TW201326119A - Novel pyrrolidine derivatives - Google Patents

Novel pyrrolidine derivatives Download PDF

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TW201326119A
TW201326119A TW101143548A TW101143548A TW201326119A TW 201326119 A TW201326119 A TW 201326119A TW 101143548 A TW101143548 A TW 101143548A TW 101143548 A TW101143548 A TW 101143548A TW 201326119 A TW201326119 A TW 201326119A
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pyrrolidine
cyclopropanecarbonyl
carboxamide
chlorophenyl
cyclopropylamino
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TW101143548A
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Chinese (zh)
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David Banner
Wolfgang Haap
Bernd Kuhn
Thomas Luebbers
Jens-Uwe Peters
Tanja Schulz-Gasch
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Hoffmann La Roche
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Abstract

The invention relates to a compound of formula (I) wherein A and R1 to R7 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

Description

新穎吡咯啶衍生物 Novel pyrrolidine derivatives

本發明係關於可用於治療及/或預防哺乳動物之有機化合物，且特定而言係關於為半胱胺酸蛋白酶組織蛋白酶、特定而言半胱胺酸蛋白酶組織蛋白酶S或L之優先抑制劑之化合物。 The present invention relates to organic compounds which are useful for the treatment and/or prevention of mammals, and in particular to a preferred inhibitor of the cysteine protease cathepsin, in particular the cysteine protease cathepsin S or L. Compound.

特定而言，本發明係關於式(I)化合物 其中A係羰基或不存在；R1係烷氧基、硝基苯基、經烷基及環烷基取代之1H-吡唑基、烷基環烷基、鹵代烷基環烷基、苯基環烷基、鹵代苯基環烷基、吡啶基環烷基或鹵代吡啶基環烷基；R2及R3係獨立地選自氫、烷基及環烷基烷基；或R2與R3連同其所連接之碳原子一起形成環烷基；R4係-C(O)NR8R9或苯并噁唑基；R5、R6及R7係獨立地選自氫、烷基、鹵素、鹵代烷基、烷氧基、鹵代烷氧基及嗎啉基；且 R8及R9中之一者係氫或烷基且另一者係烷基、烷氧基烷基、環烷基、鹵代烷基、苯基烷基、萘基烷基或四氫吡喃基；或其醫藥上可接受之鹽或酯。 In particular, the invention relates to compounds of formula (I) Wherein A is a carbonyl group or is absent; R 1 is an alkoxy group, a nitrophenyl group, a 1H-pyrazolyl group substituted by an alkyl group and a cycloalkyl group, an alkylcycloalkyl group, a halogenated alkylcycloalkyl group, a phenyl ring An alkyl group, a halophenylcycloalkyl group, a pyridylcycloalkyl group or a halopyridylcycloalkyl group; R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl and cycloalkylalkyl; or R 2 and R 3 together with the carbon atom to which it is attached forms a cycloalkyl group; R 4 is -C(O)NR 8 R 9 or benzoxazolyl; R 5 , R 6 and R 7 are independently selected from hydrogen, alkane a halogen, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, and a morpholinyl group; and one of R 8 and R 9 is hydrogen or an alkyl group and the other is an alkyl group, an alkoxyalkyl group, a cycloalkane Or a haloalkyl group, a phenylalkyl group, a naphthylalkyl group or a tetrahydropyranyl group; or a pharmaceutically acceptable salt or ester thereof.

哺乳動物組織蛋白酶係參與生物學及病理學事件之關鍵步驟之半胱胺酸型蛋白酶。由於利用小分子抑制酶促活性係可行的，因此認為組織蛋白酶係易處理之藥物靶標，且因此為醫藥工業所關注(Bromme,D.(2001)，「Papain-like cysteine proteases」，Curr Protoc Protein Sci，第21章，第212單元；Roberts,R.(2005)，「Lysosomal cysteine proteases：structure,function and inhibition of cathepsins」，Drug News Perspect,18(10),605-14)。 Mammalian cathepsins are cysteine-type proteases that are involved in key steps in biological and pathological events. Since inhibition of enzymatic activity by small molecules is feasible, cathepsins are considered to be easy to treat drug targets and are therefore of interest to the pharmaceutical industry (Bromme, D. (2001), "Papain-like cysteine proteases", Curr Protoc Protein Sci, Chapter 21, Unit 212; Roberts, R. (2005), "Lysosomal cysteine proteases: structure, function and inhibition of cathepsins", Drug News Perspect, 18(10), 605-14).

組織蛋白酶S在抗原呈遞細胞(如巨噬細胞及樹突細胞)及平滑肌細胞中突出表現。(Hsing,L.C.及Rudensky,A.Y.(2005)，「The lysosomal cysteine proteases in MHC class II antigen presentation」，Immunol Rev,207,229-41；Rudensky,A.及Beers,C.(2006)，「Lysosomal cysteine proteases and antigen presentation」，Ernst Schering Res Found Workshop,(56),81-95)。儘管組織蛋白酶S僅在正常動脈組織中弱表現，但在動脈粥樣硬化動脈觀察到強上調(Liu,J.等人(2006)，「Increased serum cathepsin S in patients with atherosclerosis and diabetes」，Atherosclerosis,186(2),411-9；Sukhova,G.K.等人 (1998)，「Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells」，J Clin Invest,102(3),576-83)。 Cathepsin S is prominent in antigen presenting cells such as macrophages and dendritic cells and smooth muscle cells. (Hsing, LC and Rudensky, AY (2005), "The lysosomal cysteine proteases in MHC class II antigen presentation", Immunol Rev, 207, 229-41; Rudensky, A. and Beers, C. (2006), "Lysosomal cysteine proteases and Antigen presentation", Ernst Schering Res Found Workshop, (56), 81-95). Although cathepsin S is only weakly expressed in normal arterial tissue, strong upregulation is observed in atherosclerotic arteries (Liu, J. et al. (2006), "Increased serum cathepsin S in patients with atherosclerosis and diabetes", Atherosclerosis, 186(2), 411-9; Sukhova, GK, etc. (1998), "Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells", J Clin Invest, 102(3), 576-83).

臨床前數據表明，組織蛋白酶S之功能對於動脈粥樣硬化至關重要，此乃因當在適當小鼠模型中測試時，組織蛋白酶S缺陷小鼠之動脈粥樣硬化表型減少。在LDL-Rec缺陷小鼠中，報導脂質累積減少、彈性蛋白-纖維分解及慢性動脈發炎。在APO E缺陷小鼠中，報導急性斑塊破裂事件顯著減少。當將慢性腎病引入CatS/In APO-E缺陷小鼠中時，除了在動脈及心臟瓣膜中觀察到抗動脈粥樣硬化活性外，亦觀察到加速鈣化顯著減少(Aikawa,E.等人(2009)，「Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease」，Circulation,119(13),1785-94；de Nooijer,R.等人(2009)，「Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis」，Arterioscler Thromb Vasc Biol,29(2),188-94；Rodgers,K.J.等人(2006)，「Destabilizing role of cathepsin S in murine atherosclerotic plaques」，Arterioscler Thromb Vasc Biol,26(4),851-6；Sukhova等人(2003)，「Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice」，J Clin Invest,111(6),897-906)。此表明組織蛋白酶S之潛在抑制劑將藉由減少細胞外基質分解、藉由減少促炎狀態及藉由減少加速鈣化及隨 後其臨床表現來穩定動脈粥樣硬化斑塊。 Preclinical data indicate that the function of cathepsin S is critical for atherosclerosis because the atherosclerotic phenotype of cathepsin S deficient mice is reduced when tested in a suitable mouse model. In LDL-Rec deficient mice, decreased lipid accumulation, elastin-fiber breakdown, and chronic arterial inflammation were reported. In APO E-deficient mice, a significant reduction in acute plaque rupture events was reported. When chronic kidney disease was introduced into CatS/In APO-E-deficient mice, in addition to the observed anti-atherosclerotic activity in arteries and heart valves, a significant reduction in accelerated calcification was observed (Aikawa, E. et al. (2009). ), "Arterial and aortic valve calcification abolished by elastolytic cathepsin S deficiency in chronic renal disease", Circulation, 119(13), 1785-94; de Nooijer, R. et al. (2009), "Leukocyte cathepsin S is a potent regulator Of both cell and matrix turnover in advanced atherosclerosis", Arterioscler Thromb Vasc Biol, 29(2), 188-94; Rodgers, KJ et al. (2006), "Destabilizing role of cathepsin S in murine atherosclerotic plaques", Arterioscler Thromb Vasc Biol , 26(4), 851-6; Sukhova et al. (2003), "Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice", J Clin Invest, 111 (6), 897-906). This suggests that potential inhibitors of cathepsin S will be reduced by reducing extracellular matrix, by reducing pro-inflammatory status and by reducing accelerated calcification and After its clinical manifestations to stabilize atherosclerotic plaque.

動脈粥樣硬化模型中所述之該等表型與組織蛋白酶S之已知細胞功能一致。首先，組織蛋白酶S參與穩定斑塊之細胞外基質之降解。特定而言，組織蛋白酶S具有有效彈性蛋白溶解活性且可在中性pH下施加此活性，此係區別組織蛋白酶S與所有其他組織蛋白酶之特徵。其次，組織蛋白酶S係參與抗原處理(特定而言抗原呈遞細胞中不變鏈之解離)從而降低T細胞對動脈粥樣硬化組織之慢性發炎之作用的主要蛋白酶。發炎升級進一步導致氧化及蛋白分解性組織損害及隨後斑塊去穩定(Cheng,X.W.等人(2004)，「Increased expression of elastolytic cysteine proteases,cathepsins S and K,in the neointima of balloon-injured rat carotid arteries」，Am J Pathol,164(1),243-51；Driessen,C.等人(1999)，「Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells」，J Cell Biol,147(4),775-90；Rudensky,A.及Beers,C.(2006)，「Lysosomal cysteine proteases and antigen presentation」，Ernst Schering Res Found Workshop,(56),81-95)。 These phenotypes described in the atherosclerosis model are consistent with known cellular functions of cathepsin S. First, cathepsin S is involved in the degradation of the extracellular matrix that stabilizes the plaque. In particular, cathepsin S has potent elastin activity and can exert this activity at neutral pH, which distinguishes between cathepsin S and all other cathepsins. Secondly, cathepsin S is involved in the main protease of antigen treatment (specifically dissociation of invariant chains in antigen presenting cells) to reduce the chronic inflammation of T cells to atherosclerotic tissues. Inflammation escalation further leads to oxidative and proteolytic tissue damage and subsequent plaque destabilization (Cheng, XW et al. (2004), "Increased expression of elastolytic cysteine proteases, cathepsins S and K, in the neointima of balloon-injured rat carotid arteries , Am J Pathol, 164(1), 243-51; Driessen, C. et al. (1999), "Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells", J Cell Biol, 147 (4) ), 775-90; Rudensky, A. and Beers, C. (2006), "Lysosomal cysteine proteases and antigen presentation", Ernst Schering Res Found Workshop, (56), 81-95).

Cat S抑制劑之抗炎及抗彈性蛋白溶解性質使其亦成為慢性阻塞性肺病之突出靶標(Williams,A.S.等人(2009)，「Role of cathepsin S in ozone-induced airway hyperresponsiveness and inflammation」，Pulm Pharmacol Ther,22(1),27-32)。此外，由於其在基質降解中之細胞外功能，因此對 組織蛋白酶S之抑制將影響新內膜形成及血管生成(Burns-Kurtis,C.L.等人(2004)，「Cathepsin S expression is up-regulated following balloon angioplasty in the hypercholesterolemic rabbit」，Cardiovasc Res,62(3),610-20；Cheng,X.W.等人(2004)，「Increased expression of elastolytic cysteine proteases,cathepsins S and K,in the neointima of balloon-injured rat carotid arteries」，Am J Pathol,164(1),243-51；Shi,G.P.等人(2003)，「Deficiency of the cysteine protease cathepsin S impairs microvessel growth」，Circ Res,92(5),493-500；Wang,B.等人(2006)，「Cathepsin S controls angiogenesis and tumor growth via matrix-derived angiogenic factors」，J Biol Chem,281(9),6020-9)。因此，組織蛋白酶S之抑制劑可用於若干不同疾病情形。 The anti-inflammatory and anti-elastolytic properties of Cat S inhibitors make it a prominent target for chronic obstructive pulmonary disease (Williams, AS et al. (2009), "Role of cathepsin S in ozone-induced airway hyperresponsiveness and inflammation", Pulm Pharmacol Ther, 22(1), 27-32). In addition, due to its extracellular function in matrix degradation, Inhibition of cathepsin S will affect neointimal formation and angiogenesis (Burns-Kurtis, CL et al. (2004), "Cathepsin S expression is up-regulated following balloon angioplasty in the hypercholesterolemic rabbit", Cardiovasc Res, 62(3) , 610-20; Cheng, XW et al. (2004), "Increased expression of elastolytic cysteine proteases, cathepsins S and K, in the neointima of balloon-injured rat carotid arteries", Am J Pathol, 164(1), 243- 51; Shi, GP et al. (2003), "Deficiency of the cysteine protease cathepsin S impairs microvessel growth", Circ Res, 92(5), 493-500; Wang, B. et al. (2006), "Cathepsin S controls Angiogenesis and tumor growth via matrix-derived angiogenic factors", J Biol Chem, 281(9), 6020-9). Thus, inhibitors of cathepsin S can be used in several different disease situations.

組織蛋白酶S亦在降低腫瘤生長及腫瘤細胞侵入中起作用，如由Roberta E.Burden，Clin Cancer Res 2009；15(19)所述。另外，當與經腎切除之野生型小鼠比較時，經腎切除之組織蛋白酶S剔除小鼠顯示動脈鈣化顯著降低。此指示，抑制組織蛋白酶S可對減少慢性腎病患者之心血管事件具有有益效應(Elena Aikawa,Circulation,2009,1785-1794)。 Cathepsin S also plays a role in reducing tumor growth and tumor cell invasion as described by Roberta E. Burden, Clin Cancer Res 2009; 15 (19). In addition, nephrectomized cathepsin S knockout mice showed a significant decrease in arterial calcification when compared to nephrectomized wild type mice. This indicates that inhibition of cathepsin S may have a beneficial effect on reducing cardiovascular events in patients with chronic kidney disease (Elena Aikawa, Circulation, 2009, 1785-1794).

組織蛋白酶L比組織蛋白酶S顯示更寬表現譜，且亦有數據表明組織蛋白酶L在動脈粥樣硬化中具有作用，例如LDLrec及Cat L缺陷小鼠顯示動脈粥樣硬化表型減少(Kitamoto,S.等人(2007)，「Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice」，Circulation,115(15),2065-75)。另外表明，Cat L參與代謝症候群，此乃因其控制脂肪生成及周邊葡萄糖耐量。在腎病中，闡述組織蛋白酶L藉由以蛋白分解方式處理發動蛋白來調節足細胞功能及(藉此)蛋白尿(Sever,S.等人(2007)，「Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease」，J Clin Invest,117(8),2095-104)。 Cathepsin L shows a broader spectrum of expression than cathepsin S, and there are also data suggesting that cathepsin L has a role in atherosclerosis, such as LDLrec and Cat L-deficient mice showing a reduction in atherosclerotic phenotype (Kitamoto, S Et al. (2007), "Cathepsin L deficiency Reducing diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice", Circulation, 115(15), 2065-75). It is also shown that Cat L is involved in metabolic syndrome because it controls fat production and peripheral glucose tolerance. In nephropathy, it is stated that cathepsin L regulates podocyte function and (by this) proteinuria by treating the protein with proteolytic processes (Sever, S. et al. (2007), "Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease", J Clin Invest, 117(8), 2095-104).

組織重塑、細胞外基質降解、活性神經肽之產生及在胸腺上皮細胞中之抗原呈遞中之作用係針對組織蛋白酶L所述之細胞活性(Funkelstein等人2008；Rudensky及Beers 2006)。 The role of tissue remodeling, extracellular matrix degradation, production of active neuropeptides, and antigen presentation in thymic epithelial cells is directed to the cellular activity described for cathepsin L (Funkelstein et al. 2008; Rudensky and Beers 2006).

本發明化合物係半胱胺酸蛋白酶組織蛋白酶(Cat)(特定而言組織蛋白酶S或組織蛋白酶L)之優先抑制劑，且因此可用於治療代謝性疾病(如糖尿病)、動脈粥樣硬化、腹部主動脈瘤、周邊動脈疾病、癌症，減少慢性腎病、腎小球腎炎、年齡相關性黃斑變性、糖尿病腎病變及糖尿病視網膜病變中之心血管事件。另外，免疫介導疾病(如類風濕性關節炎、克隆氏病(crohn's disease)、多發性硬化、休格倫症候群(sjorgen syndrome)、紅斑狼瘡、神經性疼痛、I型糖尿病、哮喘及過敏症及皮膚相關免疫疾病)係欲用組織蛋白酶S抑制劑治療之適宜疾病。本發明目標係式(I)化 合物及其上述鹽本身及其作為治療活性物質之用途；製造該等化合物、中間體、含有該等化合物、其醫藥上可接受之鹽之醫藥組合物、藥劑之方法；該等化合物及鹽用於預防及/或治療疾病，尤其用以治療或預防糖尿病、動脈粥樣硬化、腹部主動脈瘤、周邊動脈疾病、癌症，減少慢性腎病及糖尿病腎病變中之心血管事件之用途；及該等化合物及鹽用於製造用以治療或預防糖尿病、動脈粥樣硬化、腹部主動脈瘤、周邊動脈疾病、癌症，減少慢性腎病及糖尿病腎病變中之心血管事件之藥劑之用途。 The compounds of the invention are preferred inhibitors of the cysteine protease catalase (Cat), in particular cathepsin S or cathepsin L, and are therefore useful for the treatment of metabolic diseases such as diabetes, atherosclerosis, abdomen Aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease, glomerulonephritis, age-related macular degeneration, diabetic nephropathy, and diabetic retinopathy. In addition, immune-mediated diseases (such as rheumatoid arthritis, crohn's disease, multiple sclerosis, sjorgen syndrome, lupus erythematosus, neuropathic pain, type 1 diabetes, asthma, and allergies) And skin-related immune diseases) are suitable diseases to be treated with cathepsin S inhibitors. The object of the present invention is (I) And the above salts themselves and their use as therapeutically active substances; methods of making such compounds, intermediates, pharmaceutical compositions, and medicaments containing such compounds, pharmaceutically acceptable salts thereof; and such compounds and salts For the prevention and/or treatment of diseases, especially for treating or preventing diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reducing cardiovascular events in chronic kidney disease and diabetic nephropathy; and The use of such compounds and salts for the manufacture of a medicament for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, and reduction of cardiovascular events in chronic kidney disease and diabetic nephropathy.

在本說明書中，術語「烷基」(單獨或呈組合形式)表示具有1個至8個碳原子之直鏈或具支鏈烷基，較佳為具有1個至6個碳原子之直鏈或具支鏈烷基，且尤佳為具有1個至4個碳原子之直鏈或具支鏈烷基。直鏈及具支鏈C1-C8烷基之實例係甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基、同分異構戊基、同分異構己基、同分異構庚基及同分異構辛基。特定烷基係甲基、乙基、丙基、異丙基及丁基。 In the present specification, the term "alkyl" (alone or in combination) means a straight or branched alkyl group having 1 to 8 carbon atoms, preferably a linear chain having 1 to 6 carbon atoms. Or a branched alkyl group, and particularly preferably a linear or branched alkyl group having 1 to 4 carbon atoms. Examples of straight chain and branched C 1 -C 8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomeric pentyl, homo-identities Isomerized hexyl, isomeric heptyl and isomeric octyl. Specific alkyl groups are methyl, ethyl, propyl, isopropyl and butyl.

術語「環烷基」(單獨或呈組合形式)表示具有3個至8個碳原子之環烷基環，且較佳為具有3個至6個碳原子之環烷基環。C3-C8環烷基之實例係環丙基、環丁基、環戊基、環己基、環庚基及環辛基。特定環烷基係環丙基及環丁基。 The term "cycloalkyl" (alone or in combination) means a cycloalkyl ring having 3 to 8 carbon atoms, and preferably a cycloalkyl ring having 3 to 6 carbon atoms. Examples of C 3 -C 8 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Specific cycloalkyl groups are cyclopropyl and cyclobutyl.

術語「烷氧基」(單獨或呈組合形式)表示術語「烷基」 具有上文所給出含義之式烷基-O-基團，例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基及第三丁氧基。特定烷氧基係乙氧基、異丙氧基及第三丁氧基。 The term "alkoxy" (alone or in combination) means the term "alkyl". An alkyl-O- group having the meaning given above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy Base and third butoxy group. Specific alkoxy groups are ethoxy, isopropoxy and tert-butoxy groups.

術語「氧基」(單獨或呈組合形式)表示-O-基團。 The term "oxy" (alone or in combination) denotes an -O- group.

術語「鹵素」或「鹵代」(單獨或呈組合形式)表示氟、氯、溴或碘。 The term "halogen" or "halo" (alone or in combination) means fluoro, chloro, bromo or iodo.

術語「鹵代烷基」、「鹵代環烷基」、「鹵代烷氧基」、「鹵代苯基」、「鹵代吡啶基」(單獨或呈組合形式)表示經至少一個鹵素取代、較佳經1至5個鹵素、較佳1至3個鹵素取代之烷基、環烷基、烷氧基、苯基及吡啶基。特定鹵代烷基係三氟甲基。特定鹵代烷氧基係三氟乙基及三氟異丙氧基。 The terms "haloalkyl", "halocycloalkyl", "haloalkoxy", "halophenyl", "halopyridyl" (alone or in combination) mean substituted with at least one halogen, preferably 1 to 5 halogens, preferably 1 to 3 halogen-substituted alkyl groups, cycloalkyl groups, alkoxy groups, phenyl groups and pyridyl groups. A specific haloalkyl group is a trifluoromethyl group. Particular haloalkoxy-trifluoroethyl and trifluoroisopropoxy.

術語「羥基(hydroxyl及hydroxy)」(單獨或呈組合形式)表示-OH基團。 The term "hydroxyl and hydroxy" (alone or in combination) denotes an -OH group.

術語「醫藥上可接受之鹽」係指彼等保留游離鹼或游離酸之生物學有效性及性質且並非在生物上或其他方面不期望之鹽。鹽係由無機酸(例如，氫氯酸、氫溴酸、硫酸、硝酸、磷酸，較佳為氫氯酸)及有機酸(例如，乙酸、丙酸、乙醇酸、丙酮酸、乙醛酸、馬來酸、丙二酸、琥珀酸、富馬酸、酒石酸、檸檬酸、苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、乙烷磺酸、對甲苯磺酸、水楊酸、N-乙醯基半胱胺酸)形成。另外，該等鹽可自向游離酸中添加無機鹼或有機鹼來製備。衍生自無機鹼之鹽包括(但不限於) 鈉鹽、鉀鹽、鋰鹽、銨鹽、鈣鹽及鎂鹽。衍生自有機鹼之鹽包括(但不限於)以下之鹽：一級胺、二級胺及三級胺、經取代胺(包括天然經取代胺)、環狀胺及鹼性離子交換樹脂(例如，異丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、離胺酸、精胺酸、N-乙基六氫吡啶、六氫吡啶、聚乙烯亞胺樹脂)。式(I)化合物亦可以兩性離子存在。式(I)化合物之尤佳醫藥上可接受之鹽係氫氯酸、氫溴酸、硫酸、磷酸及甲烷磺酸之鹽。 The term "pharmaceutically acceptable salts" refers to salts which retain the biological effectiveness and properties of the free base or free acid and which are not biologically or otherwise undesirable. The salt is composed of a mineral acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, preferably hydrochloric acid) and an organic acid (for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, glyoxylic acid, Maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-B Mercaptocysteine is formed. Additionally, the salts can be prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include (but are not limited to) Sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines (including naturally substituted amines), cyclic amines, and basic ion exchange resins (eg, Isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylhexahydropyridine, hexahydropyridine, polyethyleneimine resin). The compounds of formula (I) may also exist as zwitterions. Particularly preferred pharmaceutically acceptable salts of the compounds of formula (I) are the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

「醫藥上可接受之酯」意指通式(I)化合物可在官能基上加以衍生以提供能夠在活體內重新轉化成母體化合物之衍生物。此等化合物之實例包括生理上可接受且代謝不穩定之酯衍生物，例如甲氧基甲基酯、甲基硫甲基酯及新戊醯氧基甲基酯。另外，類似於能夠在活體內產生通式(I)母體化合物之代謝不穩定酯，通式(I)化合物之任一生理上可接受之等效物在本發明範圍內。 "Pharmaceutically acceptable ester" means that the compound of formula (I) can be derivatized on a functional group to provide a derivative which can be reconverted in vivo to the parent compound. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ester, methylthiomethyl ester and neopentyloxymethyl ester. Further, similar to the metabolically labile ester capable of producing a parent compound of the formula (I) in vivo, any physiologically acceptable equivalent of the compound of the formula (I) is within the scope of the invention.

若起始材料之一或式(I)化合物含有一或多個於一或多個反應步驟之反應條件下不穩定或具有反應性之官能基，則可於重要步驟前應用業內所熟知之方法引入適當保護基團(如(例如)「Protective Groups in Organic Chemistry」，T.W.Greene及P.G.M.Wutts，第3版，1999，Wiley New York中所述)。此等保護基團可在隨後合成階段使用文獻中所述之標準方法來去除。保護基團之實例係第三丁氧基羰基(Boc)、胺基甲酸9-茀基甲基酯(Fmoc)、胺基甲酸2-三甲基甲矽烷基乙基酯(Teoc)、羰苄氧基(Cbz)及對甲氧基苄 氧基羰基(Moz)。 If one of the starting materials or the compound of formula (I) contains one or more functional groups which are unstable or reactive under the reaction conditions of one or more reaction steps, the methods well known in the art can be applied prior to the important step. Suitable protecting groups are introduced (for example, "Protective Groups in Organic Chemistry", TW Greene and PGM Wuts, 3rd edition, 1999, Wiley New York). Such protecting groups can be removed in subsequent synthetic stages using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylformamidinyl urethane (Teoc), benzyl chloride Oxy (Cbz) and p-methoxybenzyl Oxycarbonyl (Moz).

式(I)化合物可含有若干不對稱中心且可以下列形式存在：光學純對映異構物、對映異構物(例如外消旋物)之混合物、非對映異構物之混合物、非對映異構物外消旋物或非對映異構物外消旋物之混合物。 The compounds of formula (I) may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers (such as racemates), mixtures of diastereomers, non- Enantiomeric racemate or a mixture of diastereomeric racemates.

術語「不對稱碳原子」意指具有4個不同取代基之碳原子。根據Cahn-Ingold-Prelog慣例，不對稱碳原子可具有「R」或「S」構型。 The term "asymmetric carbon atom" means a carbon atom having four different substituents. According to the Cahn-Ingold-Prelog convention, asymmetric carbon atoms can have an "R" or "S" configuration.

特定而言，本發明係關於以下：式(I)化合物，其中A係羰基或不存在；R1係烷氧基、硝基苯基、經烷基及環烷基取代之1H-吡唑基、烷基環烷基、鹵代烷基環烷基、苯基環烷基、鹵代苯基環烷基、吡啶基環烷基或鹵代吡啶基環烷基；R2及R3係獨立地選自氫、烷基及環烷基烷基；或R2與R3連同其所連接之碳原子一起形成環烷基；R4係-C(O)NR8R9或苯并噁唑基；R5、R6及R7係獨立地選自氫、烷基、鹵素、鹵代烷基、烷氧基及鹵代烷氧基；且R8及R9中之一者係氫或烷基且另一者係烷基、環烷基、鹵代烷基、苯基烷基或萘基烷基；或其醫藥上可接受之鹽或酯；式(I)化合物，其中R1係鹵代苯基環烷基或鹵代吡啶基環 烷基；式(I)化合物，其中R1係第三丁氧基、硝基苯基、經甲基及環丁基取代之1H-吡唑基、三氟甲基環丙基、苯基環烷基、氯苯基環丙基、溴苯基環丙基、碘苯基環丙基、氯氟苯基環丙基、溴氟苯基環丙基、吡啶基環烷基或氯氟吡啶基環丙基或溴氟吡啶基環丙基；式(I)化合物，其中R1係氯苯基環丙基、氯氟苯基環丙基、溴苯基環丙基、溴氟苯基環丙基或氯氟吡啶基環丙基；式(I)化合物，其中R2及R3係獨立地選自氫及烷基；式(I)化合物，其中R2及R3係獨立地選自氫、甲基、乙基、丙基及丁基；式(I)化合物，其中R5、R6及R7係獨立地選自鹵素、鹵代烷基及鹵代烷氧基；式(I)化合物，其中R5、R6及R7係獨立地選自氫、氯、三氟甲基及三氟乙氧基；式(I)化合物，其中R5係甲基、三氟甲基或氯；式(I)化合物，其中R5係氯或三氟甲基；式(I)化合物，其中R6係氫；式(I)化合物，其中R7係氫、甲基、氯、氟、溴、氟、三氟乙氧基或三氟丙氧基；式(I)化合物，其中R7係氫、氯或三氟乙氧基；式(I)化合物，其中R8及R9中之一者係氫且另一者係烷基或環烷基； 式(I)化合物，其中R8及R9中之一者係氫且另一者係乙基、丙基、丁基或環丙基；選自以下之式(I)化合物：(2S,4R)-2-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基胺基甲醯基)-4-(2,4-二甲基苯基磺醯基)吡咯啶-1-甲酸第三丁基酯；(2S,4R)-4-(4-氯-2-甲基苯基磺醯基)-2-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基胺基甲醯基)吡咯啶-1-甲酸第三丁基酯；(2S,4R)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-1-(2-硝基苯基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-環丁基-3-甲基-1H-吡唑-5-基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(4-氟-2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(2-硝基-苯基)-4-(2-三氟甲基-苯磺醯基)-吡咯啶-2-甲酸[(S)-1-(苯并噁唑-2-羰基)-丙基]-醯胺；(2S,4R)-4-(4-溴-2-(三氟甲基)苯基磺醯基)-1-(1-環丁基-3-甲基-1H-吡唑-5-基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-1-(1-(三氟甲基)環丙烷羰基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯 基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(4-(2,2,2-三氟乙氧基)-2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(苯并[d]噁唑-2-基)-1-側氧基丁-2-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯-2-氟苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-溴-2-氟苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-溴苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-溴苯基)環丙烷羰基)-4-(2-氯苯基磺醯 基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-1-(1-(4-碘苯基)環丙烷羰基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-1-(1-(4-碘苯基)環丙烷羰基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-溴-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯 苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-(4-(環丙基胺基)-2-甲基-3,4-二側氧基丁-2-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-(1-(2-(環丙基胺基)-2-側氧基乙醯基)環丙基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-4-甲基-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-5-甲基-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-環己基-4-(環丙基胺基)-3,4-二側氧基丁-2-基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基戊-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基己-3-基)-1- (1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(苄基胺基)-1,2-二側氧基戊-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-4-(環丙基胺基)-3,4-二側氧基丁-2-基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(苄基胺基)-1,2-二側氧基己-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((3S)-1,2-二側氧基-1-(戊-2-基胺基)戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((3S)-1,2-二側氧基-1-(戊-2-基胺基)己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2,4-二氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-氟苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯 基)-N-((S)-1,2-二側氧基-1-(2,2,2-三氟乙胺基)己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(異丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-4-(2,4-二氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(乙胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙-2-基氧基)苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙-2-基氧基)苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基(甲基)胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-氟苯基磺醯基)-1-(1-(4-氯苯基)環丙 烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1,2-二側氧基-1-(苯乙胺基)戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(2-(萘-1-基)乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(2-(萘-2-基)乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(萘-1-基甲基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1,2-二側氧基-1-(四氫-2H-吡喃-4-基胺基)戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(2-甲氧基乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(異丁基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-嗎啉基苯基磺醯基)-1-(1-(4-氯苯基) 環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-嗎啉基苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-4-甲基-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-5-甲基-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基戊-3-基)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基己-3-基)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；及(2S,4R)-N-((S)-1-(苄基胺基)-1,2-二側氧基己-3-基)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；選自以下之式(I)化合物：(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺； (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(4-(2,2,2-三氟乙氧基)-2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(苯并[d]噁唑-2-基)-1-側氧基丁-2-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯-2-氟苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺； (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-4-甲基-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-5-甲基-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基戊-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-4-(環丙基胺基)-3,4-二側氧基丁-2-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2,4-二氯苯基磺醯基)吡咯啶-2-甲醯胺； (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(異丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；及(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(乙胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺。 In particular, the invention relates to the following: a compound of formula (I) wherein A is a carbonyl group or is absent; R 1 is an alkoxy group, a nitrophenyl group, a 1H-pyrazolyl group substituted with an alkyl group and a cycloalkyl group , alkylcycloalkyl, haloalkylcycloalkyl, phenylcycloalkyl, halophenylcycloalkyl, pyridylcycloalkyl or halopyridylcycloalkyl; R 2 and R 3 are independently selected From hydrogen, alkyl and cycloalkylalkyl; or R 2 and R 3 together with the carbon atom to which they are attached form a cycloalkyl; R 4 is -C(O)NR 8 R 9 or benzoxazolyl; R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, alkoxy and haloalkoxy; and one of R 8 and R 9 is hydrogen or alkyl and the other An alkyl, cycloalkyl, haloalkyl, phenylalkyl or naphthylalkyl group; or a pharmaceutically acceptable salt or ester thereof; a compound of formula (I) wherein R 1 is halophenylcycloalkyl or Halopyridylcycloalkyl; a compound of formula (I) wherein R 1 is a third butoxy group, a nitrophenyl group, a 1H-pyrazolyl group substituted by a methyl group and a cyclobutyl group, a trifluoromethylcyclopropane group Base, phenylcycloalkyl, chlorophenylcyclopropyl, bromophenylcyclopropyl Iodophenylcyclopropyl, chlorofluorophenylcyclopropyl, bromofluorophenylcyclopropyl, pyridylcycloalkyl or chlorofluoropyridylcyclopropyl or bromofluoropyridylcyclopropyl; compound of formula (I) Wherein R 1 is chlorophenylcyclopropyl, chlorofluorophenylcyclopropyl, bromophenylcyclopropyl, bromofluorophenylcyclopropyl or chlorofluoropyridylcyclopropyl; a compound of formula (I) wherein R 2 and R 3 are independently selected from the group consisting of hydrogen and alkyl; compounds of formula (I) wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and butyl; formula (I) a compound, wherein R 5 , R 6 and R 7 are independently selected from halogen, haloalkyl and haloalkoxy; a compound of formula (I), wherein R 5 , R 6 and R 7 are independently selected from hydrogen, chloro, tri And fluoromethyl and trifluoroethoxy; a compound of formula (I), wherein R 5 is methyl, trifluoromethyl or chloro; a compound of formula (I), wherein R 5 is chloro or trifluoromethyl; a compound, wherein R 6 is hydrogen; a compound of formula (I), wherein R 7 is hydrogen, methyl, chloro, fluoro, bromo, fluoro, trifluoroethoxy or trifluoropropoxy; a compound of formula (I), Wherein R 7 is hydrogen, chloro or trifluoroethoxy; a compound of formula (I) wherein R 8 and R 9 One of which is hydrogen and the other is an alkyl or cycloalkyl group; a compound of formula (I) wherein one of R 8 and R 9 is hydrogen and the other is ethyl, propyl, butyl or Cyclopropyl; a compound of formula (I) selected from the group consisting of: (2S,4R)-2-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl Aminomethylmercapto)-4-(2,4-dimethylphenylsulfonyl)pyrrolidine-1-carboxylic acid tert-butyl ester; (2S,4R)-4-(4-chloro-2- Methylphenylsulfonyl)-2-((S)-1-(cyclopropylamino)-1,2-di- oxypentan-3-ylaminomethylindenyl)pyrrolidine-1- Tert-butyl formate; (2S,4R)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypent-3-yl)-1-(2- Nitrophenyl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-cyclobutyl-3-methyl -1H-pyrazol-5-yl)-N-((S)-1-(cyclopropylamino)-1,2-di- oxypentan-3-yl)-4-(4-fluoro -2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(2-nitro-phenyl)-4-(2-trifluoromethyl) (-phenylsulfonyl)-pyrrolidine-2-carboxylic acid [(S)-1-(benzoxazol-2-carbonyl)-propyl]-decylamine; (2S,4R)-4-(4- Bromo-2-(trifluoromethyl)phenylsulfonyl)-1-(1-cyclobutyl-3-methyl-1H-pyridyl -5-yl)-N-((S)-1-(cyclopropylamino)-1,2-di- oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S, 4R )-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)- 4-(2-(Trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4 -(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamidine Amine; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropane) (amino) benzyl-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5-chloro-3-fluoropyridine-2 -yl)cyclopropanecarbonyl)-4-(2-chloro-4-(2,2,2-trifluoroethoxy)phenylsulfonyl)-N-((S)-1-(cyclopropyl) Amino)-1,2-di-oxypenten-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)- N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)-4-(4-(2,2,2-trifluoroethoxy) -2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-N-((S)-1-(benzo[d]oxazole-2- ))-1-oxobutan-2-yl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2 -Chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chloro-2-fluorophenyl)cyclopropanecarbonyl)-4-(2-chloro Phenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di- oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S, 4R)-1-(1-(4-bromo-2-fluorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropyl) Amino)-1,2-di-oxypenten-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-bromophenyl)cyclopropanecarbonyl)- 4-(2-Chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidin-2-yl Indoleamine; (2S,4R)-1-(1-(4-bromophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclo) Propylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-4-(2-chlorophenylsulfonyl)-N- ((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)-1-(1-(4-iodophenyl)cyclopropanecarbonyl)pyrrolidine-2 -carbamamine; (2S,4R)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxyl -3-yl)-1-(1-(4-iodophenyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5-chloro-3-fluoro) Pyridin-2-yl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropyl) Amino)-1,2-di-oxypentan-3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R) 1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxyl Hex-3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl) Cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)-4-(2-(trifluoromethyl)benzene (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropyl) Amino)-1,2-dihydroxyhex-3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R) 1-(1-(5-bromo-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropane) (amino)phenyl-1,2-di-oxypenten-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5-chloro-3-fluoropyridine-2 -yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di- oxyhex-3- Pyrrolidine-2-carbamide; (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonate Indenyl)-N-((S)-1-(cyclopropylamino)-1,2- (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonate Indenyl)-N-(4-(cyclopropylamino)-2-methyl-3,4-dioxabutan-2-yl)pyrrolidine-2-carboxamide; (2S,4R) 1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-(2-(cyclopropylamino)-2- side Ethyloxy)cyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenyl) Sulfhydryl)-N-((S)-1-(cyclopropylamino)-4-methyl-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamine) (5-methyl-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl) ring Propane carbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-cyclohexyl-4-(cyclopropylamino)-3,4-di-oxybutyl-2 -yl)pyrrolidine-2-carboxamide; (2S,4R)-N-((S)-1-(butylamino)-1,2-di-oxypent-3-yl)-1 -(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-N-((S)- 1-(butylamino)-1,2-dioxy 3-yl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)- N-((S)-1-(benzylamino)-1,2-di-oxypentan-3-yl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4- (2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenyl) Sulfhydryl)-N-((S)-4-(cyclopropylamino)-3,4-dioxabutan-2-yl)pyrrolidine-2-carboxamide; (2S,4R) -N-((S)-1-(benzylamino)-1,2-dihydroxyhex-3-yl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4 -(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorobenzene -Sulphonyl)-N-((3S)-1,2-di-oxy-1-(pentan-2-ylamino)pentan-3-yl)pyrrolidine-2-carboxamide; (2S , 4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((3S)-1,2-di-oxyl- 1-(pent-2-ylamino)hex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N -((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)-4-(2,4-dichlorophenylsulfonyl)pyrrolidine-2 -carbamamine; (2S,4R)-4-(2-chloro-4-fluorophenylsulfonate )-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypent-3-yl) Pyrrrolidine-2-carbamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S -1,2-di-oxy-1-(2,2,2-trifluoroethylamino)hex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-( 1-(4-Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(isopropylamino)-1,2-di-side Oxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-( Cyclopropylamino)-1,2-dihydrohexyl-3-yl)-4-(2,4-dichlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S, 4R )-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(ethylamino)-1,2 -2-sided oxypent-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorobenzene -Sulphonyl)-N-((S)-1-(ethylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)- 4-(2-Chloro-4-((S)-1,1,1-trifluoropropan-2-yloxy)phenylsulfonyl)-1-(1-(4-chlorophenyl) ring Propane carbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypent-3-yl)pyridinium (2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoropropan-2-yloxy)phenylsulfonyl )-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxyhex-3-yl) Pyrrrolidine-2-carbamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S )-1-(cyclopropyl(methyl)amino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-4-(2- Chloro-4-fluorophenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2- Bis-oxo-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenyl) Sulfhydryl)-N-((S)-1,2-di-oxy-1-(phenylethylamino)pentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)- 1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(2-(naphthalen-1-yl)ethyl Amino)-1,2-di-oxypenten-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)- 4-(2-Chlorophenylsulfonyl)-N-((S)-1-(2-(naphthalen-2-yl)ethylamino)-1,2-di-oxypentan-3-yl Pyrrolidine-2-carbamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2- Chlorophenylsulfonyl)-N-((S)-1-(naphthalen-1-ylmethylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamidine Amine; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1,2-di Sideoxy-1-(tetrahydro-2H-pyran-4-ylamino)pent-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4- Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(2-methoxyethylamino)-1,2-di-oxyl Pent-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl) -N-((S)-1-(isobutylamino)-1,2-di-oxypenten-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-4-( 2-Chloro-4-morpholinylphenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)- 1,2-di- oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-4-(2-chloro-4-morpholinylphenylsulfonyl)-1- (1-(4-Chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2 -carbamamine; (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N- ((S)-1-(cyclopropylamino)-4-methyl-1,2-dioxy (2,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2 -chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-5-methyl-1,2-dihydroxyhex-3-yl)pyrrolidine-2- Methionine; (2S,4R)-N-((S)-1-(butylamino)-1,2-di-oxypentan-3-yl)-1-(1-(5-chloro) 3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-N-((S)-1 -(butylamino)-1,2-dihydroxyhex-3-yl)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-( 2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; and (2S,4R)-N-((S)-1-(benzylamino)-1,2-di-oxyl 3-yl)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide a compound of the formula (I) selected from the group consisting of (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-( (S)-1-(cyclopropylamino)-1,2-di-oxypenten-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4 -Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxyl- 3-yl)pyrrolidine-2-carboxamide; (2S,4R)- 1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chloro-4-(2,2,2-trifluoroethoxy)phenylsulfonate -N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1 -(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypent-3-yl)-4- (4-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-N-(( S)-1-(Benzo[d]oxazol-2-yl)-1-oxobutan-2-yl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4- (2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chloro-2-fluorophenyl)cyclopropanecarbonyl)-4-(2 -chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide; 2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2- Bis-oxomethoxy-3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5) -Chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)-4 -(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1- (1-(4-Chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypent-3-yl)-4-( 2-(Trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-(( S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2- Methionine; (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-( (S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5 -Chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2 -2-sided oxypent-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorobenzene Sulfosyl)-N-((S)-1-(cyclopropylamino)-4-methyl-1,2-di- oxypentan-3-yl)pyrrolidine-2-carboxamide (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropyl) Amino)-5-methyl-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-N-((S)-1-(butyl Amino)-1,2-di-oxypentan-3-yl)-1-(1-(4-chlorobenzene) Cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)- 4-(2-Chlorophenylsulfonyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxabutan-2-yl)pyrrolidin-2-yl Indoleamine; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-dihydroxyloxy (pentyl-3-yl)-4-(2,4-dichlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl) Cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(isopropylamino)-1,2-dihydroxyhex-3-yl)pyrrole (2-S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S) 1-(ethylamino)-1,2-di-oxypenten-3-yl)pyrrolidine-2-carboxamide; and (2S,4R)-1-(1-(4-chlorophenyl) Cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(ethylamino)-1,2-di-oxyhex-3-yl)pyrrolidine 2-carbamamine.

本發明化合物可藉由(例如)下文所述一般合成程序製備。 The compounds of the invention can be prepared, for example, by the general synthetic procedures described below.

在以下方案及說明中，除非另有說明，否則R1至R7及A具有如上文所定義R1至R7及A之含義。 In the following schemes and descriptions, R 1 to R 7 and A have the meanings of R 1 to R 7 and A as defined above unless otherwise stated.

縮寫：BOP：六氟磷酸苯并***基-N-氧基-叁(二甲基胺基)-鏻；BOP-Cl：雙-(2-側氧基-3-噁唑啶基)-次膦醯氯；CDI：1,1'-羰基二咪唑；DCC：N,N'-二環己基碳化二亞胺；DIPEA：二異丙基乙胺；DMA：N,N-二甲基乙醯胺；DMF：N,N-二甲基甲醯胺；EDCI：N-(3-二甲基胺基丙基)-N'-乙基-碳化二醯亞胺鹽酸鹽；HATU：六氟磷酸O-(7-氮雜苯并***-1-基)-1,1,3,3-四甲基 脲鎓鹽；HOBT：1-羥基苯并***；LiHMDS：雙(三甲基甲矽烷基)醯胺鋰；MCPBA：3-氯過苯甲酸；NMP=N-甲基吡咯啶酮；PyBOP：六氟磷酸苯并***-1-基-氧基三吡咯啶鏻；TEA：三乙胺；TBTU：四氟硼酸O-(苯并***-1-基)-N,N,N',N'-四甲基脲鎓鹽；THF：四氫呋喃；藉由(例如)在諸如三乙胺等鹼存在下與磺醯基氯反應將以正交方式保護之順-4-羥基-脯胺酸衍生物A(例如(2S,4S)-4-羥基-吡咯啶-1,2-二甲酸1-第三丁基酯2-甲基酯)之羥基官能基轉化成適當離去基團，以產生化合物B(方案1)。在適當鹼(例如NaH、LiHMDS、DIPEA、TEA等)存在下使B與硫代苯酚反應，以產生C型化合物。所得硫醚之氧化係藉由適當氧化劑(例如H2O2、過硫酸氫鉀製劑(Oxone)、MCPBA等)來達成，以產生碸D。在適當條件(端視保護基團PG之性質而定)下去保護獲得E。可藉由眾多種條件將E轉化成F，該等條件端視取代基R1-A-之性質而定且應為熟習此項技術者已知。例如，若R1-A-係芳基烷基羰基取代基，則可藉由E與適當羧酸反應達成轉化，該反應係藉由各種偶合劑(例如BOP-Cl、TBTU、BOP、PyBop、HATU、EDCI/HOBT、DIC/HOBT、DCC/HOBT) 中之一者活化。用鹼(例如LiOH、NaOH、KOH或K2CO3、Na2CO3、Cs2CO3)皂化，產生化合物G。G與「彈頭前體」O或Y係之醯胺偶合係藉由各種偶合劑(例如BOP-Cl、TBTU、BOP、PyBop、HATU、EDCI/HOBT、DIC/HOBT、DCC/HOBT等)中之一者達成，以獲得H。由諸如戴斯-馬丁過碘烷(Dess-Martin Periodinane)等氧化劑將H氧化，獲得最終產物I。熟習此項技術者應瞭解，可在反應順序之不同階段轉化基團R5、R6及R7。例如，可藉由在諸如Cs2CO3等鹼存在下與適當醇反應將鹵素轉化成烷氧基取代基。 Abbreviations: BOP: benzotriazolyl-hexafluoro-phosphonium (dimethylamino)-hydrazine; BOP-Cl: bis-(2-o-oxy-3-oxazolidinyl)- Phosphine chlorochloride; CDI: 1,1'-carbonyldiimidazole; DCC: N,N'-dicyclohexylcarbodiimide; DIPEA: diisopropylethylamine; DMA: N,N-dimethyl Guanidine; DMF: N,N-dimethylformamide; EDCI: N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride; HATU: six O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium salt of fluorophosphate; HOBT: 1-hydroxybenzotriazole; LiHMDS: double (triple Lithium decyl lithium amide lithium; MCPBA: 3-chloroperbenzoic acid; NMP = N-methylpyrrolidone; PyBOP: benzotriazol-1-yl-oxytripyrrolidinium hexafluorophosphate; TEA : triethylamine; TBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium salt of tetrafluoroborate; THF: tetrahydrofuran; by (for example) The cis-4-hydroxy-proline derivative A (for example, (2S, 4S)-4-hydroxy-pyrrolidine-1) which is protected in an orthogonal manner by reaction with sulfonyl chloride in the presence of a base such as triethylamine. Hydroxy functional group of 2-tert-butyl 2-dicarboxylate 2-methyl ester) is converted into appropriate departure a group to give compound B (Scheme 1). B is reacted with a thiophenol in the presence of a suitable base (e.g., NaH, LiHMDS, DIPEA, TEA, etc.) to yield a Form C compound. The resulting thioether-based oxide by a suitable oxidizing agent (e.g. H 2 O 2, potassium hydrogen persulfate formulations (Oxone), MCPBA, etc.) to achieve, to produce a sulfone D. The protection is obtained under appropriate conditions (depending on the nature of the protecting group PG). E can be converted to F by a wide variety of conditions, depending on the nature of the substituent R 1 -A- and should be known to those skilled in the art. For example, if the R 1 -A- arylalkylcarbonyl substituent is substituted by E with a suitable carboxylic acid by various coupling agents (eg, BOP-Cl, TBTU, BOP, PyBop, One of HATU, EDCI/HOBT, DIC/HOBT, DCC/HOBT) is activated. Saponification with a base such as LiOH, NaOH, KOH or K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 gives compound G. The coupling of G with the "warhead precursor" O or Y system is carried out by various coupling agents (such as BOP-Cl, TBTU, BOP, PyBop, HATU, EDCI/HOBT, DIC/HOBT, DCC/HOBT, etc.). One is achieved to obtain H. H is oxidized by an oxidizing agent such as Dess-Martin Periodinane to obtain the final product I. Those skilled in the art will appreciate that the groups R 5 , R 6 and R 7 can be converted at different stages of the reaction sequence. For example, a halogen can be converted to an alkoxy substituent by reaction with a suitable alcohol in the presence of a base such as Cs 2 CO 3 .

「彈頭前體」O可藉由多種條件製備，該等條件可例示為下文一般合成程序，在本文中命名為「Boc-Passerini-途徑」(方案2)及「Bn-醯胺-偶合途徑」(方案3)。熟習此項技術者應瞭解，化合物O亦可藉由該等程序之變化形式、特定而言藉由涉及替代保護基團之程序製備。 The "warhead precursor" O can be prepared by a variety of conditions, which can be exemplified by the following general synthetic procedures, which are designated herein as "Boc-Passerini-pathway" (Scheme 2) and "Bn-guanamine-coupling pathway". (Scheme 3). Those skilled in the art will appreciate that Compound O can also be prepared by variations of such procedures, particularly by procedures involving substitution of protecting groups.

藉由(例如)在鹼存在下與二碳酸二第三丁基酯反應將2-胺基烷醇J轉化成對應胺基甲酸第三丁基酯。在適宜條件(例如斯文氏條件(Swern's condition))下氧化獲得醛L。在稱作Passerini反應之轉化中與異氰化物及乙酸反應，獲得化合物M。由諸如NaOH等鹼皂化獲得化合物，N最終藉由在酸性條件(例如，三氟乙酸)下Boc-去保護轉化成「彈頭前體」O1。 The 2-aminoalkanol J is converted to the corresponding tert-butyl carbamate by, for example, reacting with a di-tert-butyl dicarbonate in the presence of a base. Oxidation of the aldehyde L is obtained under suitable conditions (e.g., Swern's condition). Reaction with isocyanide and acetic acid in a conversion called the Passerini reaction gives compound M. The compound is obtained by saponification with an alkali such as NaOH, and N is finally converted into a "warhead precursor" O1 by Boc-deprotection under acidic conditions (for example, trifluoroacetic acid).

或者，可如方案3(「Bn-醯胺-偶合途徑」)中所概述製備「彈頭前體」O。 Alternatively, the "warhead precursor" O can be prepared as outlined in Scheme 3 ("Bn-Amidoxime-Coupling Pathway").

在鹼存在下使胺基酸P與過量苄基鹵反應，獲得化合物Q，Q可由鹼(例如LiOH、NaOH、KOH或K2CO3、Na2CO3、Cs2CO3)皂化成化合物R。然後將R之羧酸官能基還原成如化合物T中之醛。此可藉由若干方式達成，例如，藉由將R轉化成「Weinreb醯胺」S且隨後與諸如LiAlH4等適宜還原劑反應，以獲得T。與亞硫酸氫鹽(例如亞硫酸氫鈉)及氰化物鹽(例如氰化鉀)反應，產生2-羥基腈U。化合物U可在酸性條件下皂化成羧酸V。然後使用各種偶合劑(例如BOP-Cl、TBTU、BOP、PyBop、HATU、EDCI/HOBT、DIC/HOBT、DCC/HOBT等)中之一者使酸V與一級或二級胺偶合，獲得醯胺W。在最終步驟中，藉由在適當條件下氫解(例如藉由在升高壓力下在諸如皮爾曼氏觸媒(Pearlman's catalyst)等觸媒存在下與氫反應)將化合物去保護，獲得「彈頭前體」O2。 The amino acid P is reacted with an excess of a benzyl halide in the presence of a base to obtain a compound Q, which can be saponified into a compound R by a base such as LiOH, NaOH, KOH or K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 . . The carboxylic acid functional group of R is then reduced to an aldehyde such as in compound T. This can be achieved in several ways, for example, by converting R to "Weinreb decylamine" S and then reacting with a suitable reducing agent such as LiAlH 4 to obtain T. Reaction with bisulfite (such as sodium bisulfite) and a cyanide salt (such as potassium cyanide) produces 2-hydroxynitrile U. Compound U can be saponified to the carboxylic acid V under acidic conditions. Then, using one of various coupling agents (for example, BOP-Cl, TBTU, BOP, PyBop, HATU, EDCI/HOBT, DIC/HOBT, DCC/HOBT, etc.), the acid V is coupled with a primary or secondary amine to obtain a guanamine. W. In the final step, the compound is deprotected by hydrogenolysis under suitable conditions (for example, by reacting with hydrogen under elevated pressure in the presence of a catalyst such as Pearlman's catalyst) to obtain a "warhead". Precursor" O2.

可如方案4中所概述製備含苯并噁唑「彈頭前體」。使適宜N-保護之胺基-醛M與苯并噁唑之負碳離子等效物反應，該負碳離子等效物進而可藉由苯并噁唑與金屬化劑(例如異丙基氯化鎂)反應來製備。然後在適當條件將所得N-保護之胺基醇X去保護，獲得「彈頭前體」O3。 The benzoxazole-containing "warhead precursor" can be prepared as outlined in Scheme 4. The N-protected amine-aldehyde M is reacted with a carbanion equivalent of benzoxazole, which in turn can be supported by a benzoxazole and a metallizing agent (eg, isopropylmagnesium chloride) The reaction is prepared. The resulting N-protected amino alcohol X is then deprotected under appropriate conditions to obtain a "warhead precursor" O3.

本發明亦係關於製備如上文所定義式(I)化合物之方法， 其包含使式(II)化合物 在氧化劑存在下反應，其中A及R1至R7係如上文所述定義。 The invention also relates to a process for the preparation of a compound of formula (I) as defined above, which comprises a compound of formula (II) The reaction is carried out in the presence of an oxidizing agent wherein A and R 1 to R 7 are as defined above.

適宜氧化劑為彼等熟習此項技術者已知。特定而言，可在戴斯-馬丁過碘烷、CrO3、PDC(重鉻酸吡啶鎓鹽)、O2/V2O5、NaIO4、NaOCl/2,2,6,6-四甲基六氫吡啶-1-氧基或IBX(2-二氧碘基苯甲酸)下實施本發明方法。 Suitable oxidizing agents are known to those skilled in the art. In particular, it can be used in Dess-Martin periodine, CrO 3 , PDC (pyridinium dichromate), O 2 /V 2 O 5 , NaIO 4 , NaOCl/ 2 , 2,6,6-tetra The process of the invention is carried out under hexahydropyridin-1-oxyl or IBX (2-dioxyiodobenzoic acid).

可在-20℃至150℃之溫度下實施上述方法。 The above method can be carried out at a temperature of from -20 ° C to 150 ° C.

用於本發明方法之適宜溶劑係二氯甲烷、吡啶、甲苯、DMSO、丙酮、水或乙酸。 Suitable solvents for use in the process of the invention are dichloromethane, pyridine, toluene, DMSO, acetone, water or acetic acid.

式(I)化合物當根據上述方法製造時，亦為本發明目標。 The compounds of formula (I) are also the object of the invention when produced according to the above process.

式(I)化合物及其醫藥上可接受之鹽可用作藥劑(例如，呈醫藥製劑形式)。該等醫藥製劑可以(例如)經口(例如，以錠劑、包衣錠劑、糖衣藥丸、硬明膠及軟明膠膠囊、溶液、乳液或懸浮液形式)、經鼻(例如，以鼻腔噴霧劑形式)或經直腸(例如，以栓劑形式)方式投與體內。然而，亦可採用非經腸方式投藥，例如，經肌內或經靜脈內(例如，以注射溶液形式)。 The compound of the formula (I) and a pharmaceutically acceptable salt thereof can be used as a medicament (for example, in the form of a pharmaceutical preparation). Such pharmaceutical preparations can be, for example, orally (for example, in the form of lozenges, coated lozenges, dragees, hard gelatin and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example, nasal sprays) Formally) or administered to the body via the rectum (eg, in the form of a suppository). However, it can also be administered parenterally, for example, intramuscularly or intravenously (for example, in the form of an injection solution).

式(I)化合物及其醫藥上可接受之鹽可與用於生產錠劑、包衣錠劑、糖衣藥丸及硬明膠膠囊之醫藥惰性無機或有機佐劑一起處理。乳糖、玉米澱粉或其衍生物、滑石粉、硬脂酸或其鹽等皆可用作(例如)錠劑、糖衣藥丸及硬明膠膠囊之佐劑。 The compounds of formula (I) and their pharmaceutically acceptable salts can be treated with pharmaceutically inert inorganic or organic adjuvants for the manufacture of lozenges, coated lozenges, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used, for example, as adjuvants for lozenges, dragees and hard gelatin capsules.

軟明膠膠囊之適宜佐劑係(例如)植物油、蠟、脂肪、半固體物質及液體多元醇等。 Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid materials, liquid polyols and the like.

用於製備溶液及糖漿之適宜佐劑係(例如)水、多元醇、蔗糖、轉化糖、葡萄糖等。 Suitable adjuvants for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

用於注射溶液之適宜佐劑係(例如)水、醇、多元醇、甘油、植物油等。 Suitable adjuvants for injectable solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

用於栓劑之適宜佐劑係(例如)天然油或硬化油、蠟、脂肪、半固體及液體多元醇等。 Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid and liquid polyols and the like.

此外，醫藥製劑可含有防腐劑、增溶劑、增黏物質、穩定劑、潤濕劑、乳化劑、甜味劑、著色劑、矯味劑、用於改變滲透壓之鹽、緩衝劑、遮蔽劑或抗氧化劑。其仍可含有其他有治療價值之物質。 In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying the osmotic pressure, buffers, masking agents or Antioxidants. It may still contain other therapeutically valuable substances.

因此，特定而言，本發明亦係關於以下：用作治療活性物質之式(I)化合物；包含式(I)化合物及治療惰性載劑之醫藥組合物；式(I)化合物用於製備藥劑之用途，該等藥劑用以治療或預防糖尿病、動脈粥樣硬化、腹部主動脈瘤、周邊動脈疾病、癌症，減少慢性腎病、糖尿病腎病變、糖尿病視網膜病變或年齡相關性黃斑變性中之心血管事件； 用於以下目的之式(I)化合物：治療或預防糖尿病、動脈粥樣硬化、腹部主動脈瘤、周邊動脈疾病、癌症，減少慢性腎病、糖尿病腎病變、糖尿病視網膜病變或年齡相關性黃斑變性中之心血管事件；及用於以下目的之方法，治療或預防糖尿病、動脈粥樣硬化、腹部主動脈瘤、周邊動脈疾病、癌症，減少慢性腎病、糖尿病腎病變、糖尿病視網膜病變或年齡相關性黃斑變性中之心血管事件，該方法包含投與有效量之式(I)化合物。 Thus, in particular, the invention also relates to the following: a compound of formula (I) for use as a therapeutically active substance; a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier; a compound of formula (I) for use in the preparation of a medicament For the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular disease in chronic kidney disease, diabetic nephropathy, diabetic retinopathy or age-related macular degeneration event; A compound of formula (I) for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of chronic kidney disease, diabetic nephropathy, diabetic retinopathy or age-related macular degeneration Cardiovascular events; and methods for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of chronic kidney disease, diabetic nephropathy, diabetic retinopathy or age-related macular In a cardiovascular event in degeneration, the method comprises administering an effective amount of a compound of formula (I).

現在將藉由以下實例來闡釋本發明，該等實例不具有限制性特性。 The invention will now be illustrated by the following examples which are not limiting.

實例Instance 縮寫abbreviation

DIPEA：二異丙基乙胺；DMF：N,N-二甲基甲醯胺；EDC：N-(3-二甲基胺基丙基)-N'-乙基-碳化二醯亞胺鹽酸鹽；Eq：當量HATU：六氟磷酸O-(7-氮雜苯并***-1-基)-1,1,3,3-四甲基脲鎓鹽；HOBt：1-羥基苯并***；LiHMDS：雙(三甲基甲矽烷基)醯胺鋰；MCPBA：3-氯過苯甲酸；Satd.：飽和 RT：室溫；TBTU：四氟硼酸O-(苯并***-1-基)-N,N,N',N'-四甲基脲鎓鹽；THF：四氫呋喃；TFA：三氟乙酸 DIPEA: diisopropylethylamine; DMF: N,N-dimethylformamide; EDC: N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide salt Acid salt; Eq: equivalent HATU: O-(7-azabenzotriazol-1-yl)hexafluorophosphate-1,1,3,3-tetramethyluronium salt; HOBt: 1-hydroxybenzoate Triazole; LiHMDS: lithium bis(trimethylformamido) guanamine; MCPBA: 3-chloroperbenzoic acid; Satd.: saturated RT: room temperature; TBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium salt of tetrafluoroborate; THF: tetrahydrofuran; TFA: trifluoroacetic acid

中間體之合成Synthesis of intermediates 代表性程序A(「Boc-Passerini-途徑」)：中間體(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸之合成：Representative procedure A ("Boc-Passerini-pathway"): Synthesis of intermediate (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride: 步驟A1：(S)-1-羥基丁-2-基胺基甲酸第三丁基酯 Step A1: (S)-1-Hydroxybutan-2-ylcarbamic acid tert-butyl ester

在氬氛圍中，將(S)-2-胺基丁-1-醇(5.12 g,56.3 mmol,Eq：1.00)與水(20 ml)及二噁烷(20 ml)合併，獲得無色溶液。在0℃下，添加NaOH(2.7 g,67.5 mmol,Eq：1.2)及二碳酸二第三丁基酯(14.7 g,67.5 mmol,Eq：1.2)，且在RT下將反應物攪拌2 h。將反應混合物傾倒至50 ml H2O中並用EtOAc(2×75 ml)萃取，經Na2SO4乾燥有機層且在真空中濃縮。獲得無色液體狀標題化合物(11.62 g，定量，MS(m/e)=190.3[M+H+])。 (S)-2-Aminobutan-1-ol (5.12 g, 56.3 mmol, Eq: 1.00) was combined with water (20 ml) and dioxane (20 ml) to give a colorless solution. NaOH (2.7 g, 67.5 mmol, Eq: 1.2) and di-tert-butyl dicarbonate (14.7 g, 67.5 mmol, Eq: 1.2) were added at 0 ° C and the mixture was stirred at RT for 2 h. The reaction mixture was poured into 50 ml H 2 O and (2 × 75 ml) extracted with EtOAc, and concentrated in vacuo The organic layer was dried over Na 2 SO 4. The title compound was obtained as a colorless liquid (11.62 g, quantitative, MS (m/e) = 190.3 [M+H + ]).

步驟A2：(S)-1-側氧基丁-2-基胺基甲酸第三丁基酯 Step A2: (S)-1-tert-oxybut-2-ylaminocarbamic acid tert-butyl ester

在氬氛圍中，將草醯氯(7.01 g,4.75 ml,55.3 mmol,Eq：1.00)與CH2Cl2(100 ml)合併，獲得無色溶液。將反應物冷卻至-60℃。然後在-60℃下逐滴添加在CH2Cl2(20 ml)中稀釋之二甲亞碸(10.8 g,9.8 ml,138 mmol,Eq：2.5)。在-60℃下將反應物攪拌10 min。然後在-70℃下逐滴添加溶於20ml CH2Cl2中之(S)-1-羥基丁-2-基胺基甲酸第三丁基酯(11.62 g,55.3 mmol,Eq：1.00)。將反應物升溫至-40℃並保持10 min且隨後再次冷卻至-70℃。逐滴添加三乙胺(15.7 g,21.6 ml,155 mmol,Eq：2.8)存於20 ml CH2Cl2中之溶液。經2小時將反應混合物升溫至室溫。將反應混合物傾倒至100 ml飽和磷酸二氫鈉溶液中並用乙酸乙酯(2×150 mL)萃取。用鹽水(1×50 mL)反萃取有機層。經Na2SO4乾燥有機層，並在真空中濃縮。獲得淡黃色油狀標題化合物(11.12 g，定量，MS(m/e)=188.2[M+H+])。 The grass chloroform (7.01 g, 4.75 ml, 55.3 mmol, Eq: 1.00) was combined with CH 2 Cl 2 (100 ml) to give a colorless solution. The reaction was cooled to -60 °C. Dimethyl hydrazine (10.8 g, 9.8 ml, 138 mmol, Eq: 2.5) diluted in CH 2 Cl 2 (20 ml) was then added dropwise at -60 °C. The reaction was stirred at -60 °C for 10 min. Then, (S)-1-hydroxybutan-2-ylcarbamic acid tert-butyl ester (11.62 g, 55.3 mmol, Eq: 1.00) dissolved in 20 ml of CH 2 Cl 2 was added dropwise at -70 °C. The reaction was warmed to -40 °C for 10 min and then cooled again to -70 °C. Was added dropwise triethylamine (15.7 g, 21.6 ml, 155 mmol, Eq: 2.8) kept in CH 2 Cl 2 in a solution of 20 ml. The reaction mixture was warmed to room temperature over 2 hours. The reaction mixture was poured into 100 mL of saturated aqueous sodium hydrogen sulfate and extracted with ethyl acetate (2×150 mL). The organic layer was back extracted with brine (1 x 50 mL). The organic layer was dried over Na 2 SO 4, and concentrated in vacuo. The title compound was obtained as a pale yellow oil (11.12 g, quantitative, MS (m/e) = 188.2 [M+H + ]).

步驟A3：(2S,3S)-乙酸-3-(第三丁氧基羰基胺基)-1-(環丙基胺基)-1-側氧基戊-2-基酯 Step A3: (2S, 3S)-acetic acid-3-(t-butoxycarbonylamino)-1-(cyclopropylamino)-1-oxoxypentan-2-yl ester

在氬氛圍中，將(S)-1-側氧基丁-2-基胺基甲酸第三丁基酯(650 mg,3.47 mmol,Eq：1.00)、異氰基環丙烷(256 mg,3.82 mmol,Eq：1.1)及乙酸(417 mg,397 μl,6.94 mmol,Eq：2)與CH2Cl2(24.0 ml)合併，獲得淡黃色溶液。在RT下將反應物攪拌過夜。在減壓下去除溶劑。藉由急驟層析(矽膠，20 g，20%至60%存於庚烷中之EtOAc)純化殘餘物。獲得褐色油狀標題化合物(1.09 g，定量，MS(m/e)=315.4[M+H+])。 (S)-1-Phenyloxybutan-2-ylcarbamic acid tert-butyl ester (650 mg, 3.47 mmol, Eq: 1.00), isocyanocyclopropane (256 mg, 3.82) in an argon atmosphere Methyl acetate (Eq: 1.1) and acetic acid (417 mg, 397 μl, 6.94 mmol, Eq: 2) were combined with CH 2 Cl 2 (24.0 ml) to give a pale yellow solution. The reaction was stirred at RT overnight. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (EtOAc:EtOAcEtOAcEtOAc The title compound was obtained as a brown oil (1. <RTI ID=0.0></RTI></RTI><RTIgt;

步驟A4：(2S,3S)-1-(環丙基胺基)-2-羥基-1-側氧基戊-3-基胺基甲酸第三丁基酯 Step A4: (2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxomethoxypent-3-ylaminocarbamic acid tert-butyl ester

在氬氛圍中，將存於H2O(5.2 ml,5.2 mmol,Eq：1.5)中之(2S,3S)-乙酸-3-(第三丁氧基羰基胺基)-1-(環丙基胺基)-1-側氧基戊-2-基酯(1.09 g,3.47 mmol,Eq：1.00)及NaOH 1N與甲醇(10 ml)合併，獲得無色溶液。在RT下將反應物 攪拌2 h。將反應混合物傾倒至25 mL H2O中並用乙酸乙酯(2×50 mL)萃取。經Na2SO4乾燥有機層，並在真空中濃縮。獲得淡褐色固體狀標題化合物(540 mg,57.2%,MS(m/e)=273.4[M+H+])。 (2S,3S)-acetic acid-3-(t-butoxycarbonylamino)-1-(cyclopropane) in H 2 O (5.2 ml, 5.2 mmol, Eq: 1.5) in an argon atmosphere The aminoamino)-1-oxopentyl-2-yl ester (1.09 g, 3.47 mmol, Eq: 1.00) and NaOH 1N were combined with methanol (10 ml) to give a colourless solution. The reaction was stirred at RT for 2 h. The reaction mixture was poured into 25 mL H 2 O and extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over Na 2 SO 4, and concentrated in vacuo. The title compound (540 mg, 57.2%, MS (m/e) = 273.4 [M+H + ])

步驟A5：(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽 Step A5: (2S,3S)-3-Amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride

在氬氛圍中，合併(2S,3S)-1-(環丙基胺基)-2-羥基-1-側氧基戊-3-基胺基甲酸第三丁基酯(540 mg,1.98 mmol)與存於二噁烷(10.4 ml)中之4 N HCl，獲得淡褐色溶液。在RT下將反應物攪拌4 h。蒸發溶劑。在真空中去除殘餘溶劑。獲得褐色固體狀標題化合物(480 mg，定量，MS(m/e)=173.2[M+H+])。 Combined (2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxomethoxypent-3-ylcarbamic acid tert-butyl ester (540 mg, 1.98 mmol) in argon And 4 N HCl in dioxane (10.4 ml) afforded a pale brown solution. The reaction was stirred at RT for 4 h. Evaporate the solvent. The residual solvent was removed in vacuo. The title compound was obtained as a brown solid (480 mg, quantitative, MS (m / e) = 173.2 [M + H +]).

代表性程序B(「Bn-醯胺-偶合途徑」)：中間體(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺之合成Representative procedure B ("Bn-guanamine-coupling pathway"): Synthesis of intermediate (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine 步驟B1：(S)-2-(二苄基胺基)丁酸苄基酯 Step B1: (S)-2-(dibenzylamino)butyric acid benzyl ester

在氬氛圍中，在0℃下將氫氧化鈉(15.5 g,388 mmol,Eq：2)及碳酸鉀(53.6 g,388 mmol,Eq：2)與水(300 ml)合併，獲得無色溶液。在0與5℃之間緩慢添加(S)-2-胺基丁酸(20 g,194 mmol,Eq：1.00)。然後將懸浮液加熱至90℃。然後逐滴添加苄基溴(133 g,92.1 ml,776 mmol,Eq：4)。在90℃下將反應物攪拌過夜。將反應混合物傾倒至水(300 ml)中並用乙酸乙酯萃取。經Na2SO4乾燥有機層並在真空中濃縮。獲得淡黃色液體標題化合物(84 g,98.6%,MS(m/e)=374.3[M+H+])。 Sodium hydroxide (15.5 g, 388 mmol, Eq: 2) and potassium carbonate (53.6 g, 388 mmol, Eq: 2) were combined with water (300 ml) at 0 ° C to give a colorless solution. (S)-2-Aminobutyric acid (20 g, 194 mmol, Eq: 1.00) was slowly added between 0 and 5 °C. The suspension was then heated to 90 °C. Then benzyl bromide (133 g, 92.1 ml, 776 mmol, Eq: 4) was added dropwise. The reaction was stirred at 90 °C overnight. The reaction mixture was poured into water (300 ml) and evaporated. The organic layer was concentrated, and Na 2 SO 4 dried in vacuo. The title compound (84 g, 98.6%, MS (m/e) = 374.3 [M+H + ]).

步驟B2：(S)-2-(二苄基胺基)丁酸 Step B2: (S)-2-(dibenzylamino)butyric acid

在氬氛圍中，將(S)-2-(二苄基胺基)丁酸苄基酯(84 g,191 mmol,Eq：1.00)與甲醇(136 ml)合併，獲得淡黃色溶液。然後立即將冷(0℃)NaOH溶液(15.3 g，存於150 ml水中，382 mmol,Eq：2)添加至反應混合物。在90℃下將反應物攪拌4 h。在冷卻至RT後，將反應混合物傾倒至水(75 ml)中並用第三丁基甲基醚：庚烷=1：1(2×150 ml)萃取，去除水解中形成之苄基醇。用HCl(濃)將鹼性水層酸化至pH 2。然後用乙酸乙酯(2×150 ml)萃取水層。經Na2SO4乾燥有機層，過濾並在減壓下濃縮。在真空中去除殘餘溶劑。獲得白色固體狀標題化合物(68.13 g，定量，MS(m/e)=284.1[M+H+]，MS(m/e)=282.3[M-H+])。 (S)-2-(Dibenzylamino)butyric acid benzyl ester (84 g, 191 mmol, Eq: 1.00) was combined with methanol (136 ml) to give a pale yellow solution. A cold (0 ° C) NaOH solution (15.3 g, stored in 150 ml water, 382 mmol, Eq: 2) was then immediately added to the reaction mixture. The reaction was stirred at 90 °C for 4 h. After cooling to RT, the reaction mixture was poured into water (75 ml) and extracted with th. butyl methyl ether: heptane = 1:1 (2 x 150 ml) to remove the benzyl alcohol formed in the hydrolysis. The basic aqueous layer was acidified to pH 2 with HCl (concentrated). The aqueous layer was then extracted with ethyl acetate (2×150 mL). The organic layer was dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residual solvent was removed in vacuo. The title compound is obtained as a white solid (68.13 g, quantitative, MS (m / e) = 284.1 [M + H +], MS (m / e) = 282.3 [MH +]).

步驟B3：(S)-2-(二苄基胺基)-N-甲氧基-N-甲基丁醯胺 Step B3: (S)-2-(dibenzylamino)-N-methoxy-N-methylbutyramine

在氬氛圍中，將(S)-2-(二苄基胺基)丁酸(27 g,80.0 mmol,Eq：1.00)與二氯甲烷(250 ml)合併，獲得白色懸浮液。在0℃下，添加TBTU(36.0 g,112 mmol,Eq：1.4)。在0℃下將反應物攪拌2 h。然後添加N-甲基嗎啉(24.3 g,26.4 ml,240 mmol,Eq：3)及N,O-二甲基羥基胺鹽酸鹽(19.5 g,200 mmol,Eq：2.5)。在RT下將反應物攪拌過夜。用水(2×75 ml)及鹽水(50 ml)萃取反應混合物。經Na2SO4乾燥有機層且在真空中濃縮。在真空中去除殘餘溶劑。獲得淡黃色油狀標題化合物(35.5 g,95.1%,MS(m/e)=327.3[M+H+])。 (S)-2-(Dibenzylamino)butanoic acid (27 g, 80.0 mmol, Eq: 1.00) was combined with dichloromethane (250 ml) to give a white suspension. TBTU (36.0 g, 112 mmol, Eq: 1.4) was added at 0 °C. The reaction was stirred at 0 °C for 2 h. N-methylmorpholine (24.3 g, 26.4 ml, 240 mmol, Eq: 3) and N,O-dimethylhydroxylamine hydrochloride (19.5 g, 200 mmol, Eq: 2.5) were then added. The reaction was stirred at RT overnight. The reaction mixture was extracted with water (2×75 ml) and brine (50 ml). The organic layer was concentrated, and Na 2 SO 4 dried in vacuo. The residual solvent was removed in vacuo. The title compound was obtained as a pale yellow oil (35.5 g, 95.1%, MS (m/e)=327.3 [M+H + ]).

步驟B4：(S)-2-(二苄基胺基)丁醛 Step B4: (S)-2-(dibenzylamino)butanal

在氬氛圍中，在-20℃至-30℃下，將LiAlH4(2.34 g,61.8 mmol,Eq：1.2)與THF(150 ml)合併，獲得淡灰色懸浮液。然後在-30℃下添加在THF(50 ml)中稀釋之(S)-2-(二苄基胺基)-N-甲氧基-N-甲基丁醯胺(24 g,51.5 mmol,Eq：1.00)。在-30℃下將反應物攪拌2.5 h。藉由逐滴添加乙酸乙酯及水(1/1，約30 ml)來猝滅過量試劑。在RT下將反應物劇烈攪拌15 min。在經由矽藻土過濾後，用水(100 ml)稀釋混合物並用乙酸乙酯萃取。經Na2SO4乾燥有機層並在真空中濃縮。獲得淡褐色液體狀標題化合物(13.41 g,97.5%,MS(m/e)=268.3[M+H+])。 LiAlH 4 (2.34 g, 61.8 mmol, Eq: 1.2) was combined with THF (150 ml) at -20 ° C to -30 ° C under argon to give a pale-gray suspension. (S)-2-(Dibenzylamino)-N-methoxy-N-methylbutyramine (24 g, 51.5 mmol, diluted in THF (50 ml) was then added at -30 °C. Eq: 1.00). The reaction was stirred at -30 °C for 2.5 h. Excess reagent was quenched by the dropwise addition of ethyl acetate and water (1/1, ca. 30 ml). The reaction was stirred vigorously at RT for 15 min. After filtration through celite, the mixture was diluted with water (100 ml) and extracted with ethyl acetate. The organic layer was concentrated, and Na 2 SO 4 dried in vacuo. The title compound (13.41 g, 97.5%, MS (m/e) = 268.3 [M+H + ]).

步驟B5：(2S,3S)-3-(二苄基胺基)-2-羥基戊腈 Step B5: (2S,3S)-3-(dibenzylamino)-2-hydroxyvaleronitrile

在氬氛圍中，將(S)-2-(二苄基胺基)丁醛(8.55 g,32.0 mmol,Eq：1.00)與二噁烷(70 ml)合併，獲得淡黃色溶液。在0℃下將反應物攪拌10 min。然後添加存於水中之亞硫酸氫鈉(40%,26.5 ml)。在0℃下將反應物再攪拌10 min。然後添加在水(35 ml)中稀釋之氰化鉀(8.33 g,128 mmol,Eq：4)。在RT下將反應物攪拌過夜。將反應混合物傾倒至水(75 ml)中並用乙酸乙酯(2×75 ml)萃取。經Na2SO4乾燥有機層並在真空中濃縮。藉由急驟層析(矽膠，50 g，0%至40%存於庚烷中之乙酸乙酯)純化粗製材料。獲得淡黃色油狀標題化合物(6.49 g,68.9%,MS(m/e)=295.3[M+H+])。 (S)-2-(Dibenzylamino)butanal (8.55 g, 32.0 mmol, Eq: 1.00) was combined with dioxane (70 ml) to give a pale yellow solution. The reaction was stirred at 0 °C for 10 min. Sodium bisulfite (40%, 26.5 ml) in water was then added. The reaction was stirred for a further 10 min at 0 °C. Potassium cyanide (8.33 g, 128 mmol, Eq: 4) diluted in water (35 ml) was then added. The reaction was stirred at RT overnight. The reaction mixture was poured into water (75 ml) The organic layer was concentrated, and Na 2 SO 4 dried in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 40% ethyl acetate in heptane). The title compound (6.49 g, 68.9%, MS (m/e)=295.3 [M+H + ]).

步驟B6：(2S,3S)-3-(二苄基胺基)-2-羥基戊酸 Step B6: (2S,3S)-3-(dibenzylamino)-2-hydroxyvaleric acid

在氬氛圍中，合併(2S,3S)-3-(二苄基胺基)-2-羥基戊腈(7.05 g,23.9 mmol,Eq：1.00)與HCl(37%,47.2 g,39.3 ml,479 mmol,Eq：20)，獲得淡褐色溶液。在100℃下將反應物 攪拌2.5 h。用冰浴冷卻反應物且藉由添加NaOH溶液將其調節至pH 6。然後用二氯甲烷萃取反應物並用鹽水反萃取。經Na2SO4乾燥有機層並在真空中濃縮。在真空中去除殘餘溶劑。獲得褐色發泡體狀標題化合物(6.85 g,91.3%,MS(m/e)=312.3[M-H+],MS(m/e)=314.0[M+H+])。 (2S,3S)-3-(Dibenzylamino)-2-hydroxyvaleronitrile (7.05 g, 23.9 mmol, Eq: 1.00) and HCl (37%, 47.2 g, 39.3 ml, 479 mmol, Eq: 20), obtained as a light brown solution. The reaction was stirred at 100 ° C for 2.5 h. The reaction was cooled with an ice bath and adjusted to pH 6 by addition of a NaOH solution. The reaction was then extracted with dichloromethane and back extracted with brine. The organic layer was concentrated, and Na 2 SO 4 dried in vacuo. The residual solvent was removed in vacuo. The title compound (6.85 g, 91.3%, MS (m/e) = 312.3 [MH + ], MS (m/e) = 314.0 [M+H + ]).

步驟B7：(2S,3S)-N-環丙基-3-(二苄基胺基)-2-羥基戊醯胺 Step B7: (2S,3S)-N-cyclopropyl-3-(dibenzylamino)-2-hydroxypentamidine

在氬氛圍中，將(2S,3S)-3-(二苄基胺基)-2-羥基戊酸(5.85 g,18.7 mmol,Eq：1.00)、環丙胺(2.13 g,2.62 ml,37.3 mmol,Eq：2)與二氯甲烷(100 ml)合併，獲得淡黃色溶液。在0℃下，將HOBt(4.29 g,28.0 mmol,Eq：1.5)、EDC(5.37 g,28.0 mmol,Eq：1.5)及N-甲基嗎啉(3.78 g,4.1 ml,37.3 mmol,Eq：2)添加至反應物。在RT下將反應物攪拌過夜。將反應混合物傾倒至水(150 ml)中並用二氯甲烷萃取。用水反萃取有機層。經Na2SO4乾燥有機層並在真空中濃縮。藉由急驟層析(矽膠，70 g，0%至60%存於庚烷中之乙酸乙酯)純化粗製材料。獲得淡褐色結晶狀標題化合物(4.42 g,67.2%,MS(m/e)=353.3[M+H+])。 (2S,3S)-3-(Dibenzylamino)-2-hydroxyvaleric acid (5.85 g, 18.7 mmol, Eq: 1.00), cyclopropylamine (2.13 g, 2.62 ml, 37.3 mmol) in argon , Eq: 2) combined with dichloromethane (100 ml) to give a pale yellow solution. HOBt (4.29 g, 28.0 mmol, Eq: 1.5), EDC (5.37 g, 28.0 mmol, Eq: 1.5) and N-methylmorpholine (3.78 g, 4.1 ml, 37.3 mmol, Eq: 2) Add to the reactants. The reaction was stirred at RT overnight. The reaction mixture was poured into water (150 ml) and evaporated with dichloromethane. The organic layer was back extracted with water. The organic layer was concentrated, and Na 2 SO 4 dried in vacuo. The crude material was purified by flash chromatography (silica gel, 70 g, 0% to 60% ethyl acetate in heptane). The title compound (4.42 g, 67.2%, MS (m/e)=353.3 [M+H + ]).

步驟B8：(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺 Step B8: (2S,3S)-3-Amino-N-cyclopropyl-2-hydroxypentamidine

在3.5巴之氫壓下用存於甲醇(50 ml)中之Pd(OH)2(20%載於碳上，890 mg,1.27 mmol,Eq：0.101)將(2S,3S)-N-環丙基-3-(二苄基胺基)-2-羥基戊醯胺(4.42 g,12.5 mmol,Eq：1.00)氫化4 h。藉由過濾去除觸媒，並在真空中去除殘餘溶劑。獲得淡黃色固體狀標題化合物(2.09 g,96.8%,MS(m/e)=173.2[M+H+])。 (2S,3S)-N-ring was carried out under a hydrogen pressure of 3.5 bar using Pd(OH) 2 (20% on carbon, 890 mg, 1.27 mmol, Eq: 0.101) in methanol (50 ml). Propyl-3-(dibenzylamino)-2-hydroxypentanamine (4.42 g, 12.5 mmol, Eq: 1.00) was hydrogenated for 4 h. The catalyst was removed by filtration and the residual solvent was removed in vacuo. The title compound (2.09 g, 96.8%, MS (m/e) = 173.2 [M+H + ]).

(2S,3S)-3-胺基-N-環丙基-2-羥基己醯胺：(2S,3S)-3-Amino-N-cyclopropyl-2-hydroxyhexylamine:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺(代表性程序B)類似之方式在第一步驟(步驟B1)中使用(S)-2-胺基戊酸來製備標題化合物。 (S)-2- in the first step (step B1) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide (representative procedure B) Aminopentanoic acid was used to prepare the title compound.

3-胺基-N-環丙基-2-羥基-3-甲基丁醯胺：3-Amino-N-cyclopropyl-2-hydroxy-3-methylbutanamine:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第二步驟(A2)中以1-羥基-2-甲基丙-2-基胺基甲酸第三丁基酯開始來製備標題化合物。 1-hydroxyl in the second step (A2) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) The title compound was prepared starting from the tert-butyl 2-methylpropan-2-ylcarbamate.

2-(1-胺基環丙基)-N-環丙基-2-羥基乙醯胺：2-(1-Aminocyclopropyl)-N-cyclopropyl-2-hydroxyacetamidine:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第三步驟(A3)中以1-甲醯基環丙基胺基甲酸第三丁基酯開始來製備標題化合物。 1-methyl in the third step (A3) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) The title compound was prepared starting from the tert-butyl propyl propyl carbamic acid.

(2S,3S)-3-胺基-N-環丙基-2-羥基-4-甲基戊醯胺二鹽酸：(2S,3S)-3-Amino-N-cyclopropyl-2-hydroxy-4-methylpentanamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第一步驟(A1)中以(S)-2-胺基-3-甲基丁-1-醇開始來製備標題化合物。 (S) in the first step (A1) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) 2-Amino-3-methylbutan-1-ol was started to prepare the title compound.

(2S,3S)-3-胺基-N-環丙基-2-羥基-5-甲基己醯胺二鹽酸鹽：(2S,3S)-3-Amino-N-cyclopropyl-2-hydroxy-5-methylhexylamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第一步驟(A1)中以(S)-2-胺基-4-甲基戊-1-醇開始來製備標題化合物。 (S) in the first step (A1) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) 2-Amino-4-methylpentan-1-ol was started to prepare the title compound.

(2S,3S)-3-胺基-4-環己基-N-環丙基-2-羥基丁醯胺二鹽酸鹽：(2S,3S)-3-Amino-4-cyclohexyl-N-cyclopropyl-2-hydroxybutanamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第二步驟(A2)中以(S)-1-環己 基-3-羥基丙-2-基胺基甲酸第三丁基酯開始來製備標題化合物。 (S) in a second step (A2) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) -1-cyclohexyl Starting from the tert-butyl 3-hydroxypropan-2-ylcarbamate, the title compound was prepared.

(2S,3S)-3-胺基-N-丁基-2-羥基戊醯胺二鹽酸鹽：(2S,3S)-3-Amino-N-butyl-2-hydroxypentanamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第三步驟(A3)中使用1-異氰基丁烷來製備標題化合物。 1-dimer in the third step (A3) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) The title compound was prepared from cyanobutane.

(2S,3S)-3-胺基-N-丁基-2-羥基己醯胺二鹽酸鹽：(2S,3S)-3-Amino-N-butyl-2-hydroxyhexylamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第一步驟(A1)中使用(S)-2-胺基戊-1-醇且在第三步驟(A3)中使用1-異氰基丁烷來製備標題化合物。 (S) is used in the first step (A1) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) 2-Aminopentan-1-ol and the title compound was prepared using 1-isocyanobutane in the third step (A3).

(2S,3S)-3-胺基-N-苄基-2-羥基戊醯胺二鹽酸鹽：(2S,3S)-3-Amino-N-benzyl-2-hydroxypentanylamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第三步驟(A3)中使用(異氰基甲基)苯來製備標題化合物。 Used in the third step (A3) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) (isocyanide) The title compound is prepared from benzyl)benzene.

(2S,3S)-3-胺基-N-環丙基-2-羥基丁醯胺二鹽酸鹽：(2S,3S)-3-Amino-N-cyclopropyl-2-hydroxybutanamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第二步驟(A2)中以(S)-1-羥基丙-2-基胺基甲酸第三丁基酯開始來製備標題化合物。 (S) in a second step (A2) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) Starting from 1-butylpropan-2-ylaminocarbamate, the title compound was prepared.

(2S,3S)-3-胺基-N-苄基-2-羥基己醯胺二鹽酸鹽：(2S,3S)-3-Amino-N-benzyl-2-hydroxyhexylamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第一步驟(A1)中以(S)-2-胺基戊-1-醇開始且在第三步驟(A3)中使用(異氰基甲基)苯來製備標題化合物。 (S) in the first step (A1) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) The title compound is prepared starting from 2-aminopentan-1-ol and using (isocyanomethyl)benzene in the third step (A3).

(2S,3S)-3-胺基-2-羥基-N-(戊-2-基)戊醯胺二鹽酸鹽：(2S,3S)-3-Amino-2-hydroxy-N-(pent-2-yl)pentanylamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第三步驟(A3)中使用2-異氰基戊烷來製備標題化合物。 2-isomeric in the third step (A3) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) The title compound was prepared from cyanopentane.

(2S,3S)-3-胺基-2-羥基-N-(戊-2-基)己醯胺二鹽酸鹽：(2S,3S)-3-Amino-2-hydroxy-N-(pent-2-yl)hexylamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第一步驟(A1)中以(S)-2-胺基戊-1-醇開始且在第三步驟(A3)中使用2-異氰基戊烷來製備標題化合物。 (S) in the first step (A1) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) The title compound is prepared starting from 2-aminopentan-1-ol and using 2-isocyanopentane in the third step (A3).

(2S,3S)-3-胺基-2-羥基-N-(2,2,2-三氟乙基)己醯胺：(2S,3S)-3-Amino-2-hydroxy-N-(2,2,2-trifluoroethyl)hexylamine:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺(代表性程序B)類似之方式在第一步驟(步驟B1)中使用(S)-2-胺基戊酸且在第7步驟(步驟B7)中使用2,2,2-三氟-乙基胺來製備標題化合物。 (S)-2- in the first step (step B1) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide (representative procedure B) The title compound is prepared using the amido valeric acid and the 2,2,2-trifluoro-ethylamine in the 7th step (step B7).

(2S,3S)-3-胺基-2-羥基-N-異丙基己醯胺：(2S,3S)-3-Amino-2-hydroxy-N-isopropylhexylamine:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺(代表性程序B)類似之方式在第一步驟(步驟B1)中使用(S)-2-胺基戊酸且在第7步驟(步驟B7)中使用異丙基胺來製備標題化合物。 (S)-2- in the first step (step B1) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide (representative procedure B) The title compound is prepared using isopropylamine in the seventh step (step B7).

(2S,3S)-3-胺基-N-乙基-2-羥基戊醯胺二鹽酸鹽：(2S,3S)-3-Amino-N-ethyl-2-hydroxypentanamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第三步驟(A3)中使用異氰基乙烷來製備標題化合物。 Isocyanyl is used in the third step (A3) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) Ethane was used to prepare the title compound.

(2S,3S)-3-胺基-N-乙基-2-羥基己醯胺二鹽酸鹽：(2S,3S)-3-Amino-N-ethyl-2-hydroxyhexylamine dihydrochloride:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(代表性程序A)類似之方式在第一步驟(A1)中以(S)-2-胺基戊-1-醇開始且在第三步驟(A3)中使用異氰基乙烷來製備標題化合物。 (S) in the first step (A1) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (representative procedure A) The title compound is prepared starting from 2-aminopentan-1-ol and using isocyanoethane in the third step (A3).

(2S,3S)-3-胺基-N-環丙基-2-羥基-N-甲基己醯胺：(2S,3S)-3-Amino-N-cyclopropyl-2-hydroxy-N-methylhexylamine:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺(代表性程序B)類似之方式在第一步驟(步驟B1)中使用(S)-2-胺基戊酸且在第7步驟(步驟B7)中使用N-甲基環丙胺來製備標題化合物。 (S)-2- in the first step (step B1) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide (representative procedure B) Aminopentanoic acid and the title compound are prepared using N-methylcyclopropylamine in the 7th step (step B7).

(2S,3S)-3-胺基-2-羥基-N-苯乙基戊醯胺：(2S,3S)-3-Amino-2-hydroxy-N-phenethylpentalamine:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺(代表性程序B)類似之方式在第7步驟(步驟B7)中使用2-苯基乙胺來製備標題化合物。 2-Phenylethylamine is used in step 7 (step B7) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide (representative procedure B) To prepare the title compound.

(2S,3S)-3-胺基-2-羥基-N-(2-(萘-1-基)乙基)戊醯胺：(2S,3S)-3-Amino-2-hydroxy-N-(2-(naphthalen-1-yl)ethyl)pentanylamine:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺(代表性程序B)類似之方式在第7步驟(步驟B7)中使用2-(萘-1-基)乙胺來製備標題化合物。 2-(naphthalene-1) is used in the seventh step (step B7) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide (representative procedure B) The base compound was prepared by the reaction of ethylamine.

(2S,3S)-3-胺基-2-羥基-N-(2-(萘-2-基)乙基)戊醯胺：(2S,3S)-3-Amino-2-hydroxy-N-(2-(naphthalen-2-yl)ethyl)pentanylamine:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺(代表性程序B)類似之方式在第7步驟(步驟B7)中使用2-(萘-2-基)乙胺鹽酸鹽來製備標題化合物。 2-(naphthalene-2) is used in the seventh step (step B7) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide (representative procedure B) -Base)ethylamine hydrochloride to prepare the title compound.

(2S,3S)-3-胺基-2-羥基-N-(萘-1-基甲基)戊醯胺：(2S,3S)-3-Amino-2-hydroxy-N-(naphthalen-1-ylmethyl)pentanylamine:

以與(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺(代表性程序B)類似之方式在第7步驟(步驟B7)中使用萘-1-基甲胺來 製備標題化合物。 Naphthalen-1-yl group was used in step 7 (step B7) in a similar manner to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide (representative procedure B) Amine The title compound was prepared.

「α-酮基苯并噁唑前體」結構單元(2S)-2-胺基-1-(苯并[d]噁唑-2-基)丁-1-醇二鹽酸鹽之製備Preparation of "α-ketobenzoxazole precursor" structural unit (2S)-2-amino-1-((benzo[d]oxazol-2-yl)butan-1-ol dihydrochloride 步驟1：(2S)-1-(苯并[d]噁唑-2-基)-1-羥基丁-2-基胺基甲酸第三丁基酯 Step 1: (2S)-1-(Benzo[d]oxazol-2-yl)-1-hydroxybutan-2-ylcarbamic acid tert-butyl ester

在氬氛圍中，將苯并[d]噁唑(5 g,42.0 mmol,Eq：1.00)與THF(100 ml)合併，獲得淡黃色溶液。在-5℃下逐滴添加存於THF中之2 M異丙基氯化鎂(21.0 ml,42.0 mmol,Eq：1.00)。在-5℃下將反應物攪拌1.5 h。然後添加在20 mlTHF中稀釋之(S)-1-側氧基丁-2-基胺基甲酸第三丁基酯(4.72 g,25.2 mmol,Eq：0.6)。在RT下將反應物攪拌過夜。將飽和氯化銨溶液(6 ml)添加至反應物。在真空中蒸發THF。將反應混合物傾倒至50 ml H2O中並用乙酸乙酯(2×100 ml)萃取。藉由急驟層析(矽膠，20g，0%至40%存於庚烷中之乙酸乙酯)純化粗製材料。獲得褐色膠狀標題化合物(5.08 g,39.5%,MS(m/e)=307.2[M+H+])。 Benzo[d]oxazole (5 g, 42.0 mmol, Eq: 1.00) was combined with THF (100 ml) in argon to give a pale yellow solution. 2 M isopropylmagnesium chloride (21.0 ml, 42.0 mmol, Eq: 1.00) in THF was added dropwise at -5 °C. The reaction was stirred at -5 °C for 1.5 h. Then, (S)-1-tert-oxybutan-2-ylcarbamic acid tert-butyl ester (4.72 g, 25.2 mmol, Eq: 0.6) diluted in 20 ml of THF was added. The reaction was stirred at RT overnight. A saturated ammonium chloride solution (6 ml) was added to the reaction. The THF was evaporated in vacuo. The reaction mixture was poured into 50 ml H 2 O and extracted with ethyl acetate (2 × 100 ml). The crude material was purified by flash chromatography (EtOAc, 20 g, 0% to 40% ethyl acetate). The title compound (5.08 g, 39.5%, MS (m/e) = 307.2 [M+H + ]).

步驟2：(2S)-2-胺基-1-(苯并[d]噁唑-2-基)丁-1-醇二鹽酸鹽 Step 2: (2S)-2-Amino-1-(benzo[d]oxazol-2-yl)butan-1-ol dihydrochloride

在氬氛圍中，合併(2S)-1-(苯并[d]噁唑-2-基)-1-羥基丁-2-基胺基甲酸第三丁基酯(800 mg,2.61 mmol,Eq：1.00)與存於二噁烷(17.3 ml)中之4 M HCl，獲得深褐色溶液。在RT下將反應物攪拌2 h。在真空中濃縮粗製反應混合物，且在真空中去除殘餘溶劑。獲得深褐色膠狀標題化合物(910 mg，定量，MS(m/e)=207.1[M+H+])。 Combined (2S)-1-(benzo[d]oxazol-2-yl)-1-hydroxybutan-2-ylcarbamic acid tert-butyl ester (800 mg, 2.61 mmol, Eq) in argon : 1.00) 4 M HCl in dioxane (17.3 ml) afforded a dark brown solution. The reaction was stirred at RT for 2 h. The crude reaction mixture was concentrated in vacuo and the residual solvent was removed in vacuo. The title compound (910 mg, quantitative, MS (m/e) = 207.1 [M+H + ]).

1-(5-氯-3-氟吡啶-2-基)環丙烷甲酸1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarboxylic acid 步驟1：1-(5-氯-3-氟吡啶-2-基)環丙烷甲腈 Step 1: 1-(5-Chloro-3-fluoropyridin-2-yl)cyclopropane carbonitrile

在氬氛圍中，將5-氯-2,3-二氟吡啶(6 g,4.17 ml,40.1 mmol,Eq：1.00)與甲苯(60.0 ml)合併。然後將環丙烷甲腈(2.69 g,3.02 ml,40.1 mmol,Eq：1.00)添加至該溶液。在-5℃下，經30 min逐滴添加雙(三甲基甲矽烷基)醯胺鉀(80.3 ml,40.1 mmol,Eq：1.00)。在-5℃下將深褐色反應物攪拌1小時，且然後在室溫下攪拌2 h。將反應混合物傾倒至飽和NH4Cl溶液(50 ml)中並用2×100 ml乙酸乙酯萃取。經Na2SO4乾燥有機層，過濾且在真空中濃縮。藉由急驟層析(70 g管柱，100%至50%庚烷之乙酸乙酯溶液)純化粗製材料。獲得橙色油狀標題化合物(1.55 g,13.8%,MS(m/e)=197.2[M+H+])。 5-Chloro-2,3-difluoropyridine (6 g, 4.17 ml, 40.1 mmol, Eq: 1.00) was combined with toluene (60.0 ml) in an argon atmosphere. Then cyclopropanecarbonitrile (2.69 g, 3.02 ml, 40.1 mmol, Eq: 1.00) was added to the solution. Potassium bis(trimethylformamido)guanamine (80.3 ml, 40.1 mmol, Eq: 1.00) was added dropwise at -5 °C over 30 min. The dark brown reaction was stirred at -5 °C for 1 hour and then at room temperature for 2 h. The reaction mixture was poured into saturated NH 4 Cl solution (50 ml) and extracted with 2 × 100 ml of ethyl acetate. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (70 g column, 100% to 50% heptane in ethyl acetate). The title compound (1.55 g, 13.8%, MS (m/e) = 197.2 [M+H + ])

步驟2：1-(5-氯-3-氟吡啶-2-基)環丙烷甲酸 Step 2: 1-(5-Chloro-3-fluoropyridin-2-yl)cyclopropanecarboxylic acid

在氬氛圍中，將1-(5-氯-3-氟吡啶-2-基)環丙烷甲腈(1.55 g,7.88 mmol,Eq：1.00)溶於飽和KOH(0.2 M,43.4 ml,8.67 mmol,Eq：1.10)中。在100℃下將反應物攪拌過夜。藉由添加HCl(1 M)將反應混合物之pH調節至pH 6。然後用二氯甲烷萃取反應混合物。經Na2SO4乾燥有機層，過濾且在真空中濃縮。藉由急驟層析(50 g管柱，50%至100%存於庚烷中之乙酸乙酯)純化粗製產物。獲得橙色固體狀標題化合物(800 mg,47.1%,MS(m/e)=216.3[M+H+])。 1-(5-Chloro-3-fluoropyridin-2-yl)cyclopropanecarbonitrile (1.55 g, 7.88 mmol, Eq: 1.00) was dissolved in saturated KOH (0.2 M, 43.4 ml, 8.67 mmol). , Eq: 1.10). The reaction was stirred at 100 ° C overnight. The pH of the reaction mixture was adjusted to pH 6 by the addition of HCl (1 M). The reaction mixture was then extracted with dichloromethane. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (50 g column, 50% to 100% ethyl acetate in heptane). The title compound (800 mg, 47.1%, MS (m/e) = 216.3 [M+H + ])

1-(5-溴-3-氟吡啶-2-基)環丙烷甲酸1-(5-bromo-3-fluoropyridin-2-yl)cyclopropanecarboxylic acid 步驟1：1-(5-溴-3-氟吡啶-2-基)環丙烷甲腈 Step 1: 1-(5-Bromo-3-fluoropyridin-2-yl)cyclopropanecarbonitrile

在氬氛圍中，將5-溴-2,3-二氟吡啶(5 g,25.8 mmol,Eq： 1.00)及環丙烷甲腈(1.78 g,2.00 ml,25.8 mmol,Eq：1.00)與甲苯(50.0 ml)合併，獲得無色溶液。將反應混合物冷卻至-5℃。在-5℃下逐滴添加雙(三甲基甲矽烷基)醯胺鉀(0.5 M,51.6 ml,25.8 mmol,Eq：1.00)。在-5℃下將反應混合物攪拌1 hr，且在RT下攪拌整個週末。然後將反應混合物傾倒至NH4Cl溶液(飽和，50 ml)中。用乙酸乙酯(3×60 ml)萃取水層。合併有機層且經Na2SO4乾燥，並在真空中濃縮。藉由急驟層析(矽膠，70 g，0%至50%存於庚烷中之乙酸乙酯作為溶析劑)純化粗製材料，產生淡褐色蠟質固體狀標題化合物(0.49 g,7.89%,MS(m/e)=248.1[M+H+])。 5-Bromo-2,3-difluoropyridine (5 g, 25.8 mmol, Eq: 1.00) and cyclopropanecarbonitrile (1.78 g, 2.00 ml, 25.8 mmol, Eq: 1.00) and toluene (under argon) 50.0 ml) were combined to give a colorless solution. The reaction mixture was cooled to -5 °C. Potassium bis(trimethylformamethyl)guanamine (0.5 M, 51.6 ml, 25.8 mmol, Eq: 1.00) was added dropwise at -5 °C. The reaction mixture was stirred at -5 °C for 1 hr and stirred at RT over the weekend. The reaction mixture was poured into NH 4 Cl solution (saturated, 50 ml) in. The aqueous layer was extracted with ethyl acetate (3×60 mL). The organic layers were combined and dried over Na 2 SO 4, and concentrated in vacuo. The crude material was purified by flash chromatography eluting eluting elut elut elut elut elut elut elut MS (m/e) = 248.1 [M + H + ]).

步驟2：1-(5-溴-3-氟吡啶-2-基)環丙烷甲酸 Step 2: 1-(5-Bromo-3-fluoropyridin-2-yl)cyclopropanecarboxylic acid

在氬氛圍中，將1-(5-溴-3-氟吡啶-2-基)環丙烷甲腈(0.49 g,2.03 mmol,Eq：1.00)與KOH溶液(1%,12.5 ml)合併，獲得淡褐色懸浮液。將反應混合物加熱至100℃並攪拌過夜。在冷卻至RT後，添加HCl(1 N,3 ml)。用二氯甲烷(3×15 ml)萃取混合物。經Na2SO4乾燥有機層且在真空中濃縮，產生淡褐色固體狀標題化合物(0.420 g,61.4%,MS(m/e)=260.1[M+H+])。化合物未經進一步純化即用於下一步驟。 1-(5-Bromo-3-fluoropyridin-2-yl)cyclopropanecarbonitrile (0.49 g, 2.03 mmol, Eq: 1.00) was combined with a KOH solution (1%, 12.5 ml) under argon. Light brown suspension. The reaction mixture was heated to 100 ° C and stirred overnight. After cooling to RT, HCl (1 N, 3 mL) was added. The mixture was extracted with dichloromethane (3 x 15 mL). Concentrated in vacuo and the organic layer was dried over Na 2 SO 4, to produce the title compound as a pale brown solid (0.420 g, 61.4%, MS (m / e) = 260.1 [M + H +]). The compound was used in the next step without further purification.

代表性程序C：(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲酸Representative procedure C: (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxylic acid 步驟C1：(2S,4S)-4-(3-硝基苯基磺醯基氧基)吡咯啶-1,2-二甲酸1-第三丁基酯2-甲酯 Step C1: (2S,4S)-4-(3-nitrophenylsulfonyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

在氬氛圍中，將(2S,4S)-4-羥基吡咯啶-1,2-二甲酸1-第 三丁基酯2-甲酯(10 g,39.5 mmol,Eq：1.00)與二氯甲烷(75 ml)合併，獲得無色溶液。然後在0℃下，添加3-硝基苯-1-磺醯基氯(9.58 g,41.9 mmol,Eq：1.06)。亦在0℃下，將三乙胺(12.0 g,16.5 ml,119 mmol,Eq：3.00)逐滴添加至反應混合物。在0℃下將反應物攪拌1.5 h且然後在室溫下攪拌2天。在二氯甲烷(200 ml)中稀釋反應混合物且然後用2×50 ml 0.5 N HCl、70 ml飽和NaHCO3溶液及50 ml飽和NaCl溶液萃取。經Na2SO4攪拌有機層，過濾並在減壓下濃縮。獲得褐色膠狀標題化合物(17.25 g，定量，MS(m/e)=431.3[M+H+]。產物未經進一步純化即用於下一步驟。 (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (10 g, 39.5 mmol, Eq: 1.00) and methylene chloride in an argon atmosphere (75 ml) combined to give a colorless solution. 3-Nitrobenzene-1-sulfonyl chloride (9.58 g, 41.9 mmol, Eq: 1.06) was then added at 0 °C. Triethylamine (12.0 g, 16.5 ml, 119 mmol, Eq: 3.00) was also added dropwise to the reaction mixture at 0 °C. The reaction was stirred at 0 °C for 1.5 h and then at room temperature for 2 days. The reaction mixture was diluted in dichloromethane (200 ml) and then extracted with 2×50 ml 0.5 N HCl, 70 ml saturated NaHCO 3 solution and 50 ml of saturated NaCl. It was stirred over Na 2 SO 4 organic layer was filtered and concentrated under reduced pressure. The title compound is obtained as a brown gum (17.25 g, quantitative, MS (m / e) = 431.3 [M + H +]. The product was used without further purification in the next step.

步驟C2：(2S,4R)-4-(2-氯苯基硫代)吡咯啶-1,2-二甲酸1-第三丁基酯2-甲酯 Step C2: (2S,4R)-4-(2-Chlorophenylthio)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

在氬氛圍中，將(2S,4S)-4-(3-硝基苯基磺醯基氧基)吡咯啶-1,2-二甲酸1-第三丁基酯2-甲酯(8.5 g,19.7 mmol,Eq：1.00)與丙腈(82.0 ml)合併，獲得淡褐色溶液。然後滴加2-氯苯硫醇(4.28 g,3.38 ml,29.6 mmol,Eq：1.50)及三乙胺(4.00 g,5.5 ml,39.5 mmol,Eq：2.00)。在回流(100℃)下將反應物攪拌過夜。將反應物冷卻至室溫，並傾倒於50 ml Na2CO3溶液(10%)中，且用2×100 ml乙酸乙酯萃取。用50 ml HCl 0.1 M及50 ml飽和NaCl溶液洗滌有機層。經Na2SO4乾燥有機層，過濾且在真空中濃縮。藉由急驟層析(70 g管柱，100%至80%庚烷之乙酸乙酯溶液)純化粗製材料。獲得黃色油狀標題化合物(5.7 g,77.6%,MS(m/e)=372.1[M+H+])。 (2S,4S)-4-(3-Nitrophenylsulfonyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (8.5 g) under argon atmosphere , 19.7 mmol, Eq: 1.00) was combined with propionitrile (82.0 ml) to give a pale brown solution. 2-Chlorobenzenethiol (4.28 g, 3.38 ml, 29.6 mmol, Eq: 1.50) and triethylamine (4.00 g, 5.5 ml, 39.5 mmol, Eq: 2.00) were then added dropwise. The reaction was stirred at reflux (100 ° C) overnight. The reaction was cooled to room temperature and poured into 50 ml Na 2 CO 3 solution (10%) and extracted with 2 × 100 ml of ethyl acetate. The organic layer was washed with 50 ml of HCl 0.1 M and 50 ml of saturated NaCl. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (70 g column, 100% to 80%EtOAc in ethyl acetate). The title compound (5.7 g, 77.6%, MS (m/e) = 372.1 [M+H + ]).

步驟C3：(2S,4R)-4-(2-氯苯基磺醯基)吡咯啶-1,2-二甲酸1-第三丁基酯2-甲酯 Step C3: (2S,4R)-4-(2-Chlorophenylsulfonyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

在氬氛圍中，將(2S,4R)-4-(2-氯苯基硫代)吡咯啶-1,2-二甲酸1-第三丁基酯2-甲酯(5.7 g,15.3 mmol,Eq：1.00)與二氯甲烷(80.0 ml)合併，獲得淡黃色溶液。在0℃下，緩慢添加3-氯過苯甲酸(7.21 g,32.2 mmol,Eq：2.10)。在室溫下將反應物攪拌過夜。用二氯甲烷萃取反應混合物並用80 ml飽和Na2CO3溶液及50 ml鹽水洗滌。經Na2SO4乾燥有機層，過濾並在真空中濃縮。藉由急驟層析(70 g管柱，100%至60%庚烷之乙酸乙酯溶液)純化粗製材料。獲得淡黃色膠狀標題化合物(5.76 g,93.0%,MS(m/e)=404.3[M+H+])。 (2S,4R)-4-(2-Chlorophenylthio)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.7 g, 15.3 mmol, argon atmosphere) Eq: 1.00) combined with dichloromethane (80.0 ml) gave a pale yellow solution. 3-Chloroperbenzoic acid (7.21 g, 32.2 mmol, Eq: 2.10) was slowly added at 0 °C. The reaction was stirred at room temperature overnight. The reaction mixture was extracted with dichloromethane and washed with 80 ml saturated Na 2 CO 3 solution and 50 ml brine. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (70 g column, 100% to 60% heptane in ethyl acetate). The title compound (5.76 g, 93.0%, MS (m/e) = 404.3 [M+H + ]).

步驟C4：(2S,4R)-4-(2-氯苯基磺醯基)吡咯啶-2-甲酸甲酯 Step C4: (2S,4R)-4-(2-Chlorophenylsulfonyl)pyrrolidine-2-carboxylic acid methyl ester

在氬氛圍中，將(2S,4R)-4-(2-氯苯基磺醯基)吡咯啶-1,2-二甲酸1-第三丁基酯2-甲酯(5.76 g,14.3 mmol,Eq：1.00)與二氯甲烷(35.0 ml)合併，獲得淡黃色溶液。在0℃下，逐滴添加2,2,2-三氟乙酸(24.4 g,16.5 ml,214 mmol,Eq：15.0)。將反應物升溫至室溫並攪拌3 h。將反應混合物蒸發至乾燥。將粗製材料溶於100 ml二氯甲烷中，然後用50 ml飽和Na2CO3溶液及50 ml H2O萃取。用40 ml二氯甲烷洗滌水層。經Na2SO4乾燥有機層，過濾且在真空中濃縮。獲得橙色黏性油狀標題化合物(4.02 g,92.8%,MS(m/e)=304.2[M+H+])。 (2S,4R)-4-(2-Chlorophenylsulfonyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.76 g, 14.3 mmol) under argon , Eq: 1.00) was combined with dichloromethane (35.0 ml) to give a pale yellow solution. 2,2,2-Trifluoroacetic acid (24.4 g, 16.5 ml, 214 mmol, Eq: 15.0) was added dropwise at 0 °C. The reaction was warmed to room temperature and stirred for 3 h. The reaction mixture was evaporated to dryness. The crude material was dissolved in 100 ml of dichloromethane and then extracted with 50 mL of saturated Na 2 CO 3 and 50 mL H 2 O. The aqueous layer was washed with 40 ml of dichloromethane. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo. The title compound (4.02 g, 92.8%, MS (m/e) = 304.2 [M+H + ]).

步驟C5：(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基 磺醯基)吡咯啶-2-甲酸甲酯 Step C5: (2S,4R)-1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenyl) Methyl sulfonyl pyrrolidine-2-carboxylate

在氬氛圍中，將1-(4-氯苯基)環丙烷甲酸(1.57 g,7.9 mmol,Eq：1.20)與四氫呋喃(70.0 ml)合併，獲得無色溶液。然後添加EDC(3.09 g,15.8 mmol,Eq：2.40)、HOBt(2.47 g,15.8 mmol,Eq：2.40)及三乙胺(6.66 g,9.18 ml,65.8 mmol,Eq：10.0)。(獲得白色懸浮液。)在室溫下將反應混合物攪拌15 min。逐滴添加(2S,4R)-4-(2-氯苯基磺醯基)吡咯啶-2-甲酸甲酯(2 g,6.58 mmol,Eq：1.00)存於四氫呋喃(14.0 ml)中之溶液。在室溫下將反應物攪拌3天。將反應混合物傾倒至75 ml 1 M HCl中並用2×100 ml乙酸乙酯萃取。用75 ml飽和Na2CO3溶液及75 ml鹽水洗滌有機層。經Na2SO4乾燥有機層，過濾且在真空中濃縮。藉由急驟層析(50 g管柱，0%至100%存於庚烷中之乙酸乙酯)純化粗製材料。獲得淡黃色固體狀標題化合物(1.5 g,47.2%,MS(m/e)=482.3[M+H+])。 1-(4-Chlorophenyl)cyclopropanecarboxylic acid (1.57 g, 7.9 mmol, Eq: 1.20) was combined with tetrahydrofuran (70.0 ml) to give a colorless solution. EDC (3.09 g, 15.8 mmol, Eq: 2.40), HOBt (2.47 g, 15.8 mmol, Eq: 2.40) and triethylamine (6.66 g, 9.18 ml, 65.8 mmol, Eq: 10.0) were then added. (A white suspension was obtained.) The reaction mixture was stirred at room temperature for 15 min. A solution of methyl (2S,4R)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxylate (2 g, 6.58 mmol, Eq: 1.00) in tetrahydrofuran (14.0 ml) was added dropwise. . The reaction was stirred at room temperature for 3 days. The reaction mixture was poured into 75 mL 1 M EtOAc and EtOAc. The organic layer was washed with 75 ml of a saturated Na 2 CO 3 solution and 75 ml of brine. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (50 g column, 0% to 100% ethyl acetate in heptane). The title compound (1.5 g, 47.2%, MS (m/e) = 482.3 [M+H + ])

步驟C6：(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲酸 Step C6: (2S,4R)-1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxylic acid

在氬氛圍中，將(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲酸甲酯(1.5 g,3.11 mmol,Eq：1.00)與THF(20 ml)合併，獲得淡黃色溶液。然後添加存於4 ml水及4 ml甲醇中之氫氧化鋰單水合物(196 mg,4.66 mmol,Eq：1.5)。在RT下將反應物攪拌2 h。蒸發溶劑。用乙酸乙酯、H2O及鹽水萃取反應物。經Na2SO4乾燥有機層並在真空中濃縮。獲得白色發泡體狀標題化合物 (1.52 g,97.1%,MS(m/e)=468.2[M+H+]；MS(m/e)=466.1[M-H+])。 Methyl (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxylate (under argon) 1.5 g, 3.11 mmol, Eq: 1.00) was combined with THF (20 ml). Then, lithium hydroxide monohydrate (196 mg, 4.66 mmol, Eq: 1.5) in 4 ml of water and 4 ml of methanol was added. The reaction was stirred at RT for 2 h. Evaporate the solvent. The reaction was extracted with ethyl acetate, H 2 O and brine. The organic layer was concentrated, and Na 2 SO 4 dried in vacuo. The title compound (1.52 g, 97.1%, MS (m/e) = 468.2 [M+H + ]; MS (m/e) = 466.1 [MH + ]).

(2S,4R)-1-(1-(三氟甲基)環丙烷羰基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲酸之製備Preparation of (2S,4R)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxylic acid

以與代表性程序C類似之方式在步驟C2中使用2-三氟甲基-苯硫醇且在步驟C5中使用1-三氟甲基-環丙烷甲酸/HATU來製備標題化合物。 The title compound was prepared in a similar manner to the procedure C, using 2-trifluoromethyl-benzenethiol in step C2 and using 1-trifluoromethyl-cyclopropanecarboxylic acid/HATU in step C5.

(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯基磺醯基)吡咯啶-2-甲酸之製備(2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chloro-4-(2,2,2-trifluoroethoxy) Preparation of phenylsulfonyl)pyrrolidine-2-carboxylic acid 步驟1：(2S,4R)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯基磺醯基)吡咯啶-1,2-二甲酸1-第三丁基酯2-甲酯： Step 1: (2S,4R)-4-(2-chloro-4-(2,2,2-trifluoroethoxy)phenylsulfonyl)pyrrolidine-1,2-dicarboxylic acid 1-third Butyl ester 2-methyl ester:

在氬氛圍中，將(2S,4R)-4-(2-氯-4-氟苯基磺醯基)吡咯啶-1,2-二甲酸1-第三丁基酯2-甲酯([以與一般程序C步驟C1至C3類似之方式在步驟C2使用2-氯-4-氟硫代苯酚製備]1.5 g,1.0 eq.)與N,N-二甲基乙醯胺(15 ml)合併，獲得淡黃色溶液。添加2,2,2-三氟乙醇(854 mg,617 μl,8.53 mmol,Eq：2.4)及碳酸銫(2.09 g,6.4 mmol,Eq：1.8)。在RT下將該反應混合物攪拌過夜。在真空中濃縮粗製反應混合物。藉由急驟層析(矽膠，50 g，0%至50%存於庚烷中之乙酸乙酯)純化粗製材料，產生白色發泡體狀標題化合物(0.95 g,53.2%,MS(m/e)=502.09[M+H+])。 (2S,4R)-4-(2-Chloro-4-fluorophenylsulfonyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in argon atmosphere ([ Prepared in step C2 using 2-chloro-4-fluorothiophenol in a similar manner to the general procedure C steps C1 to C3] 1.5 g, 1.0 eq.) with N,N-dimethylacetamide (15 ml) Combine to obtain a pale yellow solution. 2,2,2-Trifluoroethanol (854 mg, 617 μl, 8.53 mmol, Eq: 2.4) and cesium carbonate (2.09 g, 6.4 mmol, Eq: 1.8) were added. The reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut eluting elut ) = 502.09 [M + H + ]).

步驟2：(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯基磺醯基)吡咯啶-2-甲酸： Step 2: (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chloro-4-(2,2,2-tri) Fluoroethoxy)phenylsulfonyl)pyrrolidine-2-carboxylic acid:

以與一般程序C步驟C4至C6類似之方式在步驟C4中使用 (2S,4R)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯基磺醯基)吡咯啶-1,2-二甲酸1-第三丁基酯2-甲酯且在步驟C5中使用1-(5-氯-3-氟-吡啶-2-基)-環丙烷甲酸來製備標題化合物。MS(m/e)=584.9[M+H+]。 (2S,4R)-4-(2-Chloro-4-(2,2,2-trifluoroethoxy)phenylsulfonyl is used in step C4 in a similar manner to the general procedure C steps C4 to C6. Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester and prepared in step C5 using 1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarboxylic acid Title compound. MS (m/e) = 584.9 [M+H + ].

(2S,4R)-1-[1-(4-氯-苯基)-環丙烷羰基]-4-[4-(2,2,2-三氟-乙氧基)-2-三氟甲基-苯磺醯基]-吡咯啶-2-甲酸之製備 (2S,4R)-1-[1-(4-Chloro-phenyl)-cyclopropanecarbonyl]-4-[4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl Preparation of phenylsulfonyl]-pyrrolidine-2-carboxylic acid 步驟1：(2S,4R)-2-甲酯4-(4-(2,2,2-三氟乙氧基)-2-(三氟甲基)苯基磺醯基)吡咯啶-1,2-二甲酸1-第三丁基酯： Step 1: (2S,4R)-2-methyl 4-(4-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-1 1,2-dicarboxylic acid 1-tert-butyl ester:

在氬氛圍中，將(2S,4R)-4-(4-氟-2-(三氟甲基)苯基磺醯基)吡咯啶-1,2-二甲酸1-第三丁基酯2-甲酯[以與一般程序C步驟C1至C3類似之方式在步驟C2中使用2-三氟甲基-4-氟硫代苯酚製備]0.79 g,1.73 mmol,Eq：1.00)與N,N-二甲基乙醯胺(10 ml)合併，獲得淡黃色溶液。添加2,2,2-三氟乙醇(416 mg,301 μl,4.16 mmol,Eq：2.4)及碳酸銫(1.02 g,3.12 mmol,Eq：1.8)。在RT下將該反應混合物攪拌過夜。在真空中濃縮粗製反應混合物。將殘餘物傾倒至HCl(0.5 M,20 ml)中並用乙酸乙酯萃取。經Na2SO4乾燥有機層並在真空中濃縮。藉由急驟層析(矽膠，50 g，0%至40%存於庚烷中之乙酸乙酯)純化粗製材料，產生白色發泡體狀標題化合物(610 mg,65.7%,MS(m/e)=536.1[M+H+])。 (2S,4R)-4-(4-Fluoro-2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2 in an argon atmosphere -Methyl ester [prepared using 2-trifluoromethyl-4-fluorothiophenol in step C2 in a similar manner to General Procedure C Steps C1 to C3] 0.79 g, 1.73 mmol, Eq: 1.00) and N, N -Dimethylacetamide (10 ml) was combined to give a pale yellow solution. 2,2,2-Trifluoroethanol (416 mg, 301 μl, 4.16 mmol, Eq: 2.4) and cesium carbonate (1.02 g, 3.12 mmol, Eq: 1.8) were added. The reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuo. The residue was poured into HCl (0.5 M, 20 mL)EtOAc. The organic layer was concentrated, and Na 2 SO 4 dried in vacuo. The crude material was purified by flash chromatography eluting eluting elut elut elut elut elut elut elut ) = 536.1 [M + H + ]).

步驟2：(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(4-(2,2,2-三氟乙氧基)-2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲酸： Step 2: (2S,4R)-1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-4-(4-(2,2,2-trifluoroethoxy)-2-(trifluoro) Methyl)phenylsulfonyl)pyrrolidine-2-carboxylic acid:

以與一般程序C步驟C4至C6類似之方式在步驟C4中使用(2S,4R)-4-(4-(2,2,2-三氟乙氧基)-2-(三氟甲基)苯基磺醯基) 吡咯啶-1,2-二甲酸1-第三丁基酯2-甲酯來製備標題化合物。MS(m/e)=600.0[M+H+]。 (2S,4R)-4-(4-(2,2,2-Trifluoroethoxy)-2-(trifluoromethyl) is used in step C4 in a similar manner to the general procedure C steps C4 to C6. The title compound was prepared from phenylsulfonyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. MS (m/e) = 600.0 [M+H + ].

(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(4-氯-2-氟-苯基)-環丙烷羰基]-吡咯啶-2-甲酸之製備Preparation of (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[1-(4-chloro-2-fluoro-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

以與代表性程序C類似之方式在步驟C5中使用1-(4-氯-2-氟-苯基)-環丙烷甲酸來製備標題化合物。 The title compound was prepared using 1-(4-chloro-2-fluoro-phenyl)-cyclopropanecarboxylic acid in step C5 in a procedure similar to the procedure C.

(2S,4R)-1-[1-(4-溴-2-氟-苯基)-環丙烷羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-甲酸之製備Preparation of (2S,4R)-1-[1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid

以與代表性程序C類似之方式在步驟C5中使用1-(4-溴-2-氟-苯基)-環丙烷甲酸來製備標題化合物。 The title compound was prepared using 1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarboxylic acid in step C5 in a similar manner to the procedure C.

(2S,4R)-1-[1-(4-溴-苯基)-環丙烷羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-甲酸之製備Preparation of (2S,4R)-1-[1-(4-bromo-phenyl)-cyclopropanecarbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid

以與代表性程序C類似之方式在步驟C5中使用1-(4-溴-苯基)-環丙烷甲酸來製備標題化合物。 The title compound was prepared using 1-(4-bromo-phenyl)-cyclopropanecarboxylic acid in step C5 in a similar manner to the procedure C.

(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(4-碘-苯基)-環丙烷羰基]-吡咯啶-2-甲酸之製備Preparation of (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[1-(4-iodo-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid

以與代表性程序C類似之方式在步驟C5中使用1-(4-碘-苯基)-環丙烷甲酸來製備標題化合物。 The title compound was prepared using 1-(4-iodo-phenyl)-cyclopropanecarboxylic acid in step C5 in a similar manner to the procedure C.

(2S,4R)-1-[1-(5-氯-3-氟-吡啶-2-基)-環丙烷羰基]-4-(2-三氟甲基-苯磺醯基)-吡咯啶-2-甲酸之製備(2S,4R)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine Preparation of -2-carboxylic acid

以與代表性程序C類似之方式在步驟C5中使用1-(5-氯-3-氟吡啶-2-基)環丙烷甲酸且在步驟C2中使用2-(三氟甲基)硫代苯酚來製備標題化合物。 1-(5-Chloro-3-fluoropyridin-2-yl)cyclopropanecarboxylic acid is used in step C5 and 2-(trifluoromethyl)thiophenol is used in step C2 in a similar manner to the representative procedure C To prepare the title compound.

(2S,4R)-1-[1-(4-氯-苯基)-環丙烷羰基]-4-(2-三氟甲基-苯(2S,4R)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-4-(2-trifluoromethyl-benzene 磺醯基)-吡咯啶-2-甲酸之製備Preparation of sulfonyl)-pyrrolidine-2-carboxylic acid

以與代表性程序C類似之方式在步驟C2中使用2-(三氟甲基)硫代苯酚來製備標題化合物。 The title compound was prepared using 2-(trifluoromethyl)thiophenol in step C2 in a similar manner to the procedure C.

(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(5-氯-3-氟-吡啶-2-基)-環丙烷羰基]-吡咯啶-2-甲酸之製備(2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-pyrrolidine-2- Preparation of formic acid

以與代表性程序C類似之方式在步驟C5中使用1-(5-氯-3-氟吡啶-2-基)環丙烷甲酸來製備標題化合物。 The title compound was prepared using 1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarboxylic acid in step C5 in a procedure similar to the procedure C.

(2S,4R)-1-[1-(4-氯-苯基)-環丙烷羰基]-4-(2,4-二氯-苯磺醯基)-吡咯啶-2-甲酸之製備：Preparation of (2S,4R)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-4-(2,4-dichloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid:

以與代表性程序C類似之方式在步驟C2中使用2,4-二氯硫代苯酚來製備標題化合物。 The title compound was prepared in a similar manner to the representative procedure C using 2,4-dichlorothiophenol in step C2.

(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-1-[1-(4-氯-苯基)-環丙烷羰基]-吡咯啶-2-甲酸之製備：Preparation of (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid :

以與代表性程序C類似之方式在步驟C2中使用2-氯-4-氟硫代苯酚來製備標題化合物。 The title compound was prepared in a similar manner to the representative procedure C using 2-chloro-4-fluorothiophenol in step C2.

(2S,4R)-1-[1-(4-氯-苯基)-環丙烷羰基]-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-吡咯啶-2-甲酸之製備：(2S,4R)-1-[1-(4-Chloro-phenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1- Preparation of methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid: 步驟1：(2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙-2-基氧基)苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)吡咯啶-2-甲酸甲酯： Step 1: (2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoroprop-2-yloxy)phenylsulfonyl)-1-(1) -(4-Chlorophenyl)cyclopropanecarbonyl)pyrrolidine-2-carboxylic acid methyl ester:

在氬氛圍中，將(2S,4R)-4-(2-氯-4-氟苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)吡咯啶-2-甲酸甲酯(200 mg,331 μmol,Eq：1.00，[以與一般程序C步驟C1至C5類似之方式 在步驟C2中使用2-氯-4-氟硫代苯酚製備])及碳酸銫(194 mg,595 μmol,Eq：1.8)與N,N-二甲基乙醯胺(2 ml)合併，獲得無色溶液。添加(R)-1,1,1-三氟丙-2-醇(90.5 mg,793 μmol,Eq：2.4)。在rt下將該反應混合物攪拌過夜。在真空中濃縮粗製反應混合物。將殘餘物傾倒至HCl(0.5 M,5 ml)中並用乙酸乙酯(5×20 ml)萃取。經Na2SO4乾燥有機層並在真空中濃縮。藉由急驟層析(矽膠，50 g，0%至40%存於庚烷中之EtOAc)純化粗製材料，產生白色發泡體狀標題化合物(178 mg,67.1%,MS(m/e)=594.07[M+H+])。 (2S,4R)-4-(2-Chloro-4-fluorophenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)pyrrolidine-2- in an argon atmosphere Methyl formate (200 mg, 331 μmol, Eq: 1.00, [prepared using 2-chloro-4-fluorothiophenol in step C2 in a similar manner to General Procedure C Steps C1 to C5]) and cesium carbonate (194) Mg, 595 μmol, Eq: 1.8) was combined with N,N-dimethylacetamide (2 ml) to give a colourless solution. (R)-1,1,1-Trifluoropropan-2-ol (90.5 mg, 793 μmol, Eq: 2.4) was added. The reaction mixture was stirred at rt overnight. The crude reaction mixture was concentrated in vacuo. The residue was poured into EtOAc (0.5 M, 5 mL)EtOAc. The organic layer was concentrated, and Na 2 SO 4 dried in vacuo. The crude material was purified by flash chromatography eluting eluting elut elut elut elut elut elut elut elut elut elut elut 594.07 [M+H + ]).

步驟2：(2S,4R)-1-[1-(4-氯-苯基)-環丙烷羰基]-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-吡咯啶-2-甲酸： Step 2: (2S,4R)-1-[1-(4-Chloro-phenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro -1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid:

以與一般程序C步驟C6類似之方式使用(2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙-2-基氧基)苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)吡咯啶-2-甲酸甲酯來製備標題化合物。 Use of (2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoroprop-2-yloxy)phenylsulfonate in a similar manner to General Procedure C, Step C6 The title compound was prepared from methyl benzyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)pyrrolidine-2-carboxylate.

實例1Example 1 (2S,4R)-2-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基胺基甲醯基)-4-(2,4-二甲基苯基磺醯基)吡咯啶-1-甲酸第三丁基酯(2S,4R)-2-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-ylaminomethylindolyl)-4-(2,4- Dimethyl phenylsulfonyl pyrrolidine-1-carboxylic acid tert-butyl ester

步驟1(「偶合」)：(2S,4R)-2-((2S,3S)-1-(環丙基胺基)-2-羥基-1-側氧基戊-3-基胺基甲醯基)-4-(2,4-二甲基苯基磺醯基)吡咯啶-1-甲酸第三丁基酯 Step 1 ("Coupling"): (2S,4R)-2-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-yloxypent-3-ylaminomethyl Tert-butyl)-4-(2,4-dimethylphenylsulfonyl)pyrrolidine-1-carboxylic acid tert-butyl ester

將(2S,4R)-1-(第三丁氧基羰基)-4-(2,4-二甲基苯基磺醯基)吡咯啶-2-甲酸(120 mg,313 μmol,Eq：1.00，如美國專利申請案US 20100267722中所述製備)、(2S,3S)-3-胺基-N-環丙基-2-羥基戊醯胺二鹽酸鹽(99.7 mg,407 μmol,Eq：1.3)、N,N-二異丙基乙基胺(121 mg,164 μl,939 μmol,Eq：3)及HATU(202 mg,532 μmol,Eq：1.7)與DMF(2 ml)合併，獲得淡褐色溶液。在RT下將反應物攪拌過夜。藉由製備型HPLC(管柱：ymc C18(120A)，75×30 mm，乙腈/水(+0.1%甲酸)=95%-5%至5%-95%，8 min，流速：25 ml/min)純化粗製材料。在蒸發溶劑後，獲得淡褐色發泡體狀標題化合物(64.3 mg,38.2%,MS(m/e)=538.3[M+H+])。 (2S,4R)-1-(Tertibutoxycarbonyl)-4-(2,4-dimethylphenylsulfonyl)pyrrolidine-2-carboxylic acid (120 mg, 313 μmol, Eq: 1.00 , (2S,3S)-3-Amino-N-cyclopropyl-2-hydroxypentanamine dihydrochloride (99.7 mg, 407 μmol, Eq: as described in US Patent Application No. US20100267722) 1.3), N,N-diisopropylethylamine (121 mg, 164 μl, 939 μmol, Eq: 3) and HATU (202 mg, 532 μmol, Eq: 1.7) were combined with DMF (2 ml) to obtain Light brown solution. The reaction was stirred at RT overnight. By preparative HPLC (column: ymc C18 (120A), 75 x 30 mm, acetonitrile / water (+0.1% formic acid) = 95% - 5% to 5% - 95%, 8 min, flow rate: 25 ml / Min) Purification of the crude material. The title compound (64.3 mg, 38.2%, MS (m/e) = 538.3 [M+H + ]).

步驟2(「氧化」)：(2S,4R)-2-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基胺基甲醯基)-4-(2,4-二甲基苯基磺醯基)吡咯啶-1-甲酸第三丁基酯 Step 2 ("Oxidation"): (2S,4R)-2-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-ylaminocarbamyl) -4-(2,4-dimethylphenylsulfonyl)pyrrolidine-1-carboxylic acid tert-butyl ester

將(2S,4R)-2-((2S,3S)-1-(環丙基胺基)-2-羥基-1-側氧基戊-3-基胺基甲醯基)-4-(2,4-二甲基苯基磺醯基)吡咯啶-1-甲酸第三丁基酯(64 mg,119 μmol,Eq：1.00)及戴斯-馬丁過碘烷(572 mg,202 μmol,Eq：1.7)與CH2Cl2(1 ml)合併。在RT下將反應物攪拌過夜。再次添加戴斯-馬丁過碘烷(280 mg)並攪拌5 h，直至接近完全轉化。用15 ml CH2Cl2及2×5 ml飽和Na2S2O3萃取反應物。經Na2SO4乾燥有機層並在真空中濃縮。藉由製備型HPLC純化粗製材料。獲得淡黃色膠狀標題化合物(52.5 mg,82.3%,MS(m/e)=536.24[M+H+])。 (2S,4R)-2-((2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxooxypent-3-ylaminocarbazyl)-4-( 2,4-Dimethylphenylsulfonylpyrrolidine-1-carboxylic acid tert-butyl ester (64 mg, 119 μmol, Eq: 1.00) and Dess-Martin periodinane (572 mg, 202 μmol, Eq: 1.7) combined with CH 2 Cl 2 (1 ml). The reaction was stirred at RT overnight. Dess-Martin periodinane (280 mg) was added again and stirred for 5 h until near complete conversion. The reaction was extracted with 15 ml of CH 2 Cl 2 and 2×5 mL of saturated Na 2 S 2 O 3 . The organic layer was concentrated, and Na 2 SO 4 dried in vacuo. The crude material was purified by preparative HPLC. The title compound was obtained as a pale yellow gum (52.5 mg, 82.3%, MS (m/e) = 536.24 [M+H + ]).

實例2Example 2 (2S,4R)-4-(4-氯-2-甲基苯基磺醯基)-2-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基胺基甲醯基)吡咯啶-1-甲酸第三丁基酯(2S,4R)-4-(4-chloro-2-methylphenylsulfonyl)-2-((S)-1-(cyclopropylamino)-1,2-di- oxypentyl 3-butylaminomethylmercapto)pyrrolidine-1-carboxylic acid tert-butyl ester

以與實例1類似之方式在步驟1中使用(2S,4R)-1-(第三丁氧基羰基)-4-(4-氯-2-甲基苯基磺醯基)吡咯啶-2-甲酸(如美國專利申請案US 20100267722中所述製備)來製備標題化合物。MS(m/e)=556.19[M+H+]。 (2S,4R)-1-(Tertibutoxycarbonyl)-4-(4-chloro-2-methylphenylsulfonyl)pyrrolidine-2 was used in Step 1 in a similar manner to Example 1. - The formic acid (prepared as described in U.S. Patent Application No. US20100267722) to prepare the title compound. MS (m/e) = 556.19 [M+H + ].

實例3Example 3 (2S,4R)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-1-(2-硝基苯基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)-1-(2-nitrophenyl)-4 -(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-(2-硝基苯基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲酸(如美國專利申請案US 20100267722中所述製備)來製備標題化合物。MS(m/e)=597.16[M+H+]。 (2S,4R)-1-(2-Nitrophenyl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2 was used in Step 1 in a similar manner to Example 1. - The formic acid (prepared as described in U.S. Patent Application No. US20100267722) to prepare the title compound. MS (m/e) = 597.16 [M+H + ].

實例4Example 4 (2S,4R)-1-(1-環丁基-3-甲基-1H-吡唑-5-基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(4-氟-2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-cyclobutyl-3-methyl-1H-pyrazol-5-yl)-N-((S)-1-(cyclopropylamino)-1,2 -di- oxypentan-3-yl)-4-(4-fluoro-2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-(1-環丁基-3-甲基-1H-吡唑-5-基)-N-((2S,3S)-1-(環丙基胺基)-2-羥基-1-側氧基戊-3-基)-4-(4-氟-2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺(如美國專利申請案US 20100267722中所述製備)來製備標題化合物。MS(m/e)=628.22[M+H+]。 (2S,4R)-1-(1-Cyclobutyl-3-methyl-1H-pyrazol-5-yl)-N-((2S,3S) was used in Step 1 in a similar manner to Example 1. 1-(cyclopropylamino)-2-hydroxy-1-oxoethoxy-3-yl)-4-(4-fluoro-2-(trifluoromethyl)phenylsulfonyl)pyrrolidine 2-Metamine (prepared as described in U.S. Patent Application No. US20100267722) to prepare the title compound. MS (m/e) = 628.22 [M+H + ].

實例5Example 5 (2S,4R)-1-(2-硝基-苯基)-4-(2-三氟甲基-苯磺醯基)-吡咯啶-2-甲酸[(S)-1-(苯并噁唑-2-羰基)-丙基]-醯胺(2S,4R)-1-(2-nitro-phenyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid [(S)-1-(benzo Oxazole-2-carbonyl)-propyl]-guanamine

以與實例1類似之方式在步驟1中使用(2S,4R)-1-(2-硝基苯基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲酸(如美國專利申請案US 20100267722中所述製備)及(2S)-2-胺基-1-(苯并[d]噁唑-2-基)丁-1-醇二鹽酸鹽來製備標題化合物。MS(m/e)=631.15[M+H+]。 (2S,4R)-1-(2-Nitrophenyl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2 was used in Step 1 in a similar manner to Example 1. - formic acid (prepared as described in U.S. Patent Application No. US20100267722) and (2S)-2-amino-1-(benzo[d]oxazol-2-yl)butan-1-ol dihydrochloride The title compound was prepared. MS (m/e) = 631.15 [M+H + ].

實例6Example 6 (2S,4R)-4-(4-溴-2-(三氟甲基)苯基磺醯基)-1-(1-環丁基-3-甲基-1H-吡唑-5-基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-4-(4-bromo-2-(trifluoromethyl)phenylsulfonyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazole-5-yl )-N-((S)-1-(cyclopropylamino)-1,2-di- oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-(2-硝基苯基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲酸(如美國專利申請案US 20100267722中所述製備)來製備標題化合物。MS(m/e)=690.14[M+H+]。 (2S,4R)-1-(2-Nitrophenyl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2 was used in Step 1 in a similar manner to Example 1. - The formic acid (prepared as described in U.S. Patent Application No. US20100267722) to prepare the title compound. MS (m/e) = 690.14 [M+H + ].

實例7Example 7 (2S,4R)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-1-(1-(三氟甲基)環丙烷羰基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-N-((S)-1-(cyclopropylamino)-1,2-di- oxypentan-3-yl)-1-(1-(trifluoromethyl) ring Propane carbonyl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-(1-(三氟甲基)環丙烷羰基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=612.16[M+H+]。 (2S,4R)-1-(1-(Trifluoromethyl)cyclopropanecarbonyl)-4-(2-(trifluoromethyl)phenylsulfonyl) was used in Step 1 in a similar manner to Example 1. Pyrrolidine-2-carboxylic acid to prepare the title compound. MS (m/e) = 612.16 [M+H + ].

實例8Example 8 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamine) -1,2-di- oxypent-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=620.13[M+H+]。 (2S,4R)-1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine- was used in Step 1 in a similar manner to Example 1. 2-carboxylic acid to prepare the title compound. MS (m/e) = 620.13 [M+H + ].

實例9Example 9 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamine) 1,1,2-di-hydroxyhex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-環丙基-2-羥基己醯胺及(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲酸來製備標題化合 物。MS(m/e)=634.15[M+H+]。 (2S,3S)-3-Amino-N-cyclopropyl-2-hydroxyhexylamine and (2S,4R)-1-(1-(4-) were used in Step 1 in a similar manner to Example 1. The title compound was prepared from chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidin-2-carboxylic acid. MS (m/e) = 634.15 [M+H + ].

實例10Example 10 (2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chloro-4-(2,2,2-trifluoroethoxy) Phenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯基磺醯基)吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=737.12[M+H+]。 (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chloro-4) was used in Step 1 in a similar manner to Example 1. -(2,2,2-Trifluoroethoxy)phenylsulfonyl)pyrrolidine-2-carboxylic acid to give the title compound. MS (m/e) = 737.12 [M+H + ].

實例11Example 11 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(4-(2,2,2-三氟乙氧基)-2-三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypenta- 3-yl)-4-(4-(2,2,2-trifluoroethoxy)-2-trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-[1-(4-氯-苯基)-環丙烷羰基]-4-[4-(2,2,2-三氟-乙氧基)-2-三氟甲基-苯磺醯基]-吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=752.16[M+H+]。 (2S,4R)-1-[1-(4-Chloro-phenyl)-cyclopropanecarbonyl]-4-[4-(2,2,2-three) was used in step 1 in a similar manner to Example 1. The title compound was prepared from fluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid. MS (m/e) = 752.16 [M+H + ].

實例12Example 12 (2S,4R)-N-((S)-1-(苯并[d]噁唑-2-基)-1-側氧基丁-2-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-N-((S)-1-(benzo[d]oxazol-2-yl)-1-yloxybutan-2-yl)-1-(1-(4-chloro) Phenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用2-胺基-1-苯并噁唑-2-基-丁-1-醇來製備標題化合物。MS(m/e)=654.12[M+H+]。 The title compound was prepared in a similar manner to Example 1 using 2-amino-1-benzoxazol-2-yl-butan-1-ol in Step 1. MS (m/e) = 654.12 [M+H + ].

實例13Example 13 (2S,4R)-1-(1-(4-氯-2-氟苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chloro-2-fluorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-( Cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(4-氯-2-氟-苯基)-環丙烷羰基]-吡咯啶-2-甲 酸來製備標題化合物。MS(m/e)=638.13[M+H+]。 (2S,4R)-4-(2-Chloro-phenylsulfonyl)-1-[1-(4-chloro-2-fluoro-phenyl)-cyclo was used in Step 1 in a similar manner to Example 1. Propane carbonyl]-pyrrolidine-2-carboxylic acid to give the title compound. MS (m/e) = 638.13 [M+H + ].

實例14Example 14 (2S,4R)-1-(1-(4-溴-2-氟苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-bromo-2-fluorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-( Cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-[1-(4-溴-2-氟-苯基)-環丙烷羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=684.08[M+H+]。 (2S,4R)-1-[1-(4-Bromo-2-fluoro-phenyl)-cyclopropanecarbonyl]-4-(2-chloro-benzenesulfonate) was used in Step 1 in a similar manner to Example 1. The title compound was prepared from fluorenyl)-pyrrolidine-2-carboxylic acid. MS (m/e) = 684.08 [M+H + ].

實例15Example 15 (2S,4R)-1-(1-(4-溴苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-bromophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamine) -1,2-di- oxypent-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-[1-(4-溴-苯基)-環丙烷羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=666.08[M+H+]。 (2S,4R)-1-[1-(4-Bromo-phenyl)-cyclopropanecarbonyl]-4-(2-chloro-phenylsulfonyl)- was used in Step 1 in a similar manner to Example 1. The title compound was prepared by pyrrolidine-2-carboxylic acid. MS (m/e) = 666.08 [M+H + ].

實例16Example 16 (2S,4R)-1-(1-(4-溴苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-(2S,4R)-1-(1-(4-bromophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)- N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺N-((S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-[1-(4-溴-苯基)-環丙烷羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-甲酸及(2S,3S)-3-胺基-N-環丙基-2-羥基己醯胺來製備標題化合物。MS(m/e)=680.1[M+H+]。 (2S,4R)-1-[1-(4-Bromo-phenyl)-cyclopropanecarbonyl]-4-(2-chloro-phenylsulfonyl)- was used in Step 1 in a similar manner to Example 1. The title compound was prepared by pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexylamine. MS (m/e) = 680.1 [M+H + ].

實例17Example 17 (2S,4R)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-1-(1-(4-碘苯基)環丙烷羰基)吡咯啶-2-甲醯胺(2S,4R)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypent-3-yl) 1-(1-(4-iodophenyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(4-碘-苯基)-環丙烷羰基]-吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=712.07[M+H+]。 (2S,4R)-4-(2-Chloro-phenylsulfonyl)-1-[1-(4-iodo-phenyl)-cyclopropanecarbonyl]- was used in Step 1 in a similar manner to Example 1. The title compound was prepared by pyrrolidine-2-carboxylic acid. MS (m/e) = 712.07 [M+H + ].

實例18Example 18 (2S,4R)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-1-(1-(4-碘苯基)環丙烷羰基)吡咯啶-2-甲醯胺(2S,4R)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl) 1-(1-(4-iodophenyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(4-碘-苯基)-環丙烷羰基]-吡咯啶-2-甲酸及(2S,3S)-3-胺基-N-環丙基-2-羥基己醯胺來製備標題化合物。MS(m/e)=726.09[M+H+]。 (2S,4R)-4-(2-Chloro-phenylsulfonyl)-1-[1-(4-iodo-phenyl)-cyclopropanecarbonyl]- was used in Step 1 in a similar manner to Example 1. The title compound was prepared by pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexylamine. MS (m/e) = 726.09 [M+H + ].

實例19Example 19 (2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2 -2-sided oxypent-3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-[1-(5-氯-3-氟-吡啶-2-基)-環丙烷羰基]-4-(2-三氟甲基-苯磺醯基)-吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=673.15[M+H+]。 (2S,4R)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-4-(2-tri) was used in step 1 in a similar manner to Example 1. The title compound was prepared from fluoromethyl-phenylsulfonyl)-pyrrolidine-2-carboxylic acid. MS (m/e) = 673.15 [M+H + ].

實例20Example 20 (2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2 -di-side oxyhex-3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-[1-(5-氯-3-氟-吡啶-2-基)-環丙烷羰基]-4-(2-三氟甲基-苯磺醯基)-吡咯啶-2-甲酸及(2S,3S)-3-胺基-N-環丙基-2-羥基己醯胺來製備標題化合物。MS(m/e)=687.17[M+H+]。 (2S,4R)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-4-(2-tri) was used in step 1 in a similar manner to Example 1. The title compound was prepared from fluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexylamine. MS (m/e) = 687.17 [M+H + ].

實例21Example 21 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypenta- 3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-[1-(4-氯-苯基)-環丙烷羰基]-4-(2-三氟甲基-苯磺醯基)-吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=654.16[M+H+]。 (2S,4R)-1-[1-(4-Chloro-phenyl)-cyclopropanecarbonyl]-4-(2-trifluoromethyl-benzenesulfonate) was used in Step 1 in a similar manner to Example 1. The title compound was prepared from pyridin-2-carboxylic acid. MS (m/e) = 654.16 [M+H + ].

實例22Example 22 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxyl- 3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-[1-(4-氯-苯基)-環丙烷羰基]-4-(2-三氟甲基-苯磺醯基)-吡咯啶-2-甲酸及(2S,3S)-3-胺基-N-環丙基-2-羥基己醯胺來製備標題化合物。MS(m/e)=668.18[M+H+]。 (2S,4R)-1-[1-(4-Chloro-phenyl)-cyclopropanecarbonyl]-4-(2-trifluoromethyl-benzenesulfonate) was used in Step 1 in a similar manner to Example 1. The title compound was prepared from pyridin-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexylamine. MS (m/e) = 668.18 [M+H + ].

實例23Example 23 (2S,4R)-1-(1-(5-溴-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(5-bromo-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)- 1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用1-(5-溴-3-氟吡啶-2-基)環丙烷甲酸來製備標題化合物。MS(m/e)=685.07[M+H+]。 The title compound was prepared in Step 1 using 1-(5-bromo-3-fluoropyridin-2-yl)cyclopropanecarboxylic acid in a similar manner as in Example 1. MS (m/e) = 685.07 [M+H + ].

實例24Example 24 (2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)- 1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(5-氯-3-氟-吡啶-2-基)-環丙烷羰基]-吡咯啶-2-甲酸及(2S,3S)-3-胺基-N-環丙基-2-羥基己醯胺來製備標題化合物。MS(m/e)=653.14[M+H+]。 (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl) was used in Step 1 in a similar manner to Example 1. The title compound is prepared by the formation of the title compound as a cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexylamine. MS (m/e) = 653.14 [M+H + ].

實例25Example 25 (2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)- 1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(5-氯-3-氟-吡啶-2-基)-環丙烷羰基]-吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=639.12[M+H+]。 (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl) was used in Step 1 in a similar manner to Example 1. The title compound is prepared as cyclopropylpropancarbonyl]-pyrrolidine-2-carboxylic acid. MS (m/e) = 639.12 [M+H + ].

實例26Example 26 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-(4-(環丙基胺基)-2-甲基-3,4-二側氧基丁-2-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(4-(cyclopropylamino)-2 -methyl-3,4-dioxabutan-2-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用3-胺基-N-環丙基-2-羥基-3-甲基丁醯胺來製備標題化合物。MS(m/e)=620.13[M+H+]。 The title compound was prepared in Step 1 using 3-amino-N-cyclopropyl-2-hydroxy-3-methylbutanamine in a similar manner as in Example 1. MS (m/e) = 620.13 [M+H + ].

實例27Example 27 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-(1-(2-(環丙基胺基)-2-側氧基乙醯基)環丙基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-(2-(cyclopropylamino) -2-oxoethoxyethyl)cyclopropyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用2-(1-胺基環丙基)-N-環丙基-2-羥基乙醯胺來製備標題化合物。MS(m/e)=618.12[M+H+]。 The title compound was prepared in Step 1 using 2-(1-aminocyclopropyl)-N-cyclopropyl-2-hydroxyacetamide in the same manner as in Example 1. MS (m/e) = 618.12 [M+H + ].

實例28Example 28 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-4-甲基-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamine) 4-methyl-1,2-di-oxypent-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-環丙基-2-羥基-4-甲基戊醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=632.14[M-H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-N-cyclopropyl-2-hydroxy-4-methylpentalamine dihydrochloride as the title compound. MS (m/e) = 632.14 [MH + ].

實例29Example 29 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-5-甲基-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamine) 5-)-5-methyl-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-環丙基-2-羥基-5-甲基己醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=646.15[M-H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-N-cyclopropyl-2-hydroxy-5-methylhexylamine dihydrochloride as the title compound. MS (m/e) = 646.15 [MH + ].

實例30Example 30 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-環己基-4-(環丙基胺基)-3,4-二側氧基丁-2-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-cyclohexyl-4- (cyclopropylamino)-3,4-dioxabutan-2-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-4-環己基-N-環丙基-2-羥基丁醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=686.19[M-H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-4-cyclohexyl-N-cyclopropyl-2-hydroxybutanamine dihydrochloride. MS (m/e) = 686.19 [MH + ].

實例31Example 31 (2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基戊-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-N-((S)-1-(butylamino)-1,2-di- oxypentan-3-yl)-1-(1-(4-chlorophenyl) ring Propane carbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-丁基-2-羥基戊醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=634.15[M-H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-N-butyl-2-hydroxypentalamine dihydrochloride as the title compound. MS (m/e) = 634.15 [MH + ].

實例32Example 32 (2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基己-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-N-((S)-1-(butylamino)-1,2-dihydroxyhex-3-yl)-1-(1-(4-chlorophenyl) ring Propane carbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-丁基-2-羥基己醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=648.17[M-H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-N-butyl-2-hydroxyhexylamine dihydrochloride. MS (m/e) = 648.17 [MH + ].

實例33Example 33 (2S,4R)-N-((S)-1-(苄基胺基)-1,2-二側氧基戊-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲(2S,4R)-N-((S)-1-(benzylamino)-1,2-di-oxypentan-3-yl)-1-(1-(4-chlorophenyl) ring Propane carbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-methyl 醯胺Guanamine

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-苄基-2-羥基戊醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=668.14[M-H+]。 The title compound was prepared in Step 1 using (2S,3S)-3-amino-N-benzyl-2-hydroxypentanamine dihydrochloride in the same manner as in Example 1. MS (m/e) = 668.14 [MH + ].

實例34Example 34 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-4-(環丙基胺基)-3,4-二側氧基丁-2-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-4-(cyclopropylamine) -3,4-di- oxybutan-2-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-環丙基-2-羥基丁醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=604.11[M-H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-N-cyclopropyl-2-hydroxybutanamine dihydrochloride. MS (m/e) = 604.11 [MH + ].

實例35Example 35 (2S,4R)-N-((S)-1-(苄基胺基)-1,2-二側氧基己-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-N-((S)-1-(benzylamino)-1,2-dihydroxyhex-3-yl)-1-(1-(4-chlorophenyl) ring Propane carbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-苄基-2-羥基己醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=682.15[M-H+]。 The title compound was prepared in Step 1 using (2S,3S)-3-amino-N-benzyl-2-hydroxyhexylamine dihydrochloride in a similar manner as in Example 1. MS (m/e) = 682.15 [MH + ].

實例36Example 36 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((3S)-1,2-二側氧基-1-(戊-2-基胺基)戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((3S)-1,2-di-oxo 1-(pent-2-ylamino)pent-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-2-羥基-N-(戊-2-基)戊醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=648.17[M-H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-2-hydroxy-N-(pent-2-yl)pentalinamine hydrochloride. MS (m/e) = 648.17 [MH + ].

實例37Example 37 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((3S)-1,2-二側氧基-1-(戊-2-基胺基)己-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((3S)-1,2-di-oxo 1-(pent-2-ylamino)hex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-2-羥基-N-(戊-2-基)己醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=664.2[M-H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-2-hydroxy-N-(pent-2-yl)hexylamine dihydrochloride as the title compound. MS (m/e) = 664.2 [MH + ].

實例38Example 38 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2,4-二氯苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypenta- 3-yl)-4-(2,4-dichlorophenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-[1-(4- 氯-苯基)-環丙烷羰基]-4-(2,4-二氯-苯磺醯基)-吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=656.09[M+H+]。 (2S,4R)-1-[1-(4-Chloro-phenyl)-cyclopropanecarbonyl]-4-(2,4-dichloro-benzenesulfonate) was used in Step 1 in a similar manner to Example 1. The title compound was prepared from pyridin-2-carboxylic acid. MS (m/e) = 656.09 [M+H + ].

實例39Example 39 (2S,4R)-4-(2-氯-4-氟苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-( Cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-1-[1-(4-氯-苯基)-環丙烷羰基]-吡咯啶-2-甲 酸來製備標題化合物。MS(m/e)=638.12[M+H+]。 (2S,4R)-4-(2-chloro-4-fluoro-phenylsulfonyl)-1-[1-(4-chloro-phenyl)-cyclo was used in Step 1 in a similar manner to Example 1. Propane carbonyl]-pyrrolidine-2-carboxylic acid to give the title compound. MS (m/e) = 638.12 [M+H + ].

實例40Example 40 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1,2-二側氧基-1-(2,2,2-三氟乙胺基)己-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1,2-di-oxo 1-(2,2,2-trifluoroethylamino)hex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-2-羥基-N-(2,2,2-三氟乙基)己醯胺來製備標題化合物。MS(m/e)=676.12[M+H+]。 The title compound was prepared in Step 1 using (2S,3S)-3-amino-2-hydroxy-N-(2,2,2-trifluoroethyl)hexylamine in the same manner as in Example 1. MS (m/e) = 676.12 [M+H + ].

實例41Example 41 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(異丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(isopropylamine 1,1,2-di-hydroxyhex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-2-羥基-N-異丙基己醯胺來製備標題化合物。MS(m/e)=636.17[M+H+]。 The title compound was prepared in Step 1 using (2S,3S)-3-amino-2-hydroxy-N-isopropylhexylamidine in the same manner as in Example 1. MS (m/e) = 636.17 [M+H + ].

實例42Example 42 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamine) 基)-1,2-二側氧基己-3-基)-4-(2,4-二氯苯基磺醯基)吡咯啶-2-甲醯胺-1,2-di-oxyhex-3-yl)-4-(2,4-dichlorophenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2,4-二氯苯基磺醯基)吡咯啶-2-甲酸及(2S,3S)-3-胺基-N-環丙基-2-羥基己醯胺來製備標題化合物。MS(m/e)=670.11[M+H+]。 (2S,4R)-1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-4-(2,4-dichlorophenylsulfonyl) was used in Step 1 in a similar manner to Example 1. The title compound was prepared by pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexylamine. MS (m/e) = 670.11 [M+H + ].

實例43Example 43 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(ethylamino) -1,2-di-oxypent-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-乙基-2-羥基戊醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=606.12[M-H+]。 The title compound was prepared in Step 1 using (2S,3S)-3-amino-N-ethyl-2-hydroxypentanamine dihydrochloride in the same manner as in Example 1. MS (m/e) = 606.12 [MH + ].

實例44Example 44 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(乙胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(ethylamino) -1,2-di-hydroxyhex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-乙基-2-羥基己醯胺二鹽酸鹽來製備標題化合物。MS(m/e)=622.15[M+H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-N-ethyl-2-hydroxyhexylamine dihydrochloride. MS (m/e) = 622.15 [M+H + ].

實例45Example 45 (2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙-2-基氧基)苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoroprop-2-yloxy)phenylsulfonyl)-1-(1-(4) -Chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-1-[1-(4-氯-苯基)-環丙烷羰基]-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=732.15[M+H+]。 (2S,4R)-1-[1-(4-Chloro-phenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-((S) was used in Step 1 in a similar manner to Example 1. -2,2,2-Trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid to give the title compound. MS (m/e) = 732.15 [M+H + ].

實例46Example 46 (2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙-2-基氧基)苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺(2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoroprop-2-yloxy)phenylsulfonyl)-1-(1-(4) -Chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-環丙基-2-羥基己醯胺及(2S,4R)-1-[1-(4-氯-苯基)-環丙烷羰基]-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=746.17[M+H+]。 (2S,3S)-3-Amino-N-cyclopropyl-2-hydroxyhexylamine and (2S,4R)-1-[1-(4-) were used in Step 1 in a similar manner to Example 1. Chloro-phenyl)-cyclopropanecarbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]- The title compound was prepared by pyrrolidine-2-carboxylic acid. MS (m/e) = 746.17 [M+H + ].

實例47Example 47 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基(甲基)胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropyl) Methyl)amino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-環丙基-2-羥基-N-甲基己醯胺來製備標題化合物。MS(m/e)=648.17[M+H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-N-cyclopropyl-2-hydroxy-N-methylhexylamine. MS (m/e) = 648.17 [M+H + ].

實例48Example 48 (2S,4R)-4-(2-氯-4-氟苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯(2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-( Cyclopropylamino)-1,2-di-oxyhex-3-yl)pyrrole 啶-2-甲醯胺Pyridyl-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-N-環丙基-2-羥基己醯胺及(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-1-[1-(4-氯-苯基)-環丙烷羰基]-吡咯啶-2-甲酸來製備標題化合物。MS(m/e)=652.14[M+H+]。 (2S,3S)-3-Amino-N-cyclopropyl-2-hydroxyhexylamine and (2S,4R)-4-(2-chloro-4) were used in Step 1 in a similar manner to Example 1. -Fluoro-phenylsulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid to give the title compound. MS (m/e) = 652.14 [M+H + ].

實例49Example 49 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1,2-二側氧基-1-(苯乙胺基)戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1,2-di-oxo 1-(phenylethylamino)pent-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-2-羥基-N-苯乙基戊醯胺來製備標題化合物。MS(m/e)=684.16[M+H+]。 The title compound was prepared in Step 1 using (2S,3S)-3-amino-2-hydroxy-N-phenylethylpentalamine in the same manner as in Example 1. MS (m/e) = 684.16 [M+H + ].

實例50Example 50 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(2-(萘-1-基)乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(2-(naphthalene) -1-yl)ethylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-2-羥基-N-(2-(萘-1-基)乙基)戊醯胺來製備標題化合物。MS(m/e)=734.18[M+H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-2-hydroxy-N-(2-(naphthalen-1-yl)ethyl)pentalamine in Step 1. MS (m/e) = 734.18 [M+H + ].

實例51Example 51 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(2-(萘-2-基)乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(2-(naphthalene) -2-yl)ethylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-2-羥基-N-(2-(萘-2-基)乙基)戊醯胺來製備標題化合物。MS(m/e)=734.18[M+H+]。 The title compound was prepared in the same manners as in Example 1 using (2S,3S)-3-amino-2-hydroxy-N-(2-(naphthalen-2-yl)ethyl)pentalamine. MS (m/e) = 734.18 [M+H + ].

實例52Example 52 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(萘-1-基甲基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(naphthalene-1- Methylamino)-1,2-di- oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,3S)-3-胺基-2-羥基-N-(萘-1-基甲基)戊醯胺來製備標題化合物。MS(m/e)=720.17[M+H+]。 The title compound was prepared in the same manner as in Example 1 using (2S,3S)-3-amino-2-hydroxy-N-(naphthalen-1-ylmethyl)pentalamine in Step 1. MS (m/e) = 720.17 [M+H + ].

實例53Example 53 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1,2-二側氧基-1-(四氫-2H-吡喃-4-基胺基)戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1,2-di-oxo -1-(tetrahydro-2H-pyran-4-ylamino)pent-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(4-氯-苯基)-環丙烷羰基]-吡咯啶-2-甲酸及(S)-3-胺基-2-側氧基-戊酸(四氫-吡喃-4-基)-醯胺來製備標題化合物。MS(m/e)=664.16[M+H+]。 (2S,4R)-4-(2-Chloro-phenylsulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]- was used in Step 1 in a similar manner to Example 1. The title compound was prepared by pyrrolidine-2-carboxylic acid and (S)-3-amino-2-oxo-pentanoic acid (tetrahydro-pyran-4-yl)-guanamine. MS (m/e) = 664.16 [M+H + ].

實例54Example 54 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(2-甲氧基乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(2-methoxy Ethylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(4-氯-苯基)-環丙烷羰基]-吡咯啶-2-甲酸及 (S)-3-胺基-2-側氧基-戊酸(2-甲氧基-乙基)-醯胺來製備標題化合物。MS(m/e)=638.15[M+H+]。 (2S,4R)-4-(2-Chloro-phenylsulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]- was used in Step 1 in a similar manner to Example 1. The title compound was prepared by pyrrolidine-2-carboxylic acid and (S)-3-amino-2-oxo-pentanoic acid (2-methoxy-ethyl)-decylamine. MS (m/e) = 638.15 [M+H + ].

實例55Example 55 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(異丁基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(isobutylamine) -1,2-di- oxypent-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(4-氯-苯基)-環丙烷羰基]-吡咯啶-2-甲酸及(S)-3-胺基-2-側氧基-戊酸異丁基-醯胺來製備標題化合物。MS(m/e)=636.17[M+H+]。 (2S,4R)-4-(2-Chloro-phenylsulfonyl)-1-[1-(4-chloro-phenyl)-cyclopropanecarbonyl]- was used in Step 1 in a similar manner to Example 1. The title compound was prepared by pyrrolidine-2-carboxylic acid and (S)-3-amino-2-oxo-pivalan isobutyl-decylamine. MS (m/e) = 636.17 [M+H + ].

實例56Example 56 (2S,4R)-4-(2-氯-4-嗎啉基苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-4-(2-chloro-4-morpholinylphenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1 -(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-4-嗎啉-4-基-苯磺醯基)-1-[1-(4-氯-苯基)-環丙烷羰基]-吡咯 啶-2-甲酸及(S)-3-胺基-2-側氧基-戊酸環丙基醯胺來製備標題化合物。MS(m/e)=705.19[M+H+]。 (2S,4R)-4-(2-Chloro-4-morpholin-4-yl-benzenesulfonyl)-1-[1-(4-chloro-) was used in Step 1 in a similar manner to Example 1. The title compound was prepared from phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-amino-2-oxo-pentanoic acid cyclopropyl decylamine. MS (m/e) = 705.19 [M+H + ].

實例57Example 57 (2S,4R)-4-(2-氯-4-嗎啉基苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺(2S,4R)-4-(2-chloro-4-morpholinylphenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1 -(cyclopropylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-4-嗎啉-4-基-苯磺醯基)-1-[1-(4-氯-苯基)-環丙烷羰基]-吡咯啶-2-甲酸及(S)-3-胺基-2-側氧基-己酸環丙基醯胺來製備標題化合物。MS(m/e)=719.20[M+H+]。 (2S,4R)-4-(2-Chloro-4-morpholin-4-yl-benzenesulfonyl)-1-[1-(4-chloro-) was used in Step 1 in a similar manner to Example 1. The title compound was prepared from phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-amino-2-oxo-hexanoic acid cyclopropyl decylamine. MS (m/e) = 719.20 [M+H + ].

實例58Example 58 (2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-4-甲基-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)- 1-(cyclopropylamino)-4-methyl-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯 磺醯基)-1-[1-(5-氯-3-氟-吡啶-2-基)-環丙烷羰基]-吡咯啶-2-甲酸及(S)-3-胺基-4-甲基-2-側氧基-戊酸環丙基醯胺來製備標題化合物。MS(m/e)=653.14[M+H+]。 (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl) was used in Step 1 in a similar manner to Example 1. The title compound was prepared as the cyclopropylpropanylcarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-amino-4-methyl-2-oxo-pentanoic acid cyclopropyl decylamine. MS (m/e) = 653.14 [M+H + ].

實例59Example 59 (2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-5-甲基-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺(2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)- 1-(cyclopropylamino)-5-methyl-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(5-氯-3-氟-吡啶-2-基)-環丙烷羰基]-吡咯啶-2-甲酸及(S)-3-胺基-5-甲基-2-側氧基-己酸環丙基醯胺來製備標題化合物。MS(m/e)=667.15[M+H+]。 (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl) was used in Step 1 in a similar manner to Example 1. The title compound was prepared as the cyclopropylpropanylcarbonyl]-pyrrolidine-2-carboxylic acid and (S)-3-amino-5-methyl-2-oxo-hexanoic acid cyclopropyl decylamine. MS (m/e) = 667.15 [M+H + ].

實例60Example 60 (2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基戊-3-基)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-N-((S)-1-(butylamino)-1,2-di-oxypent-3-yl)-1-(1-(5-chloro-3-fluoro) Pyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(5-氯-3-氟-吡啶-2-基)-環丙烷羰基]-吡咯啶- 2-甲酸及(S)-3-胺基-2-側氧基-戊酸丁基醯胺來製備標題化合物。MS(m/e)=655.15[M+H+]。 (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl) was used in Step 1 in a similar manner to Example 1. The title compound was prepared as the cyclopropylpropanylcarbonyl-pyrrolidine-2-carboxylic acid and (S)-3-amino-2-oxo-pentanoic acid butyl decylamine. MS (m/e) = 655.15 [M+H + ].

實例61Example 61 (2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基己-3-基)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-N-((S)-1-(butylamino)-1,2-dihydroxyhex-3-yl)-1-(1-(5-chloro-3-fluoro) Pyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(5-氯-3-氟-吡啶-2-基)-環丙烷羰基]-吡咯啶-2-甲酸及(S)-3-胺基-2-側氧基-己酸丁基醯胺來製備標題化合物。MS(m/e)=669.17[M+H+]。 (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl) was used in Step 1 in a similar manner to Example 1. The title compound was prepared as the cyclopropylpropanylcarbonyl-pyrrolidine-2-carboxylic acid and (S)-3-amino-2-oxo-hexanoic acid butyl decylamine. MS (m/e) = 669.17 [M+H + ].

實例62Example 62 (2S,4R)-N-((S)-1-(苄基胺基)-1,2-二側氧基己-3-基]-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺(2S,4R)-N-((S)-1-(benzylamino)-1,2-dihydroxyhex-3-yl]-1-(1-(5-chloro-3-fluoro) Pyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide

以與實例1類似之方式在步驟1中使用(2S,4R)-4-(2-氯-苯磺醯基)-1-[1-(5-氯-3-氟-吡啶-2-基)-環丙烷羰基]-吡咯啶-2-甲酸及(S)-3-胺基-2-側氧基-己酸苄基醯胺來製備標題化 合物。MS(m/e)=703.15[M+H+]。 (2S,4R)-4-(2-Chloro-benzenesulfonyl)-1-[1-(5-chloro-3-fluoro-pyridin-2-yl) was used in Step 1 in a similar manner to Example 1. The title compound was prepared as the cyclopropylpropanylcarbonyl-pyrrolidine-2-carboxylic acid and (S)-3-amino-2-oxo-hexanoic acid benzyl decylamine. MS (m/e) = 703.15 [M+H + ].

實例63Example 63 組織蛋白酶酶抑制分析Cathepsin inhibition assay

酶活性係藉由觀察因含有螢光團之肽受質解離所引起螢光強度之增加來量測，該螢光團之發射在完整肽中猝滅。 The enzyme activity is measured by observing an increase in the fluorescence intensity caused by the dissociation of the peptide containing the fluorophore, and the emission of the fluorophore is quenched in the intact peptide.

分析緩衝液：100 mM磷酸鉀pH 6.5，EDTA-Na 5 mM，Triton X-100 0.001%，DTT 5 mM。 Analytical buffer: 100 mM potassium phosphate pH 6.5, EDTA-Na 5 mM, Triton X-100 0.001%, DTT 5 mM.

酶(全部為1 nM)：人類及小鼠組織蛋白酶S、Cat K、Cat B、Cat L。 Enzymes (all 1 nM): human and mouse cathepsin S, Cat K, Cat B, Cat L.

受質(20 μM)：Z-Val-Val-Arg-AMC，只是Cat K使用Z-Leu-Arg-AMC(二者皆購自Bachem)。 Acceptance (20 μM): Z-Val-Val-Arg-AMC, except that Cat K uses Z-Leu-Arg-AMC (both from Bachem).

Z=苄基氧基羰基。 Z = benzyloxycarbonyl.

AMC=7-胺基-4-甲基-香豆素。 AMC = 7-amino-4-methyl-coumarin.

DTT=二硫代蘇糖醇。 DTT = dithiothreitol.

最終體積：100 μL。 Final volume: 100 μL.

激發360 nm，發射465 nm。 Excited 360 nm and emitted 465 nm.

將酶添加至96孔微量滴定板中之物質稀釋液中且利用受質開始反應。經20分鐘量測螢光發射，在此期間，在抑制劑不存在下觀察到線性增加。藉由標準方法計算IC50。 The enzyme was added to the material dilution in a 96-well microtiter plate and the reaction was started using the substrate. Fluorescence emission was measured over 20 minutes, during which a linear increase was observed in the absence of inhibitor. The IC 50 is calculated by standard methods.

已單獨地量測對人類Cat S、小鼠Cat S、人類Cat K、小鼠Cat K、人類Cat B、小鼠Cat B、人類Cat L及小鼠Cat L之抑制。對於本發明代表性化合物而言，針對人類Cat S、L、K及B獲得之結果在下表中以μM表示。 Inhibition of human Cat S, mouse Cat S, human Cat K, mouse Cat K, human Cat B, mouse Cat B, human Cat L, and mouse Cat L has been separately measured. For representative compounds of the invention, the results obtained for human Cat S, L, K and B are indicated in μM in the table below.

本發明化合物對組織蛋白酶S或對組織蛋白酶L或對組織蛋白酶S與組織蛋白酶L二者之IC50係0.00001 μM及100 μM、較佳介於0.00001 μM與50 μM之間、更佳介於0.00001 μM與20 μM之間。本發明特定化合物對組織蛋白酶S或對組織蛋白酶L或對組織蛋白酶S與組織蛋白酶L二 者之IC50低於0.03 μM。 The compound of the invention has an IC 50 of 0.00001 μM and 100 μM for cathepsin S or for cathepsin L or for both cathepsin S and cathepsin L, preferably between 0.00001 μM and 50 μM, more preferably between 0.00001 μM and Between 20 μM. The particular compound of the present invention to cathepsin S or cathepsin L or both of cathepsin S and cathepsin L IC 50 is below 0.03 μM.

實例AExample A

式(I)化合物可以本身已知之方式用作用於產生包含下列組份之錠劑的活性成份： The compounds of the formula (I) can be used in a manner known per se for the production of active ingredients comprising the following ingredients:

實例BInstance B

式(I)化合物可以本身已知之方式用作用於產生包含下列組份之膠囊的活性成份： The compounds of the formula (I) can be used in the form known per se as active ingredients for the production of capsules comprising the following components:

Claims (20)

一種式(I)化合物， 其中A係羰基或不存在；R1係烷氧基、硝基苯基、經烷基及環烷基取代之1H-吡唑基、烷基環烷基、鹵代烷基環烷基、苯基環烷基、鹵代苯基環烷基、吡啶基環烷基或鹵代吡啶基環烷基；R2及R3係獨立地選自氫、烷基及環烷基烷基；或R2與R3連同其所連接之碳原子一起形成環烷基；R4係-C(O)NR8R9或苯并噁唑基；R5、R6及R7係獨立地選自氫、烷基、鹵素、鹵代烷基、烷氧基、鹵代烷氧基及嗎啉基；且R8及R9中之一者係氫或烷基且另一者係烷基、烷氧基烷基、環烷基、鹵代烷基、苯基烷基、萘基烷基或四氫吡喃基；或其醫藥上可接受之鹽或酯。 a compound of formula (I), Wherein A is a carbonyl group or is absent; R 1 is an alkoxy group, a nitrophenyl group, a 1H-pyrazolyl group substituted by an alkyl group and a cycloalkyl group, an alkylcycloalkyl group, a halogenated alkylcycloalkyl group, a phenyl ring An alkyl group, a halophenylcycloalkyl group, a pyridylcycloalkyl group or a halopyridylcycloalkyl group; R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl and cycloalkylalkyl; or R 2 and R 3 together with the carbon atom to which it is attached forms a cycloalkyl group; R 4 is -C(O)NR 8 R 9 or benzoxazolyl; R 5 , R 6 and R 7 are independently selected from hydrogen, alkane a halogen, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, and a morpholinyl group; and one of R 8 and R 9 is hydrogen or an alkyl group and the other is an alkyl group, an alkoxyalkyl group, a cycloalkane Or a haloalkyl group, a phenylalkyl group, a naphthylalkyl group or a tetrahydropyranyl group; or a pharmaceutically acceptable salt or ester thereof. 如請求項1之化合物，其中R1係鹵代苯基環烷基或鹵代 吡啶基環烷基。 The compound of claim 1, wherein R 1 is halophenylcycloalkyl or halopyridylcycloalkyl. 如請求項1或2之化合物，其中R1係氯苯基環丙基、氯氟苯基環丙基、溴苯基環丙基、溴氟苯基環丙基或氯氟吡啶基環丙基。 The compound of claim 1 or 2, wherein R 1 is chlorophenylcyclopropyl, chlorofluorophenylcyclopropyl, bromophenylcyclopropyl, bromofluorophenylcyclopropyl or chlorofluoropyridylcyclopropyl . 如請求項1或2之化合物，其中R2及R3係獨立地選自氫及烷基。 The compound of claim 1 or 2, wherein R 2 and R 3 are independently selected from the group consisting of hydrogen and alkyl. 如請求項1或2之化合物，其中R2及R3係獨立地選自氫、甲基、乙基、丙基及丁基。 The compound of claim 1 or 2, wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl and butyl. 如請求項1或2之化合物，其中R5、R6及R7係獨立地選自鹵素、鹵代烷基及鹵代烷氧基。 The compound of claim 1 or 2, wherein R 5 , R 6 and R 7 are independently selected from the group consisting of halogen, haloalkyl and haloalkoxy. 如請求項1或2之化合物，其中R5、R6及R7係獨立地選自氫、氯、三氟甲基及三氟乙氧基。 The compound of claim 1 or 2, wherein R 5 , R 6 and R 7 are independently selected from the group consisting of hydrogen, chloro, trifluoromethyl and trifluoroethoxy. 如請求項1或2之化合物，其中R5係氯或三氟甲基。 The compound of claim 1 or 2, wherein R 5 is chloro or trifluoromethyl. 如請求項1或2之化合物，其中R6係氫。 A compound of claim 1 or 2 wherein R 6 is hydrogen. 如請求項1或2之化合物，其中R7係氫、氯或三氟乙氧基。 The compound of claim 1 or 2, wherein R 7 is hydrogen, chloro or trifluoroethoxy. 如請求項1或2之化合物，其中R8及R9中之一者係氫且另一者係烷基或環烷基。 A compound according to claim 1 or 2, wherein one of R 8 and R 9 is hydrogen and the other is alkyl or cycloalkyl. 如請求項1或2之化合物，其中R8及R9中之一者係氫且另一者係乙基、丙基、丁基或環丙基。 The compound of claim 1 or 2, wherein one of R 8 and R 9 is hydrogen and the other is ethyl, propyl, butyl or cyclopropyl. 如請求項1或2之化合物，其係選自(2S,4R)-2-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基胺基甲醯基)-4-(2,4-二甲基苯基磺醯基)吡咯啶-1-甲酸第三丁基酯； (2S,4R)-4-(4-氯-2-甲基苯基磺醯基)-2-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基胺基甲醯基)吡咯啶-1-甲酸第三丁基酯；(2S,4R)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-1-(2-硝基苯基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-環丁基-3-甲基-1H-吡唑-5-基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(4-氟-2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(2-硝基-苯基)-4-(2-三氟甲基-苯磺醯基)-吡咯啶-2-甲酸[(S)-1-(苯并噁唑-2-羰基)-丙基]-醯胺；(2S,4R)-4-(4-溴-2-(三氟甲基)苯基磺醯基)-1-(1-環丁基-3-甲基-1H-吡唑-5-基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-1-(1-(三氟甲基)環丙烷羰基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯- 4-(2,2,2-三氟乙氧基)苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(4-(2,2,2-三氟乙氧基)-2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(苯并[d]噁唑-2-基)-1-側氧基丁-2-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯-2-氟苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-溴-2-氟苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-溴苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-溴苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-1-(1-(4-碘苯基)環丙烷羰基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2- 二側氧基己-3-基)-1-(1-(4-碘苯基)環丙烷羰基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-溴-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯 基)-N-(4-(環丙基胺基)-2-甲基-3,4-二側氧基丁-2-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-(1-(2-(環丙基胺基)-2-側氧基乙醯基)環丙基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-4-甲基-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-5-甲基-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-環己基-4-(環丙基胺基)-3,4-二側氧基丁-2-基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基戊-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基己-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(苄基胺基)-1,2-二側氧基戊-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯 基)-N-((S)-4-(環丙基胺基)-3,4-二側氧基丁-2-基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(苄基胺基)-1,2-二側氧基己-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((3S)-1,2-二側氧基-1-(戊-2-基胺基)戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((3S)-1,2-二側氧基-1-(戊-2-基胺基)己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2,4-二氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-氟苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1,2-二側氧基-1-(2,2,2-三氟乙胺基)己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(異丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺 基)-1,2-二側氧基己-3-基)-4-(2,4-二氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(乙胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙-2-基氧基)苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙-2-基氧基)苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基(甲基)胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-氟苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1,2-二側氧基-1-(苯乙胺基)戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯 基)-N-((S)-1-(2-(萘-1-基)乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(2-(萘-2-基)乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(萘-1-基甲基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1,2-二側氧基-1-(四氫-2H-吡喃-4-基胺基)戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(2-甲氧基乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(異丁基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-嗎啉基苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-氯-4-嗎啉基苯基磺醯基)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯 苯基磺醯基)-N-((S)-1-(環丙基胺基)-4-甲基-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-5-甲基-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基戊-3-基)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基己-3-基)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；及(2S,4R)-N-((S)-1-(苄基胺基)-1,2-二側氧基己-3-基)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺。 A compound according to claim 1 or 2 which is selected from the group consisting of (2S,4R)-2-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-ylamine Tert-butyl)-4-(2,4-dimethylphenylsulfonyl)pyrrolidine-1-carboxylic acid tert-butyl ester; (2S,4R)-4-(4-chloro-2-methylphenylsulfonyl)-2-((S)-1-(cyclopropylamino)-1,2-di- oxypentyl 3-butylaminomercaptopyrrolidin-1-carboxylic acid tert-butyl ester; (2S,4R)-N-((S)-1-(cyclopropylamino)-1,2-di Phenoxylan-3-yl)-1-(2-nitrophenyl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S, 4R)-1-(1-cyclobutyl-3-methyl-1H-pyrazol-5-yl)-N-((S)-1-(cyclopropylamino)-1,2-di-side Oxypentan-3-yl)-4-(4-fluoro-2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(2- Nitro-phenyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid [(S)-1-(benzoxazole-2-carbonyl)-propyl] - guanamine; (2S,4R)-4-(4-bromo-2-(trifluoromethyl)phenylsulfonyl)-1-(1-cyclobutyl-3-methyl-1H-pyrazole -5-yl)-N-((S)-1-(cyclopropylamino)-1,2-di- oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S, 4R )-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)- 4-(2-(Trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4 -(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)- 1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2 -chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; 2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chloro- 4-(2,2,2-trifluoroethoxy)phenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di- oxypentane-3 -yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino) -1,2-di-oxypentan-3-yl)-4-(4-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)phenylsulfonyl) Pyrrrolidine-2-carbamide; (2S,4R)-N-((S)-1-(benzo[d]oxazol-2-yl)-1-yloxybutan-2-yl)- 1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-( 4-chloro-2-fluorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di Phenoxylan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-bromo-2-fluorophenyl)cyclopropanecarbonyl)-4-(2- Chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S ,4R)-1-(1-(4-bromophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino) -1,2-di-oxypenten-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-bromophenyl)cyclopropanecarbonyl)-4-( 2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-two side (2,4R)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino) -1,2-di-oxypentan-3-yl)-1-(1-(4-iodophenyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide; (2S,4R)-4- (2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2- Bisyloxyhex-3-yl)-1-(1-(4-iodophenyl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5- Chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypent-3-yl)-4- (2-(Trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl) ring Propane carbonyl)-N-((S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)-4-(2-(trifluoromethyl)phenylsulfonate Pyridyl-2-pyridinium; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino) -1,2-di-oxypentan-3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1 -(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-dihydrohex-3-yl)-4- (2-(Trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5-bromo-3-fluoropyridin-2-yl) ring Propane carbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypent-3-yl)pyrrolidine 2-carbamamine; (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)- N-((S)-1-(cyclopropylamino)-1,2-di (2-S,4-R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4- (2-Chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonate) -N-(4-(cyclopropylamino)-2-methyl-3,4-dioxabutan-2-yl)pyrrolidine-2-carboxamide; (2S,4R)- 1-(1-(4-Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-(2-(cyclopropylamino)-2-oxanoxy) (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-cyclopropyl)pyrrolidin-2-carboxamide Mercapto)-N-((S)-1-(cyclopropylamino)-4-methyl-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide; 2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino) -5-Methyl-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropane Carbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-cyclohexyl-4-(cyclopropylamino)-3,4-di- oxybutan-2- ()pyrrolidine-2-carboxamide; (2S,4R)-N-((S)-1-(butylamino)-1,2-di-oxypent-3-yl)-1- (1-(4-Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-N-((S)-1 -(butylamino)-1,2-dihydrohexyl-3-yl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonate) Pyrrolidine-2-carbamide; (2S,4R)-N-((S)- 1-(Benzylamino)-1,2-di-oxypentan-3-yl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonate Pyridyl-2-pyridinium; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonate) -N-((S)-4-(cyclopropylamino)-3,4-dioxabutan-2-yl)pyrrolidine-2-carboxamide; (2S,4R)-N -((S)-1-(benzylamino)-1,2-dihydroxyhex-3-yl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-( 2-Chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonate Indenyl)-N-((3S)-1,2-di-oxy-1-(pent-2-ylamino)pentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R )-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((3S)-1,2-di- oxy-1- (penta-2-ylamino)hex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-( (S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)-4-(2,4-dichlorophenylsulfonyl)pyrrolidine-2-yl Indoleamine; (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)- 1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl) Cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1,2-di-oxy-1-(2,2,2-trifluoroethylamino) Hex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropane Alkylcarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(isopropylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine 2-carbamamine; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamine) (1,2-di-oxyhex-3-yl)-4-(2,4-dichlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1- (1-(4-Chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(ethylamino)-1,2-di-oxo (2,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl) -N-((S)-1-(ethylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-4-(2 -Chloro-4-((S)-1,1,1-trifluoropropan-2-yloxy)phenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)- N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-4-(2 -Chloro-4-((S)-1,1,1-trifluoropropan-2-yloxy)phenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)- N-((S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1) -(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropyl(methyl)amino)-1,2 -2-sided oxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-1-(1-(4) -chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di- oxyhex-3 -yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N- ((S)-1,2-di-oxy-1-(phenylethylamino)pentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4 -chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonate) -N-((S)-1-(2-(naphthalen-1-yl)ethylamino)-1,2-di- oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(2-(naphthalene) -2-yl)ethylamino)-1,2-di-oxypenten-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl) Cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(naphthalen-1-ylmethylamino)-1,2-di-oxypenta- 3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N -((S)-1,2-di-oxy-1-(tetrahydro-2H-pyran-4-ylamino)pent-3-yl)pyrrolidine-2-carboxamide; (2S, 4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(2-methoxyethylamine) (1,2-di-oxypenten-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4 -(2-chlorophenylsulfonyl)-N-((S)-1-(isobutylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamidine Amine; (2S,4R)-4-(2-chloro-4-morpholinylphenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S) 1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide (2S,4R)-4-(2-chloro-4-morpholinylphenylsulfonyl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1 -(cyclopropylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5-chloro-3- Fluoridin-2-yl)cyclopropanecarbonyl)-4-(2-chloro Phenylsulfonyl)-N-((S)-1-(cyclopropylamino)-4-methyl-1,2-di-oxypent-3-yl)pyrrolidine-2-carboxamidine Amine; (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S )-1-(cyclopropylamino)-5-methyl-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-N-(( S)-1-(butylamino)-1,2-di-oxypentan-3-yl)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl) -4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-N-((S)-1-(butylamino)-1,2-two side Oxyhex-3-yl)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2- Methionine; and (2S,4R)-N-((S)-1-(benzylamino)-1,2-dihydroxyhex-3-yl)-1-(1-(5- Chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide. 如請求項1或2之化合物，其係選自(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺； (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(4-(2,2,2-三氟乙氧基)-2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(苯并[d]噁唑-2-基)-1-側氧基丁-2-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯-2-氟苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)-4-(2-(三氟甲基)苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺； (2S,4R)-1-(1-(5-氯-3-氟吡啶-2-基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-4-甲基-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(環丙基胺基)-5-甲基-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-N-((S)-1-(丁基胺基)-1,2-二側氧基戊-3-基)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-4-(環丙基胺基)-3,4-二側氧基丁-2-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-N-((S)-1-(環丙基胺基)-1,2-二側氧基戊-3-基)-4-(2,4-二氯苯基磺醯基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(異丙基胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺；(2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(乙胺基)-1,2-二側氧基戊-3-基)吡咯啶-2-甲醯胺；及 (2S,4R)-1-(1-(4-氯苯基)環丙烷羰基)-4-(2-氯苯基磺醯基)-N-((S)-1-(乙胺基)-1,2-二側氧基己-3-基)吡咯啶-2-甲醯胺。 A compound according to claim 1 or 2 which is selected from the group consisting of (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N -((S)-1-(cyclopropylamino)-1,2-di-oxypenten-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1- (4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxyl Hex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2- Chloro-4-(2,2,2-trifluoroethoxy)phenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypenta -3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypenta- 3-yl)-4-(4-(2,2,2-trifluoroethoxy)-2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S, 4R)-N-((S)-1-(benzo[d]oxazol-2-yl)-1-yloxybutan-2-yl)-1-(1-(4-chlorophenyl) Cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chloro-2-fluorophenyl)cyclopropane Carbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypent-3-yl)pyrrolidine- 2-carbamamine; (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamine) (1,2-di-oxypenten-3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)- 1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxyl -3-yl)-4-(2-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl) Cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)-4-(2-(trifluoromethyl)phenyl Sulfhydryl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl) ring Propane carbonyl)-N-((S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)-4-(2-(trifluoromethyl)phenylsulfonate (醯S)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenyl) Sulfhydryl)-N-((S)-1-(cyclopropylamino)-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(5-chloro-3-fluoropyridin-2-yl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)- 1-(cyclopropylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl) Cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(cyclopropylamino)-4-methyl-1,2-di-oxypenta -3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)- N-((S)-1-(cyclopropylamino)-5-methyl-1,2-dihydroxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R) -N-((S)-1-(butylamino)-1,2-di- oxypentan-3-yl)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4 -(2-chlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorobenzene -Sulphonyl)-N-((S)-4-(cyclopropylamino)-3,4-dioxabutan-2-yl)pyrrolidine-2-carboxamide; (2S,4R )-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-N-((S)-1-(cyclopropylamino)-1,2-di-oxypent-3-yl) -4-(2,4-dichlorophenylsulfonyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4- (2-chlorophenylsulfonyl)-N-((S)-1-(isopropylamino)-1,2 -2-sided oxyhex-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorobenzene -Sulphonyl)-N-((S)-1-(ethylamino)-1,2-di-oxypentan-3-yl)pyrrolidine-2-carboxamide; (2S,4R)-1-(1-(4-chlorophenyl)cyclopropanecarbonyl)-4-(2-chlorophenylsulfonyl)-N-((S)-1-(ethylamino) -1,2-di-hydroxyhex-3-yl)pyrrolidine-2-carboxamide. 一種製備如請求項1至14中任一項之式(I)化合物之方法，其包含使式(II)化合物 在氧化劑存在下反應，其中A及R1至R7係如請求項1至12中任一項中所定義。 A process for the preparation of a compound of formula (I) according to any one of claims 1 to 14, which comprises a compound of formula (II) The reaction is carried out in the presence of an oxidizing agent, wherein A and R 1 to R 7 are as defined in any one of claims 1 to 12. 如請求項1或2之化合物，其係根據如請求項15之方法製造。 A compound of claim 1 or 2, which is produced according to the method of claim 15. 如請求項1或2之化合物，其用作治療活性物質。 A compound of claim 1 or 2 for use as a therapeutically active substance. 一種醫藥組合物，其包含如請求項1至14中任一項之化合物及治療惰性載劑。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a therapeutically inert carrier. 一種如請求項1至14中任一項之化合物之用途，其用於製備用於以下目的之藥劑：治療或預防糖尿病、動脈粥樣硬化、腹部主動脈瘤、周邊動脈疾病、癌症，減少慢性腎病、糖尿病腎病變、糖尿病視網膜病變或年齡相關性黃斑變性中之心血管事件。 Use of a compound according to any one of claims 1 to 14 for the preparation of a medicament for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of chronic Cardiovascular events in nephropathy, diabetic nephropathy, diabetic retinopathy, or age-related macular degeneration. 如請求項1或2之化合物，其用於治療或預防糖尿病、動 脈粥樣硬化、腹部主動脈瘤、周邊動脈疾病、癌症，減少慢性腎病、糖尿病腎病變、糖尿病視網膜病變或年齡相關性黃斑變性中之心血管事件。 A compound according to claim 1 or 2 for use in the treatment or prevention of diabetes, Atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease, diabetic nephropathy, diabetic retinopathy or age-related macular degeneration.
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