TW201336837A - Novel azetidine derivatives - Google Patents

Abstract

The invention relates to a compound of formula (I) wherein A1, A2 and R1 to R8 are defined as in the description and in the claims. The compound of formula (I) can be used as a medicament.

Description

新穎氮雜環丁烷衍生物 Novel azetidine derivatives

本發明係關於適用於哺乳動物之治療及/或預防的有機化合物，且特定言之係關於半胱胺酸蛋白酶組織蛋白酶(特定言之係半胱胺酸蛋白酶組織蛋白酶S或L)之選擇性抑制劑化合物。 The present invention relates to organic compounds suitable for the treatment and/or prophylaxis of mammals, and in particular to the selectivity of the cysteine protease cathepsin (specifically, the cysteine protease cathepsin S or L) Inhibitor compound.

特定言之，本發明係關於式(I)的化合物或其醫藥上可接受之鹽或酯： In particular, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof:

其中A¹及A²之一為-NR⁹-且另一者為-CH₂-；R¹為鹵素；R²為氫、鹵素、烷基或鹵代烷基；R³為氫、鹵素、烷基或鹵代烷基；R⁴及R⁵同時為氫；或者，R⁴及R⁵與其等所鍵接之碳原子共同形成環烷基； R⁶為氫、鹵素、烷基、鹵代烷基或環烷基；R⁷為氫、鹵素、烷基、鹵代烷基或環烷基；R⁸為氫、烷基、鹵代烷基、烷氧基、鹵代烷氧基、環烷基、烷基吡啶基、烷基-1H-吡唑基、苯基、經取代之苯基、雜環基或經取代之雜環基，其中雜環基為吡啶基、嘧啶基、吡嗪基、噠嗪基、吡咯基、吡唑基、咪唑基、***基、噁唑基、異噁唑基、噁二唑基、噻吩基、噻唑基、噻二唑基、哌啶基、哌嗪基、吡咯啶基或嗎啉基，其中經取代之苯基為經一至三個獨立地選自下列之取代基取代之苯基：烷基、鹵素、環烷基、鹵代烷基、烷氧基、鹵代烷氧基、鹵代環烷基及腈，且其中經取代之雜環基為經一至三個獨立地選自下列之取代基取代之雜環基：烷基、鹵素、環烷基、鹵代烷基、烷氧基、鹵代烷氧基、鹵代環烷基及腈；且R⁹為氫、烷基、鹵代烷基、環烷基、醯基或烷氧羰基。 Wherein one of A ¹ and A ² is -NR ⁹ - and the other is -CH ₂ -; R ¹ is halogen; R ² is hydrogen, halogen, alkyl or haloalkyl; R ³ is hydrogen, halogen, alkyl Or a haloalkyl group; R ⁴ and R ^{5 are} simultaneously hydrogen; or R ⁴ and R ^{5 together} with the carbon atom to which they are bonded form a cycloalkyl group; R ⁶ is hydrogen, halogen, alkyl, haloalkyl or cycloalkyl ; R ⁷ is hydrogen, halogen, alkyl, haloalkyl or cycloalkyl; R ⁸ is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, alkylpyridyl, alkyl-1H a pyrazolyl group, a phenyl group, a substituted phenyl group, a heterocyclic group or a substituted heterocyclic group, wherein the heterocyclic group is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl , imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl or morpholinyl, wherein The substituted phenyl group is a phenyl group substituted with one to three substituents independently selected from the group consisting of alkyl, halogen, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halocycloalkyl and nitrile And its The substituted heterocyclic group is a heterocyclic group substituted with one to three substituents independently selected from the group consisting of alkyl, halogen, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halocycloalkane And nitrile; and R ⁹ is hydrogen, alkyl, haloalkyl, cycloalkyl, decyl or alkoxycarbonyl.

本發明化合物為半胱胺酸蛋白酶組織蛋白酶(Cat)(特定言之係組織蛋白酶S或組織蛋白酶L)的選擇性抑制劑且因此適用於治療代謝疾病，如：糖尿病、動脈粥樣硬化、腹主動脈瘤、外周動脈疾病、癌症、減少慢性腎病中的心血管事件、腎小球性腎炎、與年齡相關的黃斑變性、糖尿病性腎病及糖尿病性視網膜病變。此外，免疫介導性疾病(如類風濕性關節炎、克羅恩氏病(crohn’s disease)、多發性硬化症、休格蘭氏症候群(sjorgen syndrome)、紅斑狼瘡、神經性疼痛、I型糖尿病、哮喘及過敏症及與皮膚相關的免疫疾病)係適合經組織蛋白酶S抑制劑治療的疾病。 The compounds of the invention are selective inhibitors of the cysteine protease catalase (Cat) (specifically, cathepsin S or cathepsin L) and are therefore suitable 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 I diabetes) , asthma and allergies and skin-related immune diseases) are diseases suitable for treatment with cathepsin S inhibitors.

本發明之目標為一種式(I)化合物及其前述鹽本身及其作為治療活性物質的用途；一種製造該等化合物、中間物、醫藥組合物、包含該等化合物之藥物、其醫藥上可接受之鹽之方法；一種該等化合物及鹽用於預防及/或治療疾病，尤其係治療或預防糖尿病、動脈粥樣硬 化、腹主動脈瘤、外周動脈疾病、癌症、減少慢性腎病中的心血管事件及糖尿病性腎病之用途；及一種該等化合物及鹽於製造用於治療或預防糖尿病、動脈粥樣硬化、腹主動脈瘤、外周動脈疾病、癌症、減少慢性腎病中的心血管事件及糖尿病性腎病之藥物之用途。 The object of the invention is a compound of the formula (I) and the aforementioned salts themselves and their use as therapeutically active substances; a medicament for the manufacture of such compounds, intermediates, pharmaceutical compositions, medicaments comprising such compounds, which are pharmaceutically acceptable Method of using a salt; a compound and a salt thereof for preventing and/or treating a disease, particularly for treating or preventing diabetes, atherosclerosis , abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease and use of diabetic nephropathy; and a compound and salt thereof for the treatment or prevention of diabetes, atherosclerosis, abdomen Use of drugs for aortic aneurysm, peripheral arterial disease, cancer, cardiovascular events in reducing chronic kidney disease, and diabetic nephropathy.

哺乳動物的組織蛋白酶係與生物及病理事件之關鍵步驟相關的半胱胺酸型蛋白酶。組織蛋白酶被認為係易處理的藥物標靶，因為可利用小分子抑制酶活性，且因此受到醫藥工業的關注(Bromme,D.(2001)，「Papain-like cysteine proteases」，Curr Protoc Protein Sci，第21章，第21 2單元；Roberts,R.(2005)，「Lysosomal cysteine proteases：structure,function and inhibition of cathepsins」，Drug News Perspect，18(10)，605-14)。 Mammalian cathepsins are a cysteine-type protease associated with key steps in biological and pathological events. Cathepsins are considered to be easy-to-handle drug targets because small molecules can be used to inhibit enzyme activity and are therefore of interest to the pharmaceutical industry (Bromme, D. (2001), "Papain-like cysteine proteases", Curr Protoc Protein Sci, Chapter 21, Unit 21 2; 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係主要表現在抗原呈現細胞(如：巨噬細胞及樹突細胞及平滑肌細胞)中。(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)。雖然組織蛋白酶S在正常動脈組織中僅有微弱表現，但在動脈粥樣硬化性動脈中觀察到強烈的正調控(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)。 The cathepsin S system is mainly expressed 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 Protease and antigen presentation", Ernst Schering Res Found Workshop, (56), 81-95). Although cathepsin S showed only weak expression in normal arterial tissue, strong positive regulation was 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 et al. (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).

臨床前資料顯示組織蛋白酶S的功能對於動脈粥樣硬化係很重要，因為當在適合的小鼠模型中測試組織蛋白酶S缺陷小鼠時，其具 有減少之動脈粥樣硬化表型。有報告指出在LDL-Rec缺陷小鼠中出現脂肪堆積減少、彈性蛋白纖維分解及慢性動脈發炎。在APO E缺陷小鼠中報導了急性斑塊破裂事件的顯著減少。當在CatS/APO-E缺陷小鼠中引入慢性腎病時，在動脈及心臟瓣膜之抗動脈粥樣硬化活性之最高點時發現加速鈣化現象大幅減少(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)。此表示組織蛋白酶S之潛在抑制劑將會藉由減少細胞外基質分解、減少促炎狀態及減少加速鈣化及其隨後的臨床表現來穩定動脈粥樣硬化斑塊。 Preclinical data suggest that the function of cathepsin S is important for atherosclerosis because when cathepsin S deficient mice are tested in a suitable mouse model, There is a reduced atherosclerotic phenotype. There have been reports of decreased fat accumulation, elastin fiber breakdown, and chronic arterial inflammation in LDL-Rec deficient mice. A significant reduction in acute plaque rupture events was reported in APO E deficient mice. When chronic kidney disease was introduced in CatS/APO-E-deficient mice, accelerated calcification was found to be significantly reduced at the highest point of anti-atherosclerotic activity of arteries and heart valves (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 indicates that potential inhibitors of cathepsin S will stabilize atherosclerotic plaque by reducing extracellular matrix breakdown, reducing proinflammatory conditions, and reducing accelerated calcification and subsequent clinical manifestations.

此等在動脈粥樣硬化模型中描述的表型係與組織蛋白酶S之已知細胞功能一致。首先，組織蛋白酶S參與使斑塊穩定之細胞外基質的降解。特定言之，組織蛋白酶S具有強力的彈性蛋白酶分解活性且可在中性pH下發揮此功能，其係組織蛋白酶S區別於所有其他組織蛋白酶的一個特徵。其次，組織蛋白酶S係參與抗原加工(特定言之，在抗原呈現細胞中恆定鏈的裂解)的主要蛋白酶，此降低T細胞對動脈粥樣硬化組織之慢性發炎之影響。促進發炎進一步導致氧化性及蛋白質水解性組織損害並隨之造成斑塊不穩定(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 phenotypic lines described in the atherosclerosis model are consistent with the 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 elastase-decomposing activity and can function at neutral pH, which is a feature of cathepsin S that distinguishes it from all other cathepsins. Second, cathepsin S is involved in the major proteases of antigen processing (specifically, cleavage of the invariant chain in antigen-presenting cells), which reduces the effect of T cells on chronic inflammation of atherosclerotic tissue. Promoting inflammation further leads to oxidative and proteolytic tissue damage and consequent plaque instability (Cheng, X.W. 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酶分解特性亦使其成為慢性阻塞性肺病之顯著標靶(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，由於其在細胞外之基質降解功能，抑制組織蛋白酶S將會影響新生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)。組織蛋白酶S抑制劑因此可適用於若干不同的疾病模式中。 The anti-inflammatory and anti-elastase decomposition properties of Cat S inhibitors also make it a significant 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 matrix degradation function, 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). Cathepsin S inhibitors are therefore suitable for use in several different disease modes.

組織蛋白酶S同樣扮演了減緩腫瘤生長及腫瘤細胞侵入之角色(如Roberta E.Burden於Clin Cancer Res 2009；15(19)中所描述)。此外，腎切除之組織蛋白酶S基因剔除小鼠的動脈鈣化比腎切除的野生型小鼠顯著減少。此表示抑制組織蛋白酶S可對減少慢性腎病患者之心血 管事件具有有利影響(Elena Aikawa,Circulation,2009,1785-1794)。 Cathepsin S also plays a role in slowing tumor growth and tumor cell invasion (as described by Roberta E. Burden in Clin Cancer Res 2009; 15 (19)). In addition, arterial calcification in nephrectomized cathepsin S knockout mice was significantly reduced compared to nephrectomized wild-type mice. This means that inhibition of cathepsin S can reduce the efforts of patients with chronic kidney disease. Tube events have a beneficial effect (Elena Aikawa, Circulation, 2009, 1785-1794).

組織蛋白酶L顯示比組織蛋白酶S具有更廣泛的表現型態且同樣有數據顯示組織蛋白酶L在動脈粥樣硬化中的作用，例如：LDLrec與Cat L缺陷小鼠顯示減少的動脈粥樣硬化表型(Kitamoto,S.等人(2007)，「Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice」，Circulation，115(15)，2065-75)。此外，Cat L顯示與代謝症候群有關，因為其控制脂肪形成及周邊葡萄糖耐受性。在腎臟疾病中，組織蛋白酶L被描述為藉由蛋白質水解處理發動蛋白(dynamin)調節足細胞的功能並由此引起蛋白尿(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 showed a broader phenotype than cathepsin S and there is also data showing the role of cathepsin L in atherosclerosis, eg, LDLrec and Cat L-deficient mice show a reduced atherosclerotic phenotype (Kitamoto, S. et al. (2007), "Cathepsin L deficiency reduces diet-induced atherosclerosis in low-density lipoprotein receptor-knockout mice", Circulation, 115 (15), 2065-75). In addition, Cat L has been shown to be associated with metabolic syndrome because it controls adipogenesis and peripheral glucose tolerance. In kidney disease, cathepsin L is described as a dynamin that regulates podocyte function and thereby causes proteinuria by protein hydrolysis (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).

組織重建、細胞外基質降解、活性神經肽的生成及於胸腺上皮細胞中的抗原呈現作用均係組織蛋白酶L之細胞活性(Funkelstein等人(2008)，(a)「Major role of cathepsin L for producing the peptide hormones ACTH,β-Endorphin,and α-MSH,illustrated by protease gene knockout and expression」，Journal of Biological Chemistry，283(51)，35652-35659；(b)「Cathepsin L participates in the production of neuropeptide Y in secretory vesicles,demonstrated by protease gene knockout and expression」，Journal of Neurochemistry,106(1)，384-391；Rudensky and Beers 2006)。 Tissue remodeling, degradation of extracellular matrix, production of active neuropeptides, and antigen presentation in thymic epithelial cells are all cellular activities of cathepsin L (Funkelstein et al. (2008), (a) "Major role of cathepsin L for producing" The peptide hormones ACTH, β-Endorphin, and α-MSH, illustrated by protease gene knockout and expression", Journal of Biological Chemistry, 283(51), 35652-35659; (b) "Cathepsin L participates in the production of neuropeptide Y In secretory vesicles, demonstrated by protease gene knockout and expression", Journal of Neurochemistry, 106 (1), 384-391; Rudensky and Beers 2006).

在本文中，術語「烷基」單獨或組合地表示含有1至8個碳原子的直鏈或分支鏈烷基，特定言之含有1至6個碳原子的直鏈或分支鏈烷基及尤其含有1至4個碳原子的直鏈或分支鏈烷基。直鏈及分支鏈C1-C8烷基之實例為甲基、乙基、丙基、異丙基、丁基、異丁基、第三 丁基、異構化戊基、異構化己基、異構化庚基及異構化辛基，特定言之為甲基、乙基、丙基、異丙基、異丁基及第三丁基，更特定言之為甲基及乙基。 As used herein, the term "alkyl", alone or in combination, denotes a straight or branched alkyl group containing from 1 to 8 carbon atoms, in particular a straight or branched alkyl group having from 1 to 6 carbon atoms and especially A linear or branched alkyl group having 1 to 4 carbon atoms. Examples of straight-chain and branched C1-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and third. Butyl, isomerized pentyl, isomerized hexyl, isomerized heptyl and isomerized octyl, specifically methyl, ethyl, propyl, isopropyl, isobutyl and tert-butyl Base, more specifically methyl and ethyl.

術語「環烷基」單獨或組合地表示含有3至8個碳原子的環烷基環及特定言之3至6個碳原子的環烷基環。C3-C8環烷基之實例為環丙基、環丁基、環戊基、環己基、環庚基及環辛基。特定環烷基為環丙基、環丁基、環戊基及環己基。環丙基特定為環烷基。 The term "cycloalkyl", alone or in combination, denotes a cycloalkyl ring containing from 3 to 8 carbon atoms and, in particular, a cycloalkyl ring of from 3 to 6 carbon atoms. Examples of C3-C8 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Particular cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclopropyl group is specifically a cycloalkyl group.

術語「烷氧基」單獨或組合地表示如式為烷基-O-的基團(其中術語「烷基」係如先前所定義)，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，特定言之為甲氧基及第三丁氧基。 The term "alkoxy", alone or in combination, means a group of the formula alkyl-O- (wherein the term "alkyl" is as previously defined), eg methoxy, ethoxy, n-propoxy Isopropoxy, n-butoxy, isobutoxy, second butoxy and tert-butoxy are, in particular, methoxy and tert-butoxy.

術語「氧基」單獨或組合地表示-O-基團。 The term "oxy" refers to the -O- group, alone or in combination.

術語「鹵素」或「鹵代」單獨或組合地表示氟、氯、溴或碘，特定言之為氟、氯或溴。 The term "halogen" or "halo", alone or in combination, means fluoro, chloro, bromo or iodo, in particular fluorine, chlorine or bromine.

術語「鹵代烷基」、「鹵代環烷基」及「鹵代烷氧基」單獨或組合地表示經至少一個鹵素取代，特定言之經一至五個鹵素取代，尤其經一至三個鹵素取代之烷基、環烷基及烷氧基。氟烷基為經至少一個氟原子取代，特定言之經一至五個氟原子取代，更特定言之經一至三個氟原子取代之烷基。特定鹵代烷基為二氟乙基及三氟乙基。特定鹵代烷氧基為三氟乙氧基及三氟丙氧基。 The terms "haloalkyl", "halocycloalkyl" and "haloalkoxy", alone or in combination, mean substituted by at least one halogen, in particular by one to five halogens, especially one to three halogens. , cycloalkyl and alkoxy. A fluoroalkyl group is an alkyl group substituted with at least one fluorine atom, specifically one to five fluorine atoms, more specifically one to three fluorine atoms. Particular haloalkyl groups are difluoroethyl and trifluoroethyl. Particular haloalkoxy groups are trifluoroethoxy and trifluoropropoxy.

術語「羰基」單獨或組合地代表-C(O)-基團。 The term "carbonyl" alone or in combination represents a -C(O)- group.

術語「醯基」係單獨或組合地用於表示甲醯基(-CH(O))。 The term "mercapto" is used alone or in combination to mean a fluorenyl group (-CH(O)).

術語「醫藥上可接受之鹽」係指彼等鹽，其保持游離鹼或游離酸的並非生物上或其他方面非所欲的生物有效性及性質。該等鹽係由無機酸(如鹽酸酸、氫溴酸、硫酸、硝酸、磷酸，特定言之為鹽酸)及有機酸(如乙酸、丙酸、羥乙酸、丙酮酸、草酸、馬來酸、丙二酸、 琥珀酸、富馬酸、酒石酸、檸檬酸、苯甲酸、肉桂酸、杏仁酸、甲磺酸、乙磺酸、對甲苯磺酸、水楊酸、N-乙醯半胱胺酸)形成。此外，此等鹽可由將無機鹼或有機鹼添加至游離酸中製得。衍生自無機鹼的鹽包括(但不限於)：鈉鹽、鉀鹽、鋰鹽、銨鹽、鈣鹽、鎂鹽。衍生自有機鹼的鹽包括(但不限於)一級胺、二級胺及三級胺、經取代之胺(包括天然生成的經取代之胺)、環胺及鹼離子交換樹脂(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-乙基哌啶、哌啶、聚乙烯亞胺樹脂)的鹽。式(I)化合物亦可以兩性離子形式存在。式(I)化合物之特定醫藥上可接受之鹽為鹽酸、氫溴酸、硫酸、磷酸及甲磺酸鹽。 The term "pharmaceutically acceptable salts" refers to salts which retain the biological effectiveness and properties of the free base or free acid which are not biologically or otherwise undesirable. The salts are composed of inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, specifically hydrochloric acid) and organic acids (such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, Malonate, Formed from succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine. Further, such salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts. Salts derived from organic bases include, but are not limited to, primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and alkali ion exchange resins (eg, isopropylamine, A salt of trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyethyleneimine resin. The compounds of formula (I) may also exist in zwitterionic form. Specific pharmaceutically acceptable salts of the compounds of formula (I) are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and methanesulfonate.

「醫藥上可接受之酯」意指通式(I)化合物之官能基可經衍生以獲得可在活體內再轉化成母體化合物之衍生物。該等化合物之實例包括生理上可接受且代謝上不安定之酯衍生物，如甲氧基甲酯、甲硫基甲酯及新戊醯氧基甲酯。此外，類似於該等代謝上不安定的酯且可在活體內產生通式(I)母體化合物之通式(I)化合物之任何生理上可接受的等效物係在本發明之範圍內。 "Pharmaceutically acceptable ester" means that the functional group of the compound of formula (I) can be derivatized to obtain a derivative which can be further converted into the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically unstable ester derivatives such as methoxymethyl ester, methylthiomethyl ester and neopentyloxymethyl ester. Furthermore, any physiologically acceptable equivalent of a compound of formula (I) which is similar to such metabolically labile esters and which produces a parent compound of formula (I) in vivo is within the scope of the invention.

如果一種起始材料或式(I)化合物包含一或多個在一或多個反應步驟的反應條件下係不安定或具有反應性之官能基，則可在關鍵步驟之前利用此項技術中熟知之方法引入合適的保護基(如T.W.Greene及P.G.M.Wutts，「Protective Groups in Organic Chemistry」，第三版，1999，Wiley，New York中所描述)。該等保護基可在之後的合成階段中使用文獻資料中所述之標準方法來移除。保護基之實例係第三丁氧羰基(Boc)、胺基甲酸9-茀基甲酯(Fmoc)、胺基甲酸2-三甲基矽烷基乙酯(Teoc)、苄氧羰基(Cbz)及對甲氧基苄氧羰基(Moz)。 If a starting material or a 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, it may be well known in the art prior to the critical step. The method introduces a suitable protecting group (as described in TW Greene and PGM Wuts, "Protective Groups in Organic Chemistry", Third Edition, 1999, Wiley, New York). These 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 carbazate (Fmoc), 2-trimethyldecyl carbazate (Teoc), benzyloxycarbonyl (Cbz) and P-methoxybenzyloxycarbonyl (Moz).

式(I)化合物可包含若干個不對稱中心且可以光學純對映體、對映體混合物(例如外消旋物)、非對映異構體混合物、非對映異構體外 消旋物或非對映異構體外消旋物的混合物之形式存在。 The compound of formula (I) may contain several asymmetric centers and may be optically pure enantiomers, enantiomeric mixtures (eg racemates), diastereomeric mixtures, diastereomers in vitro The racemate or a mixture of diastereomeric racemates is present in the form of a mixture.

術語「不對稱碳原子」意指含有四個不同取代基的碳原子。根據Cahn-Ingold-Prelog規則，不對稱碳原子可為「R」或「S」構型。 The term "asymmetric carbon atom" means a carbon atom containing four different substituents. According to the Cahn-Ingold-Prelog rule, asymmetric carbon atoms can be in the "R" or "S" configuration.

特定言之，本發明係關於以下各項：一種式(I)化合物，其中A¹為-NR⁹-；一種式(I)化合物，其中A¹為-CH₂-；一種式(I)化合物，其中A²為-NR⁹-；一種式(I)化合物，其中A²為-CH₂-；一種式(I)化合物，其中R¹為氯或溴；一種式(I)化合物，其中R²為氫；一種式(I)化合物，其中R³為氫或鹵素；一種式(I)化合物，其中R³為氫或氟；一種式(I)化合物，其中R⁴及R⁵與其等所鍵接的碳原子一起形成環丙基；一種式(I)化合物，其中R⁶為鹵素；一種式(I)化合物，其中R⁶為氯；一種式(I)化合物，其中R⁷為氫；一種式(I)化合物，其中R⁸為氫、鹵素、烷氧基、鹵代烷氧基、環烷基、烷基吡啶基或烷基-1H-吡唑基；一種式(I)化合物，其中R⁸為氫、鹵素、烷氧基、鹵代烷氧基、烷基吡啶基或烷基-1H-吡唑基；一種式(I)化合物，其中R⁸為氫、氟、甲氧基、三氟乙氧基、三氟丙氧基、甲基吡啶基或甲基-1H-吡唑基；一種式(I)化合物，其中R⁹為氫、烷基、鹵代烷基、環烷基、甲醯基或烷氧羰基；一種式(I)化合物，其中R⁹為氫、烷基、鹵代烷基或烷氧羰基； 一種式(I)化合物，其中R⁹為氫或烷基；一種式(I)化合物，其中R⁹為氫、基、乙基、第三丁氧羰基或二氟乙基；一種式(I)化合物，其中R⁹為氫、甲基或乙基；一種式(I)化合物，其中R⁹為氫、烷基、鹵代烷基、甲醯基或烷氧羰基；及一種式(I)化合物，其中R⁹為氫、甲基、乙基、二氟乙基、甲醯基、甲氧羰基或三氟乙基。 In particular, the present invention relates to the following: a compound of formula (I) wherein A ¹ is -NR ⁹ -; a compound of formula (I) wherein A ¹ is -CH ₂ -; a compound of formula (I) Wherein A ² is -NR ⁹ -; a compound of formula (I) wherein A ² is -CH ₂ -; a compound of formula (I) wherein R ¹ is chloro or bromo; a compound of formula (I) wherein R ² is hydrogen; a compound of formula (I) wherein R ³ is hydrogen or halogen; a compound of formula (I) wherein R ³ is hydrogen or fluoro; a compound of formula (I) wherein R ⁴ and R ⁵ are equivalent thereto The bonded carbon atoms together form a cyclopropyl group; a compound of formula (I) wherein R ⁶ is halogen; a compound of formula (I) wherein R ⁶ is chloro; a compound of formula (I) wherein R ⁷ is hydrogen; A compound of formula (I), wherein R ⁸ is hydrogen, halogen, alkoxy, haloalkoxy, cycloalkyl, alkylpyridyl or alkyl-1H-pyrazolyl; a compound of formula (I) wherein R ⁸ is hydrogen, halogen, alkoxy, haloalkoxy, alkylpyridyl or alkyl-1H-pyrazolyl; a compound of formula (I) wherein R ⁸ is hydrogen, fluoro, methoxy, trifluoroethyl Oxyl, trifluoropropoxy, methyl Piperidinyl, or methyl -1H- pyrazol-yl; a compound of formula (I),; of formula (I) compounds wherein R ⁹ is hydrogen, alkyl, haloalkyl, cycloalkyl, methyl acyl or an alkoxycarbonyl group Wherein R ⁹ is hydrogen, alkyl, haloalkyl or alkoxycarbonyl; a compound of formula (I) wherein R ⁹ is hydrogen or alkyl; a compound of formula (I) wherein R ⁹ is hydrogen, hydryl, ethyl, a third butoxycarbonyl or difluoroethyl; a compound of formula (I) wherein R ⁹ is hydrogen, methyl or ethyl; a compound of formula (I) wherein R ⁹ is hydrogen, alkyl, haloalkyl, A acyl or alkoxycarbonyl group; and a compound of formula (the I), wherein R ⁹ is hydrogen, methyl, ethyl, difluoroethyl, methyl acyl, methoxycarbonyl or trifluoroethyl.

本發明另外係關於一種式(I)化合物，其係選自：3-[(2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-3-(5-氯-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-1-[3-(5-氯-吡啶-2-基)-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-1-[3-(5-氯-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；3-(5-氯-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；3-(5-溴-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-1-[3-(5-氯-吡啶-2-基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-吡啶-2-基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺； (2S,4R)-1-[3-(5-氯-吡啶-2-基)-1-(2,2-二氟-乙基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-吡啶-2-基)-1-(2,2-二氟-乙基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；3-[(2S,4R)-4-(2-氯-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-3-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯；3-(5-溴-3-氟吡啶-2-基)-3-((2S,4R)-4-(2-氯苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-1-(3-(5-氯-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-乙基-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-4-(2-氯-苯磺醯基)-1-[3-(5-氯-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；3-(5-氯-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；3-(5-溴-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯； (2S,4R)-1-(3-(5-溴-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；(2S,4R)-1-(3-(5-氯-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯；2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；2-(5-氯-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙烷-2-基氧基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯；2-(5-氯-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙烷- 2-基氧基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-4-(2-溴-4-氟-苯磺醯基)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；3-(5-溴-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-(2-氯-4-氟-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；2-(5-氯-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；2-(5-氯-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-(1-甲基-1H-吡唑-4-基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-(1-甲基-1H-吡唑-4-基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯； (2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(1-甲基-1H-吡唑-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；及(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(1-甲基-1H-吡唑-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺。 The invention further relates to a compound of formula (I) selected from the group consisting of: 3-[(2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-2-(1- Cyanyl-cyclopropylamine-carbamoyl)-pyrrolidine-1-carbonyl]-3-(5-chloro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester; 2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro-pyridin-2-yl)-azetidin-3-carbonyl ]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1- [3-(5-Chloro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-indole Amine; 3-(5-chloro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzene Sulfhydryl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 3-(5- Bromo-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-2- (1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1-[3-( 5-chloro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl ]-pyrrolidine-2- Acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-azetidin-3-carbonyl]-4 -[2-Chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-chloro-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4- [2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4-[ 2-Chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 3- [(2S,4R)-4-(2-Chloro-phenylsulfonyl)-2-(1-cyano-cyclopropylaminecarbamimidyl)-pyrrolidin-1-carbonyl]-3-(5- Chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester; 3-(5-bromo-3-fluoropyridin-2-yl)-3-((2S) , 4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropylaminecarboxyl)pyrrolidine-1-carbonyl)azetidin-1-carboxylic acid Butyl ester; (2S,4R)-1-(3-(5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chlorophenylsulfonyl) -N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-aza Cyclobutane-3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)-1 -[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidine 3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3 -(5-bromo-3-fluoro-pyridin-2-yl)-1-ethyl-azetidin-3-carbonyl]-4-(2-chloro-phenylsulfonyl)-pyrrolidine-2 -carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[3-(5-chloro-3-fluoro- Pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 3-(5-chloro 3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl] 2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 3-(5-bromo-3- Fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-2- (1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1-(3-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2, 2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(3-(5-chloro- 3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2,2-trifluoroethoxy)benzenesulfonyl)-N- (1-cyanocyclopropyl)pyrrolidine-2-carboxamide; 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyanide Benzyl-cyclopropylamine-mercapto)-pyrrolidin-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl Ester; 2-(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-phenylsulfonyl)-2-(1) -Cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 2-[(2S,4R)-4-(2- Chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl]-2-(5-chloro-3-fluoro-pyridine- 3-butyl)-azetidine-1-carboxylic acid tert-butyl ester; 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1 -cyano-cyclopropylaminecarbamimidyl-pyrrolidine-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid Tributyl ester; 2-(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2 S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminocarbamimidyl)-pyrrolidine-1-carbonyl]-azacyclocycle Butane-1-carboxylic acid tert-butyl ester; 2-(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro- Benzenesulfonyl)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 2-(5 -Chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoropropan-2-yloxy) Terphenyl) phenylsulfonyl)-2-(1-cyanocyclopropylaminecarboxamido)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; 2-(5- Chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoropropane- 3-butyloxy)benzenesulfonyl)-2-(1-cyanocyclopropylamine-methylindenyl)pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; -(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro-1 -methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidin-1-carbonyl]-azetidine-1-carboxylic acid Third butyl ester; 2-(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2, 2-Trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl]-azetidine (3S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridine- 2-yl)-azetidin-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-bromo- 4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-pyrrolidin-2-carboxylic acid ( 1-cyano-cyclopropyl)-guanamine; 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-( (S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1 -carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S, 4R )-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2, 2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)- 4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-pyrrole Pyridin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azacyclocycle Butane-2-carbonyl]-4-(2-chloro-4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R )-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S)-2, 2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)- 1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro- 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)- Indoleamine; (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4- ((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-[2-chloro 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl) - decylamine; 2-(5-chloro-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridine-4- Tert-butyl benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid; -(5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl)-benzenesulfonate Tertyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)- 1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2-methyl-pyridine-4 -yl)-phenylsulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R )-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2-methyl-pyridine) 4-yl)-phenylsulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; 2-(5-chloro-3-fluoropyridin-2-yl)- 2-((2S,4R)-4-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl)-2-(1-cyanocyclopropylamine) Tert-butyl pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; 2-(5-bromo-3-fluoropyridin-2-yl)-2-((2S,4R) )-4-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl)-2-(1-cyanocyclopropylaminecarboxamido)pyrrolidine- 1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1- Methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; and (2S,4R)-1-[ 2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1-methyl-1H-pyrazole-4 -yl)-phenylsulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine.

特定言之，本發明係關於一種式(I)化合物，其係選自：(2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-1-[3-(5-氯-吡啶-2-基)-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-(3-(5-氯-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-乙基-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-4-(2-氯-苯磺醯基)-1-[3-(5-氯-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-(3-(5-溴-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；(2S,4R)-1-(3-(5-氯-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-溴-4-氟-苯磺醯基)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；及(2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(1-甲基-1H-吡唑-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺。 In particular, the present invention relates to a compound of formula (I) selected from the group consisting of: (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3- (5-chloro-pyridin-2-yl)-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)- 1-(3-(5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyano ring Propyl)pyrrolidine-2-carboxamide; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]- 4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo- 3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1- Cyano-cyclopropyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-ethyl-azetidin-3 -carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro -Benzenesulfonyl)-1-[3-(5-chloro-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidine-2-carboxylate Acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-(3-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-carbonyl) -4-(2-chloro-4-(2,2) ,2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(3-(5-chloro) 3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2,2-trifluoroethoxy)benzenesulfonyl)-N -(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-4-(2-bromo-4-fluoro-benzenesulfonyl)-1-[2-(5- Chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R) 1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro- 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)- Indoleamine; (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4- ((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(( S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-[2-chloro-4 -((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-indole Amine; (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-( 2-methyl-pyridin-4-yl)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; and (2S,4R)-1-[2 -(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1-methyl-1H-pyrazole-4- () Benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine.

特定言之，本發明另外係關於一種式(I)化合物，其係選自：(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-(2,2-二氟-乙基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲醯基-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；3-(5-溴-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]- 氮雜環丁烷-1-羧酸甲酯；及(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-(2,2,2-三氟-乙基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺。 In particular, the invention relates additionally to a compound of formula (I) selected from the group consisting of: (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1- (2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl -ethoxyphenyl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-3 -fluoro-pyridin-2-yl)-1-carbenyl-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; 3-(5-bromo-3-fluoro-pyridine- 2-yl)-3-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonate 2-(1-cyano-cyclopropylaminocarboxamido)-pyrrolidine-1-carbonyl]- Methyl azetidine-1-carboxylate; and (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-(2,2,2- Trifluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy) -Benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine.

可使用此項技術中已知的步驟來製備式(I)化合物。亦可使用以下步驟來製備式(I)化合物。 The compounds of formula (I) can be prepared using procedures known in the art. The following procedure can also be used to prepare the compound of formula (I).

在本說明書中使用以下縮略詞。 The following abbreviations are used in this specification.

AcOEt：乙酸乙酯；ACN：乙腈；BOP：六氟磷酸苯并***基-N-氧基-叁(二甲胺基)-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；DCM：二氯甲烷；DIEA：二異丙基乙胺；DMF：N,N-二甲基甲醯胺；EDCI：N-(3-二甲胺基丙基)-N’-乙基-碳化二亞胺鹽酸鹽；h：小時；HATU：六氟磷酸O-(7-氮雜苯并***-1-基)-1,1,3,3-四甲基脲鎓；HOBT：1-羥基苯并***；休尼格(Hunig’s)鹼：乙基-二異丙基-胺；KHMDS：雙(三甲基矽烷基)醯胺鉀；LDA：二異丙基醯胺鋰；LHMDS：雙(三甲基矽烷基)醯胺鋰；MeOH：乙醇；Mes-Cl：甲磺醯氯；min：分鐘； Na₂SO₄：硫酸鈉；Nos-Cl：3-硝基苯磺醯氯；Pd₂(dba)₃：叁(二亞苄基丙酮)二鈀；PyBOP：六氟磷酸苯并***-1-基-氧基三吡咯啶鏻；TBTU：四氟硼酸O-(苯并***-1-基)-N,N,N’,N’-四甲基脲鎓；THF：四氫呋喃；TFA：三氟乙酸；及Tos-Cl：甲苯-4-磺醯氯。 AcOEt: ethyl acetate; ACN: acetonitrile; BOP: benzotriazolyl-N-oxy-oxime (dimethylamino)-oxime; BOP-Cl: bis-(2- oxo-3 - oxazolidinyl)-phosphinium chloride; CDI: 1,1'-carbonyldiimidazole; DCM: dichloromethane; DIEA: diisopropylethylamine; DMF: N,N-dimethylformamide ;EDCI: N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride; h: hour; HATU: hexafluorophosphate O-(7-azabenzotriazole) -1-yl)-1,1,3,3-tetramethyluronium; HOBT: 1-hydroxybenzotriazole; Hunig's base: ethyl-diisopropyl-amine; KHMDS: Bis(trimethyldecyl) potassium decylamine; LDA: lithium diisopropyl guanamine; LHMDS: lithium bis(trimethyldecyl) guanamine; MeOH: ethanol; Mes-Cl: methylsulfonium chloride; : minute; Na ₂ SO ₄ : sodium sulfate; Nos-Cl: 3-nitrobenzenesulfonyl chloride; Pd ₂ (dba) ₃ : hydrazine (dibenzylideneacetone) dipalladium; PyBOP: benzotrifluorophosphate Zindol-1-yl-oxytripyrrolidinium; TBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; THF: tetrahydrofuran TFA: trifluoroacetic acid; and Tos-Cl: toluene-4-sulfonium chloride.

R¹-R³係如上所定義；R為(例如)甲基、乙基、異丙基或苄基；鹼1為(例如)NaOtBu、KOtBu、NaH、LiHMDS、KHMDS或LDA；鹼2為(例如)LiOH、NaOH或KOH。 R ¹ -R ³ are as defined above; R is, for example, methyl, ethyl, isopropyl or benzyl; base 1 is, for example, NaOtBu, KOtBu, NaH, LiHMDS, KHMDS or LDA; base 2 is ( For example) LiOH, NaOH or KOH.

在鹼(如上所定義之鹼1)的存在下，利用Boc-保護型氮雜環丁烷衍生物2處理2-氟吡啶衍生物(例如1)，以生成氮雜環丁烷衍生物3。利用鹼(如上所定義之鹼2)處理化合物3以生成最終的羧酸衍生物7(呈游離酸或其鹽形式)。 The 2-fluoropyridine derivative (for example, 1) is treated with a Boc-protected azetidine derivative 2 in the presence of a base (base 1 as defined above) to form azetidine derivative 3. Compound 3 is treated with a base (base 2 as defined above) to form the final carboxylic acid derivative 7 (in the form of the free acid or its salt).

R¹-R³係如上所定義；R為(例如)甲基、乙基、異丙基或苄基；鹼1 為(例如)NaOtBu、KOtBu、NaH、LiHMDS、KHMDS或LDA；鹼2為(例如)LiOH、NaOH或KOH。 R ¹ -R ³ are as defined above; R is, for example, methyl, ethyl, isopropyl or benzyl; base 1 is, for example, NaOtBu, KOtBu, NaH, LiHMDS, KHMDS or LDA; base 2 is ( For example) LiOH, NaOH or KOH.

在鹼(如上所定義之鹼1)的存在下，利用Boc-保護型氮雜環丁烷衍生物5處理2-氟吡啶衍生物(例如1)，以生成氮雜環丁烷衍生物6。利用鹼(如上所定義之鹼2)處理化合物6以生成最終的羧酸衍生物7(呈游離酸或其鹽形式)。 The 2-fluoropyridine derivative (e.g., 1) is treated with a Boc-protected azetidine derivative 5 in the presence of a base (base 1 as defined above) to form the azetidine derivative 6. Compound 6 is treated with a base (base 2 as defined above) to form the final carboxylic acid derivative 7 (in the form of the free acid or its salt).

LG為離去基，如：三氟甲磺酸酯、甲磺酸酯、甲苯磺酸酯、對溴苯磺酸酯或對硝基苯磺酸酯；R⁴-R⁸係如上所定義；R為(例如)甲基、乙基、異丙基或苄基。 LG is a leaving group such as: trifluoromethanesulfonate, mesylate, tosylate, p-bromobenzenesulfonate or p-nitrobenzenesulfonate; R ⁴ -R ⁸ are as defined above; R is, for example, a methyl group, an ethyl group, an isopropyl group or a benzyl group.

使Boc-保護型脯胺酸衍生物8與2-氯苯基硫醇衍生物在鹼(如三乙胺、DIEA、2,6-二甲基吡啶等)的存在下反應以生成硫醚衍生物9。使用過氧化物試劑(如H₂O₂、過硫酸氫鉀製劑(oxone)、MCPBA)氧化9，以生成碸衍生物10。使用鹼(如LiOH、NaOH、KOH等)使該酯皂化成 酸，以生成相應的羧酸11或其鹽。藉由使11與1-胺基-環丙烷-甲腈及偶合劑(如EDCI、CDI、BOP-Cl、TBTU、HATU、PyBOP、BOP等)在鹼(如DIEA、三乙胺、二甲基吡啶等)的存在下反應來實現醯胺偶合，以生成醯胺12。最後，藉由使用酸(如TFA、含於有機溶劑(例如AcOEt、二噁烷)中之HCl或甲酸)處理化合物12來移除Boc-保護基，以生成胺13。 The Boc-protected proline derivative 8 is reacted with a 2-chlorophenylthiol derivative in the presence of a base such as triethylamine, DIEA, 2,6-lutidine, etc. to form a thioether derivative. Matter 9. Oxidation 9 is carried out using a peroxide reagent such as H ₂ O ₂ , oxone, MCPBA to form an anthracene derivative 10. The ester is saponified to an acid using a base such as LiOH, NaOH, KOH or the like to form the corresponding carboxylic acid 11 or a salt thereof. By using 11 with 1-amino-cyclopropane-carbonitrile and a coupling agent (such as EDCI, CDI, BOP-Cl, TBTU, HATU, PyBOP, BOP, etc.) in a base (such as DIEA, triethylamine, dimethyl The reaction is carried out in the presence of pyridine or the like to effect indoleamine coupling to form indoleamine 12. Finally, the Boc-protecting group is removed by treatment of compound 12 with an acid such as TFA, HCl or formic acid in an organic solvent (eg, AcOEt, dioxane) to afford amine 13.

R¹-R⁹係如上所定義；酸為(例如)TFA、HCl或甲酸；X為離去基，如Cl、Br、I、三氟甲磺酸酯、甲磺酸酯、甲苯磺酸酯、苯磺酸酯、對溴苯磺酸酯或對硝基苯磺酸酯；R¹⁰為(例如)烷基、鹵代烷基或環烷基；Y為(例如)H、烷基或鹵代烷基。 R ¹ -R ⁹ are as defined above; the acid is, for example, TFA, HCl or formic acid; X is a leaving group such as Cl, Br, I, triflate, mesylate, tosylate , benzenesulfonate, p-bromobenzenesulfonate or p-nitrobenzenesulfonate; R ¹⁰ is, for example, an alkyl group, a haloalkyl group or a cycloalkyl group; Y is, for example, H, an alkyl group or a haloalkyl group.

使羧酸4與胺13在醯胺偶合劑(如EDCI、CDI、BOP-Cl、TBTU、HATU、PyBOP、BOP等)之一及鹼(如DIEA、三乙胺、2,6-二甲基吡啶 等)的存在下反應，以生成醯胺14。使用含於有機溶劑(如二噁烷、AcOEt)中之酸(如TFA、甲酸、HCl)使化合物14去保護生成胺15。可使用烷基化試劑R⁹-X(如烷基鹵、磺酸酯等)或藉由還原胺化使該胺15烷基化，以生成胺16。對於後者而言，R¹⁰-C(O)-Y為醛或酮；R¹⁰為(例如)烷基、鹵代烷基或環烷基；Y為(例如)氫、烷基或鹵代烷基；還原劑為(例如)NaBH₄、NaCNBH₃或三乙醯氧基硼氫化鈉。 One of carboxylic acid 4 and amine 13 in a guanamine coupling agent (such as EDCI, CDI, BOP-Cl, TBTU, HATU, PyBOP, BOP, etc.) and a base (such as DIEA, triethylamine, 2,6-dimethyl The reaction is carried out in the presence of pyridine or the like to form guanamine 14. Compound 14 is deprotected to form amine 15 using an acid (e.g., TFA, formic acid, HCl) in an organic solvent (e.g., dioxane, EtOAc). The amine 15 can be alkylated using an alkylating agent R ⁹ -X (e.g., an alkyl halide, sulfonate, etc.) or by reductive amination to form the amine 16. For the latter, R ¹⁰ -C(O)-Y is an aldehyde or a ketone; R ¹⁰ is, for example, an alkyl group, a haloalkyl group or a cycloalkyl group; Y is, for example, a hydrogen, an alkyl group or a halogenated alkyl group; For example, NaBH ₄ , NaCNBH ₃ or sodium triethoxy borohydride.

R¹-R⁸係如上所定義；酸為(例如)TFA、HCl或甲酸。 R ¹ -R ⁸ are as defined above; the acid is, for example, TFA, HCl or formic acid.

使羧酸7與胺13在醯胺偶合劑(如EDCI、CDI、BOP-Cl、TBTU、HATU、PyBOP、BOP等)之一及鹼(如DIEA、三乙胺、二甲基吡啶等)的存在下反應，以生成醯胺17。使用含於有機溶劑(如二噁烷、AcOEt)中之酸(如TFA、甲酸、HCl)使化合物17去保護，以生成胺18。 Making carboxylic acid 7 and amine 13 in one of the guanamine coupling agents (such as EDCI, CDI, BOP-Cl, TBTU, HATU, PyBOP, BOP, etc.) and alkali (such as DIEA, triethylamine, lutidine, etc.) The reaction is present to form the guanamine 17. Compound 17 is deprotected using an acid (e.g., TFA, formic acid, HCl) in an organic solvent (e.g., dioxane, AcOEt) to afford amine 18.

R¹-R⁷及R⁹係如上所定義；LG為如上所定義之離去基；R⁸為烷氧基或鹵代烷氧基；R為烷基或鹵代烷基；酸為(例如)TFA、HCl或甲酸；X為離去基，如Cl、Br、I、三氟甲磺酸酯、甲磺酸酯、甲苯磺酸酯、苯磺酸酯、對溴苯磺酸酯或對硝基苯磺酸酯；R¹⁰為(例如)烷基、鹵代烷基或環烷基；Y為(例如)H、烷基或鹵代烷基。 R ¹ -R ⁷ and R ⁹ are as defined above; LG is a leaving group as defined above; R ⁸ is alkoxy or haloalkoxy; R is alkyl or haloalkyl; and the acid is, for example, TFA, HCl Or formic acid; X is a leaving group such as Cl, Br, I, triflate, mesylate, tosylate, benzenesulfonate, p-bromobenzenesulfonate or p-nitrobenzenesulfonate An acid ester; R ¹⁰ is, for example, an alkyl group, a halogenated alkyl group or a cycloalkyl group; and Y is, for example, H, an alkyl group or a halogenated alkyl group.

使化合物14與醇R-OH在鹼(如Na₂CO₃、K₂CO₃、Cs₂CO₃、三乙胺、DIEA等)的存在下反應，以生成醚19。在有機溶劑(如二噁烷、AcOEt)中使用酸(如TFA、甲酸、HCl)使醚19去保護，以生成胺20。使用烷基化試劑R⁹-X(如鹵化物、磺酸酯等)或藉由還原胺化使胺20烷基化，以生成胺21。對於後者而言，R¹⁰-C(O)-Y為醛或酮；R¹⁰(例如)為烷基、鹵代烷基或環烷基；Y為(例如)氫、烷基或鹵代烷基；還原劑為(例如)NaBH₄、NaCNBH₃或三乙醯氧基硼氫化鈉。 Compound 14 is reacted with an alcohol R-OH in the presence of a base such as Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , triethylamine, DIEA, etc. to give ether 19. Ether 19 is deprotected using an acid (e.g., TFA, formic acid, HCl) in an organic solvent (e.g., dioxane, AcOEt) to afford amine 20. The amine 20 is alkylated using an alkylating agent R ⁹ -X (e.g., a halide, sulfonate, etc.) or by reductive amination to form the amine 21. For the latter, R ¹⁰ -C(O)-Y is an aldehyde or a ketone; R ^{10 is} , for example, an alkyl group, a haloalkyl group or a cycloalkyl group; Y is, for example, a hydrogen, an alkyl group or a halogenated alkyl group; For example, NaBH ₄ , NaCNBH ₃ or sodium triethoxy borohydride.

R¹-R⁷係如上所定義；LG為如上所定義之離去基；R⁸為烷氧基或鹵代烷氧基；R為烷基或鹵代烷基；酸為(例如)TFA、HCl或甲酸。 R ¹ -R ⁷ are as defined above; LG is a leaving group as defined above; R ⁸ is alkoxy or haloalkoxy; R is alkyl or haloalkyl; and the acid is, for example, TFA, HCl or formic acid.

使化合物17與醇R-OH在鹼(如Na₂CO₃、K₂CO₃、Cs₂CO₃、三乙胺、DIEA等)的存在下反應，以生成醚22。在有機溶劑(如二噁烷、AcOEt)中使用酸(如TFA、甲酸、HCl)使醚22去保護，以生成胺23。 Compound 17 is reacted with an alcohol R-OH in the presence of a base such as Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , triethylamine, DIEA, etc. to give ether 22. The ether 22 is deprotected using an acid (e.g., TFA, formic acid, HCl) in an organic solvent (e.g., dioxane, AcOEt) to afford the amine 23.

R¹-R⁷係如上所定義；LG為離去基，如Cl、Br、I；R⁸為如上所定義之苯基、經取代之苯基、雜環基或經取代之雜環基；R為H或甲基，或兩個R與其等所鍵接的硼原子一起形成環，如2,4,4,5,5-五甲基-[1,3,2]二氧雜硼戊環；酸為(例如)TFA、HCl或甲酸。 R ¹ -R ⁷ are as defined above; LG is a leaving group such as Cl, Br, I; R ⁸ is a phenyl group, a substituted phenyl group, a heterocyclic group or a substituted heterocyclic group as defined above; R is H or methyl, or two R together with the boron atom to which it is bonded form a ring, such as 2,4,4,5,5-pentamethyl-[1,3,2]dioxaborolan Ring; acid is, for example, TFA, HCl or formic acid.

使化合物17與酸或酯衍生物26在鹼(如Na₂CO₃、K₂CO₃、Cs₂CO₃、KOtBu、K₃PO₄等)及此項技術中已知的用於鈴木(Suzuki)反應之觸媒(如Pd(PPh₃)₄、具有膦配體之Pd₂(dba)₃等)的存在下反應，以 生成聯芳衍生物24。在有機溶劑(如二噁烷、AcOEt)中使用酸(如TFA、甲酸、HCl)使化合物24去保護，以生成胺25。 Compound 17 with The acid or ester derivative 26 is in the base (e.g., Na ₂ CO ₃ , K ₂ CO ₃ , Cs ₂ CO ₃ , KOtBu, K ₃ PO _{4 ,} etc.) and the touch for the Suzuki reaction known in the art. The reaction is carried out in the presence of a medium such as Pd(PPh ₃ ) ₄ , Pd ₂ (dba) ₃ having a phosphine ligand, or the like to form a biaryl derivative 24 . Compound 24 is deprotected using an acid such as TFA, formic acid, HCl in an organic solvent such as dioxane, AcOEt to afford amine 25.

本發明另外係關於一種製備如上所定義之式(I)化合物之方法，其包含以下步驟中之一者：(a)使式(II)化合物在酸存在下反應： The invention further relates to a process for the preparation of a compound of formula (I) as defined above, which comprises one of the following steps: (a) reacting a compound of formula (II) in the presence of an acid:

其中R¹至R⁸係如上所定義，A¹及A²之一為-CH₂-且另一者為-NR¹⁰-，其中R¹⁰為胺保護基；(b)使式(III)化合物在R⁹-X的存在下反應： Wherein R ¹ to R ⁸ are as defined above, one of A ¹ and A ² is -CH ₂ - and the other is -NR ¹⁰ -, wherein R ¹⁰ is an amine protecting group; (b) a compound of formula (III) Reaction in the presence of R ⁹ -X:

其中A¹、A²及R¹至R⁹係如上所定義；或(c)使如上所定義之式(III)化合物在R¹⁰-C(O)-Y及還原劑的存在下反應，其中A¹、A²及R¹至R⁹係如上所定義，R¹⁰為烷基、鹵代烷基或環烷基且Y為氫、烷基或鹵代烷基。 Wherein A ¹ , A ² and R ¹ to R ⁹ are as defined above; or (c) reacting a compound of formula (III) as defined above in the presence of R ¹⁰ -C(O)-Y and a reducing agent, wherein A ¹ , A ² and R ¹ to R ⁹ are as defined above, R ¹⁰ is alkyl, haloalkyl or cycloalkyl and Y is hydrogen, alkyl or haloalkyl.

在步驟(a)中，該酸為(例如)TFA、HCl或甲酸。 In step (a), the acid is, for example, TFA, HCl or formic acid.

在步驟(a)中，該胺保護基為(例如)Boc、Fmoc、Cbz、Teoc、苄基或Moz。 In step (a), the amine protecting group is, for example, Boc, Fmoc, Cbz, Teoc, benzyl or Moz.

在步驟(c)中，該還原劑為(例如)NaBH₄、NaCNBH₃或三乙醯氧基硼氫化鈉。 In step (c), the reducing agent is, for example, NaBH ₄ , NaCNBH ₃ or sodium triethoxy borohydride.

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

該等式(I)化合物及其醫藥上可接受之鹽可用作藥物(例如呈醫藥製劑形式)。該等醫藥製劑可內服，例如：口服(例如呈錠劑、包衣錠劑、糖衣丸劑、硬式及軟式明膠膠囊、溶液、乳液或懸浮液形式)、經鼻(如呈鼻噴霧劑形式)或直腸給藥(例如呈栓劑形式)。然而，亦可非經腸(如肌內或靜脈內(例如呈注射液形式))給藥。 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 may be administered orally, for example, orally (for example, in the form of lozenges, coated lozenges, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example in the form of a nasal spray) or Rectal administration (for example in the form of a suppository). However, it can also be administered parenterally (e.g., intramuscularly or intravenously (e.g., in the form of an injection)).

該等式(I)化合物及其醫藥上可接受之鹽可經過用於生產錠劑、包衣錠劑、糖衣丸劑及硬明膠膠囊的醫藥上惰性的無機或有機佐劑處理。可使用(例如)乳糖、玉米澱粉或其衍生物、滑石、硬脂酸或其鹽等作為該等用於錠劑、糖衣丸劑及硬明膠膠囊的佐劑。 The compound of the formula (I) and pharmaceutically acceptable salts thereof can be treated with a pharmaceutically inert inorganic or organic adjuvant for the production of troches, coated troches, dragees and hard gelatine capsules. For example, lactose, corn starch or a derivative thereof, talc, stearic acid or a salt thereof or the like can be used as the adjuvant for the tablets, dragees and hard gelatin capsules.

適用於軟明膠膠囊的佐劑為(例如)植物油、蠟、脂肪、半固體物質及液體多元醇等。 Adjuvants suitable for use in soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid materials, liquid polyols and the like.

適用於生產溶液及糖漿的佐劑為(例如)水、多元醇、蔗糖、轉化糖、葡萄糖等。 Adjuvants suitable for use in the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, and the like.

適用於注射液的佐劑為(例如)水、醇類、多元醇、甘油、植物油等。 Adjuvants suitable for use in the injection are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

適用於栓劑的佐劑為(例如)天然或硬化油、蠟、脂肪、半固體或液體多元醇等。 Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

此外，該等醫藥製劑可包含防腐劑、增溶劑、黏度增加物質、安定劑、潤濕劑、乳化劑、甜味劑、著色劑、矯味劑、用於改變滲透壓的鹽、緩衝劑、掩味劑或抗氧化劑。其等亦可含有其他有治療價值 的物質。 In addition, the pharmaceutical preparations may contain a preservative, a solubilizer, a viscosity increasing substance, a stabilizer, a wetting agent, an emulsifier, a sweetener, a coloring agent, a flavoring agent, a salt for changing the osmotic pressure, a buffering agent, and a masking agent. Flavor or antioxidant. They may also contain other therapeutic value Substance.

因此，特定言之，本發明亦係關於以下各項：一種式(I)化合物，其係用作治療活性物質；一種醫藥組合物，其包含式(I)化合物及治療上惰性的載劑；一種式(I)化合物之用途，其係製備用於治療或預防糖尿病、動脈粥樣硬化、腹主動脈瘤、外周動脈疾病、癌症、減少慢性腎病中的心血管事件、糖尿病性腎病、糖尿病性視網膜病變或與年齡有關的黃斑變性的藥物；一種式(I)化合物，其係用於治療或預防糖尿病、動脈粥樣硬化、腹主動脈瘤、外周動脈疾病、癌症、減少慢性腎病中的心血管事件、糖尿病性腎病、糖尿病性視網膜病變或與年齡有關的黃斑變性；及一種用於治療或預防糖尿病、動脈粥樣硬化、腹主動脈瘤、外周動脈疾病、癌症、減少慢性腎病中的心血管事件、糖尿病性腎病、糖尿病性視網膜病變或與年齡有關的黃斑變性之方法，該方法包括投與有效量的式(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; Use of a compound of formula (I) for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of cardiovascular events in chronic kidney disease, diabetic nephropathy, diabetes A drug of retinopathy or age-related macular degeneration; a compound of formula (I) for use in the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of heart in chronic kidney disease Vascular events, diabetic nephropathy, diabetic retinopathy or age-related macular degeneration; and a heart for treating or preventing diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reducing chronic kidney disease a method of vascular events, diabetic nephropathy, diabetic retinopathy or age-related macular degeneration, the method comprising Compound (I) an effective amount of a formula.

本發明將藉由以下無限制特徵之實例來闡述。 The invention will be illustrated by the following examples of non-limiting features.

實例 Instance 實例1 Example 1 3-[(2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-3-(5-氯-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯 3-[(2S,4R)-4-(2-Chloro-4-methoxy-benzenesulfonyl)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1- Carbonyl]-3-(5-chloro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

A)3-(5-氯-吡啶-2-基)-氮雜環丁烷-1,3-二羧酸1-第三丁酯3-甲酯A) 3-(5-Chloro-pyridin-2-yl)-azetidine-1,3-dicarboxylic acid 1-t-butyl ester 3-methyl ester

在0℃下，向含於甲苯(5 ml)中之5-氯-2-氟吡啶(0.5 g，3.8 mmol，Eq：1.00)及氮雜環丁烷-1,3-二羧酸1-第三丁酯3-甲酯(818 mg，3.8 mmol，Eq：1.00)的溶液中滴加KHMDS之0.5 M甲苯溶液(7.6 ml，3.8 mmol，Eq：1.00)15分鐘。該無色溶液轉變成橙黃色。在0℃下攪拌45分鐘後，使該反應混合物升溫至20℃並攪拌2.5 h。添加飽和NH₄Cl水溶液(50 ml)並用AcOEt(2 x 75 ml)萃取水相。用鹵水洗滌合併的有機相，在Na₂SO₄上乾燥，過濾並在減壓下濃縮。藉由急驟層析法(矽膠，12 g，10%至60%AcOEt/庚烷)純化該粗製材料，以生成無色膠狀物(0.234 g；19%)。m/z=327.2[M+H]⁺。 To 5-chloro-2-fluoropyridine (0.5 g, 3.8 mmol, Eq: 1.00) and azetidine-1,3-dicarboxylic acid 1- contained in toluene (5 ml) at 0 °C A solution of the third butyl ester 3-methyl ester (818 mg, 3.8 mmol, Eq: 1.00) was added dropwise a 0.5 M toluene solution of KHMDS (7.6 ml, 3.8 mmol, Eq: 1.00) for 15 minutes. The colorless solution turned orange yellow. After stirring at 0 ° C for 45 minutes, the reaction mixture was allowed to warm to 20 ° C and stirred for 2.5 h. Saturated aqueous NH ₄ Cl (50 ml) and extracted with AcOEt (2 x 75 ml) the aqueous phase. In the combined organic phases were washed with brine and dried Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc EtOAc (EtOAc:EtOAc) m/z = 327.2 [M+H] ⁺ .

B)1-第三丁氧羰基-3-(5-氯-吡啶-2-基)-氮雜環丁烷-3-羧酸鋰B) 1-tert-butoxycarbonyl-3-(5-chloro-pyridin-2-yl)-azetidine-3-carboxylic acid lithium

在一10 ml的圓底燒瓶中，將實例1A)(0.21 g，643 μmol，Eq： 1.00)及氫氧化鋰(24.6 mg，1.03 mmol，Eq：1.6)與四氫呋喃(1.8 ml)及水(1.2 ml)合併，以獲得淡黃色懸浮液。在22℃下攪拌該反應混合物2 h。在真空中濃縮該粗反應混合物以獲得灰白色固體(0.241 g；100%)。m/z=311.3[M-H]^-。 In a 10 ml round bottom flask, Example 1A) (0.21 g, 643 μmol, Eq: 1.00) and lithium hydroxide (24.6 mg, 1.03 mmol, Eq: 1.6) and tetrahydrofuran (1.8 ml) and water (1.2) Ml) combined to obtain a light yellow suspension. The reaction mixture was stirred at 22 ° C for 2 h. The crude reaction mixture was concentrated in vacuo to give a white solid (0.241 g; 100%). m/z = 311.3 [MH] ^- .

C)(2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺C) (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

在一10 ml的圓底燒瓶中，將CAS號1252640-17-7(0.25 g，517 μmol，Eq：1.00)及氯化氫之4 M二噁烷溶液(517 μl，2.07 mmol，Eq：4)合併以獲得無色溶液。在22℃下攪拌該反應混合物1.5 h。攪拌20分鐘後，形成漿液。用AcOEt(30 ml)稀釋該粗反應混合物並用10%Na₂CO₃水溶液(20 ml)萃取。用AcOEt(2 x 20 ml)反萃取水層。合併有機層，用鹵水(1 x 15 ml)洗滌，在Na₂SO₄上乾燥並在真空中濃縮，以生成無色泡沫(202 mg；100%)。m/z=384.3[M+H]⁺。 Combine CAS No. 1252640-17-7 (0.25 g, 517 μmol, Eq: 1.00) with 4 M dioxane in hydrogen chloride (517 μl, 2.07 mmol, Eq: 4) in a 10 ml round bottom flask. A colorless solution was obtained. The reaction mixture was stirred at 22 ° C for 1.5 h. After stirring for 20 minutes, a slurry was formed. The crude reaction mixture was diluted with AcOEt (30 ml) and (20 ml) and extracted with 10% ₂ CO ₃ aq Na. The aqueous layer was back extracted with AcOEt (2 x 20 ml). The organic layers were combined, washed with brine (1×15 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give a colorless foam (202 mg; 100%). m/z = 384.3 [M+H] ⁺ .

D)3-[(2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-3-(5-氯-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯D) 3-[(2S,4R)-4-(2-Chloro-4-methoxy-benzenesulfonyl)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine- 3-carbonyl]-3-(5-chloro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

在一10 ml圓底燒瓶中，將實例1B)(0.165 g，518 μmol，Eq：1.00)、HATU(394 mg，1.04 mmol，Eq：2)及DIPEA(134 mg，181 μl，1.04 mmol，Eq：2)與乙腈(3 ml)合併，以獲得淡棕色溶液。將實例1C)(199 mg，518 μmol，Eq：1.00)添加至上述溶液中，並在20℃下攪拌18 h。在真空中濃縮該粗反應混合物，用AcOEt(30 ml)稀釋殘餘物並用10%Na₂CO₃水溶液(25 ml)萃取。用AcOEt(2 x 20 ml)反萃取水層，用鹵水洗滌，在Na₂SO₄上乾燥並蒸發至乾。隨後藉由急驟層析法(矽膠，12 g，30%至90%AcOEt/庚烷)純化該粗產物，以生成灰白色泡沫(0.166 g；48%)。m/z=678.3[M+H]⁺。 In a 10 ml round bottom flask, Example 1B) (0.165 g, 518 μmol, Eq: 1.00), HATU (394 mg, 1.04 mmol, Eq: 2) and DIPEA (134 mg, 181 μl, 1.04 mmol, Eq) : 2) Combine with acetonitrile (3 ml) to obtain a light brown solution. Example 1C) (199 mg, 518 μmol, Eq: 1.00) was added to the above solution and stirred at 20 ° C for 18 h. The crude reaction mixture was concentrated in vacuo and the residue was diluted with AcOEt (30 ml) and (25 ml) extracted with 10% Na ₂ CO ₃ solution. The aqueous layer was back-extracted with AcOEt (2 x 20 mL), washed with brine, dried over Na ₂ SO ₄ and evaporated to dry. The crude product was then purified by flash chromatography (EtOAc, 12 g, 30% to 90%EtOAc) m/z = 678.3 [M+H] ⁺ .

實例2 Example 2 (2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-1-[3-(5-氯-吡啶-2-基)-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro-pyridin-2-yl)-azetidin-3- Carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

在一10 ml圓底燒瓶中，合併實例1D)(0.15 g，221 μmol，Eq： 1.00)及甲酸(305 mg，254 μl，6.63 mmol，Eq：30)以獲得黃色溶液。在20℃下攪拌該混合物20 h。用水(2 ml)稀釋該反應混合物，用冰冷的10%Na₂CO₃水溶液調節至pH=8，用CH₂Cl₂萃取兩次，用鹵水洗滌合併的有機層，在Na₂SO₄上乾燥，過濾並蒸發，以獲得淡黃色固體(0.131 g；100%)。m/z=580.3[M+H]⁺。 In a 10 ml round bottom flask, Example 1D) (0.15 g, 221 μmol, Eq: 1.00) and formic acid (305 mg, 254 μl, 6.63 mmol, Eq: 30) were combined to obtain a yellow solution. The mixture was stirred at 20 ° C for 20 h. Washed with water (2 ml) and the reaction mixture was diluted, adjusted with 10% Na ₂ CO ₃ to the aqueous solution of pH = 8,, the ₂ SO ₄ and extracted twice with ₂ Cl ₂ CH, The combined organic layers were washed with brine and dried over Na Filtered and evaporated to give a pale yellow solid (0.131 g; 100%). m/z = 580.3 [M+H] ⁺ .

實例3 Example 3 (2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-1-[3-(5-氯-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro-pyridin-2-yl)-1-methyl-nitrogen heterocycle Butane-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

向含於回流甲醇(1 ml)中之實例2(0.05 g，86.4 μmol，Eq：1.00)的溶液中添加碘甲烷(9.2 mg，4.05 μl，64.8 μmol，Eq：0.75)。完成添加後，在80℃下攪拌該混合物2 h。添加額外的碘甲烷(9.2 mg，4.05 μl，64.8 μmol，Eq：0.75)並在80℃下攪拌該混合物2 h，然後在20℃下攪拌過夜。藉由製備型HPLC純化該混合物，以生成無色固體(3 mg；6%)。m/z=592.2[M+H]⁺。 Methyl iodide (9.2 mg, 4.05 μl, 64.8 μmol, Eq: 0.75) was added to a solution of Example 2 (0.05 g, 86.4 μmol, Eq: 1.00) in MeOH (1 ml). After the addition was completed, the mixture was stirred at 80 ° C for 2 h. Additional methyl iodide (9.2 mg, 4.05 μl, 64.8 μmol, Eq: 0.75) was added and the mixture was stirred at 80 ° C for 2 h and then stirred at 20 ° C overnight. The mixture was purified by preparative HPLC to give a colourless solid (3 mg; 6%). m/z = 592.2 [M+H] ⁺ .

實例4 Example 4 3-(5-氯-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 3-(5-Chloro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonate Tert-butyl 2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid

以類似於實例1之方法，自CAS號1252634-04-0開始製備該標題化合物，以生成無色非晶型固體。m/z=746.1[M+H]⁺。 The title compound was prepared starting from CAS No. 1252634-04-0 to give a colorless amorphous solid. m/z = 746.1 [M+H] ⁺ .

實例5 Example 5 3-(5-溴-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 3-(5-Bromo-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonate Tert-butyl 2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid

類似於實例1中描述的方法，自5-溴-2-氟-吡啶及CAS號1252634-04-0開始製備該標題化合物，以生成黃色泡沫。m/z=792.1[M+H]⁺。 The title compound was prepared starting from 5-bromo-2-fluoro-pyridine and CAS No. 1252634-04-0 to give a yellow foam. m/z = 792.1 [M+H] ⁺ .

實例6 Example 6 (2S,4R)-1-[3-(5-氯-吡啶-2-基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三 氟乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-1-[3-(5-chloro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2- three Fluoroethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

以類似於實例2之方法，自實例4開始製備該標題化合物，以生成無色蠟狀固體。m/z=646.1[M+H]⁺。 The title compound was prepared starting from Example 4 in a procedure analogous to Example 2 to yield a colourless waxy solid. m/z = 646.1 [M+H] ⁺ .

實例7 Example 7 (2S,4R)-1-[3-(5-溴-吡啶-2-基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三氟乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2- Trifluoroethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

以類似於實例2之方法，自實例5開始製備該標題化合物，以生成黃色泡沫。m/z=692.0[M+H]⁺。 The title compound was prepared starting from Example 5 in a procedure analogous to Example 2 to yield a yellow foam. m/z = 692.0 [M+H] ⁺ .

實例8 Example 8 (2S,4R)-1-[3-(5-氯-吡啶-2-基)-1-(2,2-二氟-乙基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三氟乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙 基)-醯胺 (2S,4R)-1-[3-(5-chloro-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4- [2-Chloro-4-(2,2,2-trifluoroethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropane Amine

在一10 ml的圓底燒瓶中，將實例6(0.082 g，127 μmol，Eq：1.00)、三氟甲磺酸2,2-二氟乙酯(40.7 mg，27.0 μl，190 μmol，Eq：1.5)及DIEA(24.6 mg，33.2 μl，190 μmol，Eq：1.5)與乙腈(1.5 ml)合併，以獲得淡黃色溶液。在22℃下攪拌該反應混合物72 h。在真空中濃縮該粗反應混合物並藉由急驟層析法(矽膠，12 g，25%至80%AcOEt/庚烷)進行純化，以生成該標題化合物之無色非晶型固體(0.014 g；16%)。m/z=710.2[M+H]⁺。 In a 10 ml round bottom flask, Example 6 (0.082 g, 127 μmol, Eq: 1.00), 2,2-difluoroethyl trifluoromethanesulfonate (40.7 mg, 27.0 μl, 190 μmol, Eq: 1.5) and DIEA (24.6 mg, 33.2 μl, 190 μmol, Eq: 1.5) were combined with acetonitrile (1.5 ml) to give a pale yellow solution. The reaction mixture was stirred at 22 ° C for 72 h. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography eluting elut elut elut elut elut elut elut elut %). m/z = 710.2 [M+H] ⁺ .

實例9 Example 9 (2S,4R)-1-[3-(5-溴-吡啶-2-基)-1-(2,2-二氟-乙基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三氟乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4- [2-Chloro-4-(2,2,2-trifluoroethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

以類似於實例8之方法，自實例7開始製備該標題化合物，以生成無色非晶型固體。m/z=756.1[M+H]⁺。 The title compound was prepared starting from Example 7 in a procedure analogous to Example 8 to yield a colorless amorphous solid. m/z = 756.1 [M+H] ⁺ .

實例10 Example 10 3-[(2S,4R)-4-(2-氯-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-3-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯 3-[(2S,4R)-4-(2-Chloro-phenylsulfonyl)-2-(1-cyano-cyclopropylaminocarbamimidyl)-pyrrolidine-1-carbonyl]-3-( 3-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

類似於實例1中描述的方法，自5-氯-2,3-二氟吡啶及CAS號1252638-10-0開始製備該標題化合物，以生成無色泡沫。m/z=666.2[M+H]⁺。 The title compound was prepared starting from 5-chloro-2,3-difluoropyridine and CAS No. 1252638-10-0 to give a colorless foam. m/z = 666.2 [M+H] ⁺ .

實例11 Example 11 3-(5-溴-3-氟吡啶-2-基)-3-((2S,4R)-4-(2-氯苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯 3-(5-bromo-3-fluoropyridin-2-yl)-3-((2S,4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropylamine A Mercapto pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester

類似於實例1中描述的方法，自5-溴-2,3-二氟吡啶及CAS號1252638-10-0開始製備該標題化合物，以生成無色泡沫。m/z=712.0[M+H]⁺。 The title compound was prepared starting from 5-bromo-2,3-difluoropyridine and CAS No. 1252638-10-0 to give a colorless foam. m/z = 712.0 [M+H] ⁺ .

實例12 Example 12 (2S,4R)-1-(3-(5-氯-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺 (2S,4R)-1-(3-(5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chlorophenylsulfonyl)-N- (1-cyanocyclopropyl)pyrrolidine-2-carboxamide

類似於實例2中描述的方法，自實例10開始製備該標題化合物，以生成無色泡沫。m/z=566.1[M+H]⁺。 The title compound was prepared starting from Example 10, similar to the method described in Example 2, to yield a colorless foam. m/z = 566.1 [M+H] ⁺ .

實例13 Example 13 (2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-(2-chloro-benzenesulfonyl) -pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

類似於實例2中描述的方法，自實例11開始製備該標題化合物，以生成無色泡沫。m/z=611.9[M+H]⁺。 The title compound was prepared starting from Example 11 to give a colorless foam, similar to the method described in Example 2. m/z = 611.9 [M+H] ⁺ .

實例14 Example 14 (2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-(2-chloro- Phenylsulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

在25℃下，將甲醛水溶液(36%；19.1 mg，17.5 μl，229 μmol，Eq：2.8)添加至含於二氯甲烷(0.5 ml)中的實例13(0.05 g，81.8 μmol，Eq：1.00)、乙酸鈉(14.8 mg，180 μmol，Eq：2.2)及乙酸(10.8 mg，10.3 μl，180 μmol，Eq：2.2)的混合物中。攪拌該混合物45分鐘，接著在0-5℃下一次性添加三乙醯氧基硼氫化鈉(55.5 mg，262 μmol，Eq：3.2)。10分鐘後移除冷卻浴並在25℃下再繼續攪拌18 h。用0.5 M NaOH水溶液(2 ml)淬滅該反應混合物，攪拌2分鐘，接著分離各層。用三份AcOEt(每份5 ml)萃取水層。用鹵水洗滌合併的有機層，在Na₂SO₄乾燥上並在真空中濃縮。藉由製備型HPLC純化該粗製材料，以生成該標題化合物之無色非晶型固體(0.0206 g；40%)。m/z =626.1[M+H]⁺。 Aqueous formaldehyde solution (36%; 19.1 mg, 17.5 μl, 229 μmol, Eq: 2.8) was added to Example 13 (0.05 g, 81.8 μmol, Eq: 1.00) in dichloromethane (0.5 ml) at 25 °C. ), a mixture of sodium acetate (14.8 mg, 180 μmol, Eq: 2.2) and acetic acid (10.8 mg, 10.3 μl, 180 μmol, Eq: 2.2). The mixture was stirred for 45 minutes, followed by one-time addition of sodium triethoxysulfonate (55.5 mg, 262 μmol, Eq: 3.2) at 0-5 °C. After 10 minutes the cooling bath was removed and stirring was continued for an additional 18 h at 25 °C. The reaction mixture was quenched with 0.5 M aqueous NaOH (2 mL) and stirred for 2 min. The aqueous layer was extracted with three portions of AcOEt (5 ml each). The combined organic layers were washed with brine, dried over Na ₂ CH ₄ and evaporated. The crude material was purified by preparative EtOAc (EtOAc): m/z = 626.1 [M+H] ⁺ .

實例15 Example 15 (2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-乙基-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-ethyl-azetidin-3-carbonyl]-4-(2-chloro- Phenylsulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

類似於實例14中描述的方法，自實例13開始製備該標題化合物，以生成淡黃色非晶型固體。m/z=640.1[M+H]⁺。 The title compound was prepared starting from Example 13 to give a pale-yellow amorphous solid, similar to the method described in Example 14. m/z = 640.1 [M+H] ⁺ .

實例16 Example 16 (2S,4R)-4-(2-氯-苯磺醯基)-1-[3-(5-氯-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[3-(5-chloro-3-fluoro-pyridin-2-yl)-1-methyl-azetidine 3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

類似於實例14中描述的方法，自實例12開始製備該標題化合物，以生成淡黃色非晶型固體。m/z=580.1[M+H]⁺。 The title compound was prepared starting from Example 12 to give a pale-yellow amorphous solid, similar to the method described in Example 14. m/z = 580.1 [M+H] ⁺ .

實例17 Example 17 3-(5-氯-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 3-(5-Chloro-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoroethoxy)- Phenylsulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

以類似於實例4中描述的方法製備該標題化合物，生成無色非晶型固體。m/z=764.3[M+H]⁺。 The title compound was prepared in a similar manner to that described in Example 4 to give a colorless amorphous solid. m/z = 764.3 [M+H] ⁺ .

實例18 Example 18 3-(5-溴-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 3-(5-Bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoroethoxy)- Phenylsulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

以類似於實例4中描述的方法製備該標題化合物，生成無色非晶型固體。m/z=710.1[M+H-Boc]⁺。 The title compound was prepared in a similar manner to that described in Example 4 to give a colorless amorphous solid. m/z = 710.1 [M+H-Boc] ⁺ .

實例19 Example 19 (2S,4R)-1-(3-(5-溴-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺 (2S,4R)-1-(3-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2, 2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide

在一10 mL圓底燒瓶中，合併溶於二噁烷(1.5 ml)中的實例18(0.210 g，260 μmol，Eq：1.00)及氯化氫的4 M二噁烷溶液(260 μl，1.04 mmol，Eq：4)以獲得無色溶液。將該反應混合物加熱至22℃並攪拌18 h。在真空中濃縮該粗反應混合物並將殘餘物稀釋於AcOEt(30 ml)中並用10%Na₂CO₃水溶液(50 ml)萃取。用AcOEt(2 x 30 ml)反萃取水層。合併有機層，用鹵水(1 x 20mL)洗滌，在Na₂SO₄上乾燥並在真空中濃縮。藉由製備型HPLC純化該粗製材料，以生成無色非晶型固體(0.038 g；21%)。m/z=710.0[M+H-Boc]⁺。 In a 10 mL round bottom flask, a solution of Example 18 (0.210 g, 260 μmol, Eq: 1.00) dissolved in dioxane (1.5 ml) and hydrogen chloride in 4 M dioxane (260 μl, 1.04 mmol, Eq: 4) to obtain a colorless solution. The reaction mixture was heated to 22 ° C and stirred for 18 h. The mixture and the residue was diluted in AcOEt (30 ml) and (50 ml) and extracted with 10% Na ₂ CO ₃ aq The crude reaction was concentrated in vacuo. The aqueous layer was back extracted with AcOEt (2 x 30 ml). The organic layers were combined, washed with brine and concentrated (1 x 20mL) dried over Na ₂ SO ₄ and in vacuo. The crude material was purified by preparative HPLC to give a colourless amorphous solid (0.038 g; 21%). m/z = 710.0 [M+H-Boc] ⁺ .

實例20 Example 20 (2S,4R)-1-(3-(5-氯-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺 (2S,4R)-1-(3-(5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2, 2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide

以類似於實例19中描述的方法製備該標題化合物，生成無色非晶型固體。m/z=664.1[M+H-Boc]⁺。 The title compound was prepared in a similar manner to that described in Example 19 to yield a colorless amorphous solid. m/z = 664.1 [M+H-Boc] ⁺ .

實例21 Example 21 2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl] 2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

A)2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1,2-二羧酸1-第三丁酯2-甲酯A) 2-(5-Chloro-3-fluoro-pyridin-2-yl)-azetidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester

在0℃下，向含於甲苯(15 ml)中的5-氯-2,3-二氟吡啶(1.39 g，9.29 mmol，Eq：1.00)及氮雜環丁烷-1,2-二羧酸1-第三丁酯2-甲酯(2 g，9.29 mmol，Eq：1.00)的溶液中滴加KHMDS之0.5 M甲苯溶液(18.6 ml，9.29 mmol，Eq：1.00)15分鐘。該無色溶液變成淡棕色。在0℃下攪拌45分鐘後，使該反應混合物升溫至25℃。攪拌該反應混合物2.5 h。添加飽和NH₄Cl水溶液(100 ml)，並用AcOEt(2x150 ml)萃取水相。用鹵水洗滌合併的有機層，在Na₂SO₄上乾燥，過濾並在減壓下濃縮。藉由急驟層析法(矽膠，40g，10%至60%AcOEt/庚烷)純化該粗製材料，以生成無色黏性油狀外消旋物(1.746 g；55%)。m/z=345.2[M+H]⁺。 To 5-chloro-2,3-difluoropyridine (1.39 g, 9.29 mmol, Eq: 1.00) and azetidine-1,2-dicarboxyl in toluene (15 ml) at 0 °C A 0.5 M toluene solution of KHMDS (18.6 ml, 9.29 mmol, Eq: 1.00) was added dropwise to a solution of the acid 1-t-butyl ester 2-methyl ester (2 g, 9.29 mmol, Eq: 1.00) for 15 min. The colorless solution turned pale brown. After stirring at 0 ° C for 45 minutes, the reaction mixture was allowed to warm to 25 °C. The reaction mixture was stirred for 2.5 h. Saturated aqueous NH ₄ Cl (100 ml), and extracted with AcOEt (2x150 ml) the aqueous phase. The combined organic layers were washed with brine, dried over Na ₂ CH ₄ The crude material was purified by flash chromatography (EtOAc EtOAc (EtOAc:EtOAc) m/z = 345.2 [M+H] ⁺ .

B)2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯B) 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxamide) 基)-吡咯啶-1-羰基]-2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯[差向異構體1：1](1)-pyrrolidin-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester [epimer 1 :1]

類似於實例1中描述的方法，自實例21A)及CAS號1252633-65-0開始製備該標題化合物，以生成呈無色非晶型固體的差向異構體混合物。m/z=684.3[M+H]⁺。 The title compound was prepared starting from Example 21A) and CAS No. 1252633-65-0, to afford a mixture of epimers as a colorless amorphous solid. m/z = 684.3 [M+H] ⁺ .

實例22 Example 22 2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyanide Benzyl-cyclopropylamine-methylpyridyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

以類似於實例21中描述的方法製備該標題化合物。藉由對掌性HPLC純化所獲得的差向異構體混合物，以獲得呈無色非晶型固體的單一差向異構體。m/z=730.1[M+H]⁺。 The title compound was prepared in a similar manner to that described in Example 21. The resulting mixture of epimers was purified by palmitic HPLC to obtain a single epimer as a colorless amorphous solid. m/z = 730.1 [M+H] ⁺ .

實例23 Example 23 2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl] 2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

在利用對掌性HPLC分離實例21後，獲得呈單一差向異構體之實例23，其係呈無色非晶型固體之單一差向異構體。m/z=684.3[M+H]⁺。 After separation of Example 21 by palm-wise HPLC, Example 23 was obtained as a single epimer, which was a single epimer of a colorless amorphous solid. m/z = 684.3 [M+H] ⁺ .

實例24 Example 24 2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl] 2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester

在利用對掌性HPLC分離實例21後，獲得呈單一差向異構體之實例24，其係呈無色非晶型固體之單一差向異構體。m/z=684.3[M+H]⁺。 After separation of Example 21 by palm-wise HPLC, Example 24 was obtained as a single epimer, which was a single epimer of a colorless amorphous solid. m/z = 684.3 [M+H] ⁺ .

實例25 Example 25 2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyanide Benzyl-cyclopropylamine-methylpyridyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

在利用對掌性HPLC分離實例22後，獲得呈單一差向異構體之實例25，其係呈無色非晶型固體之單一差向異構體。m/z=730.1[M+H]⁺。 After separation of Example 22 by palm-wise HPLC, Example 25 was obtained as a single epimer, which was a single epimer of a colorless amorphous solid. m/z = 730.1 [M+H] ⁺ .

實例26 Example 26 2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyanide Benzyl-cyclopropylamine-methylpyridyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

在利用對掌性HPLC分離實例22後，獲得呈單一差向異構體之實例26，其係呈無色非晶型固體之單一差向異構體。m/z=730.1[M+H]⁺。 After separation of Example 22 by palm-wise HPLC, Example 26 was obtained as a single epimer, which was a single epimer of a colorless amorphous solid. m/z = 730.1 [M+H] ⁺ .

實例27 Example 27 2-(5-氯-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙烷-2-基氧基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯 2-(5-chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoropropane- 2-butyloxy)benzenesulfonyl)-2-(1-cyanocyclopropylaminecarboxyl)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester

在一25 ml圓底燒瓶中，將實例21(0.1 g，146 μmol，Eq：1.00)與N,N-二甲基乙醯胺(1.5 ml)合併，以獲得淡黃色溶液。在25℃下，將(S)-1,1,1-三氟丙-2-醇(26.7 mg，234 μmol，Eq：1.6)及碳酸銫(57.1 mg，175 μmol，Eq：1.2)添加至上述溶液中並攪拌24 h。之後，將額外的(S)-1,1,1-三氟丙-2-醇(6.67 mg，58.4 μmol，Eq：0.4)添加至該反應混合物中並在25℃下再攪拌24 h。濃縮該粗反應混合物，將殘餘物溶解於AcOEt(100 ml)中，依次用0.5 N HCl水溶液(35 ml)及10%Na₂CO₃水溶液(25 ml)萃取。用AcOEt(2 x 25 ml)反萃取水層。用鹵水洗滌合併的有機層，在Na₂SO₄上乾燥，過濾並蒸發。隨後藉由急驟層析法(矽膠，40g，10%至50%EtOAc/庚烷)純化該粗製材料，以生成差向異構體混合物，然後藉由對掌性HPLC純化該混合物，以生成一種呈無色非晶型固體的差向異構體(9 mg；8%)。m/z=778.3[M+H]⁺。 In a 25 ml round bottom flask, Example 21 (0.1 g, 146 μmol, Eq: 1.00) was combined with N,N-dimethylacetamide (1.5 ml) to give a pale yellow solution. (S)-1,1,1-Trifluoropropan-2-ol (26.7 mg, 234 μmol, Eq: 1.6) and cesium carbonate (57.1 mg, 175 μmol, Eq: 1.2) were added at 25 °C. The above solution was stirred for 24 h. Thereafter, additional (S)-1,1,1-trifluoropropan-2-ol (6.67 mg, 58.4 μmol, Eq: 0.4) was added to the reaction mixture and stirred at 25 ° C for an additional 24 h. The crude reaction mixture was concentrated, the residue was dissolved in AcOEt (100 ml) sequentially, and (25 ml) extracted with 10% Na ₂ CO ₃ with 0.5 N HCl aqueous solution (35 ml). The aqueous layer was back extracted with AcOEt (2 x 25 ml). In the combined organic layers were washed with brine and dried Na ₂ SO _4, filtered and evaporated. The crude material was then purified by flash chromatography (silica gel, 40 g, 10% to 50% EtOAc/heptane) to afford the mixture of the isomers and then purified An epimer (9 mg; 8%) which is a colorless amorphous solid. m/z = 778.3 [M+H] ⁺ .

實例28 Example 28 2-(5-氯-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙烷-2-基氧基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯 2-(5-chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoropropane- 2-butyloxy)benzenesulfonyl)-2-(1-cyanocyclopropylaminecarboxyl)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester

在利用對掌性HPLC純化實例27後，獲得作為另一差向異構體之實例28。m/z=778.3[M+H]⁺。 After purification of Example 27 by palmitic HPLC, Example 28 was obtained as another epimer. m/z = 778.3 [M+H] ⁺ .

實例29 Example 29 2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1-carbonyl]-azetidin-1-carboxylate Tert-butyl acid

以類似於實例27中描述的方法製備該標題化合物。藉由對掌性HPLC純化所獲得的差向異構體混合物，以獲得呈無色非晶型固體的單一差向異構體。m/z=842.1[M+H]⁺。 The title compound was prepared in a similar manner to that described in Example 27. The resulting mixture of epimers was purified by palmitic HPLC to obtain a single epimer as a colorless amorphous solid. m/z = 842.1 [M+H] ⁺ .

實例30 Example 30 2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基- 乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl- Ethoxy)-phenylsulfonyl]-2-(1-cyano-cyclopropylamine-carbamoyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

在利用對掌性HPLC純化實例29後，獲得作為另一差向異構體之實例30。m/z=842.1[M+H]⁺。 After purification of Example 29 by palmitic HPLC, Example 30 was obtained as another epimer. m/z = 842.1 [M+H] ⁺ .

實例31 Example 31 (2S,4R)-4-(2-氯-4-氟-苯磺醯基)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺鹽酸鹽 (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine- 2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine hydrochloride

在一10 mL圓底燒瓶中，將含於二噁烷(0.1 ml)中的實例24(0.034 g，49.7 μmol，Eq：1.00)及氯化氫的4 M二噁烷溶液(62.1 μl，248 μmol，Eq：5)合併，以獲得無色溶液。將該反應混合物加熱至22℃並攪拌18 h。此後，添加氯化氫的4 M二噁烷溶液(62.1 μl，248 μmol，Eq：5)並在25℃下攪拌該反應混合物24 h。此後，添加額外的氯化氫之4 M二噁烷溶液(24.8 μl，99.3 μmol，Eq：2)並攪拌該混合物2 h。 在真空中濃縮該反應混合物以生成灰白色泡沫(0.031 g；100%)。m/z=584.0[M+H]⁺。 In a 10 mL round bottom flask, Example 24 (0.034 g, 49.7 μmol, Eq: 1.00) and 4 M dioxane in hydrogen chloride (62.1 μl, 248 μmol, in dioxane (0.1 ml). Eq: 5) Combine to obtain a colorless solution. The reaction mixture was heated to 22 ° C and stirred for 18 h. Thereafter, a solution of hydrogen chloride in 4 M dioxane (62.1 μl, 248 μmol, Eq: 5) was added and the reaction mixture was stirred at 25 ° C for 24 h. Thereafter, an additional 4 M solution of hydrogen chloride in dioxane (24.8 μl, 99.3 μmol, Eq: 2) was added and the mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo to give an off-white foam (0.031 g; 100%). m/z = 584.0 [M+H] ⁺ .

實例32 Example 32 (2S,4R)-4-(2-溴-4-氟-苯磺醯基)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺鹽酸鹽 (2S,4R)-4-(2-bromo-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine- 2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine hydrochloride

以類似於實例31之方法自實例26製備該標題化合物，以生成灰白色固體。m/z=630.2[M+H]⁺。 The title compound was prepared from Example 26 in a procedure similar to Example 31 to yield an off white solid. m/z = 630.2 [M+H] ⁺ .

實例33 Example 33 3-(5-溴-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1-carbonyl]-azetidin-1-carboxylate Tert-butyl acid

類似於實例1及11中所述的方法，自CAS號1252636-85-3開始製備該標題化合物，以生成無色蠟狀固體。m/z=824.1[M+H]⁺。 The title compound was prepared starting from CAS No. 1252636-85-3 to give a colorless waxy solid. m/z = 824.1 [M+H] ⁺ .

實例34 Example 34 (2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S -2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

使用實例31中描述的方法，自實例33製備該標題化合物。蒸發後，藉由製備型HPLC純化該化合物，以生成白色固體。m/z=724.2[M+H]⁺。 The title compound was prepared from Example 33 using the method described in Example 31. After evaporation, the compound was purified by preparative HPLC to give a white solid. m/z = 724.2 [M+H] ⁺ .

實例35 Example 35 (2S,4R)-4-(2-氯-4-氟-苯磺醯基)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺鹽酸鹽 (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine- 2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine hydrochloride

使用實例31中描述的方法，自實例23製備該標題化合物，以生成無色固體。m/z=584.2[M+H]⁺。 The title compound was prepared from Example 23 using the method described in Example 31 to yield a colourless solid. m/z = 584.2 [M+H] ⁺ .

實例36 Example 36 (2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-(2-氯-4-氟- 苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺鹽酸鹽 (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-(2-chloro-4-fluoro- Phenylsulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

使用實例31中描述的方法，自實例25製備該標題化合物，以生成無色固體。m/z=630.2[M+H]⁺。 The title compound was prepared from Example 25 using the method described in Example 31 to yield a colourless solid. m/z = 630.2 [M+H] ⁺ .

實例37 Example 37 (2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺鹽酸鹽 (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S -2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

使用實例31中描述的方法，自實例27製備該標題化合物，以生成無色固體。m/z=678.2[M+H]⁺。 The title compound was prepared from Example 27 using the method described in Example 31 to yield a colourless solid. m/z = 678.2 [M+H] ⁺ .

實例38 Example 38 (2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺鹽酸鹽 (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S -2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

使用實例31中描述的方法，自實例28製備該標題化合物，以生成無色固體。m/z=678.2[M+H]⁺。 The title compound was prepared from Example 28 using the method described in Example 31 to yield a colourless solid. m/z = 678.2 [M+H] ⁺ .

實例39 Example 39 (2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺鹽酸鹽 (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S -2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

使用實例31中描述的方法，自實例29製備該標題化合物，以生成無色固體。m/z=724.1[M+H]⁺。 The title compound was prepared from Example 29 using the method described in Example 31 to yield a colourless solid. m/z = 724.1 [M+H] ⁺ .

實例40 Example 40 (2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-[2-chloro- 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)- Guanamine

根據實例14中描述的方法，自實例34製備該標題化合物，以生成無色非晶型固體。m/z=756.3[M+H]⁺。 The title compound was prepared from Example 34 according to the procedure described in Example 14 to yield a colorless amorphous solid. m/z = 756.3 [M+H] ⁺ .

實例41 Example 41 2-(5-氯-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 2-(5-chloro-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl)-benzene Sulfhydryl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

A)(2S,4R)-4-(4-溴-2-氯-苯硫基)-吡咯啶-1,2-二羧酸1-第三丁酯2-甲酯A) (2S,4R)-4-(4-bromo-2-chloro-phenylthio)-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester

將CAS號1252633-25-2(5.3 g，12.3 mmol，Eq：1.00)溶解於丙腈(40 ml)中並添加4-溴-2-氯苯硫醇(3.3 g，14.8 mmol，Eq：1.20)。現在添加三乙胺(2.49 g，3.43 ml，24.6 mmol，Eq：2.00)。在回流下攪拌該反應混合物過夜。將該反應混合物倒入100 ml 10%Na₂CO₃中並用EtOAc(2 x 100 mL)萃取。用100 ml 0.1 N HCl萃取有機層，在Na₂SO₄上乾燥，過濾並蒸發。藉由急驟層析法(矽膠，120 g，0%至30%AcOEt/庚烷，歷時30分鐘)純化該粗製材料，以生成無色油(4.72 g；85%)。m/z=352.1[M+H-Boc]⁺。 The CAS number 1252633-25-2 (5.3 g, 12.3 mmol, Eq: 1.00) was dissolved in propionitrile (40 ml) and 4-bromo-2-chlorobenzenethiol (3.3 g, 14.8 mmol, Eq: 1.20) was added. ). Triethylamine (2.49 g, 3.43 ml, 24.6 mmol, Eq: 2.00) was now added. The reaction mixture was stirred under reflux overnight. The reaction mixture was poured into 100 ml 10% Na ₂ CO ₃ and (2 x 100 mL) and extracted with EtOAc. , In 0.1 N HCl the organic layer was extracted with 100 ml Na ₂ SO ₄ dried, filtered and evaporated. The crude material was purified by flash chromatography (EtOAc, EtOAc (EtOAc:EtOAc) m/z = 352.1 [M+H-Boc] ⁺ .

B)(2S,4R)-4-(4-溴-2-氯-苯磺醯基)-吡咯啶-1,2-二羧酸1-第三丁酯2-甲酯B) (2S,4R)-4-(4-bromo-2-chloro-benzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester

將實例41A)(4.72 g，10.5 mmol，Eq：1.00)溶解於二氯甲烷(40 ml)中，並小心地分批添加MCPBA(3.79 g，22.0 mmol，Eq：2.10)。在25℃下攪拌該反應混合物18 h。用10% Na₂CO₃水溶液，0.1 N HCl水溶液及飽和Na₂S₂O₃水溶液萃取該反應混合物。使有機層在Na₂SO₄及Na₂SO₃上乾燥2 h，過濾並小心蒸發以獲得無色蠟狀固體(4.96 g；98%)。m/z=383.9[M+H-Boc]⁺。 Example 41A) (4.72 g, 10.5 mmol, Eq: 1.00) was dissolved in dichloromethane (40 ml), and MCPBA (3.79 g, 22.0 mmol, Eq: 2.10) was carefully added portionwise. The reaction mixture was stirred at 25 ° C for 18 h. With 10% Na ₂ CO ₃ solution, 0.1 N HCl and saturated aqueous Na ₂ S ₂ O ₃ aqueous solution was extracted the reaction mixture. The organic layer was Na ₂ SO ₄ and dried over Na ₂ SO ₃ 2 h, filtered and carefully evaporated to give a colorless waxy solid (4.96 g; 98%). m/z = 383.9 [M+H-Boc] ⁺ .

C)(2S,4R)-4-(4-溴-2-氯-苯磺醯基)-吡咯啶-1,2-二羧酸1-第三丁酯C) (2S,4R)-4-(4-bromo-2-chloro-benzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester

將實例41B)(4.96 g，10.3 mmol，Eq：1.00)溶解於THF(15 ml)及水(10 ml)中。現在添加LiOH水合物(418 mg，17.5 mmol，Eq：1.70)並在22℃下攪拌該反應混合物3 h。用0.2 N HCl水溶液/二氯甲烷萃取該反應混合物。使有機層在Na₂SO₄上乾燥，過濾並在真空中濃縮成白色泡沫(4.83 g；100%)。m/z=467.9[M-H]^-。 Example 41B) (4.96 g, 10.3 mmol, Eq: 1.00) was dissolved in THF (15 ml) and water (10 ml). LiOH hydrate (418 mg, 17.5 mmol, Eq: 1.70) was now added and the reaction mixture was stirred at 22 ° C for 3 h. The reaction mixture was extracted with 0.2 N aqueous HCl / dichloromethane. The organic layer was dried over Na ₂ SO _4, filtered and concentrated to a white foam (4.83 g; 100%) in vacuo. m/z = 467.9 [MH] ^- .

D)(2S,4R)-4-(4-溴-2-氯-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羧酸第三丁酯D) (2S,4R)-4-(4-bromo-2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carboxylic acid Tributyl ester

將實例41C)(4.83 g，10.3 mmol，Eq：1.00)溶解於乙腈(40 ml)中。將HATU(7.84 g，20.6 mmol，Eq：2.00)、DIEA(2.66 g，3.6 ml，20.6 mmol，Eq：2.00)及1-胺基環丙烷-甲腈鹽酸鹽(1.47 g，12.4 mmol，Eq：1.20)添加至該溶液中並在22℃下攪拌2 h。將該反應混合物倒入0.1 M HCl水溶液(100 ml)中並用二氯甲烷(3 x 75 mL)萃取。使有機層在Na₂SO₄上乾燥並在真空中濃縮。藉由急驟層析法(矽膠，120 g，0%至60%AcOEt/庚烷)純化該粗製材料，以生成白色固體(3.2 g；58%)。m/z=531.9[M-H]^-。 Example 41C) (4.83 g, 10.3 mmol, Eq: 1.00) was dissolved in acetonitrile (40 ml). HATU (7.84 g, 20.6 mmol, Eq: 2.00), DIEA (2.66 g, 3.6 ml, 20.6 mmol, Eq: 2.00) and 1-aminocyclopropane-carbonitrile hydrochloride (1.47 g, 12.4 mmol, Eq) :1.20) was added to the solution and stirred at 22 ° C for 2 h. The reaction mixture was poured into aq. EtOAc (EtOAc) The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc EtOAc EtOAc:EtOAc m/z = 531.9 [MH] ^- .

E)(2S,4R)-4-(4-溴-2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺E) (2S,4R)-4-(4-bromo-2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine

根據實例2中描述的方法製備該標題化合物，以生成灰白色固體。m/z=434.1[M+H]⁺。 The title compound was prepared according to the method described in Example 2 to yield an off white solid. m/z = 434.1 [M+H] ⁺ .

F)2-[(2S,4R)-4-(4-溴-2-氯-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-2-(4-氯-2-氟-苯基)-氮雜環丁烷-1-羧酸第三丁酯F) 2-[(2S,4R)-4-(4-bromo-2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1- Carbonyl]-2-(4-chloro-2-fluoro-phenyl)-azetidine-1-carboxylic acid tert-butyl ester

以類似於實例21中描述的方法製備該標題化合物，以生成無色泡沫。m/z=746.0[M+H]⁺。 The title compound was prepared in a similar manner to that described in Example 21 to yield a colorless foam. m/z = 746.0 [M+H] ⁺ .

G)2-(5-氯-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯G) 2-(5-Chloro-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl) -Benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

含於水(1.0 ml)及二噁烷(2.5 ml)中之實例41F)(0.05 g，67.1 μmol，Eq：1.00)、2-甲基吡啶-4-酸頻哪醇酯(16.2 mg，73.8 μmol，Eq：1.1)、磷酸三鉀(42.7 mg，201 μmol，Eq：3)及氯化2'-(二甲胺基)-2-聯苯-鈀(II)二降冰片基膦錯合物(3.76 mg，6.71 μmol，Eq：0.1)添加至一10 ml微波小瓶中。將該小瓶加蓋並在微波中於 120℃下加熱30分鐘。藉由製備型HPLC純化該粗製材料以生成無色泡沫(0.019 g；37%)。m/z=757.4[M+H]⁺。 Example 41F) (0.05 g, 67.1 μmol, Eq: 1.00), 2-methylpyridine-4- contained in water (1.0 ml) and dioxane (2.5 ml) Acid pinacol ester (16.2 mg, 73.8 μmol, Eq: 1.1), tripotassium phosphate (42.7 mg, 201 μmol, Eq: 3) and 2'-(dimethylamino)-2-biphenyl-palladium chloride (II) The second norbornene phosphine complex (3.76 mg, 6.71 μmol, Eq: 0.1) was added to a 10 ml microwave vial. The vial was capped and heated in a microwave at 120 °C for 30 minutes. The crude material was purified by preparative HPLC to afford colourless foam (0.019 g; 37%). m/z = 757.4 [M+H] ⁺ .

實例42 Example 42 2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl)-benzene Sulfhydryl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester

以類似於實例21及41中描述的方法製備該標題化合物，生成無色非晶型固體。m/z=803.1[M+H]⁺。 The title compound was prepared in a similar manner to that described in Examples 21 and 41 to give a colorless amorphous solid. m/z = 803.1 [M+H] ⁺ .

實例43 Example 43 (2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺鹽酸鹽 (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2- Methyl-pyridin-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

類似於實例31中描述的方法，自實例41製備該標題化合物，以生成白色固體。m/z=657.4[M+H]⁺。 The title compound was prepared from Example 41 to give a white solid. m/z = 657.4 [M+H] ⁺ .

實例44 Example 44 (2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺鹽酸鹽 (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2- Methyl-pyridin-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine hydrochloride

類似於實例31中描述的方法，自實例42製備該標題化合物，以生成白色非晶型固體。m/z=703.3[M+H]⁺。 The title compound was prepared from Example 42 to give a white amorphous solid, similar to the method described in Example 31. m/z = 703.3 [M+H] ⁺ .

實例45 Example 45 2-(5-氯-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-(1-甲基-1H-吡唑-4-基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯 2-(5-Chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl) Phenylsulfonyl)-2-(1-cyanocyclopropylaminecarboxamido)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester

類似於實例41G)之方法，自實例41F)及1-甲基-4-(4,4,5,5-四甲基- 1,3,2-二氧雜硼戊環-2-基)-1H-吡唑製備該標題化合物，以生成無色泡沫。m/z=746.3[M+H]⁺。 Similar to the method of Example 41G), from Example 41F) and 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole The title compound was prepared to give a colorless foam. m/z = 746.3 [M+H] ⁺ .

實例46 Example 46 2-(5-溴-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-(1-甲基-1H-吡唑-4-基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯 2-(5-bromo-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl) Phenylsulfonyl)-2-(1-cyanocyclopropylaminecarboxamido)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester

以類似於實例42及45之方法製備該標題化合物，生成無色泡沫。m/z=746.3[M+H]⁺。 The title compound was prepared in a similar manner to the methods of Examples 42 and 45 to yield a colorless foam. m/z = 746.3 [M+H] ⁺ .

實例47 Example 47 (2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(1-甲基-1H-吡唑-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺鹽酸鹽 (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1- Methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine hydrochloride

類似於實例31之方法，自實例45製備該標題化合物，以生成白 色固體。m/z=646.5[M+H]⁺。 The title compound was prepared from Example 45 to give a white solid. m/z = 646.5 [M+H] ⁺ .

實例48 Example 48 (2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(1-甲基-1H-吡唑-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺鹽酸鹽 (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1- Methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine hydrochloride

類似於實例31之方法，自實例46製備該標題化合物，以生成無色泡沫。m/z=692.2[M+H]⁺。 The title compound was prepared from Example 46 to give a colorless foam. m/z = 692.2 [M+H] ⁺ .

實例49 Example 49 (2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-(2,2-二氟-乙基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl ]-4-[2-Chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 -cyano-cyclopropyl)-guanamine

在一5 ml圓底燒瓶中，將實例34(100 mg，138 μmol，Eq： 1.00)、三氟甲磺酸2,2-二氟乙酯(51.8 mg，34.3 μl，242 μmol，Eq：1.75)及休尼格(Hunig's)鹼(31.3 mg，42.3 μl，242 μmol，Eq：1.75)與乙腈(1.5 ml)合併以獲得淡黃色溶液。在25℃下攪拌該反應混合物4 h。在真空中濃縮該粗反應混合物。將該反應混合物倒入EtOAc(20 ml)中並用10%Na₂CO₃水溶液(1 x 15 mL)萃取。用EtOAc(2 x 20 mL)反萃取水層。合併有機層，並用飽和NaCl水溶液(1 x 15 mL)洗滌。使該等有機層在Na₂SO₄上乾燥並在真空中濃縮。藉由急驟層析法(矽膠，12 g，10%至80%EtOAc/庚烷)純化該粗製材料，以生成該標題化合物之無色非晶型固體(41 mg；38%)。m/z=786.0415[M-H]^-。 In a 5 ml round bottom flask, Example 34 (100 mg, 138 μmol, Eq: 1.00), 2,2-difluoroethyl trifluoromethanesulfonate (51.8 mg, 34.3 μl, 242 μmol, Eq: 1.75) And Hunig's base (31.3 mg, 42.3 μl, 242 μmol, Eq: 1.75) was combined with acetonitrile (1.5 ml) to give a pale yellow solution. The reaction mixture was stirred at 25 ° C for 4 h. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into EtOAc (20 ml) and extracted with 10% Na ₂ CO ₃ solution (1 x 15 mL). The aqueous layer was back extracted with EtOAc (2 x 20 mL). The organic layers were combined and washed with aq. sat. NaCI (1×15 mL). The organic layer was dried over such Na ₂ SO ₄ and concentrated in vacuo. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut m/z = 786.0415 [MH] ^- .

實例50 Example 50 (2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲醯基-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-carboxanyl-azetidin-3-carbonyl]-4-[2-chloro 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl) - guanamine

在一5 ml圓底燒瓶中，將實例34與DMSO(0.5 ml)合併，以獲得無色溶液。添加甲酸4-硝基苯酯(12.7 mg，76.1 μmol，Eq：1.10)。在25℃下攪拌該反應混合物3天。之後，將額外的甲酸4-硝基苯酯(3.47 mg，20.7 μmol，Eq：0.3)添加至上述溶液中並攪拌5天。藉由製備型HPLC純化該粗製材料，以獲得該標題化合物之無色非晶型固體(14 mg；27%)。m/z=752.0394[M+H]⁺。 In a 5 ml round bottom flask, Example 34 was combined with DMSO (0.5 ml) to give a colorless solution. 4-Nitrophenylcarboxylate (12.7 mg, 76.1 μmol, Eq: 1.10) was added. The reaction mixture was stirred at 25 ° C for 3 days. Thereafter, additional 4-nitrophenyl formate (3.47 mg, 20.7 μmol, Eq: 0.3) was added to the above solution and stirred for 5 days. The crude material was purified by preparative EtOAc (EtOAc:EtOAc) m/z = 752.0394 [M+H] ⁺ .

實例51 Example 51 3-(5-溴-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸甲酯 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1-carbonyl]-azetidin-1-carboxylate Methyl ester

在一5 ml圓底燒瓶中，將實例34(50 mg，69.2 μmol，Eq：1.00)與二氯甲烷(1.0 ml)合併，以獲得無色溶液。添加氯甲酸甲酯(13.1 mg，10.7 μl，138 μmol，Eq：2.00)及三乙胺(14.0 mg，19.3 μl，138 μmol，Eq：2.00)。在25℃下攪拌該反應混合物4 h。藉由製備型HPLC純化該粗製材料，以獲得該標題化合物之白色固體(15 mg；27%)。m/z=782.0487[M+H]⁺。 In a 5 ml round bottom flask, Example 34 (50 mg, 69.2 μmol, Eq: 1.00) was combined with dichloromethane (1.0 ml) to give a colorless solution. Methyl chloroformate (13.1 mg, 10.7 μl, 138 μmol, Eq: 2.00) and triethylamine (14.0 mg, 19.3 μl, 138 μmol, Eq: 2.00) were added. The reaction mixture was stirred at 25 ° C for 4 h. The crude material was purified by preparative EtOAc (EtOAc) m/z = 782.0487 [M+H] ⁺ .

實例52 Example 52 (2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-(2,2,2-三氟-乙基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺 (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-(2,2,2-trifluoro-ethyl)-azetidin-3 -carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine

在一5 ml圓底燒瓶中，將實例34(50 mg，69.2 μmol，Eq：1.00)與乙腈(1.5 ml)合併以獲得無色溶液。添加三氟甲磺酸2,2,2-三氟乙酯(20.1 mg，12.5 μL，86.5 μmol，Eq：1.25)及休尼格鹼(11.2 mg，15.1 μL，86.5 μmol，Eq：1.25)。在25℃下攪拌該反應混合物18 h。藉由製備型HPLC純化該粗製材料，以獲得該標題化合物的無色固體(12 mg；22%)。m/z=806.0479[M+H]⁺。 In a 5 ml round bottom flask, Example 34 (50 mg, 69.2 μmol, Eq: 1.00) was combined with acetonitrile (1.5 ml) to give a colorless solution. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (20.1 mg, 12.5 μL, 86.5 μmol, Eq: 1.25) and Hughne base (11.2 mg, 15.1 μL, 86.5 μmol, Eq: 1.25) were added. The reaction mixture was stirred at 25 ° C for 18 h. The crude material was purified by preparative EtOAc (EtOAc) m/z = 806.0479 [M+H] ⁺ .

實例53 Example 53 組織蛋白酶抑制分析 Cathepsin inhibition assay

藉由觀察由含有螢光團(其發射在完整肽中淬滅)之肽底物之裂解所引起的螢光強度增加量來測定酶活性。 Enzyme activity was determined by observing the amount of increase in fluorescence intensity caused by cleavage of a peptide substrate containing a fluorophore that was quenched in the intact peptide.

分析緩衝劑：100 mM磷酸鉀(pH6.5)、5 mM EDTA-Na、0.001% Triton X-100、5mM DTT。 Analytical buffer: 100 mM potassium phosphate (pH 6.5), 5 mM EDTA-Na, 0.001% Triton X-100, 5 mM DTT.

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

底物(20 μM)：除Cat K使用Z-Leu-Arg-AMC以外，其他為Z-Val-Val-Arg-AMC(均來自Bachem)。 Substrate (20 μM): Except for Z-Leu-Arg-AMC for Cat K, Z-Val-Val-Arg-AMC (both from Bachem).

Z=芐氧羰基。 Z = benzyloxycarbonyl.

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

DTT=二硫蘇糖醇。 DTT = dithiothreitol.

最終體積：100 μL。 Final volume: 100 μL.

激發：360 nm，發射：465 nm。 Excitation: 360 nm, emission: 465 nm.

將酶添加至96孔微量滴定板中之稀釋物中並以底物開始反應。測定螢光發射20分鐘，在此期間觀察到在不含抑制劑時呈線性增加。藉由標準方法計算IC₅₀。 The enzyme was added to the dilution in a 96-well microtiter plate and the reaction was started with the substrate. Fluorescence emission was measured for 20 minutes, during which a linear increase was observed in the absence of inhibitor. The IC ₅₀ is calculated by standard methods.

已分別測量對人類Cat S、小鼠Cat S、人類Cat K、人類Cat B、人類Cat L及小鼠Cat L之抑制作用。針對人類Cat S及L所獲得之本發明代表性化合物的結果係以μM表示於下表中。 Inhibition of human Cat S, mouse Cat S, human Cat K, human Cat B, human Cat L, and mouse Cat L has been measured separately. The results for representative compounds of the invention obtained for human Cat S and L are shown in the following table in μM.

本發明化合物係組織蛋白酶-S及L(相對於組織蛋白酶-K及B)的選擇性抑制劑。 The compounds of the invention are selective inhibitors of cathepsins-S and L (relative to cathepsins-K and B).

在前述分析中，本發明化合物對Cat S及/或L具有在0.00001至100 μM之間，較佳在0.00001至50 μM之間，更佳在0.00001至20 μM之間的IC₅₀。本發明之特定化合物在至少一個前述分析中具有低於0.09 μM之IC₅₀。 In the foregoing assay, the compounds of the present invention _{50 pairs of} Cat S and / or L has between 0.00001 to 100 μM, preferably between 0.00001 to 50 μM, more preferably between IC 20 μM to 0.00001 in. The particular compound of the present invention in at least one of the preceding assay has less than 0.09 μM of IC _50.

實例A Example A

式(I)化合物可以本身已知的方式用作用於製造具有以下組成之錠劑之活性成分： The compounds of the formula (I) can be used in the form known per se as active ingredients for the manufacture of tablets having the following composition:

實例B Instance B

式(I)化合物可以本身已知的方式用作用於製造具有以下組成之膠囊之活性成分： The compounds of the formula (I) can be used in the form known per se as active ingredients for the manufacture of capsules having the following composition:

Claims (22)

一種式(I)化合物或其醫藥上可接受之鹽或酯， 其中A¹及A²之一為-NR⁹-且另一者為-CH₂-；R¹為鹵素；R²為氫、鹵素、烷基或鹵代烷基；R³為氫、鹵素、烷基或鹵代烷基；R⁴及R⁵同時為氫；或R⁴及R⁵與其等所鍵接之碳原子共同形成環烷基；R⁶為氫、鹵素、烷基、鹵代烷基或環烷基；R⁷為氫、鹵素、烷基、鹵代烷基或環烷基；R⁸為氫、烷基、鹵代烷基、烷氧基、鹵代烷氧基、環烷基、烷基吡啶基、烷基-1H-吡唑基、苯基、經取代之苯基、雜環基或經取代之雜環基，其中雜環基為吡啶基、嘧啶基、吡嗪基、噠嗪基、吡咯基、吡唑基、咪唑基、***基、噁唑基、異噁唑基、噁二唑基、噻吩基、噻唑基、噻二唑基、哌啶基、哌嗪基、吡咯啶基或嗎啉基，其中經取代之苯基為經一至三個獨立地選自下列之取代基取代之苯基：烷基、鹵素、環烷基、鹵代 烷基、烷氧基、鹵代烷氧基、鹵代環烷基及腈，且其中經取代之雜環基為經一至三個獨立地選自下列之取代基取代之雜環基：烷基、鹵素、環烷基、鹵代烷基、烷氧基、鹵代烷氧基、鹵代環烷基及腈；且R⁹為氫、烷基、鹵代烷基、環烷基、醯基或烷氧羰基。 a compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, Wherein one of A ¹ and A ² is -NR ⁹ - and the other is -CH ₂ -; R ¹ is halogen; R ² is hydrogen, halogen, alkyl or haloalkyl; R ³ is hydrogen, halogen, alkyl Or a haloalkyl group; R ⁴ and R ^{5 are} simultaneously hydrogen; or R ⁴ and R ^{5 together} with the carbon atom to which they are bonded form a cycloalkyl group; R ⁶ is hydrogen, halogen, alkyl, haloalkyl or cycloalkyl; R ⁷ is hydrogen, halogen, alkyl, haloalkyl or cycloalkyl; R ⁸ is hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, alkylpyridyl, alkyl-1H- Pyrazolyl, phenyl, substituted phenyl, heterocyclic or substituted heterocyclic, wherein heterocyclic is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, Imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl or morpholinyl Substituted phenyl is phenyl substituted with one to three substituents independently selected from the group consisting of alkyl, halo, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halocycloalkyl and nitrile, And among them The heterocyclic group is a heterocyclic group substituted with one to three substituents independently selected from the group consisting of alkyl, halogen, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halocycloalkyl and Nitrile; and R ⁹ is hydrogen, alkyl, haloalkyl, cycloalkyl, decyl or alkoxycarbonyl. 如請求項1之化合物，其中R¹為氯或溴。 The compound of claim 1, wherein R ¹ is chlorine or bromine. 如請求項1或2之化合物，其中R²為氫。 A compound of claim 1 or 2 wherein R ² is hydrogen. 如請求項1或2之化合物，其中R³為氫或鹵素。 A compound of claim 1 or 2 wherein R ³ is hydrogen or halogen. 如請求項1或2之化合物，其中R³為氫或氟。 The compound of claim 1 or 2, wherein R ³ is hydrogen or fluoro. 如請求項1或2之化合物，其中R⁴及R⁵與其等所鍵接之碳原子共同形成環丙基。 A compound according to claim 1 or 2, wherein R ⁴ and R ^{5 together} with the carbon atom to which they are bonded form a cyclopropyl group. 如請求項1或2之化合物，其中R⁶為鹵素。 A compound of claim 1 or 2 wherein R ⁶ is halogen. 如請求項1或2之化合物，其中R⁶為氯。 A compound of claim 1 or 2 wherein R ⁶ is chloro. 如請求項1或2之化合物，其中R⁷為氫。 A compound of claim 1 or 2 wherein R ⁷ is hydrogen. 如請求項1或2之化合物，其中R⁸為氫、鹵素、烷氧基、鹵代烷氧基、環烷基、烷基吡啶基或烷基-1H-吡唑基。 A compound according to claim 1 or 2, wherein R ⁸ is hydrogen, halogen, alkoxy, haloalkoxy, cycloalkyl, alkylpyridyl or alkyl-1H-pyrazolyl. 如請求項1或2之化合物，其中R⁸為氫、鹵素、烷氧基、鹵代烷氧基、烷基吡啶基或烷基-1H-吡唑基。 A compound according to claim 1 or 2, wherein R ⁸ is hydrogen, halogen, alkoxy, haloalkoxy, alkylpyridyl or alkyl-1H-pyrazolyl. 如請求項1或2之化合物，其中R⁸為氫、氟、甲氧基、三氟乙氧基、三氟丙氧基、甲基吡啶基或甲基-1H-吡唑基。 A compound according to claim 1 or 2, wherein R ⁸ is hydrogen, fluoro, methoxy, trifluoroethoxy, trifluoropropoxy, methylpyridyl or methyl-1H-pyrazolyl. 如請求項1或2之化合物，其中R⁹為氫、烷基、鹵代烷基、甲醯基或烷氧羰基。 A compound according to claim 1 or 2, wherein R ⁹ is hydrogen, alkyl, haloalkyl, formyl or alkoxycarbonyl. 如請求項1或2之化合物，其中R⁹為氫、甲基、乙基、二氟乙基、甲醯基、甲氧羰基或三氟乙基。 A compound according to claim 1 or 2, wherein R ⁹ is hydrogen, methyl, ethyl, difluoroethyl, decyl, methoxycarbonyl or trifluoroethyl. 如請求項1或2之化合物，其係選自：3-[(2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-2-(1-氰基-環丙基胺甲 醯基)-吡咯啶-1-羰基]-3-(5-氯-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁-酯；(2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-1-[3-(5-氯-吡啶-2-基)-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-1-[3-(5-氯-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；3-(5-氯-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；3-(5-溴-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-1-[3-(5-氯-吡啶-2-基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-吡啶-2-基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-氯-吡啶-2-基)-1-(2,2-二氟-乙基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-吡啶-2-基)-1-(2,2-二氟-乙基)-氮雜環丁烷-3-羰基]-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；3-[(2S,4R)-4-(2-氯-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-3-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁 酯；3-(5-溴-3-氟吡啶-2-基)-3-((2S,4R)-4-(2-氯苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-1-(3-(5-氯-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-乙基-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-4-(2-氯-苯磺醯基)-1-[3-(5-氯-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；3-(5-氯-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；3-(5-溴-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-(2,2,2-三氟-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-1-(3-(5-溴-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；(2S,4R)-1-(3-(5-氯-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯 基)-吡咯啶-1-羰基]-2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯；2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；2-(5-氯-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙烷-2-基氧基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯；2-(5-氯-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-((S)-1,1,1-三氟丙烷-2-基氧基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯； 2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-4-(2-溴-4-氟-苯磺醯基)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；3-(5-溴-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-4-(2-氯-4-氟-苯磺醯基)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-(2-氯-4-氟-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺； (2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；2-(5-氯-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟-吡啶-2-基)-2-[(2S,4R)-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；2-(5-氯-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-(1-甲基-1H-吡唑-4-基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯；2-(5-溴-3-氟吡啶-2-基)-2-((2S,4R)-4-(2-氯-4-(1-甲基-1H-吡唑-4-基)苯磺醯基)-2-(1-氰基環丙基胺甲醯基)吡咯啶-1-羰基)氮雜環丁烷-1-羧酸第三丁酯；(2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(1-甲基-1H-吡唑-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(1-甲基-1H-吡唑-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環 丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-(2,2-二氟-乙基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲醯基-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；3-(5-溴-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸甲酯；及(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-(2,2,2-三氟-乙基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺。 A compound according to claim 1 or 2 which is selected from the group consisting of: 3-[(2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-2-(1-cyano- Cyclopropylamine Mercapto)-pyrrolidine-1-carbonyl]-3-(5-chloro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-4- (2-Chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro-pyridin-2-yl)-azetidin-3-carbonyl]-pyrrolidin-2- Carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro -pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 3-(5- Chloro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-2- (1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 3-(5-bromo-pyridin-2-yl) -3[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclo) Propylamine-mercapto)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1-[3-(5-chloro-pyridine-2 -yl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-pyrrolidin-2- Carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-azetidin-3-carbonyl]- 4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzene Mercapto]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-chloro-pyridin-2-yl)-1- (2,2-difluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonate (1), pyridin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-pyridin-2-yl)-1-( 2,2-Difluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl ]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; 3-[(2S,4R)-4-(2-chloro-phenylsulfonyl)-2-(1- Cyano-cyclopropylaminemethanyl)-pyrrolidin-1-carbonyl]-3-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid Ding Ester; 3-(5-bromo-3-fluoropyridin-2-yl)-3-((2S,4R)-4-(2-chlorophenylsulfonyl)-2-(1-cyanocyclopropyl) (3S,4R)-1-(3-(5-chloro-3-fluoropyridine-2-carboxylate) (a), azetidine-3-carbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S, 4R) 1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-(2-chloro-phenylsulfonyl)-pyrrolidine-2 -carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-nitrogen Heterocyclobutane-3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)- 1-[3-(5-Bromo-3-fluoro-pyridin-2-yl)-1-ethyl-azetidin-3-carbonyl]-4-(2-chloro-phenylsulfonyl)- Pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[3-(5-chloro- 3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; 3- (5-chloro-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-(2,2,2-trifluoro-ethoxy)-benzene Sulfhydryl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1 -carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2 -chloro-4-(2,2,2-trifluoro-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl] -azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1-(3-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-carbonyl -4-(2-chloro-4-(2,2,2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(3-(5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2, 2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; 2-[(2S,4R)-4-(2-chloro- 4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxamide) (3)-pyridyl-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester; 2-(5-bromo 3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylamine Tert-butyl)-pyrrolidin-1-carbonyl]-azetidine-1-carboxylic acid; 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonate) Mercapto)-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azacyclocycle Butane-1-carboxylic acid tert-butyl ester; 2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylamine) Mercapto)-pyrrolidin-1-carbonyl]-2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester; 2-(5 -Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropane Tert-butyl carbazino)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid; 2-(5-bromo-3-fluoro-pyridin-2-yl)-2- [(2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl]-nitrogen Tert-butyl butane-1-carboxylic acid; 2-(5-chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-() (S)-1,1,1-trifluoropropan-2-yloxy)benzenesulfonate Tertyl)-2-(1-cyanocyclopropylaminemethane)pyrrolidin-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; 2-(5-chloro-3- Fluoridin-2-yl)-2-((2S,4R)-4-(2-chloro-4-((S)-1,1,1-trifluoropropan-2-yloxy)benzenesulfonate Benzyl-2-(1-cyanocyclopropylaminemethane)pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; 2-(5-bromo-3-fluoro -pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)- Phenylsulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 2-(5-Bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-((S)-2,2,2-trifluoro- 1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidin-1-carbonyl]-azetidin-1-carboxylate Tert-butyl acid; (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)- Azetidine-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-bromo-4-fluoro-benzene Sulfhydryl)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano- Cyclopropyl)-guanamine; 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro-4-((S)-2) ,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminecarboxylidene)-pyrrolidine-1-carbonyl]-nitrogen Butane-terminated butane-1-carboxylic acid; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl ]-4-[2-Chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 -cyano-cyclopropyl)-guanamine; (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro-3-fluoro-pyridine -2-yl)-azetidin-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-(2-chloro-4-fluoro-benzene Sulfhydryl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridine-2- -Azetidine-2-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonate (2-Silyl-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl) -azetidin-2-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl] - pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-nitrogen Heterocyclobutane-2-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrole Pyridine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-[2-chloro- 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)- Indoleamine; 2-(5-chloro-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl) - Benzenesulfonyl]-2-(1-cyano-cyclopropylamine-carbamoyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; 2- (5-bromo-3-fluoro-pyridin-2-yl)-2-[(2S,4R)-4-[2-chloro-4-(2-methyl-pyridin-4-yl)-benzenesulfonate Tert-butyl 2-(1-cyano-cyclopropylaminemethanyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylic acid tert-butyl ester; (2S,4R)-1 -[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2-methyl-pyridine-4- -(Benzenesulfonyl)-pyrrolidinium-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-bromo-3-fluoro- Pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2-methyl-pyridin-4-yl)-benzenesulfonyl]-pyrrolidine-2 -carboxylic acid (1-cyano-cyclopropyl)-guanamine; 2-(5-chloro-3-fluoropyridin-2-yl)-2-((2S,4R)-4-(2-chloro- 4-(1-Methyl-1H-pyrazol-4-yl)benzenesulfonyl)-2-(1-cyanocyclopropylaminecarbamyl) Pyrrolidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester; 2-(5-bromo-3-fluoropyridin-2-yl)-2-((2S,4R)-4 -(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)benzenesulfonyl)-2-(1-cyanocyclopropylaminemethanyl)pyrrolidine-1-carbonyl Azetidine, azetidine-1-carboxylate; (2S,4R)-1-[2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidine-2 -carbonyl]-4-[2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropane (2), guanamine; (2S, 4R)-1-[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro 4-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-ring) Propyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-aza Cyclobutane-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine 2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-carboxamidine -azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl ]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)- 4-[2-Chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropyl) Methylaminopyridyl)-pyrrolidine-1-carbonyl]-azetidine-1-carboxylate; and (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridine- 2-yl)-1-(2,2,2-trifluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2, 2-Trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine. 如請求項1或2之化合物，其係選自：(2S,4R)-4-(2-氯-4-甲氧基-苯磺醯基)-1-[3-(5-氯-吡啶-2-基)-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-(3-(5-氯-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-乙基-氮雜環丁烷-3-羰基]-4-(2-氯-苯磺醯基)-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-4-(2-氯-苯磺醯基)-1-[3-(5-氯-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺； (2S,4R)-1-(3-(5-溴-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；(2S,4R)-1-(3-(5-氯-3-氟吡啶-2-基)氮雜環丁烷-3-羰基)-4-(2-氯-4-(2,2,2-三氟乙氧基)苯磺醯基)-N-(1-氰基環丙基)吡咯啶-2-甲醯胺；(2S,4R)-4-(2-溴-4-氟-苯磺醯基)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲基-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-溴-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(2-甲基-吡啶-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[2-(5-氯-3-氟-吡啶-2-基)-氮雜環丁烷-2-羰基]-4-[2-氯-4-(1-甲基-1H-吡唑-4-基)-苯磺醯基]-吡咯啶-2-羧酸(1-氰基-環丙基)-醯胺； (2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-(2,2-二氟-乙基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-甲醯基-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺；3-(5-溴-3-氟-吡啶-2-基)-3-[(2S,4R)-4-[2-氯-4-((S)-2,2,2-三氟-1-甲基-乙氧基)-苯磺醯基]-2-(1-氰基-環丙基胺甲醯基)-吡咯啶-1-羰基]-氮雜環丁烷-1-羧酸甲酯；及(2S,4R)-1-[3-(5-溴-3-氟-吡啶-2-基)-1-(2,2,2-三氟-乙基)-氮雜環丁烷-3-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-羧酸(1-氰基-環丙基)-醯胺。 A compound according to claim 1 or 2, which is selected from the group consisting of: (2S, 4R)-4-(2-chloro-4-methoxy-benzenesulfonyl)-1-[3-(5-chloro-pyridine) -2-yl)-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-(3-( 5-chloro-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine- 2-carbamamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-(2-chloro -Benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridine- 2-yl)-1-methyl-azetidin-3-carbonyl]-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl) )-decylamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-ethyl-azetidin-3-carbonyl]-4- (2-Chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-4-(2-chloro-benzenesulfonyl) 1-[3-(5-chloro-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano) -cyclopropyl)-guanamine; (2S,4R)-1-(3-(5-bromo-3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2, 2-trifluoroethoxy)benzenesulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-1-(3-(5-chloro- 3-fluoropyridin-2-yl)azetidin-3-carbonyl)-4-(2-chloro-4-(2,2,2-trifluoroethoxy)benzenesulfonyl)-N- (1-cyanocyclopropyl)pyrrolidine-2-carboxamide; (2S,4R)-4-(2-bromo-4-fluoro-benzenesulfonyl)-1-[2-(5-chloro 3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)- 1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2, 2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)-1- [2-(5-chloro-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S)-2,2,2- Trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2 -(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro -1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S, 4R)-1-[3 -(5-bromo-3-fluoro-pyridin-2-yl)-1-methyl-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2 ,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidin-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1 -[2-(5-bromo-3-fluoro-pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(2-methyl-pyridine-4- -(Benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-decylamine; (2S,4R)-1-[2-(5-chloro-3-fluoro- Pyridin-2-yl)-azetidin-2-carbonyl]-4-[2-chloro-4-(1-methyl-1H-pyrazol-4-yl)-benzenesulfonyl]-pyrrole Pyridine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-(2,2-difluoro-ethyl)-azetidin-3-carbonyl ]-4-[2-Chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1 -cyano-cyclopropyl)-guanamine; (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1-carboxanyl-azetidine 3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2- Carboxylic acid (1-cyano-cyclopropyl)-guanamine; 3-(5-bromo-3-fluoro-pyridin-2-yl)-3-[(2S,4R)-4-[2-chloro- 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenesulfonyl]-2-(1-cyano-cyclopropylaminecarbamyl)-pyrrole Methyl pyridine-1-carbonyl]-azetidine-1-carboxylate; and (2S,4R)-1-[3-(5-bromo-3-fluoro-pyridin-2-yl)-1- (2,2,2-trifluoro-ethyl)-azetidin-3-carbonyl]-4-[2-chloro-4-((S)-2,2,2-trifluoro-1- Methyl-ethoxy)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-guanamine. 一種製備如請求項1至16中任一項之式(I)化合物之方法，其包括以下步驟之一：(a)使式(II)化合物在酸存在下反應： 其中R¹至R⁸係如請求項1至14中任一項中所定義，A¹及A²之一為-CH₂-且另一者為-NR¹⁰-，其中R¹⁰為胺保護基；(b)使式(III)化合物在R⁹-X的存在下反應： 其中A¹、A²及R¹至R⁹係如請求項1至14中任一項中所定義；或(c)使如上所定義之式(III)化合物在R¹⁰-C(O)-Y及還原劑的存在下反應，其中A¹、A²及R¹至R⁹係如請求項1至14中任一項中所定義，R¹⁰為烷基、鹵代烷基或環烷基且Y為氫、烷基或鹵代烷基。 A process for the preparation of a compound of formula (I) according to any one of claims 1 to 16, which comprises the step of: (a) reacting a compound of formula (II) in the presence of an acid: Wherein R ¹ to R ⁸ are as defined in any one of claims 1 to 14, one of A ¹ and A ² is -CH ₂ - and the other is -NR ¹⁰ -, wherein R ¹⁰ is an amine protecting group (b) reacting a compound of formula (III) in the presence of R ⁹ -X: Wherein A ¹ , A ² and R ¹ to R ⁹ are as defined in any one of claims 1 to 14; or (c) a compound of formula (III) as defined above is at R ¹⁰ -C(O)- Reaction in the presence of Y and a reducing agent, wherein A ¹ , A ² and R ¹ to R ⁹ are as defined in any one of claims 1 to 14, and R ¹⁰ is alkyl, haloalkyl or cycloalkyl and Y It is hydrogen, alkyl or haloalkyl. 如請求項1或2之化合物，其係根據如請求項17之方法製得。 A compound according to claim 1 or 2, which is produced according to the method of claim 17. 如請求項1或2之化合物，其係用作治療活性物質。 A compound of claim 1 or 2 for use as a therapeutically active substance. 如請求項1或2之化合物，其係用作供治療或預防糖尿病、動脈粥樣硬化、腹主動脈瘤、外周動脈疾病、癌症、減少慢性腎病中的心血管事件、糖尿病性腎病、糖尿病性視網膜病變或與年齡有關之黃斑變性的治療活性物質。 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, diabetes A therapeutically active substance for retinopathy or age-related macular degeneration. 一種醫藥組合物，其包含如請求項1至16中任一項之化合物及治療上惰性之載劑。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a therapeutically inert carrier. 一種如請求項1至16中任一項之化合物之用途，其係用於製備供治療或預防糖尿病、動脈粥樣硬化、腹主動脈瘤、外周動脈疾病、癌症、減少慢性腎病中的心血管事件、糖尿病性腎病、糖尿病性視網膜病變或與年齡有關的黃斑變性之藥物。 Use of a compound according to any one of claims 1 to 16 for the preparation of a cardiovascular for the treatment or prevention of diabetes, atherosclerosis, abdominal aortic aneurysm, peripheral arterial disease, cancer, reduction of chronic kidney disease A drug for events, diabetic nephropathy, diabetic retinopathy, or age-related macular degeneration.