TWI395582B - Dicyclic azaalkane derivatives,preparing method and use thereof - Google Patents

Dicyclic azaalkane derivatives,preparing method and use thereof Download PDF

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TWI395582B
TWI395582B TW97117786A TW97117786A TWI395582B TW I395582 B TWI395582 B TW I395582B TW 97117786 A TW97117786 A TW 97117786A TW 97117786 A TW97117786 A TW 97117786A TW I395582 B TWI395582 B TW I395582B
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compound
alkyl
aryl
heteroaryl
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TW200946110A (en
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Peng Cho Tang
Zhigang Lin
Hejun Lu
Fuqiang Zhao
Li Li
Fanglong Yang
Jianhong Fu
Lin Wang
Guangyuan Shen
Dongliang Guan
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Shanghai Hengrui Pharm Co Ltd
Jiangsu Hansen Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Description

氮雜雙環烷類衍生物、其製備方法及其在醫藥上的用途Azabicycloalkane derivative, preparation method thereof and use thereof in medicine

本發明涉及一種氮雜雙環烷類衍生物、其製備方法及含有該衍生物的醫藥組成物以及其作為治療劑特別是作為二肽基肽酶抑制劑(DPPIV)的用途。The present invention relates to an azabicycloalkane derivative, a process for the preparation thereof, a pharmaceutical composition containing the same, and its use as a therapeutic agent, in particular as a dipeptidyl peptidase inhibitor (DPPIV).

糖尿病是一種多病因的代謝疾病，特點是慢性高血糖，伴隨因胰島素分泌及/或作用缺陷引起的糖、脂肪和蛋白質代謝紊亂。糖尿病是一種非常古老的疾病，是由於人體內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、消瘦、頭暈、乏力等症狀。Diabetes is a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or function. Diabetes is a very old disease caused by an increase in the concentration of glucose in the blood caused by absolute or relative lack of insulin in the human body. In turn, a large amount of sugar is excreted from the urine, and polydipsia, polyuria, polyphagia, weight loss, dizziness, Weakness and other symptoms.

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裏裂解N－末端之二肽酶，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，癌細胞轉移入內皮及HIV病毒進入淋巴樣細胞過程中都有重要的作用(WO98/19998)。Dipeptidyl peptidase-IV (DPPIV) is a serine protease that cleaves the N-terminal dipeptidase in the peptide chain containing a proline residue at the secondary end, despite the physiological effects of DPPIV on mammals. It has not been 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 (WO 98/19998).

最近，有研究表明DPPIV可以阻止胰升糖素樣肽(GLP)－1的分泌，尤其，它可以裂解GLP－1中N－末端的組－丙(His－Ala)二肽酶，使其從活性形式的GLP－1(7－36)NH2 降解為無活性的GLP－1(9－36)NH2 (Endocrinology，1999，140：5356~5363)。由於生理情況下，迴圈(loop)血中完整GLP－1的半衰期很短，DPPIV降解GLP－1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抑制劑能完全保護內源性甚至外源性的GLP－1不被DPPIV去活化，大幅提高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劑並能直接影響葡萄糖的分配，DPPIV抑制劑對非胰島素依賴型糖尿病(NIDDM)的治療可發揮很好的作用(US6110949)。Recently, studies have shown that DPPIV can prevent the secretion of glucagon-like peptide (GLP)-1, in particular, it can cleave the N-terminal group-His-Ala dipeptidase in GLP-1 from The active form of GLP-1(7-36)NH 2 degrades to inactive GLP-1(9-36)NH 2 (Endocrinology, 1999, 140: 5356-5536). Due to physiological conditions, the half-life of intact GLP-1 in the blood of the loop is very short. The inactive metabolites after DPPIV degrades GLP-1 can bind to the GLP-1 receptor and antagonize the activity of GLP-1, thereby shortening the GLP. -1 physiological response. DPPIV inhibitors can completely protect endogenous and even exogenous GLP-1 from DPPIV deactivation, significantly increasing the physiological activity of GLP-1 (5 to 10 times), since GLP-1 is a secretory factor for pancreatic insulin secretion. Important stimulants can directly affect the distribution of glucose, and DPPIV inhibitors can play a good role in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) (US6110949).

本發明涉及一種由通式(I)表示的化合物或其醫藥上可接受的鹽： The present invention relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:

其中：R選自烷基、環烷基、鹵代烷基、芳基、雜芳基、胺醯烷基、醯胺烷基、雜環胺醯烷基或胺烷基，其中，所述雜環為5員雜環或6員雜環，且該雜環可進一步經一個或多個烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、烷胺基、醯胺基、胺醯基、氰基、炔基、烷氧基、芳氧基、胺烷基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素取代；R1 選自氫原子、烷基、環烷基、雜環烷基、芳基、雜 芳基、－C(O)NR3 R4 、－C(O)R3 、－C(O)OR3 ，其中，該等烷基、環烷基、雜環烷基、芳基或雜芳基可以進一步經一個或多個烷基、芳基、羥基、胺基、烷氧基、芳氧基或雜環烷基取代；R2 選自氫原子或烷基，其中，該烷基可進一步經一個或多個選自環烷基或芳基的取代基取代；R3 和R4 分別選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基可以進一步經一個或多個烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、三氟甲基、羧基或羧酸酯基取代；或者，R3 和R4 可以與N原子一起形成一個3至8員的雜環基，其中，5至8員雜環內可以進一步含有一個或多個N、O或S原子，並且該3至8員雜環上可以進一步經一個或多個烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基、鹵素或－NR3 R4 取代；n是0至4。Wherein: R is selected from the group consisting of an alkyl group, a cycloalkyl group, a halogenated alkyl group, an aryl group, a heteroaryl group, an amine alkyl group, a nonylamino group, a heterocyclic amine alkyl group or an amine alkyl group, wherein the heterocyclic ring is a 5-membered heterocyclic ring or a 6-membered heterocyclic ring, and the heterocyclic ring may be further subjected to one or more alkyl groups, aryl groups, heteroaryl groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, amine groups, alkylamino groups, decylamino groups. , an amine group, a cyano group, an alkynyl group, an alkoxy group, an aryloxy group, an amine alkyl group, a hydroxyalkyl group, a heterocycloalkyl group, a carboxyl group, a carboxylate group or a halogen; R 1 is selected from a hydrogen atom, an alkane a base, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(O)NR 3 R 4 , -C(O)R 3 , -C(O)OR 3 , wherein the alkyl groups , cycloalkyl, heterocycloalkyl, aryl or heteroaryl may be further substituted by one or more alkyl, aryl, hydroxy, amine, alkoxy, aryloxy or heterocycloalkyl; R 2 It is selected from a hydrogen atom or an alkyl group, wherein the alkyl group may be further substituted with one or more substituents selected from a cycloalkyl group or an aryl group; and R 3 and R 4 are each selected from a hydrogen atom, an alkyl group, and a cycloalkyl group; An aryl group, a heteroaryl group or a heterocycloalkyl group, wherein The alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group may further be via one or more alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy Substituted, heteroaryloxy, halogen, hydroxy, amine, cyano, hydroxyalkyl, heterocycloalkyl, heterocycloalkoxy, trifluoromethyl, carboxy or carboxylate; or, R 3 and R 4 may form a 3 to 8 membered heterocyclic group together with the N atom, wherein the 5 to 8 membered heterocyclic ring may further contain one or more N, O or S atoms, and the 3 to 8 membered heterocyclic ring Further further via one or more alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amine, cyano, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxy , a carboxylate group, a halogen or a -NR 3 R 4 substituent; n is 0 to 4.

再者，本發明包括下述通式(IA)表示的化合物或其醫藥上可接受的鹽： Furthermore, the present invention includes a compound represented by the following formula (IA) or a pharmaceutically acceptable salt thereof:

其中：R選自烷基、環烷基、鹵代烷基、芳基、雜芳基、胺醯烷基、醯胺烷基、雜環胺醯烷基或胺烷基，其中，該雜環為5員雜環或6員雜環，且該雜環可進一步經一個或多個烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、烷胺基、醯胺基、胺醯基、氰基、炔基、烷氧基、芳氧基、胺烷基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素取代；R1 選自氫原子、烷基、環烷基、雜環烷基、芳基、雜芳基、－C(O)NR3 R4 、－C(O)R3 、－C(O)OR3 ，其中，該等烷基、環烷基、雜環烷基、芳基或雜芳基可以進一步經一個或多個烷基、芳基、羥基、胺基、烷氧基、芳氧基或雜環烷基取代；R2 選自氫原子或烷基，其中，該烷基可進一步經一個或多個選自環烷基或芳基的取代基取代；R3 和R4 分別選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基可以進一步經一個或多個烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、 三氟甲基、羧基或羧酸酯基取代；或者，R3 和R4 可以與N原子一起形成一個3至8員的雜環基，其中，5至8員雜環內可以進一步含有一個或多個N、O或S原子，並且該3至8員雜環上可以進一步經一個或多個烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基、鹵素或－NR3 R4 取代。Wherein: R is selected from the group consisting of an alkyl group, a cycloalkyl group, a halogenated alkyl group, an aryl group, a heteroaryl group, an amine alkyl group, a nonylamino group, a heterocyclic amine alkyl group or an amine alkyl group, wherein the heterocyclic ring is 5 a heterocyclic ring or a 6-membered heterocyclic ring, and the heterocyclic ring may further be subjected to one or more alkyl groups, aryl groups, heteroaryl groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, amine groups, alkylamino groups, decylamino groups, Amine, cyano, alkynyl, alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxy, carboxylate or halogen; R 1 is selected from a hydrogen atom, an alkyl group a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(O)NR 3 R 4 , -C(O)R 3 , -C(O)OR 3 , wherein the alkyl group, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be further substituted with one or more alkyl, aryl, hydroxyl, amino, alkoxy, aryloxy, or substituted heterocycloalkyl; R 2 is selected from a hydrogen atom or an alkyl group, wherein the alkyl group may be further substituted with one or more substituents selected from a cycloalkyl group or an aryl group; and R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, An aryl group, a heteroaryl group or a heterocycloalkyl group, wherein Or a cycloalkyl, aryl, heteroaryl or heterocycloalkyl group may further be substituted by one or more alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy groups , heteroaryloxy, halogen, hydroxy, amine, cyano, hydroxyalkyl, heterocycloalkyl, heterocycloalkoxy, trifluoromethyl, carboxy or carboxylate; or, R 3 and R 4 may form a 3 to 8 membered heterocyclic group together with the N atom, wherein the 5 to 8 membered heterocyclic ring may further contain one or more N, O or S atoms, and the 3 to 8 membered heterocyclic ring may be Further by one or more alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amine, cyano, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxy, Carboxylic acid ester group, halogen or -NR 3 R 4 substituted.

較佳地，在通式(I)所示的化合物或其鹽中，R為 Preferably, in the compound of the formula (I) or a salt thereof, R is

其中：R5 選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基可以進一步經一個或多個烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、烷胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、羧基或羧酸酯基取代；R6 和R7 分別選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、炔基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素；W為碳、硫或氧原子；當W為碳時，可以進一步經R6 或R7 取代。Wherein R 5 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group, wherein the alkyl group, cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group Further further via one or more alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amine, alkylamine, Substituted with cyano, hydroxyalkyl, heterocycloalkyl, heterocycloalkoxy, carboxy or carboxylate; R 6 and R 7 are each selected from alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy , hydroxy, amine, cyano, alkynyl, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxy, carboxylate or halogen; W is a carbon, sulfur or oxygen atom; when W is In the case of carbon, it may be further substituted with R 6 or R 7 .

再者，本發明包括下述(IB)表示的化合物或其醫藥上可接受的鹽： Furthermore, the present invention includes the compound represented by the following (IB) or a pharmaceutically acceptable salt thereof:

其中：R是 Where: R is

R1 選自氫原子、烷基、環烷基、雜環烷基、芳基、雜芳基、－C(O)NR3 R4 、－C(O)R3 、－C(O)OR3 ，其中，該等烷基、環烷基、雜環烷基、芳基或雜芳基可進一步經一個或多個選自烷基、芳基、羥基、胺基、烷氧基、芳氧基或雜環烷基的取代基取代；R2 選自氫原子或烷基，其中，該烷基可進一步經一個或多個選自環烷基或芳基的取代基取代；R3 和R4 分別選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基可進一步經一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、三氟甲基、羧基或羧酸酯基的取代基取代；或者，R3 和R4 與N原子一起形成一個3至8員的雜環基，其中5至8員雜環內可進一步含有一個或多個N、O或S原子，並且3至8員雜環可進一步經一個或多個選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、 胺基、氰基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基、鹵素或－NR3 R4 的取代基取代；R5 選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基可進一步經一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、烷胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、羧基或羧酸酯基的取代基取代；R6 和R7 分別選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、炔基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素；W為碳、硫或氧原子；當W為碳時，可以進一步經R6 或R7 所取代。R 1 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(O)NR 3 R 4 , -C(O)R 3 , -C(O)OR 3 wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group may be further selected from one or more selected from the group consisting of an alkyl group, an aryl group, a hydroxyl group, an amine group, an alkoxy group, and an aryloxy group. Substituted with a substituent of a heterocycloalkyl group; R 2 is selected from a hydrogen atom or an alkyl group, wherein the alkyl group may be further substituted with one or more substituents selected from a cycloalkyl group or an aryl group; R 3 and R 4 is each selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group, wherein the alkyl group, cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group can be further One or more selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amine, cyano, hydroxy Substituted by a substituent of an alkyl group, a heterocycloalkyl group, a heterocycloalkoxy group, a trifluoromethyl group, a carboxyl group or a carboxylate group; or, R 3 and R 4 together with the N atom form a 3 to 8 membered heterocyclic ring a base, wherein the 5 to 8 member heterocyclic ring may further contain one or more N, O or S atoms, and the 3 to 8 membered heterocyclic ring may further be selected from one or more selected from the group consisting of alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amine, cyano, alkoxy Substituted with a substituent of a aryloxy group, an aryloxy group, a hydroxyalkyl group, a heterocycloalkyl group, a carboxyl group, a carboxylate group, a halogen or a -NR 3 R 4 ; R 5 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group a heteroaryl or heterocycloalkyl group, wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group may further be selected from one or more selected from the group consisting of alkyl, cycloalkyl, aryl , heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amine, alkylamino, cyano, hydroxyalkyl, heterocycloalkyl, heterocycloalkoxy Substituted by a substituent of a carboxy group or a carboxylate group; R 6 and R 7 are each selected from alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amine, cyano, alkynyl, alkane Oxyl, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxyl, carboxylate or halogen; W is a carbon, sulfur or oxygen atom; when W is carbon, it may be further substituted by R 6 or R 7 .

再者，本發明包括下述通式(IC)表示的化合物或其醫藥上可接受的鹽： Further, the present invention includes a compound represented by the following formula (IC) or a pharmaceutically acceptable salt thereof:

其中：R是 Where: R is

R1 選自氫原子、烷基、環烷基、雜環烷基、芳基、雜芳基、－C(O)NR3 R4 、－C(O)R3 、－C(O)OR3 ，其中，該等烷 基、環烷基、雜環烷基、芳基或雜芳基可進一步經一個或多個選自烷基、芳基、羥基、胺基、烷氧基、芳氧基或雜環烷基的取代基取代；R2 選自氫原子或烷基，其中，該烷基可進一步經一個或多個選自環烷基或芳基的取代基取代；R3 和R4 分別選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基可進一步經一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、三氟甲基、羧基或羧酸酯基的取代基取代；或者，R3 和R4 與N原子一起形成3至8員的雜環基，其中，該5至8員雜環內可進一步含有一個或多個N、O或S原子，並且3至8員雜環可進一步經一個或多個選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基、鹵素或－NR3 R4 的取代基取代；R5 選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基可進一步經一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、烷胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、羧基或羧酸酯基的取代基取代；R6 和R7 分別選自烷基、芳基、雜芳基、鹵代烷基、 鹵代烷氧基、羥基、胺基、氰基、炔基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素；W為碳、硫或氧原子；當W為碳時，可以進一步經R6 或R7 所取代。R 1 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(O)NR 3 R 4 , -C(O)R 3 , -C(O)OR 3 wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group may be further selected from one or more selected from the group consisting of an alkyl group, an aryl group, a hydroxyl group, an amine group, an alkoxy group, and an aryloxy group. Substituted with a substituent of a heterocycloalkyl group; R 2 is selected from a hydrogen atom or an alkyl group, wherein the alkyl group may be further substituted with one or more substituents selected from a cycloalkyl group or an aryl group; R 3 and R 4 is each selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group, wherein the alkyl group, cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group can be further One or more selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amine, cyano, hydroxy Substituted with a substituent of an alkyl group, a heterocycloalkyl group, a heterocycloalkoxy group, a trifluoromethyl group, a carboxyl group or a carboxylate group; or, R 3 and R 4 together with the N atom form a heterocyclic group of 3 to 8 members Wherein the 5 to 8 member heterocyclic ring may further comprise one or more N, O or S atoms, and the 3 to 8 membered heterocyclic ring may further be selected from one or more selected from the group consisting of alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amine, cyano, alkoxy Substituted with a substituent of a aryloxy group, an aryloxy group, a hydroxyalkyl group, a heterocycloalkyl group, a carboxyl group, a carboxylate group, a halogen or a -NR 3 R 4 ; R 5 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group a heteroaryl or heterocycloalkyl group, wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group may further be selected from one or more selected from the group consisting of alkyl, cycloalkyl, aryl , heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amine, alkylamino, cyano, hydroxyalkyl, heterocycloalkyl, heterocycloalkoxy Substituted by a substituent of a carboxy group or a carboxylate group; R 6 and R 7 are each selected from the group consisting of alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amine, cyano, alkynyl, alkane Oxyl, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxyl, carboxylate or halogen; W is a carbon, sulfur or oxygen atom; when W is carbon, it may be further substituted by R 6 or R 7 .

本發明中所述的醫藥上可接受的鹽為本發明化合物與選自下列的酸形成的鹽：鹽酸、對甲苯磺酸、酒石酸、馬來酸、乳酸、甲磺酸、硫酸、磷酸、檸檬酸、乙酸或三氟乙酸。較佳為對甲苯磺酸、鹽酸、酒石酸或三氟乙酸。The pharmaceutically acceptable salt described in the present invention is a salt of the compound of the present invention and an acid selected from the group consisting of hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, and lemon. Acid, acetic acid or trifluoroacetic acid. Preference is given to p-toluenesulfonic acid, hydrochloric acid, tartaric acid or trifluoroacetic acid.

具體地，本發明包括如下所述結構的化合物及其鹽： Specifically, the present invention includes compounds having the structures described below and salts thereof:

進一步，本發明涉及一種如下列通式(ID)所示的化合物，其作為本發明通式(I)化合物合成的中間體： Further, the present invention relates to a compound represented by the following formula (ID) which is an intermediate for the synthesis of the compound of the formula (I) of the present invention:

其中：R1 選自氫原子、烷基、環烷基、雜環烷基、芳基、雜芳基、－C(O)NR3 R4 、－C(O)R3 、－C(O)OR3 ，其中，該等烷基、環烷基、雜環烷基、芳基或雜芳基可進一步經一個或 多個選自烷基、芳基、羥基、胺基、烷氧基、芳氧基或雜環烷基的取代基取代；R3 和R4 分別選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基可進一步經一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、三氟甲基、羧基或羧酸酯基的取代基取代；或者，R3 和R4 與N原子一起形成3至8員的雜環基，其中5至8員雜環內可進一步含有一個或多個N、O或S原子，並且該3至8員雜環可進一步經一個或多個選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基、鹵素或－NR3 R4 的取代基取代。Wherein: R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -C(O)NR 3 R 4 , -C(O)R 3 , -C(O And OR 3 , wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group may further be selected from one or more selected from the group consisting of an alkyl group, an aryl group, a hydroxyl group, an amine group, an alkoxy group, Substituted with a substituent of an aryloxy or heterocycloalkyl group; R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group, wherein the alkyl group, The cycloalkyl, aryl, heteroaryl or heterocycloalkyl group may further be selected from one or more selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy Substituted with a heteroaryloxy, halogen, hydroxy, amine, cyano, hydroxyalkyl, heterocycloalkyl, heterocycloalkoxy, trifluoromethyl, carboxy or carboxylate group; or, R 3 and R 4 together with the N atom form a 3 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring may further contain one or more N, O or S atoms, and the 3 to 8 membered heterocyclic ring may further One or more selected from the group consisting of alkyl, aryl, heteroaryl, haloalkyl Substituted by haloalkoxy, hydroxy, amine, cyano, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxy, carboxylate, halogen or substituents of -NR 3 R 4 .

本發明涉及通式(ID)所示化合物的製備方法，包括： The present invention relates to a process for the preparation of a compound of the formula (ID), comprising:

冰浴下，將原料5－側氧基－全氫－環戊并[c]吡咯－2－羧酸第三丁酯在適宜的溶劑中(如二氯甲烷)與三氟乙酸反應，得到全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽； The 5-butoxy-perhydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester is reacted with trifluoroacetic acid in a suitable solvent (for example, dichloromethane) in an ice bath to obtain the whole Hydrogen-cyclopenta[c]pyrrole-5-one trifluoroacetate;

將該全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽在鹼存在下與醯氯或酯類反應，得到通式(ID)的化合物；本發明涉及通式(IB)所示化合物的製備方法，包括： The perhydro-cyclopenta[c]pyrrole-5-one trifluoroacetate is reacted with hydrazine chloride or an ester in the presence of a base to give a compound of the formula (ID); the invention relates to the formula (IB) A method for preparing a compound, comprising:

將所述的中間體(ID)於室溫條件下在適宜的溶劑(如甲醇、乙醇)中與不同的胺、經取代的硼氫化鈉，在鹼性條件下(如三乙胺)反應，得到通式(IB)化合物。The intermediate (ID) is reacted with a different amine, a substituted sodium borohydride, under basic conditions (such as triethylamine) in a suitable solvent (such as methanol, ethanol) at room temperature. A compound of the formula (IB) is obtained.

本發明涉及通式(IB)所示化合物的製備方法，包括： The present invention relates to a process for the preparation of a compound of the formula (IB), comprising:

將第三丁醇鉀和碘化甲基三苯基鏻的甲苯溶液加熱後，在室溫下將中間體(ID)化合物加入到上述溶液中反應，得到亞甲基氮雜雙環化合物； After heating the toluene solution of potassium t-butoxide and methyltriphenylphosphonium iodide, the intermediate (ID) compound is added to the above solution at room temperature to obtain a methylene azabicyclo compound;

將該亞甲基氮雜雙環化合物在合適的溶劑中(如二氯甲烷)，在過氯酸銀存在下，於室溫與三甲基矽氰(trimethylsilyl cyanide)反應，得到異氰基氮雜雙環化合物； The methylene azabicyclo compound is reacted with trimethylsilyl cyanide in a suitable solvent (such as dichloromethane) in the presence of silver perchlorate at room temperature to give an isocyano aza Bicyclic compound;

將該異氰基氮雜雙環化合物在合適的溶劑中(如乙醇)與適宜的酸(如鹽酸)在室溫下反應，得到胺基氮雜雙環化合物； The isocyanoazabicyclo compound is reacted in a suitable solvent (such as ethanol) with a suitable acid (such as hydrochloric acid) at room temperature to obtain an amine azabicyclo compound;

將該胺基氮雜雙環化合物在溶劑(如N,N－二甲基甲醯胺)中與鹵化物反應，得到通式(IB)化合物。The amino azabicyclo compound is reacted with a halide in a solvent such as N,N-dimethylformamide to give a compound of the formula (IB).

本發明涉及通式(IB)所示化合物的製備方法，包括： The present invention relates to a process for the preparation of a compound of the formula (IB), comprising:

將中間體(ID)化合物和對甲苯磺醯甲基異腈(tosylmethylisonitrile)在適宜的溶劑中(如乙二醇二甲醚)進行氰化反應，得到氰基氮雜雙環化合物； The intermediate (ID) compound and tosylmethylisonitrile are cyanated in a suitable solvent (such as ethylene glycol dimethyl ether) to obtain a cyano azabicyclo compound;

將該氰基氮雜雙環化合物在適宜的溶劑中(如四氫呋 喃)，於六甲基二矽烷基胺化鋰存在下與鹵化物反應，得到經R2 取代的氰基氮雜雙環化合物； The cyanoazabicyclo compound is reacted with a halide in a suitable solvent (such as tetrahydrofuran) in the presence of lithium hexamethyldidecylamine to obtain an R 2 -substituted cyanoazabicyclo compound;

將該經R2 取代的氰基氮雜雙環化合物在酸的作用下水解，得到經R2 取代的羧基氮雜雙環化合物；或者，將該經R2 取代的氰基氮雜雙環化合物在適宜的溶劑(如二氯甲烷)中，在冰浴下與還原劑氫化二異丁基鋁(DIBAL－H)反應，先將氰基還原成醛基，然後將得到的醛在四氫呋喃/水混合溶劑中，在冰浴下與磷酸二氫鈉、亞氯酸鈉和2－甲基－2－丁烯反應，得到經R2 取代的羧基氮雜雙環化合物； The R 2 -substituted cyanoazabicyclo compound is hydrolyzed by an acid to obtain an R 2 -substituted carboxyazabicyclo compound; or the R 2 -substituted cyanoazabicyclo compound is suitable. In a solvent such as dichloromethane, it is reacted with a reducing agent hydrogenated diisobutylaluminum (DIBAL-H) in an ice bath to first reduce the cyano group to an aldehyde group, and then the obtained aldehyde is mixed in a tetrahydrofuran/water mixed solvent. Reacting with sodium dihydrogen phosphate, sodium chlorite and 2-methyl-2-butene in an ice bath to obtain a R 2 -substituted carboxyazabicyclo compound;

將該經R2 取代的羧基氮雜雙環化合物在鹼性條件(如三乙胺)及氯甲酸乙酯存在下，與疊氮化鹼金屬(如疊氮化鈉)反應，得到疊氮基羰基氮雜雙環化合物； The R 2 -substituted carboxyazabicyclo compound is reacted with an alkali azide (such as sodium azide) in the presence of basic conditions (such as triethylamine) and ethyl chloroformate to give an azide carbonyl group. Azabicyclo compound;

將該疊氮基羰基氮雜雙環化合物在適宜的溶劑(如甲苯)中加熱，再在酸性溶液中攪拌，並調節pH為鹼性，得到經R2 取代的胺基氮雜雙環化合物； The azidocarbonylcarbonyl azabicyclo compound is heated in a suitable solvent (such as toluene), stirred in an acidic solution, and the pH is adjusted to be basic to obtain an R 2 -substituted amino azabicyclo compound;

將該經R2 取代的胺基氮雜雙環化合物在溶劑中(如N,N－二甲基甲醯胺)與鹵化物反應，得到通式(IB)化合物。The R 2 -substituted amino azabicyclo compound is reacted with a halide in a solvent such as N,N-dimethylformamide to give a compound of the formula (IB).

本發明涉及通式(IC)所示化合物的製備方法，包括： The present invention relates to a process for the preparation of a compound of the formula (IC), comprising:

將中間體(ID)在適宜的溶劑(如四氫呋喃)中，於冰浴下與還原劑(如氫化三第三丁氧基鋁鋰)反應，得到羥基氮雜雙環化合物； The intermediate (ID) is reacted with a reducing agent (such as hydrogenated lithium trit-butoxide aluminum) in a suitable solvent (such as tetrahydrofuran) in an ice bath to obtain a hydroxyazabicyclo compound;

將該羥基氮雜雙環化合物在適宜的溶劑中(如二氯甲烷)，冰浴下與鹼性試劑(如三乙胺)、甲磺醯氯反應，得到甲磺酸基氮雜雙環化合物； The hydroxyazabicyclo compound is reacted with an alkaline reagent (such as triethylamine) or methanesulfonyl chloride in a suitable solvent (such as dichloromethane) to obtain a methanesulfonyl azabicyclo compound;

將該甲磺酸基氮雜雙環化合物在溶劑中(如N,N－二甲基甲醯胺)與鄰苯二甲醯亞胺鉀鹽加熱反應，得到經鄰苯二甲醯亞胺取代的氮雜雙環化合物； The methanesulfonyl azabicyclo compound is heated in a solvent (such as N,N-dimethylformamide) with potassium phthalimide to obtain a phthalic acid imine substituted. Azabicyclo compound;

將該經鄰苯二甲醯亞胺取代的氮雜雙環化合物在適宜的溶劑(如乙醇)中，與肼加熱，得到胺基氮雜雙環化合物； The phthalimide substituted azabicyclo compound is heated with hydrazine in a suitable solvent such as ethanol to obtain an amine azabicyclo compound;

將該胺基氮雜雙環化合物在適宜的溶劑(如二氯甲烷)中與鹵化物加熱、反應，得到通式(IC)化合物。The amine azabicyclo compound is heated and reacted with a halide in a suitable solvent such as dichloromethane to give a compound of the formula (IC).

較佳地，R為： Preferably, R is:

R5 選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基可進一步經一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、烷胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、羧基或羧酸酯基的取代基取代；R6 和R7 分別選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、炔基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素；W為碳、硫或氧原子；當W為碳時，可以進一步經R6 或R7 取代。R 5 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group, wherein the alkyl group, cycloalkyl group, aryl group, heteroaryl group or heterocycloalkyl group may be further One or more selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amine, alkylamine, Substituted with a substituent of a cyano group, a hydroxyalkyl group, a heterocycloalkyl group, a heterocycloalkoxy group, a carboxyl group or a carboxylate group; R 6 and R 7 are each selected from the group consisting of an alkyl group, an aryl group, a heteroaryl group, a halogenated alkyl group, Haloalkoxy, hydroxy, amine, cyano, alkynyl, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxy, carboxylate or halogen; W is a carbon, sulfur or oxygen atom; When W is carbon, it may be further substituted with R 6 or R 7 .

再者，本發明還包括將得到的通式(IB)或(IC)化合物純化後，在甲醇、二氯甲烷或乙酸乙酯中與酸反應，得到其酸加成產物鹽。Further, the present invention also includes the step of purifying the obtained compound of the formula (IB) or (IC) and reacting it with an acid in methanol, dichloromethane or ethyl acetate to obtain an acid addition product salt.

再者，本發明涉及一種醫藥組成物，其含有治療有效劑量的本發明化合物或其醫藥上可接受的鹽，和醫藥上可接受的載劑。Further, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

再者，本發明還涉及本發明化合物化合物或其醫藥上可接受的鹽在製備二肽基肽酶(DPPIV)抑制劑藥物的用途。Furthermore, the present invention also relates to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a dipeptidyl peptidase (DPPIV) inhibitor drug.

在本發明通式(I)所表述的化合物或其鹽中，通式(I)以游離態或者以酸加成鹽的形式存在，並提供醫藥上允許的(非毒性的，生理允許的)鹽；該等醫藥上允許的鹽包括鹽酸鹽、對甲苯磺酸鹽、酒石酸鹽、馬來酸鹽、乳酸鹽、甲 磺酸鹽、硫酸鹽、磷酸鹽、檸檬酸鹽、乙酸鹽或三氟乙酸鹽。較佳為對甲苯磺酸鹽、鹽酸鹽、酒石酸鹽及三氟乙酸鹽。In the compound of the formula (I) of the present invention or a salt thereof, the formula (I) is present in a free form or in an acid addition salt, and provides a pharmaceutically acceptable (non-toxic, physiologically acceptable) salt. Such pharmaceutically acceptable salts include hydrochloride, p-toluenesulfonate, tartrate, maleate, lactate, Sulfonate, sulfate, phosphate, citrate, acetate or trifluoroacetate. Preferred are p-toluenesulfonate, hydrochloride, tartrate and trifluoroacetate.

除非另有陳述，下列用在說明書和申請專利範圍中的術語具有下述含義。Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

“烷基”指飽和的脂族烴基團，包括1至20個碳原子的直鏈和分枝鏈基團。較佳含有1至10個碳原子的中等大小烷基，例如甲基、乙基、丙基、2－丙基、正丁基、異丁基、第三丁基、戊基等。更佳為含有1至4個碳原子的低級烷基，例如甲基、乙基、丙基、2－丙基、正丁基、異丁基或第三丁基等。烷基可以經取代或未經取代，當經取代時，較佳的取代基為鹵素、羥基、低級烷氧基、芳基、芳氧基、雜芳基、雜環烷基、C(O)R3 和C(O)NR3 R4 。"Alkyl" means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 20 carbon atoms. A medium-sized alkyl group having 1 to 10 carbon atoms is preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferably, it is a lower alkyl group having 1 to 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group or a t-butyl group. The alkyl group may be substituted or unsubstituted, and when substituted, preferred substituents are halogen, hydroxy, lower alkoxy, aryl, aryloxy, heteroaryl, heterocycloalkyl, C(O). R 3 and C(O)NR 3 R 4 .

“環烷基”指3至8員全碳單環、全碳5員/6員或6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π電子系統。環烷基的實例有環丙基、環丁基、環戊基、環戊烯、環己烷、環己二烯、金剛烷、環庚烷、環庚三烯等。環烷基可以經取代或未經取代。當經取代時，取代基較佳為一個或多個獨立地選自下列之取代基：低級烷基、三鹵烷基、鹵素、羥基、低級烷氧基、芳基(可經一個或多個獨立地選自鹵素、羥基、低級烷基或 低級烷氧基之取代基取代)、芳氧基(可經一個或多個獨立地選自鹵素、羥基、低級烷基或低級烷氧基之取代基取代)、6員雜芳基(環中具有1至3個氮原子，環中的碳視需要可經一個或多個基團取代，取代基彼此獨立地是鹵素、羥基、低級烷基或低級烷氧基)、5員雜芳基(具有1至3個選自氮、氧和硫的雜原子，該基團的碳和氮原子視需要可經一個或多個獨立地選自鹵素、羥基、低級烷基或低級烷氧基之取代基取代)、或5或6員雜環烷基(具有1至3個選自氮、氧和硫之雜原子，該基團之碳和氮原子(如果有的話)視需要可經一個或多個獨立地選自鹵素、羥基、低級烷基或低級烷氧基之取代基取代)、巰基、(低級烷基)硫基、芳硫基(視需要可經一個或多個獨立地選自鹵素、羥基、低級烷基或低級烷氧基之取代基取代)、氰基、醯基、硫代醯基、O－胺基甲醯基、N－胺基甲醯基、O－硫代胺基甲醯基、N－硫代胺基甲醯基、C－醯胺基、N－醯胺基、硝基、N－磺醯胺基、S－磺醯胺基、C(O)R3 、C(O)NR3 R4 和－C(O)OR3 。"Cycloalkyl" means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 member fused or polycyclic fused ring ("fused" ring means each in the system The rings share an adjacent pair of carbon atoms) groups with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene and the like. The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more substituents independently selected from the group consisting of lower alkyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, aryl (via one or more Substituted independently of a halogen, hydroxy, lower alkyl or lower alkoxy group, aryloxy (which may be substituted by one or more substituents independently selected from halo, hydroxy, lower alkyl or lower alkoxy) Substituted), 6 membered heteroaryl (having 1 to 3 nitrogen atoms in the ring, the carbon in the ring may be substituted by one or more groups as desired, and the substituents are independently of each other halogen, hydroxy, lower alkyl or Lower alkoxy), 5-membered heteroaryl (having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and nitrogen atoms of which may optionally be selected from halogen, by one or more a substituent of a hydroxy group, a lower alkyl group or a lower alkoxy group), or a 5- or 6-membered heterocycloalkyl group (having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, carbon and nitrogen atoms of the group) (if any) may be substituted, if desired, with one or more substituents independently selected from halo, hydroxy, lower alkyl or lower alkoxy) , mercapto, (lower alkyl)thio, arylthio (optionally substituted with one or more substituents independently selected from halogen, hydroxy, lower alkyl or lower alkoxy), cyano, fluorenyl , thiodecyl, O-aminomethylindenyl, N-aminomethylindenyl, O-thioaminomethylindenyl, N-thioaminomethylindenyl, C-decylamine, N- Amidino, nitro, N-sulfonylamino, S-sulfonylamino, C(O)R 3 , C(O)NR 3 R 4 and -C(O)OR 3 .

“烯基”指由至少兩個碳原子和至少一個碳－碳雙鍵組成的如上述定義的烷基。代表性實例包括但不限於乙烯基、1－丙烯基、2－丙烯基、1－，2－或3－丁烯基等。"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

“炔基”指至少兩個碳原子和至少一個碳－碳三鍵組成的如上所定義的烷基。代表性實例包括但不限於乙炔基、1－丙炔基、2－丙炔基、1－，2－或3－丁炔基等。"Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

“芳基”指具有至少一個芳環結構的基團，即具有共 軛的π電子體系的芳環，包括碳環芳基、雜芳基和聯芳基。該芳基視需要可經一個或多個以下的取代基取代：鹵素、三鹵甲基、羥基、SR、硝基、氰基、烷氧基和烷基。"Aryl" means a group having at least one aromatic ring structure, ie having a total The aromatic ring of the π-electron system of the yoke includes a carbocyclic aryl group, a heteroaryl group, and a biaryl group. The aryl group may be optionally substituted with one or more of the following substituents: halogen, trihalomethyl, hydroxy, SR, nitro, cyano, alkoxy and alkyl.

“雜芳基”指具有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、硫和氮。該環可以是5員或6員環。雜環芳基基團的實例包括呋喃基、噻吩基、吡啶基、吡咯基、N－烷基吡咯基、嘧啶基、吡嗪基、咪唑基等。"Heteroaryl" refers to an aryl group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, and heteroatoms including oxygen, sulfur and nitrogen. The ring can be a 5 or 6 member ring. Examples of the heterocyclic aryl group include a furyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group and the like.

“雜環烷基”指單環或稠環基團，在環中，具有5至9個環原子，其中一個或兩個環原子選自氮、氧或S(O)n(其中n是整數0至2)的雜原子，其餘環原子為碳。這些環還可以具有一個或多個雙鍵、不過，這些環不具有完全共軛的π電子系統。未經取代的雜環烷基包括但不限於吡咯烷基、哌啶－1－基、哌嗪－1－基、嗎啉基、硫代嗎啉基、高哌嗪基等、雜環烷基可以經取代或未經取代。當經取代時，取代基較佳為一個或多個，更佳一個、兩個或三個，進而更佳一個或兩個，獨立地選自由低級烷基、三鹵烷基、鹵素、羥基、低級烷氧基、氰基和醯基組成的組群。較佳地，雜芳基可經一個或兩個獨立地選自鹵素、低級烷基、三鹵烷基、羥基、巰基、氰基、N－醯胺基或羧基之取代基取代。"Heterocycloalkyl" means a monocyclic or fused ring radical having from 5 to 9 ring atoms in the ring wherein one or two ring atoms are selected from nitrogen, oxygen or S(O)n (where n is an integer) From 0 to 2), the remaining atoms are carbon. These rings may also have one or more double bonds, however, these rings do not have a fully conjugated pi-electron system. Unsubstituted heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, piperidin-1-yl, piperazin-1-yl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., heterocycloalkyl It may be substituted or unsubstituted. When substituted, the substituent is preferably one or more, more preferably one, two or three, and even more preferably one or two, independently selected from the group consisting of lower alkyl, trihaloalkyl, halogen, hydroxy, A group consisting of lower alkoxy groups, cyano groups and fluorenyl groups. Preferably, the heteroaryl group may be substituted with one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, hydroxy, decyl, cyano, N-nonylamino or carboxy.

“羥基”指－OH基團。"Hydroxy" refers to an -OH group.

“烷氧基”指－O－(烷基)和－O－(未經取代的環烷基)。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。"Alkoxy" means -O-(alkyl) and -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

“鹵代烷氧基”指－O－(鹵代烷基)。代表性實例包括但不限於三氟甲氧基、三溴甲氧基等。"Haloalkoxy" means -O-(haloalkyl). Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like.

“芳氧基”指－O－芳基和－O－雜芳基，芳基和雜芳基定義同上。代表性實例包括但不限於苯氧基、吡啶氧基、呋喃氧基、噻吩氧基、嘧啶氧基、吡嗪氧基等及其衍生物。"Aryloxy" means -O-aryl and -O-heteroaryl, and aryl and heteroaryl are as defined above. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanoxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.

“巰基”指－SH基團。"Amidino" refers to a -SH group.

“烷硫基”指－O－(烷基)和－O－(未經取代的環烷基)。代表性實例包括但不限於甲硫基、乙硫基、丙硫基、丁硫基、環丙硫基、環丁硫基、環戊硫基、環己硫基等。"Alkylthio" means -O-(alkyl) and -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.

“芳硫基”指－S－芳基和－S－雜芳基，芳基和雜芳基定義同上。代表性實例包括但不限於苯硫基、吡啶硫基、呋喃硫基、噻吩硫基、嘧啶硫基等及其衍生物、“醯基”指－C(O)－R”基團，其中R”選自由氫、低級烷基、三鹵甲基、未經取代的環烷基、芳基(視需要可經一個或多個，較佳一個、兩個或三個取代基取代，該取代基選自由低級烷基、三鹵甲基、低級烷氧基和鹵素組成的組)、雜芳基(由環碳鍵結)(視需要可經一個或多個，較佳一個、兩個或三個取代基取代，該取代基選自由低級烷基、三鹵甲基、低級烷氧基和鹵素組成的組)和雜脂環基(經由環碳鍵結)(視需要可經一個或多個，較佳一個、兩個或三個取代基取代，該取代基選自由低級烷基、三鹵甲基、低級烷氧基和鹵素組成的組)。代表性醯基包括但不限於乙醯基、三氟乙醯基、苯甲醯基等。"Arylthio" means -S-aryl and -S-heteroaryl, and aryl and heteroaryl are as defined above. Representative examples include, but are not limited to, phenylthio, pyridylthio, furanthio, thiophenothionyl, pyrimidinyl, and the like, and derivatives thereof, "mercapto" refers to a -C(O)-R" group, wherein R "selected from hydrogen, lower alkyl, trihalomethyl, unsubstituted cycloalkyl, aryl (optionally substituted by one or more, preferably one, two or three substituents, the substituent) Selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy and halogen), heteroaryl (bonded by ring carbon) (optionally one or more, preferably one, two or three) Substituted by a substituent selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy and halogen) and heteroalicyclic (via ring carbon bonding) (optionally one or more Preferably, one, two or three substituents are selected which are selected from the group consisting of lower alkyl, trihalomethyl, lower alkoxy and halogen). Representative sulfhydryl groups include, but are not limited to, ethenyl, trifluoroethenyl, benzhydryl, and the like.

“硫代醯基”指－C(S)－R”基團，其中R”的定義同上。"Thiodecyl" refers to a -C(S)-R" group wherein R" is as defined above.

“乙醯基”指－C(O)CH3 基團。"Acetyl" group refers to a -C (O) CH 3 group.

“鹵素”指氟、氯、溴或碘，較佳為氟或氯。"Halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

“三氟甲基”指－CF3 。"Trifluoromethyl" means -CF 3 .

“氰基”指－CN。"Cyano" means -CN.

“胺基”指－NH2 。"Amino" means -NH 2.

“羧酸”指－COOH。"Carboxylic acid" means -COOH.

“羧酸酯”指－COOR，其中R為烷基或環烷基。"Carboxylic acid ester" means -COOR wherein R is alkyl or cycloalkyl.

“羥烷基”指－(CH2)rNH2，其中r是1至4。"Hydroxyalkyl" means -(CH2)rNH2 wherein r is from 1 to 4.

“視需要可以”或“視需要可以地”意味著隨後所描述地事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生地場合。例如，“視需要可經烷基取代的雜環基團”意味著烷基可以存在但非必須存在，該說明包括雜環基團經烷基取代的情形和雜環基團未經烷基取代的情形。"As needed" or "as needed" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group which may be optionally substituted by an alkyl group" means that an alkyl group may exist but is not necessarily present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not substituted with an alkyl group. The situation.

“醫藥組成物”表示一種或多種本文所述化合物或其生理學上/醫藥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/醫藥上可接受的載劑和賦形劑。醫藥組成物的目的是促進化合物對生物體的給藥。"Pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

本發明化合物的合成方法Method for synthesizing the compound of the present invention

為了完成本發明的目的，本發明採用如下技術方案：In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

合成方案ISynthetic scheme I

冰浴下，將5－側氧基－全氫－環戊并[c]吡咯－2－羧酸第三丁酯在適宜的溶劑中(如二氯甲烷)中與三氟乙酸反應，得到全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽；將全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽在鹼存在下與醯氯或酯類反應，得到通式(ID)的化合物；將該中間體(ID)於室溫條件下在適宜的溶劑(如甲醇、乙醇)中與的不同胺、經取代的硼氫化鈉，在鹼性條件下(如三乙胺)反應，得到通式(IB)化合物。5-butyloxy-perhydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester is reacted with trifluoroacetic acid in a suitable solvent (such as dichloromethane) in an ice bath to obtain the whole Hydrogen-cyclopenta[c]pyrrole-5-one trifluoroacetate; reacting perhydro-cyclopenta[c]pyrrole-5-one trifluoroacetate with hydrazine or an ester in the presence of a base a compound of the formula (ID); a different amine, substituted sodium borohydride of the intermediate (ID) in a suitable solvent (such as methanol, ethanol) at room temperature under basic conditions (eg Triethylamine) is reacted to give a compound of the formula (IB).

合成方案IISynthetic Scheme II

將第三丁醇鉀和碘化甲基三苯基鏻的甲苯溶液加熱後，在室溫下將中間體(ID)化合物加入到上述溶液中反應，得到亞甲基氮雜雙環化合物；將該亞甲基氮雜雙環化合物在適宜的溶劑中(如二氯甲烷)，於過氯酸銀存在下，於室溫下與三甲基矽氰反應，得到異氰基氮雜雙環化合物；將該異氰基氮雜雙環化合物在合適的溶劑中(如乙醇)與適宜的酸(如鹽酸)在室溫下反應，得到胺基氮雜雙環化合物；將該胺基氮雜雙環化合物在溶劑(如N,N－二甲基甲 醯胺)溶劑中與鹵化物反應，得到通式(IB)化合物。After heating the toluene solution of potassium t-butoxide and methyltriphenylphosphonium iodide, the intermediate (ID) compound is added to the above solution at room temperature to obtain a methylene azabicyclo compound; The methylene azabicyclo compound is reacted with trimethylocyanine at room temperature in a suitable solvent (such as dichloromethane) in the presence of silver perchlorate to give an isocyanoazabicyclo compound; The isocyanoazabicyclo compound is reacted in a suitable solvent (such as ethanol) with a suitable acid (such as hydrochloric acid) at room temperature to obtain an amine azabicyclo compound; the amine azabicyclo compound is in a solvent (eg N,N-dimethyl A The reaction with a halide in a solvent gives the compound of the formula (IB).

合成方案IIISynthetic scheme III

將中間體(ID)化合物和對甲苯磺醯甲基異腈在適宜的溶劑中(如乙二醇二甲醚)進行氰化反應，得到氮雜雙環化合物；將該氰基氮雜雙環化合物在在適宜的溶劑中(如四氫呋喃)，在六甲基二矽烷基胺化鋰存在下與鹵化物反應，得到經R2 取代的氰基氮雜雙環化合物；將該經R2 取代的氮雜雙環化合物在酸的作用下水解得到經R2 取代的羧基氮雜雙環化合物，或者將該經R2 取代的氰基氮雜雙環化合物在適宜的溶劑中(如二氯甲烷)，在冰浴下與還原劑氫化二異丁基鋁(DIBAL－H)反應，先將氰基還原成醛基，然後將得到的醛在四氫呋喃/水混合溶劑中，在冰浴下與磷酸二氫鈉、亞氯酸鈉和2－甲基－2－丁烯反應，得到經R2 取代的羧基氮雜雙環化合物；將該經R2 取代的羧基氮雜雙環化合物在鹼性條件下(如三乙胺)及氯甲酸乙酯存在下，與疊氮化鹼金屬(如疊氮化鈉)反應，得到疊氮基羰基氮雜雙環化合物；將該疊氮基羰基氮雜雙環化合物在適宜的溶劑中(如甲 苯)加熱，再在酸性溶液中攪拌，並調節pH為鹼性，得到經R2 取代的胺基氮雜雙環化合物；將該經R2 取代的胺基氮雜雙環化合物在溶劑中(如N,N－二甲基甲醯胺)，與鹵化物反應，得到通式(IB)化合物。The intermediate (ID) compound and p-toluenesulfonylmethyl isocyanide are cyanated in a suitable solvent (such as ethylene glycol dimethyl ether) to obtain an azabicyclo compound; the cyano azabicyclo compound is Reacting with a halide in the presence of lithium hexamethyldidecylamine in a suitable solvent (such as tetrahydrofuran) to give an R 2 -substituted cyanoazabicyclo compound; the R 2 -substituted azabicyclo ring The compound is hydrolyzed by an acid to give an R 2 -substituted carboxyazabicyclo compound, or the R 2 -substituted cyanoazabicyclo compound is dissolved in a suitable solvent (such as dichloromethane) in an ice bath. The reducing agent hydrogenated diisobutylaluminum (DIBAL-H) reaction, first reducing the cyano group to an aldehyde group, and then the obtained aldehyde in a tetrahydrofuran / water mixed solvent, in an ice bath with sodium dihydrogen phosphate, chlorous acid Reaction of sodium with 2-methyl-2-butene to give a R 2 -substituted carboxyazabicyclo compound; the R 2 -substituted carboxyazabicyclo compound under basic conditions (such as triethylamine) and chlorine In the presence of ethyl formate, reacting with an azide alkali metal such as sodium azide An azidocarbonylcarbonyl azabicyclo compound; heating the azidocarbonyl azabicyclo compound in a suitable solvent (such as toluene), stirring in an acidic solution, and adjusting the pH to be basic to obtain an R 2 -substituted An amino azabicyclo compound; reacting the R 2 -substituted amino azabicyclo compound in a solvent (such as N,N-dimethylformamide) with a halide to give a compound of the formula (IB).

合成方案IVSynthetic Scheme IV

將中間體(ID)在適宜的溶劑中(如四氫呋喃)，冰浴下與還原劑(如氫化三第三丁氧基鋁鋰反應，得到羥基氮雜雙環化合物；將該羥基氮雜雙環化合物在適宜的溶劑中(如二氯甲烷)，冰浴下與鹼性試劑(如三乙胺)、甲磺醯氯反應，得到甲磺酸基氮雜雙環化合物；將該甲磺酸基氮雜雙環化合物在溶劑中(如N,N－二甲基甲醯胺)與鄰苯二甲醯亞胺鉀鹽加熱反應得到經鄰苯二甲醯亞胺取代的氮雜雙環化合物；將該經鄰苯二甲醯亞胺取代的氮雜雙環化合物在適宜的溶劑中(如乙醇)，與肼加熱，得到胺基氮雜雙環化合物；將該胺基氮雜雙環化合物在適宜的溶劑中(如二氯甲烷)，與鹵化物加熱，反應得到通式(IC)化合物。The intermediate (ID) is reacted with a reducing agent (such as hydrogenated lithium trit-butoxide aluminum) in a suitable solvent (such as tetrahydrofuran) to obtain a hydroxyazabicyclo compound; the hydroxyazabicyclo compound is In a suitable solvent (such as dichloromethane), react with an alkaline reagent (such as triethylamine) or methanesulfonyl chloride in an ice bath to obtain a methanesulfonyl azabicyclo compound; the methanesulfonyl azabicyclo ring The compound is heated in a solvent (such as N,N-dimethylformamide) and potassium phthalimide to obtain an azabibiamine substituted with phthalimide; the orthobenzene The dimethyl quinone substituted azabicyclo compound is heated with hydrazine in a suitable solvent (such as ethanol) to give an amine azabicyclo compound; the amine azabicyclo compound is in a suitable solvent (eg dichloro Methane), heated with a halide, is reacted to give a compound of the formula (IC).

進一步，將通式(IB)或(IC)化合物純化後，在甲醇、二氯甲烷或乙酸乙酯中與酸反應，得到其酸加成產物鹽。Further, after purifying the compound of the formula (IB) or (IC), it is reacted with an acid in methanol, dichloromethane or ethyl acetate to obtain an acid addition product salt.

本發明涉及一種醫藥組成物，其含有治療有效劑量的化合物或其鹽和醫藥載劑，或者本發明通式(I)化合物或其 鹽在製備二肽基肽酶抑制劑藥物的用途。換言之，本發明還提供含有藥物有效劑量的上述化合物的組成物，以及該等化合物在製備二肽基肽酶抑制劑的用途。The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound or a salt thereof and a pharmaceutical carrier, or a compound of the formula (I) of the present invention or The use of a salt for the preparation of a dipeptidyl peptidase inhibitor drug. In other words, the invention also provides compositions comprising the above-described compounds in a pharmaceutically effective amount, and the use of such compounds in the preparation of dipeptidyl peptidase inhibitors.

具體實施方式detailed description

以下用實施例進一步描述本發明，但這些實施例並非限制著本發明的範圍。The invention is further described by the following examples, which are not intended to limit the scope of the invention.

實施例Example

化合物的結構是經由核磁共振(1 H NMR)或質譜(MS)來確定。1 H NMR位移(δ)以百萬分之一(ppm)為單位來表示。NMR的測定是用Bruker AVANCE－400核磁儀，測定溶劑為氘代氯仿(CDCl3 )、氘代二甲基亞碸(DMSO－D6 )、氘代甲醇(CD3 OD)，內標為四甲基矽烷(TMS)，化學位移是以10－6 (ppm)作為單位來表示。The structure of the compound is determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS). The 1 H NMR shift (δ) is expressed in parts per million (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated chloroform (CDCl 3 ), deuterated dimethyl hydrazine (DMSO-D 6 ), deuterated methanol (CD 3 OD), and the internal standard was four. Methyl decane (TMS), chemical shift is expressed in units of 10 -6 (ppm).

MS的測定用FINNIGAN LCQAd(ESI)質譜儀。The MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer.

激酶平均抑制率及IC50 值的測定用NovoStar酶標儀(德國BMG公司)Determination of average kinase inhibition rate and IC 50 value using NovoStar microplate reader (BMG, Germany)

薄層矽膠使用煙臺黃海HSGF254或青島GF254矽膠板Thin layer of silicone rubber using Yantai Yellow Sea HSGF254 or Qingdao GF254 rubber sheet

管柱層析一般使用煙臺黃海矽膠200~300目矽膠為載體。Pipe column chromatography generally uses Yantai Huanghai Tanji 200~300 mesh silicone as carrier.

DMSO－D6 ：氘代二甲基亞碸；CDCl3 ：氘代氯仿；CD3 OD：氘代甲醇；DMSO-D 6 : deuterated dimethyl hydrazine; CDCl 3 : deuterated chloroform; CD 3 OD: deuterated methanol;

實施例1Example 1

順－5－(2－(S)－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲 基－全氫－環戊并[c]吡咯－2－甲醯胺鹽酸鹽 Cis-5-(2-(S)-(2-cyanopyrrolidin-1-yl)-2-oxoethoxyethylamino)-N,N-dimethyl-perhydro-cyclopenta[c Pyrrole-2-carboxamide hydrochloride

第一步first step

[2－(2－胺基甲醯基－吡咯烷－1－基)－2－側氧基－乙基]－胺基甲酸第三丁酯1b 的製備Preparation of [2-(2-aminomethylindenyl-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b

將N－第三丁氧基羰基－甘胺酸1a (5 g，28.56 mmol)和L－脯胺醯胺(3.25 g，28.50 mmol)溶於75 mL N,N－二甲基甲醯胺中，冷卻到0℃，攪拌下加入1－羥基苯并***(11.8 g，87.3 mmol)，N－乙基－N’－(二甲胺基丙基)－碳二亞胺(11.3 g，59 mmol)，三乙胺(12.1 mL，87.3 mmol)，自然升至室 溫，攪拌過夜，次日以薄層層析跟蹤反應至原料完全消失後，在低於50℃蒸去N,N－二甲基甲醯胺，用乙酸乙酯萃取反應液(200 mL×3)，合併有機相，用50 mL飽和氯化鈉溶液洗滌，有機相用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，殘留物用乙酸乙酯再結晶，得到標題產物[2－(2－胺基甲醯－吡咯烷－1－基)－2－側氧基－乙基]－胺基甲酸第三丁酯1b (7.42 g，白色粉末)，產率95.8%。N-Tertioxycarbonyl-glycine 1a (5 g, 28.56 mmol) and L-amine amine (3.25 g, 28.50 mmol) were dissolved in 75 mL of N,N-dimethylformamide. , cooled to 0 ° C, and added 1-hydroxybenzotriazole (11.8 g, 87.3 mmol), N-ethyl-N'-(dimethylaminopropyl)-carbodiimide (11.3 g, 59) with stirring. Methyl) (12.1 mL, 87.3 mmol), naturally warmed to room temperature, stirred overnight, and the next day was followed by thin layer chromatography to trace the reaction until the material disappeared completely, and the N, N-di was evaporated at less than 50 ° C. Methyl carbamide, the reaction mixture was extracted with ethyl acetate (200 mL×3), and the organic phase was combined and washed with 50 mL of saturated sodium chloride. Recrystallization from ethyl acetate gave the title product [2-(2-aminocarbazin-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1b (7.42 g, white powder), yield 95.8%.

MS m/z(ESI)：272.1(M＋1)。MS m/z (ESI): 2721. (M + 1).

第二步Second step

[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基]－胺基甲酸第三丁酯1c 的製備Preparation of [2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester 1c

氮環境下，在一個乾燥的三口瓶中依次加入286 mL吡啶，[2－(2－胺基甲醯－吡咯烷－1－基)－2－側氧基－乙基]－胺基甲酸第三丁酯1b (13.5 g，49.8 mmol)，咪唑(7.11 g，104.6 mmol)，反應體系冷卻到－35℃，攪拌下滴加三氯氧磷(19 mL，204.2 mmol)，並在該溫度下繼續反應1小時，隨後自然升至室溫，反應0.5小時後，低溫蒸乾吡啶，用乙酸乙酯稀釋，加水，用乙酸乙酯萃取反應液(200 mL×3)，合併有機相，用50 mL飽和氯化鈉溶液洗滌，有機相用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得標題產物[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基]－胺基甲酸第三丁酯1c (10.7 g，白色粉末)，產率84.9%。Under a nitrogen atmosphere, 286 mL of pyridine was added to a dry three-necked flask, [2-(2-aminoformamidine-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid Tributyl ester 1b (13.5 g, 49.8 mmol), imidazole (7.11 g, 104.6 mmol), the reaction system was cooled to -35 ° C, and phosphorus oxychloride (19 mL, 204.2 mmol) was added dropwise with stirring at this temperature. The reaction was continued for 1 hour, then naturally warmed to room temperature. After 0.5 hours of reaction, the pyridine was evaporated to dryness, diluted with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate (200 mL×3). The residue was washed with EtOAc (EtOAc m.) 1-Bis-2-yloxy-ethyl]-carbamic acid tert-butyl ester 1c (10.7 g, white powder), yield 84.9%.

MS m/z(ESI)：254.3(M＋1)。MS m/z (ESI): 254.3 (M + 1).

第三步third step

1－(2－胺基乙醯基)－2－氰基－吡咯烷鹽酸鹽1d 的製備Preparation of 1-(2-aminoethenyl)-2-cyano-pyrrolidine hydrochloride 1d

將[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基]－胺基甲酸第三丁酯1c (13.7g，54.2 mmol)攪拌下溶解於140 mL***和40 mL水中，冰浴下滴加37%的鹽酸溶液(90 mL)，冰浴下反應1小時，蒸乾溶劑，用***分散離心，得到標題產物1－(2－胺基乙醯基)－2－氰基－吡咯烷鹽酸鹽1d (10 g，白色粉末)，產率98%。[2-(2-Cyano-pyrrolidin-1-yl)-2-yloxy-ethyl]-carbamic acid tert-butyl ester 1c (13.7 g, 54.2 mmol) was dissolved in 140 mL of diethyl ether with stirring. And 40 mL of water, 37% hydrochloric acid solution (90 mL) was added dropwise in an ice bath, and the reaction was carried out for 1 hour in an ice bath, and the solvent was evaporated to dryness, and the mixture was evaporated to give the title product 1-(2-aminoethyl hydrazyl). 2-cyano-pyrrolidine hydrochloride 1d (10 g, white powder), yield 98%.

MS m/z(ESI)：154.4(M＋1)。MS m/z (ESI): 154.4 (M + 1).

第四步the fourth step

全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽1f 的製備Preparation of perhydro-cyclopenta[c]pyrrole-5-one trifluoroacetate 1f

將5－側氧基－全氫－環戊并[c]吡咯－2－羧酸第三丁酯1e (0.32 g，1.42 mmol)攪拌下溶解於10 mL二氯甲烷中，冰浴下加入三氟乙酸(3.27 mL，42.7 mmol)，0℃下反應30分鐘，減壓蒸乾溶劑，得到標題產物全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽1f 的粗產品，其直接用於下一步。5-tert-oxy-perhydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 1e (0.32 g, 1.42 mmol) was dissolved in 10 mL of dichloromethane under stirring, and added to the ice bath. trifluoroacetic acid (3.27 mL, 42.7 mmol), at 0 ℃ 30 minutes, the solvent was evaporated under reduced pressure to give the title product perhydro - cyclopenta [c] pyrrol-5-one trifluoroacetate 1f the crude product, which Used directly in the next step.

MS m/z(ESI)：126.4(M＋1)。MS m/z (ESI): 126.4 (M + 1).

第五步the fifth step

N,N－二甲基－5－側氧基－全氫－環戊并[c]吡咯－2－甲醯胺1g 的製備Preparation of N,N-Dimethyl-5-oxo-perhydro-cyclopenta[c]pyrrole-2-carboxamide 1g

將上一步全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽1f 的粗產品攪拌下溶解於15 mL乙腈中，冰浴冷卻下加入碳酸鉀(0.24 g，1.71 mmol)，再滴加N,N－二甲基胺甲醯氯(0.14 mL，1.56 mmol)，室溫下反應2小時，蒸掉溶劑，加入50 mL水，用乙酸乙酯(50 mL×3)萃取，合併有機相，用50 mL飽和氯化鈉溶液洗滌，乙酸乙酯相用無水硫酸鎂乾燥，過濾，將濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物N,N－二甲基－5－側氧基－全氫－環戊并[c]吡咯－2－甲醯胺1g (0.19 g，淺黃色油狀物)，產率68.3%。The crude product of the previous step of perhydro-cyclopenta[c]pyrrole-5-one trifluoroacetate 1f was dissolved in 15 mL of acetonitrile with stirring, and potassium carbonate (0.24 g, 1.71 mmol) was added thereto under ice cooling. N,N-dimethylamine formazan chloride (0.14 mL, 1.56 mmol) was added dropwise, and the mixture was reacted for 2 hr at room temperature. The solvent was evaporated, 50 mL water was added, and ethyl acetate (50 mL×3) The organic phase was washed with 50 mL of EtOAc EtOAc. Dimethyl-5-oxo-perhydro-cyclopenta[c]pyrrole-2-carboxamide 1 g (0.19 g, pale yellow oil), yield 68.3%.

MS m/z(ESI)：197.4(M＋1)。MS m/z (ESI): 197.4 (M + 1).

1 H NMR(DMSO－D6 ,400MHz)δ 3.56(m,2H),2.85(m,2H),2.7(s,6H),2.81(m,2H),2.5(m,2H),2.01(m,2H)。 1 H NMR (DMSO-D 6 , 400MHz) δ 3.56 (m, 2H), 2.85 (m, 2H), 2.7 (s, 6H), 2.81 (m, 2H), 2.5 (m, 2H), 2.01 (m , 2H).

第六步Step 6

順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺1h 的製備Cis-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2 - Preparation of methotrexate 1h

將1－(2－胺基乙醯基)－2－氰基－吡咯烷鹽酸鹽1d (0.36 g，1.91 mmol)攪拌下溶解於20 mL甲醇，加入N,N－二甲基－5－側氧基－全氫－環戊并[c]吡咯－2－甲醯胺1g (0.25 g，1.28 mmol)及三乙醯氧基硼氫化鈉(1.22 g，5.74 mmol)，於室溫反應3小時，將反應液濃縮，用20 mL飽和碳酸鈉溶液，然後用二氯甲烷(20 mL×10)萃取反應液，合併有機相，用10 mL飽和氯化鈉溶液洗滌，二氯甲烷層用無水硫酸鈉乾燥，過濾，將濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺1h (0.3 g，白色粉末)，產率53%。1-(2-Aminoethyl fluorenyl)-2-cyano-pyrrolidine hydrochloride 1d (0.36 g, 1.91 mmol) was dissolved in 20 mL of methanol with stirring, and N,N-dimethyl-5- was added. 1-oxy-perhydro-cyclopenta[c]pyrrole-2-carboxamide 1g (0.25 g, 1.28 mmol) and sodium triethoxysulfonylborohydride (1.22 g, 5.74 mmol), 3 at room temperature The reaction solution was concentrated, extracted with 20 mL of saturated sodium carbonate solution and then dichloromethane (20 mL×10). The organic phase was combined and washed with 10 mL of saturated sodium chloride. The organic layer was dried (MgSO4), filtered Oxyethylamino)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 1 h (0.3 g, white powder), yield 53%.

MS m/z(ESI)：334.5(M＋1)。MS m/z (ESI): 334.5 (M + 1).

第七步Seventh step

順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺鹽酸鹽1的製備Cis-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2 -Preparation of methotrexate hydrochloride 1

將順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺1h (200 mg，0.687 mmol)分散於10 mL二氯甲烷中，冰浴下加入2 mL 0.5N的鹽酸***溶液，蒸乾溶劑，加入10 mL***，沉澱物離心，得標題產物順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺鹽酸鹽1 (180 mg，白色粉末)，產率80%。Cis-5-(2-(2-cyanopyrrolidin-1-yl)-2-oneoxyethylamino)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole- 2-Methylamine 1h (200 mg, 0.687 mmol) was dispersed in 10 mL of dichloromethane, and 2 mL of 0.5N hydrochloric acid diethyl ether solution was added to an ice bath, and the solvent was evaporated to dryness. The product cis-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole- 2-Metamine hydrochloride 1 (180 mg, white powder), yield 80%.

1 H NMR(CD3 OD,400MHz)δ 4.82(dd,1H,J1 ＝4Hz,J2 ＝5.2Hz),4.02(dd,2H,J1 ＝J2 ＝16.4Hz),3.62－3.25(m,7H),2.76(s,6H),2.51－1.49(m,10H)。 1 H NMR (CD 3 OD, 400 MHz) δ 4.82 (dd, 1H, J 1 = 4 Hz, J 2 = 5.2 Hz), 4.02 (dd, 2H, J 1 = J 2 = 16.4 Hz), 3.62-3.25 (m) , 7H), 2.76 (s, 6H), 2.51-1.49 (m, 10H).

實施例2Example 2

順－5－(2－(S)－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－全氫－環戊并[c]吡咯－2－羧酸甲酯鹽酸鹽 Cis-5-(2-(S)-(2-cyanopyrrolidin-1-yl)-2-oxoethoxyethylamino)-perhydro-cyclopenta[c]pyrrole-2-carboxylic acid Ester hydrochloride

第一步first step

5－側氧基－全氫－環戊并[c]吡咯－2－羧酸甲酯2a 的製備Preparation of 5-sided oxy-perhydro-cyclopenta[c]pyrrole-2-carboxylic acid methyl ester 2a

將全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽1f (0.559 g，2.34 mmol)於攪拌下溶解於20 mL乙腈中，於冰水浴下依次加入碳酸鉀(0.646 g，4.68 mmol)和氯甲酸甲酯(0.22 mL，2.8 mmol)，自然升溫，室溫反應過夜，減壓蒸乾溶劑，加入50 mL水，用乙酸乙酯(50 mL×3)萃取，合併有機相，依次用50 mL飽和氯化鈉溶液和50 mL水洗滌，乙酸乙酯相用無水硫酸鎂乾燥過夜，過濾，將濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－側氧基－全氫－環戊并[c]吡咯－2－羧酸甲酯2a (0.25 g，無色油狀物)，產率58.4%。The perhydro-cyclopenta[c]pyrrole-5-one trifluoroacetate 1f (0.559 g, 2.34 mmol) was dissolved in 20 mL of acetonitrile with stirring, and potassium carbonate (0.646 g, 4.68) was added to the ice water bath. Methyl chloroformate (0.22 mL, 2.8 mmol), mp EtOAc (EtOAc: EtOAc) After washing with 50 mL of a saturated sodium chloride solution and 50 mL of water, the ethyl acetate phase was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. -Sideoxy-perhydro-cyclopenta[c]pyrrole-2-carboxylic acid methyl ester 2a (0.25 g, colorless oil), yield 58.4%.

MS m/z(ESI)：184(M＋1)。MS m/z (ESI): 184 (MH).

第二步Second step

順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－全氫－環戊并[c]吡咯－2－羧酸甲酯2b 的製備Preparation of methyl cis-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-perhydro-cyclopenta[c]pyrrole-2-carboxylate 2b

將1－(2－胺基乙醯基)－2－氰基－吡咯烷鹽酸鹽1d (0.43 g，2.29 mmol)攪拌下溶解於20 mL甲醇中，加入5－側氧基－全氫－環戊并[c]吡咯－2－羧酸甲酯2a (0.28 g，1.53 mmol)及三乙醯氧基硼氫化鈉(1.46 g，6.88 mmol)，於室溫反應3小時，反應液濃縮，用20 mL飽和碳酸鈉溶液，然後用二氯甲烷(20 mL×3)萃取反應液，合併有機相，用10 mL飽和氯化鈉溶液洗滌，二氯甲烷層用無水硫酸鈉乾燥，過濾，濾液減壓濃縮，用矽膠管柱層析法純化，得到產品順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－全氫－環戊并 [c]吡咯－2－羧酸甲酯2b (0.22 g，白色粉末)，產率41%。1-(2-Aminoethyl fluorenyl)-2-cyano-pyrrolidine hydrochloride 1d (0.43 g, 2.29 mmol) was dissolved in 20 mL of methanol with stirring. Methyl cyclopenta[c]pyrrole-2-carboxylate 2a (0.28 g, 1.53 mmol) and sodium triethoxysulfonylborohydride (1.46 g, 6.88 mmol) were reacted at room temperature for 3 hr. The reaction mixture was extracted with 20 mL of saturated sodium carbonate solution and then dichloromethane (20 mL×3). The organic phase was combined and washed with 10 mL of saturated sodium chloride. Concentration under reduced pressure and purification by silica gel column chromatography to give the product cis-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoxyethylamine)-perhydro-cyclopentane And [c]methyl pyrrole-2-carboxylate 2b (0.22 g, white powder), yield 41%.

MS m/z(ESI)：357(M＋1)。MS m/z (ESI): 357 (MH).

第三步third step

順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－全氫－環戊并[c]吡咯－2－羧酸甲酯鹽酸鹽2 的製備Cis-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-perhydro-cyclopenta[c]pyrrole-2-carboxylic acid methyl ester hydrochloride Preparation of 2

將順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－全氫－環戊并[c]吡咯－2－羧酸甲酯2b 分散於10 mL***中，冰浴下加入2 mL 0.5 N的鹽酸***溶液，將沉澱物離心，得到標題產物順－5－(2－((S)－2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－全氫－環戊并[c]吡咯－2－羧酸甲酯鹽酸鹽2 (200 mg，白色粉末)。Disperse cis-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-perhydro-cyclopenta[c]pyrrole-2-carboxylic acid methyl ester 2b 2 mL of 0.5 N hydrochloric acid diethyl ether solution was added to 10 mL of diethyl ether under ice-cooling, and the precipitate was centrifuged to obtain the title product cis-5-(2-((S)-2-cyanopyrrolidin-1-yl). 2-oxoethoxyethylamino)-perhydro-cyclopenta[c]pyrrole-2-carboxylic acid methyl ester hydrochloride 2 (200 mg, white powder).

1 H NMR(CD3 OD,400MHz)δ 4.71(m,1H),3.93(m,2H),3.59－3.28(m,10H),2.64(m,2H),2.34(m,2H),2.17(m,2H),2.08(m,2H)。 1 H NMR (CD 3 OD, 400 MHz) δ 4.71 (m, 1H), 3.93 (m, 2H), 3.59-3.28 (m, 10H), 2.64 (m, 2H), 2.34 (m, 2H), 2.17 ( m, 2H), 2.08 (m, 2H).

實施例3Example 3

順－1－(2－(2－(2－羥基乙醯基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷鹽酸鹽 Cis-1-(2-(2-(2-hydroxyethyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethenyl)-2-cyano-pyrrolidine hydrochloride salt

第一步first step

2－(2－羥基乙醯基)－全氫－環戊并[c]吡咯－2－酮3a 的製備Preparation of 2-(2-hydroxyethyl)-perhydro-cyclopenta[c]pyrrole-2-one 3a

將全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽1f (764.8 mg，3.2 mmol)和2－羥基乙酸(267.5 mg，3.52 mmol)攪拌下溶解於10 mL乙腈中，冰水浴下加入羥基乙酸(1.3 g，9.6 mmol)和1－乙基－3－二甲胺丙基－碳二亞胺鹽酸鹽(1.23 g，6.4 mmol)和三乙胺(1.3 mL，9.6 mmol)，撤掉冰水浴，在25℃下反應過夜，蒸乾溶劑，加入20 mL乙酸乙酯，抽濾，用20 mL水洗滌濾液，乙酸乙酯層用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物2－(2－羥基乙醯基)－全氫－環戊并[c]吡咯－2－酮3a (0.375 g，無色油狀物)，產率64%。All hydrogen-cyclopenta[c]pyrrole-5-one trifluoroacetate 1f (764.8 mg, 3.2 mmol) and 2-hydroxyacetic acid (267.5 mg, 3.52 mmol) were dissolved in 10 mL of acetonitrile with stirring, ice-water bath Glycolic acid (1.3 g, 9.6 mmol) and 1-ethyl-3-dimethylaminopropyl-carbodiimide hydrochloride (1.23 g, 6.4 mmol) and triethylamine (1.3 mL, 9.6 mmol) The ice water bath was removed, and the reaction was carried out at 25 ° C overnight. The solvent was evaporated to dryness. EtOAc was evaporated. concentrated and the resulting residue was purified by silica gel column chromatography to obtain the title product 2- (2-acetyl-yl) - perhydro - cyclopenta [c] pyrrol-2-one 3a (0.375 g, colorless oil ()), yield 64%.

MS m/z(ESI)：184(M＋1)。MS m/z (ESI): 184 (MH).

第二步Second step

順－1－(2－(2－(2－羥基乙醯基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷3b 的製備Cis-1-(2-(2-(2-hydroxyethyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano-pyrrolidine 3b preparation

將2－(2－羥基乙醯基)－全氫－環戊并[c]吡咯－2－酮3a (0.375 g，2.05 mmol)和1－(2－胺基乙醯基)－2－氰基－吡咯烷鹽酸鹽1d (0.78 g，4.1 mmol)攪拌下溶解於10 mL四氫呋 喃和5 mL甲醇中，室溫下反應0.5小時後，加入三乙醯氧基硼氫化鈉(0.87 g，4.1 mmol)，於室溫反應過夜，減壓濃縮反應液，加50 mL甲醇和碳酸鉀(2 g，7 mmol)並攪拌0.5小時，減壓抽濾，濾液減壓濃縮，用矽膠管柱層析法純化，得到產品順－1－(2－(2－(2－羥基乙醯基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷3 ，其直接用於下一步反應。2-(2-Hydroxyethyl)-perhydro-cyclopenta[c]pyrrole-2-one 3a (0.375 g, 2.05 mmol) and 1-(2-aminoethenyl)-2-cyanide The pyridine-pyrrolidine hydrochloride 1d (0.78 g, 4.1 mmol) was dissolved in 10 mL of tetrahydrofuran and 5 mL of methanol with stirring, and reacted at room temperature for 0.5 hour, then sodium triethyloxyborohydride (0.87 g, 4.1) was added. The reaction mixture was stirred at rt. EtOAc was evaporated. Purification to give the product cis-1-(2-(2-(2-hydroxyethyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano Pyrrolidine 3 which was used directly in the next reaction.

MS m/z(ESI)：357(M＋1)。MS m/z (ESI): 357 (MH).

第三步third step

順－1－(2－(2－(2－羥基乙醯基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷鹽酸鹽3 的製備Cis-1-(2-(2-(2-hydroxyethyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethenyl)-2-cyano-pyrrolidine hydrochloride Preparation of salt 3

將順－1－(2－(2－(2－羥基乙醯基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷3b 分散於10 mL***中，冰浴下加入2 mL 0.5 N的鹽酸***溶液，沉澱物離心，得到標題產物順－1－(2－(2－(2－羥基乙醯基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷鹽酸鹽3 (100 mg，白色粉末)。Cis-1-(2-(2-(2-hydroxyethyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano-pyrrolidine 3b Disperse in 10 mL of diethyl ether, add 2 mL of 0.5 N hydrochloric acid diethyl ether solution under ice bath, and centrifuge the precipitate to obtain the title product cis-1-(2-(2-(2-hydroxyethyl)-perhydro-ring Pentyl[c]pyrrole-5-ylamino)ethynyl)-2-cyano-pyrrolidine hydrochloride 3 (100 mg, white powder).

實施例4Example 4

順－1－(2－(2－(哌啶－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷鹽酸鹽 Cis-1-(2-(2-(piperidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethenyl)-2-cyano-pyrrolidine hydrochloride salt

第一步first step

2－(哌啶－1－羰基)－全氫－環戊并[c]吡咯－5－酮4a 的製備Preparation of 2-(piperidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-one 4a

將全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽1f (478 mg，2 mmol)攪拌下溶解於20 mL二氯甲烷中，加入碘化[3－(1－哌啶甲醯基)咪唑－1－甲基](0.96 g，3 mmol)和三乙胺(0.84 mL，6 mmol)，室溫下反應過夜，加入20 mL水使反應停止，用二氯甲烷(50 mL×3)萃取，合併有機相，依次用50 mL 10%檸檬酸溶液和50 mL飽和氯化鈉溶液洗滌，二氯甲烷相用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物2－(哌啶－1－羰基)－全氫－環戊并[c]吡咯－5－酮4a (0.41 g，無色油狀物)，產率87%。Dissolve perhydro-cyclopenta[c]pyrrole-5-one trifluoroacetate 1f (478 mg, 2 mmol) in 20 mL of dichloromethane and add iodination [3-(1-piperidine) Indole-based imidazol-1-methyl] (0.96 g, 3 mmol) and triethylamine (0.84 mL, 6 mmol), allowed to react at room temperature overnight, then quenched with 20 mL of water, with dichloromethane (50 mL) ×3) Extraction, the organic phase was combined, washed successively with 50 mL of 10% citric acid solution and 50 mL of saturated sodium chloride solution, and the dichloromethane phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography to give the title product 2- (piperidin-1-carbonyl) - perhydro - cyclopenta [c] pyrrol-5-one 4a (0.41 g, colorless oil), yield 87 %.

MS m/z(ESI)：237(M＋1)。MS m/z (ESI): 237 (MH).

第二步Second step

順－1－(2－(2－(哌啶－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷4b 的製備Cis-1-(2-(2-(piperidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano-pyrrolidine 4b preparation

將2－(哌啶－1－羰基)－全氫－環戊并[c]吡咯－5－酮4a (0.41 g，1.74 mmol)和1－(2－胺基乙醯基)－2－氰基－吡咯烷鹽酸鹽1d (0.5 g，2.6 mmol)溶解於50 mL四氫呋喃中，加入5 g硫酸鈉和0.05 mL乙酸，室溫下反應0.5小時後，加入三 乙醯氧基硼氫化鈉(1.1 g，5.2 mmol)，於室溫反應3小時後，減壓濃縮反應液，加入50 mL飽和碳酸鈉溶液，用乙酸乙酯(50 mL×3)萃取，合併有機相，依次用50 mL飽和氯化鈉溶液和50 mL水洗滌，乙酸乙酯層用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化，得到標題產物順－1－(2－(2－(哌啶－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷4b ，其直接用於下一步反應。2-(Piperidine-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-one 4a (0.41 g, 1.74 mmol) and 1-(2-aminoethenyl)-2-cyanide The pyridine-pyrrolidine hydrochloride 1d (0.5 g, 2.6 mmol) was dissolved in 50 mL of tetrahydrofuran, and 5 g of sodium sulfate and 0.05 mL of acetic acid were added thereto, and the reaction was carried out at room temperature for 0.5 hour, followed by the addition of sodium triethoxysulfonate. 1.1 g, 5.2 mmol), after reacting for 3 hours at room temperature, the reaction mixture was concentrated under reduced pressure, then 50 mL of saturated sodium carbonate solution was added and extracted with ethyl acetate (50 mL×3). The sodium chloride solution and 50 mL of water were washed, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. (Piperidine-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethynyl)-2-cyano-pyrrolidine 4b which was used directly in the next reaction.

MS m/z(ESI)：410(M＋1)。MS m/z (ESI): 410 (MH).

第三步third step

順－1－(2－(2－(哌啶－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷鹽酸鹽4 的製備Cis-1-(2-(2-(piperidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethenyl)-2-cyano-pyrrolidine hydrochloride Preparation of salt 4

將順－1－(2－(2－(哌啶－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷4b 分散於10 mL***中，冰浴下加入2 mL 0.5 N的鹽酸***溶液，將沉澱物離心，得到標題產物順－1－(2－(2－(哌啶－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷鹽酸鹽4 (0.16 g，白色粉末)。Cis-1-(2-(2-(piperidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano-pyrrolidine 4b Disperse in 10 mL of diethyl ether, add 2 mL of 0.5 N hydrochloric acid diethyl ether solution under ice bath, and centrifuge the precipitate to obtain the title product cis-1-(2-(2-(piperidin-1-carbonyl)-perhydro- Cyclopenta[c]pyrrole-5-ylamino)ethynyl)-2-cyano-pyrrolidine hydrochloride 4 (0.16 g, white powder).

1 H NMR(CD3 OD,400MHz)δ 4.83(dd,1H,J1 ＝3.0Hz,J2 ＝5.8Hz),4.09(dd,2H,J1 ＝J2 ＝13.1Hz),3.70－3.30(m,10H),2.72(m,2H),2.47(m,2H),2.31－2.00(m,5H),1.66－1.52(m,8H)。 1 H NMR (CD 3 OD, 400 MHz) δ 4.83 (dd, 1H, J 1 = 3.0 Hz, J 2 = 5.8 Hz), 4.09 (dd, 2H, J 1 = J 2 = 13.1 Hz), 3.70 - 3.30 ( m, 10H), 2.72 (m, 2H), 2.47 (m, 2H), 2.31-2.00 (m, 5H), 1.66-1.52 (m, 8H).

實施例5Example 5

順－1－(2－(2－乙醯基－全氫－環戊并[c]吡咯－5－基胺基)乙醯 基)－2－氰基－吡咯烷鹽酸鹽 Cis-1-(2-(2-ethylindenyl-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano-pyrrolidine hydrochloride

第一步first step

2－乙醯基－全氫－環戊并[c]吡咯－5－酮5a 的製備Preparation of 2-ethylindenyl-perhydro-cyclopenta[c]pyrrole-5-one 5a

將全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽1f (717 mg，3 mmol)攪拌下溶解於乙腈(20 mL)中，冰水浴下加入二碳酸二第三丁酯(0.42 mL，4.5 mmol)和三乙胺(0.98 mL，9 mmol)，冰水浴下反應過夜，蒸乾溶劑，加入50 mL水，用乙酸乙酯萃取(50 mL×3)，合併有機相，用50 mL飽和氯化鈉溶液洗滌，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化得到殘餘物，得到標題產物2－乙醯基－全氫－環戊并[c]吡咯－5－酮5a (0.36 g，無色油狀物)，產率72%。The perhydro-cyclopenta[c]pyrrole-5-one trifluoroacetate salt 1f (717 mg, 3 mmol) was dissolved in acetonitrile (20 mL) with stirring, and dibutyl succinate was added in an ice water bath ( 0.42 mL, 4.5 mmol) and triethylamine (0.98 mL, 9 mmol), EtOAc (EtOAc) EtOAc (EtOAc) The residue was washed with 50 mL of EtOAc EtOAc. [c] Pyrrol-5-one 5a (0.36 g, colorless oil), yield 72%.

MS m/z(ESI)：168.4(M＋1)。MS m/z (ESI): 168.4 (M + 1).

第二步Second step

順－1－(2－(2－乙醯基－全氫－環戊并[c]吡咯－5－基胺基)乙醯 基)－2－氰基－吡咯烷5b 的製備Preparation of cis-1-(2-(2-ethylindenyl-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano-pyrrolidine 5b

將2－乙醯基－全氫－環戊并[c]吡咯－5－酮5a (0.36 g，2.15 mmol)和1－(2－胺基乙醯基)－2－氰基－吡咯烷鹽酸鹽1d (0.614 g，3.23 mmol)溶解於50 mL四氫呋喃中，加入5 g硫酸鈉和0.05 mL乙酸，室溫下反應0.5小時後，加入三乙醯氧基硼氫化鈉(1.37 g，6.46 mmol)，室溫反應3小時後，減壓濃縮反應液，加入50 mL飽和碳酸鈉溶液，用乙酸乙酯(50 mL×3)萃取，合併有機相，依次用50 mL飽和氯化鈉溶液和50 mL水洗滌，乙酸乙酯層用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化，得到標題產物順－1－(2－(2－乙醯基－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷5b ，其直接用於下一步反應。2-Ethyl-perhydro-cyclopenta[c]pyrrole-5-one 5a (0.36 g, 2.15 mmol) and 1-(2-aminoethenyl)-2-cyano-pyrrolidine salt The acid salt 1d (0.614 g, 3.23 mmol) was dissolved in 50 mL of tetrahydrofuran, and 5 g of sodium sulfate and 0.05 mL of acetic acid were added. After reacting for 0.5 hour at room temperature, sodium triethoxysulfonate hydride (1.37 g, 6.46 mmol) was added. After reacting for 3 hours at room temperature, the reaction solution was concentrated under reduced pressure, and 50 mL of saturated sodium carbonate solution was added, and extracted with ethyl acetate (50 mL×3), and the organic phase was combined with 50 mL of saturated sodium chloride solution and 50 The title product was cis-1-(2-(2-ethenyl-perhydro). The titled product was purified by EtOAc EtOAc. -Cyclopenta[c]pyrrole-5-ylamino)ethynyl)-2-cyano-pyrrolidine 5b which was used directly in the next reaction.

MS m/z(ESI)：305.5(M＋1)。MS m/z (ESI): 305.5 (M + 1).

第三步third step

順－1－(2－(2－乙醯基－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷鹽酸鹽5 的製備Preparation of cis-1-(2-(2-ethylindenyl-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano-pyrrolidine hydrochloride 5

將上一步所得順－1－(2－(2－乙醯基－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷5b 分散於20 mL***中，冰浴下加入4 mL 0.5 N的鹽酸***溶液，沉澱物離心，得到標題產物順－1－(2－(2－乙醯基－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷酸鹽5 (0.23 g，白色粉末)。The cis-1-(2-(2-ethylindenyl-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano-pyrrolidine 5b obtained in the previous step was dispersed in In 20 mL of diethyl ether, 4 mL of 0.5 N hydrochloric acid diethyl ether solution was added to an ice bath, and the precipitate was centrifuged to obtain the title product cis-1-(2-(2-ethyl)-perhydro-cyclopenta[c]pyrrole- 5-Aminoamino)ethinyl)-2-cyano-pyrrolidine 5 (0.23 g, white powder).

1 H NMR(CD3 OD,400MHz)δ 4.71(m,1H),3.92(m,2H),3.69－3.37(m,7H),2.69(m,2H),2.33(m,2H),2.13(m,2H),2.04－2.00(m,5H),1.48(m,2H)。 1 H NMR (CD 3 OD, 400 MHz) δ 4.71 (m, 1H), 3.92 (m, 2H), 3.69-3.37 (m, 7H), 2.69 (m, 2H), 2.33 (m, 2H), 2.13 ( m, 2H), 2.04-2.00 (m, 5H), 1.48 (m, 2H).

實施例6Example 6

順－5－[2－(2－氰基吡咯烷－1－基)－2－側氧基－乙胺基]－N－異丙基全氫－環戊并[c]吡咯－2－甲醯胺鹽酸鹽 Cis-5-[2-(2-cyanopyrrolidin-1-yl)-2-yloxy-ethylamino]-N-isopropylperhydro-cyclopenta[c]pyrrole-2-yl Indoleamine hydrochloride

第一步first step

N－異丙基－5－側氧基－全氫－環戊并[c]吡咯－2－甲醯胺6a 的製備Preparation of N-isopropyl-5-sideoxy-perhydro-cyclopenta[c]pyrrole-2-carboxamide 6a

將全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽1f (717 mg，3 mmol)攪拌下溶解於20 mL二氯甲烷，冰水浴下加入異氰酸異丙酯(9 mL，9 mmol)和三乙胺(1.7 mL，12 mmol)。室溫反應過夜，加50 mL水，用二氯甲烷(50 mL×3)萃取，合併有機相，依次用50 mL 10%檸檬酸溶液和50 mL飽和氯化鈉溶液洗滌，二氯甲烷相用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物N－異丙基－5－側氧基－全氫－環戊并[c]吡咯－2－甲醯胺6a (0.3 g，無色油狀物)，產率47.6%Dissolve perhydro-cyclopenta[c]pyrrole-5-one trifluoroacetate 1f (717 mg, 3 mmol) in 20 mL of dichloromethane with stirring and add isopropyl isocyanate (9 mL). , 9 mmol) and triethylamine (1.7 mL, 12 mmol). After reacting at room temperature overnight, add 50 mL of water, extract with dichloromethane (50 mL×3), combine the organic phases, and wash with 50 mL of 10% citric acid solution and 50 mL of saturated sodium chloride solution, respectively. The organic layer was dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated,,,,,,,,,,,, 2-carbamamine 6a (0.3 g, colorless oil), yield 47.6%

MS m/z(ESI)：211(M＋1)。MS m/z (ESI): 211 (M + 1).

第二步Second step

順－5－[2－(2－氰基吡咯烷－1－基)－2－側氧基－乙胺基]－N－異丙基－全氫－環戊并[c]吡咯－2－甲醯胺6b 的製備Cis-5-[2-(2-cyanopyrrolidin-1-yl)-2-yloxy-ethylamino]-N-isopropyl-perhydro-cyclopenta[c]pyrrole-2- Preparation of formamide 6b

將N－異丙基－5－側氧基－全氫－環戊并[c]吡咯－2－甲醯胺6a (0.3 g，1.43 mmol)和(S)－1－(2－胺基乙醯基)－2－氰基－吡咯烷鹽酸鹽1d (0.407 g，2.14 mmol)溶解於50 mL四氫呋喃中，加入5 g硫酸鈉和0.05 mL乙酸，室溫下反應0.5小時後，加入三乙醯氧基硼氫化鈉(0.9 g，4.3 mmol)，於室溫反應3小時後，減壓濃縮反應液，加入50 mL飽和碳酸鈉溶液，用乙酸乙酯(50 mL×3)萃取，合併有機相，依次用50 mL飽和氯化鈉溶液和50 mL水洗滌，乙酸乙酯層用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化，得到標題產物順－5－[2－(2－氰基吡咯烷－1－基)－2－側氧基－乙胺基]－N－異丙基－全氫－環戊并[c]吡咯－2－甲醯胺6b ，其直接用於下一步反應。N-Isopropyl-5-sideoxy-perhydro-cyclopenta[c]pyrrole-2-carboxamide 6a (0.3 g, 1.43 mmol) and (S)-1-(2-amino B Hydrazinyl-2-cyano-pyrrolidine hydrochloride 1d (0.407 g, 2.14 mmol) was dissolved in 50 mL of tetrahydrofuran, 5 g of sodium sulfate and 0.05 mL of acetic acid were added, and reacted at room temperature for 0.5 hour, then added with triethyl Sodium bis oxyborohydride (0.9 g, 4.3 mmol) was reacted at room temperature for 3 hr. The reaction mixture was evaporated. mjjjjjjjjjjj The phase was washed with 50 mL of a saturated sodium chloride solution and 50 mL of water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. -[2-(2-cyanopyrrolidin-1-yl)-2-oxo-ethylamino]-N-isopropyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 6b , which is used directly for the next reaction.

MS m/z(ESI)：384(M＋1)。MS m/z (ESI): 384 (MH).

第三步third step

順－5－[2－(2－氰基吡咯烷－1－基)－2－側氧基－乙胺基]－N－異丙基－全氫－環戊并[c]吡咯－2－甲醯胺鹽酸鹽6 的製備Cis-5-[2-(2-cyanopyrrolidin-1-yl)-2-yloxy-ethylamino]-N-isopropyl-perhydro-cyclopenta[c]pyrrole-2- Preparation of formamide hydrochloride 6

將上一步所得的順－5－[2－(2－氰基吡咯烷－1－基)－2－側氧基－乙胺基]－N－異丙基－全氫－環戊并[c]吡咯－2－甲醯胺6b 分散於10 mL***中，冰浴下加入2 mL 0.5 N的鹽酸***溶液，將沉澱物離心，得到標題產物順－5－[2－(2－氰基吡咯烷－1－基)－2－側氧基－乙胺基]－N－異丙基－全氫－環戊并[c]吡咯 －2－甲醯胺鹽酸鹽6 (80 mg，白色粉末)。The cis-5-[2-(2-cyanopyrrolidin-1-yl)-2-oxo-ethylamino]-N-isopropyl-perhydro-cyclopenta[c]c[c] obtained in the previous step. Pyrrole-2-carboxamide 6b was dispersed in 10 mL of diethyl ether, and 2 mL of 0.5 N hydrochloric acid diethyl ether solution was added thereto under ice-cooling, and the precipitate was centrifuged to obtain the title product cis-5-[2-(2-cyanopyrrole). Alkyl-1-yl)-2-oxo-ethylamino]-N-isopropyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide hydrochloride 6 (80 mg, white powder ).

1 H NMR(CD3 OD,400MHz)δ 4.70(m,1H),3.92(m,2H),3.76－3.32(m,8H),2.63－1.41(m,10H),1.01(d,6H,J＝6Hz)。 1 H NMR (CD 3 OD, 400MHz) δ 4.70 (m, 1H), 3.92 (m, 2H), 3.76-3.32 (m, 8H), 2.63-1.41 (m, 10H), 1.01 (d, 6H, J =6Hz).

實施例7Example 7

順－1－(2－(2－(嗎啉－4－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷鹽酸鹽 Cis-1-(2-(2-(morpholine-4-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethenyl)-2-cyano-pyrrolidine hydrochloride salt

第一步first step

2－(嗎啉－4－羰基)－全氫－環戊并[c]吡咯－5－酮7a 的製備Preparation of 2-(morpholine-4-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-one 7a

將全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽1f (574 mg，2.4 mmol)攪拌下溶解於20 mL乙腈中，冰水浴下加入碳酸鉀(0.397 g，2.88 mmol)，滴加嗎啉－4－甲醯氯(0.323 mL，2.64 mmol)，冰水浴下反應過夜，蒸乾溶劑，加入50 mL水，用乙酸乙酯萃取(50 mL×3)，合併有機相，用50 mL飽和氯化鈉溶液洗滌，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物 2－(嗎啉－4－羰基)－全氫－環戊并[c]吡咯－5－酮7a (0.572 g，無色油狀物)，產率77.3%。The perhydro-cyclopenta[c]pyrrole-5-one trifluoroacetate salt 1f (574 mg, 2.4 mmol) was dissolved in 20 mL of acetonitrile with stirring, and potassium carbonate (0.397 g, 2.88 mmol) was added under ice water bath. Morpholine-4-methylhydrazine chloride (0.323 mL, 2.64 mmol) was added dropwise, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated The residue was washed with aq. Hydrogen-cyclopenta[c]pyrrole-5-one 7a (0.572 g, colorless oil), yield 77.3%.

MS m/z(ESI)：239(M＋1)。MS m/z (ESI): 239 (MH).

第二步Second step

順－1－(2－(2－(嗎啉－4－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷7b 的製備Cis-1-(2-(2-(morpholine-4-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano-pyrrolidine 7b preparation

將2－(嗎啉－4－羰基)－全氫－環戊并[c]吡咯－5－酮7a (0.64 g，2.69 mmol)和1－(2－胺基乙醯基)－2－氰基－吡咯烷鹽酸鹽1d (0.764 g，4.03 mmol)溶解於50 mL四氫呋喃中，加入5 g硫酸鈉和0.05 mL乙酸，室溫下反應0.5小時後，加入三乙醯氧基硼氫化鈉(1.71 g，8.07 mmol)，於室溫反應3小時後，減壓濃縮反應液，加入50 mL飽和碳酸鈉溶液，用乙酸乙酯(50 mL×3)萃取，合併有機相，依次用50 mL飽和氯化鈉溶液和50 mL水洗滌，乙酸乙酯層用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化，得到標題產物順－1－(2－(2－(嗎啉－4－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷7b ，其直接用於下一步反應。2-(morpholine-4-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-one 7a (0.64 g, 2.69 mmol) and 1-(2-aminoethenyl)-2-cyanide The pyridine-pyrrolidine hydrochloride 1d (0.764 g, 4.03 mmol) was dissolved in 50 mL of tetrahydrofuran, and 5 g of sodium sulfate and 0.05 mL of acetic acid were added thereto, and the mixture was reacted at room temperature for 0.5 hour, and then sodium triethoxysulfonate (sodium hydride) was added. 1.71 g, 8.07 mmol), after reacting for 3 hours at room temperature, the reaction mixture was concentrated under reduced pressure, then 50 mL of saturated sodium carbonate solution, and ethyl acetate (50 mL×3) The sodium chloride solution and 50 mL of water were washed, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. (morpholine-4-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethynyl)-2-cyano-pyrrolidine 7b which was used directly in the next reaction.

MS m/z(ESI)：376.7(M＋1)。MS m/z (ESI): 376.7 (M + 1).

第三步third step

順－1－(2－(2－(嗎啉－4－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷鹽酸鹽7 的製備Cis-1-(2-(2-(morpholine-4-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethenyl)-2-cyano-pyrrolidine hydrochloride Preparation of salt 7

將上一步所得的順－1－(2－(2－(嗎啉－4－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷7b 分散於10 mL***中，冰浴下加入2 mL 0.5 N的鹽酸***溶液，將沉澱物離心，得到標題產物順－1－(2－(2－(嗎啉－4－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷鹽酸鹽7 (30 mg，白色粉末)，產率3%。The cis-1-(2-(2-(morpholine-4-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano group obtained in the previous step Pyrrolidine 7b was dispersed in 10 mL of diethyl ether, and 2 mL of a 0.5 N solution of hydrochloric acid in diethyl ether was added to an ice bath, and the precipitate was centrifuged to give the title product cis-1-(2-(2-(morpholin-4-carbonyl)). -hydrogen-cyclopenta[c]pyrrole-5-ylamino)ethenyl)-2-cyano-pyrrolidine hydrochloride 7 (30 mg, white powder), 3% yield.

實施例8Example 8

順－1－(2－(2－(吡咯烷－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)2－氰基－吡咯烷鹽酸鹽 Cis-1-(2-(2-(pyrrolidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethenyl)2-cyano-pyrrolidine hydrochloride

第一步first step

2－(吡咯烷－1－羰基)－全氫－環戊并[c]吡咯－5－酮8a 的製備Preparation of 2-(pyrrolidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-one 8a

將全氫－環戊并[c]吡咯－5－酮三氟乙酸鹽1f (478 mg，2 mmol)攪拌下溶解於20 mL二氯甲烷中，加入吡咯烷－1－甲醯氯(0.276 mL，2.5 mmol)和三乙胺(0.84 mL，6 mmol)，室溫下反應過夜，加入10%檸檬酸溶液調節pH值為4，用二氯甲烷(50 mL×3)萃取，合併有機相，用50 mL飽和氯化鈉溶液洗滌，二氯甲烷相用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化得到殘餘物，得到 標題產物2－(吡咯烷－1－羰基)－全氫－環戊并[c]吡咯－5－酮8a (0.26 g，無色油狀物)，產率58.5%。Dissolve perhydro-cyclopenta[c]pyrrole-5-one trifluoroacetate 1f (478 mg, 2 mmol) in 20 mL of dichloromethane with stirring and add pyrrolidine-1-methylhydrazine chloride (0.276 mL). , 2.5 mmol) and triethylamine (0.84 mL, 6 mmol), react at room temperature overnight, add 10% citric acid solution to adjust pH 4, extract with dichloromethane (50 mL × 3), and combine the organic phase. The residue was washed with 50 mL of aq. -carbonyl)-perhydro-cyclopenta[c]pyrrole-5-one 8a (0.26 g, colorless oil), yield 58.5%.

MS m/z(ESI)：223(M＋1)。MS m/z (ESI): 223 (MH).

第二步Second step

順－1－(2－(2－(吡咯烷－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)－2－氰基－吡咯烷8b 的製備Cis-1-(2-(2-(pyrrolidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl)-2-cyano-pyrrolidine 8b preparation

將2－(吡咯烷－1－羰基)－全氫－環戊并[c]吡咯－5－酮8a (0.26 g，1.17 mmol)和1－(2－胺基乙醯基)－2－氰基－吡咯烷鹽酸鹽1d (0.33 g，1.75 mmol)溶解於50 mL四氫呋喃中，加入5 g硫酸鈉和0.05 mL乙酸，室溫下反應0.5小時後，加入三乙醯氧基硼氫化鈉(0.75 g，3.5 mmol)，於室溫反應3小時後，減壓濃縮反應液，加入50 mL飽和碳酸鈉溶液，用乙酸乙酯(50 mL×3)萃取，合併有機相，依次用50 mL飽和氯化鈉溶液和50 mL水洗滌，乙酸乙酯層用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化，得到標題產物順－1－(2－(2－(吡咯烷－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)2－氰基－吡咯烷8b ，其直接用於下一步反應。2-(Pyrrolidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-one 8a (0.26 g, 1.17 mmol) and 1-(2-aminoethenyl)-2-cyanide Base-pyrrolidine hydrochloride 1d (0.33 g, 1.75 mmol) was dissolved in 50 mL of tetrahydrofuran, and 5 g of sodium sulfate and 0.05 mL of acetic acid were added thereto. After reacting for 0.5 hour at room temperature, sodium triethoxysulfonate hydride ( 0.75 g, 3.5 mmol), after reacting for 3 hours at room temperature, the reaction mixture was concentrated under reduced pressure, and then 50 mL of saturated sodium carbonate solution was taken and extracted with ethyl acetate (50 mL×3). The sodium chloride solution and 50 mL of water were washed, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. (Pyrrolidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethynyl)2-cyano-pyrrolidine 8b which was used directly in the next reaction.

MS m/z(ESI)：396(M＋1)。MS m/z (ESI): 396 (MH).

第三步third step

順－1－(2－(2－(吡咯烷－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)2－氰基－吡咯烷鹽酸鹽8 的製備Cis-1-(2-(2-(pyrrolidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethenyl)2-cyano-pyrrolidine hydrochloride Preparation of 8

將上一步所得的順－1－(2－(2－(吡咯烷－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)2－氰基－吡咯烷8b 分散於10 mL***中，冰浴下加入2 mL 0.5 N的鹽酸***溶液，將沉澱物離心，得到標題產物順－1－(2－(2－(吡咯烷－1－羰基)－全氫－環戊并[c]吡咯－5－基胺基)乙醯基)2－氰基－吡咯烷鹽酸鹽8 (90 mg，白色粉末)。The cis-1-(2-(2-(pyrrolidin-1-carbonyl)-perhydro-cyclopenta[c]pyrrole-5-ylamino)ethyl) 2-cyano group obtained in the previous step- The pyrrolidine 8b was dispersed in 10 mL of diethyl ether, and 2 mL of a 0.5 N solution of hydrochloric acid in diethyl ether was added thereto under ice-cooling, and the precipitate was centrifuged to obtain the title product cis-1-(2-(2-(pyrrolidin-1-carbonyl)- All hydrogen-cyclopenta[c]pyrrole-5-ylamino)ethenyl)2-cyano-pyrrolidine hydrochloride 8 (90 mg, white powder).

1 H NMR(CD3 OD,400MHz)δ 4.72(m,1H),4.09(m,2H),3.43－3.30(m,11H),2.62(m,2H),2.35(m,2H),2.18(m,2H),2.08(m,2H),1.77(m,4H)。 1 H NMR (CD 3 OD, 400 MHz) δ 4.72 (m, 1H), 4.09 (m, 2H), 3.43-3.30 (m, 11H), 2.62 (m, 2H), 2.35 (m, 2H), 2.18 ( m, 2H), 2.08 (m, 2H), 1.77 (m, 4H).

實施例9Example 9

順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺三氟乙酸鹽 Cis-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2 -carbamidine trifluoroacetate

將實施例1所得的順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺1h (157 mg，0.54 mmol)分散於10 mL二氯甲烷中，冰浴下加入2 mL三氟乙酸並攪拌0.5小時，將沉澱物離心，得到標題產物順－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺三氟乙酸鹽9 (201 mg，白色粉末)。The cis-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethoxyethyl)-N,N-dimethyl-perhydro-cyclopentayl group obtained in Example 1 was obtained. [c] Pyrrole-2-carboxamide 1h (157 mg, 0.54 mmol) was dispersed in 10 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added and stirred for 0.5 hour in an ice bath, and the precipitate was centrifuged to give the title product. -5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethoxyethylamino)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2- Formamide trifluoroacetate 9 (201 mg, white powder).

1 H NMR(CDCl3 ,400MHz)δ 4.74(t,1H,J＝5.2Hz),3.98(d,1H,J＝15.6Hz),3.79(d,1H,J＝15.6Hz),3.57－3.25(m,7H), 2.75(s,6H),2.55(m,2H),2.33(m,2H),2.20－2.08(m,4H),1.74(m,2H)。 1 H NMR (CDCl 3 , 400 MHz) δ 4.74 (t, 1H, J = 5.2 Hz), 3.98 (d, 1H, J = 15.6 Hz), 3.79 (d, 1H, J = 15.6 Hz), 3.57 - 3.25 ( m, 7H), 2.75 (s, 6H), 2.55 (m, 2H), 2.33 (m, 2H), 2.20-2.08 (m, 4H), 1.74 (m, 2H).

實施例10Example 10

反－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺三氟乙酸鹽 Trans-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2 -carbamidine trifluoroacetate

第一步first step

順－5－羥基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺10a 的製備Preparation of cis-5-hydroxy-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 10a

在氮氣保護下，在一個乾燥的三口燒瓶中，將N,N－二甲基－5－側氧基－全氫－環戊并[c]吡咯－2－甲醯胺1g (1.58 g,8.06 mmol)攪拌下溶解於30 mL四氫呋喃中，冷卻到－25 ℃，並在該溫度下，滴加30 mL氫化三第三丁氧基鋁鋰(2.45 g,9.6 mmol)的四氫呋喃溶液，在－25℃反應2.5小時後，加水使反應停止，加入20 mL飽和氯化銨溶液，自然升至室溫，分液，水相用二氯甲烷(50 mL×3)萃取，合併有機相，用50 mL飽和氯化鈉溶液洗滌，硫酸鎂乾燥有機相，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物順－5－羥基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺10a (1.27 g，無色油狀物)，產率80%。N,N-Dimethyl-5-oxo-perhydro-cyclopenta[c]pyrrole-2-carboxamide 1 g (1.58 g, 8.06) in a dry three-necked flask under nitrogen. Ment) dissolved in 30 mL of tetrahydrofuran with stirring, cooled to -25 ° C, and at this temperature, 30 mL of a solution of hydrogenated lithium trit-butoxide aluminum (2.45 g, 9.6 mmol) in tetrahydrofuran was added dropwise at -25 After reacting for 2.5 hours at °C, add water to stop the reaction, add 20 mL of saturated ammonium chloride solution, naturally raise to room temperature, separate the liquid, extract the aqueous phase with dichloromethane (50 mL×3), combine the organic phase, use 50 mL The organic layer was washed with a saturated aqueous solution of sodium chloride, and filtered, filtered, filtered, and evaporated. All hydrogen-cyclopenta[c]pyrrole-2-carboxamide 10a (1.27 g, colorless oil), yield 80%.

MS(m/z)(ESI)：199(M＋1)。MS (m/z) (ESI): 195 (MH).

第二步Second step

甲磺酸[順－2－二甲基胺甲醯基－全氫－環戊并[c]吡咯－5－基]酯10b 的製備Preparation of [cis-2-dimethylaminecarbamyl-perhydro-cyclopenta[c]pyrrole-5-yl]ester 10b

在氮氣的保護下，在乾燥的單口燒瓶中將順－5－羥基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺10a (1.69 g，8.5 mmol)攪拌下溶解於30 mL二氯甲烷中，用冰鹽浴冷卻至－5℃至0℃之間，依次加入三乙胺(1.66 g，14.45 mmol)和甲基磺醯氯(2.2g，21.74 mmol)，攪拌0.5小時後自然升至室溫，在室溫下反應2小時，減壓濃縮反應液，加入20 mL水，用乙酸乙酯(50 mL×6)萃取，合併有機相，用50 mL飽和氯化鈉溶液洗滌，用硫酸鎂乾燥有機相，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得的殘餘物，得到標題產物甲磺酸[順－2－二甲基胺甲醯基－全氫－環戊并[c]吡咯－5－基]酯10b (1.94 g，白色固體)，產率83%。cis-5-Hydroxy-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 10a (1.69 g, 8.5 mmol) in a dry single-necked flask under nitrogen. Dissolved in 30 mL of dichloromethane with stirring, cooled to -5 ° C to 0 ° C with an ice salt bath, and then added triethylamine (1.66 g, 14.45 mmol) and methyl sulfonium chloride (2.2 g, 21.74). After stirring for 0.5 hours, it was naturally warmed to room temperature, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The title compound was methanesulfonic acid [cis-2-dimethyl]. The residue was purified by chromatography. Aminomethylmercapto-perhydro-cyclopenta[c]pyrrole-5-yl]ester 10b (1.94 g, white solid), yield 83%.

MS(m/z)(ESI)：277(M＋1)MS (m/z) (ESI): 277 (M+1)

第三步third step

反－5－(1,3－二側氧基－1,3－二氫－異吲哚－2－基)－N,N－二甲基－全氫－環戊并[c]吡咯－甲醯胺10c 的製備Trans-5-(1,3-di- oxy-1,3-dihydro-isoindol-2-yl)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-A Preparation of guanamine 10c

在氮氣的保護下，在乾燥的單口瓶中將甲磺酸[順－2－二甲基胺甲醯基－全氫－環戊并[c]吡咯－5－基]酯10b (1 g，3.6 mmol)攪拌下溶解於20 mL N,N－二甲基甲醯胺中，加入鄰苯二甲醯亞胺鉀鹽(993 mg，5.4 mmol)，升溫到70℃，反應3小時，減壓濃縮該N,N－二甲基甲醯胺溶液，加入20 mL水，用乙酸乙酯(50 mL×3)萃取，合併有機相，用50 mL飽和氯化鈉溶液洗滌，用硫酸鎂乾燥，抽濾，濾液減壓濃縮，得到標題產物反－5－(1,3－二側氧基－1,3－二氫－異吲哚－2－基)－N,N－二甲基－全氫－環戊并[c]吡咯－甲醯胺10c (1.06 g，白色固體)，產率90%，該產物直接用於下一步反應。Under the protection of nitrogen, methanesulfonic acid [cis-2-dimethylamine-mercapto-perhydro-cyclopenta[c]pyrrole-5-yl]ester 10b (1 g, in a dry single-mouth bottle 3.6 mmol) was dissolved in 20 mL of N,N-dimethylformamide with stirring, and potassium phthalate (993 mg, 5.4 mmol) was added, and the temperature was raised to 70 ° C for 3 hours. The N,N-dimethylformamide solution was concentrated, added with 20 mL of water, and extracted with ethyl acetate (50 mL×3). The organic phase was combined, washed with 50 mL of saturated sodium chloride and dried over magnesium sulfate. Filtration and concentration of the filtrate under reduced pressure afforded the title product, <RTI ID=0.0> Hydrogen-cyclopenta[c]pyrrole-carboxamide 10c (1.06 g, white solid), yield 90%.

MS(m/z)(ESI)：328(M＋1)。MS (m/z) (ESI): 328 (M + 1).

第四步the fourth step

反－5－胺基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺10d 的製備Preparation of trans-5-amino-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 10d

在單口瓶中將反－5－(1,3－二側氧基－1,3－二氫－異吲哚－2－基)－N,N－二甲基－全氫－環戊并[c]吡咯－甲醯胺10c (1g，3.06mmol)於攪拌下溶解於20 mL 95%乙醇中，加入肼(490 mg，15.3 mmol)，加熱回流反應8小時，冷卻到室溫，抽濾，濾液減壓濃縮，得到白色的固體，加入25 mL甲醇，抽濾，將濾液減壓濃縮，用鹼性氧化鋁管柱層析法純化所得殘餘物，得到標題產物反－5－胺基－N,N－二甲基－全氫－環戊 并[c]吡咯－2－甲醯胺10d (290 mg，無色油狀物)，產率48%。In the single-mouth bottle, trans-5-(1,3-di-oxy-1,3-dihydro-isoindol-2-yl)-N,N-dimethyl-perhydro-cyclopenta[ c] Pyrrole-carbamide 10c (1 g, 3.06 mmol) was dissolved in 20 mL of 95% ethanol with stirring, and hydrazine (490 mg, 15.3 mmol) was added, and the mixture was heated to reflux for 8 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure to dryness crystals crystals crystals crystalssssssssssssssssssssssssssssssssssssss , N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 10d (290 mg, colorless oil), yield 48%.

MS(m/z)(ESI)：198(M＋1)。MS (m/z) (ESI): 198 (M+1).

第五步the fifth step

反－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺10e 的製備Trans-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2 -Preparation of methotrexate 10e

在乾燥的單口燒瓶中加入反－1－(2－氯－乙醯基)－2－氰基－吡咯烷(334 mg，1.94 mmol)，加入20 mL反－5－胺基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺10d (290 mg，1.46 mmol)的二氯甲烷溶液，加熱回流48小時，減壓濃縮反應液，用矽膠管柱層析法純化所得到的殘餘物，得到反－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺10e ，其直接用於下一步反應。Add de-1-(2-chloro-ethenyl)-2-cyano-pyrrolidine (334 mg, 1.94 mmol) to a dry one-neck flask and add 20 mL of trans-5-amino-N,N- a solution of dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 10d (290 mg, 1.46 mmol) in dichloromethane, heated under reflux for 48 hr. The obtained residue was purified by an analytical method to give trans-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoxyethylamine)-N,N-dimethyl-perhydro - cyclopenta[c]pyrrole-2-carboxamide 10e , which was used directly in the next reaction.

第六步Step 6

反－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺三氟乙酸鹽10 的製備Trans-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2 -Preparation of methotrexate trifluoroacetate 10

將上一步得到的反－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺10e 攪拌下溶解於10 mL二氯甲烷中，加入2 mL三氟乙酸並攪拌0.5小時，得到反－5－(2－(2－氰基吡咯烷－1－基)－2－側氧基乙胺基)－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺三氟乙酸鹽10 (201 mg，白色固體)。The trans-5-(2-(2-cyanopyrrolidin-1-yl)-2-oxoethylamino)-N,N-dimethyl-perhydro-cyclopenta[B] obtained in the previous step. c] Pyrrole-2-carboxamide 10e was dissolved in 10 mL of dichloromethane with stirring, 2 mL of trifluoroacetic acid was added and stirred for 0.5 hour to obtain trans-5-(2-(2-cyanopyrrolidine-1-) 2-(Ethyloxyethylamino)-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide trifluoroacetate 10 (201 mg, white solid).

MS(m/z)(ESI)：334(M＋1)。MS (m/z) (ESI): 356 (M + 1).

1 H NMR(CDCl3 ,400MHz)δ 4.65(m,1H),3.93(d,1H,J＝15.2Hz),3.74(d,1H,J＝15.2Hz),3.69－3.19(m,7H),2.77(s, 6H),2.18－1.96(m,10H)。 1 H NMR (CDCl 3, 400MHz ) δ 4.65 (m, 1H), 3.93 (d, 1H, J = 15.2Hz), 3.74 (d, 1H, J = 15.2Hz), 3.69-3.19 (m, 7H), 2.77 (s, 6H), 2.18-1.96 (m, 10H).

實施例11Example 11

5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺對甲苯磺酸鹽 5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole 2-carbamamine p-toluenesulfonate

第一步first step

5－亞甲基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-methylene-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

氮氣保護下，將第三丁醇鉀(7.17 g,0.064 mol)和碘化甲基三苯基鏻(25.8 g,0.064 mol)在攪拌下溶解於150 mL甲苯中，加熱回流3小時，冷卻至室溫，加入30 mL的N,N－二甲基－5－側氧基－全氫－環戊并[c]吡咯－2－甲醯胺1g (5.0 g,0.0255 mol)甲苯溶液，30分鐘後，以薄層層析跟蹤反應，原料消失，加入30 mL水和30 mL飽和氯化鈉溶液，用乙酸乙酯(200 mL×4)萃取，合併有機相，乾燥過夜。抽濾，濾液減壓濃縮，用矽膠管柱層析法純化，得到標題產物5－亞甲基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺11a (4.0 g,淺黃色油狀透明液體)，收率：80%。Potassium tert-butoxide (7.17 g, 0.064 mol) and methyltriphenylphosphonium iodide (25.8 g, 0.064 mol) were dissolved in 150 mL of toluene with stirring under nitrogen, and heated to reflux for 3 hours. At room temperature, add 30 mL of N,N-dimethyl-5-oxo-perhydro-cyclopenta[c]pyrrole-2-carboxamide 1g (5.0 g, 0.0255 mol) in toluene for 30 minutes. Thereafter, the reaction was followed by thin layer chromatography, and the starting material was evaporated. <RTI ID=0.0>>> After suction filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 5-methylene-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 11a (4.0 g, light yellow oily clear liquid), yield: 80%.

MS m/z(ESI)：195.2(M＋1)。MS m/z (ESI): 195.2 (M + 1).

第二步Second step

5－異氰基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-isocyano-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

在氮氣保護下，將5－亞甲基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺11a (1.6 g,8.23 mmol)在攪拌下溶解於30 mL二氯甲烷中，再依次加入三甲基矽氰(4.08 g,41.2 mmol)和過氯酸銀(5.12 g,24.7 mmol)，室溫下攪拌過夜後，用飽和碳酸氫鈉溶液處理部分反應液，以薄層層析跟蹤反應，仍有大部分的原料剩餘，冰浴下，加入20 mL飽和碳酸氫鈉溶液，反應放熱，10分鐘後，過濾，除去固體，分液後，用乙酸乙酯(50 mL×4)萃取，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化，得到標題產物5－異氰基－N,N.5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺11b (0.33 g,淡黃色油狀物)，收率：18.1%。5-Methylene-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 11a (1.6 g, 8.23 mmol) was dissolved in 30 under a nitrogen atmosphere. Trichloromethane cyanide (4.08 g, 41.2 mmol) and silver perchlorate (5.12 g, 24.7 mmol) were added to dichloromethane, and stirred at room temperature overnight, then partially reacted with saturated sodium hydrogen carbonate solution. The liquid was traced by thin layer chromatography. Most of the raw materials remained. Under ice bath, 20 mL of saturated sodium bicarbonate solution was added, and the reaction was exothermic. After 10 minutes, it was filtered to remove solids. After liquid separation, use acetic acid. The ester was extracted (50 mL×4), EtOAcjjjjjjjjjjjjjjjjjj Trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 11b (0.33 g, pale yellow oil), yield: 18.1%.

GC－MS：221.1(M＋ )。GC-MS: 221.1 (M + ).

1 H NMR(CDCl3 ,400MHz)δ 3.31(m,4H),2.97(m,2H),2.84(s,6H),2.32(m,2H),1.52(s,3H),1.46(m,2H)。 1 H NMR (CDCl 3, 400MHz ) δ 3.31 (m, 4H), 2.97 (m, 2H), 2.84 (s, 6H), 2.32 (m, 2H), 1.52 (s, 3H), 1.46 (m, 2H ).

第三步third step

5－胺基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-amino-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

在冰浴下，將0.38 mL的6N的鹽酸加入5－異氰基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺11b (0.388 g,1.75 mmol)的15 mL乙醇溶液中，撤掉冰浴，在室溫下反 應1.5小時，以薄層層析跟蹤反應，原料消失，加入20 mL飽和碳酸氫鈉溶液以使反應停止，用二氯甲烷(50 mL×3)萃取，合併有機相，蒸乾溶劑，用矽膠管柱層析法純化，得到標題產物5－胺基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺11c (0.28 g,黃色油狀物)，收率：75.7%。0.38 mL of 6N hydrochloric acid was added to 5-isocyano-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 11b (0.388 g, under ice bath). 1.75 mmol) in 15 mL ethanol solution, remove the ice bath, react at room temperature for 1.5 hours, trace the reaction by thin layer chromatography, disappear the raw materials, add 20 mL of saturated sodium bicarbonate solution to stop the reaction, use dichloro The methane (50 mL×3) was extracted, the organic phase was combined, and the solvent was evaporated to dryness and purified to the title product product 5-amino-N,N,5-trimethyl-perhydro-cyclopenta [c] Pyrrole-2-carboxamide 11c (0.28 g, yellow oil), yield: 75.7%.

MS m/z(ESI)：212.2(M＋1)。MS m/z (ESI):21.21.

第四步the fourth step

5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole Preparation of 2-carbamamine

將5－胺基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺11c (200 mg,0.92 mmol)在攪拌下溶解於8 mL的N,N－二甲基甲醯胺中，加入1－(2－氯－乙醯基)－2－氰基－吡咯烷(175 mg,1.02 mmol)，室溫下反應過夜後，在40~50℃水浴中，減壓除去N,N－二甲基甲醯胺，用矽膠管柱層析法純化，得到標題產物5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺11d (135 mg,無色油狀液體)，收率：42.3%。回收5－胺基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺11c (130 mg)。5-Amino-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 11c (200 mg, 0.92 mmol) was dissolved in 8 mL of N with stirring. To N-dimethylformamide, 1-(2-chloro-ethenyl)-2-cyano-pyrrolidine (175 mg, 1.02 mmol) was added, and the reaction was carried out at room temperature overnight at 40-50 ° C. In a water bath, N,N-dimethylformamide was removed under reduced pressure and purified by silica gel column chromatography to give the title product 5-[2-(2-cyano-pyrrolidin-1-yl)-2- Side oxy-ethylamino]-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 11d (135 mg, colorless oily liquid), yield: 42.3 %. 5-Amino-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 11c (130 mg) was recovered.

MS m/z(ESI)：348.2(M＋1)。MS m/z (ESI): 348.2 (M + 1).

第五步the fifth step

5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺對甲苯磺酸鹽的製備5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole Preparation of 2-carbamamine p-toluenesulfonate

在冰浴下，將5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺11d (20 mg,0.057 mmol)和一水合對甲苯磺酸(12 mg,0.063 mmol)在攪拌下溶解於2 mL的二氯甲烷中，攪拌10分鐘後，撤掉冰浴，蒸乾反應液中溶劑，得到油狀物，加入5 mL乙酸乙酯，劇烈攪拌，有白色固體析出，抽濾，得到的白色固體為標題產物5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺對甲苯磺酸鹽11 (26 mg,白色固體)，收率：86.8%。5-[2-(2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro-ring under ice bath Ethylene [c]pyrrole-2-carboxamide 11d (20 mg, 0.057 mmol) and p-toluenesulfonic acid monohydrate (12 mg, 0.063 mmol) were dissolved in 2 mL of dichloromethane with stirring and stirred for 10 min. After that, the ice bath was removed, and the solvent was evaporated to dryness crystals crystals crystals crystals crystals crystals 2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide p-Toluenesulfonate 11 (26 mg, white solid), yield: 86.8%.

MS m/z(ESI)：348.2(M＋1)。MS m/z (ESI): 348.2 (M + 1).

1 H NMR(CDCl3 ,400MHz)δ 7.68(d,2H),7.17(d,2H),3.72(m,1H),3.68(m,1H),3.58(m,1H),3.30(m,4H),2.98(s,2H),2.81(s,6H),2.55(m,2H),2.22(m,4H),2.05(m,2H),1.62(m,2H),1.56(s,3H)。 1 H NMR (CDCl 3, 400MHz ) δ 7.68 (d, 2H), 7.17 (d, 2H), 3.72 (m, 1H), 3.68 (m, 1H), 3.58 (m, 1H), 3.30 (m, 4H ), 2.98 (s, 2H), 2.81 (s, 6H), 2.55 (m, 2H), 2.22 (m, 4H), 2.05 (m, 2H), 1.62 (m, 2H), 1.56 (s, 3H) .

實施例12Example 12

5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺對甲苯磺酸鹽 5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole 2-carbamamine p-toluenesulfonate

第一步first step

5－氰基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-cyano-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

在冰浴下，將N,N－二甲基－5－側氧基－全氫－環戊并[c]吡咯－2－甲醯胺1g (12.9 g,0.066 mol)和對甲苯磺醯甲基異腈(14.2 g,0.0727 mol)攪拌下溶解於240 mL乙二醇二甲醚中，滴加第三丁醇鉀(14.8 g,0.132 mol)的第三丁醇溶液，滴畢，撤掉冰浴，室溫下反應過夜，以薄層層析跟蹤，反應完全時，加入100 mL水，50 mL飽和氯化鈉溶液，用乙酸乙酯(200 mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化，得到標題產物5－氰基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺12a (7.0 g,淺黃色油狀液)，收率：51%。N,N-Dimethyl-5-oxo-perhydro-cyclopenta[c]pyrrole-2-carboxamide 1 g (12.9 g, 0.066 mol) and p-toluenesulfonate under ice bath The isomeric nitrile (14.2 g, 0.0727 mol) was dissolved in 240 mL of ethylene glycol dimethyl ether with stirring, and a solution of potassium terp-butoxide (14.8 g, 0.132 mol) in a third butanol was added dropwise, and the mixture was removed. The mixture was stirred at room temperature overnight, and traced by thin layer chromatography. When the reaction was completed, 100 mL of water, 50 mL of saturated sodium chloride solution was added, and extracted with ethyl acetate (200 mL×3), and the organic phase was combined. Drying over anhydrous sodium sulfate, suction filtration, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to give the title product 5-cyano-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2 -Procarbamide 12a (7.0 g, pale yellow oily), yield: 51%.

MS m/z(ESI)：208.1(M＋1)。MS m/z (ESI): 208.1 (M + 1).

1 H NMR(DMSO－D6 ,400MHz)δ 3.5－3.0(m,4H),2.75(s,6H),2.6(m,1H),2.1－1.5(m,6H)。 1 H NMR (DMSO-D 6 , 400 MHz) δ 3.5-3.0 (m, 4H), 2.75 (s, 6H), 2.6 (m, 1H), 2.1-1.5 (m, 6H).

第二步Second step

5－氰基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-cyano-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

在氮氣保護下，將5－氰基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺12a (4.2 g,20.2 mmol)和碘甲烷(11.5 g,80.8 mmol)在攪拌下溶解於100 mL無水四氫呋喃，在室溫下，滴加六甲基二矽烷基胺化鋰(80.8 mL,80.8 mmol)，室溫下反應2小時，MS檢測反應結束，加入100 mL水，用乙酸乙酯(200 mL×3)萃取，用無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，得到油狀物，薄層層析顯示有兩個較近的點，用矽膠管柱層析法純化，下面的點為5－氰基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺12b (2.411 g,淺黃色油狀物)。5-Cyano-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12a (4.2 g, 20.2 mmol) and methyl iodide (11.5 g, under N2) 80.8 mmol) was dissolved in 100 mL of anhydrous tetrahydrofuran under stirring. At room temperature, lithium hexamethyldidecylamine (80.8 mL, 80.8 mmol) was added dropwise, and the reaction was carried out for 2 hours at room temperature. 100 mL of water, extracted with ethyl acetate (200 mL × 3), dried over anhydrous sodium sulfate, filtered, filtered, and evaporated. Purified by column chromatography, the following point is 5-cyano-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12b (2.411 g, pale yellow oil Shape).

MS m/z(ESI)：222.2(M＋1)。MS m/z (ESI): 2221.

1 H NMR(CDCl3 ,400MHz)δ 3.44(m,2H),3.3(m,2H),2.85(s,6H),2.77(m,2H),2.06(m,2H),2.00(m,2H),1.36(s,3H)。 1 H NMR (CDCl 3, 400MHz ) δ 3.44 (m, 2H), 3.3 (m, 2H), 2.85 (s, 6H), 2.77 (m, 2H), 2.06 (m, 2H), 2.00 (m, 2H ), 1.36 (s, 3H).

第三步third step

2－二甲基胺甲醯基－5－甲基－全氫－環戊并[c]吡咯－5－羧酸的製備Preparation of 2-dimethylamine-mercapto-5-methyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid

將5－氰基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺12b (6.99 g,31.6 mmol)在攪拌下溶解於90 mL的36%鹽酸中，在油浴中於50℃下攪拌48小時，以薄層層析跟蹤反應，當原料消失，反應結束時，加入150 mL水，冰浴 下用碳酸鉀固體中和反應液，調節pH為6左右，用乙酸乙酯(150 mL×3)萃取，再用二氯甲烷(150 mL×3)萃取，合併有機相，用無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，得到標題產物2－二甲基胺甲醯基－5－甲基－全氫－環戊并[c]吡咯－5－羧酸12c (7.0 g,黃色液體)，收率：92%，其直接用於下一步反應。5-Cyano-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12b (6.99 g, 31.6 mmol) was dissolved in 90 mL of 36% with stirring In hydrochloric acid, the mixture was stirred at 50 ° C for 48 hours in an oil bath, and the reaction was followed by thin layer chromatography. When the starting material disappeared, 150 mL of water was added at the end of the reaction, and the reaction solution was neutralized with potassium carbonate solid in an ice bath to adjust the pH. The mixture was extracted with ethyl acetate (150 mL×3), and extracted with dichloromethane (150 mL×3). 2-Dimethylamine-mercapto-5-methyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid 12c (7.0 g, yellow liquid), yield: 92%, which was used directly under One step reaction.

MS m/z(ESI)：241.2(M＋1)。MS m/z (ESI): 242.

第四步the fourth step

5－胺基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-amino-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

在冰浴下，將2－二甲基胺甲醯基－5－甲基－全氫－環戊并[c]吡咯－5－羧酸12c (1.0 g,4.2 mmol)在攪拌下溶解於25 mL丙酮中，在－5℃下，滴加三乙胺(463.5 mg,4.58 mmol)和氯甲酸乙酯(497 mg,4.58 mmol)的10 mL丙酮溶液，在－5℃下，反應15分鐘，加入疊氮化鈉(546 mg,8.4 mmol)的10 mL水溶液，在－5℃繼續反應30分鐘，加入25 mL水使反應停止，用乙酸乙酯(50 mL×3)萃取，用無水硫酸鈉乾燥，抽濾，減壓濃濾液，得到粗產品－5－(疊氮基羰基)－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺12d (700 mg,黃色油狀物)。2-Dimethylamine-mercapto-5-methyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid 12c (1.0 g, 4.2 mmol) was dissolved in 25 under ice-cooling. Triethylamine (463.5 mg, 4.58 mmol) and ethyl chloroformate (497 mg, 4.58 mmol) in 10 mL of acetone were added dropwise at -5 ° C in acetone for 15 minutes at -5 °C. A 10 mL aqueous solution of sodium azide (546 mg, 8.4 mmol) was added, and the reaction was continued at -5 °C for 30 minutes. The reaction was quenched by the addition of 25 mL of water and extracted with ethyl acetate (50 mL×3). Drying, suction filtration, and concentration of the filtrate under reduced pressure afforded crude product-5-(azidocarbonyl)-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12d (700 mg, yellow oil).

第五至第六步Fifth to sixth steps

將此黃色油狀物5－(疊氮基羰基)－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺12d (700 mg)加入到20 mL甲苯中回流2小時，蒸乾甲苯，得到產品(3aS,5r,6aR)－5－異氰酸基 －N,N,5－三甲基－全氫－環戊并[c]吡咯－2(1H)－甲醯胺12e ，冰浴下滴加8 mL的8N鹽酸，攪拌30分鐘，以薄層層析跟蹤至反應原料消失，在冰浴下，用3N氫氧化鈉調節至pH>12，用乙酸乙酯(15 mL×3)萃取，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化，得到標題產物5－胺基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺12f (500 mg,淺黃色油狀液體)。Add the yellow oil 5-(azidocarbonyl)-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12d (700 mg) to 20 mL The mixture was refluxed for 2 hours in toluene, and toluene was evaporated to give the product (3aS, 5r, 6aR)-5-isocyano-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2 ( 1H)-carbalamine 12e , 8 mL of 8N hydrochloric acid was added dropwise under ice bath, stirred for 30 minutes, traced by thin layer chromatography until the reaction material disappeared, and adjusted to pH>12 with 3N sodium hydroxide in an ice bath. The mixture was extracted with ethyl acetate (15 mL×3). EtOAcjjjjjjjjjj , 5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12f (500 mg, pale yellow oily liquid).

MS m/z(ESI)：212.2(M＋1)。MS m/z (ESI):21.21.

1 H NMR(DMSO－D6 ,400MHz)δ 3.5－3.0(m,4H),2.72(s,6H),1.7－1.3(m,6H),1.04(s,3H)。 1 H NMR (DMSO-D 6 , 400 MHz) δ 3.5-3.0 (m, 4H), 2.72 (s, 6H), 1.7-1.3 (m, 6H), 1.04 (s, 3H).

第七步Seventh step

5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole Preparation of 2-carbamamine

將5－胺基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺12f (332 mg,1.57 mmol)在攪拌下溶解於10 mL的N,N－二甲基甲醯胺/CH2 Cl2 (1：1)混合溶劑中，加入1－(2－氯－乙醯基)－2－氰基－吡咯烷(217 mg,1.26 mmol)，於室溫下反應過夜，抽乾溶劑，用矽膠管柱層析法純化，得到標題產物5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺12g (240 mg,無色油狀物)，收率：55%。5-Amino-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12f (332 mg, 1.57 mmol) was dissolved in 10 mL of N with stirring. To a mixed solvent of N-dimethylformamide/CH 2 Cl 2 (1:1), 1-(2-chloro-ethenyl)-2-cyano-pyrrolidine (217 mg, 1.26 mmol) was added. After reacting at room temperature overnight, the solvent was evaporated and purified with EtOAc EtOAc EtOAc. Base]-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12 g (240 mg, colorless oil), yield: 55%.

MS m/z(ESI)：348.2(M＋1)。MS m/z (ESI): 348.2 (M + 1).

第八步Eighth step

5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲 基－全氫－環戊并[c]吡咯－2－甲醯胺對甲苯磺酸鹽的製備5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl Preparation of thio-perhydro-cyclopenta[c]pyrrole-2-carboxamide p-toluenesulfonate

將5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺12g (150 mg,0.43 mmol)和一水合對甲苯磺酸(82 mg,0.43 mmol)在攪拌下溶解於4 mL的二氯甲烷中，攪拌10分鐘後，蒸乾反應液中溶劑，得到標題產物5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺對甲苯磺酸鹽12 (220 mg,淡黃色固體)，收率：95.3%。5-[2-(2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro-cyclopenta[c] Pyrrole-2-carboxamide 12g (150 mg, 0.43 mmol) and p-toluenesulfonic acid monohydrate (82 mg, 0.43 mmol) were dissolved in 4 mL of dichloromethane with stirring, stirred for 10 min and evaporated to dryness Solvent in the solvent gave the title product 5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro- Cyclopenta[c]pyrrole-2-carboxamide p-toluenesulfonate 12 (220 mg, pale yellow solid), yield: 95.3%.

MS m/z(ESI)：348.2(M＋1)。MS m/z (ESI): 348.2 (M + 1).

1 H NMR(DMSO－D6 ,400MHz)δ 4.82(m,1H),3.97(s,2H),3.79(m,2H),3.49(m,2H),3.21(m,4H),2.75(s,6H),2.62(m,2H),2.19(m,2H),1.92－1.61(m,3H),2.06(m,3H),1.2(s,3H)。 1 H NMR (DMSO-D 6 , 400MHz) δ 4.82 (m, 1H), 3.97 (s, 2H), 3.79 (m, 2H), 3.49 (m, 2H), 3.21 (m, 4H), 2.75 (s , 6H), 2.62 (m, 2H), 2.19 (m, 2H), 1.92-1.61 (m, 3H), 2.06 (m, 3H), 1.2 (s, 3H).

實施例13Example 13

5－(2－(－2－氰基－4－氟吡咯烷－1－基)－2－側氧基乙基胺基)－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽 5-(2-(2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-N,N,5-trimethyl-perhydro-cyclopenta [c]pyrrole-2-carboxamide tartrate

第一步first step

(2S,4R)－1－(第三丁氧羰基)－4－羥基吡咯烷－2－羧酸的製備Preparation of (2S,4R)-1-(t-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid

將羥脯胺酸13a (60 g,0.458 mol)加入到750 mL四氫呋喃/水(2：1)混合溶劑中，加入252 mL 10%的氫氧化鈉溶液，加入750 mL二碳酸二第三丁酯(136 g,0.624 mol)的四氫呋喃/水(2：1)溶液，室溫下反應過夜，加入500 mL乙酸乙酯，分液，將有機層丟棄，水相用濃鹽酸調節pH為2，用1.5 L乙酸乙酯萃取，飽和氯化鈉溶液洗滌，以無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，得到標題產物(2S,4R)－1－(第三丁氧羰基)－4－羥基吡咯烷－2－羧酸13b (86.4 g,無色油狀物)，收率：80%。Hydroxyproline 13a (60 g, 0.458 mol) was added to a 750 mL tetrahydrofuran/water (2:1) mixed solvent, 252 mL of 10% sodium hydroxide solution was added, and 750 mL of di-tert-butyl dicarbonate was added. (136 g, 0.624 mol) in tetrahydrofuran/water (2:1) solution, react at room temperature overnight, add 500 mL of ethyl acetate, separate the layers, discard the organic layer, and adjust the pH to 2 with concentrated hydrochloric acid. 1.5 L of ethyl acetate was extracted, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. Pyrrolidine-2-carboxylic acid 13b (86.4 g, colorless oil), yield: 80%.

第二步Second step

(2S,4R)－2－胺甲醯基－4－羥基吡咯烷－1－羧酸第三丁酯的製備Preparation of (2S,4R)-2-aminoformamido-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

氬環境下，將(2S,4R)－1－(第三丁氧羰基)－4－羥基吡咯烷－2－羧酸13b (86.4 g,0.374 mol)在攪拌下溶解於1.2 L四氫呋喃中，加入三乙胺(41 g,0.411 mol)，冷卻至－15℃，加入氯甲酸乙酯(43.84 g,0.411 mol)，攪拌10分鐘後，加入236.8 mL氨水，在2小時內慢慢升溫至5℃，再加入32 g 氯化銨，攪拌30分鐘後停止，分液，有機相用無水硫酸乾燥，水相用乙酸乙酯(100 mL×2)萃取，合併有機相，蒸乾溶劑，真空抽乾溶劑，得到標題產物(2S,4R)－2－胺甲醯基基－4－羥基吡咯烷－1－羧酸第三丁酯13c (74g,白色固體)，收率：86%。(2S,4R)-1-(Tertixobutoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid 13b (86.4 g, 0.374 mol) was dissolved in 1.2 L of tetrahydrofuran under stirring in an argon atmosphere. Triethylamine (41 g, 0.411 mol), cooled to -15 ° C, added ethyl chloroformate (43.84 g, 0.411 mol), stirred for 10 minutes, then added 236.8 mL of ammonia water, slowly warmed to 5 ° C within 2 hours Then add 32 g of ammonium chloride, stir for 30 minutes, stop, separate the liquid, the organic phase is dried over anhydrous sulfuric acid, the aqueous phase is extracted with ethyl acetate (100 mL×2), the organic phase is combined, the solvent is evaporated, and dried in vacuo. The title compound (2S,4R)-2-amine-carbazyl-4-hydroxypyrrolidine-l-carboxylic acid tert-butyl ester 13c (74 g, white solid).

第三步third step

(2S,4R)－2－氰基－4－羥基吡咯烷－1－羧酸第三丁酯的製備Preparation of (2S,4R)-2-cyano-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

氬環境下，將(2S,4R)－2－胺甲醯基－4－羥基吡咯烷－1－羧酸第三丁酯13c (74 g,0.3217 mol)攪拌下溶解於740 mL吡啶中，冷卻至－20℃，滴加三氟乙酸酐(169 g,0.804 mol)，滴畢升至室溫反應，薄層層析跟蹤反應至原料消失，加入水使反應停止，加入0.8 L乙酸乙酯，攪拌，分液，有機相用500 mL飽和氯化鈉溶液洗滌，再用400 mL濃鹽酸中和吡啶至微酸性，再用300 mL 2M氫氧化鈉溶液洗滌，用500 mL飽和氯化鈉溶液洗滌，無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，得到標題產物(2S,4R)－2－氰基－4－羥基吡咯烷－1－羧酸第三丁酯13d (49.7g,黃褐色油狀物)，收率：73%。(2S,4R)-2-Aminoformamido-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester 13c (74 g, 0.3217 mol) was dissolved in 740 mL of pyridine under stirring, and cooled. To -20 ° C, trifluoroacetic anhydride (169 g, 0.804 mol) was added dropwise, and the mixture was added dropwise to room temperature. The reaction was traced by thin layer chromatography until the starting material disappeared. Water was added to stop the reaction, and 0.8 L of ethyl acetate was added. Stir, separate the liquid, wash the organic phase with 500 mL of saturated sodium chloride solution, neutralize the pyridine with 400 mL of concentrated hydrochloric acid to slightly acidic, wash with 300 mL of 2M sodium hydroxide solution, and wash with 500 mL of saturated sodium chloride solution. , dried over anhydrous magnesium sulfate, suction filtered, the filtrate was concentrated under reduced pressure to give the title product (2S, 4R) -2- cyano-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester 13d (49.7g, brown oil (form), yield: 73%.

第四步the fourth step

(2S,4S)－2－氰基－4－氟吡咯烷－1－羧酸第三丁酯的製備Preparation of (2S,4S)-2-cyano-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester

氬環境下，將(2S,4R)－2－氰基－4－羥基吡咯烷－1－羧酸第三丁酯13d (49.7 g,0.2344 mol)攪拌下溶解於1130 mL二氯乙烷中，冷卻至－30℃，加入三氟化二乙胺基硫(56.7 g,0.3516 mol)，反應45分鐘後升至－5℃，自然升至室溫，反應過夜，以薄層層析跟蹤反應，原料消失時，緩慢加入飽 和碳酸氫鈉溶液，劇烈冒泡，冷卻，使溫度控制在20℃以下，直到反應液pH大於7，加入冰水，加入500 mL二氯甲烷，分液，依次用500 mL飽和硫酸氫鈉溶液和500 mL飽和氯化鈉溶液洗滌，無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，濃縮過程中溫度低於38℃，得到標題產物(2S,4S)－2－氰基－4－氟吡咯烷－1－羧酸第三丁酯13e (50g,棕黃色固體)，產率：100%。(2S,4R)-2-Cyano-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester 13d (49.7 g, 0.2344 mol) was dissolved in 1130 mL of dichloroethane under stirring in an argon atmosphere. After cooling to -30 ° C, diethylphosphonium trifluoride (56.7 g, 0.3516 mol) was added, and after reacting for 45 minutes, it was raised to -5 ° C, naturally raised to room temperature, and reacted overnight, and the reaction was followed by thin layer chromatography. When the raw material disappears, slowly add saturated sodium bicarbonate solution, vigorously bubbling, cooling, and keep the temperature below 20 °C until the pH of the reaction solution is greater than 7, add ice water, add 500 mL of dichloromethane, separate the liquid, and then use 500 The title product (2S, 4S)-2-cyanide is obtained by washing with saturated sodium hydrogen sulfate solution and 500 mL of saturated sodium chloride solution, dried over anhydrous magnesium sulfate, suction filtration, and the filtrate is concentrated under reduced pressure. Base 4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester 13e (50 g, brownish yellow solid), yield: 100%.

第五步the fifth step

(2S,4S)－4－氟－2－氰基吡咯烷的製備Preparation of (2S,4S)-4-fluoro-2-cyanopyrrolidine

氬環境下，將(2S,4S)－2－氰基－4－氟吡咯烷－1－羧酸第三丁酯13e (1 g,4.6 mmol)在攪拌下溶解於2 mL乙酸乙酯中，冷卻至15℃，加入2.5 mL 3M氯化氫的1,4－二烷溶液，室溫下攪拌2小時，在25℃以下反應5小時，薄層層析顯示生成之反應液含有原料，把渾濁的反應液過濾，母液再在室溫下攪拌2小時，又有白色固體析出，過濾，母液繼續攪拌2小時，過濾，合併過濾出來的白色固體，得到標題產物(2S,4S)－4－氟－2－氰基吡咯烷13f (15.6 g,白色固體)，收率：76.6%。(2S,4S)-2-Cyano-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester 13e (1 g, 4.6 mmol) was dissolved in 2 mL of ethyl acetate under stirring. Cool to 15 ° C, add 2.5 mL of 3M hydrogen chloride 1,4-two The alkane solution was stirred at room temperature for 2 hours, and reacted at 25 ° C or lower for 5 hours. The thin layer chromatography showed that the resulting reaction solution contained a raw material, and the turbid reaction solution was filtered, and the mother liquid was further stirred at room temperature for 2 hours, and white again. The solid was precipitated, filtered, and the m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ : 76.6%.

第六步Step 6

(2S,4S)－1－(2－氯乙醯基)－4－氟－2－氰基吡咯烷的製備Preparation of (2S,4S)-1-(2-chloroethyl)-4-fluoro-2-cyanopyrrolidine

氬環境下，將氯代乙醯氯(11.13 g,98.5 mmol)在攪拌下溶解於120 mL二氯甲烷中，冷卻至0℃，將(2S,4S)－4－氟－2－氰基吡咯烷13f (11.4g,75.7 mmol)在攪拌下溶解於400 mL二氯甲烷中，加入三乙胺(16.1 g,158.97 mmol)， 在30分鐘內將此溶液滴加到氯代乙醯氯的二氯甲烷溶液中，在0℃反應2小時，加入200 mL水，150 mL二氯甲烷，萃取分液，有機相用少量飽和硫酸氫鈉溶液洗滌至中性，再依次用300 mL水和300 mL飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物(2S,4S)－1－(2－氯乙醯基)－4－氟－2－氰基吡咯烷13g (8 g,白色晶體)，收率：60%。Chloroacetate chloride (11.13 g, 98.5 mmol) was dissolved in 120 mL of dichloromethane under stirring, cooled to 0 ° C, (2S,4S)-4-fluoro-2-cyanopyrrole Alkane 13f (11.4 g, 75.7 mmol) was dissolved in 400 mL of dichloromethane with stirring, triethylamine (16.1 g, 158.97 mmol) was added, and the solution was added dropwise to the chloroethyl chloride in 30 minutes. In a solution of methyl chloride, react at 0 ° C for 2 hours, add 200 mL of water, 150 mL of dichloromethane, extract and separate the organic phase with a small amount of saturated sodium bisulfate solution to neutral, then use 300 mL of water and 300 mL. The residue was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate -4-fluoro-2-cyanopyrrolidine 13 g (8 g, white crystal), yield: 60%.

參考文獻：WO2003002553。Reference: WO2003002553.

第七步Seventh step

5－(2－(2－氰基－4－氟吡咯烷－1－基)－2－側氧基乙基胺基)－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備5-(2-(2-cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-N,N,5-trimethyl-perhydro-cyclopenta[ c] Preparation of pyrrole-2-carboxamide

氮環境下，將5－胺基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺12f (130 mg,0.616 mmol)，(2S,4S)－1－(2－氯乙醯基)－4－氟－2－氰基吡咯烷13g (117.4 mg,0.616 mmol)和碳酸鉀(85 mg,0.616 mmol)在攪拌下溶解於2 mL二氯甲烷與2 mL N,N－二甲基甲醯胺的混合溶劑中，室溫下反應過夜，以薄層層析跟蹤反應，原料基本消失，減壓濃縮除掉反應液中的二氯甲烷和N,N－二甲基甲醯胺，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－(2－(2－氰基－4－氟吡咯烷－1－基)－2－側氧基乙基胺基)－N,N,5－三甲基－全氫－環戊并[c]吡咯－2(1H)－甲醯胺13h (0.13 g,無色油狀液體)，收率：58%。5-Amino-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12f (130 mg, 0.616 mmol), (2S, 4S) 1-(2-chloroethenyl)-4-fluoro-2-cyanopyrrolidine 13g (117.4 mg, 0.616 mmol) and potassium carbonate (85 mg, 0.616 mmol) were dissolved in 2 mL dichloromethane with stirring The reaction was carried out in a mixed solvent of 2 mL of N,N-dimethylformamide at room temperature overnight, and the reaction was followed by thin layer chromatography, the starting material was substantially disappeared, and the dichloromethane and N in the reaction mixture were removed under reduced pressure. , N-dimethylformamide, the residue obtained was purified by silica gel column chromatography to give the title product 5-(2-(2-cyano-4-fluoropyrrolidin-1-yl)-2-one Oxyethylamino)-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2(1H)-carbenamide 13h (0.13 g, colorless oily liquid), yield : 58%.

第八步Eighth step

5－(2－(2－氰基－4－氟吡咯烷－1－基)－2－側氧基乙基胺基)－N,N,5－ 三甲基－全氫－環戊并[c]吡咯－2(1H)－甲醯胺酒石酸鹽的製備5-(2-(2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-N,N,5- Preparation of trimethyl-perhydro-cyclopenta[c]pyrrole-2(1H)-carbenamide tartrate

室溫下，將5－(2－(2－氰基－4－氟吡咯烷－1－基)－2－側氧基乙基胺基)－N,N,5－三甲基－全氫－環戊并[c]吡咯－2(1H)－甲醯胺13 (0.16 g,0.44 mmol)在攪拌下溶解於5 mL二氯甲烷中，滴加5 mL酒石酸(65.6 mg,0.44 mmol)的丙酮溶液，室溫下反應30分鐘，有白色固體析出，過濾，用丙酮洗滌固體，得到標題產物5－(2－(2－氰基－4－氟吡咯烷－1－基)－2－側氧基乙基胺基)－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽13 (0.18 g,白色固體)，收率：82%。5-(2-(2-Cyano-4-fluoropyrrolidin-1-yl)-2-oxoethylamino)-N,N,5-trimethyl-perhydrogen at room temperature -cyclopenta[c]pyrrole-2(1H)-carbenamide 13 (0.16 g, 0.44 mmol) was dissolved in 5 mL of dichloromethane with stirring, and 5 mL of tartaric acid (65.6 mg, 0.44 mmol) was added dropwise. The acetone solution was reacted at room temperature for 30 minutes, and a white solid was precipitated, which was filtered, and the solid was washed with acetone to give the title product 5-(2-(2-cyano-4-fluoropyrrolidin-1-yl)-2-one Oxyethylamino)-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide tartrate 13 (0.18 g, white solid), yield: 82% .

1 H NMR(DMSO－D6 ,400MHz)δ 5.76(m,1H),5.46(m,1H),5.0(m,1H),4.08－4.05(m,4H),3.97(m,2H),3.69(m,2H),2.73(s,6H),2.61(m,2H),1.87(m,3H),1.57(m,3H),1.18(s,3H),1.9(m,2H)。 1 H NMR (DMSO-D 6 , 400MHz) δ 5.76 (m, 1H), 5.46 (m, 1H), 5.0 (m, 1H), 4.08-4.05 (m, 4H), 3.97 (m, 2H), 3.69 (m, 2H), 2.73 (s, 6H), 2.61 (m, 2H), 1.87 (m, 3H), 1.57 (m, 3H), 1.18 (s, 3H), 1.9 (m, 2H).

實施例14Example 14

5－苄基－5－[2－(2－氰基－4－氟－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽 5-benzyl-5-[2-(2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro -cyclopenta[c]pyrrole-2-carboxamide tartrate

第一步first step

5－苄基－5－氰基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-benzyl-5-cyano-perhydro-cyclopenta[c]pyrrole-2-carboxamide

氮環境下，將5－氰基－全氫－環戊并[c]吡咯－2－甲醯胺12a (4.0 g,19.3 mmol)在攪拌下溶解於60 mL四氫呋喃中，加入苄氯(5.4 g,42.5 mmol)，於室溫攪拌下滴加六甲基二矽烷基胺化鋰(42.5 mL,42.5 mmol)，室溫下攪拌4小時，以薄層層析跟蹤反應至原料消失，加入50 mL水使反應停止，用乙酸乙酯萃取，合併有機相，用無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－苄基－5－氰基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺14a (2.6 g,淡黃色固體)，收率：46%。5-Cyano-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12a (4.0 g, 19.3 mmol) was dissolved in 60 mL of tetrahydrofuran under stirring, and benzyl chloride (5.4 g) was added. , 42.5 mmol), lithium hexamethyldidecylamine (42.5 mL, 42.5 mmol) was added dropwise with stirring at room temperature, and stirred at room temperature for 4 hours. The reaction was traced by thin layer chromatography until the starting material disappeared, and 50 mL was added. The reaction was quenched with water, EtOAc (EtOAc m.jjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -Cyano-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 14a (2.6 g, pale yellow solid), yield: 46%.

第二步Second step

5－苄基－5－甲醯基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-benzyl-5-methylindenyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

將5－苄基－5－氰基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺14a (2.0 g,6.7 mmol)在攪拌下溶於100 mL二氯甲 烷中，在0℃下滴加氫化二異丁基鋁(20.2 mL,20.2 mmol)，以薄層層析跟蹤反應至原料消失，加水使反應停止，用乙酸乙酯萃取，合併有機相，用無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－苄基－5－甲醯基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺14b (729 mg,無色油狀液體)，收率：36%。5-Benzyl-5-cyano-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 14a (2.0 g, 6.7 mmol) was dissolved in 100 mL with stirring Di-isobutylaluminum (20.2 mL, 20.2 mmol) was hydrogenated at 0 ° C in dichloromethane, and the reaction was followed by thin layer chromatography until the disappearance of the starting material. The reaction was stopped with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, filtered, and evaporated. Hydrogen-cyclopenta[c]pyrrole-2-carboxamide 14b (729 mg, colorless oily liquid), yield: 36%.

第三步third step

5－苄基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸的製備Preparation of 5-benzyl-2-dimethylaminomethylindenyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid

氮環境下，將5－苄基－5－甲醯基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺14b (0.729 g,2.43 mmol)在攪拌下溶解於28 mL四氫呋喃和14 mL水的混合溶劑中，在0℃下，加入二水合磷酸二氫鈉(1.14 g,7.29 mmol)，亞氯酸鈉(0.66 g,7.29 mmol)和2－甲基－2－丁烯(0.513 g,7.32 mmol)，在0℃下反應2小時，以薄層層析跟蹤反應至原料消失，加入乙酸乙酯萃取反應液，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－苄基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸14c (0.76 g,無色油狀液體)，收率：98%。Under a nitrogen atmosphere, 5-benzyl-5-methylindenyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 14b (0.729 g, 2.43 mmol) was stirred. Dissolved in a mixed solvent of 28 mL of tetrahydrofuran and 14 mL of water, and added sodium dihydrogen phosphate dihydrate (1.14 g, 7.29 mmol), sodium chlorite (0.66 g, 7.29 mmol) and 2-A at 0 °C. Base-2-butene (0.513 g, 7.32 mmol), reacted at 0 ° C for 2 hours, the reaction was traced by thin layer chromatography until the disappearance of the starting material, and the mixture was extracted with ethyl acetate. The organic phase was combined and dried over anhydrous magnesium sulfate. After suction filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel column chromatography to give the title product 5-benzyl-2-dimethylaminocarbazyl-perhydro-cyclopenta[c]pyrrole. -5-carboxylic acid 14c (0.76 g, colorless oily liquid), yield: 98%.

MS m/z(ESI)：317.3(M＋1)。MS m/z (ESI): 317.3 (M + 1).

1 H NMR(DMSO－D6 ,400MHz)δ 7.5－7.0(m,5H),3.24(m,2H),3.1(m,2H),2.76(s,2H),2.7(s,6H),2.68(m,2H),1.99－1.55(m,4H)。 1 H NMR (DMSO-D 6 , 400MHz) δ 7.5-7.0 (m, 5H), 3.24 (m, 2H), 3.1 (m, 2H), 2.76 (s, 2H), 2.7 (s, 6H), 2.68 (m, 2H), 1.99-1.55 (m, 4H).

第四步the fourth step

5－苄基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物的製備Preparation of 5-benzyl-2-dimethylaminomethylmercapto-perhydro-cyclopenta[c]pyrrole-5-carbonyl azide

冰浴下，將5－苄基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸14c (0.86 g,2.72 mmol)攪拌下溶解於30 mL丙酮中，在－5℃下，依次滴加三乙胺(0.303 g,2.99 mmol)，15 mL氯甲酸乙酯(0.325 g,2.99 mmol)的丙酮溶液，攪拌15分鐘，滴加15 mL疊氮化鈉(0.353 g,5.44 mmol)的水溶液，攪拌30分鐘，以薄層層析跟蹤反應至原料消失，濃縮掉丙酮，用乙酸乙酯萃取，合併有機相，用無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，得到標題產物5－苄基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物14d (0.9 g,淺黃色油狀液體)，收率：97%。5-benzyl-2-dimethylaminocarbazyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid 14c (0.86 g, 2.72 mmol) was dissolved in 30 mL with stirring under ice-cooling In acetone, triethylamine (0.303 g, 2.99 mmol), 15 mL of ethyl chloroformate (0.325 g, 2.99 mmol) in acetone were added dropwise at -5 ° C, stirred for 15 minutes, and 15 mL of azide was added dropwise. Aqueous solution of sodium (0.353 g, 5.44 mmol) was stirred for 30 minutes. The reaction was evaporated to dryness eluting with EtOAc (EtOAc). The filtrate was concentrated under reduced pressure to give the title product: 5-benzyl-2-dimethylaminocarbazyl-perhydro-cyclopenta[c]pyrrole-5-carbonyl azide 14d (0.9 g, pale yellow oil Liquid), yield: 97%.

第五步the fifth step

5－苄基－5－異氰酸基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-benzyl-5-isocyanato-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

將5－苄基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物14d (1.0 g,2.72 mmol)在攪拌下溶解於20 mL甲苯中，加熱回流1.5小時，濃縮掉甲苯，所得殘餘物為標題產物5－苄基－5－異氰酸基－全氫－環戊并[c]吡咯－2－甲醯胺14e ，其直接用於下一步反應。5-Benzyl-2-dimethylaminocarbazyl-perhydro-cyclopenta[c]pyrrole-5-carbonyl azide 14d (1.0 g, 2.72 mmol) was dissolved in 20 mL of toluene with stirring The mixture was heated under reflux for 1.5 hours, and toluene was concentrated. The residue obtained was obtained from the title product 5-benzyl-5-isocyanyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 14e . In the next step.

第六步Step 6

5－胺基－5－苄基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-amino-5-benzyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

室溫下，將上一步得到的5－苄基－5－異氰酸基－全氫－環戊并[c]吡咯－2－甲醯胺14e 中滴加12 mL的8 N的鹽酸，攪拌30分鐘，用4 N的氫氧化鈉溶液調節pH為9，用乙酸乙酯萃取，合併有機相，以無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－胺基－5－苄基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺14f (0.55 g,無色油狀液體)，收率：70%。To the 5-benzyl-5-isocyanato-perhydro-cyclopenta[c]pyrrole-2-carboxamide 14e obtained in the previous step, 12 mL of 8 N hydrochloric acid was added dropwise and stirred at room temperature. After 30 minutes, the pH was adjusted to 9 with 4 N sodium hydroxide solution, extracted with ethyl acetate, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, filtered, and the filtrate was concentrated under reduced pressure. To give the title product 5-amino-5-benzyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 14f (0.55 g, colorless oily). Yield: 70%.

第七步Seventh step

5－苄基－5－[2－(2－氰基－4－氟－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備5-benzyl-5-[2-(2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro -Preparation of cyclopenta[c]pyrrole-2-carboxamide

將5－胺基－5－苄基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺14f (0.1 g,0.35 mmol)在攪拌下溶解於4 mL二氯甲烷/N,N－二甲基甲醯胺(V/V＝1/1)混合溶劑中，加入(2S,4S)－1－(2－氯乙醯基)－4－氟－2－氰基吡咯烷13g (66.5 mg,0.35 mmol)和碳酸鉀(49 mg,0.35 mmol)，在40℃下反應12小時，薄層層析跟蹤反應至原料消失，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5－苄基－5－[2－(2－氰基－4－氟－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺14g (87 mg,白色固體)，收率：56%。5-Amino-5-benzyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 14f (0.1 g, 0.35 mmol) was dissolved in 4 mL with stirring (2S,4S)-1-(2-chloroethenyl)-4-fluoro-2 was added to a mixed solvent of dichloromethane/N,N-dimethylformamide (V/V=1/1). -Cyanopyrrolidine 13g (66.5 mg, 0.35 mmol) and potassium carbonate (49 mg, 0.35 mmol), reacted at 40 ° C for 12 hours, traced the reaction by thin layer chromatography until the starting material disappeared, concentrated the reaction mixture, using a rubber tube column The obtained residue was purified by chromatography to give the titled product 5-benzyl-5-[2-(2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino] -N,N-Dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 14 g (87 mg, white solid), yield: 56%.

MS m/z(ESI)：442.2(M＋1)。MS m/z (ESI): 4421.

第八步Eighth step

5－苄基－5－[2－(2－氰基－4－氟－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽 的製備5-benzyl-5-[2-(2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro -cyclopenta[c]pyrrole-2-carboxamide tartrate Preparation

將5－苄基－5－[2－(2－氰基－4－氟－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺14g (87 mg,0.197 mmol)在攪拌下溶解於3 mL二氯甲烷中，滴加3 mL酒石酸的丙酮溶液，室溫下反應30分鐘，濃縮掉溶劑，加入乙酸乙酯及丙酮進行再結晶，得到標題產物5－苄基－5－[2－(2－氰基－4－氟－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽14 (80 mg,白色固體)，收率：68%。5-Benzyl-5-[2-(2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-all Hydrogen-cyclopenta[c]pyrrole-2-carboxamide 14g (87 mg, 0.197 mmol) was dissolved in 3 mL of dichloromethane with stirring, 3 mL of tartaric acid in acetone was added dropwise, and reacted for 30 minutes at room temperature. The solvent was concentrated, and ethyl acetate and acetone were added to recrystallize to give the title product 5-benzyl-5-[2-(2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxoxy Benzyl-ethylamino]-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide tartrate 14 (80 mg, white solid), yield: 68%.

1 H NMR(DMSO－D6 ,400MHz)δ 7.32－7.2(m,5H),5.55(d,1H),5.41(d,1H),4.97(m,1H),4.31(s,2H),4.08(m,1H),4.0－3.5(m,6H),2.81(s,2H),2.78(s,6H),2.5(m,2H),2.0(m,3H),1.6－1.3(m,6H)。 1 H NMR (DMSO-D 6 , 400MHz) δ 7.32-7.2 (m, 5H), 5.55 (d, 1H), 5.41 (d, 1H), 4.97 (m, 1H), 4.31 (s, 2H), 4.08 (m, 1H), 4.0-3.5 (m, 6H), 2.81 (s, 2H), 2.78 (s, 6H), 2.5 (m, 2H), 2.0 (m, 3H), 1.6-1.3 (m, 6H) ).

實施例15Example 15

5－環己基甲基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽 5-cyclohexylmethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-ring Pentyl[c]pyrrole-2-carboxamide tartrate

第一步first step

5－氰基－5－環己基甲基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-cyano-5-cyclohexylmethyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

將5－氰基－全氫－N,N－二甲基－環戊并[c]吡咯－2－甲醯胺12a (3.66 g,17.6 mmol)在攪拌下溶解於150 mL四氫呋喃中，滴入溴甲基環己烷(6.2 g,35.2 mmol)，滴加六甲基二矽烷基胺化鋰(35.2 mL,35.2 mmol)，於室溫下反應2小時，以薄層層析跟蹤反應至原料消失，加入150 mL飽和氯化銨溶液，用乙酸乙酯(60 mL×3)萃取，合併有機相，無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－氰基－5－環己基甲基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺15a (2.2 g,黃色固體)，收率：41.5%。5-Cyano-perhydro-N,N-dimethyl-cyclopenta[c]pyrrole-2-carboxamide 12a (3.66 g, 17.6 mmol) was dissolved in 150 mL of tetrahydrofuran with stirring and dripped Bromomethylcyclohexane (6.2 g, 35.2 mmol), lithium hexamethyldidecylamine (35.2 mL, 35.2 mmol) was added dropwise, and reacted at room temperature for 2 hours. The reaction was traced to the starting material by thin layer chromatography. After disappearing, 150 mL of saturated ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (60 mL×3). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, filtered, and the filtrate was concentrated under reduced pressure. To give the title product 5-cyano-5-cyclohexylmethyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 15a (2.2 g, yellow solid). Yield: 41.5%.

MS m/z(ESI)：304.5(M＋1)。MS m/z (ESI): 304.5 (M + 1).

第二步Second step

5－環己基甲基－5－甲醯基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-cyclohexylmethyl-5-methylindenyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

在0℃下，將5－氰基－5－環己基甲基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺15a (1.2 g,3.95 mmol)在攪拌下溶解於30 mL二氯甲烷中，冰浴下滴加氫化二異丁基鋁(11.8 mL,11.8 mmol)，反應1小時後，薄層層析跟蹤反應至原料消失，加入100 mL飽和酒石酸鉀鈉溶液，攪拌至溶液透明，用乙酸乙酯(100 mL×3)萃取，合併有機相，以無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－環己基甲基－5－甲醯基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺15b (0.4 g,微黃色油狀物)，收率：33%。5-Cyano-5-cyclohexylmethyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 15a (1.2 g, 3.95 mmol) at 0 °C Dissolve in 30 mL of dichloromethane under stirring, dilute hydrogenated diisobutylaluminum (11.8 mL, 11.8 mmol) in an ice bath, react for 1 hour, trace the reaction by thin layer chromatography until the starting material disappears, add 100 mL of saturation. Potassium sodium tartrate solution, stirred until the solution was transparent, extracted with ethyl acetate (100 mL×3), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, filtered, and the filtrate was concentrated under reduced pressure and purified by gel column chromatography. To give the title product 5-cyclohexylmethyl-5-carbamimidyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 15b (0.4 g, slightly yellow oil ()), yield: 33%.

MS m/z(ESI)：307.4(M＋1)。MS m/z (ESI): 307.4 (M + 1).

第三步third step

5－環己基甲基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸的製備Preparation of 5-cyclohexylmethyl-2-dimethylaminomethylindenyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid

將5－環己基甲基－5－甲醯基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺15b (0.713 g,2.33 mmol)攪拌下溶解於60 mL四氫呋喃和30 mL水的混合溶劑中，在0℃下，加入二水合磷酸二氫鈉(1.09 g,6.99 mmol)，亞氯酸鈉(0.79 g,6.99 mmol)和2－甲基－2－丁烯(0.62 mL,7.0 mmol)，在0℃下反應2小時，以薄層層析跟蹤反應至原料消失，蒸乾四氫呋喃，加入乙酸乙酯萃取水相，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－環己基甲基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸15c (0.75 g,黃色固體)，收 率：100%。Dissolving 5-cyclohexylmethyl-5-methylindenyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 15b (0.713 g, 2.33 mmol) with stirring To a mixed solvent of 60 mL of tetrahydrofuran and 30 mL of water, sodium dihydrogen phosphate dihydrate (1.09 g, 6.99 mmol), sodium chlorite (0.79 g, 6.99 mmol) and 2-methyl-2 were added at 0 °C. -butene (0.62 mL, 7.0 mmol), reacted at 0 ° C for 2 hours, followed by thin layer chromatography to trace the disappearance of the starting material, evaporated to dryness of tetrahydrofuran, ethyl acetate was added to extract aqueous phase, and the organic phase was combined with anhydrous magnesium sulfate. The mixture was dried, suction filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj c] pyrrole-5-carboxylic acid 15c (0.75 g, yellow solid), yield: 100%.

MS m/z(ESI)：323.3(M＋1)。MS m/z (ESI): 323.3 (M + 1).

第四步the fourth step

5－環己基甲基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物的製備Preparation of 5-cyclohexylmethyl-2-dimethylaminomethylmercapto-perhydro-cyclopenta[c]pyrrole-5-carbonyl azide

冰浴下，將5－環己基甲基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸15c (0.75 g,2.33 mmol)在攪拌下溶解於20 mL丙酮中，在0至－5℃下滴加三乙胺(0.36 mL,2.56 mmol)，加入2 mL氯甲酸乙酯(0.25 mL,2.56 mmol)的丙酮溶液，攪拌15分鐘，加入2 mL疊氮化鈉(0.303 g,4.66 mmol)的水溶液，維持溫度在0至－5℃，繼續反應30分鐘，以薄層層析跟蹤反應至原料消失，蒸乾反應液中的丙酮，加入10 mL水，用乙酸乙酯(10 mL×5)萃取，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，所得殘餘物為標題產物5－環己基甲基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物15d (0.79 g,黃色油狀物)，其直接用於下一步反應。5-Cyclohexylmethyl-2-dimethylaminomethylindenyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid 15c (0.75 g, 2.33 mmol) was dissolved under stirring in an ice bath Add triethylamine (0.36 mL, 2.56 mmol) at 0 to -5 ° C in 20 mL of acetone, add 2 mL of ethyl chloroformate (0.25 mL, 2.56 mmol) in acetone, stir for 15 minutes, add 2 An aqueous solution of sodium azide (0.303 g, 4.66 mmol) was maintained at a temperature of 0 to -5 ° C, and the reaction was continued for 30 minutes. The reaction was traced by thin layer chromatography until the starting material disappeared, and the acetone in the reaction mixture was evaporated to dryness. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. Aminomethylmercapto-perhydro-cyclopenta[c]pyrrole-5-carbonyl azide 15d (0.79 g, yellow oil) was used directly in the next step.

第五步the fifth step

5－環己基甲基－5－異氰酸基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-cyclohexylmethyl-5-isocyanato-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

將5－環己基甲基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物15d (0.79 g,2.27 mmol)在攪拌下溶解於20 mL甲苯中，加熱回流1小時，以薄層層析跟蹤反應至原料消失，蒸乾反應液，得到的殘餘物為標題產物5－ 環己基甲基－5－異氰酸基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺15e (0.65 g,灰色固體)，其直接用於下一步反應。5-Cyclohexylmethyl-2-dimethylaminomethylindenyl-perhydro-cyclopenta[c]pyrrole-5-carbonyl azide 15d (0.79 g, 2.27 mmol) was dissolved in 20 with stirring The mixture was heated under reflux for 1 hour, and the reaction was traced by thin-layer chromatography to the disappearance of the starting material, and the residue was evaporated to give the titled product: 5-cyclohexylmethyl-5-isocyanyl-N,N- Dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 15e (0.65 g, gray solid) was used directly in the next step.

MS m/z(ESI)：320.4(M＋1)。MS m/z (ESI): 320.4 (M + 1).

第六步Step 6

5－胺基－5－環己基甲基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-amino-5-cyclohexylmethyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

冰浴下，將10 mL的8 N鹽酸滴入5－環己基甲基－5－異氰酸基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺15e (0.65 g,2.03 mmol)中，撤掉冰浴，在50℃下反應20分鐘，以薄層層析跟蹤反應至原料消失，加入濃氨水至反應液以將pH調成大於8，用乙酸乙酯(30 mL*5)萃取水相，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－胺基－5－環己基甲基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺15f (0.5 g,灰色油狀物)，收率：84%。Under ice bath, 10 mL of 8 N hydrochloric acid was added dropwise to 5-cyclohexylmethyl-5-isocyanato-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamidine In the amine 15e (0.65 g, 2.03 mmol), the ice bath was removed, and the reaction was carried out at 50 ° C for 20 minutes. The reaction was traced by thin layer chromatography until the disappearance of the starting material. Concentrated aqueous ammonia was added to the reaction solution to adjust the pH to more than 8. The aqueous layer was extracted with ethyl acetate (30 mL, EtOAc). -5-Cyclohexylmethyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 15f (0.5 g, gray oil), yield: 84%.

MS m/z(ESI)：294.3(M＋1)。MS m/z (ESI): 299.

第七步Seventh step

5－環己基甲基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備5-cyclohexylmethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-ring Preparation of pentato[c]pyrrole-2-carboxamide

將5－胺基－5－環己基甲基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺15f (0.115 g,0.39 mmol)在攪拌下溶解於10 mL二氯甲烷/N,N－二甲基甲醯胺(V/V＝1/1)中，加入1－(2－氯－乙醯基)－2－氰基－吡咯烷(54 mg,0.31 mmol)，在50℃下反應2小時，以薄層層析跟蹤反應至原料消失，減壓濃縮 除掉反應液中的二氯甲烷和N,N－二甲基甲醯胺，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－環己基甲基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺15g (113 mg,無色油狀液體)，收率：67%。5-Amino-5-cyclohexylmethyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 15f (0.115 g, 0.39 mmol) was dissolved in stirring Add 10-methylene chloride/N,N-dimethylformamide (V/V=1/1) to 1-(2-chloro-ethenyl)-2-cyano-pyrrolidine (54 mg , 0.31 mmol), reacted at 50 ° C for 2 hours, the reaction was traced by thin layer chromatography until the disappearance of the starting material, and the dichloromethane and N,N-dimethylformamide in the reaction mixture were removed by concentration under reduced pressure. The obtained residue was purified by column chromatography to give the titled product 5--cyclohexylmethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-yloxy-ethylamino] -N,N-Dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 15 g (113 mg, colorless oily liquid), yield: 67%.

MS m/z(ESI)：430.5(M＋1)。MS m/z (ESI): 430.5 (M + 1).

第八步Eighth step

5－環己基甲基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽的製備5-cyclohexylmethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-ring Preparation of pentato[c]pyrrole-2-carboxamide tartrate

將5－環己基甲基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺15g (113 mg,0.263 mmol)在攪拌下溶解於10 mL乙酸乙酯中，滴加2 mL酒石酸的丙酮溶液，攪拌30分鐘後，過濾，得到標題產物5－環己基甲基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽15 (40 mg,白色固體)。5-Cyclohexylmethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro- 15 g (113 mg, 0.263 mmol) of cyclopenta[c]pyrrole-2-carboxamide was dissolved in 10 mL of ethyl acetate with stirring, 2 mL of a solution of tartaric acid in acetone was added dropwise, stirred for 30 minutes, and filtered. The title product 5-cyclohexylmethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro - Cyclopenta[c]pyrrole-2-carboxamide tartrate 15 (40 mg, white solid).

1 H NMR(DMSO－D6 ,400MHz)δ 5.2(m,1H),4.77(s,2H),4.18(m,3H),4.02(m,1H),3.63(m,2H),3.32(m,2H),2.73(s,6H),2.58(m,2H),2.16－1.87(m,9H),1.59－1.19(m,8H)。 1 H NMR (DMSO-D 6 , 400MHz) δ 5.2 (m, 1H), 4.77 (s, 2H), 4.18 (m, 3H), 4.02 (m, 1H), 3.63 (m, 2H), 3.32 (m , 2H), 2.73 (s, 6H), 2.58 (m, 2H), 2.16-1.87 (m, 9H), 1.59-1.19 (m, 8H).

實施例16Example 16

5－環戊基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽 5-cyclopentyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopentyl And [c]pyrrole-2-carboxamide tartrate

第一步first step

5－氰基－5－環戊基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-cyano-5-cyclopentyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

氮環境下，將5－氰基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺12a 攪拌下溶解於30 mL N,N－二甲基甲醯胺中，加入碘代環戊烷(5.4 g,27.5 mmol)，滴加六甲基二矽烷基胺化鋰(27.5 mL,27.5 mmol)，於室溫下攪拌2小時，以薄層層析跟蹤反應至原料消失，加入10 mL水，濃縮掉N,N－二甲基甲醯胺，用乙酸乙酯萃取，合併有機相，用無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－氰基－5－環戊基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺16a (2.6 g,淺黃色固 體)，收率：42%。Dissolving 5-cyano-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12a in 30 mL of N,N-dimethylformamidine under nitrogen To the amine, iodine cyclopentane (5.4 g, 27.5 mmol) was added, lithium hexamethyldidecylamine (27.5 mL, 27.5 mmol) was added dropwise, and stirred at room temperature for 2 hours, followed by thin layer chromatography. After the reaction was completed, the mixture was evaporated to dryness. EtOAc was evaporated. The resulting residue was purified by column chromatography to give the title product 5-cyano-5-cyclopentyl-yl -N, N- dimethyl - perhydro - cyclopenta [c] pyrrole-2-acyl-amine 16a (2.6 g, pale yellow solid), yield: 42%.

MS m/z(ESI)：276.2(M＋1)。MS m/z (ESI): 266.

1 H NMR(DMSO－D6,400MHz)δ 3.35－3.0(m,4H),2.24(s,6H),1.34－2.5(m,15H)。 1 H NMR (DMSO-D6, 400 MHz) δ 3.35-3.0 (m, 4H), 2.24 (s, 6H), 1.34-2.5 (m, 15H).

第二步Second step

5－環戊基－5－甲醯基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-cyclopentyl-5-methylindenyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

在0℃下，將5－氰基－5－環戊基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺16a (0.817 g,2.97 mmol)攪拌下溶解於40 mL二氯甲烷中，冰浴下滴加氫化二異丁基鋁(8.9 mL,8.9 mmol)，反應45分鐘後，以薄層層析跟蹤反應至原料消失，蒸乾二氯甲烷，加入100 mL飽和酒石酸鉀鈉溶液，攪拌至溶液透明，用乙酸乙酯(100 mL×4)萃取，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－環戊基－5－甲醯基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺16b (0.266 g,淡黃色油狀物)，收率：32%。Stirring 5-cyano-5-cyclopentyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 16a (0.817 g, 2.97 mmol) at 0 °C Dissolved in 40 mL of dichloromethane, and distilled hydrogenated diisobutylaluminum (8.9 mL, 8.9 mmol) in an ice bath. After reacting for 45 minutes, the reaction was traced by thin layer chromatography until the starting material disappeared. Add 100 mL of saturated sodium potassium tartrate solution, stir until the solution is clear, extract with ethyl acetate (100 mL×4), combine the organic phase, dry over anhydrous magnesium sulfate, suction filtration, and concentrate the filtrate under reduced pressure. The obtained residue was purified by chromatography to give the titled product 5- 5-pentyl-5-carbazyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 16b (0.266 g , light yellow oil), yield: 32%.

MS m/z(ESI)：279.3(M＋1)。MS m/z (ESI): 299.

第三步third step

5－環戊基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸的製備Preparation of 5-cyclopentyl-2-dimethylaminomethylindenyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid

將5－環戊基－5－甲醯基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺16b (0.266 g,0.955 mmol)攪拌下溶解於20 mL四氫呋喃和10 mL水的混合溶劑中，在0℃下，加入二水 合磷酸二氫鈉(0.448 g,2.87 mmol)，亞氯酸鈉(0.26 g,2.87 mmol)和2－甲基－2－丁烯(0.24 mL,2.88 mmol)，在0℃下反應2小時，以薄層層析跟蹤反應至原料消失，蒸乾四氫呋喃，加入乙酸乙酯萃取水相，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－環戊基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸16c (0.28 g,黃色固體)，收率：99.6%。Dissolving 5-cyclopentyl-5-methylindenyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 16b (0.266 g, 0.955 mmol) in 20 In a mixed solvent of mL tetrahydrofuran and 10 mL of water, sodium dihydrogen phosphate dihydrate (0.448 g, 2.87 mmol), sodium chlorite (0.26 g, 2.87 mmol) and 2-methyl-2- at 0 ° C were added. Butene (0.24 mL, 2.88 mmol) was reacted at 0 °C for 2 hours. The reaction was traced by thin-layer chromatography to dryness of material, evaporated to dryness, and the aqueous phase was extracted with ethyl acetate. The organic phase was combined and dried over anhydrous magnesium sulfate. After suction filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified to silica gel column chromatography to give the title product 5-cyclopentyl-2-dimethylaminocarbamoyl-perhydro-cyclopenta[c] Pyrrole-5-carboxylic acid 16c (0.28 g, yellow solid), yield: 99.6%.

MS m/z(ESI)：295.5(M＋1)。MS m/z (ESI): 295.5 (M + 1).

第四步the fourth step

5－環戊基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物的製備Preparation of 5-cyclopentyl-2-dimethylaminomethylmercapto-perhydro-cyclopenta[c]pyrrole-5-carbonyl azide

冰浴下，將5－環戊基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸16c (0.28 g,6.95 mmol)攪拌下溶解於20 mL丙酮中，在0至－5℃下滴加三乙胺(0.15 mL,1.05 mmol)，2 mL氯甲酸乙酯(0.1 mL,1.05 mmol)的丙酮溶液，攪拌15分鐘後，加入疊氮化鈉(0.124 g,1.9 mmol)的水溶液，再反應30分鐘，以薄層層析跟蹤反應至原料消失，蒸乾丙酮，加入10 mL水，用乙酸乙酯萃取，合併有機相，用無水硫酸鎂乾燥，抽濾，將濾液減壓濃縮，得到標題產物5－環戊基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物16d (0.287 g,黃色油狀物)，收率：95%，其直接用於下一步反應。5-Cyclopentyl-2-dimethylaminocarbazyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid 16c (0.28 g, 6.95 mmol) was dissolved in 20 under ice-cooling. Triethylamine (0.15 mL, 1.05 mmol), 2 mL of ethyl chloroformate (0.1 mL, 1.05 mmol) in acetone was added dropwise from 0 to -5 ° C, and stirred for 15 min. An aqueous solution of sodium (0.124 g, 1.9 mmol) was further reacted for 30 minutes. The reaction was traced by thin-layer chromatography to dryness of material, evaporated to dryness, and evaporated to ethyl acetate. Drying, suction filtration, and concentrating the filtrate under reduced pressure afforded the title product 5-cyclopentyl-2-dimethylaminocarbazyl-perhydro-cyclopenta[c]pyrrole-5-carbonyl azide 16d ( 0.287 g, yellow oil), yield: 95%, which was used directly in the next step.

第五步the fifth step

5－環戊基－5－異氰酸基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-cyclopentyl-5-isocyanato-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

將5－環戊基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物16d (0.287 g,0.9 mmol)攪拌下溶解於10 mL甲苯中，加熱回流1小時，以薄層層析跟蹤反應至原料消失，蒸乾溶劑，得到標題產物5－環戊基－5－異氰酸基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺16e ，其直接用於下一步反應。Dissolving 5-cyclopentyl-2-dimethylaminocarbazyl-perhydro-cyclopenta[c]pyrrole-5-carbonyl azide 16d (0.287 g, 0.9 mmol) in 10 mL of toluene with stirring The mixture was heated under reflux for 1 hour, and the reaction was traced by thin layer chromatography to yield disappearance, and the solvent was evaporated to give the title product 5-cyclopentyl-5-isocyanyl-N,N-dimethyl-perhydro-ring. Pentac[c]pyrrole-2-carboxamide 16e , which was used directly in the next reaction.

MS m/z(ESI)：292.3(M＋1)。MS m/z (ESI): 299.

第六步Step 6

5－胺基－5－環戊基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-amino-5-cyclopentyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

冰浴下，向上一步得到的5－環戊基－5－異氰酸基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺16e 中滴加10 mL 8N的鹽酸，撤掉冰浴，在50℃下反應15分鐘，以薄層層析跟蹤反應至原料消失，加入濃氨水調節反應液pH至大於8，用乙酸乙酯萃取，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－胺基－5－環戊基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺16f (0.18 g,黃色油狀液體)，收率：81.8%。10 parts of 5-cyclopentyl-5-isocyanato-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 16e obtained in the next step under ice bath HCl 8N hydrochloric acid, remove the ice bath, react at 50 ° C for 15 minutes, follow the reaction by thin layer chromatography until the disappearance of the raw materials, add concentrated ammonia water to adjust the pH of the reaction solution to more than 8, extract with ethyl acetate, and combine the organic phase, The organic layer was dried over anhydrous magnesium sulfate, filtered, filtered, evaporated, evaporated,,,,,,,,,,,,, - cyclopenta[c]pyrrole-2-carboxamide 16f (0.18 g, yellow oily liquid), yield: 81.8%.

MS m/z(ESI)：266.2(M＋1)。MS m/z (ESI): 266.2 (M + 1).

第七步Seventh step

5－環戊基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺 基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備5-cyclopentyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamine Preparation of ]-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

氮環境下，將5－胺基－5－環戊基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺16f (0.108 g,0.407 mmol)和1－(2－氯－乙醯基)－2－氰基－吡咯烷(70 mg,0.407 mmol)攪拌下溶解於3 mL的N,N－二甲基甲醯胺，加入碳酸鉀(57 mg,0.407 mmol)，於油浴中80℃下反應過夜，以薄層層析跟蹤反應至原料消失，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5－環戊基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺16g (100 mg,無色油狀液體)，收率：61.3%。5-Amino-5-cyclopentyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 16f (0.108 g, 0.407 mmol) and 1 under nitrogen atmosphere -(2-Chloro-ethenyl)-2-cyano-pyrrolidine (70 mg, 0.407 mmol) was dissolved in 3 mL of N,N-dimethylformamide with stirring, and potassium carbonate (57 mg, 0.407 mmol), the reaction was carried out in an oil bath at 80 ° C overnight, and the reaction was followed by thin layer chromatography until the disappearance of the starting material, the reaction mixture was concentrated, and the residue obtained was purified by the column chromatography to give the title product 5-cyclopentyl- 5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole- 2-Protonamine 16 g (100 mg, colorless oily liquid), yield: 61.3%.

MS m/z(ESI)：402.3(M＋1)。MS m/z (ESI): 4021.

第八步Eighth step

5－環戊基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽的製備5-cyclopentyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopentyl And [c] Preparation of pyrrole-2-carboxamide tartrate

將5－環戊基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺16g (102 mg,0.254 mmol)攪拌下溶解於2 mL乙酸乙酯中，加入3 mL酒石酸的丙酮溶液，攪拌30分鐘，有白色固體析出，加入少量正己烷，繼續攪拌，過濾，得到標題產物5－環戊基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽16 (88 mg,白色固體)，收率：65%。5-Cyclopentyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-ring Pentacene [c]pyrrole-2-carboxamide 16g (102 mg, 0.254 mmol) was dissolved in 2 mL of ethyl acetate with stirring, and 3 mL of tartaric acid in acetone was added and stirred for 30 minutes. A white solid precipitated and added a small amount. Hexane, stirring was continued, and filtration gave the title product 5-cyclopentyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N, N-Dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide tartrate 16 (88 mg, white solid), yield: 65%.

實施例17Example 17

5－苄基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽 5-benzyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopenta [c]pyrrole-2-carboxamide tartrate

第一步first step

5－苄基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備5-benzyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopenta [c]Preparation of pyrrole-2-carboxamide

氮環境下，將5－胺基－5－苄基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺14f (0.1 g,0.35 mmol)、1－(2－氯－乙醯基)－2－氰基－吡咯烷(120.4 mg,0.7 mmol)和碳酸鉀(49 mg,0.35 mmol)攪拌下溶解於3 mL的N,N－二甲基甲醯胺，於油浴中80℃下反應過夜，以薄層層析跟蹤反應至原料消失，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5－苄基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺17a (56 mg,無色油狀液體)，收率：40%。5-Amino-5-benzyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 14f (0.1 g, 0.35 mmol), 1- (2-Chloro-ethenyl)-2-cyano-pyrrolidine (120.4 mg, 0.7 mmol) and potassium carbonate (49 mg, 0.35 mmol) dissolved in 3 mL of N,N-dimethylformamide with stirring The amine was reacted in an oil bath at 80 ° C overnight, and the reaction was followed by thin layer chromatography until the disappearance of the starting material. The reaction mixture was concentrated, and the residue obtained was purified by silica gel column chromatography to give the title product 5-benzyl-5-[ 2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-yl Indoleamine 17a (56 mg, colorless oily liquid), yield: 40%.

MS m/z(ESI)：424.3(M＋1)。MS m/z (ESI): 42.

第二步Second step

5－苄基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽的製備5-benzyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopenta [c]Preparation of pyrrole-2-carboxamide tartrate

將5－苄基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺17a (56 mg,0.132 mmol)攪拌下溶解於1 mL乙酸乙酯中，加入1 mL酒石酸的丙酮溶液，攪拌30分鐘，有白色固體析出，加入少量正己烷，繼續攪拌，過濾，得到標題產物5－苄基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽17 (50 mg,白色固體)，收率：67%。5-Benzyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopentyl And [c]pyrrole-2-carboxamide 17a (56 mg, 0.132 mmol) was dissolved in 1 mL of ethyl acetate with stirring, and 1 mL of tartaric acid in acetone was added and stirred for 30 minutes. A white solid precipitated and a small amount of hexane was added. The alkane was stirred and filtered to give the title product 5-benzyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-yloxy-ethylamino]-N,N- Dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide tartrate 17 (50 mg, white solid), yield: 67%.

1 H NMR(DMSO－D6 ,400MHz)δ 7.32－7.19(m,5H),4.78(m,1H),4.23(s,2H),3.8－3.0(m,8H),2.75(s,2H),2.73(s,6H),2.18(m,2H),2.16(m,2H),1.87(m,3H),1.35(m,3H)。 1 H NMR (DMSO-D 6 , 400MHz) δ 7.32-7.19 (m, 5H), 4.78 (m, 1H), 4.23 (s, 2H), 3.8-3.0 (m, 8H), 2.75 (s, 2H) , 2.73 (s, 6H), 2.18 (m, 2H), 2.16 (m, 2H), 1.87 (m, 3H), 1.35 (m, 3H).

實施例18Example 18

5－[2－(2－氰基－4－氟－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺對甲苯磺酸鹽 5-[2-(2-Cyano-4-fluoro-pyrrolidin-1-yl)-2-yloxy-ethylamino]-N,N,5-trimethyl-perhydro-cyclopentyl And [c]pyrrole-2-carboxamide p-toluenesulfonate

第一步first step

5－[2－(2－氰基－4－氟－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備5-[2-(2-Cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro-cyclopenta [c]Preparation of pyrrole-2-carboxamide

氮環境下，將5－胺基－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺11c (1.3 g,7.58 mmol)、(2S,4S)－1－(2－氯乙醯基)－4－氟－2－氰基吡咯烷13g (1.74 g,9.1 mmol)、碳酸鉀(1.26 g,9.1 mmol)及30 mL的N,N－二甲基甲醯胺和18 mL二氯甲烷加入反應瓶中，油浴30℃下反應過夜後，薄層層析跟蹤反應，原料消失，減壓除去N,N－二甲基甲醯胺，用矽膠管柱層析法純化，得到標題產物5－[2－(2－氰基－4－氟－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺18a (1.39 g,白色固體)，收率：50%。5-Amino-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 11c (1.3 g, 7.58 mmol), (2S, 4S) under nitrogen atmosphere 1-(2-chloroethenyl)-4-fluoro-2-cyanopyrrolidine 13g (1.74 g, 9.1 mmol), potassium carbonate (1.26 g, 9.1 mmol) and 30 mL of N,N-dimethyl Baseamylamine and 18 mL of dichloromethane were added to the reaction flask, and the reaction was carried out in an oil bath at 30 ° C overnight. The reaction was followed by thin layer chromatography, the starting material disappeared, and N,N-dimethylformamide was removed under reduced pressure. Purification by column chromatography gave the title product 5-[2-(2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5 Trimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 18a (1.39 g, white solid), yield: 50%.

MS m/z(ESI)：348.2(M＋1)。MS m/z (ESI): 348.2 (M + 1).

第二步Second step

5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺對甲苯磺酸鹽的製備5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro-cyclopenta[c]pyrrole Preparation of 2-carbamamine p-toluenesulfonate

室溫下，將5－[2－(2－氰基－4－氟－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺18a (0.9 g,2.47 mmol)攪拌下溶解於5 mL的二氯甲烷中， 再將一水合對甲苯磺酸(469 mg,2.47 mmol)攪拌下溶解於3 mL丙酮中，將對甲苯磺酸的丙酮溶液滴加入上述溶液中，滴加過程中有白色沉澱逐漸產生，攪拌30分鐘後，加1 mL正己烷攪拌，過濾，得到的標題產物5－[2－(2－氰基－4－氟－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N,5－三甲基－全氫－環戊并[c]吡咯－2－甲醯胺對甲苯磺酸鹽18 (1.3 g,白色固體)，收率：93%。5-[2-(2-Cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl- at room temperature Perhydro-cyclopenta[c]pyrrole-2-carboxamide 18a (0.9 g, 2.47 mmol) was dissolved in 5 mL of dichloromethane with stirring, then p-toluenesulfonic acid monohydrate (469 mg, 2.47 mmol) Dissolved in 3 mL of acetone under stirring, and added a solution of p-toluenesulfonic acid in acetone to the above solution. A white precipitate gradually formed during the dropwise addition. After stirring for 30 minutes, 1 mL of n-hexane was added and stirred, and the obtained was obtained. The title product 5-[2-(2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N,5-trimethyl-perhydro- Cyclopenta[c]pyrrole-2-carboxamide p-toluenesulfonate 18 (1.3 g, white solid), yield: 93%.

MS m/z(ESI)：366.1(M＋1)。MS m/z (ESI): 366.1 (M + 1).

1 H NMR(DMSO－D6 ,400MHz)δ 7.74(d,2H),7.29(d,2H),5.57－5.44(m,1H),5.07(m,1H),4.19－4.07(m,4H),3.49(m,2H),3.35(m,2H),3.0(m,2H),2.9(s,6H),2.6(m,2H),2.39(m,5H),1.57(m,2H),1.34(s,3H)。 1 H NMR (DMSO-D 6 , 400MHz) δ 7.74 (d, 2H), 7.29 (d, 2H), 5.57-5.44 (m, 1H), 5.07 (m, 1H), 4.19-4.07 (m, 4H) , 3.49 (m, 2H), 3.35 (m, 2H), 3.0 (m, 2H), 2.9 (s, 6H), 2.6 (m, 2H), 2.39 (m, 5H), 1.57 (m, 2H), 1.34 (s, 3H).

實施例19Example 19

5－乙基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽 5-ethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopenta [c]pyrrole-2-carboxamide tartrate

第一步first step

5－氰基－5－乙基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺5-cyano-5-ethyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

在氮氣保護下，將5－氰基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺12a (3.0 g,14.5 mmol)攪拌下溶解於60 mL無水四氫呋喃，加入碘乙烷(4.52 g,29 mmol)在室溫下，滴加六甲基二矽烷基胺化鋰(29 mL,29 mmol)，室溫下反應2小時，以薄層層析跟蹤反應至原料消失，加入20 mL水，用乙酸乙酯(200 mL×3)萃取，無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，得到油狀物，薄層層析顯示為兩個較近的點，用矽膠管柱層析法純化，得到5－氰基－5－乙基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺19a (1.64 g,淺黃色油狀物)。5-Cyano-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 12a (3.0 g, 14.5 mmol) was dissolved in 60 mL of anhydrous under stirring with nitrogen. Tetrahydrofuran, adding ethyl iodide (4.52 g, 29 mmol) at room temperature, dropwise adding lithium hexamethyldidecylamine (29 mL, 29 mmol), reacting at room temperature for 2 hours, followed by thin layer chromatography After the reaction was completed, the mixture was evaporated to dryness, and ethyl acetate (200 mL×3) was evaporated. Purification by hydrazine column chromatography to give 5-cyano-5-ethyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 19a (1.64 g, light yellow oil).

MS m/z(ESI)：236.3(M＋1)。MS m/z (ESI): 236.3 (M + 1).

1 H NMR(DMSO－D6 ,400MHz)δ 3.5－3.0(m,4H),2.7(s,6H),1.9－1.2(m,8H),1.19(m,3H)。 1 H NMR (DMSO-D 6 , 400 MHz) δ 3.5-3.0 (m, 4H), 2.7 (s, 6H), 1.9-1.2 (m, 8H), 1.19 (m, 3H).

第二步Second step

2－二甲基胺甲醯基－5－乙基－全氫－環戊并[c]吡咯－5－羧酸的 製備2-Dimethylamine-mercapto-5-ethyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid preparation

將5－氰基－5－乙基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺19a (1.54 g,6.55 mmol)攪拌下溶解於60 mL二氯甲烷中，在0℃下滴加氫化二異丁基鋁(19.6 mL,19.6 mmol)，滴畢，在0℃下攪拌30分鐘，以薄層層析跟蹤反應至原料消失，反應結束，加入1.5 mL水，用無水硫酸鈉乾燥，抽濾，濾液減壓濃縮，得到標題產物5－乙基－5－甲醯基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺19b (0.4 g,淡黃色液體)，收率：26%。Dissolve 5-cyano-5-ethyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 19a (1.54 g, 6.55 mmol) in 60 mL two with stirring In methyl chloride, diisobutylaluminum hydride (19.6 mL, 19.6 mmol) was added dropwise at 0 ° C, and the mixture was stirred at 0 ° C for 30 minutes. The reaction was traced by thin layer chromatography until the starting material disappeared. 1.5 mL of water, dried over anhydrous sodium sulfate, filtered, filtered, and then evaporated to give the title compound 5-ethyl-5-carbazyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole 2-carbamamine 19b (0.4 g, pale yellow liquid), yield: 26%.

MS m/z(ESI)：239.1(M＋1)。MS m/z (ESI): 239.1 (M + 1).

第三步third step

5－乙基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸的製備Preparation of 5-ethyl-2-dimethylaminomethylindenyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid

將5－乙基－5－甲醯基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺19b (0.4 g,1.68 mmol)攪拌下溶解於18 mL四氫呋喃和9 mL水的混合溶劑中，加入二水合磷酸二氫鈉(787 mg,5.04 mmol)，亞氯酸鈉(0.454 g,5.04 mmol)和2－甲基－2－丁烯(354 mg,5.06 mmol)，氮環境下，在0℃下反應2小時，以薄層層析跟蹤反應至原料消失，加入乙酸乙酯萃取水相，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，得到標題產物5－乙基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸19c (0.426 g,淡黃色油狀液體)，收率：100%，其直接用於下一步反應。Dissolve 5-ethyl-5-methylindenyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 19b (0.4 g, 1.68 mmol) in 18 mL with stirring To a mixed solvent of tetrahydrofuran and 9 mL of water, sodium dihydrogen phosphate dihydrate (787 mg, 5.04 mmol), sodium chlorite (0.454 g, 5.04 mmol) and 2-methyl-2-butene (354 mg, 5.06 mmol), the reaction was carried out at 0 ° C for 2 hours under nitrogen atmosphere, and the reaction was followed by thin layer chromatography until the disappearance of the starting material. The aqueous phase was extracted with ethyl acetate. The organic phase was combined, dried over anhydrous magnesium sulfate and filtered. Concentration by pressure gave the title product 5-ethyl-2-dimethylaminocarbazyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid 19c (0.426 g, pale yellow oily liquid). Rate: 100%, which is used directly for the next reaction.

MS m/z(ESI)：255.2(M＋1)。MS m/z (ESI): 255.2 (M + 1).

第四步the fourth step

5－乙基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物的製備Preparation of 5-ethyl-2-dimethylaminomethylmercapto-perhydro-cyclopenta[c]pyrrole-5-carbonyl azide

冰浴下，將5－乙基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羧酸19c (0.56 g,2.2 mmol)攪拌下溶解於60 mL丙酮中，在－5℃下滴加三乙胺(0.245 mg,2.43 mmol)，加入2 mL氯甲酸乙酯(263 mg,2.43 mmol)的丙酮溶液，攪拌15分鐘，加入2 mL疊氮化鈉(0.286 g,4.4 mmol)的水溶液，維持溫度在0至－5℃，繼續反應30分鐘，以薄層層析跟蹤反應至原料消失，加入10 mL水，用乙酸乙酯(10 mL×5)萃取，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，所得殘餘物為標題產物5－乙基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物19d (0.5 g,淡黃色油狀物)，其直接用於下一步反應。5-Ethyl-2-dimethylaminomethylindenyl-perhydro-cyclopenta[c]pyrrole-5-carboxylic acid 19c (0.56 g, 2.2 mmol) was dissolved in 60 mL with stirring under ice-cooling In acetone, triethylamine (0.245 mg, 2.43 mmol) was added dropwise at -5 ° C, 2 mL of ethyl chloroformate (263 mg, 2.43 mmol) in acetone was added, stirred for 15 minutes, and 2 mL of sodium azide was added. (0.286 g, 4.4 mmol) of aqueous solution, maintaining the temperature at 0 to -5 ° C, continue the reaction for 30 minutes, trace the reaction by thin layer chromatography until the disappearance of the starting material, add 10 mL of water, with ethyl acetate (10 mL × 5) The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, filtered, evaporated, evaporated, evaporated. Pyrrole-5-carbonyl azide 19d (0.5 g, pale yellow oil) which was used directly in the next step.

第五步the fifth step

5－乙基－5－異氰酸基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-ethyl-5-isocyanato-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

將5－乙基－2－二甲基胺基甲醯基－全氫－環戊并[c]吡咯－5－羰基疊氮化物19d (0.5 g,1.86 mmol)攪拌下溶解於30 mL甲苯中，加熱回流2小時，以薄層層析跟蹤反應至原料消失，蒸乾反應液，得到的殘餘物為標題產物5－乙基－5－異氰酸基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺19e ，其直接用於下一步反應。5-Ethyl-2-dimethylaminocarbazyl-perhydro-cyclopenta[c]pyrrole-5-carbonyl azide 19d (0.5 g, 1.86 mmol) was dissolved in 30 mL of toluene with stirring. After heating under reflux for 2 hours, the reaction was followed by thin layer chromatography until the disappearance of the starting material, and the reaction mixture was evaporated to dryness to give the titled product 5-ethyl-5-isocyano-N,N-dimethyl-all. Hydrogen-cyclopenta[c]pyrrole-2-carboxamide 19e was used directly in the next reaction.

第六步Step 6

5－胺基－5－乙基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備Preparation of 5-amino-5-ethyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide

室溫下，將12 mL的8 N鹽酸滴入上一步得到的5－乙基－5－異氰酸基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺19e 中，攪拌30分鐘，用8N氫氧化鈉溶液調節pH為9－10，用二氯甲烷(30 mL×5)萃取水相，合併有機相，用無水硫酸鎂乾燥，抽濾，濾液減壓濃縮，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－胺基－5－乙基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺19f (0.3 g,無色油狀物)，收率：71%。12 mL of 8 N hydrochloric acid was added dropwise to the 5-ethyl-5-isocyanato-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2- obtained in the previous step at room temperature. The megamine 19e was stirred for 30 minutes, and the pH was adjusted to 9-10 with 8N sodium hydroxide solution. The aqueous phase was extracted with dichloromethane (30 mL×5). The filtrate was concentrated under reduced pressure, and the obtained residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -Metformamide 19f (0.3 g, colorless oil), yield: 71%.

MS m/z(ESI)：226.2(M＋1)。MS m/z (ESI): 226.2 (M + 1).

第七步Seventh step

5－乙基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺的製備5-ethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopenta [c]Preparation of pyrrole-2-carboxamide

氮環境下，將5－胺基－5－乙基－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺19f (0.202 g,0.897 mmol)、1－(2－氯－乙醯基)－2－氰基－吡咯烷(185 mg,1.07 mmol)、碳酸鉀(148 mg,1.07 mmol)及9 mL二氯甲烷/N,N－二甲基甲醯胺(V/V＝1/1)混合溶劑加入反應瓶中，在60℃下反應2小時，以薄層層析跟蹤反應至原料消失，減壓濃縮除掉反應液中的二氯甲烷和N,N－二甲基甲醯胺，用矽膠管柱層析法純化所得殘餘物，得到標題產物5－乙基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺19g (120 mg,淡黃色油狀液體)，收率：40%。5-Amino-5-ethyl-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 19f (0.202 g, 0.897 mmol), 1- (2-Chloro-ethenyl)-2-cyano-pyrrolidine (185 mg, 1.07 mmol), potassium carbonate (148 mg, 1.07 mmol) and 9 mL dichloromethane/N,N-dimethylformamide A mixed solvent of amine (V/V=1/1) was added to the reaction flask, and the reaction was carried out at 60 ° C for 2 hours. The reaction was traced by thin layer chromatography until the disappearance of the starting material, and the dichloromethane and N in the reaction mixture were removed by concentration under reduced pressure. , N-dimethylformamide, the residue obtained was purified by silica gel column chromatography to give the title product 5-ethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2 -Sideoxy-ethylamino]-N,N-dimethyl-perhydro-cyclopenta[c]pyrrole-2-carboxamide 19 g (120 mg, light yellow oily liquid), yield: 40%.

MS m/z(ESI)：362.2(M＋1)。MS m/z (ESI): 362.2 (M + 1).

第八步Eighth step

5－乙基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽的製備5-ethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopenta [c]Preparation of pyrrole-2-carboxamide tartrate

將5－乙基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺19g (120 mg,0.33 mmol)攪拌下溶解於1 mL乙酸乙酯中，滴加2 mL酒石酸(50 mg,0.33 mmol)的丙酮溶液，攪拌30分鐘後，過濾，得到標題產物5－乙基－5－[2－(2－氰基－吡咯烷－1－基)－2－側氧基－乙基胺基]－N,N－二甲基－全氫－環戊并[c]吡咯－2－甲醯胺酒石酸鹽19 (160 mg,白色固體)，收率：94%。5-Ethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl-perhydro-cyclopentyl And [c]pyrrole-2-carboxamide 19g (120 mg, 0.33 mmol) was dissolved in 1 mL of ethyl acetate with stirring, and 2 mL of tartaric acid (50 mg, 0.33 mmol) in acetone was added dropwise, and stirred for 30 minutes. Filtration gave the title product 5-ethyl-5-[2-(2-cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-N,N-dimethyl- All hydrogen-cyclopenta[c]pyrrole-2-carboxamide tartrate 19 (160 mg, white solid), yield: 94%.

MS m/z(ESI)：362.2(M＋1)。MS m/z (ESI): 362.2 (M + 1).

1 H NMR(DMSO－D6 ,400MHz)δ 4.79(m,1H),4.11(s,2H),3.65(m,2H),3.49(m,2H),3.22(m,4H),2.75(s,6H),2.55(m,2H),2.19(m,2H),2.09(m,2H),1.99(m,2H),1.51(m,4H),0.86(t,3H)。 1 H NMR (DMSO-D 6 , 400MHz) δ 4.79 (m, 1H), 4.11 (s, 2H), 3.65 (m, 2H), 3.49 (m, 2H), 3.22 (m, 4H), 2.75 (s , 6H), 2.55 (m, 2H), 2.19 (m, 2H), 2.09 (m, 2H), 1.99 (m, 2H), 1.51 (m, 4H), 0.86 (t, 3H).

測試例Test case 生物學評價Biological evaluation

DPP IV/DPP8/DPP9抑制活性的測定Determination of inhibitory activity of DPP IV/DPP8/DPP9

下面的方法是用來測定本發明化合物抑制DPPIV/DPP8/DPP9酶活性的。檢測了本發明中化合物抑制純DPPIV/DPP8/DPP9酶活性的抑制能力。每個化合物的抑制率或半抑制濃度IC50 (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受質及不同濃度的待測化合物來測定的。The following method was used to determine the inhibition of DPPIV/DPP8/DPP9 enzymatic activity by the compounds of the invention. The ability of the compounds of the invention to inhibit the inhibition of pure DPPIV/DPP8/DPP9 enzyme activity was examined. The inhibition rate or semi-inhibitory concentration IC 50 of each compound (the concentration of the compound measured when the enzyme activity is inhibited to 50%) is determined by a fixed amount of the enzyme mixed substrate and different concentrations of the test compound.

DPP IV抑制活性的測定Determination of DPP IV inhibitory activity

材料和方法：Materials and Method:

材料：material:

a.白色96孔板(BMG)a. White 96-well plate (BMG)

b. Tris緩衝液：製備100mL 2mM的Tris緩衝液，將0.0242g Tris溶解於約90mL dH2 O中，用HCl和NaOH調節pH到8.00，最後加dH2 O至100mL。b. Tris Buffer: Prepare 100 mL of 2 mM Tris buffer, dissolve 0.0242 g of Tris in approximately 90 mL of dH 2 O, adjust pH to 8.00 with HCl and NaOH, and finally add dH 2 O to 100 mL.

c. DPPIV酶(CalBiochem Catalog no.317630)，溶解於Tris緩衝液中至2mM。c. DPPIV enzyme (CalBiochem Catalog no. 317630), dissolved in Tris buffer to 2 mM.

d. DPPIV－GloTM 受質(Promega Catalog no.G8350)，溶解於dH2 O中至1 mM。d. DPPIV-Glo TM by mass (Promega Catalog no.G8350), dissolved in dH 2 O to 1 mM.

e. DPPIV－Glo.緩衝液(Promega Catalog no.G8350)e. DPPIV-Glo. Buffer (Promega Catalog no.G8350)

f.螢光素檢測試劑(Promega Catalog no.G8350)f. Luciferin detection reagent (Promega Catalog no.G8350)

g. DMSOg. DMSO

h. dH2 Oh. dH 2 O

操作：operating:

按以下操作順序進行：In the following sequence of operations:

1.解凍DPPIV－Glo.使用前緩衝並平衡到室溫。1. Thaw DPPIV-Glo. Buffer before use and equilibrate to room temperature.

2.使用前緩衝凍存的螢光素檢測試劑。2. Buffer frozen luciferin detection reagent before use.

3.懸浮DPPIV－Glo.在受質中加入超純水輕微混合均勻後，製成1mM的受質。3. Suspension DPPIV-Glo. After adding ultrapure water to the substrate and mixing gently, a 1 mM substrate was prepared.

4.將螢光素檢測試劑放入茶色瓶中，加入DPPIV－Glo.。螢光素檢測試劑應在1分鐘內溶解。4. Place the luciferin test reagent in a brown bottle and add DPPIV-Glo. The luciferin detection reagent should be dissolved within 1 minute.

5.用DMSO溶解所測化合物至最終操作濃度的50倍。5. Dissolve the test compound in DMSO to 50 times the final working concentration.

6.每個試管中加入50倍濃度的所測化合物2μL，在陰性對照及空白對照中加入2μLDMSO。6. Add 50 μl of the test compound to 2 μL of each test tube, and add 2 μL of DMSO to the negative control and the blank control.

7.在每個試管中加入46μL Tris緩衝液，在空白對照中加入48μL Tris緩衝液。7. 46 μL of Tris buffer was added to each tube, and 48 μL of Tris buffer was added to the blank.

8.在陰性對照和測試樣品的每個試管中加入2μLDPPIV酶。8. Add 2 μ LDPPIV enzyme to each tube of the negative control and test samples.

9.振動混合並離心試管。將試管中物質全部轉移到96－孔平板上。9. Vibrate and centrifuge the tube. Transfer all of the material in the tube to a 96-well plate.

10.混合受質和DPPIV－Glo.比例為1：49。振動混合至充分混合。使用前在室溫下靜置30－60分鐘。10. The ratio of mixed substrate and DPPIV-Glo. was 1:49. Mix the vibrations to mix thoroughly. Allow to stand at room temperature for 30-60 minutes before use.

11.在每個96－孔平板孔中加入50 μL DPPIV－Glo.和受質的混合液，用封膜封住平板。11. Add 50 μL of DPPIV-Glo. and the substrate mixture to each 96-well plate well and seal the plate with a sealing film.

12.用平板振盪器在300－500rpm/30s下慢慢混合96孔中物質。在室溫下培養30分鐘到3小時。12. Slowly mix the 96-well material with a plate shaker at 300-500 rpm / 30 s. Incubate for 30 minutes to 3 hours at room temperature.

13.記錄發光。13. Record the luminescence.

抑制率定義：[1－(S－B)/(N－B)]*100% S：樣品B：空白對照N：陰性對照Inhibition rate definition: [1-(S-B)/(N-B)]*100% S: Sample B: blank control N: negative control

DPP 8抑制活性的測定Determination of DPP 8 inhibitory activity

材料和方法：Materials and Method:

材料：material:

i.白色96孔板(BMG)i. White 96-well plate (BMG)

j. Tris緩衝液：製備100mL 2mM的Tris緩衝液，將0.0242g Tris溶解於約90mL dH2 O中，用HCl和NaOH調節pH到8.00，最後加dH2 O至100mL。j. Tris Buffer: Prepare 100 mL of 2 mM Tris buffer, dissolve 0.0242 g of Tris in approximately 90 mL of dH 2 O, adjust pH to 8.00 with HCl and NaOH, and finally add dH 2 O to 100 mL.

k. DPP8酶(Bioscience Catalog no.80080)，溶解於25 mM Tris－HCl,pH8.0,100 mM NaCl,0.05 % Tween－20,50 % 甘油，3 mM DTT緩衝液中。反應使用終濃度為0.1 ng/100 μL assay。k. DPP8 enzyme (Bioscience Catalog no. 80080), dissolved in 25 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.05% Tween-20, 50% glycerol, 3 mM DTT buffer. The assay used a final concentration of 0.1 ng/100 μL assay.

l. DPP8－GloTM 受質(Promega Catalog no.G8350)，溶解於dH2 O中至1mM。l. DPP8-Glo TM by mass (Promega Catalog no.G8350), dissolved in dH 2 O to 1mM.

m. DPP8－Glo.緩衝液(Promega Catalog no.G8350)m. DPP8-Glo. Buffer (Promega Catalog no.G8350)

n.螢光素檢測試劑(Promega Catalog no.G8350)n. Luciferin detection reagent (Promega Catalog no.G8350)

o. DMSOo. DMSO

p. dH2 Op. dH 2 O

操作：operating:

按以下操作順序進行：In the following sequence of operations:

14.解凍DPP8－Glo.使用前緩衝並平衡到室溫。14. Thaw DPP8-Glo. Buffer before use and equilibrate to room temperature.

15.使用前緩衝凍存的螢光素檢測試劑。15. Buffer frozen luciferin detection reagent before use.

16.懸浮DPP8－Glo.在受質中加入超純水輕微混合均勻後，製成1mM的受質。16. Suspension DPP8-Glo. After adding ultrapure water to the substrate and mixing gently, a 1 mM substrate was prepared.

17.將螢光素檢測試劑放入茶色瓶中，加入DPP8－Glo.。螢光素檢測試劑應在1分鐘內溶解。17. Place the luciferin test reagent in a brown bottle and add DPP8-Glo. The luciferin detection reagent should be dissolved within 1 minute.

18.用DMSO溶解所測化合物至最終操作濃度的50倍。18. Dissolve the test compound in DMSO to 50 times the final working concentration.

19.每個試管中加入50倍濃度的所測化合物2μL，在陰性對照及空白對照中加入2μLDMSO。19. Add 50 μl of the test compound to 2 μL of each test tube, and add 2 μL of DMSO to the negative control and the blank control.

20.在每個試管中加入46μL Tris緩衝液，在空白對照中加入48μL Tris緩衝液。20. 46 μL of Tris buffer was added to each tube, and 48 μL of Tris buffer was added to the blank.

21.在陰性對照和測試樣品的每個試管中加入2μLDPP8酶。21. Add 2 μl of LDPP8 enzyme to each tube of the negative control and test samples.

22.振動混合並離心試管。將試管中物質全部轉移到96－孔平板上。22. Vibrate and centrifuge the tube. Transfer all of the material in the tube to a 96-well plate.

23.混合受質和DPP8－Glo.比例為1：49。振動混合至充分混合。使用前在室溫下靜置30－60分鐘。23. The ratio of mixed substrate and DPP8-Glo. was 1:49. Mix the vibrations to mix thoroughly. Allow to stand at room temperature for 30-60 minutes before use.

24.在每個96－孔平板孔中加入50μL DPP8－Glo.和受質的混合液，用封膜封住平板。24. Add 50 μL of DPP8-Glo. and the substrate mixture to each 96-well plate well and seal the plate with a sealing film.

25.用平板振盪器在300－500rpm/30s下慢慢混合96孔中物質。在室溫下培養30分鐘到3小時。25. Slowly mix the 96-well material with a plate shaker at 300-500 rpm / 30 s. Incubate for 30 minutes to 3 hours at room temperature.

26.記錄發光。26. Record the luminescence.

抑制率定義：[1－(S－B)/(N－B)]*100% S：樣品B：空白對照N：陰性對照Inhibition rate definition: [1-(S-B)/(N-B)]*100% S: Sample B: blank control N: negative control

DPP 9抑制活性的測定Determination of DPP 9 inhibitory activity

材料和方法：Materials and Method:

材料：material:

q.白色96孔板(BMG)q. White 96-well plate (BMG)

r. Tris緩衝液：製備100mL 2mM的Tris緩衝液，將0.0242g Tris溶解於約90mL dH2 O中，用HCl和NaOH調節pH到8.00，最後加dH2 O至100mL。r. Tris Buffer: Prepare 100 mL of 2 mM Tris buffer, dissolve 0.0242 g of Tris in approximately 90 mL of dH 2 O, adjust pH to 8.00 with HCl and NaOH, and finally add dH 2 O to 100 mL.

s. DPP9酶(Bioscience Catalog no.80090)，溶解於25 mM Tris－HCl,pH8.0,100 mM NaCl,0.05 % Tween－20,50 % glycerol,3 mM DTT緩衝液中。反應使用終濃度為0.01 ng/100 μL assay。s. DPP9 enzyme (Bioscience Catalog no. 80090), dissolved in 25 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.05% Tween-20, 50% glycerol, 3 mM DTT buffer. The reaction was used at a final concentration of 0.01 ng/100 μL assay.

t. DPP9－GloTM 受質(Promega Catalog no.G8350)，溶解於dH2 O中至1mM。t. DPP9-Glo TM by mass (Promega Catalog no.G8350), dissolved in dH 2 O to 1mM.

u. DPP9－Glo.緩衝液(Promega Catalog no.G8350)u. DPP9-Glo. Buffer (Promega Catalog no.G8350)

v.螢光素檢測試劑(Promega Catalog no.G8350)v. Luciferin detection reagent (Promega Catalog no.G8350)

w.DMSOw.DMSO

x.dH2 Ox.dH 2 O

操作：operating:

按以下操作順序進行：In the following sequence of operations:

27.解凍DPP9－Glo.使用前緩衝並平衡到室溫。27. Thaw DPP9-Glo. Buffer before use and equilibrate to room temperature.

28.使用前緩衝凍存的螢光素檢測試劑。28. Buffer frozen luciferin detection reagent before use.

29.懸浮DPP9－Glo.在受質中加入超純水輕微混合均勻後，製成1mM的受質。29. Suspension DPP9-Glo. After adding ultrapure water to the substrate and mixing gently, a 1 mM substrate was prepared.

30.將螢光素檢測試劑放入茶色瓶中，加入DPP9－Glo.。螢光素檢測試劑應在1分鐘內溶解。30. Put the luciferin detection reagent into a brown bottle and add DPP9-Glo. The luciferin detection reagent should be dissolved within 1 minute.

31.用DMSO溶解所測化合物至最終操作濃度的50倍。31. Dissolve the test compound in DMSO to 50 times the final working concentration.

32.每個試管中加入50倍濃度的所測化合物2μL，在陰性 對照及空白對照中加入2μLDMSO。32. Add 50 μl of the tested compound to each tube 2 μL, negative 2 μL of DMSO was added to the control and blank controls.

33.在每個試管中加入46μL Tris緩衝液，在空白對照中加入48μL Tris緩衝液。33. 46 μL of Tris buffer was added to each tube, and 48 μL of Tris buffer was added to the blank.

34.在陰性對照和測試樣品的每個試管中加入2μLDPP9酶。34. Add 2 μl of LDPP9 enzyme to each tube of the negative control and test samples.

35.振動混合並離心試管。將試管中物質全部轉移到96－孔平板上。35. Vibration mix and centrifuge the tube. Transfer all of the material in the tube to a 96-well plate.

36.混合受質和DPP9－Glo.比例為1：49。振動混合至充分混合。使用前在室溫下靜置30－60分鐘。36. The ratio of mixed substrate and DPP9-Glo. was 1:49. Mix the vibrations to mix thoroughly. Allow to stand at room temperature for 30-60 minutes before use.

37.在每個96－孔平板孔中加入50μL DPP9－Glo.和受質的混合液，用封膜封住平板。37. Add 50 μL of DPP9-Glo. and the substrate mixture to each 96-well plate well, and seal the plate with a sealing film.

38.用平板振盪器在300－500rpm/30s下慢慢混合96孔中物質。在室溫下培養30分鐘到3小時。38. The 96-well material was slowly mixed using a plate shaker at 300-500 rpm / 30 s. Incubate for 30 minutes to 3 hours at room temperature.

39.記錄發光。39. Record the luminescence.

抑制率定義：[1－(S－B)/(N－B)]*100% S：樣品B：空白對照N：陰性對照Inhibition rate definition: [1-(S-B)/(N-B)]*100% S: Sample B: blank control N: negative control

DPPIV抑制劑降血糖作用的初步評價Preliminary evaluation of hypoglycemic effect of DPPIV inhibitor

試驗目的：Test purposes:

觀察DPPIV抑制劑類受試化合物實施例1和實施例2對正常ICR小鼠口服糖耐量的影響，初步評價其在體內的降血糖作用。The effects of DPPIV inhibitor test compound Example 1 and Example 2 on oral glucose tolerance in normal ICR mice were observed, and its hypoglycemic effect in vivo was initially evaluated.

受試動物：Test animals:

種屬、品系：ICR小鼠來源：中國科學院上海實驗動物中心，合格證號：SYXK(滬)2004－2005體重：25至30g性別：雄性動物數：40隻飼養條件：SPF級動物房飼養，溫度：22－24℃，濕度：45－80%，光照：150－300Lx，12小時晝夜交替。Species, strains: ICR mouse Source: Shanghai Experimental Animal Center, Chinese Academy of Sciences, certificate number: SYXK (Shanghai) 2004-2005 Weight: 25 to 30g Gender: Number of male animals: 40 Feeding conditions: SPF animal house, Temperature: 22-24 ° C, humidity: 45-80%, light: 150-300 Lx, 12 hours day and night alternate.

受試藥物：Test drug:

名稱：實施例1化合物批號：01顏色、形態：白色粉末純度：96.97%提供單位：上海恒瑞醫藥有限公司研發中心配製方法：準確稱取藥物，加入雙蒸水,分別配製成0.5、0.15及0.05mg/mL的混懸液。(注：該化合物雖供試品接收單上顯示易溶於水，但實驗中發現其水溶性較差，低濃度時基本能溶解，但濃度為0.5mg/mL時仍有肉眼可見的顆粒存在。我們也曾試用1%CMC配製該化合物，但效果比雙蒸水配製差。)給藥劑量：口服給藥：1、3、10mg/kg，容積20mL/kg。Name: Example 1 compound batch number: 01 color, form: white powder purity: 96.97% Provided by: Shanghai Hengrui Pharmaceutical Co., Ltd. R & D center preparation method: accurately weigh the drug, add double distilled water, respectively, 0.5, 0.15 And a suspension of 0.05 mg/mL. (Note: Although the compound is shown to be soluble in water on the receiving sample, it is found to be poorly water-soluble in the experiment, and can be dissolved at a low concentration, but there are still visible particles at a concentration of 0.5 mg/mL. We have also tried to formulate this compound with 1% CMC, but the effect is worse than that of double distilled water.) Dosage: Oral administration: 1, 3, 10 mg/kg, volume 20 mL/kg.

名稱：實施例2化合物批號：01顏色、形態：白色粉末純度：99.62%提供單位：上海恒瑞醫藥有限公司研發中心配製方法：準確稱取藥物，加入雙蒸水溶解，充分混勻，配成1.5mg/mL的溶液，然後稀釋成0.5、0.15及0.05mg/mL的透明溶液。給藥劑量：口服給藥：1、3、10mg/kg，容積20mL/kg。Name: Example 2 Compound Lot No.: 01 Color, Form: White Powder Purity: 99.62% Provided by: Shanghai Hengrui Pharmaceutical Co., Ltd. R&D Center Preparation Method: Accurately weigh the drug, add double distilled water to dissolve, mix thoroughly, and prepare A 1.5 mg/mL solution was then diluted to a clear solution of 0.5, 0.15 and 0.05 mg/mL. Dosage: Oral administration: 1, 3, 10 mg/kg, volume 20 mL/kg.

試驗方法：experiment method:

一、藥物對正常ICR小鼠血糖的影響First, the effect of drugs on blood glucose in normal ICR mice

取正常雄性ICR小鼠，按體重隨機分組，每組6隻，分別為空白對照、陽性對照組，以及不同劑量的給藥組。 具體分組如下：Normal male ICR mice were randomly divided into groups, with 6 rats in each group, which were blank control, positive control group, and different dose administration groups. The specific grouping is as follows:

試驗1：Test 1:

空白對照：口服雙蒸水給藥組1：口服實施例1化合物1mg/kg口服實施例1化合物3mg/kg口服實施例1化合物10mg/kg給藥組2：口服實施例2化合物1mg/kg口服實施例2化合物3mg/kg口服實施例2化合物10mg/kgBlank control: oral double distilled water administration group 1: Oral Example 1 compound 1 mg/kg Oral Example 1 Compound 3 mg/kg Oral Example 1 Compound 10 mg/kg Administration group 2: Oral Example 2 Compound 1 mg/kg orally Example 2 Compound 3 mg/kg Oral Example 2 Compound 10 mg/kg

試驗2：Trial 2:

空白對照：口服雙蒸水給藥組1：口服實施例1化合物1mg/kg口服實施例1化合物3mg/kg口服實施例1化合物10mg/kg給藥組2：口服實施例2化合物1mg/kg口服實施例2化合物3mg/kg口服實施例2化合物10mg/kgBlank control: oral double distilled water administration group 1: Oral Example 1 compound 1 mg/kg Oral Example 1 Compound 3 mg/kg Oral Example 1 Compound 10 mg/kg Administration group 2: Oral Example 2 Compound 1 mg/kg orally Example 2 Compound 3 mg/kg Oral Example 2 Compound 10 mg/kg

各組動物禁食6小時後，分別單次給予受試藥物或雙蒸水，於給藥後30分鐘時口服葡萄糖2.5g/kg，於給糖前及給糖後30、60和120分鐘時取血，測定血清葡萄糖濃度。After fasting for 6 hours, the animals in each group were given a single test or double distilled water, and oral glucose 2.5 g/kg was given 30 minutes after the administration, 30 minutes before the sugar supply and 30, 60 and 120 minutes after the sugar supply. Blood was taken and serum glucose concentration was measured.

二、血清葡萄糖測定方法：Second, serum glucose determination method:

採用葡萄糖試劑盒測定血清中的葡萄糖含量，取250 μl酶工作液，加入5 μl血清，同時設立空白管(加入5 μl雙蒸水)及標準管(加入5 μl葡萄糖標液)，混勻，37℃水浴20分鐘，以空白管調零，OD505nm處比色測定。Use glucose kit to determine the glucose content in the serum, take 250 μl of enzyme working solution, add 5 μl of serum, set up a blank tube (add 5 μl of double distilled water) and standard tube (add 5 μl of glucose standard solution), mix, The water bath was incubated at 37 ° C for 20 minutes, and the blank tube was adjusted to zero, and the color was measured at OD 505 nm.

血清葡萄糖含量BG(mmol/l)＝OD樣品管 /OD標準管 ×5.55Serum glucose content BG (mmol / l) = OD sample tube / OD standard tube × 5.55

資料處理和統計分析：Data processing and statistical analysis:

1、採用均值±SD及Student －t test對資料進行統計學分析1. Statistical analysis of data using mean ± SD and Student - t test

2、計算給糖後30分鐘時血糖下降百分率以及曲線下面積AUC2. Calculate the percentage of blood glucose drop at 30 minutes after feeding sugar and the area under the curve AUC

試驗結果：test results:

試驗1：Test 1:

雄性ICR小鼠於禁食6小時後口服雙蒸水、不同劑量的受試物實施例1、實施例2，各組於給藥30分鐘後，做口服糖耐量試驗。結果顯示，空白對照組小鼠口服葡萄糖2.5g/kg後血清葡萄糖濃度明顯升高，30分鐘時達到峰值。實施例1化合物低、中、高3個劑量組小鼠的血糖在30分鐘時均明顯低於空白對照組，其血糖下降百分率分別達19.16%、22.85和31.85%。實施例2化合物各劑量組小鼠給糖後30分鐘時血糖明顯低於空白對照組(P<0.01)，與空白對照組相比，分別下降了25.54%、25.92和26.93%。Male ICR mice were orally administered with double distilled water, different doses of the test article, Example 1, and Example 2, after 6 hours of fasting, and each group was given an oral glucose tolerance test after 30 minutes of administration. The results showed that the serum glucose concentration of the blank control group was significantly increased after oral administration of 2.5 g/kg of glucose, and reached a peak at 30 minutes. The blood glucose of the mice of the low, medium and high doses of the compound of Example 1 was significantly lower than that of the blank control group at 30 minutes, and the percentages of blood glucose decreased were 19.16%, 22.85 and 31.85%, respectively. The blood glucose of the mice in each dose group of Example 2 was significantly lower than that of the blank control group at 30 minutes after the administration of sugar (P<0.01), and decreased by 25.54%, 25.92 and 26.93%, respectively, compared with the blank control group.

試驗2：Trial 2:

雄性ICR小鼠於禁食6小時後口服雙蒸水、不同劑量 的受試實施例1化合物、實施例2化合物，各組於給藥30分鐘後，做口服糖耐量試驗。結果顯示，空白對照組小鼠口服葡萄糖2.5g/kg後血清葡萄糖濃度明顯升高，30分鐘時達到峰值；SHR1039各劑量組小鼠給糖後30分鐘時血糖明顯低於空白對照組(P<0.01)，與空白對照組相比，分別下降了26.10%、30.24和32.05%。SHR1040低、中、高3個劑量組小鼠的血糖在30分鐘時均明顯低於空白對照組，其血糖下降百分率分別達24.51%、26.96%和27.75%。Male ICR mice were given double distilled water and different doses after fasting for 6 hours. The compound of Example 1 and the compound of Example 2 were administered to each group for 30 minutes after administration for oral glucose tolerance test. The results showed that the serum glucose concentration of the mice in the blank control group was significantly increased after oral administration of 2.5 g/kg of glucose, and reached the peak at 30 minutes. The blood glucose of the mice in each dose of SHR1039 was significantly lower than that of the blank control group at 30 minutes after the administration of sugar (P< 0.01), compared with the blank control group, decreased by 26.10%, 30.24 and 32.05%, respectively. The blood glucose of the SHR1040 low, medium and high dose groups was significantly lower than that of the blank control group at 30 minutes, and the percentage of blood glucose decreased by 24.51%, 26.96% and 27.75%, respectively.

結論：in conclusion:

本報告中的兩次試驗結果均顯示，受試之實施例1化合物、實施例2化合物在正常ICR小鼠口服糖耐量試驗中均具有明顯的降血糖作用。其中，受試之實施例1化合物顯示出較好的量效關係。The results of the two tests in this report showed that the compound of Example 1 and the compound of Example 2 had significant hypoglycemic effects in the oral glucose tolerance test in normal ICR mice. Among them, the compound of Example 1 tested showed a good dose-effect relationship.

DPPIV抑制類化合物對KKAy小鼠口服糖耐量的影響試驗目的：Effect of DPPIV inhibitory compounds on oral glucose tolerance in KKAy mice

觀察受試之實施例1化合物和實施例2化合物對II型糖尿病KKAy小鼠口服糖耐量的影響，初步評價其在體內的降血糖作用。The effects of the compound of Example 1 and the compound of Example 2 on oral glucose tolerance in type 2 diabetic KKAy mice were observed, and the hypoglycemic effect in vivo was initially evaluated.

受試動物：Test animals:

種屬、品系：KKAy小鼠來源：中國科學院上海實驗動物中心，合格證號：SYXK(滬)2004－2005體重：40至55g 性別：雌性：52只；雄性：33只飼養條件：SPF級動物房飼養，溫度：22－24℃，濕度：45－80%，光照：150－300Lx，12小時晝夜交替。Species, strains: KKAy mouse Source: Shanghai Experimental Animal Center, Chinese Academy of Sciences, Certificate No.: SYXK (Shanghai) 2004-2005 Weight: 40 to 55g Gender: Female: 52; Male: 33 Feeding conditions: SPF animal house, temperature: 22-24 ° C, humidity: 45-80%, light: 150-300 Lx, 12 hours day and night alternate.

受試藥物：Test drug:

名稱：實施例1化合物和實施例2化合物配製方法：準確稱取藥物，加入雙蒸水溶解，充分混勻，配成3mg/mL的混懸液，然後稀釋成1、0.3和0.1mg/mL的透明溶液。給藥劑量：口服給藥：1、3、10、30mg/kg，容積10mL/kg。Name: Compound of Example 1 and compound of Example 2 Preparation method: Accurately weigh the drug, dissolve it in double distilled water, mix well, prepare a suspension of 3 mg/mL, and then dilute to 1, 0.3 and 0.1 mg/mL. Transparent solution. Dosage: Oral administration: 1, 3, 10, 30 mg/kg, volume 10 mL/kg.

試驗方法：experiment method:

受試物對KKAy小鼠血糖的影響Effect of test substance on blood glucose of KKAy mice

取正常KKAy小鼠，禁食6小時後按體重和空腹血糖分組，每組5隻，分別為空白對照以及不同劑量的給藥組。 具體實驗如下：Normal KKAy mice were divided into body weight and fasting blood glucose after 6 hours of fasting, and 5 rats in each group were blank control and different dose administration groups. The specific experiment is as follows:

試驗1：雄性0704空白對照：口服雙蒸水SHR1039組：口服實施例1化合物10mg/kg口服實施例1化合物30mg/kg試驗2：雌性0816空白對照：口服雙蒸水SHR1039組：口服實施例1化合物3mg/kg口服實施例1化合物10mg/kg試驗3：雄性0712 空白對照：口服雙蒸水SHR1040組：口服實施例2化合物3mg/kg口服實施例2化合物10mg/kg試驗4：雌性0907空白對照：口服雙蒸水SHR1040組：口服實施例2化合物3mg/kg口服實施例2化合物10mg/kgTest 1: Male 0704 blank control: Oral double distilled water SHR1039 group: Oral Example 1 Compound 10 mg/kg Oral Example 1 Compound 30 mg/kg Test 2: Female 0816 blank control: Oral double distilled water SHR1039 group: Oral Example 1 Compound 3 mg/kg Oral Example 1 Compound 10 mg/kg Trial 3: Male 0712 Blank control: Oral double distilled water SHR1040 group: Oral Example 2 Compound 3 mg/kg Oral Example 2 Compound 10 mg/kg Test 4: Female 0907 blank control: Oral double distilled water SHR1040 group: Oral Example 2 compound 3 mg/kg orally Example 2 Compound 10 mg/kg

各組動物禁食6小時後，分別單次給予受試化合物或雙蒸水，於給藥後30分鐘時口服葡萄糖2.5g/kg(雌性KKAy小鼠)或1.5g/kg(雄性KKAy小鼠)，於給糖後0、30、60和120分鐘時用血糖儀測定血清葡萄糖濃度。After 6 hours of fasting, the animals in each group were given a single test or double distilled water, and oral glucose 2.5 g/kg (female KKAy mice) or 1.5 g/kg (male KKAy mice) 30 minutes after the administration. The serum glucose concentration was measured with a blood glucose meter at 0, 30, 60, and 120 minutes after the sugar administration.

資料處理和統計分析：Data processing and statistical analysis:

3、採用均值±SD及Student －t test或Anova對資料進行統計學分析3. Statistical analysis of data using mean ± SD and Student - t test or Anova

4、計算給糖後30分鐘時血糖下降百分率以及曲線下面積AUC4. Calculate the percentage of blood glucose drop at 30 minutes after giving sugar and the area under the curve AUC

試驗結果：test results:

四、化合物實施例1：試驗1、2Compound Example 1: Test 1, 2

雄性KKAy小鼠於禁食6小時後口服雙蒸水及不同劑量之受試實施例1化合物，各組於給藥30分鐘後，做口服糖耐量試驗。結果顯示，空白對照組小鼠口服葡萄糖1.5g/kg後血清葡萄糖濃度明顯升高，30分鐘時達到峰值；實施例1在10和30mg/kg組小鼠給糖後30分鐘時血糖比 空白對照組有所降低，與空白對照組相比，分別下降了16.22%和17.15%。Male KKAy mice were orally administered with double distilled water and different doses of the test compound of Example 1 after 6 hours of fasting. Each group was given an oral glucose tolerance test after 30 minutes of administration. The results showed that the serum glucose concentration of the blank control group was significantly increased after oral administration of 1.5 g/kg of glucose, and peaked at 30 minutes. The blood glucose ratio of the mice in the 10 and 30 mg/kg groups at 30 minutes after the administration of sugar in Example 1 The blank control group decreased, which was 16.22% and 17.15% lower than the blank control group, respectively.

雌性KKAy小鼠於禁食6小時後口服雙蒸水及不同劑量之受試實施例1化合物，各組於給藥30分鐘後，做口服糖耐量試驗。結果顯示，空白對照組小鼠口服葡萄糖2.5g/kg後血清葡萄糖濃度明顯升高，30分鐘時達到峰值；實施例1在3和10mg/kg組小鼠給糖後30分鐘時血糖與空白對照組相比明顯降低，其下降率為40.63%和24.68%。Female KKAy mice were orally administered with double distilled water and different doses of the test compound of Example 1 after 6 hours of fasting. Each group was given an oral glucose tolerance test after 30 minutes of administration. The results showed that the serum glucose concentration of the blank control group was significantly increased after oral administration of 2.5 g/kg of glucose, and peaked at 30 minutes. The blood glucose and blank control of the mice in the 3 and 10 mg/kg groups were given 30 minutes after the glucose administration. Compared with the group, the decrease rate was 40.63% and 24.68%.

五、化合物實施例2：試驗3、4V. Compound Example 2: Test 3, 4

雄性KKAy小鼠於禁食6小時後口服雙蒸水及不同劑量之受試實施例2化合物，各組於給藥30分鐘後，做口服糖耐量試驗。結果顯示，空白對照組小鼠口服葡萄糖1.5g/kg後血清葡萄糖濃度明顯升高，30分鐘時達到峰值；實施例2在10和30mg/kg組小鼠給糖後30分鐘時血糖比空白對照組有所降低，與空白對照組相比，分別下降了13.79%和12.23%。Male KKAy mice were orally administered with double distilled water and different doses of the test compound of Example 2 after 6 hours of fasting. Each group was given an oral glucose tolerance test after 30 minutes of administration. The results showed that the serum glucose concentration of the blank control group was significantly increased after oral administration of 1.5 g/kg of glucose, and peaked at 30 minutes. The blood glucose of the mice in the 10 and 30 mg/kg groups at 30 minutes after glucose administration was compared with the blank control. The group decreased, compared with the blank control group, decreased by 13.79% and 12.23%, respectively.

雌性KKAy小鼠於禁食6小時後口服雙蒸水及不同劑量之受試實施例2化合物，各組於給藥30分鐘後，做口服糖耐量試驗。結果顯示，空白對照組小鼠口服葡萄糖2.5g/kg後血清葡萄糖濃度明顯升高，30分鐘時達到峰值；實施例2化合物10mg/kg組小鼠給糖後30分鐘時血糖較空白對照組有所降低(P＝0.075，anova)，降幅達21.55%，但由於個體差異較大，無顯著性差異。Female KKAy mice were orally administered with double distilled water and different doses of the test compound of Example 2 after 6 hours of fasting. Each group was given an oral glucose tolerance test after 30 minutes of administration. The results showed that the serum glucose concentration of the mice in the blank control group was significantly increased after oral administration of 2.5 g/kg of glucose, and peaked at 30 minutes. The blood glucose of the mice in the 10 mg/kg group of Example 2 was 30 minutes after the glucose administration. The decrease (P=0.075, anova) decreased by 21.55%, but there was no significant difference due to individual differences.

結論：in conclusion:

受試之實施例1化合物和實施例2化合物在II型糖尿病KKAy小鼠口服糖耐量試驗中均具有一定的降血糖作用。The compound of Example 1 and the compound of Example 2 had a certain hypoglycemic effect in the oral glucose tolerance test of type 2 diabetes KKAy mice.

Claims (21)

一種由通式(IA)表示的化合物或其醫藥上可接受的鹽： 其中：R為；R1 選自-C(O)NR3 R4 、-C(O)R3 或-C(O)OR3 ；R2 選自氫原子或烷基，其中，該烷基任選進一步被一個或多個選自環烷基或芳基的取代基取代；R3 和R4 分別選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基任選進一步被一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、三氟甲基、羧基或羧酸酯基的取代基取代；或者，R3 和R4 與N原子一起形成一個3至8員的雜環基，其中，5至8員雜環內任選進一步含有一個或多個N、O或S原子，並且該3至8員雜環任選進一步被一個或多個選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、烷氧基、芳氧基、羥烷 基、雜環烷基、羧基、羧酸酯基或鹵素的取代基取代；R5 選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基任選進一步被一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、烷胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、羧基或羧酸酯基的取代基取代；R6 和R7 分別選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、炔基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素；W為碳、硫或氧原子；當W為碳時，可以進一步經R6 或R7 所取代。A compound represented by the formula (IA): or a pharmaceutically acceptable salt thereof: Where: R is R 1 is selected from -C(O)NR 3 R 4 , -C(O)R 3 or -C(O)OR 3 ; R 2 is selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further Substituted with one or more substituents selected from cycloalkyl or aryl; R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group, wherein The isoalkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group is further optionally further selected from one or more selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy Substituents for aryl, aryloxy, heteroaryloxy, halogen, hydroxy, amine, cyano, hydroxyalkyl, heterocycloalkyl, heterocycloalkoxy, trifluoromethyl, carboxy or carboxylate groups Substituting; or, R 3 and R 4 together with the N atom form a 3 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring optionally further contains one or more N, O or S atoms, and The 3- to 8-membered heterocyclic ring is optionally further further selected from one or more selected from the group consisting of alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amine, cyano, alkoxy, aryloxy, hydroxy Alkyl, heterocycloalkyl, carboxyl, carboxylate or halogen Substituent group; R 5 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl, wherein such alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl Further optionally further selected from one or more selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amine, Substituted with a substituent of an alkylamino group, a cyano group, a hydroxyalkyl group, a heterocycloalkyl group, a heterocycloalkoxy group, a carboxyl group or a carboxylate group; R 6 and R 7 are each selected from an alkyl group, an aryl group, and a heteroaryl group. , haloalkyl, haloalkoxy, hydroxy, amine, cyano, alkynyl, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxy, carboxylate or halogen; W is carbon, sulfur Or an oxygen atom; when W is carbon, it may be further substituted by R 6 or R 7 . 如申請專利範圍第1項之化合物或其醫藥上可接受的鹽，包括下述通式(IB)表示的化合物或其醫藥上可接受的鹽： 其中：R是 R1 選自-C(O)NR3 R4 、-C(O)R3 或-C(O)OR3 ；R2 選自氫原子或烷基，其中，該烷基任選進一步被 一個或多個選自環烷基或芳基的取代基取代；R3 和R4 分別選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基任選進一步被一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、三氟甲基、羧基或羧酸酯基的取代基取代；或者，R3 和R4 與N原子一起形成一個3至8員的雜環基，其中，5至8員雜環內任選進一步含有一個或多個N、O或S原子，並且該3至8員雜環任選進一步被一個或多個選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素的取代基取代；R5 選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基任選進一步被一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、烷胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、羧基或羧酸酯基的取代基取代；R6 和R7 分別選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、炔基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素；W為碳、硫或氧原子；當W為碳時，可以進一步 經R6 或R7 所取代。A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises a compound represented by the following formula (IB) or a pharmaceutically acceptable salt thereof: Where: R is R 1 is selected from -C(O)NR 3 R 4 , -C(O)R 3 or -C(O)OR 3 ; R 2 is selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further subjected to a Or a plurality of substituents selected from a cycloalkyl group or an aryl group; R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group, wherein The alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group is further optionally further selected from one or more selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy Substituent substitution of aryloxy, heteroaryloxy, halogen, hydroxy, amine, cyano, hydroxyalkyl, heterocycloalkyl, heterocycloalkoxy, trifluoromethyl, carboxy or carboxylate groups Or, R 3 and R 4 together with the N atom form a 3 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring optionally further contains one or more N, O or S atoms, and the 3 The 8-membered heterocyclic ring is optionally further further selected from one or more selected from the group consisting of alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amine, cyano, alkoxy, aryloxy, hydroxyalkane Substituent, heterocycloalkyl, carboxyl, carboxylate or halogen substitution Substituted; R 5 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl, wherein such alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl Optionally further selected from one or more selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amine, alkane Substituted with a substituent of an amine group, a cyano group, a hydroxyalkyl group, a heterocycloalkyl group, a heterocycloalkoxy group, a carboxyl group or a carboxylate group; and R 6 and R 7 are each selected from an alkyl group, an aryl group, a heteroaryl group, Haloalkyl, haloalkoxy, hydroxy, amine, cyano, alkynyl, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxy, carboxylate or halogen; W is carbon, sulfur or An oxygen atom; when W is carbon, it may be further substituted with R 6 or R 7 . 如申請專利範圍第1項之化合物或其醫藥上可接受的鹽，包括下述通式(IC)表示的化合物或其醫藥上可接受的鹽： 其中：R是 R1 選自-C(O)NR3 R4 、-C(O)R3 或-C(O)OR3 ；R2 選自氫原子或烷基，其中，該烷基任選進一步被一個或多個選自環烷基或芳基的取代基取代；R3 和R4 分別選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基任選進一步被一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、三氟甲基、羧基或羧酸酯基的取代基取代；或者，R3 和R4 與N原子一起形成3至8員的雜環基，其中，5至8員雜環內任選進一步含有一個或多個N、O或S原子，並且該3至8員雜環任選進一步被一 個或多個選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素的取代基取代；R5 選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基任選進一步被一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、烷胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、羧基或羧酸酯基的取代基取代；R6 和R7 分別選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、炔基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素；W為碳、硫或氧原子；當W為碳時，可以進一步經R6 或R7 所取代。A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises a compound represented by the following formula (IC) or a pharmaceutically acceptable salt thereof: Where: R is R 1 is selected from -C(O)NR 3 R 4 , -C(O)R 3 or -C(O)OR 3 ; R 2 is selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further subjected to a Or a plurality of substituents selected from a cycloalkyl group or an aryl group; R 3 and R 4 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group, wherein The alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group is further optionally further selected from one or more selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy Substituent substitution of aryloxy, heteroaryloxy, halogen, hydroxy, amine, cyano, hydroxyalkyl, heterocycloalkyl, heterocycloalkoxy, trifluoromethyl, carboxy or carboxylate groups Or, R 3 and R 4 together with the N atom form a 3 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring optionally further contains one or more N, O or S atoms, and the 3 to The 8-membered heterocyclic ring is optionally further further selected from one or more selected from the group consisting of alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amine, cyano, alkoxy, aryloxy, hydroxyalkyl a heterocyclic alkyl group, a carboxyl group, a carboxylate group or a halogen substituent ; R 5 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl, wherein such alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl any Further selected from one or more selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amine, alkylamine Substituted with a substituent of a cyano group, a cyano group, a hydroxyalkyl group, a heterocycloalkyl group, a heterocycloalkoxy group, a carboxyl group or a carboxylate group; and R 6 and R 7 are each selected from the group consisting of an alkyl group, an aryl group, a heteroaryl group, and an alkyl halide. , haloalkoxy, hydroxy, amine, cyano, alkynyl, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxyl, carboxylate or halogen; W is carbon, sulfur or oxygen Atom; when W is carbon, it may be further substituted by R 6 or R 7 . 如申請專利範圍第1項之化合物或其醫藥上可接受的鹽，其中，該鹽為通式(I)化合物與選自下列的酸形成的鹽：鹽酸、對甲苯磺酸、酒石酸、馬來酸、乳酸、甲磺酸、硫酸、磷酸、檸檬酸、乙酸或三氟乙酸。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the salt is a salt of a compound of the formula (I) with an acid selected from the group consisting of hydrochloric acid, p-toluenesulfonic acid, tartaric acid, and Malay. Acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid. 如申請專利範圍第4項之化合物或其醫藥上可接受的鹽，其中，該酸為對甲苯磺酸、鹽酸、酒石酸或三氟乙酸。 The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein the acid is p-toluenesulfonic acid, hydrochloric acid, tartaric acid or trifluoroacetic acid. 如申請專利範圍第1項之化合物或其醫藥上可接受的鹽，其包括如下結構的化合物： A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises a compound having the following structure: 如申請專利範圍第1項之化合物或其醫藥上可接受的鹽，其包括如下結構的化合物： A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises a compound having the following structure: 一種醫藥組成物，其含有治療有效劑量的如申請專利範圍第1至7項中任一項之化合物或其醫藥上可接受的鹽和醫藥上可接受的載體。 A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 一種如下列通式(ID)所示的化合物，其係作為合成如申請專利範圍第1項之通式(I)化合物的中間體： 其中：R1 選自-C(O)NR3 R4 、-C(O)R3 或-C(O)OR3 ；R3 和R4 分別選自氫原子、烷基、環烷基、芳基、雜芳基或雜環烷基，其中，該等烷基、環烷基、芳基、雜芳基或雜環烷基任選進一步被一個或多個選自烷基、環烷基、芳基、雜芳基、烷氧基、環烷氧基、芳氧基、雜芳氧基、鹵素、羥基、胺基、氰基、羥烷基、雜環烷基、雜環烷氧基、三氟甲基、羧基或羧酸酯基的取代基取代；或者，R3 和R4 與N原子一起形成3至8員的雜環基，其中，5至8員雜環內任選進一步含有一個或多個N、O或S原子，並且該3至8員雜環任選進一步被一個或多個選自烷基、芳基、雜芳基、鹵代烷基、鹵代烷氧基、羥基、胺基、氰基、烷氧基、芳氧基、羥烷基、雜環烷基、羧基、羧酸酯基或鹵素的取代基取代。A compound of the following formula (ID) which is an intermediate for the synthesis of a compound of the formula (I) as in claim 1 of the patent application: Wherein R 1 is selected from -C(O)NR 3 R 4 , -C(O)R 3 or -C(O)OR 3 ; and R 3 and R 4 are each selected from a hydrogen atom, an alkyl group, a cycloalkyl group, Aryl, heteroaryl or heterocycloalkyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl group is further further selected from one or more selected from the group consisting of alkyl, cycloalkyl , aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amine, cyano, hydroxyalkyl, heterocycloalkyl, heterocycloalkoxy Substituting a substituent of a trifluoromethyl group, a carboxyl group or a carboxylate group; or, R 3 and R 4 together with the N atom form a heterocyclic group of 3 to 8 members, wherein the 5- to 8-membered heterocyclic ring is optionally further Containing one or more N, O or S atoms, and the 3 to 8 membered heterocyclic ring is optionally further further selected from one or more selected from the group consisting of alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amine Substituent substitution of a cyano group, a cyano group, an alkoxy group, an aryloxy group, a hydroxyalkyl group, a heterocycloalkyl group, a carboxyl group, a carboxylate group or a halogen. 一種製備如申請專利範圍第9項之中間體(ID)的方法，該方法包括： 冰浴下，將5-側氧基-全氫-環戊并[c]吡咯-2-羧酸第三丁酯在溶劑中與三氟乙酸(TFA)反應，得到全氫-環戊并[c]吡咯-5-酮三氟乙酸鹽； 將該全氫-環戊并[c]吡咯-5-酮三氟乙酸鹽在鹼存在下與醯氯或酯類反應，得到通式(ID)的化合物；其中R1 定義如申請專利範圍第9項所述。A method of preparing an intermediate (ID) according to claim 9 of the patent application, the method comprising: 5-sided oxy-perhydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester was reacted with trifluoroacetic acid (TFA) in a solvent under ice bath to obtain a perhydro-cyclopenta[ c] pyrrol-5-one trifluoroacetate; The perhydro-cyclopenta[c]pyrrole-5-one trifluoroacetate is reacted with hydrazine chloride or an ester in the presence of a base to give a compound of the formula (ID); wherein R 1 is as defined in the patent application 9 items mentioned. 如申請專利範圍第10項之方法，其中，該溶劑為二氯甲烷。 The method of claim 10, wherein the solvent is dichloromethane. 一種製備如申請專利範圍第2項之通式(IB)化合物的方法，該方法包括： 將中間體(ID)於室溫條件下在溶劑中與不同的胺、經取代的硼氫化鈉在鹼性條件下反應，得到通式(IB)化合物；其中R，R1 ，R2 定義如申請專利範圍第2項所述。A method of preparing a compound of the formula (IB) according to claim 2 of the patent application, the method comprising: The intermediate (ID) is reacted with a different amine, substituted sodium borohydride in a solvent under basic conditions at room temperature to give a compound of the formula (IB); wherein R, R 1 , R 2 are as defined above The scope of patent application is mentioned in item 2. 如申請專利範圍第12項之方法，其中，該溶劑為甲醇或乙醇。 The method of claim 12, wherein the solvent is methanol or ethanol. 一種製備如申請專利範圍第3項之通式(IC)化合物的方 法，該方法包括： 將第三丁醇鉀和碘化甲基三苯基鏻的甲苯溶液加熱後，在室溫下將中間體(ID)化合物加入到上述溶液中反應，得到亞甲基氮雜雙環化合物； 將該亞甲基氮雜雙環化合物在溶劑中，於過氯酸銀存在下，於室溫與三甲基矽氰反應得到異氰基氮雜雙環化合物； 將該異氰基氮雜雙環化合物在溶劑中與酸在室溫下反應得到胺基氮雜雙環化合物； 將該胺基氮雜雙環化合物在溶劑中與鹵化物反應， 得到通式(IC)化合物；其中R，R1 ，R2 定義如申請專利範圍第3項所述。A method of preparing a compound of the general formula (IC) according to claim 3 of the patent application, the method comprising: After heating the toluene solution of potassium t-butoxide and methyltriphenylphosphonium iodide, the intermediate (ID) compound is added to the above solution at room temperature to obtain a methylene azabicyclo compound; The methylene azabicyclo compound is reacted with trimethyl decanoyl at room temperature in the presence of silver perchlorate in a solvent to obtain an isocyanoazabicyclo compound; The isocyanoazabicyclo compound is reacted with an acid at room temperature in a solvent to obtain an amine azabicyclo compound; The amino azabicyclo compound is reacted with a halide in a solvent to obtain a compound of the formula (IC); wherein R, R 1 , R 2 are as defined in claim 3 of the scope of the patent application. 如申請專利範圍第14項之方法，其中，該亞甲基氮雜雙環化合物與該三甲基矽氰之反應所採用的溶劑為二氯甲烷；該異氰基氮雜雙環化合物與該酸之反應所採用的溶劑為乙醇且該酸為鹽酸。 The method of claim 14, wherein the solvent used for the reaction of the methylene azabicyclo compound with the trimethylcyanamide is dichloromethane; the isocyanoazabicyclo compound and the acid The solvent used in the reaction is ethanol and the acid is hydrochloric acid. 一種製備如申請專利範圍第2項之通式(IB)化合物的方法，該方法包括： 將中間體(ID)化合物和對甲苯磺醯甲基異腈在溶劑中進行氰化反應，得到氰基氮雜雙環化合物； 將該氰基氮雜雙環化合物在溶劑中，在六甲基二矽烷基胺化鋰存在下與鹵化物反應，得到經R2 取代的氰基氮雜雙環化合物； 將該經R2 取代的氰基氮雜雙環化合物在酸的作用 下水解，得到經R2 取代的羧基氮雜雙環化合物；或者將該經R2 取代的氰基氮雜雙環化合物溶劑中，在冰浴下與還原劑氫化二異丁基鋁(DIBAL-H)反應，先將氰基還原成醛基，然後將得到的醛在四氫呋喃/水混合溶劑中，在冰浴下與磷酸二氫鈉、亞氯酸鈉和2-甲基-2-丁烯反應，得到經R2 取代的羧基氮雜雙環化合物； 將該經R2 取代的羧基氮雜雙環化合物在鹼性條件及氯甲酸乙酯存在下與疊氮化鹼金屬反應，得到經R2 取代的疊氮基羰基氮雜雙環化合物； 將該經R2 取代的疊氮基羰基氮雜雙環化合物在溶劑中加熱，再在酸性溶液中攪拌，然後將pH調為鹼性，得到經R2 取代的胺基氮雜雙環化合物； 將該經R2 取代的胺基氮雜雙環化合物在溶劑中，與鹵化物反應得到通式(IB)化合物；其中R，R1 ，R2 定義如申請專利範圍第2項所述。A method of preparing a compound of the formula (IB) according to claim 2 of the patent application, the method comprising: The intermediate (ID) compound and p-toluenesulfonylmethyl isocyanide are cyanated in a solvent to obtain a cyanoazabicyclo compound; The cyanoazabicyclo compound is reacted with a halide in a solvent in the presence of lithium hexamethyldidecylalkylamine to obtain an R 2 -substituted cyanoazabicyclo compound; The R 2 -substituted cyanoazabicyclo compound is hydrolyzed by an acid to obtain an R 2 -substituted carboxyazabicyclo compound; or the R 2 -substituted cyanoazabicyclo compound is solvent Under the ice bath, it is reacted with reducing agent hydrogenated diisobutylaluminum (DIBAL-H). The cyano group is first reduced to an aldehyde group, and then the obtained aldehyde is mixed in a tetrahydrofuran/water mixed solvent with sodium dihydrogen phosphate in an ice bath. , sodium chlorite and 2-methyl-2-butene are reacted to obtain a R 2 -substituted carboxyazabicyclo compound; The R 2 -substituted carboxyazabicyclo compound is reacted with an alkali metal azide in the presence of an alkaline condition and ethyl chloroformate to obtain an R 2 -substituted azidocarbonyl azabicyclo compound; The R 2 -substituted azidocarbonylcarbonyl azabicyclo compound is heated in a solvent, stirred in an acidic solution, and then adjusted to a basic pH to obtain an R 2 -substituted amino azabicyclo compound; The R 2 -substituted amino azabicyclo compound is reacted with a halide in a solvent to obtain a compound of the formula (IB); wherein R, R 1 , R 2 are as defined in the second item of the patent application. 一種製備如申請專利範圍第3項之通式(IC)化合物的方法，該方法包括： 將中間體(ID)在溶劑中，冰浴下與還原劑反應，得到羥基氮雜雙環化合物； 將該羥基氮雜雙環化合物在溶劑中，冰浴下與鹼性試劑、甲磺醯氯反應，得到甲磺酸基氮雜雙環化合物； 將該甲磺酸基氮雜雙環化合物在溶劑中與鄰苯二甲醯亞胺鉀鹽加熱反應，得到經鄰苯二甲醯亞胺取代的氮雜雙環化合物； 將該經鄰苯二甲醯亞胺取代的氮雜雙環化合物在溶劑中，與肼加熱，得到胺基氮雜雙環化合物； 將該經胺基取代的氮雜雙環化合物在溶劑中與鹵化物加熱反應，得到通式(IC)化合物；其中R，R1 ，R2 定義如申請專利範圍第3項所述。A method of preparing a compound of the general formula (IC) according to claim 3 of the patent application, the method comprising: The intermediate (ID) is reacted with a reducing agent in a solvent under ice bath to obtain a hydroxyazabicyclo compound; The hydroxyazabicyclo compound is reacted with an alkaline reagent or methanesulfonyl chloride in a solvent under ice to obtain a methanesulfonyl azabicyclo compound; The methanesulfonyl azabicyclo compound is heated and reacted with potassium phthalimide in a solvent to obtain an azabibicyclic compound substituted with phthalimide; The phthalimide substituted azabicyclo compound is heated in a solvent with hydrazine to obtain an amine azabicyclo compound; The amine-substituted azabicyclo compound is heated in a solvent with a halide to give a compound of the formula (IC); wherein R, R 1 , R 2 are as defined in claim 3 of the scope of the patent application. 如申請專利範圍第17項之方法，其中，該還原劑為氫化三(第三丁氧基)鋁鋰。 The method of claim 17, wherein the reducing agent is lithium tris(t-butoxy)aluminum hydride. 如申請專利範圍第11至第18項中任一項之方法，其中，還包括將得到的通式(IB)或(IC)化合物純化後，在甲醇、二氯甲烷或乙酸乙酯中與酸反應，得到其酸加成鹽。 The method of any one of claims 11 to 18, which further comprises purifying the obtained compound of the formula (IB) or (IC) in methanol, dichloromethane or ethyl acetate with an acid The reaction is carried out to obtain an acid addition salt thereof. 一種如申請專利範圍第1至第7項中任一項之化合物或其醫藥上可接受的鹽在製備二肽基肽酶抑制劑藥物上的用途。 A use of a compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the preparation of a dipeptidyl peptidase inhibitor. 一種如申請專利範圍第8項之組成物在製備二肽基肽酶抑制劑藥物上的用途。A use of the composition of claim 8 in the preparation of a dipeptidyl peptidase inhibitor.
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