- fVF (A〇-7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-3 -trifluoromethyl-5,6,8-tetrahydroimidazolium,5-8]»p-pyrene-1-carboxylic acid acidate 3 fVF C)P)-7-[3-amino-4 -(2, 4, 5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]*ntD well-1-曱Acid 7 94968 201211043 4 ί ^ fVF (,)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]_3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyridin-1-one sodium 5 F fVF (y?)-7-[3-amino-4-(2, 4, 5-three Phenyl)-butanyl]_3_three defeat Base-5, 6, 7, 8-tetrahydroindolo[1,5-a]pyridin-1-yl lithium 6 such as Γ^κ. F fVF U)-7-[3-amino-4 -(2, 4, 5-trifluorophenyl)-butanyl]-3-trimethylsulfonyl-5, 6, 7, 8-tetrahydroimidazo[1, 5-a]pyrazole-1- Potassium formate 7 F k^N·^ pVF Λ 2* Ca 2 (I-7-[3-amino-4-(2, 4, 5-trifluorophenyl)-butanyl]-3_three defeat Mercapto-5, 6, 7, 8-tetrahydropyrano[1,5-a]pyrazine-1-carboxylic acid calcium 8 F k^N 丫/ V_ pVF (妁-7-[3-amino- 4-(2,4,5-trifluorophenyl)-butanyl]_3_trimethylsulfonyl-5, 6, 7, 8-tetrahydroimidazo[1, 5-a]pyrazole-1- Triethylamine formate 9 i — λρ (Fantasy-7-[3-amino-4-(2,4,5-triphenyl)-butanyl]_3_trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1, 5-a]pyrazine-1-decanoic acid ethanolamine salt 8 94968 201211043

U)~7-[3-Amino-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazolium, 5- a] pyridin-1-carboxylate _ (2, 4, 5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,6-tetrahydroimidazo[1,5- a]° 哄-I-formic acid malate U)-7-[3-Amino-(2,4,5-trifluorophenyl)~butanyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-8]indole 哄-1_ citrate tartar salt ______ (amino-4-(2,4,5-trisene)-butyl ]]-3-trimethylmethyl-5, 6, 7, 8-tetrahydromymidine. Sit and [1,5-a]n is more than 哄-1-decanoic acid to avoid double salts __ Usually prepared above~ '~ Carry out, it is worth noting the effects of cooling, normal temperature or heating conditions, this is also the case; choose to react to different salt formation reactions. 疋 熟知 熟知 盐 、 、 、 、 、 、 、 、 、 、 、 、 、 The point of the ambient temperature to the solvent used is preferably: 〇 to 4 ° C. The person skilled in the art can easily determine the optimum reaction temperature for the specific salt formation reaction by the technical means of the art. a pharmaceutically acceptable salt of a compound of formula (I) Preparation method, the 94868 9 201211043 method includes an acid addition salt preparation method and an additive addition salt preparation method, wherein the acid addition salt preparation method includes (illusion-7-[3-amino-4-(2,4,5-three) Fluoryl)-butanyl]-3-tri-1methyl-5,6,8-tetrahydro-W and [丨,5_哄哄_卜曱酸酸反应反应反应The obtained (the _7_[3_amino group ^-., 斗^--trifluoro-phenyl) butyl sulfonyl-trifluoro-hydrazin-^^ four-terrain hydrogen miso and [l,5-a> 哄+曱The acid is reacted with an inorganic or organic acid, wherein the inorganic or organic acid is selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, sulfurous acid, acetic acid, oxalic acid, malonic acid, valeric acid, glutamic acid, oleic acid, and cedar Acid, stearic acid, lauric acid, boric acid, p-toluene rhyme, methyl acid, saic acid, tartaric acid, benzoic acid, behenic acid, salicylic acid, vanillic acid, eyebrow acid, lysine, gluconic acid, Lactobionic acid or lysine. The method for the addition of salt includes 〇p)-7-[3_amino-4-4((2,4,5-triphenyl)-butanyl]-3-trifluoromethyl a 5,6,7,8-tetrahydroimidazolium u'La]pyrazine-p-formic acid and gold test;|hydroxide, substituted amine Or shouting the compound to carry out the reaction, wherein the metal hydroxide is selected from the group consisting of sodium hydroxide, nitrogen oxide clock, hydrogen peroxide, magnesium hydroxide, and the amine or quaternary compound is selected from the group consisting of Tetramethyl quaternary, tetraethyl quaternary, ethanolamine, choline, lysine, arginine, methylamine, dimethylamine, trimethylamine, triethylamine or ethylamine. The present invention relates to the use of a pharmaceutically acceptable salt of a compound of formula (1) for the manufacture of a medicament for the treatment of n-type urinary blood glucose, obesity or insulin resistance. The present invention relates to the use of a salt of a compound of formula (1) in the preparation of a sulphur IV inhibitor. The present invention relates to a method of treating diarrhea, hyperglycemia, obesity 94968 10 201211043, or insulin resistance comprising administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I). The present invention relates to a method for inhibiting the catalytic activity of dipeptidyl peptidase IV, which comprises contacting the dipeptidyl peptidase IV with a pharmaceutically acceptable salt of a compound of formula (I). The present invention relates to a pharmaceutically acceptable salt of a compound of the formula (I) as a medicament for the treatment of π-type diabetes, hyperglycemia, obesity or insulin resistance. The present invention relates to a pharmaceutically acceptable salt of a compound of formula (I) as a medicament for inhibiting dipeptide @-peptidase IV. The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I), and a pharmaceutically acceptable carrier, and to a pharmaceutical composition for the treatment of type 2 diabetes, Use of drugs for hyperglycemia, obesity or insulin resistance. The present invention relates to a method of treating type II diabetes, hyperglycemia, obesity or insulin resistance, which comprises administering to a subject in need of treatment a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I). Things. The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of formula (I) as a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance. [Embodiment] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Pharmaceutical composition" means one or more compounds described herein. 94968 201211043 A pharmaceutically acceptable salt or mixture of prodrugs with other chemical components, such as a physiological/pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the compound to the organism. [Synthesis method of the compound of the present invention] In order to accomplish the object of the present invention, the present invention adopts the following technical scheme: The method for synthesizing the compound of the formula (0) According to the application submitted by the applicant of the present application on November 27, 2008 pCT/CN2 〇〇8/〇〇1936 was prepared by the method described in Example 10, and the disclosure is hereby incorporated by reference.

-Ή3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]|trifluoromethyl-5, 6, 7, 8-tetrahydro. The rice saliva and π, 5_ 哄 哄 + formic acid addition salt and base addition salt are used as follows: The acid addition salt method includes: "(7)-7-[3-amino group_4 one (2, 4,5-three-gas phenyl)_ butyl-based] 1 虱'-yl- 5'6'7'8-tetrahydroimidazo[1,5 state pyridin-bromide and experimental solution岐 ,, the receiving material will get (10)) _7 priming μ

Hydrogen 4::di-Si-fluorophenyl)-butyl-aryl]I-trifluoromethyl-6, 7, 8~4: Open [1,5' small _+ formic acid and inorganic acid or organic acid for reverse inspection The method of salt formation includes: ((-, 3-amino+(2,4, fluorenylphenyl)-butanyl)_3^methyl, 5'6, 7, 8_tetrahydro' sit and 5_a> + "There is no metal hydroxide, amine or tetrahydrogen or inorganic base in the dish. The reaction is carried out. Han Zhigu Detailed Embodiment 94968 12 201211043 * The following examples are used to further describe the present invention, but these The examples do not limit the scope and spirit of the invention. EXAMPLES The structure of a compound is determined by nuclear magnetic resonance (H NMR 10 or mass spectrometry (MS). 1H NMR shift (δ) in parts per million One (ppm) unit was produced. The NMR measurement was performed using a Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was determined to be deuterated sterol (CDsOD). The chemical shift was measured in units of 1 〇 6 (ppm). FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Ihermo, model: Finnigan LCQ advantage MAX); thin layer chromatography tantalum sheet using Yantai Yellow Sea HSGF254 or Qingdao GF254 Shi Xi The specification for the TLC is 〇15mm to 0 · 2 mm. The specification for the separation and purification of thin layer chromatography is 〇. 4 颜至0. 5 mm. The column chromatography is generally used in Yantai Huanghai 200 200 to 300 mesh. Silicone is a carrier. # The starting materials of the present invention are known and commercially available from ABCR GmbH & Co. KG, Acros Organics, Aldrich.

Chemical Company, AccelaChem Bi〇 Inc, Dari Chemicals, etc., or can be synthesized by or according to methods known in the art. No specific instructions in the examples, the reaction is carried out under a nitrogen atmosphere; The atmosphere means that the reaction flask is connected to a nitrogen balloon of about 丨L volume; the hydrogen atmosphere means that the reaction flask is connected to a hydrogen gas of about 丨L volume of 94968 13 201211043 balls. Unless otherwise stated in the examples, the solution means an aqueous solution. There is no special description in the examples. The temperature of the reaction was room temperature. Room temperature is the most suitable reaction temperature, from 2 ° C to 3 Torr. Hey. The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was as follows: a gas-fired and methanol system, a n-hexane and ethyl acetate system, petroleum ether and ethyl acetate. The volume ratio of the system, acetone, and solvent is adjusted depending on the polarity of the compound. The eluent system of the column chromatography includes: a: a gas-fired and methanol system, and a system of B: n-hexane and acetic acid. The volume ratio of the solvent is adjusted according to the polarity of the compound. It can be adjusted by adding a small amount of amine water and acetic acid. HPLC refers to high performance liquid chromatography; HPLC determination using Agilent 2695-2996 high pressure liquid chromatography (Gimini C18 150x4. 6mm column); HPLC test conditions: run time: 30 min column temperature: 30 ° C PDA: 230 nm mobile phase: decyl alcohol: water (〇·1% amine water) = 25: 75 flow rate: 1.0 mL/min Example 1 0〇-7-[3-Amino-4-(2,4, 5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,8-tetrahydroimidazo[1,5-a]pyridin-1-one hydrochloride 14 94968 201211043

Private 4 first step 2, 2-dimercapto-5-[2-(2, 4, 5-trisylphenyl)-acetic acid keb [1,3] dihistral burn-4,6-dione will 2, 2-Dimercapto-[1,3]diπ-iso--4,6-dione (5. 69 g, 39.5 mmol) was dissolved in 400 mL of di-methane, added to ice bath, and added 2 , 4, 5-trifluorophenylacetic acid la (7. 15 g, 37.6 mmol) and p-dimethylaminopyridine (7. 35 g, 60.2 mmol), 250 mL· 1-(3- A suspension of the dimethylamino-propyl)-3-ethyl-carbamidoamine hydrochloride (8. 28 g, 43.2 mmol) in a two-gas suspension was allowed to react for 36 hours. The reaction mixture was washed with 5% aqueous potassium hydrogensulfate (250 mL×7) <RTI ID=0.0>>&&&&&&&&&&&& 2-(2,4,5-trifluorophenyl)-ethinyl]-[丨,3]dioxane_4,6_2 15 94968 201211043 Ketone lb (11.4 g, white solid), yield: 96%. MS m/z (ESI): 315.5 [Ml]. Step 2: 3-oxo-4-(2,4, 5-trifluorophenyl)-butyric acid ethyl ester 2, 2-dimercapto-5- [2-(2,4,5-Trifluorophenyl)-ethinyl]~[1,3]dioxane-4,6-dione lb (15.72 g, 49.6 mmol) was dissolved in The reaction was stirred at 70 ° C for 12 hours in 280 mL of ethanol. The mixture was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified from EtOAc EtOAc EtOAc EtOAc. Ethyl ester lc (12 g, yellow liquid), yield: 88%. MS m/z (ESI): 259 [Ml] The third step 3~month female base - 4_(2,4,5-difluorophenyl)-butyl-2-dibasic acid -(2,4,5-trifluorophenyl)-ethyl butyrate lc (24.6 g, 94.5 mmol) was dissolved in 240 mL of methanol, and ammonium acetate (36.4 g, 473 mmol) was added. 'Reflow reaction for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. . Add 50 mL of ethyl acetate to the obtained pale yellow solid, dissolve '50 mL of n-hexane' seed crystals at 80 °C, cool to room temperature, 〇5 hours later, add 100 mL of n-hexane, and chill in the refrigerator. After 12 hours, filtration gave ethyl 3-amino-4-(2,4,5-trifluorophenyl)-but-2-enoate Id (19·5 g 'white solid), yield: %. MS m/z (ESI): 260.1 [M+1] 16 94968 201211043 . The fourth step d)-3-2,2-butoxyaminoamino-4-(2,4,5-trifluorophenyl)- Butyric acid is intended to add 3_oxo~4-(2,4,5-trifluorophenyl)-butyrate ethyl ester ld (4.1 g' ' 15. 8 mmo 1) to high pressure dad, add 7 〇mL methanol, dicarbonate; third butyl ester (3·8 g, 17.4 mmol), gas (1,5-cyclooctadiene) ruthenium (I) dimer (32 mg '0.063 mmol) and (A〇-l-[(6〇-2-(diphenylphosphino)ferrocenyl]-ethyl-tert-butylphosphine (68 mg, 0.13 mmol) at 30 ° C, 6. The reaction was carried out for 24 hours in 67 atmospheres of hydrogen. Filtration, the filtrate was concentrated under reduced pressure, and 34 mL of decyl alcohol was added at 50 ° C. After completely dissolving, 12 mL of water was added, and after cooling to room temperature, it was allowed to stand in the refrigerator for 12 hours. Filtration, washing the solid product with a mixed solvent of decyl alcohol and water (V/V = 1:1), and drying under vacuum to obtain (,β)-3-second butoxymethylamino-4-(2, 4, 5- Trifluorophenyl)-butyric acid acetonitrile (4 g 'light yellow solid), yield: 70%. MS m/z (ESI): 362. 4 [M+l] Step 5 • (and)~ 3-tert-butyl carbonylamino-4-(2,4,5-trifluorophenyl)- The acid is a well-known method Tetrahedron Asymnetry, 2 (10) color, 17 (2), 205-209, and (θ)-3-tert-butylamino-4-(2,4,5-trifluorophenyl) Ethyl butyrate le (l〇g, 27. 7 mmol) and sodium hydroxide (3.32 g '83·1 mmol) are dissolved in 150 mL of methanol and water (v/v = l: 1) in a mixed solvent Stir the reaction for 1 to 5 hours at 40 to 45 t, remove some of the solvent under reduced pressure, and then add a small amount of water, and add 1 Μ hydrochloric acid to the reaction solution at pH 2 to 3 with acetic acid. Ethyl acetate (200 mL×3) was extracted, and the organic phase was combined and washed with brine (2 mL). The third butoxycarbonylamino group __4_(2,4,5-trifluorophenyl)-butyric acid lf (9.2 g' white solid) was obtained, which was used directly for the next reaction. MS m/z (ESI): 332.3 [Ml] Step 6 C-pyridin-2-yl-methylamine Dissolve 2-cyanoindole!g (i〇· 5 g '1〇〇1〇1) in 150 mL 1,4- In dioxane, 'add ΐ· 〇g lannickin in 25 〇mL high pressure reaction dad, at 60 ° C, 40 The reaction was stirred for 8 hours under atmospheric pressure of hydrogen. Filtration and concentration of the filtrate under reduced pressure afforded C-~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ MS m/z (ESI): 110 [M+1] Step 7 2, 2, 2-trifluoropyranyl-2-mercapto-nonylamine C-pyridin-2-yl-indoleamine lh ( L〇. 9 g, 1〇〇mmol) was added to the reaction flask under the 'ice bar' and 2 mL of trifluoroacetic acid needle was added dropwise over 1 hour. The reaction was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue obtained was purified by eluent column chromatography eluting to afford the title product 2, 2, 2-trifluoro-N-pyridin-2-methyl-indoleamine 1 i (21 · 〇g, Brown oil). MS m/z (ESI) ·· 206. ltM+1] The eighth step 3-difluoromethyl-miso-[1,5-a]D than D well 2, 2, 2-difluoro-Ν-卩 卩 卩 曱 曱 曱 曱 曱 曱 曱 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 94 2 2 2 94 94 94 94 94 8 g, 125 mmol). The reaction was refluxed for 5 hours and concentrated under reduced pressure. The reaction was quenched with EtOAc (EtOAc) (EtOAc) (EtOAc) Filtration and concentration of the filtrate under reduced pressure. The residue obtained was purified from the eluent column system A to elute to afford the title product 3-trifluoromethyl-imidazo[1,5-a]pyramine 1 j (12 . 0 g 'yellow solid), yield:. MS m/z (ESI): 188.0 [M+l] H NMR (400 MHz, CDCH, ppm): δ 9.15 (s, 1H), 8.06 <, d, 1H), 7.92 (s, 1H), 7.81 (d, 1H) ninth step 3 - trifluoromethyl _5, 6, 7, 8-tetrahydroimidazo[1,5-a] pyridinium 3 difluoromethyl-imidazolium d,5_a]pyridin哄υ(ΐ2. 〇舀n 2

Coffee = dissolved in 15G mL of absolute ethanol, adding 5 (10) mg _ bar / carbon. Under the hydrogen-milk wind, the reaction was carried out for 12 hours. The crude hydrazine reaction mixture was concentrated under reduced pressure to give the title product: 3-trifluoromethyl- 5,6,7,8-tetrazole 1k (12.2 g, brown solid). (HmNM4RH=MHz, _, _) iu4(s, n〇, 4.n) (, 4H), 3.26 (m, 2H), 1.81 (s, 1H) Ten steps of oxygen: Γ _ (2' 4, 5 _Trifluoromethane)l(3-trimethylmethyl-5,6-a wind pupa[1,5-coffee+yl)_]-carbamic acid &butyl ester 94868 19 201211043 Will U)- 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid If (8.6 g '45 mmol) and 9.4 mL of triethylamine dissolved in 3 mL After stirring for 5 minutes in dichloromethane, 3-trifluoromethyl-5,6,7-tetrahydroimidazo[L 5_a]e is added in sequence to 哄ikdy 〇g '45 mmol) and double (2) -Oxo-3-oxazolidinyl)phosphinium chloride (n 1 g, 67.3 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified from the eluent column system B to obtain (the _[3_oxo-1-(2,4, 5-trifluoro) Benzyl)-3-(3-trifluoromethyl_5,6-dihydro-8H-imidazo[1,5-a>pyr-7-yl)-propyl]-carbamic acid tert-butyl Ester (20. 'g 'white solid), yield: 88% Ή NMR (400 MHz, CDaOD, ppm): 5 7.25 (m, 1H), 7.11 (m, 1H), 7.032 (s, 1H), 4.93 (ra, 2H), 4.35 (m, 3H), 4.05 (m, 2H), 2.99 (m, 2H), 2.73 (ra, 2H), 1.34 (s, 9H) Step 11 (then-[3 -oxo-l-(2,4,5-trifluorobenzyl)-3-(bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a] Pyridin-7-yl)-propyl]-aminocarboxylic acid tert-butyl vinegar ((-Oxo-1-(2,4, 5-trifluorobenzyl)-3-(3-three) Gas methyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin-7-yl)-propyl]-carbamic acid tert-butyl ester lm (20. 0 g, 39 6克,79. 2。 After adding 1 hour, after adding 1 hour, adding potassium carbonate (10. 9g, 79.2) Ment) and dibutyltributyl dicarbonate (8 6 g, 39. 6 mmol), stirring the reaction for an hour. The reaction mixture was filtered with a crude gel. The filtrate was concentrated under reduced pressure, using a silica gel column chromatography, s. Obtained (Fantasy_[3_oxo-dibu(2,4,5-trifluorobenzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-811-imidazo[ 1,5-a]pyridin-7-yl)-propyl]-carbamic acid tert-butyl ester in • (20. 0 g, white solid), yield: 86%. * lH (4 〇〇 MHz , CDC13, ppm): 7. 06 (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 (A〇-7-[3-Tertidinoxycarbonylamino-4-(2, 4,5-trifluorophenyl)-butanthene]-3-trifluoromethyl-5,6,8-tetrahydroimidazo[1,5-a]pyridin-1-carboxylic acid methyl ester red Method Journal of Organometal Iic (3⁄4(10)/shy, 1985, 285(1-3), 293-303, octacarbonyl bis(cobalt) (4.02 g, 11.76 mmol), ethyl acetate (〇71 g, 5 88 mm〇1) ), potassium carbonate (1.62 g, 11.76 mmol) and 50 mL·nonanol were added to the reaction flask and stirred for 5 minutes. Thereafter, ((-[3_ oxotrifluorobenzyl))-(1-bromo-3-difluoroindolyl-5,6-dihydro-8H-sodium hydrazino and [1,5-a] 0 耕-7-yl)-propyl]-amino decanoic acid tert-butyl ester ln (2.3 g, 3.92 mmol). The reaction was stirred for 2 hours at 60 C, and the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by column column chromatography to elute to afford (β-7-[3- 2 butyloxycarbonylamino group. _4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7-tetrahydroimidazolium,5_a]pyridinium-dibenzoate 1ρ(1·1 g, white solid), yield: 5〇%. MS m/z (ESI): 565.0[M+1] 94968 21 201211043 Step 13 (10)-7-[3-Terbic Oxygen County - 4-(2,4,5-trifluorophenyl)-butanyl;|_3_ trifluoromethyl 巧^'_川~tetrahydroimidazole and ^^一"pyridinium-dibenzoic acid will be (-7 -[3-Tertiyloxycarbonylamino-4_(2,4,5-trifluoromethyl)-butanyl]-3-trifluorofyl_5, 6, 7, 8_tetrahydroimidazo[ 5_^pyridin-1-carboxylic acid formazan lp (1.8 g, 3.2 mmol) was dissolved in 50 mL of methanol, and 10 mL of 4 Μ sodium hydroxide solution was added. The reaction was stirred for 1 hour under ice bath. The reaction mixture was extracted with ethyl acetate (1 mL mL). 7-[3-Tertiyloxycarbonyl 4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyridin-1- Formic acid 1q (1. 76 g, pale yellow solid), yield: 100%. MS m/z (ESI): 550.9[M+1] NMR (400 MHz, CDsOD, ppm): d 7.29-7.23 (m, 1H), 7. 121-7. 08(m, 1H), 5.15-5.03 (m, 2H), 4.41-4.06 (m, 5H), 2.98-2. 77(m, 4H), 1.42-1.26(m , 9H) Fourteenth step U)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8 - Tetrahydro glutinous rice 0 sit and [1,5-&] 〇 哄 曱 曱 曱 曱 将 ( ((~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ -trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyrazine-1 -carboxylic acid lq (1.77 g, 3 2 mmol) was added to the reaction flask, 10 mL of a vaporized hydrogen acetate solution was added, and the reaction was stirred for 1 hour, and the reaction mixture was concentrated under reduced pressure to give the title product (milk-7-[3-amino-4-(2, 4, 5-trifluorophenyl)-butanthene 22 94968 201211043 base]-3-trifluoromethyl_5, 6, 7, ^tetrahydroimidazo[i,5_a]lf than hydrazine hydrochloride Salt 1 (1. 56 g 'white solid), yield: 1%. MS m/z (ESI): 451.2 [M+l] NMR (400 MHz, CD3 〇D, ppm): 5 7.42-7.37 (m 1H), • ^-28-7.23 (m, 1H), 5.19- 5.05 (m, 2H), 4.36-4^29 〇ni 1H), 4.15-4.00 (m, 2H), 3.94-3.93 (m, 2H), 3.21-2.88 (m, 2H), 2.86-2.81 (m, 2H) Example 2 (R)-7-[3-Amino-4_(2,4,5-trifluorophenyl)-butanyl]trimethylmethyl-5, 6, 7, 8-tetrahydroimidazole And [1, well-acid phosphate

Will (pseudo-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]_3-difluoroindolyl-5,6,7-tetrahydromime 0 sit and [1,5-a]n is more soluble than 哄-1-曱 hydrochloride 1 (1.45 g, 2.97 mmol) in 14 虬 dichloromethane, washed with 6 mL of saturated sodium bicarbonate solution, water layer 5 6 虬 2 曱 萃取 , , , , , , , 138 138 138 138 138 138 138 138 138 138 138 138 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 The propanol was dissolved rapidly and 85% tartaric acid (343 mg, 2.97 mmol) in 2 mL of isopropanol was added rapidly. A solid precipitated, stirred for 2 hours, filtered, and the filter cake was washed with cold isopropanol. Drying under reduced pressure at 4 ° ° C to give a crude product 1.44 g, yield 88· 6%. The crude product (1. 44 g, 2. 63 mmol) was dissolved in 23 94968 201211043 26 mL isopropanol, stirred for 1 hour, filtered ', The filter cake was washed with isopropyl alcohol, and the solid was dissolved in deionized water. 4 (concentrated under reduced pressure at TC, and taken at 4 〇. (: vacuum drying to give the title product (the -7-[3-amino-4 -(2,4,5-tris|1 stylyl)-butanyl]-3-trimethyl-5,6,7-tetrahydroimidazo[[,5 _a] pyridin-1-pyruic acid phosphate 2 (1.33 g, white powder), yield · 92.6%. MS m/z (ESI): 451.2 [M+1] H NMR (400 MHz, CDaOD, ppm): δ 7.36-7.42 (in, 1H), 7.19-7.25 (m, 1H), 5.01-5.15 (m, 2H), 4.24-4.34 (m, 2H), 4. 06-4. 11 ( m, 1H), 3.91-3.98 (m, 1H), 3.07-3.12 2H), 2.8-3.09 (m, 2H) Example 3 (妁-7-[3-Amino-4_(2, 4, 5_) Trifluorophenyl)-butanyl]_3_trifluoromethyl

Base-5,6,7,8-tetrahydroimidazo[1,5-antipyridinium_1-carboxylic acid F

一#U)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-trifluoromethyl^,"-tetrahydroimidazolium "Pyghuric acid-formate 1 (1·02 g, 2·1 mm〇i) was dissolved in 3 〇 pyridine, and sodium hydroxide: solution was added (2.1, 2. 1 'mixed The reaction was allowed to proceed for 15 minutes. The reaction mixture was solidified. The obtained solid was dissolved in 15 mL of a methane and methanol mixture (V-κκ·ν) = dissolved, filtered, and the filtrate was concentrated under reduced pressure to give the title product U)-7 -[3-Amino+(2,4,5-trifluorophenyl)-τ醯yl]-3- 24 94968 201211043 ° Ratio of hexanoic acid: 100%. Trifluoromethyl-5 , 6, 7, 8-tetrahydroindolizine 0 and [1,5-a] (943 mg, white solid, HPLC: 99·89%), MS m/z (ESI): 451.2 [M+1] !H NMR (400 MHz, CDaOD, ppm)· δ Ί η *^'7·41 (m, 1Η) 7.n-7.21(m,1Η),5.00-5.07 (m,2Η) 4 1R ,...' » 10-4. z4 (m 2H), 4.05-4.08 (m, 1H), 3.85-3.97 (m ' VIU, 3.05-3 17 (in, 2H), 2.91-2.93 (m, 2H) Example (7)- 7-[3-Amino-4-(2,4' 5-trifluorophenyl)--butanyl]_3_trimethylmethyl-5, 6, 7, 8-tetrahydroimidazo[1, 5-a]pyridinium 曱:

(8)-7-[3-Amino-4-(2,4'5-trifluorophenyl)-butyryl]-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[ 1,5-a]pyrrolidin-3 (100 mg, 0.22 mmol) was dissolved in 5 mL of methanol, and a solution of sodium & sodium oxide (0.44 mL, 0.22 mmol) was added and the reaction was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure to give the title product (y-7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7 , 8-tetrahydroimidazo[5,3_3]pyridin-1-carboxylate 4 (104 mg, white solid, HPLC: 99.65%), yield: 99. 7% MS m/z (ESI): 451.2 M+1] 'H NMR (400 MHz, CD3〇D, ppm): δ 7.26-7.30 (m 1H) 94968 25 201211043 UH.13(m,1H),5 shoulders_5 2()(m,2h) , 4 26_4 27 (m, 2H), 4.00 4.11 (m, 2H), 3.44-3.48 (m, jh), 2.72-2.83 (m, 2H), 2.59-2.60 (m, 2H) Example 5 [3_ Amino-4-(2, 4,5-= ϋ poor |, '-random base)-butyl sulfhydryl]-3_trifluoromethyl-5'6'7'8-tetrahydropyrene [n* Than 哄 + formic acid

F will be (y-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-difluoromethyl-5, 6, 7, 8-tetrahydroimidazolium [1,5-a] Pyridin-1-carboxylic acid 3 (100 mg, 0.22 mmol) was dissolved in 5 mL of decyl alcohol, and a lithium hydroxide solution (0.44 mL, 0.22 mmol) was added, and the reaction was stirred for 15 minutes. Concentration under reduced pressure gave the title product (--7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8 - tetrahydroimidate [1,5-a] 0 卩 -1- -1 -1 carboxylic acid clock 5 (48 mg, white solid, HPLC: 99. 66%), yield: 98.6% MS m/z (ESI): 451. 2[M+1] 4 I^JMR (400 MHz, CD3〇D, ppm): <5 7. 31-7. 38 (m,1H), 7.13-7.22 (m, 1H) ), 5.07-5.27 (m, 2H), 4.26-4.36 (m, 2H), 4.01-4. 15 (m, 2H), 3. 53-3. 60 (m, 1H), 2.80-2.91 (m, 2H), 2.59-2.72 (m, 2H) Example 6 26 94968 201211043 -(7-[3_Amino-4-(2,4,5-trifluorophenyl)-butanyl]~3_trifluoro Methyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyridin-potassium formate

Difluoromethyl-5,6,6-tetrahydroimidazo[1,5-a]pyridinic acid 3 _ (1〇〇mg, 0·22 〇1) was dissolved in 5 mL of methanol. Potassium hydroxide solution (0.44 mL, 0.22 mmol) was added and the reaction was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure to give the title product ((-7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-difluoromethyl-5, 6, 7 , 8-tetrahydroimidazolium 5_&]pyrazine-potassium formate 6 (108 mg 'white solid, HPLC: 92.78%), yield: 100%. MS m/z (ESI): 451.2 [M+ 1] ^ '.H NMR (400 MHz, CDaOD, ppm): δ 7.31-7.38 (m, 1H), 7.14-7. 23(m,1H), 5.07-5. 27 (m,2H), 4.26- 4. 36 (m, 2H), 4. 01-4. 15(m, 2H), 3. 52-3. 60(m, 1H), 2. 8〇-2. 92 (m, 2H), 2.59 -2.74 (m, 2H) Example 7 (if)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-trifluoromethyl-5 , 6, 7, 8-tetrahydroindolo[1,5-&]° than morphine-1_carboxylic acid about 27 94968 201211043

(y?)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]_3_difluoromethyl_5, 6, 7, 8-tetrahydro miso [1,5-a] Sakai_formic acid 3 (100 mg '0.22 mmol) was dissolved in 1 sterol, and a nitrogen oxidation (8.1 mg, 0.11 mmol) was added, and the reaction was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure to give the titled product (yield)~7-[3-amino-4-(2,4,5-trifluorophenylene)-butenyl]-3-trifluoromethyl-5, 7, 8-tetrahydroimidazo[1,5-&]0-p-morphine-calcium citrate 7 (103 mg, white solid, HPLC: 99.60%), yield: 100%. MS m/z (ESI): 451.2 [M+1] NMR (400 MHz, CDAOD, ppm): δ 7.28-7.34 (m, i^) 7.11-7.21 (m, 1H), 5.10-5.21 (m, 2H), 4.22-4.36 (m 2H), 4. 03-4. 09 (m, 2H), 3. 55-3. 59 (m, 1H), 2.76-2.85 (m, 2H), 2.60-2.71 ( m, 2H) Example 8 (1-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]- 3 to trimethylmethyl-5, 6, 7, 8 - tetrahydroimidazo[1,5-a]pyridinium-indole-tridecanoic acid triethyl

94968 28 6 201211043 , will (burn 7-[3-amino-4-(2, 4, 5-trifluorophenyl)-butanyl]_3-difluoroanthryl-5, 6, 7, 8- four Hydrogen oxime 0 and [1,5-a]n than phenyl-1-, acid 3 (100 mg '〇· 22 mmol) was dissolved in 5 mL of methanol, and a solution of triethylamine in methanol (0.767 mL, 0.22 mmol) was added. The preparation method comprises the following steps: adding 丨mL of triethylamine to methanol to prepare 25 mL of a triethylamine decyl alcohol solution), and stirring the reaction for 40 hours. The reaction liquid is concentrated under reduced pressure to obtain the title product (Fantasy_7_[3_Amine 4 -(2,4,5-difluorophenyl)-butenyl]-3-trifluoromethyl_5, 6, 7, 8_tetrahydroimidazo[l,5-a]pyroxy-1-carboxylic acid Triethylamine salt 8 (112, white solid, HPLC·· 99. 34%), yield: 99. 8%. MS m/z (ESI): 451.2 [M+1] H NMR (400 MHz, CDaOD , ppm): δ 7.28-7 35 (m 1H) 7. 10-7. 19 (m, 1H), 5.03-5. 13 (m, 2H), 4 17-4 25 (m ^ 3.88-, 03 ( , 2H), ,,0-, 73(m, 1H), ,12-3. Π (m, 6H), 2.93-2.95 (m, 2H), 2.71-2.80 (m, 2H), 1.27-1.30 ( m, 9H) Example 9

(i〇-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-' 5-a]pyridin-1-indole 3 sterol , trifluoromethyl-5,6,6-tetrahydroimidazolium,5~a]pyridinium (100 mg, 0.22 mmol) added with ethanolamine dissolved in 5 sterols, (100 mg, 0 94968 29 201211043 MeOH solution (0·33 mL, 0.22 mmol, prepared by adding i 'ethanolamine to methanol to make a solution of 25 mL of ethanolamine in methanol), stirring for 40 hours. The reaction mixture was concentrated under reduced pressure to give the title product. (and Amino-4_(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl_5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyrazine '• benzoic acid ethanolamine salt 9 (114 gram white solid, HPLC: 99.62%), yield: 1 〇〇% MS m/z (ESI): 451.2 [M+1] NMR (400 MHz, CDsOD, ppm ): 5 7.27-7.32(ni, 1H)> 7.〇7-7.16(m, 1H), 4.96-5.17 (m> 2H), 4.12_4.26 (m, 2H), 3. 9 Bu 4. 09(m,2H), 3.70-3.72(t, 2H), 3 56-3.57(m, 1H), 2.95-2.98 (t, 2H), 2.80-2.89 (m, 2H) 2. 58-2. 70 (m, 2H) 〇»_7-[3-Amino-4-(2'4'5-trifluorophenylbutanyl)}trifluoromethyl-5, 6, 7, 8-four odor. Sit and (1) 5_ small guide choline formate

Λ~τόη 10 - Ο0-Ή3-amino-4-(2,4,5-trifluorophenyl)-τ醯yl]-trifluoromethyl-5, 6, 7, 8-tetrahydrogen And [丨,5_小小]_carboxylic acid 3 (100 mg '0.22 mmol) was dissolved in 5 mL of methanol, 4 alcohol solution (1.55 mL, 0.22 gab was prepared by adding the methylamine to the methanol In the 'methanol solution of 25 choline, it seems to be biliary. The reaction solution was concentrated under reduced pressure to give the titled product (m.p. 2) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> , 7, 8-tetrahydroimidazo[l,5-a]pyridin-1-phthalic acid choline salt 1 〇 (12 〇 mg, white solid, HPLC: 99. 41%), yield: 98. % MS m/z (ESI) : 451.2 [M+1]

NMR (400 MHz, CDsOD, ppm): s 7.23--7. 3〇(m, 1H) 7.06-7.15(m, 1H), 4.99-5.19 (m, 2H), 4.19-4.26 (m, 2H), 3.89-4.07(m, 4H), 3.60-3.7l(m, 1H), 3. 50-3. 55(3⁄4^ 2H), 3. 21(s, 9H), 2.72-2.84 (m, 2H), 2. 55-2. 66(m, 2H) Example 11 U)-7-[3-Sis-4-(2,4,5-Tri 1 stupyl)~醯醯]_3—Three Mice Methyl -5, 6' 7, 8-tetrahydroimidazo[i,5_a]pyrazine-丨_capric acid malate hoof

L-malic acid (368 mg, 2.74 mmol) was dissolved in a mixture of 25 mL of decyl alcohol and water (V/V = 4:1) to prepare a solution of 〇.u M, which was used. 〇P)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]_3_trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[ 1,5~a]pyridinium diborate 3 d〇〇mg, 0.22 mmol) was dissolved in 10 mL of methanol, 2 虬 of the above-mentioned standby solution was added, and the reaction was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title product (yield: -7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]_3-trifluoromethyl Imidazole ' ' 卜 哄 哄 哄 129 129 129 (129 mg, white solid, HPLC: 98. 92%), yield: 1 〇 (10). 94968 31 201211043 MS m / z (ESI): 451.1 [ M+l] NMR (400 MHz, CDsOD, ppm): 3 7 32—7 4i (m ih) 7.16-7.23 (m, 1H), 4.96-5.13 (m&gt; 2H), 4.35-4.39 (m, 1H) , 4.2G-4.30 (m, 2H), 4.04-4. 13 (m, 1H), 3 9〇-4 〇〇 (,, 2H), 3.07-3.13 (m, 2H), 2.77^2.97 (m, 3H), 2.56-2.62 (m, 1H) Example 12 Amine II I stupyl) ~ butyl aryl]_3_三败曱 base 5, 6, 7, 8-tetrahydropyrene [1, has -^ ❹井-卜carboxylic acid tartrate

D-tartaric acid (413 mg '2·75 mmol) was dissolved in a mixed solvent of 25 mL of decyl alcohol and water (V/V = 4:1) to prepare a solution of 〇11 M, which was used. (8)-H3-Amino-4-(2,4,5-trifluorophenyl)-butanyl bromide 3-trimethyl-5,6,7-tetrahydroimidazo[1,5_a]咣哄_bucarboxylic acid 3 (1 〇〇 =, 0·22 mm 〇l) was dissolved in 10 mL of sterol, 2 乩 of the above-mentioned standby solution was added, and the reaction was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title product ((-7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[丨,5_a]pyridinium-indole-carboxylic acid tartrate 12 (131 mg, white solid, HPLC: 99 35%), yield: (10). MS m/z (ESI): 451.1 [ M+1] H NMR (400 MHz, CDsOD, ppm): δ 7.32-7.41 (m, 1H) 94968 32 201211043 7. 17-7.26 (m,1H), 5.01-5. 14 (m,2Η),4 ·51 (s,1H) 4.20-4.35 (m, 2H), 4. 〇〇-4. 13 (m, 1H), 3.89-3.96 2H), 3.04-3.13 (ffl, 2H), 2.90-3.00 (m , 1H), 2.77-2 87 Cm, 1H) Example 13 Amino-4 must be 4,5-trifluorophenyl)_Tindolyl]_3_trimethylmethyl-5' 6' 7' 8-tetrahydro Imidazo[丨,5_a]pyridinium_i_carboxylic acid arginine

L-arginine (239 mg, 1.37 mmol) was dissolved in 25 mL of a mixed solvent of methanol and water (V/V = 4:1) to prepare a solution of 〇55 M, which was used. ((-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]_3_trifluoromethyl-5,6,7-tetrahydroimidazo[1] , 5--amp;&gt; 哄-i_capric acid 3 (ι〇〇# mg, 0.22 mmol) was dissolved in 15 mL of methanol, and 4 乩 of the above-mentioned standby solution was added to stir the reaction for 4 hours. The reaction solution was concentrated under reduced pressure. The title product was obtained (Λ-7-[3-amino-4~(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7-tetrahydroimidazole And [1,5-a]pyridin-1-furoate sulphate (139 mg, white solid, HPLC: 98. 89%), yield: 1%. MS m/z (ESI) 451.1[M+l] ^ NMR (400 MHz, CD3〇D, ppm): δ 7.24-7.32 (m, 1H) 7.09-7.14 (m, 1H), 4.98-5.18 (m, 2H), 4.25-4.28 ( m, 1H), 4. 18-4. 19 (m, 1H), 3.93-4.04 (m, 2H), 3. 50-3. 54 94968 a 201211043 (m, 2H), 3.18-3.23 (m, 2H ), 2.76-2.87 (m, 2H), 2. 58-2.69 (m, 2H), 1.77-1.90 (m, 2H), 1.67-1.75 (m 2H) Test Example: Solubility test according to conventional solubility measurement method, test Solubility of the compounds of the invention in four different systems: phosphate buffer PBS (pH 7.4), sterol, hydrazine, 1% HCl, and water. Shown: Table 1 Example Solubility Value (mg/mL) PBS (pH 7.4) Methanol 0.1% HCl Water Example 1 18. 6 31.3 17.2 ~ 20:9~~ _ Example 2 20.2 37.5 32.5 ~~26ΠΓ Example 3 7.0 32.7 20.5 9. 2 Example 4 57.4 46. 7 94.8 Example 5 60. 5 50. 3 100. 6 40.2 Example 8 0. 2 Bu 20· 1 8. 3 0. 5~~ Example 9 0. 3 Γ 35.2 12. 6 ----—^ 1. 0 Example 10 L2 Γ&quot;40. 3 15. 2 1.5—· Example 11 19. 5 5.4 32. 6 22. 2 Example 12 12.3 0.5 33.8 19. 5 Conclusions · The solubility of Example 2, Example 4 and Example 5 was significantly improved. Biological Evaluation The following method can be used to determine the ability of the compounds of the invention to inhibit the activity of DPP IV, DPP V111 and DPP IX enzymes. The half-inhibitory concentration of the compound, the IC5 enthalpy (the concentration of the compound required to inhibit the enzymatic activity to 50%), is 34 94968 201211043 lin, by mixing a certain amount of enzyme with a substance and a different concentration of the test compound. After the reaction, it was measured and calculated. The following test by using Promega DPPIV-G1otm Protease

Assay CCat No. G8350/G8351) kit to determine the inhibition of DPP iv, DPP VIII and DPP IX enzyme activities by the compounds of the present invention. Among them: a. DPP IV enzyme purchased from caibiochem, Catalog no. 317630 I b. DPP VIII enzyme purchased from Bi〇science, Catalog no. 80080 c. DPP IX enzyme purchased from Bioscience, Catalog no. 80090 The specific preparation process of the reagent (DpPlv_G1 buffer, luciferin reagents, etc.) and the detailed operation of the test can be referred to the specification of the above kit. The brief test method is as follows: The test compound is dissolved in DMS0 and formulated into the concentration required for the experiment. The DPP IV-Glo buffer and the lyophilized fluorescein detection reagent powder were first equilibrated to room temperature, and then the fluorescein detection reagent powder was dissolved in a suitable amount of buffer to prepare a solution. Subsequently, the DPPIV-Glo substrate was dissolved in ultrapure water to prepare the concentration required for the test, and then the substrate solution and the luciferase detection reagent solution (the ratio used in the test was 1:49) were thoroughly mixed in an appropriate ratio. Allow to stand at room temperature for 30 to 60 minutes. After mixing a certain amount of Tris buffer (2 mM, pH 8.0), test compound and DPPIV (DPPVIII or DPPIX) enzyme, transfer to 96-well reaction plate, set up duplicate or 3-well control for each test, blank well and A negative volume of DMS0 equivalent to the test compound was added to the negative control well. Subsequently, the prepared substrate-luciferin detection reagent was mixed with 35 94968 201211043 solution to start the reaction, and the 96-well plate was collected and cultured for 4 G minutes on a plate shaker. Then, the fluorescence signal of each well was read by a microplate reader to calculate the inhibition rate of the compound at the concentration, and the calculation formula is as follows. The inhibition rate IR=[1~(S~B)/(4))**s: Sample well signal reading β · blank control signal reading Ν: negative control signal reading 匕 of the test compound. The value can be calculated by the inhibition rate at different concentrations.

EXAMPLES---------- - IC50( &quot; PP, DPPIV DPP8 DPP9 1 0. 021 87. 9 63. 6 2 〇· 015 399. 7 185. 0 3 0. 013 235. 7 125. 4 a 4 0. 022 77.3 42. 3 5 0. 025 80. 5 50. 6 8 0. 021 152.5 135. 6 9 0. 012 ll3. 7 128. 3 a 10 1 1 &quot; 0. 023 210 I 165. 6 II 0. 009 279. 7 180. I 12 〇· 012 243.8 135. 5 Activity, Example 2 has better selectivity

Pharmacokinetic test test example 1 The pharmacokinetic test of the compound of the present invention 36 94968 201211043 1. The purpose of the test is to test the rat gavage and tail vein by LC/MS/MS method. Example 3 and Administration of Drugs/Expansion in Plasma at Different Time After Example 1 to 4 Example 9 and Example 11 to 12 The pharmacokinetic behavior of the compound of the present invention in rats was evaluated. Kinetic characteristics and their oral bioavailability were examined. 2. Test protocol 2. Test compound 1 to 4 compounds 'Example 9 compound, Examples 11 to 12 compound 2. 2. Test animals Healthy adult SD rats 28, male and female, from Shanghai Sippur-Beikai Experimental Animals Limited 3 ' Secret Production License No. 2008-0016. , exhibition) 2.3, equipment

Mass spectrometer, American ApPlied API 4000 Q-trap linear ionic brown Biosystems; National Agilent.

Agilent 1200 high performance liquid chromatography system, the United States 2. 4, the drug preparation intravenous group: weigh the appropriate amount of drugs, add υινΐύυ u. 5 mL super sonic turbidity, then diluted with physiological saline to 15 this, _ and . 3 mg / mL solution. Add 5% CMC-Na Ultrasonics Oral administration group: Weigh the appropriate amount of the drug to make a suspension of 0.3 mg / mL. 94968 37 201211043 2. 5. Administration 32 healthy adult SD rats, half male and half female, were divided into 8 groups, 4 in each group. After fasting overnight, Example 3 was administered by tail vein injection and Example 3 and its salt were administered intragastrically at a dose of 3 〇mg/kg (in terms of alkali form). The administration volume was 1 〇 mL/kg. 2 · 6, sample collection intravenous administration group before administration and 2 minutes, 15 minutes, 30 minutes, 1. 〇 hours, 2. 〇 hours, 4. 〇 hours, 6. 〇 hours, 8. Blood samples were collected from the eyelids at 2 hours, 12.0 hours, 24.0 hours, placed in heparinized tubes, centrifuged at 3500 rpm for 1 minute to separate plasma, stored at _2 〇t, and fed 2 hours after administration. The intragastric administration group was administered before and after administration for 5 hours, 丨·〇 hours, 2.0 hours, 3.0 hours, 4.〇 hours, 6.〇 hours, 8 hours, 12. hours, 24.0 hours. Blood collection and sample processing methods were the same as intravenous administration. 2. 7. Analytical method Take 50//L of the blood in rats at each time after administration, add 5内AL, sterol 150//L of internal standard solution for 3 minutes, centrifuge for 1 minute (135〇) 〇 / / min), take the supernatant l 〇 #L for LC-MS / MS analysis. 2. Calculation of pharmacokinetic parameters The pharmacokinetic behavior of the test compound was fitted to the compartment model and the main pharmacokinetic parameters were calculated. The DAS 2.0 software was used to calculate, c_, Measured value. The absolute bioavailability of oral administration according to the age of intragastric and tail vein administration. 94968 38 201211043 • Λ, 3. Pharmacokinetic parameter results The pharmacokinetic parameters of the compounds of the present invention are shown in Table 2. Conclusion: Example 2 showed significant pharmacokinetic properties and bioavailability compared to other compounds with significant pharmacokinetic advantages. - Table 3: Implementation of F 0, muscle t 1/2 L· MRT CI7F Vz/ F Example (%) (ng/mL) (ng.h/mL) (h) (h) (h) (L/h/kg) (l/kg) 1 2.90 18.0+7.5 66.6+19.5 1_ 7410.16 2. 50+1.00 3.17+0.36 45.6+11.5 114±27 2 8.63 66.6+36.4 198.1+57.4 1.69+1.24 0.92+0.58 4.05+3.66 16.2+4.55 41+29. 7 0 2.54 13.4+5.6 58.3+17.3 2.73+0.73 1.00+ 0.00 4.45 soil] .01 51.7+16.0 193+38 0 vein 2295+353 2.35+1.90 — 0.22±0.06 1.33+0.20 6.0516.53 4 2.90 14.2+2.0 66.6±10.6 2.65+0.94 1.75+0.96 4.30+0.60 43.7+7.1 164±56 9 4.06 25.1+13.9 93.2+36.4 3.18±0. 71 1. 25+0.50 4.34±0.66 32. 9±10. 0 I55 soil 63 11 3.03 13.5+3.9 69.5±25.2 2.21+0.69 1.63+1.11 4.50± 1.32 46. 6+17.7 140+39 12 3.25 17 .0+6.9 74.6+21.7 2.54±0.86 1.75+0.50 4.23+0.84 40.3+9.9 154±77

Preliminary evaluation of hypoglycemic effect of the compound of the present invention I. Test purpose The effects of test compound Examples 1 to 4 and Examples 8 to 12 on oral glucose tolerance of normal ICR mice (Shanghai Slack Laboratory Animal Co., Ltd.) were observed, and blood glucose was used. The instrument measured and analyzed the sugar content in the tail blood of mice at different times within 2 hours after administration of the sugar, and initially evaluated its hypoglycemic effect in the body. 2. Test method 2.1 Dosage setting The dose was 10 mg/kg, and the blank (Β1 ank) group was given water (both containing 5% DMS0). 2. 2 Administration method Administration by intragastric administration, after 15 minutes of administration, 10% glucose was administered at 4 g/kg 39 94968 201211043 solution (0. 8 mL per mouse). 2.3 Measurement of blood glucose level The blood glucose value (-15 minutes) was measured by dosing (Blank group was given water containing 5% DMS sputum). After 15 minutes of administration, a 2% by weight glucose solution was administered at 4 g/kg, and the blood glucose level of each mouse was measured by using a 罗Rokang whole blood glucose meter at 〇, 15, 3G, 45, 6G, and 12G minutes. 2.4 The test results are shown in Table 3: Table 3: % of blood glucose decline after 30 minutes of administration of the number of mice in the example (1〇mg/k£T, 1 16. 06 2 29. 96 3 4 9.49 8 19. 82 9 27. 56 10 2〇2 _ 11 20. 18 _ 12 24.11 ' Conclusion: Example 2 has significant hypoglycemic effect relative to other compounds. [Simplified illustration] No [Main component symbol description] No 94968 40

Claims (1)

201211043 磉• VII. Patent application scope: 1': species (illusion~7-[3~amino-4-(2,4,5-trisphenyl)-butanyl]-3-difluoromethyl-5 , 6' 7, 8-tetrahydroimidazolium u,5_a]pyridinium-p-carboxylic acid salt 'where 'the salt is (phan 7-[3-amino-4-(2, 4, 5-trifluoro) Phenyl)-butyl&amp;yl]3-difluoromethyl-5,6,8-tetrahydroimidate and [1,5-a]0-indol-1-nonanoic acid with inorganic base or organic a base-addition salt formed by a base. 2. a species (fanta-7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-oxan-methyl--5, a salt of 6,7' 8-tetrahydroimidazo[1,5-a]pyridin-1-carboxylic acid, wherein the salt is selected from the group consisting of phosphates, hydrogen phosphates, sulfates, hydrogen sulfates, sulfites, Acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, sulfonate Salt, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactoblate or lauryl sulfonate, preferably Squama. _ 3 •--(burn-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]-3~difluorodecyl-5, 6, 7, 8-tetrahydroimidazole And [1,5-a]pyrazine-1-decanoic acid salt 'wherein the salt is selected from the group consisting of sodium salt, salt, salt, salt, salt, tetramethyl quaternary ammonium salt, tetraethyl a quaternary ammonium salt, an ethanolamine salt, a choline salt, an amide salt, a arginine salt, a methylamine salt, a dimethylamine salt, a tridecylamine salt, a diethylamine salt or an ethylamine salt, preferably an ethanolamine salt. And salt test. 4. One (burning 7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]~ difluoromethyl-5, 6, 7, 8- Tetrahydro σ m 0 sits and [1,5-a] 〇 哄-1 - 甲 jun, wherein the salt is selected from: 94968 41 201211043 F 5. - The scope of application for patents is 丨 to = . The use of a salt for the treatment of the 11_^=; term, a drug for tyrosin resistance. Symptoms, obesity, or islets 6. - Patent application Nos. 1-4 to 4 for the preparation of dipeptidyl peptidase JV inhibitors. 々 Use, 7) A patent for the treatment of type 2 diabetes, high-resistance method, obesity or insulin resistance. Salt to any of the four items. A method for inhibiting the dipeptidyl peptidase (IV) activity, which comprises contacting the peptidyl peptidase IV with a salt of any one of claims 1-4. 9. The oral application of the patent scope, to any of the salts of 4, is used as a medicine for the treatment of type 1 diabetes, hyperglycemia, obesity or sputum resistance 94968 42 201211043. The salt of any one of 4, which is a drug for inhibiting two. 10. The drug of the first peptidyl peptidase IV of the patent application range 11·-Preparation of U)-7-[3_Amino+(2,4,5-trifluorophenyl)-butyl-aryl]-3-trifluoromethyl _5, 6, 7, 8_4 Hydrogen feed # [丨, 5-a] 吼卩井小曱, the method of salt, including (7) _7_[3-amino-4_(2,4,5,3*1-based)-butyl-based] 3-trifluorodecyl-5,6,7,8-tetrahydro-sodium and 5-a]pyridin-indole-carboxylic acid is reacted with an acid selected from the group consisting of phosphoric acid, thioindigo, sulfurous acid, acetic acid, Oxalic acid, malonic acid, valeric acid, facial acid, arbor Palmetto, hard lauric acid, lauric acid, boric acid, p-toluene acid, tartaric acid, tartaric acid, benzoic acid, pamoic acid, water Salicylic acid, vanillic acid, mandelic acid, succinic acid, gluconic acid, lactobionic acid or lauryl sulfonic acid. 12. Preparation (Fantasy_7-[3-Amino-4-(2,4,5-tri-l-phenyl)-butyl-branched]-3-trifluoromethyl-5, 6, 7, 8- A method of the salt of tetrahydroimidazo[1,5-a]pyridinic acid, which comprises: 〇P)-7-[3-amino~4~(2,4,5-trifluorophenyl) -丁醯基]_3-trifluoromethyl_5, 6, n tetrahydroimidazo[1,5-a]pyrazine-1 _nonanoic acid and face metal hydroxide, amine or quaternary compound reaction. 13. The method of claim 12, wherein the alkali metal hydroxide is selected from the group consisting of sodium hydroxide, hydrogen peroxide, potassium hydroxide, hydroxide dance, oxyhydroxide, the amine or the quaternary class The compound is selected from the group consisting of tetramethyl quaternary ammonium 'tetraethyl quaternary ammonium, ethanolamine, choline, lysine, arginine, methylamine, dimethylamine, trimethylamine, triethylamine or ethylamine. A pharmaceutical composition comprising a salt of a therapeutically effective amount of any one of the claims 94968 43 201211043 1 to 4 and a pharmaceutically acceptable carrier. 15. Use of a pharmaceutical composition of claim 14 in the scope of the patent application for the preparation of a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance. 16. A method of treating type 2 diabetes, hyperglycemia, obesity or insulin resistance, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical composition of claim 14. 17. The pharmaceutical composition of claim 14 is for use as a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance. 44 94968 201211043 IV. Designated representative map: There is no schema in this case (1) The representative representative map of this case is: (). (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 2 94968