TW201026314A

TW201026314A - Tetrahydroimidazo [1,5-a]Pyrazine derivatives, preparation process and pharmaceutical use thereof

Info

Publication number: TW201026314A
Application number: TW98101005A
Authority: TW
Inventors: Peng-Cho Tang; fang-long Yang; Jiang Fan; Hu Feng; Yang Wang; Tao Yang
Original assignee: Shanghai Hengrui Pharm Co Ltd
Priority date: 2009-01-13
Filing date: 2009-01-13
Publication date: 2010-07-16
Also published as: TWI439271B

Abstract

The present invention relates to novel Tetrahydroimidazo[1,5-a]Pyrazine Derivatives of formula (I), methods for their preparation, pharmaceutical compositions containing the same and their use as a therapeutic agent, especially as a dipeptidyl peptidase IV inhibitor. The definition of substituents in formula (I) are the same as the description.

Description

201026314 • % 六、發明說明：【發明所屬之技術領域】本發明涉及一種通式（I)所示新穎的四氫咪唑並[1，5-a] ' 吡畊類衍生物、其製備方法以及含有該衍生物的醫藥組合物、以及其作為治療劑的用途，特別是作為二肽基肽酶IV 抑制劑的用途。【先前技術】糖尿病是一種多病因的代謝疾病，特點是慢性高血 ❹糖，伴隨因胰島素分泌及/或作用的缺陷引起的糖、脂肪和蛋白質代謝紊亂。糖尿病是一種非常古老的疾病，是由於人體内胰島素絕對或相對缺乏而引起的血中葡萄糖濃度升高，進而糖大量從尿中排出，並出現多飲、多尿、多食、消痩、頭暈、乏力等症狀。永久性的或不受控制的高血糖症導致發病率與死亡率.. 的增加。通常血糖怪定（glucose homeostasis)的異常直接 _或間接地與脂質、脂蛋白質、脂蛋白元新陳代謝的變更或其他的代謝和血液動力學疾病有關。11型糖尿病患者患有大多孔脂質體及微血管綜合症，如冠狀心臟病、中風、周邊血管性疾病、高jk壓、腎病、神經病和視網膜病等疾病危險性顯著增加。因此，對血糖怪定、脂類代謝、高血壓等疾病進行治療控制，對於臨床上治療糖尿病是極其重要的。通常來說，有兩種類型的糖尿病。I型糖尿病人，即胰島素依賴型糖尿病（IDDM)，患者自身產生的胰島素很少或 3 94579 201026314 * s _ '幾乎沒有。胰島素是體内用來調節葡萄糖#!]㈣-種荷爾 .蒙。11型糖尿病人，即胰島素非依賴型糖尿病（腸DM)，患 .者與非糖尿病患者的血聚内騰島素漢度是相同的或者更高，然而’此類患者卻對姨島素產生抵抗性，這些姨島素對於主要的騰島素敏感的組織細胞，如肌肉、肝臟、25個脂肪組織等的葡萄糖和脂類代謝起著刺激作用。即使血聚膜島素濃度提高，也無法克服患者對於騰島素顯著的抵抗力。 ❹ 姨島素抵抗性主要是因為騰島素受體數量的減少而產生的，以及騰島素受體缺陷’到目前為止此機制還未能理解。胰島素應答性的抵抗性導致胰島素無法在肌肉組織中，對葡萄糖攝取、氧化、存儲進行啟動，無法有效抑制脂肪組織脂解作用，和肝臟葡萄糖的產生和分泌。二肽基肽酶-IV(DPPIV)是一種絲胺酸蛋白酶，它可以在次末端含有一個脯胺酸殘基的肽鏈中裂解N__末端二肽， ❹儘管DPPIV對哺乳動物的生理作用還沒有得到完全的證實，但其在神經酶代謝、T—細胞啟動、癌細胞轉移入内皮及HIV病毒進入淋巴樣細胞過程中都發生重要的作用（專利文獻 W098/19998)。最近，有研究表示DPPIV可以阻止類胰升糖素肽 (GLP)-l的分泌，尤其，它可以裂解中卜末端的組胺酸-丙胺酸二肽’使其從活性形式的GLP-1(7-36)NH2降解為無/舌性的 GLP-l(9-36)NH2(Endocrinology ’ 1999，140 : 5356至5363)。由於生理情況下，循環血中完整GLp—丨的 4 94579 201026314 半衰期很短’ DPPIV降解GLP-l後的無活性代謝物能與 GLP-1受體結合拮抗活性GLP-1從而縮短了對GLP-1的生理反應。而DPPIV抑制劑能完全保護内源性甚至外源性的 GLP-1不因DPPIV失去活性，極大為提高GLP-1的生理活性（5至10倍)。由於GLP-1對胰腺胰島素的分泌是一個重要的刺激器並能直接影響葡萄糖的分配，此？1¥抑制劑對非胰島素依賴型糖尿病（NIDDM)的治療發生很好的作用（專利文獻 US6110949)。 ❹201026314 • % Description of the Invention: [Technical Field] The present invention relates to a novel tetrahydroimidazo[1,5-a]' pyridin derivative represented by the general formula (I), a preparation method thereof, and a preparation method thereof A pharmaceutical composition containing the derivative, and its use as a therapeutic agent, in particular as a dipeptidyl peptidase IV inhibitor. [Prior Art] Diabetes is a multi-pathogenic metabolic disease characterized by chronic high blood sugar, accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or action. Diabetes is a very old disease. It is caused by the absolute or relative lack of insulin in the human body. The blood glucose level is increased, and then a large amount of sugar is excreted from the urine, and there are polydipsia, polyuria, polyphagia, phlegm, dizziness. , fatigue and other symptoms. Permanent or uncontrolled hyperglycemia leads to an increase in morbidity and mortality. Usually 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 11 diabetes have a significant increase in the risk of large porous liposomes and microvascular syndromes such as coronary heart disease, stroke, peripheral vascular disease, high jk pressure, kidney disease, neuropathy and retinopathy. Therefore, the treatment and control of diseases such as 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 very little insulin or 3 94579 201026314 * s _ 'almost none. Insulin is used in the body to regulate glucose #!] (4) - species of hormones. People with type 11 diabetes, insulin-independent diabetes mellitus (intestinal DM), have the same or higher blood-staining hormones than those with non-diabetic patients, but 'these patients are producing sputum. Resistant, these scorpion stimulants are stimulating glucose and lipid metabolism in the main tissue cells that are sensitive to the island, such as muscle, liver, and 25 adipose tissue. Even if the concentration of plasma membrane is increased, it is impossible to overcome the patient's significant resistance to temsin.抵抗姨素素素素素素素素素素素素素素素素素素素素素素素素素素素素素素素素素素素素The resistance to insulin responsiveness causes insulin to fail to initiate glucose uptake, oxidation, and storage in muscle tissue, and is not effective in inhibiting lipolysis of adipose tissue and production and secretion of hepatic glucose. Dipeptidyl peptidase-IV (DPPIV) is a serine protease that cleaves the N_terminal dipeptide in a peptide chain containing a proline residue at the secondary end, despite the physiological effects of DPPIV on mammals. Not 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 W098/19998). Recently, studies have shown that DPPIV can block the secretion of glucagon-like peptide (GLP)-1, in particular, it can cleave the end of histidine-alanine dipeptide' from the active form of GLP-1 ( 7-36) NH2 degrades into no/tongue GLP-1 (9-36) NH2 (Endocrinology '1999, 140: 5356 to 5363). Due to physiological conditions, the complete half-life of GLp-丨4 94579 201026314 in circulating blood is very short 'DPPIV degraded GLP-1 after inactive metabolites can bind to GLP-1 receptor antagonistic activity GLP-1 and thus shorten the GLP- 1 physiological response. DPPIV inhibitors can completely protect endogenous and even exogenous GLP-1 from DPPIV loss of activity, greatly increasing the physiological activity of GLP-1 (5 to 10 fold). Since GLP-1 is an important stimulator of pancreatic insulin secretion and can directly affect glucose distribution, this? The inhibitor of 1 ¥ has a good effect on the treatment of non-insulin-dependent diabetes mellitus (NIDDM) (patent document US6110949). ❹

目前一些DPP-IV抑制劑已被公開（專利文獻 US5462928 、 US5543396 、 WO9515309 、 W02003004498 、 W02003082817、W02004032836、W02004085661)，其中 Merck 公司製造的DPP IV抑制劑MK-0431顯示了良好的DPP丨v抑制活性及選擇性，並已於2〇〇6年上市。然而，儘管已有若干DPPIV抑制劑被公開’但是目前還未有長效的藥物，仍然需要性質得到改善的1)沖1¥抑劑。本發明的目的是提供一種具有抑制DppIV活性並且可用於糖尿病或類似疾病的治療或緩解性藥物的化合物。【發明内容】為了克服現有技術的不足之處，本發明的目的在於提供-種通式⑴所示的四氫輕仙心]娜類化合物，以及它們的互變異構體、對映體、非對映體、消旋體和藥學上可接受的鹽，以及代謝產物和代謝前驅物或前藥。 94579 5 201026314At present, some DPP-IV inhibitors have been disclosed (Patent Documents US5462928, US5543396, WO9515309, W02003004498, W02003082817, W02004032836, W02004085661), wherein the DPP IV inhibitor MK-0431 manufactured by Merck Company shows good DPP丨v inhibitory activity and Selective and has been listed in 2002. However, although several DPPIV inhibitors have been disclosed', but there are currently no long-acting drugs, there is still a need for an improved 1) inhibitor. 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. SUMMARY OF THE INVENTION In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a tetrahydro-sphingolipid compound represented by the general formula (1), and their tautomers, enantiomers, and non- Enantiomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs. 94579 5 201026314

其中： R選自氫原子、烷基、三氟甲基、環烷基、芳基或雜芳基，其中烷基、雜環炫基、芳基、雜芳基進一步視需要地經一個或多個選自齒素、氰基、芳基、羥基或胺基的取代基所取代’較佳為三氟曱基；Wherein: R 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, the heterocyclic group, the aryl group, the heteroaryl group are further optionally one or more Substituents selected from the group consisting of dentate, cyano, aryl, hydroxy or amine are substituted 'preferably trifluoroindolyl;

R選自羥基、胺基、烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基或-NW，其中烷基、烷氧基、環烷基、雜環燒基、芳基或雜芳基進一步視需要地經一個或多個選自鹵素胺基、氰基、羥基、燒基、環烷基、烷氧基、芳基、雜芳基、-nr4r5、—0C(0)0R8、羧酸或羧酸酯的取代基所取代，. R3選自氫原子或烷基； © 1和R5各自獨立地選自氫原子、烷基、環烷基、雜環烷基、芳基或雜芳基，其中烷基、環烷基、雜環烷基、芳基，雜芳基進一步視需要地經一個或多個選自鹵素、羥基、知基燒氧基、烧基、氰基、芳基、環烧基、雜環燒基、 =芳基、羥烷基、-S〇2R7、-NR4R5、羧酸或綾酸酯的取代基 8。或者，R4和R5 —起形成4至8員雜環基’其中該4互。貝雜環内含有一個或多個N、〇、S原子，並且該4至,R is selected from hydroxy, amine, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or -NW, wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl Or an aryl or heteroaryl group, further optionally one or more selected from the group consisting of haloamine, cyano, hydroxy, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, -nr4r5, -0C (0) 0R8, substituted by a substituent of a carboxylic acid or a carboxylate, R3 is selected from a hydrogen atom or an alkyl group; and 1 and R5 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group. An aryl or heteroaryl group wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group is further optionally one or more selected from the group consisting of halogen, hydroxy, alkoxy groups, and alkyl groups. Substituent 8 of cyano, aryl, cycloalkyl, heterocycloalkyl, =aryl, hydroxyalkyl, -S〇2R7, -NR4R5, carboxylic acid or phthalate. Alternatively, R4 and R5 together form a 4- to 8-membered heterocyclic group wherein the 4 are mutually. The beta heterocycle contains one or more N, 〇, S atoms, and the 4 to

貝 JT1P ”衣上進一步視需要地經一個或多個選自鹵素、羥基、 6 94579 201026314 胺基、烷氧基、烷基、氰基、芳基、雜環烷基、雜芳基、羰基、羥烷基、-s〇2r7、-NR4R5、-C(0)NR4R5、-C(0)R7、= 0、羧酸或羧酸酯的取代基所取代； R6選自鹵素、氰基、羥基、烷基或者烷氧基，其中烷基或者烷氧基是未取代或進一步地經一個或多個鹵素取代； R7為烷基； R8為烷基或環烷基。本發明中所述的藥學上可接受的鹽為本發明化合物與 ® 選自下列的酸形成的鹽：蘋果酸、乳酸、馬來酸、鹽酸、甲磺酸、硫酸、磷酸、檸檬酸、酒石酸、乙酸或三氟乙酸。本發明的典型化合物包括，但不限於：實施例結構命名 1 F fVF (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁蕴基]-3_三氣曱基-5, 6， 7, 8_四氮°米〇坐並[1，5-a]fl比哄-1-甲酸曱酯鹽酸鹽 2 F 1 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁酿基]-3-三氣甲基_5, 6， 7, 8-四氫ϋ米0坐並[1, 5-a]fl比哄-1-羧酸(2-甲磺醯基-乙基)-醯胺鹽酸鹽 94579 201026314 * <. 3 fVf (R)-3-胺基-l-[l-(嗎啉-4-羰基)-3-三氟曱基_5, 6-二氮-8Η-σ米唑並[1，5-a>比畊-7-基]-4-(2， 4, 5-三氣苯基)-丁-1_綱鹽酸鹽 4 F k/N^ fV (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁醯基]-3-三氣曱基-5, 6， 7, 8-四氳咪σ坐並[1，5-a]n比口井 -1-(氰基甲基）甲醯胺鹽酸鹽 5 fVF (R)-3-胺基-l-[l-(4-曱基-六氫吡哄-1-羰基)-3-三氟甲基-5, 6-二氮坐並[1，基]-4-(2, 4, 5-三氟苯基)-丁銅二鹽酸鹽 6 钟啦 (R)-3-胺基-1-[1-(1，1-二氧代-硫代嗎淋-4-幾基)-3-三氟曱基 _5, 6-二氮-8H-ϋ米π坐並[1，5_8·]σ比畊-7-基]-4-(2,4,5-三氟苯基)-丁-1-酮鹽酸鹽 8 94579 201026314Shell JT1P" further optionally one or more selected from the group consisting of halogen, hydroxy, 6 94579 201026314 amine, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, Substituted by a hydroxyalkyl group, -s〇2r7, -NR4R5, -C(0)NR4R5, -C(0)R7, = 0, a carboxylic acid or a carboxylic acid ester; R6 is selected from the group consisting of halogen, cyano, and hydroxy Or an alkyl or alkoxy group, wherein the alkyl or alkoxy group is unsubstituted or further substituted with one or more halogens; R7 is an alkyl group; R8 is an alkyl group or a cycloalkyl group. An acceptable salt is a salt of a compound of the invention with an acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid. Typical compounds of the invention include, but are not limited to: Example Structure Nomenclature 1 F fVF (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3_ Triseocarbyl-5, 6, 7, 8_tetranitrogen 〇并 and [1,5-a]fl than 哄-1-carboxylic acid oxime ester hydrochloride 2 F 1 (R)-7-[3 -amino-4-(2,4,5-trifluorophenyl)-butanyl]-3- Gas methyl _5, 6, 7, 8-tetrahydro glutinous rice 0 sitting and [1, 5-a] fl than hydrazine-1-carboxylic acid (2-methylsulfonyl-ethyl)-guanamine hydrochloride Salt 94579 201026314 * <. 3 fVf (R)-3-Amino-l-[l-(morpholin-4-carbonyl)-3-trifluoromethyl-7,6-diaza-8Η-σm Azolo[1,5-a>tough-7-yl]-4-(2,4,5-trisylphenyl)-butan-1-hydrochloride 4 F k/N^ fV (R) -7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trimethylsulfonyl-5, 6, 7, 8-tetramium σ sit and [1 ,5-a]n ratio well-1-(cyanomethyl)formamidine hydrochloride 5 fVF (R)-3-amino-l-[l-(4-mercapto-hexahydropyridinium -1-carbonyl)-3-trifluoromethyl-5,6-diaza-[1,yl]-4-(2,4,5-trifluorophenyl)-butyl copper dihydrochloride 6 cho. (R)-3-Amino-1-[1-(1,1-dioxo-thio-indol-4-yl)-3-trifluoromethyl-7,6-diaza-8H - ϋ米π sit and [1,5_8·]σ ratio till-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 8 94579 201026314

7 (R)-l-{7-[3-胺基~4-(2, 4, 5-三氟苯基)-丁醯基]-3-三氟甲基 -5, 6, 7, 8-四 4/米0坐並[1，5-a]B比畊-1-羰基}-六氫吡啶-4-甲醯胺鹽酸鹽 8 F k/N-^ (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁醢基]-3-三氟i曱基-5, 6, 7， 8-四氫味β坐並[1，5-a]n比哄-1-(N-甲基）甲醯胺鹽酸鹽 9 F fVF (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁酿基]-3-三氣甲基-5, 6, 7， 8-四氮°米嗤並[1，5-&]'1比哄-1-(N，N-二曱基）甲醯胺鹽酸鹽 10 T CQ fVF (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁酿基]-3-三氣甲基_5, 6, 7， 8-四复味峻並[1，5-&]。比啡-1-叛酸鹽酸鹽 9 94579 201026314 ❿ ❹ 11 FV (R)-3-胺基-l-[l-(3-胺基-六氩吼11 定-1-幾基)-3-三氟^甲基-5, 6-二氮_8H_P米嗤並[1，5-3]°比啡_7-基]-4-(2, 4, 5-三氟苯基)-丁-1-酮二鹽酸鹽 12 F^〇^0 fVF 00-3-胺基-1-[1-(吼洛烧-1-幾基)-3-三氟甲基-5, 6-二氫-8H-咪〇坐並[1，5-&]°比卩井-7-基]-4-(2， 4, 5-三氟苯基)-丁-1-酮鹽酸鹽 13 fTF (R)-3-胺基-1-[1-六氳吡哄-1-羰基]-3-三氟甲基-5, 6-二負Γ·8Η-σ米〇坐並[1,5-&]°比哄-7-基]-4-(2,4, 5-三氟苯基)_ 丁-1-麵二鹽酸鹽 14 F k/N^ fVF (R)-3-胺基-l-[ l-((R)-3-經基-0比11 各燒-1-幾基)-3-三氟甲基 -5, 6-二复-8Η-^β坐並[1，5-a]*1 比口井-7-基]-4-(2, 4, 5-三氟苯基)-丁-1-酮鹽酸鹽 10 94579 2010263147 (R)-l-{7-[3-Amino~4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8- 4/m0 sit and [1,5-a]B than plough-1-carbonyl}-hexahydropyridine-4-carboxamide hydrochloride 8 F k/N-^ (R)-7-[3- Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoroifluorenyl-5, 6, 7, 8-tetrahydro-flavor β-[1,5-a] n 哄-1-(N-methyl)formamidine hydrochloride 9 F fVF (R)-7-[3-amino-4-(2, 4, 5-trifluorophenyl)-butyl ]]-3-trimethylmethyl-5, 6, 7, 8-tetrazole ° 嗤[1,5-&]'1 哄-1-(N,N-dimercapto) formazan Amine hydrochloride 10 T CQ fVF (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trimethylmethyl_5, 6 , 7, 8- four complex tastes and [1,5-&]. Peptide-1-testinic acid hydrochloride 9 94579 201026314 ❿ F 11 FV (R)-3-aminol-l-[l-(3-amino-hexahydrofluorene-11--1-yl)-3 -Trifluoromethane-5,6-diaza-8H_P moxazepine [1,5-3]° than phenyl-7-yl]-4-(2,4,5-trifluorophenyl)-butyl 1-ketone dihydrochloride 12 F^〇^0 fVF 00-3-amino-1-[1-(indolyl-1-yl)-3-trifluoromethyl-5, 6-di Hydrogen-8H-imipenone and [1,5-&]° ratio 卩-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 13 fTF (R)-3-Amino-1-[1-hexapyridin-1-carbonyl]-3-trifluoromethyl-5,6-di-negative Γ8Η-σ米〇 sits and [1, 5-&]°哄哄-7-yl]-4-(2,4,5-trifluorophenyl)-but-1-one dihydrochloride 14 F k/N^ fVF (R)-3 -Amino-l-[ l-((R)-3-carbyl-0 to 11 each pyridin-1-yl)-3-trifluoromethyl-5,6-di-compound-8Η-^β And [1,5-a]*1 than well-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 10 94579 201026314

15 F柄 F fV (1〇-7-[3-胺基-4-(2，'4,5-三氟苯基)-丁酿基]-3-三就甲基-5, 6， 7, 8-四氫咪α坐並[1，5-8]°比哄-1-環丙基甲醯胺鹽酸鹽 16 F fVF (R)-({7-[3-胺基-4-(2,4, 5-三氟苯基)_丁驢基]-3-三氣甲基-5, 6， 7, 8-四氫'1 米0坐並[1，5-a]a比啡-1 -羰基}-胺基)-乙酸甲酯鹽酸鹽 17 (R)-l-[l-(4-乙醯基-六氫吼哄 _1_裁基)-3-三氟甲基-5, 6-二氣 _8H-11 米唾並[1，5_&]°比啡-7_ 基]_3-胺基-4-(2, 4, 5-三氟苯基)_ 丁-1'嗣鹽酸鹽 18 F^〇^〇 F ^Ni <〇H fV 00-3-胺基-l-[ 1-(2-羥基甲基-0比洛烧-1-幾_基)-3-三氟甲基 -5, 6-二氮-8H-13米嗤並[1，5-a]n比哄-7-基]-4-(2,4,5-三氟苯基)-丁-1-酮鹽酸鹽 11 94579 20102631415 F-handle F fV (1〇-7-[3-amino-4-(2,'4,5-trifluorophenyl)-butanyl]-3-trimethyl-5, 6, 7 , 8-tetrahydromethane α sits and [1,5-8]° 哄-1-cyclopropylcarbamamine hydrochloride 16 F fVF (R)-({7-[3-Amino-4- (2,4,5-trifluorophenyl)-butanyl]-3-trimethylmethyl-5, 6, 7, 8-tetrahydro'1 m 0 sits and [1,5-a]a ratio Phenyl-1 -carbonyl}-amino)-acetic acid methyl ester hydrochloride 17 (R)-l-[l-(4-Ethyl-hexahydroindole_1_cutting)-3-trifluoromethyl Base-5, 6-digas _8H-11 m salido[1,5_&]° than phenyl-7-yl]-3-amino-4-(2,4, 5-trifluorophenyl)-but- 1'嗣 hydrochloride 18 F^〇^〇F ^Ni <〇H fV 00-3-amino-l-[ 1-(2-hydroxymethyl-0-pyrrol-1-yl-yl) -3-trifluoromethyl-5,6-diaza-8H-13 m 嗤[1,5-a]n than 哄-7-yl]-4-(2,4,5-trifluorophenyl )-but-1-one hydrochloride 11 94579 201026314

19 FV (R)-4-{7-[3-胺基-4-(2,4, 5-三氟苯基)_丁酿基]_3-三氟甲基-5, 6， 7, 8_四氮0米0坐並[1，5-a]n比哄-1_ 羰基}-六氳吡哄-2-酮鹽酸鹽 20 F^e^〇 F 1 00-3-胺基-H 1-(噻唑烷-3-羰基)-3-三氟甲基-5, 6-二氮-8Η-σ米唑並[1，5-a：h比畊-7-基]-4-(2,4， 5-三氟苯基)-丁-1-酮鹽酸鹽 21 F pVF HC， (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁酿]-3-三氟甲基-5, 6, 7, 8-_ 四氫咪唾並[1，5-a]°比哄-1-〇比唆 -3-基）曱醯胺二鹽酸鹽 22 I 〇 (R)-3-胺基-1-[ 1-(4-甲磺醯基-六氫α比哄-1-裁基)-3-三氟曱基 -5, 6-二氮_8H_p米唾並[1，5_a]0比畊-7-基]-4-(2,4,5-三氟苯基)-丁-1-酮鹽酸鹽 23 FX^n^〇- T CCN fV (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁酿]-3-三氣甲基-5, 6, 7, 8_ 四氫味唾並[1，5-8]°比哄-1-叛酸乙酯鹽酸鹽 12 94579 20102631419 FV (R)-4-{7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]_3-trifluoromethyl-5, 6, 7, 8 _ four nitrogen 0 m 0 sit and [1,5-a]n than 哄-1_ carbonyl}-hexapyridin-2-one hydrochloride 20 F^e^〇F 1 00-3-amino-H 1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-diaza-8Η-σ-moxazolo[1,5-a:h than till-7-yl]-4-( 2,4,5-trifluorophenyl)-butan-1-one hydrochloride 21 F pVF HC, (R)-7-[3-amino-4-(2, 4, 5-trifluorophenyl) )-丁丁]-3-trifluoromethyl-5, 6, 7, 8-_ tetrahydropyrano[1,5-a]° than 哄-1-〇 than 唆-3-yl)曱醯Amine dihydrochloride 22 I 〇(R)-3-amino-1-[1-(4-methylsulfonyl-hexahydro-α-pyridin-1-yl)-3-trifluoromethyl-5 , 6-diaza-8H_p rice saliva[1,5_a]0 than cultivable-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 23 FX^ N^〇- T CCN fV (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butyl]-3-trimethyl-5, 6, 7 , 8_ Tetrahydro-sodium sulphate [1,5-8]° than 哄-1-teric acid ethyl ester hydrochloride 12 94579 201026314

24 ί (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁酸基]-3-三氣曱基-5, 6, 7, 8-四氫咪嗤並[1，5-8]0比哄-1-曱醯胺鹽酸鹽 25 F 1 (R)-3-胺基-l-[l-((R)-3-氣-α 比哈院-1-幾基)-3-三氟甲基-5, 6-二氮_8Η-ϋ米唾並[1, 5_a]ai：b哄-7_ 基]-4-(2, 4, 三氣苯基)-丁-1-酮鹽酸鹽 26 F I HCI 〇 F fVF (R)-3_ 胺基_1_[ 1-( (S)-3-氟-° 比洛烧_1_幾基)_3-三氟曱基-5, 6-二氳 -8H-咪唑並[1，5-a]吡畊-7-基]-4-(2,4,5-三氟苯基)-丁-1-綱鹽酸鹽 27 1 HCI ΐ k/ίν fVF (R)_l_(l_乙酿基_3_三氟甲基 _5, 6-二氮坐並[1，5_a]w比畊-7-基)-3-胺基-4-(2,4, 5-三氟苯基)-丁-1-酮鹽酸鹽 28 丄 HCI 〇 (1〇-3-胺基-1-(1-環戊基獄基-3-三氟甲基-5, 6-二氫-8H-咪唑並 [1，5~a]n比哄-7-基）-4-(2, 4, 5-三氟苯基)-丁-1-酮鹽酸鹽 13 94579 201026314 Λ « 29 (R)-7-[3-胺基-4-(2, 4, 5-三氟^苯基)-丁酸基]-3-三氟1曱基-5, 6, 7, 8-四氮13米σ坐並[1，5-&]°比哄-1- (2-二甲胺基-乙基)-甲醯胺二鹽酸鹽 30 1 HCI 〇 ^f0h (R)-3-胺基-l-[ 1-( (S)2-羥基甲基 -π比洛烧-1-幾基)-3-三氟甲基 -5, 6-二氫-8Η-^α坐並[1，5-&]。比哄 -7-基]-4-(2, 4, 5-三氟苯基)-丁 -1-酮鹽酸鹽 31 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁酸基]-3-三氣曱基-5, 6， 7, 8-四氫1^米β坐並[1，5-a ]吼口并 -1-(吡啶-2-基）甲醯胺二鹽酸鹽 32 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁酿基]“3-三氣曱基-5, 6， 7, 8-四氳呼坐並[1，5-a]σ比啡-l-(4-氟苯基)-甲醯胺鹽酸鹽 33 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁酿基]-3_三氣曱基-5, 6， 7,8-四氳味吐並[1,5-&]11比哄-1-叛酸苄酯鹽酸鹽 14 94579 20102631424 ί (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butyric acid]-3-trimethylsulfonyl-5, 6, 7, 8- Hydroquinone [1,5-8]0 is more than 哄-1-decylamine hydrochloride 25 F 1 (R)-3-aminol-l-[l-((R)-3-gas-α Biha-1--1-yl)-3-trifluoromethyl-5,6-diaza-8Η-ϋ米唾[1, 5_a]ai:b哄-7_yl]-4-(2, 4 , tris-phenyl)-butan-1-one hydrochloride 26 FI HCI 〇F fVF (R)-3_ Amino_1_[ 1-( (S)-3-fluoro-° 洛洛烧_1_ _3-trifluoromethyl-5,6-diindole-8H-imidazo[1,5-a]pyrrol-7-yl]-4-(2,4,5-trifluorophenyl)- Butyl-1-yl hydrochloride 27. 1 HCI ΐ k/ίν fVF (R)_l_(l_ethyl-branched_3_trifluoromethyl_5,6-diaza sits [1,5_a]w -7-yl)-3-amino-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 28 丄HCI 〇(1〇-3-amino-1-( 1-cyclopentyl-phenyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5~a]n than 哄-7-yl)-4-(2, 4, 5 -Trifluorophenyl)-butan-1-one hydrochloride 13 94579 201026314 Λ « 29 (R)-7-[3-Amino-4-(2, 4, 5-trifluorophenyl)-butyl Acid group]-3-trifluoroindolyl-5, 6, 7, 8-tetrazole 13 m σ sit and [1,5-&]° 哄-1-(2-dimethylamino-B -carbamamine II Acid salt 30 1 HCI 〇^f0h (R)-3-Amino-l-[ 1-((S)2-hydroxymethyl-πpyroxy-1-yl)-3-trifluoromethyl- 5,6-Dihydro-8Η-^α sits and [1,5-&]. 哄-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one Hydrochloride 31 (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butyric acid]-3-trimethylsulfonyl-5, 6, 7, 8 -tetrahydro 1 ^ m β sita and [1,5-a ] mouthwash and-1-(pyridin-2-yl)carbenamide dihydrochloride 32 (R)-7-[3-amino-4 -(2, 4, 5-trifluorophenyl)-butanyl] "3-trimethyl fluorenyl-5, 6, 7, 8- 氲氲并 and [1,5-a]σ than morphine - L-(4-Fluorophenyl)-carbenamide hydrochloride 33 (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3 _ 三气曱基-5, 6, 7,8- 四氲味吐吐[1,5-&]11 than 哄-1--remediate benzyl ester hydrochloride 14 94579 201026314

34 「麵4丄。V F fTF (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁酿基]-3-三氟i曱基-5, 6, 7, 8-四氮味σ坐並[1，5-&]°比哄_1-幾_酸 -(1-乙氧醯氧基）乙酯鹽酸鹽 35 人 F fV (R)-7-(3-胺基-4-(2, 4, 5-三氟苯基）丁酸基)-3-(三氣甲基)-5, 6， 7, 8-四氫咪唑並[1，5-8]吼啡-1-缓酸異丙酯鹽酸鹽 36 F (R)- 7-(3-胺基-4-(2,4,5-三氟苯基）丁醯基)-3-(三氟甲基)-5, 6, 7， 8-四氫咪0坐並[1，5-a]n比卩井-1-叛酸第三丁基酯鹽酸鹽 37 (R)-7-(3-胺基-4-(2, 4, 5-三氟苯基)丁醯基)-3-(三氟曱基)-5, 6, 7， 8-四氮p米σ坐並[1，5~a]n比哄_1-叛酸 (1-異丙氧基醯氧基）乙酯鹽酸鹽 38 ψίχ^νΜ叉。〇 F 1 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁酿基]-3-三氣甲基-5, 6, 7, 8-四氳咪嗤並[1，5-3]°比哄-1-叛酸 -(1-環己基醯氧基）乙酯鹽酸鹽 15 94579 201026314 ❹ 39 F fVF (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基)-丁醯基]-8-曱基-3-三氟甲基 -5, 6, 7, 8-四氫味°坐並[1，5-a]e比哄 -1-羧酸曱酯鹽酸鹽 40 ΐ FV (R)-7-(3-胺基-4-(2, 4, 5-三敦苯基）丁醯基)-(S)-8-甲基-3-(三氟甲基)_5, 6, 7, 8-四氮p米唾並 [1，5-a]吡畊-1-羧酸甲酯鹽酸鹽 41 i fVF (R)-7-(3-胺基-4-(2, 4, 5-三氟苯基）丁醯基)-(R)-8-甲基-3-(三氟曱基)_5, 6, 7, 8-四氯口米σ坐並 [1，5-a]吡畊-1-羧酸甲酯鹽酸鹽 42 ΐ ki^N fVF (R)-7-[3-胺基-4-(2, 4, 5-三氟-苯基)-丁酿基]_3_三氣甲基-5, 6，7， 8-四氮-味β坐並[1，5-a]D比哄-1-(N-乙基）曱醯胺 43 fVF (R)_7-[3-胺基-4-(2, 4, 5-三氟-苯基)-丁醯基]-3-三氟曱基-5, 6, 7, 8-四氮-味0坐並[1, 5-a]n比哄_1-(N-丁基）曱醯胺 16 94579 201026314 F FT^l JT2 i 人^/ (R)-7-[3-胺基-4-(2, 4, 5-三氟-苯基)-丁醯基]-3-三氟甲基-5, 6, 7， 44 8-四氮-σ米σ坐並[1，5-a]n比哄-1-(N- 丙基）甲醯胺或它們藥學上可接受的鹽。進一步，本發明包括下述通式（IA)所示的化合物，其 @作為通式（I)化合物合成的中間體：34 "Face 4". VF fTF (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoroi-yl-5, 6, 7, 8-tetrazine σ sit and [1,5-&]° 哄_1-mono-acid-(1-ethoxyantoxy)ethyl ester hydrochloride 35 persons F fV (R - 7-(3-Amino-4-(2,4,5-trifluorophenyl)butyric acid)-3-(trimethylmethyl)-5, 6, 7, 8-tetrahydroimidazolium [1,5-8] morphine-1-iso-acid isopropyl ester 36 F (R)-7-(3-amino-4-(2,4,5-trifluorophenyl)butanyl) -3-(trifluoromethyl)-5, 6, 7, 8-tetrahydromethane 0 and [1,5-a]n ratio 卩井-1-teric acid tert-butyl ester hydrochloride 37 ( R)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5, 6, 7, 8-tetrazine pm σ Sit and [1,5~a]n than 哄_1-rebel (1-isopropoxy methoxy)ethyl ester hydrochloride 38 ψίχ^νΜ. 〇F 1 (R)-7-[3 -amino-4-(2,4,5-trifluorophenyl)-butyl-branched]-3-trimethylmethyl-5, 6, 7, 8-tetramidine [1,5-3 ]° 比哄-1-Resin-(1-cyclohexyldecyloxy)ethyl ester hydrochloride 15 94579 201026314 ❹ 39 F fVF (R)-7-[3-Amino-4-(2, 4, 5-trifluorophenyl)-butenyl]-8-mercapto-3-trifluoromethyl-5, 6, 7, 8-tetrahydrogen °Sit and [1,5-a]e 哄-1-carboxylic acid oxime ester hydrochloride 40 ΐ FV (R)-7-(3-amino-4-(2, 4, 5-triphenyl) ())-(S)-8-methyl-3-(trifluoromethyl)_5, 6, 7, 8-tetrazole p-salt[1,5-a]pyrrol-1-carboxylic acid Methyl ester hydrochloride 41 i fVF (R)-7-(3-amino-4-(2,4,5-trifluorophenyl)butanyl)-(R)-8-methyl-3-(three Fluorinyl)_5, 6, 7, 8-tetrachloromethane σ and [1,5-a] pyridin-1-carboxylic acid methyl ester hydrochloride 42 ΐ ki^N fVF (R)-7- [3-Amino-4-(2,4,5-trifluoro-phenyl)-butanyl]_3_trimethylmethyl-5, 6,7, 8-tetrazole-flavor β sit and [1 ,5-a]D is more than 哄-1-(N-ethyl)decylamine 43 fVF (R)_7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butenyl ]-3-Trifluoromethyl-5, 6, 7, 8-tetrazine-flavor 0 sitting and [1, 5-a]n than 哄_1-(N-butyl) decylamine 16 94579 201026314 F FT^l JT2 i human^/(R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 44 8-tetrazine-σm σ sits and [1,5-a]n is more than 哄-1-(N-propyl) formamide or a pharmaceutically acceptable salt thereof. 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):

其中：among them:

Ar是苯基，該苯基是未取代的或者進一步經1至5個R6 所取代； _ R1選自氳原子、烷基、三氟曱基、環烷基、芳基或雜芳 ❹ 基，其中烷基、雜環烷基、芳基、雜芳基進一步視需要地經一個或多個選自鹵素、氰基、芳基、輕基或胺基的取代基所取代，較佳為三氟曱基； R3選自氫原子或烷基； R6選自鹵素、氰基、羥基、烷基或烷氧基，其中烷基或烷氧基是未取代的或者進一步視需要地經一個或多個鹵素取代； X為鹵素。 17 94579 201026314Ar is a phenyl group which is unsubstituted or further substituted with 1 to 5 R6; _R1 is selected from a halogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, an aryl group or a heteroarylalkyl group, Wherein alkyl, heterocycloalkyl, aryl, heteroaryl is further optionally substituted with one or more substituents selected from halogen, cyano, aryl, light or amine, preferably trifluoro a fluorenyl group; R3 is selected from a hydrogen atom or an alkyl group; R6 is selected from halogen, cyano, hydroxy, alkyl or alkoxy, wherein the alkyl or alkoxy group is unsubstituted or further optionally one or more Halogen substituted; X is halogen. 17 94579 201026314

(旧) 其中：進一步，本發明包括下述通式（IB)所示的化合物，其(Old) wherein: Further, the present invention includes a compound represented by the following formula (IB), which

Ο R選自氫原子、烷基、三氟曱基、環烷基、芳基或雜芳基，其中烷基、雜環烷基、芳基、雜芳基進一步視需要地經一俯或多個選自鹵素、氰基、芳基、羥基或胺基的取代基所取代，較佳為三氟曱基； R2選自輕基、胺基、烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基或-NR4R5 ’其中烷基、烷氧基、環烷基、雜環院基务基或雜芳基進一步視需要地經一個或多個選自齒素、胺基、氰基、羥基、烷基、環烷基、烷氧基、芳基、雜芳基、〜NR4R5、-〇C(〇)〇R8、羧酸或羧酸酯的取代基所取代； R3選自氫原子或烷基; R和R5各自獨立地選自氫原子、烷基、環烷基、雜環烷基、芳基或雜芳基，其中烷基、環烷基、雜環烷基、芳基或者雜芳基進一步視需要地經一傭或多個選自鹵素、羥基胺基、烷氧基、烷基、氰基、芳基、環烷基、雜環烷基、雜芳基、羥烷基、-S〇2R7、-fTR5、綾酸或羧酸酯的取代基所取代；或者，R4和R5 —起形成4至8員雜環基，其中該4至 94579 18 201026314 8員雜環内含有一個或多個N、0、S原子，並且該4至8 員雜環上進一步視需要地經一個或多個選自_素、經基、胺基、烷氧基、烷基、氰基、芳基、雜環烷基、雜芳基、羰基、羥烷基、-S〇2R7、-NR4R5、-C(0)NR4R5、-C(0)R7、羧酸或羧酸酯的取代基所取代； R7為炫基； R8選自烷基或環烷基。在本發明的另一個方面，是提供中間體（IA)所示化合 ®物的製備方法，包括以下步驟：Ο R 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 more Substituted by a substituent selected from a halogen, a cyano group, an aryl group, a hydroxyl group or an amine group, preferably a trifluoromethyl group; R2 is selected from the group consisting of a light group, an amine group, an alkyl group, an alkoxy group, a cycloalkyl group, and a hetero group. a cycloalkyl, aryl, heteroaryl or -NR4R5 ' wherein alkyl, alkoxy, cycloalkyl, heterocyclic, or heteroaryl is further optionally selected from one or more selected from dentate, Substituted with a substituent of an amine group, a cyano group, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, an aryl group, a heteroaryl group, a NR4R5, a 〇C(〇)〇R8, a carboxylic acid or a carboxylic acid ester; R3 is selected from a hydrogen atom or an alkyl group; R and R5 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 heterocycloalkane group The base, aryl or heteroaryl group is further optionally, if desired, one or more selected from the group consisting of halogen, hydroxylamine, alkoxy, alkyl, cyano, aryl, cycloalkyl, heterocycloalkyl, heteroaryl Hydroxyalkyl Substituted with a substituent of -S〇2R7, -fTR5, decanoic acid or a carboxylic acid ester; or R4 and R5 together form a 4- to 8-membered heterocyclic group, wherein the 4 to 94,549 18 201026314 8 member heterocyclic ring contains a Or a plurality of N, 0, S atoms, and the 4 to 8 membered heterocyclic ring is further optionally one or more selected from the group consisting of _, thiol, amide, alkoxy, alkyl, cyano, aryl Substituted by a substituent of a heterocycloalkyl group, a heteroaryl group, a heteroaryl group, a carbonyl group, a hydroxyalkyl group, -S〇2R7, -NR4R5, -C(0)NR4R5, -C(0)R7, a carboxylic acid or a carboxylic acid ester ; R7 is a stilbene; R8 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), comprising the steps of:

- w R1 在冰浴下向原料吡哄2-甲胺中滴加酸酐，然後在室溫下反應，生成醯胺產物；- w R1 is added dropwise to the raw material pyridinium 2-methylamine in an ice bath, and then reacted at room temperature to form a guanamine product;

將醯胺產物與三氯氧磷在室溫下混合攪拌後，加入五氧化二鱗，加熱回流縮合生成味唾並[l，5-a]ib哄環；After the guanamine product and the phosphorus oxychloride are mixed and stirred at room temperature, the scalar pentoxide is added, and the mixture is heated and refluxed to form a scented saliva [l,5-a] ib ring;

將咪唑並[l，5-a]吡啡環在乙醇溶劑中，於鈀/碳催化下，以氫氣還原生成R1，R3取代的四氳咪唑並[1, 5-a]D比哄產物； 19 94579 201026314The imidazo[l,5-a]pyridin ring is reduced in hydrogen under the catalysis of palladium on carbon to form R1,R3 substituted tetraimidazo[1,5-a]D ratio hydrazine product; 19 94579 201026314

將R1，R3取代的咪唑並[1，5-a]吡畊產物溶解在二氯甲烧溶劑中，並在縮合劑雙（2-氧代-3-^^院基）次膦醯氯及三乙胺作用下與羧酸發生縮合反應；The R1, R3 substituted imidazo[1,5-a] pyridinium product is dissolved in a methylene chloride solvent, and in the condensing agent bis(2-oxo-3-^^^) phosphinium chloride and Condensation reaction with carboxylic acid under the action of triethylamine;

得到的縮合產物在室溫下於無水乙醇溶劑中與鹵代琥珀醯亞胺反應生成中間體（IA)。在本發明的另一個方面，是製備中間體（IB)所示化合物的製備方法，包括以下步驟：The resulting condensation product is reacted with halo-succinimide in an anhydrous ethanol solvent at room temperature to give the intermediate (IA). In another aspect of the invention, there is provided a process for the preparation of a compound of the intermediate (IB), which comprises the steps of:

將R1取代的咪唑並[1，5-a]吡畊在室溫下，於乙醇溶劑中氫化還原，然後與二碳酸二（第三丁酯）在乙醇溶劑中反應，對胺基進行保護，得到胺基經保護的R1取代的四氫咪唾並[1，5-a]°比哄；R1 substituted imidazo[1,5-a] pyridinium is hydrogenated and reduced in an ethanol solvent at room temperature, and then reacted with di(tert-butyl ester) dicarbonate in an ethanol solvent to protect the amine group. Obtaining an amine-protected R1-substituted tetrahydro-imido[1,5-a]° ratio hydrazine;

所得到的胺基經保護的R1取代的四氫咪峻並[1, 5-a] 吡畊在乙醇溶劑中，於室溫與鹵代琥珀醯亞胺反應得到鹵 20 94579 201026314 代產物；The obtained amine group is protected by a protected R1 substituted tetrahydroribanol [1, 5-a] pyridinium in an ethanol solvent at room temperature to obtain a halogen 20 94579 201026314 generation product;

所得到的鹵代產物在甲醇溶劑中，在油浴下與八羰基二鈷及氯乙酸酯在一氧化碳氛圍中反應，得到酯基經取代的四氫咪唾並[l，5-a]%b哄；The obtained halogenated product is reacted in a solvent of methanol with dicobalt octacarbonyl and chloroacetate in a carbon monoxide atmosphere to obtain an ester group-substituted tetrahydropyrimidin [l,5-a]%. b哄;

所得到的酯基經取代的四氫咪唑並[1，5-a] °比哄在驗性條件下水解成酸；The obtained ester group is hydrolyzed to an acid under the test conditions by a substituted tetrahydroimidazo[1,5-a] ° hydrazine;

所得到的羧酸化合物在乾冰-丙酮浴下，與鹵代烷基反The obtained carboxylic acid compound is reacted with a halogenated alkyl group in a dry ice-acetone bath

烷基取代的酸可進一步酯化，得到酮取代的四氩咪唑並[1，5-a]n&啡；The alkyl-substituted acid can be further esterified to give a ketone-substituted tetraarsenazo[1,5-a]n&

或者，烷基取代的酸可以在二氯甲烷溶劑中，在縮合試劑雙（2 -氧代-3 -噁唑烷基）次磷醯氯作用下與N -甲氧基曱胺反應； 21 94579 201026314Alternatively, the alkyl-substituted acid can be reacted with N-methoxydecylamine in a dichloromethane solvent under the action of the condensing reagent bis(2-oxo-3-oxazolidinyl)phosphorus chloride; 21 94579 201026314

經縮合反應得到的產物與袼利雅試劑在中反應，得到酮取代的四氫咪唑並[丨5__a]吡畊次°南溶劑The product obtained by the condensation reaction is reacted with the Julia reagent to obtain a ketone-substituted tetrahydroimidazo[丨5__a]pyrazine sub-solvent.

(旧) 將_取代的四氫咪唑並[151]吡哄在酸性掉胺基保護基，得到中間體（IB)。 μ 件下脫是通式化合物（I)的製備方進一步，本發明的另一方面法，該方法包括：(Old) The _substituted tetrahydroimidazo[151]pyridinium is acid-reduced in the amine protecting group to give the intermediate (IB). The removal of the μ member is a preparation of the compound of the formula (I). Further, in another aspect of the invention, the method comprises:

中間體（ΙΑ)在曱醇溶劑中’於油浴在八羰基二録的作用下與氯乙酸酯在一氧化碳氛圍中反應，然後在室溫，鹼性條件下水解再酸化成羧酸；The intermediate (hydrazine) is reacted with chloroacetate in a carbon monoxide atmosphere in an oil bath under the action of octacarbonyldicarbonate, and then hydrolyzed to a carboxylic acid at room temperature under basic conditions;

所得到的羧酸在縮合試劑作用下與胺或與醇在室溫下生缩5反應，或者與卜鹵代碳酸酯反應，然後在酸件下脫掉胺基保護基得到通式化合物（τ)。 ” 94579 22 201026314 本發明的另一方面是通式化合物（法包括以下步驟：僙方法，該方 * ηThe obtained carboxylic acid is reacted with an amine or an alcohol at room temperature by a condensation reagent, or reacted with a halogenated carbonate, and then the amine protecting group is removed under an acid to obtain a compound of the formula (τ ). 94579 22 201026314 Another aspect of the invention is a compound of the formula (the method comprises the following steps: 僙 method, the party * η

(IB) -R2 〇rt(IB) -R2 〇rt

+ ΝΗ Ο - 川 Μ Ο 中間體（IB)與羧酸在縮合試劑雙（2、衰次膦醯氯的條件下進行縮合，得到的產燒基, 件下脫掉胺基賴基得到it式化合物（1}。纟在酸性條進一步，所述通式化合物（1)的製備方通式化合物⑴的酸加成產物鹽。其中 ’其中還包括人铷淑、联&、的鹽為上述化合物與選自以下的酸形成的鹽：磷酸、蘋果酸、乳來酸:鹽酸、甲績酸、硫酸、填酸、檸檬酸、酒石酸、乙酸或二氟乙酸，較佳的酸是鹽酸。本發明涉及-種藥用組合物、其含有治療有效劑量的本發明化合物或其藥學上可接受的鹽，及藥學的載體或賦形劑。又進一步，本發明還涉及本發明化合物或其藥學上可接受的鹽在製備治療Π型糖尿病、高血糖症、肥素抵抗症的藥物的用途。 ^ 、本發明的-方面是抑制二肽基肽酶ly催化活性的方法，其特徵在於將所述的二肽基肽酶ίν與通式⑴中任何一個所述的化合物或鹽接觸。本發明的另一方面是通式⑴_任何一個所述化合物、鹽或㈣組合㈣於治療Π型糖尿病、高血糖症、肥 94579 23 201026314 胖症或騰島素抵抗症等疾病的用途^ 【實施方式】除非有相反陳述，下列用的術語具有下述含義。 t說明書和申請專利範圍中烧基指飽和的脂族煙基團，包括1至20個碳原子 Ο μ赫錢i i lG個碳原子的烧基，例如甲基、乙基、丙基、2-丙基、正丁基、異丁基、第三丁基、戊基等。更較佳的是含有1至4個碳原子的低級烧基，例如曱基、乙基、丙基、24基、正丁基、異丁基或第三丁基等。絲可以是取代的或未取代的，倾取代時，取代基較佳為一個或多個，獨立地選自鹵素、羥基、胺基、烷氧基、烷基、氰基、芳基、雜環烷基、雜芳基、羰基、羥烧基、-SO2R7、-NR4R5、-C(0)N W⑼⑽8、竣酸或叛酸醋。+ ΝΗ Ο - Chuanxiong Ο Intermediate (IB) and carboxylic acid are condensed under the conditions of condensing reagent bis (2, phosphine phosphine), and the resulting alkyl group is obtained by removing the amine lysyl group. Compound (1). Further, in the acid strip, the acid addition product salt of the compound of the formula (1) of the formula (1), wherein the salt of the above-mentioned compound, the salt of the compound a salt of a compound with an acid selected from the group consisting of phosphoric acid, malic acid, milk acid: hydrochloric acid, methyl acid, sulfuric acid, acid, citric acid, tartaric acid, acetic acid or difluoroacetic acid, and the preferred acid is hydrochloric acid. The invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. Still further, the invention relates to a compound of the invention or a pharmaceutical thereof Use of an acceptable salt for the preparation of a medicament for the treatment of diabetes mellitus, hyperglycemia, and fertility resistance. ^ The aspect of the invention is a method for inhibiting the catalytic activity of dipeptidyl peptidase ly, characterized in that Dipeptidyl peptidase ίν The compound or salt of any one of the formula (1) is contacted. Another aspect of the invention is the compound of the formula (1) - any one of the compounds, a salt or a combination of (d) for the treatment of sputum type diabetes, hyperglycemia, fat 94579 23 201026314 Uses of diseases such as disease or tamsin resistance^ [Embodiment] Unless otherwise stated, the following terms have the following meanings: In the specification and the patent application, the alkyl group refers to a saturated aliphatic group, including 1 To 20 carbon atoms Ο 赫钱 l l l l l 个 l l , , , , , , , , , , , 。。。。。。。。。。。。。。。。。。. More preferred are lower alkyl groups having 1 to 4 carbon atoms, such as decyl, ethyl, propyl, 24, n-butyl, isobutyl or tert-butyl, etc. The silk may be substituted or Unsubstituted, 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, -SO2R7, -NR4R5, -C(0)N W(9)(10)8, citric acid or oleic acid.

“環烷基”指3至8員全碳單環、全碳5員/6員或6 ❹員/6員稠合環或多環稠合環（“稠合”環系意味著系統中的每個環與體系中的其他環共用毗鄰的一對碳原子）基團’其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的；r電子系統。環烷基的實例有環丙基、環丁基、環戊基、環戊烯基、環己烷基、環己二烯基、金剛烷基、環庚烷基、環庚三烯基等。環烷基可以是取代或未取代的，當被取代時，取代基較佳為一個或多個，獨立地選自卣素、幾基、胺基、炫《氧基、烧基、氰基、芳基、雜環烷基、雜芳基、羰基、經烷基、-S〇2R7、_NR4R5、-C(〇)N 24 94579 201026314 R4R5、-C(0)R7、羧酸或羧酸酯。 “芳基”指具有至少一個芳環輛的T t子齡的芳環，包括^㈣基團’即具有共基。芳基可以是取代的或未取代的^基和聯方較佳為-個或多個，獨立地選自_ 、時，取代基基、燒基、氛基、芳基、雜環貌基素雜=、絲、燒氧 *、-S〇2R7、-NR4R5、-C_R4R5、〜c( lg^ 4t 竣酸或羧酸酯。 ❹ ❹ 雜方基才曰具有1至3個雜原子作為環原子，其餘的環原子為碳的芳基，雜原子包括氧原：：餘員或6員環。雜環芳基基圏的實例包括七 11Γ基、轉基鱗基、錢基"比哄基、味唾基4。雜芳基可叫取代的或未取代的，當被取取代基較佳為一個或多個，獨立地田、 w ^ ^吧破自鹵素、羥基、胺基、基、芳基、雜環燒基、雜芳基、幾基、 =基、舊、-NR4r5、_c_r4r5、_c(())r7、缓酸錢 “雜觀m環或㈣麵，在環巾，具有5至 ::原：’其中一個或兩個環原子選自氣、氧或此I夢n疋整數0至2)的雜原子’其餘環原子為碳。這二以具有—個❹個魏。不過，這些環不具有完二二，的'電子系統。未取代的雜環烧基包括但不限於η比古二^ 氫^疋基、六氫吡哄基、嗎啉基、硫代嗎啉基、 ^、虱^基等’雜環烧基可以是取代的或未取代的。芳土可乂疋取代的或未取代的’當被取代時，取代基較佳為 94579 25 201026314 一個或多個，獨立地選自鹵素、羥基、胺基、烷氧基、烷基、氰基、芳基、雜環烷基、雜芳基、羰基、羥烷基、-s〇2r7、 -NR4R5、-C(0)N R4R5、-C(0)R7、羧酸或羧酸酯。 “羥基”指-0H基團。 “烷氧基”指-0-(烷基）和-〇-(未取代的環烷基）。代表性實例包括但不限於甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基等。烷氧基可以是取代的或未取代的，當被取代時，取代基較佳為一個 ® 或多個，獨立地選自為鹵素、羥基、胺基、烷氧基、烷基、氰基、芳基、雜環烷基、雜芳基、羰基、羥烷基、-S〇2R7、 -NR4R5、-C(0)N R4R5、-C(0)R7、羧酸或羧酸酯。 “鹵素”指氟、氯、溴或碘，較佳為氟或氯。 “三氟曱基”指-cf3。 “胺基”指-nh2。 “氰基”指-CN。 0 “羰基”指C(=0)。 “羧酸”指（烷基）C(=0)0H。 “缓酸S旨”指（烧基）c(=o)o(烧基）。經烧基指被輕基取代的烧基。 “醫藥組合物”表示一種或多種本文所述化合物或其生理學上/藥學上可接受的鹽或前體藥物與其他化學組分的混合物，其他組分例如生理學/藥學上可接受的載體和賦形劑。醫藥組合物的目的是促進化合物對生物體的給藥。本發明化合物的合成方法 26 94579 201026314 為了 70成本發明的目的，本發明採用如下技術方案：本發明的通式化合物⑴的製備方法，包括以下步驟： ?3 R3 、I /"Cycloalkyl" means a 3 to 8 membered all carbon monocyclic, all carbon 5/6 member or 6 member/6 member fused ring or a polycyclic fused ring ("fused" ring system means in the system Each ring shares an adjacent pair of carbon atoms with other rings in the system. One or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated; 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, a few groups, an amine group, a methoxy group, an alkyl group, a cyano group, Aryl, heterocycloalkyl, heteroaryl, carbonyl, alkyl, -S〇2R7, _NR4R5, -C(〇)N 24 94579 201026314 R4R5, -C(0)R7, carboxylic acid or carboxylic acid ester. "Aryl" means an aromatic ring of the T t age having at least one aromatic ring, including a ^(tetra) group' having a common group. The aryl group may be a substituted or unsubstituted group and a combination preferably one or more, independently selected from the group consisting of _, hr, a substituent, an alkyl group, an aryl group, an aryl group, and a heterocyclic form factor. Miscellaneous =, silk, burning oxygen *, -S〇2R7, -NR4R5, -C_R4R5, ~c ( lg ^ 4t decanoic acid or carboxylate. ❹ ❹ Heteroaryl has 1 to 3 heteroatoms as ring atoms The remaining ring atom is an aryl group of carbon, and the hetero atom includes an oxygenogen:: a remainder or a 6-membered ring. Examples of the heterocyclic aryl group include a 7-fluorenyl group, a cyclyl group, a ke group, and a fluorenyl group. , sinyl 4. Heteroaryl may be substituted or unsubstituted, and when the substituent is preferably one or more, independently, the field is broken, and the halogen, hydroxyl group, amine group, group, Aryl, heterocycloalkyl, heteroaryl, aryl, =yl, old, -NR4r5, _c_r4r5, _c(())r7, slow acid "much m ring or (tetra) face, in a ring towel, with 5 To:: original: 'One or two ring atoms selected from gas, oxygen or this I want n integer 0 to 2) heteroatoms 'The remaining ring atoms are carbon. These two have - one Wei. But These rings do not have two or two. 'Electronic system. Unsubstituted heterocyclic alkyl groups include, but are not limited to, η than the ancient bis-hydrogen hydrazino, hexahydropyridinyl, morpholinyl, thiomorpholinyl, ^, fluorenyl, etc. The alkyl group may be substituted or unsubstituted. The aromatic ring may be substituted or unsubstituted. When substituted, the substituent is preferably one of 94579 25 201026314, independently selected from the group consisting of halogen, hydroxyl, and amine. Alkyl, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -s〇2r7, -NR4R5, -C(0)N R4R5, -C(0 R7, carboxylic acid or carboxylate. "Hydroxy" refers to the -OH group. "Alkoxy" refers to -0-(alkyl) and -〇-(unsubstituted cycloalkyl). Representative examples include Not limited to methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc. The alkoxy group may be substituted or unsubstituted 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, -S〇2R7 -NR4R5, -C(0)N R4R5, -C(0)R7, a carboxylic acid or a carboxylic acid ester. "Halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro. "指-cf3. "Amine" means -nh2. "Cyano" means -CN. 0 "Carbonyl" means C(=0). "Carboxylic acid" means (alkyl)C(=0)0H. Acid S means "(alkyl)c(=o)o (alkyl). A burnt group refers to a burnt group substituted with a light base. "Pharmaceutical composition" means one or more compounds described herein or physiologically thereof / pharmaceutically acceptable salts or mixtures of prodrugs with other chemical components, other components such as physiological/pharmaceutically acceptable carriers 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 26 94579 201026314 For the purpose of the present invention, the present invention adopts the following technical solution: The preparation method of the compound of the formula (1) of the present invention comprises the following steps: ?3 R3, I /

❹ \〆〇γ〇 NH Q R3 y (ΙΑ) R，十〇γ〇 ο. ΝΗ Ο R3 * αγ-^ΛνΧ^0¾双 χ>2L Ι/,Ν 將原料吼哄2-甲胺在冰洛下滴加酸針，再於室溫下」 f，生成雜產物；將_產物與三氯氧磷在室溫混糾拌：，加入五氧化二•，加熱回流缩合生成味顿i，5-S 2環；將料並U，5-環在乙醇溶劑中，絲λ !=氳氣還原生成R1取代的•坐並[⑽比, =’將R取代的四氩料並[仏啦啦物在二氯甲文 :=在下？試劑雙(2、氣代〜咖^ 一乙胺作用下與羧酸發生縮合室溫下無水乙醇溶劑中與；所传到的縮合產物1 合物⑽；中間體通式化合=，亞胺反應生成通以在八縣二銘的作用下與氯乙酸,甲：中’油… 應，然後在室溫下，魏條件碳氛圍〇酸化合物縮合試劑作用下與胺或_、^所得到的；應，或者與卜齒代碳酸醋反應然: 保護基得到u化合物⑴。料Τ脫掉胺! 本發明的通式化合物⑴的製備方法，包括以下步驟 94579 27 201026314❹ \〆〇γ〇NH Q R3 y (ΙΑ) R, 十〇γ〇ο. ΝΗ Ο R3 * αγ-^ΛνΧ^03⁄4 双χ>2L Ι/,Ν The raw material 吼哄2-methylamine in ice Add the acid needle dropwise, and then at room temperature to produce a hetero product; mix the product with phosphorus oxychloride at room temperature: add pentoxide, heat and reflux to form a miso i, 5- S 2 ring; feed material U, 5-ring in ethanol solvent, silk λ ! = helium gas reduction to form R1 substituted • sit and [(10) ratio, = 'R will replace the four argon and [仏啦啦In Dichloro-A: What is the next? Reagent double (2, gas generation ~ coffee ^ ethylamine condensation with carboxylic acid at room temperature in anhydrous ethanol solvent; condensation product 1 compound (10); intermediate formula = imine reaction Produced by the action of the eight counties and the chloroacetic acid, A: medium 'oil... should be, and then at room temperature, under the condition of a carbonic acid phthalic acid compound condensation reagent with amine or _, ^; Should, or react with the chopped carbonic acid vinegar: the protecting group gives the u compound (1). The hydrazine is removed from the amine! The preparation method of the compound of the formula (1) of the present invention comprises the following steps 94587 27 201026314

將原料R1取代的四氫咪唾並[1，5-a]吡畊在室溫下，乙 ©醇溶劑中氫化還原，然後與二碳酸二（第三丁酯）在乙醇溶劑中反應，得到胺基保護的R1取代的四氫咪唑並[丨，5_a] 吡哄；所得到的胺基保護的R1取代的四氫咪唑並[1，5_a] β比畊在乙醇溶劑中’室溫下與_代琥珀醯亞胺反應得到鹵代產物；所得到的鹵代產物在曱醇溶劑中，在油浴下與八羰基二鈷及氯乙酸酯在一氧化碳氛圍下反應，得到酯基取^ 代的四氫咪唑並[l，5-a]吡畊；所得到的酯基取代的四氫咪 w坐並[1，5-a]11 比卩井在驗性條件下水解成酸；所得到的羧酸化合物在乾冰—兩酮浴下，與鹵代烷基反應得到烧基取代的產物；烧基取代產物中的缓基可進一步，化#到中間體（IB);所得到的竣酸化合物也可以在 :氯甲烷溶财，在縮合試劑雙(2，代+噁唑烷基)次膦盥2用：與N''甲氧基甲胺反應；經縮合反應得到的產物 :米《坐劑在四氫"夫喃溶劑中反應，得到酮取代的四氫在酿叫；將酮取代的四氫咪哇並[丨，5*^]11比哄 “件下脫掉絲保護基，㈣通式化合物⑽；中 94579 28 201026314 間體通式化合物（IB)與羧酸在縮合試劑雙（2-氧代_3_喔唾燒基）次膦醯氯的條件下進行縮合’得到的產物進—步在酸性條件下脫掉胺基保護基得到通式化合物（I)。通式化合物（I)經純化後在酸的甲醇、二氯甲燒或乙酸乙酯溶液中反應，得到其酸加成產物鹽。【實施方式】以下結合實施例用於進一步描述本發明，但這些實施例並非限制著本發明的範圍。 Ο 贵施例化合物的結構是通過核磁共振（Wnmr )或質譜（MS)來確定的。1HNMR位移（δ)以百萬分之一（ppm)的單位出示。 WmiR的測定是用BrukerAVANCE-4〇〇核磁儀，測定溶劑為氣代甲醇（CD3〇D )、氣代氯仿（CDCI3)，六氛代二甲基亞硬 (DMS0-d6)内標準為四甲基矽烧(TMS)，化學位務是以 l(T6(ppm)作為單位出示；〇 MS的測定用FINNIGAN LCQAd (ESI)質譜儀（生產商： Therm，型號：Finnigan LCQ advantage MAX); IGd值的測定用NovoStar酶標儀（德國BMG公司）；薄層矽膠使用煙臺黃海HSGF254或青島GF254矽膠板；管柱層析一般使用煙臺黃海矽膠管柱2〇〇至3〇〇網目矽膠為載體。實施例中無特殊說明，反應均在氮氛圍下進行。氮氛圍是指反應瓶連接一個約1L容積的氮氣氣球。氫氛圍是指反應瓶連接一個約1L容積的氫氣氣球。 29 94579 201026314 實施例1 〇〇-7-[3-胺基-4_(2,4, 5-三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-羧酸甲酯鹽酸鹽The tetrahydropyrimido[1,5-a]pyridine substituted by the starting material R1 is hydrogenated and reduced at room temperature in a solvent of ethyl alcohol, and then reacted with di(tert-butyl ester) dicarbonate in an ethanol solvent to obtain Amine-protected R1 substituted tetrahydroimidazo[5,5-a]pyridinium; the resulting amine-protected R1 substituted tetrahydroimidazo[1,5-a] beta is more ploughed in ethanol solvent at room temperature _ Amber quinone imine reaction to obtain a halogenated product; the obtained halogenated product is reacted in a decyl alcohol solvent with octacarbonyl dicobalt and chloroacetate under a carbon monoxide atmosphere to obtain an ester group. Tetrahydroimidazo[1,5-a]pyrazine; the obtained ester-substituted tetrahydromethane w and [1,5-a]11 are hydrolyzed to an acid under the test conditions; The carboxylic acid compound is reacted with a haloalkyl group in a dry ice-diketone bath to obtain a mercapto-substituted product; the suspending group in the alkyl-substituted product can be further converted to the intermediate (IB); the obtained tannic acid compound is also Can be used in: chloromethane, in the condensation reagent bis (2, + oxazolidinyl) phosphine 2: with N' methoxymethylamine; condensation reaction The product obtained: the rice "sit in the tetrahydro" solvent, the ketone-substituted tetrahydrogen in the brewing; the ketone-substituted tetrahydro-imi-[丨, 5*^]11 than the 哄Lower silk protecting group, (iv) compound of formula (10); medium 94579 28 201026314 intermediate compound (IB) and carboxylic acid in the condensation reagent bis(2-oxo_3_indolyl) phosphinium chloride The product obtained by condensation is subjected to the step of removing the amino group protecting group under acidic conditions to obtain the compound of the formula (I). The compound of the formula (I) is purified in methanol, dichloromethane or acetic acid. The reaction is carried out in an ester solution to obtain an acid addition product salt. [Embodiment] The following examples are used to further describe the present invention, but these examples are not intended to limit the scope of the invention. 结构 The structure of the compound of the application is by nuclear magnetic Resonance (Wnmr) or mass spectrometry (MS). The 1H NMR shift (δ) is expressed in parts per million (ppm). The WmiR is measured using a Bruker AVANCE-4 〇〇 NMR instrument and the solvent is determined to be methanol. (CD3〇D), gas chloroform (CDCI3), six atmospheres of dimethyl hard The standard in (DMS0-d6) is tetramethylsulfonium (TMS), the chemical position is presented in units of 1 (T6 (ppm); the measurement of 〇MS is performed using FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, Model: Finnigan LCQ advantage MAX); IGd value is determined by NovoStar microplate reader (BMG, Germany); thin layer tannin is used Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet; tube column chromatography is generally used Yantai Huanghai gel column 2〇〇 To 3 〇〇 mesh gelatin as a 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. 29 94579 201026314 Example 1 〇〇-7-[3-Amino-4_(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5, 6, 7, 8- Hydrogenimidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride

第一步 2，2_二甲基_5-[2-（2，4，5_三氣苯基乙酿基]-[1，3]二 ❿噁烷-4, 6-二酮將 2, 2-二曱基-[1，3]二 °惡烧 _4，6-二 S同（5. 69g， 39.5mmol)攪拌下溶解於400niL二氯甲烷中，在冰浴冷卻下，加入2, 4, 5-三氟苯乙酸la(7. 15g，37. 6mmol)和對二曱胺基0比0定（7. 35g，60. 2mmol)，緩慢滴加 250mL 1-(3-二甲基胺基-丙基）-3-乙基-碳二亞胺鹽酸鹽（8. 28g， 43. 2mmol)的二氯甲烷懸濁液，室溫下攪拌36小時後，用 5%硫酸氳卸溶液（250mLx7)和飽和氯化鈉溶液（250mLx2)洗滌反應液，無水硫酸鎂乾燥，抽氣過濾，減壓濃縮濾液， 30 94579 201026314 得到標題產物2, 2-二曱基-5-[2-(2, 4, 5-三氟苯基）-乙酿基]-[1，3]二噁烷-4, 6-二酮lb(ll. 4g，白色固體），收率： 96%。 MS m/z (ESI) : 315. 5(M-1)。第二步 3-氧代-4-(2, 4, 5-三氟苯基）-丁酸乙酯將2, 2-二甲基-5-[2-(2, 4，5-三氟苯基）-乙酿基]-[1，3]二噁烷-4, 6-二酮 lb(15· 72g，49. 6mmol)攪拌下溶解 ® 於280mL乙醇中，油浴70°C下攪拌過夜。冷卻，減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物3-氧代 -4-(2,4, 5-三氟苯基）-丁酸乙酯lc(12g，黃色液體），收率：88% 。 MS m/z (ESI) : 259CM-1)。第三步 3-胺基-4-(2, 4，5-三氟苯基）-丁-2-稀酸乙醋 q 將3-氧代-4-(2, 4, 5-三氟苯基）-丁酸乙酯 lc(24. 6g，94. 5mmol)溶解於240mL甲醇中，加入醋酸錢 (36. 4g，473mmol)，加熱回流3小時後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，加入lOOmL水，用乙酸乙酯（200mLx3)萃取，合併有機相，依次用200mL飽和氯化鈉溶液洗滌，無水硫酸鎂乾燥，過濾，濾液經減壓濃縮得到的淡黃色固體中，加入50mL乙酸乙酯，在80°C下溶解，加入5OmL正己院，晶種，冷卻至室溫下，0. 5小時後，加入lOOmL正己烷，置於冰箱中過夜，抽氣過濾，得到標題 31 94579 201026314 產物3-胺基-4-(2, 4, 5-三氟苯基）-丁 —2-稀酸乙酉旨 ld(19. 5g，白色固體），收率：80%。 MS m/z (ESI) ： 260.1 [M+1] 第四步 (R)-3-第三丁氧羰基胺基-4-(2, 4, 5-三氟苯基）_丁酸乙酉旨將3-胺基-4-(2,4,5-三氟苯基）-丁酸乙酯14(41§， 15. 8mmol)加入高壓蚤中，再加入70mL甲醇，二碳酸_ (第三丁酯）（3. 8g，17. 4mmol)，氯（1，5-環辛二埽）錄（丨）_聚 ❹體（32mg’ 0. 0632mmol)和（R)-l-[(S)-2-(二苯基膊基）二茂鐵基]-乙基-第三丁基膦（68mg，0.126mmol)，在3(rc下， 6. 67個大氣壓的虱氣中反應24小時。過濾，減壓濃縮遽液，在50°C下加入34mL甲醇，完全溶解後加入靜置至室溫後，在冰箱中過夜，過濾，用曱醇/水^1=3.2) 混合溶劑洗滌固體產品，真空乾燥，得到標題產物（]^)13一第三丁氧羰基胺基-4-(2, 4, 5-三氟苯基）_ 丁酸乙酿 ❹ le(4g，淡黃色固體），收率：70%。曰 MS m/z (ESI) : 362.4[M+1]。、第五步 (R)-3-第三丁氧羰基胺基-4-(2,4,5-三氟笨基）__丁酸將（R)-3-第二丁氧幾基胺基-4-(2, 4, 5-三氣笨基）酸乙酯 le(l〇g，27. 7mmol)和氫氧化鈉（3. 32g，83 i 丁攪拌下溶解於lOOmL曱醇和50mL水的混合溶劑中，至45 C反應1至1. 5小時後，減壓濃縮除去部分溶劑入少量水，在冰浴下，加入1N鹽酸調節溶液為2至3 94579 32 201026314 用乙酸乙酯（200mLx3)萃取，合併有機相，用200mL飽和氯化鈉溶液洗滌，用無水硫酸鈉乾燥，過濾，減壓濃縮濾液，用乙酸乙酯/正己烷再結晶，得到標題產物（R)-3-第三丁氧羰基胺基-4-(2,4,5-三氟苯基）-丁酸1汽9.2运，白色固體），直接用於下一步反應。 MS m/z (ESI) : 332.3[M-1]。參考文獻：Tetrahedron Asymmetry, 2006，17(2)，205-209 第六步 ❹C-10比哄-2-基-曱胺將2-氰基啦畊lg(i〇.5g，l〇〇mm〇i)攪拌下溶解於 150mL 1,4-二氧環己烷中，加入l 〇g蘭尼鎳於25〇mL高壓反應釜中，在60°C下’40個大氣壓的氫氣中反應8小時。過濾，減壓濃縮濾液，得到標題產物c_吡畊_2_基_甲胺ih (10. 7g，棕色油狀物），收率：98%。 MS m/z (ESI) : ll〇[M+l]。 ❹ 第七步 2, 2, 2_二氣哄-2 -甲基_乙酿胺將C-吡畊~2-基-曱胺lh(10.9g，1〇〇mmol)加入到反應瓶中，冰浴冷卻至，在！小時内慢慢滴加2〇乩三氟乙酸酐，室溫下攪拌2小時，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化，得到標題產物 2,2,2-三氟-卜吡哄-2-曱基-乙醯胺11(21.〇§，棕色油狀物）。 MS m/z (ESI) : 206·1[M+1]。 94579 33 201026314 第八步 3-二氟甲基-〇米嗤並[i，5-a]u比n弁至溫條件下，將2,2,2-三氟〜N_吡畊_2—甲基_乙醯胺 li(21.0g’i〇0mmol)加入反應瓶中，加入1〇〇乩三氯氧磷，至溫擾拌30分鐘後，加入五氧化二構（17 8g，125丽〇1)，加熱回流反應5小時，薄層層析追蹤反應至原料消失，除去溶劑三氣化磷，反應體系用去離子水淬滅反應，再用2〇% 氫氧化鈉溶液在冰浴中調節pH為5至6，用乙酸乙酯 (250mLx4)萃取，合併有機相，用無水硫酸鎂乾燥，過濾，減壓濃縮濾液，用矽膠管柱層析法純化，得到標題產物3一二氟曱基-咪唑並[1，5-a]吡畊1 j(i2. 〇g，黃色固體），收率：65%。 MS m/z(ESI) : 188. 0[M+1]。 1HNMR(400MHz, CDCh)： δ -9. 15(s, 1Η), 8. 06(d, 1H), 7.92(s, 1H), 7. 81(d, 1H) ❹ 第九步 3-二氟曱基-5, 6, 7, 8-四氫咪唑並[i，5_a]吡啡將3-二氟甲基_咪唑並[L 5_&]吡哄^(12. ， 64. 2mmol)攪拌下溶解於15〇mL無水乙醇中，加入5〇〇呢ι〇% 把/碳’在氮氛圍下攪拌過夜。用粗矽膠管柱將反應液過滤、’減壓濃縮據液’得到標題產物3_三氟甲基_5, 6, 7, 8_ 四虱味嗤並[1，5姊比口井lk(12. 2g.，棕色固體），收率：犠。 HNMR(400MHz, CDC13)； ^ 6.84(s, 1H), 4. l〇(ra, 4H), 3.26(m, 2H), 1.81(s, 1H) , ， 94579 34 201026314 第十步 (R)-[3-氧代-1-(2, 4, 5-三氟苄基）-3-(3-三 It 曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基）-丙基]-胺基曱酸第三丁酯氮氛圍下，將3-第三丁氧羰基胺基-4-(2, 4, 5-三氟苯基）-丁酸lf(8. 6g，45mmol)、9. 4mL三乙胺授拌下溶解於 300mL二氯甲烷中，室溫下攪拌5分鐘後，依次加入3-三氟甲基-5, 6, 7, 8-四氳咪唑並[1，5-a]吡哄lk(15. Og， 45mmol)及雙（2-氧代-3-噁唑烷基）次膦醯氯〇7. lg， 67. 3mm〇l)，室溫下反應2小時’薄層層析追蹤反應至原料消失’減壓?辰縮反應液’用石夕膠管柱層析法純化所得殘餘物，得到標題產物（RH3-氧代-i-(2, 4, 5_三氟苄基）-3-(3-三氟甲基-5, 6-二氫-8H_咪唑並n，5_a]吡哄 -7-基）-丙基]-胺基曱酸第三丁酯u (2〇.〇g，白色固體），收率：88% 〇The first step 2,2_dimethyl_5-[2-(2,4,5_trisphenylphenyl)-[1,3]dioxan-4,6-dione will be 2 , 2-dimercapto-[1,3] oxalate _4,6-di-S (5. 69g, 39.5mmol) was dissolved in 400niL of dichloromethane under stirring, and added under ice cooling, 2 , 4, 5-trifluorophenylacetic acid la (7. 15g, 37.6 mmol) and p-diamine amine 0 to 0 (7. 35g, 60. 2mmol), slowly add 250mL 1- (3-dimethyl A suspension of methylene-propyl)-3-ethyl-carbodiimide hydrochloride (8. 28 g, 43.2 mmol) in methylene chloride, stirred at room temperature for 36 hours, then 5% succinate The reaction solution was washed with a solution (250 mL×7) and a saturated sodium chloride solution (250 mL×2), dried over anhydrous magnesium sulfate, filtered, and evaporated. -(2,4,5-trifluorophenyl)-ethenyl]-[1,3]dioxane-4,6-dione lb (ll. 4 g, white solid), yield: 96%. MS m/z (ESI): 315. 5 (M-1). Step 2 3-oxo-4-(2,4, 5-trifluorophenyl)-butyric acid ethyl ester 2, 2- Methyl-5-[2-(2,4,5-trifluorophenyl)-ethenyl]-[1,3]dioxane-4,6-dione Lb (15·72 g, 49.6 mmol) was dissolved in 280 mL of ethanol, stirred in an oil bath at 70 ° C overnight, cooled and concentrated under reduced pressure. -Oxo-4-(2,4,5-trifluorophenyl)-butyric acid ethyl ester lc (12 g, yellow liquid), yield: 88%. MS m/z (ESI): 259CM-1). Step 3 3-Amino-4-(2,4,5-trifluorophenyl)-but-2-dicarboxylic acid ethyl acetate q 3-oxo-4-(2,4, 5-trifluorobenzene Ethyl butyrate lc (24.6 g, 94.5 mmol) was dissolved in 240 mL of methanol, and acetic acid (36. 4 g, 473 mmol) was added thereto, and the mixture was heated under reflux for 3 hours, and the reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Add 50 mL of ethyl acetate, dissolve at 80 ° C, add 5OmL Zhengjiyuan, seed crystals, cool to room temperature, 0. 5 hours, add 100 mL of n-hexane, placed in the refrigerator overnight, suction filtration, Obtained title titled <RTI ID=0.0># </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS m/z (ESI): 260.1 [M+1] Step 4 (R)-3-3 -butoxycarbonylamino-4-(2,4, 5-trifluorophenyl)-butyric acid Ethyl 3-amino-4-(2,4,5-trifluorophenyl)-butyrate 14 (41 §, 15. 8 mmol) was added to a high pressure crucible, followed by the addition of 70 mL of methanol, dicarbonic acid _ (third Butyl ester) (3.8 g, 17.4 mmol), chlorine (1,5-cyclooctanedifluoride) recorded (丨)_polysteroid (32 mg' 0. 0632 mmol) and (R)-l-[(S) 2-(Diphenylphenyl)ferrocenyl]-ethyl-t-butylphosphine (68 mg, 0.126 mmol) was reacted for 3 hours at 3 (rc, 6.67 atmospheres of helium). Filtration, concentrated sputum under reduced pressure, adding 34 mL of methanol at 50 ° C, completely dissolved, and then allowed to stand at room temperature, overnight in a refrigerator, filtered, and washed with a mixed solvent of decyl alcohol / water ^ 1 = 3.2) Drying in vacuo afforded the title product (1), 13-t-butyloxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid, s. Yield: 70%.曰 MS m/z (ESI): 362.4 [M+1]. , the fifth step (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)_-butyric acid (R)-3-second butoxy-amine Base 4-(2,4,5-trisyl)ethyl ester le (l〇g, 27. 7 mmol) and sodium hydroxide (3.32 g, 83 i, dissolved in 100 mL of decyl alcohol and 50 mL of water with stirring) In a mixed solvent, after reacting to 45 C for 1 to 1.5 hours, a portion of the solvent was removed under reduced pressure to a small amount of water, and 1N hydrochloric acid was added to adjust the solution to 2 to 3 94579 32 201026314 with ethyl acetate (200 mL×3). The organic phase was combined, washed with 200 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate. Butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid 1 9.2, white solid) was used directly in the next step. MS m/z (ESI): 332.3 [M-1]. References: Tetrahedron Asymmetry, 2006, 17(2), 205-209. The sixth step, ❹C-10, 哄-2-yl-decylamine, 2-cyano cultivating lg (i〇.5g, l〇〇mm〇 i) Dissolved in 150 mL of 1,4-dioxane under stirring, and added 1 〇g of Raney nickel in a 25 〇mL autoclave, and reacted at 40 ° C for 8 hours in hydrogen gas at 40 ° C. Filtration, and the filtrate was concentrated under reduced pressure to give the title product: mjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS m/z (ESI): ll 〇 [M+l].第七 Step 7 2, 2, 2_dioxane-2-methyl-ethylamine C-pyrazine~2-yl-guanamine lh (10.9g, 1〇〇mmol) was added to the reaction flask. Cool down in the ice bath, at! 2〇乩 trifluoroacetic anhydride was slowly added dropwise during the hour, and the mixture was 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 to give the title product 2 2,2-Trifluoro-pyridin-2-mercapto-acetamide 11 (21.〇§, brown oil). MS m/z (ESI): 206·1 [M+1]. 94579 33 201026314 The eighth step 3-difluoromethyl-indomethacin and [i,5-a]u ratio n弁 to temperature, 2,2,2-trifluoro~N_pyridine_2 Methyl-acetamide li (21.0g'i〇0mmol) was added to the reaction flask, and 1 〇〇乩 phosphorus oxychloride was added. After mixing for 30 minutes, the pentoxide structure (17 8g, 125 〇) was added. 1), heating and refluxing reaction for 5 hours, thin layer chromatography to trace the reaction until the disappearance of the raw materials, remove the solvent tri-phosphorus phosphorus, the reaction system is quenched with deionized water, and then adjusted with 2% sodium hydroxide solution in an ice bath The mixture was extracted with ethyl acetate (250 mL×4). - Imidazo[1,5-a]pyrazine 1 j (i2. 〇g, yellow solid), yield: 65%. MS m/z (ESI): 188. 1HNMR (400MHz, CDCh): δ -9. 15(s, 1Η), 8. 06(d, 1H), 7.92(s, 1H), 7. 81(d, 1H) 第九 ninth step 3-difluoro Mercapto-5, 6, 7, 8-tetrahydroimidazo[i,5_a]pyridinyl 3-trifluoromethyl-imidazo[L 5_&]pyridinium (12., 64. 2mmol) Dissolved in 15 mL of absolute ethanol, added 5 〇〇〇〇 % / carbon ' stirred under nitrogen overnight. The reaction solution was filtered through a crude ruthenium column, and the title product was obtained as the title product: 3-trifluoromethyl _5, 6, 7, 8 _ 虱虱嗤嗤 [1,5 姊口 lk (12 2g., brown solid), yield: 犠. HNMR (400MHz, CDC13); ^ 6.84(s, 1H), 4. l〇(ra, 4H), 3.26(m, 2H), 1.81(s, 1H) , , 94579 34 201026314 Step 10(R)- [3-Oxo-1-(2,4,5-trifluorobenzyl)-3-(3-trit-decyl-5,6-dihydro-8H-imidazo[1,5-a]pyridyl 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyl under nitrogen atmosphere of argon-7-yl)-propyl]-amino decanoic acid Acid lf (8.6 g, 45 mmol), 9.4 mL of triethylamine was dissolved in 300 mL of dichloromethane and stirred at room temperature for 5 minutes, then 3-trifluoromethyl-5,6,7 was added sequentially. 8-lg, imidazo[1,5-a]pyridinium lk (15. Og, 45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride 〇 7. lg, 67. 3mm 〇l), reacting at room temperature for 2 hours 'Through layer chromatography to trace the reaction to the disappearance of the starting material' decompression? condensing reaction liquid' The residue obtained by purifying the column chromatography to obtain the title product (RH3-oxo) -i-(2, 4, 5-trifluorobenzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[,5-a]pyridin-7-yl)-propane ]]-aminobutyric acid tert-butyl ester u (2〇.〇g, white solid), yield: 88% 〇

7. ll(m，1H)， 4. 〇5(m, 2H), !HNMR (400MHz, CD3〇D): 5 7.25(m, 1H) 7.032(s，1H)，4.93(m, 2H)，4.35(m，3H) 2.99(m，2H)，2. 73(m，2H)，i.34(s，9H) 第十一步 (RH3-氧代-1-(2, 4, 5-三氟苄基）__3_(1_溴_3_三氟甲 -5, 6-二氫-8H-咪唾並[1’5-a]叫_7_基）_ 丙酸第三丁酯 & 94579 35 201026314 酸第三TS旨ll(2G，()g’ 39.6mmol)·下溶解於·此無水乙醇中，室溫下加入N一溴化琥珀醯亞胺（141g， 79. 2mmol)，繼續攪拌1小時後，加入碳酸鉀（1〇竑， 79. 2mmol)和二碳酸二（第三丁酯）（8. 6g，39. 6咖〇1)，反應 1小時後，薄層層析追蹤反應至原料消失，粗石夕膠管柱過濾反應液，除去碳酸鉀，減壓濃縮濾液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（1〇_[3_氧代三氟苄基）-3-(1-溴-3-三氟甲基_5, 6_二氳_8H_咪唑並 ❻[l，5-a>比哄-7-基）-丙基]-胺基曱酸第三丁酯lm(2〇〇g，白色固體），收率：86%。 'HNMR (400MHz, CDCh) ： ^ 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) 第十二步 (R)-7-[3-弟二丁氧幾基胺基_4-(2, 4, 5-三氟笨基）-丁醯 ❹基]-3-三氟甲基-5, 6, 7, 8-四氫咪嗤並[1，5-a]吼哄-1-羧酸甲醋將八幾基二銘（4. 02g，11. 76mmol)、氯乙酸乙酯7. ll(m,1H), 4. 〇5(m, 2H), !HNMR (400MHz, CD3〇D): 5 7.25(m, 1H) 7.032(s,1H), 4.93(m, 2H), 4.35(m,3H) 2.99(m,2H), 2.73(m,2H),i.34(s,9H) Step 11 (RH3-oxo-1-(2, 4, 5-3) Fluorobenzyl)__3_(1_bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1'5-a] is called _7_yl)-tert-butyl propionate & 94579 35 201026314 Acidic third TS ll (2G, () g' 39.6mmol) · dissolved in this anhydrous ethanol, added N-brominated amber iminoimide (141g, 79.2mmol) at room temperature, continue After stirring for 1 hour, potassium carbonate (1 〇竑, 79.2 mmol) and di(tert-butyl phthalate) (8.6 g, 39. 6 Curry 1) were added, and after 1 hour of reaction, thin layer chromatography was followed. The reaction was carried out until the disappearance of the starting material, and the reaction mixture was filtered to remove the potassium carbonate. The filtrate was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography to give the title product (1 〇[[3] 3-(1-bromo-3-trifluoromethyl_5,6-dioxin_8H-imidazolium [l,5-a> 哄-7-yl)-propyl]-amino Tert-butyl citrate lm (2 〇〇g, white solid), yield: 86%. 'HNMR (40 0MHz, CDCh) : ^ 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) The twelfth step (R)-7-[3-di-dibutoxymethylamino-4-(2 , 4, 5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimiphtho[1,5-a]indole-1-carboxylate Acidic vinegar will be octabase II (4.22g, 11.76mmol), ethyl chloroacetate

(0.71g，5. 88mmol)、碳酸鉀（l.62g，11.76mmol)以及 50mL 曱醇放入反應瓶中，攪拌5分鐘後，加入（R)-[3-氧代 -1-(2,4, 5-三氟苄基）-3-(1-溴-3-三氟曱基-5, 6-二氫 -8H-咪唑並[1，5-a]吡畊-7-基）-丙基]-胺基曱酸第三丁酯 lm(2. 3g，3. 92mmol)，油浴60°C下反應，顏色由深褐色變成紫色，2小時後ESI追蹤反應，原料消失，減壓濃縮反 36 94579 201026314 應液’用石夕膠官柱層析法純化所得殘餘物，得到標題產物 ⑻-7-[3:第三丁氧m基胺基+ (2,4,5_三氟苯基）_丁酿基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1 5_a]吡畊一卜羧甲S曰ln(l.lg,白色固體），收率：5〇%。 MS m/z (ESI) : 565·0(Μ+1)。參考文獻：Journal of 〇rganometallicChemistry，1985, 285(1-3), 293-303 ’ 第十三步 ❹（ί〇-7-[3_胺基-4-(2,4,5-三氟苯基）-丁醯基]_3_三氟曱基-5, 6, 7, 8-四氳咪嗤並[1，5-a]i*比π井-1-羧酸曱酯鹽酸鹽將（R)-7-[3-第三丁氧羰基胺基_4_(2,4,5_三氟苯基）-丁醯基]-3-二I甲基-5, 6, 7, 8-四氫咪0坐並[1，5-a]n比哄-1-幾·酸甲酯 ln(0. 12g，2.12mmol)加入到 5mL 2. 2N 的氯化氫的乙酸乙酯溶液中，室溫下反應5小時後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到樣題產物 ❹（R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯]-3-三氟甲基 -5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-羧酸甲酯鹽酸鹽 1(0· 12g，淡黃色固體），收率：94. 3%。 MS m/z (ESI) : 465.2(M+1)。 1HNMR(400MHz, CDsOD): <5 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)。實施例2 37 94579 201026314 (R)-7-[3-胺基~4-(2, 4, 5-三氟苯基)-丁醯基]三氟曱基-5’6,7,8-四氫咪唑並[1，5_&]吡畊_1_(2_甲磺醯_乙基）-甲酿胺鹽酸鹽(0.71 g, 5.88 mmol), potassium carbonate (1.62 g, 11.76 mmol) and 50 mL of decyl alcohol were placed in a reaction flask, and after stirring for 5 minutes, (R)-[3-oxo-1-(2, 4, 5-trifluorobenzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrylene-7-yl)- Propyl]-amino phthalic acid tert-butyl ester lm (2.3 g, 3.92 mmol), oil bath reaction at 60 ° C, the color changed from dark brown to purple, after 2 hours, ESI traced the reaction, the raw materials disappeared, decompression Concentrated anti-36 94579 201026314 Reagents were purified by chromatography on silica gel column chromatography to give the title product (8)-7-[3:3:3,4,5-trifluoro Phenyl)-butanyl]-3-trifluoromethyl-5,6,8-tetrahydroimidazo[1 5_a]pyrazine-carboxyl S曰ln (l.lg, white solid), Yield: 5% by weight. MS m/z (ESI): 565·0 (Μ +1). References: Journal of 〇rganometallicChemistry, 1985, 285(1-3), 293-303 'Step 13 ❹(ί〇-7-[3_Amino-4-(2,4,5-trifluorobenzene) ))-丁醯基]_3_Trifluoromethyl-5, 6, 7, 8-tetramidine and [1,5-a]i* ratio π well-1-carboxylic acid oxime ester hydrochloride (R )-7-[3-Tertiyloxycarbonylamino-4_(2,4,5-trifluorophenyl)-butanyl]-3-di-Imethyl-5, 6, 7, 8-tetrahydromethane 0 sit and [1,5-a]n than 哄-1-methyl acid ln (0. 12g, 2.12mmol) was added to 5mL 2. 2N hydrogen chloride in ethyl acetate solution, react at room temperature 5 After an hour, 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 ❹(R)-7-[3-amino-4-(2,4, 5-trifluorophenyl)-醯]]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride 1 (0·12g, light yellow Solid), Yield: 94.3%. MS m/z (ESI): 465.2 (M+1) 1HNMR (400MHz, CDsOD): <5 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). 2 37 94579 201026314 (R)-7-[3-Amino~4-(2,4,5-trifluorophenyl)-butanyl]trifluoromethyl-5'6,7,8-tetrahydroimidazolium [1,5_&]pyrazine_1_(2_methanesulfonyl-ethyl)-caraamine hydrochloride

第一步 (R)-7-[3-弟二丁氧幾基-4-(2, 4, 5-三氟苯基）-丁酿基]一％三氟甲基-5, 6, 7, 8-四氳咪唑並[1，5-a]吡哄-1-鲮酸將（R) 7-[3-第二丁氧幾基胺基—4-(2，4, 5~三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唾並[1，5一a]0比畊-1-羧酸甲酯ln(2. Og，3.5mmol)攪拌下溶解於50mL甲 ❹醇中’加入30mL 4N的氫氧化鈉溶液，室溫下反應1小時後，薄層層析追蹤反應至原料消失，加入2N鹽酸調節反應液pH值為3，用乙酸乙酯（5〇mLx4)萃取反應液，合併有機相，用無水硫酸鎂乾燥，過濾，減壓濃縮濾液，得到標題產物(1〇-7-[3-第三丁氧羰基-4-(2,4,5-三氟苯基）-丁醯基]-3-三氟曱基-5, 6, 7, 8-四氫咪嗤並[1，5-a]σ比13井-1-羧酸2a(1.9g，淡黃色固體）。 1HNMR(400MHz, CDsOD): 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), 38 94579 201026314 2. 984-2. 769(m，4H)，l 417_1 255(m，9H)。第一步 ⑻:[3-[l-(2-甲磺醯基—乙基胺基甲醯)_3_三氟甲基一虱鲁咪唑並[1，5-a]吡畊-7-基]-3-氧代+(2, 4, 5-三氟-节基）-丙基]-胺基曱酸第三丁醋將⑻-7-[3-第三丁氧羰基_4_(2,4,5_三氟苯基丁醯基]一3一三氟曱基一5, 6, 7, 8-四氫咪唑並[1，5-a]吡哄-1- 叛酸 2a(0. 15g，〇.27mmol)、2-甲績酸基乙胺（65.5mg， 0.41mmol)和雙（2-氧代噁唑烷基）次膦醯氣（〇· 1〇知， 0.41nm〇l)攪拌下溶解於5此二氯曱烷中，加入三乙胺 (0. 25mL，1.62醜〇1)，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（幻-以—以—㈡-曱磺醯基_乙基胺基曱醯）-3-三氟曱基-5, 6-二氫-8H二咪唑並[1，5-a]吡畊 -7-基]-3-氧代-1-(2, 4, 5-三氟-苄基）-丙基]-胺基甲酸第 ❹三丁酯2b(60mg，白色固體），收率：34%。 MS m/z (ESI) : 678.2(M+23)。參考文獻：Journal of Organic Chemistry, 2006，71(3)， 1220-1225 第三步 α〇-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡哄-1-(2-曱磺醯-乙基）-曱醯胺鹽酸鹽將00-[3-[1-(2-曱磺醯基-乙基胺基曱醯）-3-三氟曱 39 94579 201026314First step (R)-7-[3-didobutoxy-4-yl(2,4,5-trifluorophenyl)-butanyl]-% trifluoromethyl-5, 6, 7 , 8-tetraimidazo[1,5-a]pyridin-1-decanoic acid (R) 7-[3- 2,4,5,5-trifluoro Phenyl)-butanyl]-3-trifluoromethyl-5,6,8-tetrahydropyrano[1,5-a]0 is more than methyl ol-carboxylate ln (2. Og, 3.5mmol) dissolved in 50mL of methanol in stirring. 'Add 30mL of 4N sodium hydroxide solution, react at room temperature for 1 hour, trace the reaction to trace disappearance by thin layer chromatography, add 2N hydrochloric acid to adjust the pH of the reaction solution to 3 The reaction mixture was extracted with ethyl acetate (5 mL EtOAc). -(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimiphtho[1,5-a]σ ratio 13 well-1 - carboxylic acid 2a (1.9 g, pale yellow solid). 1H NMR (400 MHz, CDs 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), 38 94579 201026314 2. 984-2. 769 (m, 4H), l 417_1 255 (m, 9H). (8): [3-[l-(2-Methanesulfonyl-ethylaminocarbamidine)_3_trifluoromethyl-indolizyl[1,5-a]pyrylene-7-yl]-3 -oxo+(2,4,5-trifluoro-nodal)-propyl]-aminopyruic acid tert-butyl vinegar (8)-7-[3-tert-butoxycarbonyl_4_(2,4, 5_Trifluorophenylbutanyl]-trifluoroindolyl-5,6,6,8-tetrahydroimidazo[1,5-a]pyridin-1-retat 2a (0.15 g, 〇. 27 mmol), 2-methyl acid ethylamine (65.5 mg, 0.41 mmol) and bis(2-oxooxazolidinyl)phosphine helium (〇·1〇 know, 0.41 nm〇l) were dissolved under stirring 5 In the dichlorosilane, triethylamine (0.25 mL, 1.62 ugly 1) was added, and the reaction was carried out 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 resulting residue was purified by EtOAc (EtOAc): [1,5-a]pyridin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tributyl butyl 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. Step 3 α〇-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]- 3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyridin-1-(2-indolesulfonyl-ethyl)-indoleamine hydrochloride will be 00 -[3-[1-(2-oxasulfonyl-ethylaminopurine)-3-trifluoroanzide 39 94579 201026314

基-5, 6-二氫-8H-咪唑並[i，5_a]吡哄_7_基]-3-氧代 -1-(2, 4, 5-三氟-苄基）-丙基;胺基甲酸第三丁酯2b (0. 06g，0. 091mmol)溶解於少量乙酸乙酯中，加入4mL 3. IN 的氯化氫的乙酸乙酯溶液，室溫下反應4小時後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物 (R)-7-[3-胺基-4-(2’ 4, 5-三氟苯基）-丁醯基]-3〜三氣甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-(2~曱石黃酿〜乙基）-甲醯胺鹽酸鹽2(60mg，白色固體）。 ❹ MS m/z (ESI) : 556.3(M+1)。 1HNMR(400MHz, CDsOD)： (5 7. 44-7. 35(m, 1H), 7. 3〇-7> 2l(ffi 1H)，5·15-5·02(ιη，2H), 4. 53-4.45(m, 2H), 4. 34-4. 27(m 2H)’ 4.05-3.94(瓜，4H)，3.89-3. 62(s，4H), 3. I2~3.07(m 2H)，3. 03-2. 82(m，2H)。 ’ 實施例3 (R)-3-胺基-l-[l-(嗎啉_4_羰基一三氟甲基—5, 6一二氫 ❹-8H-咪唑並[l，5-a]吡畊-7-基]-4-(2, 4, 5-三氟苯基）〜丁 -1-酮鹽酸鹽-5,6-dihydro-8H-imidazo[i,5-a]pyridin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl; The third butyl carbazate 2b (0. 06g, 0. 091mmol) was dissolved in a small amount of ethyl acetate, and 4 mL of a solution of 3. IN hydrogen chloride in ethyl acetate was added thereto. After reacting for 4 hours at room temperature, thin layer chromatography was carried out. The reaction was traced 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]-3~3 Base-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyrylene-1-(2~ vermiculite~ethyl)-carbamidine hydrochloride 2 (60 mg, white solid ). ❹ MS m/z (ESI): 556.3 (M+1). 1H NMR (400 MHz, CDsOD): (5 7. 44-7. 35 (m, 1H), 7. 3〇-7> 2l (ffi 1H), 5·15-5·02 (ιη, 2H), 4. 53-4.45(m, 2H), 4. 34-4. 27(m 2H)' 4.05-3.94 (melon, 4H), 3.89-3. 62(s,4H), 3. I2~3.07(m 2H) , 3. 03-2. 82 (m, 2H). 'Example 3 (R)-3-Amino-l-[l-(morpholine-4-carbonyl-trifluoromethyl--5, 6-two Hydroquinone-8H-imidazo[l,5-a]pyrrol-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

第一步 40 94579 201026314 (R)-[3-[l-(嗎啉-4-羰基）-3-三氟曱基-5, 6-二氫-8H-咪唾並[1，5-a]n比哄-7-基]-3-氧代-1-(2, 4,5-三說-苄基）-丙基]-胺基曱酸第三丁酯將化）-7-[3-第三丁氧羰基-4-(2,4,5-三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1- 竣酸 2a(60mg，〇.l〇9mmol)、嗎啉（19mg，0.218mmol)和雙 (2-氧代-3-噁唑烷基）次膦醯氯（53· 5mg，〇. 218mm〇1)攪拌下溶解於5mL二氯曱烷中，加入三乙胺（〇. imL，〇· 65mmol)，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-[3-[l-(嗎啉-4-羰基）-3-三氟曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-3-氧代-1-(2, 4, 5-三氟-苄基）-丙基]-胺基甲酸第三丁酯3a(60mg，白色固體），收率：89%。 MS m/z (ESI) : 620.0(M+1)。 ❹ 第二步 (R)-3-胺基-1-[1-(嗎啉-4-羰基）_3_三氟甲基_5, 6-二氫 -8H-咪唑並[1，5-a>比哄-7-基]-4-(2, 4, 5-三氟苯基）-丁 -1-酮鹽酸鹽將（R)-[3-[l-(嗎啉-4-羰基）-3-三氟甲基_5, 6-二氳 -8H-咪唑並[1，5-a]吡卩井-7-基]-3-氧代-1-(2,4, 5-三氟- 节基）-丙基]-胺基甲酸第三丁酯3a (〇. 〇7g，〇.11111111〇1)溶解於少量乙酸乙酯中，加入6mL 3. in的氯化氫的乙酸乙酯 /谷液，至溫下反應4小時後，薄層層析追縱反應至原料消 41 94579 201026314 失’減壓濃縮反應液，得到標題產物（r)_3-胺基嗎啉-4-羰基）-3-三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-4-(2, 4, 5-三氟苯基）-丁_；[_酮鹽酸鹽3(7〇mg，淡黃色固體）。 MS m/z (ESI) : 520. 2(M+1)。 HNMR(400MHz, CD3OD): ^ 7. 42-7. 37(m, 1H) 7.26-7 22(m 1H), 5.15-5.05(m, 2H), 4. 53-4. 44(m, 2H), 4.34-4.26¾ 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, 2fl) 〇實施例4 ’ (R” [3 胺基-4-(2’4,5-二氟笨基^^-四氫咪唾並…斗轉“一氣^ 胺鹽酸鹽井小(氰基甲基)_甲画First step 40 94579 201026314 (R)-[3-[l-(morpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a ]n than 哄-7-yl]-3-oxo-1-(2,4,5-tris-benzyl)-propyl]-amino decanoic acid tert-butyl ester will be converted to -7-[ 3-tert-butoxycarbonyl-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5- a] pyridin-1-decanoic acid 2a (60 mg, 〇.l〇9 mmol), morpholine (19 mg, 0.218 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (53· 5mg, 〇. 218mm〇1) Dissolved in 5mL of dichloromethane with stirring, added triethylamine (〇.imL, 〇·65mmol), reacted at room temperature overnight, trace the reaction by thin layer chromatography until the raw material disappears, minus The reaction mixture was concentrated, and the residue was purified to purified crystals eluted eluted eluted Dihydro-8H-imidazo[1,5-a]pyrrol-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid Third butyl ester 3a (60 mg, white solid), yield: 89%. MS m/z (ESI): 620.0 (M+1). ❹ Second step (R)-3-Amino-1-[1-(morpholin-4-carbonyl)_3_trifluoromethyl_5,6-dihydro-8H-imidazo[1,5-a&gt (哄)-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride (R)-[3-[l-(morpholine-4-carbonyl) )-3-trifluoromethyl_5,6-diindole-8H-imidazo[1,5-a]pyridin-7-yl]-3-oxo-1-(2,4, 5- Trifluoro-succinyl)-propyl]-carbamic acid tert-butyl ester 3a (〇. 〇7g, 〇.11111111〇1) was dissolved in a small amount of ethyl acetate, and 6 mL of 3. in hydrogen chloride in ethyl acetate was added. / gluten solution, after reacting for 4 hours at room temperature, thin layer chromatography to trace the reaction to the raw material elimination 41 94579 201026314 Loss of 'concentration of the reaction mixture under reduced pressure to give the title product (r)-3-aminomorpholine-4-carbonyl) -3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrylene-7-yl]-4-(2,4,5-trifluorophenyl)-butyl _;[_ketohydrochloride 3 (7 〇 mg, pale yellow solid). MS m/z (ESI): 520. 2 (M+1). HNMR (400MHz, CD3OD): ^ 7. 42-7. 37(m, 1H) 7.26-7 22(m 1H), 5.15-5.05(m, 2H), 4. 53-4. 44(m, 2H) , 4.34-4.263⁄4 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, 2fl) 〇 Example 4 '(R" [3 Amino-4-(2'4,5-difluoro-phenyl]--tetrahydropyrene ...fighting "one gas ^ amine hydrochloride well small (cyanomethyl) _ a painting

第一步 ⑻-[3-[卜（氰基？基_胺基甲 -8H-咪唑並[1，5~a]n比啡一卜基]〜卜-氟’基-5, 6-二氫基）-丙基]-胺基曱酸第二丁铲虱代— Κ2,4,5-三氟苄將（R)-7-[3~第三 5-三氟苯基）-丁 94579 42 201026314 酿基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[i，5-a]吡哄一卜羧酸2a(150mg，0. 27mmol)、胺基乙腈硫酸鹽（85mg， 0.41im〇l)、雙（2-氧代-3-噁唑烷基）次膦醯氣（〇2〇6g， 0. 81mmol)和三乙胺（〇. 37mL，2. 7mmol)攪拌下溶解於1〇mL 一氯甲烧中’室溫下反應過夜，薄層層析追縱反應至原料消失，減壓濃縮反應液，用碎膠管柱層析法純化所得殘餘物，得到標題產物（R)-[3-[l-(氰基甲基-胺基曱醯）一3一三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡啡-7-基]-3-氧代 1 (2, 4, 5-二氣午基）-丙基]-胺基甲酸第三丁醋.知 (150mg，白色固體），收率：94.4%。第二步〇〇-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]_3_三氟曱基-5’ 6, 7’ 8-四氫咪唑並[1，5-a]吡畊-1-(氰基甲基曱醯胺鹽酸鹽將（R)-[3-[l-(氰基甲基-胺基甲醯）-3-三銳甲基_5, 6_ ❹二氳-8H-咪唑並[1，5-a]吡畊-7-基]-3-氧代-1-(2, 4, 5-三氟苄基）-丙基]-胺基甲酸第三丁酯4a(0. 3g，〇. 25mmol)溶解於10mL二氯甲烧中，加入5mL三氟乙酸，室溫下反應1 小時後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物（R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）—丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a>比畊-i_(氰基甲基）-甲醯胺鹽酸鹽4(130mg,淡黃色固體）。 MS m/z (ESI) : 489. 2(M+1)。實施例5 94579 43 201026314 (R)-3-胺基-1 -[ 1 -（4一甲其 ^ L L甲基/、虱〇比啡-1-羰基）-3-三氟甲氟苯基）-丁-1-酿|二鹽酸鹽The first step (8)-[3-[Bu(cyano-based-aminomethyl-8H-imidazo[1,5~a]n than morphyl]-bu-fluoro-yl-5, 6-di Hydrogen)-propyl]-amino decanoic acid second shovel deuterium - Κ2,4,5-trifluorobenzyl (R)-7-[3~third 5-trifluorophenyl)-butyl 94579 42 201026314 Styrene]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[i,5-a]pyridinium carboxylic acid 2a (150 mg, 0.25 mmol), aminoacetonitrile Sulfate (85 mg, 0.41 im 〇l), bis(2-oxo-3-oxazolidinyl)phosphinium oxime (〇2〇6g, 0.81 mmol) and triethylamine (〇. 37 mL, 2. 7 mmol) was dissolved in 1 mL of monochloromethane while stirring, 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, and the residue was purified by column chromatography. The title product (R)-[3-[l-(cyanomethyl-aminoindole)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a] is obtained. Pyridin-7-yl]-3-oxo 1 (2,4,5-di-indolyl)-propyl]-carbamic acid tert-butyl vinegar. (150 mg, white solid), yield: 94.4 %. The second step is 〇〇-7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]_3_trifluoromethyl-5' 6,7' 8-tetrahydroimidazolium [1,5-a]pyroxy-1-(cyanomethylguanamine hydrochloride)(R)-[3-[l-(cyanomethyl-aminocarbamidine)-3-tris Methyl _5, 6_ ❹ 氲-8H-imidazo[1,5-a]pyrazine-7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-prop The tert-butyl carbamic acid tert-butyl ester 4a (0.3 g, 〇. 25 mmol) was dissolved in 10 mL of methylene chloride, and 5 mL of trifluoroacetic acid was added thereto. After reacting for 1 hour at room temperature, the reaction was traced by thin layer chromatography. 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> ratio tillage-i_(cyanomethyl)-carbenamide hydrochloride 4 (130 mg, pale yellow solid) MS m/z (ESI ): 489. 2(M+1). Example 5 94579 43 201026314 (R)-3-Amino-1 -[ 1 -(4-methylmethylate LL methyl/, oximemorphin-1-carbonyl )-3-trifluoromethylfluorophenyl)-but-1-flavor|dihydrochloride

第一步 (R)-[3-[l-(4-曱基-六氫吡畊—j一羰基）_3_三氟甲基一5, 6一 =氫-8H-咪唑並"，5_a]吡畊_7—基]一3_氧代_卜(2,（ 5:三氟-苄基）-丙基]-胺基甲酸第三丁酯將（R)-7-[3-第三丁氧羧基_4—(2, 4, 5_三氟苯基）_丁醯基]-3-二氟甲基-5, 6,7, 8-四氫咪唑並以，5_a]吡哄一卜〇羧酸 2a(150mg，〇·27ππηο1)、卜甲基六氫^比啡（54mg，〇. 54咖〇1)和雙（2-氧代_3__噁唑烷基）次膦醯氯（〇.丨38g，〇.54mm〇l)攪拌下溶解於8此二氯甲烷中，加入三乙胺 (〇.25mL，1.62mniol)，室溫下反應過夜，薄層層析追蹤反應至原料消失’減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-[3-[l-(4-甲基-六氫吡哄 1 %基）-3-二氟甲基_5, 6一二氫-8H-咪®坐並[1，5-a]%ti井二-基]-3-氧代-1-(2,4, 5—三氟_苄基）_丙基]_胺基甲酸第二丁酯5a(80mg，白色固體），收率：49%。 44 94579 201026314 MS m/z (ESI) : 633. 2(M+1)。第二步〇〇-3-胺基-l-[ 1-(4-甲基-六氫吡π井一i-羰基）-3-三氟甲基-5,6-二氫-811-咪》坐並[1，5-8]°比哄-7-基]-4-(2,4,5-三氟苯基）-丁-1-酮二鹽酸鹽將(R)-[3-[l-(4-甲基-六氫吡啡—i一羰基一三氟甲基 -5, 6-二氫-8H-咪唑並[1，5-a]吡D井-7-基]-3-氧代-卜春（2,4,5-二氟-苄基）-丙基]-胺基甲酸第三丁酯53(〇.〇8§， 0.126mmol)溶解於6niL3. 1N的氯化氳的乙酸乙酯溶液，室溫下反應過夜後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物（R)-3-胺基[卜（4_甲基-六氫吡畊-1-羰基）-3-三氟甲基-5, 6-二氫-8H-咪唑並d 5_a] 吡畊-7-基]_4—(2,4,5—三氟苯基卜丁—丨—酮二鹽酸越 (90mg，-白色固體）。 MS m/z (ESI) : 533.2(M+1)。 ❹ WNMRUOOMHz，CD3〇D): (5 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)。 ’ 實施例6 (R)-3-胺基二氧代-硫代嗎啉-4_羰基）_3-三氟甲基-5,6-二氫-811-_〇坐並[1，5-3]〇比卩井-7-基]-4-(2 4 5-三氟苯基）-丁-1-酮鹽酸鹽 5 94579 45 201026314First step (R)-[3-[l-(4-mercapto-hexahydropyrazine-j-carbonyl)_3_trifluoromethyl-5,6-=hydro-8H-imidazole",5_a Pyridinium-7-yl]-3_oxo-b (2,(5:trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (R)-7-[3- Tributyloxycarboxyl_4-(2,4,5-trifluorophenyl)-butanyl]-3-difluoromethyl-5,6,7,8-tetrahydroimidazolium, 5_a]pyridinium 〇 carboxylic acid 2a (150mg, 〇 · 27ππηο1), benzyl hexahydropyrazine (54mg, 〇. 54 咖〇1) and bis(2-oxo_3__oxazolidinyl)phosphinium chloride (〇.丨38g, 〇.54mm〇l) was dissolved in 8 methylene chloride with stirring, added with triethylamine (〇.25mL, 1.62mniol), reacted at room temperature overnight, and traced by thin layer chromatography until the raw material disappeared. The reaction mixture was concentrated under pressure and the residue obtained was purified by silica gel column chromatography to give the title product (R)-[3-[(4-methyl-hexahydropyridinium). Base _5,6-dihydro-8H-mi®® sits and [1,5-a]% ti di-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl) - propyl] _ butyl carbamic acid 2 butyl ester 5a (80 mg, white solid), yield: 49%. 44 94579 201026314 MS m / z (ESI): 633. 2(M+1). The second step is indole-3-ylamino-l-[ 1-(4-methyl-hexahydropyridinium-i-carbonyl)-3-tri Fluoromethyl-5,6-dihydro-811-mi" sits and [1,5-8]° 哄-7-yl]-4-(2,4,5-trifluorophenyl)-butyl- 1-keto-dihydrochloride salt (R)-[3-[l-(4-methyl-hexahydropyridin-i-carbonyl-trifluoromethyl-5,6-dihydro-8H-imidazo[ 1,5-a]pyridyl D-7-yl]-3-oxo-buchun (2,4,5-difluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 53 (〇〇8§, 0.126 mmol) was dissolved in 6 niL of a 1 N solution of ruthenium chloride in ethyl acetate. After reacting at room temperature overnight, the reaction was traced by thin layer chromatography until the material disappeared. R)-3-Amino[b (4-methyl-hexahydropyrrolin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazolium d 5_a] pyridin-7 - 。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。 , CD3〇D): (5 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-Aminodioxy-thiomorpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-811-_〇 sits and [1,5- 3]〇比卩井-7-yl]-4-(2 4 5-trifluorophenyl)-butan-1-one hydrochloride 5 94579 45 201026314

第一步 ⑩（R)_[3-[l-(l，1-二氧代-硫代嗎淋-4-幾基）-3-三氟甲基 -5, 6-二氫-8H- p米唾並[1，5-a]β比 D并-7-基]-3-氧代-1 — (2, 4, 5-三氟苄基）-丙基]-胺基甲酸第三丁酯將（幻-7-[3-第三丁氧幾基-4-(2,4,5-三氟苯基）-丁酿基]-3-三氟甲基-5, 6, 7, 8-四氫喷嗤並[1，5-a]〇比D井甲酸2a(150mg，0. 27mmol)、硫嗎啉-1，1-二氧化物鹽酸鹽 (73mg，0.54mmol)、雙（2-氧代-3-噁唑烷基）次膦醯氯 ❹（0. 138g，0. 54mmol)和三乙胺（〇.25mL，1.62mmol)攪拌下 >谷解於8mL —氯曱燒中，加入4mL N，N-二甲基曱酿胺，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-[3-[l-(l，1-二氧代-硫代嗎琳_4~羰基）_3_三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡啡-7-基]-3-氧代 -1-(2,4, 5-二氟苄基）-丙基]-胺基甲酸第三丁酯6&(17〇呢，白色固體），收率：94%。 MS m/z (ESI) : 668.1(M+1)。 94579 46 201026314 第二步 00-3-胺基-l-[ 1-(1，i-二氧代_硫代嗎啉-4-羰基）-3-三 .氟曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-4-(2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽將（R)-[3-[l-(1，1-二氧代_硫代嗎啉-4-羰基）-3-三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-3-氧代 -1-(2,4,5-三氟苄基）-丙基]_胺基甲酸第三丁酯63 (〇. 〇· 22mmol)溶解於4mL 3· 1N的氯化氫的乙酸乙酯 ί谷液，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物（R)_3_胺基^ — 二氧代-硫代嗎啉-4-羰基）-3-三氟甲基-5, 6-二氫-8H-咪唑並[l，5-a]吡啡-7-基]-^^，々。-三氟苯基卜丁-丨-輞鹽酸鹽6(140mg，淡黃色固體）。 MS m/z (ESI) : 568·2(M+1)。 1HNMR(400MHz, CD3〇D): 5 7. 45-7. 39(m, 1H), 7 29-7 20(m ❹ 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. l3(ln, 4H)^ 3.18-3^04(^ 2H)，2. 99-2. 85(m，2H)。 ’ 實施例7 基丁酿基]_3一三氟曱基-5, 6, 7, 8-四氫咪唑並[1，5-a]，]_羰基卜六氫吡啶-4-甲醯胺鹽酸鹽 94579 47 201026314First step 10(R)_[3-[l-(l,1-dioxo-thio-indol-4-yl)-3-trifluoromethyl-5,6-dihydro-8H- Pm-salt[1,5-a]β is more than D--7-yl]-3-oxo-1 - (2,4,5-trifluorobenzyl)-propyl]-carbamic acid Butyl ester will (Phantom-7-[3-Tertioxybutyryl-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5, 6, 7 , 8-tetrahydropyrene and [1,5-a] oxime ratio D well formic acid 2a (150 mg, 0.25 mmol), thiomorpholine-1,1-dioxide hydrochloride (73 mg, 0.54 mmol), Bis(2-oxo-3-oxazolidinyl)phosphinium hydrazide (0.18 g, 0.54 mmol) and triethylamine (〇25 mL, 1.62 mmol) with stirring > glutamic solution in 8 mL of chlorine In the simmering, 4 mL of N,N-dimethylamine was added, and the reaction was carried out at room temperature overnight, 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 was purified by silica gel column chromatography. To give the title product (R)-[3-[l-(l,1-dioxo-thio- lin- 4~carbonyl)_3_trifluoromethyl-5,6-dihydro-8H-imidazole [1,5-a]pyridin-7-yl]-3-oxo-1-(2,4,5-difluorobenzyl)-propyl]-carbamic acid tert-butyl ester 6&(17 Oh, white solid), Rate: 94% MS m/z (ESI): 668.1 (M+1). 94579 46 201026314 Second step 0-3-amino-l-[ 1-(1,i-dioxo-thio? Porphyrin-4-carbonyl)-3-trifluoroindol-5,6-dihydro-8H-imidazo[1,5-a]pyrrol-7-yl]-4-(2, 4, 5- Trifluorophenyl)-butan-1-one hydrochloride (R)-[3-[l-(1,1-dioxo-thiomorpholin-4-carbonyl)-3-trifluoromethyl -5,6-Dihydro-8H-imidazo[1,5-a]pyrrol-7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl] _Amino carboxylic acid tert-butyl ester 63 (〇. 〇·22mmol) was dissolved in 4mL of 3·1N hydrogen chloride in ethyl acetate gluten solution, reacted at room temperature overnight, traced by thin layer chromatography until the starting material disappeared, decompression The reaction mixture was concentrated to give the title compound (D) </ </ </ </ </ </ </ </ </ , 5-a]pyridin-7-yl]-^^, 々. -Trifluorophenylbutine-indole-hydrazine hydrochloride 6 (140 mg, pale yellow solid). MS m/z (ESI): 568·2 (M+1). 1HNMR (400MHz, CD3〇D): 5 7. 45-7. 39(m, 1H), 7 29-7 20(m ❹ 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. l3(ln, 4H)^ 3.18-3^04(^ 2H), 2. 99-2. 85 (m, 2H). 'Example 7 butyl aryl] -3-trifluoromethyl-5,6,7-tetrahydroimidazo[1,5-a],]-carbonyldihydropyridin-4-carboxamide Acid salt 94579 47 201026314

第一步 (R)-[3-[l-(4-胺基甲酿-六氫〇比淀_1-幾基）-3-三氣甲基 ❹-5, 6-二氫-8H-咪嗤並[1，5-a] °比哄-7-基]-3~氧代_ι_ (2, 4, 5-三氟-苄基）-丙基]-胺基甲酸第三丁酯將〇〇-7-[3-第三丁氧幾基-4-(2,4,5-三氟笨基）_丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唾並[1，5-a>比π井-i_ 羧酸2a(150mg，0. 27mmol)、4-氨甲醯基六氫吡咬（7〇mg， 0. 54mmol)和雙（2-氧代-3"·噁唑烷基）次膦醯氯（〇. 138g， 0. 54mmol)攪拌下溶解於8mL二氯甲烷中，加入三乙胺 ❹（0. 25mL, 1. 62mmol)，再加入4inL N，N-二甲基甲酿胺，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物00-[3-[1-(4-胺基甲醯基-六氫吼啶羰基）_3一三氟甲基-5, 6-二氫-8H-咪峻並[1，5-a]。比哄_7_基]_3_氧代 -1-(2, 4, 5-二氟-苄基）-丙基]一胺基甲酸第三丁醋7a (180mg,白色固體），收率：98%。 MS m/z (ESI) : 660.9(M+1)。第二步 94579 48 201026314 (R)-l-{7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪嗤並[1，5-a]°比哄_1_幾基}-六氫吡咬-4-甲醯胺鹽酸鹽將（R)-[3-[l-(4-胺基甲醯-六氫η比定-1-幾基）-3_三乱甲基一5, 6-二氫-8H-咪0坐並[1，5-a]n比哄-7-基]-3-氧代 -1-(2, 4, 5-三氟-苄基）-丙基]-胺基甲酸第三丁酯7a (〇.18g，0.27mmol)及2mL乙酸乙酯加入反應瓶中，加入 6mL之2. 3N的氣化氫的乙酸乙酯溶液，室溫下反應3. 5小 ®時後’薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物（R)-l-{7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟曱基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡Π井-1 — 羰基}-六氫吡啶-4-甲醯胺鹽酸鹽7(0.12g，白色固體），收率：74%。 MS m/z (ESI) : 561.2CM+1)。 'HNMRCdOOMHz, CDsOD): ^ 7. 42-7. 31 (m, 1H), 7. 28-7. 16(m, ❹ 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. 〇6(m, 2H), 3. 03-2. 72(m, 4H), 2. 65-2. 53(m, 1H), 2. 15-2. 〇3(ms 2H), 1.93-1.83(m，2H)，1.77-1.6〇(m，2H)。實施例8 (R)-7-[3-胺基-4-(2’ 4, 5-三氟苯基）_丁醯基]_3_三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊曱基）甲醯胺鹽酸鹽 94579 49 201026314First step (R)-[3-[l-(4-Amino-branched-hexahydroindole-dead-1-mono)-3-trimethylmethylindole-5,6-dihydro-8H- Dimethyl hydrazide [1,5-a] ° 哄-7-yl]-3~oxo_ι_ (2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 〇〇-7-[3-Tertioxybutyryl-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5, 6, 7, 8- Hydrogen iodide [1,5-a> than pi well-i_carboxylic acid 2a (150 mg, 0.25 mmol), 4-carbamoyl hexahydropyridyl (7 〇 mg, 0. 54 mmol) and bis (2) - oxo-3"-oxazolidinyl)phosphinium chloride (〇. 138g, 0. 54mmol) was dissolved in 8 mL of dichloromethane with stirring, and triethylamine hydrazine (0.25 mL, 1.62 mmol) was added. Further, 4 inL of N,N-dimethylacetamide 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. The reaction mixture was concentrated under reduced pressure. Product 00-[3-[1-(4-Aminomethylindenyl-hexahydroacridinylcarbonyl)_3-trifluoromethyl-5,6-dihydro-8H-mithio[1,5-a] .哄_7_基]_3_oxo-1-(2,4,5-difluoro-benzyl)-propyl]monocarbamic acid terpene vinegar 7a (180 mg, white solid), yield: 98%. MS m/z (ESI): 660.9 (M+1). Second step 94579 48 201026314 (R)-l-{7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroindolizine [1,5-a] ° 哄_1_ _}}-hexahydropyridyl-4-carboxamide hydrochloride (R)-[3-[l- (4-Aminoformamidine-hexahydro-n-but-1-butyryl)-3_tri-chaotic methyl-5,6-dihydro-8H-m-oxime and [1,5-a]n 哄-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 7a (〇.18 g, 0.27 mmol) and 2 mL of acetic acid The ethyl ester was added to the reaction flask, and 6 mL of a 2.3 N solution of hydrogenated hydrogen in ethyl acetate was added, and the reaction was carried out at room temperature for 3. 5 hours after the small layer chromatography to trace the reaction until the starting material disappeared, and the reaction liquid was concentrated under reduced pressure. , the title product (R)-l-{7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluorodecyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyridinium-1 -carbonyl}-hexahydropyridine-4-carboxamide hydrochloride 7 (0.12 g, white solid), yield: 74%. MS m/z (ESI): 561.2. 'HNMRCdOOMHz, CDsOD): ^ 7. 42-7. 31 (m, 1H), 7. 28-7. 16(m, ❹ 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 〇6(m, 2H), 3. 03-2. 72(m, 4H), 2. 65-2. 53(m, 1H), 2. 15-2. 〇3(ms 2H), 1.93- 1.83 (m, 2H), 1.77-1.6 〇 (m, 2H). Example 8 (R)-7-[3-Amino-4-(2' 4, 5-trifluorophenyl)-butanyl]_3 _Trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyrylene)carbamidine hydrochloride 94579 49 201026314

❹（RH3-(卜甲基胺基甲醯基-3-三氟甲基-5, 6-二氫-8H-«米〇坐並[1，51]吡啡-7-基）-3-氧代-1-(2,4,5-三氟-苄基）_ 丙基]-胺基甲酸第三丁酯將（R)-7-[3-第三丁氧羰基-4-(2,4,5-三氟苯基）—丁酿基]3-二亂甲基_5,6,7,8-四氫味唾並[1，5-a]n比π井-i_ 叛酸 2a(150mg，〇.27mmol)、甲胺鹽酸鹽（36.5mg，0.54mmol) 和雙（2-氧代-3-噁唑烷基）次膦醯氯（〇. 138g，0. 54mmol) ❹擾拌下溶解於8mL二氯甲烷中’加入三乙胺（〇.25mL， 1. 62mmol)，室溫下反應過夜’薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)- [3-(1-甲基胺基甲醯基一3_三氟甲基 -5, 6-二氫-8H-咪唑並[1，5~a]吡畊-7-基）-3-氧代-1-(2, 4, 5-二氟-苄基）-丙基]-胺基甲酸第三丁酯8a(15〇mg，白色固體)，收率：98. 6%。 MS m/z (ESI) : 563.9(M+1)。第二步 94579 50 201026314 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三敦甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-(N-曱基）甲醯胺鹽酸鹽將（1〇-[3-(1-甲基胺基甲醯基-3-三氟甲基-5,6-二氫 -8H-咪唑並[1，5-a>比畊-7-基）-3-氧代-1-(2, 4, 5-三氟-苄基）-丙基]-胺基曱酸第三丁醋8a (0. 15g, 0.27mmol)及 2mL乙酸乙酯加入反應瓶中，加入5mL之2. 3N的氯化氫的乙酸乙酯溶液’室溫下反應4小時後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物（r)-7-[3- 胺基-4-(2, 4, 5-三氟苯基）-丁醢基]-3-三氟甲基-5, 6, 7, 8-四氫咪嗤並[1，5-a]σ比哄-1-(N-甲基）甲醯胺鹽酸鹽 8(0. 135g，白色固體），收率：90%。 MS m/z (ESI) : 464. 2(M+1)。 HNMR(400MHz, CDsOD) : ^ 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(in，2H)，2. 99-2. 76(in 5H)。實施例9 00-7-[3-胺基-4-(2,4,5-三氟苯基）_丁醯基]_3_三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡□井— Ν_二甲基）甲醯胺鹽酸鹽❹(RH3-(Methylaminomethylmercapto-3-trifluoromethyl-5,6-dihydro-8H-« milano[1,51]pyridin-7-yl)-3-oxo 1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester (R)-7-[3-tert-butoxycarbonyl-4-(2,4 , 5-trifluorophenyl)-butyl-branched]3-dihydromethyl_5,6,7,8-tetrahydro-salt [1,5-a]n ratio π well-i_ tacrotic acid 2a ( 150 mg, 〇.27 mmol), methylamine hydrochloride (36.5 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (〇. 138 g, 0. 54 mmol) Dissolved in 8 mL of dichloromethane, 'Add triethylamine (〇.25 mL, 1.62 mmol), and react 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-methylaminocarbazinyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5 ~a]pyridin-7-yl)-3-oxo-1-(2,4,5-difluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 8a (15 mg, white Solid), Yield: 98.6% MS m/z (ESI): 563.9 (M + 1). Step 2, s, s, s, s, s, s, s, s, s , 5-three Phenyl)-butanyl]-3-tridylmethyl-5,6,7-tetrahydroimidazo[1,5-a]pyroxy-1-(N-indenyl)carhamamine hydrochloride Will (1〇-[3-(1-methylaminocarbamimido-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a> than tillage-7-yl) )-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-amino phthalic acid terpene vinegar 8a (0.15 g, 0.27 mmol) and 2 mL of ethyl acetate 5 mL of 2. 3N hydrogen chloride in ethyl acetate solution was added to react at room temperature for 4 hours, and 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-tetrahydroimiphtho[1,5- a] σ 哄-1-(N-methyl)formamidine hydrochloride 8 (0.15 g, white solid), yield: 90%. MS m/z (ESI): 464. 2 (M+ 1) HNMR (400MHz, CDsOD): ^ 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 (in, 2H), 2.99-2. 76 (in 5H). Example 9 00-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]_3_trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[ 1,5-a]pyrazine well - Ν_dimethyl)carbamamine hydrochloride

94579 51 20102631494579 51 201026314

第一步 (R)-[3-(1-二曱基胺基曱醯基-3-三氟甲基-5, 6-二氫-8H〜咪唑並[1，5-a]吼畊-7-基）_3-氧代-1-(2,4, 5-三氟-苄基）-丙基]-胺基曱酸第三丁酯 ® 將（R)-7-[3-第三丁氧羰基-4-(2, 4, 5-三氟笨基)-丁醢基]-3-三氟曱基-5, 6, 7, 8-四氫ϋ米唾並[1，5-a]0比哄-1-竣酸 2a(150mg，0.27mmol)、二甲胺鹽酸鹽（44mg，0.54mmol) 和雙（2-氧代-3-噁唑烷基）次膦醯氯（0· 138g, 0. 54mmol) 攪拌下溶解於8mL二氯曱院中，加入三乙胺（〇.25mL， 1. 62min〇l)，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物， ❹得到標題產物（R)-[3-(l-二甲基胺基甲醯基一3_三氟甲基 -5’ 6-二氫-8H-咪唑並[1，5-a]吡 D井-7-基）-3-氧代-ΙΟ, 4, 5-二氟-苄基）-丙基]-胺基甲酸第三丁酯 9a(i2〇mg，白色固體），收率：77%。 MS m/z (ESI) : 578.1(M+1)。第二步 ⑻7 [3胺基-4-(2’4,5-二氟笨基）_丁醯基]_3_三氣甲醯胺鹽酸鹽 94579 52 201026314First step (R)-[3-(1-didecylaminodecyl-3-trifluoromethyl-5,6-dihydro-8H~imidazo[1,5-a] 7-yl)_3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-amino decanoic acid tert-butyl ester® (R)-7-[3-third Butoxycarbonyl-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroindenyl saliva [1,5-a] 0 to 哄-1-decanoic acid 2a (150 mg, 0.27 mmol), dimethylamine hydrochloride (44 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0· 138g, 0. 54mmol) was dissolved in 8mL of dichlorohydrazine, stirred with triethylamine (〇.25mL, 1. 62min〇l), reacted at room temperature overnight, traced by thin layer chromatography until the raw material disappeared, minus The reaction mixture was concentrated, and the residue obtained was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -dihydro-8H-imidazo[1,5-a]pyridyl D-7-yl)-3-oxo-indole, 4,5-difluoro-benzyl)-propyl]-carbamic acid Tributyl ester 9a (i2 〇 mg, white solid), yield: 77%. MS m/z (ESI): 578.1 (M+1). The second step (8) 7 [3Amino-4-(2'4,5-difluorophenyl)-butanyl]_3_trioxalamine hydrochloride 94579 52 201026314

將（R)-[3-(l-二甲基胺基甲醯-3-三氟甲基-5, 6-二氫 -8H-味哇並[1，5-a]n比哄-7-基）_3-氧代-1-(2, 4, 5-三氟-苄基）-丙基]-胺基甲酸第三丁酯9a(0.138g，0. 245mmol) 及2mL乙酸乙酯加入反應瓶中，加入4mL之2. 3N的氯化氫的乙酸乙酯溶液，室溫下反應3小時後’薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物（R)_7_[3_ 胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]n比哄-1-(N，N-二曱基）曱醯胺鹽酸鹽9(0. 12g，白色固體），收率：98%。 MS m/z (ESI) : 478. 2(M+1)。實施例10 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]三氟曱基-5, 6’ 7, 8-四氫咪唑並[1，5-a]吡畊-1-羧酸鹽酸鹽 F 孤(R)-[3-(l-Dimethylaminocarbazol-3-trifluoromethyl-5,6-dihydro-8H-flavored [1,5-a]n is compared to 哄-7 -yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 9a (0.138 g, 245 mmol) and 2 mL of ethyl acetate In 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) _7_[ 3_Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]n ratio Indole-1-(N,N-diindenyl)guanamine 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]trifluoromethyl-5,6' 7, 8-tetrahydroimidazo[ 1,5-a] pyridin-1-carboxylic acid hydrochloride F

GG

第一步 (R)-7-[3-胺基-4-(2,4,5-三氟苯基）_丁醯基]—3_三氟甲基-5,6,7,8-四氫咪唑並[1，51]吡畊_1__羧酸鹽酸鹽將⑻-H3-第三丁氧羰基_4一(2, 4,卜三氟苯基)〜丁 94579 53 201026314 酿基]-3-三氟甲基-5, 6, 7, 8-四氫0米0坐並[1, 比_~·ΐ- 緩酸2a(218mg, 0.4mmol)加入反應瓶中，加入5mL氯化氯乙醇溶液，室溫下反應，薄層層析追縱反應至原料消失，減壓濃縮反應液，得到標題產物（R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁酿基]-3-三氟甲基-5, 6, 7, 8-四氫咪唾並 [1，5-a]吡哄-1-羧酸鹽酸鹽10(60mg,白色固體），收率： 30.8%。 MS m/z (ESI) : 451.2(M+1)。 IHNMR(400MHz, CDaOD): 5 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(ra, 2H), 3. 941-3. 925(m, 2H), 3.212-2. 883(m, 2H)，2.861-2.805(m，2H)。實施例11 (R)-3-胺基-l-[l-(3-胺基二六氫n比咬-i-幾基）一3-三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡哄-7-基]-4-(2, 4, 5-三 © 氟苯基）-丁-1-酮二鹽酸鹽First step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7,8-tetrahydro Imidazo[1,51]pyrazine_1__carboxylic acid hydrochloride salt (8)-H3-tert-butoxycarbonyl_4-(2,4,difluorophenyl)~butyl 94579 53 201026314 3-trifluoromethyl-5, 6, 7, 8-tetrahydro 0 m0 sits and [1, _~·ΐ- tempering acid 2a (218 mg, 0.4 mmol) is added to the reaction flask, and 5 mL of chlorinated chlorine is added. The ethanol solution is reacted at room temperature, and the reaction is traced by thin layer chromatography until the starting material disappears. The reaction mixture is concentrated under reduced pressure to give the title product (R)-7-[3-amino-4-(2, 4, 5- Fluorophenyl)-butyl-branched]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimido[1,5-a]pyridin-1-carboxylic acid hydrochloride 10 (60 mg , white solid), yield: 30.8%. MS m/z (ESI): 451.2 (M+1). IHNMR (400 MHz, CDaOD): 5 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 (ra, 2H), 3. 941-3. 925 (m, 2H), 3.212-2. 883 (m, 2H), 2.861-2.805 (m, 2H). Example 11 (R)-3-Amino-l-[l-(3-aminodihexahydron-by-biti-i-yl)-3-trifluoromethyl-5,6-dihydro-8H -Imidazo[1,5-a]pyridin-7-yl]-4-(2,4,5-tri-fluorophenyl)-butan-1-one dihydrochloride

第一步 54 94579 201026314 六氫吡啶-3-基-胺基曱酸第三丁酯將（R)-3-胺基六氫11比咬鹽酸鹽lla(3g，22.1mmol)和破酸鉀（6. lg，44· 2mmol)擾拌下溶解於60mL甲醇中，授掉 30分鐘後’加入二碳酸二（第三丁酯）（4. 8g，22. linmol)，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物六氫吡啶-3-基-胺基曱酸第三丁酯llb(l· 3g，油狀液體），收率：29%。 ® MS m/z (ESI) : 201.0(M+1)。第二步 (1〇-(1-{7-[3-第三丁氧幾基胺基_4-(2,4,5-三氟苯基）_ 丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫味0坐並[1，5-a]n比卩井 -卜羰基}-六氳吡啶-3-基）-胺基甲酸第三丁酯將（R)-7-[3-第三丁氧羰基-4-(2, 4, 5-三氟苯基）_丁 . 酿基]_3-二氟曱基-5, 6, 7, 8-四氫味0坐並[1，5~a]n比π井-1 — q叛酸2a(0.12g，0.218mmol)、六氫σ比咬-3-基-胺基甲酸第三丁酯 llb(0. 173g，0. 545mmol)和三乙胺（0. 275g， 2. 18丽〇1)攪拌下溶解於12mL二氯甲烷中，室溫下加入雙 (2-氧代-3-噁唑烷基）次膦醯氯（0. 138g，〇. 545mmol)，反應過夜’減壓濃縮反應液，用砍膠管柱層析法純化所得殘餘物，得到標題產物（R)-(l-{7-[3_第三丁氧羰基胺基 -4-（2, 4, 5-三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四風味嗤並[1，5-a]β比哄-1-幾基}-六氫吼°定-3-基）~胺基甲酸第三丁酯llc(〇· lg，油狀液體），收率·· 63%。 55 94579 201026314 MS m/z (ESI) : 733.1(M+1)。第三步 00-3-胺基-l-[ 1-(3-胺基-六氫吡啶-l-羰基）-3-三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡D井-7-基]-4-(2, 4, 5-三氟苯基）-丁-1-酮鹽二酸鹽將（R)-(l-{7-[3-第三丁氧緩基胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氣曱基-5, 6, 7, 8-四氫咪0坐並[1，5-a] 0比哄-1-羰基}-六氫吡啶-3-基）-胺基曱酸第三丁酯11c (〇. lg，0· 163nmol)加入10mL之2. 3N的氯化氫的乙酸乙酯溶液中，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物（r)-3-胺基-l-[ 1-(3-胺基 -六氫吡啶-1-羰基）-3-三氟甲基-5, 6-二氫-8H-咪唑並 [1，5-a]吡畊-7-基]-4-(2, 4, 5-三氟苯基）-丁-1-酮二鹽酸鹽11(0· 09g，白色固體)，收率：98%。 MS m/z (ESI) : 533.3(M+1)。 Q iHNMR(400MHz, CDsOD)： d 7.415-7.396(m, 1H), 7.26-^.2154(10, 1H), 5. 131-4. 085 Cm, 11H), 3. 994-2. 837 (m, 8H)，2.11-1.846(m，5H)。實施例12 00-3-胺基-l-[l-(吡咯烷羰基）一3_三氟甲基一5, 6_二氫-8H-咪唑並[1，5-a]吼啡基]_4_(2,4,5-三氟苯基）一丁-1-酿I鹽酸鹽 56 94579 201026314First step 54 94579 201026314 Hexahydropyridin-3-yl-amino decanoic acid tert-butyl ester (R)-3-Amino hexahydro 11-bitate hydrochloride lla (3 g, 22.1 mmol) and potassium bromate (6. lg, 44·2 mmol) was dissolved in 60 mL of methanol under stirring, and after 30 minutes of incorporation, 'dibutyl dicarbonate (4.8 g, 22. linmol) was added and allowed to react at room temperature overnight. The reaction was traced to the disappearance of the material by the thin layer chromatography, and the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give the title product, hexahydropyridin-3-yl-amino phthalic acid tert-butyl ester llb (l · 3g, oily liquid), yield: 29%. ® MS m/z (ESI): 201.0 (M+1). The second step (1〇-(1-{7-[3-t-butoxyaminoamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl- 5, 6, 7, 8-tetrahydrogen 0 sitting and [1,5-a]n than 卩 well-bucarbonyl}-hexapyridin-3-yl)-carbamic acid tert-butyl ester (R) -7-[3-Tertiyloxycarbonyl-4-(2,4,5-trifluorophenyl)-butyl. Styrene]_3-difluoroindolyl-5, 6, 7, 8-tetrahydrogen 0 sit and [1,5~a]n than π well-1 - q rebel 2a (0.12g, 0.218mmol), hexahydro σ ratio -3-yl-aminocarbamic acid tert-butyl ester llb (0. 173 g, 0. 545 mmol) and triethylamine (0. 275 g, 2. 18 〇1) were dissolved in 12 mL of dichloromethane with stirring, and bis(2-oxo-3-oxazolidinyl) was added at room temperature. The phosphinium chloride (0. 138 g, 545. 545 mmol) was reacted overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified to the titled product (R)-(l-{7-[3 _Tertidinoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroanzepine [1,5 -a]β is more than 哄-1-decyl}-hexahydroindole decyl-3-yl)~tributic acid tert-butyl ester llc (〇· lg, oily liquid), yield ·· 63%. 55 94579 201026314 MS m/ z (ESI): 733.1 (M+1). Step 3 00-3-Amino-l-[ 1-(3-amino-hexahydropyridine-l-carbonyl)-3-trifluoromethyl-5 , 6-Dihydro-8H-imidazo[1,5-a]pyridinyl D-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one salt (R)-(l-{7-[3-Tertioxybutyrylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trimethyl fluorenyl-5, 6, 7, 8-tetrahydromethane 0 and [1,5-a] 0 to 哄-1-carbonyl}-hexahydropyridin-3-yl)-amino decanoic acid tert-butyl ester 11c (〇. lg </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -amino-l-[ 1-(3-amino-hexahydropyridine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin Plough-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). Q iHNMR (400 MHz, CDs OD): d 7.415-7.396 (m, 1H), 7.26-^.2154 (10, 1H), 5. 131-4. 085 Cm, 11H), 3. 994-2. 837 (m, 8H), 2.11-1.846 (m, 5H). Example 12 00-3-Amino-l-[l-(pyrrolidinylcarbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]nonanoyl] _4_(2,4,5-trifluorophenyl)-but-1-ol I hydrochloride 56 94579 201026314

第一步 ❹（ί〇-[3-氧代-3-Π-(吡咯烷一卜羰基）_3_三氟甲基_5, 6_二氫-8H-咪唑並[1，5-a]吼畊-7-基]-1-(2, 4, 5-三氟-苄基）- 丙基]-胺基甲酸第三丁酯將（R)-7-[3-第三丁氧羰基_4—(2, 4, 5_三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1- 羧酸 2a(150mg，0. 27mmol)、吡咯烷（38. 4mg，0.54mmol) 和雙（2-氧代-3-噁唑烷基）次膦醯氯（〇. 138g，〇. 54随〇1) ❹攪拌下溶解於gmL二氯曱烷中，加入三乙胺（〇. 25mL， 1· 62mni〇l)，室温下反應過夜，薄層層析追蹤反應至原料消失’減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，知"到標題產物（R)-[3-氧代-3-[ 1-〇比嘻烧_ι_幾基）三氟甲基-5, 6~二氫-8Η-_ο坐並[1，5-a]%n井-7-基]-1-(2, 4 5-二氟-苄基）_丙基]-胺基甲酸第三丁酯12a(12〇mg，白色固體）’收率：74%。第二步 (R) 3-胺基一（吡π各烧一1一羰基）_3_三氟曱基一5, 6一二 94579 57 201026314 氫-811-咪唑並[1，51>比啡-7-基]-4-(2,4,5-三氟苯基）-丁-1-酮鹽酸鹽將（R)-[3-氧代-3-[1-(π比p各烧-1-魏基）-3-三氟曱基 -5, 6-二氫-8H-咪唑並[1，5-a]吡啡-7-基]-1-(2, 4, 5-三氟 -苄基）-丙基]-胺基甲酸第三丁酯12a(0.12g，0.199mmol) 及2mL乙酸乙酯加入反應瓶中，加入4mL之2. 3N的氯化氫的乙酸乙醋；谷液’室溫下反應3小時後，薄層層析追縱反應至原料消失，減壓濃縮反應液，得到標題產物（r)_3-胺 ❹基-1-[1-(吡咯烷-1-羰基）-3-三氤甲基-5, 6-二氳-8H-咪唑並[1，5-a]吡畊-7-基]-4-(2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽12(0. 10g，白色固體），收率：94%。 MS m/z (ESI) : 504·2(Μ+1)。實施例13 00-3-胺基-1-[1-六氫《比畊-1 —羰基;)_3一三氟曱基_5, 6_二氫-8Η-咪嗤並[1，5-a]%b卩井-7-基]-4-(2, 4, 5-三氟苯基）- ❹ 丁-~1_-嗣二鹽酸鹽_First step 〇(ί〇-[3-oxo-3-indole-(pyrrolidin- carbonyl)_3_trifluoromethyl_5,6-dihydro-8H-imidazo[1,5-a] (R)-7-[3-Tertioxycarbonyl, tert-butyl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid _4-(2, 4, 5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyrazole-1- Carboxylic acid 2a (150 mg, 0.25 mmol), pyrrolidine (38.4 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride (〇. 138 g, 〇. 1) Dissolve in gmL of dichloromethane with stirring, add triethylamine (〇.25mL, 1.62mni〇l), react overnight at room temperature, trace the reaction by thin layer chromatography until the starting material disappears. , the residue obtained by purifying the column chromatography, knowing " to the title product (R)-[3-oxo-3-[1-pyridylpyrazine_ι_yl)trifluoromethyl-5 , 6~Dihydro-8Η-_ο sit and [1,5-a]%n well-7-yl]-1-(2, 4 5-difluoro-benzyl)-propyl]-carbamic acid Tributyl ester 12a (12 mg, white solid) 'yield: 74%. The second step (R) 3-aminol-(pyridylpyran-one-monocarbonyl)_3_trifluoromethyl- 5,6-two 94,579, 57, 2010,263,14, hydrogen-811-imidazo[1,51> 7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride (R)-[3-oxo-3-[1-(π ratio p each burned) -1-Weiyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin-7-yl]-1-(2, 4, 5-tri Fluoro-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, and 4 mL of 2. 3N hydrogen chloride in ethyl acetate; 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-aminomercapto-1-[1-(pyrrolidin-1-carbonyl) )-3-trimethyl-5,6-dioxa-8H-imidazo[1,5-a]pyrrol-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 (Μ +1). Example 13 00-3-Amino-1-[1-hexahydro"Biplough-1 -carbonyl;)_3-trifluorodecyl_5,6-dihydro-8Η-imiphthene[1,5- a]%b卩井-7-yl]-4-(2,4,5-trifluorophenyl)-indole-~1_-indole dihydrochloride _

(R)-4-{7-[3-第三τ氧縣絲_4_(2,4,5_三氟苯基）_ 丁 94579 58 201026314 酿基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡哄-1-羰基}-六氫吡哄-1-羧酸第三丁酯將00-7-[3-第三丁氧羰基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-羧酸2a(150mg，〇.27mmol)、六氫吼哄-1-緩酸第三丁酯 (100. 6mg，0· 54mmol)、雙（2-氧代-3-噁唑烷基）次膦醯氣 (〇.138g，0.54mmol)和三乙胺（〇.25mL，1.62mmol)攪拌下 •溶解於6mL二氯曱烷中’室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（r)_4-{7-[3-第三丁氧羰基胺基-4-(2, 4, 5-三氟苯基）-丁醯基]_3_三氟甲基-5, 6, 7, 8-四氫味吐並[1，5-a]吡畊-1-羰基卜六氫吡畊-丨-羧酸第三丁酯13a (200mg，白色固體），收率：99%。 MS m/z(ESI) : 719.0(M+1)。第二步 ❿00-3-胺基-l-[l-呱哄》^一羰基）_3_三氟甲基_5,6一二氫 -8H-味峻並[1，5-a]吡啡-7-基]-4-(2,4, 5-三氟苯基）-丁 -1-酮二鹽酸鹽將（R)-4-{7-[3-第三丁氧羰基胺基_4_(2,4, 5-三氟苯基）-丁醯基]-3-三氟曱基—5, 6, 7, 8_四氫咪唑並[丨，5_a]吡哄-1-幾基}-六氫呢啡-卜羧酸第三丁酯13a(0.12g， 0· 199mmol)加入反應瓶中，加入5mL之2. 3N的氯化氫的甲醇溶液，室溫下反應過夜，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)_3_胺基—^卜 59 94579 201026314 六氫吡D井_1-羰基）-3-三氟曱基_5, 6-二氫-8H-咪唑並 [1，5-a]n比畊-7-基]-4-(2, 4, 5-三氟苯基）_丁_1_酮二鹽酸鹽13(0. l〇g，白色固體），收率：94%。 MS m/z (ESI) : 504.2(M+1)。 !ΗΝΜΚ(400ΜΗζ, CDsOD): 5 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)。實施例14 (R)-3-胺基-l-[l-((R)-3-羥基-吡咯烷-卜羰基）_3_三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-4-(2, 4, 5- 三氟苯基）-丁 -1 -酮鹽酸鹽(R)-4-{7-[3-third τ oxygen county silk_4_(2,4,5-trifluorophenyl)_ butyl 94579 58 201026314 aryl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyridin-1-carbonyl}-hexahydropyridinium-1-carboxylic acid tert-butyl ester 00-7-[3-third butoxide Carbonyl-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyrazine-1 -carboxylic acid 2a (150 mg, 〇. 27 mmol), hexahydroindole-1-teletonic acid tert-butyl ester (100. 6 mg, 0. 54 mmol), bis(2-oxo-3-oxazolidinyl) Phosphonium helium (〇.138g, 0.54mmol) and triethylamine (〇25mL, 1.62mmol) were stirred and dissolved in 6mL of dichloromethane at room temperature for overnight reaction. The reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was concentrated under reduced pressure, and then purified, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Trifluorophenyl)-butenyl]_3_trifluoromethyl-5, 6, 7, 8-tetrahydro-sodium spit[1,5-a]pyrrol-1-carbonyldihexahydropyrazine-indole-carboxylate Tributyl acrylate 13a (200 mg, white solid), yield: 99%. MS m/z (ESI): 71:21. The second step is ❿00-3-aminol-l-[l-呱哄"^-carbonyl)_3_trifluoromethyl_5,6-dihydro-8H-weijun[1,5-a]pyridin -7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one dihydrochloride salt (R)-4-{7-[3-tert-butoxycarbonylamino group _4_(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl- 5, 6, 7, 8-tetrahydroimidazo[丨,5_a]pyridin-1-yl} - hexahydromorphine-polycarboxylic acid tert-butyl ester 13a (0.12 g, 0 · 199 mmol) was added to the reaction flask, and 5 mL of a 2.3 N solution of hydrogen chloride in methanol was added, and the reaction was allowed to stand overnight at room temperature, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title product (R) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ - dihydro-8H-imidazo[1,5-a]n than arbut-7-yl]-4-(2,4,5-trifluorophenyl)-but-1-one dihydrochloride 13 ( 0. l〇g, white solid), yield: 94%. MS m/z (ESI): 504.2 (M+1). !ΗΝΜΚ(400ΜΗζ, CDsOD): 5 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-l-[l-((R)-3-hydroxy-pyrrolidine-pocarbonyl)_3_trifluoromethyl-5,6-dihydro-8H-imidazole [1,5-a]pyrrol-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-3-氧代-1 -(2, 4, 5-二氟苄基）-丙基]—胺基曱酸第三丁酯將（R)-7-[3-第三丁氧羰基-4-(2, 4, 5-三氟苯基）-丁 60 94579 201026314 酿基]-3-三氣甲基-5,6,7,8-四氫味唾並[1，5-3]*1比〇井-1-甲酸 2a(150mg，0.27mmol)、（R)-3-羥基 η 比洛烧（47mg，〇.54mmol)、雙（2-氧代-3-噁唑烷基）次膦醯氣（〇. i38g，-5,6-Dihydro-8H-imidazo[1,5-a]pyrrol-7-yl]-3-oxo-1 -(2,4,5-difluorobenzyl)-propyl] - Acryl phthalic acid tert-butyl ester (R)-7-[3-t-butoxycarbonyl-4-(2,4,5-trifluorophenyl)-butyl 60 94579 201026314 Tris-methyl-methyl-5,6,7,8-tetrahydro-sodium [1,5-3]*1 is better than Sakai-1-carboxylic acid 2a (150 mg, 0.27 mmol), (R)-3-hydroxyl Biluo (47mg, 〇.54mmol), bis(2-oxo-3-oxazolidinyl)phosphinium oxime (〇. i38g,

〇· 54mmol)和三乙胺（0. 25mL，1. 62mmol)攪拌下溶解於6mL 一氣甲烧中’室溫下反應過夜’薄層層析追蹤反應至原料消失’減壓濃縮反應液，用梦耀·管柱層析法純化所得殘餘物’得到標題產物（R)-[3-[l-((R)-3-經基比洛烧_ι_幾基）-3-三氟甲基-5, 6-二氫-8Η-咪唑並[1，5-a]吡哄-7-❹基]氧代-1-(2, 4, 5-三氟节基）-丙基]—胺基甲酸第三丁酯14a(90mg，白色固體），收率：53%。 MS m/z (ESI) : 620. 0(M+1)。第二步 (R)-3-胺基-l-[ l-((R)-3-經基-a比洛燒_ι_幾基）三氟甲基-5’ 6-二氫-8H-咪唑並[1，5-a>比畊-7-基]-4-(2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽 ❹ 將（R)_[3-[卜（00-3-羥基-吡咯烷羰基）_3_三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊_7_基]一3_氧代 -1-(2’ 4’ 5-二氟苄基）-丙基]-胺基甲酸第三丁酯14a(9〇呢， 0. 15丽〇1)加入l〇mL 2. 3N的氯化氫的乙酸乙酯溶液，室溫下反應過夜’薄層層析追縱反應至原料消失，減屢濃縮反應液，用石夕膠管柱層析法純化所得殘餘物，得到標題產物 (R)_3-胺基一 ⑻一 3一羥基_吡咯烷一卜羰基)_3_三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡哄基]_4_(2, 4, 5_ 三氟苯基）-丁-1-酮鹽酸鹽14(6〇mg，白色固體），收率： 94579 61 201026314 72%。 MS m/z (ESI) : 520·3(M+1)。 1HNMR(400MHz, CDaOD): 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)。實施例15 0〇-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟曱基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-(N-環丙基）曱醯胺鹽酸鹽〇·54mmol) and triethylamine (0.25 mL, 1.62mmol) were dissolved in 6mL of a gas-fired agitation under stirring at room temperature overnight. The reaction was traced by thin layer chromatography until the starting material disappeared. Purification of the obtained residue by syllabary column chromatography to give the title product (R)-[3-[l-((R)-3- carbazol. -5,6-dihydro-8Η-imidazo[1,5-a]pyridin-7-fluorenyl]oxo-1-(2,4,5-trifluoro)-propyl]- Tributyl carbamic acid 14a (90 mg, white solid), yield: 53%. MS m/z (ESI): 620. 0 (M+1). The second step (R)-3-aminol-l-[ l-((R)-3-carbyl-a piroxicam_ι_yl)trifluoromethyl-5' 6-dihydro-8H -Imidazo[1,5-a>pyrylene-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride ❹ (R)_[3- [Bu (00-3-hydroxy-pyrrolidinylcarbonyl)_3_trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine_7_yl]-3_oxo 1-(2' 4' 5-difluorobenzyl)-propyl]-carbamic acid tert-butyl ester 14a (9 〇, 0. 15 〇1) added l〇mL 2. 3N of hydrogen chloride The ethyl acetate solution was reacted at room temperature overnight. The reaction was followed by thin layer chromatography to remove the starting material. The reaction mixture was concentrated, and the residue was purified by column chromatography to give the title product (R)- 3-amine.一-(8)-3-hydroxy-pyrrolidine-p-carbonyl)_3_trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridinyl]_4_(2, 4, 5_ Trifluorophenyl)-butan-1-one hydrochloride 14 (6 mg, white solid), yield: 94579 61 201026314 72%. MS m/z (ESI): 520·3 (M+1). 1H NMR (400MHz, CDaOD): 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 0〇-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7-tetrahydroimidazole And [1,5-a]pyrrol-1-(N-cyclopropyl)decylamine hydrochloride

第一步 (R)-[3-[1-(環丙基胺基曱醯基）_3一三氟甲基_5, 6_二氳 ~811-咪唑並[1，5-&]吡哄-7-基]-3-氧代-1-(2,4,5-三氟- 节基）-丙基]-胺基曱酸第三丁酯將（R)-7-[3-第三丁氧羰基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟曱基-5, 6, 7, 8-四氫咪唑並[1，5_a]吡畊_i-綾酸 2a(〇.2g，0.36mmol)、環丙基胺（0.05g，〇 54細!〇1) 和雙（2-氧代-3-噁唑烷基）次膦醯氯（〇. 18g, 〇. 72mm〇1)攪 94579 62 201026314 拌下溶解於20mL二氯甲烧中，室溫下加入三乙胺（〇. ggg, 3. 6mmol) ’室溫下反應2小時’減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物(環丙基胺基曱酿基）-3-三氟曱基-5, 6-二氫-8H-咪唑並[1，5-a] 11比哄-7-基]-3-氧代-1-(2, 4’ 5-三氟-苄基）_丙基]_胺基曱酸第二丁醋15a(0. lg，油狀液體），收率：45%。第二步 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]一3一三氟甲基-5,6,7’8-四氫咪唑並[1，5-8]吡畊-1-(^[-環丙基）甲醯胺鹽酸鹽將（R)-[3-[l-(環丙基胺基甲醯基）_3一三氟甲基_5, 6— 二氫-8H-咪唑並[1，5-a]吡畊-7-基]-3-氧代-1-(2, 4, 5-三氟-苄基）-丙基]-胺基曱酸第三丁酯15a(〇. ig，016mm〇1；) 加入5mL 2. 2N的氯化氫的乙酸乙g旨溶液，室溫下反應過夜’薄層層析追蹤反應至原料消失，減壓濃縮反應液，得 ❹到標題產物（R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁職基]-3-三氟曱基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1~環丙基甲醯胺鹽酸鹽15(82mg，淡黃色固體），收率：95%。 MS m/z (ESI) : 490.2(M+1)。 !ΗΝΜΚ(400ΜΗζ, CDaOD)： ^ 7.423-7. 174(m, 2H), 5.284^ 4.872Cm, 2H), 4.716-2.019(m, 10H), 2. 〇19(s, 2H), 1.349-1. 191(m，2H), 0.907-0.596 (m, 2H)。實施例16 00-({7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醢基]-3-三氟 63 94579 201026314 氯味°坐並[1’5'a]°比哄+幾基卜胺基）一甲基-5，6，7，8-四乙酸甲酯鹽酸鹽First step (R)-[3-[1-(cyclopropylaminoindolyl)_3-trifluoromethyl_5,6-dioxan-811-imidazo[1,5-&]pyridin哄-7-yl]-3-oxo-1-(2,4,5-trifluoro-succinyl)-propyl]-amino decanoic acid tert-butyl ester (R)-7-[3- Third butoxycarbonyl-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7-tetrahydroimidazo[1,5_a]pyrazine _i-capric acid 2a (〇.2g, 0.36mmol), cyclopropylamine (0.05g, 〇54fine!〇1) and bis(2-oxo-3-oxazolidinyl)phosphinium chloride ( 〇. 18g, 〇. 72mm〇1) Stirring 94579 62 201026314 Mix and dissolve in 20mL of methylene chloride, add triethylamine (〇.ggg, 3. 6mmol) at room temperature and react at room temperature for 2 hours. The reaction mixture was concentrated, and the residue obtained was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1,5-a] 11 than 哄-7-yl]-3-oxo-1-(2,4' 5-trifluoro-benzyl)-propyl]-amino decanoic acid second vinegar 15a ( 0. lg, oily liquid), yield: 45%. The second step (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,7'8-tetrahydro Imidazo[1,5-8]pyrazine-1-(^[-cyclopropyl)carbamamine hydrochloride (R)-[3-[l-(cyclopropylaminocarbamimidyl)_3 Trifluoromethyl_5,6-dihydro-8H-imidazo[1,5-a]pyrrol-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl ))-propyl]-amino decanoic acid tert-butyl ester 15a (〇. ig, 016 mm 〇 1;) Add 5 mL of 2. 2N hydrogen chloride in ethyl acetate solution, react at room temperature overnight 'thin layer chromatography The reaction was traced 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)-butylidene]-3 -Trifluoromethyl-5,6,7-tetrahydroimidazo[1,5-a]pyrazine-1~cyclopropylcarboxamide hydrochloride 15 (82 mg, pale yellow solid), yield : 95%. MS m/z (ESI): 490.2 (M+1). !ΗΝΜΚ(400ΜΗζ, CDaOD): ^ 7.423-7. 174(m, 2H), 5.284^ 4.872Cm, 2H), 4.716-2.019(m, 10H), 2. 〇19(s, 2H), 1.349-1 191 (m, 2H), 0.907-0.596 (m, 2H). Example 16 00-({7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoro 63 94579 201026314 Chlorinated ° Sitting and [1'5' a]° 哄+ 几卜胺 )) monomethyl-5,6,7,8-tetraacetic acid methyl ester hydrochloride

F 1β 一步將（R)-7-[3-第三丁氧羰基-4-(2, 4, 5-三氟苯基）一丁醯基]-3-三氟曱基-5, 6, 7, 8-四氫咪唑並[i，5_a]吡哄一卜竣酸2a(150mg，0· 27丽〇1)和胺基-乙酸曱醋鹽酸睡 (512mg，0.408mmol)攪拌下溶解於8mL二氣曱烷中，加入三乙胺（0.25mL，1.62mmol)，攪拌5分鐘後，加入雙（2_ 氧代_3_11惡β圭烧基）次鱗酿乳（0. 138g, 0. 54ππηο1)，室溫下反應20小時，薄層層析追蹤反應至原料消失，減壓濃縮反應液’用矽膠管柱層析法純化所得殘餘物’得到標題產物 (设）-({7-[3-第三丁氧羰基胺基-4-(2,4,5-三氟笨基）一丁酿基]-3-三氟曱基-5, 6, 7, 8-四氫口米《坐並[1，5-&]°比啡-1_ 幾基丨-胺基）-乙酸曱醋16a(90mg，淡黃色油狀物），收率： 53. 6% ° 第二步將（RM{7-[3-第三丁氧羰基胺基-4-(2, 4, 5-三氟^苯 64 94579 201026314 基）-丁醢基]-3-三氟甲基_5, 6, 7, 8-四氫σ米β坐並[1，5-a]〇比口井-1_幾基}-胺基）-乙酸甲醋16a(0.09g，〇.l45mmol)及 2mL乙酸乙酯加入反應瓶中，加入4mL 2· 3N的氯化氫的乙酸乙酯溶液，室溫下反應3小時後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物（r)-G7-[3 -胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟甲基一5, 6， 7, 8-四氳咪唑並[1，5-a]吡啡-1-羰基卜胺基乙酸甲酯鹽酸鹽16(80mg,白色固體），收率：99%。 ® MS m/z(ESI) : 522. 2(M+1)。 HNMR(400MHz，CDsOD): 5 7.47-7. 30(m，1H)，7. 30-7. 14(m，F 1β a step of (R)-7-[3-t-butoxycarbonyl-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[i,5_a]pyridinium dibenzoic acid 2a (150 mg, 0·27 〇1) and amine-acetic acid vinegar hydrochloric acid (512 mg, 0.408 mmol) dissolved in 8 mL of two gas under stirring To the decane, triethylamine (0.25 mL, 1.62 mmol) was added, and after stirring for 5 minutes, a bis (2 oxo_3_11 oxa ketone) sub-scale milk (0. 138 g, 0.54 ππηο1) was added. The reaction was carried out for 20 hours under temperature, and the reaction was traced by thin layer chromatography until the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure to purify the residue obtained by the column chromatography to obtain the title product (set)-({7-[3-third Butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydromethane "Sit and [1 ,5-&]°-p-mental-1_ benzyl-amino-acetic acid vinegar 16a (90 mg, light yellow oil), yield: 53. 6% ° The second step will be (RM{7- [3-Tertiary oxycarbonylamino-4-(2,4,5-trifluorobenzophenone 64 94579 201026314 yl)-butanyl]-3-trifluoromethyl_5, 6, 7, 8-tetrahydrogen σ米β sits and [1,5-a]〇 is compared to the well-1_几基}- Amino)-acetic acid methyl vinegar 16a (0.09g, 〇.l45mmol) and 2mL of ethyl acetate were added to the reaction flask, 4mL of 2,3N hydrogen chloride in ethyl acetate solution was added, and the reaction was carried out for 3 hours at room temperature, thin layer The reaction was traced to the disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure to give the title product (r)-G7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoro Methyl-5,6,7,8-tetraimidazo[1,5-a]pyridin-1-carbonylamidoacetate methyl ester hydrochloride 16 (80 mg, white solid), yield: 99% . ® MS m/z (ESI): 522. 2 (M+1). HNMR (400MHz, CDsOD): 5 7.47-7. 30(m,1H), 7. 30-7. 14(m,

3H), 3. 20-2.76(m, 4H) 〇實施例173H), 3. 20-2.76(m, 4H) 实施 Example 17

氟苯基）-丁-1-酮鹽酸鹽Fluorophenyl)-butan-1-one hydrochloride

F F、义 HCIF F, Yi HCI

第一步 94579 65 201026314 (R)-[3-[l-(4-乙醯基-六氫吡啡_丨_羰基）_3_三氟曱基 -5, 6-二氫-8H-咪唑並[丨，5_a]吡畊_7_基]_3_氧代一卜 (2, 4, 5-二氟苄基）-丙基]一胺基曱酸第三丁醋將⑻-7-[3-第三丁氧縣_4_(2,4,5_三氟苯基）_丁醯基]-3-三氟曱基—5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-羧酸2a(150mg，〇.27mmol)、i —六氫吡畊—丨―基-乙酮鹽酸鹽（90mg, 0. 54mmol)和雙（2-氧代_3_噁唑烷基）次膦醯氯 (0. 138g，0· 54mmol)攪拌下溶解於8mL二氯曱烷中，加入二乙胺（0.25mL，1.62mmol)，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物乙醯基— 六氫吡啡-1-M基）-3-三氟曱基_5, 6_二氫_8H-咪唑並 [1，5-a；h比畊-7-基]-3-氧代-1-(2, 4, 5-三氟苄基）-丙基]-胺基甲酸第三丁酯17a(80mg,白色固·體），收率：45%。 MS m/z (ESI) : 660.9(M+1)。 ❹ 第二步 (R) 1 [1_(4_乙酿基-六氣α比u井—1_戴基）_3-三氣甲基-5，6~ 二氫-8Η-咪唑並[1，5-a]吡哄-7-基]-3-胺基-4-(2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽將（R)-[3-[l-(4-乙醯基-六氫吡畊-1-羰基）-3-三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a] °比啡-7-基]-3-氧代 -1-（2,4,5-三氟苄基)-丙基]-胺基曱酸第三丁酯17&(0.08§， 0. 12mmol)及2mL乙酸乙酯加入反應瓶中，加入2mL 2. 7N 的氯化氫的乙酸乙酯溶液，室溫下反應過夜，薄層層析追 66 94579 201026314 蹤反應至原料消失，減壓濃縮反應液，得到標題產物 (R)-l-[ 1-(4-乙醯基-六氫^^比畊羰基）_3_三氟甲基_5, 6_ 二氫-8H-咪唑並[l，5-a]吡明：_7_基]_3_胺基—4-(2,4,5-三氟苯基）-丁-1-酮鹽酸鹽1T(7〇mg，白色固體），收率：98%。 MS m/z (ESI) ： 561. 2(M+1) 〇 1HNMR(400MHz, CDaOD): (5 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, ❹ 3H)。 ’ 實施例18 (R)-3-胺基-l-[l-(2-羥基曱基-吡咯烷―卜羰基）三氟曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-4-(2, 4, 5- 三氟苯基）-丁-1-酮鹽酸鹽First step 94579 65 201026314 (R)-[3-[l-(4-Ethyl-hexahydropyridinyl-indole-carbonyl)_3_trifluoromethyl-5,6-dihydro-8H-imidazole [丨,5_a]pyrazine_7_yl]_3_oxo-bu (2,4,5-difluorobenzyl)-propyl]monoamine decanoic acid third vinegar (8)-7-[3 - Third Butan County _4_(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl- 5, 6, 7, 8-tetrahydroimidazo[1,5-a] Pyridin-1-carboxylic acid 2a (150 mg, 〇.27 mmol), i-hexahydropyrazine-indole-keto-ketone hydrochloride (90 mg, 0.54 mmol) and bis(2-oxo_3_eox) The oxazolidinium phosphinium chloride (0. 138 g, 0·54 mmol) was dissolved in 8 mL of dichloromethane, stirred with diethylamine (0.25 mL, 1.62 mmol), 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, and the residue obtained was purified to the title compound (ethyl hexyl hexahydropyridin-1-M)-3-trifluoromethyl _5 , 6_Dihydro-8H-imidazo[1,5-a; h than arbut-7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]- Tert-butyl carbamic acid 17a (80 mg, white solid), yield: 45%. MS m/z (ESI): 660.9 (M+1). ❹ The second step (R) 1 [1_(4_乙牛基-六气α比乌井-1_戴基)_3-三气methyl-5,6~ dihydro-8Η-imidazo[1, 5-a]pyridin-7-yl]-3-amino-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride (R)-[3-[l -(4-Ethyl-hexahydropyrrolin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a] ° than phenyl-7-yl ]-3-Oxo-1-(2,4,5-trifluorobenzyl)-propyl]-amino decanoic acid tert-butyl ester 17 & (0.08 §, 0.12 mmol) and 2 mL of ethyl acetate 2 mL of 2. 7N hydrogen chloride in ethyl acetate solution was added to the reaction flask, and the reaction was carried out at room temperature overnight, and the reaction was carried out by thin layer chromatography, followed by the disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure to give the title product (R)- L-[ 1-(4-Ethyl-hexahydro^^ hydroxycarbonyl)_3_trifluoromethyl_5,6-dihydro-8H-imidazo[l,5-a]pyridin: _7_yl ]_3_Amino- 4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 1T (7 mg, white solid), yield: 98%. MS m/z (ESI): 561. 2 (M+1) 〇1HNMR (400 MHz, CDaOD): (5 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, ❹ 3H). Example 18 (R)-3-Amino-l-[l-(2-hydroxyindolyl- Pyrrolidine-b-carbonyl)trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrrol-7-yl]-4-(2,4, 5-trifluorophenyl) )-but-1-one hydrochloride

第一步 (1〇-[3-[1-(2-羥基甲基-»比咯烷-1-羰基）_3_三氟甲基_5, 6-二氫-8Η-_σ坐並[1，5-a]°比哄-7~基]-3-氧代-1-(2, 4 5~ 三氟苄基）-丙基]-胺基甲酸第三丁酯將00-7-[3-第三丁氧羰基-4-(2,4,5-三氟苯基）-丁 94579 67 201026314 酿基]-3-三氟曱基-5, 6, 7, 8-四氫咪唾並[1，5-a]«比α井-i_ 羧酸 2a(150mg，0. 27mmol)、（R)-吡咯烷-2-基甲醇（54. 6mg，〇.54mmol)、雙（2-氧代-3-噁唑烷基）次膦醯氣<;0.138g, 〇.54mmol)和三乙胺（〇. 25mL, 1.62mmol)攪拌下溶解於8mL 一氯甲烧中’室溫下反應過夜’薄層層析追縱反應至1原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物’得到標題產物（R)-[3-[l-(2-經基甲基-η比嘻烧-1一觀基）-3-三氟甲基-5, 6-二氩-8H-咪唑並[1，5-a]吡哄-7-❹基]-3-氧代-1-(2, 4, 5-三氟苄基）-丙基]-胺基甲酸第三丁酯18a(120mg，無色油狀物），收率：70%。 MS m/z (ESI) : 633. 9(M+1)。第二步 00-3-胺基-l-[ 1-(2-羥基甲基-η比哈烧-1-幾基）—3-三氟甲基-5, 6-二氫-8Η-咪唑並[1，5-a]吡畊-7-基]-4-(2, 4, 5- 二乱苯基）_ 丁-1-嗣鹽酸鹽 ❹ 將（R)-[3-[l-(2-羥基曱基-吡咯烷-1-羰基）-3-三氟甲基-5,6-二氫-811-咪峻並[1，5-&]°比哄-7-基]-3-氧代-1-(2,4,5-三氟苄基）-丙基]-胺基甲酸第三丁酯183(012§,The first step (1〇-[3-[1-(2-hydroxymethyl-»pyrrolidine-1-carbonyl)_3_trifluoromethyl_5,6-dihydro-8Η-_σ sits and [1 , 5-a]° 哄-7~yl]-3-oxo-1-(2, 4 5~trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 00-7-[ 3-tert-butoxycarbonyl-4-(2,4,5-trifluorophenyl)-butyl 94579 67 201026314 aryl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydropyrene And [1,5-a]« than α-i-carboxylic acid 2a (150 mg, 0.25 mmol), (R)-pyrrolidin-2-ylmethanol (54.6 mg, 〇.54 mmol), bis (2- Oxo-3-oxazolidinyl)phosphinium oxime <; 0.138 g, 〇.54 mmol) and triethylamine (〇. 25 mL, 1.62 mmol) were dissolved in 8 mL of trichloromethane while stirring at room temperature The reaction was carried out overnight. The reaction of the thin layer chromatography was carried out 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)-[3-[l-(2- Methyl-n-rhenium-pyrrol-1-carbenyl)-3-trifluoromethyl-5,6-di-argon-8H-imidazo[1,5-a]pyridin-7-mercapto]-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). The second step 0-3-amino-l-[ 1-(2-hydroxymethyl-n-bihafen-1-yl)-3-trifluoromethyl-5,6-dihydro-8Η-imidazole And [1,5-a]pyrazine-7-yl]-4-(2,4,5-disorganophenyl)-butan-1-indole hydrochloride ❹ (R)-[3-[l -(2-hydroxyindolyl-pyrrolidin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-811-mi-[1,5-&]° than 哄-7-yl ]-3-Oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 183 (012§,

0. 19mmol)及2mL乙酸乙醋加入反應瓶中，加入4mL之2. 3N 的氯化氫的乙酸乙酯溶液，室溫下反應3小時後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物 (R)-3-胺基-l-[i-(2-羥基甲基-吡咯烷-1-羰基）-3-三氟甲基_5，6_ — 風-8H-味 β坐並[1，5_a]D比啡-7-基]_4_(2，4，5~ 三氟苯基）-丁-1-酮鹽酸鹽18(0. 12g，白色固體），收率： 68 94579 201026314 88% 〇 MS m/z (ESI) : 534.2(M+1)。 1HNMR(400MHz, CD3〇D): ^ 7.39-7 •的（®, 1H)，7.23-7. 19(m, 1H), 5.16-5.04(,, 2H), 4.33-4.^ ^ 4> 15.4 〇g(m> 2H)’ 3.98(m，1H)’ 3.86-3.57(m，5h)，3〇4(m，肌 2. 93-2.86(m，1H), 2. 82-2. 72(m, 1H) 實施例190. 19mmol) and 2mL of ethyl acetate were added to the reaction flask, 4mL of 2. 3N hydrogen chloride in ethyl acetate solution was added, and the reaction was carried out for 3 hours at room temperature, and the reaction was traced by thin layer chromatography until the starting material disappeared. The title product (R)-3-amino-1-[i-(2-hydroxymethyl-pyrrolidin-1-carbonyl)-3-trifluoromethyl_5,6_-wind-8H-flavor坐,[1,5_a]D is more than phenyl-7-yl]_4_(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 18 (0.12 g, white solid), yield : 68 94579 201026314 88% 〇MS m/z (ESI): 534.2 (M+1). 1HNMR (400MHz, CD3〇D): ^ 7.39-7 • (®, 1H), 7.23-7. 19(m, 1H), 5.16-5.04(,, 2H), 4.33-4.^^ 4> 15.4 〇g(m> 2H)' 3.98(m,1H)' 3.86-3.57(m,5h), 3〇4(m, muscle 2.93-2.86(m,1H), 2. 82-2.72( m, 1H) Example 19

(R)-4-{7-[3-胺基-4-(2,4,5-三氟笨基）_丁酿基]_3一甲基切’^四氫哺唑並。，^^〶…“ 哄-2-嗣鹽酸鹽(R)-4-{7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]_3-methyl-[-tetrahydrocarbazide. ,^^〒..." 哄-2-嗣 hydrochloride

第一步 (1〇-[3-氧代-3-[1-(3-氧代-六氫吡哄-1一羰基）_3—三氟曱基-5,6-二氳-811-咪唾並[1，5-&]°比哄-7-基]-1-(2,4,5-三氟苄基）-丙基]-胺基甲酸第三丁酯將（R)-7-[3-第三丁氧羰基-4-(2, 4, 5-三氟苯基）-丁醢基]-3-三敗曱基-5, 6, 7, 8-四氳w米0坐並[1，5-a]11比π井-i_ 羧酸 2a(150mg，0. 27mmol)、2-羰基六氫吡畊（60mg， 0. 6mmol)、雙（2-氧代-3-噁唑烧基）次膦醯氣（〇· 138g， 69 94579 201026314 0. 54mmol)、三乙胺（0. 25mL，1. 62mmol)和 8mL 二氯甲燒加入反應瓶中，加入lOmL N，N-二甲基甲醯胺，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（r)_[3-氧代-3-[ 1-(3-氧代-六氫吡畊-1-羰基）-3-三氟甲基-5, 6-二氫-811-咪嗤並[1，5-&]°比哄-7-基]-1-(2,4：，5-三氟苄基）-丙基]-胺基曱酸第三丁酯19a(140mg，無色油狀物），收率：82% 〇 ® MS m/z(ESI) :632. 7(M+1)。苐二步 (R)-4-{7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁酿基]-3_三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a>比畊-1-羰基}—六氫吡口井-2-嗣鹽酸鹽將（R)-[3-氧’代-3-[ 1-(3-氧代-六氫η比π井-1-幾基）_3_ 三氟曱基-5, 6-二氫-8Η-咪0坐並[1，5-a]〇比口井-7-基]-1-❾（2, 4,5-三氟苄基）-丙基]-胺基曱酸第三丁酯i9a (0.14g， 0. 22mmol)及2mL乙酸乙醋加入反應瓶中，加入4mL之2. 3N 的氯化氫的乙酸乙酯溶液，室溫下反應過夜後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物 (1〇-4-{7-[3-胺基-4-(2,4,5-三氟苯基）-丁酿基]_3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡哄-1-羰基}_六氫吡哄-2-S同鹽酸鹽19(0. 12g,白色固體），收率：93%。 MS m/z(ESI) : 533. 2(M+1)。 !ΗΝΜΚ(400ΜΗζ, CD3〇D): (5 7. 38(m, 1H), 7. 24-7. 22Cm, 1H), 94579 70 201026314 5. 08-5. 01(m, 2H), 4. 57(ro, 2H), 4. 32-4. 27(m, 2H), 4.08 (m, 1H), 3. 97-3. 94(m, 4H), 3.47(m, 2H), 3. ll(m, 2H), 2. 97-2. 84(m，2H)。實施例20 (R)-3-胺基噻唑烷_3_羰基）_3_三氟甲基一5,6_二氫-8H-咪嗤並[l，5-a]吡D井_7_基]_4_(2,4,5_三氟苯基）一丁-1-酮鹽酸鹽The first step (1〇-[3-oxo-3-[1-(3-oxo-hexahydropyridin-1-carbonyl)_3-trifluoromethyl-5,6-diindole-811-mi Salivation of [1,5-&]° 哄-7-yl]-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester (R)- 7-[3-Tertiyloxycarbonyl-4-(2,4,5-trifluorophenyl)-butanyl]-3-tris-decyl-5, 6, 7, 8-tetrazol And [1,5-a]11 than pi well-i_carboxylic acid 2a (150 mg, 0.25 mmol), 2-carbonyl hexahydropyrazine (60 mg, 0.6 mmol), bis(2-oxo-3-oxo Iridinyl) phosphinium oxime (〇·138g, 69 94579 201026314 0. 54mmol), triethylamine (0.25 mL, 1.62mmol) and 8mL of dichloromethane were added to the reaction flask, and 10 mL of N, N- was added. Dimethylformamide was reacted overnight at room temperature, and the reaction was traced to the disappearance of the material by thin layer chromatography. 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 -oxo-3-[1-(3-oxo-hexahydropyrrolin-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-811-imiphthene[1,5-&amp ;] 哄-7-yl]-1-(2,4:,5-trifluorobenzyl)-propyl]-amino decanoic acid tert-butyl ester 19a (140 mg, colorless oil), : 82% 〇® MS m/z (ESI): 632.7 (M+1). 苐 two steps (R) -4-{7-[3-amino-4-(2, 4, 5-three Fluorophenyl)-butyl-branched]-3_trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a> than plough-1-carbonyl}-hexahydropyrazine well- 2-Hydrazine hydrochloride will be (R)-[3-oxo-substituted-3-[1-(3-oxo-hexahydron-ratio pi--1-yl)_3_trifluoromethyl-5,6 -Dihydro-8Η-M. 0 sits and [1,5-a] 〇比井-7-yl]-1-❾(2,4,5-trifluorobenzyl)-propyl]-amino hydrazine The acid tert-butyl ester i9a (0.14 g, 0.22 mmol) and 2 mL of ethyl acetate were added to the reaction flask, and 4 mL of a 2.3 N solution of hydrogen chloride in ethyl acetate was added, and the reaction was carried out overnight at room temperature, followed by thin layer chromatography. The reaction was completed until the starting material disappeared, and the reaction mixture was concentrated to give the title product (1 〇-4-{7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]-3- Trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-1-carbonyl}-hexahydropyridin-2-S as the hydrochloride salt 19 (0. 12 g, The yield was 93%. MS m/z (ESI): 533. !ΗΝΜΚ(400ΜΗζ, CD3〇D): (5 7. 38(m, 1H), 7. 24-7. 22Cm, 1H), 94579 70 201026314 5. 08-5. 01(m, 2H), 4. 57(ro, 2H), 4. 32-4. 27(m, 2H), 4.08 (m, 1H), 3. 97-3. 94(m, 4H), 3.47(m, 2H), 3. ll (m, 2H), 2. 97-2. 84 (m, 2H). Example 20 (R)-3-Aminothiazolidine_3_carbonyl)_3_trifluoromethyl-5,6-dihydro-8H-imiindole[l,5-a]pyridinium D_7_ Base]_4_(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

第一步 (R)-[3-氧代-3-[1-(噻嗤烷_3一羰基）一3_三氟甲基_5, 6一二氫-8H-咪唑並[1，5-a]吡啡-7-基]—1_(2, 4, 5-三氟苄基）- 丙基]-胺基曱酸第三丁酯中’室溫下攪拌2小時，將00-7-[ 3-第三丁氧羰基_4_(2, 4, 5_三氟苯基）一丁醯基]-3-二氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-羧酸 2a(0.15g，〇.27mmol)、噻唑烷（57mg，〇 6mmol)、三乙胺（0. 275g，2. 72mmol)和雙（2-氧代_3一嗯咬烧基）次鱗醯氣（〇.138g，〇,544mmol)攪拌下溶解於1〇mL二氣甲烷薄層層析追蹤反應至原料消失， 94579 71 201026314 減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-[3-氧代-3-[1-(噻唾烷_3_羰基—三氟甲基-5,6-二氫-8H-咪唑並[i，5—a]吡哄-7_基]_卜（2 4 5_ 三氟苄基）-丙基]-胺基曱酸第三丁酯2〇a(〇. 15g，白色固體），收率：89%。 ’ MS m/z (ESI) : 644. 1(Μ+23)。第二步 (R)-3-胺基噻唑烷一3一羰基）_3_三氟甲基_5,6_二籲氫-811-咪唑並[1，51]吡畊-7-基]-4-(2,4,5-三氟苯基）- 丁-1-網鹽酸鹽將（R)-[3-氧代-3-[1-(噻唑烷-3一羰基）_3_三氟曱基 -5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-1-(2, 4, 5-三氟苄基）-丙基]-胺基甲酸第三丁酯2〇a(〇.i5g, 0.24mm〇1)加入到5mL之2. 2 N氣化虱的乙酸乙g旨溶液.中，室溫下反應 4小時’薄層層析追蹤反應至原料消失，減壓濃縮反應液， ❹用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)_3_ 胺基-l-[l-(噻唑烷-3-羰基）-3-三氟曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-4-(2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽20(100mg，淡黃色固體），收率：75%。 MS m/z (ESI) : 522·1(M+1)。 1HNMR(400MHz, CDsOD): δ 7.447-7.358(m, 1Η), 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- 72 94579 201026314 2. 784(m, 2H)。實施例21 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯]-3-三氟甲基 -5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-(吡啶_3~基）甲醯胺二鹽酸鹽First step (R)-[3-oxo-3-[1-(thiamidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5 -a]pyridin-7-yl]-1_(2,4,5-trifluorobenzyl)-propyl]-amino decanoic acid tert-butyl ester, stirred at room temperature for 2 hours, 00-7 -[ 3-Tertiyloxycarbonyl_4_(2,4,5-trifluorophenyl)-butanyl]-3-difluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5 -a] pyridin-1-carboxylic acid 2a (0.15 g, 〇. 27 mmol), thiazolidine (57 mg, 〇6 mmol), triethylamine (0. 275 g, 2.72 mmol) and bis(2-oxo_3)嗯咬烧 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) The obtained residue was purified by column chromatography to give the titled product(R)-[3-oxo-3-[1-(thiathiane-3-carbonyl-trifluoromethyl-5,6-dihydro-8H) -Imidazo[i,5-a]pyridin-7-yl]-Bu(2 4 5_trifluorobenzyl)-propyl]-amino decanoic acid tert-butyl ester 2〇a (〇. 15g, white Solid), yield: 89%. ' MS m/z (ESI): 644. 1 (Μ+23). Step 2 (R)-3-Aminothiazolidine-3 Carbonyl)_3_trifluoromethyl_5,6-di-hydrogen-811-imidazo[1,51]pyrylene-7-yl]-4-(2,4,5-trifluorophenyl)-butyl 1-Net hydrochloride salt (R)-[3-oxo-3-[1-(thiazolidine-3-carbonyl)_3_trifluoromethyl-5,6-dihydro-8H-imidazo[ 1,5-a]pyrazine-7-yl]-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 2〇a (〇.i5g, 0.24mm 〇1) Add to 5 mL of 2. 2 N vaporized hydrazine acetic acid solution, react at room temperature for 4 hours' thin layer chromatography to trace the reaction until the starting material disappears, concentrate the reaction solution under reduced pressure, and use a silicone tube The residue obtained is purified by column chromatography to give the title compound (D) </ </RTI> <RTIgt; </RTI> <RTIgt; And [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): 522·1 (M+1). 1H NMR (400MHz, CDsOD): δ 7.447-7.358 (m, 1 Η), 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- 72 94579 201026314 2. 784 (m, 2H). Example 21 (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanindole-3-trifluoromethyl-5, 6, 7, 8- Hydrozimidazo[1,5-a]pyrazine-1-(pyridine-3-yl)carbendamine dihydrochloride

第一步 (ί〇-[3-氧代-3-[1-(吼啶-3-基胺基甲醯基）-3-三氟甲基 -5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-1-(2, 4, 5-三氟 -苄基）-丙基]-胺基甲酸第三丁酯 ❹ 將（R)-7-[3-第三丁氧羰基_4_(2, 4, 5-三氟苯基）一丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡哄一1_ 鲮酸2a(0. 15g，0.272mmol)攪拌下溶解於1〇虬二氯甲烷中，加入3-胺基°比咬（38. 4mg，0. 41mmol)、三乙胺（〇. 275g， 2.72mm〇l)和雙（2-氧代-3-噁唑烷基）次膦醯氣（〇 138忌 0.544麵D ’室溫下攪拌過夜’薄層層析追蹤反應至原料核，減壓濃縮反應液，时膠管柱層析法純化所得殘餘 =得到標題產物（RH3-氧代〜基胺基甲酿土）—3-二氟甲基-5, 6_二氫一8H—w米唾並[^ 小比畊一厂 94579 73 201026314 基]-1-(2, 4, 5-三氟-苄基）-丙基]-胺基甲酸第三丁酯 21a(0. lg，白色固體），收率：58. 8%。 MS m/z (ESI) : 627.1(M+1)。第二步 (R)-7-[3-胺基- 4-(2，4, 5-二氟苯基）-丁酿]-3-三氟甲基 -5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-(吡啶-3-基）甲醯胺二鹽酸鹽將（R)-[3-氧代-3-[1-(吡啶-3-基胺基甲醯基）-3-三 ®氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-1-(2,4, 5-三氟_苄基）-丙基]-胺基甲酸第三丁酯21a(0. lg， 0. 16mmol)加入到10mL之2. 2 N氯化氫的乙酸乙酯溶液中，室溫下反應4小時’薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-7-[3-胺基-4-.(2, 4,5-三氟苯基）-丁醯基]一3-三氟甲基-5, 6, 7, 8-四氫口米唾並[1， ❹啶-3-基）曱醢胺二鹽酸鹽21(80mg，白色固體），收率：89%。 MS m/z (ESI) : 527·2(Μ+1)。 !HNMR (400MHz, CDsOD): δ 9. 584(s, 1Η), 8. 88-8. 857(m, 1H), 8. 63-8. 601 (in, 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)。實施例22 (R)-3-胺基-l-[l-(4-曱石黃醢基-六氫比π井-i-徵基）_3_三氣曱基-5, 6-二氫-8H-味0坐並[1，5-a] η比哄-7-基]-Α ν* 94579 201026314 (2, 4, 5-二氟本基）-丁-i__j鹽酸鹽The first step (ί〇-[3-oxo-3-[1-(acridin-3-ylaminocarbamimidyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazole [1,5-a]pyridin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester ❹ (R)-7- [3-Tertiyloxycarbonyl_4_(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5- a] pyridinium 1_ decanoic acid 2a (0.15g, 0.272mmol) was dissolved in 1 〇虬 dichloromethane under stirring, and added 3-amino group ratio bit (38. 4 mg, 0.41 mmol), triethylamine (〇. 275g, 2.72mm〇l) and bis(2-oxo-3-oxazolidinyl)phosphinium oxime (〇138 0.50.544面 D 'stirring at room temperature overnight' thin layer chromatography to trace the reaction to The raw material core, the reaction liquid is concentrated under reduced pressure, and the residue obtained by gel column chromatography is purified to obtain the title product (RH3-oxo-ylaminomethyl-branched soil)-3-difluoromethyl-5,6-dihydrogen 8H-w rice saliva [^ small than the cultivation of a plant 94579 73 201026314 base]-1-(2, 4, 5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 21a (0. Lg, white solid), yield: 58. 8%. MS m/z (ESI): 627.1 (M+1). Step 2 (R)-7-[3-Amino- 4-(2,4,5-difluorophenyl)-butyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyrazole-1- (pyridin-3-yl)metholamine dihydrochloride salt (R)-[3-oxo-3-[1-(pyridin-3-ylaminocarbamoyl)-3-trisfluoromethyl -5,6-Dihydro-8H-imidazo[1,5-a]pyrrol-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid The third butyl ester 21a (0. lg, 0.16 mmol) was added to 10 mL of 2. 2 N hydrogen chloride in ethyl acetate solution, and reacted at room temperature for 4 hours. The reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was purified by silica gel column chromatography to give the title product (R)-7-[3-amino-4-.(2,4,5-trifluorophenyl)-butanyl]-3 -trifluoromethyl-5, 6, 7, 8-tetrahydro-m-disodium [1, acridin-3-yl)guanamine dihydrochloride 21 (80 mg, white solid), yield: 89% MS m/z (ESI): 527·2 (Μ+1). !HNMR (400 MHz, CDsOD): δ 9. 584 (s, 1 Η), 8. 88-8. 857 (m, 1H), 8 63-8. 601 (in, 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-l-[l-(4-曱石黄醢基-六氢比π井-i-征)_3_三气曱基-5,6-Dihydro-8H - taste 0 sits and [1,5-a] η is more than 哄-7-yl]-Α ν* 94579 201026314 (2, 4, 5-difluoro-based)-butyl-i__j hydrochloride

-，-一虱-8H-咪唑並[u—a]吡畊_7_基卜3_氧代一卜 (2, 4, 5-二氟-苄基）-丙基]_胺基甲酸第三丁酯將⑻-7-[3-第三丁氧裁基胺基_4_(2, 4, 5_三敗笨基）-丁醯基]-3-三氟曱基-5, 6, 了，8〜四氫咪嗤[丨，5_a]„比哄 -卜羧酸2a(0.15g，0.27咖〇1)、1-甲磺醯基-六氫吡哄 (〇.l〇9g’ 0.55mm〇l)和三乙胺（0.38mL，2 7mm〇1)攪拌下溶 ❹解於10mL二氯甲烷中，加入雙（2一氧代_3_噁唑烷基）次膦醯氯（0. 139g，0. 55mmol)，室溫下攪拌反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物甲磺醯基-六氫吡畊-1-羰基）-3-三氟甲基-5, 6-二氫-8H-咪唑並 [1，5-a>比卩井-7-基]-3-氧代-1-(2, 4, 5-三氟-苄基）-丙基]-胺基曱酸第三丁酯22a(0.2g，白色固體）。 MS m/z (ESI) : 696.9(M+1)。第二步 75 94579 201026314 (R)-3-胺基-l-[l-(4-曱石黃醯基-六氫D比哄—卜幾基）_3_二氟甲基-5,6-二氫-8H-咪唑並[1，5〜a]^哄_7_基]_4_ (2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽將（R)-[3-[l-(4_曱石黃醯基-六氫〇t匕口井_ι_幾基）_3一三氣甲基-5, 6-二風-8Η-ϋ米唾並[1，5-a]%哄_7_基]_3_氧代 -1-(2, 4, 5-二氟-苄基）-丙基]-胺基甲酸第三丁酯22a (0.19g，0.27顏〇1)及2mL乙酸乙酯加入反應瓶中，加入 4mL之2. 7N的氯化氫的乙酸乙酯溶液，室溫下反應3小時 ❹後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物（R)-3-胺基-l-[l-(4-甲磺醯基-六氫吡哄―卜氣基）3二氣曱基_5，6_.一風-8H-σ米〇坐並[1，5_a]π比啡-7- 基]-4-(2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽22(i70mg，白色固體），收率：99%。 MS m/z (ESI) : 597.2<M+1)。 1HNMR(400MHz, CDaOD): ¢5 7. 46-7. 34(m, 1H), 7. 33-7. 20(m, ❹ 1H)，5. 18-5. 07(s，lH)，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)。實施例23 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）_丁醯基]_3_三氟甲基-5, 6, 7, 8-四氫t坐，[1，卜護酸乙g旨鹽酸鹽-,-虱-8H-imidazo[u-a]pyrazine_7_kib3_oxo-bu (2,4,5-difluoro-benzyl)-propyl]-aminocarboxylic acid Tributyl ester will be (8)-7-[3-tert-butoxymethylamino-4_(2,4,5-trisyl)-butanyl]-3-trifluoromethyl-5, 6, 8~tetrahydropyrene [丨, 5_a]„ 哄-bu-carboxylic acid 2a (0.15g, 0.27 curry 1), 1-methylsulfonyl-hexahydropyridinium (〇.l〇9g' 0.55mm〇 l 139g, dimethylglycolate (0. 139g) was added to a solution of bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0. 139g) with triethylamine (0.38 mL, 2 7 mm 〇1). The reaction mixture was stirred at room temperature overnight. Hydropyridyl-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a> than 卩井-7-yl]-3-oxo-1- (2,4,5-trifluoro-benzyl)-propyl]-amino decanoic acid tert-butyl ester 22a (0.2 g, white solid). m. The second step 75 94579 201026314 (R)-3-Amino-l-[l-(4-曱石黄醯基-六氢D比哄-卜基基_3_Difluoromethyl-5,6-dihydro-8H-imidazo[1,5~a]^哄_7_yl]_4_ (2, 4, 5-trifluorophenyl)-but-1- Ketone hydrochloride will be (R)-[3-[l-(4_曱石黄醯基-六氢〇t匕口井_ι_几基)_3一三气methyl-5, 6-二风-8Η - glutinous rice and [1,5-a]% 哄_7_yl]_3_oxo-1-(2,4,5-difluoro-benzyl)-propyl]-carbamic acid tert-butyl Ester 22a (0.19g, 0.27 〇1) and 2mL of ethyl acetate were added to the reaction flask, 4mL of 2. 7N hydrogen chloride in ethyl acetate solution was added, and reacted at room temperature for 3 hours, then traced by thin layer chromatography. The disappearance of the starting material and concentration of the reaction mixture under reduced pressure afforded the title product (R)-3-amino-l-[l-(4-methanesulfonyl-hexahydropyridinium-p-carbyl) 3 diazide. 5,6_.一风-8H-σ米〇 sits and [1,5_a]π than phenyl-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride Salt 22 (i 70 mg, mp. 1H), 7. 33-7. 20(m, ❹ 1H), 5. 18-5. 07(s,lH), 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)-butanyl]_3_trifluoromethyl-5, 6, 7, 8-tetrahydro t Sit, [1,

94579 76 20102631494579 76 201026314

第一步 (R)-7-[3-第三丁氧羰基胺基_4._(2 4 5_三氟苯基）_丁醯基]3 一氟甲基·~5, 6, 7, 8-四氫味σ坐並[1，5-a]·»比哄-1-缓酸乙酯 ❹ 將00-7-[3~第三丁氧羰基胺基_4_(2, 4, 5_三氟苯基）_丁醯基]三氟甲基-5, 6, 7, 8-四氫咪唑[1，5-a]*»比畊 -1-羧酸2a(0.l6g，〇·29_〇1)攪拌下溶解於10ηΛ二氯甲烷中，加入乙醇（〇.〇5mL，0 87mm〇1)、三乙胺（〇.2〇2‘， 1. 45imnol)和雙（2-氧代_3_噁唑烷基）次膦醯氯⑶.U8g， 0. 58mmol)，室溫'下攪拌反應5小時後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所 ❹得殘餘物’得到標題產物（R)_7_[3_第三丁氧羰基胺基 -4-(2, 4, 5-二氟苯基）一丁醯基]一3_三氟曱基_5, 6, 7, 8_四氫咪唑並[1，5-a]吡畊_丨_羧酸乙酯23a(〇. lg，無色油狀液體）。 MS m/z(ESI) : 579.0(M+1)。第二步〇〇-7-[3_胺基_4_(2,4,5_三氟苯基）_ 丁醯基]_3_三氟甲基5, 6, 7, 8-四氫咪唑並[1，卜^吡卩井-丨—羧酸乙酯鹽酸鹽將（R)-7-[3-第三丁氧羰基胺基_4_(2, 4, 5_三氟苯 77 94579 201026314 基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-羧酸乙酯23a(0. 09g, 0. 156mmol)及2mL乙酸乙酯加入反應瓶中，加入4mL之2. 7N的氯化氫的乙酸乙酯溶液，室溫下反應3小時後’薄層層析追蹤反應至原料消失，減壓濃縮反應液’得到標題產物（R)-7-[3-胺基-4-(2 4 5_ 三氟苯基）-丁醯基]-3-三氟曱基-5, 6, 7, 8-四氫咪η坐並 [1，5-a]°比卩井-1-叛酸乙酯鹽酸鹽23(80mg，白色固體），收率：99%。 ® MS m/z (ESI) ： 479.1(M+1) ° 1HNMR(400MHz, CDsOD): ^ 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. 〇6(m, 1H), 4. 06-3. 89(m, 2H), 3. 23-2. 78(m, 4H), 1.40-1.48(m, 3H)。 .，實施例24 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）_丁醯基]_3_三氟曱 ❹基-5, 6, 7, 8_四氮味嗤子[1，5-a>比啡_卜曱醯胺鹽酸鹽First step (R)-7-[3-Tertidinoxycarbonylamino-4._(2 4 5-trifluorophenyl)-butanyl]3-fluoromethyl·~5, 6, 7, 8 - tetrahydrogen σ sit and [1,5-a]·» than 哄-1-acidic ethyl ester ❹ 00-7-[3~3 butyloxycarbonylamino _4_(2, 4, 5_ Trifluorophenyl)-butanyl]trifluoromethyl-5,6,8-tetrahydroimidazole[1,5-a]*» than tillic-1-carboxylic acid 2a (0.l6g, 〇·29_ 〇1) Dissolved in 10ηΛ dichloromethane with stirring, adding ethanol (〇.〇5mL, 0 87mm〇1), triethylamine (〇.2〇2', 1. 45imnol) and double (2-oxo_ 3_oxazolidinyl)phosphinium chloride (3).U8g, 0. 58mmol), the reaction was 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. Chromatography purification of the residue obtained to give the title product (R)_7_[3_t-butoxycarbonylamino-4-(2,4,5-difluorophenyl)-butanyl]-trifluoro Mercapto_5, 6, 7, 8_tetrahydroimidazo[1,5-a]pyrrolidine-carboxylic acid ethyl ester 23a (〇. lg, colorless oily liquid). MS m/z (ESI): 579.0 (M + 1). The second step is 〇〇-7-[3_Amino_4_(2,4,5-trifluorophenyl)-butanyl]_3_trifluoromethyl 5, 6, 7, 8-tetrahydroimidazo[1 , 卜卩卩卩丨丨丨羧酸 carboxylic acid ethyl ester hydrochloride will (R)-7-[3-t-butoxycarbonylamino _4_ (2, 4, 5-trifluorobenzene 77 94579 201026314 base) -Butyl]-3-trifluoromethyl-5,6,8-tetrahydroimidazo[1,5-a]pyroxy-1-carboxylate 23a (0. 09g, 0. 156mmol) and 2 mL of ethyl acetate was added to the reaction flask, and 4 mL of a 2. 7N solution of hydrogen chloride in ethyl acetate was added. 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-tetrahydromime η sits and [1 , 5-a]° 卩 Well-1-Retinic acid ethyl ester hydrochloride 23 (80 mg, white solid), yield: 99%. ® MS m/z (ESI): 479.1 (M+1) ° 1H NMR (400 MHz, CDs OD): ^ 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. 〇6(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)-butanyl]_3_trifluoromethyl-5, 6, 7, 8_ Tetrazoate scorpion [1,5-a> than morphine-detamine hydrochloride

94579 78 201026314 (RM3-(1-胺基甲醯-3-三氟甲基一5, 6_二氫_8H_咪唑並 [1’ 5-a]吼畊-7-基）-3-氧代-1 -（2,4,5-三氟苄基）-丙基]_ .胺基曱酸第三丁酯將（R)-7-[3-第三丁氧羰基胺基_4_(2, 4, 5_三氟苯基）-丁醯基]-3-三氟曱基-5, 6, 7, 8-四氫咪唑[丨，5_a]吡畊 -卜羧酸2a(0.15g，0.27mmol)、雙（2-氧代-3-噁唑烷基）次膦醯氯（0.206g，1.08mm〇l)和三乙胺（0 25mL，162mm〇1) 攪拌下溶解於10mL四氫呋喃中，攪拌1〇分鐘後，加入碳 ❹酸銨（78mg，0.81mm〇l)，室溫下攪拌反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（幻_[3_(1_胺基甲酿_3_ 二氣甲基-5, 6- —虱咪®坐並[1，5-a]〇比哄-7-基）-3-氧代-1-(2,4,5-二氟苄基）-丙基]-胺基曱酸第三丁酯243 (0. 162g，白色固體）。 MS m/z (ESI) : 549·9(Μ+1)。 ❹ 第二步 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）—丁醯基三說曱基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-甲醯胺鹽酸鹽將（R)-[3-(卜胺基甲醯-3-三氟甲基一5, 6-二氫-8H-味唑並[1，5-a；hb畊-7-基）-3-氧代-1-(2, 4, 5-三氟苄基）-丙基]-胺基曱酸第三丁醋24a(〇· I6g，〇· 29mmol)及2mL乙酸乙酯加入反應瓶中’加入5mL之2. 7N的氯化氫的乙酸乙醋溶液，室溫下反應3小時後’薄層層析追蹤反應至原料消失’減壓濃縮反應液’得到標題產物（r)_7_[3-胺基一4一 94579 79 201026314 (2, 4, 5-三氟苯基）-丁酿基]-3-三氟甲基_5, 6, 7, 8-四氫味唑並[l，5-a]吡哄-1-甲醯胺鹽酸鹽24(150mg，白色固體），收率：95%。 MS m/z (ESI) : 450.2CM+1)。 1HNMR(400MHz, CD3〇D): ^ 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)。 ®實施例25 (R)-3-胺基-l-[ l-((R)-3-氟-吡咯烷-i 一羰基）_3_三氟甲基-5, 6-二氫-8H-咪嗤並[1，5-8]°比哄-7-基]-4-(2, 4, 5-三氟苯基）-丁-1-嗣鹽酸鹽94579 78 201026314 (RM3-(1-aminocarbazin-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1' 5-a]indole-7-yl)-3-oxo -1 -(2,4,5-trifluorobenzyl)-propyl]-. Aminobutyric acid tert-butyl ester (R)-7-[3-t-butoxycarbonylamino group _4_( 2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazole [丨, 5_a] pyridin-bucarboxylic acid 2a (0.15 g, 0.27 Methyl) bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0.206 g, 1.08 mm 〇l) and triethylamine (0 25 mL, 162 mm 〇1) were dissolved in 10 mL of tetrahydrofuran with stirring. After stirring for 1 minute, ammonium carbamate (78 mg, 0.81 mm 〇l) 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, and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified to give the title product (Fantasy_[3_(1_Amino-branched_3_dimethylmethyl-5,6-- 虱 ®® sitting and [1,5-a] 〇哄-7- 3-oxo-1-(2,4,5-difluorobenzyl)-propyl]-amino decanoic acid tert-butyl ester 243 (0. 162 g, white solid). MS m/z ( ESI): 549·9 (Μ+1). ❹ Step 2 (R)-7-[3-Amino-4-(2,4, 5-trifluorophenyl) —丁醯基三说曱基-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyrylene-1-carboxamide hydrochloride (R)-[3-(i-aminocarba) Indole-3-trifluoromethyl-5,6-dihydro-8H-isoxazo[1,5-a;hb-t-7-yl)-3-oxo-1-(2, 4, 5- Trifluorobenzyl)-propyl]-amino decanoic acid terpene vinegar 24a (〇·I6g, 〇·29mmol) and 2mL of ethyl acetate were added to the reaction flask to add 5mL of 2. 7N hydrogen chloride in ethyl acetate The solution was reacted at room temperature for 3 hours, and the reaction product was traced by thin layer chromatography until the disappearance of the starting material. The title product (r)_7_[3-amino- 4:94579 79 201026314 (2, 4, 5) -trifluorophenyl)-butyryl]-3-trifluoromethyl_5, 6, 7, 8-tetrahydroisoxazo[l,5-a]pyridin-1-carboxamide hydrochloride 24 (150 mg, white solid), yield: 95%. MS m/z (ESI): 450.2 <RTIgt; </ RTI> </ RTI> 1 NMR (400 MHz, CD3 〇D): ^ 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-l-[ l-((R)-3-fluoro-pyrrolidine-i-carbonyl)_3_trifluoromethyl-5,6-dihydro-8H-嗤[[,5-8]°哄哄-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-indole hydrochloride

第一步 (R)-[3-[l-((R)-3-氟-比咯烷一卜羰基）_3_三氟甲基_5, 6_ 二氫-8H-咪唑並[l，5-a]吡哄〜7_基]_3_氧代氟节基）-丙基]-胺基曱峻第三丁酉旨將（R)-7-[3-第三丁氧羰基胺基_4_(2,4,5_三氟苯 80 94579 201026314 基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a>比哄-1-羧酸2a(0· 15g，〇. 27mmol)、雙（2-氧代-3-噁唑烷基）次鱗酿氯（〇. 14〇g，〇. 54_〇1)、三乙胺（〇· 4mL，2· 6mmol) 和00-3-氟吡咯烷鹽酸鹽（68mg，〇. 54mmol)攪拌下溶解於 lOmL二氯甲烷中’室溫下攪拌反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-[3-[卜（（R)-3-氟-吡咯烷 1 Ik·基）-3-二氣甲基-5，6-二氨-8H-口米0坐並[1，5-a]σ比哄 ❹基]-3-氧代-1-(2, 4, 5-三氟苄基）-丙基]-胺基甲酸第三丁酯25a(0. 162g，白色固體）。 MS m/z (ESI) : 622. 0(M+1)。第二步 00-3-胺基-l-[l-((R)-3-氟比咯烷—1-羰基）_3一三氟曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-4-(2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽 ❹ 將〇〇一[3-U-((R)-3-氟-吡咯烷-1-羰基）一3-三氟曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡哄-7-基]-3-氧代-1-(2,4,5-二氟1苄基）-丙基]-胺基甲酸第三丁酯253(〇.15忌， 0· 27mmo 1)及2mL乙酸乙醋加入反應瓶中，加入5虹之2 7N 的氯化氫的乙酸乙酯溶液’室溫下反應3小時後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物 (R)-3-胺基-l-[l-((R)-3-氟比π各燒羰基）_3_三氟甲基-5,6-二氳-8Η-味嗤並[l，5-a]°比哄-7-基]-4-(2 4 5-二氟苯基）-丁-1-酮鹽酸鹽25(140mg，白色固體），收率：94〇/〇。 94579 81 201026314 MS m/z (ESI) : 522.2(M+1)。 'HNMRC^OMHz, CDaOD): 5 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. ll(m，2H)，3. 07-2. 77(m，2H)，2.39-2. 〇3(ro 2H)。，實施例26 (R)-3-胺基-l-[l-((S)-3-氟-吡略烧-1-羰基）-3-三氟甲 ◎基-5,6-二氫-811-咪唑並[1，5-8]吡畊-7-基]-4-(2,4 5-= 氟苯基）-丁-1-酮鹽酸鹽First step (R)-[3-[l-((R)-3-fluoro-pyrrolidine-p-carbonyl)_3_trifluoromethyl_5,6-dihydro-8H-imidazo[1,5 -a]pyridin~7_yl]_3_oxofluoro)-propyl]-amino group 曱君三丁酉(R)-7-[3-t-butoxycarbonylamino group_4_ (2,4,5-trifluorobenzene 80 94579 201026314 yl)-butanyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a> 哄-1- Carboxylic acid 2a (0·15g, 〇. 27mmol), bis(2-oxo-3-oxazolidinyl) sub-scaled chlorine (〇. 14〇g, 〇. 54_〇1), triethylamine ( 〇· 4 mL, 2·6 mmol) and 00-3-fluoropyrrolidine hydrochloride (68 mg, 〇. 54 mmol) were dissolved in 10 mL of dichloromethane with stirring. The reaction was stirred at room temperature overnight, and the reaction was traced by thin layer chromatography. The starting material disappeared, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified to silica gel column chromatography to afford the title product (R)-[3-[((()))) 3-dimethylmethyl-5,6-diamino-8H-mouth rice 0 sits and [1,5-a]σ is more than fluorenyl]-3-oxo-1-(2, 4, 5-three Fluorobenzyl)-propyl]-carbamic acid tert-butyl ester 25a (0. 162 g, white solid). MS m/z (ESI): 622. (M+1). The second step 0-3-amino-l-[l-((R)-3-fluoropyrrolidine-l-carbonyl)_3-trifluorodecyl-5,6-dihydro-8H-imidazo[ 1,5-a]pyrazine-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride ❹ 〇〇[3-U-((R )-3-fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin-7-yl]-3-oxo Generation of 1-(2,4,5-difluoro 1benzyl)-propyl]-carbamic acid tert-butyl ester 253 (〇.15 忌, 0·27mmo 1) and 2mL of ethyl acetate in the reaction flask After adding 5 liters of 2N hydrogen chloride in ethyl acetate solution 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. -l-[l-((R)-3-Fluorine ratio π each calcined carbonyl)_3_trifluoromethyl-5,6-diindole-8Η- miso and [l,5-a]° 哄- 7-yl]-4-(2 4 5-difluorophenyl)-butan-1-one hydrochloride 25 (140 mg, white solid). 94579 81 201026314 MS m/z (ESI): 522.2 (M+1). 'HNMRC^OMHz, CDaOD): 5 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. ll (m, 2H), 3. 07-2. 77 (m, 2H), 2.39-2. 〇 3 (ro 2H). Example 26 (R)-3-Amino-l-[l-((S)-3-fluoro-pyrrolidino-1-carbonyl)-3-trifluoromethyl-6,6-dihydro -811-imidazo[1,5-8]pyrrol-7-yl]-4-(2,4 5-= fluorophenyl)-butan-1-one hydrochloride

第一步 (R)-[3-[l-((S)-3-氟^比咯烷―卜羰基）_3_三氟曱基_5, 二氫-8H-咪唑並[1，5-a]吡卩井-7-基]-3-氧代_M2, 4, 5—三氟苄基）-丙基]-胺基曱酸第三丁醋將（R)-7-[3-第三丁氧羰基胺基_4_(2, 4, 5_三氟苯基）:丁醯基]-3-三I甲基_5, 6, 7, 8_四氫味則，5_a>比哄 -卜羧酸2a(0. 15g’ 0.27mmol)、雙（2-氧代~3-噁唑烷基） 82 94579 201026314 次膦醯氯（0. 140g，〇. 54mmol)、三乙胺（〇. 4mL，2. 6mmol) 和洛烧鹽酸鹽（68mg，0. 54mmol)擾拌下溶解於 l〇mL二氯甲烷中，室溫下攪拌反應過夜，薄層層析追蹤反應至原料消失’減壓濃縮反應液，用石夕膠管柱層析法純化所得殘餘物，得到標題產物氟—吡咯烷 _1-羰基）-3-三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡口井 -7-基]-3-氧代-1-(2, 4, 5-三氟苄基）-丙基]-胺基曱酸第三丁酯26a(0. 15g，白色固體），收率：89%。 ❾ MS m/z (ESI) : 622.0(M+1)。第二步 00-3-胺基-l-[l-((s)-3-氟-吡咯烷-1-羰基）_3_三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡π井-7-基]-4-(2, 4, 5-三氟苯基）-丁-1-酿I鹽酸鹽將（R)-[3-[l-((S)-3-氟-吡咯烷-1-羰基）_3_三氟曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-3-氧代-1-〇(2,4,5-三氟苄基）-丙基]-胺基甲酸第三丁酯263(〇15§， 0· 24mino 1)及2mL乙酸匕醋加入反應瓶中，加入5瓜[之2 7N 的氯化氫的乙酸乙酯溶液’室溫下反應3小時後，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物 (R)-3-胺基-1-[1-((S)-3-氟-吡咯烷-1 —羰基）_3_三氟曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-4-(2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽26(140mg，白色固體），收率：94%。 MS m/z(ESI) : 522.2(M+1)。 HNMR(400MHz, CD3OD): 7. 42-7. 37(m, 1H), 7.26-7 22(m 94579 83 201026314 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. ll(m, 2H), 3. 07-2. 77(m, 2H), 2. 39-2. 03(m, 2H)。實施例27 (R)_l_(l -乙酿基- 3_三氣曱基_5，6-二氮_8H-口米σ坐並 [1, 5-a>比畊-7-基）-3-胺基-4-(2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽First step (R)-[3-[l-((S)-3-fluoro^pyrrolidine-po-carbonyl)_3_trifluoromethyl]5, dihydro-8H-imidazo[1,5- a] pyridazine-7-yl]-3-oxo_M2,4,5-trifluorobenzyl)-propyl]-amino decanoic acid tert-butyl vinegar (R)-7-[3- Third butoxycarbonylamino group_4_(2,4,5-trifluorophenyl):butanyl]-3-tri-Imethyl_5, 6, 7, 8_tetrahydrogen, 5_a> Carboxylic acid 2a (0.15g '0.27mmol), bis(2-oxo-3-oxazolidinyl) 82 94579 201026314 phosphine ruthenium chloride (0. 140g, 〇. 54mmol), triethylamine (〇. 4mL, 2. 6mmol) and sulphonic acid hydrochloride (68mg, 0. 54mmol) were dissolved in l〇mL dichloromethane, stirred at room temperature overnight, and traced by thin layer chromatography until the disappearance of raw materials The reaction mixture was concentrated, and the residue obtained was purified eluted eluted eluted eluted eluted eluted eluted 1,5-a]pyrazine-7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-aminodecanoic acid tert-butyl ester 26a (0 15 g, white solid), yield: 89%. ❾ MS m/z (ESI): 622.0 (M+1). The second step 0-3-amino-l-[l-((s)-3-fluoro-pyrrolidin-1-carbonyl)_3_trifluoromethyl-5,6-dihydro-8H-imidazo[ 1,5-a]pyridin-7-yl]-4-(2,4,5-trifluorophenyl)-but-1-ol I hydrochloride will be (R)-[3-[l- ((S)-3-fluoro-pyrrolidine-1-carbonyl)_3_trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrylene-7-yl]-3 -oxo-1-indole (2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester 263 (〇15§, 0·24mino 1) and 2 mL of acetic acid vinegar were added to the reaction flask The reaction was carried out for 3 hours at room temperature by adding 5 melons [2 7 N of hydrogen chloride in ethyl acetate solution], and 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-pyrrolidine-1 -carbonyl)_3_trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin Phenyl-7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 26 (140 mg, white solid), yield: 94%. MS m/z (ESI): 5221. HNMR (400MHz, CD3OD): 7. 42-7. 37(m, 1H), 7.26-7 22(m 94579 83 201026314 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. ll(m, 2H), 3. 07-2. 77(m, 2H), 2. 39-2. 03(m, 2H). Example 27 (R)_l_(l-Ethyl-3_trimethylsulfonyl_5,6-diaza-8H-mouth σ sita[1, 5-a> than plough-7-yl)- 3-amino-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

第一步 3-三氟曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡啡-7-羧酸第三丁酯將3-三氟曱基-σ米唾並[1，5-a]n比哄1 j(3. 5g， 18. 7mmol)溶解於50mL乙醇中，授拌下加入0· 5g之10%Ιε 84 94579 201026314 /碳，在氫氛圍下攪拌過夜，反應完畢。用矽藻土將反應液過濾，減壓濃縮濾液，得到的殘留物用乙醇洗條，得到的溶液在攪拌下，逐漸滴加二碳酸二（第三丁酯） (6. 2g，28· lmniol)的1 乙酵溶液’滴加完畢後，繼續攪拌30分鐘後反應完畢。減壓濃縮反應液，用;ε夕膠管柱層析法純化所得殘餘物，得到本標題產物3-三氟甲基_5,6_ 二氫-8Η-^唾並[1，5-a]°比哄-7-叛酸第三丁酯27a(3. 7g，白色固體），產率·· 68%。 © 第二步 1-澳-3-三氟曱基-5, 6-二氫-8H-咪0坐並[1，5-a]〇比卩井一7_叛酸第三丁酯在100mL乾燥的燒瓶中加入上述步驟所得的化合物3_ 三敗曱基-5, 6-二氳-8H-^w坐並[1，5-a]〇比哄-7-敌酸第二丁酯27a(300mg，1.04mmol)和50mL乙醇，擾拌溶解後，加入N-溴琥珀醯亞胺（369mg，2. 08mmol)，得到的混合物 ◎在至下擾摔’ 1小時後反應完畢’將反應液在減壓下濃縮’用破膠管柱層析法純化所得殘餘物，得到本標題產物 1-漠-3-二氟曱基-5, 6-二氫-8H-味σ坐並[1，5-a] °比啡-7-竣酸第三丁酯27b (220mg，白色固體），產率：57. 8%。第三步 3-三氟曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡口井-1，7-二羧酸7-第三丁酯1-甲酯將八獄基二始（5. 54g, 16· 2mmol)和碳酸钟（11. 2g， 81. lmmol)攪拌下溶解於1〇〇mL甲醇中，在6(rc攪拌15分 85 94579 201026314 鐘，加入1-溴-3-三氟甲基-5, 6-二氫-8Η-咪唑並5 吡畊-7-羧酸第三丁酯27b(3g，8.11mm〇l)和氯乙酸甲酉旨 (5. 25g，48· 6mmol)，在一氧化碳氛圍下，反應6小時' 層層析追蹤反應至原料消失，將反應液冷卻至室溫，用= 膠管柱過濾，曱醇淋洗，減壓濃縮濾液，用矽膠管栓法純化所得殘餘物’得到標題產物3-三氟甲基6〜一 / -8H-咪唑並[1，5-a]吡畊-1，7-二羧酸7-第三丁酯_丨、甲^ 27c(l. 92g，白色固體），收率：67%。（參考文獻：】曰 Organomet. Chem, 1985, 293) MS m/z(ESI) : 350.5(M+1)。第四步二氟甲基-5, 6-二氫-8H-咪哇並[i, 5-a]吡口井y 7、一酸7-第三丁酯一後將3-二氟曱基-5,6-二氫__8H_♦唑並[^一引吡二紐7-第三丁醋卜甲黯27c〇.92g，5 5咖 ❹拌下溶解於50mL甲醇中，加入3〇mL之4N氫氧化納溶液環至溫下反應30分鐘，薄層層析追蹤反應至原料消失，加入 2N鹽酸調節反應液PH為4至5，用乙酸乙酯（1〇〇mLx3)萃取，合併有機相，用無水硫酸鎂乾燥，過濾，減壓濃縮濾液，得到標題產物3-三氟甲基〜5,6_二氫_8H_咪唑並[^4] 吡啡-1，7-二羧酸7-第三丁酯27d(2g，白色固體直接用於下一步反應。第五步 1-(甲氧基-曱基-胺基曱醯基三氟曱基_5,6_二氫_8H_ 94579 86 201026314 咪唑並[1，5-a]吡啡-7-羧酸第三丁酯將3-三氟甲基_5,6-二氫-8H-咪唑並[ika]吡畊 -1’ 7-二羧酸 7-第三丁酯 27d(l. 84g，5. 5mm〇l)、N一曱氧基曱胺（0.805g，8.25mmol)攪拌下溶解於50mL二氯甲烷中，加入三乙胺（3mL，22mmol)，加入雙（2-氧代勺〜噁唑烷基）次膦醯氣（2. lg，8.25mmol)，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管^層析法純化所得殘餘物，得到標題產物丨_(甲氧基〜甲基-胺基 ❹甲醯基）-3-三氟甲基-5,6-二氫-8H-咪唑並[丨5 lirtbD# -7,酸第三丁醋27e(2.lg，白色固體)。，“]比哄 MS m/z (ESI) : 379. 1(M+1)。第六步 1-乙醯基-3-三氟曱基-5, 6_二氫_8H一咪唑並5_a]吡哄 -7-羧酸第三丁酯將1-(甲氧基-甲基-胺基甲醯基）_3_三氟甲基_5, 6_二 ❹氫-8H-咪唑並[l，5-a]吡畊—7__甲酸第三丁酯27e(〇 3g， 0.79mmol)攪拌下溶解於20mL四氫呋喃中，在滴加+ 基溴化鎂（1. 13mL，1. 58mmol)，在（Tc反應1. 5小時，薄層層析追蹤反應至原料消失，加入5〇mL飽和氯化銨溶液及 10mL飽和氯化鈉溶液，用乙酸乙酯（5〇mLx3)萃取，合併有機相，用無水硫酸鎂乾燥，過濾，減壓濃縮濾液，用矽膠管柱層析法純化所得殘餘物，得到標題產物卜乙醯基_3_ 三氟曱基-5, 6-二氫-8H-咪唑並[丨，5_a]吡畊_7_羧酸第三丁酯27f(0.24g，黃色油狀液體），收率：9〇%。 87 94579 201026314 MS m/z (ESI) : 334.0(M+1)。第七步 1-(3_三氟曱基-5,6,7,8-四氫0米哇並[1，5-&]〇比11井~；[_基）乙酮將卜乙酿基-3-三氟甲基-5, 6-二氫-8H-w米唾並[1 5_a] 〇比哄-7-叛酸第三丁醋27f(0.24g，0.72mmol)攪拌下溶解於少量乙酸乙酯中’加入5mL 2· 7N氯化氫的乙酸乙醋溶液中，室溫下反應，薄層層析追蹤反應至原料消失，減壓濃 ®縮反應液’得到標題產物1-(3-三氟曱基-5, 6, 7, 8-四氫味唑並[1，5-a]吡畊-1-基）-乙酮27g’直接用於下一步反應。第八步 (1〇-[3-（1-乙醯基-3-三氟曱基-5,6-二氫-811-味嗤並 [1，5-8]°比哄-7-基）-3-氧代-1-(2, 4, 5-三氟苄基）-丙基]-_胺基甲酸第三丁酯將1-(3-三氟曱基-5, 6, 7, 8-四氫ϋ米嗤並[1，5-a]n&_ ❹-1-基）-乙酮 27g(192mg，〇.72mmol)和（R)-3-第三丁氧羰基胺基-4-(2,4,5-三氟苯基）-丁酸1£(〇.24运，0.72111111〇1) 擾拌下溶解於20mL二氯甲烷中，加入三乙胺（〇. 4mL， 2. 88mmol) ’授拌均勻後’加入雙（2_氧代惡ττ坐炫基）次膦醯氯（0.275g，1.08賴〇1)，室溫下反應過夜，薄層層析追縱反應至原料消失，減壓濃縮反應液，用梦膠管柱層析法純化所得殘餘物，得到標題產物（R)_[3_(卜乙醯基_3 一三氟甲基-5, 6-二氫-8H-咪唑並[1，5_a]吼畊-7-基）-3-氧代-1-(2, 4, 5-三氟苄基）-丙基]—胺基甲酸第三丁酯27h 88 94579 201026314 (0. 3g，白色固體）。 MS m/z (ESI) : 449.2(M+1)。第九步 (R)-l-(l-乙醯基-3-三氟甲基-5,6-二氫-811-咪唑教 [1，5-a]吼畊-7-基）-3-胺基-4-(2, 4, 5-三氟苯基）-丁〜h 酮鹽酸鹽將（R)-[3-(l-乙醯基-3-三氟曱基-5, 6-二氫-8H-咪唆並[1，5-&]咐1畊-7-基）-3-氧代-1-(2,4,5-三氟苄基）〜兩 ❹基]-胺基甲酸第三丁酯27h(0.3g，0.55顏〇1)攪拌下溶解於2mL乙酸乙酯中，加入5mL之2. 4N氯化氫的乙酸乙酿溶液’室溫下攪拌，薄層層析追蹤反應至原料消失，減壓濃縮反應液’用梦膠管柱層析法純化所得殘餘物，得到標題產物（R)-l-(l_乙醯基-3-三氟甲基-5,6-二氩-8H-咪唑並 [1，5-a>比畊-7-基）-3-胺基-4-(2, 4, 5-三氟苯基）-丁酮鹽酸鹽27(0.15g，白色固體），收率：5了％。 ❹ MS m/z (ESI) : 548.9(M+1)。 ^NMR (400MHz, CDsOD)： δ 7.37(m, 1H), 7.26(m, m) 5.09(m, 1H), 5.02(d, 1H), 4.87-3.92(m, 5H), 3. i- 2.78(m，4H), 2.57(d，2H)，2.04(d，1H)。 . 實施例28 00-3-胺基-1-(1-環戊基羰基-3_三氟甲基_5, 6_二氫咪唑並[l，5-a]咄哄-7-基）_4_(2,4,5_三氟苯基）_丁η一嗣鹽酸鹽 94579 89 201026314First step 3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyridin-7-carboxylic acid tert-butyl ester 3-trifluoroindolyl-σ-salt And [1,5-a]n is dissolved in 50mL of ethanol than 哄1 j (3. 5g, 18. 7mmol), and 0. 5g of 10% Ιε 84 94579 201026314 / carbon is added under mixing, and stirred under hydrogen atmosphere. Overnight, the reaction is complete. The reaction solution was filtered with celite, and the filtrate was concentrated under reduced pressure. The residue obtained was washed with ethanol, and the obtained solution was gradually added dropwise with di(dibutyl carbonate) (6. 2 g, 28 lmniol). After the completion of the dropwise addition of the 1 B fermentation solution, the reaction was completed after stirring for 30 minutes. The reaction mixture was concentrated under reduced pressure, and then purified, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj哄-7-Resorcinated tert-butyl ester 27a (3.7 g, white solid), yield 68%. © Step 2 1-A-3-trifluoromethyl-5,6-dihydro-8H-m0 sits and [1,5-a] 〇卩一 7 7 7 7 7 7 7 7 7 7 7 7 In the dried flask, the compound obtained in the above step was added to the compound 3-3-trisyl-5,6-diindole-8H-^w and [1,5-a]pyridinium-7-carbamic acid second butyl ester 27a ( 300 mg, 1.04 mmol) and 50 mL of ethanol, after dissolving and dissolving, N-bromosuccinimide (369 mg, 2.08 mmol) was added, and the obtained mixture was ◎ after the reaction was completed for 1 hour, the reaction was completed. Concentration under reduced pressure 'The residue obtained was purified by gel column chromatography to give the title product 1- </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; a 。。。。。。。。。。。。。。。。。。。。。。。。。。。。. The third step is 3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-t-butyl ester 1-methyl ester Eight prisons (2. 54g, 16. 2mmol) and carbonic acid clock (11.2g, 81. lmmol) were dissolved in 1 mL of methanol with stirring, and stirred at 6 (rc, 15 minutes, 85 94579, 201026314 minutes). 1-Bromo-3-trifluoromethyl-5,6-dihydro-8Η-imidazolium 5 pyridin-7-carboxylic acid tert-butyl ester 27b (3 g, 8.11 mm〇l) and chloroacetic acid methyl hydrazine ( 5. 25g, 48·6mmol), reacted for 6 hours under a carbon monoxide atmosphere. The reaction was traced to the disappearance of the starting material. The reaction solution was cooled to room temperature, filtered through a column of hexane, and the solvent was evaporated. Purification of the obtained residue by a silica gel plug method to give the title product 3-trifluoromethyl 6~1/-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid 7-third Butyl ester 丨, 甲 27c (1.92 g, white solid), yield: 67%. (Reference: 曰Organomet. Chem, 1985, 293) MS m/z (ESI): 350.5 (M+1) The fourth step is difluoromethyl-5,6-dihydro-8H-imi-[i, 5-a] pyridinium y 7, monoacid 7-tert-butyl ester, then 3-difluoro Mercapto-5,6-dihydro__8H_♦ And [^ a pyridinium 7-third vinegar buckwheat 黯 27c 〇.92g, 5 5 curry mixed in 50mL of methanol, add 3 〇mL of 4N sodium hydroxide solution ring to the temperature reaction 30 After the minute, the reaction was traced to the disappearance of the material by the thin layer chromatography. The reaction mixture was adjusted to pH 4 to 5 with 2N hydrochloric acid, and extracted with ethyl acetate (1 〇〇mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The filtrate was concentrated to give the title product 3-trifluoromethyl~5,6-dihydro_8H-imidazo[^4]pyridin-1,7-dicarboxylic acid 7-t-butyl ester 27d (2 g, white solid Directly used in the next step. Step 5 1-(Methoxy-fluorenyl-amino-mercaptotrifluoromethyl _5,6-dihydro _8H_ 94579 86 201026314 Imidazo[1,5-a] 3,3,3,3-butylidene ester of pyridin-7-carboxylic acid, 3-trifluoromethyl-5,6-dihydro-8H-imidazo[ika]pyrazine-1'7-dicarboxylic acid 7-t-butyl ester 27d (l. 84g, 5. 5mm〇l), N-decyloxyguanamine (0.805 g, 8.25 mmol) was dissolved in 50 mL of dichloromethane with stirring, triethylamine (3 mL, 22 mmol) was added, and bis (2) - oxo scoop ~ oxazolidinyl) phosphine helium (2. lg, 8.25 mmol), reaction at room temperature overnight, thin layer chromatography The reaction was carried out until the disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure. The residue obtained was purified by chromatography to give the title product 丨 _(methoxy~methyl-amino carbamoyl)-3-trifluoromethyl Base-5,6-dihydro-8H-imidazo[丨5 lirtbD# -7, acid tert-butyl vinegar 27e (2. lg, white solid). ,]] 哄MS m/z (ESI): 379. 1 (M+1). Step 6 1-Ethyl-3-trifluoromethyl-5,6-dihydro_8H-imidazole and 5_a Pyridinium-7-carboxylic acid tert-butyl ester 1-(methoxy-methyl-aminomethylmercapto)_3_trifluoromethyl_5,6-dihydrogen-8H-imidazo[l , 5-a] pyridin-7-_carboxylic acid tert-butyl ester 27e (〇3g, 0.79mmol) was dissolved in 20mL of tetrahydrofuran with stirring, and added + magnesium bromide (1.33mL, 1.58mmol), (Tc reaction 1. 5 hours, the reaction was traced by thin layer chromatography until the disappearance of the starting material, 5 mL of saturated ammonium chloride solution and 10 mL of saturated sodium chloride solution were added, and extracted with ethyl acetate (5 〇mL×3), and the organic phase was combined. The organic layer was dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,, [丨, 5_a] pyridinium-7-carboxylic acid tert-butyl ester 27f (0.24 g, yellow oily liquid), yield: 9〇%. 87 94579 201026314 MS m/z (ESI): 334.0 (M+1) Step 7 1-(3_Trifluoromethyl-5,6,7,8-tetrahydro 0 mwa and [1,5-&]〇 ratio 11 well~;[_base) Ethyl ketone will乙乙酿基-3- Fluoromethyl-5,6-dihydro-8H-w mini[1 5_a] 〇哄-7- oxalic acid butyl vinegar 27f (0.24 g, 0.72 mmol) was dissolved in a small amount of ethyl acetate with stirring 'Add 5 mL of 2·7N hydrogen chloride in ethyl acetate solution, react at room temperature, trace the reaction by thin layer chromatography until the disappearance of the starting material, and dilute the reaction solution to give the title product 1-(3-trifluoromethyl)- 5, 6, 7, 8-tetrahydroisoxazo[1,5-a]pyrylene-1-yl)-ethanone 27g' is used directly in the next step. Step 8 (1〇-[3-( 1-Ethyl-3-trifluoroindolyl-5,6-dihydro-811- miso[1,5-8]°哄哄-7-yl)-3-oxo-1-(2) , 4, 5-trifluorobenzyl)-propyl]--aminocarbamic acid tert-butyl ester 1-(3-trifluoromethyl-5,6,7-tetrahydroindole , 5-a]n&_ ❹-1-yl)-ethanone 27g (192mg, 〇.72mmol) and (R)-3-t-butoxycarbonylamino-4-(2,4,5-three Fluorophenyl)-butyric acid 1 £ (〇.24 transport, 0.72111111〇1) Dissolved in 20 mL of dichloromethane under stirring, and added triethylamine (〇. 4 mL, 2. 88 mmol) 'After mixing evenly' Bis(2_oxooxoττ) phosphinium chloride (0.275 g, 1.08 lysine 1), reacted overnight at room temperature, thin layer The title compound (R)_[3_(b-ethylidene-3-trifluoromethyl-5) was obtained by chromatography chromatography. , 6-Dihydro-8H-imidazo[1,5_a]indole-7-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid Third butyl ester 27h 88 94579 201026314 (0. 3g, white solid). MS m/z (ESI): 449.2 (M+1). The ninth step (R)-l-(l-ethinyl-3-trifluoromethyl-5,6-dihydro-811-imidazole teaches [1,5-a] 吼-7-yl)-3 -Amino-4-(2,4,5-trifluorophenyl)-butan-h ketone hydrochloride (R)-[3-(l-ethinyl-3-trifluoromethyl-5, 6-Dihydro-8H-imiphtho[1,5-&]咐1 -7-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)~-diyl ]--tributic acid tert-butyl ester 27h (0.3g, 0.55 〇1) was dissolved in 2mL of ethyl acetate with stirring, and added 5mL of 2. 4N hydrogen chloride in ethyl acetate solution 'stirred at room temperature, thin layer The reaction was traced to the disappearance of the starting material, and the residue was evaporated to purified crystals. 6-Diar Argon-8H-imidazo[1,5-a>pyrylene-7-yl)-3-amino-4-(2,4,5-trifluorophenyl)-butanone hydrochloride 27 (0.15 g, white solid), yield: 5 %. ❹ MS m/z (ESI): 548.9 (M+1). ^NMR (400MHz, CDsOD): δ 7.37(m, 1H), 7.26(m, m) 5.09(m, 1H), 5.02(d, 1H), 4.87-3.92(m, 5H), 3. i- 2.78 (m, 4H), 2.57 (d, 2H), 2.04 (d, 1H). Example 28 00-3-Amino-1-(1-cyclopentylcarbonyl-3-trifluoromethyl-5,6-dihydroimidazo[l,5-a]indol-7-yl) _4_(2,4,5-trifluorophenyl)-butyl hydrazine hydrochloride 94579 89 201026314

第一步卜=基羰基I三氟甲基_5,6_二氫_. 吡畊-7-綾酸第三丁酯 U’b刎將卜(甲氧基-甲基一胺基曱醯)一3一三氟甲基一 ❹ -8H-味唾並[!’ 5_a]:比哄_7，酸第三丁酉旨％ :虱 0.79動⑽拌下溶料施L四氫d夫 · ^ 層層析追蹤反應至原料消失，加入5〇一和氯二 10mL飽和氯化納溶液，用乙酸乙醋（⑽咖）萃取，合併用無水硫酸難燥，㈣，減壓濃_液，用石夕 =官柱層析法純化所得殘餘物，得題絲卜環戊綠基-3-三氣甲基-5, 6-二氫|♦坐並u，5_&]爾个魏第二丁酯28a(0. lg，黃色油狀液體），收率：3〇%。 MS m/z (ESI) : 388. 1(M+1)。 94579 90 201026314 第二步環戊基-（3-三氟甲基-5, 6, 7, 8-四氳口米σ坐並[1，5-a]〇比卩井 -1-基）-甲酮將卜環戊基羰基-3-三氟甲基-5,6-二氫-8H-咪唑並 [l，5-a]0比哄-7-幾酸第三丁酯 28a(0. lg，0. 258mmol)擾拌下溶解於少量乙酸乙酯中，加入5mL之2. 7N氯化氫的乙酸乙酯溶液中，室溫下反應2小時，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物環戊基-(3-三氟 ❹曱基-5, 6, 7, 8-四氫咪0坐並[1，5-a]〇比哄-1-基）-甲酮28b，直接用於下一步反應。 MS m/z(ESI) : 288.2(M+1)。第三步 (R)-[3-(1_環戊基幾基-3-三氟甲基-5，6-二氮-8Η-ϋ米0坐並 [1，5-a>比畊-7-基）-3-氧代-1-(2,4, 5-三氟苄基丙基]-胺基甲酸第三丁酯鹽酸鹽 q 將環戊基-(3-三氟曱基-5,6,7,8-四氩17米〇坐並[1，5-8] 〇比口井-1-基）-甲酮 28b(83mg，0.258mmol)和（R)-3-第三丁氧羰基胺基-4-(2,4,5-三氟苯基）-丁酸七（0.129§， 0.388mmol)攪拌下溶解於10mL二氯甲烷中，加入三乙胺 (0. 143mL，1. 03mmol)，攪拌均勻後，加入雙（2-氧代-3-噁唑烷基）次膦醯氯（0. 099g，0. 388丽〇1)，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-[3-(1-環戊基羰基-3-三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a] 91 94579 201026314 吼畊-7-基）-3-氧代-1-(2, 4, 5-三氟苄基）-丙基]-胺基甲酸第三丁酯鹽酸鹽28c(0. llg,橙色油狀液體），收率：72%。 MS m/z (ESI) : 602.9(M+1)。第四步 (1〇-3-胺基-1'~(1-環戊基獄基-3-三氟甲基-5,6-二氫-811-咪唑並[1，5-a]吼哄-7-基）-4-(2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽將α〇_[3-(1-環戊基羰基-3-三氟甲基-5, 6-二氫-8H-❹咪唑並[1，5-a]吡畊-7-基）-3-氧代-1-(2,4, 5-三氟苄基）-丙基]-胺基甲酸第三丁酯28c(0. llg，〇.183mmol)攪拌下溶解於2mL乙酸乙酯中’加入5mL之2.4N氣化氫的乙酸乙酯溶液’室溫下攪拌，薄層層析追蹤反應至原料消失，減壓濃縮反應液’用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-3-胺基-1-(1-環戊基羰基-3-三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吼哄-7-基）-4-(2, 4, 5-三氟苯 ❹基）_丁-1-酮鹽酸鹽28(80mg，黃色固體），收率：8丨％。 MS m/z (ESI) : 503.2(M+1)。 HNMR(400MHz, CD3OD): δ 7.41(m, 1Η), 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)。實施例29 00-7-[3-胺基-4-(2, 4, 5-三氟苯基）一丁醯基]—3_三襄甲基-5, 6, 7, 8-四氳咪唑並[1，5-a]吡畊二甲胺基乙基）-曱醯胺二鹽酸鹽 94579 92 201026314The first step is benzyloxytrifluoromethyl _5,6-dihydro _. pyridin-7-decanoic acid tert-butyl ester U'b 刎 ( (methoxy-methyl-amino hydrazine ) 3 - Trifluoromethyl hydrazine - 8H - taste saliva and [! ' 5_a]: than 哄 _7, acid third butyl 酉 % % : 虱 0.79 ( (10) mixed with the solution of the application of L tetrahydro d Fu · ^ Layer chromatography to trace the reaction to the disappearance of the raw materials, adding 5 〇 1 and chlorine 2 10 mL of saturated sodium chloride solution, extraction with ethyl acetate (10) coffee, combined with anhydrous sulfuric acid difficult to dry, (d), decompression concentrated _ liquid, with stone The residue obtained by the purification of the column was subjected to column chromatography to obtain the title of Cyclopentanyl-3-trimethylmethyl-5,6-dihydro|♦, and u,5_&] 28a (0. lg, yellow oily liquid), yield: 3%. MS m/z (ESI): 388. 1 (M+1). 94579 90 201026314 The second step cyclopentyl-(3-trifluoromethyl-5, 6, 7, 8-tetrazole m σ sit and [1,5-a] 〇卩 well-1-yl)- Methyl ketone will be cyclopentylcarbonyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[l,5-a]0 哄-7-acid acid tert-butyl ester 28a (0. Lg,0. 258mmol) Dissolved in a small amount of ethyl acetate, added 5mL of 2. 7N hydrogen chloride in ethyl acetate solution, reacted at room temperature for 2 hours, trace the reaction by thin layer chromatography until the disappearance of the raw materials, decompression The reaction mixture was concentrated to give the titled product, pentyl-(3-trifluoromethyl-5,6,7,4-tetrahydromethane, and [1,5-a]pyridin-1-yl)- Methyl ketone 28b was used directly in the next reaction. MS m/z (ESI): 288.2 (M+1). The third step (R)-[3-(1_cyclopentylamino-3-trifluoromethyl-5,6-diaza-8Η-ϋ米0 sits and [1,5-a> than tillage- 7-yl)-3-oxo-1-(2,4,5-trifluorobenzylpropyl)-carbamic acid tert-butyl ester hydrochloride q Cyclopentyl-(3-trifluoromethyl) -5,6,7,8-tetraar argon 17 m squat and [1,5-8] 〇口 -1-yl)-methanone 28b (83 mg, 0.258 mmol) and (R)-3- Tributyloxycarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid (0.129 §, 0.388 mmol) was dissolved in 10 mL of dichloromethane with stirring, and triethylamine (0. 143 mL) was added. , 1. 03mmol), after stirring evenly, add bis(2-oxo-3-oxazolidinyl)phosphinium chloride (0. 099g, 0. 388 〇 1), react at room temperature overnight, thin layer The reaction was traced to the disappearance of the material, and the residue was evaporated to purified crystals. -5,6-dihydro-8H-imidazo[1,5-a] 91 94579 201026314 吼耕-7-yl)-3-oxo-1-(2,4, 5-trifluorobenzyl)- Propyl]-carbamic acid tert-butyl ester hydrochloride 28c (0.11 g, orange oily liquid), yield: 72%. MS m/z (ESI): 602.9 (M+1) The fourth step (1〇-3-amino-1'~(1-cyclopentyl) 3-trifluoromethyl-5,6-dihydro-811-imidazo[1,5-a]吼哄-7-yl)-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride, α〇_[3-(1-cyclopentylcarbonyl-3-trifluoromethyl) 5-,6-dihydro-8H-imidazo[1,5-a]pyrrol-7-yl)-3-oxo-1-(2,4,5-trifluorobenzyl)-propanyl Base]-tert-butyl carbamic acid tert-butyl ester 28c (0.11 g, 〇. 183 mmol) was dissolved in 2 mL of ethyl acetate under stirring. 'Add 5 mL of 2.4 N hydrogenated ether in ethyl acetate'. Stir at room temperature, thin The reaction was traced to the disappearance of the material, and the residue was purified under reduced pressure. The residue obtained was purified to the titled product (R)-3-amino-1-(1-cyclopentylcarbonyl-3). -trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]indol-7-yl)-4-(2,4,5-trifluorophenylindenyl)-but- 1-ketohydrochloride 28 (80 mg, yellow solid), yield: EtOAc: EtOAc: EtOAc (EtOAc) , 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 00-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trimethyl--5,6,8-tetraimidazole [1,5-a]pyridine dimethylaminoethyl)-guanamine dihydrochloride 94579 92 201026314

第一步 ❹（R)-[3-[l-(2-二甲基胺基-乙基胺基甲醯）_3一三氟甲基 -5, 6-二氫-8H- °米〇坐並[1，5-a]〇比哄-7-基]-3-氧代-1-(2, 4, 5-三氟苄基）-丙基]-胺基甲酸第三丁酯將（R)-7-[3-第三丁氧羰基胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-二氟曱基-5, 6, 7, 8-四氫口米唾[1，5-a]°比口井 -卜羧唪2a(0. 15g，〇.27mmol)、雙（2-氧代-3-噁唑烷基）次膦醯氯（0. 14g，〇. 54mmol)和三乙胺（〇.25mL，1.62mmol) ❹攪拌下溶解於l〇mL二氯甲烷中，加入N，N，_二甲基乙烷 -1,2-二胺（48mg，〇.54mmol)，室溫下攪拌反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物’得到標題產物（R)-[3-[l-(2-二甲基胺基_乙基胺基帽）+三氟曱基-5, 6-二氫-8H令坐並 [l，5-a>_+基]-3-氧代+ (2,4,5-三㈣基）_ 丙基胺基甲酸第二丁醋29a(0. lg，自色固體）。第二步 ⑻7-[3_胺基-4~(2, 4, 5~三氟苯基）-T醯基]-3-三說甲 93 94579 201026314 基-5, 6, 7, 8-四氫咪唾並[i，5-a]〇比哄一ι_(2-二曱胺基乙基）-甲醯胺二鹽酸鹽將（R)-[3-[l-(2-二甲基胺基-乙基胺基曱醯）_3 一三氟曱基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-3-氧代 -1-(2,4,5-二氟苄基）—丙基]—胺基甲酸第三丁酯29a (〇.l〇g，0.16mmol)攪拌下溶解於2mL乙酸乙酯中，加入 6mL之2. 4N氯化氫的乙酸乙酯溶液，室溫下反應4小時，薄層層析追蹤反應至原料消失，減壓濃縮反應液，加入5mL ❺乙酸乙酯，攪拌，過濾，用乙酸乙酯淋洗白色固體，得到標題產物（R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-二氟甲基-5，6，7, 8-四氫咪〇坐並[1，5~a]〇比啡-1 -(2- 一甲胺基-乙基）_甲醢胺二鹽酸鹽29(80mg，白色固體），收率：63%。 HNMR(400MHz, CD3OD): 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. 〇9(m, ❹ 1H), 4.00-3. 95(m，1H)，3·77-3·75(πι，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)。實施例30 (R)-3-胺基-1-[1-((S)2-經基甲基-η比洛烧幾基）_3_三氟甲基-5, 6-二氫-8H-咪嗤並[1，5-a] n比哄一基]一4_ (2, 4, 5-三氟苯基）-丁-1-酮鹽酸鹽 94579 94 201026314The first step is ❹(R)-[3-[l-(2-dimethylamino-ethylaminocarbamyl)_3-trifluoromethyl-5,6-dihydro-8H-° rice bran And [1,5-a]pyridin-7-yl]-3-oxo-1-(2,4,5-trifluorobenzyl)-propyl]-carbamic acid tert-butyl ester ( R)-7-[3-Tertidinoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butenyl]-3-difluoroindolyl-5, 6, 7, 8- Hydrogen mouth rice saliva [1,5-a] ° than well - Bucaridine 2a (0.15g, 〇.27mmol), bis(2-oxo-3-oxazolidinyl) phosphinium chloride (0 14g, 〇. 54mmol) and triethylamine (〇.25mL, 1.62mmol) were dissolved in 1〇mL of dichloromethane with stirring, and added N,N,_dimethylethane-1,2-diamine (48 mg, 54. 54 mmol), the reaction was stirred at room temperature overnight, and the mixture was evaporated to dryness, and the mixture was evaporated to dryness, and the mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography to give the title product (R)- [3-[l-(2-Dimethylamino-ethylamine cap) + trifluoromethyl-5,6-dihydro-8H to sit and [l,5-a>_+yl]- 3-oxo+ (2,4,5-tris(tetra)yl)-propylaminocarbamic acid second butyl vinegar 29a (0.1 g, color solid). The second step (8) 7-[3_Amino-4~(2,4,5~trifluorophenyl)-Tindolyl]-3-three said A 93 94579 201026314 base-5, 6, 7, 8-four Hydrogenimidazo[i,5-a]pyridinium 哄一ι_(2-diamidoethyl)-carbenamide dihydrochloride (R)-[3-[l-(2-dimethyl Amino-ethylaminopurine)_3 trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrrol-7-yl]-3-oxo-1 -(2,4,5-Difluorobenzyl)-propyl]-aminocarboxylic acid tert-butyl ester 29a (〇.l〇g, 0.16 mmol) was dissolved in 2 mL of ethyl acetate with stirring, and added 6 mL of 2 4N hydrogen chloride in ethyl acetate solution, reacted at room temperature for 4 hours, trace the reaction to the disappearance of the starting material by thin layer chromatography, concentrate the reaction mixture under reduced pressure, add 5 mL of ethyl acetate, stir, filter, and rinse with ethyl acetate. The title compound (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-difluoromethyl-5,6,7, 8- Tetrahydropyristin and [1,5~a]pyridin-1 -(2-methylamino-ethyl)-carbamamine dihydrochloride 29 (80 mg, white solid), yield: 63 %. HNMR (400MHz, CD3OD): 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. 〇9(m, ❹ 1H), 4.00-3. 95(m,1H),3·77-3·75(πι,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-radiomethyl-n-pyridyl)-3-trifluoromethyl-5,6-dihydro-8H -Mimidazo[1,5-a] n is more than 哄-yl]- 4_(2, 4, 5-trifluorophenyl)-butan-1-one hydrochloride 94579 94 201026314

第一步 ❹（R)-[3-[l-((S)-2-羥基甲基_吡咯烷y一羰基)一3_三氟甲基-5, 6-二氫-8H-咪唑並[丨，5_a]吡啡_7_基]_3_氧代 -1-(2, 4, 5-二氟苄基）—丙基]_胺基甲酸第三丁酯將⑻-H3-第三丁氧羰基胺基-4_(2, 4, 5一三氟苯基）-丁醯基]-3-二氟甲基_5, 6, 了，8_四氫咪唑|^，5_a]吡哄 •—卜羧酸 2a(0.15g，〇.27min〇l)、（S)-吡咯烷-2-基甲醇 (54.62mg，0.54mmol)和三乙胺（〇.25mL，1.62mmol)擾拌下溶解於lOmL二氯甲烷中，加入雙（2_氧代_3_噁唑烷基）次膦醯氣（0· 14g，0.54mmol)，室溫下攪拌反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物羥基甲基-吡咯烷-1-羰基）-3-三氟甲基一5, 6一二氫_811_咪唑並[l，5-a>比畊-7-基]-3-氧代-1 —(2,4,5_三氟苄基）_丙基]-胺基曱酸第二丁醋30a(0. 2g，白色固體）。第二步 (R)-3-胺基-1-[1-((S)2-羥基甲基-吡咯烷_丨_羰基）_3_三 94579 95 201026314 氟甲基-5, 6-二氫-8H-咪唑並[i，5—a] π比畊-7_基]一4_ (2, 4, 5-二氟苯基）-丁酿|鹽酸鹽將（R)-[3-[l-((S)-2-羥基甲基一吡咯烷_卜羰基）_3_ 二氟甲基-5’ 6-二氫-8H-咪唑並[L 5_a;|吡畊_7_基]_3一氧代1 (2, 4,5-二氟苄基）_丙基]_胺基甲酸第三丁酯3〇a (〇. 16g，0. 25mmol)及2mL二氯甲烷加入反應瓶中，加入 5mL之2. 7N的氣化氫的曱醇溶液，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)_3_胺基 ~1-[1-((S)2-羥基甲基—吡咯烷_丨_羰基）_3_三氟甲基 -5, 6-二氫-8H-咪唑並[1，5_a]吡哄_7_基]_4_(2, 4, 5_三氟苯基）-丁-1-酮鹽酸鹽3〇(12〇mg，白色固體），收率：84%。 HNMR(400MHz, CDaOD): (5 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. 21-4. 18(m, 1H), 4.06-3.98(m, 2H), 3.91~3.90(m, 1H), 3.84-3.80(m, ❹ 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)。實施例31 00-7-[3-胺基-4-(2, 4, 5-三氟笨基）_丁醯基]_3_三氟曱基5, 6’7, 8-四氫咪唑並[1，5一ap比畊一卜（吡咬—2-基）曱醯胺二鹽酸鹽The first step is R(R)-[3-[l-((S)-2-hydroxymethyl-pyrrolidine y-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazole [丨,5_a]pyridyl-7-yl]_3_oxo-1-(2,4,5-difluorobenzyl)-propyl]-aminocarboxylic acid tert-butyl ester (8)-H3-third Butoxycarbonylamino-4_(2,4,5-trifluorophenyl)-butanyl]-3-difluoromethyl_5, 6, 8-tetrahydroimidazole|^,5_a]pyridinium— Dicarboxylic acid 2a (0.15g, 〇.27min〇l), (S)-pyrrolidin-2-ylmethanol (54.62mg, 0.54mmol) and triethylamine (〇.25mL, 1.62mmol) were dissolved and dissolved in In 10 mL of dichloromethane, bis(2-oxo-3-oxazolidinyl)phosphinium hydrazine (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 starting material disappeared. The reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted eluted eluted eluted eluted eluted eluted Imidazo[l,5-a> than cultivable-7-yl]-3-oxo-1 -(2,4,5-trifluorobenzyl)-propyl]-amino phthalic acid second butyl vinegar 30a (0. 2g, white solid). The second step (R)-3-amino-1-[1-((S)2-hydroxymethyl-pyrrolidine-indole-carbonyl)_3_three 94579 95 201026314 fluoromethyl-5,6-dihydrogen -8H-imidazo[i,5-a] π ratio tillage-7_yl]-4_(2,4,5-difluorophenyl)-butane|hydrochloride salt (R)-[3-[ L-((S)-2-Hydroxymethyl-pyrrolidine- _carbonyl)_3_difluoromethyl-5' 6-dihydro-8H-imidazo[L 5_a;|pyrrol _7_yl]_3 Oxygen 1 (2,4,5-difluorobenzyl)-propyl]-aminocarboxylic acid tert-butyl ester 3〇a (〇. 16g, 0.25 mmol) and 2 mL of dichloromethane were added to the reaction flask and added 5 mL of a 2.N hydrogenated hydrogen sterol solution, reacted at room temperature overnight, 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 was purified by column chromatography to give title. Product (R)_3_Amino~1-[1-((S)2-hydroxymethyl-pyrrolidine-丨-carbonyl)_3_trifluoromethyl-5,6-dihydro-8H-imidazo[ 1,5_a]pyridinium-7-yl]_4_(2,4,5-trifluorophenyl)-butan-1-one hydrochloride 3 hydrazine (12 mg, white solid), yield: 84%. HNMR (400MHz, CDaOD): (5 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. 21-4. 18(m, 1H), 4.06-3.98(m, 2H), 3.91~3.90(m, 1H), 3.84-3.80(m, ❹ 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 00-7-[ 3-amino-4-(2,4,5-trifluorophenyl)-butanyl]_3_trifluoromethyl 5,6'7, 8-tetrahydroimidazo[1,5-ap (pyridine bite-2-yl) guanamine dihydrochloride

96 94579 20102631496 94579 201026314

第一步 (RM3-氧代-3-[1 -（吡啶一2_基胺基曱醯）_3_三氟甲基 -5’6-二氫-811-咪唑並[1，5-&]吡11井_7_基]_1_(2,4,5—三氟苄基）-丙基]-胺基曱醯基第三丁醋 © 將（R)-7~[3-第三丁氧羰基胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟曱基-5, 6, 7, 8-四氩咪唑[1，5~a]吡口井 -1-曱酸 2a(0. 15g，0.27mmol)、2-胺基吡啶（51g，〇.54mmol) 和二乙胺（0.25mL，1.62mmol)攪拌下溶解於1〇此二氯甲烷中，攪拌20分鐘後，加入雙（2_氧代_3_噁唑烷基）次膦醯氯（〇. 14g，〇.54mmol).，室溫下攪拌反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法 ❹純化所得殘餘物，得到標題產物（R)_[3_氧代_3_π_(吡啶 -2-基胺基甲醯）-3-三氟甲基一5, 6-二氫-8Η-咪唑並[1，5-a] 吡畊-7-基]-1-(2, 4, 5-三氟苄基）-丙基]-胺基甲醯基第三丁酯31a(0. lg，白色固體），收率：59%。 MS m/z(ESI) : 627.1(M+1)。第二步 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唾並[1，5-a]°比哄-1-(〇比唆-2-基）甲醯胺二鹽酸鹽 97 94579 201026314 將（R)-[3-氧代-3-[l-比u定-2-基胺基甲醢）-3-三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊-7-基]-1-(2, 4, 5-三敦苄基）-丙基]—胺基曱醯基第三丁酯31a(0.10g,The first step (RM3-oxo-3-[1 -(pyridin-2-ylaminopurine)_3_trifluoromethyl-5'6-dihydro-811-imidazo[1,5-& ]Pyr 11 well _7_yl]_1_(2,4,5-trifluorobenzyl)-propyl]-aminoindenyl third vinegar © (R)-7~[3-third Oxycarbonylamino-4-(2,4,5-trifluorophenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazole [1,5~a] pyridine Well-1-nonanoic acid 2a (0.15 g, 0.27 mmol), 2-aminopyridine (51 g, 〇.54 mmol) and diethylamine (0.25 mL, 1.62 mmol) were dissolved in 1 dichloromethane. After stirring for 20 minutes, bis(2-oxo-3-oxazolidinyl)phosphinium chloride (〇. 14g, 〇.54mmol) was added. The reaction was stirred at room temperature overnight, and the reaction was traced by thin layer chromatography. The starting material disappeared, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title product (R) _[3_oxo_3_π_(pyridin-2-ylaminocarbazide)-3- Trifluoromethyl-5,6-dihydro-8Η-imidazo[1,5-a]pyrylene-7-yl]-1-(2,4,5-trifluorobenzyl)-propyl]- Aminomethylmercapto-tert-butyl 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)-butanyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrogen Sodium (1), [1,5-a]°, 哄-1-(〇比唆-2-yl)carhamamine dihydrochloride 97 94579 201026314 (R)-[3-oxo-3-[l -l-but-2-ylaminocarbamidine)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-yl]-1-( 2, 4, 5-Tridylbenzyl)-propyl]-aminomercapto-tert-butyl ester 31a (0.10 g,

〇. 16mmol)及2mL二氣曱烷加入反應瓶中，加入5mL 2. 7N 的氯化氫的甲醇溶液，室溫下反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液’用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-7-[3_胺基_4_(2,4, 5_三氟 ❹本基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪哇並[1，5-a] 吡畊-1-(吡啶-2-基）曱醯胺二鹽酸鹽31(80mg，白色固體），收率：95. 2%。 MS m/z (ESI) : 527. 1(M+1)。 ^NMR (400MHz, CDsOD): 5 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(ffi, 2H), 4. 14(m· 1H), 4. 05(m, 1H), 3. 96(m, 1H), 3. 21-3. 〇3(m，2H), 2· 96-2. 72 ❾（ni，2H)。實施例32 (尺）7-[3-胺基-4-(2,4,5-二氟笨基）__丁醯基]_3_三氣甲 ^-5, 6, 7,.8-^16. 16mmol) and 2mL dioxane were added to the reaction flask, 5mL 2. 7N hydrogen chloride in methanol was added, and the reaction was carried out 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 column chromatography to give the titled product(R)-7-[3-amino-4-4(2,4,5-trifluorodecyl)-butanyl]-3-trifluoromethyl- 5, 6, 7, 8-tetrahydroimi-[1,5-a] pyridin-1-(pyridin-2-yl)decylamine dihydrochloride 31 (80 mg, white solid), yield: 95. 2%. MS m/z (ESI): 527. 1 (M+1). ^NMR (400MHz, CDsOD): 5 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(ffi, 2H), 4. 14(m· 1H), 4. 05(m, 1H ), 3. 96(m, 1H), 3. 21-3. 〇3(m, 2H), 2· 96-2. 72 ❾ (ni, 2H). Example 32 (foot) 7-[3-amino-4-(2,4,5-difluorophenyl)__butanyl]_3_trisole ^-5, 6, 7,.8-^

醯胺鹽酸鹽 94579 98 201026314Indoleamine hydrochloride 94579 98 201026314

_第一步 (R)-第三丁基-4-(1-((4__氟苯基）氨曱醯）_3_(三氟甲基）一 5, 6-二氮味吐並[1，5-a]%D井―7(8H)_基）_4_氧U2, 4, 5_ 三氟苯基）胺基甲酸第三丁醋 © 將（R)-7-[3-第三丁氧羰基胺基_4_(2, 4, 5_三氟苯基）-丁醯基]-3-三氟甲基_5, 6, 7, 8_四氫咪唑!^，5_a]吡啡 -1-甲酸2a(0. 15g，〇· 27_〇1)、雙（2-氧代一3一噁唑烷基）次膦醯氯（0· 14g，0. 54mmol)、三乙胺（〇. 25mL，1. 62mmol)攪拌溶解於lGmL二氯甲燒中，將4_氟苯胺（(). Q6g，54随⑷ 一次加入，.攪拌過夜，薄層層析追蹤反應至原料消失，減壓?辰縮反應液’用矽膠管柱層析法純化所得殘餘物，得到 ❹標題產物⑻-第三丁基+ = 氟曱基）-5’ 6-二氫咪唑並[1，5-a]n比哄_7(8H)_基）一4_氧 4, 5-三氟苯基）胺基曱酸第三丁酯32a(〇.丨仏，白色固體），收率：69%。 MS m/z (ESI) : 643. 9(M+1)。第二步〇〇-7-[3-胺基-4-(2, 4, 5-三氟苯基）__丁醯基]_3〜三氟曱基-5, 6, 7’ 8-四氫㈣並[1，5-小叫卜（4_氟苯基）_甲酿胺鹽酸鹽 94579 99 201026314 將（R)-第三丁基-4-(1-((4-氟苯基）氨甲醯）-3-(三氟甲基）-5, 6-二氫咪唑並[1，5-a]吡畊-7(8H)-基）-4-氧 -1-(2,4,5-三氟苯基）胺基曱酸第三丁酯323(〇.12§， 0. 186mmol)以及2mL乙酸乙醋加入到反應瓶中，再加入gmL 之2· 7N的氯化氫的乙酸乙酯溶液，攪拌反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟甲基-5,6,7,8-四氫味嗤並[1，5-3]°比0井-1-(4-氟苯基）_甲 ❹醯胺鹽酸鹽32(110mg，白色固體），收率：i〇〇%。 MS m/z (ESI) : 544.1(M+1)。 HNMR(400MHz, DMSO): ^10. 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(ιη，4H)，2.0(m，2H)。實施例33 (R)-7-[3-胺基-4-(2, 4’ 5-三氟苯基）一丁醯基]_3一三氟曱 ❹基-5, 6, 7, 8-四氫咪气並[1，5-a]鱗——叛酸，輯鹽酸鹽_First step (R)-t-butyl-4-(1-((4-fluorophenyl)aminopurine)_3_(trifluoromethyl)-5,6-diaza taste spit [1, 5-a]%D Well-7(8H)_Base)_4_Oxygen U2, 4, 5_trifluorophenyl)carbamic acid tert-butyl vinegar © (R)-7-[3-Tertibutoxy Carbonylamino 4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl_5, 6, 7, 8-tetrahydroimidazole!^,5_a]pyridin-1-carboxylic acid 2a (0. 15g, 〇·27_〇1), bis(2-oxo-1,3-oxazolidinyl)phosphinium chloride (0·14g, 0.54mmol), triethylamine (〇. 25mL, 1. 62mmol) stirred and dissolved in lGmL of methylene chloride, 4_fluoroaniline ((). Q6g, 54 with (4) added once. Stir overnight, trace the reaction by thin layer chromatography until the disappearance of the raw materials, decompression? The reaction mixture was purified by column chromatography to give the titled product (8)-t-butyl+ = fluoromethyl)-5'6-dihydroimidazo[1,5-a]n. _7(8H)-yl)- 4-oxo-4, 5-trifluorophenyl)amino decanoic acid tert-butyl ester 32a (yttrium, white solid), yield: 69%. MS m/z (ESI): 643. 9 (M+1). The second step is 〇〇-7-[3-amino-4-(2,4,5-trifluorophenyl)--butanyl]_3~trifluoromethyl-5,6,7' 8-tetrahydro (tetra) And [1,5-small called (4_fluorophenyl)_cartoamine hydrochloride 94579 99 201026314 (R)-tert-butyl-4-(1-((4-fluorophenyl)) ammonia Indole)-3-(trifluoromethyl)-5,6-dihydroimidazo[1,5-a]pyrazine-7(8H)-yl)-4-oxo-1-(2,4, 5-trifluorophenyl)amino decanoic acid tert-butyl ester 323 (〇.12§, 0. 186mmol) and 2mL of ethyl acetate were added to the reaction flask, followed by the addition of gmL of 2·7N hydrogen chloride in ethyl acetate The solution was stirred overnight, and the reaction was traced to EtOAc (EtOAc). )-Butyl]-3-trifluoromethyl-5,6,7,8-tetrahydromylon and [1,5-3]° ratio 0 well-1-(4-fluorophenyl)-formamidine Amine hydrochloride 32 (110 mg, white solid), yield: i. MS m/z (ESI): 544.1 (MI). HNMR (400MHz, DMSO): ^10. 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 (ιη, 4H), 2.0 (m, 2H). Example 33 (R)-7-[3-Amino-4-(2,4' 5-trifluorophenyl)-butanyl]_3-trifluorodecyl-5, 6, 7, 8-tetrahydrol Mimi and [1,5-a] scales - tick, acid hydrochloride

第一步 94579 100 201026314 (R)-7-[3-第三丁氧羰基胺基_4_(2,4, 5_三氟苯基）_丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑[1，5-a]吡哄-1-甲酸苄酯將（R)-7-[3-第三丁氧羰基胺基_4_(2,4, 5-三氟苯基）〜丁醯基]-3-三氟曱基-5, 6, 7, 8-四氫°米〇坐[1，5-a]otbD井-1-後酸 2a(0. 24g，0.44mmol)、1-羥基-苯並-三氮唑（〇. 〇72g，〇.53mmol)以及N-(3-二曱胺丙基）—Ν’ _乙基碳二亞胺鹽酸鹽（0.102g，0. 53mmol)攪拌溶解於i〇mL二氣曱烷中，再加〇入苯甲醇（〇. lml，〇. 88mmol)，室溫下攪拌反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（r)-7-[3-第三丁氧羰基胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟曱基_5 6 7,8-四氫咪唑[1，54]吡畊-1-羧酸苄酯338(0.056运，白色固體）’收率：· 20%。 MS m/z (ESI) : 640.9(M+1)。 ❹ 第二步 00-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三敦甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]°比哄-1-羧酸苄酯鹽酸鹽將（R)-7” [3-第三丁氧裁基胺基-4-(2, 4, 5-三氟笨基）-丁醯基]-3-三I甲基-5, 6, 7, 8-四氫0米嗤[1，5-a]〇比α井 -1-曱酸苄酯 33a(0. 056g，0. 087mmol)與 2mL 之 2· 7Ν 的氯化氫的乙酸乙酯溶液加入反應瓶中，室溫下攪拌2小時，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物（R)-7-[3-胺基-4-(2,4,5-三氟苯基）-丁醯基]__3〜 101 94579 201026314 三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-羧酸苄酯鹽酸鹽33(0. 043g，白色固體），收率：86%。 MS m/z (ESI) : 541.2(M+1)。 1HNMR(400MHz, CDsOD) ： 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)。實施例34 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟甲 ❹基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-羧酸（1-乙氧醯氧基）乙酯鹽酸鹽First step 94579 100 201026314 (R)-7-[3-Tertiyloxycarbonylamino-4_(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5, 6 , 7, 8-tetrahydroimidazolium [1,5-a]pyridin-1-carboxylic acid benzyl ester (R)-7-[3-t-butoxycarbonylamino group _4_(2,4, 5-three Fluorophenyl)~ Butyryl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydro-methane [[1,5-a]otbD well-1-post acid 2a (0. 24g, 0.44 Ment), 1-hydroxy-benzo-triazole (〇. 〇72g, 〇.53mmol) and N-(3-diamidinyl)-Ν' _ethylcarbodiimide hydrochloride (0.102 g,0. 53mmol) was dissolved in i〇mL dioxane, and then added to benzyl alcohol (〇.lml, 〇. 88mmol), stirred at room temperature overnight, 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 Phenyl)-butanyl]-3-trifluoromethyl _5 6 7,8-tetrahydroimidazole [1,54] benzylidene-1-carboxylate 338 (0.056, white solid) 'yield: · 20%. MS m/z (ESI): 640.9 (M+1). ❹ Step 2 00-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-triditymethyl-5, 6, 7, 8-tetrahydroimidazole And [1,5-a]° 哄-1-carboxylic acid benzyl ester hydrochloride will be (R)-7" [3-t-butoxy-amino--4-(2, 4, 5-three Fluoryl)-butanyl]-3-tri-Imethyl-5, 6, 7, 8-tetrahydro 0 m hydrazine [1,5-a] 〇 ratio α well-1-benzyl benzoate 33a (0. 056g, 0. 087mmol) was added to a reaction flask with 2 mL of a solution of 2,7 Torr of hydrogen chloride in ethyl acetate. The mixture was stirred at room temperature for 2 hours, and the reaction was traced by thin layer chromatography until the material disappeared. (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]__3~ 101 94579 201026314 Trifluoromethyl-5, 6, 7, 8-tetrahydroimidazole And [1,5-a] pyridin-1-carboxylic acid benzyl ester hydrochloride 33 (0. 043 g, white solid), yield: 86%. MS m/z (ESI): 541.2 (M+1) 1HNMR (400MHz, CDsOD): 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) )-丁醯基]-3-trifluoromethylindolyl-5, 6, 7, 8-four Hydrogenimidazo[1,5-a]pyroxy-1-carboxylic acid (1-ethoxyantoxy)ethyl ester hydrochloride

第一步 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟曱基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1 —羧酸（1-乙氧醯氧基）甲乙酯將（R)-7-[3-第三丁氧羰基胺基-4-(2, 4, 5-三氟苯基）-丁酿基]-3-三氟甲基-5, 6, 7, 8-四氫味0坐Π，5-a]〇比哄 _1-羧酸 2a(0. 275g, 0.5mmol)以及 4mL N，N-二曱基曱醯胺加入到反應管中，攪拌下依次加入1-氯乙基碳酸乙酯 102 94579 201026314 (0. 092g，0. 6mmol)、碘化鉀（0. 0415忌，〇· 25mmo1)、以及碳酸鉀（0. 083g，0. 6mmol)，封管置於油浴中控制外溫65°c反應2小時，薄層層析追蹤反應至原料消失，將反應管冷卻至室溫後加入40mL水，用乙酸乙酯萃取（25mLx3) ’合併有機相用水洗（20mLx2)，用無水硫酸鎮乾燥，過滤，減麼濃縮濾液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-敌酸（1-乙氧醯 β 氧基）甲酸乙酯34a(0.26g，白色固體），收率：78. 1%。 MS m/z (ESI) : 666· 9(M+1)，689.1(Μ+23)。 1HNMR(400MHz, CDCh): 5 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)。第二步 ❹（R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）一丁醯基]_3_三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡啡_ι_羧酸（1_乙氧醯氧基）乙酯鹽酸鹽將00-7-[3-胺基-4-(2,4, 5-三氟苯基）一丁醯基]_3_ 三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5~a]吡畊―卜羧酸（1_乙氧醯氧基）乙S旨34a(G. 26g，G.39刪）以及5mL乙酸乙醋一同力:入到反應瓶中’再加入3虬之6.5N的氯化氫的乙酸乙，溶液至/凰下搜拌反應6小時，薄層層析追縱反應至原料消失，減壓濃縮反應液，用石夕膠管柱層析法純化所得殘 94579 103 201026314 餘物，得到標題產物（R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁酿基]-3 -三氟1曱基-5，6，7，8 -四氫σ米0坐並[l，5-a]a比哄 -1-羧酸（1-乙氧醯氧基）乙酯鹽酸鹽34(0. 2g，白色固體），收率：85%。 MS m/z (ESI) ·· 567. 0(M+1)。 !ΗΝΜΚ(400ΜΗζ, CD3〇D): 5 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, ❹ 1H), 1.65(t, 3H)。實施例35 (1〇-7-(3-胺基-4-（2,4,5-三氟苯基）丁醯基）-3-(三氟甲基）-5，6，7, 8-四氮σ米e坐並[1，5-&]°比哄-1-竣酸異丙酯鹽酸鹽First step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydrol Imidazo[1,5-a]pyrazine-1 -carboxylic acid (1-ethoxymethoxyoxy)methylethyl ester (R)-7-[3-t-butoxycarbonylamino-4-(2) , 4, 5-trifluorophenyl)-butyl-branched]-3-trifluoromethyl-5, 6, 7, 8-tetrahydro-flavored 0-sodium, 5-a]pyridyl-1-carboxylic acid 2a (0. 275g, 0.5mmol) and 4mL of N,N-didecylguanamine were added to the reaction tube, and 1-chloroethyl carbonate was added in sequence with a solution of 102 94579 201026314 (0. 092g, 0. 6mmol ), potassium iodide (0. 0415 bogey, 〇 · 25mmo1), and potassium carbonate (0. 083g, 0.6 mmol), sealed tube placed in an oil bath to control external temperature 65 ° c reaction for 2 hours, thin layer chromatography to trace the reaction After the reaction mixture was cooled to room temperature, 40 mL of water was added, and extracted with ethyl acetate (25 mL×3). The combined organic phases were washed with water (20 mL×2), dried over anhydrous sulfuric acid, filtered, and concentrated. The residue obtained was purified by column chromatography to afford the title product (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5 , 6, 7, 8-tetrahydroimidazole And a yield of 78.1%. [1,5-a] pyridin-1-butanic acid (1-ethoxyxanthraceneoxy)carboxylate 34a (0.26 g, white solid). MS m/z (ESI): 666·9 (M+1), 689.1 (Μ+23). 1H NMR (400MHz, CDCh): 5 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). The second step is ❹(R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]_3_trifluoromethyl-5, 6, 7, 8-tetrahydrogen Imidazo[1,5-a]pyrimidin-carboxylic acid (1-ethoxymethoxy)ethyl ester hydrochloride 00-7-[3-amino-4-(2,4, 5- Trifluorophenyl)-butanyl]_3_trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5~a]pyrrolin-bucarboxylic acid (1-ethoxyoxoxy)ethyl S The purpose of the 34a (G. 26g, G.39 deletion) and 5mL of acetic acid vinegar together: into the reaction bottle 'add 3 6.5N of hydrogen chloride in acetic acid B, the solution to / phoenix search reaction for 6 hours, The reaction was traced by thin layer chromatography until the disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure. The residue obtained from the residue was obtained from the residue eluted from the column chromatography to afford the title product (R)-7-[3-amino-4 -(2,4,5-trifluorophenyl)-butanyl]-3-trifluoroindolyl-5,6,7,8-tetrahydro-sigma-m-[S,5-a]a哄-1-carboxylic acid (1-ethoxymethoxy)ethyl ester hydrochloride 34 (0.2 g, white solid), yield: 85%. MS m/z (ESI) ·· 567. 0 (M+1). !ΗΝΜΚ(400ΜΗζ, CD3〇D): 5 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, ❹ 1H), 1.65(t, 3H). Example 35 (1〇-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7, 8-tetra Nitrogen σ m e sits and [1,5-&]° 哄-1-isopropyl isopropylate hydrochloride

第一步 (R)-7-(3-(第三丁氧獄基胺基）-4-(2, 4, 5-三氟苯基）丁醯基）_3-（三氟曱基）-5，6，7，8-四氮口米0坐並[1, 5-a]σ比哄-1_ 羧酸異丙酯將（R)-7-[3-第三丁氧幾基胺基-4-(2, 4, 5-三氣苯 104 94579 201026314 基）_丁醯基]-3—三氟曱基-5, 6’ 7, 8-四氫咪唑Π，5_a>比畊 -1-羧酸2a(0.3g，0.54mmol)放入50mL·反應瓶中，加入 10mL二氯甲烷，再加入2mL異丙醇，隨後再加入〇. 3乩三乙胺，1分鐘後加入雙（2_氧代_3_噁唑烷基）次膦醯氯 (0.277g，1.09mmol)’室溫下攪拌反應2小時，再加入丨紙異丙醇以及異丙醇鈉（〇.177g，216mm〇1)，室温下攪拌反應1.5小時，薄層層析追蹤反應至原料消失，加入約1〇乩飽和氯化銨溶液，有白色固體析出，墊矽膠管柱過濾，收 ❹集濾、液，加入50mL水，用乙酸乙酯萃取（25mLX5)，合併有機相，用30mL飽和食鹽水洗滌，用無水硫酸鈉乾燥，過廣減壓濃縮濾液，用矽膠管柱層析法純化所得殘餘物，〜標題產物（R)-異丙基-7-(3-(第三丁氧羰基胺基四氫白色固 (2, 4, 5-三氟苯基）丁醯基）-3-(三氟甲基）-5, 6, 7, ^ : 咪唑並[1，5-a]吡畊-1-羧酸異丙酯35a(0. 185g，體），收率：57·8%。First step (R)-7-(3-(T-butoxy-phenylamino)-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5, 6,7,8-tetrazine m-sodium and [1, 5-a]σ ratio 哄-1_ carboxylic acid isopropyl ester (R)-7-[3-t-butoxy-aminoamine-4 -(2, 4, 5-trisole benzene 104 94579 201026314 base)_丁醯基]-3-trifluoromethyl-5,6' 7, 8-tetrahydroimidazolium, 5_a> specific tillage-1-carboxylic acid 2a (0.3 g, 0.54 mmol) was placed in a 50 mL·reaction flask, 10 mL of dichloromethane was added, and 2 mL of isopropanol was added, followed by the addition of 乩.3乩 triethylamine, and after 1 minute, double (2_oxo) was added. 3 oxazolidinyl phosphinium chloride (0.277 g, 1.09 mmol) was stirred at room temperature for 2 hours, and then crepe paper isopropanol and sodium isopropoxide (〇.177 g, 216 mm 〇1) were added at room temperature. The reaction was stirred for 1.5 hours, and the reaction was traced by thin layer chromatography until the disappearance of the starting material. About 1 Torr of 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. The mixture was extracted with ethyl acetate (25 mL EtOAc). Purify the residue by hydrazine column chromatography, ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Phenyl)butanyl)-3-(trifluoromethyl)-5, 6, 7, ^ : Imidazo[1,5-a]pyridin-1-carboxylic acid isopropyl ester 35a (0. 185 g, body) , yield: 57.8%.

MS m/z (ESI) : 593. 0(Μ+1)。 1HNMR(400MHz,CDC13): δΊ. 146-7. 082(m, 1H), (m, 1H), 5. 405-5. 010(m, 3H), 4. 219-3. 937(m, 2. 307(瓜，4H)，1.484-1. 242(m，15H)。第二步 (R)_7-(3-(第三丁氧幾基胺基）-4-(2, 4, 5-三氟笨基）丁基）-3-(三氟曱基）-5, 6, 7, 8-四氫咪唑並[1，羧酸異丙酯鹽酸鹽將（R)-7-(3-(第三丁氧羰基胺基）-4-(2, 4, 5〜三氣苯 94579 105 201026314 基）丁酿基）-3-(三氟甲基）-5, 6, 7, 8-四氫咪σ坐並[i，5-a] 0比哄-1-幾酸異丙酯35a(0. 17g，〇· 29mmol)以及10mL乙酸乙酯一同放入到反應瓶中，在冰浴下加入5mL之5. 5N的氣化氫的乙酸乙酯溶液，加畢撤去冰浴，室溫下攪拌2小時，薄層層析追縱反應至原料消失’減愿遭縮反應液，用正己烷洗滌（10mLx2)，減壓濃縮濾液，得到標題產*(r)_7_ (3-(第三丁氧幾基胺基）-4-(2, 4, 5-三I苯基）丁酿基）_3_ (二氣曱基）-5，6，7，8_四風口米〇坐並[1，5-a]〇比啡-1 -竣酸異 ❹丙酯鹽酸鹽35(0. 15g，白色固體），收率：97.8%。 MS m/z (ESI) : 493. 1 (M+1)。 ^NMRC^OMHz^MSO): (5 7.631-7.482(m, 2H), 5.159-4 308 (in, 3H), 4. 285-3. 742(m, 5H), 3. 110-2. 735(m, 4H) 1 473-L 063(m, 6H)。實施例36 (R)-7-(3-胺基-4-(2, 4, 5-三氟苯基）丁醯基）_3_(三氣甲 ❹基）-5, 6, 7, 8-四氫咪唑並[1，5-a]吡啡-卜羧酸第三丁基醋鹽酸鹽MS m/z (ESI): 593. 0 (Μ +1). 1H NMR (400MHz, CDC13): δΊ. 146-7. 082(m, 1H), (m, 1H), 5. 405-5. 010(m, 3H), 4. 219-3. 937(m, 2 307 (melon, 4H), 1.484-1. 242 (m, 15H). The second step (R)_7-(3-(t-butoxyamino)-4-(2, 4, 5- Trifluorophenyl)butyl)-3-(trifluoromethyl)-5, 6, 7, 8-tetrahydroimidazo[1, isopropyl carboxylic acid hydrochloride (R)-7-(3 -(t-butoxycarbonylamino)-4-(2,4,5~trisolebenzene 94579 105 201026314 base) butyl-)-3-(trifluoromethyl)-5, 6, 7, 8- Tetrahydropyrimidine sits and [i,5-a] 0 is placed in a reaction flask in an ice bath along with isopropyl-1-acetic acid isopropyl ester 35a (0.17 g, 〇·29 mmol) and 10 mL of ethyl acetate. 5 mL of a 5. 5N solution of hydrogenated hydrogen in ethyl acetate was added, and the ice bath was removed. The mixture was stirred at room temperature for 2 hours, and the reaction was traced by thin layer chromatography until the disappearance of the raw material. The alkane was washed (10 mL×2), and the filtrate was concentrated under reduced pressure to give the title product (*)(7) (3-(t-butoxy- ylamino)-4-(2, 4, 5-tri-l-phenyl) butyl )_3_ (dimethyl sulfhydryl)-5,6,7,8_ four wind mouth rice bran and [1,5-a] 〇啡啡 -1 -1 -1 竣竣 35 35 35 35 35 35 15g, white solid), yield: 97.8%. MS m/z (ESI): 493. 1 (M+1). NMRC^OMHz^MSO): (5 7.631-7.482(m, 2H), 5.159- 4 308 (in, 3H), 4. 285-3. 742(m, 5H), 3. 110-2. 735(m, 4H) 1 473-L 063(m, 6H). Example 36 (R) -7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)_3_(trimethylcarbenyl)-5, 6, 7, 8-tetrahydroimidazo[1,5 -a]pyridin-b carboxylic acid tert-butyl vine hydrochloride

第一步 94579 106 201026314 (R)-7-(3-胺基_4—(2,4,5_三氟苯基）丁醯基）_3_(三氟曱基）-5, 6, 7, 四氳咪唑並[1，5-a]^D并-1-緩酸第三丁基酯將（f〇-7-[3-第三丁氧羰基胺基-4-(2,4, 5-三氟苯基）-丁醯基]-3-三氟甲基—5, 6, 7, 8-四氫咪唑[1，5-a]吡畊 -卜叛酸 2a(〇· 3g，〇. 54mmol)、10mL 二氯甲烷、5mL 第三丁醇加入到lOOmL反應瓶中，攪拌下依次加入0.3mL三乙胺和雙（2-氧代_3_噁唑烷基）次磷醯氯（〇. 277g， 1. 09mmol)，室溫下攪拌反應2小時，再加入1〇mL第三丁 _醇以及第三丁醇鉀（0. 24g，2. 16mmol)，繼續於室溫下攪拌反應2小時’薄層層析追蹤反應至原料消失。向反應液中加入10mL飽和氯化銨溶液，有白色固體析出，墊ι〇〇—2〇〇目矽膠管柱過濾，收集濾液，加入50mL水，用乙酸乙酯萃取（25mLx5) ’合併的有機相依次用3〇mL飽和食鹽水洗滌，用無水硫酸鈉乾燥·，過濾，減壓濃縮濾液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（r)-7-(3-胺基-4-_ (2, 4, 5-三氟苯基）丁醯基）-3-(三氟甲基）-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-羧酸第三丁基酯36a(0. llg，白色固體），收率：33. 6%。 MS m/z (ESI) : 629.2(M+23)。 !ΗΝΜΚ(400ΜΗζ, CH3〇D): (5 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)。第二步 (R)_7_ (3-胺基-4-(2, 4, 5-三氟苯基）丁醯基）-3-(三氟甲 107 94579 201026314 基）5’6’7’8四氫》叫―卜竣酸第三丁基醋鹽酸鹽 _將00-7-(3-胺基+(2, 4, 5一三氣苯基）丁酿基）一3_ (三氟甲基)-5’6’7, 8-四氫咪唑並my吡畊一卜甲酸第二丁基酯36a(0. 〇94g，〇· 1511111]〇1)與1〇mL乙酸乙酯加入到反應瓶中，在冰浴下向反應瓶中加人3mI^5 5_氣化氮的乙酸乙酯溶液，滴加完畢後撤去冰浴，室溫下擾拌3小時，薄層層析追縱反應至原料消失，減壓濃縮反應液，加 ❹入20mL正己烧洗務，減壓濃縮，得到標題產物⑻_7_(3_ 胺基-4-（2, 4, 5-二氟苯基）丁醯基）_3—(三氟曱基）_5, 6， 7, 8-四氫咪唑並[1，5-a>比哄-1-竣酸第三丁基酯鹽酸鹽 36(0· 084g，白色固體），收率： MS m/z (ESI) : 507.0(M+1)。 HNMR(400MHz, CH3OD): δ Ί. 431-7. 387(m, 1Η), 7. 246-7. 198 (m, 1H), 5. 108-4.981(m, 2H), 4.354-3. 926(m, 5H), ❹ 3.174-3. 095(m，2H), 2·996-2·896(πι，2H), 1.276(s, 9H)。實施例37 (R)-7-(3-胺基-4-(2, 4, 5-三氟苯基）丁醯基）_3_(三氟曱基）-5, 6’ 7, 8-四氫咪》坐並[1，哄_i_竣酸（i_異丙氧基甲醯氧基）乙酯鹽酸鹽First step 94579 106 201026314 (R)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)_3_(trifluoromethyl)-5, 6, 7, tetradecene Imidazo[1,5-a]^D and-1-butylic acid tert-butyl ester (f〇-7-[3-t-butoxycarbonylamino-4-(2,4, 5-tri) Fluorophenyl)-butenyl]-3-trifluoromethyl-5,6,7-tetrahydroimidazole [1,5-a]pyrrolidine-inferior acid 2a (〇·3g, 〇. 54mmol), 10 mL of dichloromethane and 5 mL of third butanol were added to a 100 mL reaction flask, and 0.3 mL of triethylamine and bis(2-oxo-3-oxazolidinyl)phosphorus chloride (〇.277 g, 1. 09mmol), stir the reaction at room temperature for 2 hours, then add 1 〇 mL of the third butanol and potassium butoxide (0.24 g, 2.16 mmol), continue to stir at room temperature for 2 hours. The reaction was traced to the disappearance of the starting material. 10 mL of saturated ammonium chloride solution was added to the reaction solution, and a white solid was precipitated. The mixture was filtered through a pad of 〇〇〇〇〇〇〇〇 , , , , , , , , , , , , Ester extraction (25mLx5) 'The combined organic phases were washed sequentially with 3 mL of brine, dried over anhydrous sodium sulfate, filtered and evaporated The filtrate was purified by silica gel column chromatography 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]pyrylene-1-carboxylic acid tert-butyl ester 36a (0.11 g, white solid), yield : 33. 6% MS m/z (ESI): 629.2 (M+23). ΗΝΜΚ (400ΜΗζ, CH3〇D): (5 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). The second step (R)_7_(3-amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl 107 94579 201026314 base) 5'6' 7'8 tetrahydrogen is called "di-butyl vinegar hydrochloride" _ 00-7-(3-amino + (2, 4, 5 - tri-phenylphenyl) butyl) 3-_ ( Trifluoromethyl)-5'6'7, 8-tetrahydroimidazolium and pyridinium benzoic acid dibutyl ester 36a (0. 〇94g, 〇·1511111) 〇1) with 1 mL of ethyl acetate Adding to the reaction flask, adding 3mI^5 5_vaporized nitrogen ethyl acetate solution to the reaction flask under ice bath, after the addition is completed, the ice bath is removed, and the mixture is stirred for 3 hours at room temperature. The reaction was traced to the disappearance of the starting material. The reaction mixture was concentrated under reduced pressure, and the mixture was evaporated to 20 mL of hexanes, and concentrated under reduced pressure to give the title product (8) _7_(3_amino-4-(2,4,5-difluorobenzene) )3)(醯丁基)_3—(Trifluoromethyl)_5, 6, 7, 8-tetrahydroimidazo[1,5-a> 哄-1-decanoic acid tert-butyl ester hydrochloride 36 (0· </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; HNMR (400MHz, CH3OD): δ Ί. 431-7. 387(m, 1Η), 7. 246-7. 198 (m, 1H), 5. 108-4.981(m, 2H), 4.354-3. 926 (m, 5H), ❹ 3.174-3. 095 (m, 2H), 2·996-2·896 (πι, 2H), 1.276 (s, 9H). Example 37 (R)-7-(3-Amino-4-(2,4,5-trifluorophenyl)butanyl)_3_(trifluoromethyl)-5,6' 7, 8-tetrahydromethane 》Sit and [1, 哄_i_decanoic acid (i_isopropoxymethyl methoxy) ethyl ester hydrochloride

108 94579 201026314108 94579 201026314

(R)-7-(3-胺基-4-(2, 4, 5-三氣苯基）丁醯基）-3.-(三氟甲基）-5, 6，7，8_四氮口米0坐並[1，5-&]°比啡-1-緩酸（1-異丙氧基曱醯氧基）乙酯將（R)-7-[3-第三丁氧裁基胺基-4-(2, 4, 5-三敗苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑[1，5-a>比畊 -1-叛酸 2a(0. 275g，0. 5mmol)與 4mL N，N-二曱基曱醯胺加入到反應管中，攪拌使其溶解，依次向反應管中加入碳酸 -1-氯乙酯-異丙醋（O.lg，0.6mmol)、埃化卸（0.0415g， 0· 25mmol)、碳酸钟（0. 083g，0. 6mmol)，加畢，封管，置於油浴中控制油浴外溫65°C，反應2小時，薄層層析追蹤反應至原料消失。將反應管從油浴中取出，待其冷至室溫 ❹後，向其中加水40mL，用乙酸乙酯萃取（25mLx3)，薄層層析檢測水相中無產物，收集有機相，用水洗（20mLx2)，合併有機相，用無水硫酸鎂乾燥，過濾，減壓濃縮濾液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-7-(3-胺基_4-（2, 4，5-三氟苯基）丁酿基）-3-(三氟甲基）-5，6，7， 8-四氳咪唑並[1，5-a]吡畊-1-羧酸1-(異丙氧基甲醯氧基）乙酯37a(0. 29g，淡黃色固體），收率：85. 3%。 MS m/z (ESI) : 698. 0(M+18)。 109 94579 201026314 !ΗΝΜΚ(400ΜΗζ, CDCh): ά 7. 12(m, 1Η), 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)。第二步 (R)-7-(3-胺基-4-(2, 4, 5-三氟苯基）丁醯基）-3-(三氟甲基）-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-甲酸（異丙氧基甲醯氧基）乙酯鹽酸鹽 ❹ 將（R)-7-(3-胺基-4-(2, 4, 5-三氟苯基）丁醯基）-3-(三氟甲基）-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊-1-曱酸（異丙氧基甲醯氧基）乙酯37a(0. 29g, 0.43mmol)與5mL乙酸乙酉旨加入到反應瓶中，再加入3mL 6. 5N的氯化氳的乙酸乙酯溶液，室溫下攪拌反應4小時，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-7-(3-胺基-4-(2,4, 5-三氟苯基） Ο 丁醯基）-3-(三氟甲基）-5, 6, 7, 8-四氫咪唑並[1，5-a>比畊 -1-曱酸（異丙氧基甲醯氧基）乙酯鹽酸鹽37(0.24g，白色固體），收率：91. 2%。 MS m/z (ESI) : 581. KM+1)。 'ΗΝΜΕ(400ΜΗζ, CD3〇D): (5 7. 38(m, 1H), 7. 25(m, 1H), 6.96 (m, 1H), 5.10(111, 2H), 4. 88(m, 1H), 4. 33(m, 2H), 4. ll(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)。實施例38 110 94579 201026314 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]_3_三氣甲基-5, 6, 7, 8-四氫咪嗤並[1，5-a]"比〇并-1-緩酸環已基醯氧基）乙酯鹽酸鹽(R)-7-(3-Amino-4-(2,4,5-triphenylphenyl)butanyl)-3.-(Trifluoromethyl)-5, 6,7,8-tetrazine Rice 0 sits and [1,5-&]° is equivalent to cyano-1-acid (1-isopropoxy methoxy)ethyl ester to (R)-7-[3-Tertioxine Amino-4-(2,4,5-triphenylphenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazole [1,5-a> - Resin 2a (0. 275 g, 0.5 mmol) and 4 mL of N,N-didecylguanamine were added to the reaction tube, stirred to dissolve, and then 1-hexyl carbonate was added to the reaction tube in turn - Isopropyl vinegar (O.lg, 0.6mmol), Anhua unloading (0.0415g, 0·25mmol), carbonic acid clock (0. 083g, 0.6 mmol), added, sealed, placed in an oil bath to control the oil bath The external temperature was 65 ° C, and the reaction was carried out for 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 the mixture was extracted with ethyl acetate (25 mL×3), and the product was collected from the aqueous phase by thin layer chromatography, and the organic phase was collected and washed with water ( The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5,6,7, 8-tetraimidazo[1,5-a]pyrrol-1-carboxylate 3%。 The acid 1-(isopropoxymethyl methoxy) ethyl ester 37a (0. 29g, pale yellow solid), yield: 85.3%. MS m/z (ESI): 698. (M+18). 109 94579 201026314 !ΗΝΜΚ(400ΜΗζ, CDCh): ά 7. 12(m, 1Η), 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). The second step (R)-7-(3-amino-4-(2,4,5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5, 6, 7, 8- four Hydrogenimidazo[1,5-a]pyroxy-1-carboxylic acid (isopropoxymethyl methoxy)ethyl ester hydrochloride ❹ (R)-7-(3-Amino-4-(2, 4, 5-trifluorophenyl)butanyl)-3-(trifluoromethyl)-5, 6, 7, 8-tetrahydroimidazo[1,5-a]pyrazine-1-decanoic acid (isopropyl Oxymethyl methoxy) ethyl ester 37a (0. 29g, 0.43mmol) and 5mL of ethyl acetate were added to the reaction flask, and then added with 3mL of 6. 5N ethyl acetate solution of ruthenium chloride, and stirred at room temperature. After 4 hours, the reaction was traced to the disappearance of the material by the thin layer chromatography, and the reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by the column chromatography to give the title product (R)-7-(3-amino-4-(2) , 4, 5-trifluorophenyl) Ο 醯 )))-3-(trifluoromethyl)-5, 6, 7, 8-tetrahydroimidazo[1,5-a> 2%。 Isopropoxymethyl methoxy) ethyl ester hydrochloride 37 (0.24 g, white solid), yield: 91.2%. MS m/z (ESI): 581. KM+1). 'ΗΝΜΕ(400ΜΗζ, CD3〇D): (5 7. 38(m, 1H), 7. 25(m, 1H), 6.96 (m, 1H), 5.10(111, 2H), 4. 88(m, 1H), 4. 33(m, 2H), 4. ll(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 38 110 94579 201026314 (R)-7-[3-Amino-4-(2,4, 5-trifluorophenyl)-丁醯基]_3_三气methyl-5, 6, 7, 8-tetrahydroimiphtho[1,5-a]"比〇和-1--acidocyclohexyloxy)ethyl ester hydrochloride salt

第一步 (R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基；μ3—三氣甲基-5, 6, 7, 8-四氫咪嗤並[1，5-a]°比啡-1-緩酸-(卜環己基醯氧基）乙酯將（R) - 7-[3-第二丁氧幾基胺基-4-(2，4，5 -三氣笨基）-丁醯基]-3-三氟曱基-5, 6, 7, 8-四氫咪唑[1，井 ❹-1-羧酸2a(0.275g，0.5mmol)與4mLN，N-二甲基甲酿胺放入反應管中，攪拌使2a溶解，依次向反應管中加入碳酸乳乙醋-環己基醋（〇. 124g，0. 6mmol)、埃化卸（〇. 〇415泛〇.25mmol)、碳酸鉀（〇.〇83g，0.6minol)，加畢，封管，至於油浴中控制外溫65〇C攪拌反應2小時，薄層層析追蹤反應至原料消失。將反應管從油浴中取出，待反應液冷卻至至溫後，向其中加入4〇mL水，用乙酸乙酯萃取（3〇mLx3)，合併有機相，用3〇mL水洗，再用30mL飽和食鹽水洗，合併有機相，用無水硫酸鎂乾燥，過濾，減壓濃縮濾液，用 94579 111 201026314 法純化所得殘餘物，得到標題產物⑻+[3-土 ’ 4, 5~二氣苯基）-丁酿基]'3-三氟甲基-5, 6, 7, 酉曰38a(0.25g，白色固體），收率：69,4%。 MS ffi/z (ESI) : 721.〇(m+1)。第二步 (f〇-7-[3-胺基-4-(2, 4, 5-三氟苯基）—丁醯基]_3_三氟甲基^^”-四氫咪唑並^乃-心吡啡—丨—羧酸气卜環己基 11醯氧基）乙酯鹽酸鹽將（R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基]_3一三氟甲基-5’ 6,7,8-四氫咪唑並[1，5一&]吡畊一卜甲酸—（卜環己基醯氧基）乙酯38a(0.25g，0.347mmol)與5mL乙酸乙酯放入反應瓶中，攪拌下加入3mL之6. 5N的氯化氫的乙酸乙酯溶液，室溫下攪拌反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘 ◎餘物’得到標題產物（R)-7-[3-胺基-4-(2, 4, 5-三氟笨基）— 丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑並[1，5-a]n比哄 -1-甲酸-(1-環己基醯氧基）乙酯鹽酸鹽38(0. 22g，白色固體），收率：96. 1%。 MS m/z (ESI) : 621. 1(M+1)。 1HNMR(400MHz, CDsOD): 5 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. 〇2(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), i.47(m 94579 112 201026314 • -- - 3H)，1.31(m，3H)。實施例39 (尺）-7-[3-胺基-4-(2,4,5-三氟苯基）-丁醯基]-8一甲基_3_ 三氟甲基-5, 6, 7, 8-四氫咪唑並[i，5-a]吡啡-1-甲酸甲酯鹽酸鹽First step (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl; μ3-trimethylmethyl-5, 6, 7, 8-tetrahydromethane嗤[1,5-a]° than morphine-1-hypoacid-(bucyclohexyl decyloxy)ethyl ester (R)-7-[3- 2 -butoxymethylamino-4-( 2,4,5-trisyl)butylinyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazole [1, well ❹-1-carboxylic acid 2a (0.275 g, 0.5 mmol And 4 mL of N,N-dimethyl ketoamine was placed in a reaction tube, and 2a was dissolved by stirring, and ethylene carbonate-cyclohexyl vinegar (〇. 124 g, 0.6 mmol) was added to the reaction tube in turn, and the solution was discharged. (〇. 〇 415 ubiquinone. 25mmol), potassium carbonate (〇.〇83g, 0.6minol), add, seal the tube, as in the oil bath to control the external temperature 65 ° C stirring reaction for 2 hours, thin layer chromatography to trace the reaction Until the raw materials disappear. The reaction tube was taken out from the oil bath, and after the reaction liquid was cooled to the temperature, 4 mL of water was added thereto, and extracted with ethyl acetate (3 mL mL 3), and the organic phase was combined, washed with 3 mL of water, and then 30 mL. The organic layer was combined with EtOAc EtOAc (EtOAc m. - butyl aryl] '3-trifluoromethyl-5, 6, 7, 酉曰38a (0.25 g, white solid), yield: 69, 4%. MS ffi/z (ESI): 721. 〇 (m+1). The second step (f〇-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]_3_trifluoromethyl^^"-tetrahydroimidazolium (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butanyl group, pyridinium-indole-carboxylic acid gas cyclohexyl 11 methoxy)ethyl ester hydrochloride ]_3-Trifluoromethyl-5' 6,7,8-tetrahydroimidazo[1,5-&]pyrazine-p-carboxylic acid-(b-cyclohexyloxy)ethyl ester 38a (0.25 g, 0.347 (mmol) and 5 mL of ethyl acetate were placed in a reaction flask, and 3 mL of a 6. 5N solution of hydrogen chloride in ethyl acetate was added 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)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butenyl]-3 -trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[1,5-a]n than 哄-1-carboxylic acid-(1-cyclohexyldecyloxy)ethyl ester hydrochloride 38 (0 </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 16(m, 1H), 6 95 (m, 1H), 5. 10(m, 1H), 4. 64(m, 1H), 4. 29(d, 2H), 4. 〇2(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), i.47 (m 94579 112 201026314 • -- - 3H), 1.31 (m, 3H). Example 39 (foot)-7-[3-amino-4-(2,4) ,5-trifluorophenyl)-butenyl]-8-methyl_3_trifluoromethyl-5, 6, 7, 8-tetrahydroimidazo[i,5-a]pyridin-1-carboxylate Hydrochloride

第一步 8-甲基-3-三氟甲基-5, 6-二氫-8H-咪唑並[1，5-a]吡畊 -1，7-二羧酸-7-第三丁酯將3_二氣甲基5，6-一風-8丑-〇米σ坐並[1，5_a]°比哄-1，7_ 二竣酸 7-第二丁酯 27d(0. 85g，2. 54mmol)溶解於 25mL 無 ©水曱苯和8mL無水四氫呋喃的混合溶劑中，將反應瓶置於乾冰-丙酮浴中冷卻至-78°C，加入四甲基乙二胺（i.32mL， 8087mmol)，逐滴加入正丁基鋰（5. 55mL，8. 87mmol)，五分鐘滴加完畢，保持外溫-78°C，反應15分鐘’逐滴加入碘甲烷（0.4mL，6·34ππηο1)，保持-78°C反應10分鐘，然後升至室溫反應2小時’薄層層析追蹤反應至原料消失。向反應液中加入15mL氣化銨的飽和溶液，然後加入20mL水，用2N 的鹽酸調節pH值至3至4,用乙酸乙酯萃取（30mLx3)，合併 113 94579 201026314 有機相，用無水硫酸鋼乾燥，過滤，減壓濃縮滤液，用紗膠管柱層析法純化所得殘餘物，得到標題產物8-甲基-3-三氟甲基-5, 6-二氫-8H-咪唾並[1，5-a>比哄-1，7-二幾:酸-7-第三丁酯39a(0· 215g，白色固體），收率：24. 3%。第二步 8-甲基-3-三氟曱基-5, 6-二氳-8H-咪0坐並[1，5-a] 比口井 -1，7-二羧酸-7-第三丁酯-1-甲酯將8-甲基-3-三氟甲基-5, 6-二氩-8Η-咪唑並[1，5-aJ ❹吼哄-1，7-二羧酸-7-第三丁酯39a(0.349g，lmmol)溶解於 15mLN，N-二甲基曱醯胺中，攪拌下加入碳酸氫鈉（〇. 84g， lOmmol) ’逐滴加入破甲烧（〇.43g，3mm〇l)，室溫下擾拌反應40小時’薄層層析追蹤反應至原料消失，減壓濃縮反應液’用矽膠管柱層析法純化所得殘餘物，得到標題產物8_ 甲基-3-三氟曱基-5, 6-二氫-8H-咪唑並5一a]吡哄7一二竣酸-7-第三丁酯-1-曱醋39b(〇.5g，黃色油狀物），收 A 率：100% 〇 MS m/z (ESI) : 364. 0(M+1)。 ^JMRGOOMHz，CDCh): (5 5.85(t，1H)，4.24(t 2H) 4.04(t，2H), 3.93(s，3H)，1.56(d，3H)，1.51(S，9H)。第三步 8-曱基-3-三氟曱基-5, 6, 7, 8-四氫咪唾並[i，5_a]o比哄_i_ 羧酸甲酯鹽酸鹽將8-甲基-3-三氟甲基-5, 6-二氫-8H-咪唾並[1，5-a] °比口井-1，7-二叛酸-7-第三丁酯-1-甲酯39b(0. 35g， 94579 114 201026314 0. 96mmol)放入反應瓶中，加入lOmL之2. 3N的氯化氫的乙酸乙酯溶液，室溫下攪拌反應2小時，薄層層析追蹤反應至原料消失，減壓濃縮反應液，得到標題產物8-甲基-3-三氟*甲基-5，6，7, 8-四氫味〇坐並[1，5-&]〇比哄-1-曱酸甲酉旨鹽酸鹽39c粗品（0.4g，黃色油狀物）。 1HNMR(400MHz, CDCh): 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)。 ❻ 第四步 (R)-7-[3-第三丁氧裁基胺基-4-(2, 4, 5-三氟1苯基）-丁醯基]_3-三氟曱基-5，6，7，8-四氮咪唾並[1，5-a]〇比啡-1 -叛酸曱酯將8-曱基-3-三氟1甲基-5, 6, 7, 8-四氫味〇坐並[1，5-a] 吡畊-1-羧酸甲酯鹽酸鹽39c粗品（0.289g，0.96mmol)與 (R)-3-第三丁氧幾基胺基-4-( 2, 4, 5-三氣苯基）-丁酸 ❹lf(0.353g，1.06mmol)溶於10mL二氯曱烧中，授拌下依次加入三乙胺（0. 4mL，2. 9mmol)和雙（2-氧代-3-°惡峻院基）次膦酸氯（0.368g，1.45mmol)，室溫下授拌反應過夜，薄層層析追蹤反應至原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-7-[3-第三丁氧羰基胺基-4-(2, 4, 5 -三氟苯基）-丁醯基]-3-三氟甲基 -5, 6, 7, 8-四氫口米0坐並[1，5-a]n比哄-1-缓酸甲酉旨39d(0. 43g，黃色油狀物），收率：77. 2°/〇。 MS m/z (ESI) : 579. 1(M+1)。 115 94579 201026314 第五步 ⑻;7-[3-胺基-4-(2,4,5-三氟苯基）-丁醯基]_8_甲基_3— 一氟曱基5, 6, 7, 8-四氫p米唾並[1，5-a]0比啡_ι一叛酸曱酯鹽酸鹽將7-[3-第三丁氧羰基胺基_4_(2,4,5_三氟苯基）一丁酿基]-3-三氟甲基~5, 6, 7, 8_四氩咪唑並[u 5_a]吡畊曱酸甲醋39d(0. 23g，〇.4mm〇i)放入反應甑中，加入5mL之 2. 3N的氯化氫的乙酸乙酯溶液，室溫下攪拌反應2小時， ❹薄層層析追蹤反應至原料消失，減壓下濃縮反應液，得到標題產物（R)-7-[3-胺基-4-(2, 4, 5-三氟苯基）-丁醯基] -8-曱基-3-三氟曱基-5, 6, 7, 8-四氫咪唑並[1，5-a]吡畊 -1-羧酸-曱酯鹽酸鹽39(0· 205g，白色固體），收率：1〇〇%。 MS m/z (ESI) : 479. KM+1)。 1HNMR(400MHz, CDCh): (5 7.33(m, 1H), - 6.93(ffi, 1H), 5.58(m, 1H), 5. 02(m, 1H), 4.33(ra, 2H), 3.86(s, 3H), ❾ 3.43(t, 2H), 3. 06(m，2H)，2.49(m, 2H), 1.57(d, 3H)。實施例40、41 (尺）-7-(3-胺基-4-(2,4,5-三說苯基）丁醢基）-(§)_8_甲基 -3-(二氣曱基）-5, 6, 7, 8-四氫啼。坐並[1，5-a]〇比卩井-i-叛酸甲酯鹽酸鹽 (1〇-7-(3-胺基-4-(2,4,5-三氟苯基）丁醯基）-(只）_8_甲基 3-（二氣甲基）-5，6, 7, 8 -四氫p米〇坐並[1，5-a]11比Q井叛酸甲酯鹽酸鹽 94579 116 201026314First step 8-methyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-1,7-dicarboxylic acid-7-t-butyl ester 3_2 gas methyl 5,6-a wind-8 ugly-glutinous rice σ sit and [1,5_a] ° 哄-1,7_ didecanoic acid 7-second butyl ester 27d (0. 85g, 2 54 mmol) was dissolved in a mixed solvent of 25 mL of hydrazine-free benzene and 8 mL of anhydrous tetrahydrofuran. The reaction flask was placed in a dry ice-acetone bath and cooled to -78 ° C, and tetramethylethylenediamine (i.32 mL, 8087 mmol) was added. ), n-butyllithium (5. 55 mL, 8.87 mmol) was added dropwise, and the addition was completed in five minutes, and the external temperature was maintained at -78 ° C for 15 minutes. 'Methyl iodide (0.4 mL, 6·34ππηο1) was added dropwise. The reaction was kept at -78 ° C for 10 minutes, and then raised to room temperature for 2 hours. The reaction was traced by thin layer chromatography until the starting material disappeared. Add 15 mL of a saturated solution of ammonium hydride to the reaction solution, then add 20 mL of water, adjust the pH to 3 to 4 with 2N hydrochloric acid, extract with ethyl acetate (30 mL×3), and combine 113 94579 201026314 organic phase with anhydrous sulfuric acid steel. The mixture was dried, filtered, and the filtrate was evaporatedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 5%。 The ratio of -5-a> 哄-1,7-two: acid-7-t-butyl ester 39a (0· 215g, white solid), yield: 24.3%. The second step is 8-methyl-3-trifluoroindolyl-5,6-diindole-8H-m-[0,1[5,5-a] than well-1,7-dicarboxylic acid-7- Tributyl ester-1-methyl ester 8-methyl-3-trifluoromethyl-5,6-diar-8-imidazo[1,5-aJ ❹吼哄-1,7-dicarboxylic acid- 7-T-butyl ester 39a (0.349 g, 1 mmol) was dissolved in 15 mL of N,N-dimethyl decylamine, and sodium hydrogencarbonate (〇. 84 g, 10 mmol) was added with stirring. 43g, 3mm〇l), the reaction was scrambled for 40 hours at room temperature. The reaction was traced by thin layer chromatography until the starting material disappeared. The reaction mixture was concentrated under reduced pressure. The residue obtained was purified by column chromatography to give the title product. -3-trifluorodecyl-5,6-dihydro-8H-imidazolium-5-a]pyridinium-7-didecanoic acid-7-t-butyl ester-1-indole vinegar 39b (〇.5g, yellow oil A), A rate: 100% 〇MS m/z (ESI): 364. 0 (M+1). ^JMRGOOMHz, CDCh): (5 5.85(t,1H), 4.24(t 2H) 4.04(t,2H), 3.93(s,3H), 1.56(d,3H),1.51(S,9H). Step 8-mercapto-3-trifluoromethyl-5,6,7-tetrahydropyrimidin[i,5_a]o than 哄_i_carboxylic acid methyl ester hydrochloride 8-methyl-3 -trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a] ° ratio well-1,7-detreic acid-7-t-butyl ester-1-methyl ester 39b (0. 35g, 94579 114 201026314 0. 96mmol) was placed in a reaction flask, and 10 mL of a 3.0 N solution of hydrogen chloride in ethyl acetate 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 solution was concentrated under reduced pressure to give the titled product, <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The crude product of the hydrazine hydrazide hydrochloride 39c (0.4 g, yellow oil). 1HNMR (400MHz, CDCh): 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). ❻ Fourth step (R)-7-[3-Tertioxetine-4-(2,4,5-trifluoro-phenyl) )-丁醯基]_3-Trifluoromethyl-5,6,7,8- Nitromethico[1,5-a]indole-p-pyrrolidone ester will sit 8-mercapto-3-trifluoro-1methyl-5, 6, 7, 8-tetrahydro miso and [ 1,5-a] pyridin-1-carboxylic acid methyl ester hydrochloride 39c crude (0.289 g, 0.96 mmol) and (R)-3-tert-butoxyamino-4-(2, 4, 5-trisylphenyl)-butyric acid ❹lf (0.353 g, 1.06 mmol) was dissolved in 10 mL of dichloropyrene, and triethylamine (0.4 mL, 2.9 mmol) and bis (2-oxygen) were added sequentially. -3- 恶院 ) ) 次次次 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 0.3 The obtained residue was purified by chromatography to give the titled product(R)-7-[3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoro Methyl-5, 6, 7, 8-tetrahydromethane 0 satisfies and [1,5-a]n is more than 哄-1--hypo-acidic hydrazine 39d (0. 43g, yellow oil), yield : 77. 2°/〇. MS m/z (ESI): 579. 1 (M+1). 115 94579 201026314 The fifth step (8); 7-[3-amino-4-(2,4,5-trifluorophenyl)-butanyl]_8_methyl_3-fluorofluoroalkyl 5, 6, 7, 8-tetrahydro-p-saltino[1,5-a]0-pyridyl-ι- retinoic acid ester hydrochloride 7-[3-t-butoxycarbonylamino group_4_(2,4,5_ Trifluorophenyl)-butyryl]-3-trifluoromethyl~5, 6, 7, 8_tetraarsenazo[u 5_a]pyrrolic acid methyl vinegar 39d (0. 23g, 〇.4mm〇 i) Put in a reaction hydrazine, add 5 mL of a 2.N solution of hydrogen chloride in ethyl acetate, stir the reaction at room temperature for 2 hours, trace the reaction by thin layer chromatography until the starting material disappears, and concentrate the reaction mixture under reduced pressure to give the title. Product (R)-7-[3-Amino-4-(2,4,5-trifluorophenyl)-butenyl]-8-indolyl-3-trifluoromethyl-5, 6, 7, 8 - tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid-nonyl ester hydrochloride 39 (0·205 g, white solid), yield: 1%. MS m/z (ESI): 479. KM+1). 1H NMR (400MHz, CDCh): (5 7.33 (m, 1H), - 6.93 (ffi, 1H), 5.58 (m, 1H), 5. 02 (m, 1H), 4.33 (ra, 2H), 3.86 (s , 3H), ❾ 3.43(t, 2H), 3. 06(m, 2H), 2.49(m, 2H), 1.57(d, 3H). Example 40, 41 (foot)-7-(3-amine Base-4-(2,4,5-trisylphenyl)butanyl)-(§)_8_methyl-3-(dioxamethyl)-5, 6, 7, 8-tetrahydroindole. [1,5-a]〇比卩井-i-Resinic acid methyl ester hydrochloride (1〇-7-(3-amino-4-(2,4,5-trifluorophenyl)butanyl)- (only) _8_methyl 3-(dimethylmethyl)-5,6,7-8-tetrahydrop-methane sputum and [1,5-a]11 than Q well reductive methyl ester hydrochloride 94579 116 201026314

❹❹

將（R)-7-[3-胺基-4-(2, 4, 5-三 It 苯基）-丁酿基]一8一曱基-3-三氟甲基-5, 6, 7, 8-四氳咪唑並[1，5~a]吡哄一1-缓酸甲酯鹽酸鹽39(141mg，29.5mmol)進行手性拆分，採用 HPLC法，用手性柱對異構體進行分離（分離條件：手性柱 Chiralcel AD-H，流動相：正己烷：異丙醇：二乙胺=7〇 : 3〇 : 〇. 1，流速：1. 〇 ml/min)，收集其相應組分，旋轉蒸發除去溶劑，並在室溫下真空乾燥4小時，得到標題產物 00-7-(3-胺基-4-(2,4,5-三氟苯基）丁醯基）_(5)—8_甲基 -3-(三氟甲基）_5, 6, 7, 8_四氫咪唑並[丨，5—a]吡啡_丨_羧酸甲酯鹽酸鹽 40(57mg’ 11.9mmol)和（R)-7-(3-胺基一 (2,4, 5-二I笨基）丁醯基）_(R)_g_曱基一3一（三氟甲基）一 5, 6, 7’8-四氫咪唑並[i，5_a]吡畊4一羧酸曱酯鹽 (5〇mg ， 10.5mm〇l)。實施例42 (ί〇-7-[3-胺基-4-(2, 4, 5-三氟-苯基）—丁醯基]_3_三氟甲基一5’ 6, 7, 8-四氫-咪1並[1，5-a]吡哄乙基）甲醯胺(R)-7-[3-Amino-4-(2,4,5-tri-It phenyl)-butyl-aryl]-8-fluorenyl-3-trifluoromethyl-5, 6, 7 , 8-tetraimidazo[1,5~a]pyridin-1-sutonic acid methyl ester hydrochloride 39 (141 mg, 29.5 mmol) was subjected to chiral separation using HPLC method, chiral column toomer Separation of the body (separation conditions: chiral column Chiralcel AD-H, mobile phase: n-hexane: isopropanol: diethylamine = 7 〇: 3 〇: 〇. 1, flow rate: 1. 〇ml/min), collection The corresponding components were removed by rotary evaporation and dried under vacuum at room temperature for 4 hours to give the title product 00-7-(3-amino-4-(2,4,5-trifluorophenyl)butanyl) (5) 8-methyl-3-(trifluoromethyl)_5, 6, 7, 8_tetrahydroimidazo[丨,5-a]pyridinyl-carboxylate methyl ester hydrochloride 40 ( 57 mg '11.9 mmol) and (R)-7-(3-amino-(2,4,5-diI-phenyl)butanyl)-(R)_g-mercapto-1,3-(trifluoromethyl)- 5, 6, 7'8-tetrahydroimidazo[i,5_a] pyridinium 4-carboxylate oxime ester (5 〇 mg, 10.5 mm 〇l). Example 42 (ί〇-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butanyl]_3_trifluoromethyl-5' 6, 7, 8-tetrahydrogen -Mimi 1 and [1,5-a]pyridinium ethyl)carbenamide

94579 117 20102631494579 117 201026314

(R) [3 (1乙基氣甲酿基_3一三氟曱基_5,6_二氮-8Η-ϋ米唾並[1，5-a]"比哄-7-基）_3_氧代5—三氟-苄基）一丙基]-胺基曱酸第三丁酯 & 將（ί〇-7-[3-第三丁氧羰基胺基-4-(2, 4, 5-三氟笨基）-丁醯基]-3-三氟曱基-5, 6, 7, 8-四氫咪唑[1，5-a]吡啡 -1-羧酸2a(180mg，〇.33mmol)溶解於10mL四氫呋喃中，加入乙基胺鹽酸鹽（269mg，3. 3腿〇1)，雙（2-氧代-3-噁唑烷基）次磷醯氯（168mg，0· 66mmol)以及三乙胺（367mg， 3. 63mmol)，室溫下攪拌反應4小時，薄層層析追蹤反應，原料消失，過濾反應液，減壓濃‘濾液，用矽膠管柱層析法純化所得殘餘物’得到標題產物（R)-[3-(l-乙基氨甲醯 ❹基_3_三氟甲基-5, 6-二氫-8H-咪嗤並[1，5-a]〇比哄-7-基）-3-氧代-1-(2, 4, 5-三氟-苄基）-丙基]-胺基甲酸第三丁酯42a(190mg，白色固體），收率：>ι〇〇%。 MS m/z (ESI) : 600·1(Μ+23)。第二步 (R)-7-[3-胺基-4-(2, 4, 5-三氟-苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8_四氫-咪唑並[1，5-a]吡D井-l-(N-乙基）甲醯胺將（R)-[3-(1-乙基氨曱酿基-3-三氣甲基-5, 6-二氫 118 94579 201026314 -8H-咪唑並[1，5-a]吡啡_7_基）_3_氧代―卜^ 4, 5_三氟_苄基）-丙基]-胺基甲酸第三丁酯42a(19〇mg，〇. 33_〇1)溶解於10mL二氯甲烷中，再加入三氟乙酸（75〇mg，6. 6mm〇i), 至溫下攪拌反應2小時，薄層層析追蹤反應，原料消失，減壓辰縮反應液，用石夕膠管柱層析法純化所得殘餘物，得到標題產物（R)-7-[3-胺基-4-(2,4,5-三氟-苯基）-丁醯基]-3-二氟甲基-5, 6, 7, 8-四氫-咪唑並[L 5_a]吡畊 -1-(N-乙基）甲醯胺42(120mg，白色固體），收率：76 4%。 MS m/z (ESI) : 478. 1(M+1)。 WMRUGOMHUD·): 5 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-L23(m，1H)，7.36_7 37(d，’1H)’。實施例43 00-7-[3-胺基-4-(2, 4, 5-三氟-苯基）_丁醯基]_3_三氟曱基~5, 6, 7, 8-四氫-咪产並[1’ 5-a]吡D井^ — 丁基）甲醯胺(R) [3 (1 ethyl methoxymethyl _3-trifluoromethyl _5,6-diaza-8 Η-ϋ米唾[1,5-a]" 哄-7-yl) _3_oxo-5-trifluoro-benzyl)-propyl]-amino decanoic acid tert-butyl ester & ((〇-7-[3-t-butoxycarbonylamino-4-(2, 2, 4, 5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydroimidazole [1,5-a]pyrone-1-carboxylic acid 2a (180 mg, hydrazine .33 mmol) was dissolved in 10 mL of tetrahydrofuran, and ethylamine hydrochloride (269 mg, 3.3 leg 〇1), bis(2-oxo-3-oxazolidinyl)phosphorus chloride (168 mg, 0·) was added. 66 mmol) and triethylamine (367 mg, 3.63 mmol), stirred at room temperature for 4 hours, the reaction was traced by thin layer chromatography, the starting material disappeared, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography. The residue obtained 'is obtained the title product (R)-[3-(l-ethylcarbamoyl_3_trifluoromethyl-5,6-dihydro-8H-imiphthene[1,5-a 〇哄-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 42a (190 mg, white solid) Yield: > ι〇〇% MS m/z (ESI): 600·1 (Μ+23). The second step (R)-7-[3-amino-4-(2, 4, 5-Trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8_tetrahydro-imidazo[1,5-a]pyridyl-l-(N- Ethyl)carboxamide will be (R)-[3-(1-ethylamino hydrazin-3-trimethylmethyl-5,6-dihydro 118 94579 201026314 -8H-imidazo[1,5- a]pyridin-7-yl)_3_oxo-bu^4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 42a (19〇mg, 〇. 33_〇1 Dissolved in 10 mL of dichloromethane, then added trifluoroacetic acid (75 〇 mg, 6.6 mm 〇i), stirred at room temperature for 2 hours, traced the reaction by thin layer chromatography, the disappearance of the starting materials, the reaction solution The residue obtained was purified by chromatography eluting to afford titled product (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butanyl]-3- Difluoromethyl-5,6,7-tetrahydro-imidazo[L 5_a]pyrylene-1-(N-ethyl)formamide 42 (120 mg, white solid), yield: 76 4% . MS m/z (ESI): 478. 1 (M + 1). WMRUGOMHUD·): 5 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-L23(m, 1H), 7.36_7 37(d, '1H)'. Example 43 00-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butanyl]_3_trifluoromethyl~5, 6, 7, 8-tetrahydro-mi Produced and [1' 5-a] pyridinium D ^ butyl) carbamide

第一步 -5, 6-一^氣-8H-口米°坐 (R)-[3-(l-丁基氨曱醯基-3-三氟曱基 94579 119 201026314 並[1，5-a]吼畊-7-基）-3-氧代-1-(2, 4, 5-三氟-苄基）-丙基]-胺基曱酸第三丁酯將（R)-7-[3-第三丁氧羰基胺基_4-(2,4,5-三氟苯基）-丁醯基]-3-三氟甲基-5, 6, 7, 8-四氫咪唑[1，5-a]吡卩井 -1-羧酸2a(180mg，0.33mmol)溶解於i〇mL二氯甲烷中，加入丁基胺鹽酸鹽（193mg，2. 64mmol)，雙（2-氧代-3-»惡唾院基）次膦醯氯（167mg，0. 66mmol)以及三乙胺（i〇〇mg，〇. 99mmol)，室溫下攪拌反應過夜’薄層層析追蹤反應，原 ®料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物’得到標題產物（R)-[3-(1-丁基氨曱酿基-3-三氟甲基 -5, 6-二氫-8H-嗓嗤並[1，5-a] *»比哄-7-基）-3-氧代 5-二氟-卡基）—丙基]一胺基甲酸第三丁酉旨 43a(120mg，白色固體），收率：60%。 MS m/z (ESI) : 606·0(M+1)。第二步 ❹00-7-[3-胺基-4-(2, 4, 5-三氟-苯基）-丁醯基]-3-三氟甲基一5, 6, 7, 8-四氫-咪唾並[1，5-a]0比哄-1-(N-丁基）甲醢胺將（R)-[3-(1-丁基氨甲醯基-3-三氟甲基-5, 6-二氫 -811-咪唾並[1，5-a]吡畊-7-基）-3-氧代-1-(2, 4, 5-三氟-节基）-丙基]-胺基甲酸第三丁酯43a(120mg，0. 198mmol) 溶解於l〇mL二氯甲烷中，再加入三氟乙酸（452mg， 3· Wmmol)，室溫下攪拌反應2小時，薄層層析追蹤反應，原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（r)-7-[3-胺基-4-(2,4,5-三氟-苯 120 94579 201026314 基）-丁醢基]-3-三氟曱基-5, 6, 7, 8-四氫-咪唾並[1 5-a] 0比D井-1-(N-丁基）甲醯胺43(70mg，白色固體），收率：7〇%。 MS m/z (ESI) : 506. KM+1)。 1HNMR(400MHz, CDsOD): 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. 15(m, 2H), 3. 37(m, 1H), 3. 90-3. 91 (d, 2H), 4.06-4.07 (m, 1H), 4.27-4.34(m, 2H), 5. 03-5. 15(m, 2H), 7.20- 7. 37(m, 2H)。 ❹實施例44 (R)-7-[3-胺基-4-(2, 4, 5-三氟-苯基）一丁酿基]一3_三氟曱基-5, 6, 7, 8-四氩-咪嗤並[1，5-a]nit_-i-(N-丙基）甲醯胺The first step -5, 6-a ^ gas - 8H - mouth meter ° sit (R)-[3-(l-butylaminomethyl-3-trifluoromethyl 94,949 119 201026314 and [1,5- a] tertino-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-amino decanoic acid tert-butyl ester (R)-7- [3-Tertiyloxycarbonylamino-4-(2,4,5-trifluorophenyl)-butanyl]-3-trifluoromethyl-5,6,8-tetrahydroimidazole [1, 5-a]pyridinium-1-carboxylic acid 2a (180 mg, 0.33 mmol) was dissolved in dichloromethane, butylamine hydrochloride (193 mg, 2.64 mmol), bis(2-oxo) -3-» 唾院 )) phosphinium chloride (167 mg, 0.66 mmol) and triethylamine (i 〇〇 mg, 〇. 99 mmol), stirred at room temperature overnight, 'thin layer chromatography to trace the reaction, the original The disappearance of the product, the reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by column chromatography to give the title product (R)-[3-(1-butylaminoglycan-3-trifluoromethyl-5) , 6-Dihydro-8H-indolo[1,5-a]*»~哄-7-yl)-3-oxo-5-difluoro-carbyl)-propyl]monocarbamic acid Dingzhi 43a (120 mg, white solid), yield: 60%. MS m/z (ESI): 606·0 (M+1). The second step is ❹00-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butenyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydro- Sodium(1,5-a)0 is compared to 哄-1-(N-butyl)carbamamine (R)-[3-(1-butylcarbamoyl-3-trifluoromethyl- 5,6-Dihydro-811-imidazo[1,5-a]pyrrol-7-yl)-3-oxo-1-(2,4,5-trifluoro-nodal)-propyl ]--tributic acid tert-butyl ester 43a (120 mg, 0. 198 mmol) was dissolved in 10 mL of dichloromethane, then trifluoroacetic acid (452 mg, 3 · Wmmol) was added, and the reaction was stirred at room temperature for 2 hours, thin layer The title compound (r)-7-[3-amino-4-(2,4,5-) was purified by chromatography. Trifluoro-benzene 120 94579 201026314 yl)-butanyl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo[1 5-a] 0 to D-well-1-(N- Butyl) Methotrexate 43 (70 mg, white solid), yield: 7 %. MS m/z (ESI): 506. KM+1). 1HNMR (400MHz, CDsOD): 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. 15(m, 2H), 3. 37(m, 1H), 3. 90-3. 91 (d, 2H), 4.06-4.07 (m, 1H), 4.27-4.34(m, 2H ), 5. 03-5. 15(m, 2H), 7.20- 7. 37(m, 2H). Example 44 (R)-7-[3-Amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5, 6, 7, 8-tetrahydro-imidazo[1,5-a]nit_-i-(N-propyl)formamide

(R)-[3-(l-丙基氨曱酿基-3-三氟甲基-5, 6-二氫-8H-_ 〇坐並[1，5-a]°比Π井-7-基）-3-氧代-1-(2, 4, 5-三氟-苄基）_丙基]-胺基甲酸第三丁酉旨將（R)-7-[3-第三丁氧羰基胺基-4-(2, 4, 5-三氟苯基）-丁酿基]-3-二氣甲基-5, 6, 7, 8-四氫口米嗤[1, 5~a]°比13井-1-叛酸2a(190mg，0.345mmol)溶解於i〇mL二氯甲燒中，加入第一步 94579 121 201026314 丙胺（163mg，2·76匪ol)，雙（2-氧代-3-噁唑烷基）次膦醯氣（176mg，0.69mmol)以及三乙胺（105mg, 1〇4mm〇1)，室溫下攪拌反應過夜，薄層層析追蹤反應，原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘餘物，得到標題產物（R)-[3-(l-丙基氨曱醯基_3_三氟甲基_5,6_二氫 -8H-咪唑並[l，5-a]吡哄-7-基）-3-氧代-l-(2, 4,5-三氟-苄基）-丙基]_胺基甲酸第三丁酯44a(70mg，白色固體），收率：34. 3%。 ❹ MS m/z (ESI) : 614.1(Μ+23)。第二步 (R)-7-[3-胺基-4-(2’ 4, 5-三氟-苯基）_丁醯基]_3_三氟甲基-5, 6’ 7, 8-四氫-咪唑並[1，5-a]吡畊一丨—⑺一丙基）甲醯胺將（R)-[3-(l-丙基氨甲醒基__3一三氟甲基一5,6_二氫 -8H-咪唑並[1.，5-a]吡畊-7-基）-3-氧代-1-(2, 4, 5-三氟-苄基）-丙基]-胺基曱酸第三丁S旨44a(7Gmg，0·118_〇1)溶解 ❹於10mL二氯曱烷中，再加入三氟乙酸（27〇mg，2.37職〇1)，室溫下攪拌反應1小時，薄層層析追蹤反應，原料消失，減壓濃縮反應液，用矽膠管柱層析法純化所得殘得到標題產物（R)-7-[3-胺基-4-(2,4,5_三氟—苯基）—丁醯基]-3-二氟甲基-5, 6, 7, 8-四氫-咪唑並[L π比哄 -1-(Ν-丙基）甲醯胺44(25mg，白色固體），收率：43. 1%。 MS m/z (ESI) : 492. KM+1)。 * 1HNMR(400MHz, CDsOD): δ 〇· 90-1. 〇〇(m5 3Η), 1.60-1 66 Cm, 2Η), 2. 75-2. 84(m, 1H), 2. 93-2. 99(m, 1H), 3. 〇9(s, 94579 122 201026314 2H)，3.94-3.95(d，2H)，4.07(m，1Η)，4.24-4·29(ιη，2H)， 5* °3-5.13(m, 2H), 7.19-7.23(t, 1H), 7. 36-7. 38(d, 1H) 〇測試例： DPP IV抑制活性的測定下面的方法是用來測定本發明化合物抑制DPPIV酶活性的能力。每個化合物的抑制率或半抑制濃度IC4把酶活性抑制至50%時所測化合物的濃度）是以固定量的酶混合基礎物及不同濃度的待測化合物來測定的。 DPP IV抑制活性的測定材料和方法：材料： a•白色96孔板（BMG) b，Tris緩衝液··製備i〇〇mL2mM的Tris緩衝液，將〇. 〇242g Tris溶解於約9〇mL去離子水中，用HC1和Na〇H調節〇 pH到8. 00，最後加去離子水至i〇〇mL。 c. DPPIV 酶（caiBi〇chem Catalog no. 317630)，溶解於 Tris 緩衝液中至2mM。 d’DPPlV — GloTK底物（Promega Catalog no. G8350)，溶解於去離子水中至lmM。 e.DPPlv — GloTM緩衝液（Promega Catalog no· G8350) 螢光素檢測試劑（Promega Catalog no. G8350)(R)-[3-(l-propylaminoglycine-3-trifluoromethyl-5,6-dihydro-8H-_ 〇并 [1,5-a]° than Π井-7 -yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tributyl sulfonate (R)-7-[3-t-butoxy Carbonylamino-4-(2,4,5-trifluorophenyl)-butyryl]-3-dimethylmethyl-5, 6, 7, 8-tetrahydromethane oxime [1, 5~a ]°°13 Well-1-Resin 2a (190mg, 0.345mmol) was dissolved in i〇mL dichloromethane and added to the first step 94579 121 201026314 propylamine (163mg, 2·76匪ol), double (2- Oxo-3-oxazolidinyl)phosphinium oxime (176 mg, 0.69 mmol) and triethylamine (105 mg, 1 〇 4 mm 〇1), stirred at room temperature overnight, traced by thin layer chromatography, the starting material disappeared The reaction mixture was concentrated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted eluted eluted eluted eluted Dihydro-8H-imidazo[l,5-a]pyridin-7-yl)-3-oxo-l-(2,4,5-trifluoro-benzyl)-propyl]-aminocarboxylic acid 3%。 The third butyl ester 44a (70 mg, white solid), yield: 34.3%. ❹ MS m/z (ESI): 614.1 (Μ+23). The second step (R)-7-[3-amino-4-(2' 4,5-trifluoro-phenyl)-butanyl]_3_trifluoromethyl-5,6' 7, 8-tetrahydro -Imidazo[1,5-a]pyrazine-(7)-propyl)carbenamide (R)-[3-(l-propylcarbamyl __3-trifluoromethyl-5, 6_Dihydro-8H-imidazo[1.,5-a]pyrrol-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]- Amino decanoic acid tert-butyl S is 44a (7Gmg, 0·118_〇1) dissolved in 10mL of dichloromethane, then added trifluoroacetic acid (27〇mg, 2.37) 1 and stirred at room temperature The reaction was carried out for 1 hour, the reaction was followed by thin layer chromatography, and the material was evaporated. 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)-7-[3-amino-4-(2, 4,5-trifluoro-phenyl)-butenyl]-3-difluoromethyl-5, 6, 7, 8-tetrahydro-imidazo[L π than 哄-1-(Ν-propyl) formamidine 1%。 Amine 44 (25 mg, white solid), yield: 43.1%. MS m/z (ESI): 492. KM+1). * 1HNMR (400MHz, CDsOD): δ 〇· 90-1. 〇〇(m5 3Η), 1.60-1 66 Cm, 2Η), 2. 75-2. 84(m, 1H), 2. 93-2. 99(m, 1H), 3. 〇9(s, 94579 122 201026314 2H), 3.94-3.95(d, 2H), 4.07(m,1Η), 4.24-4·29(ιη,2H), 5* ° 3-5.13(m, 2H), 7.19-7.23(t, 1H), 7. 36-7. 38(d, 1H) 〇 Test Example: Determination of DPP IV inhibitory activity The following method was used to determine the compound of the present invention. The ability to inhibit DPPIV enzyme activity. The inhibitory or semi-inhibitory concentration of each compound (the concentration of the compound tested when IC4 is inhibited to 50% by enzyme activity) is determined by a fixed amount of the enzyme mixed base and various concentrations of the test compound. Materials and methods for determination of DPP IV inhibitory activity: Materials: a• White 96-well plate (BMG) b, Tris buffer • Prepare i〇〇mL 2 mM Tris buffer, dissolve 〇. 242g Tris in approximately 9〇mL In deionized water, adjust the pH of 〇 to 8.00 with HC1 and Na〇H, and finally add deionized water to i〇〇mL. c. DPPIV enzyme (caiBi〇chem Catalog no. 317630), dissolved in Tris buffer to 2 mM. D'DPPlV - GloTK substrate (Promega Catalog no. G8350), dissolved in deionized water to lmM. e.DPPlv — GloTM Buffer (Promega Catalog no. G8350) Lucifera Detection Reagent (Promega Catalog no. G8350)

§· DMSO h.去離子水 123 94579 201026314 操作：按以下操作順序進行·· 1.解凍DPPIV—GlQ❹驗 2·使用前緩衝來存的榮光素檢測試^ ^皿。 3. 懸浮DPPIV〜G1〇.在基礎物 / 後，製成lmM的基礎物。口 °純水輕微現合均句 4. 光素檢測觸放人茶色瓶中，加人螢光素檢測試劑應在1分鐘内溶解 Gl〇.。 :·=。溶解所測化合物至最終操作 6. 母個^中加入5〇倍濃度的所測化合物倍。對照和空白對照中加入24 _。 ’在陰性 7. 在每個試管中加入4Ml THs緩衝液，加入48/zL· Tris緩衝液。二白對照中以 LDPPiv 酶。全部轉移到 8. 在陰性對照和測試樣的每個試管中加入2 ❹ 9. 振動混合並離心試管。將試管中物質 96-well平板上。 10.混合基礎物和DPPIV—Glo·比例為L49。振動混合至充分混合。使用前在室溫下靜置3〇至6〇分鐘。 11·在每個96-well平板孔中加入5〇此DPPIV — Glo.和基礎物的混合液，用封膜封住平板。 12. 用平板振盪器在300至500rpm/30s下慢慢混合96孔中物質。在室溫下培養30分鐘到3小時。 13. 記錄發光。 124 94579 201026314 s ·樣品 , B :空白對照 N:陰性對照 IC5〇值：實施例 Ι〇5〇(μΜ) MK-0431 0. 023 1 0.012 2 0. 008 3 0. 089 4 0. 022 5 0. 027 6 0. 031 7 0. 025 8 0. 008 9 0.075 10 0.021 11 0. 216 12 0. 059 13 0. 041 14 0. 047 15 0. 025 23 0. 031 34 0. 031 125 94579 201026314 36 0.221 37 0. 033 38 0. 184 39 0. 016 40 0. 314 41 0. 005 42 0.018 43 0. 063 44 0. 052 經過測試，測定的本發明化合物對DPPIV半抑制濃度 IC5。值範圍在 0. 005//M 至 0. 216//M，與 MK-0431 的 IC5D值 0. 023 相比，本發明的大部分化合物對DPPIV有良好的抑制活性。【圖式簡單說明】 ❹無【主要元件符號說明】無 126 94579§· DMSO h. Deionized water 123 94579 201026314 Operation: Perform the following sequence of operations·· 1. Thaw DPPIV—GlQ test 2·Use the buffer before storage to test the glory test. 3. Suspend DPPIV~G1〇. After the base/after, make the base of lmM. Mouth ° pure water slightly combined with the sentence 4. Photon detection touches the person in the brown bottle, adding fluorescein detection reagent should dissolve Gl 〇 in 1 minute. :·=. Dissolve the test compound to the final operation 6. Add 5 times the concentration of the tested compound to the parent. Add 24 _ to the control and blank controls. 'Negative 7. Add 4 Ml of THs buffer to each tube and add 48/zL·Tris buffer. In the two white control, the LDPPiv enzyme was used. Transfer all to 8. Add 2 每个 to each tube of the negative control and test sample. 9. Vibrate and centrifuge the tube. Place the material in the test tube on a 96-well plate. 10. The ratio of mixed base and DPPIV-Glo· is L49. Mix the vibrations until fully mixed. Allow to stand at room temperature for 3 to 6 minutes before use. 11. Add 5 〇 of this DPPIV-Glo. to the substrate in 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 illuminating. 124 94579 201026314 s ·Sample, B: blank control N: negative control IC5 〇 value: Example Ι〇5〇(μΜ) MK-0431 0. 023 1 0.012 2 0. 008 3 0. 089 4 0. 022 5 0 027 6 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.221 37 0. 033 38 0. 184 39 0. 016 40 0. 314 41 0. 005 42 0.018 43 0. 063 44 0. 052 The compound of the invention was tested for a half-inhibitory concentration of DPPIV, IC5. The value ranged from 0. 005//M to 0. 216//M, and most of the compounds of the present invention have a good inhibitory activity against DPPIV compared to the IC5D value of 0. 023 of MK-0431. [Simple description of the diagram] ❹No [Main component symbol description] None 126 94579

Claims

201026314 七、申請專利範圍： 1· 一種由通式（I)表示的化合物或其藥學上可接受的鹽：201026314 VII. Patent application scope: 1. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:

其中： Ar是本基’該本基疋未取代的或者進一步被1至$ 個R6所取代； R1選自氳原子、烷基、三氟Τ基、環烷基、芳基或雜芳基，其中烷基、環烷基、芳基、雜芳基進一步視需要地經一個或多個選自函素、氰基、芳基、經基或胺基的取代基所取代，較佳R1是三氟甲基； R2選自羥基、胺基、烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基或NR4R5，其中烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基進一步視需要地經一個或多個選自函素、胺基、氰基、羥基、烷基、環烷基、烷氧基、芳基、雜芳基、-NR4R5、_〇C(〇)〇R8、羧酸或羧酸酯的取代基所取代； R3選自氫原子或烷基； R4和R5各自獨立地選自氫原子、烷基、環烷基、雜環烷基、芳基或雜芳基，其中烷基、環烷基、雜環烷基、芳基或者雜芳基進一步視需要地經一個或多個選自卣素、羥基、胺基、烷氧基、烷基、氰基、芳基、環烷基、雜王哀烷基、雜芳基、羥烷基、_s〇2R7、_NR4R5、羧酸或羧 127 94579 201026314 酸酯的取代基所取代；或者，R4和R5 —起形成4至8員雜環基，其中該4 至8員雜環内含有一個或多個N、0、S原子，並且該4 至8員雜環上進一步視需要地經一個或多個選自鹵素、羥基、胺基、烷氧基、烷基、氰基、芳基、雜環烷基、雜芳基、羰基、羥烷基、-S〇2R7、-NR4R5、-C(0)NR4R5、 -C(0)R7、=0、羧酸或羧酸酯的取代基所取代； R6選自鹵素、氰基、羥基、烷基或烷氧基，其中烷基 ❹ 或烷氧基是未取代的或者進一步經一個或多個鹵素取代； R7為烧基； R8選自烷基或環烷基。 2.申請專利範圍第1項之化合物或其藥學上可接受的鹽，其中該化合物選自：Wherein: Ar is a group which is unsubstituted or further substituted by 1 to $ R6; R1 is selected from a halogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, an aryl group or a heteroaryl group. Wherein the alkyl, cycloalkyl, aryl, heteroaryl group is further optionally substituted with one or more substituents selected from the group consisting of a functional element, a cyano group, an aryl group, a trans group or an amine group, preferably R1 is three Fluoromethyl; R2 is selected from the group consisting of hydroxyl, amine, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl or NR4R5, wherein alkyl, alkoxy, cycloalkyl, hetero The cycloalkyl, aryl or heteroaryl group is further optionally one or more selected from the group consisting of a functional element, an amine group, a cyano group, a hydroxyl group, an alkyl group, a cycloalkyl group, an alkoxy group, an aryl group, a heteroaryl group, -NR4R5, _〇C(〇)〇R8, a substituent of a carboxylic acid or a carboxylic acid ester; R3 is selected from a hydrogen atom or an alkyl group; R4 and R5 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group a heterocycloalkyl, aryl or heteroaryl group, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further optionally optionally one or more selected from the group consisting of alizarin, hydroxyl, , alkoxy, alkyl, cyano, aryl, cycloalkyl, heteroalkyl, heteroaryl, hydroxyalkyl, _s〇2R7, _NR4R5, carboxylic acid or carboxy 127 94579 201026314 Substituting; or, R4 and R5 together form a 4 to 8 membered heterocyclic group, wherein the 4 to 8 membered heterocyclic ring contains one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring Further optionally, one or more selected from the group consisting of halogen, hydroxy, amino, alkoxy, alkyl, cyano, aryl, heterocycloalkyl, heteroaryl, carbonyl, hydroxyalkyl, -S〇2R7 Substituting -NR4R5, -C(0)NR4R5, -C(0)R7, =0, a substituent of a carboxylic acid or a carboxylic acid ester; R6 is selected from the group consisting of halogen, cyano, hydroxy, alkyl or alkoxy. Wherein the alkyl hydrazine or alkoxy group is unsubstituted or further substituted with one or more halogens; R7 is alkyl; R8 is selected from alkyl or cycloalkyl. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

128 94579 201026314128 94579 201026314

FF

94579 129 20102631494579 129 201026314

或or

© 3.申請專利範圍第1項或第2項之化合物或其藥學上可接受的鹽，其中，該鹽為該化合物與選自以下的酸形成的鹽：蘋果酸、.乳酸、馬來酸、鹽酸、曱續酸、硫酸、構酸、檸檬酸、酒石酸、乙酸或三氟乙酸，較佳的該鹽是鹽酸鹽。 4. 一種通式（IA)所示的化合物，該化合物為合成申請專利範圍第1項之的通式（I)化合物的中間體：The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the salt is a salt of the compound with an acid selected from the group consisting of malic acid, lactic acid, and maleic acid. And hydrochloric acid, citric acid, sulfuric acid, acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid. Preferably, the salt is a hydrochloride. 4. A compound of the formula (IA) which is an intermediate of the compound of the formula (I) in the synthesis of the first application of the scope of the patent:

其中： Ar是苯基，該苯基是未取代的或者進一步被1至5 個R6所取代； R1選自氫原子、烷基、三氟曱基、環烷基、芳基或雜芳基，其中烷基、環烷基、芳基、雜芳基進一步視需要 130 94579 201026314 地經一個或多個選自鹵素、氰基、芳基、羥基或胺茂、取代基所取代，較佳Ri是三氟甲基； '"的 R3選自氫原子或烷基； R6選自鹵素、氰基、羥基、烷基或烷氧基，其中烷基或烷氧基是未取代的或者進一步經一個或多個自素取代；. X為鹵素。 5. —種通式（IB)化合物，該化合物為合成申請專利範圍第 1項之通式（I)化合物的中間體：Wherein: Ar is a phenyl group which is unsubstituted or further substituted by 1 to 5 R6; R1 is selected from a hydrogen atom, an alkyl group, a trifluoromethyl group, a cycloalkyl group, an aryl group or a heteroaryl group, Wherein alkyl, cycloalkyl, aryl, heteroaryl is further substituted, if desired, by one or more halogen, cyano, aryl, hydroxy or amine amide, substituents, preferably Ri Trifluoromethyl; '" R3 is selected from a hydrogen atom or an alkyl group; R6 is selected from halogen, cyano, hydroxy, alkyl or alkoxy, wherein the alkyl or alkoxy group is unsubstituted or further Or multiple self-substituted; X is halogen. 5. 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:

(旧) 其中： R1選自氫原子、烷基、三氟甲基'、環烷基、芳基或雜芳基，其中烷基、環烷基、芳基、雜芳基進一步視需要 ❹ 地經一個或多個選自鹵素、氰基、芳基、羥基或胺基的取代基所取代，較佳R1是三氟曱基； R2選自羥基、胺基、烷基、烷氧基、環烷基、雜環烷基、芳基、雜芳基或-nr4r5，其中烷基、烷氧基、環烷基、雜環烷基、芳基或雜芳基進一步視需要地經一個或多個選自鹵素、胺基、氰基、羥基、烷基、環烷基、烷氧基、芳基、雜芳基、〜NR4R5、_〇C(〇)〇R8、羧酸或羧酸酯的取代基所取代； 131 94579 201026314 R3選自氳原子或烷基； R4和R5各自獨立地選自氫原子、烷基、環烷基、雜環烷基、芳基或雜芳基，其中烷基、環烷基、雜環烷基、芳基或者雜芳基進一步視需要地經一個或多個選自鹵素、經基、胺基、烧氧基、烧基、氰基、芳基、環烧基、雜環烷基、雜芳基、羥烷基、-S〇2R7、-NR4R5、羧酸或羧酸酯的取代基所取代；或者，R4和R5 —起形成4至8員雜環基，其中該4 ❹ 至8員雜環内含有一個或多個N、0、S原子，並且該4 至8員雜環上進一步視需要地經一個或多個選自鹵素、羥基、胺基、烷氧基、烷基、氰基、芳基、雜環烷基、雜芳基、羰基、羥烷基、-S〇2R7、-NR4R5、-C(0)NR4R5、 -C(0)R7、羧酸或羧酸酯的取代基所取代； R7為院基； R8選自烷基或環烷基。 0 6. —種申請專利範圍第4項之通式（IA)化合物的製備方法，該方法包括：(旧) where: R1 is selected from a hydrogen atom, an alkyl group, a trifluoromethyl', a cycloalkyl group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the aryl group, the heteroaryl group are further optionally required Substituted by one or more substituents selected from halogen, cyano, aryl, hydroxy or amine groups, preferably R1 is a trifluoromethyl group; R2 is selected from the group consisting of a hydroxyl group, an amine group, an alkyl group, an alkoxy group, and a ring. An alkyl, heterocycloalkyl, aryl, heteroaryl or -nr4r5 wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is further optionally one or more Substituted from halogen, amine, cyano, hydroxy, alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, ~NR4R5, _〇C(〇)〇R8, carboxylic acid or carboxylic acid ester Substituted; 131 94579 201026314 R3 is selected from a halogen atom or an alkyl group; R4 and R5 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, heterocycloalkyl, aryl or heteroaryl group is further optionally one or more selected from the group consisting of halogen, thiol, amine, alkoxy, alkyl, cyano, aryl Substituted by a substituent of a cycloalkyl, heterocycloalkyl, heteroaryl, hydroxyalkyl, -S〇2R7, -NR4R5, carboxylic acid or carboxylic acid ester; or R4 and R5 together form a 4 to 8 member a heterocyclic group wherein the 4 ❹ to 8 membered heterocyclic ring contains one or more N, 0, 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, -S〇2R7, -NR4R5, -C(0)NR4R5, -C(0 Substituting a substituent of R7, a carboxylic acid or a carboxylic acid ester; R7 is a hospital group; and R8 is selected from an alkyl group or a cycloalkyl group. 0. A method for preparing a compound of the formula (IA) of claim 4, which comprises:

在冰浴下向原料吡畊2-曱胺中滴加酸酐，然後在室溫下反應，生成醯胺產物；An acid anhydride is added dropwise to the raw material pyridinium 2-guanamine under an ice bath, and then reacted at room temperature to form a guanamine product;

132 94579 201026314 將醯胺產物與三氯氧磷在室溫下混合攪拌後，加入五氧化二磷，加熱回流縮合生成咪唑並[1，5-a]吡畊環；132 94579 201026314 After mixing the guanamine product with phosphorus oxychloride at room temperature, adding phosphorus pentoxide, heating and refluxing condensation to form imidazo[1,5-a] pyridin ring;

將咪唑並[1，5-a]吡畊環在乙醇溶劑中，於鈀/碳催化下，以氳氣還原生成R1，R3取代的四氫咪哇並[1，5-a] 吡畊產物；The imidazo[1,5-a] pyridinium ring was reduced in helium by palladium on carbon catalyzed by palladium on carbon to form R1, R3 substituted tetrahydroimidate [1,5-a] pyridin ;

將R1，R3取代的四氫σ米峻並[1，5-a] °比哄產物溶解在二氯曱烷溶劑中，並在縮合劑雙（2-氧代-3-噁唑烷基）次膦醯氯及三乙胺作用下與羧酸發生縮合反應；The R1, R3 substituted tetrahydro σ 峻并 [1,5-a] ° 哄 product is dissolved in dichloro decane solvent, and in the condensing agent bis (2-oxo-3-oxazolidinyl) Condensation reaction with carboxylic acid under the action of phosphinium chloride and triethylamine;

(IA) 得到的縮合產物在室溫於在無水乙醇溶劑中與鹵代琥珀醯亞胺反應生成通式（IA)化合物。 7. —種申請專利範圍第5項之通式（IB)化合物的製備方法，該方法包括： 133 94579 201026314The resulting condensation product of (IA) is reacted with halo succinimide in a solvent of absolute ethanol at room temperature to give a compound of the formula (IA). 7. A method of preparing a compound of the formula (IB) of claim 5, the method comprising: 133 94579 201026314

將R取代的咪唑並[丨，5_a]吡哄在室溫下，於乙醇浴劑中氫化還原，然後與二碳酸二（第三丁酯）在乙醇溶劑中反應，對胺基進行保護，得到胺基保護的R1取代的四氫咪唑並[1，5-a]吡畊；R-substituted imidazo[5,5-a]pyridinium is hydrogenated and reduced in an ethanol bath at room temperature, and then reacted with di(tert-butyl ester) dicarbonate in an ethanol solvent to protect the amine group. Amine-protected R1 substituted tetrahydroimidazo[1,5-a] pyridin;

得到的胺基保護的R1取代的四氳咪唑並[l，5-a]吡哄在乙醇溶劑中’室溫下與_代琥珀醯亞胺反應得到鹵代產物；The resulting amine-protected R1 -substituted tetraimidazo[1,5-a]pyridinium is reacted with _ succinimide at room temperature in an ethanol solvent to give a halogenated product;

得到的齒代產物在曱醇溶劑中，於油浴下與八羰基 Ο 一始及氯乙酸1酯在一氧化碳氛圍下反應，得到酯基取代的四氫咪唑並[l，5_a]吡畊；The obtained tooth product is reacted in a decyl alcohol solvent with an octacarbonyl hydrazine and a chloroacetic acid 1 ester under a carbon monoxide atmosphere to obtain an ester-substituted tetrahydroimidazo[1,5-a] pyridin;

知到的酯基取代的四氫σ米唾並[1，5-a]0比哄在驗性條件下水解成酸； 134 94579 201026314The known ester-substituted tetrahydrothymol-salt[1,5-a]0 is hydrolyzed to an acid under the test conditions; 134 94579 201026314

得到的羧酸化合物在乾冰-丙酮浴下，與鹵代烷基反應，得到烷基取代的酸；The obtained carboxylic acid compound is reacted with a haloalkyl group in a dry ice-acetone bath to obtain an alkyl-substituted acid;

烷基取代的酸可進一步酯化，得到酮取代的四氫咪〇坐並[1，5-a]°比D井；The alkyl-substituted acid can be further esterified to give a ketone-substituted tetrahydropyrimidine and a [1,5-a]° ratio D well;

或者，烷基取代的酸在二氯甲烷溶劑中，在縮合試劑雙（2-氧代噁唑烷基）次膦醯氯作用下與N-甲氧基曱胺反應；Alternatively, the alkyl-substituted acid is reacted with N-methoxyguanamine in a dichloromethane solvent under the action of a condensation reagent bis(2-oxooxazolidinyl)phosphinium chloride;

經縮合反應得到的產物與格利雅試劑在四氫呋喃溶劑中反應，得到酮取代的四氫η米唾並[1，5-a] °比畊；The product obtained by the condensation reaction is reacted with a Grignard reagent in a tetrahydrofuran solvent to obtain a ketone-substituted tetrahydro-η-salt [1,5-a] ° ratio tillage;

將酮取代的四氳p米唾並[1，5-a] °比哄在酸性條件下脫掉胺基保護基，得到通式（IB)化合物。 135 94579 201026314 8· 了種申請專利範圍第1項或第2項之通式⑴化合物的製備方法，該方法包括：十〇γ° Ar (ΙΑ) R1 將申請專利範圍第4項之通式（IA)在甲醇溶劑 Ί由洛下在八縣二銘的作用下及氣乙_在—氧化碳氛11下反應’然後在室溫，祕條件下水成羧酸；The ketone-substituted tetrahydropalmitage [1,5-a] ° is removed from the amine group under acidic conditions to give the compound of the formula (IB). 135 94579 201026314 8. A method for preparing a compound of the formula (1) of claim 1 or 2, which comprises: 〇γ° Ar (ΙΑ) R1 will apply the formula of the fourth item of the patent scope ( IA) in methanol solvent Ί by Luo under the action of eight counts and the gas _ in the oxidized carbon atmosphere 11 reaction 'and then at room temperature, under the conditions of water into carboxylic acid;

〇 9. 仔到的竣酸在、%§合試劑作用下與胺，或與醇在室溫下發生縮合反應，或者與卜鹵代碳酸酯反應，然條:下脫掉胺基保護基得到通式（I)化合物。製專利範圍第1項或第2項之通式⑴化合物的 ’該方法包括：〇9. The citric acid obtained by the reaction with the amine, or with the alcohol at room temperature, or with the halogenated carbonate, then the amine protecting group is removed. a compound of formula (I). The method of the compound of the formula (1) of the first or second aspect of the patent range includes:

將申請專利範圍第5項之通式（ib)化合物與羧@ 在、^合試劑輪（〇 p 氧代_3_噁唑烷基)次膦醯氣的條件、 136 94579 201026314 進行縮合，得到的產物進一步在酸性條件下脫掉胺基保護基得到通式（I)化合物。 10. 如申請專利範圍第8項或第9項之製備方法，其中還包、括通式（I)化合物與酸反應生成酸加成鹽，該酸選自蘋果酸、乳酸、馬來酸、鹽酸、甲磺酸、硫酸、磷酸、檸檬酸、酒石酸、乙酸或三氟乙酸，較佳的酸是鹽酸。 11. 一種醫藥組合物，其含有治療有效劑量的申請專利範圍第1至3項中任一項之化合物或其藥學上可接受的鹽， φ 及藥學上可以接受的載體或賦形劑。 12. —種申請專利範圍第1至3項中任一項之化合物或其藥學上可接受的鹽的用途，係用於製備治療II型糖尿病、高血糖症、肥胖症或胰島素抵抗症的藥物。 13. —種抑制二肽基肽酶IV催化活性的方法，其特徵在於將所述的二肽基肽酶IV與申請專利範圍第1至3項中任一項之化合物或鹽接觸。 14. 一種申請專利範圍第11項之醫藥組合物的用途，係用於製備治療II型糖尿病、高血糖症、肥胖症或胰島素抵抗症的藥物。 137 94579 201026314 四、指定代表圖··本案無圖式。 ' (一)本案指定代表圖為：第（）圖。 - (二)本代表圖之元件符號簡單說明： ®五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：The compound of the general formula (ib) of the fifth aspect of the patent application is condensed with the carboxylic acid under the conditions of the reagent wheel (〇p oxo_3_oxazolidinyl)phosphinium, 136 94579 201026314, The product is further deprotected from the amine protecting group under acidic conditions to provide the compound of formula (I). 10. The preparation method of claim 8 or 9, wherein the compound of the formula (I) is further reacted with an acid to form an acid addition salt 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, the preferred acid is hydrochloric acid. 11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, φ, and a pharmaceutically acceptable carrier or excipient. 12. Use of a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance . A method for inhibiting catalytic activity of dipeptidyl peptidase IV, which comprises contacting said dipeptidyl peptidase IV with a compound or salt of any one of claims 1 to 3. 14. Use of a pharmaceutical composition according to claim 11 for the preparation of a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance. 137 94579 201026314 IV. Designation of the representative figure · This case has no schema. ' (1) The representative representative of the case is: (). - (b) 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:

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