TW202325706A - Pharmaceutical composition comprising a compound having kdm5 inhibitory activity - Google Patents

Abstract

The present invention provides a pharmaceutical composition comprising a compound represented by the general formula (I):

Description

包含具有KDM5抑制活性之化合物之醫藥組合物Pharmaceutical compositions comprising compounds having KDM5 inhibitory activity

本發明係關於一種醫藥組合物，該醫藥組合物包含下文所述具有KDM5抑制活性之由通式(I)表示的化合物或其鹽及其他等等。The present invention relates to a pharmaceutical composition comprising a compound represented by general formula (I) or a salt thereof and others etc. described below having KDM5 inhibitory activity.

真核DNA存在於細胞核中作為染色質結構，該染色質結構為具有組織蛋白蛋白質之複合物。組織蛋白蛋白質受制於經由各種酶進行之修改，諸如甲基化、乙醯化及磷酸化，且已知此類修改中之改變誘發染色質重構及轉錄變化。包括組織蛋白甲基化之表觀遺傳修改可逆地調節基因表現而不更改核苷酸序列且在生理過程中起重要作用。Eukaryotic DNA exists in the nucleus as a chromatin structure, which is a complex with histone proteins. Histone proteins are subject to modifications by various enzymes, such as methylation, acetylation, and phosphorylation, and changes in such modifications are known to induce chromatin remodeling and transcriptional changes. Epigenetic modifications including histone methylation reversibly regulate gene expression without altering nucleotide sequence and play important roles in physiological processes.

KDM5蛋白為JARID組織蛋白去甲基酶蛋白家族之成員，其使組織蛋白H3蛋白之第四離胺酸殘基之三甲基化(H3K4me3)去甲基化。在包括人類之哺乳動物物種中，存在四個亞家族：KDM5A、KDM5B、KDM5C及KDM5D，其具有五個保留結構域，亦即JmjN、ARID、JmjC、PHDs及C5HC2鋅指。KDM5家族在活體內廣泛地分佈於血細胞及各種器官中，且特定而言，已知為高度表現於癌症組織中。癌細胞中之表觀遺傳畸變已知在細胞增生及轉移中涉及，且KDM5抑制劑已經報告為具有抵抗癌細胞之功效。包括組織蛋白修改之表觀遺傳異常的涉及亦已經報導於諸如神經精神病症及代謝疾病之其他病變中。因此，具有KDM5抑制活性之化合物可改善表觀遺傳異常且對預防及治療此等疾病有用。The KDM5 protein is a member of the JARID histone demethylase protein family that demethylates the trimethylation of the fourth lysine residue (H3K4me3) of the histone H3 protein. In mammalian species including humans, there are four subfamilies: KDM5A, KDM5B, KDM5C and KDM5D with five conserved domains, namely JmjN, ARID, JmjC, PHDs and C5HC2 zinc fingers. The KDM5 family is widely distributed in blood cells and various organs in vivo, and in particular, is known to be highly expressed in cancer tissues. Epigenetic aberrations in cancer cells are known to be involved in cell proliferation and metastasis, and KDM5 inhibitors have been reported to be effective against cancer cells. The involvement of epigenetic abnormalities including histone modifications has also been reported in other pathologies such as neuropsychiatric and metabolic diseases. Therefore, compounds having KDM5 inhibitory activity can improve epigenetic abnormalities and are useful for the prevention and treatment of these diseases.

在本發明之先前技術中，WO2016/057924報告式(A)化合物可用作諸如KDM5之一或多個組織蛋白去甲基酶的抑制劑。 式(A)： 或其鹽，其中： A ^A係選自由以下各者組成之群： R ^1A為烷基、環狀基團或其類似者； R ^2A視情況經環狀基團、-OR ^aA、-C(O)N(R ^aA) ₂或NR ^aAR ^bA取代； R ^aA及R ^bA各自獨立地選自H、視情況經取代之烷基、視情況經取代之環狀基團等； R ^3A為H或烷基； R ^4A為H、烷基或環狀基團；且 R ^5A為H、鹵基或烷基，且 R ^6A為H、烷基或環狀基團； 或R ^5A及R ^6A連在一起以形成環狀基團(其中基團之定義經摘錄)。 In the prior art of the present invention, WO2016/057924 reported that the compound of formula (A) can be used as an inhibitor of one or more histone demethylases such as KDM5. Formula (A): or its salt, wherein: A ^A is selected from the group consisting of: R ^1A is an alkyl group, a cyclic group or the like; R ^2A is optionally substituted by a cyclic group, -OR ^aA , -C(O)N(R ^aA ) ₂ or NR ^aA R ^bA ; R ^aA and R ^bA are each independently selected from H, optionally substituted alkyl, optionally substituted cyclic groups, etc.; R ^3A is H or alkyl; R ^4A is H, alkyl, or cyclic; and R ^5A is H, halo or alkyl, and R ^6A is H, alkyl or cyclic group; or R ^5A and R ^6A are joined together to form a cyclic group (wherein the definition of the group is extracted).

此外，WO2000/039089報告由下式(B)表示之化合物可用作鴉片受體配體。 式(B)： 其中Ar ^B環表示視情況苯并稠合之苯基或5或6員雜芳環； R ^1B選自各種取代基； R ^2B為H或鹵素； R ^3B為H、鹵素、烷基、環狀基團或其類似者， R ^4B為視情況經取代之烷基、烯基或炔基， R ^5B及R ^8B各自獨立地為H或C _1-6烷基， R ^6B、R ^7B、R ^9B及R ^10B在分別採用時為H， X為鹵素、烷基、烷氧基或其類似者(其中基團之定義經摘錄)或醫藥學上或獸醫學上可接受之衍生物或其前驅藥。 Furthermore, WO2000/039089 reports that compounds represented by the following formula (B) are useful as opiate receptor ligands. Formula (B): Wherein Ar ^B ring represents a benzo-fused phenyl or a 5- or 6-membered heteroaromatic ring as appropriate; R ^1B is selected from various substituents; R ^2B is H or halogen; R ^3B is H, halogen, alkyl, cyclic or the like, R ^4B is optionally substituted alkyl, alkenyl or alkynyl, R ^5B and R ^8B are each independently H or C _1-6 alkyl, R ^6B , R ^7B , R ^9B and R ^10B are H when they are adopted respectively, X is halogen, alkyl, alkoxy or the like (wherein the definition of the group is extracted) or a pharmaceutically or veterinarily acceptable derivative or a prodrug thereof .

此外，WO2021/010492報告式(C)化合物可用作KDM5抑制劑。 式(C)： 其中ring ^C為含有1至4個氮原子、一個氧原子及/或一個硫原子之3至10員單或雙環雜環，其可經1至3個取代基取代； A ^C為R ^1-1C-L ^1C-或其類似者； B ^C為R ^2-1C-L ^2C-或其類似者； R ^1-1C為可經1至4個取代基取代之C3-8環烷基或其類似者； L ^1C為一鍵或羰基(-C(=O)-)； L ^2C為一鍵、羰基(-C(=O)-)或其類似者； R ^2-1C為可經1至4個取代基取代之5或6員單環雜環或其類似者； R ^3C為氫原子或其類似者； r ^C表示0至1之整數； 或其鹽。 [引用清單] [專利文獻] Furthermore, WO2021/010492 reports that compounds of formula (C) are useful as KDM5 inhibitors. Formula (C): Wherein ring ^C is a 3 to 10 membered mono- or bicyclic heterocyclic ring containing 1 to 4 nitrogen atoms, an oxygen atom and/or a sulfur atom, which may be substituted by 1 to 3 substituents; ^AC is R ^1-1C -L ^1C - or the like; B ^C is R ^2-1C -L ^2C - or the like; R ^1-1C is C3-8 cycloalkyl which may be substituted by 1 to 4 substituents or the like ; L ^1C is a bond or carbonyl (-C(=O)-); L ^2C is a bond, carbonyl (-C(=O)-) or the like; R ^2-1C can be 1 to 4 A 5- or 6-membered monocyclic heterocyclic ring substituted by a substituent or the like; R ^3C is a hydrogen atom or the like; r ^C represents an integer from 0 to 1; or a salt thereof. [Citation List] [Patent Literature]

[PTL 1] WO 2016/057924 [PTL 2] WO 2000/039089 [PTL 3] WO 2021/010492 [PTL 1] WO 2016/057924 [PTL 2] WO 2000/039089 [PTL 3] WO 2021/010492

[技術難題][technical challenge]

舉例而言，已需要用於預防及/或治療諸如癌症、亨廷頓氏病(Huntington's disease)、阿茲海默症(Alzheimer's disease)及其類似者之疾病的包含具有KDM5抑制活性之化合物的醫藥組合物。 [問題之解決方案] For example, there has been a need for pharmaceutical combinations comprising compounds having KDM5 inhibitory activity for the prevention and/or treatment of diseases such as cancer, Huntington's disease, Alzheimer's disease and the like thing. [Solution to problem]

本發明之發明者已進行廣泛研究以便實現以上問題，且因此，發現包含由下文中描述之通式(I)表示之化合物或其鹽的醫藥組合物可實現以上目的。The inventors of the present invention have conducted extensive research in order to achieve the above problems, and thus, found that a pharmaceutical composition comprising a compound represented by the general formula (I) described hereinafter or a salt thereof can achieve the above objects.

因此，本發明之態樣中之一者係關於： [1]一種由通式(I)表示之化合物： 其中R ¹表示Cyc1、-CO-Cyc2或-CONR ¹⁰R ¹¹； Cyc1表示5至9員芳族雜環或5員非芳族雜環，其中各者可經1至5個R ¹²取代； R ¹²表示(1) C1-4烷基、(2) C3-7環烷基、(3) C1-4鹵烷基、(4) C1-4烷氧基、(5)可經1至3個R ¹⁷取代之苯基、(6)經苯基取代之C1-4烷基、(7)二甲基胺基、(8)吡啶基或(9) 1-(環丙基甲基)吡唑-3-基； 複數個R ¹²可相同或不同； 兩個R ¹²以及附接至此等R ¹²之原子可形成C3-5環烷烴，其中C3-5環烷烴之碳原子可經選自1至2個N、O及S之雜原子置換； R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素； 複數個R ¹⁷可相同或不同； Cyc2表示C3-12單或雙環碳環或5至9員單或雙環雜環，其中各者可經1至5個R ¹³取代； R ¹³表示C1-4烷基、C1-4烷氧基或鹵素； 複數個R ¹³可相同或不同； R ¹⁰表示 其中R ¹⁸及R ¹⁹獨立地表示C1-4烷基； R ¹⁸及R ¹⁹以及附接至R ¹⁸及R ¹⁹之碳原子可形成C3-5環烷烴； R ²⁰表示氫原子、C1-4烷基、C1-4鹵烷基或腈； (在基團中，箭頭指示結合至-CON＜之氮原子)； R ¹¹表示氫原子、C1-4烷基或1至9個氘化C1-4烷基； R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷及R ⁸獨立地表示氫原子、C1-4烷基、鹵素或C1-4烷氧基； R ⁹表示可經1至3個R ¹⁴取代之咪唑或可經1至3個R ¹⁵取代之吡唑； R ¹⁴表示(1) C1-8烷基、(2)可經C1-4烷基取代之C3-7環烷基、(3) C1-8鹵烷基、(4)經可經1至3個R ¹⁶取代之Cyc3取代的C1-8烷基或(5)經苯氧基取代之C1-8烷基； Cyc3表示苯基、C3-7環烷基、吡啶基、噻唑基或四氫哌喃基； R ¹⁶表示C1-4烷基、鹵素、C1-4烷氧基或氰基； 複數個R ¹⁴可相同或不同； 複數個R ¹⁶可相同或不同； R ¹⁵表示(1) C1-8烷基、(2)可經C1-4烷基取代之C3-7環烷基、(3) C1-8鹵烷基、(4)經可經1至3個R ²¹取代之Cyc4取代的C1-8烷基或(5)經苯氧基取代之C1-8烷基； Cyc4表示苯基、C3-7環烷基、吡啶基、噻唑基或四氫哌喃基； R ²¹表示C1-4烷基、鹵素、C1-4烷氧基或氰基； 複數個R ¹⁵可相同或不同； 複數個R ²¹可相同或不同； 各氫原子可為氘原子或氚原子； 其限制條件為排除((1R,5S,6r)-6-(環丙烷羰基)-3-氮雜雙環[3.1.0]己-3-基)(5-異丙基-1H-吡唑-3-基)甲酮、(5-異丙基-1H-吡唑-3-基)-[(1R,5S)-6-[(2R)-2-甲基吡咯啶-1-羰基]-3-氮雜雙環[3.1.0]己-3-基]甲酮、(5-異丙基-1H-吡唑-3-基)-[(1S,5R)-6-[(2S)-2-甲基吡咯啶-1-羰基]-3-氮雜雙環[3.1.0]己-3-基]甲酮、[(1S,5R)-6-(2,2-二甲基吡咯啶-1-羰基)-3-氮雜雙環[3.1.0]己-3-基]-(5-異丙基-1H-吡唑-3-基)甲酮及(5-異丙基-1H-吡唑-3-基)-[(1S,5R)-6-(5-甲基-4-苯基-異㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； 或其鹽； [2]如前述項目[1]之化合物，其中R ¹表示Cyc1，且Cyc1表示可經1至5個R ¹²取代之5員非芳族雜環，或其鹽； [3]如前述項目[2]之化合物，其中5員非芳族雜環表示4,5-二氫異㗁唑或4,5-二氫-1,2,4-㗁二唑，或其鹽； [3-1]如前述項目[3]之化合物，其中由通式(I)表示之化合物由通式(I-01)表示 其中R ^12-1及R ^12-2獨立地表示C1-4烷基； R ^12-1及R ^12-2以及鍵結至該R ^12-1及R ^12-2之原子可形成C3-5環烷烴； 其他符號表示與前述項目[1]中所描述係相同之含義； 或其鹽； [4]如前述項目[1]至[3]及[3-1]中任一項之化合物，其中R ⁹表示可經1至3個R ¹⁴取代之咪唑，或其鹽； [5]如前述項目[1]至[4]及[3-1]中任一項之化合物，其中由通式(I)表示之化合物由通式(I-1)表示 其中R ^12-1及R ^12-2獨立地表示C1-4烷基； R ^12-1及R ^12-2以及鍵結至該R ^12-1及R ^12-2之原子可形成C3-5環烷烴； R ^14-1表示可經C1-4烷基取代之C1-4烷基或C3-5環烷基； 其他符號表示與[1]中所描述係相同之含義； 或其鹽； [6]如前述項目[1]至[5]及[3-1]中任一項之化合物，其中化合物為： (1) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](1-異丙基-1H-咪唑-4-基)甲酮； (2) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基][1-(1-甲基環丙基)-1H-咪唑-4-基]甲酮； (3) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基]甲酮； (4) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (5) {1-[(2S)-丁-2-基]-1H-咪唑-4-基}[(1R, 5S, 6S)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (6) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基(1-異丙基-1H-咪唑-4-基)甲酮； (7) (1-異丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (8) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮；或 (9) [1-(1-甲基環丙基)-1H-咪唑-4-基][(1R,5S,6r)-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮 或其鹽； [7]如前述項目[1]至[3]及[3-1]中任一項之化合物，其中R ⁹表示可經1至3個R ¹⁵取代之吡唑，或其鹽； [8]如前述項目[1]至[3]、[3-1]及[7]中任一項之化合物，其中由通式(I)表示之化合物由通式(I-2)表示 其中所有符號表示與前述項目[1]或[5]中所描述係相同之含義； 或其鹽； [9]如前述項目[1]至[3]、[3-1]、[7]及[8]中任一項之化合物，其中化合物為： (1) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮； (2) (5-異丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-(2-氧雜-3-氮雜雙環[3.1.0]己-3-烯-4-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (3) [5-(1-環丙基乙基)-1H-吡唑-3-基][(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (4) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮或 (5) (5-環丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮 或其鹽； [10]如前述項目[1]之化合物，其中R ¹表示-CONR ¹⁰R ¹¹或其鹽； [11]如前述項目[1]或[10]之化合物，其中R ¹⁰表示異丙基、三級丁基、1,1,1-三氟-2-甲基丙-2-基、1-甲基環丙基、1-(三氟甲基)環丙基或1-氰基環丙基，或其鹽； [11-1]如前述項目[11]之化合物，其中由通式(I)表示之化合物由通式(I-02)表示 其中R ^10-1表示異丙基、三級丁基、1,1,1-三氟-2-甲基丙-2-基、1-甲基環丙基、1-(三氟甲基)環丙基或1-氰基環丙基； 其他符號表示與前述項目[1]中所描述係相同之含義； 或其鹽； [12]如前述項目[10]、[11]或[11-1]之化合物，其中R ⁹表示可經1至3個R ¹⁴取代之咪唑，或其鹽； [13]如前述項目[1]、[10]至[12]及[11-1]中任一項之化合物，其中由通式(I)表示之化合物由通式(I-3)表示 其中R ^10-1表示異丙基、三級丁基、1,1,1-三氟-2-甲基丙-2-基、1-甲基環丙基、1-(三氟甲基)環丙基或1-氰基環丙基； 其他符號表示與前述項目[1]或[5]中所描述係相同之含義； 或其鹽； [14]如前述項目[1]、[10]至[13]及[11-1]中任一項之化合物，其中化合物為： (1) (1R,5S,6r)-N-三級丁基-6-甲基-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (2) (1R,5S,6r)-N-三級丁基-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (3) (1R,5S,6r)-N-(丙-2-基)-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺或 (4) (1R,5S,6r)-N-(1-氰基環丙基)-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺 或其鹽； [15]如前述項目[10]、[11]及[11-1]之化合物，其中R ⁹表示可經1至3個R ¹⁵取代之吡唑，或其鹽； [16]如前述項目[1]、[10]、[11]、[11-1]及[15]中任一項之化合物，其中由通式(I)表示之化合物由通式(I-4)表示 其中所有符號表示與前述項目[1]或[13]中所描述係相同之含義； 或其鹽； [17]如前述項目[1]、[10]、[11]、[11-1]、[15]及[16]中任一項之化合物，其中化合物為： (1) (1R,5S,6r)-N-(丙-2-基)-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (2) (1R,5S,6r)-N-三級丁基-6-甲基-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (3) (1R,5S,6r)-N-三級丁基-N-甲基-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺或 (4) (1R,5S,6r)-N-甲基-N-(1-甲基環丙基)-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺， 或其鹽； [A-1]一種醫藥組合物，其包含由通式(I)表示之化合物： 其中R ¹表示Cyc1、-CO-Cyc2或-CONR ¹⁰R ¹¹； Cyc1表示5至9員芳族雜環或5員非芳族雜環，其中各者可經1至5個R ¹²取代； R ¹²表示(1) C1-4烷基、(2) C3-7環烷基、(3) C1-4鹵烷基、(4) C1-4烷氧基、(5)可經1至3個R ¹⁷取代之苯基、(6)經苯基取代之C1-4烷基、(7)二甲基胺基、(8)吡啶基或(9) 1-(環丙基甲基)吡唑-3-基； 複數個R ¹²可相同或不同； 兩個R ¹²以及附接至此等R ¹²之原子可形成C3-5環烷烴，其中C3-5環烷烴之碳原子可經選自1至2個N、O及S之雜原子置換； R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素； 複數個R ¹⁷可相同或不同； Cyc2表示C3-12單或雙環碳環或5至9員單或雙環雜環，其中各者可經1至5個R ¹³取代； R ¹³表示C1-4烷基、C1-4烷氧基或鹵素； 複數個R ¹³可相同或不同； R ¹⁰表示 其中R ¹⁸及R ¹⁹獨立地表示C1-4烷基； R ¹⁸及R ¹⁹以及附接至R ¹⁸及R ¹⁹之碳原子可形成C3-5環烷烴； R ²⁰表示氫原子、C1-4烷基、C1-4鹵烷基或腈； (在基團中，箭頭指示結合至-CON＜之氮原子)； R ¹¹表示氫原子、C1-4烷基或1至9個氘化C1-4烷基； R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷及R ⁸獨立地表示氫原子、C1-4烷基、鹵素或C1-4烷氧基； R ⁹表示可經1至3個R ¹⁴取代之咪唑或可經1至3個R ¹⁵取代之吡唑； R ¹⁴表示(1) C1-8烷基、(2)可經C1-4烷基取代之C3-7環烷基、(3) C1-8鹵烷基、(4)經可經1至3個R ¹⁶取代之Cyc3取代的C1-8烷基或(5)經苯氧基取代之C1-8烷基； Cyc3表示苯基、C3-7環烷基、吡啶基、噻唑基或四氫哌喃基； R ¹⁶表示C1-4烷基、鹵素、C1-4烷氧基或氰基； 複數個R ¹⁴可相同或不同； 複數個R ¹⁶可相同或不同； R ¹⁵表示(1) C1-8烷基、(2)可經C1-4烷基取代之C3-7環烷基、(3) C1-8鹵烷基、(4)經可經1至3個R ²¹取代之Cyc4取代的C1-8烷基或(5)經苯氧基取代之C1-8烷基； Cyc4表示苯基、C3-7環烷基、吡啶基、噻唑基或四氫哌喃基； R ²¹表示C1-4烷基、鹵素、C1-4烷氧基或氰基； 複數個R ¹⁵可相同或不同； 複數個R ²¹可相同或不同； 各氫原子可為氘原子或氚原子； 其限制條件為排除((1R,5S,6r)-6-(環丙烷羰基)-3-氮雜雙環[3.1.0]己-3-基)(5-異丙基-1H-吡唑-3-基)甲酮、(5-異丙基-1H-吡唑-3-基)-[(1R,5S)-6-[(2R)-2-甲基吡咯啶-1-羰基]-3-氮雜雙環[3.1.0]己-3-基]甲酮、(5-異丙基-1H-吡唑-3-基)-[(1S,5R)-6-[(2S)-2-甲基吡咯啶-1-羰基]-3-氮雜雙環[3.1.0]己-3-基]甲酮、[(1S,5R)-6-(2,2-二甲基吡咯啶-1-羰基)-3-氮雜雙環[3.1.0]己-3-基]-(5-異丙基-1H-吡唑-3-基)甲酮及(5-異丙基-1H-吡唑-3-基)-[(1S,5R)-6-(5-甲基-4-苯基-異㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； 或其鹽； [A-2]如前述項目[A-1]之醫藥組合物，其進一步含有醫藥學上可接受之載劑； [A-3]如前述項目[A-1]或[A-2]之醫藥組合物，其中R ¹表示Cyc1，且Cyc1表示可經1至5個R ¹²取代之5員非芳族雜環。 [A-4]如前述項目[A-3]之醫藥組合物，其中5員非芳族雜環表示4,5-二氫異㗁唑或4,5-二氫-1,2,4-㗁二唑； [A-5]如前述項目[A-4]之醫藥組合物，其中由通式(I)表示之化合物或其鹽為由通式(I-01)表示之化合物 其中R ^12-1及R ^12-2獨立地表示C1-4烷基； R ^12-1及R ^12-2以及鍵結至該R ^12-1及R ^12-2之原子可形成C3-5環烷烴； 其他符號表示與前述項目[A-1]中所描述係相同之含義； 或其鹽； [A-6]如前述項目[A-1]至[A-5]中任一項之醫藥組合物，其中R ⁹表示可經1至3個R ¹⁴取代之咪唑； [A-7]如前述項目[A-1]至[A-6]中任一項之醫藥組合物，其中由通式(I)表示之化合物或其鹽為由通式(I-1)表示之化合物 其中R ^12-1及R ^12-2獨立地表示C1-4烷基； R ^12-1及R ^12-2以及鍵結至該R ^12-1及R ^12-2之原子可形成C3-5環烷烴； R ^14-1表示可經C1-4烷基取代之C1-4烷基或C3-5環烷基； 其他符號表示與[A-1]中所描述係相同之含義； 或其鹽； [A-8]如前述項目[A-1]至[A-7]中任一項之醫藥組合物，其中由通式(I)表示之化合物或其鹽係選自由以下各者組成之群的化合物： (1) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](1-異丙基-1H-咪唑-4-基)甲酮； (2) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基][1-(1-甲基環丙基)-1H-咪唑-4-基]甲酮； (3) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基]甲酮； (4) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (5) {1-[(2S)-丁-2-基]-1H-咪唑-4-基}[(1R,5S,6S)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (6) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基](1-異丙基-1H-咪唑-4-基)甲酮； (7) (1-異丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (8) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮；及 (9) [1-(1-甲基環丙基)-1H-咪唑-4-基][(1R,5S,6r)-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； 或其鹽； [A-9]如前述項目[A-1]至[A-5]中任一項之醫藥組合物，其中R ⁹表示可經1至3個R ¹⁵取代之吡唑； [A-10]如前述項目[A-1]至[A-5]及[A-9]中任一項之醫藥組合物，其中由通式(I)表示之化合物或其鹽為由通式(I-2)表示之化合物 其中所有符號表示與前述項目[A-1]或[A-7]中所描述係相同之含義； 或其鹽； [A-11]如前述項目[A-1]至[A-5]、[A-9]及[A-10]中任一項之醫藥組合物，其中由通式(I)表示之化合物或其鹽係選自由以下各者組成之群的化合物： (1) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮； (2) (5-異丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-(2-氧雜-3-氮雜雙環[3.1.0]己-3-烯-4-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (3) [5-(1-環丙基乙基)-1H-吡唑-3-基][(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (4) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮；及 (5) (5-環丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； 或其鹽； [A-12]如前述項目[A-1]之醫藥組合物，其中R ¹表示-CONR ¹⁰R ¹¹； [A-13]如前述項目[A-12]之醫藥組合物，其中R ¹⁰表示異丙基、三級丁基、1,1,1-三氟-2-甲基丙-2-基、1-甲基環丙基、1-(三氟甲基)環丙基或1-氰基環丙基； [A-14]如前述項目[A-13]之醫藥組合物，其中由通式(I)表示之化合物或其鹽為由通式(I-02)表示之化合物 其中R ^10-1表示異丙基、三級丁基、1,1,1-三氟-2-甲基丙-2-基、1-甲基環丙基、1-(三氟甲基)環丙基或1-氰基環丙基； 其他符號表示與前述項目[A-1]中所描述係相同之含義； 或其鹽； [A-15]如前述項目[A-12]至[A-14]中任一項之醫藥組合物，其中R ⁹表示可經1至3個R ¹⁴取代之咪唑； [A-16]如前述項目[A-1]及[A-12]至[A-15]中任一項之醫藥組合物，其中由通式(I)表示之化合物或其鹽為由通式(I-3)表示之化合物 其中R ^10-1表示異丙基、三級丁基、1,1,1-三氟-2-甲基丙-2-基、1-甲基環丙基、1-(三氟甲基)環丙基或1-氰基環丙基； 其他符號表示與前述項目[A-1]或[A-7]中所描述係相同之含義； 或其鹽； [A-17]如前述項目[A-1]及[A-12]至[A-16]中任一項之醫藥組合物，其中由通式(I)表示之化合物或其鹽係選自由以下各者組成之群的化合物： (1) (1R,5S,6r)-N-三級丁基-6-甲基-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (2) (1R,5S,6r)-N-三級丁基-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (3) (1R,5S,6r)-N-(丙-2-基)-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺；及 (4) (1R,5S,6r)-N-(1-氰基環丙基)-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； 或其鹽； [A-18]如前述項目[A-12]至[A-14]中任一項之醫藥組合物，其中R ⁹表示可經1至3個R ¹⁵取代之吡唑； [A-19]如前述項目[A-1]、[A-12]至[A-14]及[A-18]中任一項之醫藥組合物，其中由通式(I)表示之化合物或其鹽為由通式(I-4)表示之化合物 其中所有符號表示與前述項目[A-1]或[A-16]中所描述係相同之含義； 或其鹽； [A-20]如前述項目[A-1]、[A-12]至[A-14]、[A-18]及[A-19]中任一項之醫藥組合物，其中由通式(I)表示之化合物或其鹽係選自由以下各者組成之群的化合物： (1) (1R,5S,6r)-N-(丙-2-基)-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (2) (1R,5S,6r)-N-三級丁基-6-甲基-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (3) (1R,5S,6r)-N-三級丁基-N-甲基-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺；及 (4) (1R,5S,6r)-N-甲基-N-(1-甲基環丙基)-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； 或其鹽； [A-21]如前述項目[A-1]至[A-20]中任一項之醫藥組合物，其為KDM5抑制劑； [A-22]如前述項目[A-1]至[A-21]中任一項之醫藥組合物，其為針對KDM5相關疾病之預防劑及/或治療劑； [A-23] 如前述項目[A-22]之醫藥組合物，其中KDM5相關疾病為過度增生性疾病、癌症、中風、糖尿病、肝腫大、心血管疾病、多發性硬化症、亨廷頓氏病、阿茲海默症、囊腫纖維化、病毒性疾病、自身免疫疾病、動脈粥樣硬化、再狹窄、牛皮癬、類風濕性關節炎、發炎性腸道疾病、哮喘、過敏性病症、炎症、神經病症、激素相關疾病、與器官移植相關聯之病況、免疫缺乏症、破壞性骨症、增生性病症、傳染性疾病、與細胞死亡相關聯之病況、凝血酶誘發之血小板凝集、肝臟疾病、涉及T細胞活化之病理性免疫病況、CNS病症、骨髓增生性病症、帕金森氏症(Parkinson's disease)、路易體疾病(Lewy body disease)、額顳葉退化、輕度認知障礙、認知障礙、腦血管疾病、精神***症、抑鬱、焦慮症、躁鬱症、泛自閉症障礙、注意力缺乏/過動症、學習障礙、運動障礙、強迫症、人格障礙、睡眠障礙、譫妄、肌萎縮性脊髓側索硬化症、發育障礙、智能障礙、創傷後壓力症或肝炎； [A-24]如前述項目[A-22]之醫藥組合物，其中KDM5相關疾病為癌症或阿茲海默症； [A-25]一種針對KDM5相關疾病之預防劑及/或治療劑，其包含如項目[A-1]中敍述之由通式(I)表示之化合物或其鹽作為活性組分，其中預防劑及/或治療劑與選自由以下各者組成之群之至少一種藥品組合投與：鹽酸多奈派齊(donepezil hydrochloride)、加蘭他敏氫溴酸鹽(galantamine hydrobromide)、石杉鹼A、艾地苯醌(idebenone)、乙醯左旋肉鹼鹽酸鹽(levacecarnine hydrochloride)、鹽酸美金剛(memantine hydrochloride)、鹽酸美金剛/鹽酸多奈派齊、來自豬腦蛋白之蛋白水解肽碎片、雷斯替明酒石酸鹽(rivastigmine tartrate)、鹽酸他可林(tacrine hydrochloride)及阿杜卡努單抗(aducanumab)。 [A-26]一種針對KDM5相關疾病之預防劑及/或治療劑，其包含如項目[A-1]中敍述之由通式(I)表示之化合物或其鹽； [A-27]如前述項目[A-26]之預防劑及/或治療劑，其進一步含有醫藥學上可接受之載劑； [A-28]如項目[A-1]中敍述之由通式(I)表示之化合物或其鹽，其用於預防及/或治療KDM5相關疾病； [A-29]一種用途，其在針對KDM5相關疾病之預防劑及/或治療劑之製造中用於如項目[A-1]中敍述之由通式(I)表示之化合物或其鹽；或 [A-30]一種用途，其在用於預防及/或治療KDM5相關疾病之醫藥組合物之製造中用於如項目[A-1]中敍述之由通式(I)表示之化合物或其鹽。 [本發明之有利效應] Therefore, one of the aspects of the present invention relates to: [1] A compound represented by general formula (I): Wherein R ¹ represents Cyc1, -CO-Cyc2 or -CONR ¹⁰ R ¹¹ ; Cyc1 represents 5 to 9 members of aromatic heterocycle or 5 members of non-aromatic heterocycle, each of which can be substituted by 1 to 5 R ¹² ; R ¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl, (4) C1-4 alkoxy, (5) can be through 1 to 3 R ¹⁷ substituted phenyl, (6) C1-4 alkyl substituted by phenyl, (7) dimethylamino, (8) pyridyl or (9) 1-(cyclopropylmethyl) pyrazole -3-base; a plurality of R ¹² can be the same or different; two R ¹² and the atoms attached to these R ¹² can form a C3-5 cycloalkane, wherein the carbon atoms of the C3-5 cycloalkane can be selected from 1 to 2 N, O and S heteroatom replacement; R ¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen; multiple R ¹⁷ can be the same or different; Cyc2 represents C3-12 single or bicyclic carbocycle or 5 to 9 membered mono- or bicyclic heterocycles, each of which can be substituted by 1 to 5 R ¹³ ; R ¹³ represents C1-4 alkyl, C1-4 alkoxy or halogen; a plurality of R ¹³ can be the same or different; R ¹⁰ means Wherein R ¹⁸ and R ¹⁹ independently represent C1-4 alkyl; R ¹⁸ and R ¹⁹ and carbon atoms attached to R ¹⁸ and R ¹⁹ can form C3-5 cycloalkane; R ²⁰ represents hydrogen atom, C1-4 alkane group, C1-4 haloalkyl or nitrile; (in the group, the arrow indicates the nitrogen atom bound to -CON<); R ¹¹ represents a hydrogen atom, C1-4 alkyl or 1 to 9 deuterated C1-4 Alkyl group; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ independently represent a hydrogen atom, C1-4 alkyl, halogen or C1-4 alkoxy; R ⁹ represents that 1 Up to 3 R ¹⁴ substituted imidazoles or 1 to 3 R ¹⁵ substituted pyrazoles; R ¹⁴ represents (1) C1-8 alkyl, (2) C3-7 ring which may be substituted by C1-4 alkyl Alkyl, (3) C1-8 haloalkyl, (4) C1-8 alkyl substituted by Cyc3 which may be substituted by 1 to 3 R ¹⁶ or (5) C1-8 alkyl substituted by phenoxy ; Cyc3 represents phenyl, C3-7 cycloalkyl, pyridyl, thiazolyl or tetrahydropyranyl; R ¹⁶ represents C1-4 alkyl, halogen, C1-4 alkoxy or cyano; plural R ¹⁴ Can be the same or different; Multiple R ¹⁶ can be the same or different; R ¹⁵ represents (1) C1-8 alkyl, (2) C3-7 cycloalkyl which may be substituted by C1-4 alkyl, (3) C1- 8 haloalkyl, (4) C1-8 alkyl substituted by Cyc4 which may be substituted by 1 to 3 R ²¹ or (5) C1-8 alkyl substituted by phenoxy; Cyc4 represents phenyl, C3- 7 cycloalkyl, pyridyl, thiazolyl or tetrahydropyranyl; R ²¹ represents C1-4 alkyl, halogen, C1-4 alkoxy or cyano; multiple R ¹⁵ can be the same or different; multiple R ²¹ can be the same or different; each hydrogen atom can be a deuterium atom or a tritium atom; the restriction is to exclude ((1R,5S,6r)-6-(cyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexyl -3-yl)(5-isopropyl-1H-pyrazol-3-yl)methanone, (5-isopropyl-1H-pyrazol-3-yl)-[(1R,5S)-6- [(2R)-2-methylpyrrolidine-1-carbonyl]-3-azabicyclo[3.1.0]hex-3-yl]methanone, (5-isopropyl-1H-pyrazole-3- base)-[(1S,5R)-6-[(2S)-2-methylpyrrolidin-1-carbonyl]-3-azabicyclo[3.1.0]hex-3-yl]methanone, [( 1S,5R)-6-(2,2-Dimethylpyrrolidine-1-carbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-(5-isopropyl-1H-pyridine Azol-3-yl)methanone and (5-isopropyl-1H-pyrazol-3-yl)-[(1S,5R)-6-(5-methyl-4-phenyl-isoxazole- 3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; or a salt thereof; [2] The compound as in the aforementioned item [1], wherein R ¹ represents Cyc1, and Cyc1 represents A 5-membered non-aromatic heterocyclic ring substituted by 1 to 5 R ¹² , or a salt thereof; [3] The compound of the aforementioned item [2], wherein the 5-membered non-aromatic heterocyclic ring represents 4,5-dihydroiso Azole or 4,5-dihydro-1,2,4-oxadiazole, or a salt thereof; [3-1] The compound according to the aforementioned item [3], wherein the compound represented by the general formula (I) is represented by the general formula (I-01) indicates Wherein R ^12-1 and R ^12-2 independently represent C1-4 alkyl; R ^12-1 and R ^12-2 and atoms bonded to the R ^12-1 and R ^12-2 can form a C3-5 ring Alkanes; Other symbols represent the same meaning as described in the aforementioned item [1]; or its salt; [4] The compound of any one of the aforementioned items [1] to [3] and [3-1], wherein R ⁹ represents imidazole which may be substituted by 1 to 3 R ¹⁴ , or a salt thereof; [5] the compound according to any one of the aforementioned items [1] to [4] and [3-1], wherein the general formula ( The compound represented by I) is represented by general formula (I-1) Wherein R ^12-1 and R ^12-2 independently represent C1-4 alkyl; R ^12-1 and R ^12-2 and atoms bonded to the R ^12-1 and R ^12-2 can form a C3-5 ring Alkanes; R ^14-1 represents C1-4 alkyl or C3-5 cycloalkyl which may be substituted by C1-4 alkyl; other symbols represent the same meaning as described in [1]; or their salts; [6 ] The compound according to any one of the aforementioned items [1] to [5] and [3-1], wherein the compound is: (1) [(1R,5S,6r)-6-(5,5-dimethyl -4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl )methanone; (2) [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-aza Bicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone; (3) (1-cyclopropyl-1H-imidazole- 4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3- Azabicyclo[3.1.0]hex-3-yl]methanone; (4) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6 -(4-Oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (5) {1 -[(2S)-Butan-2-yl]-1H-imidazol-4-yl}[(1R, 5S, 6S)-6-(5,5-Dimethyl-4,5-dihydro-1, 2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (6) [(1R,5S,6r)-6-(5,5-dimethyl Base-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl(1-isopropyl-1H- imidazol-4-yl)methanone; (7) (1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5 -Azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (8) (1-cyclopropyl-1H-imidazole -4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0 ]hex-3-yl]methanone; or (9) [1-(1-methylcyclopropyl)-1H-imidazol-4-yl][(1R,5S,6r)-6-(4-oxo Hetero-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone or its salt; [7]As mentioned above [ 1] The compound of any one of [3] and [3-1], wherein R ⁹ represents pyrazole which may be substituted by 1 to 3 R ¹⁵ , or a salt thereof; [8] as in the aforementioned items [1] to The compound of any one of [3], [3-1] and [7], wherein the compound represented by the general formula (I) is represented by the general formula (I-2) All the symbols represent the same meanings as those described in the aforementioned items [1] or [5]; or their salts; [9] as in the aforementioned items [1] to [3], [3-1], [7] The compound according to any one of [8], wherein the compound is: (1) [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazole -3-yl)-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone; (2) (5-isopropyl -1H-pyrazol-3-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3- Azabicyclo[3.1.0]hex-3-yl]methanone; (3) [5-(1-cyclopropylethyl)-1H-pyrazol-3-yl][(1R,5S,6r) -6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (4) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-nitrogen Heterobicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone or (5)(5-cyclopropyl-1H-pyrazol-3-yl )[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1. 0] Hex-3-yl] ketone or its salt; [10] The compound as in the aforementioned item [1], wherein R ¹ represents -CONR ¹⁰ R ¹¹ or its salt; [11] As in the aforementioned item [1] or [ 10], wherein R ¹⁰ represents isopropyl, tertiary butyl, 1,1,1-trifluoro-2-methylprop-2-yl, 1-methylcyclopropyl, 1-(trifluoro Methyl)cyclopropyl or 1-cyanocyclopropyl, or a salt thereof; [11-1] The compound of the aforementioned item [11], wherein the compound represented by the general formula (I) is represented by the general formula (I-02 )express Where R ^10-1 represents isopropyl, tertiary butyl, 1,1,1-trifluoro-2-methylprop-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl) Cyclopropyl or 1-cyanocyclopropyl; other symbols indicate the same meaning as described in the aforementioned item [1]; or its salt; [12] as in the aforementioned item [10], [11] or [11- 1] the compound, wherein R ⁹ represents imidazole which may be substituted by 1 to 3 R ¹⁴ , or a salt thereof; [13] as in any of the aforementioned items [1], [10] to [12] and [11-1] The compound according to one item, wherein the compound represented by general formula (I) is represented by general formula (I-3) Where R ^10-1 represents isopropyl, tertiary butyl, 1,1,1-trifluoro-2-methylprop-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl) Cyclopropyl or 1-cyanocyclopropyl; other symbols indicate the same meaning as described in the aforementioned item [1] or [5]; or its salt; [14] as in the aforementioned item [1], [10] to the compound of any one of [13] and [11-1], wherein the compound is: (1) (1R,5S,6r)-N-tertiary butyl-6-methyl-3-[1-( Propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (2) (1R,5S,6r)-N-tertiary Butyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; (3) (1R, 5S,6r)-N-(prop-2-yl)-3-[1-(prop-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane- 6-Formamide or (4) (1R,5S,6r)-N-(1-cyanocyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl] -3-Azabicyclo[3.1.0]hexane-6-formamide or its salt; [15] Compounds as in the aforementioned items [10], [11] and [11-1], wherein R ⁹ represents either Pyrazole substituted by 1 to 3 R ¹⁵ , or a salt thereof; [16] The compound according to any one of the aforementioned items [1], [10], [11], [11-1] and [15], Wherein the compound represented by general formula (I) is represented by general formula (I-4) All the symbols in it represent the same meaning as described in the aforementioned items [1] or [13]; or their salts; [17] as the aforementioned items [1], [10], [11], [11-1], The compound according to any one of [15] and [16], wherein the compound is: (1) (1R,5S,6r)-N-(propan-2-yl)-3-[5-(propan-2-yl) )-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-formamide; (2) (1R,5S,6r)-N-tertiary butyl-6 -Methyl-3-[5-(prop-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-formamide; (3) ( 1R,5S,6r)-N-tertiary butyl-N-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1. 0] Hexane-6-formamide or (4) (1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl )-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-formamide, or a salt thereof; [A-1] a pharmaceutical composition comprising the formula Compound represented by (I): Wherein R ¹ represents Cyc1, -CO-Cyc2 or -CONR ¹⁰ R ¹¹ ; Cyc1 represents 5 to 9 members of aromatic heterocycle or 5 members of non-aromatic heterocycle, each of which can be substituted by 1 to 5 R ¹² ; R ¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl, (4) C1-4 alkoxy, (5) can be through 1 to 3 R ¹⁷ substituted phenyl, (6) C1-4 alkyl substituted by phenyl, (7) dimethylamino, (8) pyridyl or (9) 1-(cyclopropylmethyl) pyrazole -3-base; a plurality of R ¹² can be the same or different; two R ¹² and the atoms attached to these R ¹² can form a C3-5 cycloalkane, wherein the carbon atoms of the C3-5 cycloalkane can be selected from 1 to 2 N, O and S heteroatom replacement; R ¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen; multiple R ¹⁷ can be the same or different; Cyc2 represents C3-12 single or bicyclic carbocycle or 5 to 9 membered mono- or bicyclic heterocycles, each of which can be substituted by 1 to 5 R ¹³ ; R ¹³ represents C1-4 alkyl, C1-4 alkoxy or halogen; a plurality of R ¹³ can be the same or different; R ¹⁰ means Wherein R ¹⁸ and R ¹⁹ independently represent C1-4 alkyl; R ¹⁸ and R ¹⁹ and carbon atoms attached to R ¹⁸ and R ¹⁹ can form C3-5 cycloalkane; R ²⁰ represents hydrogen atom, C1-4 alkane group, C1-4 haloalkyl or nitrile; (in the group, the arrow indicates the nitrogen atom bound to -CON<); R ¹¹ represents a hydrogen atom, C1-4 alkyl or 1 to 9 deuterated C1-4 Alkyl group; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ independently represent a hydrogen atom, C1-4 alkyl, halogen or C1-4 alkoxy; R ⁹ represents that 1 Up to 3 R ¹⁴ substituted imidazoles or 1 to 3 R ¹⁵ substituted pyrazoles; R ¹⁴ represents (1) C1-8 alkyl, (2) C3-7 ring which may be substituted by C1-4 alkyl Alkyl, (3) C1-8 haloalkyl, (4) C1-8 alkyl substituted by Cyc3 which may be substituted by 1 to 3 R ¹⁶ or (5) C1-8 alkyl substituted by phenoxy ; Cyc3 represents phenyl, C3-7 cycloalkyl, pyridyl, thiazolyl or tetrahydropyranyl; R ¹⁶ represents C1-4 alkyl, halogen, C1-4 alkoxy or cyano; plural R ¹⁴ Can be the same or different; Multiple R ¹⁶ can be the same or different; R ¹⁵ represents (1) C1-8 alkyl, (2) C3-7 cycloalkyl which may be substituted by C1-4 alkyl, (3) C1- 8 haloalkyl, (4) C1-8 alkyl substituted by Cyc4 which may be substituted by 1 to 3 R ²¹ or (5) C1-8 alkyl substituted by phenoxy; Cyc4 represents phenyl, C3- 7 cycloalkyl, pyridyl, thiazolyl or tetrahydropyranyl; R ²¹ represents C1-4 alkyl, halogen, C1-4 alkoxy or cyano; multiple R ¹⁵ can be the same or different; multiple R ²¹ can be the same or different; each hydrogen atom can be a deuterium atom or a tritium atom; the restriction is to exclude ((1R,5S,6r)-6-(cyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexyl -3-yl)(5-isopropyl-1H-pyrazol-3-yl)methanone, (5-isopropyl-1H-pyrazol-3-yl)-[(1R,5S)-6- [(2R)-2-methylpyrrolidine-1-carbonyl]-3-azabicyclo[3.1.0]hex-3-yl]methanone, (5-isopropyl-1H-pyrazole-3- base)-[(1S,5R)-6-[(2S)-2-methylpyrrolidin-1-carbonyl]-3-azabicyclo[3.1.0]hex-3-yl]methanone, [( 1S,5R)-6-(2,2-Dimethylpyrrolidine-1-carbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-(5-isopropyl-1H-pyridine Azol-3-yl)methanone and (5-isopropyl-1H-pyrazol-3-yl)-[(1S,5R)-6-(5-methyl-4-phenyl-isoxazole- 3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; or a salt thereof; [A-2] The pharmaceutical composition according to the aforementioned item [A-1], which further contains pharmaceutical A pharmaceutically acceptable carrier; [A-3] The pharmaceutical composition of the aforementioned item [A-1] or [A-2], wherein R ¹ represents Cyc1, and Cyc1 represents that it can be substituted by 1 to 5 R ¹² 5-membered non-aromatic heterocycle. [A-4] The pharmaceutical composition according to the aforementioned item [A-3], wherein the 5-membered non-aromatic heterocycle represents 4,5-dihydroisoxazole or 4,5-dihydro-1,2,4- Diazole; [A-5] The pharmaceutical composition according to the aforementioned item [A-4], wherein the compound represented by the general formula (I) or a salt thereof is a compound represented by the general formula (I-01) Wherein R ^12-1 and R ^12-2 independently represent C1-4 alkyl; R ^12-1 and R ^12-2 and atoms bonded to the R ^12-1 and R ^12-2 can form a C3-5 ring Alkanes; Other symbols indicate the same meaning as described in the aforementioned item [A-1]; or its salt; [A-6] The medicine as described in any one of the aforementioned items [A-1] to [A-5] Composition, wherein R ⁹ represents imidazole which may be substituted by 1 to 3 R ¹⁴ ; [A-7] The pharmaceutical composition according to any one of the aforementioned items [A-1] to [A-6], wherein the general The compound represented by formula (I) or its salt is a compound represented by general formula (I-1) Wherein R ^12-1 and R ^12-2 independently represent C1-4 alkyl; R ^12-1 and R ^12-2 and atoms bonded to the R ^12-1 and R ^12-2 can form a C3-5 ring Alkanes; R ^14-1 represents C1-4 alkyl or C3-5 cycloalkyl which may be substituted by C1-4 alkyl; other symbols represent the same meaning as described in [A-1]; or their salts; [A-8] The pharmaceutical composition according to any one of the aforementioned items [A-1] to [A-7], wherein the compound represented by the general formula (I) or a salt thereof is selected from the group consisting of Compounds: (1) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo [3.1.0] Hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone; (2) [(1R,5S,6r)-6-(5,5-dimethyl Base-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl][1-(1-methylcyclopropyl)- 1H-imidazol-4-yl]methanone; (3) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4 ,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]methanone; (4) (1-cyclopropane Base-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl) -3-Azabicyclo[3.1.0]hex-3-yl]methanone; (5) {1-[(2S)-but-2-yl]-1H-imidazol-4-yl}[(1R, 5S,6S)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl ]methanone; (6) [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl -3-Azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone; (7) (1-isopropyl-1H-imidazole-4 -yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[ 3.1.0] Hex-3-yl]methanone; (8) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5- Azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; and (9) [1-(1-methylcyclopropane Base)-1H-imidazol-4-yl][(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-az Heterobicyclo[3.1.0]hex-3-yl]methanone; or a salt thereof; [A-9] The pharmaceutical composition according to any one of the aforementioned items [A-1] to [A-5], wherein R ⁹ represents pyrazole which may be substituted by 1 to 3 R ¹⁵ ; [A-10] the pharmaceutical composition according to any one of the aforementioned items [A-1] to [A-5] and [A-9], wherein A compound represented by general formula (I) or a salt thereof is a compound represented by general formula (I-2) All the symbols in it represent the same meaning as described in the aforementioned items [A-1] or [A-7]; or their salts; [A-11] as in the aforementioned items [A-1] to [A-5], The pharmaceutical composition according to any one of [A-9] and [A-10], wherein the compound represented by general formula (I) or a salt thereof is a compound selected from the group consisting of: (1) [( 1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexa-3 - Base] (5-isopropyl-1H-pyrazol-3-yl)methanone; (2) (5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)- 6-(2-Oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (3 ) [5-(1-cyclopropylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro- 1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (4) [(1R,5S,6r)-6-(5,5- Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl](5-isopropyl -1H-pyrazol-3-yl)methanone; and (5) (5-cyclopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-methyl-6-( 4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; or its salt; [A- 12] The pharmaceutical composition according to the aforementioned item [A-1], wherein R ¹ represents -CONR ¹⁰ R ¹¹ ; [A-13] The pharmaceutical composition according to the aforementioned item [A-12], wherein R ¹⁰ represents isopropyl , tertiary butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl)cyclopropyl or 1-cyano ring Propyl; [A-14] The pharmaceutical composition according to the aforementioned item [A-13], wherein the compound represented by the general formula (I) or a salt thereof is a compound represented by the general formula (I-02) Where R ^10-1 represents isopropyl, tertiary butyl, 1,1,1-trifluoro-2-methylprop-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl) Cyclopropyl or 1-cyanocyclopropyl; other symbols represent the same meaning as described in the aforementioned item [A-1]; or its salt; [A-15] as described in the aforementioned items [A-12] to [ A-14] the pharmaceutical composition according to any one of the above items, wherein R ⁹ represents imidazole which may be substituted by 1 to 3 R ¹⁴ ; A-15] The pharmaceutical composition according to any one of the above, wherein the compound represented by the general formula (I) or a salt thereof is a compound represented by the general formula (I-3) Where R ^10-1 represents isopropyl, tertiary butyl, 1,1,1-trifluoro-2-methylprop-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl) Cyclopropyl or 1-cyanocyclopropyl; Other symbols indicate the same meaning as described in the aforementioned item [A-1] or [A-7]; or its salt; [A-17] As in the aforementioned item [ A-1] and the pharmaceutical composition of any one of [A-12] to [A-16], wherein the compound represented by general formula (I) or a salt thereof is a compound selected from the group consisting of: (1) (1R,5S,6r)-N-tertiary butyl-6-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo [3.1.0] Hexane-6-formamide; (2) (1R,5S,6r)-N-tertiary butyl-3-[1-(propan-2-yl)-1H-imidazole-4 -Carbonyl]-3-azabicyclo[3.1.0]hexane-6-formamide; (3) (1R,5S,6r)-N-(propan-2-yl)-3-[1-( Propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; and (4) (1R,5S,6r)-N-( 1-cyanocyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-6-formamide; or a salt thereof; [A-18] The pharmaceutical composition according to any one of the aforementioned items [A-12] to [A-14], wherein R ⁹ represents pyrazole which may be substituted by 1 to 3 R ¹⁵ ; [ A-19] The pharmaceutical composition according to any one of the aforementioned items [A-1], [A-12] to [A-14] and [A-18], wherein the compound represented by general formula (I) or Its salt is a compound represented by general formula (I-4) Wherein all the symbols represent the same meaning as described in the aforementioned items [A-1] or [A-16]; or their salts; [A-20] as described in the aforementioned items [A-1], [A-12] The pharmaceutical composition of any one of [A-14], [A-18], and [A-19], wherein the compound represented by general formula (I) or a salt thereof is a compound selected from the group consisting of : (1) (1R,5S,6r)-N-(prop-2-yl)-3-[5-(prop-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo [3.1.0] Hexane-6-formamide; (2) (1R,5S,6r)-N-tertiary butyl-6-methyl-3-[5-(propan-2-yl)- 1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-formamide; (3) (1R,5S,6r)-N-tertiary butyl-N-form Base-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide; and (4) (1R ,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-aza Bicyclo[3.1.0]hexane-6-formamide; or a salt thereof; [A-21] The pharmaceutical composition according to any one of the aforementioned items [A-1] to [A-20], which is KDM5 Inhibitor; [A-22] The pharmaceutical composition according to any one of the aforementioned items [A-1] to [A-21], which is a preventive and/or therapeutic agent for KDM5-related diseases; [A-23 ] The pharmaceutical composition of the aforementioned item [A-22], wherein the KDM5-related disease is hyperproliferative disease, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Huntington's disease, Alzheimer's disease Mums disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic disorders, inflammation, neurological disorders, hormone-related Diseases, conditions associated with organ transplantation, immunodeficiency, destructive bone disease, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, conditions involving T cell activation Pathological immune conditions, CNS disorders, myeloproliferative disorders, Parkinson's disease, Lewy body disease, frontotemporal lobar degeneration, mild cognitive impairment, cognitive impairment, cerebrovascular disease, schizophrenia depression, anxiety, bipolar disorder, autism spectrum disorder, attention deficit/hyperactivity disorder, learning disabilities, movement disorders, obsessive compulsive disorder, personality disorders, sleep disorders, delirium, amyotrophic lateral sclerosis, Developmental disorder, mental retardation, post-traumatic stress disorder or hepatitis; [A-24] the pharmaceutical composition of the aforementioned item [A-22], wherein the KDM5-related disease is cancer or Alzheimer's disease; [A-25] a A preventive and/or therapeutic agent for KDM5-related diseases, comprising a compound represented by general formula (I) or a salt thereof as described in item [A-1] as an active ingredient, wherein the preventive and/or therapeutic agent Administration in combination with at least one drug selected from the group consisting of: donepezil hydrochloride, galantamine hydrobromide, huperzine A, idebenone ( idebenone), acetyl-L-carnitine hydrochloride (levacecarnine hydrochloride), memantine hydrochloride (memantine hydrochloride), memantine hydrochloride/donepazil hydrochloride, proteolytic peptide fragments from porcine brain protein, restigmine tartrate (rivastigmine tartrate), tacrine hydrochloride and aducanumab. [A-26] A preventive and/or therapeutic agent for KDM5-related diseases, comprising a compound represented by general formula (I) or a salt thereof as described in item [A-1]; [A-27] The preventive and/or therapeutic agent of the aforementioned item [A-26], which further contains a pharmaceutically acceptable carrier; [A-28] represented by general formula (I) as described in item [A-1] A compound or a salt thereof, which is used for the prevention and/or treatment of KDM5-related diseases; [A-29] a use, which is used in the manufacture of preventive and/or therapeutic agents for KDM5-related diseases as described in the item [A- A compound represented by general formula (I) or a salt thereof described in 1]; or [A-30] a use, which is used in the manufacture of a pharmaceutical composition for preventing and/or treating KDM5-related diseases. The compound represented by the general formula (I) described in [A-1] or a salt thereof. [Advantageous effect of the present invention]

如本文中所揭示之由通式(I)表示之化合物或其鹽(下文中統稱為本發明化合物)具有KDM5抑制活性。因此，包含本發明化合物之醫藥組合物可用作針對諸如以下各者之疾病的治療性及/或預防劑：過度增生性疾病、癌症、中風、糖尿病、肝腫大、心血管疾病、多發性硬化症、亨廷頓氏病、阿茲海默症、囊腫纖維化、病毒性疾病、自身免疫疾病、動脈粥樣硬化、再狹窄、牛皮癬、類風濕性關節炎、發炎性腸道疾病、哮喘、過敏性病症、炎症、神經病症、激素相關疾病、與器官移植相關聯之病況、免疫缺乏症、破壞性骨症、增生性病症、傳染性疾病、與細胞死亡相關聯之病況、凝血酶誘發之血小板凝集、肝臟疾病、涉及T細胞活化之病理性免疫病況、CNS病症、骨髓增生性病症、帕金森氏症、路易體疾病、額顳葉退化、輕度認知障礙、認知障礙、腦血管疾病、精神***症、抑鬱、焦慮症、躁鬱症、泛自閉症障礙、注意力缺乏/過動症、學習障礙、運動障礙、強迫症、人格障礙、睡眠障礙、譫妄、肌萎縮性脊髓側索硬化症、發育障礙、智能障礙、創傷後壓力症或肝炎。The compounds represented by the general formula (I) or salts thereof (hereinafter collectively referred to as compounds of the present invention) as disclosed herein have KDM5 inhibitory activity. Accordingly, pharmaceutical compositions comprising the compounds of the present invention are useful as therapeutic and/or preventive agents against diseases such as hyperproliferative diseases, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple Sclerosis, Huntington's disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergies Sexual disorders, inflammation, neurological disorders, hormone-related diseases, conditions associated with organ transplantation, immunodeficiency, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelets Agglutination, liver disease, pathological immune conditions involving T cell activation, CNS disorders, myeloproliferative disorders, Parkinson's disease, Lewy body disease, frontotemporal lobar degeneration, mild cognitive impairment, cognitive impairment, cerebrovascular disease, psychiatric Schizophrenia, depression, anxiety, bipolar disorder, autism spectrum disorder, attention deficit/hyperactivity disorder, learning disabilities, movement disorders, obsessive compulsive disorder, personality disorders, sleep disorders, delirium, amyotrophic lateral sclerosis , developmental disability, intellectual disability, post-traumatic stress disorder, or hepatitis.

如本文中所使用之「鹵素」之實例包括氟、氯、溴及碘原子。Examples of "halogen" as used herein include fluorine, chlorine, bromine and iodine atoms.

如本文中所使用之「C1-4烷基」包括甲基、乙基、丙基、異丙基、丁基、二級丁基、三級丁基及異丁基。"C1-4 alkyl" as used herein includes methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl and isobutyl.

如本文中所使用之「1至9個氘化C1-4烷基」包括CH ₂D-、CHD ₂-、CD ₃-、CD ₃CD ₂-、CD ₃CD ₂CD ₂-、(CD ₃) ₂CD-、CD ₃CD ₂CD ₂CD ₂-、CD ₃CD ₂CD(CD ₃)-、(CD ₃) ₃C-及(CD ₃) ₂CDCD ₂-及其類似者(D意謂氘)。 "1 to 9 deuterated C1-4 alkyl" as used herein includes CH ₂ D-, CHD ₂ -, CD ₃ -, CD ₃ CD ₂ -, CD ₃ CD ₂ CD ₂ -, (CD ₃ ) ₂ CD-, CD ₃ CD ₂ CD ₂ CD ₂ -, CD ₃ CD ₂ CD(CD ₃ )-, (CD ₃ ) ₃ C- and (CD ₃ ) ₂ CDCD ₂ - and the like (D means deuterium).

如本文中所使用之「C1-8烷基」包括甲基、乙基、丙基、異丙基、丁基、二級丁基、三級丁基、異丁基、戊基、1,2-二甲基丙基、1-乙基丙基、己基、1,3-二甲基丁基、庚基及辛基。"C1-8 alkyl" as used herein includes methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, isobutyl, pentyl, 1,2 - Dimethylpropyl, 1-ethylpropyl, hexyl, 1,3-dimethylbutyl, heptyl and octyl.

如本文中所使用之「C1-4烷氧基」包括甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、二級丁氧基、三級丁氧基及異丁氧基。"C1-4 alkoxy" as used herein includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, secondary butoxy, tertiary butoxy and isobutyl Oxygen.

如本文中所使用之「C1-4鹵烷基」包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、2,2,2-三氟乙基、全氟乙基、全氟丙基、全氟(異丙基)、全氟丁基、全氟(二級丁基)、全氟(三級丁基)及全氟(異丁基)及其類似者。"C1-4 haloalkyl" as used herein includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoromethyl, Fluoroethyl, perfluoroethyl, perfluoropropyl, perfluoro(isopropyl), perfluorobutyl, perfluoro(secondary butyl), perfluoro(tertiary butyl) and perfluoro(isobutyl base) and the like.

如本文中所使用之「C1-8鹵烷基」包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、2,2,2-三氟乙基、全氟乙基、全氟丙基、全氟(異丙基)、全氟丁基、全氟(二級丁基)、全氟(三級丁基)、全氟(異丁基)、全氟戊基、全氟己基、全氟庚基及全氟辛基及其類似者。"C1-8 haloalkyl" as used herein includes fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoromethyl, Fluoroethyl, perfluoroethyl, perfluoropropyl, perfluoro(isopropyl), perfluorobutyl, perfluoro(secondary butyl), perfluoro(tertiary butyl), perfluoro(isobutyl radical), perfluoropentyl, perfluorohexyl, perfluoroheptyl and perfluorooctyl and the like.

如本文中所使用之「C3-5環烷基」之實例包括環丙基、環丁基及環戊基。Examples of "C3-5 cycloalkyl" as used herein include cyclopropyl, cyclobutyl and cyclopentyl.

如本文中所使用之「C3 -5環烷烴」之實例包括環丙烷、環丁烷及環戊烷環。Examples of "C3-5 cycloalkane" as used herein include cyclopropane, cyclobutane and cyclopentane rings.

如本文中所使用之「C3-5環烷烴」之實例(其中C3-5環烷烴之碳原子可經選自1至2個N、O及S之雜原子置換)包括環丙烷、環丁烷、環戊烷、氮丙啶、環氧乙烷、環硫乙烷、氮雜環丁烷、氧雜環丁烷、硫雜環丁烷、吡咯啶、四氫呋喃、四氫噻吩、吡唑啶、異㗁唑啶、異噻唑啶、咪唑啶、㗁唑啶、噻唑啶及1,3-二氧雜環戊烷環及其類似者。Examples of "C3-5 cycloalkane" as used herein (wherein the carbon atoms of the C3-5 cycloalkane may be replaced by 1 to 2 heteroatoms selected from N, O and S) include cyclopropane, cyclobutane , cyclopentane, aziridine, ethylene oxide, thioethane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, Isoxazolidine, isothiazolidine, imidazolidine, fazolidine, thiazolidine, 1,3-dioxolane ring and the like.

如本文中所使用之「C3-7環烷基」之實例包括環丙基、環丁基、環戊基、環己基、環庚基、雙環[1.1.0]丁基、雙環[2.1.0]戊基、雙環[1.1.1]戊基、雙環[3.1.0]己基、雙環[2.2.0]己基、雙環[2.1.1]己基、雙環[4.1.0]庚基、雙環[3.2.0]庚基、雙環[2.2.1]庚基及雙環[3.1.1]庚基及其類似者。Examples of "C3-7 cycloalkyl" as used herein include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[1.1.0]butyl, bicyclo[2.1.0 ]pentyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.2. O]heptyl, bicyclo[2.2.1]heptyl and bicyclo[3.1.1]heptyl and the like.

如本文中所使用之「5至9員芳族雜環」之實例包括「含有1至4個氮原子、1個氧原子及/或1個硫原子之5至9員芳族雜環」及其類似者。「含有1至4個氮原子、1個氧原子及/或1個硫原子之5至9員芳族雜環」之實例包括1,2,5-㗁二唑、1,2,5-噻二唑、1,2,4-㗁二唑、1,2,4-噻二唑、異噻唑、1,3,4-噻二唑、苯并[d]異噻唑、異㗁唑、1,3,4-㗁二唑、1,2,4-***、四唑、苯并[d]異㗁唑、[1,2,3]***并[1,5-a]吡啶或[1,2,4]***并[4,3-a]吡啶環及其類似者。Examples of the "5 to 9 membered aromatic heterocycle" as used herein include "5 to 9 membered aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and/or 1 sulfur atom" and its analogues. Examples of "5 to 9 membered aromatic heterocycles containing 1 to 4 nitrogen atoms, 1 oxygen atom and/or 1 sulfur atom" include 1,2,5-oxadiazole, 1,2,5-thiazole Oxadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, isothiazole, 1,3,4-thiadiazole, benzo[d]isothiazole, isoxazole, 1, 3,4-oxadiazole, 1,2,4-triazole, tetrazole, benzo[d]isoxazole, [1,2,3]triazolo[1,5-a]pyridine or [1 ,2,4]triazolo[4,3-a]pyridine ring and the like.

如本文中所使用之「5員非芳族雜環」之實例包括「含有1至4個氮原子、1個氧原子及/或1個硫原子之5員非芳族雜環」及其類似者。「含有1至4個氮原子、1個氧原子及/或1個硫原子之5員非芳族雜環」之實例包括2,3-二氫-1,2,3-㗁二唑、2,3-二氫-1,2,3-噻二唑、2,3-二氫-1,2,4-㗁二唑、2,3-二氫-1,2,4-噻二唑、2,3-二氫-1,2,5-㗁二唑、2,3-二氫-1,2,5-噻二唑、2,3-二氫-1,3,4-㗁二唑、2,3-二氫-1,3,4-噻二唑、2,3-二氫-1H-1,2,3-***、2,3-二氫-1H-1,2,4-***、2,3-二氫-1H-咪唑、2,3-二氫-1H-吡唑、2,3-二氫-1H-吡咯、2,3-二氫-1H-四唑、2,3-二氫呋喃、2,3-二氫異噻唑、2,3-二氫異㗁唑、2,3-二氫㗁唑、2,3-二氫噻唑、2,3-二氫噻吩、4,5-二氫-1,2,3-㗁二唑、4,5-二氫-1,2,3-噻二唑、4,5-二氫-1,2,4-㗁二唑、4,5-二氫-1,2,4-噻二唑、4,5-二氫-1H-1,2,3-***、4,5-二氫-1H-1,2,4-***、4,5-二氫-1H-咪唑、4,5-二氫-1H-吡唑、4,5-二氫-1H-四唑、4,5-二氫異噻唑、4,5-二氫異㗁唑、4,5-二氫㗁唑及4,5-二氫噻唑環及其類似者。Examples of the "5-membered non-aromatic heterocycle" as used herein include "5-membered non-aromatic heterocycle containing 1 to 4 nitrogen atoms, 1 oxygen atom and/or 1 sulfur atom" and the like By. Examples of "5-membered non-aromatic heterocyclic ring containing 1 to 4 nitrogen atoms, 1 oxygen atom and/or 1 sulfur atom" include 2,3-dihydro-1,2,3-oxadiazole, 2 ,3-dihydro-1,2,3-thiadiazole, 2,3-dihydro-1,2,4-oxadiazole, 2,3-dihydro-1,2,4-thiadiazole, 2,3-dihydro-1,2,5-oxadiazole, 2,3-dihydro-1,2,5-thiadiazole, 2,3-dihydro-1,3,4-oxadiazole , 2,3-dihydro-1,3,4-thiadiazole, 2,3-dihydro-1H-1,2,3-triazole, 2,3-dihydro-1H-1,2,4 -triazole, 2,3-dihydro-1H-imidazole, 2,3-dihydro-1H-pyrazole, 2,3-dihydro-1H-pyrrole, 2,3-dihydro-1H-tetrazole, 2,3-dihydrofuran, 2,3-dihydroisothiazole, 2,3-dihydroisoxazole, 2,3-dihydroxazole, 2,3-dihydrothiazole, 2,3-dihydro Thiophene, 4,5-dihydro-1,2,3-oxadiazole, 4,5-dihydro-1,2,3-thiadiazole, 4,5-dihydro-1,2,4-oxadiazole Oxadiazole, 4,5-dihydro-1,2,4-thiadiazole, 4,5-dihydro-1H-1,2,3-triazole, 4,5-dihydro-1H-1,2 ,4-triazole, 4,5-dihydro-1H-imidazole, 4,5-dihydro-1H-pyrazole, 4,5-dihydro-1H-tetrazole, 4,5-dihydroisothiazole, 4,5-dihydroisoxazole, 4,5-dihydroxazole and 4,5-dihydrothiazole rings and the like.

如本文中所使用之「C3至12單或雙環碳環」之實例包括環丙烷、環丁烷、環戊烷、環己烷、環戊烯、環己烯、環戊二烯、環己二烯、苯、茚、二氫茚、萘、二氫萘及四氫萘環及其類似者。Examples of "C3 to 12 mono- or bicyclic carbocycle" as used herein include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexanediene alkenes, benzene, indene, indene, naphthalene, dihydronaphthalene and tetrahydronaphthalene rings and the like.

如本文中所使用之「5至9員單或雙環雜環」之實例包括「含有1至4個氮原子、1至2個氧原子及/或1個硫原子之5至9員單或雙環雜環」及其類似者。「含有1至4個氮原子、1至2個氧原子及/或1個硫原子之5至9員單或雙環雜環」之實例包括吡咯、咪唑、***、四唑、吡唑、吡啶、吡𠯤、嘧啶、噠𠯤、呋喃、哌喃、噻吩、硫代哌喃、㗁唑、異㗁唑、噻唑、異噻唑、呋呫、㗁二唑、㗁𠯤、㗁二𠯤、噻二唑、噻𠯤、噻二𠯤、吡咯啉、吡咯啶、咪唑啉、咪唑啶、***啉、***啶、四唑啉、四唑啶、吡唑啉、吡唑啶、二氫吡啶、四氫吡啶、哌啶、二氫吡𠯤、四氫吡𠯤、哌𠯤、二氫嘧啶、四氫嘧啶、全氫嘧啶、二氫噠𠯤、四氫噠𠯤、全氫噠𠯤、二氫呋喃、四氫呋喃、二氫哌喃、四氫哌喃、二氫噻吩、四氫噻吩、二氫硫代哌喃、四氫硫代哌喃、二氫㗁唑、四氫㗁唑(㗁唑啶)、二氫異㗁唑、四氫異㗁唑(異㗁唑啶)、二氫噻唑、四氫噻唑(噻唑啶)、二氫異噻唑、四氫異噻唑(異噻唑啶)、二氫呋呫、四氫呋呫、二氫㗁二唑、四氫㗁二唑(㗁二唑啶)、二氫㗁𠯤、四氫㗁𠯤、二氫㗁二𠯤、四氫㗁二𠯤、二氫噻二唑、四氫噻二唑(噻二唑啶)、二氫噻𠯤、四氫噻𠯤、二氫噻二𠯤、四氫噻二𠯤、𠰌啉、硫代𠰌啉、氧硫𠮿、二氧雜環戊烷、二㗁烷、間二氧雜環戊烯、吲哚、苯并咪唑、苯并***、吲唑、苯并呋喃、苯并噻吩、苯并㗁唑、吲哚啉、二氫苯并咪唑、二氫苯并***、二氫吲唑、二氫苯并呋喃、二氫苯并噻吩及二氫苯并㗁唑環及其類似者。Examples of "5 to 9 membered mono- or bicyclic heterocycle" as used herein include "5 to 9 membered mono or bicyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and/or 1 sulfur atom Heterocycles" and the like. Examples of "5 to 9 membered mono- or bicyclic heterocycles containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and/or 1 sulfur atom" include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine , pyrimidine, pyrimidine, da 𠯤, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furoxane, 㗁diazole, 㗁𠯤, 㗁two 𠯤, thiadiazole , thia 𠯤, thia di 𠯤, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazoline, pyrazoline, pyrazolidine, dihydropyridine, tetrahydro Pyridine, piperidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridine, tetrahydropyridine, perhydropyridine, dihydrofuran, tetrahydrofuran , dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydro Isoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofuran, tetrahydro Fufuran, Dihydro-Oxadiazole, Tetrahydro-Oxadiazole (Oxadiazolidine), Dihydro-Oxadiazole, Tetrahydro-Oxadiazole, Dihydro-Oxadiazole, Tetrahydro-Oxadiazole, Dihydrothiadiazole, Four Hydrothiadiazole (thiadiazolidine), dihydrothiadiazole, tetrahydrothiadiazole, dihydrothiadiazole, tetrahydrothiadiazole, thioline, thiothioline, oxygen sulfur Alkanes, dioxanes, dioxoles, indole, benzimidazoles, benzotriazoles, indazoles, benzofurans, benzothiophenes, benzoxazoles, indolines, dihydrobenzos imidazole, dihydrobenzotriazole, dihydroindazole, dihydrobenzofuran, dihydrobenzothiophene and dihydrobenzoxazole rings and the like.

在本發明中，除非特定陳述，否則符號： 指示鍵突出於紙之平面以上(亦即，β-組態)，且符號： 指示鍵突出於紙之平面以下(亦即，α-組態)，且符號： 指示鍵為α-組態、β-組態或此等組態在任意比例下之混合物，如熟習此項技術者所顯而易見。 In the present invention, unless specifically stated otherwise, the symbols: The indicator key protrudes above the plane of the paper (ie, the β-configuration), and the symbol: Pointing keys protrude below the plane of the paper (ie, α-configuration), and the symbols: The indicator bonds are in the α-configuration, β-configuration, or mixtures of these configurations in any proportion, as will be apparent to those skilled in the art.

在本發明中，R ¹為較佳地(例如) Cyc1或-CONR ¹⁰R ¹¹，更佳地(例如) Cyc1，且尤其較佳地(例如) 5員非芳族雜環。 In the present invention, R ¹ is preferably (for example) Cyc1 or -CONR ¹⁰ R ¹¹ , more preferably (for example) Cyc1, and especially preferably (for example) a 5-membered non-aromatic heterocycle.

在本發明中，Cyc1為較佳地(例如)可經1至5個R ¹²取代之5員非芳族雜環，更佳地(例如) 2,3-二氫-1,2,5-㗁二唑、2,3-二氫-1,2,5-噻二唑、4,5-二氫-1,2,3-㗁二唑、4,5-二氫-1,2,3-噻二唑、4,5-二氫-1,2,4-㗁二唑、4,5-二氫-1,2,4-噻二唑、4,5-二氫-1H-1,2,3-***、4,5-二氫異噻唑或4,5-二氫異㗁唑，其中各者可經1至5個R ¹²取代；尤其較佳地(例如) 4,5-二氫-1,2,4-㗁二唑或4,5-二氫異㗁唑，其中各者可經1至5個R ¹²取代；且特別較佳地(例如)可經1至5個R ¹²取代之4,5-二氫異㗁唑。 In the present invention, Cyc1 is preferably (for example) a 5-membered non-aromatic heterocycle which may be substituted by 1 to 5 R ¹² , more preferably (for example) 2,3-dihydro-1,2,5- Oxadiazole, 2,3-dihydro-1,2,5-thiadiazole, 4,5-dihydro-1,2,3-oxadiazole, 4,5-dihydro-1,2,3 -thiadiazole, 4,5-dihydro-1,2,4-oxadiazole, 4,5-dihydro-1,2,4-thiadiazole, 4,5-dihydro-1H-1, 2,3-triazole, 4,5-dihydroisothiazole or 4,5-dihydroisoxazole, each of which may be substituted by 1 to 5 R ¹² ; especially preferably (for example) 4,5- Dihydro-1,2,4-oxadiazole or 4,5-dihydroisoxazole, each of which may be substituted by 1 to 5 R ¹² ; and particularly preferably (for example) may be substituted by 1 to 5 R ¹² substituted 4,5-dihydroisoxazole.

在本發明中，Cyc1亦為較佳地(例如)可經1至5個R ¹²取代之5至9員芳族雜環；更佳地(例如) 1,2,5-㗁二唑、1,2,5-噻二唑、1,2,4-㗁二唑、1,2,4-噻二唑、異噻唑、1,3,4-噻二唑、苯并[d]異噻唑、異㗁唑、1,3,4-㗁二唑、1,2,4-***、四唑、苯并[d]異㗁唑、[1,2,3]***并[1,5-a]吡啶或[1,2,4]***并[4,3-a]吡啶，其中各者可經1至5個R ¹²取代；且尤其較佳地(例如)異㗁唑、1,3,4-㗁二唑、1,2,4-***、四唑、苯并[d]異㗁唑、[1,2,3]***并[1,5-a]吡啶或[1,2,4]***并[4,3-a]吡啶，其中各者可經1至5個R ¹²取代。 In the present invention, Cyc1 is also preferably (for example) a 5 to 9 membered aromatic heterocyclic ring which may be substituted by 1 to 5 R ¹² ; more preferably (for example) 1,2,5-oxadiazole, 1 ,2,5-thiadiazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, isothiazole, 1,3,4-thiadiazole, benzo[d]isothiazole, Isoxazole, 1,3,4-oxadiazole, 1,2,4-triazole, tetrazole, benzo[d]isoxazole, [1,2,3]triazolo[1,5- a]pyridine or [1,2,4]triazolo[4,3-a]pyridine, each of which may be substituted by 1 to 5 R ¹² ; and especially preferably (for example) isoxazole, 1, 3,4-oxadiazole, 1,2,4-triazole, tetrazole, benzo[d]isoxazole, [1,2,3]triazolo[1,5-a]pyridine or [1 ,2,4]triazolo[4,3-a]pyridine, each of which may be substituted by 1 to 5 R ¹² .

在本發明中，R ¹²為較佳地(例如) (1) C1-4烷基、(2) C3-7環烷基、(3) C1-4鹵烷基、(4) C1-4烷氧基、(5)可經1至3個R ¹⁷取代之苯基、(6)經苯基取代之C1-4烷基、(7)二甲基胺基、(8)吡啶基或(9) 1-(環丙基甲基)吡唑-3-基，或(10)兩個R ¹²以及附接至此等R ¹²之原子可形成C3-5環烷烴；更佳地(例如) (1) C1-4烷基、(2) C3-7環烷基、(3)可經1至3個R ¹⁷取代之苯基，或(4)兩個R ¹²以及附接至此等R ¹²之原子可形成C3-5環烷烴；且尤其較佳地(例如) C1-4烷基，或兩個R ¹²以及附接至此等R ¹²之原子可形成C3-5環烷烴。 In the present invention, R ¹² is preferably (for example) (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl, (4) C1-4 alkane Oxygen, (5) phenyl which may be substituted by 1 to 3 R ¹⁷ , (6) C1-4 alkyl substituted by phenyl, (7) dimethylamino, (8) pyridyl or (9 ) 1-(cyclopropylmethyl)pyrazol-3-yl, or (10) two R ¹² and atoms attached to these R ¹² can form C3-5 cycloalkane; more preferably (for example) (1 ) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) phenyl which may be substituted by 1 to 3 R ¹⁷ , or (4) two R ¹² and the atoms attached to these R ¹² A C3-5 cycloalkane can be formed; and especially preferably (for example) a C1-4 alkyl group, or two R ¹² and the atoms attached to these R ¹² can form a C3-5 cycloalkane.

在本發明中，R ¹⁷為較佳地(例如) C1-4烷基或C1-4烷氧基。 在本發明中，Cyc2為較佳地(例如)環丙烷、環丁烷、環戊烷、環己烷、環戊烯、環己烯、環戊二烯、環己二烯、苯、吡咯、咪唑、***、四唑、吡唑、吡啶、吡𠯤、嘧啶、噠𠯤、呋喃、哌喃、噻吩、硫代哌喃、㗁唑、異㗁唑、噻唑、異噻唑、呋呫、㗁二唑、㗁𠯤、㗁二𠯤、噻二唑、噻𠯤、噻二𠯤、吲哚、苯并咪唑、苯并***、吲唑、苯并呋喃、苯并噻吩、苯并㗁唑、吲哚啉、二氫苯并咪唑、二氫苯并***、二氫吲唑、二氫苯并呋喃、二氫苯并噻吩或二氫苯并㗁唑，其中各者可經1至5個R ¹³取代；且更佳地(例如)環丙烷、苯、吡啶、噻吩、噻唑或吲哚啉，其中各者可經1至5個R ¹³取代。 In the present invention, R ¹⁷ is preferably (for example) C1-4 alkyl or C1-4 alkoxy. In the present invention, Cyc2 is preferably (for example) cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pyrrole, Imidazole, Triazole, Tetrazole, Pyrazole, Pyridine, Pyridine, Pyrimidine, Pyridine, Furan, Pyran, Thiophene, Thiopyran, Pyrazole, Isoxazole, Thiazole, Isothiazole, Furan, Pyridine Azole, 㗁𠯤, 㗁2𠯤, thiadiazole, thiadiazole, thiadi𠯤, indole, benzimidazole, benzotriazole, indazole, benzofuran, benzothiophene, benzoxazole, indole phenoline, dihydrobenzimidazole, dihydrobenzotriazole, dihydroindazole, dihydrobenzofuran, dihydrobenzothiophene or dihydrobenzoxazole, each of which can be modified by 1 to 5 R ¹³ and more preferably, for example, cyclopropane, benzene, pyridine, thiophene, thiazole or indoline, each of which may be substituted by 1 to 5 R ¹³ .

在本發明中，R ¹⁰為較佳地(例如)異丙基、三級丁基、1,1,1-三氟-2-甲基丙-2-基、1-甲基環丙基、1-(三氟甲基)環丙基或1-氰基環丙基。 In the present invention, R ¹⁰ is preferably (for example) isopropyl, tertiary butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl)cyclopropyl or 1-cyanocyclopropyl.

在本發明中，R ¹³為較佳地(例如) C1-4烷基或C1-4烷氧基。 在本發明中，R ¹¹為較佳地(例如)氫原子或C1-4烷基。 在本發明中，R ²為較佳地(例如)氫原子或C1-4烷基。 在本發明中，R ³為較佳地(例如)氫原子或C1-4烷基。 在本發明中，R ⁴為較佳地(例如)氫原子或C1-4烷基。 在本發明中，R ⁵為較佳地(例如)氫原子或C1-4烷基。 在本發明中，R ⁶為較佳地(例如)氫原子或C1-4烷基。 在本發明中，R ⁷為較佳地(例如)氫原子或C1-4烷基。 在本發明中，R ⁸為較佳地(例如)氫原子或C1-4烷基。 在本發明中，R ⁹為較佳地(例如)可經1至3個R ¹⁴取代之咪唑。 在本發明中，R ⁹亦為較佳地(例如)可經1至3個R ¹⁵取代之吡唑。 In the present invention, R ¹³ is preferably (for example) C1-4 alkyl or C1-4 alkoxy. In the present invention, R ¹¹ is preferably, for example, a hydrogen atom or a C1-4 alkyl group. In the present invention, R ² is preferably, for example, a hydrogen atom or a C1-4 alkyl group. In the present invention, R ³ is preferably, for example, a hydrogen atom or a C1-4 alkyl group. In the present invention, R ⁴ is preferably, for example, a hydrogen atom or a C1-4 alkyl group. In the present invention, R ⁵ is preferably, for example, a hydrogen atom or a C1-4 alkyl group. In the present invention, R ⁶ is preferably, for example, a hydrogen atom or a C1-4 alkyl group. In the present invention, R ⁷ is preferably, for example, a hydrogen atom or a C1-4 alkyl group. In the present invention, R ⁸ is preferably, for example, a hydrogen atom or a C1-4 alkyl group. In the present invention, R ⁹ is preferably, for example, imidazole which may be substituted by 1 to 3 R ¹⁴ . In the present invention, R ⁹ is also preferably, for example, pyrazole which may be substituted by 1 to 3 R ¹⁵ .

在本發明中，R ¹⁴為較佳地(例如) (1) C1-8烷基、(2)可經C1-4烷基取代之C3-7環烷基、(3)經可經1至3個R ¹⁶取代之Cyc3取代的C1-8烷基或(4)經苯氧基取代之C1-8烷基，且更佳地(例如) (1) C1-8烷基或(2)可經C1-4烷基取代之C3-7環烷基。 In the present invention, R ¹⁴ is preferably (for example) (1) C1-8 alkyl, (2) C3-7 cycloalkyl which may be substituted by C1-4 alkyl, (3) which may be substituted by 1 to 3 R ¹⁶ substituted Cyc3 substituted C1-8 alkyl or (4) phenoxy substituted C1-8 alkyl, and more preferably (for example) (1) C1-8 alkyl or (2) can be C3-7 cycloalkyl substituted by C1-4 alkyl.

在本發明中，Cyc3為較佳地(例如)苯基或C3-7環烷基。 在本發明中，R ¹⁶為較佳地(例如) C1-4烷基或氰基。 In the present invention, Cyc3 is preferably (for example) phenyl or C3-7 cycloalkyl. In the present invention, R ¹⁶ is preferably (for example) C1-4 alkyl or cyano.

在本發明中，R ¹⁵為較佳地(例如) (1) C1-8烷基、(2)可經C1-4烷基取代之C3-7環烷基、(3)經可經1至3個R ²¹取代之Cyc3取代的C1-8烷基，且更佳地(例如) (1) C1-8烷基或(2)可經C1-4烷基取代之C3-7環烷基。 In the present invention, R ¹⁵ is preferably (for example) (1) C1-8 alkyl, (2) C3-7 cycloalkyl which may be substituted by C1-4 alkyl, (3) which may be substituted by 1 to 3 R ²¹ substituted Cyc3 substituted C1-8 alkyl, and more preferably (1) C1-8 alkyl or (2) C3-7 cycloalkyl which may be substituted by C1-4 alkyl.

在本發明中，Cyc4為較佳地(例如)苯基或C3-7環烷基。 在本發明中，R ²¹為較佳地(例如) C1-4烷基或氰基。 In the present invention, Cyc4 is preferably (for example) phenyl or C3-7 cycloalkyl. In the present invention, R ²¹ is preferably (for example) C1-4 alkyl or cyano.

在本發明中，通式(I)之實例較佳地包括通式(I-1A)： 其中所有符號具有與以上相同之含義， In the present invention, examples of general formula (I) preferably include general formula (I-1A): where all the symbols have the same meanings as above,

在本發明中，通式(I)之實例較佳地包括通式(I-1)： 其中所有符號具有與以上相同之含義， In the present invention, examples of general formula (I) preferably include general formula (I-1): where all the symbols have the same meanings as above,

通式(I-1A-1)： 其中R ²表示氫原子或C1-4烷基； R ¹⁴表示(1) C1-8烷基、(2)可經C1-4烷基取代之C3-7環烷基或(5)經苯氧基取代之C1-8烷基； 其中R ^12-1及R ^12-2獨立地表示C1-4烷基；及 R ^12-1及R ^12-2以及鍵結至該R ^12-1及R ^12-2之原子可形成C3-5環烷烴； General formula (I-1A-1): Wherein R ² represents a hydrogen atom or a C1-4 alkyl group; R ¹⁴ represents (1) a C1-8 alkyl group, (2) a C3-7 cycloalkyl group that may be substituted by a C1-4 alkyl group, or (5) a phenoxy group C1-8 alkyl group substituted; wherein R ^12-1 and R ^12-2 independently represent C1-4 alkyl; and R ^12-1 and R ^12-2 and bonded to the R ^12-1 and R ^{12 -2} atoms can form C3-5 cycloalkane;

通式(I-2)： 其中所有符號具有與以上相同之含義， General formula (I-2): where all the symbols have the same meanings as above,

通式(I-2-1)： 其中R ²表示氫原子、C1-4烷基、鹵素或C1-4烷氧基； R ¹⁵表示(1) C1-8烷基或(3) C1-8鹵烷基； 其中R ^12-1及R ^12-2獨立地表示C1-4烷基；及 R ^12-1及R ^12-2以及鍵結至該R ^12-1及R ^12-2之原子可形成C3-5環烷烴； General formula (I-2-1): Wherein R ² represents a hydrogen atom, C1-4 alkyl, halogen or C1-4 alkoxy; R ¹⁵ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; wherein R ^12-1 and R ^12-2 independently represents C1-4 alkyl; and R ^12-1 and R ^12-2 and atoms bonded to the R ^12-1 and R ^12-2 can form C3-5 cycloalkane;

通式(I-3A)： 其中所有符號具有與以上相同之含義， General formula (I-3A): where all the symbols have the same meanings as above,

通式(I-3)： 其中所有符號具有與以上相同之含義， General formula (I-3): where all the symbols have the same meanings as above,

通式(I-4)： 其中所有符號具有與以上相同之含義， General formula (I-4): where all the symbols have the same meanings as above,

通式(I-5)： 其中R ^12H表示(1)氫原子、(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3 R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基，且其他符號具有與以上相同之含義， General formula (I-5): Wherein R ^12H represents (1) hydrogen atom, (2) C1-4 alkyl group, (3) C3-7 cycloalkyl group, (4) C1-4 haloalkyl group, (5) C1-4 alkoxyl group, ( 6) 1 to 3 R ¹⁷ substituted phenyl, (7) phenyl substituted C1-4 alkyl, (8) dimethylamino, (9) pyridyl or (10) 1-(cyclo Propylmethyl) pyrazol-3-yl, and other symbols have the same meaning as above,

通式(I-6)： 其中所有符號具有與以上相同之含義， General formula (I-6): where all the symbols have the same meanings as above,

通式(I-7)： 其中所有符號具有與以上相同之含義， General formula (I-7): where all the symbols have the same meanings as above,

通式(I-7-1)： 其中R ¹⁴表示(1) C1-8烷基或(3) C1-8鹵烷基； R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基； R ^12H2表示(1)氫原子、(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H2表示(1)氫原子、(2) C1-4烷基、(4) C1-4鹵烷基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素。 General formula (I-7-1): Wherein R ¹⁴ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ^12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1- 4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8) dimethyl Amino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H1 represents (2) C1-4 alkyl, (3) C3- 7 cycloalkyl, (4) C1-4 haloalkyl, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (9) pyridyl Or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; R ^12H2 represents (1) hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4 ) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8 ) dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H2 represents (1) hydrogen atom, (2) C1- 4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl substituted by phenyl, (8) dimethylamino; and R ¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

通式(I-8)： 其中所有符號具有與以上相同之含義， General formula (I-8): where all the symbols have the same meanings as above,

通式(I-8-1)： 其中R ¹⁵表示(1) C1-8烷基或(3) C1-8鹵烷基； R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基； R ^12H2表示(1)氫原子、(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H2表示(1)氫原子、(2) C1-4烷基、(4) C1-4鹵烷基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素。 General formula (I-8-1): Wherein R ¹⁵ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ^12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1- 4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8) dimethyl Amino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H1 represents (2) C1-4 alkyl, (3) C3- 7 cycloalkyl, (4) C1-4 haloalkyl, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (9) pyridyl Or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; R ^12H2 represents (1) hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4 ) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8 ) dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H2 represents (1) hydrogen atom, (2) C1- 4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl substituted by phenyl, (8) dimethylamino; and R ¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

通式(I-9)： 其中所有符號具有與以上相同之含義， General formula (I-9): where all the symbols have the same meanings as above,

通式(I-10)： 其中所有符號具有與以上相同之含義， General formula (I-10): where all the symbols have the same meanings as above,

通式(I-11)： 其中所有符號具有與以上相同之含義， General formula (I-11): where all the symbols have the same meanings as above,

通式(I-11-1)： 其中R ¹⁴表示(1) C1-8烷基或(3) C1-8鹵烷基； R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基； R ^12H2表示(1)氫原子、(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H2表示(1)氫原子、(2) C1-4烷基、(4) C1-4鹵烷基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素。 General formula (I-11-1): Wherein R ¹⁴ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ^12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1- 4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8) dimethyl Amino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H1 represents (2) C1-4 alkyl, (3) C3- 7 cycloalkyl, (4) C1-4 haloalkyl, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (9) pyridyl Or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; R ^12H2 represents (1) hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4 ) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8 ) dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H2 represents (1) hydrogen atom, (2) C1- 4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl substituted by phenyl, (8) dimethylamino; and R ¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

通式(I-12)： 其中所有符號具有與以上相同之含義， 通式(I-12-1)： 其中R ¹⁵表示(1) C1-8烷基或(3) C1-8鹵烷基； R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基； R ^12H2表示(1)氫原子、(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H2表示(1)氫原子、(2) C1-4烷基、(4) C1-4鹵烷基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素。 General formula (I-12): All the symbols have the same meanings as above, general formula (I-12-1): Wherein R ¹⁵ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ^12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1- 4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8) dimethyl Amino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H1 represents (2) C1-4 alkyl, (3) C3- 7 cycloalkyl, (4) C1-4 haloalkyl, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (9) pyridyl Or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; R ^12H2 represents (1) hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4 ) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8 ) dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H2 represents (1) hydrogen atom, (2) C1- 4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl substituted by phenyl, (8) dimethylamino; and R ¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

通式(I-13)： 其中所有符號具有與以上相同之含義， General formula (I-13): where all the symbols have the same meanings as above,

通式(I-13-1)： 其中R ¹⁴表示(1) C1-8烷基或(3) C1-8鹵烷基； R ^12H表示(1)氫原子、(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3 R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H表示(1)氫原子、(2) C1-4烷基、(4) C1-4鹵烷基； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素。 General formula (I-13-1): Wherein R ¹⁴ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ^12H represents (1) hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl , (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8) dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H represents (1) a hydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl; and R ¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

通式(I-14)： 其中所有符號具有與以上相同之含義， General formula (I-14): where all the symbols have the same meanings as above,

通式(I-14-1)： 其中R ¹⁵表示(1) C1-8烷基或(3) C1-8鹵烷基； R ^12H表示(1)氫原子、(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3 R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H表示(1)氫原子、(2) C1-4烷基、(4) C1-4鹵烷基； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素。 General formula (I-14-1): Wherein R ¹⁵ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ^12H represents (1) hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl , (4) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8) dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H represents (1) a hydrogen atom, (2) C1-4 alkyl, (4) C1-4 haloalkyl; and R ¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen.

通式(I-15)： 其中n表示0至4之整數，且其他符號具有與以上相同之含義， General formula (I-15): Where n represents an integer from 0 to 4, and other symbols have the same meanings as above,

通式(I-15-1)： 其中R ¹⁴表示(1) C1-8烷基或(3) C1-8鹵烷基； R ¹²表示(1) C1-4烷基、(2) C3-7環烷基、(3) C1-4鹵烷基、(4) C1-4烷氧基、(5)可經1至3個R ¹⁷取代之苯基、(6)經苯基取代之C1-4烷基、(7)二甲基胺基、(8)吡啶基或(9) 1-(環丙基甲基)吡唑-3-基； n表示0至4之整數，較佳地，n為0； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素。 General formula (I-15-1): Wherein R ¹⁴ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1- 4 haloalkyl, (4) C1-4 alkoxy, (5) phenyl which may be substituted by 1 to 3 R ¹⁷ , (6) C1-4 alkyl substituted by phenyl, (7) dimethyl Amino, (8) pyridyl or (9) 1-(cyclopropylmethyl) pyrazol-3-yl; n represents an integer from 0 to 4, preferably, n is 0; and R ¹⁷ represents C1 -4 alkyl, C1-4 alkoxy or halogen.

通式(I-16)： 其中所有符號具有與以上相同之含義， General formula (I-16): where all the symbols have the same meanings as above,

通式(I-16-1)： 其中R ¹⁵表示(1) C1-8烷基或(3) C1-8鹵烷基； R ¹²表示(1) C1-4烷基、(2) C3-7環烷基、(3) C1-4鹵烷基、(4) C1-4烷氧基、(5)可經1至3個R ¹⁷取代之苯基、(6)經苯基取代之C1-4烷基、(7)二甲基胺基、(8)吡啶基或(9) 1-(環丙基甲基)吡唑-3-基； n表示0至4之整數，較佳地，n為0； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素。 General formula (I-16-1): Wherein R ¹⁵ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1- 4 haloalkyl, (4) C1-4 alkoxy, (5) phenyl which may be substituted by 1 to 3 R ¹⁷ , (6) C1-4 alkyl substituted by phenyl, (7) dimethyl Amino, (8) pyridyl or (9) 1-(cyclopropylmethyl) pyrazol-3-yl; n represents an integer from 0 to 4, preferably, n is 0; and R ¹⁷ represents C1 -4 alkyl, C1-4 alkoxy or halogen.

通式(I-17)： 其中所有符號具有與以上相同之含義， 通式(I-17-1)： 其中R ¹⁴表示(1) C1-8烷基或(3) C1-8鹵烷基； R ¹²表示(1) C1-4烷基、(2) C3-7環烷基、(3) C1-4鹵烷基、(4) C1-4烷氧基、(5)可經1至3個R ¹⁷取代之苯基、(6)經苯基取代之C1-4烷基、(7)二甲基胺基、(8)吡啶基或(9) 1-(環丙基甲基)吡唑-3-基； n表示0至4之整數，較佳地，n為0； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素； General formula (I-17): All the symbols have the same meanings as above, general formula (I-17-1): Wherein R ¹⁴ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1- 4 haloalkyl, (4) C1-4 alkoxy, (5) phenyl which may be substituted by 1 to 3 R ¹⁷ , (6) C1-4 alkyl substituted by phenyl, (7) dimethyl Amino, (8) pyridyl or (9) 1-(cyclopropylmethyl) pyrazol-3-yl; n represents an integer from 0 to 4, preferably, n is 0; and R ¹⁷ represents C1 -4 alkyl, C1-4 alkoxy or halogen;

通式(I-18)： 其中所有符號具有與以上相同之含義， General formula (I-18): where all the symbols have the same meanings as above,

通式(I-18-1)： 其中R ¹⁵表示(1) C1-8烷基或(3) C1-8鹵烷基； R ¹²表示(1) C1-4烷基、(2) C3-7環烷基、(3) C1-4鹵烷基、(4) C1-4烷氧基、(5)可經1至3個R ¹⁷取代之苯基、(6)經苯基取代之C1-4烷基、(7)二甲基胺基、(8)吡啶基或(9) 1-(環丙基甲基)吡唑-3-基；較佳地，R ¹²表示(1) C1-4烷基、(2) C3-7環烷基、(3) C1-4鹵烷基、(4) C1-4烷氧基， n表示0至4之整數，較佳地，n為1； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素。 General formula (I-18-1): Wherein R ¹⁵ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1- 4 haloalkyl, (4) C1-4 alkoxy, (5) phenyl which may be substituted by 1 to 3 R ¹⁷ , (6) C1-4 alkyl substituted by phenyl, (7) dimethyl Amino, (8) pyridyl or (9) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ¹² represents (1) C1-4 alkyl, (2) C3- 7 cycloalkyl, (3) C1-4 haloalkyl, (4) C1-4 alkoxy, n represents an integer from 0 to 4, preferably, n is 1; and R ¹⁷ represents C1-4 alkyl , C1-4 alkoxy or halogen.

通式(I-19)： 其中所有符號具有與以上相同之含義， General formula (I-19): where all the symbols have the same meanings as above,

通式(I-20)： 其中所有符號具有與以上相同之含義， General formula (I-20): where all the symbols have the same meanings as above,

通式(I-21)： 其中m表示0至2之整數，且其他符號具有與以上相同之含義， General formula (I-21): wherein m represents an integer from 0 to 2, and other symbols have the same meanings as above,

通式(I-21-1): 其中R ¹⁴表示(1) C1-8烷基或(3) C1-8鹵烷基； R ¹³表示C1-4烷基、C1-4烷氧基或鹵素；及 m表示0至2之整數。 General formula (I-21-1): wherein R ¹⁴ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ¹³ represents C1-4 alkyl, C1-4 alkoxy or halogen; and m represents an integer from 0 to 2.

通式(I-22)： 其中所有符號具有與以上相同之含義， General formula (I-22): where all the symbols have the same meanings as above,

通式(I-23)： 其中所有符號具有與以上相同之含義， General formula (I-23): where all the symbols have the same meanings as above,

通式(I-24)： 其中所有符號具有與以上相同之含義， General formula (I-24): where all the symbols have the same meanings as above,

通式(I-25)： 其中所有符號具有與以上相同之含義， General formula (I-25): where all the symbols have the same meanings as above,

通式(I-26)： 其中所有符號具有與以上相同之含義， General formula (I-26): where all the symbols have the same meanings as above,

通式(I-27)： 其中R ^13H表示氫原子、C1-4烷基、C1-4烷氧基或鹵素，且其他符號具有與以上相同之含義， General formula (I-27): Wherein R ^13H represents a hydrogen atom, C1-4 alkyl, C1-4 alkoxy or halogen, and other symbols have the same meaning as above,

通式(I-28)： 其中所有符號具有與以上相同之含義， General formula (I-28): where all the symbols have the same meanings as above,

通式(I-29)： 其中所有符號具有與以上相同之含義， General formula (I-29): where all the symbols have the same meanings as above,

通式(I-30)： 其中所有符號具有與以上相同之含義， General formula (I-30): where all the symbols have the same meanings as above,

通式(I-31)： 其中所有符號具有與以上相同之含義， General formula (I-31): where all the symbols have the same meanings as above,

通式(I-32)： 其中所有符號具有與以上相同之含義， General formula (I-32): where all the symbols have the same meanings as above,

通式(I-33)： 其中所有符號具有與以上相同之含義， General formula (I-33): where all the symbols have the same meanings as above,

通式(I-33-1)： 其中R ¹⁴表示(1) C1-8烷基或(3) C1-8鹵烷基； R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基； R ^12H2表示(1)氫原子、(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H2表示(1)氫原子、(2) C1-4烷基、(4) C1-4鹵烷基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素； General formula (I-33-1): Wherein R ¹⁴ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ^12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1- 4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8) dimethyl Amino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H1 represents (2) C1-4 alkyl, (3) C3- 7 cycloalkyl, (4) C1-4 haloalkyl, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (9) pyridyl Or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; R ^12H2 represents (1) hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4 ) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8 ) dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H2 represents (1) hydrogen atom, (2) C1- 4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl substituted by phenyl, (8) dimethylamino; and R ¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen;

通式(I-34)： 其中所有符號具有與以上相同之含義， General formula (I-34): where all the symbols have the same meanings as above,

通式(I-34-1)： 其中R ¹⁵表示(1) C1-8烷基或(3) C1-8鹵烷基； R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H1表示(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基； R ^12H2表示(1)氫原子、(2) C1-4烷基、(3) C3-7環烷基、(4) C1-4鹵烷基、(5) C1-4烷氧基、(6)可經1至3個R ¹⁷取代之苯基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基、(9)吡啶基或(10) 1-(環丙基甲基)吡唑-3-基；較佳地，R ^12H2表示(1)氫原子、(2) C1-4烷基、(4) C1-4鹵烷基、(7)經苯基取代之C1-4烷基、(8)二甲基胺基； 且R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素； General formula (I-34-1): Wherein R ¹⁵ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ^12H1 represents (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4) C1- 4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8) dimethyl Amino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H1 represents (2) C1-4 alkyl, (3) C3- 7 cycloalkyl, (4) C1-4 haloalkyl, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (9) pyridyl Or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; R ^12H2 represents (1) hydrogen atom, (2) C1-4 alkyl, (3) C3-7 cycloalkyl, (4 ) C1-4 haloalkyl, (5) C1-4 alkoxy, (6) phenyl which may be substituted by 1 to 3 R ¹⁷ , (7) C1-4 alkyl substituted by phenyl, (8 ) dimethylamino, (9) pyridyl or (10) 1-(cyclopropylmethyl) pyrazol-3-yl; preferably, R ^12H2 represents (1) hydrogen atom, (2) C1- 4 alkyl, (4) C1-4 haloalkyl, (7) C1-4 alkyl substituted by phenyl, (8) dimethylamino; and R ¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen;

通式(I-35)： 其中所有符號具有與以上相同之含義， General formula (I-35): where all the symbols have the same meanings as above,

通式(I-35-1)： 其中R ²表示氫原子、C1-4烷基、鹵素或C1-4烷氧基； R ¹⁴表示(1) C1-8烷基或(3) C1-8鹵烷基； R ¹⁰表示C1-8烷基或C1-8鹵烷基，較佳地，R ¹⁰表示異丙基、三級丁基、1,1,1-三氟-2-甲基丙-2-基；及 R ¹¹表示氫原子或C1-4烷基； General formula (I-35-1): Wherein R ² represents a hydrogen atom, C1-4 alkyl, halogen or C1-4 alkoxy; R ¹⁴ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ¹⁰ represents C1-8 Alkyl or C1-8 haloalkyl, preferably, R ¹⁰ represents isopropyl, tertiary butyl, 1,1,1-trifluoro-2-methylpropan-2-yl; and R ¹¹ represents hydrogen atom or C1-4 alkyl;

通式(I-36)： 其中所有符號具有與以上相同之含義； General formula (I-36): All the symbols have the same meaning as above;

及通式(I-36-1-1)： 其中R ²表示氫原子、C1-4烷基、鹵素或C1-4烷氧基； R ¹⁵表示(1) C1-8烷基或(3) C1-8鹵烷基； R ¹⁰表示C1-8烷基或C1-8鹵烷基，較佳地，R ¹⁰表示異丙基、三級丁基、1,1,1-三氟-2-甲基丙-2-基；及 R ¹¹表示氫原子或C1-4烷基。 And general formula (I-36-1-1): Wherein R ² represents a hydrogen atom, C1-4 alkyl, halogen or C1-4 alkoxy; R ¹⁵ represents (1) C1-8 alkyl or (3) C1-8 haloalkyl; R ¹⁰ represents C1-8 Alkyl or C1-8 haloalkyl, preferably, R ¹⁰ represents isopropyl, tertiary butyl, 1,1,1-trifluoro-2-methylpropan-2-yl; and R ¹¹ represents hydrogen atom or C1-4 alkyl.

在本發明中，通式(I)之實例較佳地包括通式(I-37)： 其中所有符號具有與以上相同之含義。 In the present invention, examples of general formula (I) preferably include general formula (I-37): All the symbols have the same meanings as above.

在本發明中，通式(I)之實例較佳地包括通式(I-01)： 其中所有符號具有與以上相同之含義。 In the present invention, examples of general formula (I) preferably include general formula (I-01): All the symbols have the same meanings as above.

在本發明中，通式(I)之實例較佳地包括通式(I-02)： 其中所有符號具有與以上相同之含義。 In the present invention, examples of general formula (I) preferably include general formula (I-02): All the symbols have the same meanings as above.

在本發明中，通式(I-1)至(I-36)之3-氮雜雙環[3.1.0]己烷環上之與由R ¹、R ³及R ⁴表示的取代基對應之取代基之立體組態較佳地在相同方向上，如通式(I-37)。 In the present invention, the substituents represented by R ¹ , R ³ and R ⁴ on the 3-azabicyclo[3.1.0]hexane ring of general formulas (I-1) to (I-36) correspond to The stereo configuration of the substituents is preferably in the same direction, such as general formula (I-37).

在本發明中，或在通式(I)或(I-1)中，化合物為較佳地(例如)： (1) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](1-異丙基-1H-咪唑-4-基)甲酮； (2) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基][1-(1-甲基環丙基)-1H-咪唑-4-基]甲酮； (3) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基]甲酮； (4) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (5) {1-[(2S)-丁-2-基]-1H-咪唑-4-基}[(1R, 5S, 6S)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (6) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基(1-異丙基-1H-咪唑-4-基)甲酮； (7) (1-異丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (8) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮；或 (9) [1-(1-甲基環丙基)-1H-咪唑-4-基][(1R,5S,6r)-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； 或其鹽。 In the present invention, or in the general formula (I) or (I-1), the compound is preferably (for example): (1) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1. 0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone; (2) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1. 0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone; (3) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-㗁Azol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]methanone; (4) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept- 5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (5) {1-[(2S)-Butan-2-yl]-1H-imidazol-4-yl}[(1R, 5S, 6S)-6-(5,5-Dimethyl-4,5- Dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (6) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-nitrogen Heterobicyclo[3.1.0]hex-3-yl(1-isopropyl-1H-imidazol-4-yl)methanone; (7) (1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept- 5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (8) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-ene-6 -yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; or (9) [1-(1-methylcyclopropyl)-1H-imidazol-4-yl][(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]heptane -5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; or its salt.

在本發明中，或在通式(I)或(I-2)中，化合物亦為較佳地(例如)： (1) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮； (2) (5-異丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-(2-氧雜-3-氮雜雙環[3.1.0]己-3-烯-4-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (3) [5-(1-環丙基乙基)-1H-吡唑-3-基][(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (4) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮；或 (5) (5-環丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； 或其鹽。 In the present invention, or in general formula (I) or (I-2), the compound is also preferred (for example): (1) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1. 0] Hex-3-yl] (5-isopropyl-1H-pyrazol-3-yl)methanone; (2) (5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hexa-3- En-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (3) [5-(1-cyclopropylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-di Hydrogen-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (4) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-nitrogen Heterobicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone; or (5) (5-cyclopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]heptane -5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; or its salt.

在本發明中，或在通式(I)或(I-3)中，化合物亦為較佳地(例如)： (1) (1R,5S,6r)-N-三級丁基-6-甲基-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (2) (1R,5S,6r)-N-三級丁基-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (3) (1R,5S,6r)-N-(丙-2-基)-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺；或 (4) (1R,5S,6r)-N-(1-氰基環丙基)-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； 或其鹽。 In the present invention, or in general formula (I) or (I-3), compounds are also preferred (for example): (1) (1R,5S,6r)-N-tertiary butyl-6-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo [3.1.0] Hexane-6-formamide; (2) (1R,5S,6r)-N-tertiary butyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0] Hexane-6-formamide; (3) (1R,5S,6r)-N-(prop-2-yl)-3-[1-(prop-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1 .0] hexane-6-carboxamide; or (4) (1R,5S,6r)-N-(1-cyanocyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo [3.1.0] Hexane-6-formamide; or its salt.

在本發明中，或在通式(I)或(I-4)中，化合物亦為較佳地(例如)： (1) (1R,5S,6r)-N-(丙-2-基)-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (2) (1R,5S,6r)-N-三級丁基-6-甲基-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (3) (1R,5S,6r)-N-三級丁基-N-甲基-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺；或 (4) (1R,5S,6r)-N-甲基-N-(1-甲基環丙基)-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； 或其鹽。 [異構體] In the present invention, or in the general formula (I) or (I-4), compounds are also preferred (for example): (1) (1R,5S,6r)-N-(prop-2-yl)-3-[5-(prop-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[ 3.1.0] hexane-6-formamide; (2) (1R,5S,6r)-N-tertiary butyl-6-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-aza Bicyclo[3.1.0]hexane-6-carboxamide; (3) (1R,5S,6r)-N-tertiary butyl-N-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-aza Bicyclo[3.1.0]hexane-6-carboxamide; or (4) (1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl] -3-Azabicyclo[3.1.0]hexane-6-carboxamide; or its salt. [isomer]

除非另外特定陳述，否則本發明化合物涵蓋所有異構體。舉例而言，烷基、烷氧基及其類似者包括線性及分支鏈基團。此外，本發明化合物涵蓋雙鍵、環及稠環之異構體(E形式、Z形式、順式形式及反式形式)、由於不對稱碳原子之異構體(R形式及S形式、α及β組態、對映異構體及非對映異構體)、具有光學旋轉活性之光學活性物質(D、L、d及l形式)、可由層析法分離之極性物質(高極性物質及低極性物質)、平衡化合物、旋轉異構體、其在任意比例下之混合物及外消旋混合物。本發明化合物亦涵蓋互變異構體。 [鹽及溶劑合物] Unless specifically stated otherwise, the compounds of the present invention encompass all isomers. For example, alkyl, alkoxy and the like include linear and branched chain groups. In addition, the compounds of the present invention cover isomers of double bonds, rings and fused rings (E form, Z form, cis form and trans form), isomers due to asymmetric carbon atoms (R form and S form, α and β configurations, enantiomers and diastereomers), optically active substances with optical rotation activity (D, L, d and l forms), polar substances that can be separated by chromatography (highly polar substances and low polar substances), equilibrium compounds, rotamers, mixtures thereof in any proportion and racemic mixtures. Compounds of the invention also encompass tautomers. [Salts and solvates]

本文中所揭示之由通式(I)表示之化合物的鹽涵蓋所有藥理學上可接受之鹽。藥理學上可接受之鹽較佳地為具有低毒性之水溶性鹽。適當之鹽之實例包括酸加成鹽(諸如無機酸鹽[實例：鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、磷酸鹽、硝酸鹽及其類似者]、有機酸鹽[實例：乙酸鹽、三氟乙酸鹽、乳酸鹽、酒石酸鹽、草酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、苯甲酸鹽、檸檬酸鹽、甲烷磺酸鹽、乙磺酸鹽、苯磺酸鹽、甲苯磺酸鹽、羥乙基磺酸鹽、葡萄糖醛酸鹽、葡糖酸鹽及其類似者]、具有酸性天然胺基酸之鹽[實例：天冬胺酸鹽、麩胺酸鹽及其類似者]及其類似者)及其類似者。The salts of the compounds represented by the general formula (I) disclosed herein encompass all pharmacologically acceptable salts. Pharmacologically acceptable salts are preferably water-soluble salts with low toxicity. Examples of suitable salts include acid addition salts (such as inorganic acid salts [examples: hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate and the like], organic acid salts [ Examples: acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate salts, besylate, tosylate, isethionate, glucuronate, gluconate and the like], salts with acidic natural amino acids [example: aspartic acid salt, glutamate and the like] and the like) and the like.

鹽亦涵蓋四級銨鹽。四級銨鹽表示由通式(I)表示之化合物，其中其氮原子經R ⁰基團四級銨化。如本文中所使用之R ⁰基團表示(例如)可經苯基取代之C1-8烷基。 Salts also encompass quaternary ammonium salts. Quaternary ammonium salts represent compounds represented by general formula (I), wherein the nitrogen atom thereof is quaternary ammonized by the ^R group. The R ⁰ group as used herein represents, for example, a C1-8 alkyl group which may be substituted by phenyl.

由通式(I)表示之化合物可根據熟知方法來轉換成鹽、N-氧化物及溶劑合物。The compounds represented by the general formula (I) can be converted into salts, N-oxides and solvates according to well-known methods.

由通式(I)表示之化合物之N-氧化物表示其中氮原子經氧化的由通式(I)表示之化合物。N-氧化物可形成如上文所描述之鹽，諸如酸加成鹽。The N-oxide of the compound represented by the general formula (I) represents the compound represented by the general formula (I) in which the nitrogen atom is oxidized. N-oxides may form salts as described above, such as acid addition salts.

由通式(I)表示之化合物、其鹽或其N-氧化物可形成具有(例如)水或醇類溶劑(諸如乙醇)之溶劑合物。溶劑合物較佳地具有低毒性且為水溶性的。The compound represented by the general formula (I), its salt or its N-oxide may form a solvate with, for example, water or an alcoholic solvent such as ethanol. Solvates preferably have low toxicity and are water soluble.

由通式(I)表示之化合物及其鹽可呈不形成溶劑合物之形式或可呈具有醫藥學上可接受之溶劑(諸如水及乙醇)之溶劑合物的形式。溶劑合物較佳地為水合物。由通式(I)表示之化合物或其鹽可根據熟知方法來轉換成溶劑合物。The compound represented by the general formula (I) and salts thereof may be in a non-solvated form or may be in a solvated form with a pharmaceutically acceptable solvent such as water and ethanol. The solvates are preferably hydrates. A compound represented by general formula (I) or a salt thereof can be converted into a solvate according to a well-known method.

由通式(I)表示之化合物及其鹽可形成具有適當共結晶體形成劑之共結晶體。共結晶體較佳地為醫藥學上可接受的，如與醫藥學上可接受之共結晶體形成劑一起形成。共結晶體經定義為典型地由2個或更多個分子藉由分子間相互作用(其不為離子鍵結)形成之結晶體。共結晶體可為中性分子與鹽之複合物。共結晶體可根據諸如熔融結晶、自溶劑再結晶或將組分一起實體研磨之熟知方法製備。適當共結晶體形成劑包括揭示於WO 2006/007448中之彼等共結晶體形成劑。The compounds represented by general formula (I) and salts thereof can form co-crystals with suitable co-crystal formers. Co-crystals are preferably pharmaceutically acceptable, eg, formed with a pharmaceutically acceptable co-crystal former. Co-crystals are defined as crystals typically formed of 2 or more molecules by intermolecular interactions that are not ionic bonds. Co-crystals can be complexes of neutral molecules and salts. Co-crystals can be prepared according to well-known methods such as melt crystallization, recrystallization from solvents, or physical grinding of the components together. Suitable co-crystal formers include those co-crystal formers disclosed in WO 2006/007448.

在本發明中，關於本發明化合物之所有敍述涵蓋由通式(I)表示之化合物、其鹽、其溶劑合物(諸如水合物)、其N-氧化物或其共結晶體，或由通式(I)表示之化合物之鹽的溶劑合物(諸如水合物)、N-氧化物或共結晶體。In the present invention, all statements about the compound of the present invention cover the compound represented by the general formula (I), its salt, its solvate (such as hydrate), its N-oxide or its co-crystal, or the compound represented by the general formula (I) A solvate (such as a hydrate), an N-oxide or a co-crystal of a salt of a compound represented by (I).

亦即，在本發明中，由通式(I)表示之化合物或其鹽涵蓋由通式(I)表示之化合物的溶劑合物(諸如水合物)、N-氧化物或共結晶體或由通式(I)表示之化合物之鹽的溶劑合物(諸如水合物)、N-氧化物或共結晶體。 [前驅藥] That is, in the present invention, the compound represented by the general formula (I) or a salt thereof encompasses a solvate (such as a hydrate), an N-oxide or a co-crystal of the compound represented by the general formula (I) or a compound represented by the general formula (I) A solvate (such as a hydrate), an N-oxide or a co-crystal of a salt of the compound represented by formula (I). [Prodrug]

由通式(I)表示之化合物之前驅藥係指藉由與酶、胃酸及其類似者反應在活體內轉換成由通式(I)表示之化合物的化合物。由通式(I)表示之化合物之前驅藥的實例包括：當由通式(I)表示之化合物具有胺基時，其中胺基醯基化、烷基化或磷酸化之化合物(例如其中其胺基轉換成二十醯基、丙胺醯基、戊基胺基羰基、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)甲氧基羰基、四氫呋喃基、吡咯啶基甲基、特戊醯氧基甲基、乙醯氧基甲基、三級丁基或其類似者之由通式(I)表示之化合物)；當由通式(I)表示之化合物具有羥基時，其中羥基醯基化、烷基化、磷酸化或轉換成硼酸酯(borate)之化合物(例如其中其羥基轉換成乙醯基、軟脂醯基、丙醯基、特戊醯基、丁二醯基、反丁烯二醯基、丙胺醯基、二甲基胺基甲基羰基或其類似者之由通式(I)表示之化合物)及其類似者。由通式(I)表示之化合物之前驅藥可為在生理條件下轉換成由通式(I)表示之化合物之一者，諸如揭示於「藥物發展(Iyakuhin no Kaihatsu)」, 第7卷「分子設計(Bunshi Sekkei)」, 第163-198頁, 1990, 廣川書店公司(Hirokawa Shoten Co.)中之彼等者。由通式(I)表示之化合物之前驅藥可藉由本身熟知之方法產生。由通式(I)表示之化合物之前驅藥可與由通式(I)表示之化合物類似地形成(例如)鹽，諸如酸加成鹽，或可形成與水或酒精類溶劑(諸如乙醇)之溶劑合物。 [經標記化合物] Propellant of the compound represented by the general formula (I) refers to a compound converted into the compound represented by the general formula (I) in vivo by reacting with enzyme, gastric acid and the like. Examples of the prodrug of the compound represented by the general formula (I) include: when the compound represented by the general formula (I) has an amine group, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, a compound in which Conversion of amine group to eicosyl, propylaminoyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl , tetrahydrofuranyl, pyrrolidinylmethyl, pivalyloxymethyl, acetyloxymethyl, tertiary butyl or similar compounds represented by the general formula (I); when the general formula ( When the compound represented by I) has a hydroxyl group, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated or converted into a borate (for example, a compound in which the hydroxyl group is converted into an acetyl group, a palmityl group, an acryl group) A compound represented by the general formula (I) of pivalyl, pivalyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl or the like) and the like . The compound represented by the general formula (I) can be expelled before being converted into one of the compounds represented by the general formula (I) under physiological conditions, such as disclosed in "Drug Development (Iyakuhin no Kaihatsu)", Vol. 7 " Molecular Design (Bunshi Sekkei)", pp. 163-198, 1990, among others in Hirokawa Shoten Co. The prodrug of the compound represented by the general formula (I) can be produced by a method known per se. The prodrug of the compound represented by the general formula (I) can form, for example, a salt, such as an acid addition salt, similarly to the compound represented by the general formula (I), or can form a compound with water or an alcoholic solvent (such as ethanol) of solvates. [labeled compound]

在本發明中，由通式(I)表示之化合物或其鹽涵蓋所謂的經標記化合物，其中構成化合物之一些或所有原子經其同位素取代。經標記化合物可根據本身熟知之方法產生。可用於適合地標記之同位素之實例包括但不限於 ²H、 ³H、 ¹³C、 ¹⁴C、 ¹⁵N、 ¹⁶N、 ¹⁷O、 ¹⁸O、 ³⁵S、 ³⁶Cl、 ⁷⁷Br、 ¹²⁵I及其類似者。 [產生方法] [用於產生本發明化合物之方法] In the present invention, the compound represented by the general formula (I) or a salt thereof encompasses a so-called labeled compound in which some or all atoms constituting the compound are substituted with isotopes thereof. Labeled compounds can be produced according to methods well known per se. Examples of isotopes that can be used for suitable labeling include, but are not limited to ^{, 2H} , ^3H , ^13C , 14C, ^15N , ^16N , ^17O , ^18O , ^{35S , 36Cl , 77Br} , ^125I , and similar. [Production method] [Method for producing the compound of the present invention]

由通式(I)表示之化合物或其鹽可藉由熟知方法產生，例如但不限於，在方案I至XII中表示之以下方法中所描述之方法、等效於此等方法之方法、在實例中所描述之方法、等效於實例中所描述之彼等者之方法或在綜合有機變換：官能基製備指南(Comprehensive Organic Transformations: A Guide to Functional Group Preparations), 第2版(Richard C. Larock, 約翰威利公司(John Wiley & Sons Inc.), 1999)中所描述之方法，改編自前述內容之方法或結合前述內容之方法。在下文中所描述之產生方法中，原材料化合物可為形成鹽之彼等者。鹽之實例包括上文所提及之彼等者，如由通式(I)表示之化合物之鹽。Compounds represented by general formula (I) or salts thereof can be produced by well-known methods, such as, but not limited to, methods described in the following methods represented in Schemes I to XII, methods equivalent to these methods, in Methods described in the Examples, methods equivalent to those described in the Examples, or in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. The method described in Larock, John Wiley & Sons Inc., 1999), was adapted from or combined with the method described above. In the production methods described hereinafter, the starting material compounds may be those that form salts. Examples of the salt include those mentioned above, such as the salt of the compound represented by the general formula (I).

其中由通式(I)表示之化合物可藉由使由通式(III)表示之化合物及由通式(IV)表示之化合物經受醯胺化反應來產生。 Among them, the compound represented by the general formula (I) can be produced by subjecting the compound represented by the general formula (III) and the compound represented by the general formula (IV) to an amidation reaction.

醯胺化為已知的。舉例而言，其包括以下方法 (1)    經由醯基鹵化物， (2)    經由混合酸酐， (3)    使用縮合劑。 Amidation is known. For example, it includes the following methods (1) via acyl halides, (2) via mixed anhydride, (3) Use a condensing agent.

此等方法解釋如下。 (1)    經由醯基鹵化物之方法可例如藉由使羧酸與醯基鹵化物(例如，乙二醯氯或亞硫醯氯)在有機溶劑(例如，三氯甲烷、二氯甲烷、二***或四氫呋喃)中或在無溶劑情況下在約-20℃至回流溫度下反應來進行。且隨後，所獲得醯基鹵化物衍生物可在存在鹼(例如，吡啶、三乙胺、二甲基苯胺、二甲胺基吡啶或二異丙基乙胺等)之情況下在約0至40℃下在有機溶劑(例如，三氯甲烷、二氯甲烷、二***或四氫呋喃)中與胺反應。作為替代方案，所獲得醯基鹵化物衍生物可在使用鹼性水溶液(例如，碳酸氫鈉、氫氧化鈉)之有機溶劑(例如，二㗁烷、四氫呋喃)中在約-78至40℃下與胺反應。 These methods are explained below. (1) The method via an acyl halide can be obtained, for example, by making a carboxylic acid and an acyl halide (for example, acetyl chloride or thionyl chloride) in an organic solvent (for example, chloroform, dichloromethane, dichloromethane, ether or tetrahydrofuran) or in the absence of solvent at about -20°C to reflux temperature. And then, the obtained acyl halide derivative can be obtained at about 0 to Reaction with the amine in an organic solvent (eg, chloroform, dichloromethane, diethyl ether or tetrahydrofuran) at 40°C. Alternatively, the obtained acyl halide derivatives can be treated at about -78 to 40°C in an organic solvent (e.g., dioxane, tetrahydrofuran) using an aqueous alkaline solution (e.g., sodium bicarbonate, sodium hydroxide) Reacts with amines.

(2)    經由混合酸酐之方法可例如藉由使羧酸與醯基鹵化物(例如，特戊醯氯、對甲苯磺醯氯或甲磺醯氯)或酸衍生物(例如，氯甲酸乙酯或氯甲酸異丁酯)在有機溶劑(例如，三氯甲烷、二氯甲烷、二***、四氫呋喃)中或在無溶劑情況下、在存在鹼(例如，吡啶、三乙胺、二甲基苯胺、二甲胺基吡啶或二異丙基乙胺)之情況下在約0至40℃下反應來進行。且隨後，所獲得混合酸酐衍生物可在有機溶劑(例如，三氯甲烷、二氯甲烷、二***或四氫呋喃)中在約0至40℃下與胺反應。(2) The method of mixing anhydrides can be achieved, for example, by combining carboxylic acids with acyl halides (for example, pivalyl chloride, p-toluenesulfonyl chloride, or methanesulfonyl chloride) or acid derivatives (for example, ethyl chloroformate or isobutyl chloroformate) in an organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran) or in the absence of a solvent, in the presence of a base (e.g., pyridine, triethylamine, dimethylaniline , dimethylaminopyridine or diisopropylethylamine) at about 0 to 40°C for reaction. And then, the obtained mixed acid anhydride derivative may be reacted with an amine in an organic solvent (for example, chloroform, dichloromethane, diethyl ether or tetrahydrofuran) at about 0 to 40°C.

(3)    使用縮合劑之方法可例如藉由使羧酸與胺在有機溶劑(例如，三氯甲烷、二氯甲烷、二甲基甲醯胺、二***或四氫呋喃)中或在無溶劑情況下、在存在或不存在鹼(例如，吡啶、三乙胺、二甲基苯胺或二甲胺基吡啶)之情況下使用縮合劑(例如，1,3-二環己基碳化二亞胺(DCC)、1-乙基-3-[3-(二甲胺基)丙基]碳化二亞胺(EDC)、1,1'-羰基二咪唑(CDI)、2-氯-1-甲基吡啶鎓碘化物或1-丙烷磷酸環酐(PPA))在存在或不存在1-羥基苯并***(HOBt)之情況下在約0至40℃下反應來進行。(3) The method of using a condensing agent can be, for example, by making a carboxylic acid and an amine in an organic solvent (for example, chloroform, dichloromethane, dimethylformamide, diethyl ether or tetrahydrofuran) or in the absence of a solvent , using a condensing agent (eg, 1,3-dicyclohexylcarbodiimide (DCC) in the presence or absence of a base (eg, pyridine, triethylamine, dimethylaniline, or dimethylaminopyridine) , 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC), 1,1'-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium The iodide or 1-propanephosphoric acid cyclic anhydride (PPA)) is reacted in the presence or absence of 1-hydroxybenzotriazole (HOBt) at about 0 to 40°C.

(1)、(2)及(3)中所描述之反應可在惰性氣體(例如，氬氣、氮氣)下進行以避免水以便獲得較佳結果。The reactions described in (1), (2) and (3) can be performed under an inert gas (eg, argon, nitrogen) to avoid water for better results.

由通式(III)表示之化合物可藉由使由通式(II)表示之化合物經受胺基之保護基之去保護反應來產生。 通式(II)中之P表示胺基之保護基。 P包括諸如苯甲氧羰基(Z)、三級丁氧基羰基(Boc)、烯丙氧基羰基(Alloc)、1-甲基-1-(4-聯二苯)乙氧羰基(Bpoc)、三氟乙醯基、9-茀基甲氧基羰基(Fmoc)、苯甲基(Bn)、對甲氧基苯甲基、苯甲氧基甲基(BOM)或2-(三甲基矽烷基)乙氧基甲基(SEM)等。 The compound represented by the general formula (III) can be produced by subjecting the compound represented by the general formula (II) to a deprotection reaction of the protecting group of the amine group. P in the general formula (II) represents a protecting group for an amine group. P includes such as benzyloxycarbonyl (Z), tertiary butoxycarbonyl (Boc), allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) , trifluoroacetyl, 9-fenylmethoxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl, benzyloxymethyl (BOM) or 2-(trimethyl silyl) ethoxymethyl (SEM), etc.

胺基之保護基之去保護反應可藉由每一保護基之適合條件進行。 舉例而言，三級丁氧基羰基(Boc)之去保護可利用酸性試劑(例如，HCl/二㗁烷、TFA或MsOH)在溶劑(例如，二㗁烷或二氯甲烷)中在0℃至40℃下進行。 舉例而言，苯甲氧羰基(Z)之去保護可藉由諸如氫及催化Pd-C之氫化條件在溶劑(例如，MeOH或EtOH等)中在20℃至60℃下進行。 The deprotection reaction of the protecting group of the amine group can be carried out by suitable conditions for each protecting group. For example, deprotection of the tertiary butoxycarbonyl (Boc) group can be accomplished using an acidic reagent (e.g., HCl/dioxane, TFA, or MsOH) in a solvent (e.g., dioxane or dichloromethane) at 0°C to 40°C. For example, deprotection of benzyloxycarbonyl (Z) can be performed by hydrogenation conditions such as hydrogen and catalytic Pd-C in a solvent (eg, MeOH or EtOH, etc.) at 20°C to 60°C.

胺基之保護基之去保護反應為熟知的且充分描述於T. W. Greene, Protective Groups in Organic Synthesis, 約翰威利(Wiley), 紐約, 1999中。 Deprotection reactions of protecting groups for amine groups are well known and fully described in TW Greene, Protective Groups in Organic Synthesis , John Wiley, New York, 1999.

其中方案I中之通式(II)中之R ¹表示： 及 通式(II)可描述為方案II中之通式(II)-1。 Wherein ^R in the general formula (II) in scheme I represents: And general formula (II) can be described as general formula (II)-1 in scheme II.

由通式(II)-1表示之化合物可藉由使由通式(VII)表示之化合物及由通式(VIII)表示之化合物經受異㗁唑啉環化反應來產生。The compound represented by the general formula (II)-1 can be produced by subjecting the compound represented by the general formula (VII) and the compound represented by the general formula (VIII) to an isoazoline cyclization reaction.

異㗁唑啉環化反應可利用鹼(例如，三甲胺或DIPEA)及溶劑(例如，DMF等)在0℃至80℃下進行。 由通式(VII)表示之化合物可藉由使由通式(VI)表示之化合物經受氯化反應來產生。 The isoxazoline cyclization reaction can be carried out at 0°C to 80°C using a base (eg, trimethylamine or DIPEA) and a solvent (eg, DMF, etc.). The compound represented by the general formula (VII) can be produced by subjecting the compound represented by the general formula (VI) to a chlorination reaction.

氯化反應可利用氯化試劑(例如，N-氯丁二醯亞胺)在溶劑(例如，DMF等)中在約0℃至40℃下進行。 由通式(VI)表示之化合物可藉由使由通式(V)表示之化合物經受肟形成反應來產生。 The chlorination reaction can be performed at about 0°C to 40°C using a chlorination reagent (eg, N-chlorobutadiimide) in a solvent (eg, DMF, etc.). The compound represented by the general formula (VI) can be produced by subjecting the compound represented by the general formula (V) to an oxime forming reaction.

肟形成反應可利用鹽酸羥胺、乙酸鉀及乙酸在溶劑(例如，EtOH等)中在約20℃至40℃下進行。The oxime formation reaction can be performed using hydroxylamine hydrochloride, potassium acetate, and acetic acid in a solvent (eg, EtOH, etc.) at about 20°C to 40°C.

其中方案I中之通式(II)中之R ¹表示 及 通式(II)可描述為方案III中之通式(II)-2。 Wherein ^R in the general formula (II) in scheme I represents And general formula (II) can be described as general formula (II)-2 in scheme III.

由通式(II)-2表示之化合物可藉由使由通式(IX)表示之化合物及由通式(X)表示之化合物經受醯胺化反應來產生。The compound represented by the general formula (II)-2 can be produced by subjecting the compound represented by the general formula (IX) and the compound represented by the general formula (X) to amidation reaction.

醯胺化可藉由上文針對方案I中之通式(I)之製備所描述之相同方法來進行。 由通式(II)-2表示之化合物可藉由使由通式(XII)表示之化合物及由通式(XIII)表示之化合物經受烷基化反應來產生。 Amidation can be performed by the same methods described above for the preparation of general formula (I) in Scheme I. The compound represented by the general formula (II)-2 can be produced by subjecting the compound represented by the general formula (XII) and the compound represented by the general formula (XIII) to an alkylation reaction.

烷基化反應可利用鹼(例如，氫化鈉、氫化鉀、氫化鋰、甲醇鈉、乙醇鈉、三級丁醇鉀、丁基鋰、LDA、LHMDS、NaHMDS、KHMDS等)在溶劑(例如，THF、DMF、DMA、二***等)中在-78℃至40℃下進行。Alkylation reaction can utilize base (for example, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium ethoxide, potassium tertiary butoxide, butyllithium, LDA, LHMDS, NaHMDS, KHMDS etc.) in solvent (for example, THF , DMF, DMA, diethyl ether, etc.) at -78°C to 40°C.

由通式(XII)表示之化合物可藉由使由通式(IX)表示之化合物及由通式(XI)表示之化合物經受醯胺化反應來產生。The compound represented by the general formula (XII) can be produced by subjecting the compound represented by the general formula (IX) and the compound represented by the general formula (XI) to amidation reaction.

醯胺化可藉由上文針對方案I中之通式(I)之製備所描述之相同方法來進行。Amidation can be performed by the same methods described above for the preparation of general formula (I) in Scheme I.

其中方案I中之通式(II)中之R ¹表示 及 通式(II)可描述為方案IV中之通式(II)-3。 Wherein ^R in the general formula (II) in scheme I represents And general formula (II) can be described as general formula (II)-3 in scheme IV.

由通式(II)-3表示之化合物可藉由使由通式(XV)表示之化合物經受羥基之氧化反應來產生。The compound represented by the general formula (II)-3 can be produced by subjecting the compound represented by the general formula (XV) to an oxidation reaction of a hydroxyl group.

羥基之氧化為已知的。舉例而言，其包括以下方法 (1)    戴斯-馬丁(Dess-Martin)氧化 (2)    DMSO氧化 (3)鉻試劑氧化。 Oxidation of hydroxyl groups is known. For example, it includes the following methods (1) Dess-Martin oxidation (2) DMSO oxidation (3) Chromium reagent oxidation.

此等方法解釋如下。 (1)    戴斯-馬丁氧化之方法可利用戴斯-馬丁高碘烷在溶劑(例如二氯甲烷)中在0℃至40℃下進行。 (2)    DMSO氧化之方法可利用DMSO及其活化劑(例如，乙二醯氯、亞硫醯氯或三氧化硫吡啶鎓複合物等)及鹼(例如三甲胺或DIPEA等)在-78℃至40℃下進行。 (3)    鉻試劑氧化之方法利用鉻氧化劑(例如PCC或PDC)在溶劑(例如二氯甲烷)中在-20℃至40℃下進行。 These methods are explained below. (1) The method of Dess-Martin oxidation can be performed at 0°C to 40°C in a solvent (such as dichloromethane) using Dess-Martin periodinane. (2) The method of DMSO oxidation can use DMSO and its activators (for example, acetyl chloride, thionyl chloride or sulfur trioxide pyridinium complex, etc.) and alkali (such as trimethylamine or DIPEA, etc.) at -78 ° C to 40°C. (3) The method of chromium reagent oxidation utilizes chromium oxidant (such as PCC or PDC) in a solvent (such as dichloromethane) at -20°C to 40°C.

由通式(XV)表示之化合物可藉由使由通式(V)表示之化合物及由通式(XIV)表示之化合物經受加成反應來產生。 其中通式(XIV)中之M表示金屬(例如，Li、Na或K)或金屬鹵化物(MgCl、MgBr、MgI、ZnCl、ZnBr或ZnI)。 The compound represented by general formula (XV) can be produced by subjecting the compound represented by general formula (V) and the compound represented by general formula (XIV) to an addition reaction. Wherein M in the general formula (XIV) represents a metal (for example, Li, Na or K) or a metal halide (MgCl, MgBr, MgI, ZnCl, ZnBr or ZnI).

加成反應可在溶劑(例如，THF)中在-78℃至0℃下在惰性氛圍(例如，乾燥氮氣或氬氣)下進行。The addition reaction can be performed in a solvent (eg, THF) at -78°C to 0°C under an inert atmosphere (eg, dry nitrogen or argon).

其中方案I中之通式(II)中之R ¹表示 ，及 通式(II)可描述為方案V中之通式(II)-4及(II)-4a。 Wherein ^R in the general formula (II) in scheme I represents , and general formula (II) can be described as general formula (II)-4 and (II)-4a in scheme V.

由通式(II)-4表示之化合物可藉由使由通式(VII)表示之化合物及由通式(XVI)表示之化合物經受異㗁唑環化反應來產生。The compound represented by the general formula (II)-4 can be produced by subjecting the compound represented by the general formula (VII) and the compound represented by the general formula (XVI) to an isoxazole cyclization reaction.

異㗁唑環化反應可利用鹼(例如三甲胺等)在溶劑(例如二氯甲烷等)中在-20℃至40℃下進行。The isoxazole cyclization reaction can be performed at -20°C to 40°C using a base (eg, trimethylamine, etc.) in a solvent (eg, dichloromethane, etc.).

由通式(II)-4a表示之化合物可藉由使由通式(XVII)表示之化合物及由通式(XVIII)表示之化合物經受偶合反應來產生。The compound represented by the general formula (II)-4a can be produced by subjecting the compound represented by the general formula (XVII) and the compound represented by the general formula (XVIII) to a coupling reaction.

偶合反應為熟知的且可藉由例如在有機溶劑(實例：苯、甲苯、二甲基甲醯胺、1,4-二㗁烷、四氫呋喃、甲醇、乙腈、二甲氧基乙烷、丙酮或其混合溶劑)中利用鹼(實例：乙醇化鈉、氫氧化鈉、氫氧化鉀、三乙胺、碳酸鈉、碳酸氫鈉、碳酸鉀、碳酸銫、碳酸鉈、磷酸三鉀、氟化銫、氫氧化鋇、氟化四丁銨及其類似者)或其水溶液或其混合物在存在催化劑(實例：雙(二-三級丁基(4-二甲胺基苯基)膦)二氯鈀(II) ((A-taPhos) ₂PdCl ₂)、四(三苯基膦)鈀(Pd(PPh ₃) ₄)、雙(三苯膦)鈀二氯化物(PdCl ₂(PPh ₃) ₂)、乙酸鈀(Pd(OAc) ₂)、鈀黑、1,1'-雙(二苯基膦基二茂鐵)二氯鈀(PdCl ₂(dppf) ₂)、二烯丙基鈀二氯化物(PdCl ₂(烯丙基) ₂)、碘苯基雙(三苯膦)鈀(PhPdI(PPh ₃) ₂)及其類似者)之情況下在室溫至150℃下的反應來進行。 Coupling reactions are well known and can be carried out, for example, in organic solvents (examples: benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone or Its mixed solvent) using alkali (example: sodium alcoholate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, Barium hydroxide, tetrabutylammonium fluoride and the like) or an aqueous solution thereof or a mixture thereof in the presence of a catalyst (example: bis(di-tertiary butyl(4-dimethylaminophenyl)phosphine) dichloropalladium ( II) ((A-taPhos) ₂ PdCl ₂ ), tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), bis(triphenylphosphine)palladium dichloride (PdCl ₂ (PPh ₃ ) ₂ ), Palladium acetate (Pd(OAc) ₂ ), palladium black, 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl ₂ (dppf) ₂ ), diallylpalladium dichloride ( The reaction in the case of PdCl ₂ (allyl) ₂ ), iodophenylbis(triphenylphosphine)palladium (PhPdI(PPh ₃ ) ₂ ) and the like) is carried out at room temperature to 150°C.

由通式(XVII)表示之化合物可藉由使由通式(II)-4表示之化合物經受溴化反應來產生。The compound represented by the general formula (XVII) can be produced by subjecting the compound represented by the general formula (II)-4 to a bromination reaction.

溴化反應可利用溴化試劑(例如，NBS或溴等)在溶劑(例如DMF等)中在-20℃至40℃下進行。The bromination reaction can be performed at -20°C to 40°C using a bromination reagent (eg, NBS or bromine, etc.) in a solvent (eg, DMF, etc.).

其中方案I中之通式(II)中之R ¹表示 及 通式(II)可描述為方案VI中之通式(II)-5。 Wherein ^R in the general formula (II) in scheme I represents And general formula (II) can be described as general formula (II)-5 in scheme VI.

由通式(II)-5表示之化合物可藉由使由通式(VII)表示之化合物及由通式(XIX)表示之化合物經受1,2,4-㗁二唑啉環化反應來產生。The compound represented by the general formula (II)-5 can be produced by subjecting the compound represented by the general formula (VII) and the compound represented by the general formula (XIX) to a 1,2,4-oxadiazoline cyclization reaction .

1,2,4-㗁二唑啉環化反應可利用鹼(例如三甲胺等)在溶劑(例如THF、甲苯或DMF等)中在0℃至40℃下進行。The cyclization reaction of 1,2,4-oxadiazoline can be carried out at 0°C to 40°C in a solvent (such as THF, toluene, or DMF) with a base (such as trimethylamine, etc.).

其中方案I中之通式(II)中之R ¹表示 及 通式(II)可描述為方案VII中之通式(II)-6。 Wherein ^R in the general formula (II) in scheme I represents And general formula (II) can be described as general formula (II)-6 in scheme VII.

由通式(II)-6表示之化合物可藉由使由通式(XXII)表示之化合物經受1,3,4-㗁二唑環化反應來產生。The compound represented by the general formula (II)-6 can be produced by subjecting the compound represented by the general formula (XXII) to a 1,3,4-oxadiazole cyclization reaction.

1,3,4-㗁二唑環化反應可利用脫水劑(例如，POCl ₃等)在80℃至120℃下進行。 由通式(XXII)表示之化合物可藉由使由通式(XX)表示之化合物及由通式(XXI)-1或(XXI)-2表示之化合物經受醯胺化反應來產生。 The cyclization reaction of 1,3,4-oxadiazole can be carried out at 80°C to 120°C using a dehydrating agent (for example, POCl _{3 ,} etc.). The compound represented by general formula (XXII) can be produced by subjecting the compound represented by general formula (XX) and the compound represented by general formula (XXI)-1 or (XXI)-2 to amidation reaction.

醯胺化可藉由上文針對方案I中之通式(I)之製備所描述之相同方法來進行。 由通式(XX)表示之化合物可藉由使由通式(IX)表示之化合物經受醯胺化反應來產生。 醯胺化可藉由上文針對方案I中之通式(I)之製備所描述之相同方法來進行。 Amidation can be performed by the same methods described above for the preparation of general formula (I) in Scheme I. The compound represented by the general formula (XX) can be produced by subjecting the compound represented by the general formula (IX) to amidation reaction. Amidation can be performed by the same methods described above for the preparation of general formula (I) in Scheme I.

其中方案I中之通式(II)中之R ¹表示 及 通式(II)可描述為方案VIII中之通式(II)-7。 Wherein ^R in the general formula (II) in scheme I represents And general formula (II) can be described as general formula (II)-7 in scheme VIII.

由通式(II)-7表示之化合物可藉由使由通式(II)-6表示之化合物及由通式(XXIII)表示之化合物經受替代反應來產生。The compound represented by general formula (II)-7 can be produced by subjecting the compound represented by general formula (II)-6 and the compound represented by general formula (XXIII) to substitution reaction.

替代反應可利用酸性催化劑(例如，TsOH等)在溶劑(例如，二甲苯等)中在120℃至150℃下進行。 由通式(II)-7表示之化合物可藉由使由通式(XXIV)表示之化合物及由通式(XXIII)表示之化合物經受1,3,4-***環化反應來產生。 1,3,4-***環化反應可利用乙酸在0℃至100℃下進行。 由通式(XXIV)表示之化合物可藉由使由通式(XX)表示之化合物經受亞肼基甲醯胺形成反應來產生。 Alternative reactions may be performed at 120°C to 150°C using an acidic catalyst (eg, TsOH, etc.) in a solvent (eg, xylene, etc.). The compound represented by the general formula (II)-7 can be produced by subjecting the compound represented by the general formula (XXIV) and the compound represented by the general formula (XXIII) to a 1,3,4-triazole cyclization reaction. The cyclization reaction of 1,3,4-triazole can be carried out at 0°C to 100°C using acetic acid. The compound represented by the general formula (XXIV) can be produced by subjecting the compound represented by the general formula (XX) to a hydrazinoformamide forming reaction.

亞肼基甲醯胺形成反應可利用1,1-二甲氧基-N,N-二甲基甲胺在溶劑(例如，乙腈或DMF等)中在100℃至120℃下進行。The hydrazonoformamide formation reaction can be performed at 100°C to 120°C in a solvent (for example, acetonitrile or DMF, etc.) using 1,1-dimethoxy-N,N-dimethylmethylamine.

其中方案I中之通式(II)中之R ¹表示 及 通式(II)可描述為方案IX中之通式(II)-8。 Wherein ^R in the general formula (II) in scheme I represents And general formula (II) can be described as general formula (II)-8 in scheme IX.

由通式(II)-8表示之化合物可藉由使由通式(XXVI)表示之化合物經受脫水四唑環化反應來產生。 脫水四唑環化反應可利用Tf ₂O及TMSN ₃在溶劑(例如，二氯甲烷等)中在0℃至30℃下進行。 The compound represented by general formula (II)-8 can be produced by subjecting the compound represented by general formula (XXVI) to anhydrotetrazole cyclization reaction. The anhydrous tetrazole cyclization reaction can be carried out at 0°C to 30°C in a solvent (eg, dichloromethane, etc.) using Tf ₂ O and TMSN ₃ .

由通式(XXVI)表示之化合物可藉由使由通式(IX)表示之化合物及由通式(XXV)表示之化合物經受醯胺化反應來產生。 醯胺化可藉由上文針對方案I中之通式(I)之製備所描述之相同方法來進行。 其中R ¹²表示H，由通式(II)-8表示之化合物可藉由使由通式(XXVIII)表示之化合物經受四唑環化反應來產生。 四唑環化反應可利用NaN ₃及NH ₄Cl在溶劑(例如，DMF等)中在100℃至140℃下進行。 The compound represented by the general formula (XXVI) can be produced by subjecting the compound represented by the general formula (IX) and the compound represented by the general formula (XXV) to an amidation reaction. Amidation can be performed by the same methods described above for the preparation of general formula (I) in Scheme I. Wherein R ¹² represents H, the compound represented by the general formula (II)-8 can be produced by subjecting the compound represented by the general formula (XXVIII) to a tetrazole cyclization reaction. The tetrazole cyclization reaction can be performed using NaN ₃ and NH ₄ Cl in a solvent (eg, DMF, etc.) at 100°C to 140°C.

由通式(XXVIII)表示之化合物可藉由使由通式(XXVII)表示之化合物經受腈形成反應來產生。 腈形成反應可利用脫水劑(例如，三聚氯化氰、亞硫醯氯或P ₂O ₅等)在溶劑(例如，DMF、苯、甲苯或二甲苯等)中在100℃至140℃下進行。 The compound represented by general formula (XXVIII) can be produced by subjecting the compound represented by general formula (XXVII) to a nitrile forming reaction. The nitrile formation reaction can utilize a dehydrating agent (for example, cyanuric chloride, thionyl chloride or _P2O5 , etc.) in a solvent (for example, DMF, benzene, toluene or _xylene , etc.) at 100 ° C to 140 ° C conduct.

由通式(XXVII)表示之化合物可藉由使由通式(IX)表示之化合物及氨經受醯胺化反應來產生。 醯胺化可藉由上文針對方案I中之通式(I)之製備所描述之相同方法來進行。 The compound represented by the general formula (XXVII) can be produced by subjecting the compound represented by the general formula (IX) and ammonia to amidation reaction. Amidation can be performed by the same methods described above for the preparation of general formula (I) in Scheme I.

其中方案I中之通式(II)中之R ¹表示 及， 通式(II)可描述如方案X中之通式(II)-9。 Wherein ^R in the general formula (II) in scheme I represents And, general formula (II) can be described as general formula (II)-9 in scheme X.

由通式(II)-9表示之化合物可藉由使由通式(XXX)表示之化合物經受[1,2,4]***并[4,3-a]吡啶環化反應來產生。 [1,2,4]***并[4,3-a]吡啶環化反應可利用柏傑士(Burgess)試劑在溶劑(例如，乙腈等)中在100℃至140℃下進行。 The compound represented by the general formula (II)-9 can be produced by subjecting the compound represented by the general formula (XXX) to a [1,2,4]triazolo[4,3-a]pyridine cyclization reaction. The [1,2,4]triazolo[4,3-a]pyridine cyclization reaction can be carried out at 100°C to 140°C in a solvent (eg, acetonitrile, etc.) using Burgess reagent.

由通式(XXX)表示之化合物可藉由使由通式(IX)表示之化合物及由通式(XXIX)表示之化合物經受醯胺化反應來產生。 醯胺化可藉由上文針對方案I中之通式(I)之製備所描述之相同方法來進行。 The compound represented by the general formula (XXX) can be produced by subjecting the compound represented by the general formula (IX) and the compound represented by the general formula (XXIX) to an amidation reaction. Amidation can be performed by the same methods described above for the preparation of general formula (I) in Scheme I.

其中方案I中之通式(II)中之R ¹表示 及 通式(II)可描述為方案IX中之通式(II)-10。 Wherein ^R in the general formula (II) in scheme I represents And general formula (II) can be described as general formula (II)-10 in scheme IX.

由通式(II)-10表示之化合物可藉由使由通式(XXXIII)表示之化合物經受[1,2,3]***并[1,5-a]吡啶環化反應來產生。 [1,2,4]***并[4,3-a]吡啶環化反應可利用水合肼在50℃至70℃下進行，繼之以乙酸銅在溶劑(例如，乙酸乙酯等)中在20℃至40℃下之處理。 The compound represented by the general formula (II)-10 can be produced by subjecting the compound represented by the general formula (XXXIII) to a [1,2,3]triazolo[1,5-a]pyridine cyclization reaction. The cyclization reaction of [1,2,4]triazolo[4,3-a]pyridine can be carried out using hydrazine hydrate at 50°C to 70°C, followed by copper acetate in a solvent (e.g., ethyl acetate, etc.) Processing at 20°C to 40°C.

由通式(XXXIII)表示之化合物可藉由使由通式(XXXII)表示之化合物經受羥基之氧化反應來產生。 羥基之氧化反應可藉由上文針對方案IV中之通式(II)-3之製備所描述之相同方法進行。 The compound represented by the general formula (XXXIII) can be produced by subjecting the compound represented by the general formula (XXXII) to an oxidation reaction of a hydroxyl group. The oxidation reaction of the hydroxyl group can be carried out by the same method described above for the preparation of general formula (II)-3 in Scheme IV.

由通式(XXXII)表示之化合物可藉由使由通式(V)表示之化合物及由通式(XXXI)表示之化合物經受加成反應來產生。 加成反應可藉由上文針對方案IV中之通式(XV)之製備所描述之相同方法進行。 The compound represented by general formula (XXXII) can be produced by subjecting the compound represented by general formula (V) and the compound represented by general formula (XXXI) to an addition reaction. The addition reaction can be performed by the same methods described above for the preparation of general formula (XV) in Scheme IV.

其中由通式(IV)、(VIII)、(X)、(XI)、(XIII)、(XIV)、(XVI)、(XVIII)、(XIX)、(XXI)-1、(XXI)-2、(XXIII)、(XXV)、(XXVII)、(XXIX)及(XXXI)表示之化合物可為可商購的，或藉由(例如)綜合有機變換：官能基製備指南, 第2版(Richard C. Larock, 約翰威利公司, 1999)中描述的熟知方法及其類似者由商業化學品容易地製備。Wherein by general formula (IV), (VIII), (X), (XI), (XIII), (XIV), (XVI), (XVIII), (XIX), (XXI)-1, (XXI)- 2. Compounds represented by (XXIII), (XXV), (XXVII), (XXIX) and (XXXI) may be commercially available, or obtained by, for example, Comprehensive Organic Transformations: A Guide to the Preparation of Functional Groups, 2nd Edition ( The well-known method described in Richard C. Larock, John Wiley Company, 1999) and its analogues are readily prepared from commercial chemicals.

其中由通式(V)表示之化合物可為可商購的或藉由方案XII中描述之方法來製備。Wherein the compound represented by the general formula (V) can be commercially available or prepared by the method described in Scheme XII.

其中由通式(V)表示之化合物可藉由使由通式(XXXIX)表示之化合物經受羥基之氧化反應來產生。 Among them, the compound represented by the general formula (V) can be produced by subjecting the compound represented by the general formula (XXXIX) to an oxidation reaction of a hydroxyl group.

羥基之氧化反應可藉由上文針對方案IV中之通式(II)-3之製備所描述之相同方法進行。The oxidation reaction of the hydroxyl group can be carried out by the same method described above for the preparation of general formula (II)-3 in Scheme IV.

由通式(XXXIX)表示之化合物可藉由使由通式(XXXVIII)表示之化合物經受保護交換反應來產生。 保護交換反應可利用氫氣、Pd催化劑(例如，Pd-C或Pd(OH) _2-C等)及於溶劑(例如，MeOH、EtOH或THF等)中之(Boc) ₂O在20℃至40℃下進行。 The compound represented by the general formula (XXXIX) can be produced by subjecting the compound represented by the general formula (XXXVIII) to a protection exchange reaction. The protection exchange reaction can use hydrogen, Pd catalyst (for example, Pd-C or Pd(OH) _2-C , etc.) and (Boc) ₂ O in solvent (for example, MeOH, EtOH or THF, etc.) at 20 ℃ to 40 at ℃.

由通式(XXXVIII)表示之化合物可藉由使由通式(XXXVII)表示之化合物經受酯還原反應來產生。 酯還原反應可利用於溶劑(例如，THF、二***或DME等)中之還原劑(例如，LiAlH ₄、DIBAL-H、紅Al等)在-20℃至20℃下進行。 The compound represented by the general formula (XXXVIII) can be produced by subjecting the compound represented by the general formula (XXXVII) to an ester reduction reaction. The ester reduction reaction can be carried out at -20°C to 20°C using a reducing agent (eg, LiAlH ₄ , DIBAL-H, red Al, etc.) in a solvent (eg, THF, diethyl ether, or DME, etc.).

由通式(XXXVII)表示之化合物可藉由使由通式(XXXVIII)表示之化合物經受醯亞胺還原反應來產生。 醯亞胺還原反應可利用於溶劑(例如，THF、二***或DME等)中之硼烷還原劑(例如，BH ₃THF、BH ₃Me ₂S或B ₂H ₆等)在20℃至80℃下進行。 The compound represented by the general formula (XXXVII) can be produced by subjecting the compound represented by the general formula (XXXVIII) to an imide reduction reaction. The imide reduction reaction can be carried out with borane reducing agent (for example, BH ₃ THF, BH ₃ Me ₂ S or B ₂ H ₆ , etc.) in solvent (for example, THF, diethyl ether or DME, etc.) at 20°C to 80°C at ℃.

由通式(XXXVII)表示之化合物可藉由使由通式(XXXV)表示之化合物及由通式(XXXVI)表示之化合物經受環丙烷化反應來產生。 環丙烷化反應可利用於溶劑(例如，二㗁烷等)中之MnO ₂在20℃至100℃下進行。 The compound represented by general formula (XXXVII) can be produced by subjecting the compound represented by general formula (XXXV) and the compound represented by general formula (XXXVI) to a cyclopropanation reaction. The cyclopropanation reaction can be performed at 20°C to 100°C using MnO ₂ in a solvent (eg, dioxane, etc.).

由通式(XXXV)表示之化合物可藉由使由通式(XXXIV)表示之化合物經受腙形成反應來產生。 腙形成反應可利用水合肼及乙酸水溶液在0℃至40℃下進行。 The compound represented by the general formula (XXXV) can be produced by subjecting the compound represented by the general formula (XXXIV) to a hydrazone forming reaction. The hydrazone formation reaction can be carried out using hydrazine hydrate and acetic acid aqueous solution at 0°C to 40°C.

其中由通式(XXXIV)及(XXXVI)表示之化合物可為可商購的，或藉由(例如)綜合有機變換：官能基製備指南, 第2版(Richard C. Larock, 約翰威利公司, 1999)中所描述之熟知方法及其類似者由商業化學品容易地製備。Wherein compounds represented by general formulas (XXXIV) and (XXXVI) are either commercially available or obtained by, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparation, 2nd Edition (Richard C. Larock, The John Wiley Company, 1999) and their analogues are readily prepared from commercial chemicals.

在本文中所例示之反應中，可使用任何加熱方式，諸如水浴、油浴、砂浴及微波。In the reactions exemplified herein, any heating means can be used, such as water bath, oil bath, sand bath, and microwave.

在本文中所例示之反應中，若適宜，則可使用支撐於聚合物(諸如聚苯乙烯、聚丙烯醯胺、聚丙烯及聚乙二醇)上之固相支撐試劑。In the reactions exemplified herein, solid phase supported reagents supported on polymers such as polystyrene, polyacrylamide, polypropylene and polyethylene glycol may be used, if appropriate.

來自本文中所例示之反應之產品可藉由習知純化方式或藉由洗滌或再結晶來純化，該習知純化方式例如在常壓或減壓下蒸餾、使用矽膠、離子交換樹脂、清除劑樹脂或矽酸鎂之層析法(諸如高效液相層析法、薄層層析法或管柱層析法)。純化可在每一反應步驟之後或在一連串反應之後進行。 [毒性] Products from the reactions exemplified herein can be purified by conventional purification means such as distillation at atmospheric or reduced pressure, use of silica gel, ion exchange resins, scavengers, or by washing or recrystallization. Resin or magnesium silicate chromatography (such as high performance liquid chromatography, thin layer chromatography or column chromatography). Purification can be performed after each reaction step or after a series of reactions. [toxicity]

本發明化合物具有低毒性且因此包含本發明化合物之醫藥組合物可安全地用作藥劑。 [藥劑之應用] The compound of the present invention has low toxicity and thus a pharmaceutical composition comprising the compound of the present invention can be safely used as a medicament. [Application of medicine]

本發明化合物具有KDM5抑制活性，且因此可用作針對哺乳動物中(特定而言，人類中)之KDM5相關疾病之預防劑及/或治療劑。本發明提供包含本發明化合物的醫藥組合物(下文中統稱為本發明醫藥組合物)，且因此本發明醫藥組合物可用作用於預防及/或治療(哺乳動物中，特定言之人類中的) KDM5相關疾病的製劑。The compound of the present invention has KDM5 inhibitory activity, and thus is useful as a preventive and/or therapeutic agent for KDM5-related diseases in mammals, in particular, humans. The present invention provides a pharmaceutical composition comprising the compound of the present invention (hereinafter collectively referred to as the pharmaceutical composition of the present invention), and thus the pharmaceutical composition of the present invention can be used for prophylaxis and/or treatment (in mammals, in particular in humans) Preparations for KDM5-associated diseases.

此類疾病之實例包括過度增生性疾病、癌症、中風、糖尿病、肝腫大、心血管疾病、多發性硬化症、亨廷頓氏病、阿茲海默症、囊腫纖維化、病毒性疾病、自身免疫疾病、動脈粥樣硬化、再狹窄、牛皮癬、類風濕性關節炎、發炎性腸道疾病、哮喘、過敏性病症、炎症、神經病症、激素相關疾病、與器官移植相關聯之病況、免疫缺乏症、破壞性骨症、增生性病症、傳染性疾病、與細胞死亡相關聯之病況、凝血酶誘發之血小板凝集、肝臟疾病、涉及T細胞活化之病理性免疫病況、CNS病症、骨髓增生性病症、帕金森氏症、路易體疾病、額顳葉退化、輕度認知障礙、認知障礙、腦血管疾病、精神***症、抑鬱、焦慮症、躁鬱症、泛自閉症障礙、注意力缺乏/過動症、學習障礙、運動障礙、強迫症、人格障礙、睡眠障礙、譫妄、肌萎縮性脊髓側索硬化症、發育障礙、智能障礙、創傷後壓力症及肝炎及其類似者。Examples of such diseases include hyperproliferative diseases, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Huntington's disease, Alzheimer's disease, cystic fibrosis, viral diseases, autoimmunity Diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic conditions, inflammation, neurological conditions, hormone-related diseases, conditions associated with organ transplantation, immunodeficiency , destructive bone disease, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, pathological immune conditions involving T cell activation, CNS disorders, myeloproliferative disorders, Parkinson's disease, Lewy body disease, frontotemporal lobar degeneration, mild cognitive impairment, cognitive impairment, cerebrovascular disease, schizophrenia, depression, anxiety, bipolar disorder, autism spectrum disorder, attention deficit/hyperactivity disorders, learning disabilities, movement disorders, obsessive-compulsive disorders, personality disorders, sleep disorders, delirium, amyotrophic lateral sclerosis, developmental disabilities, intellectual disabilities, post-traumatic stress disorder, and hepatitis and the like.

尤其，本發明化合物或本發明醫藥組合物對以下各者之預防及/或治療有用：癌症、亨廷頓氏病、阿茲海默症、帕金森氏症、路易體疾病、額顳葉退化、輕度認知障礙、認知障礙、腦血管疾病、精神***症、抑鬱、焦慮症、躁鬱症、泛自閉症障礙、注意力缺乏/過動症、學習障礙、運動障礙、強迫症、人格障礙、睡眠障礙、譫妄、肌萎縮性脊髓側索硬化症、發育障礙、智能障礙、創傷後壓力症或肝炎。本發明化合物或本發明醫藥組合物特定適合於預防及/或治療癌症及阿茲海默症。In particular, the compound of the present invention or the pharmaceutical composition of the present invention is useful for the prevention and/or treatment of cancer, Huntington's disease, Alzheimer's disease, Parkinson's disease, Lewy body disease, frontotemporal lobar degeneration, mild Cognitive impairment, cognitive impairment, cerebrovascular disease, schizophrenia, depression, anxiety disorder, bipolar disorder, autism spectrum disorder, attention deficit/hyperactivity disorder, learning disability, movement disorder, obsessive-compulsive disorder, personality disorder, sleep Disability, delirium, amyotrophic lateral sclerosis, developmental disability, intellectual disability, post-traumatic stress disorder, or hepatitis. The compounds of the present invention or the pharmaceutical compositions of the present invention are particularly suitable for the prevention and/or treatment of cancer and Alzheimer's disease.

除了具有強KDM5抑制活性之外，本發明化合物具有極佳代謝穩定性且可在高濃度下存在於大腦中。In addition to having strong KDM5 inhibitory activity, the compounds of the present invention have excellent metabolic stability and can be present in the brain at high concentrations.

用於評估本發明化合物之藥理學活性之測試方法的實例包括小鼠中之認知障礙之改善的評估系統。舉例而言，藉由本發明化合物改善認知障礙可藉由使用以下方法來評估。Examples of test methods for evaluating the pharmacological activity of the compounds of the present invention include an evaluation system for improvement of cognitive impairment in mice. For example, improvement of cognitive impairment by the compounds of the present invention can be evaluated by using the following method.

使用小鼠(16至23月齡雄性C57BL/6小鼠(日本查爾斯河實驗室公司(Charles River Laboratories Japan, Inc.)))。測試化合物及其媒劑每日一次經口投與歷時2週。此後，將藉由新穎物體識別(NOR)測試使用具有視訊攝影機之塑膠籠(ECON籠，CL-0107，345 mm * 403 mm * 177 mm，日本CLEA公司(CLEA Japan, Inc.))作為實驗設備來評估認知功能。評估執行於暗室中且光強度經調整為在實驗設備附近大致20 lux。為使動物適應評估環境，小鼠在試驗之開始之前至少1小時移動至評估室。研究將進行超過3天。對於在第1天適應實驗設備，小鼠置放於籠中且允許自由地移動10分鐘。在第2天之獲取試驗中，兩個相同物體(熟悉物體)置放於籠上且以相同方式執行10分鐘。兩個物體在平行於一個籠之長邊之線上相隔置放。物體與兩個鄰近表面之內壁之間的距離為10 cm。在第3天之測試試驗中，在獲取試驗中使用之物體中的一者由具有不同顏色及形狀之新穎物體替換，且動物以相同方式表現10分鐘。測試試驗在獲取試驗之後24小時(可接受範圍：23至25小時)開始。自測試試驗中記錄之視訊影像，量測每一物體之探索時間。自熟悉及新穎物體之探索時間，藉由以下等式計算總體探索時間與新穎物體識別比率。Mice (16- to 23-month-old male C57BL/6 mice (Charles River Laboratories Japan, Inc.)) were used. Test compounds and their vehicle were administered orally once daily for 2 weeks. Thereafter, a plastic cage with a video camera (ECON cage, CL-0107, 345 mm * 403 mm * 177 mm, CLEA Japan, Inc.) with a video camera will be used as an experimental device by the Novel Object Recognition (NOR) test to assess cognitive function. Evaluations were performed in a dark room with light intensity adjusted to approximately 20 lux near the experimental equipment. To acclimatize the animals to the assessment environment, the mice were moved to the assessment room at least 1 hour before the start of the test. The study will be conducted over 3 days. For acclimatization to the experimental equipment on day 1, mice were placed in cages and allowed to move freely for 10 minutes. In the acquisition test on day 2, two identical objects (familiar objects) were placed on the cage and performed in the same way for 10 minutes. Two objects are spaced apart on a line parallel to the long side of a cage. The distance between the object and the inner walls of two adjacent surfaces is 10 cm. In the test trial on day 3, one of the objects used in the acquisition trial was replaced by a novel object with a different color and shape, and the animals behaved in the same way for 10 minutes. The test trial started 24 hours (acceptable range: 23 to 25 hours) after the acquisition trial. The exploration time for each object was measured from the video images recorded during the test trials. From the exploration time of familiar and novel objects, the ratio of overall exploration time to novel object recognition was calculated by the following equation.

總體探索時間(秒) = 熟悉物體之探索時間 + 新穎物體之探索時間 識別指數(%) = 100 * (新穎物體之探索時間 / 總體探索時間) Total exploration time (seconds) = Exploration time of familiar objects + Exploration time of novel objects Recognition index (%) = 100 * (exploration time of novel objects / overall exploration time)

用於評估本發明化合物之藥理學活性之測試方法的實例包括細胞群落檢定及癌細胞中之細胞毒性分析。舉例而言，本發明化合物在癌細胞中之功效可藉由使用以下方法來評估。Examples of assays for assessing the pharmacological activity of compounds of the invention include cell population assays and cytotoxicity assays in cancer cells. For example, the efficacy of compounds of the invention in cancer cells can be assessed by using the following methods.

MCF-7、T47D及MBA-MB231人乳腺癌細胞購自具有認證之ATCC。細胞經培養至多10至12個傳代，隨後由來自早期傳代之細胞替換，自收集以後保持於液氮中。細胞在具有1%青黴素/鏈黴素、2 mM L-麩醯胺酸、10%先前未活化之胎牛血清之高葡萄糖杜貝克改良伊格爾培養基(DMEM)中堅持生長。細胞在37℃及5% CO ₂下維持於培養箱中且常規地傳代，移除DMEM、用PBS洗滌及使用適合量之胰蛋白酶/EDTA使其分離。 MCF-7, T47D and MBA-MB231 human breast cancer cells were purchased from certified ATCC. Cells were cultured for up to 10 to 12 passages, then replaced by cells from earlier passages and kept in liquid nitrogen since harvest. Cells were maintained in high glucose Dubecco's Modified Eagle's Medium (DMEM) with 1% penicillin/streptomycin, 2 mM L-glutamine, 10% previously unactivated fetal calf serum. Cells were maintained in an incubator at 37°C and 5% _CO2 and routinely passaged, DMEM removed, washed with PBS and detached using an appropriate amount of trypsin/EDTA.

對於細胞群落檢定，在用化合物處理之後一小時，使用設置為200 V及6 mA之MLG 300/6-D設備(Gilardoni)使細胞曝光於X射線，以便產生1cGy/s之等效吸收劑量。隨後，細胞經採集、計數且隨後稀釋於含有化合物之生長培養基中。根據細胞株之倍增時間及輻射劑量來一式四份接種適當細胞數目。在此接種之後二十四小時，具有化合物之培養基經新的DMEM替換且細胞隨後經培養14天(足夠時間以允許至少六次細胞***)。在此生長時期之後，細胞經PBS洗滌兩次且隨後固定且在室溫下經由0.3%亞甲基藍及80%乙醇所製成的適合量之溶液染色30 min。在用ddH2O洗滌細胞兩次之後，在比色模式中用ChemiDoc XRS+成像系統(伯瑞(Bio-Rad))描繪培養盤。使用存活分數來計算DMSO及化合物樣本之對X射線之輻射-劑量反應曲線。平板培養效率及存活分數計算如下： 平板培養效率 = 所計數集落之數目/所平板培養細胞之數目 存活分數 = 平板培養效率/假樣本之平板培養效率 For cell colony assays, cells were exposed to X-rays one hour after compound treatment using an MLG 300/6-D apparatus (Gilardoni) set at 200 V and 6 mA to produce an equivalent absorbed dose of 1 cGy/s. Cells are then harvested, counted and then diluted in growth medium containing compound. Inoculate the appropriate number of cells in quadruplicate according to the doubling time of the cell line and the radiation dose. Twenty-four hours after this inoculation, the medium with the compound was replaced with new DMEM and the cells were then cultured for 14 days (sufficient time to allow at least six cell divisions). After this growth period, cells were washed twice with PBS and then fixed and stained with an appropriate volume of 0.3% methylene blue and 80% ethanol for 30 min at room temperature. After washing the cells twice with ddH2O, the plates were profiled with the ChemiDoc XRS+ imaging system (Bio-Rad) in colorimetric mode. Radiation-dose response curves to X-rays for DMSO and compound samples were calculated using survival fractions. The plate culture efficiency and survival fraction were calculated as follows: Plating efficiency = number of counted colonies/number of plated cells Survival fraction = plating efficiency/plating efficiency of fake samples

對於細胞毒性分析，根據製造商說明書來使用細胞計數套組8 (#CK04，DOJINDO)。MCF-7 T47D或MDA-MB231細胞懸浮液(5000個細胞/100µL/孔)經分配於96孔培養盤中。在24小時之後，化合物或DMSO經添加於生長培養基中且隨後細胞經照射。照射後四十八小時，10 μL之CCK-8溶液經添加至培養盤之各孔且再次培養1小時。使用VICTOR2 1420讀取器(珀金埃爾默(Perkin Elmer))來讀取在450 nm下之吸收率。For cytotoxicity analysis, Cytometry Kit 8 (#CK04, DOJINDO) was used according to the manufacturer's instructions. MCF-7 T47D or MDA-MB231 cell suspensions (5000 cells/100 µL/well) were dispensed into 96-well culture dishes. After 24 hours, compound or DMSO was added to the growth medium and cells were then irradiated. Forty-eight hours after irradiation, 10 μL of CCK-8 solution was added to each well of the plate and incubated again for 1 hour. Absorbance at 450 nm was read using a VICTOR2 1420 reader (Perkin Elmer).

用於評估本發明化合物之藥理學活性之測試方法的實例包括對B型肝炎病毒抗原(HbsAg)之抑制之原代人肝細胞(PHH)分析。舉例而言，本發明化合物在PHH分析中之功效可藉由使用以下方法來評估。Examples of assays for assessing the pharmacological activity of compounds of the invention include primary human hepatocyte (PHH) assays for inhibition of hepatitis B virus antigen (HbsAg). For example, the efficacy of compounds of the invention in PHH assays can be assessed by using the following methods.

原代人肝細胞(PHH) (拜歐克萊門IVT (Bioreclamation IVT))使用含有補充有1%青黴素/鏈黴素、4 pg/mL人重組胰島素、2 mM GlutaMAX、15 mM HEPES、1μM***、5%胎牛血清及0.2%抗生素混合物之威廉姆斯培養基E (William's Medium E)之平板培養培養基(生命科技(Life Technologies))來平板培養於塗佈膠原蛋白之燒瓶上。在37℃下之4小時培養之後，細胞經切換至含有補充有0.5%青黴素/鏈黴素、6.25 pg/mL人重組胰島素、6.25 pg/mL人轉鐵蛋白、6.25 ng/mL亞硒酸、1.25mg/mL牛血清白蛋白、5.35 pg/mL亞麻油酸、2 mM GlutaMAX、15 mM HEPES、0.1μM***、2%胎牛血清、2%DMSO及0.2%抗生素混合物之威廉姆斯培養基E之維持液(生命科學)。在次日，PHH在補充有4% PEG 8000 (普洛麥格(Promega))之維持液中經500基因組當量每細胞之基因型D (AD38衍生) HBV感染。在24小時培養之後，細胞經威廉姆斯培養基E洗滌三次且經饋送有新的維持液。在感染之後3天，經感染PHH細胞接種於在125 μΐ之維持液(生命科技)之最終體積中的含有化合物或DMSO之連續稀釋溶液(1%最終濃度)之在65000細胞每孔之密度下的預塗佈有膠原蛋白之96孔培養盤上。具有化合物之培養基每2至3天經補充。在12天之培養時間之後，使用多重化學發光(Mesoscale discovery，MSD)分析使用對HBsAg具有特異性之捕獲及偵測抗體對來量測上清液中之所分泌HBsAg。自劑量反應曲線與四參數方程式之擬合計算EC50值。Primary human hepatocytes (PHH) (Bioreclamation IVT) were prepared using a protein supplemented with 1% penicillin/streptomycin, 4 pg/mL human recombinant insulin, 2 mM GlutaMAX, 15 mM HEPES, 1 μM Plating culture medium (Life Technologies) of William's Medium E (William's Medium E) of dexamethasone, 5% fetal calf serum and 0.2% antibiotic mixture was used to plate culture on collagen-coated flasks. After 4 hours of incubation at 37°C, the cells were switched to cells supplemented with 0.5% penicillin/streptomycin, 6.25 pg/mL human recombinant insulin, 6.25 pg/mL human transferrin, 6.25 ng/mL selenite, 1.25mg/mL bovine serum albumin, 5.35 pg/mL linolenic acid, 2 mM GlutaMAX, 15 mM HEPES, 0.1 μM dexamethasone, 2% fetal bovine serum, 2% DMSO and 0.2% antibiotic mixture in Williams medium E maintenance solution (Life Science). On the next day, PHH were infected with 500 genome equivalents per cell of genotype D (AD38-derived) HBV in maintenance solution supplemented with 4% PEG 8000 (Promega). After 24 hours of culture, cells were washed three times with Williams medium E and fed with new maintenance solution. Three days after infection, infected PHH cells were seeded at a density of 65,000 cells per well in a final volume of 125 μl of maintenance solution (Life Technologies) containing serial dilutions of compound or DMSO (1% final concentration) 96-well plates pre-coated with collagen. Medium with compound was replenished every 2-3 days. After an incubation time of 12 days, secreted HBsAg was measured in the supernatant using a multiplex chemiluminescent (Mesoscale discovery, MSD) assay using a capture and detection antibody pair specific for HBsAg. EC50 values were calculated from the fit of dose response curves to a four parameter equation.

用於評估本發明化合物之藥理學活性之測試方法的實例包括社會挫敗應力模型中之抑鬱症狀之改善的評估系統。舉例而言，可藉由使用以下方法來評估社會挫敗模型中之本發明化合物之功效。Examples of test methods for evaluating the pharmacological activity of compounds of the present invention include an evaluation system for improvement of depressive symptoms in a social defeat stress model. For example, the efficacy of compounds of the invention in a social frustration model can be assessed by using the following method.

八週齡雄性DBA/2小鼠用於研究。社會挫敗應力經給定至小鼠。測試小鼠經置放於高度攻擊性CD-1小鼠籠中5分鐘。此時，CD-1小鼠將單方面地攻擊測試小鼠(身體應力)。在5分鐘之後，CD-1小鼠及測試小鼠藉由透明丙烯酸板分離且維持24小時(精神應力負擔)。此過程歷時5個連續日完成。在每日的社會挫敗應力之前2小時，經口給予該化合物或媒劑。此後，進行社會互動測試及蔗糖偏好測試。Eight-week-old male DBA/2 mice were used for the study. Social defeat stress was given to mice. Test mice were placed in highly aggressive CD-1 mouse cages for 5 minutes. At this point, the CD-1 mice will unilaterally challenge the test mice (physical stress). After 5 minutes, CD-1 mice and test mice were separated by transparent acrylic plates and maintained for 24 hours (mental stress burden). This process took 5 consecutive days to complete. The compound or vehicle was administered orally 2 hours prior to daily social defeat stress. Thereafter, a social interaction test and a sucrose preference test were performed.

對於社會互動測試，CD-1小鼠作為新穎小鼠經置放於42平方cm之盒子(目標區域)中。將測試小鼠(DBA/2小鼠)置放於該盒子中且藉由視訊追蹤系統(Any-Maze軟體)來量測3分鐘內在目標區域中消耗之時間。與新穎小鼠接觸之時間在憂鬱動物中減少。For the social interaction test, CD-1 mice were placed in 42 cm2 boxes (target area) as novel mice. Test mice (DBA/2 mice) were placed in the box and the time spent in the target area was measured within 3 minutes by a video tracking system (Any-Maze software). The time spent in contact with novel mice was reduced in depressed animals.

對於蔗糖偏好測試，同時給定含有1%蔗糖溶液及普通水之瓶子。量測在4小時內消耗之蔗糖溶液及普通水之量，且所消耗蔗糖水之百分率(蔗糖偏好)用作失樂症之指示符。動物通常偏好甜的蔗糖，但處於失樂症狀態(一種抑鬱病況)之動物具有對蔗糖之降低偏好。For the sucrose preference test, bottles containing 1% sucrose solution and plain water were given simultaneously. The amount of sucrose solution and plain water consumed over a 4-hour period was measured, and the percentage of sucrose water consumed (sucrose preference) was used as an indicator of anhedonia. Animals normally have a preference for sweet sucrose, but animals in the anemic state, a depressive condition, have a decreased preference for sucrose.

在出於醫藥學上之目的而使用本發明化合物後，本發明化合物可不僅用作單一藥品且亦與額外活性組分(例如下文中列出之彼等者)組合以用於以下目的：例如，(1)補充及/或增強其對預防、治療及/或減輕症狀之效應，(2)改善動力學及吸收，減小其劑量及/或(3)緩解其副作用。After using the compounds of the present invention for pharmaceutical purposes, the compounds of the present invention can be used not only as single medicines but also in combination with additional active ingredients such as those listed below for the following purposes: e.g. , (1) supplement and/or enhance its effect on prevention, treatment and/or alleviate symptoms, (2) improve kinetics and absorption, reduce its dose and/or (3) relieve its side effects.

當本發明化合物用於預防及/或治療阿茲海默症時，可與本發明化合物組合使用之藥品的實例包括對症劑，例如已知修改膽鹼能傳遞之彼等者，諸如M1及M3蕈毒鹼受體促效劑或異位調節劑、M2蕈毒鹼拮抗劑、M4促效劑或正向異位調節劑(PAM)、乙醯膽鹼酯酶抑制劑(諸如四氫胺基吖啶、鹽酸多奈派齊及雷斯替明)、菸鹼受體促效劑或異位調節劑(諸如α7促效劑或異位調節劑或α4β2促效劑或異位調節劑)、PPAR促效劑(諸如PPARy促效劑)、5-HT ₄受體促效劑或部分促效劑、組胺H3拮抗劑、5-HT ₆受體拮抗劑或5HT _1A受體配體及NMDA受體拮抗劑或調節劑、5-HT _2A拮抗劑、5-HT ₇拮抗劑、Dl促效劑或PAM、D4促效劑或PAM、D5促效劑或PAM、GABA-A a5反向促效劑或負向異位調節劑(NAM)、GABA-A a2/3促效劑或PAM、mGluR2調節劑(PAM或NAM)、mGluR3 PAM、mGluR5 PAM、PDE 1抑制劑、PDE 2抑制劑、PDE 4抑制劑、PDE 5抑制劑、PDE 9抑制劑、PDE 10抑制劑、GlyTl抑制劑、DAAO抑制劑、ASCI抑制劑、AMPA調節劑、SIRT1活化劑或抑制劑、AT4拮抗劑、GalRl拮抗劑、GalR3配體、腺核苷Al拮抗劑、腺核苷A2a拮抗劑、a2A拮抗劑或促效劑、選擇性及非選擇性正腎上腺素再吸收抑制劑(SNRI)或潛在疾病調節劑，諸如伽瑪(gamma)分泌酵素抑制劑或調節劑、阿爾法(alpha)分泌酵素活化劑或調節劑、澱粉狀蛋白凝集抑制劑、澱粉狀蛋白抗體、tau凝集抑制劑或tau磷酸化/激酶抑制劑、tau去磷酸化/磷酸酶活化劑、促***原活化蛋白激酶激酶4 (MKK4/MEK4/MAP2K4)抑制劑、c-Jun N端激酶(JNK)抑制劑、酪蛋白激酶抑制劑、促***原活化蛋白激酶活化蛋白激酶2 (MK2)抑制劑、微管親和力調節激酶(MARK)抑制劑、週期蛋白依賴型激酶5 (CDK5)抑制劑、肝糖合成酶激酶-3 (GSK-3)抑制劑及tau微管蛋白激酶-1 (TTBK1)抑制劑。此類其他治療劑之進一步實例可為鈣通道阻斷劑、HMG-CoA (3-羥基-3-甲基-戊二醯基-CoA)還原酶抑制劑(斯他汀)及降脂劑、神經生長因子(NGF)模擬物、抗氧化劑、GPR3配體、纖維蛋白溶酶活化劑、腦啡肽酶(NEP)活化劑、胰島素降解酶(IDE)活化劑、褪黑激素MT1及/或MT2促效劑、TLX/NR2E1 (無尾X受體)配體、GluRl配體、晚期糖化最終產物受體(RAGE)拮抗劑、表皮生長因子受體(EGFR)抑制劑、甲醯基肽樣受體-1 (FPRL-1)配體、GABA拮抗劑及分子與casL相互作用(MICAL)抑制劑，例如氧化還原酶抑制劑、CB1拮抗劑/反向促效劑、非類固醇抗炎藥(NSAID)、抗炎劑(例如可藉由提高或減少神經發炎來用於處理神經發炎之製劑)、澱粉狀蛋白前驅蛋白(APP)配體、抗澱粉狀蛋白疫苗及/或抗體、促進或提高澱粉狀蛋白流出及/或清除之製劑、組織蛋白去乙醯基酶(HDAC)抑制劑、EP2拮抗劑、11-貝他HSD1 (11-beta HSD1) (羥基類固醇去氫酶)抑制劑、肝臟X受體(LXR)促效劑或PAM、脂蛋白受體相關蛋白(LRP)模擬物及/或配體及/或增強劑及/或抑制劑、丁醯基膽鹼酯酶抑制劑、犬尿喹啉酸拮抗劑及/或犬尿胺酸轉胺酶抑制劑(KAT)、孤啡肽FQ/孤菲肽(NOP)/類鴉片樣受體1 (ORL1)拮抗劑、刺激性胺基酸轉運蛋白(EAAT)配體(活化劑或抑制劑)及纖維蛋白溶酶原活化抑制劑-1 (PAI-1)抑制劑、與降膽固醇劑及/或HMGCoA還原酶抑制劑(斯他汀)組合之菸酸及/或GPR109促效劑或PAM、地美波林(dimebolin)或類似製劑、抗組織胺、金屬結合/螯合劑、抗生素、生長激素促分泌物、降膽固醇劑、維生素E、膽固醇吸收抑制劑、膽固醇流出促進劑及/或活化劑及胰島素上調劑，及其類似者。 When the compound of the present invention is used for the prevention and/or treatment of Alzheimer's disease, examples of drugs that can be used in combination with the compound of the present invention include symptomatic agents, such as those known to modify cholinergic transmission, such as M1 and M3 Muscarinic receptor agonists or ectopic modulators, M2 muscarinic antagonists, M4 agonists or positive ectopic modulators (PAMs), acetylcholinesterase inhibitors (such as tetrahydroamine-based acridine, donepazil hydrochloride and restigmine), nicotinic receptor agonists or ectopic modulators (such as α7 agonists or ectopic modulators or α4β2 agonists or ectopic modulators), PPAR agonists (such as PPARy agonists), 5-HT ₄ receptor agonists or partial agonists, histamine H3 antagonists, 5-HT ₆ receptor antagonists or 5HT _1A receptor ligands, and NMDA Receptor antagonist or modulator, 5-HT _2A antagonist, 5-HT ₇ antagonist, D1 agonist or PAM, D4 agonist or PAM, D5 agonist or PAM, GABA-A a5 reverse agonist agonist or negative ectopic modulator (NAM), GABA-A a2/3 agonist or PAM, mGluR2 modulator (PAM or NAM), mGluR3 PAM, mGluR5 PAM, PDE 1 inhibitor, PDE 2 inhibitor, PDE 4 inhibitors, PDE 5 inhibitors, PDE 9 inhibitors, PDE 10 inhibitors, GlyT1 inhibitors, DAAO inhibitors, ASCI inhibitors, AMPA modulators, SIRT1 activators or inhibitors, AT4 antagonists, GalR1 antagonists , GalR3 ligands, adenosine Al antagonists, adenosine A2a antagonists, a2A antagonists or agonists, selective and non-selective norepinephrine reuptake inhibitors (SNRIs) or potential disease modifiers such as gamma secretase inhibitors or modulators, alpha secretase activators or modulators, amyloid aggregation inhibitors, amyloid antibodies, tau aggregation inhibitors or tau phosphorylation/kinase inhibitors, tau dephosphorylation/phosphatase activator, mitogen-activated protein kinase kinase 4 (MKK4/MEK4/MAP2K4) inhibitor, c-Jun N-terminal kinase (JNK) inhibitor, casein kinase inhibitor, mitogen activation Protein kinase-activated protein kinase 2 (MK2) inhibitors, microtubule affinity-regulated kinase (MARK) inhibitors, cyclin-dependent kinase 5 (CDK5) inhibitors, glycogen synthase kinase-3 (GSK-3) inhibitors and Inhibitor of tau tubulin kinase-1 (TTBK1). Further examples of such other therapeutic agents may be calcium channel blockers, HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) and lipid-lowering agents, neurological Growth factor (NGF) mimics, antioxidants, GPR3 ligands, plasmin activators, neprilysin (NEP) activators, insulin-degrading enzyme (IDE) activators, melatonin MT1 and/or MT2 agonist, TLX/NR2E1 (tailless X receptor) ligand, GluR1 ligand, receptor for advanced glycation end products (RAGE) antagonist, epidermal growth factor receptor (EGFR) inhibitor, formyl peptide-like receptor -1 (FPRL-1) ligands, GABA antagonists and Molecular CasL Interaction (MICAL) inhibitors such as oxidoreductase inhibitors, CB1 antagonists/inverse agonists, nonsteroidal anti-inflammatory drugs (NSAIDs) , anti-inflammatory agents (such as agents that can be used to treat neuroinflammation by increasing or reducing neuroinflammation), amyloid precursor protein (APP) ligands, anti-amyloid vaccines and/or antibodies, promoting or increasing amyloid Protein efflux and/or clearance agents, histone deacetylase (HDAC) inhibitors, EP2 antagonists, 11-beta HSD1 (11-beta HSD1) (hydroxysteroid dehydrogenase) inhibitors, liver X receptors LXR agonists or PAMs, lipoprotein receptor-related protein (LRP) mimetics and/or ligands and/or enhancers and/or inhibitors, butyrylcholinesterase inhibitors, kynurenic acid Antagonists and/or kynurenine transaminase inhibitors (KAT), orphanin FQ/orphanin (NOP)/opioid receptor 1 (ORL1) antagonists, stimulatory amino acid transporter ( EAAT) ligands (activators or inhibitors) and plasminogen activation inhibitor-1 (PAI-1) inhibitors, niacin in combination with cholesterol-lowering agents and/or HMGCoA reductase inhibitors (statins) and/or GPR109 agonists or PAMs, dimebolin or similar agents, antihistamines, metal binding/chelating agents, antibiotics, growth hormone secretagogues, cholesterol-lowering agents, vitamin E, cholesterol absorption inhibitors, Cholesterol efflux enhancers and/or activators and insulin upregulators, and the like.

本發明化合物可替代地與(例如)鹽酸多奈派齊、加蘭他敏氫溴酸鹽、石杉鹼A、艾地苯醌、乙醯左旋肉鹼鹽酸鹽、鹽酸美金剛、鹽酸美金剛/鹽酸多奈派齊、來自豬腦蛋白之蛋白水解肽碎片、雷斯替明酒石酸鹽、鹽酸他可林、阿杜卡努單抗(遺傳重組)或其類似者組合使用。The compounds of the present invention may alternatively be combined with, for example, donepazil hydrochloride, galantamine hydrobromide, huperzine A, idebenone, acetyl-L-carnitine hydrochloride, memantine hydrochloride, memantine hydrochloride Combination of adamantine/donepazil hydrochloride, proteolytic peptide fragments from porcine brain protein, restigmine tartrate, taccolin hydrochloride, aducanumab (genetic recombinant) or the like.

在與額外藥品之組合中，本發明化合物與額外藥品可以併用藥物的形式投與，該併用藥物在一種調配物或可藉由相同或不同投與途徑投與之單獨調配物中含有兩種組分。單獨調配物沒有必要同時投與且單獨調配物可利用時間差依序投與。當依序投與調配物時，投與次序不受特定限制且可適當地調整以使得可獲得藥品之所要功效。In combination with an additional drug, the compound of the invention and the additional drug may be administered as a concomitant drug containing both components in one formulation or in separate formulations that may be administered by the same or different routes of administration. point. The separate formulations are not necessarily administered simultaneously and the separate formulations can be administered sequentially with a time difference. When the formulations are administered sequentially, the order of administration is not particularly limited and may be appropriately adjusted so that the desired efficacy of the drug is obtained.

與本發明化合物組合使用之額外藥品之劑量可根據其臨床劑量或類似藥品而適當地增加或減小。本發明化合物與額外藥品之間的比率可藉由考慮到受試者之年齡及體重、投與方法、投與時間、目標疾病及病況及其類似者而適當地調整。一般而言，1重量份之本發明化合物可與呈在0.01至100重量份之範圍內之量的額外藥品組合。可使用複數種額外藥品。除了上文所提及之彼等者之外，額外藥品可為具有與上文所提及之彼等者相同之機制的藥品。此類額外藥品不僅包括現已發現之額外藥品且亦包括將來將發現之額外藥品。Doses of additional drugs used in combination with the compounds of the present invention may be appropriately increased or decreased according to their clinical doses or similar drugs. The ratio between the compound of the present invention and the additional drug can be appropriately adjusted by taking into consideration the subject's age and body weight, administration method, administration time, target disease and condition, and the like. In general, 1 part by weight of a compound of the invention may be combined with an additional drug in an amount ranging from 0.01 to 100 parts by weight. A number of additional medicines may be used. In addition to those mentioned above, the additional drug may be a drug with the same mechanism as those mentioned above. Such additional drugs include not only those that have been discovered but also those that will be discovered in the future.

本發明化合物之劑量可根據年齡、體重、病況、治療效應、投與方法、處理期及其類似者而改變。本發明化合物可在每次投與0.1 mg至300 mg之量下向成人經口投與每日一次至若干次，在每次投與0.1 mg至150 mg之量下向成人非經腸投與每日一次至若干次或靜脈內及持續地投與每日超過1小時至24小時。The dose of the compound of the present invention may vary according to age, body weight, condition, therapeutic effect, administration method, treatment period and the like. The compound of the present invention can be administered orally to adults once to several times a day in an amount of 0.1 mg to 300 mg per administration, and parenterally administered to adults in an amount of 0.1 mg to 150 mg per administration One to several times daily or intravenous and continuous administration over 1 hour to 24 hours daily.

如上文所描述，劑量可根據各種病況而改變，且因此小於上文所描述之劑量的量可在一些情況下足夠且超出以上劑量之量可在其他情況下為所需的。As described above, dosages may vary according to the various conditions, and thus amounts less than those described above may be sufficient in some circumstances and amounts in excess may be required in other circumstances.

當本發明醫藥組合物作為單一藥品或與額外藥品組合而用於預防及/或治療以上疾病時，作為活性組分之本發明化合物一般與醫藥學上可接受之載劑(諸如各種添加劑或溶劑)一起調配且所獲得調配物全身性地或局部地及經口或非經腸投與。如本文中所使用之醫藥學上可接受之載劑意謂除一般用於醫藥調配物之活性組分以外的物質。醫藥學上可接受之載劑較佳地並不呈現藥理學活性，為無害的且在調配物之劑量下並不阻礙活性組分之治療效應。醫藥學上可接受之載劑亦可經使用以便提高活性組分及調配物之有用性，以促進調配物之產生，以穩定品質或改善可用性。具體而言，描述於「藥物添加劑百科全書(Iyakuhin Tenkabutsu Jiten)」, 2000, 日本化妝品成分標準(Yakuji Nippo Ltd.) (日本IPEC編(Ed. IPEC Japan))中之物質可根據需要而適當地選擇。When the pharmaceutical composition of the present invention is used as a single drug or in combination with additional drugs for the prevention and/or treatment of the above diseases, the compound of the present invention as an active component is generally mixed with a pharmaceutically acceptable carrier (such as various additives or solvents) ) are formulated together and the resulting formulation is administered systemically or topically and orally or parenterally. A pharmaceutically acceptable carrier as used herein means a substance other than the active ingredient normally used in pharmaceutical formulations. A pharmaceutically acceptable carrier preferably exhibits no pharmacological activity, is innocuous and does not interfere with the therapeutic effect of the active ingredient at the dosage of the formulation. Pharmaceutically acceptable carriers may also be used in order to increase the usefulness of the active ingredients and formulations, to facilitate production of the formulations, to stabilize quality or to improve availability. Specifically, substances described in "Encyclopedia of Pharmaceutical Additives (Iyakuhin Tenkabutsu Jiten)", 2000, Japanese Cosmetic Ingredient Standards (Yakuji Nippo Ltd.) (Edited by IPEC Japan (Ed. IPEC Japan)) may be appropriately used as needed choose.

包含本發明化合物之醫藥組合物可以各種劑量形式進行調配。劑量形式之實例包括經口投與調配物(實例：錠劑、膠囊、顆粒、粉劑、口服液體、糖漿、口服膠狀物調配物及其類似者)、口腔調配物(實例：用於口腔之錠劑、用於口腔之噴霧調配物、用於口腔之半固體調配物、漱口水及其類似者)、用於注射之調配物(實例：注射劑及其類似者)、用於透析之調配物(實例：用於透析之製劑及其類似者)、用於吸入之調配物(實例：用於吸入之製劑及其類似者)、經眼調配物(實例：經眼溶液、經眼軟膏及其類似者)、經耳調配物(實例：滴耳劑及其類似者)、經鼻(nasologic)調配物(實例：鼻滴劑及其類似者)、經直腸調配物(實例：栓劑、用於直腸投與之半固體調配物、灌腸調配物及其類似者)、經***調配物(實例：經***錠劑、經***栓劑及其類似者)、皮膚調配物(實例：外用固體調配物、外用液體、噴霧調配物、軟膏、乳膏、凝膠、硬膏劑及壓敏黏著劑及其類似者)及其類似者。 [經口投與調配物] Pharmaceutical compositions comprising compounds of the present invention can be formulated in various dosage forms. Examples of dosage forms include oral administration formulations (example: tablets, capsules, granules, powders, oral liquids, syrups, oral jelly formulations, and the like), buccal formulations (example: oral administration Tablets, spray formulations for oral cavity, semi-solid formulations for oral cavity, mouthwash and the like), formulations for injection (example: injections and the like), formulations for dialysis (Example: preparations for dialysis and the like), formulations for inhalation (example: preparations for inhalation and the like), ophthalmic formulations (examples: ophthalmic solutions, ophthalmic ointments, and and the like), aural formulations (example: ear drops and the like), nasal (nasologic) formulations (example: nasal drops and the like), rectal formulations (example: suppositories, for semisolid formulations for rectal administration, enema formulations and the like), vaginal formulations (example: vaginal lozenges, vaginal suppositories and the like), skin formulations (example: external solid formulations, Liquids for external use, spray formulations, ointments, creams, gels, plasters and pressure-sensitive adhesives and the like) and the like. [Oral administration and preparation]

經口投與調配物之實例包括錠劑、膠囊、顆粒、粉劑、口服液體、糖漿、口服膠狀物調配物及其類似者。經口投與調配物可分類為快速崩散調配物及釋放控制調配物，諸如腸道調配物及持續釋放調配物，在該等快速崩散調配物中活性組分自調配物之釋放不受特定控制，在該等釋放控制調配物中釋放根據目的藉由調整劑量設計及產生方法而控制。腸道調配物係指設計成主要在小腸中而非在胃中釋放活性組分之調配物，其目的在於避免活性組分在胃中分解或減小活性組分對胃之刺激。腸道調配物可一般藉由提供酸不溶性腸道基質(base)之包衣來產生。持續釋放調配物係指其中活性組分自調配物之釋放速率、釋放時間及釋放位點受控制之調配物，其目的在於降低投與頻率或減小副作用。持續釋放調配物可一般藉由使用用於持續釋放之適當製劑來產生。在經口投與調配物當中，膠囊、顆粒、錠劑可具備糖、糖醇、聚合物化合物及其類似者之適當塗膜，其目的在於易於攝入或避免活性組分之分解。 (1)錠劑 Examples of formulations for oral administration include tablets, capsules, granules, powders, oral liquids, syrups, oral jelly formulations and the like. Oral administration formulations can be classified as rapidly disintegrating formulations and controlled release formulations, such as enteral formulations and sustained release formulations, in which rapidly disintegrating formulations the release of the active ingredient from the formulation is not controlled. Specific control, release in such release controlled formulations is controlled according to the purpose by adjusting the dosage design and method of production. Enteral formulations refer to formulations designed to release the active ingredient primarily in the small intestine rather than the stomach, with the aim of avoiding breakdown of the active ingredient in the stomach or reducing gastric irritation of the active ingredient. Enteral formulations can generally be produced by providing a coating with an acid-insoluble enteric base. Sustained release formulations refer to formulations in which the rate, time and site of release of the active ingredient from the formulation is controlled in order to reduce the frequency of administration or to reduce side effects. Sustained release formulations can generally be produced by using appropriate formulations for sustained release. Among oral administration formulations, capsules, granules, tablets may be provided with suitable coatings of sugars, sugar alcohols, polymer compounds and the like for the purpose of easy ingestion or to avoid decomposition of the active ingredient. (1) Lozenges

錠劑為具有某一形狀之經口投與固體調配物。其實例包括一般稱作錠劑之彼等者，諸如普通錠劑、膜衣錠劑、糖衣錠劑、多層錠劑及乾包衣錠劑以及經口崩散錠劑、咀嚼錠劑、起泡錠劑、可分散錠劑、可溶性錠劑及其類似者。普通錠劑可一般根據以下程序(a)、(b)或(c)來產生： (a)活性組分與諸如媒劑、結合劑及崩散劑之添加劑混合以獲得均質混合物，該均質混合物藉由適當方法使用水或含有結合劑之溶液來粒化，與潤滑劑及其類似者混合，經壓縮及模製； (b)活性組分與諸如媒劑、結合劑及崩散劑之添加劑混合以獲得隨後直接經壓縮及模製之均質混合物，或與添加劑一起製備之顆粒與活性組分、潤滑劑及其類似者混合以獲得隨後經壓縮及模製之均質混合物； (c)活性組分與諸如媒劑及結合劑之添加劑混合以獲得均質混合物，該均質混合物隨後潤濕及與溶劑一起捏合、在某一模具中模製及藉由適當方法乾燥。膜衣錠劑可一般藉由向普通錠劑提供聚合物及其類似者之適當薄塗膜來產生。糖衣錠劑可一般藉由向普通錠劑提供含有糖或糖醇之塗膜來產生。多層錠劑可根據適當方法藉由堆疊具有不同組合物之粉末顆粒層及壓縮及模製產品來產生。乾包衣錠劑可藉由用具有不同組合物之外部層包覆內部核心錠劑來產生。錠劑可根據適當熟知方法來形成為腸道錠劑或持續釋放錠劑。經口崩散錠劑、咀嚼錠劑、起泡錠劑、可分散錠劑及可溶性錠劑為藉由適當地選擇添加劑來向其賦予唯一功能之錠劑，且可根據上文針對錠劑所描述之產生程序來產生。經口崩散錠劑係指藉由在口腔中快速溶解或崩散攝入之錠劑；咀嚼錠劑係指藉由咀嚼攝入之錠劑；起泡錠劑係指在水中藉由快速起泡溶解或分散之錠劑；可分散錠劑係指在分散於水中之後攝入之錠劑；且可溶性錠劑係指在溶解於水中之後攝入之錠劑。起泡錠劑可藉由使用添加劑來產生，該添加劑為適當酸性物質、碳酸鹽、碳酸氫鹽及其類似者。 (2)膠囊 A lozenge is a solid formulation having a certain shape for oral administration. Examples thereof include those generally called lozenges, such as plain lozenges, film-coated lozenges, sugar-coated lozenges, multi-layered lozenges, and dry-coated lozenges as well as orally disintegrating lozenges, chewable lozenges, effervescent lozenges lozenges, dispersible lozenges, soluble lozenges and the like. Common lozenges can generally be produced according to the following procedure (a), (b) or (c): (a) The active ingredient is mixed with additives such as vehicles, binders and disintegrants to obtain a homogeneous mixture which is granulated by an appropriate method using water or a solution containing a binder, and lubricants and the like Mixed, compressed and molded; (b) The active ingredient is mixed with additives such as vehicles, binders and disintegrating agents to obtain a homogeneous mixture which is then directly compressed and molded, or granules prepared with additives together with the active ingredient, lubricants and the like mixing to obtain a homogeneous mixture which is then compressed and molded; (c) The active ingredient is mixed with additives such as vehicles and binders to obtain a homogeneous mixture, which is then moistened and kneaded with a solvent, molded in a certain mold and dried by a suitable method. Film-coated tablets can generally be produced by providing ordinary tablets with an appropriate thin coating of polymers and the like. Dragees can generally be produced by providing a coating containing sugar or sugar alcohol to a plain tablet. Multilayer lozenges can be produced by stacking layers of powder particles of different compositions and compressing and molding the product according to appropriate methods. Dry-coated tablets can be produced by coating an inner core tablet with an outer layer of a different composition. The lozenges may be formed as enteral lozenges or sustained release lozenges according to suitable well known methods. Orally disintegrating lozenges, chewable lozenges, effervescent lozenges, dispersible lozenges and soluble lozenges are lozenges to which a unique function is conferred by proper selection of additives, and may be as described above for lozenges. The generation program to generate. Orally disintegrating lozenges refer to lozenges that are ingested by rapidly dissolving or disintegrating in the oral cavity; chewable lozenges refer to lozenges that are ingested by chewing; A tablet that dissolves or disperses; a dispersible tablet refers to a tablet that is ingested after being dispersed in water; and a soluble tablet refers to a tablet that is ingested after being dissolved in water. Blistering lozenges may be produced by the use of additives such as suitable acids, carbonates, bicarbonates and the like. (2) Capsules

膠囊為含有膠囊殼層之調配物，該膠囊殼層填充有活性組分或包覆有膠囊基質之活性組分。其實例包括硬膠囊、軟膠囊及其類似者。硬膠囊可藉由以下各者來產生：使活性組分與諸如媒劑之添加劑混合以獲得均質混合物，或藉由適當方法獲得顆粒或模製物質，其隨後直接或在適當地模製之後添加至膠囊殼層。軟膠囊可藉由將活性組分與添加劑之混合物包裹於膠囊內及模製為具有諸如明膠之適當膠囊基質之某一形狀來產生，該適當膠囊基質藉由添加甘油、D-山梨醇或其類似者而具有提高之可塑性。膠囊可根據適當熟知方法來形成為腸道膠囊或持續釋放膠囊。膠囊基質可添加有著色劑、防腐劑或其類似者。 (3)顆粒 Capsules are formulations comprising a capsule shell filled with the active ingredient or coated with a capsule matrix. Examples thereof include hard capsules, soft capsules and the like. Hard capsules can be produced by mixing the active ingredient with additives such as vehicles to obtain a homogeneous mixture, or by obtaining granules or molded masses by suitable methods, which are then added directly or after suitable moulding. to the capsule shell. Soft capsules can be produced by encapsulating a mixture of the active ingredient and additives and molding into a certain shape with a suitable capsule base, such as gelatin, prepared by the addition of glycerin, D-sorbitol, or Similar ones have increased plasticity. Capsules may be formed as enteric capsules or sustained release capsules according to suitable well known methods. The capsule base may be added with coloring agents, preservatives or the like. (3) particles

顆粒為粒化調配物。其實例包括一般稱作顆粒以及起泡顆粒之彼等者。顆粒可一般根據以下程序(a)、(b)或(c)來產生： (a)粉末活性組分與諸如媒劑、結合劑或崩散劑之添加劑混合以獲得隨後藉由適當方法粒化之均質混合物； (b)粒化活性組分與諸如媒劑之添加劑混合以獲得均質混合物； (c)粒化活性組分與諸如媒劑之添加劑混合以獲得隨後藉由適當方法粒化之均質混合物；顆粒可視情況具備膜或可使用適當熟知方法來形成為腸道顆粒或持續釋放顆粒。起泡顆粒可藉由使用添加劑來產生，該添加劑為適當酸性物質、碳酸鹽、碳酸氫鹽及其類似者。起泡顆粒係指藉由快速起泡在水中溶解或分散之顆粒。顆粒亦可藉由控制粒度來形成為精細顆粒。 (4)粉劑 Granules are granulated formulations. Examples thereof include those generally called granules and effervescent granules. Particles can generally be produced according to the following procedure (a), (b) or (c): (a) powdered active ingredient mixed with additives such as vehicles, binders or disintegrating agents to obtain a homogeneous mixture which is subsequently granulated by suitable means; (b) mixing the granulated active ingredient with additives such as vehicles to obtain a homogeneous mixture; (c) Granulation The active ingredient is mixed with additives such as vehicles to obtain a homogeneous mixture which is then granulated by suitable methods; the granules may optionally be provided with membranes or may be formed as enteric granules or sustained release granules using suitable well known methods. Effervescent particles can be produced through the use of additives such as suitable acids, carbonates, bicarbonates, and the like. Effervescent granules refer to granules that dissolve or disperse in water by rapid effervescence. Particles can also be formed into fine particles by controlling the particle size. (4) Powder

粉劑為粉末調配物且可一般藉由將活性組分與諸如媒劑之添加劑混合以獲得均質混合物來產生。 (5)口服液體 Dusts are powder formulations and can generally be produced by mixing the active ingredient with additives such as vehicles to obtain a homogeneous mixture. (5) oral liquid

口服液體為呈溶液或可流動及黏性凝膠之形式之調配物。其實例包括一般稱作口服液體以及酏劑、懸浮液、乳液、檸檬水(lemonade)及其類似者之彼等者。口服液體可一般藉由將活性組分與添加劑及純化水混合以均質地溶解、乳化或懸浮活性組分且視情況過濾產品來產生。酏劑係指含有具有甜味及香氣之乙醇之澄清口服液體。酏劑可一般藉由將固體活性組分或其浸液溶解在乙醇、純化水、調味劑及蔗糖、額外醣或甜味劑中且藉由過濾或其他方法獲得澄清液體來產生。懸浮液係指其中活性組分精細地及均質地懸浮之口服液體。懸浮液可一般藉由使固體活性組分懸浮在懸浮劑或額外添加劑及純化水或油中且根據適當方法使整個產品均質化來產生。乳液係指其中活性組分精細地及均質地乳化之口服液體。乳液可一般藉由將乳化劑及純化水添加至液體活性組分且根據適當方法使整個產品乳化及均質化來產生。檸檬水係指具有甜味及酸味之澄清口服液體。 (6)糖漿 Oral liquids are formulations in the form of solutions or flowable and viscous gels. Examples include those generally known as oral liquids as well as elixirs, suspensions, emulsions, lemonades and the like. Oral liquids can generally be produced by mixing the active ingredient with additives and purified water to homogeneously dissolve, emulsify or suspend the active ingredient and optionally filter the product. An elixir is a clear oral liquid containing ethanol which has a sweet taste and aroma. Elixirs can generally be produced by dissolving the solid active ingredient, or its infusion, in ethanol, purified water, flavoring and sucrose, additional sugar or sweetening agents, and obtaining a clear liquid by filtration or other methods. Suspensions are oral liquids in which the active ingredient is finely and homogeneously suspended. Suspensions can generally be produced by suspending the solid active component in suspending agents or additional additives and purified water or oils and homogenizing the entire product according to appropriate methods. Emulsions are oral liquids in which the active ingredient is finely and homogeneously emulsified. Emulsions can generally be produced by adding emulsifiers and purified water to the liquid active components and emulsifying and homogenizing the whole product according to appropriate methods. Lemonade refers to a clear oral liquid with a sweet and sour taste. (6) Syrup

糖漿為含有醣或甜味劑之黏稠液體或固體調配物。其實例包括用於糖漿之製劑。糖漿可一般藉由將活性組分溶解、混合、懸浮或乳化於蔗糖、其他醣或甜味劑之溶液或僅糖漿中且視情況煮沸產品繼之以在加熱同時過濾來產生。用於糖漿之調配物係指向其添加水以提供糖漿之顆粒狀或粉狀調配物且可有時稱為無水糖漿。用於糖漿之調配物可一般根據上文針對顆粒或粉劑所描述之產生程序藉由使用醣或甜味劑作為添加劑來產生。 (7)口服膠狀物調配物 Syrups are viscous liquid or solid formulations containing sugar or sweeteners. Examples thereof include formulations for syrups. Syrups can generally be produced by dissolving, mixing, suspending or emulsifying the active ingredient in a solution of sucrose, other sugars or sweeteners, or in syrup alone, and optionally boiling the product followed by filtering while heating. A formulation for syrup is a granular or powder formulation to which water is added to provide a syrup and may sometimes be referred to as anhydrous syrup. Formulations for syrups can generally be produced according to the production procedures described above for granules or powders by using sugar or sweeteners as additives. (7) Oral jelly formulations

口服膠狀物調配物為不具有可流動性之成形凝膠調配物。口服膠狀物調配物可一般藉由以下各者來產生：將活性組分與添加劑及聚合物凝膠基質混合，從而允許凝膠之形成且根據適當方法來塑形為某一形狀。 [口腔調配物] (1)用於口腔之錠劑 Oral jelly formulations are shaped gel formulations that are not flowable. Oral jelly formulations can generally be produced by mixing the active ingredient with additives and a polymeric gel base, allowing the gel to form and shaping into a certain shape according to appropriate methods. [Oral formulations] (1) Tablets for oral use

用於口腔之錠劑為向口腔投與之具有某一形狀之調配物。其實例包括糖衣錠、舌下錠劑、口頰錠、黏附錠劑、口嚼錠及其類似者。用於口腔之錠劑可一般根據針對錠劑所描述之產生程序來產生。糖衣錠係指在口腔中逐步地溶解或崩散且局部地應用於口腔或咽之用於口腔之錠劑；舌下錠劑係指在舌頭下快速溶解以允許經由口腔黏膜吸收活性組分之用於口腔之錠劑；口頰錠係指在臼齒與面頰之間逐步地溶解以允許經由口腔黏膜吸收活性組分之用於口腔之錠劑；黏附錠劑係指黏附於口腔黏膜之用於口腔之錠劑；且口嚼錠係指待經咀嚼以釋放活性組分之用於口腔之錠劑。 (2)用於口腔之噴霧調配物 A lozenge for oral administration is a formulation having a certain shape that is administered to the oral cavity. Examples thereof include dragees, sublingual lozenges, buccal lozenges, adhesive lozenges, chewable lozenges, and the like. Lozenges for oral administration can generally be produced according to the production procedures described for lozenges. Dragee means a lozenge for the oral cavity which gradually dissolves or disintegrates in the oral cavity and is applied topically to the mouth or pharynx; sublingual lozenge means a lozenge which dissolves rapidly under the tongue to allow absorption of the active ingredient through the oral mucosa. Tablets for the oral cavity; buccal tablets are tablets for the oral cavity which gradually dissolve between the molars and the cheek to allow absorption of the active ingredient through the oral mucosa; adhesive tablets are tablets for the oral cavity which are adhered to the oral mucosa. and chewable tablet means a tablet for oral administration which is to be chewed to release the active ingredient. (2) Spray formulations for oral cavity

用於口腔之噴霧調配物為噴灑呈霧狀物、粉末、發泡體或糊狀物之形式之活性組分的調配物。用於口腔之噴霧調配物可一般藉由以下各者產生：將活性組分及添加劑溶解或懸浮於溶劑或其類似者中，視情況將其過濾且將產品與液化氣體或壓縮氣體一起包裝至容器中，或藉由製備具有活性組分及添加劑之溶液或懸浮液且將產品包裝至噴灑泵附接至之容器中。 (3)用於口腔之半固體調配物 Spray formulations for the oral cavity are formulations for spraying on the active ingredient in the form of a mist, powder, foam or paste. Spray formulations for oral use can generally be produced by dissolving or suspending the active ingredient and additives in a solvent or the like, filtering it as appropriate and packaging the product together with liquefied or compressed gas to container, or by preparing a solution or suspension with the active ingredient and additives and packaging the product into a container to which the spray pump is attached. (3) Semi-solid formulations for oral cavity

用於口腔之半固體調配物為待應用於口腔黏膜之調配物。其實例包括乳膏、凝膠、軟膏及其類似者。用於口腔之半固體調配物可一般藉由以下各者產生：將活性組分以及添加劑乳化於純化水及諸如凡士林之油組分中，或藉由將活性組分及添加劑與諸如聚合物凝膠或油或脂肪之基質混合且獲得均質混合物。乳膏係指呈水包油或油包水乳液之形式之半固體調配物且呈油包水乳液之形式的親油性調配物亦可稱為油基乳膏。乳膏可一般藉由以下各者產生：自凡士林或高級醇或其與諸如乳化劑之添加劑之混合物製備油相，單獨自純化水或其與諸如乳化劑之添加劑之混合物製備水相，將活性組分添加至油相或水相，加熱兩種相且將油相與水相混合直至均質以獲得乳液。凝膠係指凝膠調配物且其實例包括水基凝膠、油基凝膠及其類似者。水基凝膠可藉由將活性組分溶解或懸浮於諸如聚合物化合物之添加劑及純化水中且藉由加熱及冷卻或添加膠凝劑實現交聯來產生。油基凝膠可藉由將活性組分與諸如二醇或高級醇之液體油基質及添加劑混合來產生。軟膏係指含有溶解或分散於基質中之活性組分之半固體調配物。其實例包括基於油或脂肪之軟膏、水溶性軟膏及其類似者。基於油或脂肪之軟膏可一般藉由以下各者來產生：藉由將活性組分加熱、溶解或分散於其中來熔融基於油或脂肪之基質，諸如油或脂肪、包括石蠟之蠟及烴類，且混合及捏合以獲得均質混合物。水溶性軟膏可一般藉由以下各者來產生：藉由將活性組分加熱及混合及捏合於其中來熔融諸如聚乙二醇之水溶性基質以獲得均質混合物。 (4)漱口水 Semisolid formulations for oral use are formulations to be applied to the oral mucosa. Examples thereof include creams, gels, ointments and the like. Semi-solid formulations for oral use can generally be produced by emulsifying the active ingredients and additives in purified water and oil components such as petrolatum, or by coagulating the active ingredients and additives with polymers such as Gum or oil or fat bases are mixed and a homogeneous mixture is obtained. Creams refer to semisolid formulations in the form of oil-in-water or water-in-oil emulsions and lipophilic formulations in the form of water-in-oil emulsions may also be referred to as oil-based creams. Creams can generally be produced by preparing an oily phase from petrolatum or higher alcohols or their mixtures with additives such as emulsifiers, preparing an aqueous phase from purified water alone or their mixtures with additives such as emulsifiers, adding active The components are added to the oil phase or the water phase, both phases are heated and the oil and water phases are mixed until homogeneous to obtain an emulsion. Gel refers to a gel formulation and examples thereof include water-based gels, oil-based gels, and the like. Water-based gels can be produced by dissolving or suspending active components in additives such as polymer compounds and purified water and cross-linking by heating and cooling or adding gelling agents. Oil-based gels can be produced by mixing the active ingredient with a liquid oil base such as glycols or higher alcohols and additives. Ointment refers to a semisolid formulation containing the active ingredient dissolved or dispersed in a base. Examples thereof include oil or fat based ointments, water-soluble ointments and the like. Oil- or fat-based ointments can generally be produced by melting an oil- or fat-based base, such as oils or fats, waxes including paraffins, and hydrocarbons by heating, dissolving or dispersing the active ingredient therein , and mixed and kneaded to obtain a homogeneous mixture. Water-soluble ointments can generally be produced by melting a water-soluble base such as polyethylene glycol by heating and mixing and kneading the active ingredients therein to obtain a homogeneous mixture. (4) Mouthwash

漱口水為局部地應用於口腔或咽之液體調配物且可包括在使用後溶解之固體調配物。漱口水可一般藉由將活性組分均質地溶解於溶劑及添加劑中且視情況過濾溶液來產生。在使用後溶解之固體調配物可一般根據針對錠劑及顆粒所描述之產生程序來產生。 [用於注射之調配物] (1)注射劑 Mouthwashes are liquid formulations that are topically applied to the mouth or throat and may include solid formulations that dissolve after use. Mouthwashes can generally be produced by homogeneously dissolving the active ingredient in a solvent and additives and optionally filtering the solution. Solid formulations that dissolve after use can generally be produced according to the production procedures described for tablets and granules. [Formulations for injection] (1) Injection

注射劑為呈溶液、懸浮液或乳液或待在使用後溶解或懸浮之固體之形式的無菌調配物，其直接向身體組織及器官投與，諸如在皮膚下、在肌肉中或至血管。其實例包括一般稱作注射劑之彼等者以及凍乾注射劑、粉末注射劑、預填充注射器、藥筒、輸血劑、可植入注射劑、持續釋放注射劑及其類似者。注射劑可一般根據以下程序(a)或(b)來產生： (a)活性組分或活性組分與添加劑之混合物經溶解、懸浮或乳化於注射用水或另一水性溶劑或非水性溶劑中且產品經包裝至隨後經滅菌之注射用容器中； (b)活性組分或活性組分與添加劑之混合物經溶解、懸浮或乳化於注射用水或另一水性溶劑或非水性溶劑中且產品經受無菌過濾或產品以無菌方式均質地製備且裝入隨後經密封之注射用容器中。凍乾注射劑可一般藉由以下各者產生：將活性組分或活性組分與諸如媒劑之添加劑一起溶解於注射用水中，使溶液經受無菌過濾，將溶液裝入注射用容器中，繼之以凍乾或在專用於凍乾之容器中凍乾溶液，繼之以將產品包裝在注射用容器中。粉末注射劑可一般藉由無菌過濾及結晶以獲得粉末來產生，其直接或其與滅菌添加劑之混合物裝入注射用容器中。預填充注射器可一般藉由將活性組分或活性組分與添加劑之溶液、懸浮液或乳液裝入注射器中來產生。藥筒係指呈待置放於專用注射器中之含有藥品溶液之藥筒之形式的注射劑。含有藥品溶液之藥筒可一般藉由將活性組分或活性組分與添加劑之溶液、懸浮液或乳液裝入藥筒中來產生。輸注係指靜脈內投與通常100 mL或更多之注射劑。可植入注射劑係指呈固體或凝膠形式之注射劑，其待使用可植入工具或藉由手術應用於皮膚下或肌肉中以便經由長時段釋放活性組分。可植入注射劑可一般藉由與可生物降解聚合物化合物形成丸劑、微球體或凝膠來產生。持續釋放注射劑係指應用於肌肉中以便經由長時段釋放活性組分之注射劑且可一般藉由將活性組分溶解或懸浮於植物油中或獲得與可生物降解聚合物化合物之微球體懸浮液來產生。 [用於透析之調配物] (1)用於透析之製劑 Injections are sterile formulations in the form of solutions, suspensions, or emulsions, or solids to be dissolved or suspended after use, which are administered directly to body tissues and organs, such as under the skin, in a muscle, or into a blood vessel. Examples thereof include those generally called injections, as well as lyophilized injections, powder injections, prefilled syringes, cartridges, blood transfusions, implantable injections, sustained release injections, and the like. Injections can generally be produced according to the following procedure (a) or (b): (a) the active ingredient or the mixture of active ingredient and additive is dissolved, suspended or emulsified in water for injection or another aqueous or non-aqueous solvent and the product is packaged into a container for injection which is subsequently sterilized; (b) The active ingredient or the mixture of active ingredient and additive is dissolved, suspended or emulsified in water for injection or another aqueous or non-aqueous solvent and the product is subjected to sterile filtration or the product is prepared homogeneously in a sterile manner and filled subsequently In a sealed container for injection. Freeze-dried injections can generally be produced by dissolving the active ingredient or the active ingredient together with additives such as vehicles in water for injection, subjecting the solution to sterile filtration, filling the solution into a container for injection, followed by The solution is lyophilized or lyophilized in a container dedicated for lyophilization, followed by packaging the product in a container for injection. Powder injections can generally be produced by sterile filtration and crystallization to obtain a powder which is filled into containers for injection either directly or in admixture with sterile additives. Pre-filled syringes can generally be produced by filling the syringe with the active ingredient or a solution, suspension or emulsion of the active ingredient and additives. Cartridge means an injection in the form of a cartridge containing a drug solution to be placed in a dedicated syringe. Cartridges containing pharmaceutical solutions can generally be produced by filling the active ingredient or a solution, suspension or emulsion of the active ingredient and additives into the cartridge. Infusion refers to intravenous administration of injections, usually 100 mL or more. Implantable injections refer to injections in solid or gel form to be applied under the skin or into a muscle using an implantable instrument or by surgery in order to release the active ingredient over a prolonged period of time. Implantable injections can generally be produced by forming pellets, microspheres or gels with biodegradable polymer compounds. Sustained release injections are injections that are applied in the muscle to release the active ingredient over a prolonged period of time and can generally be produced by dissolving or suspending the active ingredient in vegetable oil or by obtaining a microsphere suspension with a biodegradable polymer compound . [Formulations for dialysis] (1) Preparations for dialysis

用於透析之製劑為在使用後溶解之待用於腹膜透析或血液透析之液體調配物或固體調配物。其實例包括用於腹膜透析之製劑、用於血液透析之製劑及其類似者。用於腹膜透析之製劑係指用於腹膜透析的用於滲析之無菌劑且可一般藉由以下各者來產生：將活性組分及添加劑在某一量下於溶劑中之溶液或活性組分與添加劑之混合物裝入容器中，將其密封且視情況將其滅菌。待在使用後溶解之固體調配物可一般根據上文針對錠劑及顆粒所描述之產生程序來產生。用於血液透析之製劑係指用於血液透析的用於透析之製劑且可一般藉由將活性組分及添加劑在某一量下於溶劑中之溶液或活性組分與添加劑之混合物裝入容器中產生。待在使用後溶解之固體調配物可一般根據上文針對錠劑及顆粒所描述之產生程序來產生。 [用於吸入之調配物] (1)用於吸入之製劑 Preparations for dialysis are liquid or solid formulations to be used in peritoneal dialysis or hemodialysis which are dissolved after use. Examples thereof include preparations for peritoneal dialysis, preparations for hemodialysis, and the like. Preparations for peritoneal dialysis mean sterile preparations for dialysis used in peritoneal dialysis and can generally be produced by solutions of active ingredients and additives in a solvent or active ingredients in a certain amount The mixture with additives is filled into containers, which are sealed and optionally sterilized. Solid formulations to be dissolved after use can generally be produced according to the production procedures described above for tablets and granules. Preparations for hemodialysis means preparations for dialysis used in hemodialysis and can generally be prepared by filling a container with a solution of active ingredient and additive in a certain amount in a solvent or a mixture of active ingredient and additive produced in. Solid formulations to be dissolved after use can generally be produced according to the production procedures described above for tablets and granules. [Preparation for inhalation] (1) Preparations for inhalation

用於吸入之製劑為藉由吸入活性組分之噴霧劑來應用於支氣管或肺之調配物。其實例包括用於吸入之粉末製劑、用於吸入之液體製劑、用於吸入之噴霧劑及其類似者。用於吸入之粉末製劑係指待在預定量下作為固體顆粒之噴霧劑吸入之調配物，且可一般藉由製備活性組分之精細顆粒且視情況將其與諸如乳糖之添加劑混合以獲得均質混合物來產生。用於吸入之液體製劑係指待藉由噴霧器及其類似者應用的用於吸入之液體製劑且可一般藉由將活性組分均質地溶解或懸浮於溶劑、適當張力劑、pH控制劑及其類似者中且視情況過濾產品來產生。用於吸入之噴霧劑係指噴灑預定量之與推進劑一起包裝於容器中之活性組分的用於吸入之定量製劑。用於吸入之噴霧劑可一般藉由自活性組分、溶劑、適當分散劑、穩定劑及其類似者製備溶液或懸浮液且將產品與液體推進劑一起裝入與節流閥附接之耐壓容器中來產生。 [經眼調配物] (1)經眼溶液 Preparations for inhalation are formulations for application to the bronchi or lungs by inhalation of a spray of the active ingredient. Examples thereof include powder formulations for inhalation, liquid formulations for inhalation, sprays for inhalation, and the like. Powder preparations for inhalation refer to formulations to be inhaled in a predetermined amount as a spray of solid particles, and homogeneity can generally be obtained by preparing fine granules of the active ingredient and mixing them with an additive such as lactose as the case may be. mixture to produce. Liquid preparations for inhalation refer to liquid preparations for inhalation to be applied by nebulizers and the like and can generally be obtained by dissolving or suspending the active ingredient homogeneously in a solvent, an appropriate tonicity agent, a pH control agent, and the like. Generated among similar and optionally filtered products. Spray for inhalation means a metered dose for inhalation that sprays a predetermined amount of the active ingredient packed in a container together with a propellant. Sprays for inhalation may generally be prepared by preparing a solution or suspension of the active ingredient, solvents, suitable dispersants, stabilizers and the like and filling the product together with the liquid propellant into a resistant device with a throttle valve attached. produced in a pressurized container. [Ophthalmic formulations] (1) Eye solution

經眼溶液為待在使用後溶解或懸浮之液體無菌調配物或固體無菌調配物，其應用於眼組織，諸如結膜囊。經眼溶液可一般藉由將活性組分及添加劑在某一量下於溶劑或其類似者中之溶液或懸浮液或活性組分與添加劑之混合物裝入容器中來產生。 (2)經眼軟膏 Ophthalmic solutions are sterile liquid or solid sterile formulations to be dissolved or suspended after use, which are applied to ocular tissues, such as the conjunctival sac. Ophthalmic solutions can generally be produced by filling a container with a solution or suspension of the active ingredient and additive in a certain amount in a solvent or the like, or a mixture of the active ingredient and additive. (2) eye ointment

經眼軟膏為待應用於諸如結膜囊之眼組織之半固體無菌調配物，且可一般藉由將諸如凡士林之基質與活性組分之溶液或精細粉末之均質混合物裝入容器中來產生。 [經耳調配物] (1)滴耳劑 Ophthalmic ointments are semi-solid sterile formulations to be applied to ocular tissues such as the conjunctival sac and can generally be produced by filling a container with a homogeneous mixture of a base such as petrolatum and a solution or fine powder of the active ingredient. [Auricular formulations] (1) ear drops

滴耳劑為液體或半固體調配物或待在使用後溶解或懸浮之固體調配物，其向外耳或中耳投與。滴耳劑一般藉由將活性組分及添加劑在某一量下於溶劑或類似者中之溶液或懸浮液或活性組分與添加劑之混合物裝入容器中來產生。 [經鼻調配物] (1)鼻滴劑 Ear drops are liquid or semisolid formulations or solid formulations to be dissolved or suspended after use, which are administered to the outer or middle ear. Ear drops are generally produced by filling a container with a solution or suspension of the active ingredient and additive in a certain amount in a solvent or the like, or a mixture of the active ingredient and additive. [Nasal formulations] (1) Nasal drops

鼻滴劑為待向鼻腔或鼻黏膜投與之調配物且其實例包括鼻用粉劑、鼻用液體及其類似者。鼻粉劑係指待向鼻腔投與之精細粉末鼻滴劑且可一般藉由適當地製得活性組分之精細粉末且視情況將活性組分與添加劑混合以獲得均質混合物來產生。鼻用液體係指作為待在使用後溶解或懸浮之液體或固體且向鼻腔投與之鼻滴劑。鼻用液體可一般藉由將活性組分溶解或懸浮於溶劑及添加劑中且視情況過濾產品來產生。用於可使用之鼻用液體之添加劑包括張力劑、pH控制劑及其類似者。 [經直腸調配物] (1)栓劑 Nasal drops are formulations to be administered to the nasal cavity or nasal mucosa and examples thereof include nasal powders, nasal liquids, and the like. Nasal powder refers to fine powder nose drops to be administered into the nasal cavity and may generally be produced by suitably finely powdering the active ingredient and mixing the active ingredient with additives, as appropriate, to obtain a homogeneous mixture. Nasal liquid systems refer to nasal drops that are liquid or solid to be dissolved or suspended after use and administered to the nasal cavity. Nasal liquids can generally be produced by dissolving or suspending the active ingredient in a solvent and additives and optionally filtering the product. Additives for nasal fluids that can be used include tonicity agents, pH control agents and the like. [transrectal formulations] (1) suppositories

栓劑為具有某一形狀之半固體調配物，其應用於直腸中且藉由在體溫下熔融或在水中逐步地溶解或分散來釋放活性組分。栓劑可一般藉由以下各者來產生：將活性組分與諸如分散劑及乳化劑之添加劑之均質混合物溶解或均質地分散於藉由加熱及其類似者液化之基質中，將預定量之產品裝入容器中且將其固化/模製。用於可一般使用之栓劑之基質包括基於油或脂肪之基質及親水性基質。 (2)用於直腸投與之半固體調配物 Suppositories are semisolid formulations of a certain shape that are applied in the rectum and release the active ingredient by melting at body temperature or gradually dissolving or dispersing in water. Suppositories can generally be produced by dissolving or homogeneously dispersing a homogeneous mixture of the active ingredient and additives such as dispersants and emulsifiers in a base which is liquefied by heating and the like, dispensing a predetermined amount of the product Filled into containers and cured/molded. Bases for suppositories which can generally be used include oil or fat based bases and hydrophilic bases. (2) Semisolid formulations for rectal administration

用於直腸投與之半固體調配物為在肛門周圍或肛門中應用之調配物且其實例包括直腸乳膏、直腸凝膠、直腸軟膏及其類似者。用於直腸投與之半固體調配物可一般藉由以下各者產生：將活性組分以及添加劑乳化於純化水及諸如凡士林之油組分中，或藉由將活性組分及添加劑與作為聚合物凝膠或油或脂肪之基質均質地混合。經直腸乳膏可一般藉由以下各者產生：自凡士林或高級醇或其與諸如乳化劑之添加劑之混合物製備油相，單獨自純化水或其與諸如乳化劑之添加劑之混合物製備水相，將活性組分添加至油相或水相，加熱兩種相且將油相與水相混合直至均質以獲得乳液。經直腸凝膠係指凝膠調配物且其實例包括水基凝膠、油基凝膠及其類似者。水基凝膠可藉由將活性組分溶解或懸浮於諸如聚合物化合物之添加劑及純化水中且藉由加熱及冷卻或添加膠凝劑實現交聯來產生。油基凝膠可藉由將活性組分與諸如二醇或高級醇之液體油基質及添加劑混合來產生。經直腸軟膏係指含有溶解或懸浮於基質中之活性組分之半固體調配物且其實例包括基於油或脂肪之軟膏、水溶性軟膏及其類似者。基於油或脂肪之軟膏可一般藉由以下各者來產生：藉由將活性組分加熱、溶解或懸浮於其中來熔融基於油或脂肪之基質，諸如油或脂肪、包括石蠟之蠟及烴類，且混合及捏合以獲得均質混合物。水溶性軟膏可一般藉由以下各者來產生：藉由將活性組分加熱及混合及捏合於其中來熔融諸如聚乙二醇之水溶性基質以獲得均質混合物。 (3)灌腸調配物 Semisolid formulations for rectal administration are formulations applied perianally or in the anus and examples thereof include rectal creams, rectal gels, rectal ointments and the like. Semi-solid formulations for rectal administration can generally be produced by emulsifying the active ingredient and additives in purified water and an oil component such as petrolatum, or by combining the active ingredient and additives with as a polymerized Mix homogeneously with bases of food gels or oils or fats. Rectal creams can generally be produced by preparing an oil phase from petrolatum or higher alcohols or their mixtures with additives such as emulsifiers, preparing an aqueous phase from purified water alone or their mixtures with additives such as emulsifiers, The active ingredient is added to the oily or aqueous phase, both phases are heated and the oily and aqueous phases are mixed until homogeneous to obtain an emulsion. A rectal gel refers to a gel formulation and examples thereof include water-based gels, oil-based gels, and the like. Water-based gels can be produced by dissolving or suspending active components in additives such as polymer compounds and purified water and cross-linking by heating and cooling or adding gelling agents. Oil-based gels can be produced by mixing the active ingredient with a liquid oil base such as glycols or higher alcohols and additives. Rectal ointment refers to a semi-solid formulation containing the active ingredient dissolved or suspended in a base and examples thereof include oil- or fat-based ointments, water-soluble ointments, and the like. Oil- or fat-based ointments can generally be produced by melting an oil- or fat-based base, such as oils or fats, waxes including paraffins, and hydrocarbons by heating, dissolving or suspending the active ingredient therein , and mixed and kneaded to obtain a homogeneous mixture. Water-soluble ointments can generally be produced by melting a water-soluble base such as polyethylene glycol by heating and mixing and kneading the active ingredients therein to obtain a homogeneous mixture. (3) Enema preparations

灌腸調配物為待經由肛門應用之液體或黏性凝膠調配物。灌腸調配物一般藉由使用純化水或適當水性溶劑在某一量下將活性組分溶解或懸浮於溶劑或其類似者中且將產品裝入容器中來產生。可用於灌腸調配物之添加劑包括分散劑、穩定劑、pH控制劑及其類似者。 [經***調配物] (1)經***錠劑 Enema formulations are liquid or viscous gel formulations to be applied through the anus. Enema formulations are generally produced by dissolving or suspending the active ingredient in a certain amount in the solvent or the like using purified water or a suitable aqueous solvent and filling the product into a container. Additives that can be used in enema formulations include dispersants, stabilizers, pH control agents and the like. [Vaginal formulations] (1) transvaginal lozenge

經***錠劑為具有某一形狀之固體調配物，其應用於***中且藉由在水中逐步地溶解或分散來釋放活性組分。經***錠劑可一般根據上文針對錠劑所描述之產生程序來產生。 (2)經***栓劑 Vaginal lozenges are solid formulations of a certain shape that are applied in the vagina and release the active ingredient by gradually dissolving or dispersing in water. Vaginal lozenges can generally be produced according to the production procedures described above for lozenges. (2) transvaginal suppositories

經道陰栓劑為具有某一形狀之半固體調配物，其應用於***中且藉由在體溫下熔融或在水中逐步地溶解或分散來釋放活性組分。經***栓劑可一般根據上文針對經直腸栓劑及其類似者所描述之產生程序來產生。 [皮膚調配物] (1)外用固體調配物 Vaginal suppositories are semisolid formulations of a certain shape that are applied to the vagina and release the active ingredient by melting at body temperature or gradually dissolving or dispersing in water. Vaginal suppositories can generally be produced according to the production procedures described above for rectal suppositories and the like. [Skin formulation] (1) Solid formulations for external use

外用固體調配物為待應用或塗敷於包括頭皮或指甲之皮膚上之固體調配物且其實例包括外用粉劑。外用粉劑係指外用固體粉末調配物且可一般藉由將活性組分與諸如媒劑之添加劑混合以獲得隨後形成為粉劑之均質混合物來產生。 (2)外用液體 A solid formulation for external use is a solid formulation to be applied or spread on the skin including the scalp or nails and examples thereof include powders for external use. Powders for topical use refer to solid powder formulations for external use and can generally be produced by mixing the active ingredient with additives such as vehicles to obtain a homogeneous mixture which is then formed into a powder. (2) Liquid for external use

外用液體為待應用於包括頭皮或指甲之皮膚上之液體調配物且其實例包括擦劑、洗劑及其類似者。外用液體可一般藉由將活性組分溶解、乳化或懸浮於溶劑、添加劑及其類似者中且視情況過濾產品來產生。擦劑係指待擦進皮膚中之液體或混濁外用液體。洗劑係指含有溶解、乳化或細分散於水性液體中之活性組分之外用液體。洗劑可一般藉由製備活性組分、添加劑及純化水之溶液、懸浮液或乳液以獲得均質產品來產生。 (3)噴霧調配物 Topical liquids are liquid formulations to be applied to the skin including the scalp or nails and examples thereof include liniments, lotions, and the like. Liquids for external use can generally be produced by dissolving, emulsifying or suspending the active ingredient in solvents, additives and the like and optionally filtering the product. Liniments are liquids or cloudy topical liquids to be rubbed into the skin. Lotion means a topical liquid containing the active ingredient dissolved, emulsified or finely dispersed in an aqueous liquid. Lotions can generally be produced by preparing solutions, suspensions or emulsions of active ingredients, additives and purified water to obtain a homogeneous product. (3) Spray formulations

噴霧調配物為將呈霧狀物、粉末、發泡體或糊狀物之形式之活性組分噴灑在皮膚上的調配物且其實例包括外用噴霧劑、泵噴霧調配物及其類似者。噴霧調配物可一般藉由製備活性組分之溶液或懸浮液、視情況過濾產品且將產品裝入容器中來產生。外用噴霧劑係指噴灑活性組分以及包裝在容器中之液化氣體或壓縮氣體之噴霧調配物。外用噴霧劑可一般藉由製備活性組分之溶液或懸浮液且將產品與液體推進劑一起包裝至與連續噴射閥附接之耐壓容器中來產生。諸如分散劑及穩定劑之添加劑可視情況添加至外用噴霧劑。泵噴霧調配物係指藉助於泵噴灑容器中之活性組分之噴霧調配物。泵噴霧調配物可一般藉由溶解或懸浮活性組分及添加劑且將產品裝入泵附接至之容器中來產生。 (4)軟膏 Spray formulations are formulations in which the active ingredient in the form of a mist, powder, foam or paste is sprayed onto the skin and examples thereof include topical sprays, pump spray formulations and the like. Spray formulations can generally be produced by preparing a solution or suspension of the active ingredient, optionally filtering the product and filling the product into the container. Spray for external use means a spray formulation for spraying the active ingredient together with liquefied or compressed gas packed in a container. Topical sprays can generally be produced by preparing a solution or suspension of the active ingredient and packaging the product, with a liquid propellant, into a pressure-resistant container attached to a continuous spray valve. Additives such as dispersants and stabilizers are optionally added to topical sprays. Pump spray formulations are spray formulations in which the active ingredient in a container is sprayed by means of a pump. Pump spray formulations can generally be produced by dissolving or suspending the active ingredients and additives and filling the product into a container to which the pump is attached. (4) Ointment

軟膏為含有溶解或分散於基質中之活性組分之待應用於皮膚上的半固體調配物。其實例包括基於油或脂肪之軟膏、水溶性軟膏及其類似者。基於油或脂肪之軟膏可一般藉由以下各者來產生：藉由將活性組分加熱、溶解或懸浮於其中來熔融基於油或脂肪之基質，諸如油或脂肪、包括石蠟之蠟及烴類，且混合及捏合以獲得均質混合物。水溶性軟膏可一般藉由以下各者來產生：藉由將活性組分加熱及混合及捏合於其中來熔融諸如聚乙二醇之水溶性基質以獲得均質混合物。 (5)乳膏 Ointments are semisolid formulations to be applied to the skin containing the active ingredient dissolved or dispersed in a base. Examples thereof include oil or fat based ointments, water-soluble ointments and the like. Oil- or fat-based ointments can generally be produced by melting an oil- or fat-based base, such as oils or fats, waxes including paraffins, and hydrocarbons by heating, dissolving or suspending the active ingredient therein , and mixed and kneaded to obtain a homogeneous mixture. Water-soluble ointments can generally be produced by melting a water-soluble base such as polyethylene glycol by heating and mixing and kneading the active ingredients therein to obtain a homogeneous mixture. (5) cream

乳膏為呈水包油或油包水乳液之形式之待應用於皮膚上的半固體調配物且呈油包水乳液之形式之親油性調配物亦可稱為油基乳膏。乳膏可一般藉由以下各者產生：自凡士林或高級醇或其與諸如乳化劑之添加劑之混合物製備油相，單獨自純化水或其與諸如乳化劑之添加劑之混合物製備水相，將活性組分添加至油相或水相，加熱兩種相且將油相與水相混合直至均質以獲得乳液。 (6)凝膠 Creams are semi-solid formulations to be applied on the skin in the form of oil-in-water or water-in-oil emulsions and lipophilic formulations in the form of water-in-oil emulsions may also be called oil-based creams. Creams can generally be produced by preparing an oily phase from petrolatum or higher alcohols or their mixtures with additives such as emulsifiers, preparing an aqueous phase from purified water alone or their mixtures with additives such as emulsifiers, adding active The components are added to the oil phase or the water phase, both phases are heated and the oil and water phases are mixed until homogeneous to obtain an emulsion. (6) Gel

凝膠為待應用於皮膚上之凝膠調配物且其實例包括水基凝膠及油基凝膠。水基凝膠可一般藉由將活性組分溶解或懸浮於諸如聚合物化合物之添加劑及純化水中且藉由加熱及冷卻或添加膠凝劑實現交聯來產生。油基凝膠可藉由將活性組分與諸如二醇或高級醇之液體油基質及添加劑混合來產生。 (7)硬膏劑及壓敏黏著劑 A gel is a gel formulation to be applied on the skin and examples thereof include water-based gels and oil-based gels. Water-based gels can generally be produced by dissolving or suspending active components in additives such as polymer compounds and purified water and effecting cross-linking by heating and cooling or adding gelling agents. Oil-based gels can be produced by mixing the active ingredient with a liquid oil base such as glycols or higher alcohols and additives. (7) Plasters and pressure-sensitive adhesives

硬膏劑及壓敏黏著劑為待黏附於皮膚上之調配物且其實例包括膠帶及泥罨劑。硬膏劑及壓敏黏著劑可一般藉由將活性組分與作為聚合物化合物或其混合物之基質均質地混合、將混合物塗敷於支撐物或襯裡(釋放材料)上且將其塑形來產生。硬膏劑及壓敏黏著劑可形成為藉由使用釋放控制膜之經皮吸收調配物。諸如黏著劑或吸收促進劑之添加劑可視情況用於硬膏劑及壓敏黏著劑。膠帶係指含有包含極少水之基質之硬膏劑及壓感黏著劑且其實例包括硬膏劑及其類似者。膠帶可一般利用作為諸如樹脂、塑膠、橡膠或其類似者之不可溶於水之自然或合成聚合物化合物的基質藉由將活性組分或活性組分與添加劑之均質混合物塗敷於織物上或塗敷於塑膠膜上或併入塑膠膜中且將產品塑形來產生。膠帶亦可藉由將活性組分與基質或另一添加劑之混合物併入由釋放控制膜、支撐物及襯裡(釋放材料)製成之釋放材料中且將其塑形來產生。泥罨劑係指含有包含水之基質之硬膏劑及壓感黏著劑且可一般藉由將活性組分與諸如純化水或甘油之液體物質均質地混合或將諸如水溶性聚合物或吸水性聚合物之自然或合成聚合物化合物及純化水以及活性組分均質地混合及捏合、將混合物塗敷於織物或其類似者上且將其塑形來產生。Plasters and pressure sensitive adhesives are formulations to be adhered to the skin and examples thereof include tapes and poultices. Plasters and pressure-sensitive adhesives can generally be produced by homogeneously mixing the active ingredient with a base as a polymer compound or a mixture thereof, applying the mixture to a support or liner (release material) and shaping it . Plasters and pressure sensitive adhesives can be formed into transdermal formulations through the use of release controlling films. Additives such as adhesives or absorption enhancers are optionally used in plasters and pressure-sensitive adhesives. Tapes refer to plasters and pressure-sensitive adhesives containing a base containing little water and examples thereof include plasters and the like. Adhesive tapes can generally be utilized as a matrix of water-insoluble natural or synthetic polymer compounds such as resins, plastics, rubber or the like by applying the active ingredient or a homogeneous mixture of the active ingredient and additives to the fabric or It is produced by coating on or incorporating into a plastic film and shaping the product. Adhesive tapes can also be produced by incorporating a mixture of active components with a matrix or another additive into a release material made of release controlling film, support and liner (release material) and shaping it. Plasters are plasters and pressure-sensitive adhesives that contain a water-containing base and are prepared, generally, by mixing the active ingredient homogeneously with a liquid substance such as purified water or glycerin, or by mixing the active ingredient with a liquid substance such as a water-soluble polymer or a water-absorbing polymer. Natural or synthetic polymer compounds and purified water and active ingredients are mixed and kneaded homogeneously, the mixture is applied to fabrics or the like and shaped to produce it.

除非另外定義，否則本文中使用之所有技術及科學術語具有與本發明所屬領域之熟習此項技術者通常所理解之含義相同的含義。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

本文中明確地所引用之所有專利文獻及非專利文獻或參考之內容可併入本文中作為本說明書之一部分。 [實例] The contents of all patent documents and non-patent documents or references explicitly cited herein may be incorporated herein as part of this specification. [example]

本發明藉助於並不限制本發明之實例及生物實例在下文中特別加以描述。本發明化合物及實例中所描述之化合物根據IUPAC命名法來命名。根據IUPAC命名法之定名可使用例如ACD/Name (版本2019.2.0，可自高級化學發展公司(Advanced Chemistry Development Inc.)獲得)、ACD/Name Batch (版本12.02.45356，可自高級化學發展公司獲得)或ChemDraw Professional (版本17.1.0.105或18.0.0.231，可自珀金埃爾默公司(PerkinElmer Inc.)獲得)來完成。在以下實例中之每一者中，實例之目標化合物之名稱隨後經描述為實例之數目，且化合物有時稱為「標題化合物」。 分析方法 The invention is specifically described hereinafter by means of examples and biological examples which do not limit the invention. Compounds of the invention and those described in the Examples are named according to IUPAC nomenclature. Nomenclature according to IUPAC nomenclature can use e.g. ACD/Name (version 2019.2.0, available from Advanced Chemistry Development Inc.), ACD/Name Batch (version 12.02.45356, available from Advanced Chemistry Development Inc. obtained) or ChemDraw Professional (version 17.1.0.105 or 18.0.0.231, available from PerkinElmer Inc.). In each of the following examples, the name of the target compound of the example is described subsequently as the number of the example, and the compound is sometimes referred to as the "title compound". Analytical method

¹H NMR光譜經記錄於布魯克(Bruker) DRX-400儀器上且使用殘餘非氘化溶劑(分別在用於 ¹H NMR之7.26、2.50及3.31 ppm下之CHCl ₃、DMSO、MeOH)。化學位移(δ)以百萬分率為單位給出且參考適當NMR溶劑峰值且根據編號圖來指定；其中共振經描述為s (單峰)、d (二重峰)、t (三重峰)、q (四重峰)、其組合(亦即td指示二重峰之三重峰)或m (多重峰)及br s (寬單峰)。 ¹ H NMR spectra were recorded on a Bruker DRX-400 instrument and using residual non-deuterated solvents (CHCl ₃ , DMSO, MeOH at 7.26, 2.50 and 3.31 ppm for ¹ H NMR, respectively). Chemical shifts (δ) are given in parts per million and are referenced to the appropriate NMR solvent peak and assigned according to the numbered map; where resonances are described as s (singlet), d (doublet), t (triplet) , q (quartet), combinations thereof (ie td indicates triplet for a doublet) or m (multiplet) and br s (broad singlet).

所使用之液相層析質譜(LCMS)系統為： 通用 LCMS 程序 方法 1島津(Simadzu) LC20-MS2010，安捷倫盆斯特(Agilent Pursit) 5 C ₁₈20 × 2.0 mm，在50℃下。溶離用A：於4 L水中之1.5 mL TFA；B：於乙腈中之0.75 mL TFA。梯度： 梯度 - 時間        流速mL/min        %A           %B 0.00                           1.5           95            5 0.70                           1.5           5             95 1.10                           1.5           5             95 1.11                           1.5           95            5 1.50                           1.5           95            5 偵測 - MS，UV 220，254nm。MS電離方法 - 電噴射(陽離子)。 方法 2 ：島津LC20-MS2010，X橋盾(Xbridge Shield) RP-18，5 um，2.1 × 50mm，在50℃下。溶離用A：於4 L水中之0.8 mL NH ₃-H2O；B：乙腈。梯度： 梯度 - 時間        流速mL/min        %A          %B 0.00                           1.0           50            50 2.00                           1.0           0             100 2.48                           1.0           0             100 2.49                           1.0           5             50 3.00                           1.0           50            50 偵測 - MS，UV 220，254nm。MS電離方法 - 電噴射(陽離子)。 管柱：X橋(XBridge) C18 3.5um 2.1 × 50mm； The liquid chromatography mass spectrometry (LCMS) system used was: general LCMS program method 1 Shimadzu LC20-MS2010, Agilent Pursit 5 C ₁₈ 20×2.0 mm at 50°C. Elution with A: 1.5 mL TFA in 4 L water; B: 0.75 mL TFA in acetonitrile. Gradient: Gradient - Time Flow Rate mL/min %A %B 0.00 1.5 95 5 0.70 1.5 5 95 1.10 1.5 5 95 1.11 1.5 95 5 1.50 1.5 95 5 Detection - MS, UV 220, 254nm. MS Ionization Method - Electrospray (Cation). Method 2 : Shimadzu LC20-MS2010, Xbridge Shield RP-18, 5 um, 2.1 × 50mm, at 50°C. For elution A: 0.8 mL NH ₃ -H2O in 4 L of water; B: Acetonitrile. Gradient: Gradient - Time Flow Rate mL/min %A %B 0.00 1.0 50 50 2.00 1.0 0 100 2.48 1.0 0 100 2.49 1.0 5 50 3.00 1.0 50 50 Detection - MS, UV 220, 254nm. MS Ionization Method - Electrospray (Cation). Pipe string: XBridge C18 3.5um 2.1 × 50mm;

所使用高效液相層析(HPLC)系統為： 通用 HPLC 程序 方法 1島津20A，終極(Ultimate) C ₁₈3.0 × 50 mm，3um，在40℃下。溶離用A：於4 L水中之2.75 mL TFA；B：於乙腈中之2.5 mL TFA。梯度： 梯度 - 時間        流速mL/min        %A          %B 0.00                           1.2           70            30 6.00                           1.2           10            90 8.00                           1.2           10            90 8.01                           1.2           70            30 10.00                          1.2           70            30 偵測 - MS，UV 220，254nm。MS電離方法 - 電噴射(陽離子)。 方法 2島津20A，終極C ₁₈3.0 × 50 mm，3um，在40℃下。溶離用A：於4 L水中之2.75 mL TFA；B：於乙腈中之2.5 mL TFA。梯度： 梯度 - 時間        流速mL/min        %A          %B 0.00                           1.2           90            10 6.00                           1.2           20            80 8.00                           1.2           20            80 8.01                           1.2           90            10 10.00                          1.2           90            10 偵測 - MS，UV 220，254nm。MS電離方法 - 電噴射(陽離子)。 方法 3 ：島津LC20-MS2020，X橋盾RP-18，5 um，2.1 × 50 mm，在50℃下。溶離用A：於4 L水中之0.8 mL NH ₃·H ₂O；B：乙腈。梯度： 梯度 - 時間        流速mL/min        %A          %B 0.00                           0.8           90            10 6.00                           0.8           20            80 6.50                           0.8           20            80 6.51                           0.8           90            10 7.00                           0.8           90            10 偵測 - MS，UV 220，254nm。MS電離方法 - 電噴射(陽離子)。 The high performance liquid chromatography (HPLC) system used was: general HPLC procedure method 1 Shimadzu 20A, Ultimate (Ultimate) C ₁₈ 3.0×50 mm, 3um, at 40°C. Elution with A: 2.75 mL TFA in 4 L water; B: 2.5 mL TFA in acetonitrile. Gradient: Gradient - Time Flow Rate mL/min %A %B 0.00 1.2 70 30 6.00 1.2 10 90 8.00 1.2 10 90 8.01 1.2 70 30 10.00 1.2 70 30 Detection - MS, UV 220, 254nm. MS Ionization Method - Electrospray (Cation). Method 2 Shimadzu 20A, Ultimate C ₁₈ 3.0 × 50 mm, 3um, at 40°C. Elution with A: 2.75 mL TFA in 4 L water; B: 2.5 mL TFA in acetonitrile. Gradient: Gradient - Time Flow Rate mL/min %A %B 0.00 1.2 90 10 6.00 1.2 20 80 8.00 1.2 20 80 8.01 1.2 90 10 10.00 1.2 90 10 Detection - MS, UV 220, 254nm. MS Ionization Method - Electrospray (Cation). Method 3 : Shimadzu LC20-MS2020, X-Bridge Shield RP-18, 5 um, 2.1 × 50 mm, at 50°C. Elution A: 0.8 mL NH ₃ ·H ₂ O in 4 L water; B: Acetonitrile. Gradient: Gradient - Time Flow Rate mL/min %A %B 0.00 0.8 90 10 6.00 0.8 20 80 6.50 0.8 20 80 6.51 0.8 90 10 7.00 0.8 90 10 Detection - MS, UV 220, 254nm. MS Ionization Method - Electrospray (Cation).

所使用對掌性超臨界流體層析(SFC)系統為: 對掌性 SFC 程序 方法 1 ：管柱：ChiralPak AD-3 150 × 4.6 mm I.D.，3 um 行動相：A: CO ₂B:IPA (0.05% DEA) 等度：40% B 流速：2.5 mL/min 管柱溫度：40℃ 背壓：100 bar 方法 2 ：管柱：Chiralcel OJ-3 150 × 4.6 mm I.D.，3 um 行動相：A: CO ₂B: EtOH (0.05% DEA) 梯度：B在5 min內自5 %至40 %且B在0.5 min內自40 %至5 %，B在1.5 min內保持5 % 流速：2.5 mL/min 管柱溫度：35℃ ABPR：1500 psi 方法 3 ：管柱：Chiralcel OD-3 150 × 4.6 mm I.D.，3 um 行動相：A: CO ₂B: EtOH (0.05 % DEA) 梯度：B在5 min內自5 %至40 %且B在0.5 min內自40 %至5 %，B在1.5 min內保持5 % 流速：2.5 mL/min 管柱溫度：35℃ ABPR：1500 psi The chiral supercritical fluid chromatography (SFC) system used is: chiral SFC program method 1 : column: ChiralPak AD-3 150 × 4.6 mm ID, 3 um action phase: A: CO ₂ B:IPA ( 0.05% DEA) Isocratic: 40% B Flow rate: 2.5 mL/min Column temperature: 40°C Back pressure: 100 bar Method 2 : Column: Chiralcel OJ-3 150 × 4.6 mm ID, 3 um Mobile phase: A: CO ₂ B: EtOH (0.05% DEA) Gradient: B from 5 % to 40 % in 5 min and B from 40 % to 5 % in 0.5 min, B at 5 % in 1.5 min Flow rate: 2.5 mL/min Column temperature: 35℃ ABPR: 1500 psi Method 3 : Column: Chiralcel OD-3 150 × 4.6 mm ID, 3 um Mobile phase: A: CO ₂ B: EtOH (0.05 % DEA) Gradient: B within 5 min From 5 % to 40 % and B from 40 % to 5 % within 0.5 min, B within 1.5 min at 5 % Flow rate: 2.5 mL/min Column temperature: 35°C ABPR: 1500 psi

縮寫2-MeTHF = 2-甲基四氫呋喃； 4A MS = 分子篩，4A； DAST = N,N-二乙基胺基硫三氟化物； DCM = 二氯甲烷； DE = 二***； DEA = 二乙胺； DIPEA = 二異丙基乙胺； DMF = N,N-二甲基甲醯胺； DMP = 戴斯-馬丁高碘烷； DMSO = 二甲亞碸； dppf = 1,1'-二茂鐵雙(二苯基膦)； EA = 乙酸乙酯； EDCI = 1-乙基-3-(3-二甲胺基丙基)碳化二亞胺； HATU =1-[雙(二甲胺基)亞甲基]-1H-1,2,3-***并[4,5-b]吡啶鎓3-氧化物六氟磷酸酯； MTBE = 甲基三級丁基醚； NBS = N-溴丁二醯亞胺； NCS = N-氯丁二醯亞胺； PE = 石油醚； TBHP = 三級丁基氫過氧化物； TEA = 三乙胺； TFA = 三氟乙酸； THF = 四氫呋喃； TLC = 薄層層析法且 X-Phos = 2-二環己基膦基-2',4',6'-三異丙基聯二苯。 Abbreviations 2-MeTHF = 2-methyltetrahydrofuran; 4A MS = molecular sieve, 4A; DAST = N,N-diethylaminosulfur trifluoride; DCM = dichloromethane; DE = diethyl ether; DEA = diethylamine ; DIPEA = diisopropylethylamine; DMF = N,N-dimethylformamide; DMP = Dess-Martin periodinane; DMSO = dimethylsulfoxide; dppf = 1,1'-ferrocene Bis(diphenylphosphine); EA = ethyl acetate; EDCI = 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; HATU = 1-[bis(dimethylamino) Methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; MTBE = methyl tertiary butyl ether; NBS = N-bromobutyl NCS = N-chlorobutadiimide; PE = petroleum ether; TBHP = tertiary butyl hydroperoxide; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = TLC and X-Phos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

實例 1 [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮 (1R,5S,6r)-6-[(E)-( 羥亞胺基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向 (1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(藥石公司(Pharmablock Inc.)，目錄號PBG0012) (2 g，9.47 mmol)於EtOH (20 mL)中之溶液添加AcOH (0.54 mL，9.47 mmol，1.0當量)、KOAc (0.93 g，9.47 mmol，1.0當量)。隨後向混合物添加NH ₂OH·HCl (0.47 mL，11.36 mmol)。將混合物在25℃下攪拌2小時，得到白色懸浮液。將反應混合物傾入H ₂O (40 mL)中且用EtOAc (40 mL × 3)萃取。用鹽水(60 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈白色固體狀之標題化合物。 TLC：Rf=0.4，PE:EtOAc = 3 : 1； LC-MS方法1 0.694 min，MS (m/z) 170.8 (M -tBu, + H ⁺)； ¹H NMR (400MHz, 氯仿-d) δ = 7.16 (d, J = 7.6 Hz, 0.5H), 6.13 (d, J = 8.8 Hz, 0.5H), 3.75-3.55 (m, 2H), 3.50-3.35 (m, 2H), 2.23-2.15 (m, 0.5H), 2.10 (s, 1.5H), 1.80 (brs, 1H), 1.44 (s, 9H)。 Example 1 [(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ](1- isopropyl -1H- imidazol -4- yl ) methanone (1R,5S,6r)-6-[(E)-( hydroxyimino ) methyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R, 5S,6r)-tertiary-butyl 6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (Pharmablock Inc., catalog number PBG0012) (2 g, 9.47 mmol) in EtOH (20 mL) was added AcOH (0.54 mL, 9.47 mmol, 1.0 equiv), KOAc (0.93 g, 9.47 mmol, 1.0 equiv). Then NH ₂ OH·HCl (0.47 mL, 11.36 mmol) was added to the mixture. The mixture was stirred at 25 °C for 2 hours to give a white suspension. The reaction mixture was poured into H ₂ O (40 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were washed _with brine (60 mL), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give the title compound as a white solid. TLC: Rf=0.4, PE:EtOAc = 3 : 1; LC-MS method 1 0.694 min, MS (m/z) 170.8 (M -tBu, + H ⁺ ); ¹ H NMR (400MHz, chloroform-d) δ = 7.16 (d, J = 7.6 Hz, 0.5H), 6.13 (d, J = 8.8 Hz, 0.5H), 3.75-3.55 (m, 2H), 3.50-3.35 (m, 2H), 2.23-2.15 (m , 0.5H), 2.10 (s, 1.5H), 1.80 (brs, 1H), 1.44 (s, 9H).

(1R,5S,6r)-6-[(Z)- 氯基 ( 羥亞胺基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(E)-(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(2.2g，9.72 mmol)於DMF (18.4 mL)中之溶液添加N-氯丁二醯亞胺(1363 mg，10.21 mmol)，將混合物在20℃下攪拌2小時。將混合物傾入H ₂O (90 mL)中，由EtOAc (50 mL × 3)萃取。用鹽水(50 mL × 3)洗滌有機相，經無水Na ₂SO ₄乾燥，濃縮，得到呈白色固體狀之標題化合物。 LC-MS方法1 0.780 min，MS (m/z) 245.9 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 8.42 (s, 1H), 3.75 (d, J=11.2 Hz, 1H), 3.64 (d, J = 10.8 Hz, 1H), 3.38 (d, J = 10.8 Hz, 2H), 2.06 (s, 2H), 1.76 (t, J = 3.2 Hz, 1H), 1.45 (s, 9H). (1R,5S,6r)-6-[(Z) -Chloro ( hydroxyimino ) methyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to ( 1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (2.2g, 9.72 mmol) in DMF (18.4 mL) was added N-chlorobutadiimide (1363 mg, 10.21 mmol), and the mixture was stirred at 20°C for 2 hours. The mixture was poured into H ₂ O (90 mL), extracted with EtOAc (50 mL×3). The organic phase was washed with brine (50 mL _x 3), dried over anhydrous _Na2SO4 , concentrated to give the title compound as a white solid. LC-MS method 1 0.780 min, MS (m/z) 245.9 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 8.42 (s, 1H), 3.75 (d, J=11.2 Hz, 1H), 3.64 (d, J = 10.8 Hz, 1H), 3.38 (d, J = 10.8 Hz, 2H), 2.06 (s, 2H), 1.76 (t, J = 3.2 Hz, 1H), 1.45 (s, 9H).

(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.38 mmol)及Et ₃N (0.19 mL，1.15 mmol)於DMF (1.0 mL)中之溶液添加2-甲基丙-1-烯(0.72 mL，1.15 mmol) (於異丙基醚中15%)，且將混合物在20℃下攪拌16小時。將反應混合物傾入H ₂O (20 mL)中，用EtOAc (20 mL × 3)萃取。用鹽水(20 mL × 3)洗滌有機相，經無水Na ₂SO ₄乾燥，濃縮，得到呈黃色油狀之標題化合物(100 mg，0.356 mmol，92.9 %產率)。 LC-MS方法1 0.852 min，MS (m/z): 281 (M + H ⁺)。 ¹H NMR (400 MHz, 二甲亞碸-d6) δ ppm 3.50 (d, J=11.1 Hz, 2H), 3.30 (d, J = 10.8 Hz, 2H), 2.61 (s, 2H), 1.91 (t, J = 2.7 Hz, 2H), 1.40-1.38 (m, 1H), 1.37 (s, 9H), 1.23 (s, 6H)。 (1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexane -3- Carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane- To a solution of tertiary-butyl 3-carboxylate (100 mg, 0.38 mmol) and Et ₃ N (0.19 mL, 1.15 mmol) in DMF (1.0 mL) was added 2-methylprop-1-ene (0.72 mL, 1.15 mmol) (15% in isopropyl ether), and the mixture was stirred at 20°C for 16 hours. The reaction mixture was poured into H ₂ O (20 mL), extracted with EtOAc (20 mL×3). The organic phase was washed with brine (20 mL x 3), dried over anhydrous Na ₂ SO ₄ , concentrated to give the title compound (100 mg, 0.356 mmol, 92.9% yield) as a yellow oil. LC-MS method 1 0.852 min, MS (m/z): 281 (M + H ⁺ ). ¹ H NMR (400 MHz, dimethylsulfoxide-d6) δ ppm 3.50 (d, J=11.1 Hz, 2H), 3.30 (d, J = 10.8 Hz, 2H), 2.61 (s, 2H), 1.91 (t , J = 2.7 Hz, 2H), 1.40-1.38 (m, 1H), 1.37 (s, 9H), 1.23 (s, 6H).

(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷氫氯化物在20℃下攪拌(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.36 mmol)於HCl/二㗁烷(2.0 mL，8.0 mmol，4.0 M)中之混合物0.5小時。濃縮混合物，得到呈黃色油狀之標題化合物(100 mg，0.46 mmol，129 %產率，粗物質)。 LC-MS方法1 0.232 min，MS (m/z): 181 (M -HCl+ H ⁺)。 ¹H NMR (400 MHz, 二甲亞碸-d6) δ ppm 9.53 (brs, 1H), 9.06 (brs, 1H), 3.40-3.26 (m, 4H), 2.60 (s, 2H), 2.12 (brs, 2H), 1.99 (m, 1H), 1.23 (s, 6H)。 (1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexane (1R,5S,6r)-6-(5,5 - dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-aza A mixture of tert-butyl bicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.36 mmol) in HCl/dioxane (2.0 mL, 8.0 mmol, 4.0 M) for 0.5 h. The mixture was concentrated to afford the title compound (100 mg, 0.46 mmol, 129% yield, crude material) as a yellow oil. LC-MS method 1 0.232 min, MS (m/z): 181 (M -HCl+ H ⁺ ). ¹ H NMR (400 MHz, dimethylsulfoxide-d6) δ ppm 9.53 (brs, 1H), 9.06 (brs, 1H), 3.40-3.26 (m, 4H), 2.60 (s, 2H), 2.12 (brs, 2H), 1.99 (m, 1H), 1.23 (s, 6H).

[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮向 (1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(100 mg，0.46 mmol)、1-異丙基咪唑-4-羧酸(92 mg，0.6 mmol)及DIPEA (0.38 mL，2.31 mmol)於DMF (3.0 mL)中之溶液添加HATU (194 mg，0.51 mmol)，且在20℃下攪拌混合物16小時。將混合物傾入H ₂O (30 mL)中，由EtOAc萃取。用鹽水洗滌有機相，經無水Na ₂SO ₄乾燥，濃縮，得到殘餘物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈白色固體狀之標題化合物(4 mg，0.012 mmol，2.7 %產率)。 ¹H NMR (400 MHz, CDCl ₃- d) : δ ppm 1.38 (s, 6 H) 1.46 (t, J=3.5 Hz, 1 H) 1.51 (d, J=6.8 Hz, 6 H) 1.98 (br d, J=3.5 Hz, 1 H) 2.08 (br d, J=3.0 Hz, 1 H) 2.64 (s, 2 H) 3.62 (dd, J=12.5, 4.5 Hz, 1 H) 3.95 (dd, J=11.9, 3.6 Hz, 1 H) 4.20 (d, J=12.5 Hz, 1 H) 4.36 (dt, J=13.5, 6.7 Hz, 1 H) 4.75 (d, J=12.0 Hz, 1 H) 7.47 (d, J=1.3 Hz, 1 H) 7.67 (d, J=1.5 Hz, 1 H) LCMS 方法1 0.65 min MS (m/z) 317.0 [M+H ⁺] [(1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ](1- isopropyl -1H- imidazol -4 - yl ) methanone to (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1 ,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (100 mg, 0.46 mmol), 1-isopropylimidazole-4-carboxylic acid (92 mg, 0.6 mmol) and DIPEA (0.38 mL, 2.31 mmol) in DMF (3.0 mL) was added HATU (194 mg, 0.51 mmol) and the mixture was stirred at 20°C for 16 hours. The mixture was poured into _H2O (30 mL), extracted with EtOAc. _The organic phase was washed with brine, dried over anhydrous _Na2SO4 , concentrated to give a residue. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (4 mg, 0.012 mmol, 2.7 % yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ - d ) : δ ppm 1.38 (s, 6 H) 1.46 (t, J =3.5 Hz, 1 H) 1.51 (d, J =6.8 Hz, 6 H) 1.98 (br d , J =3.5 Hz, 1 H) 2.08 (br d, J =3.0 Hz, 1 H) 2.64 (s, 2 H) 3.62 (dd, J =12.5, 4.5 Hz, 1 H) 3.95 (dd, J =11.9 , 3.6 Hz, 1 H) 4.20 (d, J =12.5 Hz, 1 H) 4.36 (dt, J =13.5, 6.7 Hz, 1 H) 4.75 (d, J =12.0 Hz, 1 H) 7.47 (d, J =1.3 Hz, 1 H) 7.67 (d, J =1.5 Hz, 1 H) LCMS method 1 0.65 min MS (m/z) 317.0 [M+H ⁺ ]

實例 2 [(1R,5S,6r)-6-(5,5- 二甲基 - 4,5- 二氫 - 1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 - 3- 基 ](1- 甲基 -1H- 咪唑 -4- 基 ) 甲酮 [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 甲基 -1H- 咪唑 -4- 基 ) 甲酮向1-甲基-1H-咪唑-4-羧酸(52.47 mg，0.42 mmol)、EDCI (79.76 mg，0.42 mmol)於吡啶(1.0 mL)中之混合物添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(91 mg，0.42 mmol)。在20℃下攪拌懸浮液8小時。真空濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物且凍乾，獲得呈黃色固體狀之標題化合物(17.45 mg，21.8 %產率)。 LC-MS方法1：0.691 min，MS (m/z): 289.2 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.56 (d, J=1.25 Hz, 1 H), 7.38 (s, 1 H), 4.70 (d, J=12.05 Hz, 1 H), 4.19 (d, J=12.30 Hz, 1 H), 3.94 (dd, J=12.05, 4.02 Hz, 1 H), 3.72 (s, 3 H), 3.61 (dd, J=12.55, 4.27 Hz, 1 H), 2.64 (s, 2 H), 2.05 - 2.11 (m, 1 H), 1.95 - 2.01 (m, 1 H), 1.46 (t, J=3.39 Hz, 1 H), 1.38 (s, 6 H) Example 2 [(1R,5S,6r)-6-(5,5- Dimethyl - 4,5- dihydro - 1,2 - oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex - 3- yl ](1- methyl - 1H- imidazol -4 - yl ) methanone [(1R,5S,6r)-6-(5,5- dimethyl - 4,5- dihydro- 1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ](1- methyl -1H- imidazol -4- yl ) methanone to 1-methyl- A mixture of 1H-imidazole-4-carboxylic acid (52.47 mg, 0.42 mmol), EDCI (79.76 mg, 0.42 mmol) in pyridine (1.0 mL) was added to (1R,5S,6r)-6-(5,5-di Methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (91 mg, 0.42 mmol). The suspension was stirred at 20°C for 8 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC ( _NH3 ) and lyophilized to obtain the title compound (17.45 mg, 21.8% yield) as a yellow solid. LC-MS method 1: 0.691 min, MS (m/z): 289.2 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.56 (d, J =1.25 Hz, 1 H), 7.38 (s, 1 H), 4.70 (d, J =12.05 Hz, 1 H), 4.19 (d , J =12.30 Hz, 1 H), 3.94 (dd, J =12.05, 4.02 Hz, 1 H), 3.72 (s, 3 H), 3.61 (dd, J =12.55, 4.27 Hz, 1 H), 2.64 ( s, 2H), 2.05 - 2.11 (m, 1H), 1.95 - 2.01 (m, 1H), 1.46 (t, J =3.39 Hz, 1H), 1.38 (s, 6H)

實例 3 [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 乙基 -1H- 咪唑 -4- 基 ) 甲酮 1- 乙基 -1H- 咪唑 -4- 羧酸 乙 酯在40℃下攪拌(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯及乙胺(1608.2 mg，35.67 mmol，1.60mL，20 eq)之混合物16小時。隨後真空濃縮溶液。藉由製備型TLC (PE:EtOAc=0:1，Rf=0.2)純化殘餘物，得到呈黃色油狀物之標題化合物(126 mg，粗物質)。 LC-MS方法1: 0.259 min，MS (m/z): 168.8(M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.64 (s, 1H), 7.51 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.04 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H)。 Example 3 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ](1- ethyl -1H- imidazol -4- yl ) methanone 1- ethyl -1H- imidazole -4- carboxylic acid ethyl ester was stirred at 40° C. (2Z)-3-( A mixture of ethyl dimethylamino)-2-isocyanoacrylate and ethylamine (1608.2 mg, 35.67 mmol, 1.60 mL, 20 eq ) for 16 hours. The solution was then concentrated in vacuo. The residue was purified by prep-TLC (PE:EtOAc=0:1, Rf=0.2) to give the title compound (126 mg, crude) as a yellow oil. LC-MS method 1: 0.259 min, MS (m/z): 168.8 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.64 (s, 1H), 7.51 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.04 (q, J = 7.2 Hz, 2H) , 1.39 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 3H).

1- 乙基 -1H- 咪唑 -4- 羧酸向1-乙基-1H-咪唑-4-羧酸乙酯於H ₂O (0.5 mL)及THF (1.5 mL)中之混合物添加LiOH·H ₂O (47.16 mg，1.12 mmol，1.5 eq)。在40 ℃下攪拌懸浮液6小時。用H ₂O (1 mL)稀釋殘餘物，用EtOAc (5mL × 4)萃取。用1 N HCl水溶液將所獲得H ₂O層鹼化至pH=5，濃縮合併之有機層，且隨後凍乾，得到呈黃色固體狀之標題化合物(70 mg，粗物質)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.69 (s, 1H), 7.45 (s, 1H), 3.98 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H)。 1- Ethyl -1H- imidazole -4- carboxylic acid To a mixture of ethyl 1-ethyl-1H-imidazole-4-carboxylate in _H2O (0.5 mL) and THF (1.5 mL) was added LiOH·H ₂ O (47.16 mg, 1.12 mmol, 1.5 eq ). The suspension was stirred at 40 °C for 6 hours. The residue was diluted with H ₂ O (1 mL), extracted with EtOAc (5 mL×4). The obtained _H2O layer was basified to pH = 5 with 1 N aqueous HCl, the combined organic layers were concentrated and then lyophilized to give the title compound (70 mg, crude) as a yellow solid. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.69 (s, 1H), 7.45 (s, 1H), 3.98 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H) .

[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 乙基 -1H- 咪唑 -4- 基 ) 甲酮向1-乙基-1H-咪唑-4-羧酸於吡啶(1 mL)中之混合物添加EDCI (95.54 mg，0.50 mmol)及(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(72 mg，0.33mmol)。在20℃下攪拌懸浮液16小時。藉由製備型HPLC (NH ₃)純化溶液且凍乾，得到呈黃色固體狀之標題化合物(23.69 mg，23.58%產率)。 LC-MS方法1: 2.045min，MS (m/z): 303.2 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.54 (d, J=1.25 Hz, 1 H) 7.35 (d, J=1.25 Hz, 1 H) 4.65 (d, J=12.05 Hz, 1 H) 4.12 (d, J=12.30 Hz, 1 H) 3.94 (q, J=7.28 Hz, 2 H) 3.87 (dd, J=12.05, 4.02 Hz, 1 H) 3.54 (dd, J=12.55, 4.27 Hz, 1 H) 2.57 (s, 2 H) 2.00 (dt, J=7.47, 3.92 Hz, 1 H) 1.91 (br d, J=3.76 Hz, 1 H) 1.37 - 1.44 (m, 4 H) 1.30 (s, 7 H) [(1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ](1- ethyl -1H- imidazol -4- yl ) methanone To a mixture of 1-ethyl-1H-imidazole-4-carboxylic acid in pyridine (1 mL) was added EDCI (95.54 mg, 0.50 mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1. 0] Hexane hydrochloride (72 mg, 0.33 mmol). The suspension was stirred at 20°C for 16 hours. The solution was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (23.69 mg, 23.58% yield) as a yellow solid. LC-MS method 1: 2.045min, MS (m/z): 303.2 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.54 (d, J =1.25 Hz, 1 H) 7.35 (d, J =1.25 Hz, 1 H) 4.65 (d, J =12.05 Hz, 1 H) 4.12 (d, J =12.30 Hz, 1 H) 3.94 (q, J =7.28 Hz, 2 H) 3.87 (dd, J =12.05, 4.02 Hz, 1 H) 3.54 (dd, J =12.55, 4.27 Hz, 1 H ) 2.57 (s, 2 H) 2.00 (dt, J =7.47, 3.92 Hz, 1 H) 1.91 (br d, J =3.76 Hz, 1 H) 1.37 - 1.44 (m, 4 H) 1.30 (s, 7 H )

實例 4  (1- 環丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 1- 環丙基 -1H- 咪唑 -4- 羧酸 甲 酯向於DCE (30 mL)中之2,2'-聯吡啶(618.79 mg，3.96 mmol)、Cu(OAc) ₂(720.01 mg，3.96 mmol)、Na ₂CO ₃(840.54 mg，7.93 mmol)之懸浮液添加1H-咪唑-4-羧酸甲酯(500 mg，3.96 mmol)及環丙基硼酸(cyclopropylboronic acid) (681.15 mg，7.93 mmol)。在70 ℃下在O ₂下攪拌混合物16小時。TLC (PE:EtOAc = 1:4)顯示反應完成。將反應混合物冷卻至23 ℃。藉由過濾移除固體且真空濃縮濾液。藉由快速柱純化殘餘物(PE至20% EtOAc/PE)。在減壓下濃縮合併之有機層，得到呈褐色油狀之標題化合物(140 mg，0.8425 mmol，21.249%產率)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.66 (s, 1H), 7.60 (s, 1H), 3.87 (s, 3H), 3.42-3.36 (m, 1H), 1.10-0.90 (m, 4H)。 Example 4 (1- cyclopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazole -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 1- cyclopropyl -1H- imidazole -4- carboxylic acid methyl ester in DCE (30 mL) , to a suspension of 2'-bipyridine (618.79 mg, 3.96 mmol), Cu(OAc) ₂ (720.01 mg, 3.96 mmol), Na ₂ CO ₃ (840.54 mg, 7.93 mmol) was added 1H-imidazole-4-carboxylic acid Methyl ester (500 mg, 3.96 mmol) and cyclopropylboronic acid (681.15 mg, 7.93 mmol). The mixture was stirred at 70 °C under _O for 16 h. TLC (PE:EtOAc = 1:4) showed the reaction was complete. The reaction mixture was cooled to 23 °C. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column (PE to 20% EtOAc/PE). The combined organic layers were concentrated under reduced pressure to afford the title compound (140 mg, 0.8425 mmol, 21.249% yield) as a brown oil. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.66 (s, 1H), 7.60 (s, 1H), 3.87 (s, 3H), 3.42-3.36 (m, 1H), 1.10-0.90 (m, 4H ).

1- 環丙基 -1H- 咪唑 -4- 羧酸向1-環丙基-1H-咪唑-4-羧酸甲酯(140 mg，0.84 mmol)於THF (3 mL)及H ₂O (1 mL)中之溶液添加LiOH·H ₂O (0.06 mL，1.1 mmol)。在20至25 ℃下攪拌所得混合物2小時，得到白色懸浮液。TLC (PE:EtOAc = 1:4)展示反應完成(Rf = 0)。直接濃縮反應混合物。用1 M HCl水溶液將殘餘物酸化至pH = 6，隨後凍乾合併之有機層，得到呈白色固體狀之標題化合物(120 mg，0.7887 mmol，93.618%產率)。 1- cyclopropyl -1H- imidazole -4- carboxylic acid to 1-cyclopropyl-1H-imidazole-4-carboxylic acid methyl ester (140 mg, 0.84 mmol) in THF (3 mL) and H ₂ O (1 mL) was added LiOH·H ₂ O (0.06 mL, 1.1 mmol). The resulting mixture was stirred at 20 to 25 °C for 2 hours to give a white suspension. TLC (PE:EtOAc = 1:4) showed the reaction was complete (Rf = 0). The reaction mixture was directly concentrated. The residue was acidified to pH = 6 with 1 M aqueous HCl, then the combined organic layers were lyophilized to afford the title compound (120 mg, 0.7887 mmol, 93.618% yield) as a white solid.

(1- 環丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-環丙基-1H-咪唑-4-羧酸(120 mg，0.79 mmol)於DMF (3mL)中之溶液添加HATU (361.82 mg，0.95 mmol)、Et ₃N (0.51 mL，3.94mmol)、(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(142.16 mg，0.79 mmol)。在20至25℃下攪拌所得混合物14小時。藉由製備型HPLC (HCl)純化殘餘物。濃縮合併之有機層且隨後凍乾，得到呈淺黃色膠質之標題化合物(4.8 mg，0.0137 mmol，1.7347%產率)。 LC-MS方法1: 315.0 [M+H ⁺] ¹H NMR (400MHz, 甲醇-d ₄) δ = 8.68 - 8.33 (m, 1H), 7.91 (br s, 1H), 4.10 - 3.84 (m, 3H), 3.60 (br d, J=4.8 Hz, 2H), 2.63 (s, 2H), 2.16 - 1.99 (m, 2H), 1.44 (br s, 1H), 1.24 (s, 7H), 1.07 (d, J=6.5 Hz, 4H)。 (1- cyclopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazol -3 -yl ) -3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-cyclopropyl-1H-imidazole-4-carboxylic acid (120 mg, 0.79 mmol) in DMF (3 mL) HATU (361.82 mg, 0.95 mmol), Et ₃ N (0.51 mL, 3.94 mmol), (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1 ,2-(azol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (142.16 mg, 0.79 mmol). The resulting mixture was stirred at 20 to 25°C for 14 hours. The residue was purified by preparative HPLC (HCl). The combined organic layers were concentrated and then lyophilized to afford the title compound (4.8 mg, 0.0137 mmol, 1.7347% yield) as a pale yellow gum. LC-MS method 1: 315.0 [M+H ⁺ ] ¹ H NMR (400MHz, methanol-d ₄ ) δ = 8.68 - 8.33 (m, 1H), 7.91 (br s, 1H), 4.10 - 3.84 (m, 3H ), 3.60 (br d, J =4.8 Hz, 2H), 2.63 (s, 2H), 2.16 - 1.99 (m, 2H), 1.44 (br s, 1H), 1.24 (s, 7H), 1.07 (d, J =6.5 Hz, 4H).

實例 5  (1- 環丁基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 1- 環丁基 -1H- 咪唑 -4- 羧酸 乙 酯在50℃下加熱(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(400 mg，2.38mmol)及環丁胺(1.02mL，11.89mmol)之混合物16小時。真空濃縮混合物，隨後藉由快速柱純化殘餘物(0至100% EA/PE，0.5% NH ₃-H ₂O)，得到呈黃色油狀物之標題化合物(420mg，2.1624mmol，90.923%產率)。 LC-MS方法1 0.568 min，MS (M/Z) 194.9 (M + H ⁺)。 Example 5 (1- cyclobutyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazole -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 1- cyclobutyl -1H- imidazole -4- carboxylic acid ethyl ester heated at 50°C (2Z)-3 - A mixture of ethyl (dimethylamino)-2-isocyanoacrylate (400 mg, 2.38 mmol) and cyclobutylamine (1.02 mL, 11.89 mmol) for 16 hours. The mixture was concentrated in vacuo and the residue was purified by flash column (0 to 100% EA/PE, 0.5% _NH3 - _H20 ) to give the title compound (420 mg, 2.1624 mmol, 90.923% yield) as a yellow oil ). LC-MS method 1 0.568 min, MS (M/Z) 194.9 (M + H ⁺ ).

1- 環丁基 -1H- 咪唑 -4- 羧酸向1-環丁基-1H-咪唑-4-羧酸乙酯(100 mg，0.5100mmol)於THF (0.8578mL)及H ₂O (1.0722mL)中之混合物添加LiOH·H ₂O (0.09mL，1.54mmol)。隨後在20℃下攪拌所得懸浮液3.5小時。TLC (100%EA)展示新樣點(Rf=0)且反應物完全耗盡。用DCM (3mL×2)洗滌水相且用1N HCl酸化至pH=2。凍乾殘餘水溶液，得到呈淡黃色固體狀之標題化合物(160mg，0.9628mmol，187.01%產率)。 ¹H NMR (400 MHz, D ₂O) δ ppm 8.77 (s, 1H), 8.03 (s, 1H), 4.85-4.75 (m, 1H), 2.50-2.40 (m, 2H), 2.40-2.30 (m, 2H), 1.90-1.75 (m, 2H)。 1- Cyclobutyl -1H- imidazole -4- carboxylic acid was transferred to 1-cyclobutyl-1H-imidazole-4-carboxylic acid ethyl ester (100 mg, 0.5100mmol) in THF (0.8578mL) and H ₂ O (1.0722 mL) was added LiOH·H ₂ O (0.09 mL, 1.54 mmol). The resulting suspension was then stirred at 20°C for 3.5 hours. TLC (100% EA) showed a fresh spot (Rf=0) and the reactant was completely consumed. The aqueous phase was washed with DCM (3 mL x 2) and acidified to pH=2 with 1 N HCl. The residual aqueous solution was lyophilized to give the title compound (160 mg, 0.9628 mmol, 187.01% yield) as a light yellow solid. ¹ H NMR (400 MHz, D ₂ O) δ ppm 8.77 (s, 1H), 8.03 (s, 1H), 4.85-4.75 (m, 1H), 2.50-2.40 (m, 2H), 2.40-2.30 (m , 2H), 1.90-1.75 (m, 2H).

(1- 環丁基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-環丁基-1H-咪唑-4-羧酸(110 mg，0.5400mmol)於DMF (0.9736mL)中之混合物添加HATU (247.8mg，0.6500mmol)、DIPEA (0.45mL，2.7mmol)及(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(97.36mg，0.5400mmol)。在20℃下攪拌所得混合物4小時。用H ₂O (5 mL)稀釋反應混合物，用EtOAc (5mL×2)萃取。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型TLC (EA/MeOH=10/1)、隨後製備型HPLC (NH ₃)純化粗物質油且凍乾，得到呈淡黃色固體狀之標題化合物(12.15mg，0.0370mmol，6.8494%產率)。 LC-MS方法1: 328.9 [M+H+] ¹H NMR (400MHz, DMSO-d ₆) δ = 8.03 (d, J=1.3 Hz, 1H), 7.99 (s, 1H), 4.96 - 4.89 (m, 1H), 4.75 (br d, J=12.0 Hz, 1H), 4.12 (br d, J=12.3 Hz, 1H), 3.99 (br d, J=9.0 Hz, 1H), 3.66 (br s, 1H), 2.83 (s, 2H), 2.57 (t, J=8.7 Hz, 4H), 2.25 (br d, J=11.3 Hz, 1H), 2.17 (br s, 1H), 2.00 - 1.90 (m, 2H), 1.60 - 1.57 (m, 1H), 1.44 (s, 6H) (1- cyclobutyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazol -3 -yl ) -3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-cyclobutyl-1H-imidazole-4-carboxylic acid (110 mg, 0.5400mmol) in DMF (0.9736mL) HATU (247.8mg, 0.6500mmol), DIPEA (0.45mL, 2.7mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1, 2-(azol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (97.36 mg, 0.5400 mmol). The resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with H ₂ O (5 mL), extracted with EtOAc (5 mL×2). The combined organic _layers were separated, then dried over _Na2SO4 and concentrated in vacuo to give a crude oil. The crude oil was purified by prep-TLC (EA/MeOH=10/1 ), followed by prep-HPLC (NH ₃ ) and lyophilized to afford the title compound (12.15 mg, 0.0370 mmol, 6.8494% yield) as a light yellow solid. Rate). LC-MS method 1: 328.9 [M+H+] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.03 (d, J =1.3 Hz, 1H), 7.99 (s, 1H), 4.96 - 4.89 (m, 1H), 4.75 (br d, J =12.0 Hz, 1H), 4.12 (br d, J =12.3 Hz, 1H), 3.99 (br d, J =9.0 Hz, 1H), 3.66 (br s, 1H), 2.83 (s, 2H), 2.57 (t, J =8.7 Hz, 4H), 2.25 (br d, J =11.3 Hz, 1H), 2.17 (br s, 1H), 2.00 - 1.90 (m, 2H), 1.60 - 1.57 (m, 1H), 1.44 (s, 6H)

實例 6  [1-( 雙環 [1.1.1] 戊 -1- 基 )-1H- 咪唑 -4- 基 ][(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 1-( 雙環 [1.1.1] 戊 -1- 基 )-1H- 咪唑 -4- 羧酸 乙 酯向(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(100 mg，0.5900mmol)於1-丁醇(0.40 mL)中之混合物添加雙環[1.1.1]戊-1-胺(284.42mg，2.38mmol)及Et ₃N (0.58mL，4.46mmol)。在76℃下加熱所得混合物16小時。用H ₂O (5 mL)稀釋反應混合物且用EtOAc (5mL×3)萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色油狀之標題化合物(100 mg，粗產物)。 Example 6 [1-( bicyclo [1.1.1] pent - 1- yl )-1H- imidazol -4- yl ][(1R,5S,6r)-6-(5,5- dimethyl -4,5 -Dihydro - 1,2 - oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 1-( bicyclo [1.1.1] pent -1 - yl )- 1H- imidazole -4- carboxylic acid ethyl ester to (2Z)-3-(dimethylamino)-2-isocyanoacrylate ethyl ester (100 mg, 0.5900 mmol) in 1-butanol (0.40 mL) The mixture was added bicyclo[1.1.1]pentan-1-amine (284.42mg, 2.38mmol) and _Et3N (0.58mL, 4.46mmol). The resulting mixture was heated at 76°C for 16 hours. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo to give the title compound (100 mg, crude) as a yellow oil.

1-( 雙環 [1.1.1] 戊 -1- 基 )-1H- 咪唑 -4- 羧酸向1-(雙環[1.1.1]戊-1-基)-1H-咪唑-4-羧酸乙酯(100 mg，0.4800mmol)於H ₂O (1mL)及MeOH (0.80 mL)中之混合物添加LiOH.H ₂O (0.06mL，0.9700mmol)。在25℃下攪拌反應物16小時。用DCM (3mL×2)洗滌水相且用1N HCl酸化至pH = 2。凍乾水溶液，得到呈淡黃色固體狀之標題化合物(50mg，0.2806mmol，粗產物)。 1-( bicyclo [1.1.1] pent -1- yl )-1H- imidazole -4- carboxylic acid to 1-(bicyclo[1.1.1]pent-1-yl)-1H-imidazole-4-carboxylic acid ethyl A mixture of ester (100 mg, 0.4800 mmol) in _H2O (1 mL) and MeOH (0.80 mL) was added _LiOH.H2O (0.06 mL, 0.9700 mmol). The reaction was stirred at 25°C for 16 hours. The aqueous phase was washed with DCM (3 mL x 2) and acidified to pH = 2 with 1 N HCl. The aqueous solution was lyophilized to give the title compound (50 mg, 0.2806 mmol, crude) as a pale yellow solid.

[1-( 雙環 [1.1.1] 戊 -1- 基 )-1H- 咪唑 -4- 基 ][(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-(雙環[1.1.1]戊-1-基)-1H-咪唑-4-羧酸(59.54mg，0.2800mmol)於DMF (0.50 mL)中之混合物添加HATU (137.86mg，0.3600mmol)、DIPEA (0.18mL，1.11mmol)及(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(50mg，0.2800mmol)。在20℃下攪拌所得混合物4小時。用H ₂O (5 mL)稀釋反應混合物且用EtOAc (5mL×2)萃取，分離合併之有機層，用鹽水(8mL)洗滌，經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型HPLC (NH ₃)純化粗物質油，得到呈黃色固體狀之標題化合物(2.4mg，0.0071mmol，2.5416%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ = 7.76 (d, J=1.0 Hz, 1H), 7.71 (d, J=1.3 Hz, 1H), 4.53 (br d, J=11.8 Hz, 1H), 3.93 (br d, J=12.0 Hz, 1H), 3.81 (br dd, J=3.6, 11.9 Hz, 1H), 3.47 (br dd, J=3.6, 11.9 Hz, 1H), 2.65 (s, 2H), 2.24 (s, 6H), 2.08 - 1.93 (m, 3H), 1.40 (t, J=3.4 Hz, 1H), 1.26 - 1.25 (m, 1H), 1.25 (s, 5H)。 [1-( bicyclo [1.1.1] pent -1- yl )-1H- imidazol -4- yl ][(1R,5S,6r)-6-(5,5- dimethyl - 4,5- di Hydrogen -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-(bicyclo[1.1.1]pent-1-yl)-1H -A mixture of imidazole-4-carboxylic acid (59.54 mg, 0.2800 mmol) in DMF (0.50 mL) was added with HATU (137.86 mg, 0.3600 mmol), DIPEA (0.18 mL, 1.11 mmol) and (1R,5S,6r)- 6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50mg, 0.2800mmol ). The resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (5 mL×2), the combined organic layers were separated, washed with brine (8 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude oil. The crude oil was purified by preparative HPLC ( _NH3 ) to afford the title compound (2.4 mg, 0.0071 mmol, 2.5416% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.76 (d, J =1.0 Hz, 1H), 7.71 (d, J =1.3 Hz, 1H), 4.53 (br d, J =11.8 Hz, 1H), 3.93 (br d, J =12.0 Hz, 1H), 3.81 (br dd, J =3.6, 11.9 Hz, 1H), 3.47 (br dd, J =3.6, 11.9 Hz, 1H), 2.65 (s, 2H), 2.24 (s, 6H), 2.08 - 1.93 (m, 3H), 1.40 (t, J =3.4 Hz, 1H), 1.26 - 1.25 (m, 1H), 1.25 (s, 5H).

實例 7  (1- 環戊基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 1- 環戊基 -1H- 咪唑 -4- 羧酸 乙 酯在50℃下加熱(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(200 mg，1.19mmol)及環戊基胺(0.58mL，5.95mmol)之混合物16小時。真空濃縮混合物。藉由快速柱(0至100% EA/PE，0.5% NH ₃H ₂O)純化殘餘物，得到呈黃色油狀之標題化合物(240mg，1.1524mmol，96.912%產率)。 LC-MS方法1 0.668 min，MS (M/Z) 209.1 (M + H ⁺)。 Example 7 (1- cyclopentyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazole -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 1- cyclopentyl -1H- imidazole -4- carboxylic acid ethyl ester heated at 50°C (2Z)-3 - A mixture of ethyl (dimethylamino)-2-isocyanoacrylate (200 mg, 1.19 mmol) and cyclopentylamine (0.58 mL, 5.95 mmol) for 16 hours. The mixture was concentrated in vacuo. The residue was purified by flash column (0 to 100% EA/PE, 0.5% _NH3H2O ) to give _the title compound (240 mg, 1.1524 mmol, 96.912% yield) as a yellow oil. LC-MS method 1 0.668 min, MS (M/Z) 209.1 (M + H ⁺ ).

1- 環戊基 -1H- 咪唑 -4- 羧酸向1-環戊基-1H-咪唑-4-羧酸乙酯(100 mg，0.4800mmol)於THF (0.80 mL)及H ₂O (1mL)中之混合物添加LiOH·H ₂O (0.08mL，1.44mmol)。在25℃下攪拌反應混合物3.5小時。用DCM (3mL × 2)洗滌水相且用1N HCl酸化至pH=2。凍乾殘餘水溶液，得到呈淡黃色固體狀之標題化合物(150mg，粗產物)。 ¹H NMR (400 MHz, D ₂O) δ ppm 8.73 (s, 1H), 7.90 (s, 1H), 4.75-4.70 (m, 1H), 2.25-2.10 (m, 2H), 1.90-1.60 (m, 6H)。 1- cyclopentyl -1H- imidazole -4- carboxylic acid was dissolved in THF (0.80 mL) and H ₂ O (1 mL ) was added LiOH·H ₂ O (0.08 mL, 1.44 mmol). The reaction mixture was stirred at 25°C for 3.5 hours. The aqueous phase was washed with DCM (3 mL x 2) and acidified to pH=2 with 1 N HCl. The residual aqueous solution was lyophilized to give the title compound (150 mg, crude product) as a light yellow solid. ¹ H NMR (400 MHz, D ₂ O) δ ppm 8.73 (s, 1H), 7.90 (s, 1H), 4.75-4.70 (m, 1H), 2.25-2.10 (m, 2H), 1.90-1.60 (m , 6H).

(1- 環戊基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-環戊基-1H-咪唑-4-羧酸(60.38mg，0.2800mmol)於DMF (0.50 mL)中之混合物添加HATU (137.86mg，0.3600mmol)、DIPEA (0.18mL，1.11mmol)及(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(50mg，0.2800mmol)。在20℃下攪拌所得混合物4小時。用H ₂O (5 mL)稀釋反應混合物且用EtOAc (5mL×2)萃取。分離合併之有機層，用鹽水(8mL)洗滌，經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型TLC (EA/MeOH=10/1)、隨後製備型HPLC (NH ₃)純化粗物質油且凍乾，得到呈白色固體狀之標題化合物(11mg，0.0321mmol，4.6614%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ = 7.78 (d, J=1.3 Hz, 1H), 7.73 (d, J=1.3 Hz, 1H), 4.66 - 4.51 (m, 2H), 3.93 (br d, J=12.3 Hz, 1H), 3.81 (br d, J=6.5 Hz, 1H), 3.47 (br d, J=11.8 Hz, 1H), 2.65 (s, 2H), 2.19 - 2.03 (m, 3H), 1.99 (br d, J=6.0 Hz, 1H), 1.79 (br s, 4H), 1.64 (br s, 2H), 1.25 (s, 7H) (1- cyclopentyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazol -3 -yl ) -3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-cyclopentyl-1H-imidazole-4-carboxylic acid (60.38 mg, 0.2800 mmol) in DMF (0.50 mL) HATU (137.86mg, 0.3600mmol), DIPEA (0.18mL, 1.11mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1, 2-(azol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50 mg, 0.2800 mmol). The resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (5 mL×2). The combined organic layers were separated, washed with brine (8 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude oil. The crude oil was purified by prep-TLC (EA/MeOH=10/1 ), followed by prep-HPLC (NH ₃ ) and lyophilized to afford the title compound (11 mg, 0.0321 mmol, 4.6614% yield) as a white solid . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.78 (d, J =1.3 Hz, 1H), 7.73 (d, J =1.3 Hz, 1H), 4.66 - 4.51 (m, 2H), 3.93 (br d , J =12.3 Hz, 1H), 3.81 (br d, J =6.5 Hz, 1H), 3.47 (br d, J =11.8 Hz, 1H), 2.65 (s, 2H), 2.19 - 2.03 (m, 3H) , 1.99 (br d, J =6.0 Hz, 1H), 1.79 (br s, 4H), 1.64 (br s, 2H), 1.25 (s, 7H)

實例 8  (1- 環己基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 1- 環己基 -1H- 咪唑 -4- 羧酸 乙 酯在50℃下加熱(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(200 mg，1.19mmol)及環己基胺(0.68mL，5.95mmol)之混合物16小時。真空濃縮混合物。藉由快速柱(0至100% EA/PE，0.5% NH ₃H ₂O)純化殘餘物，得到呈黃色油狀之標題化合物(280mg，1.2597mmol，105.93%產率)。 LC-MS方法1 0.719 min，MS (m/z) 223.1 (M + H ⁺)。 Example 8 (1- cyclohexyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro - 1,2- oxazole- 3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 1- cyclohexyl -1H- imidazole -4- carboxylic acid ethyl ester was heated at 50°C (2Z)-3-( A mixture of ethyl dimethylamino)-2-isocyanoacrylate (200 mg, 1.19 mmol) and cyclohexylamine (0.68 mL, 5.95 mmol) for 16 hours. The mixture was concentrated in vacuo. The residue was purified by flash column (0 to 100% EA/PE, 0.5% _NH3H2O ) to give _the title compound (280 mg, 1.2597 mmol, 105.93% yield) as a yellow oil. LC-MS method 1 0.719 min, MS (m/z) 223.1 (M + H ⁺ ).

1- 環己基 -1H- 咪唑 -4- 羧酸向1-環己基-1H-咪唑-4-羧酸乙酯(110 mg，0.4900mmol)於THF (0.80 mL)及H ₂O (1mL)中之混合物添加LiOH·H ₂O (0.09mL，1.48mmol)，隨後在25℃下攪拌5小時。TLC (100%EA)展示新樣點(Rf=0)且反應物完全耗盡。用DCM (3mL×2)洗滌水相且用1N HCl酸化至pH=2。凍乾殘餘水溶液，得到呈淡黃色固體狀之標題化合物(190mg，粗產物)。 ¹H NMR (400 MHz, 甲醇- d ₄) δ ppm 9.05 (s, 1H), 8.30 (s, 1H), 4.36-4.30 (m, 1H), 2.20-2.17 (m, 2H), 1.92-1.82 (m, 2H), 1.80-1.73 (m, 3H), 1.60-1.40 (m, 2H), 1.40-1.25 (m, 1H)。 1- Cyclohexyl -1H- imidazole -4- carboxylic acid To 1-cyclohexyl-1H-imidazole-4-carboxylic acid ethyl ester (110 mg, 0.4900 mmol) in THF (0.80 mL) and H ₂ O (1 mL) LiOH·H ₂ O (0.09 mL, 1.48 mmol) was added to the mixture, followed by stirring at 25° C. for 5 hours. TLC (100% EA) showed a fresh spot (Rf=0) and the reactant was completely consumed. The aqueous phase was washed with DCM (3 mL x 2) and acidified to pH=2 with 1 N HCl. The residual aqueous solution was lyophilized to give the title compound (190 mg, crude product) as a light yellow solid. ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 9.05 (s, 1H), 8.30 (s, 1H), 4.36-4.30 (m, 1H), 2.20-2.17 (m, 2H), 1.92-1.82 ( m, 2H), 1.80-1.73 (m, 3H), 1.60-1.40 (m, 2H), 1.40-1.25 (m, 1H).

(1- 環己基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-環己基-1H-咪唑-4-羧酸(64.27mg，0.2800mmol)於DMF (0.50 mL)中之混合物添加HATU (106.05mg，0.2800mmol)、DIPEA (0.18mL，1.11mmol)及(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(50mg，0.2800mmol)。在20℃下攪拌所得混合物4小時。用H ₂O (5 mL)稀釋反應混合物且用EtOAc (5mL×2)萃取。分離合併之有機層，經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型TLC (EA/MeOH=10/1)純化粗物質油隨後凍乾，得到呈白色粉末狀之標題化合物(9.5mg，0.0267mmol，9.6077%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ = 7.77 (d, J=5.5 Hz, 2H), 4.58 (br d, J=12.0 Hz, 1H), 4.14 - 4.02 (m, 1H), 3.93 (br d, J=12.0 Hz, 1H), 3.80 (br d, J=8.5 Hz, 1H), 3.51 - 3.43 (m, 1H), 2.64 (s, 2H), 2.05 (br s, 1H), 1.95 (br d, J=12.3 Hz, 3H), 1.80 (br d, J=13.3 Hz, 2H), 1.72 - 1.61 (m, 3H), 1.41 - 1.29 (m, 3H), 1.25 (s, 7H) (1- cyclohexyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- Base )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-cyclohexyl-1H-imidazole-4-carboxylic acid (64.27mg, 0.2800mmol) in DMF (0.50 mL) The mixture was added with HATU (106.05 mg, 0.2800 mmol), DIPEA (0.18 mL, 1.11 mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2- (Zazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50 mg, 0.2800 mmol). The resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (5 mL×2). The combined organic layers were separated, dried _{over Na2SO4} and concentrated in vacuo to give a crude oil. The crude oil was purified by prep-TLC (EA/MeOH=10/1) followed by lyophilization to afford the title compound (9.5 mg, 0.0267 mmol, 9.6077% yield) as a white powder. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.77 (d, J =5.5 Hz, 2H), 4.58 (br d, J =12.0 Hz, 1H), 4.14 - 4.02 (m, 1H), 3.93 (br d, J =12.0 Hz, 1H), 3.80 (br d, J =8.5 Hz, 1H), 3.51 - 3.43 (m, 1H), 2.64 (s, 2H), 2.05 (br s, 1H), 1.95 (br d, J =12.3 Hz, 3H), 1.80 (br d, J =13.3 Hz, 2H), 1.72 - 1.61 (m, 3H), 1.41 - 1.29 (m, 3H), 1.25 (s, 7H)

實例 9  [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-(1,1,1- 三氟丙 -2- 基 )-1H- 咪唑 -4- 基 ] 甲酮 1-(1,1,1- 三氟丙 -2- 基 )-1H- 咪唑 -4- 羧酸 乙 酯在-78℃向1,1,1-三氟-2-丙胺(403.4mg，3.57mmol)於2-MeTHF (3 mL，1.19mmol)中之溶液添加n-BuLi (1.43mL，3.57mmol)。在-78℃下攪拌反應混合物15 min。隨後添加(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(200 mg，1.19mmol)。將反應混合物升溫至25℃歷時0.5小時，得到黑色溶液。將反應混合物傾入EtOH (5 mL)中且濃縮。藉由快速柱(PE至100% EtOAc/PE)純化粗產物。藉由製備型TLC (EtOAc)純化所獲得殘餘物，得到呈褐色油狀之標題化合物(50mg，0.2117mmol，17.802%產率)。 Example 9 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ][1-(1,1,1- trifluoroprop -2- yl )-1H- imidazol -4- yl ] methanone 1-(1,1,1- trifluoroprop -2 -Ethyl ) -1H- imidazole -4- carboxylate to 1,1,1-trifluoro-2- propylamine (403.4 mg, 3.57 mmol) in 2-MeTHF (3 mL, 1.19 mmol) at -78 °C To the solution was added n-BuLi (1.43 mL, 3.57 mmol). The reaction mixture was stirred at -78 °C for 15 min. Then ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (200 mg, 1.19 mmol) was added. The reaction mixture was warmed to 25 °C for 0.5 h to give a black solution. The reaction mixture was poured into EtOH (5 mL) and concentrated. The crude product was purified by flash column (PE to 100% EtOAc/PE). The obtained residue was purified by prep-TLC (EtOAc) to give the title compound (50 mg, 0.2117 mmol, 17.802% yield) as a brown oil.

1-(1,1,1- 三氟丙 -2- 基 )-1H- 咪唑 -4- 羧酸向1-(1,1,1-三氟丙-2-基)-1H-咪唑-4-羧酸乙酯(50 mg，0.2100mmol)於THF (1.5mL)及H ₂O (0.3mL，16.67mmol)中之溶液添加羥基鋰水合物(26.65mg，0.6400mmol)。在20℃下攪拌混合物3小時，得到黑色溶液。LCMS展示起始材料(50 mg，0.2100mmol)剩餘。在40℃下攪拌混合物12小時，得到黑色溶液。直接濃縮反應混合物。用1 N HCl水溶液將所獲得H ₂O層酸化至pH=5至6且凍乾，得到呈褐色固體狀之標題化合物(30mg，0.1441mmol，68.086%產率)。 1-(1,1,1- trifluoroprop -2- yl )-1H- imidazole -4- carboxylic acid to 1-(1,1,1-trifluoroprop-2-yl)-1H-imidazole-4 - To a solution of ethyl carboxylate (50 mg, 0.2100 mmol) in THF (1.5 mL) and _H2O (0.3 mL, 16.67 mmol) was added hydroxylithium hydrate (26.65 mg, 0.6400 mmol). The mixture was stirred at 20 °C for 3 hours to obtain a black solution. LCMS showed starting material (50 mg, 0.2100 mmol) remaining. The mixture was stirred at 40°C for 12 hours to obtain a black solution. The reaction mixture was directly concentrated. The obtained _H2O layer was acidified to pH = 5-6 with 1 N aqueous HCl and lyophilized to give the title compound (30 mg, 0.1441 mmol, 68.086% yield) as a brown solid.

[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-(1,1,1- 三氟丙 -2- 基 )-1H- 咪唑 -4- 基 ] 甲酮向1-(1,1,1-三氟丙-2-基)-1H-咪唑-4-羧酸(30 mg，0.1400mmol)於DMF (1.5mL)中之溶液添加HATU (66.12mg，0.1700mmol)、DIPEA (0.12mL，0.7200mmol)。攪拌混合物30 min。隨後向混合物添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(36.48mg，0.1400mmol)。在25℃下攪拌混合物3小時，得到褐色溶液。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈白色粉末狀之標題化合物(16.87mg，0.0455mmol，17.802%產率)。 LC-MS方法1: 371.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.72 (1 H, s) 7.53 (1 H, s) 4.59 - 4.78 (2 H, m) 4.19 (1 H, dd, J=12.80, 5.77 Hz) 3.95 (1 H, dd, J=12.05, 7.91, 4.14 Hz) 3.63 (1 H, br d, J=12.30 Hz) 2.65 (2 H, s) 2.09 (1 H, m d, J=3.76 Hz) 2.01 (1 H, m d, J=6.53 Hz) 1.76 (3 H, d, J=7.28 Hz) 1.44 - 1.50 (1 H, m) 1.38 (6 H, s) [(1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ][1-(1,1,1- trifluoropropan -2- yl )-1H- imidazol -4- yl ] methanone to 1-(1,1,1-trifluoropropan-2- HATU (66.12mg, 0.1700mmol), DIPEA (0.12mL, 0.7200mmol) was added to a solution of 1H-1H-imidazole-4-carboxylic acid (30 mg, 0.1400mmol) in DMF (1.5mL). The mixture was stirred for 30 min. (1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1. 0] Hexane hydrochloride (36.48 mg, 0.1400 mmol). The mixture was stirred at 25 °C for 3 hours to give a brown solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (NH ₃ ) to afford the title compound (16.87 mg, 0.0455 mmol, 17.802% yield) as a white powder. LC-MS method 1: 371.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.72 (1 H, s) 7.53 (1 H, s) 4.59 - 4.78 (2 H, m) 4.19 (1 H, dd, J =12.80, 5.77 Hz) 3.95 (1 H, dd, J =12.05, 7.91, 4.14 Hz) 3.63 (1 H, br d, J =12.30 Hz) 2.65 (2 H, s) 2.09 (1 H, md, J =3.76 Hz) 2.01 (1 H, md, J =6.53 Hz) 1.76 (3 H, d, J =7.28 Hz) 1.44 - 1.50 (1 H, m) 1.38 (6 H, s )

實例 10      [(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(2S)-3- 甲基丁 -2- 基 ]-1H- 咪唑 -4- 基 } 甲酮 (R)-2- 甲基 -N-[(1E)-2- 甲基亞丙基 ]-2- 丙烷亞磺醯胺在20℃下向 (R)-三級BuS(O)NH ₂(8403.83mg，69.34mmol)於THF (36.369mL)中之溶液添加2-甲基丙醛(6.3mL，69.34mmol)及Ti(OEt) ₄(21.57mL，104.01mmol)。在60℃下攪拌所得混合物0.5小時，得到黃色溶液。逐滴添加H ₂O (3 mL)且在20℃下將其攪拌5 min，隨後經由矽藻土墊過濾且真空濃縮，得到呈白色固體狀之標題化合物(8330mg，47.521mmol，68.535%產率)。其直接用於下一步驟。 LC-MS方法1 0.825 min，MS (m/z) 176.2 (M + H ⁺)。 Example 10 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ]{1-[(2S)-3- methylbut -2- yl ]-1H- imidazol -4- yl } methanone (R)-2- methyl -N-[(1E )-2- methylpropylene ]-2- propanesulfinamide to (R)-tertiary BuS(O)NH ₂ (8403.83mg, 69.34mmol) in THF (36.369mL) at 20°C To the solution was added 2-methylpropanal (6.3 mL, 69.34 mmol) and Ti(OEt) ₄ (21.57 mL, 104.01 mmol). The resulting mixture was stirred at 60 °C for 0.5 hours to obtain a yellow solution. _H2O (3 mL) was added dropwise and stirred at 20 °C for 5 min, then filtered through a pad of celite and concentrated in vacuo to afford the title compound (8330 mg, 47.521 mmol, 68.535% yield) as a white solid. ). It was used directly in the next step. LC-MS method 1 0.825 min, MS (m/z) 176.2 (M + H ⁺ ).

(R)-2- 甲基 -N-[(2S)-3- 甲基 -2- 丁基 ]-2- 丙烷亞磺醯胺向冷卻至-40℃之 (R)-2-甲基-N-[(1E)-2-甲基亞丙基]-2-丙烷亞磺醯胺(2500 mg，14.26mmol)於THF (30mL)中之經攪拌溶液逐滴添加MeMgBr (5.7mL，17.11mmol)。在-40℃下攪拌反應物3小時且在13小時內緩慢地升溫直至20℃。TLC (DCM/EA=6/1，RF=0.3)展示兩個新樣點。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(PE/EA=10/1至3/1)來純化粗物質，得到呈無色油狀之標題化合物(2200 mg，11.498mmol，80.623%產率)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 3.35-3.10 (m, 1H), 2.90-2.75 (m, 1H), 1.80-1.60 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H), 1.20 (s, 9H), 0.886 (d, J = 6.8 Hz, 3H), 0.871 (d, J = 6.8 Hz, H)。 (R)-2- methyl -N-[(2S)-3- methyl -2- butyl ]-2- propanesulfinamide To a stirred solution of N-[(1E)-2-methylpropylene]-2-propanesulfinamide (2500 mg, 14.26 mmol) in THF (30 mL) was added MeMgBr (5.7 mL, 17.11 mmol) dropwise. ). The reaction was stirred at -40°C for 3 hours and slowly warmed to 20°C over 13 hours. TLC (DCM/EA=6/1, RF=0.3) showed two new samples. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (PE/EA=10/1 to 3/1) to give the title compound (2200 mg, 11.498 mmol, 80.623% yield) as a colorless oil. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 3.35-3.10 (m, 1H), 2.90-2.75 (m, 1H), 1.80-1.60 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H ), 1.20 (s, 9H), 0.886 (d, J = 6.8 Hz, 3H), 0.871 (d, J = 6.8 Hz, H).

(2S)-3- 甲基 -2- 丁胺在20℃下攪拌(R)-2-甲基-N-[(2S)-3-甲基-2-丁基]-2-丙烷亞磺醯胺(2200 mg，11.5mmol)於HCl/MeOH (10 mL，40mmol)中之溶液4小時，得到無色溶液。真空蒸發反應混合物，得到白色固體。其用甲苯/PE=1/6濕磨，得到呈白色固體狀之標題化合物(1350 mg，10.921 mmol)。 (2S)-3- Methyl -2- butylamine Stirring (R)-2-methyl-N-[(2S)-3-methyl-2-butyl]-2-propanesulfinic acid at 20°C A solution of the amide (2200 mg, 11.5 mmol) in HCl/MeOH (10 mL, 40 mmol) for 4 hours gave a colorless solution. The reaction mixture was evaporated in vacuo to give a white solid. It was triturated with toluene/PE=1/6 to afford the title compound (1350 mg, 10.921 mmol) as a white solid.

1-[(2S)-3- 甲基丁 -2- 基 ]-1H- 咪唑 -4- 羧酸 乙 酯向5 mL微波小瓶添加(2S)-3-甲基-2-丁胺(500 mg，4.04mmol)、(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(680.27mg，4.04mmol)、1-丁醇(3mL)及Et ₃N (0.84mL，6.07mmol)。在130℃下用微波照射反應混合物1小時，得到褐色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(PE/EA=10/1至3/2)來純化粗物質，得到呈褐色油狀之標題化合物(161mg，0.7657mmol，18.931%產率)。 LC-MS方法1 0.691 min，MS (m/z) 211.2 (M + H ⁺)。 1-[(2S)-3- Methylbutan -2- yl ]-1H- imidazole -4- carboxylic acid ethyl ester To a 5 mL microwave vial was added (2S)-3-methyl-2-butylamine (500 mg , 4.04mmol), (2Z)-3-(dimethylamino)-2-isocyanoacrylate ethyl ester (680.27mg, 4.04mmol), 1-butanol (3mL) and Et ₃ N (0.84mL, 6.07 mmol). The reaction mixture was irradiated with microwaves at 130 °C for 1 hour to give a brown solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (PE/EA=10/1 to 3/2) to give the title compound (161 mg, 0.7657 mmol, 18.931% yield) as a brown oil. LC-MS method 1 0.691 min, MS (m/z) 211.2 (M + H ⁺ ).

1-[(2S)-3- 甲基丁 -2- 基 ]-1H- 咪唑 -4- 羧酸向1-[(2S)-3-甲基丁-2-基]-1H-咪唑-4-羧酸乙酯(150.0 mg，0.7600mmol)於1,4-二㗁烷(3mL)中之經攪拌溶液添加LiOH·H ₂O (48.11mg，1.15mmol)之溶液。在20℃下攪拌反應混合物4小時，得到黃色溶液。添加H ₂O (10 mL)且用EtOAc (10 mL×2)對其進行萃取。用1M HCl水溶液將H ₂O相調整為5且凍乾，得到呈褐色固體狀之標題化合物(110mg，0.6037mmol，78.98%產率)。 LC-MS方法1 0.306 min，MS (m/z) 183.0 (M + H ⁺)。 1-[(2S)-3- methylbut - 2- yl ]-1H- imidazole -4- carboxylic acid to 1-[(2S)-3-methylbut-2-yl]-1H-imidazole-4 - To a stirred solution of ethyl carboxylate (150.0 mg, 0.7600 mmol) in 1,4-dioxane (3 mL) was added a solution of LiOH·H ₂ O (48.11 mg, 1.15 mmol). The reaction mixture was stirred at 20 °C for 4 hours to obtain a yellow solution. H ₂ O (10 mL) was added and it was extracted with EtOAc (10 mL×2). The _H2O phase was adjusted to 5 with 1 M aq. HCl and lyophilized to afford the title compound (110 mg, 0.6037 mmol, 78.98% yield) as a tan solid. LC-MS method 1 0.306 min, MS (m/z) 183.0 (M + H ⁺ ).

[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(2S)-3- 甲基丁 -2- 基 ]-1H- 咪唑 -4- 基 } 甲酮向1-[(2S)-3-甲基丁-2-基]-1H-咪唑-4-羧酸(100 mg，0.5500mmol)及HATU (251.76mg，0.6600mmol)於DMF (3mL)中之經攪拌溶液添加N-乙基-N-異丙基丙-2-胺(0.47mL，2.74mmol)。在攪拌30 min之後，添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(138.94mg，0.5500mmol)且在20℃下攪拌反應物16小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (NH ₃)純化粗物質且凍乾，得到呈白色固體狀之標題化合物(108.71mg，0.3156mmol，57.509%產率)。 LC-MS方法1: 345.3 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ 7.61 (d, J=1.00 Hz, 1H), 7.40 (d, J=1.25 Hz, 1H), 4.76 (br d, J=12.05 Hz, 1H), 4.18 (d, J=12.55 Hz, 1H), 3.94 (br dd, J=4.02, 11.80 Hz, 1H), 3.84 (quin, J=7.09 Hz, 1H), 3.61 (dd, J=4.27, 12.55 Hz, 1H), 2.64 (s, 2H), 2.07 (br dd, J=3.51, 7.28 Hz, 1H), 1.95-1.99 (m, 1H), 1.87-1.94 (m, 1H), 1.47 (d, J=6.78 Hz, 4H), 1.36 (s, 6H), 0.96 (d, J=6.78 Hz, 3H), 0.78 (d, J=6.53 Hz, 3H)。 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ]{1-[(2S)-3- methylbut -2- yl ]-1H- imidazol -4- yl } methanone to 1-[(2S)-3-methylbutan-2- N-ethyl-N-isopropylpropane- 2-Amine (0.47 mL, 2.74 mmol). After stirring for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo [3.1.0] Hexane hydrochloride (138.94mg, 0.5500mmol) and the reaction was stirred at 20°C for 16 hours to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (108.71 mg, 0.3156 mmol, 57.509% yield) as a white solid. LC-MS method 1: 345.3 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ 7.61 (d, J=1.00 Hz, 1H), 7.40 (d, J=1.25 Hz, 1H), 4.76 (br d, J=12.05 Hz, 1H), 4.18 (d, J=12.55 Hz, 1H), 3.94 (br dd, J=4.02, 11.80 Hz, 1H), 3.84 (quin, J=7.09 Hz, 1H) , 3.61 (dd, J=4.27, 12.55 Hz, 1H), 2.64 (s, 2H), 2.07 (br dd, J=3.51, 7.28 Hz, 1H), 1.95-1.99 (m, 1H), 1.87-1.94 ( m, 1H), 1.47 (d, J=6.78 Hz, 4H), 1.36 (s, 6H), 0.96 (d, J=6.78 Hz, 3H), 0.78 (d, J=6.53 Hz, 3H).

實例 11 {1-[(2R)- 丁 -2- 基 ]-1H- 咪唑 -4- 基 }[(1R,5S,6R)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 1-[(2R)- 丁 -2- 基 ]-1H- 咪唑 -4- 羧酸 乙 酯在50℃下攪拌(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(300 mg，1.78mmol)及(2R)-2-丁胺(0.54mL，5.35mmol)之混合物16小時，得到褐色混合物。TLC (PE:EA=1:1)展示偵測到新樣點(Rf = 0.2)。濃縮混合物，得到殘餘物。藉由快速柱(PE:EA=1:0至1:4)純化殘餘物，得到呈褐色固體狀之標題化合物(240mg，1.2229mmol，68.562%產率)。 LC-MS方法1 0.586 min，MS (m/z) 196.9 (M + H ⁺)。 Example 11 {1-[(2R) -but -2- yl ]-1H- imidazol -4- yl }[(1R,5S,6R)-6-(5,5- dimethyl - 4,5- di Hydrogen -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 1-[(2R) -butan - 2 - yl ]-1H - imidazole- ( 2Z ) -3-( dimethylamino )-2-isocyanoacrylate ethyl ester (300 mg, 1.78mmol) and (2R)-2-butylamine (0.54 mL, 5.35 mmol) for 16 hours to give a brown mixture. TLC (PE:EA=1:1) showed detection of a new sample (Rf = 0.2). The mixture was concentrated to give a residue. The residue was purified by flash column (PE:EA = 1:0 to 1:4) to give the title compound (240 mg, 1.2229 mmol, 68.562% yield) as a brown solid. LC-MS method 1 0.586 min, MS (m/z) 196.9 (M + H ⁺ ).

1-[(2 R)- 丁 -2- 基 ]-1H- 咪唑 -4- 羧酸向1-[(2R)-丁-2-基]-1H-咪唑-4-羧酸乙酯(240 mg，1.22mmol)於THF (3mL)及H ₂O (1.5mL)中之混合物添加LiOH·H ₂O (0.11mL，1.83mmol)。在25℃下攪拌反應混合物16小時，得到黃色混合物。TLC (PE:EtOAc = 1:1)展示大部分起始物料耗盡。用H ₂O (15 mL)稀釋反應混合物且用EtOAc (8 mL × 5)萃取。用1 N HCl水溶液將水相酸化至pH = 4。真空乾燥所得水相，得到呈黃色油狀之標題化合物(200 mg，1.1891mmol，97.236%產率) (粗物質)。 1-[(2 R ) -but -2- yl ]-1H- imidazole -4- carboxylic acid to 1-[(2R)-but-2-yl]-1H-imidazole-4-carboxylic acid ethyl ester (240 mg, 1.22 mmol) in THF (3 mL) and _H2O (1.5 mL) was added LiOH- _H2O (0.11 mL, 1.83 mmol). The reaction mixture was stirred at 25°C for 16 hours to give a yellow mixture. TLC (PE:EtOAc = 1:1) showed that most of the starting material was consumed. The reaction mixture was diluted with H ₂ O (15 mL) and extracted with EtOAc (8 mL×5). The aqueous phase was acidified to pH = 4 with 1 N aqueous HCl. The resulting aqueous phase was dried in vacuo to afford the title compound (200 mg, 1.1891 mmol, 97.236% yield) as a yellow oil (crude material).

{1-[(2R)- 丁 -2- 基 ]-1H- 咪唑 -4- 基 }[(1R,5S,6R)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向 (1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(70 mg，0.3900mmol)於DMF (1mL)中之混合物添加1-[(2 R)-丁-2-基]-1H-咪唑-4-羧酸(65.32mg，0.3900mmol)、DIPEA (0.26mL，1.55mmol)及HATU (178.16mg，0.4700mmol)。在25℃下攪拌反應混合物16小時，得到褐色混合物。真空濃縮反應混合物，得到殘餘物。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色固體狀之標題化合物(4.09mg，0.0108mmol，2.7864%產率)。 LC-MS方法1: 331.1 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (br s, 1 H), 8.19 (br s, 1 H), 4.31 - 4.44 (m, 1 H), 4.15 (br d, J=11.3 Hz, 1 H), 3.96 (br d, J=12.8 Hz, 1 H), 3.90 (br d, J=9.0 Hz, 1 H), 3.50 - 3.65 (m, 1 H), 2.65 (s, 2 H), 2.16 (br d, J=3.3 Hz, 1 H), 2.07 (br d, J=3.5 Hz, 1 H), 1.82 (quin, J=7.2 Hz, 2 H), 1.55 (t, J=3.4 Hz, 1 H), 1.48 (d, J=6.8 Hz, 3 H), 1.26 (s, 6 H), 0.76 (t, J=7.4 Hz, 3 H)。 {1-[(2R) -But -2- yl ]-1H- Imidazol -4- yl }[(1R,5S,6R)-6-(5,5- Dimethyl -4,5 - dihydro- 1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to (1R,5S,6r)-6-(5,5-dimethyl- A mixture of 4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (70 mg, 0.3900 mmol) in DMF (1 mL) was added 1-[( 2R )-Butan-2-yl]-1H-imidazole-4-carboxylic acid (65.32mg, 0.3900mmol), DIPEA (0.26mL, 1.55mmol) and HATU (178.16mg, 0.4700mmol). The reaction mixture was stirred at 25°C for 16 hours to give a brown mixture. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (4.09 mg, 0.0108 mmol, 2.7864% yield) as a yellow solid. LC-MS method 1: 331.1 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (br s, 1 H), 8.19 (br s, 1 H), 4.31 - 4.44 (m, 1 H), 4.15 (br d, J=11.3 Hz, 1 H), 3.96 (br d, J=12.8 Hz, 1 H), 3.90 (br d, J=9.0 Hz, 1 H), 3.50 - 3.65 ( m, 1 H), 2.65 (s, 2 H), 2.16 (br d, J=3.3 Hz, 1 H), 2.07 (br d, J=3.5 Hz, 1 H), 1.82 (quin, J=7.2 Hz , 2 H), 1.55 (t, J=3.4 Hz, 1 H), 1.48 (d, J=6.8 Hz, 3 H), 1.26 (s, 6 H), 0.76 (t, J=7.4 Hz, 3 H ).

實例 12      {1-[(2S)- 丁 -2- 基 ]-1H- 咪唑 -4- 基 }[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 1-[(2S)- 丁 -2- 基 ]-1H- 咪唑 -4- 羧酸 乙 酯在50℃下攪拌(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(300 mg，1.78mmol)及(S)-丁-2-胺(0.54mL，5.35mmol)之混合物12小時，得到褐色混合物。TLC (PE:EA=1:1)展示偵測到新樣點(Rf = 0.2)。濃縮混合物，得到殘餘物。藉由快速柱(PE:EA=1:0至1:4)純化殘餘物，得到呈黃色固體狀之標題化合物(160mg，0.8153mmol，45.708%產率)。 LC-MS方法1 0.580 min，MS (m/z) 196.1 (M + H ⁺)。 Example 12 {1-[(2S) -but -2- yl ]-1H- imidazol -4- yl }[(1R,5S,6S)-6-(5,5- dimethyl - 4,5- di Hydrogen -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 1-[(2S) -Butan -2- yl ]-1H- imidazole -4- carboxylic acid ethyl ester Stir (2Z)-3-(dimethylamino)-2-isocyanoacrylate ethyl ester at 50°C (300 mg, 1.78 mmol) and (S)-butan-2-amine (0.54 mL, 5.35 mmol) for 12 hours gave a brown mixture. TLC (PE:EA=1:1) showed detection of a new sample (Rf = 0.2). The mixture was concentrated to give a residue. The residue was purified by flash column (PE:EA = 1:0 to 1:4) to give the title compound (160 mg, 0.8153 mmol, 45.708% yield) as a yellow solid. LC-MS method 1 0.580 min, MS (m/z) 196.1 (M + H ⁺ ).

1-[(2S)- 丁 -2- 基 ]-1H- 咪唑 -4- 羧酸向1-[(2S)-丁-2-基]-1H-咪唑-4-羧酸乙酯(160 mg，0.8200mmol)於THF (4mL)及H ₂O (2mL)中之混合物添加LiOH·H ₂O (0.07mL，1.22mmol)。在20℃下攪拌反應混合物16小時，得到黃色混合物。用H ₂O (15 mL)稀釋反應混合物且用EtOAc (8 mL × 5)萃取。用1N HCl水溶液將水相酸化至pH =4。真空乾燥所得水相，得到呈黃色固體狀之標題化合物(150mg，0.8918mmol，109.39%產率) (粗物質)。 1-[(2S) -But -2- yl ]-1H- imidazole -4- carboxylic acid to 1-[(2S)-But-2-yl]-1H-imidazole-4-carboxylic acid ethyl ester (160 mg , 0.8200 mmol) in THF (4 mL) and H ₂ O (2 mL) was added LiOH·H ₂ O (0.07 mL, 1.22 mmol). The reaction mixture was stirred at 20 °C for 16 hours to give a yellow mixture. The reaction mixture was diluted with H ₂ O (15 mL) and extracted with EtOAc (8 mL×5). The aqueous phase was acidified to pH=4 with 1N aqueous HCl. The resulting aqueous phase was dried in vacuo to afford the title compound (150 mg, 0.8918 mmol, 109.39% yield) (crude material) as a yellow solid.

{1-[(2S)- 丁 -2- 基 ]-1H- 咪唑 -4- 基 }[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向 (1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(70 mg，0.3900mmol)於DMF (1.5mL)中之混合物添加1-[(2S)-丁-2-基]-1H-咪唑-4-羧酸(65.32mg，0.3900mmol)、DIPEA (0.26mL，1.55mmol)及HATU (178.16mg，0.4700mmol)。在25℃下攪拌反應混合物16小時，得到褐色混合物。LCMS展示起始材料耗盡。過濾反應混合物。藉由製備型HPLC (NH ₃)純化濾液。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(34.59mg，0.1002mmol，25.797%產率)。 LC-MS方法2 1.516 min，MS (m/z) 331.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.64 (s, 1 H), 7.44 (s, 1 H), 4.76 (br d, J=12.0 Hz, 1 H), 4.19 (br d, J=12.5 Hz, 1 H), 4.02 - 4.10 (m, 1 H), 3.95 (br d, J=7.8 Hz, 1 H), 3.58 - 3.65 (m, 1 H), 2.64 (s, 2 H), 2.08 (br s, 1 H), 1.93 - 2.01 (m, 1 H), 1.93 - 2.01 (m, 1 H), 1.74 - 1.84 (m, 2 H), 1.49 (d, J=6.8 Hz, 3 H), 1.47 (br s, 1 H), 1.37 (s, 6 H), 0.85 (t, J=7.4 Hz, 3 H) {1-[(2S) -But -2- yl ]-1H- Imidazol -4- yl }[(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro- 1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to (1R,5S,6r)-6-(5,5-dimethyl- A mixture of 4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (70 mg, 0.3900 mmol) in DMF (1.5 mL) 1-[(2S)-Butan-2-yl]-1H-imidazole-4-carboxylic acid (65.32 mg, 0.3900 mmol), DIPEA (0.26 mL, 1.55 mmol) and HATU (178.16 mg, 0.4700 mmol) were added. The reaction mixture was stirred at 25°C for 16 hours to give a brown mixture. LCMS showed consumption of starting material. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (NH ₃ ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (34.59 mg, 0.1002 mmol, 25.797% yield) as a white solid. LC-MS method 2 1.516 min, MS (m/z) 331.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.64 (s, 1 H), 7.44 (s, 1 H), 4.76 (br d, J=12.0 Hz, 1 H), 4.19 (br d, J=12.5 Hz, 1 H), 4.02 - 4.10 (m, 1 H), 3.95 (br d, J=7.8 Hz, 1 H ), 3.58 - 3.65 (m, 1 H), 2.64 (s, 2 H), 2.08 (br s, 1 H), 1.93 - 2.01 (m, 1 H), 1.93 - 2.01 (m, 1 H), 1.74 - 1.84 (m, 2 H), 1.49 (d, J=6.8 Hz, 3 H), 1.47 (br s, 1 H), 1.37 (s, 6 H), 0.85 (t, J=7.4 Hz, 3 H )

實例 13 [(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(2S)-4- 甲基戊 -2- 基 ]-1H- 咪唑 -4- 基 } 甲酮 (R)-2- 甲基 -N-[(2E)-1,3- 二甲基亞丁基 ]-2- 丙烷亞磺醯胺向4-甲基-2-戊酮(1.25mL，9.98mmol)於THF (10mL)中之混合物添加(R)-2-甲基丙烷-2-亞磺醯胺(1210.06mg，9.98mmol)及Ti(OEt) ₄(3414.54mg，14.98mmol)。在60℃下攪拌反應混合物2小時，得到無色混合物。用EtOAc (30 mL)稀釋反應混合物。將混合物添加至H ₂O (10 mL)且攪拌1 min，得到黃色懸浮液。過濾懸浮液。用H ₂O (20 mL × 3)洗滌濾液，用無水Na ₂SO ₄乾燥，過濾且真空濃縮，得到呈無色油狀之標題化合物(900 mg，4.4261mmol，44.332%產率)。 LC-MS方法1 0.778 min，MS (m/z) 204.0 (M + H ⁺)。 Example 13 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ]{1-[(2S)-4- methylpent - 2 - yl ]-1H- imidazol -4- yl } methanone (R)-2- methyl- N-[(2E )-1,3- Dimethylbutylene ]-2- propanesulfinamide To a mixture of 4-methyl-2-pentanone (1.25 mL, 9.98 mmol) in THF (10 mL) was added (R)- 2-Methylpropane-2-sulfinamide (1210.06 mg, 9.98 mmol) and Ti(OEt) ₄ (3414.54 mg, 14.98 mmol). The reaction mixture was stirred at 60 °C for 2 hours to obtain a colorless mixture. The reaction mixture was diluted with EtOAc (30 mL). The mixture was added to H ₂ O (10 mL) and stirred for 1 min to give a yellow suspension. Filter the suspension. The filtrate was washed with H ₂ O (20 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (900 mg, 4.4261 mmol, 44.332% yield) as a colorless oil. LC-MS method 1 0.778 min, MS (m/z) 204.0 (M + H ⁺ ).

(R)-2- 甲基 -N-[(2S)-4- 甲基戊 -2- 基 ]-2- 丙烷亞磺醯胺在0℃下向(R)-2-甲基-N-[(2E)-1,3-二甲基亞丁基]-2-丙烷亞磺醯胺(900 mg，4.43mmol)於THF (9mL)中之混合物添加三二級丁基硼氫化鋰(13.28mL，13.28mmol)。在25℃下攪拌反應混合物2小時，得到無色混合物。TLC (PE:EtOAc = 2:1)展示偵測到一個新樣點(Rf = 0.2)。藉由H ₂O (3 mL)淬滅反應。真空濃縮反應混合物，得到殘餘物。藉由快速柱(PE至30% EtOAc/PE)純化殘餘物，得到呈無色油狀之標題化合物(260mg，1.026mmol，45.252%產率)。 ¹H NMR (400 MHz, 氯仿-d) δ ppm 3.50-3.30 (m, 1H), 2.81 (d, J = 8.0 Hz, 1H), 1.80-1.60 (m, 1H), 1.60-1.30 (m, 2H), 1.28 (d, J = 6.4 Hz, 3H), 1.21 (s, 9H), 0.90 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H)。 (R)-2- Methyl -N-[(2S)-4- Methylpent -2- yl ]-2- propanesulfinamide at 0°C to (R)-2-Methyl-N- To a mixture of [(2E)-1,3-dimethylbutylene]-2-propanesulfinamide (900 mg, 4.43 mmol) in THF (9 mL) was added three secondary butyl lithium borohydride (13.28 mL , 13.28 mmol). The reaction mixture was stirred at 25°C for 2 hours to give a colorless mixture. TLC (PE:EtOAc = 2:1) showed detection of a new spot (Rf = 0.2). The reaction was quenched by _H2O (3 mL). The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by flash column (PE to 30% EtOAc/PE) to give the title compound (260 mg, 1.026 mmol, 45.252% yield) as a colorless oil. ¹ H NMR (400 MHz, Chloroform-d) δ ppm 3.50-3.30 (m, 1H), 2.81 (d, J = 8.0 Hz, 1H), 1.80-1.60 (m, 1H), 1.60-1.30 (m, 2H ), 1.28 (d, J = 6.4 Hz, 3H), 1.21 (s, 9H), 0.90 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H).

(2 S)-4- 甲基 -2- 戊胺氫氯化物在25℃下攪拌 (R)-2-甲基-N-[(2S)-4-甲基戊-2-基]-2-丙烷亞磺醯胺(610 mg，2.97mmol)於MeOH/HCl (10 mL，2.97mmol)中之溶液2小時，得到無色混合物。真空濃縮反應混合物，得到殘餘物。用PE (20 mL)濕磨殘餘物且真空乾燥，得到呈白色固體狀之標題化合物(240mg，1.7436mmol，58.698%產率)。 ( 2S )-4- Methyl -2- pentylamine hydrochloride Stirring (R)-2-methyl-N-[(2S)-4-methylpent-2-yl]-2 - A solution of propanesulfinamide (610 mg, 2.97 mmol) in MeOH/HCl (10 mL, 2.97 mmol) for 2 hours gave a colorless mixture. The reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with PE (20 mL) and dried in vacuo to afford the title compound (240 mg, 1.7436 mmol, 58.698% yield) as a white solid.

1-[(2S)-4- 甲基戊 -2- 基 ]-1H- 咪唑 -4- 羧酸 乙 酯向(2S)-4-甲基-2-戊胺氫氯化物(240 mg，1.74mmol)於1-丁醇(2.5mL)中之混合物添加(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(293.25mg，1.74mmol)及Et ₃N (0.34mL，2.62mmol)。用微波系統在130℃下攪拌反應混合物1小時，得到褐色混合物。TLC (PE: EtOAc = 1: 1)展示偵測到一個新樣點(Rf = 0.2)。真空濃縮反應混合物，得到殘餘物。藉由製備型TLC (PE:EtOAc = 1:1)純化殘餘物，得到呈黃色油狀之標題化合物(60mg，0.2675mmol，15.342%產率)。 LC-MS方法1 0.681 min，MS (m/z) 225.0 (M + H ⁺)。 1-[(2S)-4- Methylpent- 2- yl ]-1H- imidazole -4- carboxylic acid ethyl ester to (2S)-4-methyl-2-pentylamine hydrochloride (240 mg, 1.74 mmol) in 1-butanol (2.5 mL) was added (2Z)-ethyl 3-(dimethylamino)-2-isocyanoacrylate (293.25 mg, 1.74 mmol) and Et ₃ N (0.34 mL) , 2.62 mmol). The reaction mixture was stirred at 130° C. for 1 hour using a microwave system to obtain a brown mixture. TLC (PE: EtOAc = 1: 1) showed detection of a new spot (Rf = 0.2). The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (PE:EtOAc = 1:1) to give the title compound (60 mg, 0.2675 mmol, 15.342% yield) as a yellow oil. LC-MS method 1 0.681 min, MS (m/z) 225.0 (M + H ⁺ ).

1-[(2 S)-4- 甲基戊 -2- 基 ]-1H- 咪唑 -4- 羧酸向1-[(2S)-4-甲基戊-2-基]-1H-咪唑-4-羧酸乙酯(60 mg，0.2700mmol)於THF (1.5mL)及H ₂O (0.50 mL)中之混合物添加LiOH·H ₂O (0.02mL，0.4000mmol)。在40℃下攪拌反應混合物16小時，得到黃色混合物。TLC (PE:EtOAc =1:1)展示起始物質完全耗盡。用H ₂O (5 mL)稀釋反應混合物且用EtOAc (3 mL × 2)萃取。用1 N HCl水溶液將水相酸化至pH = 5且凍乾，得到呈黃色固體狀之標題化合物(50mg，0.2548mmol，95.244%產率)。 1-[( 2S )-4- methylpent- 2- yl ]-1H- imidazole -4- carboxylic acid to 1-[(2S)-4-methylpent-2-yl]-1H-imidazole- A mixture of ethyl 4-carboxylate (60 mg, 0.2700 mmol) in THF (1.5 mL) and _H2O (0.50 mL) was added LiOH- _H2O (0.02 mL, 0.4000 mmol). The reaction mixture was stirred at 40 °C for 16 hours to give a yellow mixture. TLC (PE:EtOAc = 1:1) showed complete consumption of starting material. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (3 mL×2). The aqueous phase was acidified to pH = 5 with 1 N aqueous HCl and lyophilized to afford the title compound (50 mg, 0.2548 mmol, 95.244% yield) as a yellow solid.

[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(2S)-4- 甲基戊 -2- 基 ]-1H- 咪唑 -4- 基 } 甲酮向1-[(2 S)-4-甲基戊-2-基]-1H-咪唑-4-羧酸(50 mg，0.2500mmol)於吡啶(2.5mL)中之混合物添加EDCI (58.61mg，0.3100mmol)。在25℃下攪拌混合物10 min且繼之以添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(55.21mg，0.2500mmol)。允許在25℃下攪拌混合物16小時，得到黃色混合物。LCMS展示起始材料完全耗盡。真空濃縮反應混合物，得到殘餘物。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色固體狀之標題化合物(16.26mg，0.0449mmol，17.643%產率)。 LC-MS方法1: 359.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.64 (s, 1 H), 7.46 (s, 1 H), 4.76 (br d, J=12.0 Hz, 1 H), 4.13 - 4.33 (m, 2 H), 3.95 (dd, J=12.0, 3.8 Hz, 1 H), 3.62 (dd, J=12.3, 4.0 Hz, 1 H), 2.64 (s, 2 H), 2.08 (br d, J=3.5 Hz, 1 H), 1.98 (br d, J=3.5 Hz, 1 H), 1.68 - 1.78 (m, 1 H), 1.50 - 1.57 (m, 2 H), 1.47 (d, J=6.8 Hz, 4 H), 1.38 (s, 6 H), 0.92 (d, J=6.5 Hz, 3 H), 0.87 (d, J=6.8 Hz, 3 H) [(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ]{1-[(2S)-4- methylpent -2- yl ]-1H- imidazol -4- yl } methanone to 1-[( 2S )-4-methylpent-2 -yl]-1H-imidazole-4-carboxylic acid (50 mg, 0.2500 mmol) in pyridine (2.5 mL) was added EDCI (58.61 mg, 0.3100 mmol). The mixture was stirred at 25 °C for 10 min and followed by the addition of (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl) - 3-Azabicyclo[3.1.0]hexane hydrochloride (55.21 mg, 0.2500 mmol). The mixture was allowed to stir at 25 °C for 16 hours to give a yellow mixture. LCMS showed complete consumption of starting material. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (16.26 mg, 0.0449 mmol, 17.643% yield) as a yellow solid. LC-MS method 1: 359.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.64 (s, 1 H), 7.46 (s, 1 H), 4.76 (br d, J=12.0 Hz, 1 H), 4.13 - 4.33 (m, 2 H), 3.95 (dd, J=12.0, 3.8 Hz, 1 H), 3.62 (dd, J=12.3, 4.0 Hz, 1 H), 2.64 (s, 2 H), 2.08 (br d, J=3.5 Hz, 1 H), 1.98 (br d, J=3.5 Hz, 1 H), 1.68 - 1.78 (m, 1 H), 1.50 - 1.57 (m, 2 H ), 1.47 (d, J=6.8 Hz, 4 H), 1.38 (s, 6 H), 0.92 (d, J=6.5 Hz, 3 H), 0.87 (d, J=6.8 Hz, 3 H)

實例 14 (1-((S)-1- 環丙基乙基 )-1H- 咪唑 -4- 基 )((1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫異 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ) 甲酮 1-[(1 S)-1- 環丙基乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯向圓底燒瓶中裝入(S)-1-環丙基乙胺氫氯化物(903.81mg，7.43mmol)、Et ₃N (1.57mL，11.15mmol)、(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(250 mg，1.49mmol)及1-丁醇(0.50 mL)。在70℃下攪拌所得混合物36小時，得到黃色溶液。將反應混合物傾入H ₂O (30 mL)中且用EtOAc (30 mL × 2)萃取。用鹽水(30 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到黃色油狀物。藉由快速柱(PE至100% EtOAc/PE)純化粗產物，得到呈黃色油狀之標題化合物(100 mg，0.4802mmol，32.304%產率)。 LC-MS方法1 0.652 min，MS (m/z) 209.2 (M + H ⁺)。 Example 14 (1-((S)-1- cyclopropylethyl )-1H- imidazol -4- yl )((1R,5S,6S)-6-(5,5- dimethyl -4,5 -Dihydroisozol - 3- yl )-3- azabicyclo [3.1.0] hex -3- yl ) methanone 1-[(1 S )-1- cyclopropylethyl ]-1H - imidazole -Ethyl 4- carboxylate A round bottom flask was charged with (S)-1-cyclopropylethylamine hydrochloride (903.81 mg, 7.43 mmol), Et ₃ N (1.57 mL, 11.15 mmol), (2Z) - Ethyl 3-(dimethylamino)-2-isocyanoacrylate (250 mg, 1.49 mmol) and 1-butanol (0.50 mL). The resulting mixture was stirred at 70°C for 36 hours to give a yellow solution. The reaction mixture was poured into H ₂ O (30 mL) and extracted with EtOAc (30 mL×2). The combined organic layers _were washed with brine (30 mL x 2), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a yellow oil. The crude product was purified by flash column (PE to 100% EtOAc/PE) to give the title compound (100 mg, 0.4802 mmol, 32.304% yield) as a yellow oil. LC-MS method 1 0.652 min, MS (m/z) 209.2 (M + H ⁺ ).

1-[(1 S)-1- 環丙基乙基 ]-1H- 咪唑 -4- 羧酸向1-[(1S)-1-環丙基乙基]-1H-咪唑-4-羧酸乙酯(150 mg，0.7200mmol)於H ₂O (0.50 mL)、THF (0.50 mL)、MeOH (0.50 mL)中之溶液添加羥基鋰水合物(60.44mg，1.44mmol)。在20至25℃下攪拌所得混合物14小時，得到白色懸浮液。將反應混合物傾入H ₂O中且用EtOAc (20 mL × 4)萃取。用鹽水(20 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈黃色油狀之標題化合物(150mg，粗產物)。 LC-MS方法1 0.227 min，MS (m/z) 180.9 (M + H ⁺)。 1-[( 1S )-1- cyclopropylethyl ]-1H- imidazole -4- carboxylic acid to 1-[(1S)-1-cyclopropylethyl]-1H-imidazole-4-carboxylic acid To a solution of the ethyl ester (150 mg, 0.7200 mmol) in _H2O (0.50 mL), THF (0.50 mL), MeOH (0.50 mL) was added hydroxylithium hydrate (60.44 mg, 1.44 mmol). The resulting mixture was stirred at 20 to 25°C for 14 hours to give a white suspension. The reaction mixture was poured into H ₂ O and extracted with EtOAc (20 mL×4). The combined organic layers were washed with brine (20 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (150 mg, crude) as a yellow oil. LC-MS method 1 0.227 min, MS (m/z) 180.9 (M + H ⁺ ).

(1-((S)-1- 環丙基乙基 )-1H- 咪唑 -4- 基 )((1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫異 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ) 甲酮在20℃下向1-[(1S)-1-環丙基乙基]-1H-咪唑-4-羧酸(70 mg，0.3900mmol)於DMF (3mL)中之溶液添加HATU (193.06mg，0.5000mmol)及N-乙基-N-異丙基丙-2-胺(0.33mL，1.94mmol)歷時30 min。添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(98.35mg，0.3900mmol)。在20至25℃下攪拌所得混合物14小時，得到黃色溶液。將反應混合物傾入飽和NH ₄Cl水溶液(50 mL)中，且用EtOAc (50 mL × 4)萃取。用鹽水(50 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由製備型HPLC (FA)純化殘餘物，得到呈黃色油狀之標題化合物(10.65mg，0.0311mmol，8.0061%產率)。 LC-MS方法1: 343.1 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.70 (s, 1H), 7.64 (s, 1H), 4.63 (br d, J=10.0 Hz, 1H), 4.19 (br d, J=12.5 Hz, 1H), 3.95 (br dd, J=3.4, 11.2 Hz, 1H), 3.63 (br d, J=11.5 Hz, 1H), 3.48 - 3.43 (m, 1H), 2.64 (s, 2H), 2.08 (br s, 2H), 1.58 (d, J=6.8 Hz, 3H), 1.47 (t, J=3.4 Hz, 1H), 1.36 (s, 6H), 1.19 - 1.13 (m, 1H), 0.75 - 0.61 (m, 2H), 0.36 (q, J=4.9 Hz, 2H) (1-((S)-1- cyclopropylethyl )-1H- imidazol -4- yl )((1R,5S,6S)-6-(5,5- dimethyl -4,5- di Hydroisozol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ) methanone to 1-[(1S)-1-cyclopropylethyl]-1H at 20° C - A solution of imidazole-4-carboxylic acid (70 mg, 0.3900 mmol) in DMF (3 mL) was added with HATU (193.06 mg, 0.5000 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.33 mL , 1.94mmol) for 30 min. Add (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane Alkyl hydrochloride (98.35 mg, 0.3900 mmol). The resulting mixture was stirred at 20 to 25°C for 14 hours to obtain a yellow solution. The reaction mixture was poured into saturated aqueous NH ₄ Cl (50 mL), and extracted with EtOAc (50 mL×4). The combined organic layers were washed with brine (50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (FA) to give the title compound (10.65 mg, 0.0311 mmol, 8.0061% yield) as a yellow oil. LC-MS method 1: 343.1 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.70 (s, 1H), 7.64 (s, 1H), 4.63 (br d, J =10.0 Hz, 1H ), 4.19 (br d, J =12.5 Hz, 1H), 3.95 (br dd, J =3.4, 11.2 Hz, 1H), 3.63 (br d, J =11.5 Hz, 1H), 3.48 - 3.43 (m, 1H ), 2.64 (s, 2H), 2.08 (br s, 2H), 1.58 (d, J =6.8 Hz, 3H), 1.47 (t, J =3.4 Hz, 1H), 1.36 (s, 6H), 1.19 - 1.13 (m, 1H), 0.75 - 0.61 (m, 2H), 0.36 (q, J =4.9 Hz, 2H)

實例 15      {1-[(1R)-1- 環丙基乙基 ]-1H- 咪唑 -4- 基 }[(1R,5S,6R)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 1-[( 1R)-1- 環丙基乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯在20℃下向(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(500 mg，2.97mmol)於1-丁醇(1 mL)中之溶液添加(1R)-1-環丙基乙胺(253.14mg，2.97mmol)。在130℃下用微波照射反應混合物40 min，得到黃色溶液。將反應混合物傾入飽和NH ₄Cl水溶液(50 mL)中，且用EtOAc (50 mL × 4)萃取。用飽和NaCl溶液(50 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由二氧化矽管柱(PE至PE:EtOAc=1:1)純化粗產物，得到呈黃色油狀之標題化合物(190 mg，0.9123mmol，30.689%產率)。 LC-MS方法1 0.608 min，MS (m/z) 209.0 (M + H ⁺) Example 15 {1-[(1R)-1- cyclopropylethyl ]-1H- imidazol -4- yl }[(1R,5S,6R)-6-(5,5- dimethyl -4,5 -Dihydro - 1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 1-[( 1R )-1- cyclopropylethyl ]- Ethyl 1H- imidazole -4- carboxylate was dissolved in ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (500 mg, 2.97mmol) in 1- butanol (1 mL) was added (1R)-1-cyclopropylethylamine (253.14 mg, 2.97 mmol). The reaction mixture was irradiated with microwaves at 130 °C for 40 min to obtain a yellow solution. The reaction mixture was poured into saturated aqueous NH ₄ Cl (50 mL), and extracted with EtOAc (50 mL×4). The combined organic layers were washed with saturated NaCl solution (50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica column (PE to PE:EtOAc=1:1) to give the title compound (190 mg, 0.9123 mmol, 30.689% yield) as a yellow oil. LC-MS method 1 0.608 min, MS (m/z) 209.0 (M + H ⁺ )

1-[( 1R)-1- 環丙基乙基 ]-1H- 咪唑 -4- 羧酸在20℃下向1-[(1R)-1-環丙基乙基]-1H-咪唑-4-羧酸乙酯(190 mg，0.9100mmol)於H ₂O (1.9mL)、THF (1.9mL)、MeOH (1.9mL)中之溶液添加羥基鋰水合物(76.56mg，1.82mmol)。在20至25℃下攪拌所得混合物2小時，得到白色懸浮液。將反應混合物傾入H ₂O中且用EtOAc (20 mL × 4)萃取。用飽和NaCl溶液(20 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈黃色油狀之標題化合物(180mg，0.9989mmol，109.49%產率)。 LC-MS方法1 0.214 min，MS (m/z) 180.0 (M + H ⁺)。 1-[( 1R )-1- cyclopropylethyl ]-1H- imidazole -4- carboxylic acid is converted to 1-[(1R)-1-cyclopropylethyl]-1H-imidazole-4 - To a solution of ethyl carboxylate (190 mg, 0.9100 mmol) in _H2O (1.9 mL), THF (1.9 mL), MeOH (1.9 mL) was added hydroxylithium hydrate (76.56 mg, 1.82 mmol). The resulting mixture was stirred at 20 to 25°C for 2 hours to give a white suspension. The reaction mixture was poured into H ₂ O and extracted with EtOAc (20 mL×4). The combined organic layers were washed with saturated NaCl solution (20 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (180 mg, 0.9989 mmol, 109.49% yield) as a yellow oil . LC-MS method 1 0.214 min, MS (m/z) 180.0 (M + H ⁺ ).

{1-[(1R)-1- 環丙基乙基 ]-1H- 咪唑 -4- 基 }[(1R,5S,6R)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮在20℃下向1-[(1R)-1-環丙基乙基]-1H-咪唑-4-羧酸(70 mg，0.3900mmol)於DMF (2mL)中之溶液添加HATU (193.06mg，0.5000mmol)及N-乙基-N-異丙基丙-2-胺(0.33mL，1.94mmol)。攪拌反應混合物30 min。添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(98.35mg，0.3900mmol)。在20至25℃下攪拌所得混合物14小時，得到黃色溶液。將反應混合物傾入飽和NH ₄Cl水溶液(50 mL)中，且用EtOAc (50 mL × 4)萃取。用飽和NaCl溶液(50 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由製備型HPLC (FA)純化殘餘物，得到呈黃色油狀之標題化合物(14.08mg，0.0411mmol，10.585%產率)。 LC-MS方法1: 343.3 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.70 (d, J=1.3 Hz, 1H), 7.64 (s, 1H), 4.65 (br d, J=11.5 Hz, 1H), 4.19 (br d, J=12.3 Hz, 1H), 3.94 (br dd, J=3.8, 11.8 Hz, 1H), 3.62 (br dd, J=4.1, 12.4 Hz, 1H), 3.45 (dd, J=6.8, 8.8 Hz, 1H), 2.64 (s, 2H), 2.11 - 2.05 (m, 2H), 1.58 (d, J=6.8 Hz, 3H), 1.46 (t, J=3.4 Hz, 1H), 1.36 (s, 6H), 1.19 - 1.13 (m, 1H), 0.77 - 0.70 (m, 1H), 0.65 - 0.60 (m, 1H), 0.36 (q, J=5.4 Hz, 2H) {1-[(1R)-1- cyclopropylethyl ]-1H- imidazol -4- yl }[(1R,5S,6R)-6-(5,5- dimethyl - 4,5- di Hydrogen -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-[(1R)-1-cyclopropyl ethyl To a solution of -1H-imidazole-4-carboxylic acid (70 mg, 0.3900 mmol) in DMF (2 mL) was added HATU (193.06 mg, 0.5000 mmol) and N-ethyl-N-isopropylpropane-2- Amine (0.33 mL, 1.94 mmol). The reaction mixture was stirred for 30 min. Add (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane Alkyl hydrochloride (98.35 mg, 0.3900 mmol). The resulting mixture was stirred at 20 to 25°C for 14 hours to obtain a yellow solution. The reaction mixture was poured into saturated aqueous NH ₄ Cl (50 mL), and extracted with EtOAc (50 mL×4). The combined organic layers were washed with saturated NaCl solution (50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (FA) to give the title compound (14.08 mg, 0.0411 mmol, 10.585% yield) as a yellow oil. LC-MS method 1: 343.3 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.70 (d, J =1.3 Hz, 1H), 7.64 (s, 1H), 4.65 (br d, J =11.5 Hz, 1H), 4.19 (br d, J =12.3 Hz, 1H), 3.94 (br dd, J =3.8, 11.8 Hz, 1H), 3.62 (br dd, J =4.1, 12.4 Hz, 1H), 3.45 (dd, J =6.8, 8.8 Hz, 1H), 2.64 (s, 2H), 2.11 - 2.05 (m, 2H), 1.58 (d, J =6.8 Hz, 3H), 1.46 (t, J =3.4 Hz , 1H), 1.36 (s, 6H), 1.19 - 1.13 (m, 1H), 0.77 - 0.70 (m, 1H), 0.65 - 0.60 (m, 1H), 0.36 (q, J =5.4 Hz, 2H)

實例 16      (1-((S)-1- 環丁基乙基 )-1H- 咪唑 -4- 基 )((1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫異 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ) 甲酮 (R)-N-[(E)- 環丁基亞甲基 ]-2- 甲基 -2- 丙烷亞磺醯胺向環丁烷醛(1.07mL，11.89mmol)於THF (15mL)中之混合物添加(R)-2-甲基丙烷-2-亞磺醯胺(1.44g，11.89mmol)及Ti(OEt) ₄(4065.62mg，17.83mmol)。在60℃下攪拌反應混合物2小時，得到黃色混合物。TLC (PE:EtOAc = 10:1)展示起始材料完全耗盡，偵測到之一個新樣點為(Rf = 0.2)。用EtOAc (40 mL)稀釋反應混合物。將混合物添加至H ₂O (10 mL)且攪拌1 min，得到白色懸浮液。過濾懸浮液。用H ₂O (20 mL × 3)洗滌濾液，用無水Na ₂SO ₄乾燥，過濾且真空濃縮，得到呈無色油狀之標題化合物(1.77g，9.4501mmol，79.494%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 8.12 (d, J = 4.8 Hz, 1H), 3.45-3.30 (m, 1H), 2.35-2.10 (m, 4H), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 1H), 1.20 (s, 9H)。 Example 16 (1-((S)-1- cyclobutylethyl )-1H- imidazol -4- yl )((1R,5S,6S)-6-(5,5- dimethyl -4,5 -Dihydroisozol - 3- yl )-3- azabicyclo [3.1.0] hex -3- yl ) methanone ( R)-N-[(E) -cyclobutylmethylene ]-2 -Methyl -2- propanesulfinamide To a mixture of cyclobutanal (1.07 mL, 11.89 mmol) in THF (15 mL) was added (R)-2 - methylpropane-2-sulfinamide (1.44 g, 11.89 mmol) and Ti(OEt) ₄ (4065.62 mg, 17.83 mmol). The reaction mixture was stirred at 60 °C for 2 hours to give a yellow mixture. TLC (PE:EtOAc = 10:1) showed complete consumption of starting material and one new spot was detected (Rf = 0.2). The reaction mixture was diluted with EtOAc (40 mL). The mixture was added to H ₂ O (10 mL) and stirred for 1 min to give a white suspension. Filter the suspension. The filtrate was washed with H ₂ O (20 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to afford the title compound (1.77 g, 9.4501 mmol, 79.494% yield) as a colorless oil. ¹ H NMR (400MHz, Chloroform-d) δ = 8.12 (d, J = 4.8 Hz, 1H), 3.45-3.30 (m, 1H), 2.35-2.10 (m, 4H), 2.10-2.00 (m, 1H) , 2.00-1.90 (m, 1H), 1.20 (s, 9H).

(R)-N-[(1S)-1- 環丁基乙基 ]-2- 甲基 -2- 丙烷亞磺醯胺在-40℃下向於THF (6mL)中之(R)-N-[(E)-環丁基亞甲基]-2-甲基-2-丙烷亞磺醯胺(0.5g，2.67mmol)溶液添加氯基(甲基)鎂(2.67mL，8.01mmol)。在-40℃下攪拌反應混合物2小時，得到黃色混合物。TLC (DCM:EtOAc = 1:1)展示起始材料完全耗盡，偵測到一個新樣點(Rf = 0.3)。用NH ₄Cl (當量，25 mL)淬滅反應混合物且隨後用EtOAc (15 mL × 3)萃取。用鹽水(20 mL)洗滌合併之有機相，經無水Na ₂SO ₄乾燥，過濾且真空濃縮，得到殘餘物。藉由快速柱(DCM至20% EtOAc/DCM)純化殘餘物，得到呈無色油狀之標題化合物(360mg，1.7704mmol，66.32%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.35-3.15 (m, 1H), 2.84 (d, J = 8.0 Hz, 1H), 2.40-2.20 (m, 1H), 2.10-1.90 (m, 1H), 2.00-1.90 (m, 1H), 1.90-1.60 (m, 4H), 1.20 (s, 9H), 1.18 (d, J = 6.8 Hz, 3H)。 (R)-N-[(1S)-1- cyclobutylethyl ]-2- methyl -2- propanesulfinamide was dissolved in (R)-N in THF (6mL) at -40°C To a solution of [(E)-cyclobutylmethylene]-2-methyl-2-propanesulfinamide (0.5 g, 2.67 mmol) was added chloro(methyl)magnesium (2.67 mL, 8.01 mmol). The reaction mixture was stirred at -40°C for 2 hours to give a yellow mixture. TLC (DCM:EtOAc = 1:1) showed complete consumption of starting material and detection of a new spot (Rf = 0.3). The reaction mixture was quenched with NH ₄ Cl (eq., 25 mL) and then extracted with EtOAc (15 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by flash column (DCM to 20% EtOAc/DCM) to give the title compound (360 mg, 1.7704 mmol, 66.32% yield) as a colorless oil. ¹ H NMR (400MHz, chloroform-d) δ = 3.35-3.15 (m, 1H), 2.84 (d, J = 8.0 Hz, 1H), 2.40-2.20 (m, 1H), 2.10-1.90 (m, 1H) , 2.00-1.90 (m, 1H), 1.90-1.60 (m, 4H), 1.20 (s, 9H), 1.18 (d, J = 6.8 Hz, 3H).

(1 S)-1- 環丁基乙胺 氫氯化物在25℃下攪拌 (R)-N-[(1S)-1-環丁基乙基]-2-甲基-2-丙烷亞磺醯胺(360 mg，1.77mmol)於MeOH/HCl (0.44mL，1.77mmol)中之溶液2小時，得到無色混合物。TLC (DCM:EtOAc = 1:1)展示起始材料完全耗盡。真空濃縮反應混合物，得到呈黃色固體狀之標題化合物(330mg，2.4329mmol，137.42%產率)。 (1 S )-1- cyclobutylethylamine hydrochloride Stirring (R)-N-[(1S)-1-cyclobutylethyl]-2-methyl-2-propanesulfinic acid at 25°C A solution of the amide (360 mg, 1.77 mmol) in MeOH/HCl (0.44 mL, 1.77 mmol) for 2 hours gave a colorless mixture. TLC (DCM:EtOAc = 1:1) showed complete consumption of starting material. The reaction mixture was concentrated in vacuo to afford the title compound (330 mg, 2.4329 mmol, 137.42% yield) as a yellow solid.

1-[(1 S)-1- 環丁基乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯向(1S)-1-環丁基乙胺氫氯化物(240 mg，1.77mmol)於1-丁醇(2mL)中之混合物添加(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(297.59mg，1.77mmol)及Et ₃N (0.37mL，2.65mmol)。在130℃下使用MW攪拌反應混合物1小時，得到褐色混合物。LCMS展示起始材料完全耗盡。TLC (PE:EtOAc = 2:1)展示偵測到一個新樣點(Rf = 0.2)。真空濃縮反應混合物，得到殘餘物。藉由製備型TLC (100% EtOAc)純化殘餘物，得到呈褐色固體狀之標題化合物(36mg，0.1620mmol，9.1533%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 7.61 (s, 1H), 7.50 (s, 1H), 4.37 (q, J = 6.8 Hz, 2H), 4.15-4.00 (m, 1H), 2.70-2.50 (m, 1H), 2.20-2.10 (m, 1H), 2.00-1.60 (m, 5H), 1.40 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 6.8Hz, 3H)。 1-[( 1S )-1- cyclobutylethyl ]-1H- imidazole -4- carboxylic acid ethyl ester to (1S)-1-cyclobutylethylamine hydrochloride (240 mg, 1.77mmol) in To the mixture in 1-butanol (2 mL) was added ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (297.59 mg, 1.77 mmol) and _Et3N (0.37 mL, 2.65 mmol) . The reaction mixture was stirred using MW at 130 °C for 1 hour to give a brown mixture. LCMS showed complete consumption of starting material. TLC (PE:EtOAc = 2:1) showed detection of a new spot (Rf = 0.2). The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (100% EtOAc) to afford the title compound (36 mg, 0.1620 mmol, 9.1533% yield) as a tan solid. ¹ H NMR (400MHz, chloroform-d) δ = 7.61 (s, 1H), 7.50 (s, 1H), 4.37 (q, J = 6.8 Hz, 2H), 4.15-4.00 (m, 1H), 2.70-2.50 (m, 1H), 2.20-2.10 (m, 1H), 2.00-1.60 (m, 5H), 1.40 (d, J = 6.8 Hz, 3H), 1.39 (t, J = 6.8Hz, 3H).

1-[(1 S)-1- 環丁基乙基 ]-1H- 咪唑 -4- 羧酸向1-[(1 S)-1-環丁基乙基]-1H-咪唑-4-羧酸乙酯(36 mg，0.1600mmol)於THF (1.5mL)及H ₂O (0.50 mL)中之混合物添加LiOH·H ₂O (0.01mL，0.2400mmol)。在25℃下攪拌反應混合物16小時，得到褐色混合物。TLC (PE:EtOAc = 1:1)展示起始材料完全耗盡。用H ₂O (4 mL)稀釋反應混合物且用EtOAc (2 mL × 2)萃取。用1 N HCl水溶液將水相酸化至pH = 4且凍乾，得到呈褐色固體狀之標題化合物(31mg，0.1596mmol，98.547%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ = 7.91 (s, 1H), 7.84 (s, 1H), 4.40-4.20 (m, 1H), 2.75-2.65 (m, 1H), 2.15-2.00 (m, 1H), 1.95-1.60 (m, 5H), 1.38 (d, J = 6.8 Hz, 3H)。 1-[(1 S )-1- cyclobutylethyl ]-1H- imidazole -4- carboxylic acid to 1-[(1 S )-1-cyclobutylethyl]-1H-imidazole-4-carboxylic acid To a mixture of ethyl acetate (36 mg, 0.1600 mmol) in THF (1.5 mL) and _H2O (0.50 mL) was added LiOH- _H2O (0.01 mL, 0.2400 mmol). The reaction mixture was stirred at 25°C for 16 hours to give a brown mixture. TLC (PE:EtOAc = 1:1) showed complete consumption of starting material. The reaction mixture was diluted with H ₂ O (4 mL) and extracted with EtOAc (2 mL×2). The aqueous phase was acidified to pH = 4 with 1 N aqueous HCl and lyophilized to afford the title compound (31 mg, 0.1596 mmol, 98.547% yield) as a tan solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.91 (s, 1H), 7.84 (s, 1H), 4.40-4.20 (m, 1H), 2.75-2.65 (m, 1H), 2.15-2.00 (m , 1H), 1.95-1.60 (m, 5H), 1.38 (d, J = 6.8 Hz, 3H).

(1-((S)-1- 環丁基乙基 )-1H- 咪唑 -4- 基 )((1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫異 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ) 甲酮向1-[(1 S)-1-環丁基乙基]-1H-咪唑-4-羧酸(30 mg，0.1500mmol)於DMF (1.5mL)中之溶液添加HATU (70.86mg，0.1900mmol)、DIPEA (99.81mg，0.7700mmol)。攪拌混合物10 min。隨後向混合物添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(39.1mg，0.1500mmol)。在25℃下攪拌混合物12小時，得到褐色溶液。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈褐色固體狀之標題化合物(25.52mg，0.0716mmol，46.352%產率)。 LC-MS方法1: 357.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.61 (1 H, d, J=1.25 Hz), 7.42 (1 H, d, J=1.25 Hz), 4.76 (1 H, d, J=12.05 Hz), 4.19 (1 H, d, J=12.55 Hz), 3.99 - 4.08 (1 H, m), 3.94 (1 H,  dd, J=12.17, 4.14 Hz), 3.61 (1 H, dd, J=12.55, 4.27 Hz), 2.64 (2 H, s), 2.53 - 2.63 (1 H, m), 2.05 - 2.18 (2 H, m), 1.94 - 2.01 (1 H, m), 1.85 - 1.94 (2 H, m), 1.67 - 1.84 (3 H, m), 1.46 (1 H, br s), 1.36 - 1.41 (9 H, m) (1-((S)-1- cyclobutylethyl )-1H- imidazol -4- yl )((1R,5S,6S)-6-(5,5- dimethyl -4,5- di Hydroisozol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ) methanone to 1-[(1 S )-1-cyclobutylethyl]-1H-imidazole- To a solution of 4-carboxylic acid (30 mg, 0.1500 mmol) in DMF (1.5 mL) was added HATU (70.86 mg, 0.1900 mmol), DIPEA (99.81 mg, 0.7700 mmol). The mixture was stirred for 10 min. (1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1. 0] Hexane hydrochloride (39.1 mg, 0.1500 mmol). The mixture was stirred at 25°C for 12 hours to give a brown solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (25.52 mg, 0.0716 mmol, 46.352% yield) as a tan solid. LC-MS method 1: 357.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.61 (1 H, d, J=1.25 Hz), 7.42 (1 H, d, J=1.25 Hz ), 4.76 (1 H, d, J=12.05 Hz), 4.19 (1 H, d, J=12.55 Hz), 3.99 - 4.08 (1 H, m), 3.94 (1 H, dd, J=12.17, 4.14 Hz), 3.61 (1 H, dd, J=12.55, 4.27 Hz), 2.64 (2 H, s), 2.53 - 2.63 (1 H, m), 2.05 - 2.18 (2 H, m), 1.94 - 2.01 ( 1 H, m), 1.85 - 1.94 (2 H, m), 1.67 - 1.84 (3 H, m), 1.46 (1 H, br s), 1.36 - 1.41 (9 H, m)

實例 17      {1-[(1R)-1- 環丁基乙基 ]-1H- 咪唑 -4- 基 }[(1R,5S,6R)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 1-[(1R)-1- 環丁基乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯向(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(100 mg，0.5900mmol)於Et ₃N (0.58mL，4.46mmol)中之溶液添加(1R)-1-環丁基乙胺氫氯化物(241.94mg，1.78mmol)於1-丁醇(0.30 mL)中之混合物。在70℃下攪拌所得混合物16小時，得到黃色混合物。TLC (PE:EtOAc = 1:1)展示偵測到一個新樣點(Rf = 0.3)。真空濃縮反應混合物，得到殘餘物。藉由製備型TLC (PE:EtOAc = 1:1)純化殘餘物，得到呈黃色油狀之標題化合物(25mg，0.1125mmol，18.916%產率)。 LC-MS方法1 0.667 min，MS (m/z) 222.9 (M + H ⁺)。 Example 17 {1-[(1R)-1- cyclobutylethyl ]-1H- imidazol -4- yl }[(1R,5S,6R)-6-(5,5- dimethyl -4,5 -Dihydro - 1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 1-[(1R)-1- cyclobutylethyl ]- 1H- Imidazole -4- carboxylic acid ethyl ester to (2Z)-3-(dimethylamino)-2-isocyanoacrylate ethyl ester (100 mg, 0.5900mmol) in Et ₃ N (0.58mL, 4.46mmol) To the solution in was added a mixture of (1R)-1-cyclobutylethylamine hydrochloride (241.94 mg, 1.78 mmol) in 1-butanol (0.30 mL). The resulting mixture was stirred at 70°C for 16 hours to give a yellow mixture. TLC (PE:EtOAc = 1:1) showed detection of a new spot (Rf = 0.3). The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (PE:EtOAc = 1:1) to give the title compound (25 mg, 0.1125 mmol, 18.916% yield) as a yellow oil. LC-MS method 1 0.667 min, MS (m/z) 222.9 (M + H ⁺ ).

1-[(1R)-1- 環丁基乙基 ]-1H- 咪唑 -4- 羧酸向1-[(1R)-1-環丁基乙基]-1H-咪唑-4-羧酸乙酯(25 mg，0.1100mmol)於THF (0.75 mL)及H ₂O (0.25 mL)中之混合物添加LiOH·H ₂O (0.01mL，0.1700mmol)。在40℃下攪拌反應混合物16小時，得到黃色混合物。TLC (PE:EtOAc =1:1)展示起始材料完全耗盡。用H ₂O (6 mL)稀釋反應混合物且濃縮以移除大部分THF。用1 N HCl水溶液將水相酸化至pH = 5且凍乾，得到呈黃色固體狀之標題化合物(21mg，0.1081mmol，96.131%產率)。 LC-MS方法1 0.414 min，MS (m/z) 194.9 (M + H ⁺)。 1-[(1R)-1- cyclobutylethyl ]-1H- imidazole -4- carboxylic acid to 1-[(1R)-1-cyclobutylethyl]-1H-imidazole-4-carboxylic acid ethyl To a mixture of ester (25 mg, 0.1100 mmol) in THF (0.75 mL) and _H2O (0.25 mL) was added LiOH- _H2O (0.01 mL, 0.1700 mmol). The reaction mixture was stirred at 40 °C for 16 hours to give a yellow mixture. TLC (PE:EtOAc = 1:1) showed complete consumption of starting material. The reaction mixture was diluted with H ₂ O (6 mL) and concentrated to remove most of the THF. The aqueous phase was acidified to pH = 5 with 1 N aqueous HCl and lyophilized to afford the title compound (21 mg, 0.1081 mmol, 96.131% yield) as a yellow solid. LC-MS method 1 0.414 min, MS (m/z) 194.9 (M + H ⁺ ).

{1-[(1R)-1- 環丁基乙基 ]-1H- 咪唑 -4- 基 }[(1R,5S,6R)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-[(1R)-1-環丁基乙基]-1H-咪唑-4-羧酸(21 mg，0.1100mmol)於DMF (0.50 mL)中之混合物添加HATU (49.6mg，0.1300mmol)及DIPEA (0.09mL，0.5400mmol)。在50℃下攪拌混合物30 min且繼之以添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(29.23mg，0.1600mmol)。在25℃下攪拌混合物16小時，得到黃色混合物。藉由製備型HPLC (NH ₃)純化反應混合物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色固體狀之標題化合物(1.64mg，0.0046mmol，4.2553%產率)。 LC-MS方法1: 357.1 [M+H ⁺] ¹H NMR (400 MHz, 甲醇-d4) δ ppm 7.73 (s, 1 H), 7.68 (s, 1 H), 4.42 (br d, J=11.3 Hz, 1 H), 4.18 - 4.29 (m, 1 H), 4.11 (br d, J=12.8 Hz, 1 H), 3.94 (br dd, J=12.2, 3.9 Hz, 1 H), 3.60 (br dd, J=12.4, 3.6 Hz, 1 H), 2.73 (s, 2 H), 2.62 - 2.71 (m, 1 H), 2.10 - 2.20 (m, 2 H), 2.03 - 2.10 (m, 1 H), 1.78 - 1.94 (m, 4 H), 1.72 (br t, J=8.5 Hz, 1 H), 1.49 (t, J=3.4 Hz, 1 H), 1.40 (d, J=6.5 Hz, 3 H), 1.34 (s, 6 H), 0.89 (br d, J=9.8 Hz, 1 H) {1-[(1R)-1- cyclobutylethyl ]-1H- imidazol -4- yl }[(1R,5S,6R)-6-(5,5- dimethyl - 4,5- di Hydrogen -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-[(1R)-1-cyclobutylethyl]-1H - A mixture of imidazole-4-carboxylic acid (21 mg, 0.1100 mmol) in DMF (0.50 mL) was added with HATU (49.6 mg, 0.1300 mmol) and DIPEA (0.09 mL, 0.5400 mmol). The mixture was stirred at 50 °C for 30 min and followed by the addition of (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl) - 3-Azabicyclo[3.1.0]hexane hydrochloride (29.23 mg, 0.1600 mmol). The mixture was stirred at 25°C for 16 hours to give a yellow mixture. The reaction mixture was purified by preparative HPLC (NH ₃ ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (1.64 mg, 0.0046 mmol, 4.2553% yield) as a yellow solid. LC-MS method 1: 357.1 [M+H ⁺ ] ¹ H NMR (400 MHz, methanol-d4) δ ppm 7.73 (s, 1 H), 7.68 (s, 1 H), 4.42 (br d, J=11.3 Hz, 1 H), 4.18 - 4.29 (m, 1 H), 4.11 (br d, J=12.8 Hz, 1 H), 3.94 (br dd, J=12.2, 3.9 Hz, 1 H), 3.60 (br dd , J=12.4, 3.6 Hz, 1 H), 2.73 (s, 2 H), 2.62 - 2.71 (m, 1 H), 2.10 - 2.20 (m, 2 H), 2.03 - 2.10 (m, 1 H), 1.78 - 1.94 (m, 4 H), 1.72 (br t, J=8.5 Hz, 1 H), 1.49 (t, J=3.4 Hz, 1 H), 1.40 (d, J=6.5 Hz, 3 H), 1.34 (s, 6 H), 0.89 (br d, J=9.8 Hz, 1 H)

實例 18      (1-((S)-1- 環戊基乙基 )-1H- 咪唑 -4- 基 )((1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫異 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ) 甲酮 (1-((S)-1- 環戊基乙基 )-1H- 咪唑 -4- 基 )((1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫異 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ) 甲酮向1-[(1S)-1-環戊基乙基]-1H-咪唑-4-羧酸(50 mg，0.2400mmol，利用實例19中所描述之相同方案使用(R)-2-甲基丙烷-2-亞磺醯胺代替(S)-2-甲基丙烷-2-亞磺醯胺而製備)於DMF (5mL)中之溶液添加HATU (137.68mg，0.3600mmol)及Et ₃N (0.12mL，0.9600mmol)。在25℃下攪拌混合物30min。隨後添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(43.28mg，0.2400mmol)。在25℃下攪拌所得混合物3小時，得到褐色溶液。真空濃縮反應混合物以移除大部分DMF。藉由製備型HPLC (NH ₃)純化粗產物且凍乾，得到呈白色固體狀之標題化合物(70mg，0.1889mmol，78.697%產率)。 LC-MS方法1: 371.3 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.65 (d, J=1.1 Hz, 1H), 7.44 (d, J=0.9 Hz, 1H), 4.76 (br d, J=11.9 Hz, 1H), 4.19 (br d, J=12.6 Hz, 1H), 3.95 (br dd, J=3.9, 11.9 Hz, 1H), 3.87 (qd, J=6.8, 9.5 Hz, 1H), 3.62 (br dd, J=4.1, 12.5 Hz, 1H), 3.66 - 3.57 (m, 1H), 2.64 (s, 2H), 2.20 - 2.04 (m, 2H), 2.02 - 1.94 (m, 1H), 1.88 (dtd, J=3.9, 7.6, 11.7 Hz, 1H), 1.64 - 1.55 (m, 3H), 1.49 (d, J=6.8 Hz, 6H), 1.38 (s, 6H), 1.23 (qd, J=8.8, 12.6 Hz, 1H), 1.14 - 1.01 (m, 1H) Example 18 (1-((S)-1- cyclopentylethyl )-1H- imidazol -4- yl )((1R,5S,6S)-6-(5,5- dimethyl -4,5 -Dihydroisozol - 3- yl )-3- azabicyclo [3.1.0] hex -3- yl ) methanone (1-((S)-1- cyclopentylethyl )-1H - imidazole -4- yl )((1R,5S,6S)-6-(5,5- dimethyl -4,5- dihydroisoxazol -3- yl )-3- azabicyclo [ 3.1.0] Hex -3- yl ) methanone was dissolved in 1-[(1S)-1-cyclopentylethyl]-1H-imidazole-4-carboxylic acid (50 mg, 0.2400 mmol, using the same protocol as described in Example 19 To a solution of (R)-2-methylpropane-2-sulfinamide instead of (S)-2-methylpropane-2-sulfinamide) in DMF (5 mL) was added HATU (137.68 mg, 0.3600 mmol) and _Et3N (0.12 mL, 0.9600 mmol). The mixture was stirred at 25 °C for 30 min. Then add (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0] Hexane hydrochloride (43.28 mg, 0.2400 mmol). The resulting mixture was stirred at 25°C for 3 hours to give a brown solution. The reaction mixture was concentrated in vacuo to remove most of the DMF. The crude product was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (70 mg, 0.1889 mmol, 78.697% yield) as a white solid. LC-MS method 1: 371.3 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.65 (d, J =1.1 Hz, 1H), 7.44 (d, J =0.9 Hz, 1H), 4.76 (br d, J =11.9 Hz, 1H), 4.19 (br d, J =12.6 Hz, 1H), 3.95 (br dd, J =3.9, 11.9 Hz, 1H), 3.87 (qd, J =6.8, 9.5 Hz , 1H), 3.62 (br dd, J =4.1, 12.5 Hz, 1H), 3.66 - 3.57 (m, 1H), 2.64 (s, 2H), 2.20 - 2.04 (m, 2H), 2.02 - 1.94 (m, 1H), 1.88 (dtd, J =3.9, 7.6, 11.7 Hz, 1H), 1.64 - 1.55 (m, 3H), 1.49 (d, J =6.8 Hz, 6H), 1.38 (s, 6H), 1.23 (qd , J =8.8, 12.6 Hz, 1H), 1.14 - 1.01 (m, 1H)

實例 19 {1-[(1R)-1- 環戊基乙基 ]-1H- 咪唑 -4- 基 }[(1R,5S,6R)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (S)-N-[(E)- 環戊基亞甲基 ]-2- 甲基 -2- 丙烷亞磺醯胺向環戊基醛於THF (20 mL)中之混合物添加(S)-2-甲基丙烷-2-亞磺醯胺(2.47 g，20.38 mmol)、鈦(IV)乙醇化物(6.97 g，30.57 mmol)。在20℃下攪拌懸浮液16小時。用EtOAc (60 mL)稀釋反應混合物。將混合物添加至H ₂O (10 mL)且攪拌1 min，得到白色懸浮液。過濾懸浮液。用H ₂O (30 mL×3)洗滌濾液，用無水Na ₂SO ₄乾燥，過濾且真空濃縮，獲得呈黃色液體狀之標題化合物(3.6 g，粗物質)。 LC-MS方法1: 0.833 min，MS (m/z): 201.9 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.92 (t, d = 4.8 Hz, 1H), 2.90-2.80 (m, 1H), 1.90-1.75 (m, 3H), 1.75-1.50 (m, 5H), 1.15 (s, 9H)。 Example 19 {1-[(1R)-1- cyclopentylethyl ]-1H- imidazol -4- yl }[(1R,5S,6R)-6-(5,5- dimethyl -4,5 -Dihydro -1,2- oxazol - 3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (S)-N-[(E) -cyclopentylmethylene [S ]-2- methyl -2- propanesulfinamide To a mixture of cyclopentylaldehyde in THF (20 mL) was added (S)-2-methylpropane-2-sulfinamide (2.47 g, 20.38 mmol), titanium (IV) ethanolate (6.97 g, 30.57 mmol). The suspension was stirred at 20°C for 16 hours. The reaction mixture was diluted with EtOAc (60 mL). The mixture was added to H ₂ O (10 mL) and stirred for 1 min to give a white suspension. The suspension is filtered. The filtrate was washed with H ₂ O (30 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain the title compound (3.6 g, crude) as a yellow liquid. LC-MS method 1: 0.833 min, MS (m/z): 201.9 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.92 (t, d = 4.8 Hz, 1H), 2.90-2.80 (m, 1H), 1.90-1.75 (m, 3H), 1.75-1.50 (m, 5H ), 1.15 (s, 9H).

(S)-N-[(1R)-1- 環戊基乙基 ]-2- 甲基 -2- 丙烷亞磺醯胺在-40℃下於N ₂下向(S)-N-[(E)-環戊基亞甲基]-2-甲基-2-丙烷亞磺醯胺於THF (20 mL)中之混合物逐滴添加MeMgCl (742.96 mg，9.93 mmol，3.31 mL)歷時10 min。在20℃下攪拌懸浮液16小時。用NH ₄Cl (15 mL)稀釋殘餘物，用EtOAc (30 mL×4)萃取，用飽和NaCl (30 mL×2)洗滌，用無水Na ₂SO ₄乾燥，過濾且真空濃縮。藉由快速柱(PE至30% EtOAc/PE)純化溶液，得到呈黃色液體狀之標題化合物(595 mg，粗物質)。 LC-MS方法1: 0.827 min，MS (m/z): 218 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 3.20-3.05 (m, 1H), 2.82 (brd, J = 8.4 Hz, 1H), 1.90-1.40 (m, 8H), 1.20 (d, J = 7.2 Hz, 3H), 1.14 (s, 9H)。 (S)-N-[(1R)-1- cyclopentylethyl ]-2- methyl - ₂ - propanesulfinamide was converted to (S)-N-[( E)-Cyclopentylmethylene]-2-methyl-2-propanesulfinamide in THF (20 mL) was added MeMgCl (742.96 mg, 9.93 mmol, 3.31 mL) dropwise over 10 min. The suspension was stirred at 20°C for 16 hours. The residue was diluted with NH ₄ Cl (15 mL), extracted with EtOAc (30 mL×4), washed with saturated NaCl (30 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The solution was purified by flash column (PE to 30% EtOAc/PE) to give the title compound (595 mg, crude) as a yellow liquid. LC-MS method 1: 0.827 min, MS (m/z): 218 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 3.20-3.05 (m, 1H), 2.82 (brd, J = 8.4 Hz, 1H), 1.90-1.40 (m, 8H), 1.20 (d, J = 7.2 Hz, 3H), 1.14 (s, 9H).

(1R)-1- 環戊基乙胺 氫氯化物向(S)-N-[(1R)-1-環戊基乙基]-2-甲基-2-丙烷亞磺醯胺之混合物添加MeOH/HCl (5 mL)。在25℃下攪拌懸浮液1小時。真空濃縮殘餘物，得到呈黃色固體狀之標題化合物(257 mg，粗物質)。 Addition of (1R)-1- cyclopentylethylamine hydrochloride to a mixture of (S)-N-[(1R)-1-cyclopentylethyl]-2-methyl-2-propanesulfinamide MeOH/HCl (5 mL). The suspension was stirred at 25°C for 1 hour. The residue was concentrated in vacuo to give the title compound (257 mg, crude) as a yellow solid.

1-[(1R)-1- 環戊基乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯向(1R)-1-環戊基乙胺氫氯化物(52.0 mg，0.35 mmol)之混合物添加1-丁醇(0.5 mL)。隨後向溶液中添加(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(58.44 mg，0.35 mmol)、Et ₃N (52.64 mg，0.52 mmol，0.07 mL)。懸浮液在微波反應器中經受反應(時間：1小時，溫度：130℃)。真空濃縮殘餘物，得到呈黃色油狀之標題化合物(77 mg，粗物質)。 LC-MS方法1: 0.690 min，MS (m/z): 237.0 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.57 (s, 1H), 7.43 (s, 1H), 4.30 (q, J = 6.8 Hz, 2H), 3.80-3.70 (m, 1H), (q, J = 7.2  Hz, 2H), 1.70-1.40 (m, 8H), 1.42 (d, J = 6.8 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H)。 Mixture of 1-[(1R)-1- cyclopentylethyl ]-1H- imidazole -4- carboxylic acid ethyl ester to (1R)-1-cyclopentylethylamine hydrochloride (52.0 mg, 0.35 mmol) 1-Butanol (0.5 mL) was added. Then ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (58.44 mg, 0.35 mmol), Et ₃ N (52.64 mg, 0.52 mmol, 0.07 mL) was added to the solution. The suspension was subjected to reaction in a microwave reactor (time: 1 hour, temperature: 130° C.). The residue was concentrated in vacuo to give the title compound (77 mg, crude) as a yellow oil. LC-MS method 1: 0.690 min, MS (m/z): 237.0 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.57 (s, 1H), 7.43 (s, 1H), 4.30 (q, J = 6.8 Hz, 2H), 3.80-3.70 (m, 1H), (q , J = 7.2 Hz, 2H), 1.70-1.40 (m, 8H), 1.42 (d, J = 6.8 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H).

1-[(1R)-1- 環戊基乙基 ]-1H- 咪唑 -4- 羧酸向1-[(1R)-1-環戊基乙基]-1H-咪唑-4-羧酸乙酯於H ₂O (0.5 mL)及THF (1.5 mL)中之混合物添加LiOH·H ₂O (20.5 mg，0.49 mmol，1.5當量)。在20℃下攪拌懸浮液2小時。用H ₂O (1 mL)稀釋殘餘物，用EtOAc (5mL × 4)萃取。用1 N HCl水溶液將所獲得H ₂O層鹼化至pH=5。濃縮合併之有機層且隨後凍乾，獲得呈黃色固體狀之標題化合物(39 mg，粗物質)。 LC-MS方法1: 0.571 min，MS (m/z): 209 (M + H ⁺)。 1-[(1R)-1- cyclopentylethyl ]-1H- imidazole -4- carboxylic acid to 1-[(1R)-1-cyclopentylethyl]-1H-imidazole-4-carboxylic acid ethyl To a mixture of the ester in _H2O (0.5 mL) and THF (1.5 mL) was added LiOH- _H2O (20.5 mg, 0.49 mmol, 1.5 equiv). The suspension was stirred at 20°C for 2 hours. The residue was diluted with H ₂ O (1 mL), extracted with EtOAc (5 mL×4). The obtained H ₂ O layer was basified to pH=5 with 1 N aqueous HCl. The combined organic layers were concentrated and then lyophilized to obtain the title compound (39 mg, crude) as a yellow solid. LC-MS method 1: 0.571 min, MS (m/z): 209 (M + H ⁺ ).

{1-[(1R)-1- 環戊基乙基 ]-1H- 咪唑 -4- 基 }[(1R,5S,6R)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-[(1R)-1-環戊基乙基]-1H-咪唑-4-羧酸(30.0 mg，0.14 mmol)於吡啶(0.5 mL)中之混合物添加EDCI (27.6 mg，0.14 mmol)及(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(26.0 mg，0.14mmol)。在20℃下攪拌懸浮液16小時。用H ₂O (10 mL)淬滅反應混合物。用EtOAc (20 mL×3)稀釋殘餘物，用飽和NaCl (5 mL)洗滌，用無水Na ₂SO ₄乾燥，過濾且真空濃縮。藉由製備型HPLC (NH ₃)純化溶液且凍乾，得到呈白色固體狀之標題化合物(1.88 mg，3.5%產率)。 LC-MS方法1: 3.486min，MS (m/z): 371.3 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.58 (d, J=1.25 Hz, 1 H), 7.36 (s, 1 H), 4.70 (br d, J=12.30 Hz, 1 H), 4.12 (d, J=12.30 Hz, 1 H), 3.87 (br d, J=12.30 Hz, 1 H), 3.79 (dd, J=9.41, 6.65 Hz, 1 H), 3.54 (br d, J=8.53 Hz, 1 H), 2.57 (s, 2 H), 1.80 - 2.10 (m, 4 H), 1.51 - 1.60 (m, 2 H), 1.41 (br d, J=6.78 Hz, 9 H), 1.30 (s, 7 H), 1.18 (s, 7 H)。 {1-[(1R)-1- cyclopentylethyl ]-1H- imidazol -4- yl }[(1R,5S,6R)-6-(5,5- dimethyl - 4,5- di Hydrogen -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-[(1R)-1-cyclopentylethyl]-1H - A mixture of imidazole-4-carboxylic acid (30.0 mg, 0.14 mmol) in pyridine (0.5 mL) was added with EDCI (27.6 mg, 0.14 mmol) and (1R,5S,6r)-6-(5,5-dimethyl yl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (26.0 mg, 0.14 mmol). The suspension was stirred at 20°C for 16 hours. The reaction mixture was quenched with _H2O (10 mL). The residue was diluted with EtOAc (20 mL×3), washed with sat. NaCl (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The solution was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (1.88 mg, 3.5% yield) as a white solid. LC-MS method 1: 3.486min, MS (m/z): 371.3 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.58 (d, J =1.25 Hz, 1 H), 7.36 (s, 1 H), 4.70 (br d, J =12.30 Hz, 1 H), 4.12 ( d, J =12.30 Hz, 1 H), 3.87 (br d, J =12.30 Hz, 1 H), 3.79 (dd, J =9.41, 6.65 Hz, 1 H), 3.54 (br d, J =8.53 Hz, 1 H), 2.57 (s, 2 H), 1.80 - 2.10 (m, 4 H), 1.51 - 1.60 (m, 2 H), 1.41 (br d, J =6.78 Hz, 9 H), 1.30 (s, 7 H), 1.18 (s, 7 H).

實例 20      [(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1-( 四氫 -2H- 哌喃 -4- 基 ) 乙基 ]-1H- 咪唑 -4- 基 } 甲酮 (R)-2- 甲基 -N-[(E)- 四氫 -2H- 哌喃 -4- 基亞甲基 ]-2- 丙烷亞磺醯胺向100 mL圓底燒瓶裝入四氫-2H-哌喃-4-甲醛(5000 mg，43.81mmol)、(R)-2-甲基丙烷-2-亞磺醯胺(5309.27mg，43.81mmol)、Ti(OEt) ₄(13.5mL，65.71mmol)及THF (25mL)。在60℃下於N ₂保護下加熱反應30 min，得到黃色溶液。TLC (PE/EA= 3/1，Rf =0.4)展示偵測到新樣點。逐滴添加H ₂O (3 mL)且在20℃下將其攪拌5 min，隨後經由矽藻土墊過濾且真空濃縮濾液，得到呈白色固體狀之標題化合物(8700 mg，40.031mmol，91.383%產率)。 LC-MS方法1 0.745 min，MS (m/z) 218.1 (M + H ⁺)。 Example 20 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ]{1-[(1S)-1-( tetrahydro -2H- pyran -4- yl ) ethyl ]-1H- imidazol -4- yl } methanone (R)-2- Methyl -N-[(E) -tetrahydro -2H- pyran -4- ylmethylene ]-2- propanesulfinamide A 100 mL round bottom flask was charged with tetrahydro-2H-pyran-4 - Formaldehyde (5000 mg, 43.81 mmol), (R)-2-methylpropane-2-sulfinamide (5309.27 mg, 43.81 mmol), Ti(OEt) ₄ (13.5 mL, 65.71 mmol) and THF (25 mL ). The reaction was heated at 60 °C for 30 min under the protection of _N2 to obtain a yellow solution. TLC (PE/EA=3/1, Rf=0.4) showed detection of new samples. _H2O (3 mL) was added dropwise and stirred at 20 °C for 5 min, then filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (8700 mg, 40.031 mmol, 91.383% Yield). LC-MS method 1 0.745 min, MS (m/z) 218.1 (M + H ⁺ ).

(R)-2- 甲基 -N-[(1S)-1-( 四氫 -2H- 哌喃 -4- 基 ) 乙基 ]-2- 丙烷亞磺醯胺將裝有(R)-2-甲基-N-[(E)-四氫-2H-哌喃-4-基亞甲基]-2-丙烷亞磺醯胺(3000 mg，13.8mmol)及THF (30mL)之圓底燒瓶冷卻至-48℃，向混合物逐滴添加MeMgBr (5.06mL，15.18mmol)。在此溫度下攪拌反應物2小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(DCM/EA=3/1至1/1)來純化粗物質，得到呈無色油狀之標題化合物(1700 mg，7.2846mmol，52.772%產率)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 4.05-3.95 (m, 2H), 3.40 (dt, J = 4.0, 1.6 Hz, 2H), 3.25-3.10 (m, 1H), 2.90 (d, J = 7.6 Hz, 1H), 1.85-1.75 (m, 1H), 1.70-1.20 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H), 1.25 (s, 9H)。 (R)-2- methyl -N-[(1S)-1-( tetrahydro -2H- pyran -4- yl ) ethyl ]-2- propanesulfinamide will be equipped with (R)-2 -Methyl-N-[(E)-tetrahydro-2H-pyran-4-ylmethylene]-2-propanesulfinamide (3000 mg, 13.8 mmol) and THF (30 mL) in a round bottom flask Cooled to -48°C, MeMgBr (5.06 mL, 15.18 mmol) was added dropwise to the mixture. The reaction was stirred at this temperature for 2 hours to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (DCM/EA = 3/1 to 1/1 ) to afford the title compound (1700 mg, 7.2846 mmol, 52.772% yield) as a colorless oil. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 4.05-3.95 (m, 2H), 3.40 (dt, J = 4.0, 1.6 Hz, 2H), 3.25-3.10 (m, 1H), 2.90 (d, J = 7.6 Hz, 1H), 1.85-1.75 (m, 1H), 1.70-1.20 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H), 1.25 (s, 9H).

(1S)-1-( 四氫 -2H- 哌喃 -4- 基 ) 乙胺氫氯化物向100ml圓底燒瓶裝入(R)-2-甲基-N-[(1S)-1-(四氫-2H-哌喃-4-基)乙基]-2-丙烷亞磺醯胺(1700 mg，7.28 mmol)及HCl/MeOH (10 mL，7.28mmol)。在25℃下攪拌反應混合物3小時，得到無色油狀物。在真空中蒸發，得到呈無色油狀之標題化合物(1250mg，7.5456mmol，103.58%產率)。 (1S)-1-( tetrahydro -2H- pyran - 4- yl ) ethylamine hydrochloride is charged into (R)-2-methyl-N-[(1S)-1-( Tetrahydro-2H-pyran-4-yl)ethyl]-2-propanesulfinamide (1700 mg, 7.28 mmol) and HCl/MeOH (10 mL, 7.28 mmol). The reaction mixture was stirred at 25°C for 3 hours to give a colorless oil. Evaporation in vacuo gave the title compound (1250 mg, 7.5456 mmol, 103.58% yield) as a colorless oil.

1-[(1S)-1-( 四氫 -2H- 哌喃 -4- 基 ) 乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯向微波管裝入(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(400.29mg，2.38mmol)、(1S)-1-(四氫-2H-哌喃-4-基)乙胺氫氯化物(394.27mg，2.38mmol)、三乙胺(0.5 mL，3.57mmol)及1-丁醇(0.6004mL)。在130℃下用微波照射1小時，得到褐色溶液。添加H ₂O (15 mL)且用EtOAc (15mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(PE/EA= 1/1至0/1)來純化粗物質，得到呈黃色油狀之標題化合物(135mg，0.5351mmol，22.481%產率)。 LC-MS方法1 0.638, MS (m/z) 253.2 (M + H ⁺)。 1-[(1S)-1-( Tetrahydro -2H- pyran -4- yl ) ethyl ]-1H- imidazole -4- carboxylic acid ethyl ester was loaded into (2Z)-3-(dimethyl Amino)-ethyl 2-isocyanoacrylate (400.29mg, 2.38mmol), (1S)-1-(tetrahydro-2H-pyran-4-yl)ethylamine hydrochloride (394.27mg, 2.38mmol ), triethylamine (0.5 mL, 3.57 mmol) and 1-butanol (0.6004 mL). Microwave irradiation at 130 °C for 1 hour gave a brown solution. H ₂ O (15 mL) was added and it was extracted with EtOAc (15 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (PE/EA = 1/1 to 0/1) to afford the title compound (135 mg, 0.5351 mmol, 22.481% yield) as a yellow oil. LC-MS method 1 0.638, MS (m/z) 253.2 (M + H ⁺ ).

1-[(1S)-1-( 四氫 -2H- 哌喃 -4- 基 ) 乙基 ]-1H- 咪唑 -4- 羧酸向100 mL圓底燒瓶裝入1-[(1S)-1-(四氫-2H-哌喃-4-基)乙基]-1H-咪唑-4-羧酸乙酯(130 mg，0.5200mmol)、羥基鋰水合物(43.24mg，1.03mmol)、THF (3mL)。在20℃下攪拌3小時，得到黃色溶液。添加H ₂O (15 mL)且用EtOAc (15 mL×2)對其進行萃取。凍乾水相，得到呈黃色固體狀之標題化合物(110mg，0.4905mmol，95.199%產率)。其直接用於下一步驟。 1-[(1S)-1-( Tetrahydro -2H- pyran -4- yl ) ethyl ]-1H- imidazole -4- carboxylic acid A 100 mL round bottom flask was charged with 1-[(1S)-1 -(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylic acid ethyl ester (130 mg, 0.5200 mmol), hydroxy lithium hydrate (43.24 mg, 1.03 mmol), THF ( 3mL). Stirring at 20°C for 3 hours gave a yellow solution. H ₂ O (15 mL) was added and it was extracted with EtOAc (15 mL×2). The aqueous phase was lyophilized to afford the title compound (110 mg, 0.4905 mmol, 95.199% yield) as a yellow solid. It was used directly in the next step.

[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1-( 四氫 -2H- 哌喃 -4- 基 ) 乙基 ]-1H- 咪唑 -4- 基 } 甲酮向1-[(1S)-1-(四氫-2H-哌喃-4-基)乙基]-1H-咪唑-4-羧酸(110 mg，0.4900mmol)及HATU (243.77mg，0.6400mmol)於DMF (5mL)中之混合物添加N-乙基-N-異丙基丙-2-胺(0.59mL，3.43mmol)。在攪拌30min之後，添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(384.3mg，0.7400mmol)。攪拌反應混合物另16小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (NH ₃)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(9.57mg，0.0248mmol，5.0482%產率)。 LC-MS方法1: 387.3 [M+H ⁺] ¹H NMR (400 MHz, 氯仿- d) δ ppm 1.12 - 1.17 (m, 1 H) 1.23 (dd, J=12.30, 4.02 Hz, 1 H) 1.37 (s, 6 H) 1.46 (br d, J=3.01 Hz, 1 H) 1.50 (d, J=6.78 Hz, 3 H) 1.68 (br d, J=13.05 Hz, 1 H) 1.78 (br d, J=8.78 Hz, 1 H) 1.94 - 1.99 (m, 1 H) 2.04 - 2.11 (m, 1 H) 2.63 (s, 2 H) 3.25 (td, J=11.80, 2.26 Hz, 1 H) 3.36 (td, J=11.92, 2.01 Hz, 1 H) 3.61 (dd, J=12.42, 3.89 Hz, 1 H) 3.81 - 3.88 (m, 1 H) 3.92 (br t, J=11.80 Hz, 2 H) 4.02 (br dd, J=11.54, 3.76 Hz, 1 H) 4.18 (br d, J=13.05 Hz, 1 H) 4.75 (dd, J=12.05, 4.27 Hz, 1 H) 7.40 (s, 1 H) 7.62 (s, 1 H) [(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ]{1-[(1S)-1-( tetrahydro -2H- pyran -4- yl ) ethyl ]-1H- imidazol -4- yl } methanone to 1-[(1S)- 1-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-imidazole-4-carboxylic acid (110 mg, 0.4900mmol) and HATU (243.77mg, 0.6400mmol) in DMF (5mL) To the mixture was added N-ethyl-N-isopropylpropan-2-amine (0.59 mL, 3.43 mmol). After stirring for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[ 3.1.0] Hexane hydrochloride (384.3 mg, 0.7400 mmol). The reaction mixture was stirred for another 16 hours to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC ( _NH3 ). The resulting fluid was concentrated in vacuo to remove most of the _CH3CN and lyophilized to afford the title compound (9.57 mg, 0.0248 mmol, 5.0482% yield) as a white solid. LC-MS method 1: 387.3 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform- d ) δ ppm 1.12 - 1.17 (m, 1 H) 1.23 (dd, J =12.30, 4.02 Hz, 1 H) 1.37 (s, 6 H) 1.46 (br d, J =3.01 Hz, 1 H) 1.50 (d, J =6.78 Hz, 3 H) 1.68 (br d, J =13.05 Hz, 1 H) 1.78 (br d, J =8.78 Hz, 1 H) 1.94 - 1.99 (m, 1 H) 2.04 - 2.11 (m, 1 H) 2.63 (s, 2 H) 3.25 (td, J =11.80, 2.26 Hz, 1 H) 3.36 (td, J =11.92, 2.01 Hz, 1 H) 3.61 (dd, J =12.42, 3.89 Hz, 1 H) 3.81 - 3.88 (m, 1 H) 3.92 (br t, J =11.80 Hz, 2 H) 4.02 (br dd , J =11.54, 3.76 Hz, 1 H) 4.18 (br d, J =13.05 Hz, 1 H) 4.75 (dd, J =12.05, 4.27 Hz, 1 H) 7.40 (s, 1 H) 7.62 (s, 1 h)

實例 21      [(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1- 苯基乙基 ]-1H- 咪唑 -4- 基 } 甲酮 1-[(1S)-1- 苯基乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯在0℃下攪拌異氰基乙酸乙酯(1.0 g，8.84mmol)及1,1-二甲氧基-N,N-二甲基甲胺(1.53mL，11.49mmol)之混合物3小時。TLC (PE:EA=3:1)展示2-異氰基乙酸乙酯(1.g，8.84mmol) (Rf=0.6)完全耗盡且偵測到新樣點(Rf=0.4)。向混合物添加(S)-1-苯乙胺(4.5mL，35.36mmol)。在50℃下攪拌所得混合物16小時，得到褐色混合物。TLC (PE:EA=1:1)展示偵測到新樣點(Rf = 0.1)。濃縮混合物，得到殘餘物。藉由快速柱(PE:EA=1:0至0:1)純化殘餘物，得到呈褐色油狀之標題化合物(0.9300g，3.807mmol，43.06%產率) (PE:EA=1:1，Rf=0.1)。 LC-MS方法1 0.685 min，MS (m/z) 244.9 (M + H ⁺)。 Example 21 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ]{1-[(1S)-1- phenylethyl ]-1H- imidazol -4- yl } methanone 1-[(1S)-1- phenylethyl ]-1H- Ethyl imidazole - 4- carboxylate Stir ethyl isocyanoacetate (1.0 g, 8.84 mmol) and 1,1-dimethoxy-N, N-dimethylmethylamine (1.53 mL, 11.49 mmol) mixture for 3 hours. TLC (PE:EA=3:1) showed complete consumption of ethyl 2-isocyanoacetate (1.g, 8.84 mmol) (Rf=0.6) and detection of a new spot (Rf=0.4). To the mixture was added (S)-1-phenethylamine (4.5 mL, 35.36 mmol). The resulting mixture was stirred at 50°C for 16 hours to give a brown mixture. TLC (PE:EA=1:1) showed detection of a new sample (Rf = 0.1). The mixture was concentrated to give a residue. The residue was purified by flash column (PE:EA=1:0 to 0:1) to give the title compound (0.9300 g, 3.807 mmol, 43.06% yield) as a brown oil (PE:EA=1:1, Rf=0.1). LC-MS method 1 0.685 min, MS (m/z) 244.9 (M + H ⁺ ).

1-[(1S)-1- 苯基乙基 ]-1H- 咪唑 -4- 羧酸向1-[(1S)-1-苯基乙基]-1H-咪唑-4-羧酸乙酯(930 mg，3.81mmol)於THF (6mL)及H ₂O (3mL)中之混合物添加LiOH·H ₂O (0.33mL，5.71mmol)。在20℃下攪拌反應混合物16小時，得到黃色混合物。TLC (PE:EtOAc = 1:1)展示起始材料完全耗盡。用H ₂O (15 mL)稀釋反應混合物且用EtOAc (8 mL × 5)萃取。用1 N HCl水溶液將水相酸化至pH = 4。真空乾燥所得水相，得到呈褐色固體狀之標題化合物(900mg，4.162mmol，109.33%產率) (粗物質)。 LC-MS方法1 0.539 min，MS (m/z) 216.9 (M + H ⁺)。 1-[(1S)-1- phenylethyl ]-1H- imidazole -4- carboxylic acid to 1-[(1S)-1-phenylethyl]-1H-imidazole-4-carboxylic acid ethyl ester ( To a mixture of 930 mg, 3.81 mmol) in THF (6 mL) and _H2O (3 mL) was added LiOH- _H2O (0.33 mL, 5.71 mmol). The reaction mixture was stirred at 20 °C for 16 hours to give a yellow mixture. TLC (PE:EtOAc = 1:1) showed complete consumption of starting material. The reaction mixture was diluted with H ₂ O (15 mL) and extracted with EtOAc (8 mL×5). The aqueous phase was acidified to pH = 4 with 1 N aqueous HCl. The resulting aqueous phase was dried in vacuo to afford the title compound (900 mg, 4.162 mmol, 109.33% yield) as a tan solid (crude material). LC-MS method 1 0.539 min, MS (m/z) 216.9 (M + H ⁺ ).

[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1- 苯基乙基 ]-1H- 咪唑 -4- 基 } 甲酮向(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(100 mg，0.5500mmol)於DMF (2mL)中之混合物添加1-[(1S)-1-苯基乙基]-1H-咪唑-4-羧酸(143.96mg，0.6700mmol)、DIPEA (0.37mL，2.22mmol)及HATU (254.51mg，0.6700mmol)。在25℃下攪拌反應混合物16小時，得到褐色混合物。TLC (DCM:MeOH = 40:1，一滴Et ₃N)展示偵測到一個新樣點(Rf = 0.5)。用H ₂O (10 mL)稀釋反應混合物。用EtOAc (5 mL×4)萃取所得混合物。合併之有機相經無水Na ₂SO ₄乾燥，過濾且真空濃縮，得到殘餘物。藉由製備型TLC (DCM:MeOH = 40: 1，1% Et ₃N於溶劑中)純化殘餘物，得到粗產物。藉由製備型HPLC (NH ₃)純化粗產物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(3.85mg，0.0102mmol，1.8336%產率)。 LC-MS方法1: 379.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.67 (br s, 1 H), 7.48 (s, 1 H), 7.31 - 7.40 (m, 3 H), 7.18 (br d, J=6.5 Hz, 2 H), 5.35 (q, J=6.9 Hz, 1 H), 4.75 (br d, J=8.0 Hz, 1 H), 4.18 (br d, J=12.3 Hz, 1 H), 3.88 - 4.01 (m, 1 H), 3.61 (br d, J=8.8 Hz, 1 H), 2.64 (s, 2 H), 2.07 (br s, 1 H), 1.98 (br s, 1 H), 1.88 (d, J=7.0 Hz, 3 H), 1.46 (br s, 1 H), 1.38 (s, 6 H), 1.26 (s, 1 H) [(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ]{1-[(1S)-1- phenylethyl ]-1H- imidazol -4- yl } methanone to (1R,5S,6r)-6-(5,5-dimethyl A mixture of -4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (100 mg, 0.5500 mmol) in DMF (2 mL) 1-[(1S)-1-Phenylethyl]-1H-imidazole-4-carboxylic acid (143.96 mg, 0.6700 mmol), DIPEA (0.37 mL, 2.22 mmol) and HATU (254.51 mg, 0.6700 mmol) were added. The reaction mixture was stirred at 25°C for 16 hours to give a brown mixture. TLC (DCM:MeOH = 40:1, one drop of Et ₃ N) showed detection of a new spot (Rf = 0.5). The reaction mixture was diluted with H ₂ O (10 mL). The resulting mixture was extracted with EtOAc (5 mL×4). The combined organic phases were dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (DCM:MeOH = 40:1, 1% Et ₃ N in solvent) to give crude product. The crude product was purified by preparative HPLC (NH ₃ ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to afford the title compound (3.85 mg, 0.0102 mmol, 1.8336% yield) as a white solid. LC-MS method 1: 379.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.67 (br s, 1 H), 7.48 (s, 1 H), 7.31 - 7.40 (m, 3 H), 7.18 (br d, J=6.5 Hz, 2 H), 5.35 (q, J=6.9 Hz, 1 H), 4.75 (br d, J=8.0 Hz, 1 H), 4.18 (br d, J =12.3 Hz, 1 H), 3.88 - 4.01 (m, 1 H), 3.61 (br d, J=8.8 Hz, 1 H), 2.64 (s, 2 H), 2.07 (br s, 1 H), 1.98 (br s, 1 H), 1.88 (d, J=7.0 Hz, 3 H), 1.46 (br s, 1 H), 1.38 (s, 6 H), 1.26 (s, 1 H)

實例 22      2-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 羰基 }-1H- 咪唑 -1- 基 ) 乙基 ] 苯甲腈 (R)-N-[(E)-(2- 溴苯基 ) 亞甲基 ]-2- 甲基 -2- 丙烷亞磺醯胺向100 mL圓底燒瓶裝入2-溴苯甲醛(2000 mg，10.81mmol)、(R)-2-甲基丙烷-2-亞磺醯胺(1310.13mg，10.81mmol)、Ti(OEt) ₄(3.33mL，16.21mmol)及THF (9.2536mL)。在60℃下於N ₂保護下加熱反應30min，得到黃色溶液。TLC (PE/EA=3/1，Rf =0.4)展示偵測到新樣點。逐滴添加H ₂O (3 mL)且在20℃下將其攪拌5 min，隨後經由矽藻土墊過濾且真空濃縮，得到呈白色固體狀之標題化合物(3050mg，10.583mmol，97.903%產率)。 Example 22 2-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-dimethyl- 4,5 - dihydro -1,2- oxazole -3 -yl )-3- azabicyclo [3.1.0] hex -3- yl ] carbonyl }-1H- imidazol - 1- yl ) ethyl ] benzonitrile (R)-N-[(E)-(2 -Bromophenyl ) methylene ]-2- methyl -2- propanesulfinamide A 100 mL round bottom flask was charged with 2-bromobenzaldehyde (2000 mg, 10.81 mmol), (R)-2-methyl Propan-2-sulfinamide (1310.13 mg, 10.81 mmol), Ti(OEt) ₄ (3.33 mL, 16.21 mmol) and THF (9.2536 mL). The reaction was heated at 60 °C for 30 min under the protection of N ₂ to obtain a yellow solution. TLC (PE/EA=3/1, Rf=0.4) showed detection of new samples. _H2O (3 mL) was added dropwise and stirred at 20 °C for 5 min, then filtered through a pad of celite and concentrated in vacuo to give the title compound (3050 mg, 10.583 mmol, 97.903% yield) as a white solid ).

(R)-N-[(1S)-1-(2- 溴苯基 ) 乙基 ]-2- 甲基 -2- 丙烷亞磺醯胺將裝有(R)-N-[(E)-(2-溴苯基)亞甲基]-2-甲基-2-丙烷亞磺醯胺(3000 mg，10.41mmol)及THF (25mL)之圓底燒瓶冷卻至-48℃，且向混合物逐滴添加氯基(甲基)鎂(4.16mL，12.49mmol)。在此溫度下攪拌反應物2小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(DCM/EA= 10/1至3/1)來純化粗物質，得到呈白色固體狀之標題化合物(960mg，3.1553mmol，30.312%產率)。 ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.54 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.0, 0.8 Hz, 1H), 7.40-7.20 (m, 1H), 7.20-7.10 (m, 1H), 5.05-4.95 (m, 1H), 3.37 (d, J = 4.0 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.21 (s, 9H)。 (R)-N-[(1S)-1-(2- bromophenyl ) ethyl ]-2- methyl -2- propanesulfinamide will be equipped with (R)-N-[(E)- A round bottom flask of (2-bromophenyl)methylene]-2-methyl-2-propanesulfinamide (3000 mg, 10.41 mmol) and THF (25 mL) was cooled to -48 °C, and the mixture was gradually Chloro(methyl)magnesium (4.16 mL, 12.49 mmol) was added dropwise. The reaction was stirred at this temperature for 2 hours to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (DCM/EA = 10/1 to 3/1 ) to afford the title compound (960 mg, 3.1553 mmol, 30.312% yield) as a white solid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.54 (d, J = 8.0 Hz, 1H), 7.43 (dd, J = 8.0, 0.8 Hz, 1H), 7.40-7.20 (m, 1H), 7.20- 7.10 (m, 1H), 5.05-4.95 (m, 1H), 3.37 (d, J = 4.0 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H), 1.21 (s, 9H).

(1S)-1-(2- 溴苯基 ) 乙胺氫氯化物在30℃下攪拌(R)-N-[(1S)-1-(2-溴苯基)乙基]-2-甲基-2-丙烷亞磺醯胺(900 mg，2.96 mmol)於HCl/MeOH (105.31mg，2.96 mmol)中之溶液16小時，得到無色溶液。在真空中蒸發反應混合物，得到呈黃色油狀之標題化合物(700 mg，2.95 mmol，100.04%產率)。其直接用於下一步驟。 LC-MS 方法 1 0.592 min，MS (m/z) 202.1 (M + H ⁺)。 (1S)-1-(2- bromophenyl ) ethylamine hydrochloride was stirred at 30°C (R)-N-[(1S)-1-(2-bromophenyl)ethyl]-2-methyl A solution of 2-propanesulfinamide (900 mg, 2.96 mmol) in HCl/MeOH (105.31 mg, 2.96 mmol) for 16 hours gave a colorless solution. The reaction mixture was evaporated in vacuo to afford the title compound (700 mg, 2.95 mmol, 100.04% yield) as a yellow oil. It was used directly in the next step. LC-MS method 1 0.592 min, MS (m/z) 202.1 (M + H ⁺ ).

1-[(1S)-1-(2- 溴苯基 ) 乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯向8 mL微波小瓶裝入(1S)-1-(2-溴苯基)乙胺氫氯化物(780 mg，3.3mmol)、(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(554.61mg，3.3mmol)、Et ₃N (0.69mL，4.95mmol)及1-丁醇(3mL)。在130℃下用微波照射反應物1小時，得到紅褐色溶液。用飽和Na ₂CO ₃水溶液(10 mL)稀釋反應混合物且用EtOAc (20mL ×2)萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(DCM/EA= 10/1至6/1)來純化粗物質，得到呈黃色油狀之標題化合物(230mg，0.7117mmol，21.581%產率)。 LC-MS方法1 0.726 min，MS (m/z) 324.9 (M + H ⁺)。 1-[(1S)-1-(2- Bromophenyl ) ethyl ]-1H- imidazole -4- carboxylic acid ethyl ester Charge (1S)-1-(2-bromophenyl) to an 8 mL microwave vial Ethylamine hydrochloride (780 mg, 3.3mmol), ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (554.61mg, 3.3mmol), Et ₃ N (0.69mL, 4.95 mmol) and 1-butanol (3 mL). The reactant was irradiated with microwaves at 130 °C for 1 hour to obtain a reddish-brown solution. The reaction mixture was diluted with saturated aqueous Na ₂ CO ₃ (10 mL) and extracted with EtOAc (20 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (DCM/EA = 10/1 to 6/1 ) to afford the title compound (230 mg, 0.7117 mmol, 21.581% yield) as a yellow oil. LC-MS method 1 0.726 min, MS (m/z) 324.9 (M + H ⁺ ).

1-[(1S)-1-(2- 氰基苯基 ) 乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯向50mL圓底燒瓶裝入1-[(1S)-1-(2-溴苯基)乙基]-1H-咪唑-4-羧酸乙酯(180 mg，0.5600mmol)、Zn(CN) ₂(130.78mg，1.11mmol)、Pd ₂(dba) ₃(25.5mg，0.0300mmol)、P(t-Bu) ₃.HBF ₄(32.32mg，0.1100mmol)、Zn (14.57mg，0.2200mmol)及DMF (2mL)。在120℃下攪拌反應混合物16小時，得到黃色溶液。添加H ₂O (15 mL)且用EtOAc (20 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。在真空中蒸發反應混合物，得到呈黃色油狀之標題化合物(60mg，0.2228mmol，40.004%產率)。其直接用於下一步驟。 1-[(1S)-1-(2- cyanophenyl ) ethyl ]-1H- imidazole -4- carboxylic acid ethyl ester was charged into 1-[(1S)-1-(2- Bromophenyl)ethyl]-1H-imidazole-4-carboxylic acid ethyl ester (180 mg, 0.5600mmol), Zn(CN) ₂ (130.78mg, 1.11mmol), Pd ₂ (dba) ₃ (25.5mg, 0.0300 mmol), P(t-Bu) ₃ .HBF ₄ (32.32 mg, 0.1100 mmol), Zn (14.57 mg, 0.2200 mmol), and DMF (2 mL). The reaction mixture was stirred at 120 °C for 16 hours to obtain a yellow solution. H ₂ O (15 mL) was added and it was extracted with EtOAc (20 mL×2). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a yellow oil. The reaction mixture was evaporated in vacuo to afford the title compound (60 mg, 0.2228 mmol, 40.004% yield) as a yellow oil. It was used directly in the next step.

1-[(1S)-1-(2- 氰基苯基 ) 乙基 ]-1H- 咪唑 -4- 羧酸向1-[(1S)-1-(2-氰基苯基)乙基]-1H-咪唑-4-羧酸乙酯(150 mg，0.5600mmol)於1,4-二㗁烷(5 mL)中之混合物添加LiOH·H ₂O (46.74mg，1.11mmol)於H ₂O (1.5mL，0.5600mmol)中之溶液。在20℃下反應物16小時，得到黃色溶液。在真空中蒸發反應混合物，得到呈白色固體狀之標題化合物(160mg，0.6632mmol，119.07%產率)。 LC-MS方法1 0.688 min，MS (m/z) 242.2 (M + H ⁺)。 1-[(1S)-1-(2- cyanophenyl ) ethyl ]-1H- imidazole -4- carboxylic acid to 1-[(1S)-1-(2-cyanophenyl)ethyl] - A mixture of ethyl 1H-imidazole-4-carboxylate (150 mg, 0.5600 mmol) in 1,4-dioxane (5 mL) was added LiOH·H ₂ O (46.74 mg, 1.11 mmol) in H ₂ O (1.5 mL, 0.5600 mmol). The reaction was incubated at 20°C for 16 hours to give a yellow solution. The reaction mixture was evaporated in vacuo to afford the title compound (160 mg, 0.6632 mmol, 119.07% yield) as a white solid. LC-MS method 1 0.688 min, MS (m/z) 242.2 (M + H ⁺ ).

2-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 羰基 }-1H- 咪唑 -1- 基 ) 乙基 ] 苯甲腈在20℃下向1-[(1S)-1-(2-氰基苯基)乙基]-1H-咪唑-4-羧酸(50 mg，0.2100mmol)於DMF (2mL)中之溶液添加N-乙基-N-異丙基丙-2-胺(0.18mL，1.04mmol)及HATU (118.85mg，0.3100mmol)。在攪拌30 min之後，添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(52.47mg，0.21mmol)並攪拌歷時16小時，得到黑色懸浮液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (NH ₃)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(37.35 mg，0.0926 mmol)。 LC-MS方法1: 404.3 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ 7.70 (dd, J=1.00, 7.53 Hz, 1H), 7.67 (d, J=1.51 Hz, 1H), 7.56-7.63 (m, 2H), 7.41-7.48 (m, 1H), 7.20 (d, J=8.03 Hz, 1H), 5.78 (q, J=7.03 Hz, 1H), 4.73 (dd, J=2.89, 12.17 Hz, 1H), 4.16 (d, J=12.55 Hz, 1H), 3.93 (br d, J=10.29 Hz, 1H), 3.60 (dd, J=4.14, 12.42 Hz, 1H), 2.63 (d, J=2.26 Hz, 2H), 2.07 (br d, J=3.51 Hz, 1H), 1.95-1.99 (m, 1H), 1.94 (d, J=7.03 Hz, 3H), 1.45 (br d, J=3.26 Hz, 1H), 1.36 (s, 6H) 2-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] carbonyl }-1H- imidazol -1- yl ) ethyl ] benzonitrile to 1-[(1S)-1-( A solution of 2-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid (50 mg, 0.2100 mmol) in DMF (2 mL) was added with N-ethyl-N-isopropylpropan-2-amine (0.18mL, 1.04mmol) and HATU (118.85mg, 0.3100mmol). After stirring for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo [3.1.0] Hexane hydrochloride (52.47 mg, 0.21 mmol) and stirred for 16 hours to give a black suspension. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC ( _NH3 ). The resulting fluid was concentrated in vacuo to remove most of the _CH3CN and lyophilized to give the title compound (37.35 mg, 0.0926 mmol) as a white solid. LC-MS method 1: 404.3 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ 7.70 (dd, J=1.00, 7.53 Hz, 1H), 7.67 (d, J=1.51 Hz, 1H) , 7.56-7.63 (m, 2H), 7.41-7.48 (m, 1H), 7.20 (d, J=8.03 Hz, 1H), 5.78 (q, J=7.03 Hz, 1H), 4.73 (dd, J=2.89 , 12.17 Hz, 1H), 4.16 (d, J=12.55 Hz, 1H), 3.93 (br d, J=10.29 Hz, 1H), 3.60 (dd, J=4.14, 12.42 Hz, 1H), 2.63 (d, J=2.26 Hz, 2H), 2.07 (br d, J=3.51 Hz, 1H), 1.95-1.99 (m, 1H), 1.94 (d, J=7.03 Hz, 3H), 1.45 (br d, J=3.26 Hz, 1H), 1.36 (s, 6H)

實例 23      3-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 羰基 }-1H- 咪唑 -1- 基 ) 乙基 ] 苯甲腈 (R)-N-[(E)-(3- 氰基苯基 ) 亞甲基 ]-2- 甲基 -2- 丙烷亞磺醯胺在60℃下向(R)-2-甲基丙烷-2-亞磺醯胺(4621.37mg，38.13mmol)於THF (20mL)中之溶液添加3-甲醯基苯甲腈(5000 mg，38.13mmol)及四乙氧基鈦(11.86mL，57.2mmol)。在60℃下攪拌所得混合物0.5小時，得到黃色溶液。逐滴添加H ₂O (3 mL)且將其攪拌5 min。隨後經由矽藻土墊過濾固體且真空濃縮濾液，得到呈白色固體狀之標題化合物(7630mg，32.562mmol，85.398%產率)。其直接用於下一步驟而無需進一步純化。 LC-MS方法1 0.858 min，MS (m/z) 235.2 (M + H ⁺)。 Example 23 3-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5-dimethyl- 4,5 - dihydro -1,2- oxazole -3 -yl )-3- azabicyclo [3.1.0] hex -3- yl ] carbonyl }-1H- imidazol - 1- yl ) ethyl ] benzonitrile (R)-N-[(E)-(3 -cyanophenyl ) methylene ]-2- methyl -2- propanesulfinamide at 60°C to (R)-2-methylpropane-2-sulfinamide (4621.37mg, 38.13mmol ) in THF (20 mL) was added 3-formylbenzonitrile (5000 mg, 38.13 mmol) and tetraethoxytitanium (11.86 mL, 57.2 mmol). The resulting mixture was stirred at 60 °C for 0.5 hours to obtain a yellow solution. H ₂ O (3 mL) was added dropwise and it was stirred for 5 min. The solid was then filtered through a pad of celite and the filtrate was concentrated in vacuo to afford the title compound (7630 mg, 32.562 mmol, 85.398% yield) as a white solid. It was used directly in the next step without further purification. LC-MS method 1 0.858 min, MS (m/z) 235.2 (M + H ⁺ ).

(R)-N-[(1S)-1-(3- 氰基苯基 ) 乙基 ]-2- 甲基 -2- 丙烷亞磺醯胺在-48℃下向(R)-N-[(E)-(3-氰基苯基)亞甲基]-2-甲基-2-丙烷亞磺醯胺(3000 mg，12.8mmol)於THF (32.054mL)中之溶液添加氯基(甲基)鎂(4.69mL，14.08mmol)。在-40℃下攪拌所得混合物14小時，得到黃色溶液。將反應混合物傾入飽和NH ₄Cl水溶液(30 mL)中且用EtOAc (30 mL × 4)萃取。用鹽水(30 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈黃色固體狀之標題化合物(960mg，3.8345mmol，29.95%產率)。 LC-MS方法1 0.845 min，MS (m/z) 251.2 (M + H ⁺)。 (R)-N-[(1S)-1-(3- cyanophenyl ) ethyl ]-2- methyl -2- propanesulfinyl amide transforms into (R)-N-[ To a solution of (E)-(3-cyanophenyl)methylene]-2-methyl-2-propanesulfinamide (3000 mg, 12.8 mmol) in THF (32.054 mL) was added chloro(methanol) base) magnesium (4.69 mL, 14.08 mmol). The resulting mixture was stirred at -40°C for 14 hours to give a yellow solution. The reaction mixture was poured into saturated aqueous NH ₄ Cl (30 mL) and extracted with EtOAc (30 mL×4). The combined organic layers were washed with brine (30 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the title compound (960 mg, 3.8345 mmol, 29.95% yield) as a yellow solid. LC-MS method 1 0.845 min, MS (m/z) 251.2 (M + H ⁺ ).

3-[(1S)-1- 胺基乙基 ] 苯甲腈氫氯化物在20℃下向(R)-N-[(1S)-1-(3-氰基苯基)乙基]-2-甲基-2-丙烷亞磺醯胺(960 mg，3.83mmol)添加HCl/MeOH (10 mL，3.83mmol)。在20至25℃下攪拌所得混合物0.5小時，得到黃色溶液。在真空中蒸發反應混合物，得到呈黃色油狀之標題化合物(643 mg，粗產物)。 LC-MS方法1 0.258 min，MS (m/z) 147. (M -HCl + H ⁺)。 3-[(1S)-1- Aminoethyl ] benzonitrile hydrochloride to (R)-N-[(1S)-1-(3-cyanophenyl)ethyl]- 2-Methyl-2-propanesulfinamide (960 mg, 3.83 mmol) was added HCl/MeOH (10 mL, 3.83 mmol). The resulting mixture was stirred at 20 to 25°C for 0.5 hours to obtain a yellow solution. The reaction mixture was evaporated in vacuo to give the title compound (643 mg, crude product) as a yellow oil. LC-MS method 1 0.258 min, MS (m/z) 147. (M -HCl + H ⁺ ).

1-[(1S)-1-(3- 氰基苯基 ) 乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯向3-[(1S)-1-胺基乙基]苯甲腈氫氯化物(250 mg，1.49mmol)於1-丁醇(2.5mL)中之溶液添加Et ₃N (0.31mL，2.23mmol)及(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(271.49mg，1.49mmol)。在130℃下用微波照射反應混合物60 min，得到黃色溶液。將反應混合物傾入飽和NH ₄Cl水溶液(30 mL)中，且用EtOAc (30 mL × 2)萃取。用鹽水(30 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈黃色油狀之標題化合物(90mg，0.3342mmol，22.484%產率)。 LC-MS方法1 0.732 min，MS (m/z) 270.2 (M + H ⁺)。 1-[(1S)-1-(3- cyanophenyl ) ethyl ]-1H- imidazole -4- carboxylic acid ethyl ester to 3-[(1S)-1-aminoethyl]benzonitrile hydrogen A solution of chloride (250 mg, 1.49 mmol) in 1-butanol (2.5 mL) was added with _Et3N (0.31 mL, 2.23 mmol) and (2Z)-3-(dimethylamino)-2-isocyan Ethyl acrylate (271.49 mg, 1.49 mmol). The reaction mixture was irradiated with microwaves at 130 °C for 60 min to obtain a yellow solution. The reaction mixture was poured into saturated aqueous NH ₄ Cl (30 mL), and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (90 mg, 0.3342 mmol, 22.484% yield) as a yellow oil. LC-MS method 1 0.732 min, MS (m/z) 270.2 (M + H ⁺ ).

1-[(1S)-1-(3- 氰基苯基 ) 乙基 ]-1H- 咪唑 -4- 羧酸在20℃下向1-[(1S)-1-(3-氰基苯基)乙基]-1H-咪唑-4-羧酸乙酯(90 mg，0.3300mmol)之溶液添加於THF (0.90 mL)、H ₂O (0.90 mL)及MeOH (0.90 mL)中之羥基鋰水合物(28.05mg，0.6700mmol)。在20至25℃下攪拌所得混合物14小時，得到黃色溶液。將反應混合物傾入H ₂O中且用EtOAc (20 mL × 4)萃取。濃縮水層且凍乾，得到呈白色固體狀之標題化合物(132 mg，粗產物)。 LC-MS方法1 0.468 min，MS (m/z) 241.9 (M + H ⁺)。 1-[(1S)-1-(3- cyanophenyl ) ethyl ]-1H- imidazole -4- carboxylic acid is converted to 1-[(1S)-1-(3-cyanophenyl) A solution of ethyl]-1H-imidazole-4-carboxylate (90 mg, 0.3300 mmol) in THF (0.90 mL), H ₂ O (0.90 mL) and MeOH (0.90 mL) was hydrated with hydroxylithium (28.05mg, 0.6700mmol). The resulting mixture was stirred at 20 to 25°C for 14 hours to obtain a yellow solution. The reaction mixture was poured into H ₂ O and extracted with EtOAc (20 mL×4). The aqueous layer was concentrated and lyophilized to give the title compound (132 mg, crude product) as a white solid. LC-MS method 1 0.468 min, MS (m/z) 241.9 (M + H ⁺ ).

3-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 羰基 }-1H- 咪唑 -1- 基 ) 乙基 ] 苯甲腈在20℃下向1-[(1S)-1-(3-氰基苯基)乙基]-1H-咪唑-4-羧酸(60 mg，0.2500mmol)於DMF (1.8mL)中之溶液添加HATU (123.6mg，0.3200mmol)及N-乙基-N-異丙基丙-2-胺(0.3mL，1.74mmol)。在20℃下攪拌反應混合物30 min。隨後添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(62.96mg，0.2500mmol)。在20至25℃下攪拌所得混合物14小時，得到黃色溶液。將反應混合物傾入飽和NH ₄Cl水溶液(80 mL)中且用EtOAc (50 mL × 4)萃取。用飽和NaCl溶液(50 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由製備型HPLC (FA)純化殘餘物，得到呈白色固體狀之標題化合物(10mg，0.0248mmol，9.9654%產率)。 LC-MS方法1: 404.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.63 (br d, J=7.8 Hz, 2H), 7.52 - 7.46 (m, 2H), 7.44 (s, 1H), 7.37 (br d, J=8.0 Hz, 1H), 5.40 (q, J=6.9 Hz, 1H), 4.73 (br d, J=12.3 Hz, 1H), 4.17 (br d, J=12.3 Hz, 1H), 3.98 - 3.91 (m, 1H), 3.64 - 3.58 (m, 1H), 2.64 (s, 2H), 2.08 (br s, 1H), 1.98 (br d, J=3.3 Hz, 1H), 1.90 (d, J=7.0 Hz, 3H), 1.46 (t, J=3.3 Hz, 1H), 1.36 (s, 6H) 3-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] carbonyl }-1H- imidazol -1- yl ) ethyl ] benzonitrile to 1-[(1S)-1-( To a solution of 3-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid (60 mg, 0.2500 mmol) in DMF (1.8 mL) was added HATU (123.6 mg, 0.3200 mmol) and N-ethyl- N-Isopropylpropan-2-amine (0.3 mL, 1.74 mmol). The reaction mixture was stirred at 20 °C for 30 min. Then add (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0] Hexane hydrochloride (62.96 mg, 0.2500 mmol). The resulting mixture was stirred at 20 to 25°C for 14 hours to obtain a yellow solution. The reaction mixture was poured into saturated aqueous NH ₄ Cl (80 mL) and extracted with EtOAc (50 mL×4). The combined organic layers were washed with saturated NaCl solution (50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (FA) to afford the title compound (10 mg, 0.0248 mmol, 9.9654% yield) as a white solid. LC-MS method 1: 404.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.63 (br d, J =7.8 Hz, 2H), 7.52 - 7.46 (m, 2H), 7.44 (s , 1H), 7.37 (br d, J =8.0 Hz, 1H), 5.40 (q, J =6.9 Hz, 1H), 4.73 (br d, J =12.3 Hz, 1H), 4.17 (br d, J =12.3 Hz, 1H), 3.98 - 3.91 (m, 1H), 3.64 - 3.58 (m, 1H), 2.64 (s, 2H), 2.08 (br s, 1H), 1.98 (br d, J =3.3 Hz, 1H) , 1.90 (d, J =7.0 Hz, 3H), 1.46 (t, J =3.3 Hz, 1H), 1.36 (s, 6H)

實例 24      4-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 羰基 }-1H- 咪唑 -1- 基 ) 乙基 ] 苯甲腈 (R)-N-[(E)-(4- 氰基苯基 ) 亞甲基 ]-2- 甲基 -2- 丙烷亞磺醯胺在60℃下向(R)-2-甲基丙烷-2-亞磺醯胺(4621.37mg，38.13mmol)於THF (20mL)中之溶液添加4-甲醯基苯甲腈(5000 mg，38.13mmol)及四乙氧基鈦(13.05g，57.2mmol)。在60℃下攪拌所得混合物0.5小時，得到黃色溶液。逐滴添加H ₂O (3 mL)且將其攪拌5 min。隨後藉由經由矽藻土墊過濾移除固體且真空濃縮濾液，得到呈白色固體狀之標題化合物(8340mg，35.592mmol，93.345%產率)。 LC-MS方法1 0.858 min，MS (m/z) 234.8 (M + H ⁺)。 Example 24 4-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazole -3 -yl )-3- azabicyclo [3.1.0] hex -3- yl ] carbonyl }-1H- imidazol - 1- yl ) ethyl ] benzonitrile (R)-N-[(E)-(4 -cyanophenyl ) methylene ]-2- methyl -2- propanesulfinamide at 60°C to (R)-2-methylpropane-2-sulfinamide (4621.37mg, 38.13mmol ) in THF (20 mL) was added 4-formylbenzonitrile (5000 mg, 38.13 mmol) and tetraethoxytitanium (13.05 g, 57.2 mmol). The resulting mixture was stirred at 60°C for 0.5 hours to obtain a yellow solution. H ₂ O (3 mL) was added dropwise and it was stirred for 5 min. The solids were then removed by filtration through a pad of Celite and the filtrate was concentrated in vacuo to afford the title compound (8340 mg, 35.592 mmol, 93.345% yield) as a white solid. LC-MS method 1 0.858 min, MS (m/z) 234.8 (M + H ⁺ ).

(R)-N-[(1S)-1-(4- 氰基苯基 ) 乙基 ]-2- 甲基 -2- 丙烷亞磺醯胺在-48℃下向(R)-N-[(E)-(4-氰基苯基)亞甲基]-2-甲基-2-丙烷亞磺醯胺(2340 mg，9.99mmol)於THF (30mL)中之溶液添加氯基(甲基)鎂(4.99mL，14.98mmol)。在-40℃下攪拌所得混合物14小時，得到黃色溶液。用NH ₄Cl淬滅混合物且用EA (30 mL × 3)萃取水層。用鹽水洗滌合併之有機層，經Na ₂SO ₄乾燥且隨後真空濃縮。藉由二氧化矽管柱(PE至PE:EtOAc=1:1)純化粗產物。用EtOAc/己烷(20 mL/10 mL)濕磨所獲得固體且在空氣中乾燥，得到呈黃色固體狀之標題化合物(1310mg，5.2325mmol，52.396%產率)。 LC-MS方法1 0.732 min，MS (m/z) 250.9 (M + H ⁺)。 (R)-N-[(1S)-1-(4- cyanophenyl ) ethyl ]-2- methyl -2- propanesulfinyl amide transforms into (R)-N-[ To a solution of (E)-(4-cyanophenyl)methylene]-2-methyl-2-propanesulfinamide (2340 mg, 9.99 mmol) in THF (30 mL) was added chloro(methyl ) Magnesium (4.99 mL, 14.98 mmol). The resulting mixture was stirred at -40°C for 14 hours to give a yellow solution. The mixture was quenched with NH ₄ Cl and the aqueous layer was extracted with EA (30 mL×3). The combined organic layers were _washed with brine, dried over _Na2SO4 and then concentrated in vacuo. The crude product was purified by silica column (PE to PE:EtOAc=1:1). The obtained solid was triturated with EtOAc/hexanes (20 mL/10 mL) and dried in air to afford the title compound (1310 mg, 5.2325 mmol, 52.396% yield) as a yellow solid. LC-MS method 1 0.732 min, MS (m/z) 250.9 (M + H ⁺ ).

4-[(1S)-1- 胺基乙基 ] 苯甲腈氫氯化物在20℃下向(R)-N-[(1S)-1-(4-氰基苯基)乙基]-2-甲基-2-丙烷亞磺醯胺(1310 mg，5.23mmol)添加HCl/MeOH (10 mL，5.23mmol)。在20至25℃下攪拌所得混合物0.5小時，得到黃色溶液。在真空中蒸發反應混合物，得到呈黃色油狀之標題化合物(1 g，粗產物)。 LC-MS方法1 0.302 min，MS (m/z) 146.8 (M + H ⁺)。 4-[(1S)-1- Aminoethyl ] benzonitrile hydrochloride is converted to (R)-N-[(1S)-1-(4-cyanophenyl)ethyl]- 2-Methyl-2-propanesulfinamide (1310 mg, 5.23 mmol) was added HCl/MeOH (10 mL, 5.23 mmol). The resulting mixture was stirred at 20 to 25°C for 0.5 hours to obtain a yellow solution. The reaction mixture was evaporated in vacuo to give the title compound (1 g, crude) as a yellow oil. LC-MS method 1 0.302 min, MS (m/z) 146.8 (M + H ⁺ ).

1-[(1S)-1-(4- 氰基苯基 ) 乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯向(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(300 mg，1.78mmol)於1-丁醇(3mL)中之溶液添加Et ₃N (0.38mL，2.68mmol)及4-[(1S)-1-胺基乙基]苯甲腈氫氯化物(300 mg，1.78mmol)。在130℃下用微波照射反應混合物60 min，得到黃色溶液。將反應混合物傾入飽和NH ₄Cl水溶液(30 mL)中，且用EtOAc (30 mL × 2)萃取。用飽和NaCl溶液(30 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈黃色油狀之標題化合物(110mg，0.4085mmol，22.9%產率)。 LC-MS方法1 0.732 min，MS (m/z) 270.2 (M + H ⁺)。 1-[(1S)-1-(4- cyanophenyl ) ethyl ]-1H- imidazole -4- carboxylic acid ethyl ester to (2Z)-3-(dimethylamino)-2-isocyano A solution of ethyl acrylate (300 mg, 1.78 mmol) in 1-butanol (3 mL) was added with _Et3N (0.38 mL, 2.68 mmol) and 4-[(1S)-1-aminoethyl]benzonitrile Hydrochloride (300 mg, 1.78 mmol). The reaction mixture was irradiated with microwaves at 130 °C for 60 min to obtain a yellow solution. The reaction mixture was poured into saturated aqueous NH ₄ Cl (30 mL), and extracted with EtOAc (30 mL×2). The combined organic layers were washed with saturated NaCl solution (30 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (110 mg, 0.4085 mmol, 22.9% yield) as a yellow oil . LC-MS method 1 0.732 min, MS (m/z) 270.2 (M + H ⁺ ).

1-[(1S)-1-(4- 氰基苯基 ) 乙基 ]-1H- 咪唑 -4- 羧酸在20℃下向1-[(1S)-1-(4-氰基苯基)乙基]-1H-咪唑-4-羧酸乙酯(110 mg，0.4100mmol)於THF (1.1mL)、H ₂O (1.1mL)及MeOH (1.1mL)中之溶液添加羥基鋰水合物(34.28mg，0.8200mmol)。在20至25℃下攪拌所得混合物14小時，得到黃色溶液。將反應混合物傾入H ₂O中且用EtOAc (20 mL × 4)萃取。濃縮水層且凍乾，得到呈黃色固體狀之標題化合物(130 mg，粗產物)。 LC-MS方法1 0.443 min，MS (m/z) 241.9 (M + H ⁺)。 1-[(1S)-1-(4- cyanophenyl ) ethyl ]-1H- imidazole -4- carboxylic acid is converted to 1-[(1S)-1-(4-cyanophenyl) )ethyl]-1H-imidazole-4-carboxylic acid ethyl ester (110 mg, 0.4100 mmol) in THF (1.1 mL), H ₂ O (1.1 mL) and MeOH (1.1 mL) was added with hydroxylithium hydrate (34.28 mg, 0.8200 mmol). The resulting mixture was stirred at 20 to 25°C for 14 hours to obtain a yellow solution. The reaction mixture was poured into H ₂ O and extracted with EtOAc (20 mL×4). The aqueous layer was concentrated and lyophilized to give the title compound (130 mg, crude) as a yellow solid. LC-MS method 1 0.443 min, MS (m/z) 241.9 (M + H ⁺ ).

4-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 羰基 }-1H- 咪唑 -1- 基 ) 乙基 ] 苯甲腈在20℃下向1-[(1S)-1-(4-氰基苯基)乙基]-1H-咪唑-4-羧酸(100 mg，0.4100mmol)於DMF (3mL)中之溶液添加HATU (206.01mg，0.5400mmol)及N-乙基-N-異丙基丙-2-胺(0.5 mL，2.9mmol)。攪拌反應混合物30 min。隨後添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(104.94mg，0.4100mmol)。在20至25℃下攪拌所得混合物14小時，得到黃色溶液。將反應混合物傾入飽和NH ₄Cl水溶液(20 mL)中，且用EtOAc (20 mL × 3)萃取。藉由製備型HPLC (FA)純化粗產物，得到呈黃色固體狀之標題化合物(2mg，0.0050mmol，1.1958%產率)。 LC-MS方法1: 404.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.66 (br d, J=8.0 Hz, 3H), 7.51 (br d, J=9.0 Hz, 1H), 7.23 (br s, 2H), 5.42 (br d, J=7.0 Hz, 1H), 4.72 (br s, 1H), 4.17 (br d, J=12.8 Hz, 1H), 3.93 (br d, J=12.0 Hz, 1H), 3.61 (br d, J=14.8 Hz, 1H), 2.63 (s, 2H), 2.08 (br s, 1H), 1.98 (br s, 1H), 1.90 (br d, J=7.0 Hz, 3H), 1.47 (br s, 1H), 1.37 (s, 6H) 4-[(1S)-1-(4-{[(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] carbonyl }-1H- imidazol -1- yl ) ethyl ] benzonitrile to 1-[(1S)-1-( To a solution of 4-cyanophenyl)ethyl]-1H-imidazole-4-carboxylic acid (100 mg, 0.4100mmol) in DMF (3mL) was added HATU (206.01mg, 0.5400mmol) and N-ethyl-N - Isopropylpropan-2-amine (0.5 mL, 2.9 mmol). The reaction mixture was stirred for 30 min. Then add (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0] Hexane hydrochloride (104.94 mg, 0.4100 mmol). The resulting mixture was stirred at 20 to 25°C for 14 hours to obtain a yellow solution. The reaction mixture was poured into saturated aqueous NH ₄ Cl (20 mL), and extracted with EtOAc (20 mL×3). The crude product was purified by preparative HPLC (FA) to afford the title compound (2 mg, 0.0050 mmol, 1.1958% yield) as a yellow solid. LC-MS method 1: 404.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.66 (br d, J =8.0 Hz, 3H), 7.51 (br d, J =9.0 Hz, 1H) , 7.23 (br s, 2H), 5.42 (br d, J =7.0 Hz, 1H), 4.72 (br s, 1H), 4.17 (br d, J =12.8 Hz, 1H), 3.93 (br d, J = 12.0 Hz, 1H), 3.61 (br d, J =14.8 Hz, 1H), 2.63 (s, 2H), 2.08 (br s, 1H), 1.98 (br s, 1H), 1.90 (br d, J =7.0 Hz, 3H), 1.47 (br s, 1H), 1.37 (s, 6H)

實例 25      [(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1-(2- 吡啶基 ) 乙基 ]-1H- 咪唑 -4- 基 } 甲酮 1-[(1S)-1-(2- 吡啶基 ) 乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯在50℃下攪拌(1S)-1-(2-吡啶基)乙胺(500 mg，4.09mmol)及(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(137.67mg，0.8200mmol)之混合物16小時。直接濃縮反應混合物。藉由製備型TLC (PE:EtOAc=0:1)純化殘餘物，得到呈褐色油狀之標題化合物。 ¹H NMR (400MHz, 氯仿-d) δ = 8.61 (d, J = 4.0 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.70-7.60 (m, 2H), 7.30-7.20 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.50-5.35 (m, 1H), 4.36 (q, J= 6.8 Hz, 2H), 1.94 (d, J = 7.6 Hz, 3H), 1.38 (t, J = 6.8 Hz, 3H)。 Example 25 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ]{1-[(1S)-1-(2- pyridyl ) ethyl ]-1H- imidazol -4 -yl } methanone 1-[(1S)-1-(2- pyridine Base ) ethyl ]-1H- imidazole -4- carboxylic acid ethyl ester stirred (1S)-1-(2-pyridyl)ethylamine (500 mg, 4.09mmol) and (2Z)-3-( A mixture of ethyl dimethylamino)-2-isocyanoacrylate (137.67 mg, 0.8200 mmol) for 16 hours. The reaction mixture was directly concentrated. The residue was purified by prep-TLC (PE:EtOAc=0:1) to give the title compound as a brown oil. ¹ H NMR (400MHz, chloroform-d) δ = 8.61 (d, J = 4.0 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.70-7.60 (m, 2H), 7.30-7.20 (m , 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.50-5.35 (m, 1H), 4.36 (q, J= 6.8 Hz, 2H), 1.94 (d, J = 7.6 Hz, 3H), 1.38 (t, J = 6.8 Hz, 3H).

1-[(1S)-1-(2- 吡啶基 ) 乙基 ]-1H- 咪唑 -4- 羧酸向1-[(1S)-1-(2-吡啶基)乙基]-1H-咪唑-4-羧酸乙酯(160 mg，0.6500mmol)於THF (5mL)及H ₂O (1 mL，55.56mmol)中之溶液添加LiOH·H ₂O (0.11mL，1.96mmol)。在20℃下攪拌混合物12小時，得到褐色懸浮液。LCMS展示起始材料消耗完。濃縮反應混合物。用1 N HCl水溶液將所獲得H ₂O層酸化至pH=5至7且凍乾，得到呈白色固體之標題化合物(130mg，0.5985mmol，91.746%產率)。 1-[(1S)-1-(2- pyridyl ) ethyl ]-1H- imidazole -4- carboxylic acid to 1-[(1S)-1-(2-pyridyl)ethyl]-1H-imidazole - To a solution of ethyl 4-carboxylate (160 mg, 0.6500 mmol) in THF (5 mL) and H ₂ O (1 mL, 55.56 mmol) was added LiOH·H ₂ O (0.11 mL, 1.96 mmol). The mixture was stirred at 20°C for 12 hours to give a brown suspension. LCMS showed consumption of starting material. The reaction mixture was concentrated. The obtained H ₂ O layer was acidified to pH = 5-7 with 1 N aqueous HCl and lyophilized to give the title compound (130 mg, 0.5985 mmol, 91.746% yield) as a white solid.

[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1-(2- 吡啶基 ) 乙基 ]-1H- 咪唑 -4- 基 } 甲酮向1-[(1S)-1-(2-吡啶基)乙基]-1H-咪唑-4-羧酸(130 mg，0.6000mmol)於DMF (2mL)中之溶液添加HATU (274.55mg，0.7200mmol)、DIPEA (0.49mL，2.99mmol)、(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(108 mg，0.6000mmol)。在30℃下攪拌混合物3小時，得到褐色溶液。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物且合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈淺黃色固體狀之標題化合物(48.15mg，0.1269mmol，21.202%產率)。 LC-MS方法1: 380.0 [M+H ⁺] ¹H NMR (400 MHz, 氯仿 -d) δ ppm 8.60 (1 H, d, J=4.63 Hz), 7.74 (1 H, br d, J=2.38 Hz), 7.67 (1 H, td, J=7.75, 1.50 Hz), 7.60 (1 H, s), 7.24 (1 H, dd, J=7.44, 4.82 Hz), 7.03 (1 H, d, J=7.88 Hz), 5.43 (1 H, q, J=7.00 Hz), 4.74 (1 H, dd, J=12.07, 3.69 Hz), 4.18 (1 H, d, J=12.51 Hz), 3.90 - 4.01 (1 H, m), 3.61 (1 H, dd, J=12.51, 4.13 Hz), 2.64 (2 H, s), 2.07 (1 H, br d, J=3.38 Hz), 1.97 (1 H, br dd, J=7.13, 3.50 Hz), 1.92 (3 H, d, J=7.00 Hz), 1.45 (1 H, t, J=3.31 Hz), 1.31 - 1.43 (6 H, m) [(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ]{1-[(1S)-1-(2- pyridyl ) ethyl ]-1H- imidazol -4- yl } methanone to 1-[(1S)-1-(2-pyridyl )ethyl]-1H-imidazole-4-carboxylic acid (130 mg, 0.6000 mmol) in DMF (2 mL) was added with HATU (274.55 mg, 0.7200 mmol), DIPEA (0.49 mL, 2.99 mmol), (1R, 5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (108 mg, 0.6000 mmol). The mixture was stirred at 30°C for 3 hours to obtain a brown solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (NH ₃ ) and the resulting fluids were combined, concentrated to remove most of CH ₃ CN and lyophilized to give the title compound (48.15 mg, 0.1269 mmol, 21.202% yield) as a light yellow solid. Rate). LC-MS method 1: 380.0 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform -d ) δ ppm 8.60 (1 H, d, J =4.63 Hz), 7.74 (1 H, br d, J =2.38 Hz), 7.67 (1 H, td, J =7.75, 1.50 Hz), 7.60 (1 H, s), 7.24 (1 H, dd, J =7.44, 4.82 Hz), 7.03 (1 H, d, J = 7.88 Hz), 5.43 (1 H, q, J =7.00 Hz), 4.74 (1 H, dd, J =12.07, 3.69 Hz), 4.18 (1 H, d, J =12.51 Hz), 3.90 - 4.01 (1 H, m), 3.61 (1 H, dd, J =12.51, 4.13 Hz), 2.64 (2 H, s), 2.07 (1 H, br d, J =3.38 Hz), 1.97 (1 H, br dd, J =7.13, 3.50 Hz), 1.92 (3 H, d, J =7.00 Hz), 1.45 (1 H, t, J =3.31 Hz), 1.31 - 1.43 (6 H, m)

實例 26      [(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1-(4- 吡啶基 ) 乙基 ]-1H- 咪唑 -4- 基 } 甲酮 (1R)-1-(4- 吡啶基 ) 乙基 4- 甲基苯磺酸酯在0℃下向(1R)-1-(4-吡啶基)乙醇於THF (5 mL)中之溶液添加NaH (148.11 mg，6.17mmol)。在0℃下攪拌混合物0.5小時。添加4-甲基苯-1-磺醯基氯化物(0.29 mL，1.95mmol)且在20至25℃下攪拌混合物16小時。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (10 mL × 4)萃取。合併之有機層經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由快速柱(PE至30% EtOAc/PE)純化粗產物，得到呈白色固體狀之標題化合物(330 mg，1.1899 mmol，73.267%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 8.54 - 8.48 (m, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 7.13 - 7.10 (m, 2H), 5.54 (q, J=6.6 Hz, 1H), 2.42 (s, 3H), 1.59 (d, J=6.8 Hz, 3H) Example 26 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ]{1-[(1S)-1-(4- pyridyl ) ethyl ]-1H- imidazol -4- yl } methanone (1R)-1-(4- pyridyl ) ethyl 4 - Methylbenzenesulfonate To a solution of (1R)-1-(4-pyridyl)ethanol in THF (5 mL) was added NaH (148.11 mg, 6.17 mmol) at 0°C. The mixture was stirred at 0°C for 0.5 hours. 4-Methylbenzene-1-sulfonyl chloride (0.29 mL, 1.95 mmol) was added and the mixture was stirred at 20 to 25 °C for 16 hours. The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (10 mL×4). The combined organic layers were dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The crude product was purified by flash column (PE to 30% EtOAc/PE) to give the title compound (330 mg, 1.1899 mmol, 73.267% yield) as a white solid. ¹ H NMR (400MHz, chloroform-d) δ = 8.54 - 8.48 (m, 2H), 7.69 (d, J =8.5 Hz, 2H), 7.25 (d, J =8.0 Hz, 2H), 7.13 - 7.10 (m , 2H), 5.54 (q, J =6.6 Hz, 1H), 2.42 (s, 3H), 1.59 (d, J =6.8 Hz, 3H)

1-[(1S)-1-(4- 吡啶基 ) 乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯向(1R)-1-(4-吡啶基)乙基4-甲基苯磺酸酯(280 mg，1.01 mmol)於DMF (11.2 mL)中之溶液添加1H-咪唑-5-羧酸甲酯(127.32 mg，1.01 mmol)及Cs ₂CO ₃(164.47 mg，0.50 mmol)。在40℃下攪拌混合物16小時。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (15 mL × 4)萃取。合併之有機層經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由製備型TLC (DCM:MeOH = 10:1)純化殘餘物，得到呈黃色油狀之標題化合物(28 mg，0.1211 mmol，11.993%產率)。 LC-MS方法1: 232.1 [M+H] ^{+ 1}H NMR (400MHz, 氯仿-d) δ = 8.64 - 8.60 (m, 2H), 7.68 - 7.59 (m, 2H), 7.05 - 7.01 (m, 2H), 5.39 (q, J=7.0 Hz, 1H), 3.95 - 3.84 (m, 3H), 1.91 (d, J=7.3 Hz, 3H) 1-[(1S)-1-(4- pyridyl ) ethyl ]-1H- imidazole -4- carboxylic acid ethyl ester to (1R)-1-(4-pyridyl)ethyl 4-methylbenzenesulfonate A solution of the ester (280 mg, 1.01 mmol) in DMF (11.2 mL) was added methyl 1H-imidazole-5-carboxylate (127.32 mg, 1.01 mmol) and _Cs2CO3 ( _164.47 mg, 0.50 mmol). The mixture was stirred at 40°C for 16 hours. The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (15 mL×4). The combined org. layers were dried over _Na2SO4 , _filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM:MeOH = 10:1 ) to give the title compound (28 mg, 0.1211 mmol, 11.993% yield) as a yellow oil. LC-MS method 1: 232.1 [M+H] ^{+ 1} H NMR (400MHz, chloroform-d) δ = 8.64 - 8.60 (m, 2H), 7.68 - 7.59 (m, 2H), 7.05 - 7.01 (m, 2H ), 5.39 (q, J =7.0 Hz, 1H), 3.95 - 3.84 (m, 3H), 1.91 (d, J =7.3 Hz, 3H)

1-[(1S)-1-(4- 吡啶基 ) 乙基 ]-1H- 咪唑 -4- 羧酸向1-[(1S)-1-(4-吡啶基)乙基]-1H-咪唑-4-羧酸乙酯(50 mg，0.22 mmol)於THF (2 mL)及H ₂O (1 mL)中之溶液添加LiOH·H ₂O (13.61 mg，0.32 mmol)。在20至25℃下攪拌混合物2小時。直接濃縮反應混合物。用1 N HCl水溶液將反應混合物酸化至pH = 6且隨後凍乾，得到呈黃色油狀之標題化合物(40 mg，0.1841 mmol，85.167%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ = 8.59 - 8.50 (m, 2H), 7.95 (s, 1H), 7.83 (s, 1H), 7.25 (d, J=6.3 Hz, 2H), 5.66 (q, J=7.1 Hz, 1H), 1.81 (d, J=7.3 Hz, 3H) 1-[(1S)-1-(4- pyridyl ) ethyl ]-1H- imidazole -4- carboxylic acid to 1-[(1S)-1-(4-pyridyl)ethyl]-1H-imidazole - To a solution of ethyl 4-carboxylate (50 mg, 0.22 mmol) in THF (2 mL) and H ₂ O (1 mL) was added LiOH·H ₂ O (13.61 mg, 0.32 mmol). The mixture was stirred at 20 to 25°C for 2 hours. The reaction mixture was directly concentrated. The reaction mixture was acidified to pH = 6 with 1 N aqueous HCl and then lyophilized to afford the title compound (40 mg, 0.1841 mmol, 85.167% yield) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.59 - 8.50 (m, 2H), 7.95 (s, 1H), 7.83 (s, 1H), 7.25 (d, J =6.3 Hz, 2H), 5.66 ( q, J =7.1 Hz, 1H), 1.81 (d, J =7.3 Hz, 3H)

[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1-(4- 吡啶基 ) 乙基 ]-1H- 咪唑 -4- 基 } 甲酮向1-[(1S)-1-(4-吡啶基)乙基]-1H-咪唑-4-羧酸(20 mg，0.09 mmol)於吡啶(1 mL)中之溶液添加EDCI (26.48 mg，0.14 mmol)及(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(19.95 mg，0.0900mmol)。在20至25℃下攪拌所得混合物16小時。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色固體狀之標題化合物(24.99 mg，0.0659 mmol，71.527%產率)。 LC-MS方法1: 380.1 [M+H] ^{+ 1}H NMR (400MHz, 氯仿-d) δ = 8.61 (d, J=5.8 Hz, 2H), 7.68 (s, 1H), 7.51 (s, 1H), 7.03 (d, J=5.8 Hz, 2H), 5.36 (q, J=6.9 Hz, 1H), 4.76 (dd, J=2.9, 12.2 Hz, 1H), 4.19 (br d, J=12.3 Hz, 1H), 4.02 - 3.89 (m, 1H), 3.62 (dd, J=4.1, 12.7 Hz, 1H), 2.64 (s, 2H), 2.13 - 1.96 (m, 2H), 1.90 (d, J=7.3 Hz, 3H), 1.48 (t, J=3.4 Hz, 1H), 1.38 (s, 6H) [(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ]{1-[(1S)-1-(4- pyridyl ) ethyl ]-1H- imidazol -4- yl } methanone to 1-[(1S)-1-(4-pyridyl )ethyl]-1H-imidazole-4-carboxylic acid (20 mg, 0.09 mmol) in pyridine (1 mL) was added with EDCI (26.48 mg, 0.14 mmol) and (1R,5S,6r)-6-( 5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (19.95 mg, 0.0900 mmol). The resulting mixture was stirred at 20 to 25°C for 16 hours. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (24.99 mg, 0.0659 mmol, 71.527% yield) as a yellow solid. LC-MS method 1: 380.1 [M+H] ^{+ 1} H NMR (400MHz, chloroform-d) δ = 8.61 (d, J =5.8 Hz, 2H), 7.68 (s, 1H), 7.51 (s, 1H) , 7.03 (d, J =5.8 Hz, 2H), 5.36 (q, J =6.9 Hz, 1H), 4.76 (dd, J =2.9, 12.2 Hz, 1H), 4.19 (br d, J =12.3 Hz, 1H ), 4.02 - 3.89 (m, 1H), 3.62 (dd, J =4.1, 12.7 Hz, 1H), 2.64 (s, 2H), 2.13 - 1.96 (m, 2H), 1.90 (d, J =7.3 Hz, 3H), 1.48 (t, J =3.4 Hz, 1H), 1.38 (s, 6H)

實例 27      [(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1-(1,3- 噻唑 -2- 基 ) 乙基 ]-1H- 咪唑 -4- 基 } 甲酮 1-[(1S)-1-(1,3- 噻唑 -2- 基 ) 乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯在25℃下向(1S)-1-(1,3-噻唑-2-基)乙胺(131.19mg，0.7800mmol)於1-丁醇(1.4mL)中之溶液添加(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(100 mg，0.7800mmol)及Et ₃N (0.16mL，1.17mmol)。所得混合物在微波反應器中經受反應(時間：1小時，溫度：130℃)。將反應混合物傾入H ₂O (5 mL)中且用EA (5 mL × 3)萃取。用鹽水(10 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到粗產物。藉由製備型TLC (EA)純化粗產物，得到呈黃色油狀之標題化合物(50mg，0.1990mmol，25.507%產率)。 Example 27 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ]{1-[(1S)-1-(1,3- thiazol -2- yl ) ethyl ]-1H- imidazol -4- yl } methanone 1-[(1S)-1 -(1,3- thiazol- 2- yl ) ethyl ]-1H- imidazole -4- carboxylic acid ethyl ester at 25°C to (1S)-1-(1,3-thiazol-2-yl)ethylamine (131.19 mg, 0.7800 mmol) in 1-butanol (1.4 mL) was added (2Z)-3-(dimethylamino)-2-isocyanoacrylate ethyl ester (100 mg, 0.7800 mmol) and Et ₃ N (0.16 mL, 1.17 mmol). The resulting mixture was subjected to reaction in a microwave reactor (time: 1 hour, temperature: 130° C.). The reaction mixture was poured into H ₂ O (5 mL) and extracted with EA (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude product. The crude product was purified by prep-TLC (EA) to afford the title compound (50 mg, 0.1990 mmol, 25.507% yield) as a yellow oil.

1-[(1S)-1-(1,3- 噻唑 -2- 基 ) 乙基 ]-1H- 咪唑 -4- 羧酸向1-[(1S)-1-(1,3-噻唑-2-基)乙基]-1H-咪唑-4-羧酸乙酯(50mg，0.2000mmol)於THF (3mL)及H ₂O (1mL)中之溶液添加LiOH·H ₂O (41.75mg，0.9900mmol)。在25℃下攪拌反應混合物16小時，得到黃色混合物。真空濃縮反應混合物以移除大部分THF。用H ₂O (5 mL)稀釋殘餘物且用0.5 M HCl水溶液酸化至pH = 6。隨後凍乾溶液，得到呈黃色固體狀之標題化合物。 1-[(1S)-1-(1,3- thiazol -2- yl ) ethyl ]-1H- imidazole -4- carboxylic acid to 1-[(1S)-1-(1,3-thiazole-2 -yl)ethyl]-1H-imidazole-4-carboxylic acid ethyl ester (50 mg, 0.2000 mmol) in THF (3 mL) and H ₂ O (1 mL) was added LiOH·H ₂ O (41.75 mg, 0.9900 mmol) ). The reaction mixture was stirred at 25°C for 16 hours to give a yellow mixture. The reaction mixture was concentrated in vacuo to remove most of the THF. The residue was diluted with _H2O (5 mL) and acidified to pH = 6 with 0.5 M aqueous HCl. The solution was then lyophilized to afford the title compound as a yellow solid.

[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1-(1,3- 噻唑 -2- 基 ) 乙基 ]-1H- 咪唑 -4- 基 } 甲酮向1-[(1S)-1-(1,3-噻唑-2-基)乙基]-1H-咪唑-4-羧酸(44mg，0.2000mmol)於吡啶(2mL)中之溶液添加EDCI (56.67mg，0.3000mmol)。在25℃下於N ₂下攪拌混合物10min。隨後添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(42.71mg，0.2000mmol)。在25℃下攪拌所得混合物2小時，得到黃色溶液。將反應混合物傾入H ₂O (5 mL)中且用EA (5 mL × 3)萃取。用鹽水(20 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到殘餘物。藉由製備型HPLC (NH ₃)純化粗產物，得到呈白色固體狀之標題化合物(60mg，0.1557mmol，78.975%產率)。 LC-MS方法1: 386.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.79 (d, J=3.3 Hz, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 7.35 (d, J=3.3 Hz, 1H), 5.70 (q, J=6.9 Hz, 1H), 4.73 (dd, J=8.8, 11.9 Hz, 1H), 4.18 (br d, J=12.3 Hz, 1H), 3.99 - 3.91 (m, 1H), 3.61 (dd, J=4.2, 12.7 Hz, 1H), 2.64 (s, 2H), 2.11 - 2.06 (m, 1H), 2.03 (d, J=7.0 Hz, 3H), 2.00 - 1.95 (m, 1H), 1.37 (s, 6H) [(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ]{1-[(1S)-1-(1,3- thiazol- 2- yl ) ethyl ]-1H- imidazol -4- yl } methanone to 1-[(1S)-1- To a solution of (1,3-thiazol-2-yl)ethyl]-1H-imidazole-4-carboxylic acid (44 mg, 0.2000 mmol) in pyridine (2 mL) was added EDCI (56.67 mg, 0.3000 mmol). The mixture was stirred at 25 °C under _N2 for 10 min. Then add (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0] Hexane hydrochloride (42.71 mg, 0.2000 mmol). The resulting mixture was stirred at 25°C for 2 hours to obtain a yellow solution. The reaction mixture was poured into H ₂ O (5 mL) and extracted with EA (5 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC (NH ₃ ) to afford the title compound (60 mg, 0.1557 mmol, 78.975% yield) as a white solid. LC-MS method 1: 386.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.79 (d, J =3.3 Hz, 1H), 7.75 (s, 1H), 7.62 (s, 1H) , 7.35 (d, J =3.3 Hz, 1H), 5.70 (q, J =6.9 Hz, 1H), 4.73 (dd, J =8.8, 11.9 Hz, 1H), 4.18 (br d, J =12.3 Hz, 1H ), 3.99 - 3.91 (m, 1H), 3.61 (dd, J =4.2, 12.7 Hz, 1H), 2.64 (s, 2H), 2.11 - 2.06 (m, 1H), 2.03 (d, J =7.0 Hz, 3H), 2.00 - 1.95 (m, 1H), 1.37 (s, 6H)

實例 28 [(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1-(1,3- 噻唑 -5- 基 ) 乙基 ]-1H- 咪唑 -4- 基 } 甲酮 (R)-2- 甲基 -N-[(E)-1,3- 噻唑 -5- 基亞甲基 ]-2- 丙烷亞磺醯胺向5-甲醯基噻唑(2.14mL，17.68mmol)於THF (20mL)中之混合物添加(R)-2-甲基丙烷-2-亞磺醯胺(2142.48mg，17.68mmol)及Ti(OEt) ₄(6045.61mg，26.52mmol)。在60℃下攪拌反應混合物2小時，得到黃色混合物。TLC (PE:EtOAc = 2:1)展示起始材料完全耗盡，且偵測到之一個新樣點為(Rf = 0.5)。用EtOAc (30 mL)稀釋反應混合物。向混合物添加H ₂O (10 mL)且攪拌1 min，得到黃色懸浮液。過濾懸浮液。用H ₂O (20 mL × 3)洗滌濾液，用無水Na ₂SO ₄乾燥，過濾且真空濃縮，得到呈黃色固體狀之標題化合物(3.77g，17.428mmol，98.59%產率)。 Example 28 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ]{1-[(1S)-1-(1,3- thiazol -5- yl ) ethyl ]-1H- imidazol -4- yl } methanone (R)-2- methyl -N-[(E)-1,3- thiazol -5- ylmethylene ]-2- propanesulfinamide to 5-formylthiazole (2.14mL, 17.68mmol) in THF (20mL) (R)-2-Methylpropane-2-sulfinamide (2142.48 mg, 17.68 mmol) and Ti(OEt) ₄ (6045.61 mg, 26.52 mmol) were added to the mixture. The reaction mixture was stirred at 60 °C for 2 hours to give a yellow mixture. TLC (PE:EtOAc = 2:1) showed complete consumption of starting material and one new spot was detected (Rf = 0.5). The reaction mixture was diluted with EtOAc (30 mL). _H2O (10 mL) was added to the mixture and stirred for 1 min to give a yellow suspension. The suspension is filtered. The filtrate was washed with H ₂ O (20 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to afford the title compound (3.77 g, 17.428 mmol, 98.59% yield) as a yellow solid.

(R)-2- 甲基 -N-[(1S)-1-(1,3- 噻唑 -5- 基 ) 乙基 ]-2- 丙烷亞磺醯胺在-40℃下向(R)-2-甲基-N-[(E)-1,3-噻唑-5-基亞甲基]-2-丙烷亞磺醯胺(3.77g，17.43mmol)於THF (37mL)中之混合物添加氯基(甲基)鎂(9.88mL，29.63mmol)。在25℃下攪拌反應混合物16小時，得到黑褐色混合物。TLC (100% EtOAc)展示起始材料完全耗盡，且偵測到一個新樣點(Rf = 0.3)。用NH ₄Cl (60 mL)淬滅反應混合物。用EtOAc (40 mL × 4)萃取所得混合物。用鹽水(80 mL × 2)洗滌合併之有機相，經無水Na ₂SO ₄乾燥，過濾且真空濃縮，得到殘餘物。藉由快速柱(10% EtOAc/PE至100% EtOAc)純化殘餘物，得到呈褐色油狀之標題化合物(1.7g，7.3159mmol，41.978%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 8.77 (s, 1H), 7.84 (s, 1H), 5.00-4.60 (m, 1H), 3.52 (d, J = 3.2 Hz, 1H), 1.69 (d, J = 6.4 Hz, 3H), 1.23 (s, 9H)。 (R)-2- Methyl -N-[(1S)-1-(1,3- thiazol -5- yl ) ethyl ]-2- propanesulfinamide is converted to (R)- A mixture of 2-methyl-N-[(E)-1,3-thiazol-5-ylmethylene]-2-propanesulfinamide (3.77 g, 17.43 mmol) in THF (37 mL) was added with chlorine (Methyl)magnesium (9.88 mL, 29.63 mmol). The reaction mixture was stirred at 25°C for 16 hours to give a dark brown mixture. TLC (100% EtOAc) showed complete consumption of starting material and detection of a new spot (Rf = 0.3). The reaction mixture was quenched with NH ₄ Cl (60 mL). The resulting mixture was extracted with EtOAc (40 mL x 4). The combined organic phases were washed with brine (80 mL _x 2), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by flash column (10% EtOAc/PE to 100% EtOAc) to give the title compound (1.7 g, 7.3159 mmol, 41.978% yield) as a brown oil. ¹ H NMR (400MHz, chloroform-d) δ = 8.77 (s, 1H), 7.84 (s, 1H), 5.00-4.60 (m, 1H), 3.52 (d, J = 3.2 Hz, 1H), 1.69 (d , J = 6.4 Hz, 3H), 1.23 (s, 9H).

(1S)-1-(1,3- 噻唑 -5- 基 ) 乙胺在25℃下攪拌(R)-2-甲基-N-[(1S)-1-(1,3-噻唑-5-基)乙基]-2-丙烷亞磺醯胺(500 mg，2.15mmol)於MeOH/HCl (8 mL，2.15mmol)中之溶液2小時，得到褐色混合物。TLC (100% EtOAc)展示起始材料完全耗盡。真空濃縮反應混合物，得到殘餘物。用MTBE (20 mL)濕磨殘餘物且真空乾燥，得到呈褐色固體狀之標題化合物(504mg，3.0609mmol，142.25%產率) (粗物質)。 (1S)-1-(1,3- thiazol -5- yl ) ethylamine was stirred at 25°C with (R)-2-methyl-N-[(1S)-1-(1,3-thiazole-5 A solution of -yl)ethyl]-2-propanesulfinamide (500 mg, 2.15 mmol) in MeOH/HCl (8 mL, 2.15 mmol) for 2 h gave a brown mixture. TLC (100% EtOAc) showed complete consumption of starting material. The reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with MTBE (20 mL) and dried in vacuo to afford the title compound (504 mg, 3.0609 mmol, 142.25% yield) as a tan solid (crude material).

1-[(1S)-1-(1,3- 噻唑 -5- 基 ) 乙基 ]-1H- 咪唑 -4- 羧酸 乙 酯向(1S)-1-(1,3-噻唑-5-基)乙胺(350 mg，2.13mmol)於1-丁醇(3.5mL)中之混合物添加(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(357.5mg，2.13mmol)及Et ₃N (0.41mL，3.19mmol)。在130℃下使用MW攪拌反應混合物1小時，得到褐色混合物。真空濃縮反應混合物，得到殘餘物。藉由製備型TLC (100% EtOAc)純化殘餘物，得到呈褐色固體狀之標題化合物(46mg，0.1830mmol，8.6116%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 8.83 (s, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 5.75-5.60 (m, 1H), 4.37 (q, J = 7.6 Hz, 2H), 2.00 (d, J = 7.2 Hz, 3H), 1.39 (t, J = 7.6 Hz, 3H)。 1-[(1S)-1-(1,3- thiazol -5- yl ) ethyl ]-1H- imidazole -4- carboxylic acid ethyl ester to (1S)-1-(1,3-thiazole-5- (2Z)-3-(Dimethylamino)-2-isocyanoacrylate ethyl (357.5mg, 2.13 mmol) and _Et3N (0.41 mL, 3.19 mmol). The reaction mixture was stirred using MW at 130 °C for 1 hour to give a brown mixture. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (100% EtOAc) to afford the title compound (46 mg, 0.1830 mmol, 8.6116% yield) as a tan solid. ¹ H NMR (400MHz, chloroform-d) δ = 8.83 (s, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 5.75-5.60 (m, 1H), 4.37 (q, J = 7.6 Hz, 2H), 2.00 (d, J = 7.2 Hz, 3H), 1.39 (t, J = 7.6 Hz, 3H).

1-[(1S)-1-(1,3- 噻唑 -5- 基 ) 乙基 ]-1H- 咪唑 -4- 羧酸向1-[(1S)-1-(1,3-噻唑-5-基)乙基]-1H-咪唑-4-羧酸乙酯(46 mg，0.1800mmol)於THF (1.5mL)及H ₂O (0.50 mL)中之混合物添加LiOH·H ₂O (0.02mL，0.2700mmol)。在25℃下攪拌反應混合物16小時，得到黃色混合物。用H ₂O (4 mL)稀釋反應混合物且用EtOAc (2 mL × 3)萃取。用1 N HCl水溶液將水相酸化至pH = 5且凍乾，得到呈褐色固體狀之標題化合物(40mg，0.1792mmol，97.882%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ = 9.06 (s, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 6.05-5.95 (m, 1H), 1.89 (d, J = 6.8 Hz, 3H)。 1-[(1S)-1-(1,3- thiazol -5- yl ) ethyl ]-1H- imidazole -4- carboxylic acid to 1-[(1S)-1-(1,3-thiazole-5 -yl)ethyl]-1H-imidazole-4-carboxylic acid ethyl ester (46 mg, 0.1800 mmol) in THF (1.5 mL) and H ₂ O (0.50 mL) was added LiOH·H ₂ O (0.02 mL , 0.2700mmol). The reaction mixture was stirred at 25°C for 16 hours to give a yellow mixture. The reaction mixture was diluted with H ₂ O (4 mL) and extracted with EtOAc (2 mL×3). The aqueous phase was acidified to pH = 5 with 1 N aqueous HCl and lyophilized to afford the title compound (40 mg, 0.1792 mmol, 97.882% yield) as a tan solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.06 (s, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.76 (s, 1H), 6.05-5.95 (m, 1H), 1.89 (d, J = 6.8 Hz, 3H).

[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(1S)-1-(1,3- 噻唑 -5- 基 ) 乙基 ]-1H- 咪唑 -4- 基 } 甲酮向1-[(1S)-1-(1,3-噻唑-5-基)乙基]-1H-咪唑-4-羧酸(40 mg，0.1800mmol)於DMF (0.8286mL)中之混合物添加HATU (82.2mg，0.2200mmol)及DIPEA (0.15mL，0.9000mmol)。在50℃下攪拌混合物30 min且繼之以添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(48.44mg，0.2700mmol)。在25℃下攪拌混合物16小時，得到黃色混合物。藉由製備型HPLC (NH ₃)純化反應混合物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色固體狀之標題化合物(14.11mg，0.0366 mmol，20.34%產率)。 LC-MS方法1: 386.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 8.80 (s, 1 H), 7.79 (s, 1 H), 7.67 (s, 1 H), 7.52 (d, J=1.4 Hz, 1 H), 5.68 (d, J=7.0 Hz, 1 H), 4.71 (t, J=11.3 Hz, 1 H), 4.16 (dd, J=12.6, 1.9 Hz, 1 H), 3.87 - 3.99 (m, 1 H), 3.60 (dd, J=12.6, 4.2 Hz, 1 H), 2.63 (s, 2 H), 2.08 (dt, J=7.3, 3.7 Hz, 1 H), 1.98 (d, J=7.0 Hz, 4 H), 1.45 (br d, J=4.0 Hz, 1 H), 1.37 (s, 6 H)。 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ]{1-[(1S)-1-(1,3- thiazol - 5- yl ) ethyl ]-1H- imidazol -4- yl } methanone to 1-[(1S)-1- To a mixture of (1,3-thiazol-5-yl)ethyl]-1H-imidazole-4-carboxylic acid (40 mg, 0.1800 mmol) in DMF (0.8286 mL) was added HATU (82.2 mg, 0.2200 mmol) and DIPEA (0.15 mL, 0.9000 mmol). The mixture was stirred at 50 °C for 30 min and followed by the addition of (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl) - 3-Azabicyclo[3.1.0]hexane hydrochloride (48.44 mg, 0.2700 mmol). The mixture was stirred at 25°C for 16 hours to give a yellow mixture. The reaction mixture was purified by preparative HPLC (NH ₃ ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (14.11 mg, 0.0366 mmol, 20.34% yield) as a yellow solid. LC-MS method 1: 386.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 8.80 (s, 1 H), 7.79 (s, 1 H), 7.67 (s, 1 H), 7.52 (d, J=1.4 Hz, 1 H), 5.68 (d, J=7.0 Hz, 1 H), 4.71 (t, J=11.3 Hz, 1 H), 4.16 (dd, J=12.6, 1.9 Hz, 1 H), 3.87 - 3.99 (m, 1 H), 3.60 (dd, J=12.6, 4.2 Hz, 1 H), 2.63 (s, 2 H), 2.08 (dt, J=7.3, 3.7 Hz, 1 H ), 1.98 (d, J=7.0 Hz, 4 H), 1.45 (br d, J=4.0 Hz, 1 H), 1.37 (s, 6 H).

實例 29      [(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(2S)-1- 苯基丙 -2- 基 ]-1H- 咪唑 -4- 基 } 甲酮 (2R)-1- 苯基 -2- 丙基 4- 甲基苯磺酸酯向(2R)-1-苯基-2-丙醇(400 mg，2.94mmol)於DCM (5mL)中之溶液添加Et ₃N (0.45mL，3.23mmol)及4-甲基苯-1-磺醯基氯化物(0.44mL，2.94mmol)。在20℃下攪拌反應物16小時，得到黃色溶液。TLC (PE/EA=10/1，rf = 0.3)展示新的主樣點。添加H ₂O (30 mL)且用DCM (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(PE/EA= 1/0至10/1)來純化粗物質，得到呈白色固體狀之標題化合物(680mg，2.3418mmol，79.731%產率)。 Example 29 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ]{1-[(2S)-1- phenylpropan -2- yl ]-1H- imidazol -4- yl } methanone (2R)-1- phenyl -2- propyl 4 -Tosylate _ _{_} Tolylbenzene-1-sulfonyl chloride (0.44 mL, 2.94 mmol). The reaction was stirred at 20°C for 16 hours to give a yellow solution. TLC (PE/EA=10/1, rf=0.3) showed a new main sample. H ₂ O (30 mL) was added and it was extracted with DCM (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (PE/EA = 1/0 to 10/1) to afford the title compound (680 mg, 2.3418 mmol, 79.731% yield) as a white solid.

1-[(2S)-1- 苯基丙 -2- 基 ]-1H- 咪唑 -4- 羧酸 甲 酯在80℃下攪拌1H-咪唑-4-羧酸甲酯(300 mg，2.38mmol)及(2R)-1-苯基-2-丙基4-甲基苯磺酸酯(690.78mg，2.38mmol)於DMF (4mL)中之溶液16小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(DCM/EA= 10/1至3/1)來純化粗物質，得到標題化合物(120mg，0.4912mmol，20.649%產率)。 ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.61 (s, 1H), 7.35-7.15 (m, 5H), 6.95-6.85 (m, 2H), 4.45-4.35 (m, 1H), 3.88 (s, 3H), 3.10-2.90 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H)。 1-[(2S)-1- Phenylpropan -2- yl ]-1H- imidazole -4- carboxylic acid methyl ester Stir 1H-imidazole-4-carboxylic acid methyl ester (300 mg, 2.38 mmol) at 80°C and a solution of (2R)-1-phenyl-2-propyl 4-methylbenzenesulfonate (690.78 mg, 2.38 mmol) in DMF (4 mL) for 16 hours gave a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (DCM/EA = 10/1 to 3/1 ) to afford the title compound (120 mg, 0.4912 mmol, 20.649% yield). ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.61 (s, 1H), 7.35-7.15 (m, 5H), 6.95-6.85 (m, 2H), 4.45-4.35 (m, 1H), 3.88 (s , 3H), 3.10-2.90 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H).

1-[(2S)-1- 苯基丙 -2- 基 ]-1H- 咪唑 -4- 羧酸向1-[(2S)-1-苯基丙-2-基]-1H-咪唑-4-羧酸甲酯(120 mg，0.4900mmol)於1,4-二㗁烷(3mL)中之經攪拌溶液添加LiOH·H ₂O (41.22mg，0.9800mmol)於H ₂O (1 mL，0.4900mmol)中之溶液。在20℃下攪拌反應混合物16小時，得到無色油狀物。TLC (PE/EA =1/1，Rf=0)展示新樣點。在真空中蒸發反應混合物且凍乾，得到呈白色固體狀之標題化合物(110mg，0.4777mmol，97.252%產率)。 1-[(2S)-1- phenylpropan -2- yl ]-1H- imidazole -4- carboxylic acid to 1-[(2S)-1-phenylpropan-2-yl]-1H-imidazole-4 - To a stirred solution of methyl carboxylate (120 mg, 0.4900 mmol) in 1,4-dioxane (3 mL) was added LiOH·H ₂ O (41.22 mg, 0.9800 mmol) in H ₂ O (1 mL, 0.4900 mmol) solution. The reaction mixture was stirred at 20°C for 16 hours to give a colorless oil. TLC (PE/EA=1/1, Rf=0) showed a fresh sample. The reaction mixture was evaporated in vacuo and lyophilized to afford the title compound (110 mg, 0.4777 mmol, 97.252% yield) as a white solid.

[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(2S)-1- 苯基丙 -2- 基 ]-1H- 咪唑 -4- 基 } 甲酮向1-[(2S)-1-苯基丙-2-基]-1H-咪唑-4-羧酸(100 mg，0.4300mmol)及HATU (199.24mg，0.5200mmol)於DMF (3mL)中之經攪拌溶液添加N-乙基-N-異丙基丙-2-胺(0.37mL，2.17mmol)。在攪拌30 min之後，添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(109.95mg，0.4300mmol)且在20℃下攪拌反應物16小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (NH ₃)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(104.7mg，0.2668mmol，61.424%產率)。 LC-MS方法1: 393.3 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ 7.64 (s, 1H), 7.21-7.26 (m, 3H), 7.17 (br s, 1H), 6.96 (br d, J=7.03 Hz, 2H), 4.69 (br d, J=12.05 Hz, 1H), 4.30-4.38 (m, 1H), 4.18 (br d, J=10.54 Hz, 1H), 3.86-3.95 (m, 1H), 3.60 (br dd, J=3.89, 12.42 Hz, 1H), 2.94-3.04 (m, 2H), 2.63 (s, 2H), 2.06 (br d, J=3.51 Hz, 1H), 1.97 (br d, J=3.51 Hz, 1H), 1.54 (d, J=6.78 Hz, 3H), 1.46 (br d, J=11.29 Hz, 1H), 1.37 (s, 6H) [(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ]{1-[(2S)-1- phenylpropan -2- yl ]-1H- imidazol -4- yl } methanone to 1-[(2S)-1-phenylpropan-2- N-ethyl-N-isopropylpropane- 2-Amine (0.37 mL, 2.17 mmol). After stirring for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo [3.1.0] Hexane hydrochloride (109.95mg, 0.4300mmol) and the reaction was stirred at 20°C for 16 hours to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC ( _NH3 ). The obtained fluid was concentrated in vacuo to remove most of _CH3CN and lyophilized to give the title compound (104.7 mg, 0.2668 mmol, 61.424% yield) as a white solid. LC-MS method 1: 393.3 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ 7.64 (s, 1H), 7.21-7.26 (m, 3H), 7.17 (br s, 1H), 6.96 (br d, J=7.03 Hz, 2H), 4.69 (br d, J=12.05 Hz, 1H), 4.30-4.38 (m, 1H), 4.18 (br d, J=10.54 Hz, 1H), 3.86-3.95 (m, 1H), 3.60 (br dd, J=3.89, 12.42 Hz, 1H), 2.94-3.04 (m, 2H), 2.63 (s, 2H), 2.06 (br d, J=3.51 Hz, 1H), 1.97 (br d, J=3.51 Hz, 1H), 1.54 (d, J=6.78 Hz, 3H), 1.46 (br d, J=11.29 Hz, 1H), 1.37 (s, 6H)

實例 30      [(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(2S)-4- 苯基丁 -2- 基 ]-1H- 咪唑 -4- 基 } 甲酮 (R)-2- 甲基 -N-[(1E)-1- 甲基 -3- 苯基亞丙基 ]-2- 丙烷亞磺醯胺向4-苯基-2-丁酮(1.01mL，6.75mmol)於THF (10mL)中之混合物添加(R)-2-甲基丙烷-2-亞磺醯胺(817.81mg，6.75mmol)及Ti(OEt) ₄(2307.69mg，10.12mmol)。在60℃下攪拌反應混合物16小時，得到黃色混合物。用EtOAc (30 mL)稀釋反應混合物。將混合物添加至H ₂O (10 mL)且攪拌1 min，得到黃色懸浮液。過濾懸浮液。用H ₂O (20 mL×3)洗滌濾液，用無水Na ₂SO ₄乾燥，過濾且真空濃縮，得到殘餘物。藉由快速柱(PE至30% EtOAc/PE)純化殘餘物，得到呈黃色油狀之標題化合物(570mg，2.2674mmol，33.603%產率)。 LC-MS方法1 0.823 min，MS (m/z) 252 (M + H ⁺)。 Example 30 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ]{1-[(2S)-4- phenylbut -2- yl ]-1H- imidazol -4- yl } methanone (R)-2- methyl- N-[(1E )-1- methyl -3- phenylpropylene ]-2- propanesulfinamide To a mixture of 4-phenyl-2-butanone (1.01 mL, 6.75 mmol) in THF (10 mL) was added ( R)-2-methylpropane-2-sulfinamide (817.81 mg, 6.75 mmol) and Ti(OEt) ₄ (2307.69 mg, 10.12 mmol). The reaction mixture was stirred at 60 °C for 16 hours to give a yellow mixture. The reaction mixture was diluted with EtOAc (30 mL). The mixture was added to H ₂ O (10 mL) and stirred for 1 min to give a yellow suspension. The suspension is filtered. The filtrate was washed with H ₂ O (20 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by flash column (PE to 30% EtOAc/PE) to give the title compound (570 mg, 2.2674 mmol, 33.603% yield) as a yellow oil. LC-MS method 1 0.823 min, MS (m/z) 252 (M + H ⁺ ).

(R)-2- 甲基 -N-[(2S)-4- 苯基丁 -2- 基 ]-2- 丙烷亞磺醯胺在0℃下向(R)-2-甲基-N-[(1E)-1-甲基-3-苯基亞丙基]-2-丙烷亞磺醯胺(570 mg，2.27mmol)於THF (6mL)中之混合物添加三二級丁基硼氫化鋰(6.8mL，6.8mmol)。在25℃下攪拌混合物3小時，得到無色混合物。TLC (PE:EtOAc = 2:1)展示偵測到一個新樣點(Rf = 0.3)。用H ₂O (3 mL)淬滅反應物。真空濃縮反應混合物，得到殘餘物。藉由快速柱(PE至30% EtOAc/PE)純化殘餘物，得到呈黃色油狀之標題化合物(260mg，1.026mmol，45.252%產率)。 ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.40-7.25 (m, 2H), 7.25-7.10 (m, 3H), 3.41 (qn, J = 6.8 Hz, 1H), 2.93 (d, J = 7.2 Hz, 1H), 2.80-2.55 (m, 2H), 1.95-1.75 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H), 1.24 (s, 9H)。 (R)-2- Methyl -N-[(2S)-4- phenylbut -2- yl ]-2- propanesulfinamide is converted to (R)-2-methyl-N- To a mixture of [(1E)-1-methyl-3-phenylpropylene]-2-propanesulfinamide (570 mg, 2.27 mmol) in THF (6 mL) was added lithium tris-2-butylborohydride (6.8 mL, 6.8 mmol). The mixture was stirred at 25°C for 3 hours to obtain a colorless mixture. TLC (PE:EtOAc = 2:1) showed detection of a new spot (Rf = 0.3). The reaction was quenched with _H2O (3 mL). The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by flash column (PE to 30% EtOAc/PE) to give the title compound (260 mg, 1.026 mmol, 45.252% yield) as a yellow oil. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.40-7.25 (m, 2H), 7.25-7.10 (m, 3H), 3.41 (qn, J = 6.8 Hz, 1H), 2.93 (d, J = 7.2 Hz, 1H), 2.80-2.55 (m, 2H), 1.95-1.75 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H), 1.24 (s, 9H).

(2S)-4- 苯基 -2- 丁胺在25℃下攪拌(R)-2-甲基-N-[(2S)-4-苯基丁-2-基]-2-丙烷亞磺醯胺(260 mg，1.03mmol)於MeOH/HCl (5 mL，1.03mmol)中之溶液1小時，得到黃色混合物。真空濃縮反應混合物，得到呈黃色固體狀之標題化合物(190mg，1.0232mmol，99.724%產率) (粗物質)。 (2S)-4- Phenyl -2- butylamine Stirring (R)-2-methyl-N-[(2S)-4-phenylbut-2-yl]-2-propanesulfinic acid at 25°C A solution of the amide (260 mg, 1.03 mmol) in MeOH/HCl (5 mL, 1.03 mmol) for 1 h gave a yellow mixture. The reaction mixture was concentrated in vacuo to afford the title compound (190 mg, 1.0232 mmol, 99.724% yield) (crude material) as a yellow solid.

1-[(2S)-4- 苯基丁 -2- 基 ]-1H- 咪唑 -4- 羧酸 乙 酯向(2S)-4-苯基-2-丁胺(190 mg，1.02mmol)於1-丁醇(2mL)中之混合物添加(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(172.09mg，1.02mmol)及Et ₃N (0.2mL，1.53mmol)。反應混合物在微波系統中在130℃下加熱1小時，得到褐色混合物。TLC (PE:EtOAc = 1:1)展示偵測到一個新樣點(Rf = 0.2)。真空濃縮反應混合物，得到殘餘物。藉由製備型TLC (PE: EtOAc=1: 1)純化殘餘物，得到呈褐色油狀之標題化合物(40mg，0.1469mmol，14.354%產率)。 LC-MS方法1 0.718 min，MS (m/z) 273 (M + H ⁺)。 1-[(2S)-4- phenylbut- 2- yl ]-1H- imidazole -4- carboxylic acid ethyl ester to (2S)-4-phenyl-2-butylamine (190 mg, 1.02mmol) in To the mixture in 1-butanol (2 mL) was added ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (172.09 mg, 1.02 mmol) and _Et3N (0.2 mL, 1.53 mmol) . The reaction mixture was heated at 130° C. for 1 hour in a microwave system to obtain a brown mixture. TLC (PE:EtOAc = 1:1) showed detection of a new spot (Rf = 0.2). The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (PE:EtOAc=1:1) to give the title compound (40 mg, 0.1469 mmol, 14.354% yield) as a brown oil. LC-MS method 1 0.718 min, MS (m/z) 273 (M + H ⁺ ).

1-[(2S)-4- 苯基丁 -2- 基 ]-1H- 咪唑 -4- 羧酸向1-[(2S)-4-苯基丁-2-基]-1H-咪唑-4-羧酸乙酯(40 mg，0.1500mmol)於THF (1.5mL)及H ₂O (0.50 mL)中之混合物添加LiOH·H ₂O (0.01mL，0.2200mmol)。在40℃下攪拌反應混合物16小時，得到黃色混合物。TLC (PE:EtOAc = 1:1)展示起始材料完全耗盡。用H ₂O (5 mL)稀釋反應混合物且用EtOAc (3 mL × 2)萃取。用1 N HCl水溶液將水相酸化至pH = 5且凍乾，得到呈黃色固體狀之標題化合物(30mg，0.1228mmol，83.612%產率)。 LC-MS方法1 0.677 min，MS (m/z) 245 (M + H ⁺)。 1-[(2S)-4- phenylbut -2- yl ]-1H- imidazole -4- carboxylic acid to 1-[(2S)-4-phenylbut-2-yl]-1H-imidazole-4 - A mixture of ethyl carboxylate (40 mg, 0.1500 mmol) in THF (1.5 mL) and _H2O (0.50 mL) was added LiOH- _H2O (0.01 mL, 0.2200 mmol). The reaction mixture was stirred at 40 °C for 16 hours to give a yellow mixture. TLC (PE:EtOAc = 1:1) showed complete consumption of starting material. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (3 mL×2). The aqueous phase was acidified to pH = 5 with 1 N aqueous HCl and lyophilized to afford the title compound (30 mg, 0.1228 mmol, 83.612% yield) as a yellow solid. LC-MS method 1 0.677 min, MS (m/z) 245 (M + H ⁺ ).

[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(2S)-4- 苯基丁 -2- 基 ]-1H- 咪唑 -4- 基 } 甲酮向1-[(2S)-4-苯基丁-2-基]1H-咪唑-4-羧酸(30 mg，0.1200mmol)於吡啶(1.5mL)中之混合物添加EDCI (28.25mg，0.1500mmol)。在25℃下攪拌混合物10 min且繼之以添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(26.61mg，0.1200mmol)。在25℃下攪拌混合物16小時，得到黃色混合物。LCMS展示起始材料完全耗盡。真空濃縮反應混合物，得到殘餘物。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色固體狀之標題化合物(16.26mg，0.0449mmol，17.643%產率)。 LC-MS 方法 1: 407.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.68 (s, 1 H), 7.43 (s, 1 H), 7.28 - 7.32 (m, 2 H), 7.19 - 7.24 (m, 1 H), 7.12 (s, 1 H), 7.10 (s, 1 H), 4.78 (dd, J=11.8, 3.8 Hz, 1 H), 4.21 (br d, J=12.5 Hz, 1 H), 4.04 - 4.15 (m, 1 H), 3.97 (br d, J=11.5 Hz, 1 H), 3.63 (dd, J=12.4, 3.9 Hz, 1 H), 2.65 (s, 2 H), 2.39 - 2.60 (m, 2 H), 2.05 - 2.19 (m, 3 H), 1.99 (br d, J=3.5 Hz, 1 H), 1.50 (d, J=6.8 Hz, 3 H), 1.46 - 1.49 (m, 1 H), 1.38 (s, 6 H) [(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ]{1-[(2S)-4- phenylbut -2- yl ]-1H- imidazol -4- yl } methanone to 1-[(2S)-4-phenylbutan-2- To a mixture of 1H-imidazole-4-carboxylic acid (30 mg, 0.1200 mmol) in pyridine (1.5 mL) was added EDCI (28.25 mg, 0.1500 mmol). The mixture was stirred at 25 °C for 10 min and followed by the addition of (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl) - 3-Azabicyclo[3.1.0]hexane hydrochloride (26.61 mg, 0.1200 mmol). The mixture was stirred at 25°C for 16 hours to give a yellow mixture. LCMS showed complete consumption of starting material. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (16.26 mg, 0.0449 mmol, 17.643% yield) as a yellow solid. LC-MS method 1 : 407.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.68 (s, 1 H), 7.43 (s, 1 H), 7.28 - 7.32 (m, 2 H ), 7.19 - 7.24 (m, 1 H), 7.12 (s, 1 H), 7.10 (s, 1 H), 4.78 (dd, J=11.8, 3.8 Hz, 1 H), 4.21 (br d, J= 12.5 Hz, 1 H), 4.04 - 4.15 (m, 1 H), 3.97 (br d, J=11.5 Hz, 1 H), 3.63 (dd, J=12.4, 3.9 Hz, 1 H), 2.65 (s, 2 H), 2.39 - 2.60 (m, 2 H), 2.05 - 2.19 (m, 3 H), 1.99 (br d, J=3.5 Hz, 1 H), 1.50 (d, J=6.8 Hz, 3 H) , 1.46 - 1.49 (m, 1H), 1.38 (s, 6H)

實例 31      [(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(2S)-1- 苯氧基丙 -2- 基 ]-1H- 咪唑 -4- 基 } 甲酮 [(2S)-1- 苯氧基丙 -2- 基 ] 胺基羧酸三級丁酯向苯酚(0.51mL，5.84mmol)、[(2S)-1-羥基丙-2-基]胺基羧酸三級丁酯(1024.08mg，5.84mmol)、PPh ₃(2299.32mg，8.77mmol)於甲苯(12mL)中之溶液緩慢添加DIAD (1.73mL，8.77mmol)。在20℃下攪拌反應物16小時，得到黃色溶液。TLC (PE/EA =10/1，Rf =0.8)展示新樣點。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(PE/EA= 10/1至3/1)來純化粗物質，得到呈白色固體狀之標題化合物(600 mg，2.3874mmol，40.85%產率)。 Example 31 [(1R,5S,6S)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ]{1-[(2S)-1- phenoxyprop- 2- yl ]-1H- imidazol -4-yl } methanone [ (2S)-1- phenoxyprop -2 -yl ] aminocarboxylic acid tertiary butyl ester to phenol (0.51mL, 5.84mmol), [(2S)-1-hydroxypropan-2-yl] aminocarboxylic acid tertiary butyl ester (1024.08mg, 5.84mmol) , _PPh3 (2299.32 mg, 8.77 mmol) in toluene (12 mL) was slowly added DIAD (1.73 mL, 8.77 mmol). The reaction was stirred at 20°C for 16 hours to give a yellow solution. TLC (PE/EA = 10/1, Rf = 0.8) showed a fresh sample. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (PE/EA = 10/1 to 3/1 ) to afford the title compound (600 mg, 2.3874 mmol, 40.85% yield) as a white solid.

(2S)-1- 苯氧基 -2- 丙胺氫氯化物向[(2S)-1-苯氧基丙-2-基]胺基羧酸三級丁酯(1100 mg，4.38mmol)於MeOH (1mL)中之溶液添加HCl/二㗁烷(5 mL，20mmol)且在20℃下攪拌反應混合物3小時，得到無色溶液。LCMS展示新峰值給出所要ms。在真空中蒸發反應混合物，得到呈黃色固體狀之標題化合物(800 mg，4.2628mmol，97.393%產率)。其直接用於下一步驟。 LC-MS方法1 0.498 min，MS (m/z) 151.8 (M + H ⁺)。 (2S)-1- Phenoxy -2- propylamine hydrochloride to [(2S)-1-phenoxypropan-2-yl]aminocarboxylate tertiary butyl ester (1100 mg, 4.38 mmol) in MeOH (1 mL) was added HCl/dioxane (5 mL, 20 mmol) and the reaction mixture was stirred at 20 °C for 3 hours to give a colorless solution. LCMS showed the new peak giving the desired ms. The reaction mixture was evaporated in vacuo to afford the title compound (800 mg, 4.2628 mmol, 97.393% yield) as a yellow solid. It was used directly in the next step. LC-MS method 1 0.498 min, MS (m/z) 151.8 (M + H ⁺ ).

1-[(2S)-1- 苯氧基丙 -2- 基 ]-1H- 咪唑 -4- 羧酸 乙 酯向5 mL MW小瓶添加(2S)-1-苯氧基-2-丙胺氫氯化物(1100 mg，5.86mmol)、(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(985.82mg，5.86mmol)、1-丁醇(3mL)及Et ₃N (1.22mL，8.79mmol)。在130℃下用微波照射反應物1小時，得到褐色溶液。LCMS展示新峰值給出所要ms。用飽和Na ₂CO ₃水溶液(20 mL)稀釋反應物。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(PE/EA= 10/1至1/1)來純化粗物質，得到呈白色固體狀之標題化合物(310mg，1.1301mmol，19.28%產率)。 LC-MS方法1 0.765 min，MS (m/z) 275.2 (M + H ⁺)。 1-[(2S)-1- Phenoxypropan -2- yl ]-1H- imidazole -4- carboxylic acid ethyl ester To a 5 mL MW vial add (2S)-1-phenoxy-2-propanamine hydrochloride compound (1100 mg, 5.86mmol), (2Z)-3-(dimethylamino)-2-isocyanoacrylate ethyl ester (985.82mg, 5.86mmol), 1-butanol (3mL) and Et ₃ N ( 1.22 mL, 8.79 mmol). The reaction was irradiated with microwaves at 130 °C for 1 hour to obtain a brown solution. LCMS showed the new peak giving the desired ms. _The reaction was diluted with saturated aqueous _Na2CO3 (20 mL). H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (PE/EA = 10/1 to 1/1) to afford the title compound (310 mg, 1.1301 mmol, 19.28% yield) as a white solid. LC-MS method 1 0.765 min, MS (m/z) 275.2 (M + H ⁺ ).

1-[(2S)-1- 苯氧基丙 -2- 基 ]-1H- 咪唑 -4- 羧酸向1-[(2S)-1-苯氧基丙-2-基]-1H-咪唑-4-羧酸乙酯(310 mg，1.13mmol)於1,4-二㗁烷(3mL)中之經攪拌溶液添加LiOH·H ₂O (61.64mg，1.47mmol)於H ₂O (1ml)中之溶液。在20℃下攪拌反應混合物16小時，得到黃色溶液。LCMS展示新峰值給出所要ms。添加H ₂O (30 mL)且用EtOAc (30 mL)對其進行萃取。隨後藉由1M HCl水溶液酸化水層且凍乾，得到呈黃色固體狀之標題化合物(240mg，0.9746mmol，86.241%產率)。 LC-MS方法1 0.645 min，MS (m/z) 247.2 (M + H ⁺)。 1-[(2S)-1- phenoxyprop -2- yl ]-1H- imidazole -4- carboxylic acid to 1-[(2S)-1-phenoxyprop-2-yl]-1H-imidazole - To a stirred solution of ethyl 4-carboxylate (310 mg, 1.13 mmol) in 1,4-dioxane (3 mL) was added LiOH·H ₂ O (61.64 mg, 1.47 mmol) in H ₂ O (1 ml) solution in. The reaction mixture was stirred at 20 °C for 16 hours to give a yellow solution. LCMS showed the new peak giving the desired ms. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL). The aqueous layer was then acidified by 1M aqueous HCl and lyophilized to afford the title compound (240 mg, 0.9746 mmol, 86.241% yield) as a yellow solid. LC-MS method 1 0.645 min, MS (m/z) 247.2 (M + H ⁺ ).

[(1R,5S,6S)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ]{1-[(2S)-1- 苯氧基丙 -2- 基 ]-1H- 咪唑 -4- 基 } 甲酮向1-[(2S)-1-苯氧基丙-2-基]-1H-咪唑-4-羧酸(130 mg，0.5300mmol)及N-乙基-N-異丙基丙-2-胺(0.45mL，2.64mmol)於DMF (2mL)中之經攪拌溶液添加HATU (300.9mg，0.7900mmol)。在攪拌30 min之後，添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(114.4mg，0.5300mmol)，得到褐色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (NH ₃)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(51.22mg，0.1254mmol，23.752%產率)。 LC-MS方法1: 409.3 [M+H ⁺] ¹H NMR (400 MHz, 氯仿- d) δ ppm 1.33 (s, 6 H) 1.47 (br s, 1 H) 1.64 (d, J=7.03 Hz, 3 H) 2.00 - 2.15 (m, 2 H) 2.72 (s, 2 H) 3.53 - 3.67 (m, 1 H) 3.92 (br d, J=8.53 Hz, 1 H) 4.10 (br d, J=12.30 Hz, 1 H) 4.15 - 4.28 (m, 2 H) 4.37 (br d, J=10.79 Hz, 1 H) 4.75 (br dd, J=11.04, 6.78 Hz, 1 H) 6.88 (br d, J=8.03 Hz, 2 H) 6.92 (br t, J=7.53 Hz, 1 H) 7.24 (br t, J=7.65 Hz, 2 H) 7.82 (br d, J=6.78 Hz, 2 H) [(1R,5S,6S)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ]{1-[(2S)-1- phenoxypropan -2- yl ]-1H- imidazol -4- yl } methanone to 1-[(2S)-1-phenoxypropan- 2-yl]-1H-imidazole-4-carboxylic acid (130 mg, 0.5300mmol) and N-ethyl-N-isopropylpropan-2-amine (0.45mL, 2.64mmol) in DMF (2mL) HATU (300.9 mg, 0.7900 mmol) was added via the stirred solution. After stirring for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo [3.1.0] Hexane hydrochloride (114.4mg, 0.5300mmol) to give a brown solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC ( _NH3 ). The resulting fluid was concentrated in vacuo to remove most of the _CH3CN and lyophilized to give the title compound (51.22 mg, 0.1254 mmol, 23.752% yield) as a white solid. LC-MS method 1: 409.3 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform- d ) δ ppm 1.33 (s, 6 H) 1.47 (br s, 1 H) 1.64 (d, J =7.03 Hz, 3 H) 2.00 - 2.15 (m, 2 H) 2.72 (s, 2 H) 3.53 - 3.67 (m, 1 H) 3.92 (br d, J =8.53 Hz, 1 H) 4.10 (br d, J =12.30 Hz , 1 H) 4.15 - 4.28 (m, 2 H) 4.37 (br d, J =10.79 Hz, 1 H) 4.75 (br d, J =11.04, 6.78 Hz, 1 H) 6.88 (br d, J =8.03 Hz , 2 H) 6.92 (br t, J =7.53 Hz, 1 H) 7.24 (br t, J =7.65 Hz, 2 H) 7.82 (br d, J =6.78 Hz, 2 H)

實例 32      [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-( 戊 -3- 基 )-1H- 咪唑 -4- 基 ] 甲酮 1-( 戊 -3- 基 )-1H- 咪唑 -4- 羧酸 乙 酯在80℃下攪拌戊-3-胺(1.73mL，14.86mmol)及(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(500 mg，2.97mmol)之混合物16小時。藉由快速柱(PE:EA=2:1)純化粗產物，得到呈褐色油狀之標題化合物(500 mg，2.3779mmol，79.988%產率)。 Example 32 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ][1-( pent - 3- yl )-1H- imidazol -4- yl ] methanone 1-( pent - 3- yl )-1H- imidazole -4- carboxylic acid ethyl ester at 80 A mixture of pent-3-amine (1.73 mL, 14.86 mmol) and ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (500 mg, 2.97 mmol) was stirred at °C for 16 hours. The crude product was purified by flash column (PE:EA=2:1) to give the title compound (500 mg, 2.3779 mmol, 79.988% yield) as a brown oil.

1-( 戊 -3- 基 )-1H- 咪唑 -4- 羧酸向1-(戊-3-基)-1H-咪唑-4-羧酸乙酯於THF (15mL)及H ₂O (5 mL)中之溶液添加LiOH·H ₂O (0.41mL，7.13mmol)。在40℃下攪拌反應混合物16小時，得到黃色混合物。真空濃縮反應混合物以移除大部分THF。用H ₂O (5 mL)稀釋殘餘物且用0.5 M HCl水溶液酸化至pH = 6。隨後凍乾溶液，得到呈黃色固體狀之標題化合物。 1-( pent -3- yl )-1H- imidazole -4- carboxylic acid to ethyl 1-(pent-3-yl)-1H-imidazole-4-carboxylate in THF (15mL) and H ₂ O (5 mL) was added LiOH·H ₂ O (0.41 mL, 7.13 mmol). The reaction mixture was stirred at 40 °C for 16 hours to give a yellow mixture. The reaction mixture was concentrated in vacuo to remove most of the THF. The residue was diluted with _H2O (5 mL) and acidified to pH = 6 with 0.5 M aqueous HCl. The solution was then lyophilized to afford the title compound as a yellow solid.

[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-( 戊 -3- 基 )-1H- 咪唑 -4- 基 ] 甲酮向1-(戊-3-基)-1H-咪唑-4-羧酸(50mg，0.2700mmol)於DMF (5mL)中之溶液添加HATU (157.35mg，0.4100mmol)及Et ₃N (0.14mL，1.1mmol)，且在25℃下攪拌反應混合物15 min。隨後添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(49.46mg，0.2700mmol)。在25℃下攪拌所得混合物2小時，得到褐色溶液，且隨後真空濃縮以移除大部分DMF，得到粗產物。藉由製備型HPLC (NH ₃)純化粗產物，得到呈白色固體狀之標題化合物。 LC-MS方法1: 345.3 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.61 (d, J=1.3 Hz, 1H), 7.40 (d, J=1.3 Hz, 1H), 4.80 (d, J=12.0 Hz, 1H), 4.20 (d, J=12.5 Hz, 1H), 3.95 (dd, J=4.0, 11.8 Hz, 1H), 3.74 (tt, J=4.8, 9.5 Hz, 1H), 3.62 (dd, J=4.3, 12.3 Hz, 1H), 2.65 (s, 2H), 2.13 - 2.05 (m, 1H), 2.02 - 1.95 (m, 1H), 1.91 - 1.79 (m, 2H), 1.78 - 1.69 (m, 2H), 1.48 (t, J=3.4 Hz, 1H), 1.38 (s, 6H), 0.82 (t, J=7.3 Hz, 6H) [(1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ][1-( pent -3 - yl )-1H- imidazol -4- yl ] methanone to 1-(pent-3-yl)-1H-imidazole-4-carboxylic acid (50mg, 0.2700mmol ) in DMF (5 mL) was added HATU (157.35 mg, 0.4100 mmol) and _Et3N (0.14 mL, 1.1 mmol), and the reaction mixture was stirred at 25 °C for 15 min. Then add (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0] Hexane hydrochloride (49.46 mg, 0.2700 mmol). The resulting mixture was stirred at 25 °C for 2 hours to give a brown solution, and then concentrated in vacuo to remove most of the DMF to give the crude product. The crude product was purified by preparative HPLC ( _NH3 ) to afford the title compound as a white solid. LC-MS method 1: 345.3 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.61 (d, J =1.3 Hz, 1H), 7.40 (d, J =1.3 Hz, 1H), 4.80 (d, J =12.0 Hz, 1H), 4.20 (d, J =12.5 Hz, 1H), 3.95 (dd, J =4.0, 11.8 Hz, 1H), 3.74 (tt, J =4.8, 9.5 Hz, 1H) , 3.62 (dd, J =4.3, 12.3 Hz, 1H), 2.65 (s, 2H), 2.13 - 2.05 (m, 1H), 2.02 - 1.95 (m, 1H), 1.91 - 1.79 (m, 2H), 1.78 - 1.69 (m, 2H), 1.48 (t, J =3.4 Hz, 1H), 1.38 (s, 6H), 0.82 (t, J =7.3 Hz, 6H)

實例 33      [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-(1- 甲基環丙基 )-1H- 咪唑 -4- 基 ] 甲酮 1-(1- 甲基環丙基 )-1H- 咪唑 -4- 羧酸 乙 酯向(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(469.02 mg，2.79 mmol)於1-丁醇(5.5 mL)中之溶液添加1-甲基環丙胺(300 mg，2.79 mmol)及Et ₃N (0.54 mL，4.18 mmol)。所得混合物在微波反應器中經受反應(時間：1小時，溫度：130℃)。TLC (PE:EtOAc = 0:1)展示反應完成(Rf = 0.5)。直接濃縮反應混合物。藉由快速柱(PE至40% EtOAc/PE)純化粗產物，得到呈褐色油狀之標題化合物(118 mg，0.6075 mmol，21.786%產率)。 LC-MS方法1: 0.568 min，MS (m/z) 194.9 [M+H] ^{+ 1}H NMR (400MHz, 氯仿-d) δ = 7.71 - 7.69 (m, 1H), 7.60 (s, 1H), 4.36 (q, J=7.0 Hz, 2H), 1.58 (s, 3H), 1.38 (t, J=7.2 Hz, 3H), 1.17 - 1.12 (m, 2H), 0.96 - 0.91 (m, 2H) Example 33 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ][1-(1- methylcyclopropyl )-1H- imidazol -4- yl ] methanone 1-(1- methylcyclopropyl )-1H- imidazole -4- carboxylic acid ethyl ester to (2Z)-3-(dimethylamino)-2-isocyanoacrylate ethyl ester (469.02 mg, 2.79 mmol ) in 1-butanol (5.5 mL) was added 1-methylcyclopropylamine (300 mg, 2.79 mmol) and _Et3N (0.54 mL, 4.18 mmol). The resulting mixture was subjected to reaction in a microwave reactor (time: 1 hour, temperature: 130° C.). TLC (PE:EtOAc = 0:1) showed the reaction was complete (Rf = 0.5). The reaction mixture was directly concentrated. The crude product was purified by flash column (PE to 40% EtOAc/PE) to give the title compound (118 mg, 0.6075 mmol, 21.786% yield) as a brown oil. LC-MS method 1: 0.568 min, MS (m/z) 194.9 [M+H] ^{+ 1} H NMR (400MHz, chloroform-d) δ = 7.71 - 7.69 (m, 1H), 7.60 (s, 1H), 4.36 (q, J =7.0 Hz, 2H), 1.58 (s, 3H), 1.38 (t, J =7.2 Hz, 3H), 1.17 - 1.12 (m, 2H), 0.96 - 0.91 (m, 2H)

1-(1- 甲基環丙基 )-1H- 咪唑 -4- 羧酸向1-(1-甲基環丙基)-1H-咪唑-4-羧酸乙酯(118 mg，0.61 mmol)於THF (1.5 mL)及H ₂O (0.50 mL)中之溶液添加LiOH·H ₂O (0.05 mL，0.79 mmol)。在20至25℃下攪拌所得混合物2小時。直接濃縮反應混合物。用1 M HCl水溶液將殘餘物酸化至pH = 6且隨後凍乾，得到呈黃色固體狀之標題化合物(100 mg，0.6018 mmol，99.05%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ = 7.81 (d, J=1.0 Hz, 1H), 7.65 (s, 1H), 1.55 - 1.47 (m, 3H), 1.13 - 1.07 (m, 2H), 0.91 - 0.85 (m, 2H) 1-(1- methylcyclopropyl )-1H- imidazole -4- carboxylic acid to 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylic acid ethyl ester (118 mg, 0.61 mmol) To a solution in THF (1.5 mL) and _H2O (0.50 mL) was added LiOH- _H2O (0.05 mL, 0.79 mmol). The resulting mixture was stirred at 20 to 25°C for 2 hours. The reaction mixture was directly concentrated. The residue was acidified to pH = 6 with 1 M aqueous HCl and then lyophilized to afford the title compound (100 mg, 0.6018 mmol, 99.05% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.81 (d, J =1.0 Hz, 1H), 7.65 (s, 1H), 1.55 - 1.47 (m, 3H), 1.13 - 1.07 (m, 2H), 0.91 - 0.85 (m, 2H)

[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-(1- 甲基環丙基 )-1H- 咪唑 -4- 基 ] 甲酮向1-(1-甲基環丙基)-1H-咪唑-4-羧酸(100 mg，0.60 mmol)於DMF (2 mL)中之溶液添加HATU (276.06 mg，0.72 mmol)及Et ₃N (0.39 mL，3.01 mmol)。在20至25℃下攪拌混合物0.5小時。向混合物添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(108.47 mg，0.60 mmol)。在20至25℃下攪拌反應混合物1小時。LCMS展示所要MS (作為主峰)。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色固體狀之標題化合物(60.45 mg，0.1841 mmol，30.589%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 7.68 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.3 Hz, 1H), 4.70 (d, J=11.8 Hz, 1H), 4.18 (d, J=12.5 Hz, 1H), 3.92 (dd, J=4.0, 12.0 Hz, 1H), 3.60 (dd, J=4.1, 12.4 Hz, 1H), 2.63 (s, 2H), 2.07 (br dd, J=3.5, 7.0 Hz, 1H), 2.01 - 1.92 (m, 1H), 1.57 (s, 3H), 1.45 (t, J=3.4 Hz, 1H), 1.37 (s, 6H), 1.16 - 1.10 (m, 2H), 0.95 - 0.89 (m, 2H) LC-MS方法1 0.606 min，MS (m/z) 329.0 [M+H ⁺] [(1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ][1-(1- methylcyclopropyl )-1H- imidazol -4- yl ] methanone to 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylic acid ( 100 mg, 0.60 mmol) in DMF (2 mL) was added HATU (276.06 mg, 0.72 mmol) and _Et3N (0.39 mL, 3.01 mmol). The mixture was stirred at 20 to 25°C for 0.5 hours. To the mixture was added (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0 ] hexane hydrochloride (108.47 mg, 0.60 mmol). The reaction mixture was stirred at 20 to 25°C for 1 hour. LCMS showed desired MS (as main peak). The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (60.45 mg, 0.1841 mmol, 30.589% yield) as a yellow solid. ¹ H NMR (400MHz, chloroform-d) δ = 7.68 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.3 Hz, 1H), 4.70 (d, J=11.8 Hz, 1H), 4.18 ( d, J=12.5 Hz, 1H), 3.92 (dd, J=4.0, 12.0 Hz, 1H), 3.60 (dd, J=4.1, 12.4 Hz, 1H), 2.63 (s, 2H), 2.07 (br dd, J=3.5, 7.0 Hz, 1H), 2.01 - 1.92 (m, 1H), 1.57 (s, 3H), 1.45 (t, J=3.4 Hz, 1H), 1.37 (s, 6H), 1.16 - 1.10 (m , 2H), 0.95 - 0.89 (m, 2H) LC-MS Method 1 0.606 min, MS (m/z) 329.0 [M+H ⁺ ]

實例 34      [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-(1- 甲基環丁基 )-1H- 咪唑 -4- 基 ] 甲酮 1-(1- 甲基環丁基 )-1H- 咪唑 -4- 羧酸 乙 酯向(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(200 mg，1.19mmol)於1-丁醇(0.50 mL)中之混合物添加1-甲基環丁胺(583.25mg，4.76mmol)及Et ₃N (1.15mL，8.92mmol)。在76℃下加熱所得混合物16小時。用H ₂O (5 mL)稀釋反應混合物且用EtOAc (5mL × 3)萃取。分離合併之有機層，用鹽水(10mL)洗滌，經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型TLC (100% EA)純化粗物質油，得到呈黃色油狀之標題化合物(50mg，0.2401mmol，20.19%產率)。 LC-MS方法1 0.665 min，MS (m/z) 209.2 (M + H ⁺)。 Example 34 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ][1-(1- methylcyclobutyl )-1H- imidazol -4- yl ] methanone 1-(1- methylcyclobutyl )-1H- imidazole -4- carboxylic acid Ethyl ester To a mixture of ethyl (2Z)-3-(dimethylamino)-2-isocyanoacrylate (200 mg, 1.19 mmol) in 1-butanol (0.50 mL) was added 1-methylcyclobutane Amine (583.25 mg, 4.76 mmol) and _Et3N (1.15 mL, 8.92 mmol). The resulting mixture was heated at 76°C for 16 hours. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were separated, washed with brine (10 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude oil. The crude oil was purified by prep-TLC (100% EA) to afford the title compound (50 mg, 0.2401 mmol, 20.19% yield) as a yellow oil. LC-MS method 1 0.665 min, MS (m/z) 209.2 (M + H ⁺ ).

1-(1- 甲基環丁基 )-1H- 咪唑 -4- 羧酸向1-(1-甲基環丁基)-1H-咪唑-4-羧酸乙酯(50 mg，0.2400mmol)於H ₂O (0.4952mL)及MeOH (0.3961mL)中之混合物添加LiOH·H ₂O (0.04mL，0.7200mmol)。在25℃下攪拌所得混合物5小時。用DCM (3mL × 2)洗滌水相且用1N HCl酸化至pH = 2。凍乾水溶液，得到呈淡黃色固體狀之標題化合物(50mg，0.2775mmol，115.57%產率)。 1-(1- methylcyclobutyl )-1H- imidazole -4- carboxylic acid to 1-(1-methylcyclobutyl)-1H-imidazole-4-carboxylic acid ethyl ester (50 mg, 0.2400mmol) To a mixture in _H2O (0.4952 mL) and MeOH (0.3961 mL) was added LiOH- _H2O (0.04 mL, 0.7200 mmol). The resulting mixture was stirred at 25°C for 5 hours. The aqueous phase was washed with DCM (3 mL x 2) and acidified to pH = 2 with 1 N HCl. The aqueous solution was lyophilized to afford the title compound (50 mg, 0.2775 mmol, 115.57% yield) as a light yellow solid.

[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-(1- 甲基環丁基 )-1H- 咪唑 -4- 基 ] 甲酮向1-(1-甲基環丁基)-1H-咪唑-4-羧酸(48.08mg，0.2200mmol)於DMF (0.40 mL)中之混合物添加HATU (137.86mg，0.3600mmol)、DIPEA (0.18mL，1.11mmol)及(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(40 mg，0.2200mmol)。在20℃下攪拌所得混合物4小時。用H ₂O (5 mL)稀釋反應混合物且用EtOAc (5mL×2)萃取，隨後用鹽水(8mL)洗滌。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型HPLC (NH ₃)純化粗物質油且隨後凍乾，得到呈淡黃色固體狀之標題化合物(3mg，0.0088mmol，3.9478%產率)。 ¹H NMR (400MHz, CD ₃OD) δ = 7.74 (s, 1H), 7.67 (s, 1H), 4.41 (br d, J=12.0 Hz, 1H), 4.09 (br d, J=12.3 Hz, 1H), 3.93 (br dd, J=3.8, 11.8 Hz, 1H), 3.59 (br dd, J=3.9, 12.4 Hz, 1H), 2.71 (s, 2H), 2.63 - 2.52 (m, 2H), 2.30 (tt, J=3.0, 8.9 Hz, 2H), 2.14 - 2.08 (m, 1H), 2.07 - 1.92 (m, 3H), 1.68 (s, 3H), 1.48 (t, J=3.4 Hz, 1H), 1.32 (s, 6H)。 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ][1-(1- methylcyclobutyl )-1H- imidazol -4- yl ] methanone to 1-(1-methylcyclobutyl)-1H-imidazole-4-carboxylic acid ( 48.08 mg, 0.2200 mmol) in DMF (0.40 mL) was added with HATU (137.86 mg, 0.3600 mmol), DIPEA (0.18 mL, 1.11 mmol) and (1R,5S,6r)-6-(5,5-di Methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (40 mg, 0.2200 mmol). The resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (5 mL×2), then washed with brine (8 mL). The combined organic _layers were separated, then dried over _Na2SO4 and concentrated in vacuo to give a crude oil. The crude oil was purified by preparative HPLC ( _NH3 ) and then lyophilized to afford the title compound (3 mg, 0.0088 mmol, 3.9478% yield) as a light yellow solid. ¹ H NMR (400MHz, CD ₃ OD) δ = 7.74 (s, 1H), 7.67 (s, 1H), 4.41 (br d, J =12.0 Hz, 1H), 4.09 (br d, J =12.3 Hz, 1H ), 3.93 (br dd, J =3.8, 11.8 Hz, 1H), 3.59 (br dd, J =3.9, 12.4 Hz, 1H), 2.71 (s, 2H), 2.63 - 2.52 (m, 2H), 2.30 ( tt, J =3.0, 8.9 Hz, 2H), 2.14 - 2.08 (m, 1H), 2.07 - 1.92 (m, 3H), 1.68 (s, 3H), 1.48 (t, J =3.4 Hz, 1H), 1.32 (s, 6H).

實例 35      [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 丙基 -1H- 咪唑 -4- 基 ) 甲酮 1- 丙基 -1H- 咪唑 -4- 羧酸 乙 酯向(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(500 mg，2.97 mmol)於1-丁醇(0.5 M，64.98 mmol)中之溶液添加丙-1-胺(2.97 mL，1.78 mmol，1.0當量)及Et ₃N (0.25 mL，1.78 mmol，0.6當量)。在130℃下攪拌混合物6小時且隨後濃縮，得到殘餘物。藉由矽膠層析(正己烷/EtOAc = 60/40至0/100且隨後MeOH/EtOAc = 5/95)純化殘餘物，得到呈褐色油狀之標題化合物(214 mg，1.17 mmol，39.5%產率)。 LC-MS方法1 0.662 min，MS (m/z) 183.0 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿-d) δ 7.60 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.93 (t, J = 6.9 Hz, 2H), 1.90-1.80 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H), 0.94 (t, J = 9.6 Hz, 3H)。 Example 35 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ](1- propyl -1H- imidazol -4- yl ) methanone 1- propyl -1H- imidazole - 4- carboxylic acid ethyl ester to (2Z)-3-(dimethylamino )-Ethyl 2-isocyanoacrylate (500 mg, 2.97 mmol) in 1-butanol (0.5 M, 64.98 mmol) was added propan-1-amine (2.97 mL, 1.78 mmol, 1.0 equiv) and Et ₃ N (0.25 mL, 1.78 mmol, 0.6 equiv). The mixture was stirred at 130°C for 6 hours and then concentrated to give a residue. The residue was purified by silica gel chromatography (n-Hexane/EtOAc = 60/40 to 0/100 and then MeOH/EtOAc = 5/95) to give the title compound (214 mg, 1.17 mmol, 39.5% yield) as a brown oil. Rate). LC-MS method 1 0.662 min, MS (m/z) 183.0 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform-d) δ 7.60 (d, J = 1.2 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.93 ( t, J = 6.9 Hz, 2H), 1.90-1.80 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H), 0.94 (t, J = 9.6 Hz, 3H).

1- 丙基 -1H- 咪唑 -4- 羧酸向1-丙基-1H-咪唑-4-羧酸乙酯(214 mg，1.17 mmol)於THF (1.7 mL，660 mM)中之經攪拌溶液添加LiOH (70.3 mg，2.94 mmol，2.5當量)於H ₂O (0.6 mL)中之溶液。在40℃下攪拌反應混合物12小時。用H ₂O稀釋反應混合物且用DCM萃取。用1 N HCl (水性)將水相酸化至pH = 5。真空乾燥所得水相，得到呈米色固體狀之標題化合物(133 mg，0.86 mmol，73.4%產率) (粗物質)。 ¹H NMR (400 MHz, DMSO-d ₆) δ 7.81 (d, J = 1.5 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 3.94 (t, J = 6.9 Hz, 2H), 1.80-1.60 (m, 2H), 0.78 (t, J = 7.5 Hz, 3H)。 1- Propyl -1H- imidazole -4- carboxylic acid to a stirred solution of ethyl 1-propyl-1H-imidazole-4-carboxylate (214 mg, 1.17 mmol) in THF (1.7 mL, 660 mM) A solution of LiOH (70.3 mg, 2.94 mmol, 2.5 equiv) in _H2O (0.6 mL) was added. The reaction mixture was stirred at 40°C for 12 hours. The reaction mixture was diluted with _H2O and extracted with DCM. Acidify the aqueous phase to pH = 5 with 1 N HCl (aq). The resulting aqueous phase was dried in vacuo to afford the title compound (133 mg, 0.86 mmol, 73.4% yield) (crude material) as a beige solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (d, J = 1.5 Hz, 1H), 7.72 (d, J = 1.5 Hz, 1H), 3.94 (t, J = 6.9 Hz, 2H), 1.80 -1.60 (m, 2H), 0.78 (t, J = 7.5 Hz, 3H).

[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 丙基 -1H- 咪唑 -4- 基 ) 甲酮向1-丙基-1H-咪唑-4-羧酸(45.0 mg，0.14 mmol)及HATU (53.2 mg，0.14 mmol，1.0當量)於THF (0.7mL，200 mM)中之經攪拌溶液添加DIPEA (0.12 mL，0.7 mmol，5.0當量)。在50℃下攪拌30 min之後，添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(33.4 mg，0.154 mmol，1.1當量)且在20℃下攪拌反應物16小時，得到黃色溶液。添加H ₂O且用DCM對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(EtOAc/DCM = 99/1至70/30)來純化粗物質，得到呈米色粉末狀之標題化合物(23 mg，0.072 mmol，51.9%產率)。 LC-MS方法1 0.757 min，MS (m/z) 317.0 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿-d) δ 7.59 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.18 (d, J = 11.2 Hz, 1H), 4.00-3.85 (m, 1H), 3.91 (t, J = 7.2 Hz, 2H), 3.65-3.55 (m, 1H), 2.64 (s, 2H), 2.10-2.05 (m, 1H), 2.05-1.90 (m, 1H), 1.90-1.70 (m, 2H), 1.50-1.45 (m, 1H), 1.37 (s, 6H), 0.91 (t, 3H, J = 7.2 Hz, 3H)。 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ](1- propyl -1H- imidazol -4- yl ) methanone to 1-propyl-1H-imidazole-4-carboxylic acid (45.0 mg, 0.14 mmol) and HATU (53.2 mg, 0.14 mmol , 1.0 equiv) in THF (0.7 mL, 200 mM) was added DIPEA (0.12 mL, 0.7 mmol, 5.0 equiv). After stirring at 50°C for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3- Azabicyclo[3.1.0]hexane hydrochloride (33.4 mg, 0.154 mmol, 1.1 equiv) and the reaction was stirred at 20 °C for 16 hours gave a yellow solution. _H2O was added and it was extracted with DCM. _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (EtOAc/DCM = 99/1 to 70/30) to afford the title compound (23 mg, 0.072 mmol, 51.9% yield) as a beige powder. LC-MS method 1 0.757 min, MS (m/z) 317.0 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform-d) δ 7.59 (d, J = 1.5 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 4.73 (d, J = 11.2 Hz, 1H), 4.18 ( d, J = 11.2 Hz, 1H), 4.00-3.85 (m, 1H), 3.91 (t, J = 7.2 Hz, 2H), 3.65-3.55 (m, 1H), 2.64 (s, 2H), 2.10-2.05 (m, 1H), 2.05-1.90 (m, 1H), 1.90-1.70 (m, 2H), 1.50-1.45 (m, 1H), 1.37 (s, 6H), 0.91 (t, 3H, J = 7.2 Hz , 3H).

實例 36      [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丁基 -1H- 咪唑 -4- 基 ) 甲酮 1- 異丁基 -1H- 咪唑 -4- 羧酸 乙 酯向(2Z)-3-(二甲胺基)-2-異氰基丙烯酸乙酯(1.50 g，8.92 mmol)於1-丁醇(17.8 mL，0.5 M)中之溶液添加2-甲基丙-1-胺(1.0 mL，9.8 mmol，1.1當量)及Et ₃N (0.74 mL，5.35 mmol，0.6當量)。在130℃下攪拌混合物6小時且隨後濃縮，得到殘餘物。藉由矽膠層析(正己烷/EtOAc = 60/40至0/100且隨後MeOH/EtOAc = 5/95)純化殘餘物，得到呈褐色油狀之標題化合物(455 mg，2.3 mmol，26.0%產率)。 LC-MS方法1 0.743 min，MS (m/z) 197.0 (M + H ⁺)。 ¹H NMR (300 MHz, 氯仿- d) δ ppm 7.58 (d, J = 1.2 Hz, 1H), 7.44 (d, J = 1.2 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.75 (d, J = 7.8 Hz, 2H), 2.15-1.95 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H)。 Example 36 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ](1- isobutyl -1H- imidazol -4- yl ) methanone 1- isobutyl -1H- imidazole -4- carboxylic acid ethyl ester to (2Z)-3-(dimethyl Amino)-ethyl 2-isocyanoacrylate (1.50 g, 8.92 mmol) in 1-butanol (17.8 mL, 0.5 M) was added 2-methylpropan-1-amine (1.0 mL, 9.8 mmol , 1.1 eq) and _Et3N (0.74 mL, 5.35 mmol, 0.6 eq). The mixture was stirred at 130°C for 6 hours and then concentrated to give a residue. The residue was purified by silica gel chromatography (n-Hexane/EtOAc = 60/40 to 0/100 and then MeOH/EtOAc = 5/95) to give the title compound as a brown oil (455 mg, 2.3 mmol, 26.0% yield Rate). LC-MS method 1 0.743 min, MS (m/z) 197.0 (M + H ⁺ ). ¹ H NMR (300 MHz, chloroform- d ) δ ppm 7.58 (d, J = 1.2 Hz, 1H), 7.44 (d, J = 1.2 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.75 (d, J = 7.8 Hz, 2H), 2.15-1.95 (m, 1H), 1.39 (t, J = 7.2 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H).

1- 異丁基 -1H- 咪唑 -4- 羧酸向1-異丁基-1H-咪唑-4-羧酸乙酯(450 mg，2.3 mmol)於THF (3.5 mL，660 mM)中之經攪拌溶液添加LiOH (137 mg，5.7 mmol，2.5當量)於H ₂O (1.2 mL)中之溶液。在40℃下攪拌反應混合物12小時，且隨後用H ₂O稀釋且用DCM萃取。用1 N HCl (水性)將水相酸化至pH = 5。真空乾燥所得水相，得到呈黃色固體狀之標題化合物(440 mg，2.15 mmol，93.8%產率) (粗物質)。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.50 brs, 1H), 8.10 (d, J = 1.2 Hz, 1H), 3.91 (d, J = 6.9 Hz, 2H), 2.15-1.95 (m, 1H), 0.82 (d, J = 6.6 Hz, 6H)。 Conversion of 1- isobutyl -1H- imidazole -4- carboxylic acid to ethyl 1-isobutyl-1H-imidazole-4-carboxylate (450 mg, 2.3 mmol) in THF (3.5 mL, 660 mM) The stirred solution was added with a solution of LiOH (137 mg, 5.7 mmol, 2.5 equiv) in _H2O (1.2 mL). The reaction mixture was stirred at 40 °C for 12 h, and then diluted with _H2O and extracted with DCM. Acidify the aqueous phase to pH = 5 with 1 N HCl (aq). The resulting aqueous phase was dried in vacuo to afford the title compound (440 mg, 2.15 mmol, 93.8% yield) (crude material) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.50 brs, 1H), 8.10 (d, J = 1.2 Hz, 1H), 3.91 (d, J = 6.9 Hz, 2H), 2.15-1.95 (m, 1H), 0.82 (d, J = 6.6 Hz, 6H).

[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丁基 -1H- 咪唑 -4- 基 ) 甲酮向1-異丁基-1H-咪唑-4-羧酸(65.0 mg，0.15 mmol)及HATU (56.8 mg，0.15 mmol，1.0當量)於THF (0.7 mL，200 mM)中之經攪拌溶液添加DIPEA (0.13 mL，0.75 mmol，5.0當量)。在50℃下攪拌30 min之後，添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(35.6 mg，0.164 mmol，1.1當量)且在50℃下攪拌反應物1小時，得到黃色溶液。添加H ₂O且用DCM對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(EtOAc/DCM = 99/1至80/20)來純化粗物質，得到呈白色粉末狀之標題化合物(36.2 mg，0.11 mmol，73.4%產率)。 LC-MS方法1 0.800 min，MS (m/z) 331.1 (M + H ⁺)。 ¹H NMR (300 MHz, 氯仿-d) δ 7.57 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 1.8Hz, 1H), 4.74 (d, J = 12.3 Hz, 1H), 4.18 (d, J = 12.3 Hz, 1H), 3.93 (dd, J = 12.3, 4.2 Hz, 1H), 3.73 (d, J = 7.2 Hz, 2H), 3.61 (dd, J = 12.3, 4.2 Hz, 1H), 2.64 (s, 2H), 2.15-1.95 (m, 3H), 1.50-1.40 (m, 1H), 1.37 (s, 6H), 0.92 (d, J = 6.6 Hz, 6H)。 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ](1- isobutyl -1H- imidazol -4- yl ) methanone to 1-isobutyl-1H-imidazole-4-carboxylic acid (65.0 mg, 0.15 mmol) and HATU (56.8 mg, To a stirred solution of 0.15 mmol, 1.0 equiv) in THF (0.7 mL, 200 mM) was added DIPEA (0.13 mL, 0.75 mmol, 5.0 equiv). After stirring at 50°C for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3- Azabicyclo[3.1.0]hexane hydrochloride (35.6 mg, 0.164 mmol, 1.1 equiv) and the reaction was stirred at 50 °C for 1 hour gave a yellow solution. _H2O was added and it was extracted with DCM. The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (EtOAc/DCM = 99/1 to 80/20) to afford the title compound (36.2 mg, 0.11 mmol, 73.4% yield) as a white powder. LC-MS method 1 0.800 min, MS (m/z) 331.1 (M + H ⁺ ). ¹ H NMR (300 MHz, chloroform-d) δ 7.57 (d, J = 1.8 Hz, 1H), 7.36 (d, J = 1.8Hz, 1H), 4.74 (d, J = 12.3 Hz, 1H), 4.18 ( d, J = 12.3 Hz, 1H), 3.93 (dd, J = 12.3, 4.2 Hz, 1H), 3.73 (d, J = 7.2 Hz, 2H), 3.61 (dd, J = 12.3, 4.2 Hz, 1H), 2.64 (s, 2H), 2.15-1.95 (m, 3H), 1.50-1.40 (m, 1H), 1.37 (s, 6H), 0.92 (d, J = 6.6 Hz, 6H).

實例 37      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6-(5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(200 mg，0.77 mmol)於DMF (2 mL)中之混合物添加丙-1-烯(4.6 mL，2.3 mmol)及Et ₃N (0.38 mL，2.3 mmol)。在20℃下攪拌所得混合物16小時，得到淡黃色混合物。用H ₂O (10 mL)稀釋反應混合物，隨後用EtOAc (10 mL×2)萃取。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到呈淡黃色油狀之標題化合物(130 mg，粗物質)。 LC-MS方法1 0.825 min，MS (m/z) 267.0 (M + H ⁺)。 Example 37 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5- methyl -4,5- dihydro -1,2- oxazol -3- Base )-3- azabicyclo [3.1.0] hex - 3 -yl ] methanone (1R,5S,6r)-6-(5- methyl -4,5- dihydro - 1,2- oxazole -3- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino ) methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (200 mg, 0.77 mmol) in DMF (2 mL) was added prop-1-ene (4.6 mL, 2.3 mmol) and _Et3N (0.38 mL, 2.3 mmol). The resulting mixture was stirred at 20°C for 16 hours to obtain a pale yellow mixture. The reaction mixture was diluted with H ₂ O (10 mL), followed by extraction with EtOAc (10 mL×2). The combined organic layers were separated, then dried over _Na2SO4 and concentrated _in vacuo to give the title compound (130 mg, crude) as a light yellow oil. LC-MS method 1 0.825 min, MS (m/z) 267.0 (M + H ⁺ ).

(1R,5S,6r)-6-(5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷氫氯化物向(1R,5S,6r)-6-(5-甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(130 mg，0.49 mmol)添加HCl/二㗁烷(3 mL，0.49 mmol)。在0℃下攪拌反應混合物30 min，得到淡黃色混合物。直接將反應混合物濃縮至乾燥，得到標題化合物(90mg，粗物質)。 (1R,5S,6r)-6-(5- Methyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexane hydrochloride To (1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3 - tert-Butylcarboxylate (130 mg, 0.49 mmol) Add HCl/dioxane (3 mL, 0.49 mmol). The reaction mixture was stirred at 0 °C for 30 min to obtain a pale yellow mixture. The reaction mixture was directly concentrated to dryness to afford the title compound (90 mg, crude).

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向(1R,5S,6r)-6-(5-甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(50 mg，0.30 mmol)於DMF (0.50 mL)中之混合物添加DIPEA (0.2 mL，1.2 mmol)、1-異丙基咪唑-4-羧酸(46.38mg，0.30 mmol)及HATU (148.6mg，0.39 mmol)。在20℃下攪拌所得混合物16小時，得到褐色混合物。TLC (PE/EtOAc = 0/1)展示一連串新樣點且1-異丙基咪唑-4-羧酸(46.38mg，0.30 mmol)完全耗盡。LCMS偵測到所要MS。用H ₂O (5 mL)稀釋反應混合物且用EtOAc (5 mL×2)萃取，隨後用H ₂O (5 mL)及鹽水(5 mL×2)洗滌。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到粗產物。藉由製備型HPLC (NH ₃)純化粗產物，得到呈白色固體狀之標題化合物(5mg，0.0165 mmol，5.4972%產率)。 ¹H NMR (400MHz, MeOH) δ = 7.69 (br d, J=14.6 Hz, 2H), 4.76 - 4.73 (m, 1H), 4.74 - 4.73 (m, 1H), 4.42 (td, J=6.6, 13.4 Hz, 1H), 4.26 (br d, J=11.4 Hz, 1H), 4.08 - 3.98 (m, 1H), 3.86 (br dd, J=3.6, 11.6 Hz, 1H), 3.54 (br d, J=9.9 Hz, 1H), 3.02 - 2.89 (m, 1H), 2.44 (dd, J=8.1, 16.9 Hz, 1H), 2.13 - 1.95 (m, 2H), 1.42 (d, J=6.6 Hz, 6H), 1.18 (d, J=6.3 Hz, 3H) (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5- methyl -4,5- dihydro -1,2- oxazol - 3- yl ) -3- Azabicyclo [3.1.0] hex -3- yl ] methanone to (1R,5S,6r)-6-(5-methyl-4,5-dihydro-1,2-oxazole- To a mixture of 3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50 mg, 0.30 mmol) in DMF (0.50 mL) was added DIPEA (0.2 mL, 1.2 mmol), 1-isopropyl Cimidazole-4-carboxylic acid (46.38 mg, 0.30 mmol) and HATU (148.6 mg, 0.39 mmol). The resulting mixture was stirred at 20°C for 16 hours to give a brown mixture. TLC (PE/EtOAc=0/1) showed a series of fresh spots and complete consumption of 1-isopropylimidazole-4-carboxylic acid (46.38 mg, 0.30 mmol). LCMS detected the desired MS. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (5 mL×2), then washed with H ₂ O (5 mL) and brine (5 mL×2). The combined organic layers were separated, then dried over _Na2SO4 and concentrated in vacuo to give _crude product. The crude product was purified by preparative HPLC ( _NH3 ) to afford the title compound (5 mg, 0.0165 mmol, 5.4972% yield) as a white solid. ¹ H NMR (400MHz, MeOH) δ = 7.69 (br d, J =14.6 Hz, 2H), 4.76 - 4.73 (m, 1H), 4.74 - 4.73 (m, 1H), 4.42 (td, J =6.6, 13.4 Hz, 1H), 4.26 (br d, J =11.4 Hz, 1H), 4.08 - 3.98 (m, 1H), 3.86 (br dd, J =3.6, 11.6 Hz, 1H), 3.54 (br d, J =9.9 Hz, 1H), 3.02 - 2.89 (m, 1H), 2.44 (dd, J =8.1, 16.9 Hz, 1H), 2.13 - 1.95 (m, 2H), 1.42 (d, J =6.6 Hz, 6H), 1.18 (d, J =6.3 Hz, 3H)

實例 38      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(0.24 mL，24.32 mmol)之溶液添加於THF (15 mL)及Et ₃N (0.51 mL，3.65 mmol)中之亞甲基環丙烷(300 mg，1.22 mmol)。在0℃下攪拌反應混合物16小時，得到黃色溶液。LCMS展示新峰值給出所要MS。用H ₂O (30 mL)稀釋反應混合物且用EtOAc (30 mL ×2)萃取。合併之有機層經Na ₂SO ₄乾燥且濃縮，得到呈黃色油狀之標題化合物(260mg，0.9341 mmol，76.809%產率)。 LC-MS方法1 0.845min，MS (m/z) 279 (M + H ⁺)。 Example 38 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(4- oxa -5- azaspiro [2.4] hept -5- ene - 6- Base )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (1R,5S,6r)-6-(4- oxa -5- azaspiro [2.4] hept - 5 - ene -6- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino ) A solution of methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.24 mL, 24.32 mmol) was added in THF (15 mL) and Et ₃ N (0.51 mL, Methylenecyclopropane (300 mg, 1.22 mmol) in 3.65 mmol). The reaction mixture was stirred at 0 °C for 16 hours to give a yellow solution. LCMS showed a new peak giving the desired MS. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give the title compound (260 mg, 0.9341 mmol, 76.809% yield) as a yellow oil. LC-MS method 1 0.845 min, MS (m/z) 279 (M + H ⁺ ).

6-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 TFA 鹽向(1R,5S,6r)-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(260 mg，0.93 mmol)於DCM (16.25 mL)中之溶液添加2,2,2-三氟乙酸(0.07 mL，0.93 mmol)。在10℃下攪拌反應混合物3小時，得到黃色溶液。LCMS展示新峰值給出所要MS。在真空中蒸發反應混合物，得到呈黃色油狀之標題化合物(272mg，0.9307 mmol，99.64%產率)。產物直接用於下一步驟。 LC-MS方法1 0.178 min，MS (m/z) 179.1 (M + H ⁺)。 6-[(1R,5S,6r)-3- azabicyclo [3.1.0] hex -6- yl ]-4- oxa -5- azaspiro [2.4] hept -5- ene TFA salt to ( 1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[3.1.0]hexane-3-carboxy To a solution of tert-butyl acid ester (260 mg, 0.93 mmol) in DCM (16.25 mL) was added 2,2,2-trifluoroacetic acid (0.07 mL, 0.93 mmol). The reaction mixture was stirred at 10 °C for 3 hours to obtain a yellow solution. LCMS showed a new peak giving the desired MS. The reaction mixture was evaporated in vacuo to afford the title compound (272 mg, 0.9307 mmol, 99.64% yield) as a yellow oil. The product was used directly in the next step. LC-MS method 1 0.178 min, MS (m/z) 179.1 (M + H ⁺ ).

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向100 ml圓底燒瓶裝入1-異丙基咪唑-4-羧酸(143.49mg，0.93 mmol)、HATU (426.97mg，1.12 mmol)、DMF (4.5916 mL)及N-乙基-N-異丙基丙-2-胺(0.48 mL，2.79 mmol)。在攪拌30min之後，添加6-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-4-氧雜-5-氮雜螺[2.4]庚-5-烯TFA鹽(272 mg，0.93 mmol)。在10℃下攪拌反應混合物16小時，得到黃色溶液。LCMS展示反應物完全耗盡及所要MS。用H ₂O (20 mL)稀釋反應混合物且用EtOAc (30 mL × 2)萃取。合併之有機層經Na ₂SO ₄乾燥且濃縮，得到黃色油狀物。藉由製備型HPLC (FA)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(14.67mg，0.0467 mmol，5.0137%產率)。 LC-MS方法1: 315.1 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.67 (s, 1H), 7.48 (s, 1H), 4.73 (br d, J=12.0 Hz, 1H), 4.41 - 4.27 (m, 1H), 4.20 (br d, J=12.4 Hz, 1H), 3.95 (br dd, J=4.0, 12.0 Hz, 1H), 3.62 (br dd, J=4.0, 12.0 Hz, 1H), 2.96 (s, 2H), 2.80 (s, 1H), 2.12 (br d, J=3.0 Hz, 1H), 2.03 (br d, J=3.5 Hz, 1H), 1.50 (d, J=6.4 Hz, 6H), 1.14 - 1.08 (m, 2H), 0.73 - 0.67 (m, 2H) (1- isopropyl -1H- imidazol -4- yl ) [(1R,5S,6r)-6-(4- oxa- 5- azaspiro [2.4] hept -5- en -6- yl ) -3- Azabicyclo [3.1.0] hex -3- yl ] methanone 1-isopropylimidazole-4-carboxylic acid (143.49 mg, 0.93 mmol), HATU (426.97 mg , 1.12 mmol), DMF (4.5916 mL) and N-ethyl-N-isopropylpropan-2-amine (0.48 mL, 2.79 mmol). After stirring for 30 min, 6-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5 was added -ene TFA salt (272 mg, 0.93 mmol). The reaction mixture was stirred at 10 °C for 16 hours to obtain a yellow solution. LCMS showed complete consumption of reactants and desired MS. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were dried over _Na2SO4 and _concentrated to give a yellow oil. The crude material was purified by preparative HPLC (FA). The resulting fluid was concentrated in vacuo to remove most of the _CH3CN and lyophilized to give the title compound (14.67 mg, 0.0467 mmol, 5.0137% yield) as a white solid. LC-MS method 1: 315.1 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.67 (s, 1H), 7.48 (s, 1H), 4.73 (br d, J =12.0 Hz, 1H ), 4.41 - 4.27 (m, 1H), 4.20 (br d, J =12.4 Hz, 1H), 3.95 (br dd, J =4.0, 12.0 Hz, 1H), 3.62 (br dd, J =4.0, 12.0 Hz , 1H), 2.96 (s, 2H), 2.80 (s, 1H), 2.12 (br d, J =3.0 Hz, 1H), 2.03 (br d, J =3.5 Hz, 1H), 1.50 (d, J = 6.4 Hz, 6H), 1.14 - 1.08 (m, 2H), 0.73 - 0.67 (m, 2H)

實例 39      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5- 氧雜 -6- 氮雜螺 [3.4] 辛 -6- 烯 -7- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6-(5- 氧雜 -6- 氮雜螺 [3.4] 辛 -6- 烯 -7- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(E)-(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯於DMF (1.5 mL)中之混合物添加亞甲基環丁烷(78.4 mg，1.15 mmol)。在20℃下攪拌懸浮液16小時。用H ₂O (10 mL)淬滅反應混合物。用EtOAc (20 mL×3)稀釋殘餘物，用飽和NaCl (5 mL)洗滌，用無水Na ₂SO ₄乾燥，過濾且真空濃縮，得到呈黃色粉末狀之標題化合物(46 mg，粗物質)。 LC-MS方法1: 0.818 min，MS (m/z): 237.0 (M-56 + H ⁺)。 Example 39 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5- oxa -6- azaspiro [3.4] oct - 6 - ene -7- Base )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (1R,5S,6r)-6-(5- oxa -6- azaspiro [3.4] oct - 6 - ene -7- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-[(E)-(hydroxyimino)methyl To a mixture of tert-butyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate in DMF (1.5 mL) was added methylenecyclobutane (78.4 mg, 1.15 mmol). The suspension was stirred at 20°C for 16 hours. The reaction mixture was quenched with _H2O (10 mL). The residue was diluted with EtOAc (20 mL x 3), washed with sat. NaCl (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (46 mg, crude) as a yellow powder. LC-MS method 1: 0.818 min, MS (m/z): 237.0 (M-56 + H ⁺ ).

7-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-5- 氧雜 -6- 氮雜螺 [3.4] 辛 -6- 烯 TFA 鹽向(1R,5S,6r)-6-(5-氧雜-6-氮雜螺[3.4]辛-6-烯-7-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(46.0 mg，0.16 mmol)於DCM (1.5 mL)中之混合物添加2,2,2-三氟乙酸(17.9 mg，0.16 mmol)。在20℃下攪拌懸浮液2小時。在減壓下濃縮反應混合物，得到標題化合物。 LC-MS方法1: 0.822 min，MS (m/z): 193.0 (M + H ⁺)。 7-[(1R,5S,6r)-3- azabicyclo [3.1.0] hex -6- yl ]-5- oxa -6- azaspiro [3.4] oct -6- ene TFA salt to ( 1R,5S,6r)-6-(5-Oxa-6-azaspiro[3.4]oct-6-en-7-yl)-3-azabicyclo[3.1.0]hexane-3-carboxy To a mixture of tert-butyl acid ester (46.0 mg, 0.16 mmol) in DCM (1.5 mL) was added 2,2,2-trifluoroacetic acid (17.9 mg, 0.16 mmol). The suspension was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound. LC-MS method 1: 0.822 min, MS (m/z): 193.0 (M + H ⁺ ).

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5- 氧雜 -6- 氮雜螺 [3.4] 辛 -6- 烯 -7- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向7-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-5-氧雜-6-氮雜螺[3.4]辛-6-烯TFA鹽(30.0 mg，0.16 mmol)於吡啶(0.5 mL)中之混合物添加EDCI (29.9 mg，0.16 mmol)及1-異丙基咪唑-4-羧酸(24.1 mg，0.16 mmol)。在20℃下攪拌懸浮液16小時。用H ₂O (10 mL)淬滅反應混合物。用EtOAc (20 mL×3)稀釋殘餘物，用飽和NaCl (5 mL)洗滌，用無水Na ₂SO ₄乾燥，過濾且真空濃縮。藉由製備型HPLC (NH ₃)純化溶液且凍乾，得到呈黃色固體狀之標題化合物(6.49 mg，12.7%產率)。 LC-MS方法1: 2.386 min，MS (m/z): 329.2 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.69 (d, J=1.51 Hz, 1 H), 7.49 (d, J=1.51 Hz, 1 H), 4.75 (d, J=12.05 Hz, 1 H), 4.37 (dt, J=13.43, 6.84 Hz, 1 H), 4.20 (d, J=12.80 Hz, 1 H), 3.93 - 3.99 (m, 1 H), 3.63 (dd, J=12.92, 3.89 Hz, 1 H), 2.96 (s, 2 H), 2.48 (dt, J=12.55, 9.66 Hz, 2 H), 2.07 - 2.18 (m, 4 H), 2.02 (br d, J=9.03 Hz, 1 H), 1.76 - 1.85 (m, 1 H), 1.52 (d, J=6.78 Hz, 7 H), 1.49 (t, J=3.51 Hz, 1 H)。 (1- isopropyl -1H- imidazol -4- yl ) [(1R,5S,6r)-6-(5- oxa -6- azaspiro [3.4] oct -6- en -7- yl ) -3- Azabicyclo [3.1.0] hex -3- yl ] methanone to 7-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-5- A mixture of oxa-6-azaspiro[3.4]oct-6-ene TFA salt (30.0 mg, 0.16 mmol) in pyridine (0.5 mL) was added with EDCI (29.9 mg, 0.16 mmol) and 1-isopropylimidazole -4-Carboxylic acid (24.1 mg, 0.16 mmol). The suspension was stirred at 20°C for 16 hours. The reaction mixture was quenched with _H2O (10 mL). The residue was diluted with EtOAc (20 mL×3), washed with sat. NaCl (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The solution was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (6.49 mg, 12.7% yield) as a yellow solid. LC-MS method 1: 2.386 min, MS (m/z): 329.2 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.69 (d, J =1.51 Hz, 1 H), 7.49 (d, J =1.51 Hz, 1 H), 4.75 (d, J =12.05 Hz, 1 H ), 4.37 (dt, J =13.43, 6.84 Hz, 1 H), 4.20 (d, J =12.80 Hz, 1 H), 3.93 - 3.99 (m, 1 H), 3.63 (dd, J =12.92, 3.89 Hz , 1 H), 2.96 (s, 2 H), 2.48 (dt, J =12.55, 9.66 Hz, 2 H), 2.07 - 2.18 (m, 4 H), 2.02 (br d, J =9.03 Hz, 1 H ), 1.76 - 1.85 (m, 1 H), 1.52 (d, J =6.78 Hz, 7 H), 1.49 (t, J =3.51 Hz, 1 H).

實例 40      {(1R,5S,6r)-6-[5-( 二氟甲基 )-5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮 (1R,5S,6r)-6-[5-( 二羥甲基 )-5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(200 mg，0.77 mmol)及甲基丙烯醛(0.32 mL，3.84 mmol)於DMF (3 mL)中之溶液添加Et ₃N (0.22 mL，1.53 mmol)。在20℃下攪拌反應物12小時，得到淡黃色溶液。用EtOAc (15 mL)稀釋反應物，用飽和NaHCO ₃(10 mL)攪拌5min。用EtOAc (10 mL × 2)萃取水層。合併之DCM層經Na ₂SO ₄乾燥且真空濃縮，得到呈淡褐色油狀之標題化合物(240mg，0.7683 mmol，粗物質)。 Example 40 {(1R,5S,6r)-6-[5-( Difluoromethyl )-5- methyl -4,5- dihydro -1,2- oxazol -3- yl ]-3- nitrogen Heterobicyclo [3.1.0] hex -3- yl }(1- isopropyl -1H- imidazol -4- yl ) methanone (1R,5S,6r)-6-[5-( dimethylol )- 5- methyl -4,5- dihydro -1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S ,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (200 mg, 0.77 mmol ) and methacrolein (0.32 mL, 3.84 mmol) in DMF (3 mL) was added _Et3N (0.22 mL, 1.53 mmol). The reaction was stirred at 20°C for 12 hours to give a light yellow solution. The reaction was diluted with EtOAc (15 mL), stirred with saturated NaHCO ₃ (10 mL) for 5 min. The aqueous layer was extracted with EtOAc (10 mL x 2). The combined DCM layers were dried over _Na2SO4 and concentrated _in vacuo to give the title compound (240 mg, 0.7683 mmol, crude) as a light brown oil.

(1R,5S,6r)-6-[5-( 二氟甲基 )-5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在-78℃下向(1R,5S,6r)-6-[5-(二羥甲基)-5-甲基-4,5-二氫-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(240 mg，0.77 mmol)於DCM (10 mL)中之溶液添加DAST (371.11mg，2.31 mmol)。將反應物升溫至20℃且攪拌另外12小時，得到淡褐色溶液。將反應物再冷卻至             -78℃，用額外DAST (300 mg)處理且隨後升溫至20℃且攪拌另外12小時，得到淡褐色溶液。將反應物冷卻至0℃，用DCM (20 mL)稀釋，且用飽和NaHCO ₃(8 mL)淬滅。收集有機層，經Na ₂SO ₄乾燥，且真空濃縮，得到粗物質油，藉由製備型HPLC (HCl)純化該粗物質油。用飽和NaHCO ₃(2 mL)處理所獲得溶離劑且濃縮以移除MeCN。用EtOAc (10 mL × 2)萃取殘餘物。合併之EtOAc層經Na ₂SO ₄乾燥且真空濃縮，得到呈淡褐色膠質之標題化合物(55mg，0.1739 mmol，22.628%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 5.58 (t, J=56 Hz, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.56 (d, J = 11.2 Hz, 1H), 3.36-3.32 (m, 2H), 3.04 (dd, J = 17.2, 6.0 Hz, 1H), 2.60 (d, J = 17.2 Hz, 1H), 2.00-1.85 (m, 3H), 1.37 (s, 9H). 1.37 (s, 3H)。 (1R,5S,6r)-6-[5-( Difluoromethyl )-5- methyl -4,5- dihydro -1,2- oxazol -3- yl ]-3- azabicyclo [ 3.1.0] Hexane -3- carboxylic acid tertiary butyl ester at -78 ℃ to (1R,5S,6r)-6-[5-(dimethylol)-5-methyl-4,5- Dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (240 mg, 0.77 mmol) in DCM (10 mL) To the solution was added DAST (371.11 mg, 2.31 mmol). The reaction was warmed to 20 °C and stirred for an additional 12 hours to give a light brown solution. The reaction was recooled to -78°C, treated with additional DAST (300 mg) and then warmed to 20°C and stirred for an additional 12 hours to give a light brown solution. The reaction was cooled to 0 °C, diluted with DCM (20 mL), and quenched with saturated _NaHCO3 (8 mL). The organic layer was collected, dried over Na ₂ SO ₄ , and concentrated in vacuo to give a crude oil, which was purified by preparative HPLC (HCl). The resulting eluent was treated with saturated NaHCO ₃ (2 mL) and concentrated to remove MeCN. The residue was extracted with EtOAc (10 mL x 2). The combined EtOAc layers were dried over _Na2SO4 and concentrated _in vacuo to give the title compound (55 mg, 0.1739 mmol, 22.628% yield) as a light brown gum. ¹ H NMR (400MHz, chloroform-d) δ = 5.58 (t, J =56 Hz, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.56 (d, J = 11.2 Hz, 1H), 3.36- 3.32 (m, 2H), 3.04 (dd, J = 17.2, 6.0 Hz, 1H), 2.60 (d, J = 17.2 Hz, 1H), 2.00-1.85 (m, 3H), 1.37 (s, 9H). 1.37 (s, 3H).

{(1R,5S,6r)-6-[5-( 二氟甲基 )-5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮向(1R,5S,6r)-6-[5-(二氟甲基)-5-甲基-4,5-二氫-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(55 mg，0.17 mmol)於DCM (2 ml)中之溶液添加MeSO ₃H (33.38mg，0.35 mmol)。在20℃下攪拌反應物1h，得到淡黃色溶液。添加DMF (1 mL)，繼之以1-異丙基咪唑-4-羧酸(32.17mg，0.21 mmol)、HATU (66.47mg，0.17 mmol)及Et ₃N (0.12 mL，0.87 mmol)。在20℃下攪拌所得混合物12小時，得到黃色混合物。濃縮反應物且藉由製備型HPLC (NH ₃)純化。濃縮所獲得溶離劑且凍乾，得到呈淡黃色固體狀之標題化合物(7.01mg，0.0199 mmol，11.442%產率)。 LC-MS方法1: 353.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.60 (d, J=1.4 Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 5.78 - 5.37 (m, 1H), 4.70 (d, J=12.1 Hz, 1H), 4.28 (quin, J=6.7 Hz, 1H), 4.13 (d, J=12.4 Hz, 1H), 3.87 (br d, J=10.0 Hz, 1H), 3.54 (dd, J=3.9, 12.4 Hz, 1H), 3.05 (d, J=17.4 Hz, 1H), 2.61 (br dd, J=7.8, 17.6 Hz, 1H), 2.04 (br s, 1H), 1.99 - 1.89 (m, 1H), 1.43 (d, J=6.6 Hz, 6H), 1.38 (m, 3H) {(1R,5S,6r)-6-[5-( Difluoromethyl )-5- methyl -4,5- dihydro -1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0] Hex -3- yl }(1- isopropyl -1H- imidazol -4- yl ) methanone to (1R,5S,6r)-6-[5-(difluoromethyl)-5 -Methyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (55 mg, 0.17 mmol ) in DCM (2 ml) was added _MeSO3H (33.38 mg, 0.35 mmol). The reaction was stirred at 20 °C for 1 h to give a pale yellow solution. DMF (1 mL) was added followed by 1-isopropylimidazole-4-carboxylic acid (32.17 mg, 0.21 mmol), HATU (66.47 mg, 0.17 mmol) and Et ₃ N (0.12 mL, 0.87 mmol). The resulting mixture was stirred at 20°C for 12 hours to give a yellow mixture. The reaction was concentrated and purified by preparative HPLC (NH ₃ ). The obtained eluent was concentrated and lyophilized to afford the title compound (7.01 mg, 0.0199 mmol, 11.442% yield) as a light yellow solid. LC-MS method 1: 353.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.60 (d, J =1.4 Hz, 1H), 7.40 (d, J =1.4 Hz, 1H), 5.78 - 5.37 (m, 1H), 4.70 (d, J =12.1 Hz, 1H), 4.28 (quin, J =6.7 Hz, 1H), 4.13 (d, J =12.4 Hz, 1H), 3.87 (br d, J =10.0 Hz, 1H), 3.54 (dd, J =3.9, 12.4 Hz, 1H), 3.05 (d, J =17.4 Hz, 1H), 2.61 (br dd, J =7.8, 17.6 Hz, 1H), 2.04 ( br s, 1H), 1.99 - 1.89 (m, 1H), 1.43 (d, J =6.6 Hz, 6H), 1.38 (m, 3H)

實例 41      [(1R,5S,6r)-6-(5- 乙基 -5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮 (1R,5S,6r)-6-(5- 乙基 -5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯於DMF (1.5 mL)中之溶液添加2-甲基丁-1-烯(403.48 mg，5.75 mmol)、Et ₃N (116.4 mg，1.15 mmol，0.16 mL)。在20℃下攪拌懸浮液16小時。用H ₂O (10 mL)淬滅反應混合物。用EtOAc (20 mL × 3)萃取殘餘物。用飽和NaCl (5 mL)洗滌合併之有機層，用無水Na ₂SO ₄乾燥，過濾且真空濃縮。藉由製備型TLC (PE:EtOAc=2:1，Rf=0.5)純化殘餘物，得到呈黃色粉末狀之標題化合物(76 mg，粗物質)。 LC-MS方法1: 0.833 min，MS (m/z): 239.0 (M - 56 + H ⁺)。 Example 41 [(1R,5S,6r)-6-(5- Ethyl -5- methyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1 .0] hex -3- yl ](1- isopropyl -1H- imidazol -4- yl ) methanone (1R,5S,6r)-6-(5- ethyl - 5- methyl -4,5 -Dihydro - 1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-[( Z)-Chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester in DMF (1.5 mL) was added with 2-methyl But-1-ene (403.48 mg, 5.75 mmol), _Et3N (116.4 mg, 1.15 mmol, 0.16 mL). The suspension was stirred at 20°C for 16 hours. The reaction mixture was quenched with _H2O (10 mL). The residue was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with sat. NaCl (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by prep-TLC (PE:EtOAc=2:1, Rf=0.5) to give the title compound (76 mg, crude) as a yellow powder. LC-MS method 1: 0.833 min, MS (m/z): 239.0 (M − 56 + H ⁺ ).

(1R,5S,6r)-6-(5- 乙基 -5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽在20℃下攪拌化合物(1R,5S,6r)-6-(5-乙基-5-甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(76.0 mg，0.26 mmol)、2,2,2-三氟乙酸(29.4mg，0.16 mmol)於DCM (1 mL)中之混合物2小時。在減壓下濃縮反應混合物，得到呈褐色油狀之標題化合物。 LC-MS方法1: 0.357min，MS (m/z): 195.0 (M + H ⁺)。 (1R,5S,6r)-6-(5- Ethyl -5- methyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] Hexane TFA salt was stirred at 20°C for the compound (1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)- 3-Azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (76.0 mg, 0.26 mmol), 2,2,2-trifluoroacetic acid (29.4 mg, 0.16 mmol) in DCM (1 mL ) in the mixture for 2 hours. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown oil. LC-MS method 1: 0.357min, MS (m/z): 195.0 (M + H ⁺ ).

[(1R,5S,6r)-6-(5- 乙基 -5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮向(1R,5S,6r)-6-(5-乙基-5-甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(50.0 mg，0.26 mmol)於吡啶(2 mL)中之溶液添加EDCI (49.3 mg，0.26 mmol)、1-異丙基咪唑-4-羧酸(39.7 mg，0.26 mmol)。在20℃下攪拌懸浮液16小時。用H ₂O (10 mL)淬滅反應混合物。用EtOAc (20 mL × 3)萃取殘餘物，用飽和NaCl (5 mL)洗滌，用無水Na ₂SO ₄乾燥，過濾且真空濃縮。藉由製備型HPLC (NH ₃)純化殘餘物且凍乾，獲得呈黃色固體狀之標題化合物(5.77 mg，6.8 %產率)。 LC-MS方法1: 2.693 min，MS (m/z): 331.2 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.59 (s, 1 H), 7.40 (s, 1 H), 4.64 (s, 1 H), 4.28 (s, 1 H), 4.12 (br d, J=12.63 Hz, 1 H), 3.86 (br d, J=12.38 Hz, 1 H), 3.51 - 3.57 (m, 1 H), 2.59 - 2.65 (m, 1 H), 2.44 - 2.51 (m, 1 H), 2.00 (br s, 1 H), 1.90 (br s, 1 H), 1.54 - 1.61 (m, 3 H), 1.46 - 1.50 (m, 7 H), 1.43 (d, J=6.63 Hz, 7 H), 1.38 (t, J=3.25 Hz, 1 H), 1.25 (s, 4 H), 1.18 (s, 3 H), 0.85 (t, J=7.44 Hz, 4 H)。 [(1R,5S,6r)-6-(5- Ethyl -5- methyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ](1- isopropyl -1H- imidazol -4- yl ) methanone to (1R,5S,6r)-6-(5-ethyl-5-methyl-4,5- To a solution of dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane TFA salt (50.0 mg, 0.26 mmol) in pyridine (2 mL) was added EDCI (49.3 mg , 0.26 mmol), 1-isopropylimidazole-4-carboxylic acid (39.7 mg, 0.26 mmol). The suspension was stirred at 20°C for 16 hours. The reaction mixture was quenched with _H2O (10 mL). The residue was extracted with EtOAc (20 mL x 3), washed with sat. NaCl (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (5.77 mg, 6.8% yield) as a yellow solid. LC-MS method 1: 2.693 min, MS (m/z): 331.2 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.59 (s, 1 H), 7.40 (s, 1 H), 4.64 (s, 1 H), 4.28 (s, 1 H), 4.12 (br d, J =12.63 Hz, 1 H), 3.86 (br d, J =12.38 Hz, 1 H), 3.51 - 3.57 (m, 1 H), 2.59 - 2.65 (m, 1 H), 2.44 - 2.51 (m, 1 H), 2.00 (br s, 1 H), 1.90 (br s, 1 H), 1.54 - 1.61 (m, 3 H), 1.46 - 1.50 (m, 7 H), 1.43 (d, J =6.63 Hz, 7 H), 1.38 (t, J =3.25 Hz, 1 H), 1.25 (s, 4 H), 1.18 (s, 3 H), 0.85 (t, J =7.44 Hz, 4 H).

實例 42      {(1R,5S,6r)-6-[(5R)-5- 乙基 -5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮 實例 43      {(1R,5S,6r)-6-[(5S)-5- 乙基 -5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮在實例41中之製備之過程期間分別獲得實例42及43中之化合物。其藉由SFC純化與實例41之最終步驟隔離，該等化合物為{(1R,5S,6r)-6-[(5R)-5-乙基-5-甲基-4,5-二氫-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己-3-基}(1-異丙基-1H-咪唑-4-基)甲酮(63.41 mg，0.19 mmol，9.3%產率)及呈白色固體狀之{(1R,5S,6r)-6-[(5S)-5-乙基-5-甲基-4,5-二氫-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己-3-基}(1-異丙基-1H-咪唑-4-基)甲酮(69.78 mg，0.21 mmol，10.2%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 7.66 (s, 1H), 7.48 (s, 1H), 4.74 (br d, J=11.8 Hz, 1H), 4.36 (spt, J=6.7 Hz, 1H), 4.19 (d, J=12.5 Hz, 1H), 3.94 (dd, J=4.0, 12.0 Hz, 1H), 3.61 (dd, J=4.1, 12.4 Hz, 1H), 2.74 - 2.63 (m, 1H), 2.60 - 2.48 (m, 1H), 2.15 - 2.02 (m, 1H), 2.01 - 1.90 (m, 1H), 1.66 - 1.58 (m, 2H), 1.50 (d, J=6.8 Hz, 6H), 1.45 (t, J=3.4 Hz, 1H), 1.32 (s, 3H), 0.92 (t, J=7.5 Hz, 3H) Example 42 {(1R,5S,6r)-6-[(5R)-5- ethyl -5- methyl -4,5- dihydro -1,2- oxazol -3- yl ]-3- nitrogen Heterobicyclo [3.1.0] hex -3- yl }(1- isopropyl -1H- imidazol -4- yl ) methanone Example 43 {(1R,5S,6r)-6-[(5S)-5- Ethyl -5- methyl -4,5- dihydro -1,2- oxazol - 3- yl ]-3- azabicyclo [3.1.0] hex -3- yl } (1- isopropyl- 1H- Imidazol -4- yl ) methanone During the course of the preparation in Example 41 the compounds in Examples 42 and 43 were obtained respectively. It was isolated by SFC purification from the final step of Example 41, the compounds were {(1R,5S,6r)-6-[(5R)-5-ethyl-5-methyl-4,5-dihydro- 1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone (63.41 mg, 0.19 mmol, 9.3% yield) and {(1R,5S,6r)-6-[(5S)-5-ethyl-5-methyl-4,5-dihydro-1,2- Zazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}(1-isopropyl-1H-imidazol-4-yl)methanone (69.78 mg, 0.21 mmol, 10.2% Yield). ¹ H NMR (400MHz, chloroform-d) δ = 7.66 (s, 1H), 7.48 (s, 1H), 4.74 (br d, J =11.8 Hz, 1H), 4.36 (spt, J =6.7 Hz, 1H) , 4.19 (d, J =12.5 Hz, 1H), 3.94 (dd, J =4.0, 12.0 Hz, 1H), 3.61 (dd, J =4.1, 12.4 Hz, 1H), 2.74 - 2.63 (m, 1H), 2.60 - 2.48 (m, 1H), 2.15 - 2.02 (m, 1H), 2.01 - 1.90 (m, 1H), 1.66 - 1.58 (m, 2H), 1.50 (d, J =6.8 Hz, 6H), 1.45 ( t, J =3.4 Hz, 1H), 1.32 (s, 3H), 0.92 (t, J =7.5 Hz, 3H)

實例 44      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯 -4- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己烷 -6- 羧酸乙酯氫氯化物向6-乙基3-(三級丁基)(1R,5S,6r)-3-氮雜雙環[3.1.0]己烷-3,6-二羧酸酯(3.5g，13.71 mmol)添加HCl/二㗁烷(50. mL，3 mmol)。在30℃下攪拌混合物2小時，得到褐色溶液。TLC (PE:EtOAc=5:1)展示新樣點。直接濃縮反應混合物，得到呈黑色固體狀之標題化合物(2.5g，13.044 mmol，95.15%產率)。 6- 乙基 3-[2-( 三甲基矽烷基 ) 乙基 ](1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己烷 -3,6- 二羧酸酯在0℃下向(1R,5S,6r)-3-氮雜雙環[3.1.0]己烷-6-羧酸乙酯氫氯化物(2.5g，13.04 mmol)於DCM (20.27 mL)中之溶液添加DIPEA (10.78 mL，65.22 mmol)。隨後向混合物添加於DCM (20.27 mL)中之2,5-二側氧基吡咯啶-1-基(2-(三甲基矽烷基)乙基)碳酸酯(4.06g，15.65 mmol)，在30℃下攪拌12小時，得到褐色懸浮液。TLC (PE:EtOAc=3:1)展示新樣點。直接濃縮反應混合物。藉由快速柱(PE至20% EtOAc/PE)純化粗產物，得到呈黃色油狀之標題化合物(3.5g，11.688 mmol，89.609%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 4.20-4.10 (m, 4H), 3.73 (d, J = 11.2 Hz, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.49 (t, J = 11.2 Hz, 2H), 2.12 (s, 2 H), 1.48 (d, J = 3.2 Hz, 1H), 1.28 (t, J = 6.8 Hz, 3H), 1.00-0.90 (, 2H), 0.03 (s, 9H)。 Example 44 (1- isopropyl - 1H- imidazol -4- yl )[(1R,5S,6r)-6-(2- oxa -3- azabicyclo [3.1.0] hex -3- ene- 4- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (1R,5S,6r)-3- azabicyclo [3.1.0] hexane -6- carboxylic acid ethyl ester Hydrochloride to 6-ethyl 3-(tertiary butyl)(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (3.5g, 13.71 mmol) HCl/dioxane (50. mL, 3 mmol) was added. The mixture was stirred at 30 °C for 2 hours to obtain a brown solution. TLC (PE:EtOAc=5:1) showed a new spot. The reaction mixture was directly concentrated to afford the title compound (2.5 g, 13.044 mmol, 95.15% yield) as a black solid. 6- Ethyl 3-[2-( trimethylsilyl ) ethyl ](1R,5S,6r)-3- azabicyclo [3.1.0] hexane -3,6- dicarboxylate in 0 To a solution of (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester hydrochloride (2.5 g, 13.04 mmol) in DCM (20.27 mL) was added DIPEA (10.78 mL, 65.22 mmol). 2,5-Dioxopyrrolidin-1-yl(2-(trimethylsilyl)ethyl)carbonate (4.06 g, 15.65 mmol) in DCM (20.27 mL) was then added to the mixture at Stirring at 30°C for 12 hours gave a brown suspension. TLC (PE:EtOAc=3:1) showed a new spot. The reaction mixture was directly concentrated. The crude product was purified by flash column (PE to 20% EtOAc/PE) to give the title compound (3.5 g, 11.688 mmol, 89.609% yield) as a yellow oil. ¹ H NMR (400MHz, chloroform-d) δ = 4.20-4.10 (m, 4H), 3.73 (d, J = 11.2 Hz, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.49 (t, J = 11.2 Hz, 2H), 2.12 (s, 2H), 1.48 (d, J = 3.2 Hz, 1H), 1.28 (t, J = 6.8 Hz, 3H), 1.00-0.90 (, 2H), 0.03 (s , 9H).

2-( 三甲基矽烷基 ) 乙基 (1R,5S,6r)-6-( 羥甲基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸酯在0℃下向6-乙基3-[2-(三甲基矽烷基)乙基](1R,5S,6r)-3-氮雜雙環[3.1.0]己烷-3,6-二羧酸酯(3.5g，11.69 mmol)於THF (40 mL)中之溶液添加LiAlH ₄(0.67g，17.53 mmol)。在0℃下攪拌混合物20 min，得到白色懸浮液。TLC (PE:EtOAc=1:1)展示反應完成。將反應混合物傾入H ₂O (0.6 mL)、1N NaOH水溶液(0.6 mL)、H ₂O (1.8 ml)中且過濾。濃縮濾液，得到黃色油狀物。藉由快速柱(PE至40% EtOAc/PE)純化粗產物，得到呈無色油狀物之標題化合物(1.2g，4.662 mmol，39.885%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 4.15 (dd, J = 8.8, 7.6 Hz, 2H), 3.67 (d, J = 10.8 Hz, 1H), 3.60 (d, J = 10.8 Hz, 1H), 3.60-3.45 (m, 2H), 3.41 (dt, J = 8.0, 4.0 Hz, 2H), 1.50-1.40 (m, 3H), 1.00-0.85 (m, 3H), 0.03 (s, 9H)。 2-( trimethylsilyl ) ethyl (1R,5S,6r)-6-( hydroxymethyl )-3- azabicyclo [3.1.0] hexane -3- carboxylate at 0℃ 6-Ethyl 3-[2-(trimethylsilyl)ethyl](1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (3.5 g, 11.69 mmol) in THF (40 mL) was added _LiAlH4 (0.67 g, 17.53 mmol). The mixture was stirred at 0 °C for 20 min to give a white suspension. TLC (PE:EtOAc=1:1) showed the reaction was complete. The reaction mixture was poured into _H2O (0.6 mL), 1N aqueous NaOH (0.6 mL), _H2O (1.8 ml) and filtered. The filtrate was concentrated to give a yellow oil. The crude product was purified by flash column (PE to 40% EtOAc/PE) to give the title compound (1.2 g, 4.662 mmol, 39.885% yield) as a colorless oil. ¹ H NMR (400MHz, chloroform-d) δ = 4.15 (dd, J = 8.8, 7.6 Hz, 2H), 3.67 (d, J = 10.8 Hz, 1H), 3.60 (d, J = 10.8 Hz, 1H), 3.60-3.45 (m, 2H), 3.41 (dt, J = 8.0, 4.0 Hz, 2H), 1.50-1.40 (m, 3H), 1.00-0.85 (m, 3H), 0.03 (s, 9H).

2-( 三甲基矽烷基 ) 乙基 (1R,5S,6r)-6- 甲醯基 -3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸酯在0℃下向2-(三甲基矽烷基)乙基(1R,5S,6r)-6-(羥甲基)-3-氮雜雙環[3.1.0]己烷-3-羧酸酯(1.2g，4.66 mmol)於DCM (15 mL)中之溶液添加DMP (2.97g，6.99 mmol)、NaHCO ₃(979.14mg，11.66 mmol)。在30℃下攪拌混合物2小時。TLC (PE:EtOAc=1:1)展示反應完成。將反應混合物傾入H ₂O (40 mL)中且用EtOAc (30 mL × 4)萃取。用NaHCO ₃水溶液(50 mL)及Na ₂SO ₃水溶液(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由快速柱(PE至30% EtOAc/PE)純化粗產物，得到呈褐色油狀之標題化合物(0.8200g，3.2108 mmol，68.871%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 9.46 (d, J = 4.0 Hz, 1H), 4.17 (dd, J = 7.6, 4.0 Hz, 2H), 3.80 (d, J = 11.6 Hz, 1H), 3.60 (d, J = 11.6 Hz, 1H), 3.54 (t, J = 11.6 Hz, 2H), 2.24 S, 2H), 1.83 (dd, J = 6.4, 3.2 Hz, 1H), 0.99 (dd, J = 7.6, 4.0 Hz, 2H), 0.03 (s, 9H)。 2-( trimethylsilyl ) ethyl (1R,5S,6r)-6- formyl -3- azabicyclo [3.1.0] hexane -3- carboxylate at 0°C to 2- (Trimethylsilyl)ethyl (1R,5S,6r)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.2g, 4.66 mmol) To a solution in DCM (15 mL) was added DMP (2.97 g, 6.99 mmol), NaHCO ₃ (979.14 mg, 11.66 mmol). The mixture was stirred at 30°C for 2 hours. TLC (PE:EtOAc=1:1) showed the reaction was complete. The reaction mixture was poured into H ₂ O (40 mL) and extracted with EtOAc (30 mL×4). The combined organic layers were washed with aqueous NaHCO ₃ (50 mL) and aqueous Na ₂ SO ₃ (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column (PE to 30% EtOAc/PE) to give the title compound (0.8200 g, 3.2108 mmol, 68.871% yield) as a brown oil. ¹ H NMR (400MHz, chloroform-d) δ = 9.46 (d, J = 4.0 Hz, 1H), 4.17 (dd, J = 7.6, 4.0 Hz, 2H), 3.80 (d, J = 11.6 Hz, 1H), 3.60 (d, J = 11.6 Hz, 1H), 3.54 (t, J = 11.6 Hz, 2H), 2.24 S, 2H), 1.83 (dd, J = 6.4, 3.2 Hz, 1H), 0.99 (dd, J = 7.6, 4.0 Hz, 2H), 0.03 (s, 9H).

2-( 三甲基矽烷基 ) 乙基 (1R,5S,6r)-6-[(E)-( 羥亞胺基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸酯向2-(三甲基矽烷基)乙基(1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸酯(820 mg，3.21 mmol)於EtOH (10 mL)中之溶液添加KOAc (315.11mg，3.21 mmol)、HOAc (0.18 mL，3.21 mmol)、NH ₂OH·HCl (0.17 mL，4.17 mmol)。在25℃下攪拌混合物3小時，得到白色懸浮液。TLC (PE:EtOAc=2:1)展示反應完成。在減壓下移除反應混合物。向殘餘物添加H ₂O (40 mL)且用EtOAc (30 mL × 4)萃取混合物。用飽和碳酸氫鈉(30 mL × 2)及飽和鹽水(40 mL×2)洗滌合併之有機相且經Na ₂SO ₄乾燥。在減壓下移除溶劑，得到呈褐色油狀之標題化合物(850mg，3.1435 mmol，97.904%產率)。 2-( Trimethylsilyl ) ethyl (1R,5S,6r)-6-[(E)-( hydroxyimino ) methyl ]-3- azabicyclo [3.1.0] hexane -3 -carboxylate to 2-(trimethylsilyl)ethyl ( 1R ,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (820 mg, 3.21 mmol) in EtOH (10 mL) was added KOAc (315.11 mg, 3.21 mmol), HOAc (0.18 mL, 3.21 mmol), _NH2OH ·HCl (0.17 mL, 4.17 mmol). The mixture was stirred at 25°C for 3 hours to give a white suspension. TLC (PE:EtOAc=2:1) showed the reaction was complete. The reaction mixture was removed under reduced pressure. To the residue was added H ₂ O (40 mL) and the mixture was extracted with EtOAc (30 mL×4). The combined organic phases were washed with saturated sodium bicarbonate (30 mL x 2) and saturated brine (40 mL x 2) and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to afford the title compound (850 mg, 3.1435 mmol, 97.904% yield) as a brown oil.

2-( 三甲基矽烷基 ) 乙基 (1R,5S,6r)-6-[(Z)- 氯基 ( 羥亞胺基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸酯向2-(三甲基矽烷基)乙基(1R,5S,6r)-6-[(E)-(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸酯(850 mg，3.14 mmol)於DMF (9 mL)中之溶液添加NCS (503.7mg，3.77 mmol)。在25℃下攪拌混合物3小時，得到褐色溶液。TLC (PE:EtOAc=2:1)展示反應完成。將反應混合物傾入H ₂O (40 mL)中且用EtOAc (30 mL × 4)萃取。用鹽水(50 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由快速柱(PE至30% EtOAc/PE)純化粗產物，得到呈無色油狀之標題化合物(750mg，2.4602 mmol，78.264%產率)。 2-( Trimethylsilyl ) ethyl (1R,5S,6r)-6-[(Z) -chloro ( hydroxyimino ) methyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylate to 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-3-azabicyclo[3.1 .0] A solution of hexane-3-carboxylate (850 mg, 3.14 mmol) in DMF (9 mL) was added with NCS (503.7 mg, 3.77 mmol). The mixture was stirred at 25 °C for 3 hours to give a brown solution. TLC (PE:EtOAc=2:1) showed the reaction was complete. The reaction mixture was poured into H ₂ O (40 mL) and extracted with EtOAc (30 mL×4). The combined organic layers were washed with brine (50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column (PE to 30% EtOAc/PE) to give the title compound (750 mg, 2.4602 mmol, 78.264% yield) as a colorless oil.

2-( 三甲基矽烷基 ) 乙基 (1R,5S,6r)-6-[5-( 氯甲基 )-4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸酯向2-(三甲基矽烷基)乙基(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸酯(400 mg，1.31 mmol)於DMF (5.3333 mL)中之溶液添加3-氯丙-1-烯(0.54 mL，6.56 mmol)及Et ₃N (0.51 mL，3.94 mmol)。在25℃下攪拌混合物12小時，得到褐色溶液。TLC (PE:EtOAc=3:1)展示反應完成。向混合物添加H ₂O (40 mL)，用EtOAc (30 mL × 4)萃取。用飽和鹽水(40 mL×2)洗滌合併之有機相且經Na ₂SO ₄乾燥。在減壓下移除溶劑。藉由快速柱(PE至20% EtOAc/PE)純化粗產物，得到呈無色油狀之標題化合物(160mg，0.4639 mmol，35.354%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 4.85-4.75 (m, 1H), 4.16 (dd, J = 9.2, 7.2 Hz, 2H), 3.76 (d, J = 11.2 Hz, 1H), 3.70 (d, J = 11.2 Hz, 1H), 3.61 (dd, J = 7.2, 4.0 Hz, 1H), 3.55-3.40 (m, 3H), 3.15-3.05 (m, 1H), 2.95-2.80 (m, 1H), 52.00 (brs, 2H), 1.50 (brs, 1H), 1.00 (dd, J = 9.2, 7.2 Hz, 2H), 0.05 (s, 9H)。 2-( Trimethylsilyl ) ethyl (1R,5S,6r)-6-[5-( chloromethyl )-4,5- dihydro -1,2- oxazol -3- yl ]-3 -Azabicyclo [3.1.0] hexane -3- carboxylate to 2- (trimethylsilyl)ethyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimine To a solution of methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (400 mg, 1.31 mmol) in DMF (5.3333 mL) was added 3-chloroprop-1-ene ( 0.54 mL, 6.56 mmol) and _Et3N (0.51 mL, 3.94 mmol). The mixture was stirred at 25°C for 12 hours to give a brown solution. TLC (PE:EtOAc=3:1) showed the reaction was complete. H ₂ O (40 mL) was added to the mixture, extracted with EtOAc (30 mL×4). The combined organic phases were washed with saturated brine (40 mL×2) and dried over Na ₂ SO ₄ . Solvent was removed under reduced pressure. The crude product was purified by flash column (PE to 20% EtOAc/PE) to give the title compound (160 mg, 0.4639 mmol, 35.354% yield) as a colorless oil. ¹ H NMR (400MHz, chloroform-d) δ = 4.85-4.75 (m, 1H), 4.16 (dd, J = 9.2, 7.2 Hz, 2H), 3.76 (d, J = 11.2 Hz, 1H), 3.70 (d , J = 11.2 Hz, 1H), 3.61 (dd, J = 7.2, 4.0 Hz, 1H), 3.55-3.40 (m, 3H), 3.15-3.05 (m, 1H), 2.95-2.80 (m, 1H), 52.00 (brs, 2H), 1.50 (brs, 1H), 1.00 (dd, J = 9.2, 7.2 Hz, 2H), 0.05 (s, 9H).

4-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯向2-(三甲基矽烷基)乙基(1R,5S,6r)-6-[5-(氯甲基)-4,5-二氫-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸酯(20 mg，0.06 mmol)於DMSO (1 mL)中之溶液添加t-BuOK (13.01mg，0.12 mmol)。在20℃下攪拌混合物30 min，得到褐色溶液。直接凍乾反應混合物，得到呈褐色固體狀之標題化合物(8mg，0.0487 mmol，84.022%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 4.90-4.80 (m, 1H), 4.04 (d, J = 12.4 Hz, 1H), 3.80-3.60 (m, 2H), 3.40-3.30 (m, 1H), 2.40-2.30 (m, 1H), 2.20-1.90 (m, 2H), 1.60-1.50 (m, 1H), 1.00-0.85 (m, 2H), 0.40-0.30 (m, 1H)。 4-[(1R,5S,6r)-3- azabicyclo [3.1.0] hex -6- yl ]-2- oxa -3- azabicyclo [3.1.0] hex -3- ene to 2 -(Trimethylsilyl)ethyl(1R,5S,6r)-6-[5-(chloromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-3- To a solution of azabicyclo[3.1.0]hexane-3-carboxylate (20 mg, 0.06 mmol) in DMSO (1 mL) was added t-BuOK (13.01 mg, 0.12 mmol). The mixture was stirred at 20 °C for 30 min to obtain a brown solution. The reaction mixture was directly lyophilized to afford the title compound (8 mg, 0.0487 mmol, 84.022% yield) as a brown solid. ¹ H NMR (400MHz, chloroform-d) δ = 4.90-4.80 (m, 1H), 4.04 (d, J = 12.4 Hz, 1H), 3.80-3.60 (m, 2H), 3.40-3.30 (m, 1H) , 2.40-2.30 (m, 1H), 2.20-1.90 (m, 2H), 1.60-1.50 (m, 1H), 1.00-0.85 (m, 2H), 0.40-0.30 (m, 1H).

(1- 異丙基 - 1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 - 3- 烯 -4- 基 )-3- 氮雜雙環 [3.1.0] 己 - 3- 基 ] 甲酮向4-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-2-氧雜-3-氮雜雙環[3.1.0]己-3-烯(30 mg，0.18 mmol)及1-異丙基咪唑-4-羧酸(27.75mg，0.18 mmol)於吡啶(2.9557 mL)中之溶液添加EDCI (44.86mg，0.23 mmol)。在25℃下攪拌混合物3小時，得到黃色溶液。LCMS展示所要MS作為主峰。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈黃色固體狀之標題化合物(7.58mg，0.0252 mmol，14.02%產率)。 LC-MS方法1: 301.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.68 (1 H, d, J=1.51 Hz), 7.48 (1 H, d, J=1.25 Hz), 4.85 (1 H, td, J=5.33, 2.13 Hz), 4.78 (1 H, br d, J=10.79 Hz), 4.36 (1 H, m, J=13.49, 6.68 Hz), 4.23 (1 H, br d, J=11.80 Hz), 3.98 (1 H, br dd, J=12.05, 4.52 Hz), 3.60 - 3.70 (1 H, m), 2.36 (1 H, dt, J=8.85, 4.49 Hz), 1.98 - 2.15 (2 H, m), 1.66 (1 H, br d, J=3.51 Hz), 1.51 (6 H, d, J=6.78 Hz), 0.85 - 0.89 (1 H, m), 0.31 (1 H, br s) (1- isopropyl - 1H- imidazol -4- yl )[(1R,5S,6r)-6-(2- oxa -3- azabicyclo [3.1.0] hex - 3 - ene - 4- Base )-3- azabicyclo [3.1.0] hex - 3- yl ] methanone to 4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]- 2-Oxa-3-azabicyclo[3.1.0]hex-3-ene (30 mg, 0.18 mmol) and 1-isopropylimidazole-4-carboxylic acid (27.75 mg, 0.18 mmol) in pyridine (2.9557 mL) was added EDCI (44.86 mg, 0.23 mmol). The mixture was stirred at 25°C for 3 hours to obtain a yellow solution. LCMS showed the desired MS as the main peak. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (7.58 mg, 0.0252 mmol, 14.02% yield) as a yellow solid. LC-MS method 1: 301.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.68 (1 H, d, J=1.51 Hz), 7.48 (1 H, d, J=1.25 Hz ), 4.85 (1 H, td, J=5.33, 2.13 Hz), 4.78 (1 H, br d, J=10.79 Hz), 4.36 (1 H, m, J=13.49, 6.68 Hz), 4.23 (1 H , br d, J=11.80 Hz), 3.98 (1 H, br dt, J=12.05, 4.52 Hz), 3.60 - 3.70 (1 H, m), 2.36 (1 H, dt, J=8.85, 4.49 Hz) , 1.98 - 2.15 (2 H, m), 1.66 (1 H, br d, J=3.51 Hz), 1.51 (6 H, d, J=6.78 Hz), 0.85 - 0.89 (1 H, m), 0.31 ( 1 H, br s)

實例 45      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(1- 甲基 -2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯 -4- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 2-( 三甲基矽烷基 ) 乙基 (1R,5 S,6r)-6-[5-( 氯甲基 )-5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸酯向2-(三甲基矽烷基)乙基(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸酯(150 mg，0.49 mmol)於DMF (2 mL)中之溶液添加3-氯-2-甲基丙-1-烯(0.24 mL，2.46 mmol)及Et ₃N (0.19 mL，1.48 mmol)。在25℃下攪拌混合物12小時，得到褐色混合物。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (15 mL × 4)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈褐色油狀之標題化合物(150 mg，0.4179 mmol，84.931%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 4.25-4.10 (m, 2H), 3.80-3.60 (m, 2H), 3.55-3.45 (m, 4H), 3.05 (d, J = 9.2 Hz, 1H), 2.65 (d, J = 9.2 Hz, 1H), 2.00-1.90 (m, 1H), 1.55-1.45 (m, 2H), 1.05 (s, 3H), 1.50-1.40 (m, 1H), 0.99 (t, J = 8.0 Hz, 2H), 0.04 (s, 9H)。 Example 45 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(1- methyl -2- oxa -3- azabicyclo [3.1.0] hexane -3- en -4- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 2-( trimethylsilyl ) ethyl (1R,5S ,6r)-6- [5-( Chloromethyl )-5- methyl -4,5- dihydro- 1,2- oxazol - 3- yl ]-3- azabicyclo [ 3.1.0] hexane -3- carboxylic acid Ester to 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0] To a solution of hexane-3-carboxylate (150 mg, 0.49 mmol) in DMF (2 mL) was added 3-chloro-2-methylprop-1-ene (0.24 mL, 2.46 mmol) and Et ₃ N ( 0.19 mL, 1.48 mmol). The mixture was stirred at 25°C for 12 hours to give a brown mixture. The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (15 mL×4). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (150 mg, 0.4179 mmol, 84.931% yield) as a brown oil. ¹ H NMR (400MHz, Chloroform-d) δ = 4.25-4.10 (m, 2H), 3.80-3.60 (m, 2H), 3.55-3.45 (m, 4H), 3.05 (d, J = 9.2 Hz, 1H) , 2.65 (d, J = 9.2 Hz, 1H), 2.00-1.90 (m, 1H), 1.55-1.45 (m, 2H), 1.05 (s, 3H), 1.50-1.40 (m, 1H), 0.99 (t , J = 8.0 Hz, 2H), 0.04 (s, 9H).

4-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-1- 甲基 -2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯向2-(三甲基矽烷基)乙基(1R,5S,6r)-6-[5-(氯甲基)-5-甲基-4,5-二氫-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸酯(130 mg，0.36 mmol)於DMSO (4 mL)中之溶液添加t-BuOK (81.28mg，0.72 mmol)。在20℃下攪拌混合物30 min，得到褐色溶液。直接凍乾反應混合物，得到呈褐色固體狀之標題化合物(60mg，0.3366 mmol，92.95%產率)。 4-[(1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl ]-1- methyl -2- oxa -3- azabicyclo [3.1.0 ] hex- 3- ene to 2-(trimethylsilyl)ethyl(1R,5S,6r)-6-[5-(chloromethyl)-5-methyl-4,5-dihydro-1,2- To a solution of oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (130 mg, 0.36 mmol) in DMSO (4 mL) was added t-BuOK (81.28 mg, 0.72 mmol). The mixture was stirred at 20 °C for 30 min to obtain a brown solution. The reaction mixture was directly lyophilized to afford the title compound (60 mg, 0.3366 mmol, 92.95% yield) as a brown solid.

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(1- 甲基 -2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯 -4- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向4-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-1-甲基-2-氧雜-3-氮雜雙環[3.1.0]己-3-烯(60 mg，0.34 mmol)及1-異丙基咪唑-4-羧酸(51.9mg，0.34 mmol)於吡啶(5 mL)中之溶液添加EDCI (129.07mg，0.67 mmol)。在25℃下攪拌混合物3小時，得到黃色溶液。直接濃縮混合物。藉由製備型HPLC (NH ₃)純化殘餘物。藉由製備型TLC (DCM:MeOH =15:1)純化所獲得固體，得到呈淡黃色固體狀之標題化合物(11.96mg，0.0380 mmol，11.301%產率)。 LC-MS方法1: 315.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.67 (1 H, s), 7.48 (1 H, s), 4.75 (1 H, br d, J=12.05 Hz), 4.36 (1 H, m, J=13.43, 6.84 Hz), 4.22 (1 H, br d, J=12.30 Hz), 3.97 (1 H, br d, J=12.05 Hz), 3.64 (1 H, br d, J=12.30 Hz), 2.08 (2 H, br d, J=3.76 Hz), 2.01 (1 H, br s), 1.67 (3 H, s), 1.51 (6 H, d, J=6.78 Hz), 0.90 (1 H, dd, J=9.41, 5.14 Hz), 0.33 - 0.43 (1 H, m) (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(1- methyl -2- oxa -3- azabicyclo [3.1.0] hexa -3 -en -4- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 4 - [(1R,5S,6r)-3-azabicyclo[3.1.0]hex- 6-yl]-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-ene (60 mg, 0.34 mmol) and 1-isopropylimidazole-4-carboxylic acid ( 51.9 mg, 0.34 mmol) in pyridine (5 mL) was added EDCI (129.07 mg, 0.67 mmol). The mixture was stirred at 25°C for 3 hours to give a yellow solution. The mixture was concentrated directly. The residue was purified by preparative HPLC ( _NH3 ). The obtained solid was purified by preparative TLC (DCM:MeOH=15:1 ) to give the title compound (11.96 mg, 0.0380 mmol, 11.301% yield) as a light yellow solid. LC-MS method 1: 315.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.67 (1 H, s), 7.48 (1 H, s), 4.75 (1 H, br d, J=12.05 Hz), 4.36 (1 H, m, J=13.43, 6.84 Hz), 4.22 (1 H, br d, J=12.30 Hz), 3.97 (1 H, br d, J=12.05 Hz), 3.64 (1 H, br d, J=12.30 Hz), 2.08 (2 H, br d, J=3.76 Hz), 2.01 (1 H, br s), 1.67 (3 H, s), 1.51 (6 H, d , J=6.78 Hz), 0.90 (1 H, dd, J=9.41, 5.14 Hz), 0.33 - 0.43 (1 H, m)

實例 46      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向Et ₃N (0.36 mL，2.18 mmol)及2-甲基丁-2-烯(1.16 mL，10.92 mmol)於THF中之溶液添加(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(200 mg，0.73 mmol)。在20℃下攪拌混合物16小時。用H ₂O (15 mL)稀釋混合物且用EtOAc (15 mL × 3)萃取。用鹽水(50 mL)洗滌有機相，經無水Na ₂SO ₄乾燥且濃縮，得到殘餘物。藉由快速柱(PE:EtOAc=1:0至0:1)純化殘餘物，得到呈黃色油狀之標題化合物(100 mg，0.3397 mmol，46.663%產率)。 Example 46 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(4,5,5- trimethyl -4,5- dihydro -1,2- Zazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (1R,5S,6r)-6-(4,5,5- trimethyl - 4,5 -Dihydro - 1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester was dissolved in Et ₃ N (0.36 mL, 2.18 mmol) and 2 - To a solution of methylbut-2-ene (1.16 mL, 10.92 mmol) in THF was added (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3- Azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (200 mg, 0.73 mmol). The mixture was stirred at 20°C for 16 hours. The mixture was diluted with H ₂ O (15 mL) and extracted with EtOAc (15 mL×3). The organic phase was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give a residue. The residue was purified by flash column (PE:EtOAc = 1:0 to 0:1) to give the title compound (100 mg, 0.3397 mmol, 46.663% yield) as a yellow oil.

(1R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽在20℃下攪拌(1R,5S,6r)-6-(4,5,5-三甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(160 mg，0.54 mmol)於TFA (0.5 mL，0.54 mmol)及DCM (2 mL)中之混合物40 min。真空濃縮反應混合物且隨後凍乾，得到呈黃色油狀之標題化合物(100 mg，粗產物)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.60-3.40 (m, 4H), 2.30-2.20 (m, 2H), 2.00-1.70 (m, 2H), 1.24 (s, 3H), 1.15 (s, 3H), 0.95 (d, J = 7.6 Hz, 3H)。 (1R,5S,6r)-6-(4,5,5- Trimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] Hexane TFA salt stirred at 20°C (1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3 - A mixture of tert-butyl azabicyclo[3.1.0]hexane-3-carboxylate (160 mg, 0.54 mmol) in TFA (0.5 mL, 0.54 mmol) and DCM (2 mL) for 40 min. The reaction mixture was concentrated in vacuo and then lyophilized to afford the title compound (100 mg, crude) as a yellow oil. ¹ H NMR (400MHz, chloroform-d) δ = 3.60-3.40 (m, 4H), 2.30-2.20 (m, 2H), 2.00-1.70 (m, 2H), 1.24 (s, 3H), 1.15 (s, 3H), 0.95 (d, J = 7.6 Hz, 3H).

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-異丙基咪唑-4-羧酸(39.68mg，0.26 mmol)於DMF (1 mL)中之混合物添加HATU (127.91mg，0.33 mmol)及DIPEA (0.21 mL，1.29 mmol)。在50℃下加熱混合物30 min。向混合物添加(1R,5S,6r)-6-(4,5,5-三甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(50 mg，0.26 mmol)。在20℃下攪拌所得混合物4小時。用H ₂O (10 mL)稀釋反應混合物且用EtOAc (10 mL×2)萃取，隨後用鹽水(10 mL)洗滌。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型HPLC (NH ₃)純化粗物質油且凍乾，得到呈白色固體狀之標題化合物(6mg，0.0182 mmol，7.0554%產率)。 ¹H NMR (400MHz, DMSO) δ = 7.98 (d, J=2.8 Hz, 2H), 4.79 (br d, J=12.5 Hz, 1H), 4.65 (td, J=6.8, 13.2 Hz, 1H), 4.17 - 4.10 (m, 1H), 4.01 (br d, J=13.1 Hz, 1H), 3.65 (br s, 1H), 3.02 (br d, J=6.5 Hz, 1H), 2.30 - 2.07 (m, 2H), 1.60 (d, J=6.5 Hz, 6H), 1.47 (br s, 1H), 1.48 - 1.45 (m, 1H), 1.40 (s, 3H), 1.31 (s, 3H), 1.22 (d, J=7.5 Hz, 3H) (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(4,5,5- trimethyl -4,5- dihydro -1,2- oxazole -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-isopropylimidazole-4-carboxylic acid (39.68 mg, 0.26 mmol) in DMF (1 mL) HATU (127.91 mg, 0.33 mmol) and DIPEA (0.21 mL, 1.29 mmol) were added to the mixture. The mixture was heated at 50 °C for 30 min. To the mixture was added (1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1 .0] Hexane TFA salt (50 mg, 0.26 mmol). The resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with EtOAc (10 mL×2), then washed with brine (10 mL). The combined organic _layers were separated, then dried over _Na2SO4 and concentrated in vacuo to give a crude oil. The crude oil was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (6 mg, 0.0182 mmol, 7.0554% yield) as a white solid. ¹ H NMR (400MHz, DMSO) δ = 7.98 (d, J =2.8 Hz, 2H), 4.79 (br d, J =12.5 Hz, 1H), 4.65 (td, J =6.8, 13.2 Hz, 1H), 4.17 - 4.10 (m, 1H), 4.01 (br d, J =13.1 Hz, 1H), 3.65 (br s, 1H), 3.02 (br d, J =6.5 Hz, 1H), 2.30 - 2.07 (m, 2H) , 1.60 (d, J =6.5 Hz, 6H), 1.47 (br s, 1H), 1.48 - 1.45 (m, 1H), 1.40 (s, 3H), 1.31 (s, 3H), 1.22 (d, J = 7.5Hz, 3H)

實例 47      (1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(4S)-4,5,5- 三甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 實例 48      (1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(4R)-4,5,5- 三甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮向1-異丙基咪唑-4-羧酸(476.15 mg，3.09mmol)於吡啶(8 mL)中之溶液添加EDCI (592.06 mg，3.09 mmol)及(1R,5S,6r)-6-(4,5,5-三甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷(400 mg，2.06 mmol)。在20至25℃下攪拌所得混合物2小時。LCMS展示所要MS (作為主峰)。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾。藉由SFC對掌性地分離產物且凍乾，獲得均呈黃色膠質之(1-異丙基-1H-咪唑-4-基){(1R,5S,6r)-6-[(4S)-4,5,5-三甲基-4,5-二氫-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己-3-基}甲酮(48.84 mg，0.15 mmol，7.2%產率)及(1-異丙基-1H-咪唑-4-基){(1R,5S,6r)-6-[(4R)-4,5,5-三甲基-4,5-二氫-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己-3-基}甲酮(52.66 mg，0.1594 mmol，7.7403%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 7.68 (br s, 1H), 7.49 (s, 1H), 4.85 - 4.64 (m, 1H), 4.48 - 4.29 (m, 1H), 4.27 - 4.12 (m, 1H), 4.03 - 3.88 (m, 1H), 3.71 - 3.54 (m, 1H), 2.78 (quin, J=7.2 Hz, 1H), 2.30 - 1.95 (m, 2H), 1.65 (br s, 3H), 1.52 (s, 6H), 1.31 (d, J=2.8 Hz, 3H), 1.28 - 1.18 (m, 4H), 1.10 (br d, J=7.3 Hz, 3H) Example 47 (1- isopropyl - 1H- imidazol -4- yl ){(1R,5S,6r)-6-[(4S)-4,5,5- trimethyl -4,5- dihydro- 1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone example 48 (1- isopropyl -1H- imidazol -4- yl ){(1R ,5S,6r)-6-[(4R)-4,5,5- trimethyl -4,5- dihydro -1,2- oxazol -3- yl ]-3- azabicyclo [3.1. 0] Hex -3- yl } methanone To a solution of 1-isopropylimidazole-4-carboxylic acid (476.15 mg, 3.09 mmol) in pyridine (8 mL) was added EDCI (592.06 mg, 3.09 mmol) and (1R ,5S,6r)-6-(4,5,5-Trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane (400 mg, 2.06 mmol). The resulting mixture was stirred at 20 to 25°C for 2 hours. LCMS showed desired MS (as main peak). The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ). The obtained fluids were combined, concentrated to remove most of _CH3CN and lyophilized. The products were chirally isolated by SFC and lyophilized to obtain (1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4S)- 4,5,5-Trimethyl-4,5-dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone (48.84 mg , 0.15 mmol, 7.2% yield) and (1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6-[(4R)-4,5,5-trimethyl -4,5-Dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hex-3-yl}methanone (52.66 mg, 0.1594 mmol, 7.7403% yield) . ¹ H NMR (400MHz, chloroform-d) δ = 7.68 (br s, 1H), 7.49 (s, 1H), 4.85 - 4.64 (m, 1H), 4.48 - 4.29 (m, 1H), 4.27 - 4.12 (m , 1H), 4.03 - 3.88 (m, 1H), 3.71 - 3.54 (m, 1H), 2.78 (quin, J =7.2 Hz, 1H), 2.30 - 1.95 (m, 2H), 1.65 (br s, 3H) , 1.52 (s, 6H), 1.31 (d, J =2.8 Hz, 3H), 1.28 - 1.18 (m, 4H), 1.10 (br d, J =7.3 Hz, 3H)

實例 49      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(4- 甲氧基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6s)-6- 乙炔基 -3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(2000 mg，9.47 mmol)於MeOH (8 mL)中之溶液添加K ₂CO ₃(2616.87mg，18.93 mmol)及1-重氮-1-二甲氧基磷醯基-丙-2-酮(1818.71mg，9.47 mmol)。在20℃下攪拌反應混合物16小時，得到淺黃色混合物。TLC (PE/EtOAc=3:1)展示新樣點。用H ₂O (300 mL)稀釋反應混合物且用EtOAc (100 mL × 2)萃取。用鹽水(100 mL × 2)洗滌有機層且經無水硫酸鈉乾燥，得到殘餘物。藉由二氧化矽管柱(PE/EtOAc=3:1)純化殘餘物，得到呈白色固體狀之標題化合物(1800 mg，8.6843 mmol，91.733%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.35 (d, J = 11.2 Hz, 1H), 3.57 (d, J = 11.2 Hz, 1H), 3.36-3.30 (m, 2H), 1.88 (s, 1H), 1.84-1.80 (m, 2H), 1.42 (s, 9H), 1.12-1.09 (m, 1H)。 Example 49 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(4- methoxy -5,5- dimethyl - 4,5- dihydro- 1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (1R,5S,6s)-6- ethynyl- 3- azabicyclo [3.1 .0] tertiary butyl hexane -3- carboxylate to (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0] tertiary butyl hexane-3-carboxylate (2000 mg, 9.47 mmol) in MeOH (8 mL) was added K ₂ CO ₃ (2616.87 mg, 18.93 mmol) and 1-diazo-1-dimethoxyphosphoryl-propan-2-one ( 1818.71 mg, 9.47 mmol). The reaction mixture was stirred at 20 °C for 16 hours to obtain a pale yellow mixture. TLC (PE/EtOAc=3:1) showed fresh spots. The reaction mixture was diluted with H ₂ O (300 mL) and extracted with EtOAc (100 mL×2). The organic layer was washed with brine (100 mL x 2) and dried over anhydrous sodium sulfate to give a residue. The residue was purified by silica column (PE/EtOAc=3:1) to give the title compound (1800 mg, 8.6843 mmol, 91.733% yield) as a white solid. ¹ H NMR (400MHz, chloroform-d) δ = 3.35 (d, J = 11.2 Hz, 1H), 3.57 (d, J = 11.2 Hz, 1H), 3.36-3.30 (m, 2H), 1.88 (s, 1H ), 1.84-1.80 (m, 2H), 1.42 (s, 9H), 1.12-1.09 (m, 1H).

(1R,5S,6s)-6-(3- 羥基 -3- 甲基 -1- 丁炔 -1- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在-78℃下向(1R,5S,6s)-6-乙炔基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(1800 mg，8.68 mmol)於THF (90 mL)中之溶液添加n-BuLi (0.2 mL，9.55 mmol)。在-78℃下攪拌反應混合物30 min。向反應混合物添加丙酮(1109.65mg，19.11 mmol)。隨後在25℃下攪拌反應混合物16小時，得到黃色混合物。用H ₂O (100 mL)淬滅反應混合物且用EtOAc (100 mL × 2)萃取。用鹽水(100 mL)洗滌有機層且經無水硫酸鈉乾燥，得到殘餘物。藉由二氧化矽管柱(PE/EtOAc=3:1)純化殘餘物，得到呈白色固體狀之標題化合物。 ¹H NMR (400MHz, 氯仿-d) δ = 3.63 (d, J = 11.2 Hz, 1H), 3.55 (d, J = 11.2 Hz, 1H), 3.40-3.10 (m, 2H), 1.83 (s, 1H), 1.78-1.60 (m, 2H), 1.47 (s, 6H), 1.42 (s, 9H), 1.10-1.09 (m, 1H)。 (1R,5S,6s)-6-(3- Hydroxy -3- methyl -1- butyn -1- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butane (1R,5S, 6s )-6-ethynyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (1800 mg, 8.68 mmol) in THF at -78°C (90 mL) was added n-BuLi (0.2 mL, 9.55 mmol). The reaction mixture was stirred at -78 °C for 30 min. Acetone (1109.65 mg, 19.11 mmol) was added to the reaction mixture. The reaction mixture was then stirred at 25°C for 16 hours to give a yellow mixture. The reaction mixture was quenched with H ₂ O (100 mL) and extracted with EtOAc (100 mL×2). The organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulfate to give a residue. The residue was purified by silica column (PE/EtOAc=3:1) to give the title compound as a white solid. ¹ H NMR (400MHz, Chloroform-d) δ = 3.63 (d, J = 11.2 Hz, 1H), 3.55 (d, J = 11.2 Hz, 1H), 3.40-3.10 (m, 2H), 1.83 (s, 1H ), 1.78-1.60 (m, 2H), 1.47 (s, 6H), 1.42 (s, 9H), 1.10-1.09 (m, 1H).

(1R,5S,6r)-6-(5,5- 二甲基 -2- 氧離子基 -4- 側氧基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6s)-6-(3-羥基-3-甲基-1-丁炔-1-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(900 mg，3.39 mmol)於MeCN (36 mL)中之溶液添加三級BuONO (699.11mg，6.78 mmol)及Pd(OAc) ₂(152.3mg，0.68 mmol)。在25℃下攪拌反應混合物16小時，得到黃色混合物。TLC (PE/EtOAc=3:1)展示新樣點。用H ₂O (200 mL)稀釋反應混合物且用EtOAc (100 mL × 2)萃取。用鹽水(200 mL)洗滌有機層，過濾且經無水硫酸鈉乾燥，得到殘餘物。藉由二氧化矽管柱(PE/EtOAc=3:1)純化殘餘物，得到呈黃色固體狀之標題化合物(600 mg，1.9333 mmol，57%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.72 (d, J = 11.2 Hz, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.47-3.40 (m, 2H), 2.40-2.20 (m, 2H), 1.60 (s, 1H), 1.49 (s, 6H), 1.44 (s, 9H)。 (1R,5S,6r)-6-(5,5- Dimethyl -2- oxo -4- oxo -4,5- dihydro -1,2- oxazol -3- yl )- 3- Azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6s)-6-(3-hydroxy-3-methyl-1-butyn-1-yl To a solution of tert-butyl )-3-azabicyclo[3.1.0]hexane-3-carboxylate (900 mg, 3.39 mmol) in MeCN (36 mL) was added tertiary BuONO (699.11 mg, 6.78 mmol) and Pd(OAc) ₂ (152.3 mg, 0.68 mmol). The reaction mixture was stirred at 25°C for 16 hours to give a yellow mixture. TLC (PE/EtOAc=3:1) showed fresh spots. The reaction mixture was diluted with H ₂ O (200 mL) and extracted with EtOAc (100 mL×2). The organic layer was washed with brine (200 mL), filtered and dried over anhydrous sodium sulfate to give a residue. The residue was purified by silica column (PE/EtOAc=3:1) to give the title compound (600 mg, 1.9333 mmol, 57% yield) as a yellow solid. ¹ H NMR (400MHz, chloroform-d) δ = 3.72 (d, J = 11.2 Hz, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.47-3.40 (m, 2H), 2.40-2.20 (m , 2H), 1.60 (s, 1H), 1.49 (s, 6H), 1.44 (s, 9H).

(1R,5S,6r)-6-(4- 羥基 -5,5- 二甲基 -2- 氧離子基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-(5,5-二甲基-2-氧離子基-4-側氧基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(650 mg，2.09 mmol)於THF (10 mL)中之溶液添加NaBH ₄(87.15mg，2.3 mmol)於MeOH (3 mL)中之溶液。在0℃下攪拌反應混合物2小時，得到白色混合物。用H ₂O (100 mL)淬滅反應混合物且用EtOAc (100 mL × 2)萃取。有機層經無水硫酸鈉乾燥，得到呈無色油狀之標題化合物(570mg，1.8248 mmol，87.128%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 4.25 (d, J = 11.2 Hz, 1H), 4.20 (d, J = 11.2 Hz, 1H), 3.70-3.50 (m, 2H), 3.50-3.40 (m, 2H), 2.25-2.15 (m, 1H), 2.15-2.00 (m, 1H), 1.70 (d, J = 3.2 Hz, 1H), 1.43 (s, 9H), 1.43 (s, 3H), 1.35 (s, 3H)。 (1R,5S,6r)-6-(4- Hydroxy -5,5- dimethyl -2- oxionyl -4,5- dihydro -1,2- oxazol -3- yl )-3- Azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 0℃ -Oxy-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (650 mg, 2.09 mmol) in THF (10 mL) was added a solution of _NaBH4 (87.15 mg, 2.3 mmol) in MeOH (3 mL). The reaction mixture was stirred at 0 °C for 2 hours to give a white mixture. The reaction mixture was quenched with H ₂ O (100 mL) and extracted with EtOAc (100 mL×2). The organic layer was dried over anhydrous sodium sulfate to give the title compound (570 mg, 1.8248 mmol, 87.128% yield) as a colorless oil. ¹ H NMR (400MHz, chloroform-d) δ = 4.25 (d, J = 11.2 Hz, 1H), 4.20 (d, J = 11.2 Hz, 1H), 3.70-3.50 (m, 2H), 3.50-3.40 (m , 2H), 2.25-2.15 (m, 1H), 2.15-2.00 (m, 1H), 1.70 (d, J = 3.2 Hz, 1H), 1.43 (s, 9H), 1.43 (s, 3H), 1.35 ( s, 3H).

(1R,5S,6r)-6-(4- 甲氧基 -5,5- 二甲基 -2- 氧離子基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-(4-羥基-5,5-二甲基-2-氧離子基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(400 mg，1.28 mmol)於THF (20 mL)中之溶液添加NaH (36.88mg，1.54 mmol)且在0℃下攪拌0.5小時，得到黃色混合物。向反應混合物添加MeI (0.11 mL，1.79 mmol)。在20℃下攪拌反應混合物16小時，得到淺黃色混合物。TLC (PE/EtOAc=1:1)展示新樣點。用H ₂O (100 mL)淬滅反應混合物且用EtOAc (50 mL×3)萃取。濃縮有機層，得到殘餘物。藉由二氧化矽管柱(PE/EtOAc=1:1)純化殘餘物，得到呈無色油狀之標題化合物(380mg，1.1643 mmol，90.916%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 4.02 (d, J = 4.0 Hz, 1H), 3.80-3.60 (m, 2H), 3.50-3.35 (m, 2H), 3.41 (s, 3H), 2.15-2.00 (m, 2H), 1.69 (s, 1H), 1.43 (s, 9H), 1.39 (s, 3H), 1.37 (s, 3H)。 (1R,5S,6r)-6-(4- Methoxy -5,5- dimethyl -2- oxionyl -4,5- dihydro -1,2- oxazol -3- yl )- 3- Azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 0℃ to (1R,5S,6r)-6-(4-hydroxy-5,5-dimethyl-2 -Oxygen-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (400 mg, 1.28 mmol) in THF (20 mL) was added NaH (36.88 mg, 1.54 mmol) and stirred at 0 °C for 0.5 h to give a yellow mixture. MeI (0.11 mL, 1.79 mmol) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 16 hours to obtain a pale yellow mixture. TLC (PE/EtOAc=1:1) showed fresh samples. The reaction mixture was quenched with H ₂ O (100 mL) and extracted with EtOAc (50 mL×3). The organic layer was concentrated to give a residue. The residue was purified by silica column (PE/EtOAc=1:1) to give the title compound (380 mg, 1.1643 mmol, 90.916% yield) as a colorless oil. ¹ H NMR (400MHz, Chloroform-d) δ = 4.02 (d, J = 4.0 Hz, 1H), 3.80-3.60 (m, 2H), 3.50-3.35 (m, 2H), 3.41 (s, 3H), 2.15 -2.00 (m, 2H), 1.69 (s, 1H), 1.43 (s, 9H), 1.39 (s, 3H), 1.37 (s, 3H).

(1R,5S,6r)-6-(4- 甲氧基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在110℃下攪拌(1R,5S,6r)-6-(4-甲氧基-5,5-二甲基-2-氧離子基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(380 mg，1.16 mmol)於P(MeO) ₃(1. mL，1.16 mmol)中之溶液16小時，得到黃色混合物。TLC (PE/EtOAc=1:1)展示新樣點。用EtOAc (200 mL)稀釋反應混合物且用H2O (100 mL × 3)洗滌。濃縮有機層，得到殘餘物。藉由二氧化矽管柱(PE/EtOAc=1:1)純化殘餘物，得到呈無色油狀之標題化合物(320mg，1.031 mmol，88.551%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 4.01 (d, J = 11.2 Hz, 1H), 3.80-3.60 (m, 2H), 3.46 (s, 3H), 3.46-3.30 (m, 2H), 2.20-2.00 (m, 2H), 1.64 (s, 1H), 1.46 (s, 9H), 1.35 (s, 3H), 1.29 (s, 3H)。 (1R,5S,6r)-6-(4- methoxy -5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [ 3.1.0] Hexane -3- carboxylic acid tertiary butyl ester was stirred at 110°C (1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-2-oxionyl -4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (380 mg, 1.16 mmol) in P (MeO) ₃ (1. mL, 1.16 mmol) for 16 h gave a yellow mixture. TLC (PE/EtOAc=1:1) showed fresh samples. The reaction mixture was diluted with EtOAc (200 mL) and washed with H2O (100 mL x 3). The organic layer was concentrated to give a residue. The residue was purified by silica column (PE/EtOAc=1:1) to give the title compound (320 mg, 1.031 mmol, 88.551% yield) as a colorless oil. ¹ H NMR (400MHz, chloroform-d) δ = 4.01 (d, J = 11.2 Hz, 1H), 3.80-3.60 (m, 2H), 3.46 (s, 3H), 3.46-3.30 (m, 2H), 2.20 -2.00 (m, 2H), 1.64 (s, 1H), 1.46 (s, 9H), 1.35 (s, 3H), 1.29 (s, 3H).

(1R,5S,6r)-6-(4- 甲氧基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽向(1R,5S,6r)-6-(4-甲氧基-5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(200 mg，0.64 mmol)於DCM (4 mL)中之溶液添加TFA (0.8 mL，0.64 mmol)。在25℃下攪拌反應混合物1小時，得到無色混合物。移除反應混合物溶劑，得到殘餘物。殘餘物直接用於下一步驟。 LC-MS方法1 0.323 min，MS (m/z) 211.0 (M + H ⁺)。 (1R,5S,6r)-6-(4- methoxy -5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [ 3.1.0] Hexane TFA salt to (1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazole-3- To a solution of ter-butyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.64 mmol) in DCM (4 mL) was added TFA (0.8 mL, 0.64 mmol). The reaction mixture was stirred at 25°C for 1 hour to give a colorless mixture. The reaction mixture solvent was removed to give a residue. The residue was used directly in the next step. LC-MS method 1 0.323 min, MS (m/z) 211.0 (M + H ⁺ ).

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(4- 甲氧基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-異丙基咪唑-4-羧酸(49.12mg，0.32 mmol)、HATU (91.62mg，0.48 mmol)於DMF (2.393 mL)中之溶液添加DIPEA (0.16 mL，0.96 mmol)。在15℃下攪拌反應混合物30 min。隨後向反應物添加(1R,5S,6r)-6-(4-甲氧基-5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(67 mg，0.32 mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (NH ₃)純化反應混合物，得到呈白色粉末狀之標題化合物(65.26mg，0.1884 mmol，59.122%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 7.67 (s, 1H), 7.47 (s, 1H), 4.75 (dd, J=12.0, 16.8 Hz, 1H), 4.35 (m, 1H), 4.21 (m, 1H), 4.05 - 3.92 (m, 2H), 3.66 - 3.58 (m, 1H), 2.25 - 2.17 (m, 1H), 2.07 (m, 1H), 1.50 (d, J=6.8 Hz, 6H), 1.47 (m, 1H), 1.35 (s, 3H), 1.28 (d, J=4.4 Hz, 3H) (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(4- methoxy -5,5- dimethyl -4,5- dihydro -1, 2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-isopropylimidazole-4-carboxylic acid (49.12mg, 0.32 mmol), HATU ( To a solution of 91.62 mg, 0.48 mmol) in DMF (2.393 mL) was added DIPEA (0.16 mL, 0.96 mmol). The reaction mixture was stirred at 15 °C for 30 min. (1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3 - Azabicyclo[3.1.0]hexane TFA salt (67 mg, 0.32 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC (NH ₃ ) to afford the title compound (65.26 mg, 0.1884 mmol, 59.122% yield) as a white powder. ¹ H NMR (400MHz, chloroform-d) δ = 7.67 (s, 1H), 7.47 (s, 1H), 4.75 (dd, J =12.0, 16.8 Hz, 1H), 4.35 (m, 1H), 4.21 (m , 1H), 4.05 - 3.92 (m, 2H), 3.66 - 3.58 (m, 1H), 2.25 - 2.17 (m, 1H), 2.07 (m, 1H), 1.50 (d, J =6.8 Hz, 6H), 1.47 (m, 1H), 1.35 (s, 3H), 1.28 (d, J =4.4 Hz, 3H)

實例 50      [(1R,5S,6r)-6-(4- 異丁基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮 (1R,5S,6r)-6-(4- 異丁基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(200 mg，0.77 mmol)及Et ₃N (0.3 mL，2.3 mmol)於DMF (2.8571 mL)中之溶液添加2,5-二甲基己-2-烯(258.23mg，2.3 mmol)。在25℃下攪拌混合物12小時。LCMS展示偵測到所要質量。將反應混合物傾入H ₂O (50 mL)中，用EtOAc (40 mL × 3)萃取。用H ₂O (30 mL × 3)及鹽水(50 mL)洗滌有機相，經無水Na ₂SO ₄乾燥，濃縮，得到呈無色油狀之標題化合物(150 mg，58.1%產率)。 Example 50 [(1R,5S,6r)-6-(4- isobutyl -5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- nitrogen Heterobicyclo [3.1.0] hex-3 - yl ](1- isopropyl -1H- imidazol -4- yl ) methanone (1R,5S,6r)-6-(4- isobutyl - 5,5 -Dimethyl -4,5- dihydro - 1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S ,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (200 mg, 0.77 mmol ) and _Et3N (0.3 mL, 2.3 mmol) in DMF (2.8571 mL) was added 2,5-dimethylhex-2-ene (258.23 mg, 2.3 mmol). The mixture was stirred at 25°C for 12 hours. LCMS showed detection of desired mass. The reaction mixture was poured into H ₂ O (50 mL), extracted with EtOAc (40 mL×3). The organic phase was washed with H ₂ O (30 mL×3) and brine (50 mL), dried over anhydrous Na ₂ SO ₄ , concentrated to give the title compound (150 mg, 58.1% yield) as a colorless oil.

(1R,5S,6r)-6-(4- 異丁基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽在15℃下攪拌(1R,5S,6r)-6-(4-異丁基-5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(150 mg，0.45 mmol)於HCl/二㗁烷(10. mL，0.45 mmol)中之溶液1小時。TLC (PE:EtOAc=3/1)展示起始材料(Rf=0.3)完全耗盡且發現新樣點(Rf=0)。LCMS展示所要MS。在減壓下濃縮反應混合物，得到呈白色固體狀之標題化合物(105mg，0.3110 mmol，69.757%產率，粗物質)。粗產物直接用於下一步驟。 LC-MS方法1 0.725, MS (m/z) 237.1 (M + H ⁺)。 (1R,5S,6r)-6-(4- isobutyl -5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [ 3.1.0] Hexane TFA salt stirred at 15°C (1R,5S,6r)-6-(4-isobutyl-5,5-dimethyl-4,5-dihydro-1,2-㗁Azol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (150 mg, 0.45 mmol) in HCl/dioxane (10. mL, 0.45 mmol) solution for 1 hour. TLC (PE:EtOAc=3/1 ) showed complete consumption of starting material (Rf=0.3) and discovery of new spots (Rf=0). LCMS showed desired MS. The reaction mixture was concentrated under reduced pressure to afford the title compound (105 mg, 0.3110 mmol, 69.757% yield, crude material) as a white solid. The crude product was used directly in the next step. LC-MS method 1 0.725, MS (m/z) 237.1 (M + H ⁺ ).

[(1R,5S,6r)-6-(4- 異丁基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮向(1R,5S,6r)-6-(4-異丁基-5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(105 mg，0.44 mmol)及DIPEA (0.22 mL，1.33 mmol)於DMF (3mL)中之溶液添加HATU (202.58mg，0.53 mmol)及1-異丙基咪唑-4-羧酸(68.49mg，0.44 mmol)。在20℃下攪拌混合物12小時。LCMS展示偵測到所要質量。將反應混合物傾入H ₂O (30 mL)中，用EtOAc (20 mL × 3)萃取。用鹽水洗滌有機相，經無水Na ₂SO ₄乾燥且濃縮，得到殘餘物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈灰白色固體狀之標題化合物(4.86mg，0.0130 mmol，2.9368%產率)。 LC-MS方法1: 372.0 [M+H ⁺] ¹H NMR (400MHz, 甲醇-d ₄) δ = 9.11 (s, 1H), 8.21 (br s, 1H), 4.77 - 4.69 (m, 2H), 4.13 - 4.00 (m, 3H), 3.72 (br dd, J=4.4, 12.4 Hz, 1H), 3.01 - 2.92 (m, 1H), 2.36 - 2.25 (m, 1H), 2.20 - 2.06 (m, 1H), 1.79 - 1.71 (m, 1H), 1.63 (d, J=6.8 Hz, 6H), 1.36 (d, J=2.4 Hz, 3H), 1.21 (s, 3H), 0.97 (br d, J=6.5 Hz, 6H), 0.90 - 0.87 (m, 3H) [(1R,5S,6r)-6-(4- isobutyl -5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] Hex -3- yl ] (1- isopropyl -1H- imidazol -4- yl ) methanone to (1R,5S,6r)-6-(4-isobutyl-5,5- Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane TFA salt (105 mg, 0.44 mmol) and DIPEA (0.22 mL, 1.33 mmol) in DMF (3 mL) was added HATU (202.58 mg, 0.53 mmol) and 1-isopropylimidazole-4-carboxylic acid (68.49 mg, 0.44 mmol). The mixture was stirred at 20°C for 12 hours. LCMS showed detection of desired mass. The reaction mixture was poured into H ₂ O (30 mL), extracted with EtOAc (20 mL×3). The organic phase was washed with brine, dried over _{anhydrous Na2SO4} and concentrated to give a residue. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (4.86 mg, 0.0130 mmol, 2.9368% yield) as an off-white solid. LC-MS method 1: 372.0 [M+H ⁺ ] ¹ H NMR (400MHz, methanol-d ₄ ) δ = 9.11 (s, 1H), 8.21 (br s, 1H), 4.77 - 4.69 (m, 2H), 4.13 - 4.00 (m, 3H), 3.72 (br dd, J =4.4, 12.4 Hz, 1H), 3.01 - 2.92 (m, 1H), 2.36 - 2.25 (m, 1H), 2.20 - 2.06 (m, 1H) , 1.79 - 1.71 (m, 1H), 1.63 (d, J =6.8 Hz, 6H), 1.36 (d, J =2.4 Hz, 3H), 1.21 (s, 3H), 0.97 (br d, J =6.5 Hz , 6H), 0.90 - 0.87 (m, 3H)

實例 51      (1- 環丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1- 環丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向6-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-4-氧雜-5-氮雜螺[2.4]庚-5-烯氫氯化物(49.0 mg，0.27 mmol)於吡啶(1.5 mL)中之混合物添加EDCI (52.7 mg，0.27 mmol)及1-環丙基咪唑-4-羧酸(41.83 mg，0.27 mmol)。在20℃下攪拌懸浮液16小時。藉由製備型HPLC (NH ₃)純化溶液且凍乾，得到呈黃色固體狀之標題化合物(6.79mg，7.9%產率)。 LC-MS方法1: 2.058 min，MS (m/z): 313.2 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.56 (d, J=1.38 Hz, 1 H) 7.43 (d, J=1.25 Hz, 1 H) 4.63 (d, J=12.01 Hz, 1 H) 4.12 (d, J=12.38 Hz, 1 H) 3.87 (dd, J=11.82, 3.94 Hz, 1 H) 3.55 (dd, J=12.88, 4.38 Hz, 1 H) 3.26 - 3.33 (m, 1 H) 2.89 (s, 2 H) 2.05 (br d, J=3.50 Hz, 1 H) 1.93 - 1.99 (m, 1 H) 1.45 (br d, J=3.63 Hz, 1 H) 1.18 (s, 3 H) 1.02 - 1.07 (m, 2 H) 0.95 - 0.99 (m, 3 H) 0.90 - 0.94 (m, 2 H) 0.61 - 0.66 (m, 2 H) Example 51 (1- cyclopropyl -1H- imidazol -4- yl ) [(1R,5S,6r)-6-(4- oxa -5- azaspiro [2.4] hept -5- ene -6- Base )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (1- cyclopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(4- oxa - 5- azaspiro [2.4] hept -5- en -6- yl ) -3- Azabicyclo [3.1.0] hex -3- yl ] methanone to 6-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-4- A mixture of oxa-5-azaspiro[2.4]hept-5-ene hydrochloride (49.0 mg, 0.27 mmol) in pyridine (1.5 mL) was added with EDCI (52.7 mg, 0.27 mmol) and 1-cyclopropyl Imidazole-4-carboxylic acid (41.83 mg, 0.27 mmol). The suspension was stirred at 20°C for 16 hours. The solution was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (6.79 mg, 7.9% yield) as a yellow solid. LC-MS method 1: 2.058 min, MS (m/z): 313.2 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.56 (d, J =1.38 Hz, 1 H) 7.43 (d, J =1.25 Hz, 1 H) 4.63 (d, J =12.01 Hz, 1 H) 4.12 (d, J =12.38 Hz, 1 H) 3.87 (dd, J =11.82, 3.94 Hz, 1 H) 3.55 (dd, J =12.88, 4.38 Hz, 1 H) 3.26 - 3.33 (m, 1 H) 2.89 ( s, 2 H) 2.05 (br d, J =3.50 Hz, 1 H) 1.93 - 1.99 (m, 1 H) 1.45 (br d, J =3.63 Hz, 1 H) 1.18 (s, 3 H) 1.02 - 1.07 (m, 2H) 0.95 - 0.99 (m, 3H) 0.90 - 0.94 (m, 2H) 0.61 - 0.66 (m, 2H)

實例 52      [1-(1- 甲基環丙基 )-1H- 咪唑 -4- 基 ][(1R,5S,6r)-6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 [1-(1- 甲基環丙基 )-1H- 咪唑 -4- 基 ][(1R,5S,6r)-6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-(1-甲基環丙基)-1H-咪唑-4-羧酸(37.3 mg，0.22 mmol)於DMF (1.5 mL)中之溶液添加HATU (110.87 mg，0.29 mmol)及Et ₃N (0.09 mL，0.67 mmol)。在20至25℃下攪拌混合物0.5小時。向混合物添加6-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-4-氧雜-5-氮雜螺[2.4]庚-5-烯氫氯化物(40 mg，0.22 mmol)。攪拌所得混合物2小時。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色固體狀之標題化合物(11.21 mg，0.0343 mmol，15.303%產率)。 LC-MS方法1: 327.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.69 (d, J=1.3 Hz, 1H), 7.53 (d, J=1.3 Hz, 1H), 4.73 (br d, J=12.0 Hz, 1H), 4.21 (br d, J=12.3 Hz, 1H), 3.95 (br dd, J=4.0, 12.0 Hz, 1H), 3.62 (br dd, J=4.0, 12.5 Hz, 1H), 2.97 (s, 2H), 2.13 (br d, J=3.5 Hz, 1H), 2.07 - 2.01 (m, 1H), 1.58 (s, 3H), 1.53 (t, J=3.4 Hz, 1H), 1.18 - 1.08 (m, 4H), 0.98 - 0.89 (m, 2H), 0.75 - 0.68 (m, 2H) Example 52 [1-(1- methylcyclopropyl )-1H- imidazol -4- yl ][(1R,5S,6r)-6-(4- oxa- 5- azaspiro [2.4 ] hept- 5- en -6- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone [1-(1- methylcyclopropyl )-1H- imidazol - 4- yl ][( 1R,5S,6r)-6-(4- Oxa- 5- azaspiro [2.4] hept - 5- en -6- yl )-3- azabicyclo [3.1.0] hex -3- yl ] Methanone To a solution of 1-(1-methylcyclopropyl)-1H-imidazole-4-carboxylic acid (37.3 mg, 0.22 mmol) in DMF (1.5 mL) was added HATU (110.87 mg, 0.29 mmol) and Et ₃ N (0.09 mL, 0.67 mmol). The mixture was stirred at 20 to 25°C for 0.5 hours. To the mixture was added 6-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-ene hydrogen Chloride (40 mg, 0.22 mmol). The resulting mixture was stirred for 2 hours. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (11.21 mg, 0.0343 mmol, 15.303% yield) as a yellow solid. LC-MS method 1: 327.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.69 (d, J =1.3 Hz, 1H), 7.53 (d, J =1.3 Hz, 1H), 4.73 (br d, J =12.0 Hz, 1H), 4.21 (br d, J =12.3 Hz, 1H), 3.95 (br dd, J =4.0, 12.0 Hz, 1H), 3.62 (br dd, J =4.0, 12.5 Hz, 1H), 2.97 (s, 2H), 2.13 (br d, J =3.5 Hz, 1H), 2.07 - 2.01 (m, 1H), 1.58 (s, 3H), 1.53 (t, J =3.4 Hz, 1H), 1.18 - 1.08 (m, 4H), 0.98 - 0.89 (m, 2H), 0.75 - 0.68 (m, 2H)

實例 53      (1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(1S,5S)-1- 甲基 -2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯 -4- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 實例 54      (1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(1R,5R)-1- 甲基 -2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯 -4- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮實例45中產生之化合物應用於SFC對掌性分離，獲得(1-異丙基-1H-咪唑-4-基){(1R,5S,6r)-6-[(1S,5S)-1-甲基-2-氧雜-3-氮雜雙環[3.1.0]己-3-烯-4-基]-3-氮雜雙環[3.1.0]己-3-基}甲酮(22.30 mg)及呈白色固體狀之(1-異丙基-1H-咪唑-4-基){(1R,5S,6r)-6-[(1R,5R)-1-甲基-2-氧雜-3-氮雜雙環[3.1.0]己-3-烯-4-基]-3-氮雜雙環[3.1.0]己-3-基}甲酮(21.47 mg)。 Example 53 (1- isopropyl -1H- imidazol -4- yl ){(1R,5S,6r)-6-[(1S,5S)-1- methyl -2- oxa -3 -azabicyclo [3.1.0] Hex - 3-en-4- yl ]-3- azabicyclo [3.1.0] hex - 3- yl } methanone Example 54 (1- isopropyl -1H- imidazol -4- yl ){(1R,5S,6r)-6-[(1R,5R)-1- methyl -2- oxa -3- azabicyclo [3.1.0] hex -3- en - 4- yl ]- The compound produced in 3- azabicyclo [3.1.0] hex -3- yl } methanone example 45 was applied to SFC chiral separation to obtain (1-isopropyl-1H-imidazol-4-yl){( 1R,5S,6r)-6-[(1S,5S)-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl]-3-nitrogen Heterobicyclo[3.1.0]hex-3-yl}methanone (22.30 mg) and (1-isopropyl-1H-imidazol-4-yl){(1R,5S,6r)-6 -[(1R,5R)-1-methyl-2-oxa-3-azabicyclo[3.1.0]hex-3-en-4-yl]-3-azabicyclo[3.1.0]hexa -3-yl}methanone (21.47 mg).

(1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(1S,5S)-1- 甲基 -2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯 -4- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 LC-MS 方法 1: 315.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.67 (1 H, s), 7.48 (1 H, s), 4.75 (1 H, br d, J=12.05 Hz), 4.36 (1 H, m, J=13.43, 6.84 Hz), 4.22 (1 H, br d, J=12.30 Hz), 3.97 (1 H, br d, J=12.05 Hz), 3.64 (1 H, br d, J=12.30 Hz), 2.08 (2 H, br d, J=3.76 Hz), 2.01 (1 H, br s), 1.67 (3 H, s), 1.51 (6 H, d, J=6.78 Hz), 0.90 (1 H, dd, J=9.41, 5.14 Hz), 0.33 - 0.43 (1 H, m) (1- isopropyl -1H- imidazol -4- yl ){(1R,5S,6r)-6-[(1S,5S)-1-methyl- 2 - oxa -3- azabicyclo [3.1 .0] hex -3- en -4- yl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone LC-MS method 1 : 315.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.67 (1 H, s), 7.48 (1 H, s), 4.75 (1 H, br d, J=12.05 Hz), 4.36 (1 H, m, J=13.43, 6.84 Hz), 4.22 (1 H, br d, J=12.30 Hz), 3.97 (1 H, br d, J=12.05 Hz), 3.64 (1 H, br d, J=12.30 Hz), 2.08 (2 H, br d, J=3.76 Hz), 2.01 (1 H, br s), 1.67 (3 H, s), 1.51 (6 H, d, J=6.78 Hz), 0.90 (1 H, dd, J=9.41, 5.14 Hz), 0.33 - 0.43 (1 H, m)

(1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(1R,5R)-1- 甲基 -2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯 -4- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮LS-MS方法1: 315.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.67 (1 H, s), 7.48 (1 H, s), 4.75 (1 H, br d, J=12.05 Hz), 4.36 (1 H, m, J=13.43, 6.84 Hz), 4.22 (1 H, br d, J=12.30 Hz), 3.97 (1 H, br d, J=12.05 Hz), 3.64 (1 H, br d, J=12.30 Hz), 2.08 (2 H, br d, J=3.76 Hz), 2.01 (1 H, br s), 1.67 (3 H, s), 1.51 (6 H, d, J=6.78 Hz), 0.90 (1 H, dd, J=9.41, 5.14 Hz), 0.33 - 0.43 (1 H, m) (1- isopropyl -1H- imidazol -4- yl ){(1R,5S,6r)-6-[(1R,5R)-1-methyl- 2 - oxa -3- azabicyclo [3.1 .0] hex -3- en -4- yl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone LS-MS method 1: 315.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.67 (1 H, s), 7.48 (1 H, s), 4.75 (1 H, br d, J=12.05 Hz), 4.36 (1 H, m, J=13.43, 6.84 Hz), 4.22 (1 H, br d, J=12.30 Hz), 3.97 (1 H, br d, J=12.05 Hz), 3.64 (1 H, br d, J=12.30 Hz), 2.08 (2 H, br d, J=3.76 Hz), 2.01 (1 H, br s), 1.67 (3 H, s), 1.51 (6 H, d, J=6.78 Hz), 0.90 (1 H, dd, J=9.41, 5.14 Hz), 0.33 - 0.43 (1 H, m)

實例 55      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5- 甲基 -4- 苯基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6-(4- 溴 -5- 甲基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0至5℃下向(1R,5S,6r)-6-(5-甲基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(2.46g，9.31mmol，來自實例56)於DMF (25mL)中之溶液添加NBS (1.66g，9.31mmol)。在15℃下攪拌反應物5小時，得到黃色溶液。LCMS展示反應完成。用H ₂O (150 mL)稀釋反應物且用EA (40 mL × 3)萃取。用NH ₄Cl水溶液(40 mL ×2)、NaHCO ₃水溶液(40 mL)及鹽水(40 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且濃縮，得到呈淡黃色油狀之標題化合物(2.9g，90.786%產率)。 ¹H NMR (400 MHz, 氯仿-d) δ 3.75-3.60 (m, 2H), 3.55-3.40 (m, 2H), 2.38 (s, 3H), 2.20-2.00 (m, 2H), 1.70-1.65 (m, 1H), 1.46 (s, 9H)。 Example 55 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5- methyl -4- phenyl -1,2- oxazol -3- yl ) -3- Azabicyclo [3.1.0] hex - 3- yl ] methanone (1R,5S,6r)-6-(4- bromo -5- methyl -1,2- oxazol -3- yl ) -3- Azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-(5-methyl-1,2-㗁A solution of oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2.46 g, 9.31 mmol, from Example 56) in DMF (25 mL) was added with NBS ( 1.66 g, 9.31 mmol). The reaction was stirred at 15°C for 5 hours to give a yellow solution. LCMS showed the reaction was complete. The reaction was diluted with H ₂ O (150 mL) and extracted with EA (40 mL×3). The combined organic layer was washed with aq. _NH4Cl (40 mL x 2 ₎ , aq. _NaHCO3 (40 mL) and brine (40 mL), dried over _Na2SO4 , filtered and concentrated to afford the title as a light yellow oil. Compound (2.9 g, 90.786% yield). ¹ H NMR (400 MHz, chloroform-d) δ 3.75-3.60 (m, 2H), 3.55-3.40 (m, 2H), 2.38 (s, 3H), 2.20-2.00 (m, 2H), 1.70-1.65 ( m, 1H), 1.46 (s, 9H).

(1R,5S,6r)-6-(5- 甲基 -4- 苯基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯用N ₂吹掃(1R,5S,6r)-6-(4-溴-5-甲基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.29 mmol)、苯基硼酸(phenylboronic acid) (42.63mg，0.35 mmol)及NaHCO ₃(73.43mg，0.87 mmol)於DMF (1.5 mL)及H ₂O (0.2 mL)中之混合物。隨後，添加Pd(dppf)Cl ₂(21.32mg， 0.03mmol)且用N ₂吹掃混合物且在N ₂氛圍下在90℃下加熱12小時，得到黑色混合物。用EtOAc (20 mL)及H ₂O (10 mL)稀釋混合物。濾出固體。用H ₂O (10 mL)及鹽水 (10 mL)洗滌有機層，隨後，經Na ₂SO ₄乾燥且真空濃縮，得到褐色油狀物。藉由製備型TLC (PE/EtOAc=6/1)純化褐色油狀物，得到呈白色固體狀之標題化合物(50mg，0.1469 mmol，50.411%產率)。 LC-MS方法1 0.943 min，MS (m/z) 340.9 (M + H ⁺)。 (1R,5S,6r)-6-(5- Methyl -4- phenyl -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid The tertiary butyl ester was purged with N ₂ (1R,5S,6r)-6-(4-bromo-5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0 ] tert-butyl hexane-3-carboxylate (100 mg, 0.29 mmol), phenylboronic acid (42.63 mg, 0.35 mmol) and NaHCO ₃ (73.43 mg, 0.87 mmol) in DMF (1.5 mL) and _H2O (0.2 mL). Then, Pd(dppf)Cl ₂ (21.32 mg, 0.03 mmol) was added and the mixture was purged with N ₂ and heated at 90° C. for 12 hours under N ₂ atmosphere to give a black mixture. The mixture was diluted with EtOAc (20 mL) and H ₂ O (10 mL). The solid was filtered off. The organic layer was washed with H ₂ O (10 mL) and brine (10 mL), then dried over Na ₂ SO ₄ and concentrated in vacuo to give a brown oil. The brown oil was purified by prep-TLC (PE/EtOAc=6/1) to give the title compound (50 mg, 0.1469 mmol, 50.411% yield) as a white solid. LC-MS method 1 0.943 min, MS (m/z) 340.9 (M + H ⁺ ).

(1R,5S,6r)-6-(5- 甲基 -4- 苯基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷氫氯化物在0℃下攪拌(1R,5S,6r)-6-(5-甲基-4-苯基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(50 mg，0.15 mmol)於4M HCl/二㗁烷(5. mL，0.15 mmol)中之混合物50 min，得到無色溶液。真空濃縮反應物，得到呈淡黃色膠質之標題化合物(50mg，0.1807 mmol，123%產率)，其直接用於下一步驟。 (1R,5S,6r)-6-(5- methyl -4- phenyl -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexane hydrochloride in 0 Stir (1R,5S,6r)-6-(5-methyl-4-phenyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3 at ℃ - A mixture of tert-butyl carboxylate (50 mg, 0.15 mmol) in 4M HCl/dioxane (5. mL, 0.15 mmol) for 50 min gave a colorless solution. The reaction was concentrated in vacuo to afford the title compound (50 mg, 0.1807 mmol, 123% yield) as a pale yellow gum, which was used directly in the next step.

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5- 甲基 -4- 苯基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮在20℃下向1-異丙基咪唑-4-羧酸(36.21mg，0.23 mmol)於DMF (2 mL)中之溶液添加HATU (82.88mg，0.22 mmol)、Et ₃N (0.06 mL，0.45 mmol)及(1R,5S,6r)-6-(5-甲基-4-苯基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(50 mg，0.18 mmol)。在20℃下攪拌反應物4小時，得到淡褐色溶液。真空濃縮反應物，得到淡褐色膠質，藉由製備型HPLC (NH ₃)將其純化。濃縮液體餾分且凍乾，得到呈淡黃色固體狀之標題化合物(32.53mg，0.0864 mmol，47.831%產率)。 LC-MS方法1: 377.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.57 (d, J=1.3 Hz, 1H), 7.40 - 7.33 (m, 3H), 7.28 (d, J=7.4 Hz, 1H), 7.25 - 7.21 (m, 2H), 4.59 (d, J=12.1 Hz, 1H), 4.26 (spt, J=6.8 Hz, 1H), 4.07 (d, J=12.6 Hz, 1H), 3.96 (dd, J=4.4, 11.9 Hz, 1H), 3.62 (dd, J=4.2, 12.6 Hz, 1H), 2.33 (s, 3H), 2.32 - 2.28 (m, 1H), 2.13 - 2.06 (m, 1H), 1.53 - 1.53 (m, 1H), 1.41 (d, J=6.6 Hz, 6H) (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5- methyl -4- phenyl -1,2- oxazol -3- yl )-3 -Azabicyclo [3.1.0] hex -3- yl ] methanone was added to a solution of 1-isopropylimidazole-4 - carboxylic acid (36.21 mg, 0.23 mmol) in DMF (2 mL) at 20 °C HATU (82.88mg, 0.22 mmol), Et ₃ N (0.06 mL, 0.45 mmol) and (1R,5S,6r)-6-(5-methyl-4-phenyl-1,2-oxazole-3- yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50 mg, 0.18 mmol). The reaction was stirred at 20 °C for 4 hours to give a light brown solution. The reaction was concentrated in vacuo to give a light brown gum which was purified by preparative HPLC ( _NH3 ). The liquid fractions were concentrated and lyophilized to afford the title compound (32.53 mg, 0.0864 mmol, 47.831% yield) as a light yellow solid. LC-MS method 1: 377.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.57 (d, J =1.3 Hz, 1H), 7.40 - 7.33 (m, 3H), 7.28 (d, J =7.4 Hz, 1H), 7.25 - 7.21 (m, 2H), 4.59 (d, J =12.1 Hz, 1H), 4.26 (spt, J =6.8 Hz, 1H), 4.07 (d, J =12.6 Hz, 1H), 3.96 (dd, J =4.4, 11.9 Hz, 1H), 3.62 (dd, J =4.2, 12.6 Hz, 1H), 2.33 (s, 3H), 2.32 - 2.28 (m, 1H), 2.13 - 2.06 (m, 1H), 1.53 - 1.53 (m, 1H), 1.41 (d, J =6.6 Hz, 6H)

實例 56      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5- 甲基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6-(5- 甲基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(0.5g，1.92 mmol)及丙-1-烯-2-基乙酸酯(1.04 mL，9.59 mmol)於DCM (6 mL)中之溶液逐滴添加Et ₃N (0.8 mL，5.75 mmol)。隨後在20℃下攪拌反應物12小時，得到淡黃色溶液。LCMS展示所要MS。用DCM (30 mL)稀釋溶液且用H ₂O (15 mL × 2)、飽和NaHCO ₃(15 mL)及鹽水(15 mL)洗滌。有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈淡黃色油狀之標題化合物(460mg，1.7403 mmol，90.747%產率)，其直接用於下一步驟。 Example 56 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5- methyl -1,2- oxazol -3- yl )-3- aza Bicyclo [3.1.0] hex - 3- yl ] methanone (1R,5S,6r)-6-(5- methyl -1,2- oxazol -3- yl )-3- azabicyclo [3.1. 0] Hexane -3- carboxylic acid tertiary butyl ester at 0°C to (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo [3.1.0] tert-butyl hexane-3-carboxylate (0.5 g, 1.92 mmol) and prop-1-en-2-yl acetate (1.04 mL, 9.59 mmol) in DCM (6 mL) The solution was added _Et3N (0.8 mL, 5.75 mmol) dropwise. The reaction was then stirred at 20°C for 12 hours to give a pale yellow solution. LCMS showed desired MS. The solution was diluted with DCM (30 mL) and washed with H ₂ O (15 mL×2), saturated NaHCO ₃ (15 mL) and brine (15 mL). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (460 mg, 1.7403 mmol, 90.747% yield) as a pale yellow oil, which was used directly in the next step.

(1R,5S,6r)-6-(5- 甲基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽向(1R,5S,6r)-6-(5-甲基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(235 mg，0.89 mmol)於DCM (5 mL)中之溶液添加2,2,2-三氟乙酸(1. mL，13.06 mmol)。在20℃下攪拌反應混合物3小時，得到黃色溶液。在真空中蒸發反應混合物，得到呈黃色油狀之標題化合物(260mg，0.9345 mmol，105.11%產率)。其直接用於下一步驟。 (1R,5S,6r)-6-(5- Methyl -1,2- oxazol- 3- yl )-3- azabicyclo [3.1.0] hexane TFA salt to (1R,5S,6r) -6-(5-Methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (235 mg, 0.89 mmol) in To the solution in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (1. mL, 13.06 mmol). The reaction mixture was stirred at 20 °C for 3 hours to obtain a yellow solution. The reaction mixture was evaporated in vacuo to afford the title compound (260 mg, 0.9345 mmol, 105.11% yield) as a yellow oil. It was used directly in the next step.

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5- 甲基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向100 mL圓底燒瓶裝入1-異丙基咪唑-4-羧酸(70 mg，0.45 mmol)、N-乙基-N-異丙基丙-2-胺(0.24 mL，1.41 mmol)、HATU (190.94mg，0.50 mmol)及DMF (3 mL)。在攪動30 min之後，添加(1R,5S,6r)-6-(5-甲基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(126.33mg，0.45 mmol)。在20℃下攪拌反應混合物16小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL × 2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (NH ₃)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(13.06mg，0.0383 mmol，8.4313%產率)。 LC-MS方法1: 301.1 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d ₆) δ 9.22 (br s, 1H), 8.35 (s, 1H), 6.07 (s, 1H), 4.66 (td, J=6.64, 13.35 Hz, 1H), 4.11 (br d, J=10.76 Hz, 1H), 4.02 (br d, J=12.63 Hz, 1H), 3.98 (br dd, J=4.06, 10.82 Hz, 1H), 3.63 (br dd, J=4.19, 12.57 Hz, 1H), 2.34 (s, 3H), 2.14-2.20 (m, 1H), 2.05-2.10 (m, 1H), 1.84 (t, J=3.38 Hz, 1H), 1.51 (d, J=6.63 Hz, 6H) (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5- methyl -1,2- oxazol -3- yl )-3- azabicyclo [ 3.1.0] Hex -3- yl ] methanone Charge 1-isopropylimidazole-4-carboxylic acid (70 mg, 0.45 mmol), N-ethyl-N-isopropylpropyl -2-Amine (0.24 mL, 1.41 mmol), HATU (190.94 mg, 0.50 mmol) and DMF (3 mL). After stirring for 30 min, (1R,5S,6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane TFA salt ( 126.33 mg, 0.45 mmol). The reaction mixture was stirred at 20 °C for 16 hours to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC ( _NH3 ). The obtained fluid was concentrated in vacuo to remove most of _CH3CN and lyophilized to give the title compound (13.06 mg, 0.0383 mmol, 8.4313% yield) as a white solid. LC-MS method 1: 301.1 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.22 (br s, 1H), 8.35 (s, 1H), 6.07 (s, 1H), 4.66 ( td, J =6.64, 13.35 Hz, 1H), 4.11 (br d, J =10.76 Hz, 1H), 4.02 (br d, J =12.63 Hz, 1H), 3.98 (br dd, J =4.06, 10.82 Hz, 1H), 3.63 (br dd, J =4.19, 12.57 Hz, 1H), 2.34 (s, 3H), 2.14-2.20 (m, 1H), 2.05-2.10 (m, 1H), 1.84 (t, J =3.38 Hz, 1H), 1.51 (d, J =6.63 Hz, 6H)

實例 57      [(1R,5S,6r)-6-(1,2- 苯并 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮 N- 苯氧基乙醯胺在0℃下向(胺氧基)苯(200 mg，1.37 mmol)於THF (3 mL)中之溶液添加Ac ₂O (280.49mg，2.75 mmol)。在20℃下攪拌混合物3小時，得到褐色懸浮液。直接濃縮反應混合物。藉由快速柱(PE至20% EtOAc/PE)純化粗產物，得到呈白色固體狀之標題化合物(170mg，1.1246 mmol，81.868%產率)。 ¹H NMR (400MHz, DMSO-d6) δ = 11.67 (brs, 1H), 7.35-7.25 (m, 2H), 7.05-6.95 (m, 3H), 1.92 (s, 3H)。 Example 57 [(1R,5S,6r)-6-(1,2- Benzazol - 3- yl )-3- azabicyclo [3.1.0] hex -3- yl ](1- isopropyl -1H- Imidazol -4- yl ) methanone N- phenoxyacetamide To a solution of (aminooxy)benzene (200 mg, 1.37 mmol) in THF (3 mL) was added Ac ₂ O at 0 °C (280.49 mg, 2.75 mmol). The mixture was stirred at 20 °C for 3 hours to give a brown suspension. The reaction mixture was directly concentrated. The crude product was purified by flash column (PE to 20% EtOAc/PE) to give the title compound (170 mg, 1.1246 mmol, 81.868% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 11.67 (brs, 1H), 7.35-7.25 (m, 2H), 7.05-6.95 (m, 3H), 1.92 (s, 3H).

(1R,5S,6r)-6-(1,2- 苯并 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向N-苯氧基乙醯胺(50 mg，0.33 mmol)於三級戊醇(1.5 mL，0.33 mmol)中之溶液添加Pd(TFA) ₂(9.92mg，0.03 mmol)、6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(139.76mg，0.66 mmol)及TBHP (0.17 mL，0.83 mmol)。在60℃下於N ₂下攪拌混合物12小時，得到褐色溶液。將反應混合物傾入NaHSO ₃水溶液(20 mL)中且用EtOAc (20 mL × 4)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由製備型TLC (PE:EtOAc=6:1)純化殘餘物，得到呈白色膠質之標題化合物(20mg，0.0666 mmol，20.131%產率)。 (1R,5S,6r)-6-(1,2- Benzazol -3- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to N-benzene To a solution of oxyacetamide (50 mg, 0.33 mmol) in tertiary amyl alcohol (1.5 mL, 0.33 mmol) was added Pd(TFA) ₂ (9.92 mg, 0.03 mmol), 6-formyl-3-nitrogen Heterobicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (139.76 mg, 0.66 mmol) and TBHP (0.17 mL, 0.83 mmol). The mixture was stirred at 60 °C under N for ₁₂ h to give a brown solution. The reaction mixture was poured into aqueous NaHSO ₃ (20 mL) and extracted with EtOAc (20 mL×4). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EtOAc=6:1) to give the title compound (20 mg, 0.0666 mmol, 20.131% yield) as a white gum.

3-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-1,2- 苯并 㗁唑氫氯化物向(1R,5S,6r)-6-(1,2-苯并㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(20 mg，0.07 mmol)之溶液添加HCl/二㗁烷(2.0 mL，8 mmol)。在20℃下攪拌混合物1小時，得到無色溶液。TLC (PE:EtOAc=5:1)展示反應完成。直接濃縮反應混合物，得到呈褐色膠質之標題化合物(15mg，0.0634 mmol，95.168%產率)。 3-[(1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl ]-1,2- benzoxazole hydrochloride to (1R,5S,6r)-6- (1,2-Benzazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (20 mg, 0.07 mmol) was added with HCl/di Alkane (2.0 mL, 8 mmol). The mixture was stirred at 20°C for 1 hour to give a colorless solution. TLC (PE:EtOAc=5:1) showed the reaction was complete. The reaction mixture was directly concentrated to afford the title compound (15 mg, 0.0634 mmol, 95.168% yield) as a brown gum.

[(1R,5S,6r)-6-(1,2- 苯并 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮向1-異丙基咪唑-4-羧酸(22.08mg ，0.14 mmol)於DMF (1.5 mL)中之溶液添加HATU (43.79mg，0.11 mmol)、IEA (0.06 mL，0.38 mmol)及3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-1,2-苯并㗁唑氫氯化物(30 mg，0.10 mmol)。在20℃下攪拌混合物1小時，得到褐色溶液。LCMS展示所要MS且剩餘3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-1,2-苯并㗁唑氫氯化物之一部分。在20℃下攪拌混合物12小時，得到褐色溶液。LCMS展示所要MS作為主峰。將混合物傾入H ₂O (15 mL)中且用EtOAc (15 mL × 5)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥且濃縮至乾燥。藉由製備型TLC (MeOH:EtOAc=1:11)純化殘餘物且用MTBE (2 mL)濕磨所獲得固體且在空氣中乾燥，得到呈褐色固體。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(10mg，0.0297 mmol，31.14%產率)。 LC-MS方法1: 336.9 [M+H ⁺] ¹H NMR (400 MHz, 氯仿 -d) δ ppm 7.73 (1 H, d, J=1.25 Hz), 7.68 (1 H, d, J=8.03 Hz), 7.47 - 7.57 (3 H, m), 7.31 (1 H, dd, J=7.91, 3.89 Hz), 4.91 (1 H, br d, J=12.05 Hz), 4.34 - 4.40 (2 H, m), 4.08 (1 H, br dd, J=12.05, 3.76 Hz), 3.74 (1 H, br dd, J=12.55, 4.02 Hz), 2.45 - 2.53 (1 H, m), 2.31 - 2.41 (1 H, m), 2.07 (1 H, t, J=3.26 Hz), 1.53 (6 H, d, J=6.53 Hz) [(1R,5S,6r)-6-(1,2- Benzazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] (1- isopropyl -1H -imidazol -4- yl ) methanone To a solution of 1-isopropylimidazole-4-carboxylic acid (22.08 mg, 0.14 mmol) in DMF (1.5 mL) was added HATU (43.79 mg, 0.11 mmol), IEA ( 0.06 mL, 0.38 mmol) and 3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-1,2-benzoxazole hydrochloride (30 mg, 0.10 mmol). The mixture was stirred at 20 °C for 1 hour to give a brown solution. LCMS showed the desired MS and a portion of 3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-1,2-benzoxazole hydrochloride remained. The mixture was stirred at 20 °C for 12 hours to obtain a brown solution. LCMS showed the desired MS as the main peak. The mixture was poured into H ₂ O (15 mL) and extracted with EtOAc (15 mL×5). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by preparative TLC (MeOH:EtOAc=1:11) and the obtained solid was triturated with MTBE (2 mL) and dried in air to give a brown solid. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to afford the title compound (10 mg, 0.0297 mmol, 31.14% yield) as a white solid. LC-MS method 1: 336.9 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform -d ) δ ppm 7.73 (1 H, d, J =1.25 Hz), 7.68 (1 H, d, J =8.03 Hz ), 7.47 - 7.57 (3 H, m), 7.31 (1 H, dd, J =7.91, 3.89 Hz), 4.91 (1 H, br d, J =12.05 Hz), 4.34 - 4.40 (2 H, m) , 4.08 (1 H, br dd, J =12.05, 3.76 Hz), 3.74 (1 H, br dd, J =12.55, 4.02 Hz), 2.45 - 2.53 (1 H, m), 2.31 - 2.41 (1 H, m), 2.07 (1 H, t, J =3.26 Hz), 1.53 (6 H, d, J =6.53 Hz)

實例 58      [(1R,5S,6r)-6-(4- 環丙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮 N- 環丙基 -2- 丙胺向環丙胺(0.24 mL，3.5 mmol)及丙酮(1017.34mg，17.52 mmol)於DMF (2.5 mL)中之溶液添加4A MS(2000 mg，3.5 mmol)。在無監測之情況下在110℃下攪拌混合物4小時。過濾混合物，得到標題化合物(2000 mg，2.0585 mmol，58.759%產率)。粗產物直接用於下一步驟。 Example 58 [(1R,5S,6r)-6-(4- cyclopropyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )- 3- Azabicyclo [3.1.0] hex -3- yl ](1- isopropyl -1H- imidazol -4- yl ) methanone N- cyclopropyl -2- propanamine to cyclopropylamine (0.24 mL, 3.5 mmol) and acetone (1017.34 mg, 17.52 mmol) in DMF (2.5 mL) was added 4A MS (2000 mg, 3.5 mmol). The mixture was stirred at 110° C. for 4 hours without monitoring. The mixture was filtered to afford the title compound (2000 mg, 2.0585 mmol, 58.759% yield). The crude product was used directly in the next step.

(1R,5S,6r)-6-(4- 環丙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向Et ₃N (0.36 mL，2.18 mmol)及N-環丙基-2-丙胺(5000 mg，5.15 mmol)之溶液添加(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(200 mg，0.73 mmol)。在20℃下攪拌混合物16小時。LCMS展示所要質量。用H ₂O (50 mL)稀釋混合物且用EtOAc (30 mL × 2)萃取。用鹽水(50 mL)洗滌有機相，經無水Na ₂SO ₄乾燥且濃縮，得到殘餘物。藉由快速柱(PE:EtOAc=1:0至0:1)純化殘餘物，得到呈黃色油狀之標題化合物(80mg，0.2489 mmol，34.192%產率)。 ¹H NMR (400MHz, DMSO-d6) δ = 11.67 (brs, 1H), 7.35-7.25 (m, 2H), 7.05-6.95 (m, 3H), 1.92 (s, 3H)。 (1R,5S,6r)-6-(4- cyclopropyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- nitrogen Heterobicyclo [3.1.0] hexane -3- carboxylic acid tert-butyl ester was added to a solution of _Et3N (0.36 mL, 2.18 mmol) and N-cyclopropyl-2-propanamine (5000 mg, 5.15 mmol) ( 1R,5S,6r)-6-[(Z)-Chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (200 mg , 0.73 mmol). The mixture was stirred at 20°C for 16 hours. LCMS showed the desired mass. The mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (30 mL×2). The organic phase was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give a residue. The residue was purified by flash column (PE:EtOAc = 1:0 to 0:1) to give the title compound (80 mg, 0.2489 mmol, 34.192% yield) as a yellow oil. ¹ H NMR (400MHz, DMSO-d6) δ = 11.67 (brs, 1H), 7.35-7.25 (m, 2H), 7.05-6.95 (m, 3H), 1.92 (s, 3H).

(1R,5S,6r)-6-(4- 環丙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽向(1R,5S,6r)-6-(4-環丙基-5,5-二甲基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(80 mg，0.25 mmol)於DCM (4.4444 mL)中之溶液添加TFA (0.44 mL，5.98 mmol)。在20℃下攪拌混合物4小時。TLC (PE:EtOAc=1:1)展示偵測到新樣點(Rf=0)。濃縮混合物，得到呈黃色油狀之標題化合物(55mg，0.2485 mmol，99.851%產率)。粗物質直接用於下一步驟。 (1R,5S,6r)-6-(4- cyclopropyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- nitrogen Heterobicyclo [3.1.0] hexane TFA salt to (1R,5S,6r)-6-(4-cyclopropyl-5,5-dimethyl-4,5-dihydro-1,2,4- To a solution of tert-butyl (oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (80 mg, 0.25 mmol) in DCM (4.4444 mL) was added TFA (0.44 mL, 5.98 mmol). The mixture was stirred at 20°C for 4 hours. TLC (PE:EtOAc=1:1) showed detection of a new spot (Rf=0). The mixture was concentrated to afford the title compound (55 mg, 0.2485 mmol, 99.851% yield) as a yellow oil. The crude material was used directly in the next step.

[(1R,5S,6r)-6-(4- 環丙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮向(1R,5S,6r)-6-(4-環丙基-5,5-二甲基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(55 mg，0.25 mmol)、1-異丙基咪唑-4-羧酸(42.15mg，0.27 mmol)及DIPEA (0.14 mL，0.87 mmol)於DMF (2.4444 mL)中之溶液添加HATU (142.52mg，0.37 mmol)。在20℃下攪拌混合物1小時，得到褐色混合物。LCMS展示起始材料耗盡且偵測到所要峰值。用H ₂O (50 mL)稀釋反應混合物且用EtOAc (25 mL × 3)萃取。用鹽水(50 mL × 3)洗滌有機相，經無水Na ₂SO ₄乾燥且濃縮，得到殘餘物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈白色固體狀之標題化合物(7.32mg，0.0205 mmol，8.2398%產率)。 LC-MS方法1: 358.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.68 (d, J=1.6 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 4.75 (d, J=12.0 Hz, 1H), 4.35 (spt, J=6.7 Hz, 1H), 4.16 (d, J=12.6 Hz, 1H), 3.96 (dd, J=4.3, 11.9 Hz, 1H), 3.64 (dd, J=4.4, 12.8 Hz, 1H), 2.32 - 2.26 (m, 1H), 2.23 (td, J=3.8, 7.3 Hz, 1H), 2.03 (td, J=3.8, 7.4 Hz, 1H), 1.50 (d, J=6.8 Hz, 6H), 1.46 (d, J=6.0 Hz, 6H), 1.43 (t, J=3.6 Hz, 1H), 0.75 - 0.68 (m, 4H) [(1R,5S,6r)-6-(4- cyclopropyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- Azabicyclo [3.1.0] hex -3- yl ](1- isopropyl -1H- imidazol -4- yl ) methanone to (1R,5S,6r)-6-(4-cyclopropyl-5 ,5-Dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane TFA salt (55 mg, 0.25 mmol) , 1-isopropylimidazole-4-carboxylic acid (42.15 mg, 0.27 mmol) and DIPEA (0.14 mL, 0.87 mmol) in DMF (2.4444 mL) was added HATU (142.52 mg, 0.37 mmol). The mixture was stirred at 20°C for 1 hour to give a brown mixture. LCMS showed depletion of starting material and detection of the desired peak. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (25 mL×3). The organic phase was washed with brine (50 mL x 3), dried over anhydrous Na ₂ SO ₄ and concentrated to give a residue. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (7.32 mg, 0.0205 mmol, 8.2398% yield) as a white solid. LC-MS method 1: 358.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.68 (d, J =1.6 Hz, 1H), 7.47 (d, J =1.2 Hz, 1H), 4.75 (d, J =12.0 Hz, 1H), 4.35 (spt, J =6.7 Hz, 1H), 4.16 (d, J =12.6 Hz, 1H), 3.96 (dd, J =4.3, 11.9 Hz, 1H), 3.64 (dd, J =4.4, 12.8 Hz, 1H), 2.32 - 2.26 (m, 1H), 2.23 (td, J =3.8, 7.3 Hz, 1H), 2.03 (td, J =3.8, 7.4 Hz, 1H), 1.50 (d, J =6.8 Hz, 6H), 1.46 (d, J =6.0 Hz, 6H), 1.43 (t, J =3.6 Hz, 1H), 0.75 - 0.68 (m, 4H)

實例 59      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 N- 甲基 -2- 丙胺向甲胺(1.3 mL，32.2 mmol)及丙酮(9349.65mg，160.98 mmol)於DMF (22.976 mL)中之溶液添加4A MS (3000 mg，32.2 mmol)。在110℃下攪拌混合物4小時。過濾混合物，得到標題化合物(2000 mg，2.8121 mmol，8.7345%產率)。粗產物直接用於下一步驟。 Example 59 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(4,5,5- trimethyl -4,5- dihydro -1,2, 4- oxadiazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone N- methyl -2- propanamine to methylamine (1.3 mL, 32.2 mmol) and acetone ( 9349.65 mg, 160.98 mmol) in DMF (22.976 mL) was added 4A MS (3000 mg, 32.2 mmol). The mixture was stirred at 110°C for 4 hours. The mixture was filtered to afford the title compound (2000 mg, 2.8121 mmol, 8.7345% yield). The crude product was used directly in the next step.

(1R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向Et ₃N (0.36 mL，2.18 mmol)及N-甲基-2-丙胺(258.86mg，3.64 mmol)之溶液添加(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(200 mg，0.73 mmol)。在20℃下攪拌混合物16小時。LCMS展示所要質量。用H ₂O (50 mL)稀釋混合物且用EtOAc (30 mL × 2)萃取。用鹽水(50 mL)洗滌有機相，經無水Na ₂SO ₄乾燥且濃縮，得到殘餘物。藉由快速柱(PE:EtOAc=1:0至0:1)純化殘餘物，得到呈黃色油狀之標題化合物(140mg，0.4740 mmol，65.109%產率) (PE:EtOAc=1:1，Rf=0.3)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.70 (d, J = 11.2 Hz, 1H), 3.60 (d, J = 11.2 Hz, 1H), 3.50-3.40 (m, 2H), 2.78 (s, 3H), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 1H), 1.44 (s, 9H), 1.41 (s, 6H). 1.16-1.14 (m, 1H)。 (1R,5S,6r)-6-(4,5,5- Trimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- azabicyclo [3.1 .0] tert- butyl hexane -3- carboxylate To a solution of _Et3N (0.36 mL, 2.18 mmol) and N-methyl-2-propanamine (258.86 mg, 3.64 mmol) was added (1R, 5S, 6r )-6-[(Z)-Chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (200 mg, 0.73 mmol). The mixture was stirred at 20°C for 16 hours. LCMS showed the desired mass. The mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (30 mL×2). The organic phase was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give a residue. The residue was purified by flash column (PE:EtOAc=1:0 to 0:1) to give the title compound (140 mg, 0.4740 mmol, 65.109% yield) as a yellow oil (PE:EtOAc=1:1, Rf =0.3). ¹ H NMR (400MHz, Chloroform-d) δ = 3.70 (d, J = 11.2 Hz, 1H), 3.60 (d, J = 11.2 Hz, 1H), 3.50-3.40 (m, 2H), 2.78 (s, 3H ), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 1H), 1.44 (s, 9H), 1.41 (s, 6H). 1.16-1.14 (m, 1H).

(1R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽向(1R,5S,6r)-6-(4,5,5-三甲基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(140 mg，0.47 mmol)於DCM (2.8 mL)中之溶液添加TFA (0.56 mL，7.54 mmol)。在15℃下攪拌反應混合物16小時，得到褐色混合物。LCMS展示起始材料消耗完。濃縮反應混合物，得到呈棕色油狀之標題化合物。殘餘物直接用於下一步驟。 LC-MS方法1 0.214 min，MS (m/z) 195.9 (M + H ⁺)。 (1R,5S,6r)-6-(4,5,5- Trimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- azabicyclo [3.1 .0] hexane TFA salt to (1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl) - To a solution of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (140 mg, 0.47 mmol) in DCM (2.8 mL) was added TFA (0.56 mL, 7.54 mmol). The reaction mixture was stirred at 15°C for 16 hours to give a brown mixture. LCMS showed starting material was consumed. The reaction mixture was concentrated to afford the title compound as a brown oil. The residue was used directly in the next step. LC-MS method 1 0.214 min, MS (m/z) 195.9 (M + H ⁺ ).

(1- 異丙基 -1H- 咪唑 -4- 基 ) [(1R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-異丙基-1H-吡唑-3-羧酸(72.64mg，0.47 mmol)於DMF (3.5385 mL)中之溶液添加HATU (135.48mg，0.71 mmol)及DIPEA (182.7 mg，1.41 mmol)。在15℃下攪拌反應混合物30 min。隨後向反應物添加(1R,5S,6r)-6-(4,5,5-三甲基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(92 mg，0.47 mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (NH ₃)純化反應混合物，得到呈白色粉末狀之標題化合物(18.72mg，0.0565 mmol，11.989%產率)。 LC-MS方法1: 331.9 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.67 (d, J=1.2 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 4.75 (d, J=12.0 Hz, 1H), 4.35 (spt, J=6.7 Hz, 1H), 4.19 (d, J=12.4 Hz, 1H), 3.94 (dd, J=4.3, 12.0 Hz, 1H), 3.62 (dd, J=4.4, 12.8 Hz, 1H), 2.76 (s, 3H), 2.20 (td, J=3.7, 7.3 Hz, 1H), 2.06 - 2.00 (m, 1H), 1.50 (d, J=6.4 Hz, 6H), 1.40 (d, J=4.0 Hz, 6H), 1.15 (t, J=3.4 Hz, 1H) (1- isopropyl -1H- imidazol -4- yl ) [(1R,5S,6r)-6-(4,5,5- trimethyl -4,5- dihydro -1,2,4- Oxadiazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 5-isopropyl-1H-pyrazole-3-carboxylic acid (72.64mg, 0.47 mmol) To a solution in DMF (3.5385 mL) was added HATU (135.48 mg, 0.71 mmol) and DIPEA (182.7 mg, 1.41 mmol). The reaction mixture was stirred at 15 °C for 30 min. (1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3- Azabicyclo[3.1.0]hexane TFA salt (92 mg, 0.47 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC (NH ₃ ) to afford the title compound (18.72 mg, 0.0565 mmol, 11.989% yield) as a white powder. LC-MS method 1: 331.9 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.67 (d, J =1.2 Hz, 1H), 7.47 (d, J =1.2 Hz, 1H), 4.75 (d, J =12.0 Hz, 1H), 4.35 (spt, J =6.7 Hz, 1H), 4.19 (d, J =12.4 Hz, 1H), 3.94 (dd, J =4.3, 12.0 Hz, 1H), 3.62 (dd, J =4.4, 12.8 Hz, 1H), 2.76 (s, 3H), 2.20 (td, J =3.7, 7.3 Hz, 1H), 2.06 - 2.00 (m, 1H), 1.50 (d, J =6.4 Hz, 6H), 1.40 (d, J =4.0 Hz, 6H), 1.15 (t, J =3.4 Hz, 1H)

實例 60      [(1R,5S,6r)-6-(4- 乙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮 (1R,5S,6r)-6-(4- 乙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向Et ₃N (0.36 mL，2.18 mmol)及N-乙基丙-2-亞胺(309.93mg，3.64 mmol)之溶液添加(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(200 mg，0.73 mmol)。在20℃下攪拌混合物16小時。LCMS展示所要質量。用H ₂O (50 mL)稀釋混合物且用EtOAc (30 mL × 2)萃取。用鹽水(50 mL)洗滌有機相，經無水Na ₂SO ₄乾燥且濃縮，得到殘餘物。藉由快速柱(PE:EtOAc=1:0至0:1)純化殘餘物，得到呈黃色油狀之標題化合物(140mg，0.4525 mmol，62.158%產率) (PE:EtOAc=1:1，Rf=0.3)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.68 (d, J = 11.2 Hz, 1H), 3.58 (d, J = 11.2 Hz, 1H), 3.45-3.30 (m, 2H), 3.18 (q, J = 6.8 Hz, 2H), 2.30-2.20 (m, 1H), 2.00-1.90 (m, 1H), 1.45 (s, 9H), 1.42 (s, 3H), 1.21 (t, J = 6.8 Hz, 3H), 1.14-1.13 (m, 1H)。 Example 60 [(1R,5S,6r)-6-(4- ethyl -5,5- dimethyl -4,5- dihydro -1,2,4 -oxadiazol -3- yl )-3 -Azabicyclo [3.1.0] hex -3- yl ](1- isopropyl -1H- imidazol -4- yl ) methanone (1R,5S,6r)-6-(4- ethyl -5 , 5- Dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to To a solution of Et ₃ N (0.36 mL, 2.18 mmol) and N-ethylpropan-2-imine (309.93 mg, 3.64 mmol) was added (1R,5S,6r)-6-[(Z)-chloro(hydroxy Imino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (200 mg, 0.73 mmol). The mixture was stirred at 20°C for 16 hours. LCMS showed the desired mass. The mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (30 mL×2). The organic phase was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give a residue. The residue was purified by flash column (PE:EtOAc=1:0 to 0:1) to give the title compound (140 mg, 0.4525 mmol, 62.158% yield) as a yellow oil (PE:EtOAc=1:1, Rf =0.3). ¹ H NMR (400MHz, chloroform-d) δ = 3.68 (d, J = 11.2 Hz, 1H), 3.58 (d, J = 11.2 Hz, 1H), 3.45-3.30 (m, 2H), 3.18 (q, J = 6.8 Hz, 2H), 2.30-2.20 (m, 1H), 2.00-1.90 (m, 1H), 1.45 (s, 9H), 1.42 (s, 3H), 1.21 (t, J = 6.8 Hz, 3H) , 1.14-1.13 (m, 1H).

(1R,5S,6r)-6-(4- 乙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽向(1R,5S,6r)-6-(4-乙基-5,5-二甲基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(140 mg，0.45 mmol)於DCM (2.6731 mL)中之溶液添加TFA (0.53 mL，7.2 mmol)。在15℃下攪拌反應混合物16小時，得到褐色混合物。LCMS展示起始材料消耗完。濃縮反應混合物，得到呈棕色油狀之標題化合物。殘餘物直接用於下一步驟。 LC-MS方法1 0.785 min，MS (m/z) 309.9 (M + H ⁺)。 (1R,5S,6r)-6-(4- Ethyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol- 3- yl )-3- aza Bicyclo [3.1.0] hexane TFA salt to (1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-dihydro To a solution of tert-butyl-azol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (140 mg, 0.45 mmol) in DCM (2.6731 mL) was added TFA (0.53 mL, 7.2 mmol). The reaction mixture was stirred at 15°C for 16 hours to give a brown mixture. LCMS showed starting material was consumed. The reaction mixture was concentrated to afford the title compound as a brown oil. The residue was used directly in the next step. LC-MS method 1 0.785 min, MS (m/z) 309.9 (M + H ⁺ ).

[(1R,5S,6r)-6-(4- 乙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮向1-異丙基咪唑-4-羧酸(69.24mg，0.45 mmol)於DMF (3.373 mL)中之溶液添加HATU (129.15mg，0.67 mmol)及DIPEA (0.22 mL，1.35 mmol)。在15℃下攪拌反應混合物30 min。隨後向反應物添加(1R,5S,6r)-6-(4-乙基-5,5-二甲基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(94 mg，0.45 mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (NH ₃)純化反應混合物，得到呈灰白色固體狀之標題化合物(9.9mg，0.0287 mmol，6.3809%產率)。 LC-MS方法1: 346.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.67 (d, J=1.2 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 4.73 (d, J=12.0 Hz, 1H), 4.35 (m, 1H), 4.17 (d, J=12.6 Hz, 1H), 3.96 (dd, J=4.0, 12.0 Hz, 1H), 3.64 (dd, J=4.0, 12.6 Hz, 1H), 3.16 (m, 2H), 2.24 (m, 1H), 2.05 (m, 1H), 1.50 (d, J=6.8 Hz, 6H), 1.42 (d, J=5.6 Hz, 6H), 1.19 (t, J=7.2 Hz, 3H), 1.14 (t, J=3.4 Hz, 1H) [(1R,5S,6r)-6-(4- Ethyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- nitrogen Heterobicyclo [3.1.0] hex -3- yl ](1- isopropyl -1H- imidazol -4- yl ) methanone to 1-isopropylimidazole-4-carboxylic acid (69.24mg, 0.45 mmol) in To a solution in DMF (3.373 mL) was added HATU (129.15 mg, 0.67 mmol) and DIPEA (0.22 mL, 1.35 mmol). The reaction mixture was stirred at 15 °C for 30 min. (1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl) was then added to the reaction - 3-Azabicyclo[3.1.0]hexane TFA salt (94 mg, 0.45 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC ( _NH3 ) to afford the title compound (9.9 mg, 0.0287 mmol, 6.3809% yield) as an off-white solid. LC-MS method 1: 346.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.67 (d, J =1.2 Hz, 1H), 7.47 (d, J =1.2 Hz, 1H), 4.73 (d, J =12.0 Hz, 1H), 4.35 (m, 1H), 4.17 (d, J =12.6 Hz, 1H), 3.96 (dd, J =4.0, 12.0 Hz, 1H), 3.64 (dd, J = 4.0, 12.6 Hz, 1H), 3.16 (m, 2H), 2.24 (m, 1H), 2.05 (m, 1H), 1.50 (d, J =6.8 Hz, 6H), 1.42 (d, J =5.6 Hz, 6H), 1.19 (t, J =7.2 Hz, 3H), 1.14 (t, J =3.4 Hz, 1H)

實例 61      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-([1,2,4] ***并 [4,3-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6-{[2-(2- 吡啶基 ) 肼基 ] 羰基 }-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(300 mg，1.32 mmol)於DMF (5 mL)中之混合物添加2-肼基吡啶(144.06 mg，1.32 mmol)、Et ₃N (0.2 mL，1.45 mmol)及HATU (555.13 mg，1.45 mmol)。在15℃下攪拌反應混合物16小時，得到褐色混合物。真空濃縮反應混合物，得到殘餘物。藉由二氧化矽管柱(SiO ₂，石油醚:乙酸乙酯=6:1至0:1)純化殘餘物，得到呈黃色膠質之標題化合物(418 mg，1.3129 mmol，99.459%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 8.55 (dd, J = 4.4, 1.6 Hz, 1H), 8.27 (dd, J = 9.2, 1.2 Hz, 1H), 8.03 (d, J = 4.8 Hz, 1H), 7.57 (t, J = 9.2 Hz, 1H), 7.29 (dd, J = 8.4, 4.4 Hz, 1H), 6.80-6.70 (m, 1H), 3.60-3.50 (m, 2H), 3.40-3.30 (m, 3H), 2.10-2.00 (m, 2H), 1.47-1.46 (m, 1H), 1.35 (s, 9H)。 Example 61 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-([1,2,4] triazolo [4,3-a] pyridine -3- Base )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (1R,5S,6r)-6-{[2-(2- pyridyl ) hydrazino ] carbonyl }-3- nitrogen Heterobicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-3-{[(tertiary butyl)oxy]carbonyl}-3-azabicyclo[3.1 .0] A mixture of hexane-6-carboxylic acid (300 mg, 1.32 mmol) in DMF (5 mL) was added 2-hydrazinopyridine (144.06 mg, 1.32 mmol), Et ₃ N (0.2 mL, 1.45 mmol) and HATU (555.13 mg, 1.45 mmol). The reaction mixture was stirred at 15°C for 16 hours to give a brown mixture. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by silica column (SiO ₂ , petroleum ether:ethyl acetate=6:1 to 0:1) to obtain the title compound (418 mg, 1.3129 mmol, 99.459% yield) as a yellow gum. ¹ H NMR (400MHz, chloroform-d) δ = 8.55 (dd, J = 4.4, 1.6 Hz, 1H), 8.27 (dd, J = 9.2, 1.2 Hz, 1H), 8.03 (d, J = 4.8 Hz, 1H ), 7.57 (t, J = 9.2 Hz, 1H), 7.29 (dd, J = 8.4, 4.4 Hz, 1H), 6.80-6.70 (m, 1H), 3.60-3.50 (m, 2H), 3.40-3.30 ( m, 3H), 2.10-2.00 (m, 2H), 1.47-1.46 (m, 1H), 1.35 (s, 9H).

(1R,5S,6r)-6-([1,2,4] ***并 [4,3-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-{[2-(2-吡啶基)肼基]羰基}-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(200 mg，0.63 mmol)於MeCN (4 mL)中之混合物添加柏傑士試劑(149.7 mg，0.63 mmol)。在90℃下攪拌反應混合物12小時，得到黃色混合物。TLC (DCM/MeOH = 10/1)展示起始材料完全耗盡且偵測到新樣點。真空濃縮反應混合物，得到殘餘物。藉由製備型TLC (DCM/MeOH=10/1)純化殘餘物，得到呈黃色固體狀之標題化合物(64mg，0.2131 mmol，33.919%產率)。 LC-MS方法1 0.668, MS (m/z) 300.9 (M + H ⁺)。 (1R,5S,6r)-6-([1,2,4] triazolo [4,3-a] pyridin -3- yl )-3- azabicyclo [3.1.0] hexane -3- Tertiary butyl carboxylate to (1R,5S,6r)-6-{[2-(2-pyridyl)hydrazino]carbonyl}-3-azabicyclo[3.1.0]hexane-3-carboxylic acid To a mixture of tert-butyl ester (200 mg, 0.63 mmol) in MeCN (4 mL) was added Burgess reagent (149.7 mg, 0.63 mmol). The reaction mixture was stirred at 90 °C for 12 hours to give a yellow mixture. TLC (DCM/MeOH = 10/1) showed complete consumption of starting material and detection of new spots. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (DCM/MeOH=10/1) to give the title compound (64 mg, 0.2131 mmol, 33.919% yield) as a yellow solid. LC-MS method 1 0.668, MS (m/z) 300.9 (M + H ⁺ ).

3-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ][1,2,4] ***并 [4,3-a] 吡啶 TFA 鹽向(1R,5S,6r)-6-([1,2,4]***并[4,3-a]吡啶-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(66.2 mg，0.22 mmol)於DCM (2 mL)中之溶液添加TFA (0.2 mL，2.61 mmol)。在25℃下攪拌反應混合物2小時，得到黃色混合物。真空濃縮反應混合物，得到標題化合物。粗產物直接用於下一步驟。 3-[(1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl ][1,2,4] triazolo [4,3-a] pyridine TFA salt to (1R ,5S,6r)-6-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid To a solution of tert-butyl ester (66.2 mg, 0.22 mmol) in DCM (2 mL) was added TFA (0.2 mL, 2.61 mmol). The reaction mixture was stirred at 25°C for 2 hours to give a yellow mixture. The reaction mixture was concentrated in vacuo to afford the title compound. The crude product was used directly in the next step.

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-([1,2,4] ***并 [4,3-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基][1,2,4]***并[4,3-a]吡啶TFA鹽(40 mg，0.20 mmol)於DMF (2 mL)中之混合物添加1-異丙基咪唑-4-羧酸(30.8 mg，0.20 mmol)、Et ₃N (0.11 mL，0.80 mmol)及HATU (114.55mg，0.30 mmol)。在25℃下攪拌反應混合物12小時，得到黃色混合物。藉由製備型HPLC (NH ₃)純化粗產物，得到呈黃色膠質之標題化合物(8.6 mg，12.8%產率)。 ¹H NMR (400MHz, CDCl ₃) δ = 7.97 (d, J=7.0 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.44 (s, 1H), 7.18 - 7.14 (m, 1H), 6.79 (t, J=6.8 Hz, 1H), 4.90 (d, J=12.0 Hz, 1H), 4.40 - 4.19 (m, 2H), 4.00 (dd, J=4.1, 12.1 Hz, 1H), 3.69 (dd, J=4.1, 12.5 Hz, 1H), 2.50 (td, J=3.7, 7.3 Hz, 1H), 2.31 (td, J=3.7, 7.2 Hz, 1H), 1.88 (t, J=3.3 Hz, 1H), 1.45 (d, J=6.8 Hz, 6H) (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-([1,2,4] triazolo [4,3-a] pyridin -3 - yl ) -3- Azabicyclo [3.1.0] hex -3- yl ] methanone to 3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl][1, To a mixture of 2,4]triazolo[4,3-a]pyridine TFA salt (40 mg, 0.20 mmol) in DMF (2 mL) was added 1-isopropylimidazole-4-carboxylic acid (30.8 mg, 0.20 mmol), Et ₃ N (0.11 mL, 0.80 mmol) and HATU (114.55 mg, 0.30 mmol). The reaction mixture was stirred at 25°C for 12 hours to give a yellow mixture. The crude product was purified by preparative HPLC ( _NH3 ) to afford the title compound (8.6 mg, 12.8% yield) as a yellow gum. ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.97 (d, J =7.0 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.44 (s, 1H), 7.18 - 7.14 (m, 1H), 6.79 ( t, J =6.8 Hz, 1H), 4.90 (d, J =12.0 Hz, 1H), 4.40 - 4.19 (m, 2H), 4.00 (dd, J =4.1, 12.1 Hz, 1H), 3.69 (dd, J =4.1, 12.5 Hz, 1H), 2.50 (td, J =3.7, 7.3 Hz, 1H), 2.31 (td, J =3.7, 7.2 Hz, 1H), 1.88 (t, J =3.3 Hz, 1H), 1.45 (d, J =6.8 Hz, 6H)

實例 62      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-([1,2,3] ***并 [1,5-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6-[ 羥基 (2- 吡啶基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在15℃下向(1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(0.61 mL，1.42 mmol)於THF (6 mL)中之溶液添加溴基(2-吡啶基)鎂(3.2 mL，2.13 mmol)。在0℃下攪拌反應混合物4小時，得到褐色混合物。LCMS展示所要MS。TLC (PE/EtOAc=1:2)展示新樣點。用H ₂O (30 mL)淬滅反應混合物且用EtOAc (30 mL × 2)萃取。用鹽水(30 mL × 2)洗滌有機層，經無水Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到殘餘物。藉由矽膠管柱(PE/EtOAc=1:2)純化殘餘物，得到呈淺黃色膠質之標題化合物(200 mg，0.6888 mmol，48.505%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 8.53 (d, J = 8.4 Hz, 1H), 7.75-7.65 (m, 1H), 7.40-7.30 (m, 1H), 7.25-7.20 (m, 1H), 4.60-4.25 (m, 2H), 3.60-3.45 (m, 2H), 3.40-3.30 (m, 2H), 1.80-1.60 (m, 2H), 1.43 (s, 9H), 1.00-0.90 (m, 1H)。 Example 62 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-([1,2,3] triazolo [1,5-a] pyridine -3- Base )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (1R,5S,6r)-6-[ hydroxyl (2- pyridyl ) methyl ]-3- azabicyclo [3.1 .0] tertiary butyl hexane -3- carboxylate to (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid at 15°C To a solution of tert-butyl ester (0.61 mL, 1.42 mmol) in THF (6 mL) was added bromo(2-pyridyl)magnesium (3.2 mL, 2.13 mmol). The reaction mixture was stirred at 0 °C for 4 hours to give a brown mixture. LCMS showed desired MS. TLC (PE/EtOAc=1:2) showed a fresh spot. The reaction mixture was quenched with H ₂ O (30 mL) and extracted with EtOAc (30 mL×2). The organic layer was washed with brine (30 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (PE/EtOAc=1:2) to obtain the title compound (200 mg, 0.6888 mmol, 48.505% yield) as light yellow gum. ¹ H NMR (400MHz, Chloroform-d) δ = 8.53 (d, J = 8.4 Hz, 1H), 7.75-7.65 (m, 1H), 7.40-7.30 (m, 1H), 7.25-7.20 (m, 1H) , 4.60-4.25 (m, 2H), 3.60-3.45 (m, 2H), 3.40-3.30 (m, 2H), 1.80-1.60 (m, 2H), 1.43 (s, 9H), 1.00-0.90 (m, 1H).

(1R,5S,6r)-6-(2- 吡啶基羰基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在15℃下向(1R,5S,6r)-6-[羥基(2-吡啶基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(200 mg，0.69 mmol)於DCM (4.1931 mL)中之溶液添加DMP (292.15mg，0.69 mmol)。在15℃下攪拌反應混合物20 min，得到白色混合物。TLC (PE/EtOAc=1:1)展示新樣點。用NaHCO ₃(30 mL)淬滅反應混合物且用DCM (30 mL × 2)萃取。用鹽水(30 mL × 2)洗滌有機層，經無水Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到殘餘物。藉由矽膠管柱(PE/EtOAc=1:1)純化殘餘物，得到呈白色固體狀之標題化合物(200 mg，0.6936 mmol，100.7%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 8.77 (d, J = 4.0 Hz, 1H), 8.10-7.90 (m, 2H), 7.70 (dd, J = 4.8, 3.6 Hz, 1H), 3.57 (d, J = 11.2 Hz, 2H), 3.50-3.40 (m, 2H), 3.24 (s, 1H), 2.23 (s, 2H), 1.41 (s, 3H)。 (1R,5S,6r)-6-(2- pyridylcarbonyl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 15°C to (1R,5S,6r )-tert-butyl 6-[hydroxy(2-pyridyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (200 mg, 0.69 mmol) in DCM (4.1931 mL) To the solution in was added DMP (292.15 mg, 0.69 mmol). The reaction mixture was stirred at 15 °C for 20 min to give a white mixture. TLC (PE/EtOAc=1:1) showed fresh samples. The reaction mixture was quenched with NaHCO ₃ (30 mL) and extracted with DCM (30 mL×2). The organic layer was washed with brine (30 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (PE/EtOAc=1:1) to give the title compound (200 mg, 0.6936 mmol, 100.7% yield) as a white solid. ¹ H NMR (400MHz, chloroform-d) δ = 8.77 (d, J = 4.0 Hz, 1H), 8.10-7.90 (m, 2H), 7.70 (dd, J = 4.8, 3.6 Hz, 1H), 3.57 (d , J = 11.2 Hz, 2H), 3.50-3.40 (m, 2H), 3.24 (s, 1H), 2.23 (s, 2H), 1.41 (s, 3H).

(1R,5S,6r)-6-([1,2,3] ***并 [1,5-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-(2-吡啶基羰基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.35 mmol)於EtOH (2.0973 mL)中之溶液添加水合肼(26.04mg，0.52 mmol)。在60℃下攪拌反應混合物6小時，得到無色混合物。隨後向反應混合物添加乙酸銅(3.45mg，0.02 mmol)、乙酸乙酯(10 mL)。隨後在20℃下攪拌反應混合物1小時，得到無色混合物。LCMS展示所要MS。濃縮反應混合物，得到殘餘物。藉由製備型TLC (PE/EtOAc=1:1)純化殘餘物，得到呈無色油狀之標題化合物(20mg，0.0666 mmol，19.2%產率)。 LC-MS方法1 0.832 min，MS (m/z) 301.2 (M + H ⁺)。 ¹H NMR (400MHz, 氯仿-d) δ 8.65 (d, J = 7.2Hz, 1H), 7.69 (dd, J = 7.6, 1.2 Hz, 1H), 7.19 (dd, J = 8.0, 5.6 Hz, 1H), 6.95 (t, J = 6.0 Hz, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.60-3.50 (m, 2H), 2.35-2.25 (m, 1H), 2.20-2.10 (m, 1H), 1.95-1.90 (m, 1H), 1.48 (s, 9H)。 (1R,5S,6r)-6-([1,2,3] triazolo [1,5-a] pyridin -3- yl )-3- azabicyclo [3.1.0] hexane -3- Tertiary butyl carboxylate to (1R,5S,6r)-6-(2-pyridylcarbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (100 mg, 0.35 mmol) in EtOH (2.0973 mL) was added hydrazine hydrate (26.04 mg, 0.52 mmol). The reaction mixture was stirred at 60°C for 6 hours to obtain a colorless mixture. Then copper acetate (3.45 mg, 0.02 mmol), ethyl acetate (10 mL) were added to the reaction mixture. The reaction mixture was then stirred at 20° C. for 1 hour to give a colorless mixture. LCMS showed desired MS. The reaction mixture was concentrated to give a residue. The residue was purified by prep-TLC (PE/EtOAc=1:1) to give the title compound (20 mg, 0.0666 mmol, 19.2% yield) as a colorless oil. LC-MS method 1 0.832 min, MS (m/z) 301.2 (M + H ⁺ ). ¹ H NMR (400MHz, chloroform-d) δ 8.65 (d, J = 7.2Hz, 1H), 7.69 (dd, J = 7.6, 1.2 Hz, 1H), 7.19 (dd, J = 8.0, 5.6 Hz, 1H) , 6.95 (t, J = 6.0 Hz, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.60-3.50 (m, 2H), 2.35-2.25 ( m, 1H), 2.20-2.10 (m, 1H), 1.95-1.90 (m, 1H), 1.48 (s, 9H).

3-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ][1,2,3] ***并 [1,5-a] 吡啶 TFA 鹽向(1R,5S,6r)-6-([1,2,3]***并[1,5-a]吡啶-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(30 mg，0.10 mmol)於DCM (3.14 mL)中之溶液添加TFA (0.01 mL，0.10 mmol)。在20℃下攪拌反應混合物16小時，得到無色混合物。TLC (PE/EtOAc=1:1)展示新樣點。移除反應混合物溶劑，得到標題化合物。殘餘物直接用於下一步驟。 LC-MS方法1 0.289 min，MS (m/z) 200.9 (M + H ⁺)。 3-[(1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl ][1,2,3] triazolo [1,5-a] pyridine TFA salt to (1R ,5S,6r)-6-([1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid To a solution of tert-butyl ester (30 mg, 0.10 mmol) in DCM (3.14 mL) was added TFA (0.01 mL, 0.10 mmol). The reaction mixture was stirred at 20°C for 16 hours to give a colorless mixture. TLC (PE/EtOAc=1:1) showed fresh samples. The reaction mixture solvent was removed to afford the title compound. The residue was used directly in the next step. LC-MS method 1 0.289 min, MS (m/z) 200.9 (M + H ⁺ ).

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-([1,2,3] ***并 [1,5-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-異丙基咪唑-4-羧酸(23.1mg，0.15 mmol)於DMF (1.1251 mL)中之溶液添加HATU (43.08mg，0.22 mmol)及DIPEA (0.07 mL，0.45 mmol)。在15℃下攪拌反應混合物30 min。隨後向反應物添加3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基][1,2,3]***并[1,5-a]吡啶TFA鹽(30 mg，0.15 mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (FA)純化反應混合物，得到呈白色粉末狀之標題化合物(14.4mg，0.0428 mmol，28.573%產率)。 LC-MS方法1: 337.1 [M+H ⁺] ¹H NMR (400MHz, DMSO-d ₆) δ = 8.94 (d, J=7.2 Hz, 1H), 8.12 - 7.73 (m, 3H), 7.35 - 7.22 (m, 1H), 7.10 (m, 1H), 4.77 - 4.41 (m, 2H), 4.22 - 3.85 (m, 2H), 3.60 (br s, 1H), 2.35 - 2.24 (m, 1H), 2.20 - 2.08 (m, 2H), 1.44 (br d, J=5.6 Hz, 6H) (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-([1,2,3] triazolo [1,5-a] pyridin -3 - yl ) -3- Azabicyclo [3.1.0] hex -3- yl ] methanone To a solution of 1-isopropylimidazole-4-carboxylic acid (23.1 mg, 0.15 mmol) in DMF (1.1251 mL) was added HATU ( 43.08 mg, 0.22 mmol) and DIPEA (0.07 mL, 0.45 mmol). The reaction mixture was stirred at 15 °C for 30 min. 3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl][1,2,3]triazolo[1,5-a]pyridine was then added to the reaction TFA salt (30 mg, 0.15 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC (FA) to afford the title compound (14.4 mg, 0.0428 mmol, 28.573% yield) as a white powder. LC-MS method 1: 337.1 [M+H ⁺ ] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.94 (d, J =7.2 Hz, 1H), 8.12 - 7.73 (m, 3H), 7.35 - 7.22 (m, 1H), 7.10 (m, 1H), 4.77 - 4.41 (m, 2H), 4.22 - 3.85 (m, 2H), 3.60 (br s, 1H), 2.35 - 2.24 (m, 1H), 2.20 - 2.08 (m, 2H), 1.44 (br d, J =5.6 Hz, 6H)

實例 63      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(1H- 四唑 -5- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6- 胺甲醯基 -3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在10℃下攪拌(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(1000 mg，4.4mmol)、1H-苯并[d][1,2,3]***-1-醇(713.47mg，5.28mmol)、N-乙基-N-異丙基丙-2-胺(0.91mL，5.28mmol)及EDCI (1012.23mg，5.28mmol)於DCM (10mL)中之溶液30 min。隨後將其冷卻至0℃且逐滴添加NH ₃/EtOH (5 mL，40mmol)，攪拌16小時，得到白色懸浮液。TLC (DCM/MeOH =10/1 Rf =0.1)展示偵測到新樣點。添加H ₂O (10 mL)且用EtOAc (10 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈白色固體狀之標題化合物(1050mg，4.6405mmol，105.46%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 5.59 (brs, 1H), 5.29 (brs, 1H), 3.61 (d, J = 11.2 Hz, 1H), 3.59 (d, J = 11.2 Hz, 1H), 3.45-3.35 (m, 2H), 2.27 (t, J = 7.2 Hz, 1H), 2.01 (brs, 2H), 1.37 (s, 9H)。 Example 63 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(1H- tetrazol -5- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ] methanone (1R,5S,6r)-6- aminoformyl -3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester was stirred at 10°C (1R ,5S,6r)-3-{[(tertiary butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (1000 mg, 4.4mmol), 1H-benzene [d][1,2,3]triazol-1-ol (713.47mg, 5.28mmol), N-ethyl-N-isopropylpropan-2-amine (0.91mL, 5.28mmol) and EDCI ( 1012.23 mg, 5.28 mmol) in DCM (10 mL) for 30 min. It was then cooled to 0 °C and _NH3 /EtOH (5 mL, 40 mmol) was added dropwise and stirred for 16 h to give a white suspension. TLC (DCM/MeOH=10/1 Rf=0.1) showed detection of a new spot. H ₂ O (10 mL) was added and it was extracted with EtOAc (10 mL×2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (1050 mg, 4.6405 mmol, 105.46% yield) as a white solid. ¹ H NMR (400MHz, chloroform-d) δ = 5.59 (brs, 1H), 5.29 (brs, 1H), 3.61 (d, J = 11.2 Hz, 1H), 3.59 (d, J = 11.2 Hz, 1H), 3.45-3.35 (m, 2H), 2.27 (t, J = 7.2 Hz, 1H), 2.01 (brs, 2H), 1.37 (s, 9H).

(1R,5S,6r)-6- 氰基 -3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-胺甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(620 mg，2.74mmol)於DMF (12.4mL)中之溶液添加2,4,6-三氯-1,3,5-三嗪(0.57mL，5.48mmol)。在15℃下攪拌反應混合物16小時，得到黃色溶液。TLC (PE/EA =3/1 Rf =0.2)展示偵測到新樣點。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色油狀之標題化合物。藉由矽膠層析(PE/EA=10/1至3/1)來純化粗物質，得到呈無色油狀之標題化合物(380mg，1.8246mmol，66.591%產率)。 (1R,5S,6r)-6- cyano -3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-aminoformyl- To a solution of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (620 mg, 2.74 mmol) in DMF (12.4 mL) was added 2,4,6-trichloro-1,3 , 5-Triazine (0.57 mL, 5.48 mmol). The reaction mixture was stirred at 15°C for 16 hours to give a yellow solution. TLC (PE/EA =3/1 Rf =0.2) showed detection of new samples. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo to give the title compound as a yellow oil. The crude material was purified by silica gel chromatography (PE/EA = 10/1 to 3/1 ) to give the title compound (380 mg, 1.8246 mmol, 66.591% yield) as a colorless oil.

(1R,5S,6r)-6-(1H- 四唑 -5- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在120℃下攪拌(1R,5S,6r)-6-氰基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(330 mg，1.58mmol)、鹽酸氨(169.52mg，3.17mmol)及NaN ₃(206.02mg，3.17mmol)於DMF (7.3333mL)中之混合物24小時，得到黃色溶液。TLC (EA，Rf =0.1)展示偵測到新樣點。添加H ₂O (10 mL)且用EtOAc (15 mL×3)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色油狀之標題化合物(380mg，1.5123mmol，95.437%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ ppm 7.95 (brs, 1H), 3.70-3.40 (m, 4H), 2.15 (brs, 2H), 1.96 (t, J = 3.2 Hz, 1H), 1.40 (s, 9H)。 (1R,5S,6r)-6-(1H- tetrazol -5- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester was stirred at 120°C (1R, 5S,6r)-6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (330 mg, 1.58mmol), ammonium hydrochloride (169.52mg, 3.17mmol) and NaN A mixture of ₃ (206.02 mg, 3.17 mmol) in DMF (7.3333 mL) for 24 hours gave a yellow solution. TLC (EA, Rf =0.1) showed detection of a new spot. H ₂ O (10 mL) was added and it was extracted with EtOAc (15 mL×3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (380 mg, 1.5123 mmol, 95.437% yield) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 7.95 (brs, 1H), 3.70-3.40 (m, 4H), 2.15 (brs, 2H), 1.96 (t, J = 3.2 Hz, 1H), 1.40 ( s, 9H).

(1R,5S,6r)-6-(1H- 四唑 -5- 基 )-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽將(1R,5S,6r)-6-(1H-四唑-5-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(120 mg，0.4800mmol)溶解於HCl/二㗁烷(2 mL，0.4800mmol)中且在15℃下將其攪拌2小時，得到無色溶液。在真空中蒸發反應物，得到呈無色油狀之標題化合物。其直接用於下一步驟。 (1R,5S,6r)-6-(1H- tetrazol -5- yl )-3- azabicyclo [3.1.0] hexane TFA salt will (1R,5S,6r)-6-(1H-tetra Azol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (120 mg, 0.4800 mmol) was dissolved in HCl/dioxane (2 mL, 0.4800 mmol) And it was stirred at 15° C. for 2 hours to obtain a colorless solution. The reaction was evaporated in vacuo to give the title compound as a colorless oil. It was used directly in the next step.

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(1H- 四唑 -5- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向100 mL圓底燒瓶裝入1-異丙基咪唑-4-羧酸(60 mg，0.39 mmol)、HATU (163.66mg，0.43 mmol)、N-乙基-N-異丙基丙-2-胺(0.27 mL，1.56 mmol)及DMF (3 mL)。在攪拌30 min之後，添加(1R,5S,6r)-6-(1H-四唑-5-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(103.21mg，0.39 mmol)。在20℃下攪拌反應混合物16小時，得到黃色溶液。添加H ₂O (10 mL)且用EtOAc (10 mL × 2)對其進行萃取。藉由製備型HPLC (NH ₃)純化H ₂O層。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(37.35mg，0.13 mmol，33.402%產率)。 LC-MS方法1: 288.0 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d ₆) δ 9.14 (br s, 1H), 8.32 (s, 1H), 4.65 (td, J=6.64, 13.35 Hz, 1H), 4.17 (br d, J=10.88 Hz, 1H), 3.98-4.08 (m, 2H), 2.42 (br d, J=3.25 Hz, 1H), 2.32 (br d, J=3.75 Hz, 1H), 2.13 (t, J=3.31 Hz, 1H), 1.50 (d, J=6.63 Hz, 6H) (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(1H- tetrazol -5- yl )-3- azabicyclo [3.1.0] hexa -3 -yl ] methanone A 100 mL round bottom flask was charged with 1-isopropylimidazole-4-carboxylic acid (60 mg, 0.39 mmol), HATU (163.66 mg, 0.43 mmol), N-ethyl-N-isopropyl Dioxypropan-2-amine (0.27 mL, 1.56 mmol) and DMF (3 mL). After stirring for 30 min, (1R,5S,6r)-6-(1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane TFA salt (103.21 mg, 0.39 mmol) was added. The reaction mixture was stirred at 20 °C for 16 hours to give a yellow solution. H ₂ O (10 mL) was added and it was extracted with EtOAc (10 mL×2). The H ₂ O layer was purified by preparative HPLC (NH ₃ ). The obtained fluid was concentrated in vacuo to remove most of _CH3CN and lyophilized to give the title compound (37.35 mg, 0.13 mmol, 33.402% yield) as a white solid. LC-MS method 1: 288.0 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.14 (br s, 1H), 8.32 (s, 1H), 4.65 (td, J =6.64, 13.35 Hz, 1H), 4.17 (br d, J =10.88 Hz, 1H), 3.98-4.08 (m, 2H), 2.42 (br d, J =3.25 Hz, 1H), 2.32 (br d, J =3.75 Hz, 1H), 2.13 (t, J =3.31 Hz, 1H), 1.50 (d, J =6.63 Hz, 6H)

實例 64      (1R,5S,6r)-N-( 丙 -2- 基 )-3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-6-( 異丙基胺甲醯基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(100 mg，0.44 mmol)於DMF (1.5 mL)中之溶液添加HATU (201.87 mg，0.5300 mmol)、Et ₃N (0.22 mL，1.32 mmol)及丙-2-胺(52.02 mg，0.8800 mmol)。在20℃下攪拌混合物12小時，得到黃色溶液。TLC (PE:EtOAc =1:1)展示新樣點(Rf = 0，0.7)。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (10 mL × 4)萃取。用鹽水(20 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈白色固體狀之標題化合物(110 mg 0.4099mmol，93.157%產率) (粗物質)。 Example 64 (1R,5S,6r)-N-( propan -2- yl )-3-[1-(propan - 2- yl )-1H- imidazole -4- carbonyl ]-3- azabicyclo [3.1. 0] Hexane -6- formamide (1R,5S,6r)-6-( isopropylaminoformyl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl Ester to (1R,5S,6r)-3-{[(tertiary butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (100 mg, 0.44 mmol) To a solution in DMF (1.5 mL) was added HATU (201.87 mg, 0.5300 mmol), _Et3N (0.22 mL, 1.32 mmol) and propan-2-amine (52.02 mg, 0.8800 mmol). The mixture was stirred at 20 °C for 12 hours to obtain a yellow solution. TLC (PE:EtOAc =1:1) showed a fresh spot (Rf = 0, 0.7). The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (10 mL×4). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (110 mg 0.4099 mmol, 93.157% yield) as a white solid (crude material) .

(1R,5S,6r)-N- 異丙基 -3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 TFA 鹽向(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(110 mg，0.4100 mmol)於DCM (2.8947 mL)中之溶液添加TFA (0.58 mL，7.79 mmol)。在20至25℃下攪拌所得混合物30 min，得到黃色溶液。TLC (PE:EtOAc = 1:1)展示新樣點(Rf = 0，0.4)。過濾反應混合物且在減壓下濃縮，得到呈黃色油狀之標題化合物(110 mg，0.3897 mmol，95.072%產率) (粗物質)。 (1R,5S,6r)-N- isopropyl -3- azabicyclo [3.1.0] hexane -6- formamide TFA salt to (1R,5S,6r)-3-{[(tertiary Butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (110 mg, 0.4100 mmol) in DCM (2.8947 mL) was added TFA (0.58 mL, 7.79 mmol ). The resulting mixture was stirred at 20 to 25 °C for 30 min to give a yellow solution. TLC (PE:EtOAc = 1:1) showed a fresh spot (Rf = 0, 0.4). The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound (110 mg, 0.3897 mmol, 95.072% yield) (crude material) as a yellow oil.

(1R,5S,6r)-N-( 丙 -2- 基 )-3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向1-異丙基咪唑-4-羧酸(120.16 mg，0.78 mmol)於DMF (2 mL)中之溶液添加HATU (193.68 mg，0.51 mmol)、Et ₃N (0.19 mL，1.17 mmol)及(1R,5S,6r)-N-異丙基-3-氮雜雙環[3.1.0]己烷-6-甲醯胺TFA鹽(110 mg，0.39 mmol)。在20至25℃下攪拌所得混合物12小時，得到黃色溶液。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (10 mL × 4)萃取。合併之有機層經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體且濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(50.32 mg，0.1653 mmol，42.42%產率)。 LC-MS方法1: 305.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.65 (d, J=1.3 Hz, 1H), 7.47 (d, J=1.3 Hz, 1H), 5.41 (br d, J=7.8 Hz, 1H), 4.74 (d, J=11.8 Hz, 1H), 4.35 (spt, J=6.7 Hz, 1H), 4.17 - 4.02 (m, 2H), 3.90 (dd, J=4.0, 12.0 Hz, 1H), 3.61 (dd, J=4.0, 12.5 Hz, 1H), 2.19 (td, J=3.7, 7.2 Hz, 1H), 2.10 (td, J=3.4, 7.3 Hz, 1H), 1.50 (d, J=6.8 Hz, 6H), 1.16 - 1.13 (m, 6H) (1R,5S,6r)-N-(propan - 2- yl )-3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-3- azabicyclo [3.1.0] Hexane -6- carboxamide To a solution of 1-isopropylimidazole-4-carboxylic acid (120.16 mg, 0.78 mmol) in DMF (2 mL) was added HATU (193.68 mg, 0.51 mmol), Et ₃ N ( 0.19 mL, 1.17 mmol) and (1R,5S,6r)-N-isopropyl-3-azabicyclo[3.1.0]hexane-6-carboxamide TFA salt (110 mg, 0.39 mmol). The resulting mixture was stirred at 20 to 25°C for 12 hours to obtain a yellow solution. The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (10 mL×4). The combined organic layers were dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined and concentrated to remove most of _CH3CN and lyophilized to give the title compound (50.32 mg, 0.1653 mmol, 42.42% yield) as a white solid. LC-MS method 1: 305.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.65 (d, J =1.3 Hz, 1H), 7.47 (d, J =1.3 Hz, 1H), 5.41 (br d, J =7.8 Hz, 1H), 4.74 (d, J =11.8 Hz, 1H), 4.35 (spt, J =6.7 Hz, 1H), 4.17 - 4.02 (m, 2H), 3.90 (dd, J =4.0, 12.0 Hz, 1H), 3.61 (dd, J =4.0, 12.5 Hz, 1H), 2.19 (td, J =3.7, 7.2 Hz, 1H), 2.10 (td, J =3.4, 7.3 Hz, 1H) , 1.50 (d, J =6.8 Hz, 6H), 1.16 - 1.13 (m, 6H)

實例 65      (1R,5S,6r)-N- 三級丁基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-6-[( 三級丁基 ) 胺甲醯基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(200 mg，0.88 mmol)於吡啶(2 mL)中之溶液添加2-甲基丙-2-胺(0.11 mL，1.06 mmol)。在20℃下攪拌反應混合物0.5小時，得到混合物。隨後向反應混合物添加EDCI (337.41mg，1.76 mmol)。在20℃下攪拌反應混合物2小時，得到褐色混合物。TLC (PE/EtOAc=1:1)展示新樣點。用H2O (10 mL)稀釋反應混合物且用EtOAc (20 mL × 2)萃取。有機層經無水Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到殘餘物。藉由製備型TLC (PE/EtOAc=1:1)純化殘餘物，得到呈白色固體狀之標題化合物(200 mg，0.7083 mmol，80.48%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 5.43 (brs, 1H), 3.64 (d, J = 11.2 Hz, 1H), 3.55 (d, J = 11.2 Hz, 1H), 3.45-3.35 (m, 2H), 1.99 (s, 2H), 1.43 (s, 9H), 1.34 (s, 9H), 1.10-1.05 (m, 1H)。 Example 65 (1R,5S,6r)-N- tertiary butyl -3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-3- azabicyclo [3.1.0] hexyl Alkane -6- carboxamide (1R,5S,6r)-6-[( tertiary butyl ) aminoformyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl Ester to (1R,5S,6r)-3-{[(tertiary butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (200 mg, 0.88 mmol) To a solution in pyridine (2 mL) was added 2-methylpropan-2-amine (0.11 mL, 1.06 mmol). The reaction mixture was stirred at 20°C for 0.5 hours to obtain a mixture. EDCI (337.41 mg, 1.76 mmol) was then added to the reaction mixture. The reaction mixture was stirred at 20 °C for 2 hours to give a brown mixture. TLC (PE/EtOAc=1:1) showed fresh samples. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 2). The organic layer was dried _over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE/EtOAc=1:1) to give the title compound (200 mg, 0.7083 mmol, 80.48% yield) as a white solid. ¹ H NMR (400MHz, chloroform-d) δ = 5.43 (brs, 1H), 3.64 (d, J = 11.2 Hz, 1H), 3.55 (d, J = 11.2 Hz, 1H), 3.45-3.35 (m, 2H ), 1.99 (s, 2H), 1.43 (s, 9H), 1.34 (s, 9H), 1.10-1.05 (m, 1H).

(1R,5S,6r)-N-( 三級丁基 )-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲 醯胺 TFA 鹽向(1R,5S,6r)-6-[(三級丁基)胺甲醯基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.35 mmol)於DCM (1.3333 mL)中之溶液添加TFA (0.01 mL，0.07 mmol)。在20℃下攪拌反應混合物16小時，得到無色混合物。LCMS展示所要MS。移除反應混合物溶劑，得到標題化合物。化合物直接用於下一步驟。 LC-MS方法1 0.293 min，MS (m/z) 182.9 (M + H ⁺)。 (1R,5S,6r)-N-( tertiary butyl )-3- azabicyclo [3.1.0] hexane -6- formamide TFA salt to (1R,5S,6r)-6- [ ( A solution of tert-butyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.35 mmol) in DCM (1.3333 mL) was added with TFA (0.01 mL, 0.07 mmol). The reaction mixture was stirred at 20°C for 16 hours to give a colorless mixture. LCMS showed desired MS. The reaction mixture solvent was removed to afford the title compound. Compounds were used directly in the next step. LC-MS method 1 0.293 min, MS (m/z) 182.9 (M + H ⁺ ).

(1R,5S,6r)-N- 三級丁基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向1-異丙基咪唑-4-羧酸(54.14mg，0.35 mmol)於吡啶(2.6371 mL)中之溶液添加EDCI (134.63mg，0.70 mmol)。在15℃下攪拌反應混合物30 min。隨後向反應物添加(1R,5S,6r)-N-(三級丁基)-3-氮雜雙環[3.1.0]己烷-6-甲醯胺TFA鹽(64 mg，0.35 mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。用H ₂O淬滅反應混合物且藉由製備型HPLC (NH ₃)純化所得殘餘物，得到呈淡黃色固體狀之標題化合物(37.57mg，0.1180 mmol，33.602%產率)。 LC-MS方法1: 319.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.63 (d, J=1.2 Hz, 1H), 7.46 (d, J=1.2 Hz, 1H), 5.44 (s, 1H), 4.72 (d, J=11.2 Hz, 1H), 4.34 (spt, J=6.7 Hz, 1H), 4.11 (d, J=12.4 Hz, 1H), 3.87 (dd, J=3.6, 11.8 Hz, 1H), 3.58 (dd, J=4.4, 12.8 Hz, 1H), 2.16 - 2.09 (m, 1H), 2.04 (td, J=3.5, 7.3 Hz, 1H), 1.49 (d, J=6.8 Hz, 6H), 1.33 (s, 9H), 1.10 (t, J=3.1 Hz, 1H) (1R,5S,6r)-N- tertiary butyl -3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-3- azabicyclo [3.1.0 ] hexane- 6- Formamide To a solution of 1-isopropylimidazole-4-carboxylic acid (54.14 mg, 0.35 mmol) in pyridine (2.6371 mL) was added EDCI (134.63 mg, 0.70 mmol). The reaction mixture was stirred at 15 °C for 30 min. Then (1R,5S,6r)-N-(tert-butyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide TFA salt (64 mg, 0.35 mmol) was added to the reaction. The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. The reaction mixture was quenched with H ₂ O and the resulting residue was purified by preparative HPLC (NH ₃ ) to afford the title compound (37.57 mg, 0.1180 mmol, 33.602% yield) as a light yellow solid. LC-MS method 1: 319.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.63 (d, J =1.2 Hz, 1H), 7.46 (d, J =1.2 Hz, 1H), 5.44 (s, 1H), 4.72 (d, J =11.2 Hz, 1H), 4.34 (spt, J =6.7 Hz, 1H), 4.11 (d, J =12.4 Hz, 1H), 3.87 (dd, J =3.6, 11.8 Hz, 1H), 3.58 (dd, J =4.4, 12.8 Hz, 1H), 2.16 - 2.09 (m, 1H), 2.04 (td, J =3.5, 7.3 Hz, 1H), 1.49 (d, J =6.8 Hz, 6H), 1.33 (s, 9H), 1.10 (t, J =3.1 Hz, 1H)

實例 66      (1R,5S,6r)-N- 三級丁基 -N- 甲基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-6-[ 甲基 ( 三級丁基 ) 胺甲醯基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在20℃下向(1R,5S,6r)-6-[(三級丁基)胺甲醯基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(50 mg，0.18 mmol)於DMF (2.4909 mL)中之溶液添加NaH (8.5mg，0.35 mmol)。隨後在20℃下攪拌反應混合物1小時。隨後添加於DMF (2.4909 mL)中之MeI (0.04 mL，0.71 mmol)。在50℃下攪拌反應混合物2小時，得到淺黃色混合物。TLC (PE/EtOAc=1:1)展示新樣點。用H ₂O (10 mL)淬滅反應混合物且用EtOAc (10 mL)萃取。有機層經無水Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈褐色油狀之標題化合物(52mg，0.1754 mmol，99.077%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.66 (d, J = 11.2 Hz, 1H), 3.60 (d, J = 11.2 Hz, 1H), 3.50-3.40 (m, 2H), 3.02 (s, 3H), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 1H), 1.50-1.40 (m, 1H), 1.44 (s, 9H), 1.38 (s, 9H)， Example 66 (1R, 5S, 6r)-N- tertiary butyl -N- methyl -3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-3- azabicyclo [ 3.1.0] Hexane -6- formamide (1R,5S,6r)-6-[ methyl ( tertiary butyl ) carbamoyl ]-3- azabicyclo [3.1.0 ] hexane- 3- Carboxylic acid tertiary butyl ester at 20 ℃ to (1R,5S,6r)-6-[(tertiary butyl)aminoformyl]-3-azabicyclo[3.1.0]hexane-3 - To a solution of tert-butylcarboxylate (50 mg, 0.18 mmol) in DMF (2.4909 mL) was added NaH (8.5 mg, 0.35 mmol). The reaction mixture was then stirred at 20°C for 1 hour. Then MeI (0.04 mL, 0.71 mmol) in DMF (2.4909 mL) was added. The reaction mixture was stirred at 50 °C for 2 hours to obtain a pale yellow mixture. TLC (PE/EtOAc=1:1) showed fresh samples. The reaction mixture was quenched with H ₂ O (10 mL) and extracted with EtOAc (10 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (52 mg, 0.1754 mmol, 99.077% yield) as a brown oil. ¹ H NMR (400MHz, Chloroform-d) δ = 3.66 (d, J = 11.2 Hz, 1H), 3.60 (d, J = 11.2 Hz, 1H), 3.50-3.40 (m, 2H), 3.02 (s, 3H ), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 1H), 1.50-1.40 (m, 1H), 1.44 (s, 9H), 1.38 (s, 9H),

(1R,5S,6r)-N- 甲基 -N-( 三級丁基 )-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 TFA 鹽向(1R,5S,6r)-6-[甲基(三級丁基)胺甲醯基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(52 mg，0.18 mmol)於DCM (1 mL)中之溶液添加TFA (0.1 mL，1.35 mmol)。在20℃下攪拌反應混合物16小時，得到褐色混合物。TLC (PE/EtOAc=1:1)展示新樣點。在減壓下濃縮反應混合物，得到標題化合物，且其直接用於下一步驟。 (1R,5S,6r)-N- Methyl -N-( tertiary butyl )-3- azabicyclo [3.1.0] hexane -6- formamide TFA salt to (1R,5S,6r) -6-[Methyl(tertiary butyl)carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (52 mg, 0.18 mmol) in DCM (1 mL) was added TFA (0.1 mL, 1.35 mmol). The reaction mixture was stirred at 20 °C for 16 hours to give a brown mixture. TLC (PE/EtOAc=1:1) showed fresh samples. The reaction mixture was concentrated under reduced pressure to afford the title compound, which was used directly in the next step.

(1R,5S,6r)-N- 三級丁基 -N- 甲基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向1-異丙基咪唑-4-羧酸(78.54mg，0.51 mmol)於吡啶(3.826 mL)中之溶液添加EDCI (195.32mg，1.02 mmol)。在15℃下攪拌反應混合物30 min。隨後向反應物添加(1R,5S,6r)-N-甲基-N-(三級丁基)-3-氮雜雙環[3.1.0]己烷-6-甲醯胺TFA鹽(100 mg，0.51 mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (NH ₃)純化反應混合物，得到呈淡黃色固體狀之標題化合物(16.42mg，0.0494 mmol，9.6952%產率)。 LC-MS方法1: 333.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.66 (d, J=1.2 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 4.66 (d, J=12.0 Hz, 1H), 4.40 - 4.31 (m, 1H), 4.11 (d, J=12.8 Hz, 1H), 3.97 (dd, J=4.3, 12.0 Hz, 1H), 3.65 (dd, J=4.3, 12.8 Hz, 1H), 3.00 (s, 3H), 2.20 (td, J=3.8, 7.5 Hz, 1H), 2.05 (td, J=3.8, 7.4 Hz, 1H), 1.50 (d, J=6.8 Hz, 6H), 1.38 (s, 9H) (1R,5S,6r)-N- tertiary butyl -N- methyl -3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-3- azabicyclo [3.1. 0] Hexane -6- carboxamide To a solution of 1-isopropylimidazole-4-carboxylic acid (78.54 mg, 0.51 mmol) in pyridine (3.826 mL) was added EDCI (195.32 mg, 1.02 mmol). The reaction mixture was stirred at 15 °C for 30 min. (1R,5S,6r)-N-methyl-N-(tertiary butyl)-3-azabicyclo[3.1.0]hexane-6-formamide TFA salt (100 mg , 0.51 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC ( _NH3 ) to afford the title compound (16.42 mg, 0.0494 mmol, 9.6952% yield) as a light yellow solid. LC-MS method 1: 333.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.66 (d, J =1.2 Hz, 1H), 7.47 (d, J =1.2 Hz, 1H), 4.66 (d, J =12.0 Hz, 1H), 4.40 - 4.31 (m, 1H), 4.11 (d, J =12.8 Hz, 1H), 3.97 (dd, J =4.3, 12.0 Hz, 1H), 3.65 (dd, J =4.3, 12.8 Hz, 1H), 3.00 (s, 3H), 2.20 (td, J =3.8, 7.5 Hz, 1H), 2.05 (td, J =3.8, 7.4 Hz, 1H), 1.50 (d, J =6.8 Hz, 6H), 1.38 (s, 9H)

實例 67      (1R,5S,6r)-N- 甲基 -N-(1- 甲基環丙基 )-3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-6-[(1- 甲基環丙基 ) 胺甲醯基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(500 mg，2.2 mmol)於DCM (20 mL)中之混合物添加Et ₃N (0.73 mL，4.4 mmol)及HATU (1.26g，3.3 mmol)。在10 min之後，添加1-甲基環丙胺氫氯化物(236.69mg，2.2 mmol)。在20℃下攪拌所得混合物6小時，得到褐色混合物。LCMS展示發現所要峰值。用H ₂O (20 mL)稀釋反應物且用EtOAc (30 ml × 3)萃取。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到褐色油狀物。藉由製備型TLC (PE/EtOAc=1/1)純化粗物質油，得到呈白色固體狀之標題化合物(590mg，2.1044 mmol，95.651%產率)。 LC-MS方法1: 227.0 [M+H ⁺]。 ¹H NMR (400MHz, 氯仿-d) δ = 6.15 - 5.95 (m, 1H), 3.70 - 3.59 (m, 1H), 3.58 - 3.48 (m, 1H), 3.45 - 3.25 (m, 2H), 2.07 - 1.96 (m, 2H), 1.46 - 1.40 (m, 9H), 1.36 (s, 3H), 1.13 - 1.04 (m, 1H), 0.78 - 0.70 (m, 2H), 0.65 - 0.57 (m, 2H) Example 67 (1R, 5S, 6r)-N- methyl -N-(1- methylcyclopropyl )-3-[1-( prop - 2- yl )-1H- imidazole -4- carbonyl ]-3 -Azabicyclo [3.1.0] hexane -6- formamide ( 1R,5S,6r)-6-[(1- methylcyclopropyl ) aminoformyl ]-3- azabicyclo [3.1 .0] Hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-3-{[(tertiary butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane To a mixture of alkane-6-carboxylic acid (500 mg, 2.2 mmol) in DCM (20 mL) was added _Et3N (0.73 mL, 4.4 mmol) and HATU (1.26 g, 3.3 mmol). After 10 min, 1-methylcyclopropylamine hydrochloride (236.69 mg, 2.2 mmol) was added. The resulting mixture was stirred at 20°C for 6 hours to obtain a brown mixture. LCMS showed that the desired peak was found. The reaction was diluted with H ₂ O (20 mL) and extracted with EtOAc (30 ml×3). The combined organic layers were separated, then dried over _Na2SO4 and concentrated _in vacuo to give a brown oil. The crude oil was purified by prep-TLC (PE/EtOAc = 1/1) to afford the title compound (590 mg, 2.1044 mmol, 95.651% yield) as a white solid. LC-MS method 1: 227.0 [M+H ⁺ ]. ¹ H NMR (400MHz, chloroform-d) δ = 6.15 - 5.95 (m, 1H), 3.70 - 3.59 (m, 1H), 3.58 - 3.48 (m, 1H), 3.45 - 3.25 (m, 2H), 2.07 - 1.96 (m, 2H), 1.46 - 1.40 (m, 9H), 1.36 (s, 3H), 1.13 - 1.04 (m, 1H), 0.78 - 0.70 (m, 2H), 0.65 - 0.57 (m, 2H)

(1R,5S,6r)-6-[ 甲基 (1- 甲基環丙基 ) 胺甲醯基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(1-甲基環丙基)胺甲醯基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.4000mmol)於THF (5 mL)中之混合物添加NaH (23.78mg，0.5900mmol)。隨後在0℃下攪拌反應混合物15 min。隨後添加MeI (0.03mL，0.4800mmol)。在15℃下攪拌反應混合物16小時。TLC (PE/EA=1/1)展示新樣點(Rf=0.5)且反應完成。用H ₂O (20 mL)稀釋混合物，用EA (10mL×2)萃取，且隨後用H ₂O (10mL)及NH ₄Cl (10mL)洗滌。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型TLC (PE/EA=1/1)純化粗物質油，得到呈灰白色固體狀之標題化合物(100 mg，0.3755mmol，94.732%產率)。 LC-MS方法1 0.825 min，MS (m/z) 295 (M + H ⁺)。 (1R,5S,6r)-6-[ methyl (1- methylcyclopropyl ) aminoformyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-[(1-Methylcyclopropyl)aminoformyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (100 mg , 0.4000 mmol) in THF (5 mL) was added NaH (23.78 mg, 0.5900 mmol). The reaction mixture was then stirred at 0 °C for 15 min. MeI (0.03 mL, 0.4800 mmol) was then added. The reaction mixture was stirred at 15°C for 16 hours. TLC (PE/EA=1/1) showed a fresh spot (Rf=0.5) and the reaction was complete. The mixture was diluted with H ₂ O (20 mL), extracted with EA (10 mL×2), and then washed with H ₂ O (10 mL) and NH ₄ Cl (10 mL). The combined organic layers were dried over _Na2SO4 and _concentrated in vacuo to give a crude oil. The crude oil was purified by prep-TLC (PE/EA=1/1) to afford the title compound (100 mg, 0.3755 mmol, 94.732% yield) as an off-white solid. LC-MS method 1 0.825 min, MS (m/z) 295 (M + H ⁺ ).

(1R,5S,6r)-N- 甲基 -N-(1- 甲基環丙基 )-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 TFA 鹽在20℃下向(1R,5S,6r)-6-[甲基(1-甲基環丙基)胺甲醯基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.34 mmol)於DCM (2 mL)中之溶液添加TFA (0.15 mL，2.04 mmol)。在20℃下攪拌混合物2小時。LCMS展示發現所要峰值。在減壓下濃縮反應混合物，得到呈黃色油狀之標題化合物(100 mg，粗產物)。 LC-MS方法1: 195.0 [M+H ⁺]。 (1R,5S,6r)-N- methyl -N-(1- methylcyclopropyl )-3- azabicyclo [3.1.0] hexane -6- formamide TFA salt at 20°C (1R,5S,6r)-6-[Methyl(1-methylcyclopropyl)aminoformyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester ( 100 mg, 0.34 mmol) in DCM (2 mL) was added TFA (0.15 mL, 2.04 mmol). The mixture was stirred at 20°C for 2 hours. LCMS showed that the desired peak was found. The reaction mixture was concentrated under reduced pressure to give the title compound (100 mg, crude product) as a yellow oil. LC-MS method 1: 195.0 [M+H ⁺ ].

(1R,5S,6r)-N- 甲基 -N-(1- 甲基環丙基 )-3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向1-異丙基咪唑-4-羧酸(75 mg，0.49 mmol)於DCM (5 mL)中之混合物添加HATU (278.97mg，0.73 mmol)及Et ₃N (0.16 mL，0.97 mmol)。在20℃下於N ₂下攪拌混合物10 min。隨後添加於DCM (3 mL)中之(1R,5S,6r)-N-甲基-N-(1-甲基環丙基)-3-氮雜雙環[3.1.0]己烷-6-甲醯胺TFA鹽(94.51mg，0.49 mmol)。在20℃下攪拌所得混合物16小時，得到褐色混合物。LCMS展示發現所要峰值。用H ₂O (20 mL)稀釋反應物且用DCM (20 mL)萃取。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到褐色油狀物。藉由製備型HPLC (FA)純化褐色油狀物。合併所獲得流體，濃縮以移除大部分CH ₃CN，添加NH ₃H ₂O (0.5 mL)且凍乾，得到呈黃色固體狀之標題化合物(20mg，0.0605 mmol，12.442%產率)。 LC-MS方法1: 331.1 [M+H ⁺]。 ¹H NMR (400MHz, DMSO-d ₆) δ = 7.80 (br s, 2H), 4.66 - 4.37 (m, 2H), 4.00 - 3.78 (m, 2H), 3.50 (br d, J=5.1 Hz, 1H), 2.77 (s, 3H), 2.13 - 1.92 (m, 2H), 1.91 - 1.83 (m, 1H), 1.40 (d, J=6.6 Hz, 6H), 1.28 (s, 3H), 1.09 - 0.54 (m, 4H) (1R,5S,6r)-N- Methyl - N-(1- methylcyclopropyl )-3-[1-( propan - 2- yl )-1H- imidazole -4- carbonyl ]-3- nitrogen Heterobicyclo [3.1.0] hexane -6- carboxamide To a mixture of 1-isopropylimidazole-4-carboxylic acid (75 mg, 0.49 mmol) in DCM (5 mL) was added HATU (278.97 mg, 0.73 mmol) and Et ₃ N (0.16 mL, 0.97 mmol). The mixture was stirred at 20 °C under _N2 for 10 min. Then (1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-azabicyclo[3.1.0]hexane-6- Formamide TFA salt (94.51 mg, 0.49 mmol). The resulting mixture was stirred at 20°C for 16 hours to give a brown mixture. LCMS showed that the desired peak was found. The reaction was diluted with H ₂ O (20 mL) and extracted with DCM (20 mL). The combined organic layers were separated, then dried over _Na2SO4 and concentrated _in vacuo to give a brown oil. The brown oil was purified by preparative HPLC (FA). The _resulting fluids were combined, concentrated to remove most of _CH3CN , _NH3H2O (0.5 mL) was added and lyophilized to give the title compound (20 mg, 0.0605 mmol, 12.442% yield) as a yellow solid. LC-MS method 1: 331.1 [M+H ⁺ ]. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.80 (br s, 2H), 4.66 - 4.37 (m, 2H), 4.00 - 3.78 (m, 2H), 3.50 (br d, J =5.1 Hz, 1H ), 2.77 (s, 3H), 2.13 - 1.92 (m, 2H), 1.91 - 1.83 (m, 1H), 1.40 (d, J =6.6 Hz, 6H), 1.28 (s, 3H), 1.09 - 0.54 ( m, 4H)

實例 68      (1R,5S,6r)-N-(1- 氰基環丙基 )-3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己烷 -6- 羧酸乙酯 TFA 鹽向6-乙基3-(三級丁基)(1R,5S,6r)-3-氮雜雙環[3.1.0]己烷-3,6-二羧酸酯(600 mg，2.35 mmol)於DCM (10 mL)中之混合物添加TFA (1 mL，13.46 mmol)。在25℃下攪拌反應物3小時，得到褐色混合物。真空濃縮反應混合物，得到標題化合物(300 mg，粗物質)。 Example 68 (1R, 5S, 6r)-N-(1- cyanocyclopropyl )-3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-3- azabicyclo [ 3.1.0] Hexane -6- formamide (1R,5S,6r)-3- azabicyclo [3.1.0] hexane -6- carboxylate ethyl ester TFA salt to 6-ethyl 3-(tri A mixture of (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate (600 mg, 2.35 mmol) in DCM (10 mL) was added TFA (1 mL, 13.46 mmol). The reaction was stirred at 25°C for 3 hours to give a brown mixture. The reaction mixture was concentrated in vacuo to afford the title compound (300 mg, crude).

(1R,5S,6r)-3-[(1- 異丙基 -1H- 咪唑 -4- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 羧酸乙酯向(1R,5S,6r)-3-氮雜雙環[3.1.0]己烷-6-羧酸乙酯TFA鹽(300 mg，1.18 mmol)於THF (4 mL)中之溶液添加Et ₃N (0.81 mL，5.88 mmol)、1-異丙基咪唑-4-羧酸(181.16 mg，1.18 mmol)及HATU (583.98 mg，1.53 mmol)。在20℃下攪拌所得混合物12小時，得到黃色混合物。濃縮反應混合物且藉由二氧化矽管柱純化，得到呈淺黃色膠質之標題化合物(170 mg，粗物質)。 LC-MS方法1 0.598 min，MS (m/z) 291.9 (M + H ⁺)。 (1R,5S,6r)-3-[(1- isopropyl -1H- imidazol -4- yl ) carbonyl ]-3- azabicyclo [3.1.0] hexane -6- carboxylic acid ethyl ester to ( 1R,5S,6r)-3-Azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester TFA salt (300 mg, 1.18 mmol) in THF (4 mL) was added Et ₃ N (0.81 mL, 5.88 mmol), 1-isopropylimidazole-4-carboxylic acid (181.16 mg, 1.18 mmol) and HATU (583.98 mg, 1.53 mmol). The resulting mixture was stirred at 20°C for 12 hours to give a yellow mixture. The reaction mixture was concentrated and purified by silica column to give the title compound (170 mg, crude) as a pale yellow gum. LC-MS method 1 0.598 min, MS (m/z) 291.9 (M + H ⁺ ).

(1R,5S,6r)-3-[(1- 異丙基 -1H- 咪唑 -4- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 羧酸向(1R,5S,6r)-3-[(1-異丙基-1H-咪唑-4-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-羧酸乙酯(170 mg，0.58 mmol)於THF/H ₂O (4 mL，3/1)中之混合物添加羥基鋰水合物(31.83 mg，0.76 mmol)。在25℃下攪拌反應物12小時，得到黃色混合物。TLC展示起始材料消耗完。真空濃縮反應混合物，得到呈淡黃色固體狀之標題化合物(153 mg，粗物質)。 LC-MS方法1 0.218 min，MS (m/z) 263.9 (M + H ⁺)。 (1R,5S,6r)-3-[(1- isopropyl -1H- imidazol -4- yl ) carbonyl ]-3- azabicyclo [3.1.0] hexane -6- carboxylic acid to (1R, 5S,6r)-3-[(1-isopropyl-1H-imidazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (170 mg, 0.58 mmol) in THF/ _H2O (4 mL, 3/1) was added with lithium hydroxyhydrate (31.83 mg, 0.76 mmol). The reaction was stirred at 25°C for 12 hours to give a yellow mixture. TLC showed the starting material was consumed. The reaction mixture was concentrated in vacuo to afford the title compound (153 mg, crude) as a light yellow solid. LC-MS method 1 0.218 min, MS (m/z) 263.9 (M + H ⁺ ).

(1R,5S,6r)-N-(1- 氰基環丙基 )-3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向於DMF (2 mL)中之溶液(1R,5S,6r)-3-[(1-異丙基-1H-咪唑-4-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-羧酸(153 mg，0.58 mmol)添加HATU (244.37 mg，0.64 mmol)、Et ₃N (0.3 mL，2.32 mmol)及1-胺基環丙烷甲腈氫氯化物(82.68mg，0.70 mmol)。在25℃下攪拌反應混合物12小時，得到黃色混合物。真空濃縮反應混合物，得到殘餘物。藉由製備型HPLC (NH ₃)純化粗產物，得到呈白色固體狀之標題化合物(5.98 mg)。 LC-MS方法1: 328.1 [M+H ⁺] ¹H NMR (400MHz, CDCl ₃) δ = 7.56 (d, J=1.0 Hz, 1H), 7.40 (d, J=1.1 Hz, 1H), 6.69 (s, 1H), 4.63 (d, J=12.1 Hz, 1H), 4.37 - 4.23 (m, 1H), 4.02 (d, J=12.5 Hz, 1H), 3.81 (dd, J=3.9, 11.9 Hz, 1H), 3.52 (dd, J=4.1, 12.6 Hz, 1H), 2.22 - 2.15 (m, 1H), 2.11 - 2.03 (m, 1H), 1.46 (br d, J=2.5 Hz, 2H), 1.43 (d, J=6.8 Hz, 6H), 1.18 (br d, J=4.1 Hz, 2H), 1.13 (t, J=3.1 Hz, 1H) (1R,5S,6r)-N-(1- cyanocyclopropyl )-3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-3- azabicyclo [3.1. 0] A solution of hexane -6- formamide in DMF (2 mL) (1R,5S,6r)-3-[(1-isopropyl-1H-imidazol-4-yl)carbonyl]-3 -Azabicyclo[3.1.0]hexane-6-carboxylic acid (153 mg, 0.58 mmol) Add HATU (244.37 mg, 0.64 mmol), Et ₃ N (0.3 mL, 2.32 mmol) and 1-aminocyclopropane Formonitrile hydrochloride (82.68 mg, 0.70 mmol). The reaction mixture was stirred at 25°C for 12 hours to give a yellow mixture. The reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by preparative HPLC ( _NH3 ) to give the title compound (5.98 mg) as a white solid. LC-MS method 1: 328.1 [M+H ⁺ ] ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.56 (d, J =1.0 Hz, 1H), 7.40 (d, J =1.1 Hz, 1H), 6.69 ( s, 1H), 4.63 (d, J =12.1 Hz, 1H), 4.37 - 4.23 (m, 1H), 4.02 (d, J =12.5 Hz, 1H), 3.81 (dd, J =3.9, 11.9 Hz, 1H ), 3.52 (dd, J =4.1, 12.6 Hz, 1H), 2.22 - 2.15 (m, 1H), 2.11 - 2.03 (m, 1H), 1.46 (br d, J =2.5 Hz, 2H), 1.43 (d , J =6.8 Hz, 6H), 1.18 (br d, J =4.1 Hz, 2H), 1.13 (t, J =3.1 Hz, 1H)

實例 69      (1R,5S,6r)-N-(1- 氰基環丙基 )-N- 甲基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-N-(1- 氰基環丙基 )-N- 甲基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺在冰冷卻下向(1R,5S,6r)-N-(1-氰基環丙基)-3-[(1-異丙基-1H-咪唑-4-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺(15 mg，0.05 mmol)於DMF (0.50 mL)/THF (0.50 ml)中之混合物添加NaH (2.75mg，0.07 mmol)。攪拌反應混合物0.3小時。隨後添加MeI (19.51mg，0.14 mmol)。在30℃下攪拌混合物3小時。直接濃縮反應混合物。隨後藉由製備型HPLC (NH ₃)純化殘餘物，得到呈白色固體狀之標題化合物(2.8 mg，0.0176 mmol，38.356%產率)。 LC-MS方法1: 341.9 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.63 (br s, 1H), 7.41 (s, 1H), 4.64 (br s, 1H), 4.34 - 4.22 (m, 1H), 4.11 - 3.92 (m, 2H), 3.66 (br s, 1H), 3.00 - 2.85 (m, 3H), 2.28 (br s, 1H), 2.12 (br s, 1H), 1.84 (br s, 1H), 1.44 (d, J=6.8 Hz, 7H), 1.18 (s, 4H) Example 69 (1R, 5S, 6r)-N-(1- cyanocyclopropyl )-N- methyl -3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-3 -Azabicyclo [3.1.0] hexane -6- formamide (1R,5S,6r ) -N-(1- cyanocyclopropyl )-N- methyl -3-[1- ( propane- 2- yl )-1H- imidazole -4- carbonyl ]-3- azabicyclo [3.1.0] hexane -6- carboxamide to (1R,5S,6r)-N-(1- Cyanocyclopropyl)-3-[(1-isopropyl-1H-imidazol-4-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide (15 mg, 0.05 mmol) in DMF (0.50 mL)/THF (0.50 ml) was added NaH (2.75 mg, 0.07 mmol). The reaction mixture was stirred for 0.3 hours. Then MeI (19.51 mg, 0.14 mmol) was added. The mixture was stirred at 30°C for 3 hours. The reaction mixture was directly concentrated. The residue was then purified by preparative HPLC ( _NH3 ) to afford the title compound (2.8 mg, 0.0176 mmol, 38.356% yield) as a white solid. LC-MS method 1: 341.9 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.63 (br s, 1H), 7.41 (s, 1H), 4.64 (br s, 1H), 4.34 - 4.22 (m, 1H), 4.11 - 3.92 (m, 2H), 3.66 (br s, 1H), 3.00 - 2.85 (m, 3H), 2.28 (br s, 1H), 2.12 (br s, 1H), 1.84 (br s, 1H), 1.44 (d, J =6.8 Hz, 7H), 1.18 (s, 4H)

實例 70      (1R,5S,6r)-3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-N-[1-( 三氟甲基 ) 環丙基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-6-{[1-( 三氟甲基 ) 環丙基 ] 胺甲醯基 }-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(200 mg，0.88 mmol)於DMF (3 mL)中之溶液添加HATU (370.09 mg，0.97 mmol)、Et ₃N (0.34 mL，2.64 mmol)及1-(三氟甲基)環丙胺氫氯化物(170.61 mg，1.06 mmol)。在25℃下攪拌所得混合物12小時。TLC (PE:EtOAc = 1:1)展示反應完成。將反應混合物傾入H ₂O (10 ml)中且用EtOAc (10 ml×3)萃取。合併之有機層經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由快速柱(PE至40% EtOAc/PE)純化殘餘物，得到呈白色固體狀之標題化合物(328 mg，0.9811 mmol，111.48%產率，粗產物)。 ¹H NMR (400MHz, 氯仿-d) δ = 6.47 (s, 1H), 3.68 - 3.53 (m, 2H), 3.41 (br d, J=11.3 Hz, 2H), 2.12 - 2.03 (m, 2H), 1.48 - 1.46 (m, 1H), 1.44 (s, 9H), 1.31 (br s, 2H), 1.19 (t, J=3.1 Hz, 1H), 1.10 (br d, J=5.5 Hz, 2H) Example 70 (1R, 5S, 6r)-3-[1-( prop -2- yl )-1H- imidazole -4- carbonyl ]-N-[1-( trifluoromethyl ) cyclopropyl ]-3- Azabicyclo [3.1.0] hexane -6- formamide (1R,5S,6r)-6-{[1-( trifluoromethyl ) cyclopropyl ] aminoformyl }-3- aza Bicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-3-{[(tertiary butyl)oxy]carbonyl}-3-azabicyclo[3.1. 0] A solution of hexane-6-carboxylic acid (200 mg, 0.88 mmol) in DMF (3 mL) was added with HATU (370.09 mg, 0.97 mmol), Et ₃ N (0.34 mL, 2.64 mmol) and 1-(tri Fluoromethyl)cyclopropylamine hydrochloride (170.61 mg, 1.06 mmol). The resulting mixture was stirred at 25°C for 12 hours. TLC (PE:EtOAc = 1:1) showed the reaction was complete. The reaction mixture was poured into H ₂ O (10 ml) and extracted with EtOAc (10 ml×3). The combined organic layers were dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by flash column (PE to 40% EtOAc/PE) to afford the title compound (328 mg, 0.9811 mmol, 111.48% yield, crude product) as a white solid. ¹ H NMR (400MHz, Chloroform-d) δ = 6.47 (s, 1H), 3.68 - 3.53 (m, 2H), 3.41 (br d, J =11.3 Hz, 2H), 2.12 - 2.03 (m, 2H), 1.48 - 1.46 (m, 1H), 1.44 (s, 9H), 1.31 (br s, 2H), 1.19 (t, J =3.1 Hz, 1H), 1.10 (br d, J =5.5 Hz, 2H)

(1R,5S,6r)-N-[1-( 三氟甲基 ) 環丙基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 TFA 鹽向(1R,5S,6r)-6-{[1-(三氟甲基)環丙基]胺甲醯基}-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(50 mg，0.15 mmol)於DCM (2 mL)中之溶液添加2,2,2-三氟乙酸(0.3 mL，3.92mmol)。在20至25℃下攪拌所得混合物2小時。TLC (PE:EtOAc = 1:1)展示反應完成。藉由用N ₂吹掃來濃縮混合物，得到呈白色固體狀之標題化合物(30 mg，0.1281 mmol，85.645%產率)。 (1R,5S,6r)-N-[1-( trifluoromethyl ) cyclopropyl ]-3- azabicyclo [3.1.0] hexane -6- formamide TFA salt to (1R,5S, 6r)-tertiary butyl 6-{[1-(trifluoromethyl)cyclopropyl]aminoformyl}-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 0.15 mmol) in DCM (2 mL) was added 2,2,2-trifluoroacetic acid (0.3 mL, 3.92 mmol). The resulting mixture was stirred at 20 to 25°C for 2 hours. TLC (PE:EtOAc = 1:1) showed the reaction was complete. The mixture was concentrated by purging with _N2 to afford the title compound (30 mg, 0.1281 mmol, 85.645% yield) as a white solid.

(1R,5S,6r)-3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-N-[1-( 三氟甲基 ) 環丙基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向1-異丙基咪唑-4-羧酸(19.75 mg，0.13 mmol)於DMF (2 mL)中之溶液添加Et ₃N (0.08 mL，0.64 mmol)、HATU (58.76 mg，0.15 mmol)及(1R,5S,6r)-N-[1-(三氟甲基)環丙基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺TFA鹽(30 mg，0.13 mmol)。在20至25℃下攪拌所得混合物16小時。過濾混合物且藉由製備型HPLC (NH ₃)純化濾液。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(3.97 mg，0.0107 mmol，8.3687%產率)。 LC-MS方法1: 371.1 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.67 (s, 1H), 7.49 (s, 1H), 6.13 (br s, 1H), 4.77 (br d, J=12.0 Hz, 1H), 4.43 - 4.31 (m, 1H), 4.16 (br d, J=12.8 Hz, 1H), 3.90 (dd, J=3.9, 12.3 Hz, 1H), 3.62 (dd, J=3.5, 13.3 Hz, 1H), 2.23 (br d, J=3.8 Hz, 1H), 2.15 (br d, J=3.3 Hz, 1H), 1.52 (d, J=6.6 Hz, 7H), 1.37 - 1.32 (m, 2H), 1.27 (s, 2H), 1.21 (br s, 2H), 1.13 (br d, J=7.6 Hz, 2H) (1R,5S,6r)-3-[1-( Propan -2- yl )-1H- imidazole -4- carbonyl ]-N-[1-( trifluoromethyl ) cyclopropyl ]-3- aza Bicyclo [3.1.0] hexane -6- carboxamide To a solution of 1-isopropylimidazole-4-carboxylic acid (19.75 mg, 0.13 mmol) in DMF (2 mL) was added Et ₃ N (0.08 mL, 0.64 mmol), HATU (58.76 mg, 0.15 mmol) and (1R,5S,6r)-N-[1-(trifluoromethyl)cyclopropyl]-3-azabicyclo[3.1.0]hexane- 6-Formamide TFA salt (30 mg, 0.13 mmol). The resulting mixture was stirred at 20 to 25°C for 16 hours. The mixture was filtered and the filtrate was purified by preparative HPLC (NH ₃ ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to afford the title compound (3.97 mg, 0.0107 mmol, 8.3687% yield) as a white solid. LC-MS method 1: 371.1 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.67 (s, 1H), 7.49 (s, 1H), 6.13 (br s, 1H), 4.77 (br d, J =12.0 Hz, 1H), 4.43 - 4.31 (m, 1H), 4.16 (br d, J =12.8 Hz, 1H), 3.90 (dd, J =3.9, 12.3 Hz, 1H), 3.62 (dd, J =3.5, 13.3 Hz, 1H), 2.23 (br d, J =3.8 Hz, 1H), 2.15 (br d, J =3.3 Hz, 1H), 1.52 (d, J =6.6 Hz, 7H), 1.37 - 1.32 (m, 2H), 1.27 (s, 2H), 1.21 (br s, 2H), 1.13 (br d, J =7.6 Hz, 2H)

實例 71      (1R,5S,6r)-N- 甲基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-N-[1-( 三氟甲基 ) 環丙基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-6-{ 甲基 [1-( 三氟甲基 ) 環丙基 ] 胺甲醯基 }-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在攪拌0.5小時之後在冰冷卻下向(1R,5S,6r)-6-{[1-(三氟甲基)環丙基]胺甲醯基}-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(180 mg，0.54 mmol)於DMF (2.52 mL)中之混合物添加NaH (19.38 mg，0.81 mmol)。隨後添加MeI (382.1 mg，2.69 mmol)。在30℃下攪拌混合物3小時。TLC (PE:EtOAc = 5:1)展示反應完成(Rf = 0.2)。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (10 mL × 4)萃取。用飽和NaCl溶液(10 mL × 4)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈黃色油狀之標題化合物(180 mg，0.5167 mmol，95.973%產率)。 Example 71 (1R,5S,6r)-N- methyl -3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-N-[1-( trifluoromethyl ) cyclopropyl Base ]-3- azabicyclo [3.1.0] hexane -6- formamide (1R,5S,6r)-6-{ methyl [1-( trifluoromethyl ) cyclopropyl ] carbamate Base }-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester was added to (1R, 5S, 6r)-6-{[1-(three Fluoromethyl)cyclopropyl]carbamoyl}-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (180 mg, 0.54 mmol) in DMF (2.52 mL) NaH (19.38 mg, 0.81 mmol) was added to the mixture. Then MeI (382.1 mg, 2.69 mmol) was added. The mixture was stirred at 30°C for 3 hours. TLC (PE:EtOAc = 5:1) showed the reaction was complete (Rf = 0.2). The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (10 mL×4). The combined organic layers were washed with saturated NaCl solution (10 mL x 4), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give the title compound (180 mg, 0.5167 mmol, 95.973% yield ₎ as a yellow oil. ).

(1R,5S,6r)-N- 甲基 -N-[1-( 三氟甲基 ) 環丙基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 TFA 鹽向(1R,5S,6r)-6-{甲基[1-(三氟甲基)環丙基]胺甲醯基}-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(220 mg，0.63 mmol)於DCM (3 mL)中之溶液添加2,2,2-三氟乙酸(0.3 mL，3.92 mmol)。在20至25℃下攪拌所得混合物2小時。TLC (PE:EtOAc = 5:1)展示反應完成。藉由用N ₂吹掃來濃縮混合物，得到呈褐色固體狀之標題化合物(150 mg，0.6043 mmol，95.681%產率)。 (1R,5S,6r)-N- methyl -N-[1-( trifluoromethyl ) cyclopropyl ]-3- azabicyclo [3.1.0] hexane -6- formamide TFA salt to (1R,5S,6r)-6-{Methyl[1-(trifluoromethyl)cyclopropyl]aminoformyl}-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tris To a solution of butyl ester (220 mg, 0.63 mmol) in DCM (3 mL) was added 2,2,2-trifluoroacetic acid (0.3 mL, 3.92 mmol). The resulting mixture was stirred at 20 to 25°C for 2 hours. TLC (PE:EtOAc = 5:1) showed the reaction was complete. The mixture was concentrated by purging with _N2 to afford the title compound (150 mg, 0.6043 mmol, 95.681% yield) as a tan solid.

(1R,5S,6r)-N- 甲基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-N-[1-( 三氟甲基 ) 環丙基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向1-異丙基咪唑-4-羧酸(93.16 mg，0.60 mmol)於DMF (2 mL)中之溶液添加HATU (277.21 mg，0.73 mmol)及Et ₃N (0.39 mL，3.02 mmol)。在20至25℃下攪拌混合物0.5小時。添加(1R,5S,6r)-N-甲基-N-[1-(三氟甲基)環丙基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺TFA鹽(150 mg，0.60 mmol)且在20至25℃下攪拌反應混合物16小時。隨後過濾混合物且濃縮濾液。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色固體狀之標題化合物(36.84 mg，0.0958 mmol，15.86%產率)。 LC-MS方法1: 385.0 [M+H ⁺] ¹H NMR (400MHz, DMSO-d ₆) δ = 7.79 (br d, J=8.3 Hz, 2H), 4.59 - 4.39 (m, 2H), 3.94 - 3.74 (m, 2H), 3.52 (br d, J=12.0 Hz, 1H), 3.15 (s, 1H), 2.89 (s, 3H), 2.17 (br s, 1H), 2.06 (br s, 1H), 1.95 (br s, 1H), 1.80 (br s, 1H), 1.72 - 1.51 (m, 2H), 1.40 (d, J=6.8 Hz, 7H) (1R,5S,6r)-N- Methyl -3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-N-[1-( trifluoromethyl ) cyclopropyl ] -3- Azabicyclo [3.1.0] hexane -6- carboxamide To a solution of 1-isopropylimidazole-4-carboxylic acid (93.16 mg, 0.60 mmol) in DMF (2 mL) was added HATU ( 277.21 mg, 0.73 mmol) and _Et3N (0.39 mL, 3.02 mmol). The mixture was stirred at 20 to 25°C for 0.5 hours. Add (1R,5S,6r)-N-methyl-N-[1-(trifluoromethyl)cyclopropyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide TFA salt (150 mg, 0.60 mmol) and the reaction mixture was stirred at 20 to 25°C for 16 hours. The mixture was then filtered and the filtrate was concentrated. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (36.84 mg, 0.0958 mmol, 15.86% yield) as a yellow solid. LC-MS method 1: 385.0 [M+H ⁺ ] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.79 (br d, J =8.3 Hz, 2H), 4.59 - 4.39 (m, 2H), 3.94 - 3.74 (m, 2H), 3.52 (br d, J =12.0 Hz, 1H), 3.15 (s, 1H), 2.89 (s, 3H), 2.17 (br s, 1H), 2.06 (br s, 1H), 1.95 (br s, 1H), 1.80 (br s, 1H), 1.72 - 1.51 (m, 2H), 1.40 (d, J =6.8 Hz, 7H)

實例 72      (1R,5S,6r)-3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-N-(1,1,1- 三氟 -2- 甲基丙 -2- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-6-[(1,1,1- 三氟 -2- 甲基丙 -2- 基 ) 胺甲醯基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(100 mg，0.44 mmol)及HATU (126.53mg，0.66 mmol)於DMF (3.3046 mL)中之溶液添加DIPEA (0.22 mL，1.32 mmol)。在15℃下攪拌反應混合物30 min。隨後添加1,1,1-三氟-2-甲基-丙-2-胺(55.93mg，0.44 mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。TLC (PE/EtOAc=1:1)展示新樣點。用H ₂O (50 mL)稀釋反應混合物且用EtOAc (30 mL × 2)萃取。有機層經無水硫酸鈉乾燥，過濾且濃縮，得到殘餘物。藉由二氧化矽管柱(PE/EtOAc=1:1)純化殘餘物，得到呈白色固體狀之標題化合物(90 mg，0.2676 mmol，60.81%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 5.75 (s, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.57 (d, J = 11.2 Hz, 1H), 3.45-3.35 (m, 2H), 2.02 (brs, 2H), 1.59 (s, 6H), 1.45 (s, 9H)。 Example 72 (1R, 5S, 6r)-3-[1-( prop -2- yl )-1H- imidazole - 4- carbonyl ]-N-(1,1,1- trifluoro -2- methylpropane- 2- yl )-3- azabicyclo [3.1.0] hexane -6- carboxamide (1R,5S,6r)-6-[(1,1,1- trifluoro - 2 - methylpropane- 2- yl ) aminoformyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-3-{[(tertiary butyl) A solution of oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (100 mg, 0.44 mmol) and HATU (126.53 mg, 0.66 mmol) in DMF (3.3046 mL) was added with DIPEA (0.22 mL, 1.32 mmol). The reaction mixture was stirred at 15 °C for 30 min. Then 1,1,1-trifluoro-2-methyl-propan-2-amine (55.93 mg, 0.44 mmol) was added. The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. TLC (PE/EtOAc=1:1) showed fresh samples. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (30 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica column (PE/EtOAc=1:1) to give the title compound (90 mg, 0.2676 mmol, 60.81% yield) as a white solid. ¹ H NMR (400MHz, chloroform-d) δ = 5.75 (s, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.57 (d, J = 11.2 Hz, 1H), 3.45-3.35 (m, 2H ), 2.02 (brs, 2H), 1.59 (s, 6H), 1.45 (s, 9H).

(1R,5S,6r)-N-(1,1,1- 三氟 -2- 甲基丙 -2- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 TFA 鹽向(1R,5S,6r)-6-[(1,1,1-三氟-2-甲基丙-2-基)胺甲醯基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(90 mg，0.27 mmol)於DCM (2 mL)中之溶液添加TFA (9.53mg，0.27 mmol)。在25℃下攪拌反應混合物0.5小時，得到無色混合物。TLC (PE/EtOAc=1:1)展示新樣點。藉由蒸發移除溶劑，得到呈黃色油狀之標題化合物。 (1R,5S,6r)-N-(1,1,1 - Trifluoro -2- methylpropan -2- yl )-3- azabicyclo [3.1.0] hexane -6- formamide TFA Salt to (1R,5S,6r)-6-[(1,1,1-trifluoro-2-methylpropan-2-yl)aminoformyl]-3-azabicyclo[3.1.0]hexane A solution of ter-butyl alkane-3-carboxylate (90 mg, 0.27 mmol) in DCM (2 mL) was added TFA (9.53 mg, 0.27 mmol). The reaction mixture was stirred at 25°C for 0.5 hours to give a colorless mixture. TLC (PE/EtOAc=1:1) showed fresh samples. The solvent was removed by evaporation to give the title compound as a yellow oil.

(1R,5S,6r)-3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-N-(1,1,1- 三氟 -2- 甲基丙 -2- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向1-異丙基咪唑-4-羧酸(41.12mg，0.27 mmol)及HATU (76.69mg，0.40 mmol)於DMF (2.0028 mL)中之溶液添加DIPEA (0.13 mL，0.80 mmol)。在15℃下攪拌反應混合物30 min。隨後向反應物添加(1R,5S,6r)-N-(1,1,1-三氟-2-甲基丙-2-基)-3-氮雜雙環[3.1.0]己烷-6-甲醯胺TFA鹽(63 mg，0.27 mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (NH ₃)純化反應混合物，得到呈淡黃色固體狀之標題化合物(37.38mg，0.1004 mmol，37.639%產率)。 LC-MS方法1: 373.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.64 (d, J=1.2 Hz, 1H), 7.46 (d, J=1.2 Hz, 1H), 5.70 (s, 1H), 4.74 (d, J=12.0 Hz, 1H), 4.35 (m, 1H), 4.14 (d, J=12.3 Hz, 1H), 3.87 (dd, J=3.9, 11.9 Hz, 1H), 3.58 (dd, J=3.9, 12.4 Hz, 1H), 2.19 - 2.01 (m, 2H), 1.57 (d, J=5.5 Hz, 6H), 1.49 (d, J=6.8 Hz, 6H), 1.20 (t, J=3.0 Hz, 1H) (1R,5S,6r)-3-[1-( Propan -2- yl )-1H- imidazole -4- carbonyl ]-N-(1,1,1 - trifluoro -2- methylpropane -2- Base )-3- azabicyclo [3.1.0] hexane -6- carboxamide to 1-isopropylimidazole-4-carboxylic acid (41.12mg, 0.27 mmol) and HATU (76.69mg, 0.40 mmol) in To a solution in DMF (2.0028 mL) was added DIPEA (0.13 mL, 0.80 mmol). The reaction mixture was stirred at 15 °C for 30 min. (1R,5S,6r)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-azabicyclo[3.1.0]hexane-6 was then added to the reaction mass - Formamide TFA salt (63 mg, 0.27 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC (NH ₃ ) to afford the title compound (37.38 mg, 0.1004 mmol, 37.639% yield) as a pale yellow solid. LC-MS method 1: 373.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.64 (d, J =1.2 Hz, 1H), 7.46 (d, J =1.2 Hz, 1H), 5.70 (s, 1H), 4.74 (d, J =12.0 Hz, 1H), 4.35 (m, 1H), 4.14 (d, J =12.3 Hz, 1H), 3.87 (dd, J =3.9, 11.9 Hz, 1H) , 3.58 (dd, J =3.9, 12.4 Hz, 1H), 2.19 - 2.01 (m, 2H), 1.57 (d, J =5.5 Hz, 6H), 1.49 (d, J =6.8 Hz, 6H), 1.20 ( t, J =3.0 Hz, 1H)

實例 73      (1R,5S,6r)-N- 甲基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-N-(1,1,1- 三氟 -2- 甲基丙 -2- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-6-[ 甲基 (1,1,1- 三氟 -2- 甲基丙 -2- 基 ) 胺甲醯基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-[(1,1,1-三氟-2-甲基丙-2-基)胺甲醯基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(160 mg，0.48 mmol)於THF (7.4294 mL)中之溶液添加NaH (13.7mg，0.57 mmol)且在0℃下攪拌0.5小時，得到黃色混合物。向反應混合物添加MeI (0.04 mL，0.67 mmol)。在20℃下攪拌反應混合物16小時，得到淺黃色混合物。TLC (PE/EtOAc=1:1)顯示新樣點。LCMS展示所要MS。用H ₂O (100 mL)淬滅反應混合物且用EtOAc (50 mL×3)萃取。濃縮有機層，得到殘餘物。藉由二氧化矽管柱(PE/EtOAc=1:1)純化殘餘物，得到呈無色油狀之標題化合物(150mg，0.4281 mmol，89.996%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.66 (d, J = 11.2 Hz, 1H), 3.55 (d, J = 11.2Hz, 1H), 3.50-3.40 (m, 2H), 3.15 (s, 3H), 2.20-2.10 (m, 1H), 2.10-2.00 (m, 1H), 1.66 (s, 6H), 1.60-1.50 (m, 1H), 1.44 (s, 9H)。 Example 73 (1R, 5S, 6r)-N- methyl -3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-N-(1,1,1- trifluoro -2 -Methylprop - 2- yl )-3- azabicyclo [3.1.0] hexane -6- formamide (1R,5S,6r)-6-[ methyl (1,1,1- trifluoro -2- methylpropan -2- yl ) carbamoyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 0°C to (1R,5S,6r) -6-[(1,1,1-Trifluoro-2-methylpropan-2-yl)aminoformyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl A solution of the ester (160 mg, 0.48 mmol) in THF (7.4294 mL) was added NaH (13.7 mg, 0.57 mmol) and stirred at 0 °C for 0.5 h to give a yellow mixture. MeI (0.04 mL, 0.67 mmol) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 16 hours to obtain a pale yellow mixture. TLC (PE/EtOAc=1:1) showed a new spot. LCMS showed desired MS. The reaction mixture was quenched with H ₂ O (100 mL) and extracted with EtOAc (50 mL×3). The organic layer was concentrated to give a residue. The residue was purified by silica column (PE/EtOAc=1:1) to give the title compound (150 mg, 0.4281 mmol, 89.996% yield) as colorless oil. ¹ H NMR (400MHz, Chloroform-d) δ = 3.66 (d, J = 11.2 Hz, 1H), 3.55 (d, J = 11.2Hz, 1H), 3.50-3.40 (m, 2H), 3.15 (s, 3H ), 2.20-2.10 (m, 1H), 2.10-2.00 (m, 1H), 1.66 (s, 6H), 1.60-1.50 (m, 1H), 1.44 (s, 9H).

(1R,5S,6r)-N- 甲基 -N-(1,1,1- 三氟 -2- 甲基丙 -2- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 TFA 鹽向(1R,5S,6r)-6-[甲基(1,1,1-三氟-2-甲基丙-2-基)胺甲醯基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.29 mmol)於DCM (2.1332 mL)中之溶液添加TFA (10.16mg，0.29 mmol)。在25℃下攪拌反應混合物0.5小時，得到無色混合物。TLC (PE/EtOAc=1:1)展示新樣點。移除反應混合物溶劑，得到標題化合物。其直接用於下一步驟。 (1R,5S,6r)-N- Methyl -N-(1,1,1 - trifluoro -2- methylpropan -2- yl )-3- azabicyclo [3.1.0] hexane -6 - Formamide TFA salt to (1R,5S,6r)-6-[methyl(1,1,1-trifluoro-2-methylpropan-2-yl)carbamoyl]-3-aza A solution of tert-butyl bicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.29 mmol) in DCM (2.1332 mL) was added TFA (10.16 mg, 0.29 mmol). The reaction mixture was stirred at 25°C for 0.5 hours to give a colorless mixture. TLC (PE/EtOAc=1:1) showed fresh samples. The reaction mixture solvent was removed to afford the title compound. It was used directly in the next step.

(1R,5S,6r)-N- 甲基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-N-(1,1,1- 三氟 -2- 甲基丙 -2- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向1-異丙基咪唑-4-羧酸(43.74mg，0.28 mmol)、HATU (81.58mg，0.43 mmol)於DMF (2.1306 mL)中之溶液添加DIPEA (0.14 mL，0.85 mmol)。在15℃下攪拌反應混合物30 min。隨後向反應物添加(1R,5S,6r)-N-甲基-N-(1,1,1-三氟-2-甲基丙-2-基)-3-氮雜雙環[3.1.0]己烷-6-甲醯胺TFA鹽(71 mg，0.28 mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (NH ₃)純化反應混合物，得到呈白色粉末狀之標題化合物(72.14mg，0.1867 mmol，65.805%產率)。 LC-MS方法1: 387.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.67 (d, J=1.6 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 4.71 (d, J=12.3 Hz, 1H), 4.35 (m, 1H), 4.13 (d, J=12.5 Hz, 1H), 3.96 (dd, J=4.4, 12.2 Hz, 1H), 3.65 (dd, J=4.4, 12.7 Hz, 1H), 3.12 (s, 3H), 2.24 (m, 1H), 2.11 (m, 1H), 1.65 (s, 6H), 1.56 (t, J=3.1 Hz, 1H), 1.50 (d, J=6.8 Hz, 6H) (1R,5S,6r)-N- methyl -3-[1-( prop -2- yl )-1H- imidazole -4- carbonyl ]-N-(1,1,1- trifluoro -2- methyl Propan -2- yl )-3- azabicyclo [3.1.0] hexane -6- formamide to 1-isopropylimidazole-4-carboxylic acid (43.74mg, 0.28 mmol), HATU (81.58mg , 0.43 mmol) in DMF (2.1306 mL) was added DIPEA (0.14 mL, 0.85 mmol). The reaction mixture was stirred at 15 °C for 30 min. (1R,5S,6r)-N-methyl-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-3-azabicyclo[3.1.0 ] Hexane-6-formamide TFA salt (71 mg, 0.28 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC (NH ₃ ) to afford the title compound (72.14 mg, 0.1867 mmol, 65.805% yield) as a white powder. LC-MS method 1: 387.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.67 (d, J =1.6 Hz, 1H), 7.47 (d, J =1.2 Hz, 1H), 4.71 (d, J =12.3 Hz, 1H), 4.35 (m, 1H), 4.13 (d, J =12.5 Hz, 1H), 3.96 (dd, J =4.4, 12.2 Hz, 1H), 3.65 (dd, J = 4.4, 12.7 Hz, 1H), 3.12 (s, 3H), 2.24 (m, 1H), 2.11 (m, 1H), 1.65 (s, 6H), 1.56 (t, J =3.1 Hz, 1H), 1.50 ( d, J =6.8 Hz, 6H)

實例 74      [(1R,5S,6r)-6-(2,2- 二甲基 -2,3- 二氫 -1H- 吲哚 -1- 羰基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-( 丙 -2- 基 )-1H- 咪唑 -4- 基 ] 甲酮 2,2- 二甲基吲哚啉在0℃下於N ₂下向2,2-二甲基-1,2-二氫-3H-吲哚-3-酮(270 mg，1.67 mmol)及三氯鋁氧烷(223.33 mg，1.67 mmol)於THF (5 mL)中之溶液添加LiAlH ₄(95.47 mg，2.51 mmol)。在20℃下於N ₂下攪拌反應混合物2小時。TLC (PE:EtOAc = 4:1)展示反應完成。用NaHCO ₃水溶液將反應混合物鹼化至pH = 8，用EtOAc (10 mL × 3)萃取，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到殘餘物。藉由製備型TLC (PE:EtOAc = 4:1)純化殘餘物，得到呈黃色油狀之標題化合物(60 mg，0.4076 mmol，24.333%產率) (粗物質)。 Example 74 [(1R,5S,6r)-6-(2,2- Dimethyl -2,3- dihydro -1H- indole -1- carbonyl )-3- azabicyclo [3.1.0] hexyl -3- yl ][1-( propan -2- yl )-1H- imidazol -4- yl ] methanone 2,2 -dimethylindoline to _2,2 -di To a solution of methyl-1,2-dihydro-3H-indol-3-one (270 mg, 1.67 mmol) and trichloroaluminoxane (223.33 mg, 1.67 mmol) in THF (5 mL) was added LiAlH ₄ (95.47 mg, 2.51 mmol). The reaction mixture was stirred at 20 °C for 2 h under _N2 . TLC (PE:EtOAc = 4:1) showed the reaction was complete. The reaction mixture was basified to pH = 8 with aqueous NaHCO ₃ , extracted with EtOAc (10 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (PE:EtOAc = 4:1 ) to give the title compound (60 mg, 0.4076 mmol, 24.333% yield) (crude material) as a yellow oil.

(1R,5S,6r)-6-[(2,2- 二甲基 -2,3,3a,7a- 四氫 -1H- 吲哚 -1- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(92.62 mg，0.41 mmol)於DCM (1 mL)中之溶液添加HATU (233.71 mg，0.61 mmol)及Et ₃N (0.11 mL，0.82 mmol)。在20℃下於N ₂下攪拌混合物10分鐘。隨後添加2,2-二甲基吲哚啉(60 mg，0.41 mmol)。在20℃下攪拌所得混合物16小時，得到褐色混合物。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (10 mL × 4)萃取。用鹽水(10 mL)洗滌合併之有機層，經無水Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到褐色油狀物。藉由製備型TLC (PE:EtOAc = 4:1)純化殘餘物，得到呈褐色油狀之標題化合物(45 mg，0.1262 mmol，30.975%產率)。 (1R,5S,6r)-6-[(2,2- Dimethyl -2,3,3a,7a- tetrahydro -1H- indol -1- yl ) carbonyl ]-3- azabicyclo [3.1 .0] Hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-3-{[(tertiary butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane To a solution of alkane-6-carboxylic acid (92.62 mg, 0.41 mmol) in DCM (1 mL) was added HATU (233.71 mg, 0.61 mmol) and _Et3N (0.11 mL, 0.82 mmol). The mixture was stirred at 20 °C for 10 min under _N2 . Then 2,2-dimethylindoline (60 mg, 0.41 mmol) was added. The resulting mixture was stirred at 20°C for 16 hours to give a brown mixture. The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (10 mL×4). The combined organic layers _were washed with brine (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give a brown oil. The residue was purified by prep-TLC (PE:EtOAc = 4:1 ) to give the title compound (45 mg, 0.1262 mmol, 30.975% yield) as a brown oil.

(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 (2,2- 二甲基 -2,3,3a,7a- 四氫 -1H- 吲哚 -1- 基 ) 甲酮 TFA 鹽向(1R,5S,6r)-6-[(2,2-二甲基-2,3,3a,7a-四氫-1H-吲哚-1-基)羰基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(45 mg，0.13 mmol)於DCM (4 mL)中之溶液添加TFA (1 mL，13.46 mmol)。在20至25℃下攪拌所得混合物1h。用N ₂吹掃反應混合物以移除溶劑，得到呈褐色油狀之標題化合物(32 mg，0.1248 mmol，98.884%產率)。 (1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl (2,2 -dimethyl -2,3,3a,7a- tetrahydro -1H- indole -1- Base ) ketone TFA salt to (1R,5S,6r)-6-[(2,2-Dimethyl-2,3,3a,7a-tetrahydro-1H-indol-1-yl)carbonyl]- To a solution of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (45 mg, 0.13 mmol) in DCM (4 mL) was added TFA (1 mL, 13.46 mmol). The resulting mixture was stirred at 20 to 25 °C for 1 h. The reaction mixture was purged with _N2 to remove solvent to give the title compound (32 mg, 0.1248 mmol, 98.884% yield) as a brown oil.

[(1R,5S,6r)-6-(2,2- 二甲基 -2,3- 二氫 -1H- 吲哚 -1- 羰基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-( 丙 -2- 基 )-1H- 咪唑 -4- 基 ] 甲酮向1-異丙基咪唑-4-羧酸(25.02 mg，0.16 mmol)於DMF (1.5 mL)中之溶液添加HATU (57.27 mg，0.15 mmol)、Et ₃N (0.07 mL，0.50 mmol)及(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基(2,2-二甲基-2,3,3a,7a-四氫-1H-吲哚-1-基)甲酮TFA鹽(32 mg，0.12 mmol)。在20至25℃下攪拌所得混合物12小時，得到綠色溶液。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (10 mL × 4)萃取。合併之有機層經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(18 mg，0.0459 mmol，36.738%產率)。 LC-MS方法1: 393.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.68 (s, 1H), 7.48 (s, 1H), 7.26 - 7.20 (m, 1H), 7.18 - 7.13 (m, 2H), 7.00 - 6.95 (m, 1H), 4.78 (d, J=12.4 Hz, 1H), 4.36 (td, J=6.8, 13.5 Hz, 1H), 4.22 (br d, J=12.5 Hz, 1H), 4.07 (dd, J=4.5, 12.3 Hz, 1H), 3.77 (dd, J=4.2, 13.3 Hz, 1H), 2.97 (br s, 2H), 2.46 (dd, J=3.6, 7.2 Hz, 1H), 2.30 (br d, J=3.3 Hz, 1H), 1.93 (br s, 1H), 1.56 (br s, 2H), 1.56 - 1.52 (m, 4H), 1.50 (d, J=6.6 Hz, 6H) [(1R,5S,6r)-6-(2,2- Dimethyl -2,3- dihydro -1H- indole -1- carbonyl )-3- azabicyclo [3.1.0] hexa -3 -yl ][1-( propan -2- yl )-1H- imidazol - 4- yl ] methanone to 1-isopropylimidazole-4-carboxylic acid (25.02 mg, 0.16 mmol) in DMF (1.5 mL) HATU (57.27 mg, 0.15 mmol), Et ₃ N (0.07 mL, 0.50 mmol) and (1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl (2,2 -Dimethyl-2,3,3a,7a-tetrahydro-1H-indol-1-yl)methanone TFA salt (32 mg, 0.12 mmol). The resulting mixture was stirred at 20 to 25°C for 12 hours to give a green solution. The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (10 mL×4). The combined organic layers were dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (18 mg, 0.0459 mmol, 36.738% yield) as a white solid. LC-MS method 1: 393.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.68 (s, 1H), 7.48 (s, 1H), 7.26 - 7.20 (m, 1H), 7.18 - 7.13 (m, 2H), 7.00 - 6.95 (m, 1H), 4.78 (d, J =12.4 Hz, 1H), 4.36 (td, J =6.8, 13.5 Hz, 1H), 4.22 (br d, J =12.5 Hz, 1H), 4.07 (dd, J =4.5, 12.3 Hz, 1H), 3.77 (dd, J =4.2, 13.3 Hz, 1H), 2.97 (br s, 2H), 2.46 (dd, J =3.6, 7.2 Hz, 1H), 2.30 (br d, J =3.3 Hz, 1H), 1.93 (br s, 1H), 1.56 (br s, 2H), 1.56 - 1.52 (m, 4H), 1.50 (d, J =6.6 Hz, 6H)

實例 75 環丙基 {(1R,5S,6r)-3-[(1- 異丙基 -1H- 咪唑 -4- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己 -6- 基 } 甲酮 (1R,5S,6r)-6-[ 環丙基 ( 羥基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(500 mg，2.37 mmol)於THF (5 mL)中之溶液逐滴添加溴基(環丙基)鎂(7.1 mL，3.55 mmol)。在0℃下攪拌混合物45 min。將混合物緩慢傾入H ₂O (40 mL)中且用EtOAc (20 mL × 3)萃取。用鹽水(50 mL)洗滌有機相，經無水Na ₂SO ₄乾燥，過濾且濃縮，得到呈黃色油狀之標題化合物(600 mg，2.36 mmol)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.75-3.50 (m, 2H), 3.45-3.30 (m, 2H), 2.75-2.55 (m, 2H), 1.57 (s, 2H), 1.44 (s, 9H), 1.10-0.90 (m, 1H), 1.90-1.80 (m, 1H), 0.60-0.45 (m, 2H), 0.30-0.20 (m, 2H)。 Example 75 Cyclopropyl {(1R,5S,6r)-3-[(1- isopropyl -1H- imidazol -4- yl ) carbonyl ]-3- azabicyclo [3.1.0] hex -6- yl } Methanone (1R,5S,6r)-6-[ cyclopropyl ( hydroxyl ) methyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 0°C (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (500 mg, 2.37 mmol) in THF (5 mL) The solution was added dropwise with bromo(cyclopropyl)magnesium (7.1 mL, 3.55 mmol). The mixture was stirred at 0 °C for 45 min. The mixture was slowly poured into H ₂ O (40 mL) and extracted with EtOAc (20 mL×3). The organic phase was _washed with brine (50 mL), dried over anhydrous _Na2SO4 , filtered and concentrated to give the title compound (600 mg, 2.36 mmol) as a yellow oil. ¹ H NMR (400MHz, chloroform-d) δ = 3.75-3.50 (m, 2H), 3.45-3.30 (m, 2H), 2.75-2.55 (m, 2H), 1.57 (s, 2H), 1.44 (s, 9H), 1.10-0.90 (m, 1H), 1.90-1.80 (m, 1H), 0.60-0.45 (m, 2H), 0.30-0.20 (m, 2H).

(1R,5S,6r)-6-( 環丙基羰基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-[環丙基(羥基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(550 mg，2.17 mmol)於DCM (11 mL)中之溶液添加DMP (1.01 g，2.39 mmol)。在20℃下攪拌混合物2小時。TLC (PE:EtOAc=3/1)展示起始材料(Rf=0.3)完全耗盡且偵測到新樣點(Rf=0.6)。將混合物緩慢傾入H ₂O (30 mL)中，用DCM (25 mL × 3)萃取。用飽和NaHCO ₃(30 mL × 2)及鹽水(35 mL × 1)洗滌有機相，經無水Na ₂SO ₄乾燥且濃縮，得到殘餘物。藉由SiO ₂快速柱(PE:EtOAc=10:1至1:1)純化殘餘物，得到呈白色固體狀之標題化合物(280 mg，1.11 mmol，51.3%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.70 (d, J = 11.2 Hz, 1H), 3.61 (d, J = 11.2 Hz, 1H), 3.45-3.40 (m, 2H), 2.10 (s, 2H), 2.10-2.00 (m, 1H), 1.92 (s, 1H), 1.46 (s, 9H), 1.10-1.00 (m, 2H), 0.95-0.90 (m, 2H)。 (1R,5S,6r)-6-( cyclopropylcarbonyl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 0°C to (1R,5S,6r) -6-[cyclopropyl(hydroxy)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (550 mg, 2.17 mmol) in DCM (11 mL) To the solution was added DMP (1.01 g, 2.39 mmol). The mixture was stirred at 20°C for 2 hours. TLC (PE:EtOAc=3/1) showed complete consumption of starting material (Rf=0.3) and detection of new spots (Rf=0.6). The mixture was slowly poured into H ₂ O (30 mL), extracted with DCM (25 mL×3). The organic phase was washed with saturated NaHCO ₃ (30 mL×2) and brine (35 mL×1), dried over anhydrous Na ₂ SO ₄ and concentrated to give a residue. The residue was purified by _Si02 flash column (PE:EtOAc = 10:1 to 1:1) to give the title compound (280 mg, 1.11 mmol, 51.3% yield) as a white solid. ¹ H NMR (400MHz, Chloroform-d) δ = 3.70 (d, J = 11.2 Hz, 1H), 3.61 (d, J = 11.2 Hz, 1H), 3.45-3.40 (m, 2H), 2.10 (s, 2H ), 2.10-2.00 (m, 1H), 1.92 (s, 1H), 1.46 (s, 9H), 1.10-1.00 (m, 2H), 0.95-0.90 (m, 2H).

(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ( 環丙基 ) 甲酮向(1R,5S,6r)-6-(環丙基羰基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(80 mg，0.32 mmol)於DCM (5 mL)中之溶液添加TFA (1 mL，13.4 mmol)。在25℃下攪拌混合物2 小時。TLC (PE:EtOAc=3:1)展示偵測到新樣點(Rf=0)。濃縮混合物，得到呈黃色油狀之標題化合物(80 mg，0.52 mmol)。粗物質直接用於下一步驟。 (1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl ( cyclopropyl ) methanone to (1R,5S,6r)-6-(cyclopropylcarbonyl)-3- To a solution of tert-butyl azabicyclo[3.1.0]hexane-3-carboxylate (80 mg, 0.32 mmol) in DCM (5 mL) was added TFA (1 mL, 13.4 mmol). The mixture was stirred at 25°C for 2 hours. TLC (PE:EtOAc=3:1) showed detection of a new spot (Rf=0). The mixture was concentrated to give the title compound (80 mg, 0.52 mmol) as a yellow oil. The crude material was used directly in the next step.

環丙基 {(1R,5S,6r)-3-[(1- 異丙基 -1H- 咪唑 -4- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己 -6- 基 } 甲酮向(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基(環丙基)甲酮(75 mg，0.5 mmol)及DIPEA (0.41 mL，2.48 mmol)於DMF (2 mL)中之溶液添加HATU (189 mg，0.5 mmol)及1-異丙基咪唑-4-羧酸(76.4 mg，0.5 mmol)。在20℃下攪拌混合物16小時。用H2O (50 mL)稀釋混合物，用EtOAc (25 mL × 3)萃取。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈白色固體狀之標題化合物(7 mg，0.024 mmol，4.91%產率)。 LC-MS方法1: 288.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.68 (d, J=1.5 Hz, 1 H) 7.48 (d, J=1.4 Hz, 1 H) 4.75 (d, J=12.1 Hz, 1 H) 4.36 (dt, J=13.4, 6.7 Hz, 1 H) 4.17 (d, J=12.8 Hz, 1 H) 3.95 (dd, J=12.2, 3.9 Hz, 1 H) 3.63 (dd, J=12.6, 4.1 Hz, 1 H) 2.26 (dt, J=7.1, 3.5 Hz, 1 H) 2.16 (dt, J=7.2, 3.5 Hz, 1 H) 1.98 - 2.06 (m, 1 H) 1.93 (t, J=3.0 Hz, 1 H) 1.51 (d, J=6.6 Hz, 6 H) 1.02 - 1.08 (m, 2 H) 0.88 - 0.94 (m, 2 H) Cyclopropyl {(1R,5S,6r)-3-[(1- isopropyl -1H- imidazol -4- yl ) carbonyl ]-3- azabicyclo [3.1.0] hex -6- yl } methyl Ketone (1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(cyclopropyl)methanone (75 mg, 0.5 mmol) and DIPEA (0.41 mL, 2.48 mmol) in DMF (2 mL) was added HATU (189 mg, 0.5 mmol) and 1-isopropylimidazole-4-carboxylic acid (76.4 mg, 0.5 mmol). The mixture was stirred at 20°C for 16 hours. The mixture was diluted with H2O (50 mL), extracted with EtOAc (25 mL x 3). The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (7 mg, 0.024 mmol, 4.91% yield) as a white solid. LC-MS method 1: 288.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.68 (d, J =1.5 Hz, 1 H) 7.48 (d, J =1.4 Hz, 1 H) 4.75 (d, J =12.1 Hz, 1 H) 4.36 (dt, J =13.4, 6.7 Hz, 1 H) 4.17 (d, J =12.8 Hz, 1 H) 3.95 (dd, J =12.2, 3.9 Hz, 1 H) 3.63 (dd, J =12.6, 4.1 Hz, 1 H) 2.26 (dt, J =7.1, 3.5 Hz, 1 H) 2.16 (dt, J =7.2, 3.5 Hz, 1 H) 1.98 - 2.06 (m, 1 H) 1.93 (t, J =3.0 Hz, 1 H) 1.51 (d, J =6.6 Hz, 6 H) 1.02 - 1.08 (m, 2 H) 0.88 - 0.94 (m, 2 H)

實例 76      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(2- 噻吩基羰基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6-(2- 噻吩基羰基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在-78℃下向2-溴噻吩(0.28 mL，2.84 mmol)於THF (5 mL)中之混合物逐滴添加n-BuLi (1.42 mL，3.55 mmol)。在-78℃下攪拌反應混合物1h。隨後在-78℃下添加(1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(500 mg，2.37 mmol)。在25℃下攪拌所得混合物30 min。用H ₂O (10 mL)稀釋反應混合物且隨後用EtOAc (10 mL×2)萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由快速柱(0至30% EtOAc/PE)純化粗物質油，得到呈淡黃色油狀之標題化合物(30mg，0.1023 mmol，4.3205%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 7.75 (s, 1H), 7.60 (s, 1H), 7.09 (s, 1H), 3.80-3.50 (m, 2H), 3.50-3.40 (m, 2H), 2.31 (s, 1H), 2.23 (brs, 2H), 1.40 (s, 9H)。 Example 76 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(2- thienylcarbonyl )-3- azabicyclo [3.1.0] hexa -3- Base ] methanone (1R,5S,6r)-6-(2- thienylcarbonyl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at -78°C to 2 -A mixture of bromothiophene (0.28 mL, 2.84 mmol) in THF (5 mL) was added n-BuLi (1.42 mL, 3.55 mmol) dropwise. The reaction mixture was stirred at -78 °C for 1 h. (1R,5S,6r)-6-Formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (500 mg, 2.37 mmol) was then added at -78°C. The resulting mixture was stirred at 25 °C for 30 min. The reaction mixture was diluted with H ₂ O (10 mL) and then extracted with EtOAc (10 mL×2). The combined organic layers were dried over _Na2SO4 and _concentrated in vacuo to give a crude oil. The crude oil was purified by flash column (0 to 30% EtOAc/PE) to give the title compound (30 mg, 0.1023 mmol, 4.3205% yield) as a pale yellow oil. ¹ H NMR (400MHz, chloroform-d) δ = 7.75 (s, 1H), 7.60 (s, 1H), 7.09 (s, 1H), 3.80-3.50 (m, 2H), 3.50-3.40 (m, 2H) , 2.31 (s, 1H), 2.23 (brs, 2H), 1.40 (s, 9H).

(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 (2- 噻吩基 ) 甲酮 TFA 鹽在25℃下攪拌(1R,5S,6r)-6-(2-噻吩基羰基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(30 mg，0.10 mmol)於DCM (0.50 mL)及TFA (0.1 mL，0.10 mmol)中之混合物2小時。將反應混合物濃縮至乾燥，得到呈黃色油狀之標題化合物(19mg，0.0983 mmol，96.139%產率)。 (1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl (2- thienyl ) methanone TFA salt was stirred at 25°C (1R,5S,6r)-6-(2 -Thienylcarbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (30 mg, 0.10 mmol) in DCM (0.50 mL) and TFA (0.1 mL, 0.10 mmol) The mixture was left for 2 hours. The reaction mixture was concentrated to dryness to afford the title compound (19 mg, 0.0983 mmol, 96.139% yield) as a yellow oil.

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(2- 噻吩基羰基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基(2-噻吩基)甲酮TFA鹽(19 mg，0.10 mmol)於吡啶(0.50 mL)中之混合物添加EDCI (22.61mg，0.12 mmol)及1-異丙基咪唑-4-羧酸(15.16mg，0.10 mmol)。在20℃下攪拌所得混合物16小時。用H ₂O (5 mL)稀釋反應混合物且隨後用EtOAc (5 mL × 3)萃取。用鹽水(10 mL)洗滌合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到殘餘物。藉由製備型TLC (EtOAc/MeOH=20/1，0.05 %NH ₃.H ₂O)純化殘餘物，得到呈白色固體狀之標題化合物(5mg，0.0152 mmol，15.439%產率)。 ¹H NMR (400MHz, CD ₃OD) δ = 8.02 (d, J=3.0 Hz, 1H), 7.84 (d, J=4.8 Hz, 1H), 7.77 (br d, J=7.5 Hz, 2H), 7.22 - 7.18 (m, 1H), 4.50 (br d, J=8.3 Hz, 2H), 4.14 (br d, J=13.1 Hz, 1H), 4.01 (br s, 1H), 3.71 (br s, 1H), 2.59 (s, 1H), 2.38 (br d, J=17.8 Hz, 2H), 1.51 (d, J=6.5 Hz, 6H), 1.46 (s, 1H), 1.44 - 1.42 (m, 1H)。 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(2- thienylcarbonyl )-3- azabicyclo [3.1.0] hex -3- yl ] Methanone to (1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(2-thienyl)methanone TFA salt (19 mg, 0.10 mmol) in pyridine (0.50 mL) The mixture was added with EDCI (22.61 mg, 0.12 mmol) and 1-isopropylimidazole-4-carboxylic acid (15.16 mg, 0.10 mmol). The resulting mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with H ₂ O (5 mL) and then extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (10 mL), then dried over Na ₂ SO ₄ and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (EtOAc/MeOH=20/1, 0.05% NH ₃ .H ₂ O) to afford the title compound (5 mg, 0.0152 mmol, 15.439% yield) as a white solid. ¹ H NMR (400MHz, CD ₃ OD) δ = 8.02 (d, J =3.0 Hz, 1H), 7.84 (d, J =4.8 Hz, 1H), 7.77 (br d, J =7.5 Hz, 2H), 7.22 - 7.18 (m, 1H), 4.50 (br d, J =8.3 Hz, 2H), 4.14 (br d, J =13.1 Hz, 1H), 4.01 (br s, 1H), 3.71 (br s, 1H), 2.59 (s, 1H), 2.38 (br d, J =17.8 Hz, 2H), 1.51 (d, J =6.5 Hz, 6H), 1.46 (s, 1H), 1.44 - 1.42 (m, 1H).

實例 77      (1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(4- 甲基 -2- 噻吩基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 (1R,5S,6r)-6-[ 羥基 (4- 甲基 -2- 噻吩基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯 ( 化合物 1) 及三級丁基 (1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 (4- 甲基 -2- 噻吩基 ) 甲酮 ( 化合物 2)在-78℃下向3-甲基噻吩(0.24 mL，2.55 mmol)於THF (5 mL)中之溶液逐滴添加於(1.02 mL，2.55 mmol)中之2.5 M n-BuLi。在-78℃下於N ₂下攪拌混合物0.5小時。隨後，在-78℃下添加(1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(742.43mg，3.51 mmol)。將所得溶液升溫至25℃且攪拌1小時，得到褐色溶液。用EtOAc稀釋反應混合物且用飽和NH ₄Cl溶液小心地淬滅。將所得混合物傾入H ₂O (10 mL)中且用EtOAc (10 mL × 3)萃取。用鹽水(10 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由快速柱(PE:EtOAc=30:1)純化粗產物，得到呈黃色油狀之標題化合物1 (660mg，2.133 mmol，83.76%產率)及呈黃色固體狀之標題化合物2 (100 mg，0.3253 mmol，12.774%產率)。 Example 77 (1- isopropyl -1H- imidazol -4- yl ){(1R,5S,6r)-6-[(4- methyl -2- thienyl ) carbonyl ]-3- azabicyclo [3.1 .0] hex -3- yl } methanone (1R,5S,6r)-6-[ hydroxy (4- methyl -2- thienyl ) methyl ]-3- azabicyclo [3.1.0] hexane -tertiary butyl 3- carboxylate ( compound 1) and tertiary butyl (1R,5S,6r)-3- azabicyclo [3.1.0] hex -6- yl (4- methyl -2- thiophene To a solution of 3 - methylthiophene (0.24 mL, 2.55 mmol) in THF (5 mL) was added dropwise 2.5 M ketone ( compound 2 ) in (1.02 mL, 2.55 mmol) at -78°C . n-BuLi. The mixture was stirred at -78 °C under _N2 for 0.5 h. Subsequently, (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (742.43 mg, 3.51 mmol) was added at -78 °C . The resulting solution was warmed to 25 °C and stirred for 1 hour to give a brown solution. The reaction mixture was diluted with EtOAc and quenched carefully with saturated _NH4Cl solution. The resulting mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column (PE:EtOAc=30:1) to give title compound 1 (660 mg, 2.133 mmol, 83.76% yield) as yellow oil and title compound 2 (100 mg, 0.3253 mmol, 12.774% yield).

(1R,5S,6r)-6-[(4- 甲基 -2- 噻吩基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-[羥基(4-甲基-2-噻吩基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(660mg，2.13 mmol)於DCM (8 mL)中之溶液添加DMP (1357.05mg，3.2 mmol)。在25℃下攪拌混合物2小時，得到白色懸浮液。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (10 mL × 3)萃取。用NaHCO ₃水溶液(20 mL)及Na ₂SO ₃水溶液(10 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到粗產物。藉由急驟管柱層析(PE:EtOAc=30:1)純化粗產物，得到標題化合物(500 mg，1.6265 mmol，76.253%產率)。 (1R,5S,6r)-6-[(4- Methyl -2- thienyl ) carbonyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 0℃ To (1R,5S,6r)-6-[hydroxyl(4-methyl-2-thienyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester ( 660 mg, 2.13 mmol) in DCM (8 mL) was added DMP (1357.05 mg, 3.2 mmol). The mixture was stirred at 25°C for 2 hours to give a white suspension. The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with aqueous NaHCO ₃ (20 mL) and aqueous Na ₂ SO ₃ (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (PE:EtOAc=30:1) to obtain the title compound (500 mg, 1.6265 mmol, 76.253% yield).

(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 (4- 甲基 -2- 噻吩基 ) 甲酮 TFA 鹽向(1R,5S,6r)-6-[(4-甲基-2-噻吩基)羰基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.33 mmol)於DCM (5 mL)中之溶液添加TFA (0.75 mL，9.76 mmol)。在25℃下攪拌所得混合物2小時，得到黃色溶液。在真空中蒸發反應混合物，得到呈黃色油狀之標題化合物(60mg，0.2894 mmol，88.98%產率)。其直接用於下一步驟。 (1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl (4- methyl -2- thienyl ) methanone TFA salt to (1R,5S,6r)-6-[ (4-Methyl-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (100 mg, 0.33 mmol) in DCM (5 mL) The solution was added TFA (0.75 mL, 9.76 mmol). The resulting mixture was stirred at 25°C for 2 hours to obtain a yellow solution. The reaction mixture was evaporated in vacuo to afford the title compound (60 mg, 0.2894 mmol, 88.98% yield) as a yellow oil. It was used directly in the next step.

(1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(4- 甲基 -2- 噻吩基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮向(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基(4-甲基-2-噻吩基)甲酮TFA鹽(130 mg，0.63 mmol)於DMF (4 mL)中之溶液添加HATU (359.63mg，0.94 mmol)及Et ₃N (0.16 mL，1.25 mmol)。在25℃下於N ₂下攪拌混合物10 min。隨後，添加於DMF (2 mL)中之1-異丙基咪唑-4-羧酸(193.37mg，1.25 mmol)，在25℃下攪拌所得混合物16小時，得到黃色混合物。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (10 mL × 3)萃取。用鹽水(10 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到粗產物。藉由製備型HPLC (NH ₃)純化粗產物且凍乾，得到呈黃色固體狀之標題化合物(200 mg，0.5823 mmol，92.857%產率)。 LC-MS方法1: 344.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.72 (d, J=1.3 Hz, 1H), 7.59 (d, J=1.0 Hz, 1H), 7.49 (d, J=1.3 Hz, 1H), 7.24 (s, 1H), 4.79 (d, J=12.3 Hz, 1H), 4.38 (spt, J=6.7 Hz, 1H), 4.23 (d, J=12.8 Hz, 1H), 4.03 (dd, J=4.0, 12.3 Hz, 1H), 3.71 (dd, J=3.8, 12.8 Hz, 1H), 2.51 - 2.41 (m, 1H), 2.37 - 2.31 (m, 2H), 2.29 (s, 3H), 1.52 (d, J=6.8 Hz, 6H) (1- isopropyl -1H- imidazol -4- yl ){(1R,5S,6r)-6-[(4- methyl -2- thienyl ) carbonyl ]-3- azabicyclo [3.1.0 ] hex -3- yl } methanone to (1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(4-methyl-2-thienyl)methanone TFA salt (130 mg, 0.63 mmol) in DMF (4 mL) was added HATU (359.63 mg, 0.94 mmol) and Et ₃ N (0.16 mL, 1.25 mmol). The mixture was stirred at 25 °C under _N2 for 10 min. Subsequently, 1-isopropylimidazole-4-carboxylic acid (193.37 mg, 1.25 mmol) in DMF (2 mL) was added, and the resulting mixture was stirred at 25° C. for 16 hours to obtain a yellow mixture. The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude product. The crude product was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (200 mg, 0.5823 mmol, 92.857% yield) as a yellow solid. LC-MS method 1: 344.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.72 (d, J =1.3 Hz, 1H), 7.59 (d, J =1.0 Hz, 1H), 7.49 (d, J =1.3 Hz, 1H), 7.24 (s, 1H), 4.79 (d, J =12.3 Hz, 1H), 4.38 (spt, J =6.7 Hz, 1H), 4.23 (d, J =12.8 Hz , 1H), 4.03 (dd, J =4.0, 12.3 Hz, 1H), 3.71 (dd, J =3.8, 12.8 Hz, 1H), 2.51 - 2.41 (m, 1H), 2.37 - 2.31 (m, 2H), 2.29 (s, 3H), 1.52 (d, J =6.8 Hz, 6H)

實例 78      (1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(4- 甲氧基 -2- 噻吩基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 (1R,5S,6r)-6-[ 羥基 (4- 甲氧基 -2- 噻吩基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在-78℃下向3-甲氧基噻吩(0.18 mL，2.13 mmol)於THF (3 mL)中之溶液添加於正己烷(0.85 mL，2.13 mmol)中之2.5 M n-BuLi。在-78℃下於N ₂下攪拌混合物0.5小時。在-78℃下添加(1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(300 mg，1.42 mmol)。在20至25℃下攪拌所得混合物2小時。將反應混合物傾入飽和NH ₄Cl水溶液(2 mL)中且用EtOAc (10 mL × 4)萃取水層。用飽和NaCl溶液(10 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由快速柱(PE至30% EtOAc/PE)純化粗產物，得到呈黃色膠質之標題化合物(380 mg，1.1677 mmol，82.231%產率)。 Example 78 (1- isopropyl -1H- imidazol -4- yl ){(1R,5S,6r)-6-[(4- methoxy -2- thienyl ) carbonyl ]-3- azabicyclo [ 3.1.0] Hex -3- yl } methanone (1R,5S,6r)-6-[ hydroxy (4- methoxy -2- thienyl ) methyl ]-3- azabicyclo [3.1.0] To a solution of 3- methoxythiophene (0.18 mL, 2.13 mmol) in THF (3 mL) was added tert-butyl hexane-3 - carboxylate in n-hexane (0.85 mL, 2.13 mmol) at -78 °C 2.5 M of n-BuLi. The mixture was stirred at -78 °C under _N2 for 0.5 h. (1R,5S,6r)-6-Formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (300 mg, 1.42 mmol) was added at -78°C. The resulting mixture was stirred at 20 to 25°C for 2 hours. The reaction mixture was poured into saturated aqueous NH ₄ Cl (2 mL) and the aqueous layer was extracted with EtOAc (10 mL×4). The combined organic layers were washed with saturated NaCl solution (10 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column (PE to 30% EtOAc/PE) to give the title compound (380 mg, 1.1677 mmol, 82.231% yield) as a yellow gum.

(1R,5S,6r)-6-[(4- 甲氧基 -2- 噻吩基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[羥基(4-甲氧基-2-噻吩基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(380 mg，1.17 mmol)於THF (4 mL)中之溶液添加MnO ₂(507.61 mg，5.84 mmol)。在50℃下攪拌混合物16小時。TLC (PE:EtOAc = 2:1)展示新樣點且起始材料剩餘。隨後過濾混合物且真空濃縮濾液。藉由製備型TLC (PE:EtOAc = 2:1)純化殘餘物，得到呈無色油狀之標題化合物(60 mg，0.1855 mmol，15.888%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 7.43 (d, J=1.8 Hz, 1H), 6.64 (d, J=1.6 Hz, 1H), 3.85 (s, 3H), 3.75 (br d, J=11.4 Hz, 1H), 3.65 (br d, J=10.9 Hz, 1H), 3.50 (br d, J=8.9 Hz, 2H), 2.29 (s, 3H), 1.48 (s, 9H) (1R,5S,6r)-6-[(4- methoxy -2- thienyl ) carbonyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R ,5S,6r)-6-[hydroxy(4-methoxy-2-thienyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (380 mg , 1.17 mmol) in THF (4 mL) was added MnO ₂ (507.61 mg, 5.84 mmol). The mixture was stirred at 50°C for 16 hours. TLC (PE:EtOAc = 2:1 ) showed a fresh spot with starting material remaining. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (PE:EtOAc = 2:1 ) to give the title compound (60 mg, 0.1855 mmol, 15.888% yield) as a colorless oil. ¹ H NMR (400MHz, chloroform-d) δ = 7.43 (d, J =1.8 Hz, 1H), 6.64 (d, J =1.6 Hz, 1H), 3.85 (s, 3H), 3.75 (br d, J = 11.4 Hz, 1H), 3.65 (br d, J =10.9 Hz, 1H), 3.50 (br d, J =8.9 Hz, 2H), 2.29 (s, 3H), 1.48 (s, 9H)

(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 (4- 甲氧基 -2- 噻吩基 ) 甲酮 TFA 鹽向(1R,5S,6r)-6-[(4-甲氧基-2-噻吩基)羰基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(70 mg，0.22 mmol)於DCM (3.5 mL)中之溶液添加2,2,2-三氟乙酸(0.35 mL，4.57 mmol)。在20至25℃下攪拌所得混合物1小時。TLC (PE:EtOAc = 2:1)展示反應完成(Rf = 0)。藉由用N ₂吹掃來濃縮混合物，得到呈紫色固體狀之標題化合物(48 mg，0.2150 mmol，99.318%產率)。 (1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl (4- methoxy -2- thienyl ) methanone TFA salt to (1R,5S,6r)-6- [(4-Methoxy-2-thienyl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (70 mg, 0.22 mmol) in DCM (3.5 mL) To the solution in was added 2,2,2-trifluoroacetic acid (0.35 mL, 4.57 mmol). The resulting mixture was stirred at 20 to 25°C for 1 hour. TLC (PE:EtOAc = 2:1) showed the reaction was complete (Rf = 0). The mixture was concentrated by purging with _N2 to afford the title compound (48 mg, 0.2150 mmol, 99.318% yield) as a purple solid.

(1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(4- 甲氧基 -2- 噻吩基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮在20至25℃下歷時2小時向異丙基咪唑異丙基咪唑-4-羧酸(33.14 mg，0.21 mmol)於吡啶(2 mL)中之溶液添加EDCI (61.81 mg，0.32 mmol)及(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基(4-甲氧基-2-噻吩基)甲酮TFA鹽(48 mg，0.21 mmol)。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物，獲得粗產物。藉由製備型TLC (DCM:MeOH = 10:1)純化粗產物，得到呈白色固體狀之標題化合物(5.73 mg，0.0159 mmol，7.4158%產率)。 LC-MS方法1: 360.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.72 (s, 1H), 7.54 - 7.48 (m, 1H), 7.40 (d, J=1.5 Hz, 1H), 6.63 (d, J=1.8 Hz, 1H), 4.79 (d, J=12.3 Hz, 1H), 4.38 (td, J=6.9, 13.3 Hz, 1H), 4.23 (d, J=12.5 Hz, 1H), 4.04 (dd, J=4.0, 12.0 Hz, 1H), 3.83 (s, 3H), 3.71 (dd, J=3.8, 12.5 Hz, 1H), 2.46 (br d, J=3.3 Hz, 1H), 2.35 (br d, J=6.3 Hz, 1H), 2.32 - 2.27 (m, 1H), 1.52 (d, J=6.5 Hz, 8H) (1- isopropyl -1H- imidazol -4- yl ){(1R,5S,6r)-6-[(4- methoxy -2- thienyl ) carbonyl ]-3- azabicyclo [3.1. 0] Hex -3- yl } methanone To a solution of isopropylimidazole isopropylimidazole-4-carboxylic acid (33.14 mg, 0.21 mmol) in pyridine (2 mL) was added over 2 hours at 20 to 25 °C EDCI (61.81 mg, 0.32 mmol) and (1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(4-methoxy-2-thienyl)methanone TFA salt (48 mg, 0.21 mmol). The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ) to obtain crude product. The crude product was purified by prep-TLC (DCM:MeOH = 10:1 ) to afford the title compound (5.73 mg, 0.0159 mmol, 7.4158% yield) as a white solid. LC-MS method 1: 360.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.72 (s, 1H), 7.54 - 7.48 (m, 1H), 7.40 (d, J =1.5 Hz, 1H), 6.63 (d, J =1.8 Hz, 1H), 4.79 (d, J =12.3 Hz, 1H), 4.38 (td, J =6.9, 13.3 Hz, 1H), 4.23 (d, J =12.5 Hz, 1H), 4.04 (dd, J =4.0, 12.0 Hz, 1H), 3.83 (s, 3H), 3.71 (dd, J =3.8, 12.5 Hz, 1H), 2.46 (br d, J =3.3 Hz, 1H) , 2.35 (br d, J =6.3 Hz, 1H), 2.32 - 2.27 (m, 1H), 1.52 (d, J =6.5 Hz, 8H)

實例 79      (1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(4- 甲基 -1,3- 噻唑 -2- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 (1R,5S,6r)-6-[ 羥基 (4- 甲基 -1,3- 噻唑 -2- 基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在-78℃下向2-溴-4-甲基-1,3-噻唑(74.48uL，0.71 mmol)於THF (2 mL)中之溶液添加於正己烷(0.34 mL，0.86 mmol)中之2.5 M n-BuLi。在-78℃下於N ₂下攪拌混合物0.5小時。隨後在-78℃下向反應混合物添加(1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(210.89mg，1 mmol)。將所得溶液升溫至25℃且攪拌1小時，得到褐色溶液。LCMS展示所要MS。將反應混合物傾入NH ₄Cl水溶液(20 mL)中，且用EtOAc (20 mL × 4)萃取。用鹽水(50 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由快速柱(PE至20% EtOAc/PE)純化粗產物，得到呈褐色油狀之標題化合物(220mg，0.7087 mmol，99.396%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 7.68 (s, 1H), 5.00-4.85 (m, 1H), 4.06 (t, J = 10.8 Hz, 2H), 3.90-3.75 (m, 2H), 2.85 (s, 3H), 2.25-2.00 (m, 2H), 1.84 (s, 9H), 1.70-1.60 (m, 1H), 1.55-1.50 (m, 1H)。 Example 79 (1- isopropyl -1H- imidazol -4- yl ){(1R,5S,6r)-6-[(4- methyl -1,3- thiazol -2- yl ) carbonyl ]-3- Azabicyclo [3.1.0] hex -3 -yl } methanone (1R,5S,6r)-6-[ hydroxy (4- methyl -1,3- thiazol- 2 - yl ) methyl ]-3- Azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester was added to 2-bromo-4-methyl-1,3-thiazole (74.48uL, 0.71 mmol) in THF (2 mL) was added to 2.5 M n-BuLi in n-hexane (0.34 mL, 0.86 mmol). The mixture was stirred at -78 °C under _N2 for 0.5 h. Then tertiary butyl (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (210.89 mg, 1 mmol). The resulting solution was warmed to 25 °C and stirred for 1 hour to give a brown solution. LCMS showed desired MS. The reaction mixture was poured into aqueous NH ₄ Cl (20 mL), and extracted with EtOAc (20 mL×4). The combined organic layers were washed with brine (50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column (PE to 20% EtOAc/PE) to give the title compound (220 mg, 0.7087 mmol, 99.396% yield) as a brown oil. ¹ H NMR (400MHz, chloroform-d) δ = 7.68 (s, 1H), 5.00-4.85 (m, 1H), 4.06 (t, J = 10.8 Hz, 2H), 3.90-3.75 (m, 2H), 2.85 (s, 3H), 2.25-2.00 (m, 2H), 1.84 (s, 9H), 1.70-1.60 (m, 1H), 1.55-1.50 (m, 1H).

(1R,5S,6r)-6-[(4- 甲基 -1,3- 噻唑 -2- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-[羥基(4-甲基-1,3-噻唑-2-基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(220 mg，0.71 mmol)於DCM (4 mL)中之溶液添加DMP (450.91mg，1.06 mmol)。在25℃下攪拌混合物3小時，得到白色懸浮液。過濾反應混合物。用NaHCO ₃水溶液(50 mL × 2)及Na ₂SO ₃水溶液(50 mL × 2)洗滌濾液，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈褐色油狀之標題化合物(220mg，0.7134 mmol，100.65%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 7.27 (s, 1H), 3.78 (d, J = 11.2 Hz, 1H), 3.72 (d, J = 11.2 Hz, 1H), 3.55-3.45 (m, 2H), 3.15-3.10 (m, 1H), 2.57 (s, 3H), 2.35 (brs, 2H), 1.48 (s, 9H)。 (1R,5S,6r)-6-[(4- Methyl -1,3- thiazol -2- yl ) carbonyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl (1R,5S,6r)-6-[hydroxy(4-methyl-1,3-thiazol-2-yl)methyl]-3-azabicyclo[3.1.0] hexane at 0°C - To a solution of tert-butyl-3-carboxylate (220 mg, 0.71 mmol) in DCM (4 mL) was added DMP (450.91 mg, 1.06 mmol). The mixture was stirred at 25°C for 3 hours to give a white suspension. The reaction mixture was filtered. The filtrate was washed with aqueous NaHCO ₃ (50 mL × 2) and aqueous Na ₂ SO ₃ (50 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (220 mg) as a brown oil. , 0.7134 mmol, 100.65% yield). ¹ H NMR (400MHz, chloroform-d) δ = 7.27 (s, 1H), 3.78 (d, J = 11.2 Hz, 1H), 3.72 (d, J = 11.2 Hz, 1H), 3.55-3.45 (m, 2H ), 3.15-3.10 (m, 1H), 2.57 (s, 3H), 2.35 (brs, 2H), 1.48 (s, 9H).

(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 (4- 甲基 -1,3- 噻唑 -2- 基 ) 甲酮 TFA 鹽向(1R,5S,6r)-6-[(4-甲基-1,3-噻唑-2-基)羰基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.32 mmol)於DCM (5 mL)中之溶液添加TFA (1. mL，0.32 mmol)。在25℃下攪拌混合物30 min，得到褐色溶液。TLC (PE:EtOAc=3:1)展示反應完成。直接濃縮反應混合物，得到呈褐色油狀之標題化合物(100 mg，0.3103 mmol，95.687%產率，TFA鹽)。 (1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl (4- methyl -1,3- thiazol -2- yl ) methanone TFA salt to (1R,5S,6r )-6-[(4-methyl-1,3-thiazol-2-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (100 mg, 0.32 mmol) in DCM (5 mL) was added TFA (1. mL, 0.32 mmol). The mixture was stirred at 25 °C for 30 min to obtain a brown solution. TLC (PE:EtOAc=3:1) showed the reaction was complete. The reaction mixture was directly concentrated to afford the title compound (100 mg, 0.3103 mmol, 95.687% yield, TFA salt) as a brown oil.

(1- 異丙基 -1H- 咪唑 -4- 基 ){(1R,5S,6r)-6-[(4- 甲基 -1,3- 噻唑 -2- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮向1-異丙基咪唑-4-羧酸(47.83mg，0.31 mmol)於DMF (2 mL)中之溶液添加HATU (142.34mg，0.37 mmol)及DIPEA (200.5mg，1.55 mmol)。在25℃下攪拌混合物20 min。隨後添加(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基(4-甲基-1,3-噻唑-2-基)甲酮TFA鹽(100 mg，0.31 mmol，TFA鹽)。在25℃下攪拌混合物2小時，得到褐色溶液。在25℃下攪拌混合物12小時，得到褐色溶液。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈黃色固體狀之標題化合物(20.22mg，0.0587 mmol，18.921%產率)。 ¹H NMR (400 MHz, 氯仿 -d) δ ppm 7.72 (1 H, d, J=1.51 Hz), 7.48 (1 H, d, J=1.51 Hz), 7.24 (1 H, d, J=0.75 Hz), 4.81 (1 H, d, J=12.30 Hz), 4.33 - 4.43 (1 H, m), 4.28 (1 H, d, J=13.05 Hz), 4.07 (1 H, dd, J=12.30, 4.02 Hz), 3.72 (1 H, dd, J=12.80, 4.02 Hz), 3.12 (1 H, t, J=3.14 Hz), 2.53 (4 H, d, J=0.75 Hz), 2.40 (1 H, dt, J=7.09, 3.61 Hz), 1.52 (6 H, d, J=6.53 Hz) (1- isopropyl -1H- imidazol -4- yl ){(1R,5S,6r)-6-[(4- methyl -1,3- thiazol -2- yl ) carbonyl ]-3- aza Bicyclo [3.1.0] hex -3- yl } methanone To a solution of 1-isopropylimidazole-4-carboxylic acid (47.83 mg, 0.31 mmol) in DMF (2 mL) was added HATU (142.34 mg, 0.37 mmol ) and DIPEA (200.5 mg, 1.55 mmol). The mixture was stirred at 25 °C for 20 min. (1R,5S,6r)-3-Azabicyclo[3.1.0]hex-6-yl(4-methyl-1,3-thiazol-2-yl)methanone TFA salt (100 mg, 0.31 mmol, TFA salt). The mixture was stirred at 25°C for 2 hours to give a brown solution. The mixture was stirred at 25°C for 12 hours to give a brown solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (20.22 mg, 0.0587 mmol, 18.921% yield) as a yellow solid. ¹ H NMR (400 MHz, chloroform -d ) δ ppm 7.72 (1 H, d, J =1.51 Hz), 7.48 (1 H, d, J =1.51 Hz), 7.24 (1 H, d, J =0.75 Hz ), 4.81 (1 H, d, J =12.30 Hz), 4.33 - 4.43 (1 H, m), 4.28 (1 H, d, J =13.05 Hz), 4.07 (1 H, dd, J =12.30, 4.02 Hz), 3.72 (1 H, dd, J =12.80, 4.02 Hz), 3.12 (1 H, t, J =3.14 Hz), 2.53 (4 H, d, J =0.75 Hz), 2.40 (1 H, dt , J =7.09, 3.61 Hz), 1.52 (6 H, d, J =6.53 Hz)

實例 80      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(2- 吡啶基羰基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 溴基 (2- 吡啶基 ) 鎂在15℃下向2-溴吡啶(0.61mL，6.33mmol)於THF (10mL)中之溶液添加氯基(異丙基)鎂(3.2mL，6.33mmol)。在0℃下攪拌反應混合物4小時，得到呈混合物之標題化合物。反應混合物在無進一步純化之情況下用於下一步驟。 Example 80 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(2- pyridylcarbonyl )-3- azabicyclo [3.1.0] hexa -3- To a solution of 2 - bromopyridine ( 0.61 mL, 6.33 mmol ) in THF (10 mL) was added chloro ( isopropyl)magnesium (3.2 mL, 6.33 mmol). The reaction mixture was stirred at 0°C for 4 hours to afford the title compound as a mixture. The reaction mixture was used in the next step without further purification.

(1R,5S,6r)-6-[ 羥基 (2- 吡啶基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在15℃下向(1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(0.61mL，1.42mmol)於THF (6mL)中之溶液添加溴基(2-吡啶基)鎂(3.2mL，2.13mmol)。在0℃下攪拌反應混合物4小時，得到褐色混合物。TLC (PE/EA=1:2)展示新樣點。用H ₂O (30 mL)淬滅反應混合物且用EtOAc (30mL×2)萃取。用鹽水(30 mL×2)洗滌有機層，經無水Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到殘餘物。藉由矽膠管柱(PE/EA=1:2)純化殘餘物，得到呈淺黃色膠質之標題化合物(460mg，1.5842mmol，111.56%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ 8.47 (dd, J = 4.4, 0.8 Hz, 1H), 7.78 (t, J = 5.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.30-7.20 (m, 1H), 5.41(d, J = 4.8 Hz, 1H), 4.27 (t, J = 5.6 Hz, 1H), 3.40-3.20 (m, 4H), 1.62 (brs, 2H), 1.37 (s, 9H), 1.85-1.75 (m, 1H)。 (1R,5S,6r)-6-[ hydroxy (2- pyridyl ) methyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 15°C to (1R ,5S,6r)-6-Formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.61 mL, 1.42 mmol) in THF (6 mL) was added with bromine (2-pyridyl)magnesium (3.2 mL, 2.13 mmol). The reaction mixture was stirred at 0 °C for 4 hours to give a brown mixture. TLC (PE/EA=1:2) showed new samples. The reaction mixture was quenched with H ₂ O (30 mL) and extracted with EtOAc (30 mL×2). The organic layer was washed with brine (30 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (PE/EA=1:2) to obtain the title compound (460 mg, 1.5842 mmol, 111.56% yield) as light yellow gum. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.47 (dd, J = 4.4, 0.8 Hz, 1H), 7.78 (t, J = 5.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.30-7.20 (m, 1H), 5.41(d, J = 4.8 Hz, 1H), 4.27 (t, J = 5.6 Hz, 1H), 3.40-3.20 (m, 4H), 1.62 (brs, 2H), 1.37 (s, 9H), 1.85-1.75 (m, 1H).

(1R,5S,6r)-6-[(2- 吡啶基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在15℃下向(1R,5S,6r)-6-[羥基(2-吡啶基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(460 mg，1.58mmol)於DCM (9.6442mL)中之溶液添加DMP (671.94mg，1.58mmol)。在15℃下攪拌反應混合物20 min，得到白色混合物。TLC (PE/EA=1:1)展示新樣點。用NaHCO ₃(30 mL)淬滅反應混合物且用DCM (30 mL×2)萃取。用鹽水(30mL×2)洗滌有機層，經無水Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到殘餘物。藉由矽膠管柱(PE/EA=1:1)純化殘餘物，得到呈白色固體狀之標題化合物(340mg，1.1792mmol，74.431%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ 8.77 (dd, J = 4.4, 0.8 Hz, 1H), 8.02 (t, J = 5.6 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.70-7.60 (m, 1H), 3.57 (d, J = 11.4 Hz, 1H), 3.50-3.25 (m, 3H), 3.25-3.20 (m, 1H), 2.22 (brs, 2H), 1.41 (s, 9H), 1.85-1.75 (m, 1H)。 (1R,5S,6r)-6-[(2- pyridyl ) carbonyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 15°C to (1R,5S ,6r)-6-[hydroxy(2-pyridyl)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (460 mg, 1.58mmol) in DCM (9.6442 mL) was added DMP (671.94 mg, 1.58 mmol). The reaction mixture was stirred at 15 °C for 20 min to give a white mixture. TLC (PE/EA=1:1) showed new samples. The reaction mixture was quenched with NaHCO ₃ (30 mL) and extracted with DCM (30 mL×2). The organic layer was washed with brine (30 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (PE/EA=1:1) to obtain the title compound (340 mg, 1.1792 mmol, 74.431% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.77 (dd, J = 4.4, 0.8 Hz, 1H), 8.02 (t, J = 5.6 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.70-7.60 (m, 1H), 3.57 (d, J = 11.4 Hz, 1H), 3.50-3.25 (m, 3H), 3.25-3.20 (m, 1H), 2.22 (brs, 2H), 1.41 (s, 9H), 1.85-1.75 (m, 1H).

(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 (2- 吡啶基 ) 甲酮 TFA 鹽向(1R,5S,6r)-6-[(2-吡啶基)羰基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(58 mg，0.20 mmol)於DCM (1.5 mL)中之溶液添加TFA (0.02 mL，0.20 mmol)。在20℃下攪拌反應混合物2小時，得到無色混合物。在減壓下濃縮反應混合物，得到標題化合物。其直接用於下一步驟。 LC-MS方法1: 0.268 min，MS (m/z): 189.0 (M + H ⁺)。 (1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl (2- pyridyl ) methanone TFA salt to (1R,5S,6r)-6-[(2-pyridyl )carbonyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (58 mg, 0.20 mmol) in DCM (1.5 mL) was added TFA (0.02 mL, 0.20 mmol) . The reaction mixture was stirred at 20°C for 2 hours to give a colorless mixture. The reaction mixture was concentrated under reduced pressure to afford the title compound. It was used directly in the next step. LC-MS method 1: 0.268 min, MS (m/z): 189.0 (M + H ⁺ ).

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(2- 吡啶基羰基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基(2-吡啶基)甲酮TFA鹽(37 mg，0.20 mmol)於吡啶(1.5 mL)中之溶液添加1-異丙基咪唑-4-羧酸(45.46 mg，0.29 mmol)及EDCI (56.52 mg，0.29 mmol)。在20℃下攪拌反應混合物16小時。藉由製備型HPLC (NH ₃)純化溶液且凍乾，得到呈黃色固體狀之標題化合物(7.52 mg，11.79%產率)。 LC-MS方法1: 0.363 min，MS (m/z): 325.2 (M + H ⁺)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 8.68 (d, J=4.77 Hz, 1 H), 8.02 (d, J=7.78 Hz, 1 H), 7.81 - 7.86 (m, 1 H), 7.71 (s, 1 H), 7.45 - 7.49 (m, 2 H), 4.79 (d, J=12.30 Hz, 1 H), 4.37 (dt, J=13.36, 6.74 Hz, 1 H), 4.28 (d, J=12.80 Hz, 1 H), 4.08 (dd, J=12.17, 3.89 Hz, 1 H), 3.73 (dd, J=12.80, 4.02 Hz, 1 H), 3.45 (t, J=3.01 Hz, 1 H), 2.44 - 2.49 (m, 1 H), 2.36 (dt, J=7.28, 3.64 Hz, 1 H), 1.52 (d, J=6.53 Hz, 6 H) (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(2- pyridylcarbonyl )-3- azabicyclo [3.1.0] hex -3- yl ] Methanone to (1R,5S,6r)-3-Azabicyclo[3.1.0]hex-6-yl(2-pyridyl)methanone TFA salt (37 mg, 0.20 mmol) in pyridine (1.5 mL) To the solution of 1-isopropylimidazole-4-carboxylic acid (45.46 mg, 0.29 mmol) and EDCI (56.52 mg, 0.29 mmol) were added. The reaction mixture was stirred at 20°C for 16 hours. The solution was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (7.52 mg, 11.79% yield) as a yellow solid. LC-MS method 1: 0.363 min, MS (m/z): 325.2 (M + H ⁺ ). ¹ H NMR (400 MHz, chloroform- d ) δ ppm 8.68 (d, J =4.77 Hz, 1 H), 8.02 (d, J =7.78 Hz, 1 H), 7.81 - 7.86 (m, 1 H), 7.71 (s, 1 H), 7.45 - 7.49 (m, 2 H), 4.79 (d, J =12.30 Hz, 1 H), 4.37 (dt, J =13.36, 6.74 Hz, 1 H), 4.28 (d, J =12.80 Hz, 1 H), 4.08 (dd, J =12.17, 3.89 Hz, 1 H), 3.73 (dd, J =12.80, 4.02 Hz, 1 H), 3.45 (t, J =3.01 Hz, 1 H) , 2.44 - 2.49 (m, 1 H), 2.36 (dt, J =7.28, 3.64 Hz, 1 H), 1.52 (d, J =6.53 Hz, 6 H)

實例 81      [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮 (2E)-2- 亞肼基丙酸 乙 酯在0℃下向冰HOAc (1.4mL，24.5mmol)及H ₂O (1.4mL，77.78mmol)之混合物緩慢添加水合肼(0.86g，17.22mmol)。隨後在室溫下添加2-側氧基丙酸乙酯(0.95mL，8.61mmol)。添加MeOH (0.5 mL)以便獲得均質溶液。在25℃下攪拌混合物6小時，得到黃色溶液。TLC (PE:EtOAc=1:1)展示反應完成。在減壓下移除反應混合物。向殘餘物添加H ₂O (40 mL)且用EtOAc (30 mL × 4)萃取混合物。用飽和碳酸氫鈉(30 mL × 2)、飽和鹽水(40 mL×2)洗滌合併之有機相且經Na ₂SO ₄乾燥。在減壓下移除溶劑。藉由急驟管柱層析(PE至20% EtOAc/PE)純化粗產物，得到呈無色油狀之標題化合物(930mg，7.1456mmol，82.975%產率)。 LC-MS方法1 0.348 min，MS (m/z) 130.8 [M+H ⁺]。 ¹H NMR (400MHz, 氯仿-d) δ = 5.93 (brs, 2H), 4.28 (q, J = 6.8 Hz, 2H), 1.99 (s, 3H), 1.37 (t, J = 6.8 Hz, 3H)。 Example 81 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-6- methyl -3 - aza Bicyclo [3.1.0] hex -3- yl ](1- isopropyl -1H- imidazol -4- yl ) methanone (2E)-Ethyl 2- hydrazonopropionate To a mixture of glacial HOAc (1.4 mL, 24.5 mmol) and _H2O (1.4 mL, 77.78 mmol) was slowly added hydrazine hydrate (0.86 g, 17.22 mmol) at 0 °C ). Then ethyl 2-oxopropionate (0.95 mL, 8.61 mmol) was added at room temperature. MeOH (0.5 mL) was added in order to obtain a homogeneous solution. The mixture was stirred at 25°C for 6 hours to obtain a yellow solution. TLC (PE:EtOAc=1:1) showed the reaction was complete. The reaction mixture was removed under reduced pressure. To the residue was added H ₂ O (40 mL) and the mixture was extracted with EtOAc (30 mL×4). The combined organic phases were washed with saturated sodium bicarbonate (30 mL×2), saturated brine (40 mL×2) and dried over Na ₂ SO ₄ . Solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (PE to 20% EtOAc/PE) to afford the title compound (930 mg, 7.1456 mmol, 82.975% yield) as a colorless oil. LC-MS method 1 0.348 min, MS (m/z) 130.8 [M+H ⁺ ]. ¹ H NMR (400MHz, chloroform-d) δ = 5.93 (brs, 2H), 4.28 (q, J = 6.8 Hz, 2H), 1.99 (s, 3H), 1.37 (t, J = 6.8 Hz, 3H).

3- 苯甲基 -6- 甲基 -2,4- 二側氧基 -3- 氮雜雙環 [3.1.0] 己烷 -6- 羧酸乙酯向(2E)-2-亞肼基丙酸乙酯(2.5g，19.21mmol)於1,4-二㗁烷(30mL)中之溶液添加MnO ₂(10.02g，115.25mmol)。在20℃下攪拌混合物1.5小時且隨後經由矽藻土墊過濾。向濾液添加1-苯甲基-1H-吡咯-2,5-二酮(3.6g，19.21mmol)。在20℃下攪拌反應物2小時且在100℃下攪拌16小時，得到黃色溶液。TLC (PE:EtOAc=5:1)展示反應完成。直接濃縮反應混合物。藉由快速柱(PE至10% EtOAc/PE)純化粗產物。用EtOAc/ PE (2 mL/20 mL)濕磨所獲得固體且在空氣中乾燥，得到呈無色固體狀之標題化合物(1.28g，4.4551mmol，23.193%產率)。 LC-MS方法1 0.827 min，MS (m/z) 287.9 [M+H ⁺]。 ¹H NMR (400MHz, 氯仿-d) δ = 7.45-7.25 (m, 5H), 4.57 (s, 2H), 4.15 (q, J= 6.8 Hz, 2H), 2.89 (s, 2H), 1.25 (t, J = 6.8 Hz, 3H), 1.14 (s, 3H)。 3- Benzyl -6- methyl -2,4- dioxo -3- azabicyclo [3.1.0] hexane -6- carboxylic acid ethyl ester to (2E)-2-hydrazinopropane To a solution of ethyl acetate (2.5 g, 19.21 mmol) in 1,4-dioxane (30 mL) was added _MnO2 (10.02 g, 115.25 mmol). The mixture was stirred at 20°C for 1.5 hours and then filtered through a pad of celite. 1-Benzyl-1H-pyrrole-2,5-dione (3.6 g, 19.21 mmol) was added to the filtrate. The reaction was stirred at 20°C for 2 hours and at 100°C for 16 hours to give a yellow solution. TLC (PE:EtOAc=5:1) showed the reaction was complete. The reaction mixture was directly concentrated. The crude product was purified by flash column (PE to 10% EtOAc/PE). The obtained solid was triturated with EtOAc/PE (2 mL/20 mL) and dried in air to afford the title compound (1.28 g, 4.4551 mmol, 23.193% yield) as a colorless solid. LC-MS method 1 0.827 min, MS (m/z) 287.9 [M+H ⁺ ]. ¹ H NMR (400MHz, chloroform-d) δ = 7.45-7.25 (m, 5H), 4.57 (s, 2H), 4.15 (q, J= 6.8 Hz, 2H), 2.89 (s, 2H), 1.25 (t , J = 6.8 Hz, 3H), 1.14 (s, 3H).

3- 苯甲基 -6- 甲基 -3- 氮雜雙環 [3.1.0] 己烷 -6- 羧酸乙酯在25℃下向3-苯甲基-6-甲基-2,4-二側氧基-3-氮雜雙環[3.1.0]己烷-6-羧酸乙酯(2.5g，8.7mmol) (粗物質)於THF (25mL)中之溶液添加硼烷二甲基硫醚複合物(3.48mL，34.81mmol)。在70 ℃下攪拌混合物2小時，得到無色懸浮液。TLC (PE:EtOAc=5:1)展示反應完成。將反應混合物逐滴添加至MeOH/HCl (12 N) (8:1 = 5mL)中且攪拌混合物30 min。隨後直接濃縮混合物。藉由快速柱(PE至10% EtOAc/PE)純化粗產物，得到呈無色油狀之標題化合物(600 mg，2.3136mmol，26.588%產率)。 LC-MS方法1 0.781 min，MS (m/z) 260.1 [M+H ⁺]。 ¹H NMR (400MHz, 氯仿-d) δ = 7.50-7.30 (m, 5H), 4.10 (q, J = 6.8 Hz, 2H), 4.05 (s, 2H), 3.36 (dt, J = 12.0, 1.2 Hz, 2H), 2.98 (d, J = 5.2 Hz, 1H), 2.88 (d, J = 5.2 Hz, 1H), 2.45-2.40 (m, 1H), 2.20-2.10 (m, 1H), 1.40 (s, 9H), 1.25 (t, J = 6.8 Hz, 3H), 0.70 (s, 1H)。 Ethyl 3- benzyl -6- methyl -3- azabicyclo [3.1.0] hexane -6- carboxylate was converted to 3-benzyl-6-methyl-2,4- A solution of ethyl dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylate (2.5 g, 8.7 mmol) (crude material) in THF (25 mL) was added with borane dimethylsulfide Ether complex (3.48 mL, 34.81 mmol). The mixture was stirred at 70 °C for 2 hours to obtain a colorless suspension. TLC (PE:EtOAc=5:1) showed the reaction was complete. The reaction mixture was added dropwise to MeOH/HCl (12 N) (8:1 = 5 mL) and the mixture was stirred for 30 min. The mixture was then directly concentrated. The crude product was purified by flash column (PE to 10% EtOAc/PE) to give the title compound (600 mg, 2.3136 mmol, 26.588% yield) as a colorless oil. LC-MS method 1 0.781 min, MS (m/z) 260.1 [M+H ⁺ ]. ¹ H NMR (400MHz, chloroform-d) δ = 7.50-7.30 (m, 5H), 4.10 (q, J = 6.8 Hz, 2H), 4.05 (s, 2H), 3.36 (dt, J = 12.0, 1.2 Hz , 2H), 2.98 (d, J = 5.2 Hz, 1H), 2.88 (d, J = 5.2 Hz, 1H), 2.45-2.40 (m, 1H), 2.20-2.10 (m, 1H), 1.40 (s, 9H), 1.25 (t, J = 6.8 Hz, 3H), 0.70 (s, 1H).

[(1R,5S,6r)-3- 苯甲基 -6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -6- 基 ] 甲醇在0℃下向3-苯甲基-6-甲基-3-氮雜雙環[3.1.0]己烷-6-羧酸乙酯(600 mg，2.31mmol)於THF (8mL)中之溶液添加LiAlH4 (131.87mg，3.47mmol)。在0℃下攪拌混合物10 min，得到白色懸浮液。TLC (PE:EtOAc=5:1)展示反應完成。持續地向反應混合物添加H ₂O (0.15 mL)、1N NaOH水溶液(0.15mL)、H ₂O (0.5 ml)且過濾。濃縮濾液，得到無色油狀物。藉由急驟管柱層析(PE至30% EtOAc/PE)純化粗產物，得到呈無色油狀之標題化合物(270mg，1.2425mmol，53.703%產率)。 LC-MS方法1 1.643 min，MS (m/z) 218.2 [M+H ⁺]。 ¹H NMR (400MHz, 氯仿-d) δ = 7.55-7.50 (m, 2H), 7.45-7.40 (m, 3H), 4.03 (s, 2H), 3.40-3.25 (m, 2H), 3.30 (s, 2H), 3.00-2.90 (m, 2H), 1.60-1.55 (m, 2H), 1.27 (s, 3H)。藉由NoE實驗來判定相對組態。 [(1R,5S,6r)-3- Benzyl -6- methyl -3- azabicyclo [3.1.0] hex -6- yl ] methanol at 0°C to 3-benzyl-6- To a solution of ethyl methyl-3-azabicyclo[3.1.0]hexane-6-carboxylate (600 mg, 2.31 mmol) in THF (8 mL) was added LiAlH4 (131.87 mg, 3.47 mmol). The mixture was stirred at 0 °C for 10 min to give a white suspension. TLC (PE:EtOAc=5:1) showed the reaction was complete. To the reaction mixture was continuously added _H2O (0.15 mL), 1N aqueous NaOH (0.15 mL), _H2O (0.5 ml) and filtered. The filtrate was concentrated to give a colorless oil. The crude product was purified by flash column chromatography (PE to 30% EtOAc/PE) to afford the title compound (270 mg, 1.2425 mmol, 53.703% yield) as a colorless oil. LC-MS method 1 1.643 min, MS (m/z) 218.2 [M+H ⁺ ]. ¹ H NMR (400MHz, chloroform-d) δ = 7.55-7.50 (m, 2H), 7.45-7.40 (m, 3H), 4.03 (s, 2H), 3.40-3.25 (m, 2H), 3.30 (s, 2H), 3.00-2.90 (m, 2H), 1.60-1.55 (m, 2H), 1.27 (s, 3H). The relative configuration was determined by NoE experiments.

(1R,5S,6r)-6-( 羥基甲基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向[(1R,5S,6r)-3-苯甲基-6-甲基-3-氮雜雙環[3.1.0]己-6-基]甲醇(100 mg，0.4600mmol)於MeOH (3mL)中之溶液添加Pd(OH) ₂(30 mg，0.4600mmol)。在20℃下於H ₂(15 psi)下攪拌混合物12小時，得到黑色溶液。TLC (PE:EtOAc=1:1)展示反應完成。過濾反應混合物且濃縮濾液。用DCM (3 mL)稀釋殘餘物且將二碳酸二-三級丁酯(150.65mg，0.6900mmol)添加至溶液中。在20℃下攪拌混合物30 min，得到無色溶液。直接濃縮反應混合物。藉由快速柱(PE至30% EtOAc/PE)純化粗產物，得到呈白色固體狀之標題化合物(35mg，0.1540mmol，33.462%產率)。 LC-MS方法1 0.710 min，MS (m/z) 171.8 [M-tBu+H ⁺]。 ¹H NMR (400MHz, 氯仿-d) δ = 3.60-3.45 (m, 2H), 3.45-3.35 (m, 2H), 1.50-1.45 (m, 2H), 1.49 (s, 9H), 1.04 (s, 3H)。 (1R,5S,6r)-6-( Hydroxymethyl )-6- methyl -3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to [(1R,5S,6r )-3-Benzyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]methanol (100 mg, 0.4600 mmol) in MeOH (3 mL) was added Pd(OH) ₂ (30 mg, 0.4600 mmol). The mixture was stirred at 20 °C under _H2 (15 psi) for 12 h to give a black solution. TLC (PE:EtOAc=1:1) showed the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with DCM (3 mL) and di-tert-butyl dicarbonate (150.65 mg, 0.6900 mmol) was added to the solution. The mixture was stirred at 20 °C for 30 min to give a colorless solution. The reaction mixture was directly concentrated. The crude product was purified by flash column (PE to 30% EtOAc/PE) to afford the title compound (35 mg, 0.1540 mmol, 33.462% yield) as a white solid. LC-MS method 1 0.710 min, MS (m/z) 171.8 [M-tBu+H ⁺ ]. ¹ H NMR (400MHz, chloroform-d) δ = 3.60-3.45 (m, 2H), 3.45-3.35 (m, 2H), 1.50-1.45 (m, 2H), 1.49 (s, 9H), 1.04 (s, 3H).

(1R,5S,6r)-6- 甲醯基 -6- 甲基 -3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-(羥基甲基)-6-甲基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(70 mg，0.3100mmol)於DCM (2mL)中之溶液添加DMP (143.68mg，0.3400mmol)。在20℃下攪拌混合物2小時，得到白色懸浮液。TLC (PE:EtOAc=1:1)展示反應完成。將反應混合物傾入H ₂O (20 mL)中且用EtOAc (20 mL × 4)萃取。用NaHCO ₃水溶液(50 mL)、Na ₂SO ₃水溶液(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈黃色膠質之標題化合物(62mg，0.2752mmol，89.366%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 8.96 (s, 1H), 3.70-3.55 (m, 2H), 3.48 (d, J = 11.4 Hz, 1H), 3.40 (d, J = 11.4 Hz, 1H), 2.15 (d, J = 2.0 Hz, 1H), 1.45 (s, 9H), 1.72 (s, 3H)。 (1R,5S,6r)-6- formyl -6- methyl -3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 0°C to (1R,5S, 6r)-tert-butyl 6-(hydroxymethyl)-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (70 mg, 0.3100 mmol) in DCM (2 mL) To the solution was added DMP (143.68mg, 0.3400mmol). The mixture was stirred at 20°C for 2 hours to give a white suspension. TLC (PE:EtOAc=1:1) showed the reaction was complete. The reaction mixture was poured into H ₂ O (20 mL) and extracted with EtOAc (20 mL×4). The combined organic layers were washed with aqueous NaHCO ₃ (50 mL), aqueous Na ₂ SO ₃ (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the title compound (62 mg, 0.2752 mg) as a yellow gum. mmol, 89.366% yield). ¹ H NMR (400MHz, chloroform-d) δ = 8.96 (s, 1H), 3.70-3.55 (m, 2H), 3.48 (d, J = 11.4 Hz, 1H), 3.40 (d, J = 11.4 Hz, 1H ), 2.15 (d, J = 2.0 Hz, 1H), 1.45 (s, 9H), 1.72 (s, 3H).

(1R,5S,6r)-6-[(E)-( 羥亞胺基 ) 甲基 ]-6- 甲基 -3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-甲醯基-6-甲基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(62 mg，0.2800mmol)於EtOH (1.5mL)中之溶液添加HOAc (15.73uL，0.2800mmol)、KOAc (26.97mg，0.2800mmol)及鹽酸羥胺(0.01mL，0.3300mmol)。在20℃下攪拌混合物2小時，得到黃色懸浮液。TLC (PE:EtOAc=3:1)展示反應完成。將反應混合物傾入H ₂O (20 mL)中且用EtOAc (15 mL × 4)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈黃色固體狀之標題化合物(65mg，0.2705mmol，98.286%產率)。 LC-MS方法1 0.727 min，MS (m/z) 185.0 [M-tBu+H ⁺]。 ¹H NMR (400MHz, 氯仿-d) δ = 7.03 (s, 1H), 3.65-3.50 (m, 2H), 3.46 (d, J = 11.2 Hz, 1H), 3.39 (d, J = 11.2 Hz, 1H), 1.80 (d, J = 2.4 Hz, 2H), 1.45 (s, 9H), 1.15 (s, 3H)。 (1R,5S,6r)-6-[(E)-( Hydroxyimino ) methyl ]-6- methyl -3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl (1R,5S,6r)-6-formyl-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (62 mg, 0.2800mmol) in To a solution in EtOH (1.5 mL) was added HOAc (15.73 uL, 0.2800 mmol), KOAc (26.97 mg, 0.2800 mmol) and hydroxylamine hydrochloride (0.01 mL, 0.3300 mmol). The mixture was stirred at 20 °C for 2 hours to give a yellow suspension. TLC (PE:EtOAc=3:1) showed the reaction was complete. The reaction mixture was poured into H ₂ O (20 mL) and extracted with EtOAc (15 mL×4). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (65 mg, 0.2705 mmol, 98.286% yield) as a yellow solid. LC-MS method 1 0.727 min, MS (m/z) 185.0 [M-tBu+H ⁺ ]. ¹ H NMR (400MHz, chloroform-d) δ = 7.03 (s, 1H), 3.65-3.50 (m, 2H), 3.46 (d, J = 11.2 Hz, 1H), 3.39 (d, J = 11.2 Hz, 1H ), 1.80 (d, J = 2.4 Hz, 2H), 1.45 (s, 9H), 1.15 (s, 3H).

(1R,5S,6r)-6-[(Z)- 氯基 ( 羥亞胺基 ) 甲基 ]-6- 甲基 -3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(E)-(羥亞胺基)甲基]-6-甲基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(65 mg，0.2700mmol)於DMF (1.5mL)中之溶液添加NCS (39.73mg，0.3000mmol)。在20℃下攪拌混合物14小時，得到褐色溶液。將混合物傾入H ₂O (15 mL)中且用EtOAc (15 mL × 5)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥且濃縮至乾燥，得到呈黃色油狀之標題化合物(70mg，0.2548mmol，94.193%產率)。 LC-MS方法1 0.802 min，MS (m/z) 218.9 [M-tBu+H ⁺]。 ¹H NMR (400MHz, 氯仿-d) δ = 8.55 (s, 1H), 3.66-3.55 (m, 2H), 3.47 (d, J = 9.0 Hz, 1H), 3.39 (d, J = 9.0 Hz, 1H), 2.15-2.08 (m, 2H) , 1.44 (s, 9H), 1.22 (s, 3H)。 (1R,5S,6r)-6-[(Z) -Chloro ( hydroxyimino ) methyl ]-6- methyl -3- azabicyclo [3.1.0] hexane -3- carboxylic acid tris Butyl ester to (1R,5S,6r)-6-[(E)-(hydroxyimino)methyl]-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxy To a solution of tert-butyl acid (65 mg, 0.2700 mmol) in DMF (1.5 mL) was added NCS (39.73 mg, 0.3000 mmol). The mixture was stirred at 20 °C for 14 hours to give a brown solution. The mixture was poured into H ₂ O (15 mL) and extracted with EtOAc (15 mL×5). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness to give the title compound (70 mg, 0.2548 mmol, 94.193% yield) as a yellow oil. LC-MS method 1 0.802 min, MS (m/z) 218.9 [M-tBu+H ⁺ ]. ¹ H NMR (400MHz, chloroform-d) δ = 8.55 (s, 1H), 3.66-3.55 (m, 2H), 3.47 (d, J = 9.0 Hz, 1H), 3.39 (d, J = 9.0 Hz, 1H ), 2.15-2.08 (m, 2H) , 1.44 (s, 9H), 1.22 (s, 3H).

(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-6-甲基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(70 mg，0.2500mmol)於DMF (1.5mL)中之溶液添加Et ₃N (0.13mL，0.7600mmol)及2-甲基丙-1-烯(0.48mL，0.7600mmol，於THF中之2.4 M)。在20℃下攪拌混合物12小時，得到褐色溶液。將混合物傾入H ₂O (15 mL)中且用EtOAc (15 mL × 5)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥且濃縮至乾燥，得到呈黃色油狀之標題化合物(70mg，0.2378mmol，93.325%產率)。 LC-MS方法1 0.810 min，MS (m/z) 295.1 [M+H ⁺]。 ¹H NMR (400MHz, 氯仿-d) δ = 3.60-3.55 (m, 2H), 3.46 (d, J = 8.7 Hz, 1H), 3.38 (d, J = 8.7 Hz, 1H), 2.64 (s, 2H), 2.00-1.92 (m, 2H) , 1.45 (s, 9H), 1.36 (s, 6H), 1.16 (s, 3H)。 (1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-6- methyl -3- azabicyclo [3.1 .0] tertiary butyl hexane -3- carboxylate to (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-6-methyl-3-nitrogen Heterobicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (70 mg, 0.2500 mmol) in DMF (1.5 mL) was added with Et ₃ N (0.13 mL, 0.7600 mmol) and 2-methyl Prop-1-ene (0.48 mL, 0.7600 mmol, 2.4 M in THF). The mixture was stirred at 20 °C for 12 hours to obtain a brown solution. The mixture was poured into H ₂ O (15 mL) and extracted with EtOAc (15 mL×5). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness to give the title compound (70 mg, 0.2378 mmol, 93.325% yield) as a yellow oil. LC-MS method 1 0.810 min, MS (m/z) 295.1 [M+H ⁺ ]. ¹ H NMR (400MHz, chloroform-d) δ = 3.60-3.55 (m, 2H), 3.46 (d, J = 8.7 Hz, 1H), 3.38 (d, J = 8.7 Hz, 1H), 2.64 (s, 2H ), 2.00-1.92 (m, 2H) , 1.45 (s, 9H), 1.36 (s, 6H), 1.16 (s, 3H).

(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽向(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(70 mg，0.2400mmol)於DCM (5mL)中之溶液添加TFA (1 mL，13.46mmol)。在20℃下攪拌混合物30 min，得到黃色溶液。直接濃縮反應混合物，得到呈黃色油狀物之標題化合物(70 mg粗物質)。 LC-MS方法1 0.268 min，MS (m/z) 194.9 [M+H ⁺]。 ¹H NMR (400 MHz, 二甲亞碸-d6) δ ppm 9.58 (brs, 1H), 8.85 (brs, 1H), 3.65-3.50 (m, 2H), 3.20-3.10 (m, 2H), 2.68 (s, 2H), 2.25 (m, 2H), 1.25 (s, 6H), 1.18 (s, 3H)。 (1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-6- methyl -3- azabicyclo [3.1 .0] hexane TFA salt to (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl - To a solution of tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (70 mg, 0.2400 mmol) in DCM (5 mL) was added TFA (1 mL, 13.46 mmol). The mixture was stirred at 20 °C for 30 min to give a yellow solution. The reaction mixture was directly concentrated to give the title compound (70 mg crude) as a yellow oil. LC-MS method 1 0.268 min, MS (m/z) 194.9 [M+H ⁺ ]. ¹ H NMR (400 MHz, dimethylsulfoxide-d6) δ ppm 9.58 (brs, 1H), 8.85 (brs, 1H), 3.65-3.50 (m, 2H), 3.20-3.10 (m, 2H), 2.68 ( s, 2H), 2.25 (m, 2H), 1.25 (s, 6H), 1.18 (s, 3H).

[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -3- 基 ](1- 異丙基 -1H- 咪唑 -4- 基 ) 甲酮向1-異丙基咪唑-4-羧酸(61.11mg，0.4000mmol)於DMF (2mL)中之溶液添加HATU (179.08mg，0.4700mmol)、Et ₃N (0.2mL，1.44mmol)、(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己烷TFA鹽(70 mg，0.3600mmol)。在20℃下攪拌混合物12小時，得到褐色溶液。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈褐色固體狀之標題化合物(11.6mg，0.0351mmol，9.7431%產率)。 LC-MS方法1 0.610 min，MS (m/z) 331.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿 -d) δ ppm 7.69 (1 H, s), 7.48 (1 H, s), 4.17 - 4.44 (3 H, m), 3.79 - 3.95 (2 H, m), 2.66 (2 H, d, J=1.63 Hz), 2.12 - 2.19 (1 H, m), 1.99 - 2.05 (1 H, m), 1.51 (6 H, dd, J=6.69, 1.56 Hz), 1.38 (6 H, s), 1.19 (3 H, d, J=1.75 Hz) [(1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-6- methyl -3- azabicyclo [ 3.1.0] Hex -3- yl ](1- isopropyl -1H- imidazol -4- yl ) methanone to 1-isopropylimidazole-4-carboxylic acid (61.11mg, 0.4000mmol) in DMF (2mL ) was added HATU (179.08mg, 0.4700mmol), Et ₃ N (0.2mL, 1.44mmol), (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro -1,2-(azol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hexane TFA salt (70 mg, 0.3600 mmol). The mixture was stirred at 20 °C for 12 hours to obtain a brown solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (11.6 mg, 0.0351 mmol, 9.7431% yield) as a tan solid. LC-MS method 1 0.610 min, MS (m/z) 331.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform -d ) δ ppm 7.69 (1 H, s), 7.48 (1 H, s), 4.17 - 4.44 (3 H, m), 3.79 - 3.95 (2 H, m), 2.66 (2 H, d, J =1.63 Hz), 2.12 - 2.19 (1 H, m), 1.99 - 2.05 (1 H, m), 1.51 (6 H, dd, J =6.69, 1.56 Hz), 1.38 (6 H, s), 1.19 (3 H, d, J =1.75 Hz)

實例 82      (1- 環丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1- 環丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-環丙基-1H-咪唑-4-羧酸(14.81 mg，0.10 mmol)於吡啶(0.75 mL)中之溶液添加EDCI (27.98 mg，0.15mmol)。攪拌混合物20分鐘。隨後添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己烷TFA鹽；(30 mg，0.10 mmol)。在25℃下攪拌混合物1小時。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色膠質之標題化合物(9.93 mg，0.0302 mmol，31.073%產率)。 LC-MS方法2 3.650 min，MS (m/z) 329.2 [M+H] ^{+ 1}H NMR (400MHz, 氯仿-d) δ = 7.66 (d, J=1.5 Hz, 1H), 7.51 (d, J=1.3 Hz, 1H), 4.32 - 4.19 (m, 2H), 3.91 - 3.78 (m, 2H), 3.37 (tt, J=3.8, 7.2 Hz, 1H), 2.66 (s, 2H), 2.14 (dd, J=4.9, 8.2 Hz, 1H), 2.06 - 1.96 (m, 1H), 1.38 (s, 7H), 1.18 (s, 3H), 1.09 - 0.96 (m, 4H) Example 82 (1- cyclopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazole -3- yl )-6- methyl -3- azabicyclo [3.1.0] hex -3- yl ] methanone (1- cyclopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazol -3 -yl ) -6- methyl -3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-cyclopropyl-1H-imidazole-4-carboxylic acid (14.81 mg, 0.10 mmol) in To a solution in pyridine (0.75 mL) was added EDCI (27.98 mg, 0.15 mmol). The mixture was stirred for 20 minutes. Subsequent addition of (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo [3.1.0] Hexane TFA salt; (30 mg, 0.10 mmol). The mixture was stirred at 25°C for 1 hour. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (9.93 mg, 0.0302 mmol, 31.073% yield) as a yellow gum. LC-MS method 2 3.650 min, MS (m/z) 329.2 [M+H] ^{+ 1} H NMR (400MHz, chloroform-d) δ = 7.66 (d, J =1.5 Hz, 1H), 7.51 (d, J =1.3 Hz, 1H), 4.32 - 4.19 (m, 2H), 3.91 - 3.78 (m, 2H), 3.37 (tt, J =3.8, 7.2 Hz, 1H), 2.66 (s, 2H), 2.14 (dd, J =4.9, 8.2 Hz, 1H), 2.06 - 1.96 (m, 1H), 1.38 (s, 7H), 1.18 (s, 3H), 1.09 - 0.96 (m, 4H)

實例 83      [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-(1- 甲基環丙基 )-1H- 咪唑 -4- 基 ] 甲酮 [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -3- 基 ][1-(1- 甲基環丙基 )-1H- 咪唑 -4- 基 ] 甲酮向1-(1-甲基環丙基)-1H-咪唑-4-羧酸(42.77mg，0.2600mmol)於DMF (1.5mL)中之溶液添加HATU (127.14mg，0.3300mmol)及DIPEA (0.21mL，1.29mmol)。攪拌混合物30 min。隨後添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己烷TFA鹽(50 mg，0.2600mmol)。在25℃下攪拌混合物3小時，得到褐色溶液。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈褐色固體狀之標題化合物(33.31mg，0.0973mmol，37.794%產率)。 LC-MS方法1: 343.3 [M+H ⁺] ¹H NMR (400MHz, DMSO-d ₆) δ = 7.71 (s, 1H), 7.53 (d, J=1.2 Hz, 1H), 4.32 - 4.20 (m, 2H), 3.89 - 3.80 (m, 2H), 2.66 (s, 3H), 2.16 - 1.99 (m, 2H), 1.57 (s, 3H), 1.37 (s, 6H), 1.17 (s, 3H), 1.33 - 1.31 (m, 2H), 0.94 - 0.91 (m, 2H)。 Example 83 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-6- methyl -3 - aza Bicyclo [3.1.0] hex -3- yl ][1-(1- methylcyclopropyl )-1H- imidazol -4- yl ] methanone [(1R,5S,6r)-6-(5,5 -Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-6- methyl -3- azabicyclo [ 3.1.0] hex -3- yl ][1-(1 -Methylcyclopropyl )-1H- imidazol -4- yl ] methanone to 1-(1-methylcyclopropyl)-1H-imidazole-4 - carboxylic acid (42.77mg, 0.2600mmol) in DMF (1.5 mL) was added HATU (127.14 mg, 0.3300 mmol) and DIPEA (0.21 mL, 1.29 mmol). The mixture was stirred for 30 min. Subsequent addition of (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-azabicyclo [3.1.0] Hexane TFA salt (50 mg, 0.2600 mmol). The mixture was stirred at 25 °C for 3 hours to give a brown solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (33.31 mg, 0.0973 mmol, 37.794% yield) as a tan solid. LC-MS method 1: 343.3 [M+H ⁺ ] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.71 (s, 1H), 7.53 (d, J =1.2 Hz, 1H), 4.32 - 4.20 (m , 2H), 3.89 - 3.80 (m, 2H), 2.66 (s, 3H), 2.16 - 1.99 (m, 2H), 1.57 (s, 3H), 1.37 (s, 6H), 1.17 (s, 3H), 1.33 - 1.31 (m, 2H), 0.94 - 0.91 (m, 2H).

實例 84      (1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6- 甲基 -6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6- 甲基 -6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向亞甲基環丙烷(0.24mL，9.96mmol)於THF (13.469mL)中之溶液逐步地添加(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-6-甲基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(300 mg，1.09mmol)。隨後，添加Et ₃N (0.46mL，3.28mmol)。在0℃下攪拌反應混合物16小時，得到黃色溶液。用H ₂O (30 mL)稀釋反應混合物且用EtOAc (30 mL×2)萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到殘餘物。藉由二氧化矽管柱(PE/EA=2:1)純化殘餘物，得到呈白色固體狀之標題化合物(200 mg，0.6841mmol，62.647%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.65-3.55 (m, 2H), 3.47 (d, J = 11.2 Hz, 1H), 3.39 (d, J = 11.2 Hz, 1H), 2.96 (s, 2H), 2.10-1.95 (m, 2H), 1.48 (s, 9H), 1.20 (s, 3H), 1.15-1.05 (m, 2H), 0.75-0.65 (m, 2H)。 Example 84 (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6- methyl -6-(4- oxa -5- azaspiro [2.4] hept -5 -en - 6- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (1R,5S , 6r)-6- methyl -6-(4-oxa- 5- aza Heterospiro [2.4] hept -5- en -6- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to methylenecyclopropane (0.24mL, 9.96mmol) (1R,5S,6r)-6-[(Z)-Chloro(hydroxyimino)methyl]-6-methyl-3-azabicyclo[ 3.1.0] tert-butyl hexane-3-carboxylate (300 mg, 1.09 mmol). Subsequently, _Et3N (0.46 mL, 3.28 mmol) was added. The reaction mixture was stirred at 0 °C for 16 hours to give a yellow solution. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo to give a residue. The residue was purified by silica column (PE/EA=2:1) to give the title compound (200 mg, 0.6841 mmol, 62.647% yield) as a white solid. ¹ H NMR (400MHz, chloroform-d) δ = 3.65-3.55 (m, 2H), 3.47 (d, J = 11.2 Hz, 1H), 3.39 (d, J = 11.2 Hz, 1H), 2.96 (s, 2H ), 2.10-1.95 (m, 2H), 1.48 (s, 9H), 1.20 (s, 3H), 1.15-1.05 (m, 2H), 0.75-0.65 (m, 2H).

6-[(1R,5S,6r)-6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 TFA 鹽向(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(200 mg，0.6800mmol)於DCM (11.901mL)中之溶液添加2,2,2-三氟乙酸(0.05mL，0.6800mmol)。在10℃下攪拌反應混合物1小時，得到黃色溶液。TLC (PE/EA=1:1)展示新樣點。在真空中蒸發反應混合物，得到呈黃色油狀之標題化合物(200 mg，0.6530mmol，95.458%產率)。 6-[(1R,5S,6r)-6- Methyl -3- azabicyclo [3.1.0] hex -6- yl ]-4- oxa -5- azaspiro [2.4] hept -5- Alkene TFA salt to (1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept-5-en-6-yl)-3-azabicyclo[ 3.1.0] To a solution of tert-butyl hexane-3-carboxylate (200 mg, 0.6800 mmol) in DCM (11.901 mL) was added 2,2,2-trifluoroacetic acid (0.05 mL, 0.6800 mmol). The reaction mixture was stirred at 10 °C for 1 hour to give a yellow solution. TLC (PE/EA=1:1) showed new samples. The reaction mixture was evaporated in vacuo to afford the title compound (200 mg, 0.6530 mmol, 95.458% yield) as a yellow oil.

(1- 異丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6- 甲基 -6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向100 ml圓底燒瓶裝入1-異丙基咪唑-4-羧酸(50.34mg，0.3300mmol)、HATU (149.78mg，0.3900mmol)、N-乙基-N-異丙基丙-2-胺(0.17mL，0.9800mmol)及DMF (1.6108mL)。在攪拌30 min之後，添加6-[(1R,5S,6r)-6-甲基-3-氮雜雙環[3.1.0]己-6-基]-4-氧雜-5-氮雜螺[2.4]庚-5-烯TFA鹽(100 mg，0.3300mmol)。在10℃下攪拌反應混合物1小時，得到黃色溶液。LCMS展示反應物完全耗盡及所要MS。用H ₂O (20 mL)稀釋反應混合物且用EtOAc (30 mL×2)萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色油狀之殘餘物。藉由製備型HPLC (NH ₃)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(52.53mg，0.1600mmol，48.99%產率)。 LC-MS方法1: 329.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.69 (d, J=1.6 Hz, 1H), 7.48 (d, J=1.2 Hz, 1H), 4.39 - 4.22 (m, 3H), 3.89 - 3.84 (m, 2H), 2.98 (s, 2H), 2.20 (m, 1H), 2.06 (m, 1H), 1.50 (d, J=6.4 Hz, 6H), 1.22 (s, 3H), 1.16 - 1.07 (m, 2H), 0.74 - 0.67 (m, 2H) (1- isopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6- methyl -6-(4- oxa -5- azaspiro [2.4] hept -5 - ene -6- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone A 100 ml round bottom flask was charged with 1-isopropylimidazole-4-carboxylic acid (50.34 mg, 0.3300 mmol) , HATU (149.78 mg, 0.3900 mmol), N-ethyl-N-isopropylpropan-2-amine (0.17 mL, 0.9800 mmol) and DMF (1.6108 mL). After stirring for 30 min, 6-[(1R,5S,6r)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro [2.4] Hept-5-ene TFA salt (100 mg, 0.3300 mmol). The reaction mixture was stirred at 10 °C for 1 hour to give a yellow solution. LCMS showed complete consumption of reactants and desired MS. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo to give a residue as a yellow oil. The crude material was purified by preparative HPLC ( _NH3 ). The obtained fluid was concentrated in vacuo to remove most of _CH3CN and lyophilized to give the title compound (52.53 mg, 0.1600 mmol, 48.99% yield) as a white solid. LC-MS method 1: 329.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.69 (d, J =1.6 Hz, 1H), 7.48 (d, J =1.2 Hz, 1H), 4.39 - 4.22 (m, 3H), 3.89 - 3.84 (m, 2H), 2.98 (s, 2H), 2.20 (m, 1H), 2.06 (m, 1H), 1.50 (d, J =6.4 Hz, 6H), 1.22 (s, 3H), 1.16 - 1.07 (m, 2H), 0.74 - 0.67 (m, 2H)

實例 85      (1- 環丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6- 甲基 -6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1- 環丙基 -1H- 咪唑 -4- 基 )[(1R,5S,6r)-6- 甲基 -6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-環丙基咪唑-4-羧酸(25.12mg，0.1700mmol)於DMF (1mL)中之溶液添加HATU (71.11mg，0.1900mmol)及DIPEA (100.16mg，0.7800mmol)。在25℃下攪拌混合物0.5小時。隨後向混合物添加6-[(1R,5S,6r)-6-甲基-3-氮雜雙環[3.1.0]己-6-基]-4-氧雜-5-氮雜螺[2.4]庚-5-烯TFA鹽(50 mg，0.1600mmol)。在25℃下攪拌混合物12小時，得到褐色溶液。LCMS展示所要MS作為主峰。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈褐色固體狀之標題化合物(11.52mg，0.0353mmol，20%產率)。 LC-MS方法2 1.763 min，MS (m/z) 327.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.66 (1 H, d, J=1.25 Hz), 7.51 (1 H, d, J=1.25 Hz), 4.18 - 4.35 (2 H, m), 3.82 - 3.92 (2 H, m), 3.37 (1 H, tt, J=7.31, 3.73 Hz), 2.99 (2 H, s), 2.20 (1 H, dd, J=8.16, 5.14 Hz), 2.01 - 2.12 (1 H, m), 1.19 - 1.24 (3 H, m), 1.09 - 1.17 (2 H, m), 0.96 - 1.08 (4 H, m), 0.67 - 0.76 (2 H, m) Example 85 (1- cyclopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6- methyl -6-(4- oxa -5- azaspiro [2.4] hept -5 -en - 6- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (1- cyclopropyl -1H- imidazol -4- yl )[(1R,5S,6r)-6- methyl -6-(4- oxa -5- azaspiro [2.4] hept -5 - ene -6- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 1-cyclopropylimidazole-4-carboxylic acid (25.12 mg, 0.1700 mmol) in DMF (1 mL) To the solution was added HATU (71.11 mg, 0.1900 mmol) and DIPEA (100.16 mg, 0.7800 mmol). The mixture was stirred at 25°C for 0.5 hours. 6-[(1R,5S,6r)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4] was then added to the mixture Hept-5-ene TFA salt (50 mg, 0.1600 mmol). The mixture was stirred at 25°C for 12 hours to give a brown solution. LCMS showed the desired MS as the main peak. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (11.52 mg, 0.0353 mmol, 20% yield) as a tan solid. LC-MS method 2 1.763 min, MS (m/z) 327.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.66 (1 H, d, J=1.25 Hz), 7.51 (1 H, d, J=1.25 Hz), 4.18 - 4.35 (2 H, m), 3.82 - 3.92 (2 H, m), 3.37 (1 H, tt, J=7.31, 3.73 Hz), 2.99 (2 H, s), 2.20 (1 H, dd, J=8.16, 5.14 Hz), 2.01 - 2.12 (1 H, m), 1.19 - 1.24 (3 H, m), 1.09 - 1.17 (2 H, m), 0.96 - 1.08 (4 H, m), 0.67 - 0.76 (2 H, m)

實例 86      [1-(1- 甲基環丙基 )-1H- 咪唑 -4- 基 ][(1R,5S,6r)-6- 甲基 -6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 [1-(1- 甲基環丙基 )-1H- 咪唑 -4- 基 ][(1R,5S,6r)-6- 甲基 -6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向1-(1-甲基環丙基)咪唑-4-羧酸(37.98mg，0.2300mmol)於DMF (2mL)中之溶液添加HATU (104.22mg，0.2700mmol)及DIPEA (0.19mL，1.14mmol)。在25℃下攪拌混合物30 min。隨後向混合物添加6-[(1R,5S,6r)-6-甲基-3-氮雜雙環[3.1.0]己-6-基]-4-氧雜-5-氮雜螺[2.4]庚-5-烯TFA鹽(70 mg，0.2300mmol)。在25℃下攪拌混合物3小時，得到褐色溶液。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈褐色固體狀之標題化合物(15.64mg，0.0459mmol，20.102%產率)。 LC-MS方法1: 341.3 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.65 (2 H, br d, J=6.25 Hz) 4.10 - 4.26 (2 H, m) 3.77 - 3.92 (2 H, m) 3.00 (2 H, s) 2.20 - 2.29 (1 H, m) 2.07 - 2.15 (1 H, m) 1.59 (3 H, s) 1.17 - 1.23 (3 H, m) 1.08 - 1.17 (4 H, m) 0.93 - 1.00 (2 H, m) 0.69 - 0.76 (2 H, m) Example 86 [1-(1- methylcyclopropyl )-1H- imidazol -4- yl ][(1R,5S,6r)-6- methyl -6-(4- oxa -5- azaspiro [2.4] Hept -5- en -6- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone [1-(1- methylcyclopropyl )-1H- imidazole -4 -yl ][(1R,5S,6r)-6- methyl -6-(4- oxa -5- azaspiro [2.4] hept -5- en - 6- yl )-3- azabicyclo [ 3.1.0] Hex -3- yl ] methanone To a solution of 1-(1-methylcyclopropyl)imidazole-4-carboxylic acid (37.98 mg, 0.2300 mmol) in DMF (2 mL) was added HATU (104.22 mg , 0.2700mmol) and DIPEA (0.19mL, 1.14mmol). The mixture was stirred at 25 °C for 30 min. 6-[(1R,5S,6r)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4] was then added to the mixture Hept-5-ene TFA salt (70 mg, 0.2300 mmol). The mixture was stirred at 25 °C for 3 hours to give a brown solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (NH ₃ ) to afford the title compound (15.64 mg, 0.0459 mmol, 20.102% yield) as a tan solid. LC-MS method 1: 341.3 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.65 (2 H, br d, J=6.25 Hz) 4.10 - 4.26 (2 H, m) 3.77 - 3.92 (2 H, m) 3.00 (2 H, s) 2.20 - 2.29 (1 H, m) 2.07 - 2.15 (1 H, m) 1.59 (3 H, s) 1.17 - 1.23 (3 H, m) 1.08 - 1.17 (4 H, m) 0.93 - 1.00 (2 H, m) 0.69 - 0.76 (2 H, m)

實例 87      (1R,5S,6r)-N- 三級丁基 -6- 甲基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-6- 甲基 -3-{[( 三級丁基 ) 氧基 ] 羰基 }-3- 氮雜雙環 [3.1.0] 己烷 -6- 羧酸向(1R,5S,6r)-6-甲醯基-6-甲基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.44 mmol)於1-BuOH (1.7 mL，0.44 mmol)、THF (1.7 mL)及H ₂O (0.60 mL)中之溶液添加2-甲基丁-2-烯(0.94 mL，8.88  mmol)、NaClO ₂(160.58 mg，1.78 mmol)及NaH ₂PO ₄(490.02 mg，3.55 mmol)。在20至25℃下攪拌所得混合物16小時。TLC (PE:EtOAc = 2:1)展示反應完成(Rf = 0.5)。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (10 mL × 4)萃取。合併之有機層經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈白色固體狀之標題化合物(167 mg，0.6921 mmol，155.93%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.66 - 3.56 (m, 2H), 3.47 - 3.34 (m, 2H), 2.26 - 2.18 (m, 2H), 1.47 - 1.42 (m, 9H), 1.17 (s, 3H) Example 87 (1R, 5S, 6r)-N- tertiary butyl -6- methyl -3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-3- azabicyclo [ 3.1.0] Hexane -6- formamide (1R,5S,6r)-6- methyl -3-{[( tertiary butyl ) oxy ] carbonyl }-3- azabicyclo [3.1.0 ] Hexane -6- carboxylic acid to (1R, 5S, 6r)-6-formyl-6-methyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester ( 100 mg, 0.44 mmol) in 1-BuOH (1.7 mL, 0.44 mmol), THF (1.7 mL) and H ₂ O (0.60 mL) were added 2-methylbut-2-ene (0.94 mL, 8.88 mmol ), NaClO ₂ (160.58 mg, 1.78 mmol) and NaH ₂ PO ₄ (490.02 mg, 3.55 mmol). The resulting mixture was stirred at 20 to 25°C for 16 hours. TLC (PE:EtOAc = 2:1) showed the reaction was complete (Rf = 0.5). The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (10 mL×4). The combined organic layers were dried over _Na2SO4 , filtered and concentrated under reduced pressure to afford the title compound (167 mg, 0.6921 mmol, 155.93% yield ₎ as a white solid. ¹ H NMR (400MHz, chloroform-d) δ = 3.66 - 3.56 (m, 2H), 3.47 - 3.34 (m, 2H), 2.26 - 2.18 (m, 2H), 1.47 - 1.42 (m, 9H), 1.17 ( s, 3H)

(1R,5S,6r)-6- 甲基 -6-[( 三級丁基 ) 胺甲醯基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-甲基-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(100 mg，0.41 mmol)於吡啶(1 mL)中之溶液添加EDCI (119.18 mg，0.62 mmol)。在20至25℃下攪拌混合物0.5小時。隨後添加2-甲基丙-2-胺(0.04 mL，0.41 mmol)。在20至25℃下攪拌所得混合物16小時。TLC (PE:EA=1:1)展示反應完成。藉由快速柱(PE至30% EtOAc/PE)純化粗產物，得到呈褐色固體狀之標題化合物(50 mg，0.1687 mmol，40.7%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 3.67 - 3.55 (m, 2H), 3.36 (d, J=11.9 Hz, 1H), 3.28 (d, J=11.8 Hz, 1H), 2.15 - 2.04 (m, 2H), 1.48 - 1.42 (m, 9H), 1.48 - 1.42 (m, 1H), 1.39 - 1.30 (m, 9H), 1.13 (s, 3H) (1R,5S,6r)-6- methyl -6-[( tertiary butyl ) aminoformyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester (1R,5S,6r)-6-Methyl-3-{[(tertiary butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (100 mg, 0.41 mmol) in pyridine (1 mL) was added EDCI (119.18 mg, 0.62 mmol). The mixture was stirred at 20 to 25°C for 0.5 hours. Then 2-methylpropan-2-amine (0.04 mL, 0.41 mmol) was added. The resulting mixture was stirred at 20 to 25°C for 16 hours. TLC (PE:EA=1:1) showed the reaction was complete. The crude product was purified by flash column (PE to 30% EtOAc/PE) to give the title compound (50 mg, 0.1687 mmol, 40.7% yield) as a tan solid. ¹ H NMR (400MHz, chloroform-d) δ = 3.67 - 3.55 (m, 2H), 3.36 (d, J =11.9 Hz, 1H), 3.28 (d, J =11.8 Hz, 1H), 2.15 - 2.04 (m , 2H), 1.48 - 1.42 (m, 9H), 1.48 - 1.42 (m, 1H), 1.39 - 1.30 (m, 9H), 1.13 (s, 3H)

(1R,5S,6r)-6- 甲基 -N-( 三級丁基 )-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 TFA 鹽在20至25℃下攪拌(1R,5S,6r)-6-甲基-6-[(三級丁基)胺甲醯基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(50 mg，0.17 mmol)於DCM (1 mL)及2,2,2-三氟乙酸(0.1 mL，1.31 mmol)中之溶液1小時。TLC (PE:EtOAc = 1:1)展示反應完成(Rf = 0.3)。藉由用N ₂吹掃來濃縮反應混合物，得到呈褐色油狀之標題化合物(30 mg，0.1528 mmol，90.604%產率)。 (1R,5S,6r)-6- methyl -N-( tertiary butyl )-3- azabicyclo [3.1.0] hexane -6- formamide TFA salt was stirred at 20 to 25°C ( 1R,5S,6r)-6-methyl-6-[(tertiary butyl)aminoformyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (50 mg, 0.17 mmol) in DCM (1 mL) and 2,2,2-trifluoroacetic acid (0.1 mL, 1.31 mmol) for 1 h. TLC (PE:EtOAc = 1:1) showed the reaction was complete (Rf = 0.3). The reaction mixture was concentrated by purging with _N2 to afford the title compound (30 mg, 0.1528 mmol, 90.604% yield) as a brown oil.

(1R,5S,6r)-N- 三級丁基 -6- 甲基 -3-[1-( 丙 -2- 基 )-1H- 咪唑 -4- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向1-異丙基咪唑-4-羧酸(23.56 mg，0.15 mmol)於DMF (0.50 mL)中之溶液添加HATU (75.96 mg，0.20 mmol)及Et ₃N (0.06 mL，0.46 mmol)。在20至25℃下攪拌混合物0.5小時。隨後向混合物添加(1R,5S,6r)-6-甲基-N-(三級丁基)-3-氮雜雙環[3.1.0]己烷-6-甲醯胺TFA鹽(30 mg，0.15 mmol)。在20至25℃下攪拌所得混合物2小時。LCMS展示所要MS (作為主峰)。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈灰白色固體狀之標題化合物(10.28 mg，0.0309 mmol，20.233%產率)。 LC-MS方法1: 333.1 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 7.69 (s, 1H), 7.48 (s, 1H), 5.58 (s, 1H), 4.36 (td, J=6.7, 13.4 Hz, 1H), 4.24 (d, J=2.3 Hz, 2H), 3.94 - 3.85 (m, 1H), 3.74 (d, J=13.3 Hz, 1H), 2.30 - 2.25 (m, 1H), 2.12 (dd, J=5.4, 8.2 Hz, 1H), 1.51 (d, J=6.8 Hz, 6H), 1.36 (s, 9H), 1.15 (s, 3H) (1R,5S,6r)-N- tertiary butyl -6- methyl -3-[1-( propan -2- yl )-1H- imidazole -4- carbonyl ]-3- azabicyclo [3.1. 0] Hexane -6- carboxamide To a solution of 1-isopropylimidazole-4-carboxylic acid (23.56 mg, 0.15 mmol) in DMF (0.50 mL) was added HATU (75.96 mg, 0.20 mmol) and Et ₃ N (0.06 mL, 0.46 mmol). The mixture was stirred at 20 to 25°C for 0.5 hours. Then (1R,5S,6r)-6-methyl-N-(tertiary butyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide TFA salt (30 mg, 0.15 mmol). The resulting mixture was stirred at 20 to 25°C for 2 hours. LCMS showed desired MS (as main peak). The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to afford the title compound (10.28 mg, 0.0309 mmol, 20.233% yield) as an off-white solid. LC-MS method 1: 333.1 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 7.69 (s, 1H), 7.48 (s, 1H), 5.58 (s, 1H), 4.36 (td, J =6.7, 13.4 Hz, 1H), 4.24 (d, J =2.3 Hz, 2H), 3.94 - 3.85 (m, 1H), 3.74 (d, J =13.3 Hz, 1H), 2.30 - 2.25 (m, 1H ), 2.12 (dd, J =5.4, 8.2 Hz, 1H), 1.51 (d, J =6.8 Hz, 6H), 1.36 (s, 9H), 1.15 (s, 3H)

實例 88      [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向5-異丙基-1H-吡唑-3-羧酸(21.34mg，0.1400mmol)於DMF (1mL)中之溶液添加HATU (63.13mg，0.1700mmol)、DIPEA (0.08mL，0.4800mmol)及(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(30 mg，0.1400mmol)。在25℃下攪拌混合物12小時，得到褐色溶液。TLC (PE:EtOAc=1:3)展示新樣點。將反應混合物傾入H ₂O (10 mL)中且用EtOAc (20 mL × 3)萃取。用鹽水(30 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由製備型TLC (PE:EtOAc=1:3)純化殘餘物且凍乾，得到呈白色粉末狀之標題化合物(18.42mg，0.0570mmol，41.171%產率)。 LC-MS方法1 0.781 min，MS (m/z) 317.0 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 6.41 (s, 1 H), 4.13 - 4.28 (m, 2 H), 3.95 (br dd, J=11.17, 4.14 Hz, 1 H), 3.69 (br dd, J=12.92, 4.39 Hz, 1 H), 3.06 (quin, J=6.84 Hz, 1 H), 2.66 (s, 2 H), 2.15 (br dd, J=7.40, 3.39 Hz, 1 H), 2.02 - 2.08 (m, 1 H), 1.47 (t, J=3.26 Hz, 1 H), 1.38 (s, 6 H), 1.27 - 1.31 (m, 6 H) Example 88 [(1R,5S,6r)-6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone [(1R,5S,6r)-6-(5,5- Dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexyl -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone to 5-isopropyl-1H-pyrazole-3-carboxylic acid (21.34mg, 0.1400mmol) in DMF (1mL ) was added with HATU (63.13mg, 0.1700mmol), DIPEA (0.08mL, 0.4800mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1 ,2-(azol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (30 mg, 0.1400 mmol). The mixture was stirred at 25°C for 12 hours to give a brown solution. TLC (PE:EtOAc=1:3) showed fresh spot. The reaction mixture was poured into H ₂ O (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EtOAc=1:3) and lyophilized to give the title compound (18.42 mg, 0.0570 mmol, 41.171% yield) as a white powder. LC-MS method 1 0.781 min, MS (m/z) 317.0 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 6.41 (s, 1 H), 4.13 - 4.28 (m, 2 H ), 3.95 (br dd, J=11.17, 4.14 Hz, 1 H), 3.69 (br dd, J=12.92, 4.39 Hz, 1 H), 3.06 (quin, J=6.84 Hz, 1 H), 2.66 (s , 2 H), 2.15 (br dd, J=7.40, 3.39 Hz, 1 H), 2.02 - 2.08 (m, 1 H), 1.47 (t, J=3.26 Hz, 1 H), 1.38 (s, 6 H ), 1.27 - 1.31 (m, 6H)

實例 89      (5- 二級丁基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 5- 甲基 -2,4- 二側氧基庚酸 乙 酯在0℃下向3-甲基戊-2-酮(0.61mL，4.99mmol)及草酸二乙酯(0.81mL，5.99mmol)於THF (20mL)中之溶液添加NaH (239.62mg，5.99mmol)。將反應物升溫至20℃且攪拌另外6小時，得到淡褐色溶液。將反應物冷卻至0℃，用H ₂O (30 mL)處理，用2 M HCl酸化至pH=6且用EA (20 mL × 2)萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈淡褐色液體之標題化合物(1000 mg，4.9943mmol)。 ¹H NMR (400MHz, 氯仿-d) δ = 14.60 (brs, 1H), 6.40 (s, 1H), 4.26 (q, J = 6.8 Hz, 2H), 2.55-2.40 (m, 1H), 1.60-1.50 (m, 1H), 1.50-1.35 (m, 1H), 1.38 (t, J = 6.8 Hz, 3H), 1.10 (d, J = 7.4 Hz, 3H), 0.82 (t, J = 6.8 Hz, 3H)。 Example 89 (5- secondary butyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- (Zazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 5- methyl -2,4- dioxoheptanoic acid ethyl ester at 0℃ to 3- To a solution of methylpentan-2-one (0.61 mL, 4.99 mmol) and diethyl oxalate (0.81 mL, 5.99 mmol) in THF (20 mL) was added NaH (239.62 mg, 5.99 mmol). The reaction was warmed to 20 °C and stirred for an additional 6 hours to give a light brown solution. The reaction was cooled to 0 °C, treated with _H2O (30 mL), acidified with 2 M HCl to pH = 6 and extracted with EA (20 mL x 2). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo to give the title compound (1000 mg, 4.9943 mmol) as a light brown liquid. ¹ H NMR (400MHz, chloroform-d) δ = 14.60 (brs, 1H), 6.40 (s, 1H), 4.26 (q, J = 6.8 Hz, 2H), 2.55-2.40 (m, 1H), 1.60-1.50 (m, 1H), 1.50-1.35 (m, 1H), 1.38 (t, J = 6.8 Hz, 3H), 1.10 (d, J = 7.4 Hz, 3H), 0.82 (t, J = 6.8 Hz, 3H) .

5- 二級丁基 -1H- 吡唑 -3- 羧酸乙酯在20℃下向5-甲基-2,4-二側氧基庚酸乙酯(1000 mg，4.99mmol)於EtOH (20 mL)中之溶液添加水合肼(275.01mg，5.49mmol)。在攪拌20min之後，在60℃下加熱反應物另外4小時，得到黃色混合物。真空濃縮混合物，得到粗物質油。用EA (40 mL)稀釋油狀物，用H ₂O (30 mL × 2)及鹽水(30 mL)洗滌，隨後，經Na ₂SO ₄乾燥且真空濃縮，得到呈淡黃色油狀之標題化合物(950mg，4.8408mmol，96.927%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 6.55 (s, 1H), 4.31 (q, J = 6.8 Hz, 2H), 2.80-2.35 (m, 1H), 1.70-1.50 (m, 2H), 1.37 (t, J = 6.8 Hz, 3H), 1.31 (d, J = 7.4 hz, 3H), 0.82 (t, J = 6.8 Hz, 3H)。 5- Secondary butyl -1H- pyrazole - 3- carboxylic acid ethyl ester was dissolved in EtOH ( 20 mL) was added hydrazine hydrate (275.01 mg, 5.49 mmol). After stirring for 20 min, the reaction was heated at 60 °C for an additional 4 hours to give a yellow mixture. The mixture was concentrated in vacuo to give a crude oil. The oil was diluted with EA (40 mL), washed with _H2O (30 mL x 2) and brine (30 mL) _, then dried over _Na2SO4 and concentrated in vacuo to give the title compound as a light yellow oil (950 mg, 4.8408 mmol, 96.927% yield). ¹ H NMR (400MHz, chloroform-d) δ = 6.55 (s, 1H), 4.31 (q, J = 6.8 Hz, 2H), 2.80-2.35 (m, 1H), 1.70-1.50 (m, 2H), 1.37 (t, J = 6.8 Hz, 3H), 1.31 (d, J = 7.4 Hz, 3H), 0.82 (t, J = 6.8 Hz, 3H).

5- 二級丁基 -1H- 吡唑 -3- 羧酸向5-二級丁基-1H-吡唑-3-羧酸乙酯(950 mg，4.84mmol)於MeOH (15mL)及H ₂O (5 mL)中之溶液添加LiOH·H ₂O (0.42mL，7.26mmol)。在20℃下攪拌反應物12小時，得到黃色混合物。混合物經濃縮以移除MeOH。用H ₂O (5 mL)稀釋殘餘物且用DCM (5 mL × 2)洗滌。將水層冷卻至0℃且用2M HCl酸化至pH=6。沈澱物經收集且真空濃縮，得到呈白色固體狀之標題化合物(420mg，2.4972mmol，51.586%產率)。 5- Secondary butyl -1H- pyrazole -3- carboxylic acid To 5-secondary butyl-1H-pyrazole-3-carboxylic acid ethyl ester (950 mg, 4.84 mmol) in MeOH (15 mL) and H ₂ To the solution in O (5 mL) was added LiOH- _H2O (0.42 mL, 7.26 mmol). The reaction was stirred at 20°C for 12 hours to give a yellow mixture. The mixture was concentrated to remove MeOH. The residue was diluted with H ₂ O (5 mL) and washed with DCM (5 mL×2). The aqueous layer was cooled to 0°C and acidified to pH=6 with 2M HCl. The precipitate was collected and concentrated in vacuo to afford the title compound (420 mg, 2.4972 mmol, 51.586% yield) as a white solid.

(5- 二級丁基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-二級丁基-1H-吡唑-3-羧酸(50 mg，0.3000mmol)於DMF (1.5mL)中之溶液添加HATU (125.02mg，0.3300mmol)、(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(70.87mg，0.3300mmol)及Et ₃N (0.1mL，0.7400mmol)。在20℃下攪拌反應物12小時，得到淡黃色混合物。混合物經真空濃縮且藉由製備型HPLC (HCl)純化。濃縮所獲得溶離劑且凍乾，得到呈淡黃色固體狀之標題化合物(10.38mg，0.0314mmol，10.567%產率)。 LC-MS 方法 1: 331.0 [M+H ⁺] ¹H NMR (400MHz, DMSO-d ₆) δ = 6.51 - 6.28 (m, 1H), 4.30 (br d, J=11.9 Hz, 1H), 3.94 (d, J=12.3 Hz, 1H), 3.83 (dd, J=4.2, 11.8 Hz, 1H), 2.80 - 2.71 (m, 1H), 2.65 (s, 2H), 2.08 (td, J=3.7, 7.4 Hz, 1H), 2.00 (td, J=3.8, 7.3 Hz, 1H), 1.65 - 1.51 (m, 2H), 1.47 - 1.41 (m, 1H), 1.25 (s, 6H), 1.20 (d, J=6.9 Hz, 3H), 0.80 (t, J=7.4 Hz, 3H) (5- Secondary butyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazole -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 5-secondary butyl-1H-pyrazole-3-carboxylic acid (50 mg, 0.3000mmol) in DMF (1.5mL) was added HATU (125.02mg, 0.3300mmol), (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazole- 3-yl)-3-azabicyclo[3.1.0]hexane TFA salt (70.87 mg, 0.3300 mmol) and _Et3N (0.1 mL, 0.7400 mmol). The reaction was stirred at 20°C for 12 hours to give a pale yellow mixture. The mixture was concentrated in vacuo and purified by preparative HPLC (HCl). The obtained eluent was concentrated and lyophilized to afford the title compound (10.38 mg, 0.0314 mmol, 10.567% yield) as a pale yellow solid. LC-MS method 1 : 331.0 [M+H ⁺ ] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 6.51 - 6.28 (m, 1H), 4.30 (br d, J =11.9 Hz, 1H), 3.94 ( d, J =12.3 Hz, 1H), 3.83 (dd, J =4.2, 11.8 Hz, 1H), 2.80 - 2.71 (m, 1H), 2.65 (s, 2H), 2.08 (td, J =3.7, 7.4 Hz , 1H), 2.00 (td, J =3.8, 7.3 Hz, 1H), 1.65 - 1.51 (m, 2H), 1.47 - 1.41 (m, 1H), 1.25 (s, 6H), 1.20 (d, J =6.9 Hz, 3H), 0.80 (t, J =7.4 Hz, 3H)

實例 90      [5-(1- 環丙基乙基 )-1H- 吡唑 -3- 基 ][(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 5- 乙醯基 -1-{[2-( 三甲基矽烷基 ) 乙氧基 ] 甲基 }-1H- 吡唑 -3- 羧酸甲酯將5-溴-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-羧酸甲酯(1500 mg，4.47mmol，四面體(Tetrahedron) 2015, 71(39), 7250)、三丁基(1-乙氧基乙烯基)錫烷(1938.94mg，5.37mmol)及PdCl ₂(dppf) (163.68mg，0.2200mmol)於1,4-二㗁烷(25mL)中之溶液加熱至9℃歷時16小時，得到黃色溶液。添加1 M HCl水溶液(3 mL)，攪拌10 min。隨後用H ₂O (20 mL)稀釋反應物且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(PE/EA=10/1至3/1)來純化粗物質，得到呈白色固體狀之標題化合物(580mg，1.9436mmol，43.443%產率)。 LC-MS方法1 0.972 min，MS (m/z) 299.0 (M + H ⁺)。 Example 90 [5-(1- cyclopropylethyl )-1H- pyrazol -3- yl ][(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 5- acetyl- 1-{[2-( trimethylsilyl ) Ethoxy ] methyl }-1H- pyrazole -3- carboxylic acid methyl ester 5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole- Methyl 3-carboxylate (1500 mg, 4.47mmol, Tetrahedron 2015, 71(39), 7250), tributyl(1-ethoxyvinyl) stannane (1938.94mg, 5.37mmol) and A solution of PdCl ₂ (dppf) (163.68 mg, 0.2200 mmol) in 1,4-dioxane (25 mL) was heated to 9° C. for 16 hours to give a yellow solution. Add 1 M aqueous HCl (3 mL) and stir for 10 min. The reaction was then diluted with H ₂ O (20 mL) and extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (PE/EA = 10/1 to 3/1 ) to afford the title compound (580 mg, 1.9436 mmol, 43.443% yield) as a white solid. LC-MS method 1 0.972 min, MS (m/z) 299.0 (M + H ⁺ ).

5-{(1E)-N-[(4- 甲基苯基 ) 磺醯基 ] 乙烷腙醯基 }-1-{[2-( 三甲基矽烷基 ) 乙氧基 ] 甲基 }-1H- 吡唑 -3- 羧酸甲酯向100 mL圓底燒瓶裝入5-乙醯基-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-羧酸甲酯(810 mg，2.71mmol)、4-甲基苯磺醯肼(505.5mg，2.71mmol)、4-甲基苯磺酸(0.02mL，0.1400mmol)及MeOH (10mL)。在40℃下攪拌反應物16小時，得到黃色溶液。在真空中蒸發反應混合物，得到呈黃色油狀之標題化合物(1250mg，2.6788mmol，98.688%產率)。其直接用於下一步驟。 LC-MS方法1 1.012 min，MS (m/z) 467.1 (M + H ⁺)。 5-{(1E)-N-[(4- methylphenyl ) sulfonyl ] ethanehydrazoneyl }-1-{[2-( trimethylsilyl ) ethoxy ] methyl }- Methyl 1H- pyrazole -3- carboxylate Charge a 100 mL round bottom flask with 5-acetyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole - Methyl 3-carboxylate (810 mg, 2.71mmol), 4-methylbenzenesulfonylhydrazine (505.5mg, 2.71mmol), 4-methylbenzenesulfonic acid (0.02mL, 0.1400mmol) and MeOH (10mL) . The reaction was stirred at 40°C for 16 hours to give a yellow solution. The reaction mixture was evaporated in vacuo to afford the title compound (1250 mg, 2.6788 mmol, 98.688% yield) as a yellow oil. It was used directly in the next step. LC-MS method 1 1.012 min, MS (m/z) 467.1 (M + H ⁺ ).

5-(1- 環丙基乙基 )-1-{[2-( 三甲基矽烷基 ) 乙氧基 ] 甲基 }-1H- 吡唑 -3- 羧酸甲酯向圓底燒瓶裝入5-{(1E)-N-[(4-甲基苯基)磺醯基]乙烷腙醯基}-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-羧酸甲酯(500 mg，1.07mmol)、環丙基硼酸(138.06mg，1.61mmol)、K ₂CO ₃(222.14mg，1.61mmol)及1,4-二㗁烷(10mL)。將反應物加熱至110℃歷時2小時，得到白色懸浮液。TLC (PE/EA =10/1，Rf =0.7)展示新樣點。反應混合物經由矽藻土墊過濾且濾液經真空濃縮，得到無色油狀物。藉由矽膠層析(PE/EA=10/1至3/1)來純化粗物質，得到呈無色油狀之標題化合物(230mg，0.6904mmol，64.43%產率)。 LC-MS方法1 1.105 min，MS (m/z) 325.2 (M + H ⁺)。 5-(1- Cyclopropylethyl )-1-{[2-( trimethylsilyl ) ethoxy ] methyl }-1H- pyrazole -3- carboxylic acid methyl ester was charged into a round bottom flask 5-{(1E)-N-[(4-methylphenyl)sulfonyl]ethanehydrazoneyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}- 1H-Pyrazole-3-carboxylic acid methyl ester (500 mg, 1.07mmol), cyclopropylboronic acid (138.06mg, 1.61mmol), K ₂ CO ₃ (222.14mg, 1.61mmol) and 1,4-dioxane (10 mL). The reaction was heated to 110 °C for 2 hours to give a white suspension. TLC (PE/EA = 10/1, Rf = 0.7) showed a fresh sample. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give a colorless oil. The crude material was purified by silica gel chromatography (PE/EA = 10/1 to 3/1 ) to give the title compound (230 mg, 0.6904 mmol, 64.43% yield) as a colorless oil. LC-MS method 1 1.105 min, MS (m/z) 325.2 (M + H ⁺ ).

5-(1- 環丙基乙基 )-1H- 吡唑 -3- 羧酸甲酯向圓底燒瓶裝入5-(1-環丙基乙基)-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-3-羧酸甲酯(230 mg，0.7100mmol)、2,2,2-三氟乙酸(0.05mL，0.7100mmol)及DCM (10mL)。在20℃下攪拌反應混合物2小時，得到黃色溶液。在真空中蒸發反應混合物，得到呈黃色油狀之標題化合物(130mg，0.6693mmol，94.428%產率)。 LC-MS方法1 0.785 min，MS (m/z) 195.2 (M + H ⁺)。 5-(1- cyclopropylethyl )-1H- pyrazole -3- carboxylic acid methyl ester was charged into a round bottom flask with 5-(1-cyclopropylethyl)-1-{[2-(trimethyl Silylyl)ethoxy]methyl}-1H-pyrazole-3-carboxylic acid methyl ester (230 mg, 0.7100mmol), 2,2,2-trifluoroacetic acid (0.05mL, 0.7100mmol) and DCM ( 10mL). The reaction mixture was stirred at 20 °C for 2 hours to obtain a yellow solution. The reaction mixture was evaporated in vacuo to afford the title compound (130 mg, 0.6693 mmol, 94.428% yield) as a yellow oil. LC-MS method 1 0.785 min, MS (m/z) 195.2 (M + H ⁺ ).

5-(1- 環丙基乙基 )-1H- 吡唑 -3- 羧酸向100 mL圓底燒瓶裝入5-(1-環丙基乙基)-1H-吡唑-3-羧酸甲酯(130 mg，0.6700mmol)、羥基鋰水合物(84.25mg，2.01mmol)、H ₂O (1.3mL)、THF (1.3mL)及MeOH (1.3mL)。在N ₂氛圍下攪拌反應混合物3小時，得到黃色溶液。添加H ₂O (30 mL)且用1 M HCl將pH值調整為3。用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色油狀之標題化合物(120mg，0.6659mmol，99.495%產率)。 LC-MS方法1 0.732 min，MS (m/z) 181.2 (M + H ⁺)。 5-(1- Cyclopropylethyl )-1H- pyrazole -3- carboxylic acid Charge a 100 mL round bottom flask with 5-(1-cyclopropylethyl)-1H-pyrazole-3-carboxylic acid Methyl ester (130 mg, 0.6700 mmol), lithium hydroxyhydrate (84.25 mg, 2.01 mmol), _H2O (1.3 mL), THF (1.3 mL) and MeOH (1.3 mL). The reaction mixture was stirred under _N2 atmosphere for 3 h to give a yellow solution. _H2O (30 mL) was added and the pH was adjusted to 3 with 1 M HCl. It was extracted with EtOAc (30 mL×2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (120 mg, 0.6659 mmol, 99.495% yield) as a yellow oil. LC-MS method 1 0.732 min, MS (m/z) 181.2 (M + H ⁺ ).

[5-(1- 環丙基乙基 )-1H- 吡唑 -3- 基 ][(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-(1-環丙基乙基)-1H-吡唑-3-羧酸(80 mg，0.4400mmol)於DMF (2mL)中之溶液添加HATU (203.67mg，0.5300mmol)及N-乙基-N-異丙基丙-2-胺(0.46mL，2.66mmol)。在攪拌30 min之後，添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(278.26mg，0.5300mmol)。攪拌反應混合物16小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型TLC (DCM/EA=3/1)純化粗物質且凍乾，得到呈白色固體狀之標題化合物(16.86mg，0.0459mmol，10.346%產率)。 LC-MS方法1: 343.0 [M+H ⁺] ¹H NMR (400 MHz, CDCl ₃) δ ppm 6.55 (s, 1H), 3.33 (d, J = 11.2 Hz, 1H), 3.20 (d, J = 11.2 Hz, 1H), 3.95-3.85 (m, 1H), 3.70-3.60 (m, 1H), 2.65 (s, 2H), 2.20-2.10 (m, 2H), 2.05-2.00 (m, 1H), 1.45-1.40 (m, 1H), 1.38 (s, 9H), 0.95-0.85 (m, 1H), 0.58 (d, J = 7.6 Hz, 2H), 0.30-0.20 (m, 2H)。 [5-(1- cyclopropylethyl )-1H- pyrazol -3- yl ][(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1 , 2-( azol- 3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 5-(1-cyclopropylethyl)-1H-pyrazole-3-carboxy To a solution of the acid (80 mg, 0.4400 mmol) in DMF (2 mL) was added HATU (203.67 mg, 0.5300 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.46 mL, 2.66 mmol). After stirring for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo [3.1.0] Hexane TFA salt (278.26 mg, 0.5300 mmol). The reaction mixture was stirred for 16 hours to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by prep-TLC (DCM/EA=3/1) and lyophilized to give the title compound (16.86 mg, 0.0459 mmol, 10.346% yield) as a white solid. LC-MS method 1: 343.0 [M+H ⁺ ] ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.55 (s, 1H), 3.33 (d, J = 11.2 Hz, 1H), 3.20 (d, J = 11.2 Hz, 1H), 3.95-3.85 (m, 1H), 3.70-3.60 (m, 1H), 2.65 (s, 2H), 2.20-2.10 (m, 2H), 2.05-2.00 (m, 1H), 1.45 -1.40 (m, 1H), 1.38 (s, 9H), 0.95-0.85 (m, 1H), 0.58 (d, J = 7.6 Hz, 2H), 0.30-0.20 (m, 2H).

實例 91      [5-(1- 環丁基乙基 )-1H- 吡唑 -3- 基 ][(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 N'-[(1E)-1- 環丁基亞乙基 ]-4- 甲基苯磺醯肼在25℃下攪拌1-環丁基乙酮(350 mg，3.57 mmol)及TsNHNH ₂(664.16 mg，3.57 mmol)於MeOH (7 mL)中之溶液4小時。藉由減小壓力來濃縮溶劑，得到粗產物。藉由(PE:EtOAc=10:1，10 mL)濕磨粗產物，得到呈白色固體狀之標題化合物(820 mg，3.0785 mmol，86.322%產率)。 ¹H NMR (400 MHz, CDCl ₃) δ ppm 7.86 (d, J =8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 3.10-2.90 (m, 1H), 2.43 (s, 3H), 2.10-2.00 (m, 6H), 1.68 (s, 3H)。 Example 91 [5-(1- cyclobutylethyl )-1H- pyrazol -3- yl ][(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanoneN '-[(1E)-1- cyclobutylethylene ]-4 - Toluenesulfonylhydrazine A solution of 1-cyclobutylethanone (350 mg, 3.57 mmol) and _TsNHNH2 (664.16 mg, 3.57 mmol) in MeOH (7 mL) was stirred at 25 °C for 4 hours. The solvent was concentrated by reducing the pressure to give crude product. The title compound (820 mg, 3.0785 mmol, 86.322% yield) was obtained as a white solid by wet trituration of the crude product (PE:EtOAc=10:1, 10 mL). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.86 (d, J =8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 3.10-2.90 (m, 1H), 2.43 (s, 3H ), 2.10-2.00 (m, 6H), 1.68 (s, 3H).

3-(1- 環丁基乙烯基 )-1-{[2-( 三甲基矽烷基 ) 乙氧基 ] 甲基 }-1H- 吡唑 -5- 羧酸在25℃下於N ₂下向3-溴-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-羧酸甲酯(300 mg，0.89 mmol)、N'-[(1E)-1-環丁基亞乙基]-4-甲基苯磺醯肼(238.34 mg，0.89 mmol)及三級BuOLi (214.89 mg，2.68 mmol)於1,4-二㗁烷(5 mL)中之溶液添加XPhos (42.66 mg，0.09 mmol)及Pd ₂(dba) ₃(40.97 mg，0.04 mmol)。在110℃下攪拌混合物12小時。將混合物傾入H ₂O (10 mL)中，且隨後用1 M HCl將pH調整為4至5且用EtOAc (10 mL×3)萃取。用鹽水(15 mL)洗滌有機相，隨後經無水Na ₂SO ₄乾燥且移除溶劑。藉由SiO ₂管柱層析(PE:EtOAc=1:0至5:1，0.5%FA)純化殘餘物，得到呈黃色油狀之標題化合物(200 mg，0.6202mmol，69.313%產率)。 ¹H NMR (400 MHz, CDCl ₃) δ ppm 7.23 (s, 1H), 7.05 (s, 1H), 5.81 (s, 2H), 5.81 (s, 1H), 3.70-3.60 (m, 2H), 3.00-2.80 (m, 2H), 2.30-1.90 (m, 6H), 1.00-0.90 (m, 2H), 0.03 (s, 9H)。 3-(1- Cyclobutylvinyl )-1-{[2-( trimethylsilyl ) ethoxy ] methyl }-1H- pyrazole -5- carboxylic acid at 25 °C under _N2 To 3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid methyl ester (300 mg, 0.89 mmol), N'-[( 1E)-1-cyclobutylethylene]-4-methylbenzenesulfonylhydrazine (238.34 mg, 0.89 mmol) and tertiary BuOLi (214.89 mg, 2.68 mmol) in 1,4-dioxane (5 mL ) was added XPhos (42.66 mg, 0.09 mmol) and Pd ₂ (dba) ₃ (40.97 mg, 0.04 mmol). The mixture was stirred at 110°C for 12 hours. The mixture was poured into H ₂ O (10 mL), and then the pH was adjusted to 4-5 with 1 M HCl and extracted with EtOAc (10 mL×3). The organic phase was washed with brine (15 mL), then dried over anhydrous Na ₂ SO ₄ and the solvent was removed. The residue was purified by SiO ₂ column chromatography (PE:EtOAc=1:0 to 5:1, 0.5% FA) to give the title compound (200 mg, 0.6202 mmol, 69.313% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.23 (s, 1H), 7.05 (s, 1H), 5.81 (s, 2H), 5.81 (s, 1H), 3.70-3.60 (m, 2H), 3.00 -2.80 (m, 2H), 2.30-1.90 (m, 6H), 1.00-0.90 (m, 2H), 0.03 (s, 9H).

3-(1- 環丁基乙基 )-1-{[2-( 三甲基矽烷基 ) 乙氧基 ] 甲基 }-1H- 吡唑 -5- 羧酸在N ₂下向3-(1-環丁基乙烯基)-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-羧酸(200 mg，0.62 mmol)於MeOH (4 mL)中之溶液添加Pd/C (100 mg)。在25℃下於H ₂(15 psi)下攪拌混合物12小時。經由矽藻土過濾混合物且濃縮濾液，得到呈無色油狀之標題化合物(200 mg，0.6164 mmol，99.377%產率)。粗物質直接用於下一步驟。 ¹H NMR (400 MHz, CDCl ₃) δ ppm 6.77 (s, 2H), 5.80-5.70 (m, 2H), 3.60-3.50 (m, 2H), 2.80-2.70 (m, 1H), 2.45-2.30 (m, 1H), 2.20-2.00 (m, 1H), 1.80-1.60 (m, 5H), 1.43 (d, J = 6.8 Hz, 3H), 0.80-0.70 (m, 2H), 0.06 (s, 9H)。 3-(1- cyclobutylethyl )-1-{[2-( trimethylsilyl ) ethoxy ] methyl }-1H- pyrazole -5- carboxylic acid to _3- ( 1-cyclobutylvinyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid (200 mg, 0.62 mmol) in MeOH (4 mL) was added Pd/C (100 mg). The mixture was stirred under _H2 (15 psi) at 25 °C for 12 h. The mixture was filtered through celite and the filtrate was concentrated to afford the title compound (200 mg, 0.6164 mmol, 99.377% yield) as a colorless oil. The crude material was used directly in the next step. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.77 (s, 2H), 5.80-5.70 (m, 2H), 3.60-3.50 (m, 2H), 2.80-2.70 (m, 1H), 2.45-2.30 ( m, 1H), 2.20-2.00 (m, 1H), 1.80-1.60 (m, 5H), 1.43 (d, J = 6.8 Hz, 3H), 0.80-0.70 (m, 2H), 0.06 (s, 9H) .

3-(1- 環丁基乙基 )-1H- 吡唑 -5- 羧酸甲酯在25℃下向3-(1-環丁基乙基)-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑-5-羧酸(100 mg，0.310 mmol)於MeOH (4 mL)中之溶液添加TFA (175.69 mg，1.54 mmol)。在60℃下攪拌混合物12小時。在70 ℃下攪拌混合物6小時。濃縮混合物，得到呈黃色油狀之粗標題化合物(100 mg，0.2881 mmol，93.486%產率)。粗物質直接用於下一步驟。 LC-MS方法1: 0.818 min, MS (m/z) 209.1 (M + H ⁺)。 3-(1- cyclobutylethyl )-1H- pyrazole -5- carboxylic acid methyl ester at 25 ° C to 3-(1-cyclobutylethyl)-1-{[2-(trimethyl To a solution of silyl)ethoxy]methyl}-1H-pyrazole-5-carboxylic acid (100 mg, 0.310 mmol) in MeOH (4 mL) was added TFA (175.69 mg, 1.54 mmol). The mixture was stirred at 60°C for 12 hours. The mixture was stirred at 70°C for 6 hours. The mixture was concentrated to afford the crude title compound (100 mg, 0.2881 mmol, 93.486% yield) as a yellow oil. The crude material was used directly in the next step. LC-MS method 1: 0.818 min, MS (m/z) 209.1 (M + H ⁺ ).

3-(1- 環丁基乙基 )-1H- 吡唑 -5- 羧酸向3-(1-環丁基乙基)-1H-吡唑-5-羧酸甲酯(100 mg，0.480 mmol)於THF (1 mL)及H ₂O (2 mL)中之溶液添加LiOH·H ₂O (80.59 mg，1.92 mmol)。在20℃下攪拌混合物2小時。用H ₂O (10 mL)稀釋混合物，用1 M HCl將pH調整為4至5且用EA (10mL × 3)萃取。合併之有機層經Na ₂SO ₄乾燥且溶劑經移除，得到呈黃色油狀之標題化合物(80 mg，0.4119 mmol，85.779%產率)。 ¹H NMR (400 MHz, CDCl ₃) δ ppm 0.66 (s, 1H), 2.90-2.70 (m, 1H), 2.50-2.30 (m, 1H), 2.00-1.50 (m, 6H), 1.25 (d, J = 6.8 Hz, 3H)。 3-(1- cyclobutylethyl )-1H- pyrazole -5- carboxylic acid to 3-(1-cyclobutylethyl)-1H-pyrazole-5-carboxylic acid methyl ester (100 mg, 0.480 mmol) in THF (1 mL) and _H2O (2 mL) was added LiOH· _H2O (80.59 mg, 1.92 mmol). The mixture was stirred at 20°C for 2 hours. The mixture was diluted with H ₂ O (10 mL), the pH was adjusted to 4-5 with 1 M HCl and extracted with EA (10 mL×3). The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed to give the title compound (80 mg, 0.4119 mmol, 85.779% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.66 (s, 1H), 2.90-2.70 (m, 1H), 2.50-2.30 (m, 1H), 2.00-1.50 (m, 6H), 1.25 (d, J = 6.8 Hz, 3H).

[5-(1- 環丁基乙基 )-1H- 吡唑 -3- 基 ][(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向3-(1-環丁基乙基)-1H-吡唑-5-羧酸(120 mg，0.62 mmol)及EDCI (130 mg，0.68 mmol)於吡啶(5 mL)中之溶液添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(120 mg，0.67 mmol)。在20℃下攪拌混合物2小時。濃縮反應混合物，得到殘餘物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈白色固體狀之標題化合物(10 mg，0.028 mmol)。 LC-MS方法1: 357.1 [M+H ⁺] ¹H NMR (400 MHz, CDCl ₃) δ ppm 6.44 (s, 1 H) 4.32 (d, J=11.6 Hz, 1 H) 4.20 (d, J=12.6 Hz, 1 H) 3.92 (dd, J=11.4, 4.3 Hz, 1 H) 3.65 (dd, J=12.6, 4.3 Hz, 1 H) 3.60 - 3.70 (m, 1 H)2.82- 2.78 (m, 1 H) 2.66 (s, 2 H) 2.35 - 2.46 (m, 1 H) 1.73 - 2.17 (m, 8 H) 1.44 (t, J=3.4 Hz, 1 H) 1.38 (s, 6 H) 1.18 (d, J=7.0 Hz, 3 H) [5-(1- cyclobutylethyl )-1H- pyrazol -3- yl ][(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1 , 2-( azol- 3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 3-(1-cyclobutylethyl)-1H-pyrazole-5-carboxy A solution of acid (120 mg, 0.62 mmol) and EDCI (130 mg, 0.68 mmol) in pyridine (5 mL) was added to (1R,5S,6r)-6-(5,5-dimethyl-4,5- Dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane TFA salt (120 mg, 0.67 mmol). The mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC ( _NH3 ) to give the title compound (10 mg, 0.028 mmol) as a white solid. LC-MS method 1: 357.1 [M+H ⁺ ] ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.44 (s, 1 H) 4.32 (d, J=11.6 Hz, 1 H) 4.20 (d, J= 12.6 Hz, 1 H) 3.92 (dd, J=11.4, 4.3 Hz, 1 H) 3.65 (dd, J=12.6, 4.3 Hz, 1 H) 3.60 - 3.70 (m, 1 H)2.82- 2.78 (m, 1 H) 2.66 (s, 2 H) 2.35 - 2.46 (m, 1 H) 1.73 - 2.17 (m, 8 H) 1.44 (t, J=3.4 Hz, 1 H) 1.38 (s, 6 H) 1.18 (d, J=7.0Hz, 3H)

實例 92      (5- 環丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 環丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-環丙基-1H-吡唑-3-羧酸(23.0 mg，0.151 mmol)及HATU (57.5 mg，0.151 mmol)於THF (0.76 mL)中之經攪拌溶液添加DIPEA (0.13 mL，0.756 mmol)。在50℃下攪拌30 min之後，添加(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(36.0 mg，0.166 mmol)且在50℃下攪拌反應物1小時，得到黃色溶液。添加H ₂O且用DCM對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(EtOAc/DCM = 99/1至80/20)來純化粗物質，得到呈米色粉末狀之標題化合物(14.7 mg，0.047 mmol，47.5%產率)。 LC-MS方法1: 315.0[M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 6.30 (s, 1H), 4.23 (d. J=11.7 Hz, 1H), 4.18 (d. J=12.9 Hz, 1H), 3.88 (dd, J=11.1, 4.2 Hz, 1H), 3.64 (dd, J=12.9, 4.5 Hz, 1H), 2.65 (s, 2H), 2.15-2.01 (m, 2H), 1.92-1.87 (m, 1H),1.42 (t, J=3.0 Hz, 1H), 1.37 (s, 6H), 0.99-0.94 (m, 2H), 0.77-0.72 (m, 2H) Example 92 (5- cyclopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- 㗁Azol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (5- cyclopropyl-1H - pyrazol -3- yl )[(1R,5S,6r)- 6-(5,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 5 - To a stirred solution of cyclopropyl-1H-pyrazole-3-carboxylic acid (23.0 mg, 0.151 mmol) and HATU (57.5 mg, 0.151 mmol) in THF (0.76 mL) was added DIPEA (0.13 mL, 0.756 mmol) . After stirring at 50°C for 30 min, (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3- Azabicyclo[3.1.0]hexane hydrochloride (36.0 mg, 0.166 mmol) and the reaction was stirred at 50 °C for 1 hour gave a yellow solution. _H2O was added and it was extracted with DCM. _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (EtOAc/DCM = 99/1 to 80/20) to afford the title compound (14.7 mg, 0.047 mmol, 47.5% yield) as a beige powder. LC-MS method 1: 315.0[M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 6.30 (s, 1H), 4.23 (d. J=11.7 Hz, 1H), 4.18 (d. J= 12.9 Hz, 1H), 3.88 (dd, J=11.1, 4.2 Hz, 1H), 3.64 (dd, J=12.9, 4.5 Hz, 1H), 2.65 (s, 2H), 2.15-2.01 (m, 2H), 1.92-1.87 (m, 1H), 1.42 (t, J=3.0 Hz, 1H), 1.37 (s, 6H), 0.99-0.94 (m, 2H), 0.77-0.72 (m, 2H)

實例 93      (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向(1R,5S,6r)-6-(5-甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(50 mg，0.3000mmol)於DMF (0.50 mL)中之混合物添加DIPEA (0.2mL，1.2mmol)、5-異丙基-1H-吡唑-3-羧酸(46.38mg，0.3000mmol)及HATU (148.6mg，0.3900mmol)。在20℃下攪拌所得混合物16小時，得到褐色混合物。TLC (PE/EA=0/1)展示新樣點且反應物完全耗盡。用H ₂O (5 mL)稀釋反應混合物，用EtOAc (5mL×2)萃取，且隨後用H ₂O (5 mL)及鹽水(5mL×2)洗滌。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到粗產物。藉由製備型HPLC (NH ₃)純化粗產物，得到呈白色固體狀之標題化合物(2.11mg，0.0070mmol，2.3198%產率)。 ¹H NMR (400MHz, CDCl ₃) δ = 6.40 (s, 1H), 4.63 - 4.56 (m, 1H), 4.23 (br d, J=11.3 Hz, 1H), 4.13 (d, J=12.8 Hz, 1H), 3.84 (dd, J=4.3, 11.5 Hz, 1H), 3.58 (dd, J=4.0, 12.8 Hz, 1H), 2.98 - 2.88 (m, 2H), 2.47 - 2.38 (m, 1H), 2.08 (br d, J=3.5 Hz, 1H), 1.98 (br s, 1H), 1.28 - 1.20 (m, 12H) Example 93 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(5- methyl -4,5- dihydro -1,2- oxazol -3 -yl ) -3- azabicyclo [3.1.0] hex -3- yl ] methanone (5- isopropyl- 1H- pyrazol -3- yl )[(1R,5S,6r)-6-( 5- methyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to (1R,5S,6r) -6-(5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (50 mg, 0.3000mmol) To a mixture in DMF (0.50 mL) was added DIPEA (0.2 mL, 1.2 mmol), 5-isopropyl-1H-pyrazole-3-carboxylic acid (46.38 mg, 0.3000 mmol) and HATU (148.6 mg, 0.3900 mmol) . The resulting mixture was stirred at 20°C for 16 hours to give a brown mixture. TLC (PE/EA=0/1) showed fresh spots and complete consumption of reactants. The reaction mixture was diluted with H ₂ O (5 mL), extracted with EtOAc (5 mL×2), and then washed with H ₂ O (5 mL) and brine (5 mL×2). The combined organic layers were separated, then dried over _Na2SO4 and concentrated in vacuo to give _crude product. The crude product was purified by preparative HPLC ( _NH3 ) to afford the title compound (2.11 mg, 0.0070 mmol, 2.3198% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ = 6.40 (s, 1H), 4.63 - 4.56 (m, 1H), 4.23 (br d, J =11.3 Hz, 1H), 4.13 (d, J =12.8 Hz, 1H ), 3.84 (dd, J =4.3, 11.5 Hz, 1H), 3.58 (dd, J =4.0, 12.8 Hz, 1H), 2.98 - 2.88 (m, 2H), 2.47 - 2.38 (m, 1H), 2.08 ( br d, J =3.5 Hz, 1H), 1.98 (br s, 1H), 1.28 - 1.20 (m, 12H)

實例 94      {(1R,5S,6r)-6-[5,5- 二甲基 -4-(3- 甲基苯基 )-4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 (1R,5S,6r)-6-[5,5- 二甲基 -4-(3- 甲基苯基 )-4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(220 mg，0.8400mmol)及1-甲基-3-(2-甲基-1-丙烯-1-基)苯(246.78mg，1.69mmol)於DCM (5mL)中之溶液添加三乙胺(0.23mL，1.69mmol)。在10℃下攪拌反應混合物16小時，得到黃色溶液。TLC (PE/EA =3/1 Rf =0.7)展示偵測到新樣點。添加H ₂O (15 mL)且用EtOAc (15 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(PE/EA=1/0至3/1)來純化粗物質，得到呈黃色油狀之標題化合物(120mg，0.3239mmol，38.385%產率)。 ¹H NMR (400 MHz, 氯仿-d) δ 7.40-7.30 (m, 1H), 7.20-7.10 (m, 1H), 6.80-6.70 (m, 2H), 3.62 (s, 1H), 3.55-3.35 (m, 2H), 3.35-3.20 (m, 2H), 2.29 (s, 3H), 1.70-1.60 (m, 1H), 1.32 (s, 9H), 1.108 (s, 3H), 0.86 (s, 3H), 0.60-0.50 (m, 2H)。 Example 94 {(1R,5S,6r)-6-[5,5- dimethyl -4-(3- methylphenyl )-4,5- dihydro -1,2- oxazol -3- yl ]-3- Azabicyclo [3.1.0] hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone (1R,5S,6r)-6-[5,5 -Dimethyl -4-(3- methylphenyl )-4,5- dihydro -1,2- oxazol -3- yl ]-3- azabicyclo [ 3.1.0] hexane -3- Carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate A solution of tert-butyl acid ester (220 mg, 0.8400 mmol) and 1-methyl-3-(2-methyl-1-propen-1-yl)benzene (246.78 mg, 1.69 mmol) in DCM (5 mL) Triethylamine (0.23 mL, 1.69 mmol) was added. The reaction mixture was stirred at 10 °C for 16 hours to obtain a yellow solution. TLC (PE/EA =3/1 Rf =0.7) showed detection of new samples. H ₂ O (15 mL) was added and it was extracted with EtOAc (15 mL×2). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (PE/EA = 1/0 to 3/1) to give the title compound (120 mg, 0.3239 mmol, 38.385% yield) as a yellow oil. ¹ H NMR (400 MHz, chloroform-d) δ 7.40-7.30 (m, 1H), 7.20-7.10 (m, 1H), 6.80-6.70 (m, 2H), 3.62 (s, 1H), 3.55-3.35 ( m, 2H), 3.35-3.20 (m, 2H), 2.29 (s, 3H), 1.70-1.60 (m, 1H), 1.32 (s, 9H), 1.108 (s, 3H), 0.86 (s, 3H) , 0.60-0.50 (m, 2H).

(1R,5S,6r)-6-[5,5- 二甲基 -4-(3- 甲基苯基 )-4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽在10℃下攪拌(1R,5S,6r)-6-[5,5-二甲基-4-(3-甲基苯基)-4,5-二氫-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(120 mg，0.3200mmol)於HCl/二㗁烷(2 mL，0.3200mmol)中之溶液3小時，得到黃色溶液。在真空中蒸發該溶液，得到呈黃色油狀之標題化合物(110mg，0.3585mmol，110.69%產率)。 (1R,5S,6r)-6-[5,5- Dimethyl- 4-(3- methylphenyl )-4,5- dihydro -1,2- oxazol -3- yl ]-3 -Azabicyclo [3.1.0] hexane TFA salt Stirring (1R,5S,6r)-6-[5,5-dimethyl-4-(3-methylphenyl)-4 at 10° C , 5-Dihydro-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (120 mg, 0.3200mmol) in HCl/di A solution in alkanes (2 mL, 0.3200 mmol) for 3 hours gave a yellow solution. The solution was evaporated in vacuo to afford the title compound (110 mg, 0.3585 mmol, 110.69% yield) as a yellow oil.

{(1R,5S,6r)-6-[5,5- 二甲基 -4-(3- 甲基苯基 )-4,5- 二氫 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向5-異丙基-1H-吡唑-3-羧酸(12 mg，0.0800mmol)及N-乙基-N-異丙基丙-2-胺(0.04mL，0.2300mmol)於DMF (1mL)中之溶液添加HATU (32.73mg，0.0900mmol)。在攪拌30 min之後，添加(1R,5S,6r)-6-[5,5-二甲基-4-(3-甲基苯基)-4,5-二氫-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷TFA鹽(20.3mg，0.0700mmol)，攪拌16小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (FA)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(1.25mg，0.0031mmol，3.9505%產率)。 LC-MS 方法 1: 407.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ 7.22 (d, J=7.50 Hz, 1H), 7.11 (br d, J=7.38 Hz, 1H), 6.81-6.87 (m, 2H), 6.40 (s, 1H), 4.10-4.20 (m, 1H), 3.98-4.08 (m, 1H), 3.84 (ddd, J=4.44, 11.29, 19.54 Hz, 1H), 3.70 (d, J=3.00 Hz, 1H), 3.57 (td, J=4.60, 12.57 Hz, 1H), 2.99 (td, J=6.86, 13.91 Hz, 1H), 2.35 (s, 3H), 2.29 (td, J=3.86, 7.41 Hz, 1H), 2.13 (td, J=3.77, 7.35 Hz, 1H), 2.01 (td, J=3.81, 7.13 Hz, 1H), 1.89 (td, J=3.85, 7.32 Hz, 1H), 1.39 (s, 3H), 1.27 (d, J=7.00 Hz, 6H), 0.94 (s, 3H) {(1R,5S,6r)-6-[5,5- Dimethyl- 4-(3- methylphenyl )-4,5- dihydro -1,2- oxazol -3- yl ]- 3- Azabicyclo [3.1.0] hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone to 5-isopropyl-1H-pyrazole-3-carboxylic acid (12 mg, 0.0800 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.04 mL, 0.2300 mmol) in DMF (1 mL) was added HATU (32.73 mg, 0.0900 mmol). After stirring for 30 min, (1R,5S,6r)-6-[5,5-dimethyl-4-(3-methylphenyl)-4,5-dihydro-1,2-oxazole was added -3-yl]-3-azabicyclo[3.1.0]hexane TFA salt (20.3 mg, 0.0700 mmol), stirred for 16 hours to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC (FA). The resulting fluid was concentrated in vacuo to remove most of the _CH3CN and lyophilized to give the title compound (1.25 mg, 0.0031 mmol, 3.9505% yield) as a white solid. LC-MS method 1 : 407.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ 7.22 (d, J =7.50 Hz, 1H), 7.11 (br d, J =7.38 Hz, 1H), 6.81-6.87 (m, 2H), 6.40 (s, 1H), 4.10-4.20 (m, 1H), 3.98-4.08 (m, 1H), 3.84 (ddd, J =4.44, 11.29, 19.54 Hz, 1H), 3.70 (d, J =3.00 Hz, 1H), 3.57 (td, J =4.60, 12.57 Hz, 1H), 2.99 (td, J =6.86, 13.91 Hz, 1H), 2.35 (s, 3H), 2.29 (td , J =3.86, 7.41 Hz, 1H), 2.13 (td, J =3.77, 7.35 Hz, 1H), 2.01 (td, J =3.81, 7.13 Hz, 1H), 1.89 (td, J =3.85, 7.32 Hz, 1H), 1.39 (s, 3H), 1.27 (d, J =7.00 Hz, 6H), 0.94 (s, 3H)

實例 95      (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向100 ml圓底燒瓶裝入5-異丙基-1H-吡唑-3-羧酸(125 mg，0.8100mmol)、HATU (371.96mg，0.9700mmol)、DMF (4mL)、N-乙基-N-異丙基丙-2-胺(0.42mL，2.43mmol)及DMF (4mL)。在攪拌30 min之後，添加6-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-4-氧雜-5-氮雜螺[2.4]庚-5-烯氫氯化物(236.95mg，0.8100mmol)。在10℃下攪拌反應混合物16小時，得到黃色溶液。添加H ₂O (20 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (FA)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(36.35mg，0.1156mmol，14.261%產率)。 LC-MS方法1: 315.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ 6.48 (s, 1H), 4.29-4.34 (m, 1H), 4.21 (d, J=12.55 Hz, 1H), 3.93 (dd, J=4.52, 11.54 Hz, 1H), 3.66 (dd, J=4.39, 12.67 Hz, 1H), 3.00-3.06 (m, 1H), 2.98 (s, 2H), 2.19 (td, J=3.58, 7.40 Hz, 1H), 2.08 (td, J=3.89, 7.28 Hz, 1H), 1.50 (t, J=3.39 Hz, 1H), 1.30 (d, J=7.03 Hz, 6H), 1.09-1.14 (m, 2H), 0.65-0.74 (m, 2H) Example 95 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(4- oxa -5- azaspiro [2.4] hept -5 - ene -6 -yl ) -3- azabicyclo [3.1.0] hex -3- yl ] methanone (5- isopropyl- 1H- pyrazol -3- yl )[(1R,5S,6r)-6-( Charge 4- oxa -5- azaspiro [2.4] hept -5 - en -6- yl )-3- azabicyclo [3.1.0] hex - 3- yl ] methanone into a 100 ml round bottom flask 5-Isopropyl-1H-pyrazole-3-carboxylic acid (125 mg, 0.8100mmol), HATU (371.96mg, 0.9700mmol), DMF (4mL), N-ethyl-N-isopropylpropane-2 - Amine (0.42 mL, 2.43 mmol) and DMF (4 mL). After stirring for 30 min, 6-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept- 5-ene hydrochloride (236.95 mg, 0.8100 mmol). The reaction mixture was stirred at 10 °C for 16 hours to obtain a yellow solution. H ₂ O (20 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC (FA). The obtained fluid was concentrated in vacuo to remove most of _CH3CN and lyophilized to give the title compound (36.35 mg, 0.1156 mmol, 14.261% yield) as a white solid. LC-MS method 1: 315.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ 6.48 (s, 1H), 4.29-4.34 (m, 1H), 4.21 (d, J =12.55 Hz, 1H), 3.93 (dd, J =4.52, 11.54 Hz, 1H), 3.66 (dd, J =4.39, 12.67 Hz, 1H), 3.00-3.06 (m, 1H), 2.98 (s, 2H), 2.19 (td , J =3.58, 7.40 Hz, 1H), 2.08 (td, J =3.89, 7.28 Hz, 1H), 1.50 (t, J =3.39 Hz, 1H), 1.30 (d, J =7.03 Hz, 6H), 1.09 -1.14 (m, 2H), 0.65-0.74 (m, 2H)

實例 96      (5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[(1S,5S)-2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯 -4- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[(1S,5S)-2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯 -4- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮將12 mg之(5-異丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-(2-氧雜-3-氮雜雙環[3.1.0]己-3-烯-4-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮(實例97)送去用於SFC對掌性分離，得到標題化合物(4.95 mg)。 LC-MS方法1: 301.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 10.27 (1 H, br s), 6.41 (1 H, s), 4.79 (1 H, td, J=5.33, 2.13 Hz), 4.27 (1 H, br d, J=11.04 Hz), 4.16 (1 H, dd, J=12.67, 1.38 Hz), 3.82 - 3.93 (1 H, m), 3.60 (1 H, br dd, J=12.55, 5.02 Hz), 2.95 (1 H, spt, J=6.94 Hz), 2.25 - 2.36 (1 H, m), 2.13 - 2.21 (1 H, m), 2.08 (1 H, br s), 1.96 - 2.21 (1 H, m), 1.96 - 2.03 (1 H, m), 1.57 (1 H, t, J=3.39 Hz), 1.23 (6 H, d, J=7.03 Hz), 0.81 (1 H, dt, J=9.29, 5.52 Hz), 0.24 (1 H, br d, J=2.51 Hz) Example 96 (5- isopropyl -1H- pyrazol -3- yl ){(1R,5S,6r)-6-[(1S,5S)-2- oxa -3- azabicyclo [3.1.0 ] hex - 3- en -4- yl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone (5- isopropyl -1H- pyrazol -3- yl ){(1R, 5S,6r)-6-[(1S,5S)-2- oxa -3- azabicyclo [3.1.0] hex -3- en -4- yl ]-3- azabicyclo [3.1.0] Hex -3- yl } methanone with 12 mg of (5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo [3.1.0]hex-3-en-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone (Example 97) was sent for chiral separation by SFC to give the title Compound (4.95 mg). LC-MS method 1: 301.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 10.27 (1 H, br s), 6.41 (1 H, s), 4.79 (1 H, td, J=5.33, 2.13 Hz), 4.27 (1 H, br d, J=11.04 Hz), 4.16 (1 H, dd, J=12.67, 1.38 Hz), 3.82 - 3.93 (1 H, m), 3.60 (1 H, br dd, J=12.55, 5.02 Hz), 2.95 (1 H, spt, J=6.94 Hz), 2.25 - 2.36 (1 H, m), 2.13 - 2.21 (1 H, m), 2.08 (1 H , br s), 1.96 - 2.21 (1 H, m), 1.96 - 2.03 (1 H, m), 1.57 (1 H, t, J=3.39 Hz), 1.23 (6 H, d, J=7.03 Hz) , 0.81 (1 H, dt, J=9.29, 5.52 Hz), 0.24 (1 H, br d, J=2.51 Hz)

實例 97      (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯 -4- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(2- 氧雜 -3- 氮雜雙環 [3.1.0] 己 -3- 烯 -4- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-異丙基-1H-吡唑-3-羧酸(25.82mg，0.1700mmol)於DMF (2.0833mL)中之溶液添加HATU (75.67mg，0.2000mmol)及DIPEA (0.08mL，0.4600mmol)。在25℃下攪拌混合物30 min。隨後向混合物添加4-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-2-氧雜-3-氮雜雙環[3.1.0]己-3-烯(25 mg，0.1500mmol)。在25℃下攪拌混合物3小時，得到褐色溶液。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈白色固體狀之標題化合物(21.39mg，0.0712mmol，46.774%產率)。 LC-MS方法1: 301.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 10.27 (1 H, br s), 6.41 (1 H, s), 4.79 (1 H, td, J=5.33, 2.13 Hz), 4.27 (1 H, br d, J=11.04 Hz), 4.16 (1 H, dd, J=12.67, 1.38 Hz), 3.82 - 3.93 (1 H, m), 3.60 (1 H, br dd, J=12.55, 5.02 Hz), 2.95 (1 H, spt, J=6.94 Hz), 2.25 - 2.36 (1 H, m), 2.13 - 2.21 (1 H, m), 2.08 (1 H, br s), 1.96 - 2.21 (1 H, m), 1.96 - 2.03 (1 H, m), 1.57 (1 H, t, J=3.39 Hz), 1.23 (6 H, d, J=7.03 Hz), 0.81 (1 H, dt, J=9.29, 5.52 Hz), 0.24 (1 H, br d, J=2.51 Hz) Example 97 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(2- oxa -3- azabicyclo [3.1.0] hex -3- ene -4- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (5- isopropyl- 1H- pyrazol -3- yl )[(1R,5S,6r)-6 -(2- Oxa -3- azabicyclo [3.1.0] hex -3 - en -4- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 5-iso To a solution of propyl-1H-pyrazole-3-carboxylic acid (25.82 mg, 0.1700 mmol) in DMF (2.0833 mL) was added HATU (75.67 mg, 0.2000 mmol) and DIPEA (0.08 mL, 0.4600 mmol). The mixture was stirred at 25 °C for 30 min. Then 4-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-2-oxa-3-azabicyclo[3.1.0]hex-3 was added to the mixture -ene (25 mg, 0.1500 mmol). The mixture was stirred at 25°C for 3 hours to give a brown solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (21.39 mg, 0.0712 mmol, 46.774% yield) as a white solid. LC-MS method 1: 301.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 10.27 (1 H, br s), 6.41 (1 H, s), 4.79 (1 H, td, J=5.33, 2.13 Hz), 4.27 (1 H, br d, J=11.04 Hz), 4.16 (1 H, dd, J=12.67, 1.38 Hz), 3.82 - 3.93 (1 H, m), 3.60 (1 H, br dd, J=12.55, 5.02 Hz), 2.95 (1 H, spt, J=6.94 Hz), 2.25 - 2.36 (1 H, m), 2.13 - 2.21 (1 H, m), 2.08 (1 H , br s), 1.96 - 2.21 (1 H, m), 1.96 - 2.03 (1 H, m), 1.57 (1 H, t, J=3.39 Hz), 1.23 (6 H, d, J=7.03 Hz) , 0.81 (1 H, dt, J=9.29, 5.52 Hz), 0.24 (1 H, br d, J=2.51 Hz)

實例 98      [(1R,5S,6r)-6-(4- 異丁基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 [(1R,5S,6r)-6-(4- 異丁基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向(1R,5S,6r)-6-(4-異丁基-5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(300 mg，1.27 mmol)及DIPEA (1.05mL，6.35mmol)於DMF (8.5 mL)中之溶液添加HATU (578 mg，1.52 mmol)及5-異丙基-1H-吡唑-3-羧酸(195 mg，1.27 mmol)，且在20℃下攪拌混合物12小時。LCMS展示偵測到所要質量。將反應混合物傾入H ₂O (30 mL)中且用EtOAc (20 mL×3)萃取。用鹽水(50 mL)洗滌有機相，經無水Na ₂SO ₄乾燥且濃縮，得到殘餘物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈白色固體狀之標題化合物(12 mg，0.03 mmol，2.53%產率)。 LC-MS方法1: 373.2 [M+H ⁺] ¹H NMR (400 MHz, 甲醇- d ₄) δ ppm 0.93 - 1.01 (m, 6 H) 1.19 (d, J=1.6 Hz, 3 H) 1.30 (d, J=6.9 Hz, 9 H) 1.35 (d, J=2.1 Hz, 3 H) 1.41 - 1.49 (m, 2 H) 1.69 - 1.79 (m, 1 H) 1.98 - 2.25 (m, 3 H) 2.95 (br t, J=7.2 Hz, 1 H) 2.99 - 3.08 (m, 1 H) 3.57 - 3.69 (m, 1 H) 3.93 (br d, J=12.0 Hz, 1 H) 4.01 - 4.15 (m, 1 H) 4.37 (br dd, J=11.9, 5.4 Hz, 1 H) 6.45 (s, 1 H) Example 98 [(1R,5S,6r)-6-(4- isobutyl -5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- nitrogen Heterobicyclo [3.1.0] hex-3 - yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone [(1R,5S,6r)-6-(4- isobutyl -5 ,5- Dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H -Pyrazol -3- yl ) methanone to (1R,5S,6r)-6-(4-isobutyl-5,5-dimethyl-4,5-dihydro - 1,2-oxazole- To a solution of 3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (300 mg, 1.27 mmol) and DIPEA (1.05 mL, 6.35 mmol) in DMF (8.5 mL) was added HATU (578 mg , 1.52 mmol) and 5-isopropyl-1H-pyrazole-3-carboxylic acid (195 mg, 1.27 mmol), and the mixture was stirred at 20°C for 12 hours. LCMS showed detection of desired mass. The reaction mixture was poured into H ₂ O (30 mL) and extracted with EtOAc (20 mL×3). The organic phase was washed with brine (50 mL), dried over anhydrous Na ₂ SO ₄ and concentrated to give a residue. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (12 mg, 0.03 mmol, 2.53% yield) as a white solid. LC-MS method 1: 373.2 [M+H ⁺ ] ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 0.93 - 1.01 (m, 6 H) 1.19 (d, J =1.6 Hz, 3 H) 1.30 ( d, J =6.9 Hz, 9 H) 1.35 (d, J =2.1 Hz, 3 H) 1.41 - 1.49 (m, 2 H) 1.69 - 1.79 (m, 1 H) 1.98 - 2.25 (m, 3 H) 2.95 (br t, J =7.2 Hz, 1 H) 2.99 - 3.08 (m, 1 H) 3.57 - 3.69 (m, 1 H) 3.93 (br d, J =12.0 Hz, 1 H) 4.01 - 4.15 (m, 1 H) 4.37 (br dd, J =11.9, 5.4 Hz, 1 H) 6.45 (s, 1 H)

實例 99      (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-異丙基-1H-吡唑-3-羧酸(39.68mg，0.2600mmol)於DMF (0.4639mL)中之混合物添加HATU (127.91mg，0.3300mmol)及DIPEA (0.21mL，1.29mmol)。在50℃下加熱混合物30 min。添加(1R,5S,6r)-6-(4,5,5-三甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(50 mg，0.2600mmol)。在20℃下攪拌所得混合物4小時。用H ₂O (10mL)稀釋反應混合物，用EtOAc (10mL×2)萃取，且隨後用鹽水(10mL)洗滌。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型HPLC (NH ₃)純化粗物質油且凍乾，得到呈白色固體狀之標題化合物(4.91mg，0.0149mmol，5.7737%產率)。 ¹H NMR (400MHz, MeOD) δ = 6.47 (s, 1H), 4.39 (br d, J=12.0 Hz, 1H), 4.12 (dd, J=5.4, 12.7 Hz, 1H), 3.95 (br d, J=12.5 Hz, 1H), 3.64 (br d, J=12.8 Hz, 1H), 3.16 - 3.01 (m, 1H), 2.92 (q, J=7.2 Hz, 1H), 2.25 - 2.00 (m, 2H), 1.37 (br s, 1H), 1.36 - 1.27 (m, 12H), 1.22 (s, 3H) Example 99 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(4,5,5- trimethyl -4,5- dihydro -1,2 -Zazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (5- isopropyl -1H- pyrazol - 3- yl )[(1R,5S,6r )-6-(4,5,5- trimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] Methanone To a mixture of 5-isopropyl-1H-pyrazole-3-carboxylic acid (39.68 mg, 0.2600 mmol) in DMF (0.4639 mL) was added HATU (127.91 mg, 0.3300 mmol) and DIPEA (0.21 mL, 1.29 mmol). The mixture was heated at 50 °C for 30 min. Add (1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0 ] Hexane TFA salt (50 mg, 0.2600 mmol). The resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with H ₂ O (10 mL), extracted with EtOAc (10 mL×2), and then washed with brine (10 mL). The combined organic _layers were separated, then dried over _Na2SO4 and concentrated in vacuo to give a crude oil. The crude oil was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (4.91 mg, 0.0149 mmol, 5.7737% yield) as a white solid. ¹ H NMR (400MHz, MeOD) δ = 6.47 (s, 1H), 4.39 (br d, J =12.0 Hz, 1H), 4.12 (dd, J =5.4, 12.7 Hz, 1H), 3.95 (br d, J =12.5 Hz, 1H), 3.64 (br d, J =12.8 Hz, 1H), 3.16 - 3.01 (m, 1H), 2.92 (q, J =7.2 Hz, 1H), 2.25 - 2.00 (m, 2H), 1.37 (br s, 1H), 1.36 - 1.27 (m, 12H), 1.22 (s, 3H)

實例 100    [(1R,5S,6r)-6-(5- 乙基 -5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 [(1R,5S,6r)-6-(5- 乙基 -5- 甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向5-異丙基-1H-吡唑-3-羧酸(23.81mg，0.1500mmol)於DMF (0.2783mL)中之混合物添加HATU (76.75mg，0.2000mmol)、DIPEA (0.13mL，0.7700mmol)及(1R,5S,6r)-6-(5-乙基-5-甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(30 mg，0.1500mmol)。在20℃下攪拌所得混合物4小時。用H ₂O (5 mL)稀釋反應混合物，用EtOAc (5mL×2)萃取，且隨後用鹽水(8mL)洗滌。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型HPLC (NH ₃)純化粗物質油且凍乾，得到呈白色固體狀之標題化合物(1.82mg，0.0055mmol，3.5669%產率)。 ¹H NMR (400MHz, MeOD) δ = 6.47 (br s, 1H), 4.37 (br s, 1H), 4.12 (d, J=12.8 Hz, 1H), 3.95 (dd, J=3.8, 12.3 Hz, 1H), 3.64 (dd, J=4.4, 12.4 Hz, 1H), 3.08 - 3.01 (m, 1H), 2.87 - 2.74 (m, 1H), 2.73 - 2.59 (m, 1H), 2.19 - 2.04 (m, 2H), 1.68 - 1.60 (m, 2H), 1.52 - 1.48 (m, 1H), 1.32 - 1.30 (m, 9H), 0.94 (t, J=7.5 Hz, 3H) Example 100 [(1R,5S,6r)-6-(5- Ethyl -5- methyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1 .0] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone [(1R,5S,6r)-6-(5- ethyl - 5- methyl -4 ,5- Dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) Methanone To a mixture of 5-isopropyl-1H-pyrazole-3-carboxylic acid (23.81 mg, 0.1500 mmol) in DMF (0.2783 mL) was added HATU (76.75 mg, 0.2000 mmol), DIPEA (0.13 mL, 0.7700 mmol) and (1R,5S,6r)-6-(5-ethyl-5-methyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1 .0] Hexane TFA salt (30 mg, 0.1500 mmol). The resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was diluted with H ₂ O (5 mL), extracted with EtOAc (5 mL×2), and then washed with brine (8 mL). The combined organic _layers were separated, then dried over _Na2SO4 and concentrated in vacuo to give a crude oil. The crude oil was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (1.82 mg, 0.0055 mmol, 3.5669% yield) as a white solid. ¹ H NMR (400MHz, MeOD) δ = 6.47 (br s, 1H), 4.37 (br s, 1H), 4.12 (d, J =12.8 Hz, 1H), 3.95 (dd, J =3.8, 12.3 Hz, 1H ), 3.64 (dd, J =4.4, 12.4 Hz, 1H), 3.08 - 3.01 (m, 1H), 2.87 - 2.74 (m, 1H), 2.73 - 2.59 (m, 1H), 2.19 - 2.04 (m, 2H ), 1.68 - 1.60 (m, 2H), 1.52 - 1.48 (m, 1H), 1.32 - 1.30 (m, 9H), 0.94 (t, J =7.5 Hz, 3H)

實例 101    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(4- 甲氧基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(4- 甲氧基 -5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-異丙基-1H-吡唑-3-羧酸(49.12mg，0.3200mmol)於DMF (2.393mL)中之溶液添加HATU (91.62mg，0.4800mmol)及DIPEA (0.16mL，0.9600mmol)。在15℃下攪拌反應混合物30 min。隨後向反應物添加(1R,5S,6r)-6-(4-甲氧基-5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(67 mg，0.3200mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (NH ₃)純化反應混合物，得到呈白色粉末狀之標題化合物(43.85mg，0.1266mmol，39.725%產率)。 LC-MS方法1: 347.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 6.48 (s, 1H), 4.31 (br d, J=11.0 Hz, 1H), 4.22 (m, 1H), 4.03 (d, J=16.1 Hz, 1H), 3.93 (m, 1H), 3.66 (m, 1H), 3.45 (s, 3H), 3.02 (m, 1H), 2.30 - 2.19 (m, 1H), 2.11 (m, 1H), 1.47 - 1.42 (m, 1H), 1.35 (s, 3H), 1.30 (d, J=7.0 Hz, 9H) Example 101 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(4- methoxy -5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (5- isopropyl -1H- pyrazol -3- yl )[(1R ,5S,6r)-6-(4- methoxy -5,5- dimethyl -4,5 - dihydro -1,2- oxazol -3- yl )-3- azabicyclo [3.1. 0] Hex -3- yl ] methanone To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (49.12mg, 0.3200mmol) in DMF (2.393mL) was added HATU (91.62mg, 0.4800mmol ) and DIPEA (0.16 mL, 0.9600 mmol). The reaction mixture was stirred at 15 °C for 30 min. (1R,5S,6r)-6-(4-methoxy-5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3 - Azabicyclo[3.1.0]hexane TFA salt (67 mg, 0.3200 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC (NH ₃ ) to afford the title compound (43.85 mg, 0.1266 mmol, 39.725% yield) as a white powder. LC-MS method 1: 347.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 6.48 (s, 1H), 4.31 (br d, J =11.0 Hz, 1H), 4.22 (m, 1H ), 4.03 (d, J =16.1 Hz, 1H), 3.93 (m, 1H), 3.66 (m, 1H), 3.45 (s, 3H), 3.02 (m, 1H), 2.30 - 2.19 (m, 1H) , 2.11 (m, 1H), 1.47 - 1.42 (m, 1H), 1.35 (s, 3H), 1.30 (d, J =7.0 Hz, 9H)

實例 102    (5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[6a- 甲基 -4,5,6,6a- 四氫 -3aH- 環戊 [d][1,2] 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 (1R,5S,6r)-6-[6a- 甲基 -4,5,6,6a- 四氫 -3aH- 環戊 [d][1,2] 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.3800mmol)及1-甲基環戊-1-烯(0.61mL，5.75mmol)於三級丁基甲基醚(4 mL)中之混合物逐滴添加於三級丁基甲基醚(1mL)中之Et ₃N (0.07mL，0.3800mmol)超過1小時。在20℃下攪拌混合物5小時。TLC (PE/EA=3/1)展示主要新樣點(Rf=0.4)且反應完成。用H ₂O (10mL)洗滌混合物且隨後用EtOAc (10mL×2)萃取。合併之有機層經Na ₂SO ₄乾燥且濃縮，得到粗物質油。藉由製備型TLC (PE/EA=3/1)純化粗物質油，得到呈淡黃色固體狀之標題化合物(40mg，0.1305mmol，34.037%產率)。 LC-MS方法1 1.077 min，MS (m/z) 307.1 (M + H ⁺)。 Example 102 (5- isopropyl -1H- pyrazol -3- yl ){(1R,5S,6r)-6-[6a- methyl -4,5,6,6a- tetrahydro -3aH- cyclopenta [d][1,2] oxazol -3- yl ] -3- azabicyclo [3.1.0] hex -3- yl } methanone (1R,5S,6r)-6-[6a- methyl- 4,5,6,6a -tetrahydro -3aH- cyclopenta [d][1,2] oxazol -3- yl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary Butyl ester to (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl A mixture of ester (100 mg, 0.3800 mmol) and 1-methylcyclopent-1-ene (0.61 mL, 5.75 mmol) in tertiary butyl methyl ether (4 mL) was added dropwise to tertiary butyl methyl ether (1 mL ) in _Et3N (0.07 mL, 0.3800 mmol) over 1 h. The mixture was stirred at 20°C for 5 hours. TLC (PE/EA=3/1) showed major new spots (Rf=0.4) and the reaction was complete. The mixture was washed with H ₂ O (10 mL) and then extracted with EtOAc (10 mL×2). The combined organic layers were dried over _Na2SO4 and _concentrated to give a crude oil. The crude oil was purified by prep-TLC (PE/EA=3/1) to give the title compound (40 mg, 0.1305 mmol, 34.037% yield) as a light yellow solid. LC-MS method 1 1.077 min, MS (m/z) 307.1 (M + H ⁺ ).

3-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-6a- 甲基 -4,5,6,6a- 四氫 -3aH- 環戊 [d][1,2] 㗁唑氫氯化物在20℃下攪拌(1R,5S,6r)-6-[6a-甲基-4,5,6,6a-四氫-3aH-環戊[d][1,2]㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(40 mg，0.1300mmol)於HCl/二㗁烷(5 mL，4 M)中之混合物2小時。直接用EA (15mL)將混合物濃縮至乾燥，得到呈淡黃色固體狀之標題化合物(26.9mg，粗產物)。 LC-MS方法1 0.535 min，MS (m/z) 207.0 (M + H ⁺)。 3-[(1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl ]-6a- methyl -4,5,6,6a- tetrahydro -3aH- cyclopenta [d ][1,2] oxazole hydrochloride stirred at 20°C (1R,5S,6r)-6-[6a-methyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d] [1,2]oxazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (40 mg, 0.1300mmol) in HCl/dioxane (5 mL , 4 M) for 2 hours. The mixture was directly concentrated to dryness with EA (15 mL) to give the title compound (26.9 mg, crude) as a light yellow solid. LC-MS method 1 0.535 min, MS (m/z) 207.0 (M + H ⁺ ).

(5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[6a- 甲基 -4,5,6,6a- 四氫 -3aH- 環戊 [d][1,2] 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮向(3aR,6aR)-3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-6a-甲基-4,5,6,6a-四氫-3aH-環戊[d][1,2]㗁唑氫氯化物(26.9mg，0.1300mmol)於DMF (1.5mL)中之混合物添加5-異丙基-1H-吡唑-3-羧酸(20.1mg，0.1300mmol)、DIPEA (0.06mL，0.3900mmol)及HATU (64.42mg，0.1700mmol)，且在20℃下攪拌混合物16小時。TLC (PE/EA=0/1)展示主要新樣點(Rf=0.6)且反應完成。用H ₂O (10 mL)及EA (10mL×2)稀釋混合物。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型TLC (PE/EA=0/1)純化粗物質油，得到呈淡黃色固體狀之標題化合物(28mg，0.0818mmol，62.702%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ = 13.05 - 12.79 (m, 1H), 6.37 (s, 1H), 4.35 (br dd, J=4.0, 12.0 Hz, 1H), 4.01 - 3.91 (m, 1H), 3.82 (br d, J=11.8 Hz, 1H), 3.55 - 3.53 (m, 1H), 3.48 (br d, J=12.8 Hz, 1H), 3.12 (br d, J=3.3 Hz, 1H), 2.97 (td, J=7.1, 13.7 Hz, 1H), 2.09 - 1.94 (m, 1H), 2.07 - 1.90 (m, 1H), 1.90 - 1.73 (m, 4H), 1.68 - 1.49 (m, 3H), 1.42 - 1.30 (m, 4H), 1.22 (d, J=7.0 Hz, 8H)。 (5- isopropyl -1H- pyrazol -3- yl ){(1R,5S,6r)-6-[6a- methyl -4,5,6,6a- tetrahydro -3aH- cyclopenta [d ][1,2] oxazol -3- yl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone to (3aR,6aR)-3-[(1R,5S,6r)- 3-Azabicyclo[3.1.0]hex-6-yl]-6a-methyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,2]oxazole hydrochloride (26.9 mg, 0.1300 mmol) in DMF (1.5 mL) was added 5-isopropyl-1H-pyrazole-3-carboxylic acid (20.1 mg, 0.1300 mmol), DIPEA (0.06 mL, 0.3900 mmol) and HATU (64.42mg, 0.1700mmol), and the mixture was stirred at 20°C for 16 hours. TLC (PE/EA=0/1) showed major new spots (Rf=0.6) and the reaction was complete. The mixture was diluted with H ₂ O (10 mL) and EA (10 mL×2). The combined organic _layers were separated, then dried over _Na2SO4 and concentrated in vacuo to give a crude oil. The crude oil was purified by prep-TLC (PE/EA=0/1) to afford the title compound (28 mg, 0.0818 mmol, 62.702% yield) as a light yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 13.05 - 12.79 (m, 1H), 6.37 (s, 1H), 4.35 (br dd, J =4.0, 12.0 Hz, 1H), 4.01 - 3.91 (m, 1H), 3.82 (br d, J =11.8 Hz, 1H), 3.55 - 3.53 (m, 1H), 3.48 (br d, J =12.8 Hz, 1H), 3.12 (br d, J =3.3 Hz, 1H) , 2.97 (td, J =7.1, 13.7 Hz, 1H), 2.09 - 1.94 (m, 1H), 2.07 - 1.90 (m, 1H), 1.90 - 1.73 (m, 4H), 1.68 - 1.49 (m, 3H) , 1.42 - 1.30 (m, 4H), 1.22 (d, J =7.0 Hz, 8H).

實例 103    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5- 甲基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5- 甲基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向100 mL圓底燒瓶裝入5-異丙基-1H-吡唑-3-羧酸(70 mg，0.4500mmol)、N-乙基-N-異丙基丙-2-胺(0.24mL，1.41mmol)、HATU (190.94mg，0.5000mmol)及DMF (3mL)。在攪拌30 min之後，添加(1R,5S,6r)-6-(5-甲基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(126.33mg，0.4500mmol)。在20℃下攪拌反應混合物16小時，得到黃色溶液。LCMS展示新峰值給出所要ms。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (FA)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(13.52mg，0.0448mmol，9.8741%產率)。 LC-MS方法1: 301.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ 6.48 (br s, 1H), 5.75 (s, 1H), 4.21-4.33 (m, 2H), 3.96 (br dd, J=3.81, 10.94 Hz, 1H), 3.69 (br dd, J=3.69, 12.44 Hz, 1H), 3.04 (td, J=6.83, 13.73 Hz, 1H), 2.36 (s, 3H), 2.15 (br d, J=3.38 Hz, 1H), 2.04-2.09 (m, 1H), 1.75 (t, J=3.06 Hz, 1H), 1.30 (d, J=6.88 Hz, 6H) Example 103 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(5-methyl - 1,2- oxazol -3- yl )-3- nitrogen Heterobicyclo [3.1.0] hex - 3- yl ] methanone (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(5- methyl -1, 2- (azol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone Charge a 100 mL round bottom flask with 5-isopropyl-1H-pyrazole-3-carboxy Acid (70 mg, 0.4500 mmol), N-ethyl-N-isopropylpropan-2-amine (0.24 mL, 1.41 mmol), HATU (190.94 mg, 0.5000 mmol) and DMF (3 mL). After stirring for 30 min, (1R,5S,6r)-6-(5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane TFA salt ( 126.33 mg, 0.4500 mmol). The reaction mixture was stirred at 20 °C for 16 hours to give a yellow solution. LCMS showed the new peak giving the desired ms. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC (FA). The resulting fluid was concentrated in vacuo to remove most of the _CH3CN and lyophilized to afford the title compound (13.52 mg, 0.0448 mmol, 9.8741% yield) as a white solid. LC-MS method 1: 301.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ 6.48 (br s, 1H), 5.75 (s, 1H), 4.21-4.33 (m, 2H), 3.96 (br dd, J =3.81, 10.94 Hz, 1H), 3.69 (br dd, J =3.69, 12.44 Hz, 1H), 3.04 (td, J =6.83, 13.73 Hz, 1H), 2.36 (s, 3H), 2.15 (br d, J =3.38 Hz, 1H), 2.04-2.09 (m, 1H), 1.75 (t, J =3.06 Hz, 1H), 1.30 (d, J =6.88 Hz, 6H)

實例 104    {(1R,5S,6r)-6-[5-( 二氟甲基 )-4- 甲基 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 (1R,5S,6r)-6-[1- 羥丙基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在-78℃下向(1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(500 mg，2.37mmol)於THF (10mL)中之溶液逐滴添加溴基(乙基)鎂(1.6mL，4.73mmol，於Et ₂O中之3M)。將反應物升溫至0℃且攪拌另外20 min，得到淡黃色混合物。用H ₂O (15 mL)淬滅反應物，用EA (30 mL)稀釋且用2 N HCl酸化至pH=5。用EA (20 mL × 2)萃取水層。合併之EA層經Na ₂SO ₄乾燥且真空濃縮，得到呈淡黃色油狀之標題化合物(590mg，2.4448mmol，粗物質)。 Example 104 {(1R,5S,6r)-6-[5-( Difluoromethyl )-4- methyl -1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0] Hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone (1R,5S,6r)-6-[1- hydroxypropyl ]-3- azabicyclo [3.1. 0] tertiary butyl hexane -3- carboxylate to (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid at -78°C A solution of tert-butyl ester (500 mg, 2.37 mmol) in THF (10 mL) was added dropwise with bromo(ethyl)magnesium (1.6 mL, 4.73 mmol, 3M in _Et2O ). The reaction was warmed to 0 °C and stirred for another 20 min to give a pale yellow mixture. The reaction was quenched with H ₂ O (15 mL), diluted with EA (30 mL) and acidified with 2 N HCl to pH=5. The aqueous layer was extracted with EA (20 mL x 2). The combined EA layers were dried over _Na2SO4 and concentrated _in vacuo to give the title compound (590 mg, 2.4448 mmol, crude) as a light yellow oil.

(1R,5S,6r)-6- 丙醯基 -3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-[1-羥丙基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(590 mg，2.44mmol)及NaHCO ₃(410.77mg，4.89mmol)於DCM (25mL)中之混合物添加戴斯-馬丁試劑(1555.4mg，3.67mmol)。在20℃下攪拌混合物12小時，得到白色混合物。用DCM (30 mL)及H ₂O (20 mL)稀釋混合物且用飽和NaHCO ₃鹼化至pH=8。用DCM (20 mL)萃取水層。合併之DCM層經Na ₂SO ₄乾燥且真空濃縮，得到粗產物，藉由快速柱(PE/EA=1/0至3/1)將該粗產物純化，得到呈淡黃色油狀之標題化合物(500 mg，2.0893mmol，85.461%產率)。 (1R,5S,6r)-6- propionyl -3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 0°C to (1R,5S,6r)-6- [1-Hydroxypropyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (590 mg, 2.44mmol) and NaHCO ₃ (410.77mg, 4.89mmol) in DCM (25mL ) was added Dess-Martin reagent (1555.4 mg, 3.67 mmol). The mixture was stirred at 20°C for 12 hours to obtain a white mixture. The mixture was diluted with DCM (30 mL) and H ₂ O (20 mL) and basified to pH=8 with saturated NaHCO ₃ . The aqueous layer was extracted with DCM (20 mL). The combined DCM layers were dried over _Na2SO4 and concentrated in _vacuo to give the crude product which was purified by flash column (PE/EA=1/0 to 3/1) to give the title compound as pale yellow oil (500 mg, 2.0893 mmol, 85.461% yield).

(1R,5S,6r)-6-(4- 乙氧基 -2- 甲基 -3,4- 二側氧基丁醯基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在-78℃下向(1R,5S,6r)-6-丙醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(500 mg，2.09mmol)於THF (10mL)中之溶液添加LHMDS (2.5mL，2.51mmol，於THF中之1 M)。在-78℃下攪拌反應物1小時。隨後，在-78℃下添加草酸二乙酯(0.34mL，2.51mmol)於THF (2mL)中之溶液。將反應物升溫至20℃且攪拌另外12小時，得到淡黃色溶液。將反應物冷卻至0℃，用EA (30 mL)稀釋，用H ₂O (15 mL)淬滅且用2 M HCl酸化至pH=6。用EA (20 mL × 2)萃取水層。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到淡黃色油狀物。藉由快速柱(PE/EA=1/0至4/1)純化粗物質油，得到呈淡黃色油狀之標題化合物(300 mg，0.8840mmol，42.308%產率)。同時，回收約160 mg之B76-2a。 (1R,5S,6r)-6-(4- Ethoxy -2- methyl -3,4- dipentoxybutyryl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid The tertiary butyl ester was converted to (1R,5S,6r)-6-propionyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (500 mg, 2.09 mmol) in THF (10 mL) was added LHMDS (2.5 mL, 2.51 mmol, 1 M in THF). The reaction was stirred at -78°C for 1 hour. Subsequently, a solution of diethyl oxalate (0.34 mL, 2.51 mmol) in THF (2 mL) was added at -78 °C. The reaction was warmed to 20 °C and stirred for an additional 12 hours, resulting in a light yellow solution. The reaction was cooled to 0 °C, diluted with EA (30 mL), quenched with _H2O (15 mL) and acidified to pH=6 with 2 M HCl. The aqueous layer was extracted with EA (20 mL x 2). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a light yellow oil. The crude oil was purified by flash column (PE/EA = 1/0 to 4/1 ) to give the title compound (300 mg, 0.8840 mmol, 42.308% yield) as a light yellow oil. At the same time, about 160 mg of B76-2a was recovered.

(1R,5S,6r)-6-[(1E)-4- 乙氧基 -N- 羥基 -2- 甲基 -3,4- 二側氧基丁醯亞胺基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向NaOH (42.43mg，1.06mmol)於H ₂O (2mL)中之溶液添加鹽酸羥胺(0.04mL，1.06mmol)。在攪拌5min之後，在0℃下將反應物逐滴添加至(1R,5S,6r)-6-(4-乙氧基-2-甲基-3,4-二側氧基丁醯基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(300 mg，0.8800mmol)於THF (2mL)中之溶液。在20℃下攪拌反應物12小時，得到淡黃色懸浮液。用EA (20 mL)及H ₂O (10 mL)稀釋懸浮液且用2 M HCl調整為pH=7。用EA (15 mL × 2)萃取水層。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈淡黃色油狀之標題化合物(300 mg，0.8465mmol，95.762%產率)。 (1R,5S,6r)-6-[(1E)-4- Ethoxy -N - hydroxy -2- methyl -3,4- dipentoxybutyrimide ]-3- azabicyclo [3.1.0] Hexane -3- carboxylic acid tert-butyl ester To a solution of NaOH (42.43 mg, 1.06 mmol) in H ₂ O (2 mL) was added hydroxylamine hydrochloride (0.04 mL, 1.06 mmol) at 0°C. After stirring for 5 min, the reaction was added dropwise to (1R,5S,6r)-6-(4-ethoxy-2-methyl-3,4-dioxobutyryl)-3 - A solution of tert-butyl azabicyclo[3.1.0]hexane-3-carboxylate (300 mg, 0.8800 mmol) in THF (2 mL). The reaction was stirred at 20°C for 12 hours to give a pale yellow suspension. The suspension was diluted with EA (20 mL) and H ₂ O (10 mL) and adjusted to pH=7 with 2 M HCl. The aqueous layer was extracted with EA (15 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (300 mg, 0.8465 mmol, 95.762% yield) as a light yellow oil.

(1R,5S,6r)-6-[5-( 乙氧羰基 )-4- 甲基 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-[(1E)-4-乙氧基-N-羥基-2-甲基-3,4-二側氧基丁醯亞胺基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(300 mg，0.8500mmol)及Et ₃N (0.15mL，1.1mmol)於DCM (8mL)中之溶液添加甲磺醯氯(126.06mg，1.1mmol)。在20℃下攪拌反應物4小時，得到淡黃色溶液。將反應物冷卻至0℃且用額外MsCl (60 uL)及Et ₃N (0.8 mL)處理。在20℃下攪拌反應物另外1小時，得到淡黃色溶液。真空濃縮反應物。藉由製備型TLC (PE/EA=3/1)純化殘餘物，得到呈淡黃色膠質之標題化合物(75mg，0.2230mmol，26.339%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 4.36 (q, J = 6.8 Hz, 2H), 3.80-3.55 (m, 2H), 3.50-3.40 (m, 2H), 2.23 (s, 3H), 2.15-2.10 (m, 1H), 2.10-2.00 (m, 1H), 1.60-1.50 (m, 1H), 1.40 (s, 9H), 1.02 (t, J = 6.8 Hz, 3H)。 (1R,5S,6r)-6-[5-( ethoxycarbonyl )-4- methyl -1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0] hexane -3 -Tertiary butyl carboxylate at 0°C to (1R , 5S,6r)-6-[(1E)-4-ethoxy-N-hydroxyl-2-methyl-3,4-diendoxy Butyrimino]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (300 mg, 0.8500mmol) and Et ₃ N (0.15mL, 1.1mmol) in DCM (8mL ) was added methanesulfonyl chloride (126.06 mg, 1.1 mmol). The reaction was stirred at 20 °C for 4 hours to give a pale yellow solution. The reaction was cooled to 0 °C and treated with additional MsCl (60 uL) and _Et3N (0.8 mL). The reaction was stirred at 20 °C for an additional 1 hour to give a pale yellow solution. The reaction was concentrated in vacuo. The residue was purified by prep-TLC (PE/EA=3/1) to give the title compound (75 mg, 0.2230 mmol, 26.339% yield) as a pale yellow gum. ¹ H NMR (400MHz, chloroform-d) δ = 4.36 (q, J = 6.8 Hz, 2H), 3.80-3.55 (m, 2H), 3.50-3.40 (m, 2H), 2.23 (s, 3H), 2.15 -2.10 (m, 1H), 2.10-2.00 (m, 1H), 1.60-1.50 (m, 1H), 1.40 (s, 9H), 1.02 (t, J = 6.8 Hz, 3H).

(1R,5S,6r)-6-[5-( 羥甲基 )-4- 甲基 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-[5-(乙氧羰基)-4-甲基-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.3000mmol)於THF (4mL)中之溶液添加LiALH ₄(20.33mg，0.5400mmol)。在0℃下攪拌反應物20 min，得到白色混合物。用H ₂O (3滴)淬滅混合物，用EA (20 mL)稀釋且用Na ₂SO ₄(10 g)攪拌10min。濾出固體。真空濃縮濾液，得到呈淡黃色油狀之標題化合物(80mg，0.2718mmol，91.423%產率)。 (1R,5S,6r)-6-[5-( Hydroxymethyl )-4- methyl -1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0] hexane -3 -Tertiary butyl carboxylate at 0°C to (1R,5S,6r)-6-[5-(ethoxycarbonyl)-4-methyl-1,2-oxazol-3-yl] -3- To a solution of tert-butyl azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.3000 mmol) in THF (4 mL) was added _LiALH4 (20.33 mg, 0.5400 mmol). The reaction was stirred at 0 °C for 20 min to obtain a white mixture. The mixture was quenched with H ₂ O (3 drops), diluted with EA (20 mL) and stirred with Na ₂ SO ₄ (10 g) for 10 min. The solid was filtered off. The filtrate was concentrated in vacuo to afford the title compound (80 mg, 0.2718 mmol, 91.423% yield) as a pale yellow oil.

(1R,5S,6r)-6-(5- 甲醯基 -4- 甲基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-[5-(羥甲基)-4-甲基-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(80 mg，0.2700mmol)及NaHCO ₃(57.08mg，0.6800mmol)於DCM (4mL)中之混合物添加戴斯-馬丁試劑(172.91mg，0.4100mmol)。在20℃下攪拌混合物12小時，得到白色混合物。用DCM (15 mL)及H ₂O (10 mL)稀釋混合物且用飽和NaHCO ₃鹼化至pH=8。有機層經收集，濃縮且藉由製備型TLC (PE/EA=3/1，rf=0.5)純化，得到呈無色油狀之標題化合物(45mg，0.1539mmol，56.639%產率)。 (1R,5S,6r)-6-(5- Formyl -4- methyl -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexane -3- carboxy (1R,5S,6r)-6-[5-( hydroxymethyl )-4-methyl-1,2-oxazol-3-yl]-3-aza A mixture of tert-butyl bicyclo[3.1.0]hexane-3-carboxylate (80 mg, 0.2700 mmol) and NaHCO ₃ (57.08 mg, 0.6800 mmol) in DCM (4 mL) was added with Dess-Martin reagent (172.91 mg, 0.4100 mmol). The mixture was stirred at 20°C for 12 hours to obtain a white mixture. The mixture was diluted with DCM (15 mL) and H ₂ O (10 mL) and basified to pH=8 with saturated NaHCO ₃ . The organic layers were collected, concentrated and purified by prep-TLC (PE/EA=3/1, rf=0.5) to give the title compound (45 mg, 0.1539 mmol, 56.639% yield) as a colorless oil.

(1R,5S,6r)-6-[5-( 二氟甲基 )-4- 甲基 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在-78℃下向(1R,5S,6r)-6-(5-甲醯基-4-甲基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(45 mg，0.1500mmol)於DCM (3mL)中之溶液逐滴添加DAST (74.35mg，0.4600mmol)。將反應物升溫至20℃且攪拌另外12小時，得到淡黃色溶液。用DCM (10 mL)稀釋反應物，冷卻至0℃，用H ₂O (5 mL)及飽和NaHCO ₃(3 mL)處理。用EA (10 mL × 2)萃取水層。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈淡黃色油狀之標題化合物(55mg，0.1750mmol)。 (1R,5S,6r)-6-[5-( Difluoromethyl )-4- methyl -1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0 ] hexane- 3- Carboxylic acid tertiary butyl ester at -78 ℃ to (1R,5S,6r)-6-(5-formyl-4-methyl-1,2-oxazol-3-yl)-3- To a solution of tert-butyl azabicyclo[3.1.0]hexane-3-carboxylate (45 mg, 0.1500 mmol) in DCM (3 mL) was added DAST (74.35 mg, 0.4600 mmol) dropwise. The reaction was warmed to 20 °C and stirred for an additional 12 hours, resulting in a light yellow solution. The reaction was diluted with DCM (10 mL), cooled to 0 °C, treated with _H2O (5 mL) and saturated _NaHCO3 (3 mL). The aqueous layer was extracted with EA (10 mL x 2). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo to give the title compound (55 mg, 0.1750 mmol) as a light yellow oil.

(1R,5S,6r)-6-[5-( 二氟甲基 )-4- 甲基 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽用TFA (0.2mL，0.1700mmol)處理(1R,5S,6r)-6-[5-(二氟甲基)-4-甲基-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(55 mg，0.1700mmol)於DCM (2mL)中之溶液且在20℃下攪拌10 min，得到淡褐色溶液。真空濃縮反應物，得到呈淡褐色油狀之標題化合物(60mg，0.2801mmol，TFA鹽)。 (1R,5S,6r)-6-[5-( Difluoromethyl ) -4- methyl -1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0] hexaneTFA Salt Treatment with TFA (0.2 mL, 0.1700 mmol) (1R,5S,6r)-6-[5-(difluoromethyl)-4-methyl-1,2-oxazol-3-yl]-3- A solution of tert-butyl azabicyclo[3.1.0]hexane-3-carboxylate (55 mg, 0.1700 mmol) in DCM (2 mL) was stirred at 20 °C for 10 min to give a light brown solution. The reaction was concentrated in vacuo to afford the title compound (60 mg, 0.2801 mmol, TFA salt) as a light brown oil.

{(1R,5S,6r)-6-[5-( 二氟甲基 )-4- 甲基 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮在0℃下向(1R,5S,6r)-6-[5-(二氟甲基)-4-甲基-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷TFA鹽(60 mg，0.1800mmol)及5-異丙基-1H-吡唑-3-羧酸(28.2mg，0.1800mmol)於DMF (1mL)中之溶液添加HATU (69.93mg，0.1800mmol)及Et ₃N (0.05mL，0.3700mmol)。在20℃下攪拌反應物12小時，得到淡黃色溶液。真空濃縮反應物，得到淡黃色油狀物，藉由製備型TLC (PE/EA=1/2)純化該淡黃色油狀物兩次，得到所要產物。凍乾產物，得到呈白色固體狀之標題化合物(21.2mg，0.0605mmol，33.078%產率)。 LC-MS 方法 1: 350.9 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 10.05 (s, 1H), 6.78 - 6.48 (m, 1H), 6.45 (s, 1H), 4.31 (br d, J=10.3 Hz, 1H), 4.21 (d, J=12.5 Hz, 1H), 3.92 (dd, J=4.4, 11.4 Hz, 1H), 3.64 (dd, J=4.3, 12.8 Hz, 1H), 2.96 (td, J=6.9, 13.8 Hz, 1H), 2.29 (td, J=3.8, 7.4 Hz, 1H), 2.13 (td, J=3.7, 7.3 Hz, 1H), 2.06 (t, J=2.0 Hz, 3H), 1.26 - 1.21 (m, 6H) { (1R,5S,6r)-6-[5-( Difluoromethyl )-4- methyl -1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0] hexyl- 3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone to (1R,5S,6r)-6-[5-(difluoromethyl)-4-methanone at 0°C 1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane TFA salt (60 mg, 0.1800mmol) and 5-isopropyl-1H-pyrazole-3-carboxy A solution of the acid (28.2 mg, 0.1800 mmol) in DMF (1 mL) was added with HATU (69.93 mg, 0.1800 mmol) and _Et3N (0.05 mL, 0.3700 mmol). The reaction was stirred at 20°C for 12 hours to give a light yellow solution. The reaction was concentrated in vacuo to give a light yellow oil, which was purified twice by preparative TLC (PE/EA=1/2) to give the desired product. The product was lyophilized to afford the title compound (21.2 mg, 0.0605 mmol, 33.078% yield) as a white solid. LC-MS method 1 : 350.9 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 10.05 (s, 1H), 6.78 - 6.48 (m, 1H), 6.45 (s, 1H), 4.31 ( br d, J =10.3 Hz, 1H), 4.21 (d, J =12.5 Hz, 1H), 3.92 (dd, J =4.4, 11.4 Hz, 1H), 3.64 (dd, J =4.3, 12.8 Hz, 1H) , 2.96 (td, J =6.9, 13.8 Hz, 1H), 2.29 (td, J =3.8, 7.4 Hz, 1H), 2.13 (td, J =3.7, 7.3 Hz, 1H), 2.06 (t, J =2.0 Hz, 3H), 1.26 - 1.21 (m, 6H)

實例 105    {(1R,5S,6r)-6-[4-( 二甲胺基 )-5- 甲基 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 (1R,5S,6r)-6-[4-( 乙氧羰基 )-5- 甲基 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向圓底燒瓶裝入(1R,5S,6r)-6-[(E)-(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(600 mg，2.3mmol)、3-側氧基丁酸甲酯(0.5 mL，4.6mmol)及三乙胺(0.96mL，6.9mmol)及DMF (12mL)。在20℃下攪拌反應混合物16小時，得到黃色溶液。LCMS展示主峰給出所要ms。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色油狀之標題化合物(950mg，2.947mmol，128.06%產率)。其直接用於下一步驟。 LC-MS方法1 0.925, MS (m/z) 308.0 (M - CH ₂CH ₃+ H ⁺)。 Example 105 {(1R,5S,6r)-6-[4-( Dimethylamino )-5- methyl -1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0] Hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone (1R,5S,6r)-6-[4-( ethoxycarbonyl )-5- methyl -1, 2- oxazol -3- yl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester was charged into a round bottom flask with (1R,5S,6r)-6-[(E )-(hydroxyimino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (600 mg, 2.3mmol), 3-oxobutyric acid methyl ester (0.5 mL, 4.6 mmol) and triethylamine (0.96 mL, 6.9 mmol) and DMF (12 mL). The reaction mixture was stirred at 20 °C for 16 hours to give a yellow solution. LCMS showed a major peak giving the desired ms. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (950 mg, 2.947 mmol, 128.06% yield) as a yellow oil. It was used directly in the next step. LC-MS method 1 0.925, MS (m/z) 308.0 (M − CH ₂ CH ₃ + H ⁺ ).

5- 甲基 -3-[(1R,5S,6r)-3-{[( 三級丁基 ) 氧基 ] 羰基 }-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-1,2- 㗁唑 -4- 羧酸向100 mL圓底燒瓶裝入(1R,5S,6r)-6-[4-(乙氧羰基)-5-甲基-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(380 mg，1.18mmol)、羥基鋰水合物(148.39mg，3.54mmol)及THF (6mL)。在20℃下攪拌反應混合物16小時，得到黃色溶液。用H ₂O (15mL)稀釋反應物。用1 M HCl水溶液將pH調整為3且用EtOAc (30mL ×2)萃取反應混合物。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色油狀之標題化合物(330mg，1.0703mmol，90.794%產率)。 5- Methyl -3-[(1R,5S,6r)-3-{[( tertiary butyl ) oxy ] carbonyl }-3- azabicyclo [3.1.0] hex -6- yl ]-1 , 2- oxazole -4- carboxylic acid was charged into a 100 mL round bottom flask with (1R,5S,6r)-6-[4-(ethoxycarbonyl)-5-methyl-1,2-oxazole-3 -yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (380 mg, 1.18 mmol), hydroxylithium hydrate (148.39 mg, 3.54 mmol) and THF (6 mL). The reaction mixture was stirred at 20 °C for 16 hours to give a yellow solution. The reaction was diluted with _H2O (15 mL). The pH was adjusted to 3 with 1 M aqueous HCl and the reaction mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (330 mg, 1.0703 mmol, 90.794% yield) as a yellow oil.

(1R,5S,6r)-6-(4-{[( 苯甲氧基 ) 羰基 ] 胺基 }-5- 甲基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向圓底燒瓶裝入5-甲基-3-[(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己-6-基]-1,2-㗁唑-4-羧酸(300 mg，0.9700mmol)、DPPA (401.65mg，1.46mmol)、Et ₃N (0.41mL，2.92mmol)及甲苯(2.7273mL)。在110℃下攪拌反應混合物2小時，且隨後添加苯甲醇(0.4mL，3.89mmol)。在110℃下攪拌反應混合物10 min，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(PE/EA=10/1至3/1)來純化粗物質，得到呈黃色油狀之標題化合物(160mg，0.3870mmol，39.771%產率)。 ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.45-7.20 (m, 5H), 5.12 (brs, 2H), 3.80-3.25 (m, 4H), 2.25 (brs, 3H), 2.00-1.90 (m, 1H), 1.50-1.40 (m, 1H), 1.39 (s, 9H)。 (1R,5S,6r)-6-(4-{[( Benzyloxy ) carbonyl ] amino }-5- methyl -1,2- oxazol -3- yl )-3- azabicyclo [ 3.1.0] Hexane -3- carboxylic acid tertiary butyl ester, charge 5-methyl-3-[(1R,5S,6r)-3-{[(tertiary butyl)oxyl] into the round bottom flask Carbonyl}-3-azabicyclo[3.1.0]hex-6-yl]-1,2-oxazole-4-carboxylic acid (300 mg, 0.9700mmol), DPPA (401.65mg, 1.46mmol), Et ₃ N (0.41 mL, 2.92 mmol) and toluene (2.7273 mL). The reaction mixture was stirred at 110 °C for 2 hours, and then benzyl alcohol (0.4 mL, 3.89 mmol) was added. The reaction mixture was stirred at 110 °C for 10 min to obtain a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (PE/EA = 10/1 to 3/1 ) to afford the title compound (160 mg, 0.3870 mmol, 39.771% yield) as a yellow oil. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.45-7.20 (m, 5H), 5.12 (brs, 2H), 3.80-3.25 (m, 4H), 2.25 (brs, 3H), 2.00-1.90 (m , 1H), 1.50-1.40 (m, 1H), 1.39 (s, 9H).

(1R,5S,6r)-6-(4- 胺基 -5- 甲基 -1,2- 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向圓底燒瓶裝入(1R,5S,6r)-6-(4-{[(苯甲氧基)羰基]胺基}-5-甲基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(1200 mg，2.9mmol)、Pd/C (120 mg，2.9mmol)及MeOH (10mL)。在分子氫(15 psi)氛圍下攪拌反應混合物，得到黑色懸浮液。經由矽藻土墊過濾懸浮液且真空濃縮濾液，得到呈黃色固體狀之標題化合物。 LC-MS方法1 0.765 min，MS (m/z) 280.1 (M + H ⁺)。 (1R,5S,6r)-6-(4- Amino -5- methyl -1,2- oxazol -3- yl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid Charge tertiary butyl ester into a round bottom flask with (1R,5S,6r)-6-(4-{[(benzyloxy)carbonyl]amino}-5-methyl-1,2-oxazole-3 -yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1200 mg, 2.9 mmol), Pd/C (120 mg, 2.9 mmol) and MeOH (10 mL). The reaction mixture was stirred under an atmosphere of molecular hydrogen (15 psi) to give a black suspension. The suspension was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound as a yellow solid. LC-MS method 1 0.765 min, MS (m/z) 280.1 (M + H ⁺ ).

(1R,5S,6r)-6-[4-( 二甲胺基 )-5- 甲基 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-(4-胺基-5-甲基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.3600mmol)於MeOH (2.8571mL)中之溶液添加甲醛(1 mL，2.15mmol)。在攪拌15min之後，添加NaBH ₃CN (134.98mg，2.15mmol)，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色油狀之標題化合物(150 mg，粗物質)。其直接用於下一步驟。 (1R,5S,6r)-6-[4-( Dimethylamino )-5- methyl -1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0 ] hexane- 3- Carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-(4-amino-5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1. 0] A solution of tert-butyl hexane-3-carboxylate (100 mg, 0.3600 mmol) in MeOH (2.8571 mL) was added formaldehyde (1 mL, 2.15 mmol). After stirring for 15 min, NaBH ₃ CN (134.98 mg, 2.15 mmol) was added to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo to give the title compound (150 mg, crude) as a yellow oil. It was used directly in the next step.

3-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-N,N,5- 三甲基 -1,2- 㗁唑 -4- 胺 TFA 鹽向圓底燒瓶裝入(1R,5S,6r)-6-[4-(二甲胺基)-5-甲基-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(150 mg，0.4900mmol)、2,2,2-三氟乙酸(0.04mL，0.4900mmol)、DCM (6mL)及2,2,2-三氟乙酸(0.04mL，0.4900mmol)。在30℃下於N ₂保護下攪拌反應混合物，得到黃色溶液。在真空中蒸發反應混合物，得到呈黃色油狀之標題化合物(220mg，0.5054mmol，103.56%產率)。其直接用於下一步驟。 LC-MS方法1 0.443 min，MS (m/z) 207.9 (M + H ⁺)。 3-[(1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl ]-N,N,5- trimethyl -1,2- oxazol -4- amine TFA salt (1R,5S,6r)-6-[4-(dimethylamino)-5-methyl-1,2-oxazol-3-yl]-3-azabicyclo[3.1 .0] tert-butyl hexane-3-carboxylate (150 mg, 0.4900mmol), 2,2,2-trifluoroacetic acid (0.04mL, 0.4900mmol), DCM (6mL) and 2,2,2- Trifluoroacetic acid (0.04 mL, 0.4900 mmol). The reaction mixture was stirred at 30 °C under _N2 protection to give a yellow solution. The reaction mixture was evaporated in vacuo to give the title compound (220 mg, 0.5054 mmol, 103.56% yield) as a yellow oil. It was used directly in the next step. LC-MS method 1 0.443 min, MS (m/z) 207.9 (M + H ⁺ ).

{(1R,5S,6r)-6-[4-( 二甲胺基 )-5- 甲基 -1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向5-異丙基-1H-吡唑-3-羧酸(80 mg，0.5200mmol)及HATU (238.05mg，0.6200mmol)於DMF (2mL)中之溶液添加N-乙基-N-異丙基丙-2-胺(0.36 mL，2.08mmol)。在攪拌15 min之後，添加3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-N,N,5-三甲基-1,2-㗁唑-4-胺TFA鹽(225.89mg，0.5200mmol)且攪拌反應混合物16小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (NH ₃)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(38.86mg，0.1132mmol，21.807%產率)。 LC-MS方法1: 344.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ 6.49 (s, 1H), 4.19-4.37 (m, 2H), 3.99 (dd, J=4.39, 11.17 Hz, 1H), 3.71 (dd, J=4.52, 12.55 Hz, 1H), 3.03 (td, J=7.00, 13.87 Hz, 1H), 2.71 (s, 6H), 2.32-2.40 (m, 4H), 2.14 (td, J=3.83, 7.40 Hz, 1H), 1.68 (t, J=3.51 Hz, 1H), 1.30 (d, J=7.03 Hz, 6H) { (1R,5S,6r)-6-[4-( Dimethylamino )-5- methyl -1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0] hexyl- 3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone to 5-isopropyl-1H-pyrazole-3-carboxylic acid (80 mg, 0.5200mmol) and HATU (238.05mg , 0.6200 mmol) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.36 mL, 2.08 mmol). After stirring for 15 min, add 3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-N,N,5-trimethyl-1,2-㗁Azol-4-amine TFA salt (225.89 mg, 0.5200 mmol) and the reaction mixture was stirred for 16 hours to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC ( _NH3 ). The obtained fluid was concentrated in vacuo to remove most of _CH3CN and lyophilized to give the title compound (38.86 mg, 0.1132 mmol, 21.807% yield) as a white solid. LC-MS method 1: 344.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ 6.49 (s, 1H), 4.19-4.37 (m, 2H), 3.99 (dd, J =4.39, 11.17 Hz, 1H), 3.71 (dd, J =4.52, 12.55 Hz, 1H), 3.03 (td, J =7.00, 13.87 Hz, 1H), 2.71 (s, 6H), 2.32-2.40 (m, 4H), 2.14 (td, J =3.83, 7.40 Hz, 1H), 1.68 (t, J =3.51 Hz, 1H), 1.30 (d, J =7.03 Hz, 6H)

實例 106    (5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[5- 甲基 -4-(2- 吡啶基 )-1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 (1R,5S,6r)-6-[5- 甲基 -4-(2- 吡啶基 )-1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在N ₂下向(1R,5S,6r)-6-(4-溴-5-甲基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.29mmol)於1,4-二㗁烷(2mL)中之溶液添加三丁基(2-吡啶基)錫烷(214.52mg，0.58mmol)、X-Phos (27.78mg，0.0600mmol)及X-Phos-Pd-G2 (22.92mg，0.0300mmol)。在110℃下攪拌所得混合物16小時，得到黑褐色溶液。LCMS展示反應完成。用EA (15 mL)稀釋反應物且經由矽藻土墊過濾。濃縮濾液且藉由製備型TLC (EA/PE=1/1，Rf=0.5)純化殘餘物，得到呈淡黃色固體狀之標題化合物(71mg，71.379%產率)。 Example 106 (5- isopropyl -1H- pyrazol -3- yl ){(1R,5S,6r)-6-[5- methyl -4-(2- pyridyl )-1,2- oxazole -3- yl ]-3- azabicyclo [3.1.0] hex- 3- yl } methanone (1R,5S,6r)-6-[5- methyl- 4-(2- pyridyl )-1 , 2- oxazol -3- yl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid _tertiary butyl ester to (1R,5S,6r)-6-(4- Bromo-5-methyl-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (100 mg, 0.29mmol) in 1, A solution in 4-dioxane (2 mL) was added with tributyl (2-pyridyl) stannane (214.52 mg, 0.58 mmol), X-Phos (27.78 mg, 0.0600 mmol) and X-Phos-Pd-G2 ( 22.92 mg, 0.0300 mmol). The resulting mixture was stirred at 110°C for 16 hours to obtain a dark brown solution. LCMS showed the reaction was complete. The reaction was diluted with EA (15 mL) and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by prep-TLC (EA/PE=1/1, Rf=0.5) to give the title compound (71 mg, 71.379% yield) as a light yellow solid.

(1R,5S,6r)-6-[5- 甲基 -4-(2- 吡啶基 )-1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷氫氯化物在15℃下攪拌(1R,5S,6r)-6-[5-甲基-4-(2-吡啶基)-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(71 mg，0.2100mmol)於4M HCl中之於MeOH (1 mL，0.2100mmol)中之溶液10 min，得到淺黃色溶液。TLC展示起始材料消耗完且偵測到新樣點。濃縮反應物，得到呈淺黃色膠質之標題化合物(62mg，123.55%產率)。 (1R,5S,6r)-6-[5- Methyl -4-(2- pyridyl )-1,2- oxazol -3- yl ]-3- azabicyclo [3.1.0] hexanehydrogen (1R,5S, 6r )-6-[5-methyl-4-(2-pyridyl)-1,2-oxazol-3-yl]-3-azabicyclo[ 3.1.0] A solution of tert-butyl hexane-3-carboxylate (71 mg, 0.2100 mmol) in 4M HCl in MeOH (1 mL, 0.2100 mmol) for 10 min gave a pale yellow solution. TLC showed consumption of starting material and detection of new spots. The reaction was concentrated to afford the title compound (62 mg, 123.55% yield) as a pale yellow gum.

(5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[5- 甲基 -4-(2- 吡啶基 )-1,2- 㗁唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮在0至5℃下向(1R,5S,6r)-6-[5-甲基-4-(2-吡啶基)-1,2-㗁唑-3-基]-3-氮雜雙環[3.1.0]己烷氫氯化物(62 mg，0.26mmol)於DMF (1mL)中之溶液添加5-異丙基-1H-吡唑-3-羧酸(39.61mg，0.26mmol)、DIPEA (0.13mL，0.77mmol)及HATU (146.46mg，0.39mmol)。在15℃下攪拌所得混合物16小時，得到淺褐色溶液。用H ₂O (15 mL)稀釋反應物且用EA (5 mL × 3)萃取。用NH ₄Cl水溶液(5 mL ×2)及鹽水(5 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且濃縮至乾燥。藉由製備型TLC (EA/MeOH=12/1，Rf=0.6)純化殘餘物且凍乾，得到呈白色固體狀之標題化合物(34mg，35.057%產率)。 LC-MS方法1: 378.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿- d) δ ppm 1.29 (d, J=6.88 Hz, 6 H) 1.92 (t, J=3.44 Hz, 1 H) 2.18 (dt, J=7.41, 3.86 Hz, 1 H) 2.46 (dt, J=7.44, 3.91 Hz, 1 H) 2.55 (s, 3 H) 2.97 - 3.08 (m, 1 H) 3.73 (dd, J=12.69, 4.44 Hz, 1 H) 3.99 (dd, J=11.13, 4.38 Hz, 1 H) 4.20 (d, J=12.76 Hz, 1 H) 4.28 (br d, J=11.13 Hz, 1 H) 6.44 (s, 1 H) 7.23 (dd, J=7.32, 5.19 Hz, 1 H) 7.38 (d, J=7.88 Hz, 1 H) 7.75 (td, J=7.75, 1.75 Hz, 1 H) 8.66 (d, J=4.63 Hz, 1 H) (5- isopropyl -1H- pyrazol -3- yl ){(1R,5S,6r)-6-[5- methyl -4-(2- pyridyl )-1,2- oxazole -3 -yl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone to (1R,5S,6r)-6-[5 - methyl-4-(2- To a solution of pyridyl)-1,2-oxazol-3-yl]-3-azabicyclo[3.1.0]hexane hydrochloride (62 mg, 0.26 mmol) in DMF (1 mL) was added 5-iso Propyl-1H-pyrazole-3-carboxylic acid (39.61 mg, 0.26 mmol), DIPEA (0.13 mL, 0.77 mmol) and HATU (146.46 mg, 0.39 mmol). The resulting mixture was stirred at 15°C for 16 hours to give a beige solution. The reaction was diluted with H ₂ O (15 mL) and extracted with EA (5 mL×3). The combined organic layers were washed with aqueous NH ₄ Cl (5 mL×2) and brine (5 mL), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by prep-TLC (EA/MeOH=12/1, Rf=0.6) and lyophilized to give the title compound (34 mg, 35.057% yield) as a white solid. LC-MS method 1: 378.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform- d ) δ ppm 1.29 (d, J =6.88 Hz, 6 H) 1.92 (t, J =3.44 Hz, 1 H) 2.18 (dt, J =7.41, 3.86 Hz, 1 H) 2.46 (dt, J =7.44, 3.91 Hz, 1 H) 2.55 (s, 3 H) 2.97 - 3.08 (m, 1 H) 3.73 (dd, J = 12.69, 4.44 Hz, 1 H) 3.99 (dd, J =11.13, 4.38 Hz, 1 H) 4.20 (d, J =12.76 Hz, 1 H) 4.28 (br d, J =11.13 Hz, 1 H) 6.44 (s , 1 H) 7.23 (dd, J =7.32, 5.19 Hz, 1 H) 7.38 (d, J =7.88 Hz, 1 H) 7.75 (td, J =7.75, 1.75 Hz, 1 H) 8.66 (d, J = 4.63 Hz, 1H)

實例 107    [(1R,5S,6r)-6-{4-[1-( 環丙基甲基 )-1H- 吡唑 -3- 基 ]-5- 甲基 -1,2- 㗁唑 -3- 基 }-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 3- 溴 -1-( 環丙基甲基 )-1H- 吡唑向3-溴吡唑(1.g，6.8mmol)於DMF (10mL)中之溶液添加K ₂CO ₃(1.88g，13.61mmol)及(溴甲基)環丙烷(0.66mL，6.8mmol)。在15℃下攪拌反應物3小時，得到白色懸浮液。LCMS展示剩餘起始材料之約一半且攪拌反應物16小時，得到白色懸浮液。TLC (PE/EA=5/1，Rf=0.7，I ₂)展示大部分起始材料耗盡且偵測到新樣點。用H ₂O (90 mL)稀釋反應物且用EA (10 mL × 3)萃取。用NH ₄Cl水溶液(10 mL)及鹽水(10 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且濃縮，獲得呈無色油狀之標題化合物及其異構體之混合物(1.36g，99.413%產率)。 異構體a: ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.49 (d, J = 1.2 Hz, 1H), 6.28 (d, J = 1.2 Hz, 1H), 4.03 (d, J = 6.8 Hz, 2H), 1.40-1.20 (m, 2H), 0.60-0.50 (m, 1H), 0.45-0.40 (m, 1H). 異構體b; ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.39 (d, J = 1.2 Hz, 1H), 6.26 (d, J = 1.2 Hz, 1H), 3.92 (d, J = 6.8 Hz, 2H), 1.40-1.20 (m, 2H), 0.70-0.60 (m, 1H), 0.40-0.35 (m, 1H)。 Example 107 [(1R,5S,6r)-6-{4-[1-( cyclopropylmethyl )-1H- pyrazol -3- yl ]-5- methyl -1,2- oxazole -3 - Base }-3- azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone 3- bromo -1-( cyclopropylmethyl )-1H- pyrazole To a solution of 3-bromopyrazole (1.g, 6.8 mmol) in DMF (10 mL) was added K ₂ CO ₃ (1.88 g, 13.61 mmol) and (bromomethyl)cyclopropane (0.66 mL, 6.8 mmol). The reaction was stirred at 15°C for 3 hours to give a white suspension. LCMS showed about half of the starting material remaining and the reaction was stirred for 16 hours to give a white suspension. TLC (PE/EA=5/1, Rf=0.7, _I2 ) showed that most of the starting material was consumed and new spots were detected. The reaction was diluted with H ₂ O (90 mL) and extracted with EA (10 mL×3). The combined organic layers were washed with aqueous NH ₄ Cl (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give a mixture of the title compound and its isomers as a colorless oil (1.36 g , 99.413% yield). Isomer a: ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.49 (d, J = 1.2 Hz, 1H), 6.28 (d, J = 1.2 Hz, 1H), 4.03 (d, J = 6.8 Hz , 2H), 1.40-1.20 (m, 2H), 0.60-0.50 (m, 1H), 0.45-0.40 (m, 1H). Isomer b; ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.39 (d, J = 1.2 Hz, 1H), 6.26 (d, J = 1.2 Hz, 1H), 3.92 (d, J = 6.8 Hz, 2H), 1.40-1.20 (m, 2H), 0.70-0.60 (m, 1H), 0.40-0.35 (m, 1H).

1-( 環丙基甲基 )-3-( 三丁基錫烷基 )-1H- 吡唑在-75至-70℃下向3-溴-1-(環丙基甲基)-1H-吡唑及其異構體之混合物(1.39g，6.91mmol)於THF (15mL)中之溶液逐滴添加n-BuLi (3.04mL，7.6mmol)。在-75至-70℃下攪拌1小時之後，在-75至-70℃下向反應物添加於THF (5mL)中之三丁基(氯基)錫烷(2.48g，7.6mmol)。在15℃下攪拌所得混合物16小時，得到淺黃色溶液。用NH ₄Cl水溶液(5 mL)淬滅反應物。用H ₂O (50 mL)稀釋混合物且用EA (15 mL × 3)萃取。用鹽水(15 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且濃縮至乾燥。藉由快速柱(用5% EA/PE溶離，EA/PE=1/9)純化殘餘物，得到呈無色油狀之標題化合物(525 mg，Rf=0.45)。 LC-MS方法1 1.060 min，MS (m/z) 413.0 (M + H ⁺)。 1-( cyclopropylmethyl )-3-( tributylstannyl )-1H- pyrazole to 3-bromo-1-(cyclopropylmethyl)-1H-pyrazole at -75 to -70°C A solution of a mixture of its isomers (1.39 g, 6.91 mmol) in THF (15 mL) was added dropwise with n-BuLi (3.04 mL, 7.6 mmol). After stirring at -75 to -70°C for 1 hour, to the reaction was added tributyl(chloro)stannane (2.48 g, 7.6 mmol) in THF (5 mL) at -75 to -70°C. The resulting mixture was stirred at 15°C for 16 hours to obtain a pale yellow solution. The reaction was quenched with aqueous _NH4Cl (5 mL). The mixture was diluted with H ₂ O (50 mL) and extracted with EA (15 mL×3). The combined organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by flash column (eluted with 5% EA/PE, EA/PE=1/9) to give the title compound (525 mg, Rf=0.45) as a colorless oil. LC-MS method 1 1.060 min, MS (m/z) 413.0 (M + H ⁺ ).

(1R,5S,6r)-6-{4-[1-( 環丙基甲基 )-1H- 吡唑 -3- 基 ]-5- 甲基 -1,2- 㗁唑 -3- 基 }-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在N ₂下向(1R,5S,6r)-6-(4-溴-5-甲基-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(300 mg，0.87mmol)於1,4-二㗁烷(3mL)中之溶液添加1-(環丙基甲基)-3-(三丁基錫烷基)-1H-吡唑(431.31mg，1.05mmol)、X-Phos (83.34mg，0.17mmol)及X-Phos-Pd-G2 (68.77mg，0.09mmol)。在100℃下攪拌所得混合物16小時，得到黑褐色溶液。用EA (30 mL)稀釋反應物且經由矽藻土墊過濾。濃縮濾液且藉由快速柱(8% EA/PE，PE/EA=3/1，Rf=0.5)純化，得到呈淡黃色固體狀之標題化合物(205mg，16.47%產率)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.50 (d, J = 2.0 Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 4.00 (d, J = 3.2 Hz, 2H), 3.79 (d, J = 11.2 Hz, 1H), 3.70 (d, J = 11.2 Hz, 1H), 3.50-3.40 (m, 2H), 2.38 (s, 3H), 2.11 (m, 2H), 1.70-1.65 (m, 1H), 1.47 (s, 9H),.70-0.60 (m, 1H), 0.55-0.50 (m, 2H), 0.45-0.35 (m, 2H)。 (1R,5S,6r)-6-{4-[1-( Cyclopropylmethyl )-1H- pyrazol -3- yl ]-5- methyl -1,2- oxazol -3- yl } -3- Azabicyclo [3.1.0] hexane -3- carboxylic acid _tertiary butyl ester to (1R,5S,6r)-6-(4-bromo-5-methyl-1,2 -Zazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (300 mg, 0.87mmol) in 1,4-dioxane (3mL) The solution was added with 1-(cyclopropylmethyl)-3-(tributylstannyl)-1H-pyrazole (431.31 mg, 1.05 mmol), X-Phos (83.34 mg, 0.17 mmol) and X-Phos-Pd- G2 (68.77 mg, 0.09 mmol). The resulting mixture was stirred at 100°C for 16 hours to obtain a dark brown solution. The reaction was diluted with EA (30 mL) and filtered through a pad of celite. The filtrate was concentrated and purified by flash column (8% EA/PE, PE/EA = 3/1, Rf = 0.5) to give the title compound (205 mg, 16.47% yield) as a light yellow solid. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.50 (d, J = 2.0 Hz, 1H), 6.40 (d, J = 2.0 Hz, 1H), 4.00 (d, J = 3.2 Hz, 2H), 3.79 (d, J = 11.2 Hz, 1H), 3.70 (d, J = 11.2 Hz, 1H), 3.50-3.40 (m, 2H), 2.38 (s, 3H), 2.11 (m, 2H), 1.70-1.65 ( m, 1H), 1.47 (s, 9H), .70-0.60 (m, 1H), 0.55-0.50 (m, 2H), 0.45-0.35 (m, 2H).

(1R,5S,6r)-6-{4-[1-( 環丙基甲基 )-1H- 吡唑 -3- 基 ]-5- 甲基 -1,2- 㗁唑 -3- 基 }-3- 氮雜雙環 [3.1.0] 己烷氫氯化物在15℃下攪拌(1R,5S,6r)-6-{4-[1-(環丙基甲基)-1H-吡唑-3-基]-5-甲基-1,2-㗁唑-3-基}-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(205 mg，0.5300mmol)於4M HCl中之於MeOH (3 mL，0.5300mmol)中之溶液15 min，得到無色溶液。LCMS展示起始材料消耗完且偵測到具有所要質量之一個新峰值。濃縮反應物，得到呈灰白色固體狀之標題化合物(77.8mg，51.312%產率)。 LC-MS方法1 0.652 min，MS (m/z) 284.9 (M + H ⁺)。 (1R,5S,6r)-6-{4-[1-( Cyclopropylmethyl )-1H- pyrazol -3- yl ]-5- methyl -1,2- oxazol -3- yl } -3- Azabicyclo [3.1.0] hexane hydrochloride stirred at 15°C (1R,5S,6r)-6-{4-[1-(cyclopropylmethyl)-1H-pyrazole- 3-yl]-5-methyl-1,2-oxazol-3-yl}-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (205 mg, 0.5300mmol) A solution in 4M HCl in MeOH (3 mL, 0.5300 mmol) for 15 min gave a colorless solution. LCMS showed that the starting material was consumed and a new peak was detected with the desired mass. The reaction was concentrated to afford the title compound (77.8 mg, 51.312% yield) as an off-white solid. LC-MS method 1 0.652 min, MS (m/z) 284.9 (M + H ⁺ ).

[(1R,5S,6r)-6-{4-[1-( 環丙基甲基 )-1H- 吡唑 -3- 基 ]-5- 甲基 -1,2- 㗁唑 -3- 基 }-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向(1R,5S,6r)-6-{4-[1-(環丙基甲基)-1H-吡唑-3-基]-5-甲基-1,2-㗁唑-3-基}-3-氮雜雙環[3.1.0]己烷氫氯化物(77.8mg，0.27mmol)於DMF (1mL)中之溶液添加5-異丙基-1H-吡唑-3-羧酸(42.18mg，0.27mmol)、DIPEA (0.23mL，1.37mmol)及HATU (155.95mg，0.41mmol)。在15℃下攪拌所得混合物16小時，得到褐色溶液。用H ₂O (20 mL)稀釋反應物且用EA (5 mL × 3)萃取。用NH ₄Cl水溶液(8 mL)及鹽水(8 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且濃縮至乾燥。藉由製備型TLC (EA/MeOH=10/1)純化殘餘物且凍乾，得到呈白色固體狀之標題化合物(21.33mg，18.54%產率)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 0.35 (q, J=5.02 Hz, 2 H) 0.57 - 0.66 (m, 2 H) 1.21 - 1.27 (m, 1 H) 1.30 (d, J=7.03 Hz, 7 H) 2.00 (t, J=3.51 Hz, 1 H) 2.18 (dt, J=7.40, 3.83 Hz, 1 H) 2.41 (dt, J=7.40, 3.83 Hz, 1 H) 2.52 (s, 3 H) 3.02 (dt, J=13.74, 6.81 Hz, 1 H) 3.71 (dd, J=12.67, 4.39 Hz, 1 H) 3.97 (d, J=7.03 Hz, 2 H) 4.21 - 4.34 (m, 2 H) 6.31 (d, J=2.26 Hz, 1 H) 6.46 (s, 1 H) 7.53 (d, J=2.26 Hz, 1 H) [(1R,5S,6r)-6-{4-[1-( cyclopropylmethyl )-1H- pyrazol -3- yl ]-5- methyl -1,2- oxazol -3- yl }-3- Azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone to (1R,5S,6r)-6-{4- [1-(cyclopropylmethyl)-1H-pyrazol-3-yl]-5-methyl-1,2-oxazol-3-yl}-3-azabicyclo[3.1.0]hexane To a solution of hydrochloride (77.8 mg, 0.27 mmol) in DMF (1 mL) was added 5-isopropyl-1H-pyrazole-3-carboxylic acid (42.18 mg, 0.27 mmol), DIPEA (0.23 mL, 1.37 mmol) and HATU (155.95 mg, 0.41 mmol). The resulting mixture was stirred at 15°C for 16 hours to give a brown solution. The reaction was diluted with H ₂ O (20 mL) and extracted with EA (5 mL×3). The combined organic layers were washed with aqueous NH ₄ Cl (8 mL) and brine (8 mL), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residue was purified by prep-TLC (EA/MeOH=10/1) and lyophilized to give the title compound (21.33 mg, 18.54% yield) as a white solid. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 0.35 (q, J =5.02 Hz, 2 H) 0.57 - 0.66 (m, 2 H) 1.21 - 1.27 (m, 1 H) 1.30 (d, J =7.03 Hz, 7 H) 2.00 (t, J =3.51 Hz, 1 H) 2.18 (dt, J =7.40, 3.83 Hz, 1 H) 2.41 (dt, J =7.40, 3.83 Hz, 1 H) 2.52 (s, 3 H) 3.02 (dt, J =13.74, 6.81 Hz, 1 H) 3.71 (dd, J =12.67, 4.39 Hz, 1 H) 3.97 (d, J =7.03 Hz, 2 H) 4.21 - 4.34 (m, 2 H ) 6.31 (d, J =2.26 Hz, 1 H) 6.46 (s, 1 H) 7.53 (d, J =2.26 Hz, 1 H)

實例 108    [(1R,5S,6r)-6-(1,2- 苯并 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 [(1R,5S,6r)-6-(1,2- 苯并 㗁唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向5-異丙基-1H-吡唑-3-羧酸(10.75mg，0.0700mmol)於DMF (1mL)中之溶液添加HATU (33.71mg，0.0900mmol)、DIPEA (0.03mL，0.1900mmol)及3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-1,2-苯并㗁唑(15 mg，0.0600mmol)。在20℃下攪拌混合物12小時，得到黃色溶液。LCMS展示所要MS。將反應混合物傾入H ₂O (15 mL)中且用EtOAc (20 mL × 4)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由製備型TLC (PE:EtOAc=1:1)純化殘餘物且凍乾，得到呈白色固體狀之標題化合物(5.1mg，0.0152mmol，23.924%產率)。 ¹H NMR (400 MHz, DMSO-d6) δ ppm 12.96 (br s, 1 H), 7.99 (br d, J=7.78 Hz, 1 H), 7.56 - 7.75 (m, 2 H), 7.36 (br t, J=7.78 Hz, 1 H), 6.42 (s, 1 H), 4.50 (br d, J=12.05 Hz, 1 H), 4.10 (br d, J=12.30 Hz, 1 H), 3.96 (br d, J=11.80 Hz, 1 H), 3.61 (br d, J=8.03 Hz, 1 H), 2.93 - 3.04 (m, 1 H), 2.42 (br s, 1 H), 2.22 (br s, 1 H), 1.23 (br d, J=6.53 Hz, 6 H) Example 108 [(1R,5S,6r)-6-(1,2- Benzazol - 3- yl )-3- azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- Pyrazol -3- yl ) methanone [(1R,5S,6r)-6-(1,2- Benzazol - 3- yl )-3- azabicyclo [3.1.0 ] hexyl- 3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone to 5-isopropyl-1H-pyrazole-3-carboxylic acid (10.75mg, 0.0700mmol) in DMF (1mL) Add HATU (33.71mg, 0.0900mmol), DIPEA (0.03mL, 0.1900mmol) and 3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]- 1,2-Benzoxazole (15 mg, 0.0600 mmol). The mixture was stirred at 20 °C for 12 hours to obtain a yellow solution. LCMS showed desired MS. The reaction mixture was poured into H ₂ O (15 mL) and extracted with EtOAc (20 mL×4). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EtOAc=1:1) and lyophilized to give the title compound (5.1 mg, 0.0152 mmol, 23.924% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 12.96 (br s, 1 H), 7.99 (br d, J=7.78 Hz, 1 H), 7.56 - 7.75 (m, 2 H), 7.36 (br t , J=7.78 Hz, 1 H), 6.42 (s, 1 H), 4.50 (br d, J=12.05 Hz, 1 H), 4.10 (br d, J=12.30 Hz, 1 H), 3.96 (br d , J=11.80 Hz, 1 H), 3.61 (br d, J=8.03 Hz, 1 H), 2.93 - 3.04 (m, 1 H), 2.42 (br s, 1 H), 2.22 (br s, 1 H ), 1.23 (br d, J=6.53 Hz, 6 H)

實例 109    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1 R,5S,6r)-6-(4,5,5- 三甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-異丙基-1H-吡唑-3-羧酸(72.64mg，0.4700mmol)於DMF (3.5385mL)中之溶液添加HATU (135.48mg，0.7100mmol)。在15℃下攪拌反應混合物30 min。隨後添加(1R,5S,6r)-6-(4,5,5-三甲基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷(92 mg，0.4700mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (NH ₃)純化反應混合物，得到呈白色粉末狀之標題化合物(14.45mg，0.0436mmol，9.254%產率)。 LC-MS方法1: 332.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 10.62 (br s, 1H), 6.49 (s, 1H), 4.35 (br d, J=10.4 Hz, 1H), 4.22 (d, J=12.8 Hz, 1H), 3.99 - 3.89 (m, 1H), 3.65 (dd, J=4.0, 12.8 Hz, 1H), 3.02 (m, 1H), 2.78 (s, 3H), 2.33 (m, 1H), 2.04 (m, 1H), 1.41 (d, J=7.3 Hz, 6H), 1.30 (d, J=7.0 Hz, 6H), 1.14 (t, J=3.5 Hz, 1H) Example 109 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(4,5,5- trimethyl -4,5- dihydro -1,2 ,4- oxadiazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (5- isopropyl -1H- pyrazol- 3- yl )[(1 R ,5S,6r)-6-(4,5,5- trimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ] methanone To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (72.64 mg, 0.4700 mmol) in DMF (3.5385 mL) was added HATU (135.48 mg, 0.7100 mmol) . The reaction mixture was stirred at 15 °C for 30 min. Then add (1R,5S,6r)-6-(4,5,5-trimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo [3.1.0] Hexane (92 mg, 0.4700 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC (NH ₃ ) to afford the title compound (14.45 mg, 0.0436 mmol, 9.254% yield) as a white powder. LC-MS method 1: 332.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 10.62 (br s, 1H), 6.49 (s, 1H), 4.35 (br d, J =10.4 Hz, 1H), 4.22 (d, J =12.8 Hz, 1H), 3.99 - 3.89 (m, 1H), 3.65 (dd, J =4.0, 12.8 Hz, 1H), 3.02 (m, 1H), 2.78 (s, 3H ), 2.33 (m, 1H), 2.04 (m, 1H), 1.41 (d, J =7.3 Hz, 6H), 1.30 (d, J =7.0 Hz, 6H), 1.14 (t, J =3.5 Hz, 1H )

實例 110    [(1R,5S,6r)-6-(4- 乙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 [(1R,5S,6r)-6-(4- 乙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向5-異丙基-1H-吡唑-3-羧酸(69.24mg，0.4500mmol)於DMF (3.373mL)中之溶液添加HATU (129.15mg，0.6700mmol)及DIPEA (171.4 mg，1.35 mmol)。在15℃下攪拌反應混合物30 min。隨後添加(1R,5S,6r)-6-(4-乙基-5,5-二甲基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(94 mg，0.4500mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (NH ₃)純化反應混合物，得到呈白色粉末狀之標題化合物(41.23mg，0.1194mmol，26.574%產率)。 LC-MS方法1: 346.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 10.80 (br s, 1H), 6.50 (s, 1H), 4.35 (br s, 1H), 4.21 (d, J=12.8 Hz, 1H), 3.97 (dd, J=4.3, 11.6 Hz, 1H), 3.67 (dd, J=4.4, 12.8 Hz, 1H), 3.18 (q, J=7.3 Hz, 2H), 3.02 (td, J=6.9, 13.8 Hz, 1H), 2.41 (td, J=3.9, 7.4 Hz, 1H), 2.05 (td, J=3.6, 7.2 Hz, 1H), 1.43 (d, J=12.8 Hz, 6H), 1.30 (d, J=6.8 Hz, 6H), 1.20 (t, J=7.2 Hz, 3H), 1.14 (t, J=3.4 Hz, 1H) Example 110 [(1R,5S,6r)-6-(4- ethyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3 -Azabicyclo [3.1.0] hex -3- yl ](5- isopropyl - 1H- pyrazol -3- yl ) methanone [ (1R,5S,6r)-6-(4- ethyl- 5,5- Dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ](5- iso Propyl -1H- pyrazol -3- yl ) methanone To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (69.24 mg, 0.4500 mmol) in DMF (3.373 mL) was added HATU (129.15 mg, 0.6700mmol) and DIPEA (171.4 mg, 1.35 mmol). The reaction mixture was stirred at 15 °C for 30 min. Then add (1R,5S,6r)-6-(4-ethyl-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3- Azabicyclo[3.1.0]hexane TFA salt (94 mg, 0.4500 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC (NH ₃ ) to afford the title compound (41.23 mg, 0.1194 mmol, 26.574% yield) as a white powder. LC-MS method 1: 346.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 10.80 (br s, 1H), 6.50 (s, 1H), 4.35 (br s, 1H), 4.21 ( d, J =12.8 Hz, 1H), 3.97 (dd, J =4.3, 11.6 Hz, 1H), 3.67 (dd, J =4.4, 12.8 Hz, 1H), 3.18 (q, J =7.3 Hz, 2H), 3.02 (td, J =6.9, 13.8 Hz, 1H), 2.41 (td, J =3.9, 7.4 Hz, 1H), 2.05 (td, J =3.6, 7.2 Hz, 1H), 1.43 (d, J =12.8 Hz , 6H), 1.30 (d, J =6.8 Hz, 6H), 1.20 (t, J =7.2 Hz, 3H), 1.14 (t, J =3.4 Hz, 1H)

實例 111    [(1R,5S,6r)-6-(4- 環丙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 [(1R,5S,6r)-6-(4- 環丙基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向(1R,5S,6r)-6-(4-環丙基-5,5-二甲基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(90 mg，0.41 mmol)、5-異丙基-1H-吡唑-3-羧酸(68.9 mg，0.45 mmol)及DIPEA (0.34 mL，2.03 mmol)於DMF (4 mL)中之溶液添加HATU (171 mg，0.45 mmol)。在20℃下攪拌混合物16小時。用H ₂O (50 mL)稀釋反應混合物且用EA (25 mL × 3)萃取。用鹽水(50 mL × 3)洗滌有機相，經無水Na ₂SO ₄乾燥且濃縮，得到殘餘物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈白色固體狀之標題化合物(20 mg，0.056 mmol，13.7%產率)。 LC-MS方法1: 358.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿- d) δ ppm 10.39 (br s, 1 H) 6.51 (s, 1 H) 4.14 - 4.39 (m, 2 H) 3.96 (dd, J=11.4, 4.4 Hz, 1 H) 3.69 (dd, J=12.6, 4.4 Hz, 1 H) 3.03 (spt, J=6.9 Hz, 1 H) 2.28 - 2.37 (m, 2 H) 2.06 (dt, J=7.2, 3.8 Hz, 1 H) 1.48 (d, J=8.9 Hz, 6 H) 1.43 (t, J=3.5 Hz, 1 H) 1.31 (d, J=6.9 Hz, 6 H) 0.67 - 0.77 (m, 4 H) Example 111 [(1R,5S,6r)-6-(4- cyclopropyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )- 3- Azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone [(1R,5S,6r)-6-(4- cyclopropane Base -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ](5 -Isopropyl -1H- pyrazol -3- yl ) methanone to (1R,5S,6r)-6-(4-cyclopropyl-5,5-dimethyl-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane TFA salt (90 mg, 0.41 mmol), 5-isopropyl-1H-pyrazole-3-carboxy A solution of acid (68.9 mg, 0.45 mmol) and DIPEA (0.34 mL, 2.03 mmol) in DMF (4 mL) was added HATU (171 mg, 0.45 mmol). The mixture was stirred at 20°C for 16 hours. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EA (25 mL×3). The organic phase was washed with brine (50 mL x 3), dried over anhydrous Na ₂ SO ₄ and concentrated to give a residue. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (20 mg, 0.056 mmol, 13.7% yield) as a white solid. LC-MS method 1: 358.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform- d ) δ ppm 10.39 (br s, 1 H) 6.51 (s, 1 H) 4.14 - 4.39 (m, 2 H) 3.96 (dd, J =11.4, 4.4 Hz, 1 H) 3.69 (dd, J =12.6, 4.4 Hz, 1 H) 3.03 (spt, J =6.9 Hz, 1 H) 2.28 - 2.37 (m, 2 H) 2.06 (dt, J =7.2, 3.8 Hz, 1 H) 1.48 (d, J =8.9 Hz, 6 H) 1.43 (t, J = 3.5 Hz, 1 H) 1.31 (d, J =6.9 Hz, 6 H) 0.67 - 0.77 (m, 4H)

實例 112    [(1R,5S,6r)-6-(5,5- 二甲基 -4- 苯基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 N- 苯基 -2- 丙胺向苯胺(0.2 mL，2.15 mmol)於甲苯(4.6 mL)中之溶液添加丙酮(374.19 mg，6.44 mmol)，繼之以4A MS (200 mg)。隨後在110℃下攪拌混合物3小時。過濾混合物且將濾液濃縮至乾燥，得到呈黃色油狀之標題化合物(300 mg，粗物質)，其在無純化之情況下用於下一步驟。 Example 112 [(1R,5S,6r)-6-(5,5 - dimethyl -4- phenyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3 -Azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone N- phenyl -2- propylamine to aniline (0.2 mL, 2.15 mmol) To a solution in toluene (4.6 mL) was added acetone (374.19 mg, 6.44 mmol) followed by 4A MS (200 mg). The mixture was subsequently stirred at 110° C. for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (300 mg, crude) as a yellow oil which was used in the next step without purification.

(1R,5S,6r)-6-(5,5- 二甲基 -4- 苯基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在20℃下向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(115.23 mg，粗物質)於DMF (3 mL)中之溶液添加Et ₃N (0.3 mL，2.34 mmol)，繼之以N-苯基-2-丙胺(186.64 mg，粗物質)，且隨後在25℃下攪拌混合物1小時。將混合物傾入H ₂O (5 mL)中且用EtOAc (5 mL × 5)萃取。用鹽水(5 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥且濃縮至乾燥。藉由矽膠管柱(自0%至50%之EA/PE)純化殘餘物，得到呈白色固體狀之標題化合物(140 mg，0.3917 mmol，83.849%產率)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.40-7.20 (m, 3H), 7.20-7.10 (m, 2H), 3.50-3.25 (m, 4H), 2.25-2.00 (m, 2H), 1.40 (brs, 3H), 1.37 (brs, 3H), 1.30 (s, 9H), 0.89 (s, 1H)。 (1R,5S,6r)-6-(5,5- Dimethyl -4- phenyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- aza Bicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 20 ℃ to (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3 -Azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (115.23 mg, crude material) in DMF (3 mL) was added Et ₃ N (0.3 mL, 2.34 mmol), followed by With N-phenyl-2-propanamine (186.64 mg, crude material), and then the mixture was stirred at 25°C for 1 hr. The mixture was poured into H ₂ O (5 mL) and extracted with EtOAc (5 mL×5). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column (EA/PE from 0% to 50%) to afford the title compound (140 mg, 0.3917 mmol, 83.849% yield) as a white solid. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.40-7.20 (m, 3H), 7.20-7.10 (m, 2H), 3.50-3.25 (m, 4H), 2.25-2.00 (m, 2H), 1.40 (brs, 3H), 1.37 (brs, 3H), 1.30 (s, 9H), 0.89 (s, 1H).

(1R,5S,6r)-6-(5,5- 二甲基 -4- 苯基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽在20℃下攪拌(1R,5S,6r)-6-(5,5-二甲基-4-苯基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(70 mg，0.20 mmol)於TFA (0.5 mL)/DCM (2.5 mL)中之溶液0.5小時。濃縮混合物，得到標題化合物(73 mg，呈TFA鹽形式之粗物質)，其在無純化之情況下用於下一步驟。 (1R,5S,6r)-6-(5,5- Dimethyl -4- phenyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- aza Bicyclo [3.1.0] hexane TFA salt was stirred at 20°C (1R,5S,6r)-6-(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2, tertiary butyl 4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (70 mg, 0.20 mmol) in TFA (0.5 mL)/DCM (2.5 mL ) in the solution for 0.5 hours. The mixture was concentrated to afford the title compound (73 mg, crude as TFA salt), which was used in the next step without purification.

[(1R,5S,6r)-6-(5,5- 二甲基 -4- 苯基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮在15℃下向3-異丙基-1H-吡唑-5-羧酸(39.4mg，0.26 mmol)及Et ₃N (0.17 mL，0.98 mmol)於DMF (2 mL)中之溶液添加HATU (89.64 mg，0.24 mmol)且隨後在15℃下攪拌混合物20 min。在15℃下向混合物添加(1R,5S,6r)-6-(5,5-二甲基-4-苯基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(73 mg，呈TFA鹽形式之粗物質)且隨後在15℃下攪拌所得混合物16小時。濃縮混合物以移除Et ₃N且藉由製備型HPLC (NH ₃)純化殘餘物且隨後凍乾16小時，得到呈白色固體狀之標題化合物(40.08 mg，0.1019 mmol，51.816%產率)。 LC-MS方法1: 394.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 10.32 (brs, 1H), 7.44 - 7.32 (m, 3H), 7.19 (d, J=7.6 Hz, 2H), 6.43 (s, 1H), 4.30 - 4.00 (m, 1H), 3.97 - 3.90 (m, 2H), 3.65 (dd, J=4.4, 12.8 Hz, 1H), 3.05 - 2.96 (m, 1H), 2.48 - 2.40 (m, 1H), 2.22 - 2.15 (m, 1H), 1.51 (s, 3H), 1.45 (s, 3H), 1.29 (d, J=6.8 Hz, 6H), 0.99 (t, J=3.2 Hz, 1H)。 [(1R,5S,6r)-6-(5,5- Dimethyl -4- phenyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- nitrogen Heterobicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone to 3-isopropyl-1H-pyrazole-5-carboxylate at 15°C A solution of acid (39.4 mg, 0.26 mmol) and _Et3N (0.17 mL, 0.98 mmol) in DMF (2 mL) was added HATU (89.64 mg, 0.24 mmol) and the mixture was then stirred at 15 °C for 20 min. To the mixture was added (1R,5S,6r)-6-(5,5-dimethyl-4-phenyl-4,5-dihydro-1,2,4-oxadiazole-3- )-3-Azabicyclo[3.1.0]hexane TFA salt (73 mg, crude material as TFA salt) and the resulting mixture was then stirred at 15°C for 16 hours. The mixture was concentrated to remove _Et3N and the residue was purified by preparative HPLC ( _NH3 ) and then lyophilized for 16 hours to afford the title compound (40.08 mg, 0.1019 mmol, 51.816% yield) as a white solid. LC-MS method 1: 394.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 10.32 (brs, 1H), 7.44 - 7.32 (m, 3H), 7.19 (d, J =7.6 Hz, 2H), 6.43 (s, 1H), 4.30 - 4.00 (m, 1H), 3.97 - 3.90 (m, 2H), 3.65 (dd, J =4.4, 12.8 Hz, 1H), 3.05 - 2.96 (m, 1H) , 2.48 - 2.40 (m, 1H), 2.22 - 2.15 (m, 1H), 1.51 (s, 3H), 1.45 (s, 3H), 1.29 (d, J =6.8 Hz, 6H), 0.99 (t, J =3.2 Hz, 1H).

實例 113    {(1R,5S,6r)-6-[5,5- 二 甲基 -4-(3- 甲基苯基 )-4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 {(1R,5S,6r)-6-[5,5- 二甲基 -4-(3- 甲基苯基 )-4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向5-異丙基-1H-吡唑-3-羧酸(57.61mg，0.3700mmol)於DMF (2mL)中之溶液添加HATU (166.66mg，0.4400mmol)、DIPEA (0.18mL，1.09mmol)及(1R,5S,6r)-6-[5,5-二甲基-4-(3-甲基苯基)-4,5-二氫-1,2,4-㗁二唑-3-基]-3-氮雜雙環[3.1.0]己烷TFA鹽(120 mg，0.3100mmol，TFA鹽)。在20℃下攪拌混合物12小時，得到黃色溶液。將混合物傾入H ₂O (15 mL)中且用EtOAc (15 mL × 5)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥且濃縮至乾燥。藉由製備型TLC (EtOAc)純化殘餘物且凍乾，得到呈白色固體狀之標題化合物(65.74mg，0.1613mmol，51.808%產率)。 LC-MS方法1: 408.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿 -d) δ ppm 9.97 - 10.66 (1 H, m), 7.24 - 7.27 (1 H, m), 7.13 (1 H, d, J=7.75 Hz), 6.92 - 7.00 (2 H, m), 6.40 (1 H, s), 4.11 (1 H, br d, J=10.88 Hz), 3.87 - 3.97 (2 H, m), 3.64 (1 H, dd, J=12.69, 4.44 Hz), 2.94 - 3.06 (1 H, m), 2.38 - 2.47 (1 H, m), 2.37 (3 H, s), 2.18 (1 H, dt, J=7.35, 3.77 Hz), 1.49 (3 H, s), 1.43 (3 H, s), 1.28 (6 H, d, J=6.88 Hz), 0.97 (1 H, t, J=3.50 Hz) Example 113 {(1R,5S,6r)-6-[5,5- dimethyl -4-(3- methylphenyl )-4,5- dihydro - 1,2,4 - oxadiazole- 3- yl ]-3- azabicyclo [3.1.0] hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone {(1R,5S,6r)-6- [5,5- Dimethyl -4-(3- methylphenyl )-4,5- dihydro -1,2,4- oxadiazol -3- yl ]-3- azabicyclo [3.1. 0] Hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone was added to 5-isopropyl-1H-pyrazole-3-carboxylic acid (57.61mg, 0.3700mmol) in A solution in DMF (2 mL) was added with HATU (166.66 mg, 0.4400 mmol), DIPEA (0.18 mL, 1.09 mmol) and (1R,5S,6r)-6-[5,5-dimethyl-4-(3- Methylphenyl)-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexane TFA salt (120 mg, 0.3100 mmol, TFA Salt). The mixture was stirred at 20 °C for 12 hours to obtain a yellow solution. The mixture was poured into H ₂ O (15 mL) and extracted with EtOAc (15 mL×5). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by prep-TLC (EtOAc) and lyophilized to afford the title compound (65.74 mg, 0.1613 mmol, 51.808% yield) as a white solid. LC-MS method 1: 408.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform -d ) δ ppm 9.97 - 10.66 (1 H, m), 7.24 - 7.27 (1 H, m), 7.13 (1 H , d, J =7.75 Hz), 6.92 - 7.00 (2 H, m), 6.40 (1 H, s), 4.11 (1 H, br d, J =10.88 Hz), 3.87 - 3.97 (2 H, m) , 3.64 (1 H, dd, J =12.69, 4.44 Hz), 2.94 - 3.06 (1 H, m), 2.38 - 2.47 (1 H, m), 2.37 (3 H, s), 2.18 (1 H, dt , J =7.35, 3.77 Hz), 1.49 (3 H, s), 1.43 (3 H, s), 1.28 (6 H, d, J =6.88 Hz), 0.97 (1 H, t, J =3.50 Hz)

實例 114    {(1R,5S,6r)-6-[5,5- 二甲基 -4-(4- 甲基苯基 )-4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 N-(4- 甲基苯基 )-2- 丙胺向4-胺基甲苯(0.18 mL，1.87 mmol)於甲苯(4 mL)中之溶液添加丙酮(325.23 mg，5.6 mmol)，繼之以4A MS (200 mg)。隨後在110℃下攪拌混合物5小時。不監測。過濾混合物且將濾液濃縮至乾燥，得到呈黃色油狀之標題化合物(300 mg，粗物質)，其在無純化之情況下用於下一步驟。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.25 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 3.53 (brs, 6H), 2.35 (s, 3H)。 Example 114 {(1R,5S,6r)-6-[5,5- dimethyl -4-(4- methylphenyl )-4,5- dihydro -1,2,4 - oxadiazole- 3- yl ]-3- azabicyclo [3.1.0] hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone N-(4- methylphenyl )- 2- Propanamine To a solution of 4-aminotoluene (0.18 mL, 1.87 mmol) in toluene (4 mL) was added acetone (325.23 mg, 5.6 mmol) followed by 4A MS (200 mg). The mixture was subsequently stirred at 110° C. for 5 hours. Not monitored. The mixture was filtered and the filtrate was concentrated to dryness to give the title compound (300 mg, crude) as a yellow oil which was used in the next step without purification. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.25 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 3.53 (brs, 6H), 2.35 (s, 3H) .

(1R,5S,6r)-6-[5,5- 二甲基 -4-(4- 甲基苯基 )-4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在20℃下向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(115.23 mg，來自以上之粗反應物)於DMF (3 mL)中之溶液添加Et ₃N (0.3 mL，2.34 mmol)，繼之以N-(4-甲基苯基)-2-丙胺(206.3 mg，粗物質)且隨後在25℃下攪拌混合物1小時。將混合物傾入H ₂O (5 mL)中且用EtOAc (5 mL × 5)萃取。用鹽水(5 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥且濃縮至乾燥。藉由矽膠管柱(自0%至50%之EA/PE)純化殘餘物，得到呈白色固體狀之標題化合物(150 mg，0.4038mmol，86.448%產率)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.21 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 3.50-3.30 (m, 4H), 2.39 (s, 3H), 2.20-2.10 (m, 1H), 2.10-2.00 (m, 1H), 1.47 (s, 6H), 1.38 (s, 9H), 0.95-0.90 (m, 1H)。 (1R,5S,6r)-6-[5,5- Dimethyl -4-(4- methylphenyl )-4,5- dihydro -1,2,4- oxadiazol -3- yl ]-3- Azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 20℃ to (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino ) Methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (115.23 mg, crude reaction from above) in DMF (3 mL) was added Et ₃ N (0.3 mL, 2.34 mmol), followed by N-(4-methylphenyl)-2-propanamine (206.3 mg, crude material) and then the mixture was stirred at 25°C for 1 hour. The mixture was poured into H ₂ O (5 mL) and extracted with EtOAc (5 mL×5). The combined organic layers were washed with brine (5 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column (EA/PE from 0% to 50%) to afford the title compound (150 mg, 0.4038 mmol, 86.448% yield) as a white solid. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.21 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 3.50-3.30 (m, 4H), 2.39 (s, 3H), 2.20-2.10 (m, 1H), 2.10-2.00 (m, 1H), 1.47 (s, 6H), 1.38 (s, 9H), 0.95-0.90 (m, 1H).

(1R,5S,6r)-6-[5,5- 二甲基 -4-(4- 甲基苯基 )-4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽在20℃下攪拌(1R,5S,6r)-6-[5,5-二甲基-4-(4-甲基苯基)-4,5-二氫-1,2,4-㗁二唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(120 mg，0.3200mmol)於TFA (1 mL)/DCM (5 mL)中之溶液0.5小時。濃縮混合物，得到標題化合物(124.49mg，粗物質)，其在無純化之情況下用於下一步驟。 (1R,5S,6r)-6-[5,5- Dimethyl -4-(4- methylphenyl )-4,5- dihydro -1,2,4- oxadiazol -3- yl ]-3- Azabicyclo [3.1.0] hexane TFA salt Stirring (1R,5S,6r)-6-[5,5-dimethyl-4-(4-methylphenyl) at 20°C -4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (120 mg, 0.3200mmol ) in TFA (1 mL)/DCM (5 mL) for 0.5 h. The mixture was concentrated to afford the title compound (124.49 mg, crude material), which was used in the next step without purification.

{(1R,5S,6r)-6-[5,5- 二甲基 -4-(4- 甲基苯基 )-4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮在15℃下向3-異丙基-1H-吡唑-5-羧酸(64.49 mg，0.420 mmol)及Et ₃N (0.28 mL，1.61 mmol)於DMF (2 mL)中之溶液添加HATU (158.95 mg，0.420 mmol)且隨後在15℃下攪拌混合物20 min。在15℃下向混合物添加(1R,5S,6r)-6-[5,5-二甲基-4-(4-甲基苯基)-4,5-二氫-1,2,4-㗁二唑-3-基]-3-氮雜雙環[3.1.0]己烷TFA鹽(124 mg，0.320 mmol，TFA鹽)且隨後在15℃下攪拌所得混合物2小時。濃縮混合物以移除Et ₃N (約3 mL之剩餘DMF)。藉由過濾來收集沈澱物固體且用MeCN (0.5 mL × 2)洗滌濾餅，得到呈白色固體狀之標題化合物(18.1 mg，0.0444 mmol，13.804%產率)。藉由製備型HPLC (NH ₃)純化濾液且隨後凍乾，得到呈白色固體狀之標題化合物(34.44 mg，0.0845 mmol，26.266%產率)。 LC-MS 方法 1: 408.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 10.75 - 9.95 (m, 1H), 7.20 (br d, J=8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 2H), 6.62 - 6.17 (m, 1H), 4.40 - 3.55 (m, 4H), 3.11 - 2.93 (m, 1H), 2.49 - 2.05 (m, 5H), 1.45 (d, J=27.6 Hz, 6H), 1.29 (d, J=7.2 Hz, 6H), 0.96 (t, J=3.2 Hz, 1H)。 {(1R,5S,6r)-6-[5,5- Dimethyl -4-(4- methylphenyl )-4,5- dihydro -1,2,4- oxadiazole -3- base ]-3- azabicyclo [3.1.0] hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone to 3-isopropyl-1H- A solution of pyrazole-5-carboxylic acid (64.49 mg, 0.420 mmol) and _Et3N (0.28 mL, 1.61 mmol) in DMF (2 mL) was added with HATU (158.95 mg, 0.420 mmol) and then stirred at 15 °C Mixture 20 min. To the mixture was added (1R,5S,6r)-6-[5,5-dimethyl-4-(4-methylphenyl)-4,5-dihydro-1,2,4- Diazol-3-yl]-3-azabicyclo[3.1.0]hexane TFA salt (124 mg, 0.320 mmol, TFA salt) and the resulting mixture was then stirred at 15°C for 2 hours. The mixture was concentrated to remove _Et3N (-3 mL of remaining DMF). The precipitated solid was collected by filtration and the filter cake was washed with MeCN (0.5 mL x 2) to give the title compound (18.1 mg, 0.0444 mmol, 13.804% yield) as a white solid. The filtrate was purified by preparative HPLC ( _NH3 ) and then lyophilized to afford the title compound (34.44 mg, 0.0845 mmol, 26.266% yield) as a white solid. LC-MS method 1 : 408.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 10.75 - 9.95 (m, 1H), 7.20 (br d, J =8.0 Hz, 1H), 7.07 (d , J =8.0 Hz, 2H), 6.62 - 6.17 (m, 1H), 4.40 - 3.55 (m, 4H), 3.11 - 2.93 (m, 1H), 2.49 - 2.05 (m, 5H), 1.45 (d, J =27.6 Hz, 6H), 1.29 (d, J =7.2 Hz, 6H), 0.96 (t, J =3.2 Hz, 1H).

實例 115    (5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[4-(4- 甲氧苯基 )-5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 N-(4- 甲氧苯基 ) 丙 -2- 亞胺向4-甲氧基苯胺(0.83mL，8.12mmol)於甲苯(10mL)中之溶液添加丙酮(1.41g，24.36mmol)，繼之以4A MS (1.g，8.12mmol)。隨後在110℃下攪拌混合物5小時，得到褐色懸浮液。過濾混合物且將濾液濃縮至乾燥，得到呈褐色油狀之標題化合物(1.5g，9.1901mmol，113.18%產率)，其在無純化之情況下用於下一步驟。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 6.75 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 8.0 Hz, 2H), 3.77 (s, 3H), 2.15 (s, 6H)。 Example 115 (5- isopropyl -1H- pyrazol -3- yl ){(1R,5S,6r)-6-[4-(4- methoxyphenyl )-5,5- dimethyl -4 ,5- dihydro- 1,2,4- oxadiazol -3- yl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone N-(4- methoxyphenyl ) propane -2- Imine To a solution of 4-methoxyaniline (0.83 mL, 8.12 mmol) in toluene (10 mL) was added acetone (1.41 g, 24.36 mmol) followed by 4A MS (1.g, 8.12 mmol) . The mixture was then stirred at 110° C. for 5 hours, resulting in a brown suspension. The mixture was filtered and the filtrate was concentrated to dryness to afford the title compound (1.5 g, 9.1901 mmol, 113.18% yield) as a brown oil, which was used in the next step without purification. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 6.75 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 8.0 Hz, 2H), 3.77 (s, 3H), 2.15 (s, 6H) .

(1R,5S,6r)-6-[4-(4- 甲氧苯基 )-5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸 三級丁 酯在20℃下向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯於DMF (2mL)中之溶液添加Et ₃N (0.48mL，2.88mmol)，繼之以N-(4-甲氧苯基)丙-2-亞胺(375.62mg，2.3mmol)且隨後在25℃下攪拌混合物1小時，得到褐色溶液。將混合物傾入H ₂O (15 mL)中且用EtOAc (15 mL × 5)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥且濃縮至乾燥。藉由矽膠管柱(自0%至50%之EA/PE)純化殘餘物，得到呈褐色油狀之標題化合物(140mg，0.3613mmol，62.802%產率)。 ¹H NMR (400 MHz, 氯仿- d) δ ppm 7.11 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 3.83 (s, 3H), 3.50-3.30 (m, 4H), 2.20-2.10 (m, 1H), 2.10-2.00 (m, 1H), 1.45 (s, 3H), 1.42 (s, 3H), 1.40 (s, 9H), 0.95-0.90 (m, 1H)。 (1R,5S,6r)-6-[4-(4- methoxyphenyl )-5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl ]-3- Azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 20℃ to (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino )Methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester in DMF (2 mL) was added Et ₃ N (0.48 mL, 2.88 mmol), followed by N -(4-Methoxyphenyl)propan-2-imine (375.62 mg, 2.3 mmol) and then the mixture was stirred at 25 °C for 1 hour to give a brown solution. The mixture was poured into H ₂ O (15 mL) and extracted with EtOAc (15 mL×5). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by silica gel column (EA/PE from 0% to 50%) to give the title compound (140 mg, 0.3613 mmol, 62.802% yield) as a brown oil. ¹ H NMR (400 MHz, chloroform- d ) δ ppm 7.11 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 3.83 (s, 3H), 3.50-3.30 (m, 4H), 2.20-2.10 (m, 1H), 2.10-2.00 (m, 1H), 1.45 (s, 3H), 1.42 (s, 3H), 1.40 (s, 9H), 0.95-0.90 (m, 1H) .

(1R,5S,6r)-6-[4-(4- 甲氧苯基 )-5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽向(1R,5S,6r)-6-[4-(4-甲氧苯基)-5,5-二甲基-4,5-二氫-1,2,4-㗁二唑-3-基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(140 mg，0.3600mmol)於DCM (5mL)中之溶液添加TFA (1 mL，13.46mmol)。在20℃下攪拌混合物0.5小時，得到黑色溶液。TLC (PE:EtOAc=1:1)展示反應完成。直接濃縮反應混合物，得到呈褐色膠質之標題化合物(140mg，0.3488mmol，96.534%產率，TFA，鹽)。 (1R,5S,6r)-6-[4-(4- methoxyphenyl )-5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl ]-3- Azabicyclo [3.1.0] hexane TFA salt to (1R,5S,6r)-6-[4-(4-methoxyphenyl)-5,5-dimethyl-4,5 -Dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (140 mg, 0.3600mmol) in DCM ( 5 mL) was added TFA (1 mL, 13.46 mmol). The mixture was stirred at 20° C. for 0.5 hours to obtain a black solution. TLC (PE:EtOAc=1:1) showed the reaction was complete. The reaction mixture was directly concentrated to afford the title compound (140 mg, 0.3488 mmol, 96.534% yield, TFA, salt) as a brown gum.

(5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[4-(4- 甲氧苯基 )-5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮向5-異丙基-1H-吡唑-3-羧酸(64.53mg，0.4200mmol)於DMF (2mL)中之溶液添加HATU (186.68mg，0.4900mmol)、DIPEA (0.2mL，1.22mmol)及(1R,5S,6r)-6-[4-(4-甲氧苯基)-5,5-二甲基-4,5-二氫-1,2,4-㗁二唑-3-基]-3-氮雜雙環[3.1.0]己烷TFA鹽(140 mg，TFA，鹽0.3500mmol)。在20℃下攪拌混合物12小時，得到褐色溶液。將混合物傾入H ₂O (15 mL)中且用EtOAc (15 mL × 5)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥且濃縮至乾燥。藉由製備型HPLC (FA)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈褐色固體狀之標題化合物(59.06mg，0.1395mmol，39.981%產率)。 LC-MS方法1: 404.3 [M+H ⁺] ¹H NMR (400 MHz, 氯仿 -d) δ ppm 7.11 (2 H, d, J=8.76 Hz), 6.91 (2 H, d, J=8.75 Hz), 6.39 (1 H, s), 4.92 (2 H, br s), 3.96 - 4.06 (1 H, m), 3.84 - 3.95 (2 H, m), 3.83 (3 H, s), 3.62 (1 H, br dd, J=12.63, 4.25 Hz), 3.06 (1 H, dt, J=13.88, 6.94 Hz), 2.35 - 2.45 (1 H, m), 2.12 - 2.23 (1 H, m), 1.44 (6 H, d, J=15.01 Hz), 1.30 (6 H, d, J=6.88 Hz), 0.97 (1 H, t, J=3.13 Hz) (5- isopropyl -1H- pyrazol -3- yl ){(1R,5S,6r)-6-[4-(4- methoxyphenyl )-5,5- dimethyl -4,5 -Dihydro - 1,2,4- oxadiazol -3- yl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone to 5-isopropyl-1H-pyrazole-3 -A solution of carboxylic acid (64.53mg, 0.4200mmol) in DMF (2mL) was added with HATU (186.68mg, 0.4900mmol), DIPEA (0.2mL, 1.22mmol) and (1R,5S,6r)-6-[4- (4-methoxyphenyl)-5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexyl Alkane TFA salt (140 mg, TFA, salt 0.3500 mmol). The mixture was stirred at 20 °C for 12 hours to obtain a brown solution. The mixture was poured into H ₂ O (15 mL) and extracted with EtOAc (15 mL×5). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by preparative HPLC (FA). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to afford the title compound (59.06 mg, 0.1395 mmol, 39.981% yield) as a tan solid. LC-MS method 1: 404.3 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform -d ) δ ppm 7.11 (2 H, d, J =8.76 Hz), 6.91 (2 H, d, J =8.75 Hz ), 6.39 (1 H, s), 4.92 (2 H, br s), 3.96 - 4.06 (1 H, m), 3.84 - 3.95 (2 H, m), 3.83 (3 H, s), 3.62 (1 H, br dd, J =12.63, 4.25 Hz), 3.06 (1 H, dt, J =13.88, 6.94 Hz), 2.35 - 2.45 (1 H, m), 2.12 - 2.23 (1 H, m), 1.44 ( 6 H, d, J =15.01 Hz), 1.30 (6 H, d, J =6.88 Hz), 0.97 (1 H, t, J =3.13 Hz)

實例 116    (5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[4-(3- 甲氧苯基 )-5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[4-(3- 甲氧苯基 )-5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮向5-異丙基-1H-吡唑-3-羧酸(64.53mg，0.4200mmol)於DMF (2mL)中之溶液添加HATU (186.68mg，0.4900mmol)、DIPEA (0.2mL，1.22mmol)及(1R,5S,6r)-6-[4-(3-甲氧苯基)-5,5-二甲基-4,5-二氫-1,2,4-㗁二唑-3-基]-3-氮雜雙環[3.1.0]己烷TFA鹽(140 mg，0.3500mmol，TFA鹽)。在20℃下攪拌混合物12小時，得到褐色溶液。將混合物傾入H ₂O (15 mL)中且用EtOAc (15 mL × 5)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥且濃縮至乾燥。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(62.38mg，0.1473mmol，42.229%產率)。 LC-MS方法1: 424.0 [M+H ⁺] ¹H NMR (400 MHz, 氯仿 -d) δ ppm 10.34 (1 H, br s), 7.28 - 7.33 (1 H, m), 6.86 (1 H, dd, J=8.41, 1.88 Hz), 6.75 (1 H, dd, J=7.91, 1.13 Hz), 6.70 (1 H, t, J=2.13 Hz), 6.45 - 6.45 (1 H, m), 6.42 (1 H, br s), 4.14 (1 H, br s), 3.88 - 3.99 (2 H, m), 3.82 (3 H, s), 3.65 (1 H, dd, J=12.80, 4.27 Hz), 3.00 (1 H, dt, J=13.80, 6.90 Hz), 2.42 (1 H, dt, J=7.47, 3.92 Hz), 2.14 - 2.21 (1 H, m), 1.42 - 1.53 (6 H, m), 1.28 (6 H, d, J=6.78 Hz), 1.02 (1 H, t, J=3.39 Hz) Example 116 (5- isopropyl -1H- pyrazol -3- yl ){(1R,5S,6r)-6-[4-(3- methoxyphenyl )-5,5- dimethyl -4 ,5- dihydro -1,2,4- oxadiazol -3- yl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone (5- isopropyl- 1H- pyrazole -3- yl ){(1R,5S,6r)-6-[4-(3- methoxyphenyl )-5,5- dimethyl -4,5- dihydro -1,2,4- 㗁Oxadiazol -3- yl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone to 5-isopropyl-1H-pyrazole-3-carboxylic acid (64.53mg, 0.4200mmol) in To a solution in DMF (2 mL) was added HATU (186.68 mg, 0.4900 mmol), DIPEA (0.2 mL, 1.22 mmol) and (1R,5S,6r)-6-[4-(3-methoxyphenyl)-5, 5-Dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl]-3-azabicyclo[3.1.0]hexane TFA salt (140 mg, 0.3500 mmol, TFA Salt). The mixture was stirred at 20 °C for 12 hours to obtain a brown solution. The mixture was poured into H ₂ O (15 mL) and extracted with EtOAc (15 mL×5). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to afford the title compound (62.38 mg, 0.1473 mmol, 42.229% yield) as a white solid. LC-MS method 1: 424.0 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform -d ) δ ppm 10.34 (1 H, br s), 7.28 - 7.33 (1 H, m), 6.86 (1 H, dd, J =8.41, 1.88 Hz), 6.75 (1 H, dd, J =7.91, 1.13 Hz), 6.70 (1 H, t, J =2.13 Hz), 6.45 - 6.45 (1 H, m), 6.42 ( 1 H, br s), 4.14 (1 H, br s), 3.88 - 3.99 (2 H, m), 3.82 (3 H, s), 3.65 (1 H, dd, J =12.80, 4.27 Hz), 3.00 (1 H, dt, J =13.80, 6.90 Hz), 2.42 (1 H, dt, J =7.47, 3.92 Hz), 2.14 - 2.21 (1 H, m), 1.42 - 1.53 (6 H, m), 1.28 (6 H, d, J =6.78 Hz), 1.02 (1 H, t, J =3.39 Hz)

實例 117    [(1R,5S,6r)-6-(4- 苯甲基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 N- 苯甲基 -2- 丙胺向苯甲胺(0.5 mL，4.67 mmol )及丙酮(1 mL，14 mmol)於甲苯(5 mL)中之溶液添加4AMS (3 g)，且在無監測之情況下在110℃下攪拌混合物4小時。過濾混合物且濃縮濾液，得到呈無色油狀之標題化合物(330 mg，2.24 mmol)。產物直接用於下一步驟。 Example 117 [(1R,5S,6r)-6-(4- benzyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )- 3- Azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone N- benzyl -2- propylamine to benzylamine (0.5 mL , 4.67 mmol ) and acetone (1 mL, 14 mmol) in toluene (5 mL) were added 4AMS (3 g) and the mixture was stirred at 110 °C for 4 hours without monitoring. The mixture was filtered and the filtrate was concentrated to give the title compound (330 mg, 2.24 mmol) as a colorless oil. The product was used directly in the next step.

(1R,5S,6r)-6-(4- 苯甲基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(150 mg，0.58 mmol)及Et ₃N (0.29 mL，1.73mmol)於DMF (2 mL)中之溶液添加N-苯甲基-2-丙胺(330 mg，2.24 mmol)。在20℃下攪拌混合物2小時。用H ₂O (50 mL)稀釋反應物且用EtOAc (20 mL × 3)萃取。用鹽水洗滌有機相三次，經無水Na ₂SO ₄乾燥且濃縮，得到殘餘物。藉由快速柱(PE:EA=1:0至1:1)純化殘餘物，得到呈淡黃色固體狀之標題化合物(50 mg，0.1346 mmol，23.3%產率) (PE:EA=3:1，Rf=0.5)。 (1R,5S,6r)-6-(4- Benzyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- nitrogen Heterobicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-[(Z)-chloro(hydroxyimino)methyl]-3-aza To a solution of tert-butyl bicyclo[3.1.0]hexane-3-carboxylate (150 mg, 0.58 mmol) and Et ₃ N (0.29 mL, 1.73 mmol) in DMF (2 mL) was added N-benzyl - 2-Propanamine (330 mg, 2.24 mmol). The mixture was stirred at 20°C for 2 hours. The reaction was diluted with H ₂ O (50 mL) and extracted with EtOAc (20 mL×3). The organic phase was washed three _times with brine, dried over anhydrous _Na2SO4 and concentrated to give a residue. The residue was purified by flash column (PE:EA=1:0 to 1:1) to give the title compound (50 mg, 0.1346 mmol, 23.3% yield) as a pale yellow solid (PE:EA=3:1 , Rf=0.5).

(1R,5S,6r)-6-(4- 苯甲基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 TFA 鹽向(1R,5S,6r)-6-(4-苯甲基-5,5-二甲基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(50 mg，0.13 mmol)於DCM (3 mL)中之溶液添加TFA (0.3 mL，4.04 mmol)，且在20℃下攪拌混合物1小時。濃縮反應混合物，得到呈黃色油狀之標題化合物(50 mg，0.18mmol)。 (1R,5S,6r)-6-(4- Benzyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- nitrogen Heterobicyclo [3.1.0] hexane TFA salt to (1R,5S,6r)-6-(4-benzyl-5,5-dimethyl-4,5-dihydro-1,2,4- To a solution of tert-butyl (oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (50 mg, 0.13 mmol) in DCM (3 mL) was added TFA (0.3 mL, 4.04 mmol), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give the title compound (50 mg, 0.18 mmol) as a yellow oil.

[(1R,5S,6r)-6-(4- 苯甲基 -5,5- 二甲基 -4,5- 二氫 -1,2,4- 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向(1R,5S,6r)-6-(4-苯甲基-5,5-二甲基-4,5-二氫-1,2,4-㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(50 mg，0.1800mmol)、HATU (84.5 mg，0.22 mmol)及DIPEA (0.15 mL，0.92 mmol)於DMF (3 mL)中之溶液添加5-異丙基-1H-吡唑-3-羧酸 (34.0 mg，0.22 mmol)，且在20℃下攪拌混合物16小時。用H ₂O (30 mL)稀釋混合物且用EA (20 mL × 2)萃取，且用鹽水(30 mL × 3)洗滌有機相，經無水Na ₂SO ₄乾燥且濃縮，得到殘餘物。藉由製備型HPLC (FA)純化殘餘物，獲得呈白色固體狀之標題化合物(2.5 mg)。 LC-MS方法1: 357.1 [M+H ⁺] ¹H NMR (400 MHz, CDCl ₃) δ ppm 7.28 - 7.32 (m, 5 H) 6.38 (br s, 1 H) 4.29 (s, 2 H) 3.88 (br d, J=12.8 Hz, 1 H) 3.78 - 3.83 (m, 1 H) 3.69 - 3.76 (m, 1 H) 3.49 (br dd, J=12.6, 4.1 Hz, 1 H) 3.04 (dt, J=13.7, 6.8 Hz, 1 H) 2.10 - 2.16 (m, 1 H) 2.03 (dt, J=7.2, 3.7 Hz, 1 H) 1.44 (d, J=6.3 Hz, 6 H) 1.31 (dd, J=6.8, 2.3 Hz, 6 H) 0.97 (t, J=3.3 Hz, 1 H) [(1R,5S,6r)-6-(4- Benzyl -5,5- dimethyl -4,5- dihydro -1,2,4- oxadiazol -3- yl )-3- Azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone to (1R,5S,6r)-6-(4-benzyl- 5,5-Dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane TFA salt (50 mg, 0.1800mmol ), HATU (84.5 mg, 0.22 mmol) and DIPEA (0.15 mL, 0.92 mmol) in DMF (3 mL) were added 5-isopropyl-1H-pyrazole-3-carboxylic acid (34.0 mg, 0.22 mmol ), and the mixture was stirred at 20 °C for 16 hours. The mixture was diluted with H ₂ O (30 mL) and extracted with EA (20 mL×2), and the organic phase was washed with brine (30 mL×3), dried over anhydrous Na ₂ SO ₄ and concentrated to give a residue. The residue was purified by preparative HPLC (FA) to obtain the title compound (2.5 mg) as a white solid. LC-MS method 1: 357.1 [M+H ⁺ ] ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.28 - 7.32 (m, 5 H) 6.38 (br s, 1 H) 4.29 (s, 2 H) 3.88 (br d, J =12.8 Hz, 1 H) 3.78 - 3.83 (m, 1 H) 3.69 - 3.76 (m, 1 H) 3.49 (br dd, J =12.6, 4.1 Hz, 1 H) 3.04 (dt, J =13.7, 6.8 Hz, 1 H) 2.10 - 2.16 (m, 1 H) 2.03 (dt, J =7.2, 3.7 Hz, 1 H) 1.44 (d, J =6.3 Hz, 6 H) 1.31 (dd, J = 6.8, 2.3 Hz, 6 H) 0.97 (t, J =3.3 Hz, 1 H)

實例 118    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(7a- 甲基 -5,6,7,7a- 四氫吡咯并 [1,2-d][1,2,4] 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 5- 甲基 -3,4- 二氫 -2H- 吡咯在0℃下向4-氯丁腈(1.83mL，19.31mmol)於2-甲氧基-2-甲基-丙烷(20 mL，23.18mmol)中之溶液逐滴添加溴基(甲基)鎂(2763.65mg，23.18mmol)。允許其達到室溫。在15min之後，逐滴添加THF (10mL)超過5min。添加H ₂O (30 mL)且用MTBE (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色油狀之標題化合物(800 mg，9.6235mmol，49.826%產率)。其直接用於下一步驟。 Example 118 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(7a- methyl -5,6,7,7a -tetrahydropyrrolo [1, 2-d][1,2,4] oxadiazol -3- yl )-3- azabicyclo [3.1.0] hex - 3- yl ] methanone 5- methyl -3,4- dihydro- 2H- Pyrrole To a solution of 4-chlorobutyronitrile (1.83 mL, 19.31 mmol) in 2-methoxy-2-methyl-propane (20 mL, 23.18 mmol) was added dropwise bromo(methanol) at 0°C. base) Magnesium (2763.65 mg, 23.18 mmol). Allow it to come to room temperature. After 15 min, THF (10 mL) was added dropwise over 5 min. H ₂ O (30 mL) was added and it was extracted with MTBE (30 mL×2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (800 mg, 9.6235 mmol, 49.826% yield) as a yellow oil. It was used directly in the next step.

(1R,5S,6r)-6-(7a- 甲基 -5,6,7,7a- 四氫吡咯并 [1,2-d][1,2,4] 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向100 mL圓底燒瓶裝入(1R,5S,6r)-6-[(Z)-氯基(羥亞胺基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(250 mg，0.9600mmol)、5-甲基-3,4-二氫-2H-吡咯(500 mg，6.01mmol)、三乙胺(0.4mL，2.88mmol)及DMF (12.5mL)。在20℃下攪拌反應物16小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色油狀之標題化合物(300 mg，0.9760mmol，101.78%產率)。其直接用於下一步驟。 LC-MS方法1 0.810 min，MS (m/z) 307.9 (M + H ⁺)。 (1R,5S,6r)-6-(7a- Methyl -5,6,7,7a- tetrahydropyrrolo [1,2-d][1,2,4] oxadiazol- 3- yl ) -3- Azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester was charged into a 100 mL round bottom flask with (1R,5S,6r)-6-[(Z)-chloro(hydroxyl Amino)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (250 mg, 0.9600mmol), 5-methyl-3,4-dihydro-2H- Pyrrole (500 mg, 6.01 mmol), triethylamine (0.4 mL, 2.88 mmol) and DMF (12.5 mL). The reaction was stirred at 20°C for 16 hours to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (300 mg, 0.9760 mmol, 101.78% yield) as a yellow oil. It was used directly in the next step. LC-MS method 1 0.810 min, MS (m/z) 307.9 (M + H ⁺ ).

3-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-7a- 甲基 -5,6,7,7a- 四氫吡咯并 [1,2-d][1,2,4] 㗁二唑 TFA 鹽向100 mL圓底燒瓶裝入(1R,5S,6r)-6-(7a-甲基-5,6,7,7a-四氫吡咯并[1,2-d][1,2,4]㗁二唑-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(250 mg，0.8100mmol)、2,2,2-三氟乙酸(1 mL，13.06mmol)及DCM (10mL)。在20℃下攪拌反應物3小時，得到黃色溶液。在真空中蒸發反應混合物，得到呈紅色油狀之標題化合物(260mg，0.8092mmol，99.498%產率)。其直接用於下一步驟。 3-[(1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl ]-7a- methyl -5,6,7,7a- tetrahydropyrrolo [1,2- d][1,2,4] Oxadiazole TFA salt was charged into a 100 mL round bottom flask with (1R,5S,6r)-6-(7a-methyl-5,6,7,7a-tetrahydropyrrolo [1,2-d][1,2,4]oxadiazol-3-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (250 mg, 0.8100mmol ), 2,2,2-trifluoroacetic acid (1 mL, 13.06 mmol) and DCM (10 mL). The reaction was stirred at 20°C for 3 hours to give a yellow solution. The reaction mixture was evaporated in vacuo to afford the title compound (260 mg, 0.8092 mmol, 99.498% yield) as a red oil. It was used directly in the next step.

(5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(7a- 甲基 -5,6,7,7a- 四氫吡咯并 [1,2-d][1,2,4] 㗁二唑 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向100 mL圓底燒瓶裝入5-異丙基-1H-吡唑-3-羧酸(130 mg，0.8400mmol)、HATU (354.6mg，0.9300mmol)、N-乙基-N-異丙基丙-2-胺(0.58mL，3.37mmol)及DMF (6.5mL)。在攪拌30 min之後，添加3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-7a-甲基-5,6,7,7a-四氫吡咯并[1,2-d][1,2,4]㗁二唑TFA鹽(270.93mg，0.8400mmol)。在20℃下攪拌反應混合物16小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (NH ₃)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(32.74mg，0.0950mmol，11.269%產率)。 LC-MS 方法 1: 344.1 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d ₆) δ 6.36 (br s, 1H), 4.20-4.44 (m, 1H), 3.95 (br s, 1H), 3.80 (br s, 1H), 3.45-3.57 (m, 2H), 2.97 (ddd, J=6.32, 9.01, 11.44 Hz, 2H), 2.03-2.15 (m, 1H), 1.95 (br s, 1H), 1.85-1.91 (m, 1H), 1.80-1.85 (m, 1H), 1.69-1.76 (m, 1H), 1.57-1.66 (m, 1H), 1.35 (s, 3H), 1.22 (d, J=6.88 Hz, 6H) (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(7a- methyl -5,6,7,7a -tetrahydropyrrolo [1,2- d][1,2,4] oxadiazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone was charged with 5-isopropyl- 1H-pyrazole-3-carboxylic acid (130 mg, 0.8400mmol), HATU (354.6mg, 0.9300mmol), N-ethyl-N-isopropylpropan-2-amine (0.58mL, 3.37mmol) and DMF (6.5 mL). After stirring for 30 min, 3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-7a-methyl-5,6,7,7a-tetrahydro Pyrrolo[1,2-d][1,2,4]oxadiazole TFA salt (270.93 mg, 0.8400 mmol). The reaction mixture was stirred at 20 °C for 16 hours to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried _{over Na2SO4} and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC ( _NH3 ). The obtained fluid was concentrated in vacuo to remove most of _CH3CN and lyophilized to give the title compound (32.74 mg, 0.0950 mmol, 11.269% yield) as a white solid. LC-MS method 1 : 344.1 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.36 (br s, 1H), 4.20-4.44 (m, 1H), 3.95 (br s, 1H) , 3.80 (br s, 1H), 3.45-3.57 (m, 2H), 2.97 (ddd, J =6.32, 9.01, 11.44 Hz, 2H), 2.03-2.15 (m, 1H), 1.95 (br s, 1H) , 1.85-1.91 (m, 1H), 1.80-1.85 (m, 1H), 1.69-1.76 (m, 1H), 1.57-1.66 (m, 1H), 1.35 (s, 3H), 1.22 (d, J = 6.88 Hz, 6H)

實例 119    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5- 甲基 -1,3,4- 㗁二唑 -2- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-3-[(5- 異丙基 -1H- 吡唑 -3- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 羧酸乙酯向5-異丙基-1H-吡唑-3-羧酸(1.69g，10.96mmol)於DMF (20mL)中之溶液添加HATU (5.41g，14.24mmol)、DIPEA (5.43mL，32.87mmol)及(1R,5S,6r)-3-氮雜雙環[3.1.0]己烷-6-羧酸乙酯(2.1g，10.96mmol)。在15℃下攪拌混合物4小時，得到褐色溶液。將反應混合物傾入H ₂O (100 mL)中且用EtOAc (100 mL × 3)萃取。用鹽水(250 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由快速柱(PE至40% EtOAc/PE)純化粗產物，得到褐色固體。用EtOAc/ PE (10 mL/20 mL)濕磨所獲得固體且在空氣中乾燥，得到呈白色固體狀之標題化合物(1.45g，4.9768mmol，45.422%產率)。 ¹H NMR (400MHz, 氯仿-d) δ ppm = 10.58 (brs, 1H), 6.47 (s, 1H), 4.35 (d, J = 11.2 Hz, 1H), 4.20 (d, J = 11.2 Hz, 1H), 4.20 (q, J = 6.8 Hz, 2H), 3.95 (d, J = 11.6, 4.0 Hz, 1H), 3.68 (d, J = 11.6, 4.0 Hz, 1H), 3.02 (qn, J = 3.6 Hz, 1H), 2.30-2.15 (m, 2H), 1.50-1.45 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H), 1.26 (t, J = 6.8 Hz, 3H)。 Example 119 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(5- methyl -1,3,4- oxadiazol -2- yl )- 3- Azabicyclo [3.1.0] hex -3- yl ] methanone (1R,5S,6r)-3-[(5- isopropyl -1H- pyrazol -3- yl ) carbonyl ]-3- Azabicyclo [3.1.0] hexane -6- carboxylic acid ethyl ester To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (1.69 g, 10.96 mmol) in DMF (20 mL) was added HATU (5.41g, 14.24mmol), DIPEA (5.43mL, 32.87mmol) and ethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate (2.1g, 10.96mmol ). The mixture was stirred at 15°C for 4 hours to give a brown solution. The reaction mixture was poured into H ₂ O (100 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (250 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column (PE to 40% EtOAc/PE) to give a tan solid. The obtained solid was triturated with EtOAc/PE (10 mL/20 mL) and dried in air to afford the title compound (1.45 g, 4.9768 mmol, 45.422% yield) as a white solid. ¹ H NMR (400MHz, Chloroform-d) δ ppm = 10.58 (brs, 1H), 6.47 (s, 1H), 4.35 (d, J = 11.2 Hz, 1H), 4.20 (d, J = 11.2 Hz, 1H) , 4.20 (q, J = 6.8 Hz, 2H), 3.95 (d, J = 11.6, 4.0 Hz, 1H), 3.68 (d, J = 11.6, 4.0 Hz, 1H), 3.02 (qn, J = 3.6 Hz, 1H), 2.30-2.15 (m, 2H), 1.50-1.45 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H), 1.26 (t, J = 6.8 Hz, 3H).

(1R,5S,6r)-3-[(5- 異丙基 -1H- 吡唑 -3- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 碳醯肼向(1R,5S,6r)-3-[(5-異丙基-1H-吡唑-3-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-羧酸乙酯(450 mg，1.54mmol)於EtOH (4 mL)中之溶液添加水合肼(236.69mg，4.63mmol)。在80℃下於N ₂下攪拌混合物13小時，得到白色懸浮液。LCMS展示所要MS且起始材料之一部分剩餘。隨後向混合物添加水合肼(236.69mg，4.63mmol)。在80℃下於N ₂下攪拌混合物13小時，得到白色懸浮液。LCMS展示所要MS且起始材料之一部分剩餘。隨後向混合物添加水合肼(236.69mg，4.63mmol)。在80℃下於N ₂下攪拌混合物13小時，得到白色懸浮液。LCMS展示所要MS且起始材料之一部分剩餘。直接濃縮反應混合物。用PE (15 mL)濕磨所獲得固體且在空氣中乾燥，得到呈白色固體狀之標題化合物(390mg，1.4063mmol，91.051%產率)。 ¹H NMR (400 MHz, DM3SO-d ₆) δ ppm 12.96 (brs, 1H), 9.06 (s, 1H), 6.37 (brs, 1H), 4.50-3.80 (m, 6H), 3.50-3.40 (m, 1H), 3.00-2.90 (m, 1H), 2.05-1.95 (m, 1H), 1.95-1.85 (m, 1H), 1.25 (d, J = 7.2 Hz, 6H), 0.90-0.80 (m, 1H)。 (1R,5S,6r)-3-[(5- isopropyl -1H- pyrazol -3- yl ) carbonyl ]-3- azabicyclo [3.1.0] hexane -6- carbohydrazine to ( 1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (450 mg, 1.54 mmol) in EtOH (4 mL) was added hydrazine hydrate (236.69 mg, 4.63 mmol). The mixture was stirred at 80 °C under _N for 13 h to give a white suspension. LCMS showed the desired MS and a portion of starting material remained. Hydrazine hydrate (236.69 mg, 4.63 mmol) was then added to the mixture. The mixture was stirred at 80 °C under _N for 13 h to give a white suspension. LCMS showed the desired MS and a portion of starting material remained. Hydrazine hydrate (236.69 mg, 4.63 mmol) was then added to the mixture. The mixture was stirred at 80 °C under _N for 13 h to give a white suspension. LCMS showed the desired MS and a portion of starting material remained. The reaction mixture was directly concentrated. The obtained solid was triturated with PE (15 mL) and dried in air to afford the title compound (390 mg, 1.4063 mmol, 91.051% yield) as a white solid. ¹ H NMR (400 MHz, DM3SO-d ₆ ) δ ppm 12.96 (brs, 1H), 9.06 (s, 1H), 6.37 (brs, 1H), 4.50-3.80 (m, 6H), 3.50-3.40 (m, 1H), 3.00-2.90 (m, 1H), 2.05-1.95 (m, 1H), 1.95-1.85 (m, 1H), 1.25 (d, J = 7.2 Hz, 6H), 0.90-0.80 (m, 1H) .

(1R,5S,6r)-N'- 乙醯基 -3-[(5- 異丙基 -1H- 吡唑 -3- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 碳醯肼向(1R,5S,6r)-3-[(5-異丙基-1H-吡唑-3-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-碳醯肼(270 mg，0.9700mmol)於DCM (10mL)中之混合物添加乙酸酐(119.27mg，1.17mmol)及Et ₃N (0.34mL，1.95mmol)。在15℃下攪拌反應混合物12小時，得到白色懸浮液。過濾懸浮液。用DCM (5 mL × 3)洗滌濾餅且真空乾燥，得到呈白色固體狀之標題化合物(250mg，0.7828mmol，80.404%產率)。 (1R,5S,6r)-N'- Acetyl -3-[(5- isopropyl -1H- pyrazol -3- yl ) carbonyl ]-3- azabicyclo [3.1.0 ] hexane- 6- carbohydrazine to (1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6 - A mixture of carbohydrazine (270 mg, 0.9700 mmol) in DCM (10 mL) was added acetic anhydride (119.27 mg, 1.17 mmol) and _Et3N (0.34 mL, 1.95 mmol). The reaction mixture was stirred at 15°C for 12 hours to give a white suspension. Filter the suspension. The filter cake was washed with DCM (5 mL x 3) and dried in vacuo to give the title compound (250 mg, 0.7828 mmol, 80.404% yield) as a white solid.

(5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5- 甲基 -1,3,4- 㗁二唑 -2- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮在90℃下攪拌(1R,5S,6r)-N'-乙醯基-3-[(5-異丙基-1H-吡唑-3-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-碳醯肼(250 mg，0.7800mmol)於POCl ₃(5 mL，69.14mmol)中之溶液4小時，得到褐色混合物。TLC展示偵測到一個新樣點(Rf = 0.3)。真空濃縮反應混合物，得到殘餘物。用DCM (15 mL)溶解殘餘物。用NaHCO ₃(當量，15 mL×2)洗滌所得混合物。用DCM (10 mL×3)萃取水相。用無水Na ₂SO ₄乾燥合併之有機相，過濾且真空濃縮，得到殘餘物。藉由製備型TLC (SiO ₂，DCM:MeOH = 10:1)純化殘餘物且凍乾，得到呈黃色粉末狀之標題化合物(120mg，0.3799mmol，48.535%產率)。 LC-MS方法1: 301.9 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 9.99 - 10.47 (m, 1 H), 6.53 (s, 1 H), 4.45 (br d, J=10.6 Hz, 1 H), 4.29 (d, J=12.8 Hz, 1 H), 3.99 (dd, J=11.6, 4.0 Hz, 1 H), 3.72 (dd, J=12.7, 4.1 Hz, 1 H), 2.99 - 3.09 (m, 1 H), 2.49 (s, 3 H), 2.35 - 2.43 (m, 1 H), 2.26 - 2.34 (m, 1 H), 1.96 (t, J=3.4 Hz, 1 H), 1.31 (d, J=6.9 Hz, 6 H) (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(5- methyl -1,3,4- oxadiazol - 2- yl )-3- Azabicyclo [3.1.0] hex -3- yl ] methanone was stirred at 90°C (1R,5S,6r)-N'-acetyl-3-[(5-isopropyl-1H-pyrazole A solution of -3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carbohydrazide (250 mg, 0.7800 mmol) in POCl ₃ (5 mL, 69.14 mmol) for 4 hours gave brown mixture. TLC showed detection of a new spot (Rf = 0.3). The reaction mixture was concentrated in vacuo to give a residue. The residue was dissolved with DCM (15 mL). The resulting mixture was washed with NaHCO ₃ (eq, 15 mL×2). The aqueous phase was extracted with DCM (10 mL×3). The combined organic phases were dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10:1 ) and lyophilized to give the title compound (120 mg, 0.3799 mmol, 48.535% yield) as a yellow powder. LC-MS method 1: 301.9 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 9.99 - 10.47 (m, 1 H), 6.53 (s, 1 H), 4.45 (br d, J =10.6 Hz, 1 H), 4.29 (d, J=12.8 Hz, 1 H), 3.99 (dd, J=11.6, 4.0 Hz, 1 H), 3.72 (dd, J=12.7, 4.1 Hz, 1 H) , 2.99 - 3.09 (m, 1 H), 2.49 (s, 3 H), 2.35 - 2.43 (m, 1 H), 2.26 - 2.34 (m, 1 H), 1.96 (t, J=3.4 Hz, 1 H ), 1.31 (d, J=6.9 Hz, 6 H)

實例 120    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(4- 甲基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 N'-({(1R,5S,6r)-3-[(5- 異丙基 -1H- 吡唑 -3- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己 -6- 基 } 羰基 )-N,N- 二甲基亞肼基甲醯胺向(1R,5S,6r)-3-[(5-異丙基-1H-吡唑-3-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-碳醯肼(390 mg，1.41mmol)於DMF (4mL)中之溶液添加1,1-二甲氧基-N,N-二甲基甲胺(0.2mL，1.48mmol)。在100℃下攪拌混合物15小時，得到黃色溶液。直接濃縮反應混合物，得到呈白色固體狀之標題化合物(450mg，1.3538mmol，96.265%產率)。 ¹H NMR (400 MHz, DMSO-d ₆) δ ppm 12.94 (brs, 1H), 10.10 (s, 1H), 7.66 (s, 1H), 6.36 (brs, 1H), 4.40-4.30 (m, 1H), 4.00-3.70 (m, 2H), 3.50-3.40 (m, 1H), 3.00-2.90 (m, 1H), 2.80-2.75 (m, 1H), 2.76 (s, 6H), 2.00-1.80 (m, 2H), 1.21 (d, J= 7.2 Hz, 6H), 1.25-1.20 (m, 1H)。 Example 120 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(4- methyl -4H-1,2,4- triazole -3- yl ) -3- Azabicyclo [3.1.0] hex -3-yl ] methanoneN '-({(1R,5S,6r)-3-[(5- isopropyl -1H- pyrazol - 3 -yl ) carbonyl ]-3- azabicyclo [3.1.0] hex -6- yl } carbonyl )-N,N- dimethylhydrazonoformamide to (1R,5S,6r)-3-[(5 -A solution of isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carbohydrazide (390 mg, 1.41 mmol) in DMF (4 mL) 1,1-Dimethoxy-N,N-dimethylmethylamine (0.2 mL, 1.48 mmol) was added. The mixture was stirred at 100°C for 15 hours to obtain a yellow solution. The reaction mixture was directly concentrated to afford the title compound (450 mg, 1.3538 mmol, 96.265% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.94 (brs, 1H), 10.10 (s, 1H), 7.66 (s, 1H), 6.36 (brs, 1H), 4.40-4.30 (m, 1H) , 4.00-3.70 (m, 2H), 3.50-3.40 (m, 1H), 3.00-2.90 (m, 1H), 2.80-2.75 (m, 1H), 2.76 (s, 6H), 2.00-1.80 (m, 2H), 1.21 (d, J= 7.2 Hz, 6H), 1.25-1.20 (m, 1H).

(5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(4- 甲基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向N'-({(1R,5S,6r)-3-[(5-異丙基-1H-吡唑-3-基)羰基]-3-氮雜雙環[3.1.0]己-6-基}羰基)-N,N-二甲基亞肼基甲醯胺(200 mg，0.6000mmol)於THF (4mL)中之溶液添加甲胺(0.49mL，12.03mmol)。隨後在0℃下向混合物添加HOAc (2 mL，0.6000mmol)。在100℃下攪拌混合物，得到無色溶液。直接濃縮反應混合物。藉由製備型HPLC (HCl)純化殘餘物，得到呈白色固體狀之標題化合物(37.05mg，0.1234mmol，20.501%產率)。 ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.39 (br s, 1 H), 6.42 (s, 1 H), 4.46 (br d, J=11.88 Hz, 1 H), 4.10 (br d, J=12.51 Hz, 1 H), 3.95 (br dd, J=12.01, 3.88 Hz, 1 H), 3.85 (s, 3 H), 3.60 (br dd, J=12.44, 4.06 Hz, 1 H), 2.97 (spt, J=6.90 Hz, 1 H), 2.47 (br s, 2 H), 2.16 (t, J=3.25 Hz, 1 H), 1.22 (d, J=6.75 Hz, 6 H) (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(4- methyl- 4H-1,2,4- triazol -3- yl )-3 -Azabicyclo [3.1.0] hex -3- yl ] methanone to N'-({(1R,5S,6r)-3-[(5 - isopropyl-1H-pyrazol-3-yl) Carbonyl]-3-azabicyclo[3.1.0]hex-6-yl}carbonyl)-N,N-dimethylhydrazonoformamide (200 mg, 0.6000 mmol) in THF (4 mL) Methylamine (0.49 mL, 12.03 mmol) was added. To the mixture was then added HOAc (2 mL, 0.6000 mmol) at 0 °C. The mixture was stirred at 100°C to obtain a colorless solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (HCl) to afford the title compound (37.05 mg, 0.1234 mmol, 20.501% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 9.39 (br s, 1 H), 6.42 (s, 1 H), 4.46 (br d, J=11.88 Hz, 1 H), 4.10 (br d, J =12.51 Hz, 1 H), 3.95 (br dd, J=12.01, 3.88 Hz, 1 H), 3.85 (s, 3 H), 3.60 (br dd, J=12.44, 4.06 Hz, 1 H), 2.97 ( spt, J=6.90 Hz, 1 H), 2.47 (br s, 2 H), 2.16 (t, J=3.25 Hz, 1 H), 1.22 (d, J=6.75 Hz, 6 H)

實例 121    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(4- 苯基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(4- 苯基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向(1R,5S,6r)-3-[(5-異丙基-1H-吡唑-3-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-碳醯肼於MeCN (2mL)中之溶液添加1,1-二甲氧基-N,N-二甲基甲胺(21.52mg，0.1800mmol)。在50℃下攪拌混合物30 min。隨後向混合物添加苯胺(0.03mL，0.3600mmol)，繼之以AcOH (2 mL)。在120℃下攪拌混合物5小時，得到無色溶液。藉由製備型HPLC (HCl)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(24.12mg，0.0666mmol，36.912%產率)。 LC-MS方法1: 362.9 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d ₆) δ ppm 9.28 - 9.55 (1 H, m), 7.58 - 7.70 (5 H, m), 6.34 (1 H, s), 4.26 (1 H, br d, J=12.01 Hz), 3.81 - 3.92 (2 H, m), 3.54 (1 H, dd, J=12.44, 4.19 Hz), 2.93 (1 H, dt, J=13.85, 6.89 Hz), 2.54 - 2.58 (1 H, m), 2.39 (1 H, dt, J=7.19, 3.66 Hz), 1.68 (1 H, t, J=3.31 Hz), 1.19 (6 H, d, J=7.00 Hz) Example 121 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(4- phenyl -4H-1,2,4- triazole -3- yl ) -3- Azabicyclo [3.1.0] hex - 3 - yl ] methanone (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(4- benzene Base -4H-1,2,4- triazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to (1R,5S,6r)-3-[(5 -Isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carbohydrazine in MeCN (2 mL) was added with 1,1-dimethyl Oxy-N,N-dimethylmethylamine (21.52 mg, 0.1800 mmol). The mixture was stirred at 50 °C for 30 min. To the mixture was then added aniline (0.03 mL, 0.3600 mmol) followed by AcOH (2 mL). The mixture was stirred at 120°C for 5 hours to obtain a colorless solution. The residue was purified by preparative HPLC (HCl). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to afford the title compound (24.12 mg, 0.0666 mmol, 36.912% yield) as a white solid. LC-MS method 1: 362.9 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.28 - 9.55 (1 H, m), 7.58 - 7.70 (5 H, m), 6.34 (1 H, s), 4.26 (1 H, br d, J =12.01 Hz), 3.81 - 3.92 (2 H, m), 3.54 (1 H, dd, J =12.44, 4.19 Hz), 2.93 (1 H, dt , J =13.85, 6.89 Hz), 2.54 - 2.58 (1 H, m), 2.39 (1 H, dt, J =7.19, 3.66 Hz), 1.68 (1 H, t, J =3.31 Hz), 1.19 (6 H, d, J =7.00 Hz)

實例 122    {(1R,5S,6r)-6-[4-(4- 氟苯基 )-4H-1,2,4- *** -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 {(1R,5S,6r)-6-[4-(4- 氟苯基 )-4H-1,2,4- *** -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向(1R,5S,6r)-3-[(5-異丙基-1H-吡唑-3-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-碳醯肼於MeCN (2mL)中之溶液添加1,1-二甲氧基-N,N-二甲基甲胺(47.96mg，0.3600mmol)。在80℃下攪拌混合物30 min。隨後添加4-氟苯胺(0.07mL，0.7200mmol)及AcOH (216.36mg，3.61mmol)。在90℃下攪拌混合物5小時，得到無色溶液。直接濃縮反應混合物。藉由製備型HPLC (HCl)純化殘餘物，得到呈灰色固體狀之標題化合物(5.67mg，0.0149mmol，4.1333%產率)。 LC-MS方法1: 381.0 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d ₆) δ ppm 12.92 (1 H, br s), 8.67 (1 H, s), 7.62 (2 H, br dd, J=8.91, 4.89 Hz), 7.35 - 7.51 (2 H, m), 6.33 (1 H, s), 4.28 (1 H, br d, J=12.05 Hz), 3.80 - 3.94 (2 H, m), 3.52 (1 H, br d, J=8.03 Hz), 2.85 - 3.01 (1 H, m), 2.19 (1 H, br s), 1.92 - 2.04 (1 H, m), 1.51 (1 H, br s), 1.13 - 1.27 (6 H, m) Example 122 {(1R,5S,6r)-6-[4-(4- fluorophenyl )-4H-1,2,4- triazol -3- yl ]-3- azabicyclo [3.1.0] Hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone {(1R,5S,6r)-6-[4-(4- fluorophenyl )-4H-1, 2,4- triazol -3- yl ]-3- azabicyclo [3.1.0] hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone to (1R, 5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carbohydrazide in MeCN (2mL) To the solution in 1,1-dimethoxy-N,N-dimethylmethanamine (47.96 mg, 0.3600 mmol) was added. The mixture was stirred at 80 °C for 30 min. Then 4-fluoroaniline (0.07 mL, 0.7200 mmol) and AcOH (216.36 mg, 3.61 mmol) were added. The mixture was stirred at 90°C for 5 hours to obtain a colorless solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (HCl) to afford the title compound (5.67 mg, 0.0149 mmol, 4.1333% yield) as a gray solid. LC-MS method 1: 381.0 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.92 (1 H, br s), 8.67 (1 H, s), 7.62 (2 H, br dd, J =8.91, 4.89 Hz), 7.35 - 7.51 (2 H, m), 6.33 (1 H, s), 4.28 (1 H, br d, J =12.05 Hz), 3.80 - 3.94 (2 H, m ), 3.52 (1 H, br d, J =8.03 Hz), 2.85 - 3.01 (1 H, m), 2.19 (1 H, br s), 1.92 - 2.04 (1 H, m), 1.51 (1 H, br s), 1.13 - 1.27 (6 H, m)

實例 123    [(1R,5S,6r)-6-(4,5- 二甲基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 [(1R,5S,6r)-6-(4,5- 二甲基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向(5-異丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-(5-甲基-1,3,4-㗁二唑-2-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮(30 mg，0.1000mmol)於二甲苯(2 mL，0.1000mmol)中之溶液添加甲胺(0.74mL，1.99mmol)及TsOH (1.71mg，0.0100mmol)。在140℃下攪拌混合物12小時，得到褐色溶液。直接濃縮反應混合物。藉由製備型HPLC (HCl)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈淡黃色固體狀之標題化合物(11.82mg，0.0376mmol，37.765%產率)。 LC-MS方法1: 314.9 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d ₆) δ ppm 6.41 (1 H, s), 4.44 (1 H, br d, J=11.80 Hz), 4.09 (1 H, d, J=12.30 Hz), 3.94 (1 H, br dd, J=11.92, 4.14 Hz), 3.71 (3 H, s), 3.59 (1 H, br dd, J=12.55, 4.27 Hz), 2.96 (1 H, dt, J=13.80, 6.90 Hz), 2.56 (3 H, s), 2.38 (1 H, br d, J=3.76 Hz), 2.29 - 2.35 (1 H, m), 2.28 (1 H, s), 2.14 (1 H, t, J=3.39 Hz), 1.21 (6 H, dd, J=7.03, 1.00 Hz) Example 123 [(1R,5S,6r)-6-(4,5- Dimethyl -4H-1,2,4- triazol -3- yl )-3- azabicyclo [3.1.0 ] hexyl- 3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone [(1R,5S,6r)-6-(4,5- dimethyl -4H-1,2,4- Triazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone to (5-isopropyl- 1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo[3.1.0 To a solution of ]hex-3-yl]methanone (30 mg, 0.1000 mmol) in xylene (2 mL, 0.1000 mmol) was added methylamine (0.74 mL, 1.99 mmol) and TsOH (1.71 mg, 0.0100 mmol). The mixture was stirred at 140°C for 12 hours to obtain a brown solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (HCl). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (11.82 mg, 0.0376 mmol, 37.765% yield) as a light yellow solid. LC-MS method 1: 314.9 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.41 (1 H, s), 4.44 (1 H, br d, J =11.80 Hz), 4.09 (1 H, d, J =12.30 Hz), 3.94 (1 H, br dd, J =11.92, 4.14 Hz), 3.71 (3 H, s), 3.59 (1 H, br dd, J =12.55, 4.27 Hz ), 2.96 (1 H, dt, J =13.80, 6.90 Hz), 2.56 (3 H, s), 2.38 (1 H, br d, J =3.76 Hz), 2.29 - 2.35 (1 H, m), 2.28 (1 H, s), 2.14 (1 H, t, J =3.39 Hz), 1.21 (6 H, dd, J =7.03, 1.00 Hz)

實例 124    [(1R,5S,6r)-6-(4- 環丁基 -5- 甲基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 [(1R,5S,6r)-6-(4- 環丁基 -5- 甲基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向(5-異丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-(5-甲基-1,3,4-㗁二唑-2-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮(30 mg，0.1000mmol)於鄰二甲苯(1mL)中之混合物添加TsOH (0.17mg，0mmol)及環丁胺(0.02mL，0.2000mmol)。在140℃下攪拌反應混合物16小時，得到褐色混合物。真空濃縮反應混合物，得到殘餘物。藉由製備型HPLC (HCl)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色固體狀之標題化合物(10.71mg，0.0302mmol，30.351%產率)。 LC-MS方法1: 355.0 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d6) δ ppm 6.42 (s, 1 H), 4.85 - 4.98 (m, 1 H), 4.45 (br d, J=12.0 Hz, 1 H), 4.05 (d, J=12.3 Hz, 1 H), 3.93 (br dd, J=11.9, 4.1 Hz, 2 H), 3.61 (br s, 1 H), 3.58 (br s, 1 H), 2.91 - 3.01 (m, 1 H), 2.63 - 2.69 (m, 2 H), 2.60 (s, 3 H), 2.42 - 2.45 (m, 1 H), 2.36 (br d, J=3.8 Hz, 1 H), 2.04 (t, J=3.4 Hz, 1 H), 1.84 (td, J=10.2, 5.0 Hz, 2 H), 1.22 (d, J=7.0 Hz, 6 H) Example 124 [(1R,5S,6r)-6-(4- cyclobutyl -5- methyl -4H-1,2,4- triazol - 3- yl )-3- azabicyclo [3.1.0 ] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone [(1R,5S,6r)-6-(4- cyclobutyl- 5- methyl -4H- 1,2,4- triazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone to ( 5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-nitrogen To a mixture of heterobicyclo[3.1.0]hex-3-yl]methanone (30 mg, 0.1000 mmol) in o-xylene (1 mL) was added TsOH (0.17 mg, 0 mmol) and cyclobutylamine (0.02 mL, 0.2000 mmol) ). The reaction mixture was stirred at 140°C for 16 hours to obtain a brown mixture. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (HCl). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (10.71 mg, 0.0302 mmol, 30.351% yield) as a yellow solid. LC-MS method 1: 355.0 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d6) δ ppm 6.42 (s, 1 H), 4.85 - 4.98 (m, 1 H), 4.45 (br d, J =12.0 Hz, 1 H), 4.05 (d, J=12.3 Hz, 1 H), 3.93 (br dd, J=11.9, 4.1 Hz, 2 H), 3.61 (br s, 1 H), 3.58 (br s , 1 H), 2.91 - 3.01 (m, 1 H), 2.63 - 2.69 (m, 2 H), 2.60 (s, 3 H), 2.42 - 2.45 (m, 1 H), 2.36 (br d, J= 3.8 Hz, 1 H), 2.04 (t, J=3.4 Hz, 1 H), 1.84 (td, J=10.2, 5.0 Hz, 2 H), 1.22 (d, J=7.0 Hz, 6 H)

實例 125    [(1R,5S,6r)-6-(4- 環己基 -5- 甲基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 (1R,5S,6r)-6-( 環己基胺甲醯基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(500 mg，2.2mmol)於DMF (6mL)中之溶液添加HATU (1086.86mg，2.86mmol)、環己胺(0.28mL，2.42mmol)及Et ₃N (0.91mL，5.5mmol)。在20℃下攪拌混合物12小時，得到灰色懸浮液。TLC (PE:EtOAc=1:1)展示反應完成。將反應混合物傾入H ₂O (15 mL)中且過濾。用H ₂O (15 mL × 2)洗滌濾餅且在空氣中乾燥，得到呈白色固體狀之標題化合物(650mg，2.1075mmol，95.791%產率)。 ¹H NMR (400 MHz, 氯仿-d) δ ppm 5.48 (d, J = 8.0 Hz, 1H), 3.85-3.70 (m, 1H), 3.67 (d, J = 11.2 Hz, 1H), 3.59 (d, J = 11.2 Hz, 1H), 3.45-3.35 (m, 2H), 2.04 (brs, 2H), 1.91 (brd, J = 9.6 Hz, 2H), 1.80-1.70 (m, 2H), 1.65-1.55 (m, 1H), 1.44 (s, 9H), 1.50-1.20 (m, 2H), 1.25-1.05 (m, 4H)。 Example 125 [(1R,5S,6r)-6-(4- cyclohexyl -5- methyl -4H-1,2,4- triazol -3- yl )-3- azabicyclo [3.1.0] Hex -3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone (1R,5S,6r)-6-( cyclohexylaminoformyl )-3- azabicyclo [3.1 .0] Hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-3-{[(tertiary butyl)oxy]carbonyl}-3-azabicyclo[3.1.0]hexane A solution of alkane-6-carboxylic acid (500 mg, 2.2 mmol) in DMF (6 mL) was added with HATU (1086.86 mg, 2.86 mmol), cyclohexylamine (0.28 mL, 2.42 mmol) and Et ₃ N (0.91 mL, 5.5 mmol). The mixture was stirred at 20°C for 12 hours to give a gray suspension. TLC (PE:EtOAc=1:1) showed the reaction was complete. The reaction mixture was poured into H ₂ O (15 mL) and filtered. The filter cake was washed with H ₂ O (15 mL×2) and dried in air to give the title compound (650 mg, 2.1075 mmol, 95.791% yield) as a white solid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 5.48 (d, J = 8.0 Hz, 1H), 3.85-3.70 (m, 1H), 3.67 (d, J = 11.2 Hz, 1H), 3.59 (d, J = 11.2 Hz, 1H), 3.45-3.35 (m, 2H), 2.04 (brs, 2H), 1.91 (brd, J = 9.6 Hz, 2H), 1.80-1.70 (m, 2H), 1.65-1.55 (m , 1H), 1.44 (s, 9H), 1.50-1.20 (m, 2H), 1.25-1.05 (m, 4H).

(1R,5S,6r)-6-( 環己基硫代胺甲醯基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-(環己基胺甲醯基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(600 mg，1.95mmol)於THF (6mL)中之溶液添加2,4-雙(4-甲氧基苯基)-1,3,2,4-二硫雜二磷雜環丁烷2,4-二硫化物(802.59mg，1.98mmol)。在20℃下攪拌混合物12小時，得到褐色溶液。TLC (PE:EtOAc=5:1)展示新樣點。將反應混合物傾入H ₂O (20 mL)中且用EtOAc (20 mL × 4)萃取。用鹽水(50 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由快速柱(PE至10% EtOAc/PE)純化粗產物，得到呈灰色固體狀之標題化合物(350mg，1.0786mmol，55.446%產率)。 ¹H NMR (400 MHz, 氯仿-d) δ ppm 7.58 (brd, J = 7.2 Hz, 1H), 4.50-4.35 (m, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.57 (d, J = 11.2 Hz, 1H), 3.50-3.40 (m, 2H), 2.45-2.35 (m, 2H), 2.15-2.05 (m, 2H), 1.80-1.50 (m, 4H), 1.45 (s, 9H), 1.50-1.40 (m, 2H), 1.30-1.10 (m, 4H)。 (1R,5S,6r)-6-( cyclohexylthioaminoformyl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r) - A solution of tertiary-butyl 6-(cyclohexylaminoformyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (600 mg, 1.95 mmol) in THF (6 mL) was added for 2 , 4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (802.59 mg, 1.98 mmol). The mixture was stirred at 20 °C for 12 hours to obtain a brown solution. TLC (PE:EtOAc=5:1) showed a new spot. The reaction mixture was poured into H ₂ O (20 mL) and extracted with EtOAc (20 mL×4). The combined organic layers were washed with brine (50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column (PE to 10% EtOAc/PE) to give the title compound (350 mg, 1.0786 mmol, 55.446% yield) as a gray solid. ¹ H NMR (400 MHz, chloroform-d) δ ppm 7.58 (brd, J = 7.2 Hz, 1H), 4.50-4.35 (m, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.57 (d, J = 11.2 Hz, 1H), 3.50-3.40 (m, 2H), 2.45-2.35 (m, 2H), 2.15-2.05 (m, 2H), 1.80-1.50 (m, 4H), 1.45 (s, 9H) , 1.50-1.40 (m, 2H), 1.30-1.10 (m, 4H).

(1R,5S,6r)-6-[(Z)-( 環己基亞胺基 )( 甲硫基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-(環己基硫代胺甲醯基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(300 mg，0.9200mmol)、1-甲基-4-(甲磺醯基)苯(0.12mL，0.9300mmol)於DMF (6mL)中之溶液添加三級丁醇鉀(124.49mg，1.11mmol)。在20℃下攪拌混合物9小時，得到黃色溶液。將反應混合物傾入H ₂O (20 mL)中且用EtOAc (20 mL × 4)萃取。用鹽水(50 mL × 2)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈淡黃色固體狀之標題化合物(300 mg，0.8862mmol，95.855%產率)。 LC-MS方法1 0.693 min，MS (m/z) 339.0 (M + H ⁺)。 (1R,5S,6r)-6-[(Z)-( cyclohexylimino )( methylthio ) methyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary Butyl ester to (1R,5S,6r)-6-(cyclohexylthioaminoformyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (300 mg, 0.9200 mmol), 1-methyl-4-(methylsulfonyl)benzene (0.12 mL, 0.9300 mmol) in DMF (6 mL) was added potassium tert-butoxide (124.49 mg, 1.11 mmol). The mixture was stirred at 20°C for 9 hours to obtain a yellow solution. The reaction mixture was poured into H ₂ O (20 mL) and extracted with EtOAc (20 mL×4). The combined organic layers were washed with brine (50 mL x 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (300 mg, 0.8862 mmol, 95.855% yield) as a light yellow solid . LC-MS method 1 0.693 min, MS (m/z) 339.0 (M + H ⁺ ).

(1R,5S,6r)-6-(4- 環己基 -5- 甲基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(Z)-(環己基亞胺基)(甲硫基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(300 mg，0.8900mmol)及乙醯肼(98.48mg，1.33mmol)於THF (5mL)中之溶液添加2,2,2-三氟乙酸(0.03mL，0.4400mmol)。在75℃下攪拌混合物16小時，得到無色溶液。將反應混合物傾入H ₂O (20 mL)中且用EtOAc (20 mL × 4)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由快速柱(EtOAc/MeOH=1/0至5/1)純化粗產物，得到呈無色膠質之標題化合物(280mg，0.8082mmol，91.189%產率)。 LC-MS方法1 0.718 min，MS (m/z) 347.1 (M + H+)。 (1R,5S,6r)-6-(4- cyclohexyl -5- methyl -4H-1,2,4- triazol -3- yl )-3- azabicyclo [3.1.0 ] hexane- 3- Carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-[(Z)-(cyclohexylimino)(methylthio)methyl]-3-azabicyclo[3.1.0] To a solution of tert-butyl hexane-3-carboxylate (300 mg, 0.8900 mmol) and acetylhydrazine (98.48 mg, 1.33 mmol) in THF (5 mL) was added 2,2,2-trifluoroacetic acid (0.03 mL , 0.4400mmol). The mixture was stirred at 75°C for 16 hours to give a colorless solution. The reaction mixture was poured into H ₂ O (20 mL) and extracted with EtOAc (20 mL×4). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by flash column (EtOAc/MeOH = 1/0 to 5/1 ) to give the title compound (280 mg, 0.8082 mmol, 91.189% yield) as a colorless gum. LC-MS method 1 0.718 min, MS (m/z) 347.1 (M + H+).

(1R,5S,6r)-6-(4- 環己基 -5- 甲基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷氫氯化物在20℃下攪拌(1R,5S,6r)-6-(4-環己基-5-甲基-4H-1,2,4-***-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(130 mg，0.3800mmol)於HCl/二㗁烷(0.09mL，0.3800mmol)中之溶液30 min，得到無色溶液。LCMS展示所要MS且起始材料消耗完。直接濃縮反應混合物，得到呈黃色膠質之標題化合物(100 mg，0.3536mmol，94.238%產率)。 (1R,5S,6r)-6-(4- cyclohexyl -5- methyl -4H-1,2,4- triazol -3- yl )-3- azabicyclo [3.1.0] hexanehydrogen (1R,5S,6r)-6-(4 - cyclohexyl-5-methyl-4H-1,2,4-triazol-3-yl)-3-azabicyclo[ 3.1.0] A solution of tert-butyl hexane-3-carboxylate (130 mg, 0.3800 mmol) in HCl/dioxane (0.09 mL, 0.3800 mmol) for 30 min gave a colorless solution. LCMS showed desired MS and starting material was consumed. The reaction mixture was directly concentrated to afford the title compound (100 mg, 0.3536 mmol, 94.238% yield) as a yellow gum.

[(1R,5S,6r)-6-(4- 環己基 -5- 甲基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向5-異丙基-1H-吡唑-3-羧酸(65.42mg，0.4200mmol)於DMF (1.7422mL)中之溶液添加HATU (188.11mg，0.5000mmol)、Et ₃N (0.18mL，1.06mmol)及(1R,5S,6r)-6-(4-環己基-5-甲基-4H-1,2,4-***-3-基)-3-氮雜雙環[3.1.0]己烷氫氯化物(100 mg，0.3500mmol)。在20℃下攪拌混合物12小時，得到黃色溶液。LCMS展示所要MS且起始材料消耗完。將反應混合物傾入H ₂O (20 mL)中且用EtOAc (20 mL × 4)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由製備型HPLC (HCl)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到黃色固體(粗物質)。藉由製備型TLC (EtOAc)純化殘餘物且凍乾，得到呈白色固體狀之標題化合物。 ¹H NMR (400 MHz, 氯仿 -d) δ ppm 10.84 - 11.67 (1 H, m), 6.53 (1 H, s), 4.46 (1 H, br d, J=10.76 Hz), 4.26 (1 H, br d, J=12.76 Hz), 3.96 - 4.12 (2 H, m), 3.76 (1 H, br dd, J=12.88, 4.25 Hz), 3.02 - 3.18 (1 H, m), 2.74 (1 H, br s), 2.51 (3 H, br s), 2.11 (1 H, br s), 1.89 - 2.00 (5 H, m), 1.79 (1 H, br d, J=13.76 Hz), 1.67 - 1.75 (2 H, m), 1.38 - 1.50 (2 H, m), 1.33 (6 H, dd, J=6.88, 1.63 Hz), 1.25 (1 H, br d, J=6.38 Hz) [ (1R,5S,6r)-6-(4- cyclohexyl -5- methyl -4H-1,2,4- triazol -3- yl )-3- azabicyclo [3.1.0] hexyl- 3- yl ](5- isopropyl -1H- pyrazol -3- yl ) methanone was dissolved in 5-isopropyl-1H-pyrazole-3-carboxylic acid (65.42mg, 0.4200mmol) in DMF (1.7422mL ) was added HATU (188.11mg, 0.5000mmol), Et ₃ N (0.18mL, 1.06mmol) and (1R,5S,6r)-6-(4-cyclohexyl-5-methyl-4H-1, 2,4-Triazol-3-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (100 mg, 0.3500 mmol). The mixture was stirred at 20 °C for 12 hours to obtain a yellow solution. LCMS showed desired MS and starting material was consumed. The reaction mixture was poured into H ₂ O (20 mL) and extracted with EtOAc (20 mL×4). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (HCl). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give a yellow solid (crude). The residue was purified by prep-TLC (EtOAc) and lyophilized to give the title compound as a white solid. ¹ H NMR (400 MHz, chloroform -d ) δ ppm 10.84 - 11.67 (1 H, m), 6.53 (1 H, s), 4.46 (1 H, br d, J =10.76 Hz), 4.26 (1 H, br d, J =12.76 Hz), 3.96 - 4.12 (2 H, m), 3.76 (1 H, br dd, J =12.88, 4.25 Hz), 3.02 - 3.18 (1 H, m), 2.74 (1 H, br s), 2.51 (3 H, br s), 2.11 (1 H, br s), 1.89 - 2.00 (5 H, m), 1.79 (1 H, br d, J =13.76 Hz), 1.67 - 1.75 ( 2 H, m), 1.38 - 1.50 (2 H, m), 1.33 (6 H, dd, J =6.88, 1.63 Hz), 1.25 (1 H, br d, J =6.38 Hz)

實例 126    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5- 甲基 -4- 苯基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5- 甲基 -4- 苯基 -4H-1,2,4- *** -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向(5-異丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-(5-甲基-1,3,4-㗁二唑-2-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮(30 mg，0.1000mmol)於鄰二甲苯(1mL)中之混合物添加苯胺(0.02mL，0.2000mmol)及TsOH (0.17mg，0mmol)。在140℃下攪拌反應混合物16小時，得到褐色混合物。真空濃縮反應混合物，得到殘餘物。藉由製備型HPLC (HCl)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色粉末狀之標題化合物(18.55mg，0.0493mmol，49.496%產率)。 LC-MS方法1: 377.0 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.54 - 7.79 (m, 5 H), 6.32 (s, 1 H), 4.17 (br d, J=12.0 Hz, 1 H), 3.85 (br dd, J=11.8, 4.1 Hz, 2 H), 3.74 (br d, J=12.4 Hz, 2 H), 2.93 (dt, J=13.9, 7.1 Hz, 1 H), 2.68 (br d, J=1.8 Hz, 1 H), 2.35 (s, 3 H), 2.28 (dt, J=7.5, 3.6 Hz, 1 H), 1.45 (t, J=3.3 Hz, 1 H), 1.19 (d, J=6.9 Hz, 6 H) Example 126 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(5- methyl -4- phenyl -4H-1,2,4- triazole -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (5- isopropyl- 1H- pyrazol -3- yl )[(1R,5S,6r)-6 -(5- Methyl -4- phenyl -4H-1,2,4- triazol -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to (5- Isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3-azabicyclo [3.1.0] Hex-3-yl]methanone (30 mg, 0.1000 mmol) in o-xylene (1 mL) was added aniline (0.02 mL, 0.2000 mmol) and TsOH (0.17 mg, 0 mmol). The reaction mixture was stirred at 140°C for 16 hours to obtain a brown mixture. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (HCl). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (18.55 mg, 0.0493 mmol, 49.496% yield) as a white powder. LC-MS method 1: 377.0 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.54 - 7.79 (m, 5 H), 6.32 (s, 1 H), 4.17 (br d, J =12.0 Hz, 1 H), 3.85 (br dd, J=11.8, 4.1 Hz, 2 H), 3.74 (br d, J=12.4 Hz, 2 H), 2.93 (dt, J=13.9, 7.1 Hz, 1 H), 2.68 (br d, J=1.8 Hz, 1 H), 2.35 (s, 3 H), 2.28 (dt, J=7.5, 3.6 Hz, 1 H), 1.45 (t, J=3.3 Hz, 1 H), 1.19 (d, J=6.9 Hz, 6 H)

實例 127    {(1R,5S,6r)-6-[4-(4- 氟苯基 )-5- 甲基 -4H-1,2,4- *** -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 {(1R,5S,6r)-6-[4-(4- 氟苯基 )-5- 甲基 -4H-1,2,4- *** -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向(5-異丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-(5-甲基-1,3,4-㗁二唑-2-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮(25 mg，0.0800mmol)於對二甲苯(0.50 mL)中之溶液添加4-氟苯胺(0.02mL，0.1700mmol)及TsOH (0.14mg，0mmol)。在140℃下攪拌混合物12小時，得到褐色溶液。直接濃縮反應混合物。藉由製備型HPLC (HCl)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(13.91mg，0.0353mmol，42.506%產率)。 LC-MS方法1: 395.0 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d ₆) δ ppm 7.76 (1 H, dd, J=8.69, 4.82 Hz), 7.73 - 7.80 (1 H, m), 7.55 (2 H, t, J=8.63 Hz), 6.30 - 6.37 (1 H, m), 4.18 (1 H, br d, J=12.01 Hz), 3.86 (1 H, br dd, J=11.94, 4.06 Hz), 3.75 (1 H, br d, J=12.51 Hz), 3.51 (1 H, br dd, J=12.44, 4.06 Hz), 2.88 - 2.99 (1 H, m), 2.39 (3 H, s), 2.31 - 2.37 (1 H, m), 1.53 (1 H, t, J=3.25 Hz), 1.19 (6 H, d, J=7.00 Hz) Example 127 {(1R,5S,6r)-6-[4-(4- fluorophenyl )-5- methyl -4H-1,2,4- triazol -3- yl ]-3- azabicyclo [3.1.0] Hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone {(1R,5S,6r)-6-[4-(4- fluorophenyl ) -5- methyl -4H-1,2,4- triazol -3- yl ]-3- azabicyclo [ 3.1.0] hex -3- yl }(5- isopropyl -1H- pyrazole- 3- yl ) methanone to (5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-oxadiazole- To a solution of 2-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone (25 mg, 0.0800 mmol) in p-xylene (0.50 mL) was added 4-fluoroaniline (0.02 mL, 0.1700mmol) and TsOH (0.14mg, 0mmol). The mixture was stirred at 140°C for 12 hours to obtain a brown solution. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC (HCl). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to afford the title compound (13.91 mg, 0.0353 mmol, 42.506% yield) as a white solid. LC-MS method 1: 395.0 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.76 (1 H, dd, J =8.69, 4.82 Hz), 7.73 - 7.80 (1 H, m ), 7.55 (2 H, t, J =8.63 Hz), 6.30 - 6.37 (1 H, m), 4.18 (1 H, br d, J =12.01 Hz), 3.86 (1 H, br dd, J =11.94 , 4.06 Hz), 3.75 (1 H, br d, J =12.51 Hz), 3.51 (1 H, br dd, J =12.44, 4.06 Hz), 2.88 - 2.99 (1 H, m), 2.39 (3 H, s), 2.31 - 2.37 (1 H, m), 1.53 (1 H, t, J =3.25 Hz), 1.19 (6 H, d, J =7.00 Hz)

實例 128    (5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[5- 甲基 -4-(4- 甲基苯基 )-4H-1,2,4- *** -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[5- 甲基 -4-(4- 甲基苯基 )-4H-1,2,4- *** -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮向(5-異丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-(5-甲基-1,3,4-㗁二唑-2-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮(20 mg，0.0700mmol)於鄰二甲苯(1mL)中之混合物添加對甲苯胺(0.01mL，0.1300mmol)及TsOH (0.11mg)。在140℃下攪拌反應混合物12小時，得到褐色混合物。真空濃縮反應混合物，得到殘餘物。藉由製備型HPLC (HCl)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈黃色固體狀之標題化合物(11.42mg，0.0278mmol，41.954%產率)。 LC-MS方法1: 391.0 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.49 - 7.53 (m, 2 H), 7.45 - 7.49 (m, 2 H), 6.33 (s, 1 H), 4.20 (br d, J=12.1 Hz, 1 H), 3.86 (br dd, J=12.0, 4.3 Hz, 2 H), 3.75 (br d, J=12.4 Hz, 1 H), 2.93 (dt, J=13.9, 6.9 Hz, 1 H), 2.46 (br d, J=3.1 Hz, 1 H), 2.41 (s, 3 H), 2.34 (s, 3 H), 2.29 (dt, J=7.4, 3.8 Hz, 1 H), 1.46 (t, J=3.4 Hz, 1 H), 1.19 (d, J=6.9 Hz, 6 H) Example 128 (5- isopropyl -1H- pyrazol -3- yl ) {(1R, 5S, 6r)-6-[5- methyl -4-(4- methylphenyl )-4H-1, 2,4- triazol -3- yl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone (5- isopropyl -1H- pyrazol -3- yl ){(1R, 5S,6r)-6-[5- methyl -4-(4- methylphenyl )-4H-1,2,4- triazol -3- yl ]-3- azabicyclo [3.1.0] Hex -3- yl } methanone to (5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-㗁di To a mixture of oxazol-2-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone (20 mg, 0.0700 mmol) in o-xylene (1 mL) was added p-toluidine (0.01 mL, 0.1300mmol) and TsOH (0.11mg). The reaction mixture was stirred at 140 °C for 12 hours to obtain a brown mixture. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (HCl). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (11.42 mg, 0.0278 mmol, 41.954% yield) as a yellow solid. LC-MS method 1: 391.0 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.49 - 7.53 (m, 2 H), 7.45 - 7.49 (m, 2 H), 6.33 (s, 1 H), 4.20 (br d, J=12.1 Hz, 1 H), 3.86 (br dd, J=12.0, 4.3 Hz, 2 H), 3.75 (br d, J=12.4 Hz, 1 H), 2.93 ( dt, J=13.9, 6.9 Hz, 1 H), 2.46 (br d, J=3.1 Hz, 1 H), 2.41 (s, 3 H), 2.34 (s, 3 H), 2.29 (dt, J=7.4 , 3.8 Hz, 1 H), 1.46 (t, J=3.4 Hz, 1 H), 1.19 (d, J=6.9 Hz, 6 H)

實例 129    {(1R,5S,6r)-6-[4-(4- 乙基苯基 )-5- 甲基 -4H-1,2,4- *** -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 {(1R,5S,6r)-6-[4-(4- 乙基苯基 )-5- 甲基 -4H-1,2,4- *** -3- 基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 }(5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向(5-異丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-(5-甲基-1,3,4-㗁二唑-2-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮(20 mg，0.0700mmol)於鄰二甲苯(0.9535mL)中之混合物添加4-乙基苯胺(0.02mL，0.1300mmol)及TsOH (0.11mg)。在140℃下攪拌反應混合物12小時，得到褐色混合物。LCMS展示起始材料完全耗盡。真空濃縮反應混合物，得到殘餘物。藉由製備型HPLC (HCl)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色粉末狀之標題化合物(9.41mg，0.0229mmol，34.521%產率)。 LC-MS方法1: 405.0 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.47 - 7.57 (m, 4 H), 6.25 - 6.40 (m, 1 H), 4.18 (br d, J=11.9 Hz, 1 H), 3.86 (br dd, J=11.9, 4.1 Hz, 2 H), 3.75 (br d, J=12.5 Hz, 1 H), 3.49 (br s, 2 H), 2.87 - 2.97 (m, 1 H), 2.66 - 2.76 (m, 2 H), 2.36 (s, 3 H), 2.28 - 2.33 (m, 2 H), 1.46 (t, J=3.3 Hz, 1 H), 1.16 - 1.25 (m, 9 H) Example 129 {(1R,5S,6r)-6-[4-(4- ethylphenyl )-5- methyl - 4H-1,2,4- triazol -3- yl ]-3- aza Bicyclo [3.1.0] hex -3- yl }(5- isopropyl -1H- pyrazol -3- yl ) methanone {(1R,5S,6r)-6-[4-(4- ethylbenzene Base )-5- methyl -4H-1,2,4 - triazol -3- yl ]-3- azabicyclo [3.1.0] hex -3- yl }(5- isopropyl -1H- pyridine Azol -3- yl ) methanone to (5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(5-methyl-1,3,4-㗁di To a mixture of azol-2-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone (20 mg, 0.0700 mmol) in o-xylene (0.9535 mL) was added 4-ethylaniline ( 0.02 mL, 0.1300 mmol) and TsOH (0.11 mg). The reaction mixture was stirred at 140 °C for 12 hours to obtain a brown mixture. LCMS showed complete consumption of starting material. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (HCl). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (9.41 mg, 0.0229 mmol, 34.521% yield) as a white powder. LC-MS method 1: 405.0 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d6) δ ppm 7.47 - 7.57 (m, 4 H), 6.25 - 6.40 (m, 1 H), 4.18 (br d , J=11.9 Hz, 1 H), 3.86 (br dd, J=11.9, 4.1 Hz, 2 H), 3.75 (br d, J=12.5 Hz, 1 H), 3.49 (br s, 2 H), 2.87 - 2.97 (m, 1 H), 2.66 - 2.76 (m, 2 H), 2.36 (s, 3 H), 2.28 - 2.33 (m, 2 H), 1.46 (t, J=3.3 Hz, 1 H), 1.16 - 1.25 (m, 9H)

實例 130    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(6- 甲基 [1,2,4] ***并 [4,3-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6-{[2-(5- 甲基 -2- 吡啶基 ) 肼基 ] 羰基 }-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(300 mg，1.32mmol)於DMF (5mL)中之混合物添加2-肼基-5-甲基吡啶(162.58mg，1.32mmol)、Et ₃N (0.24mL，1.45mmol)及HATU (551.79mg，1.45mmol)。在15℃下攪拌反應混合物16小時，得到褐色混合物。真空濃縮反應混合物，得到殘餘物。藉由管柱層析(SiO ₂，PE/EA=6/1)純化殘餘物，得到呈黃色固體狀之標題化合物(330mg，0.9928mmol，75.206%產率)。 LC-MS方法1 0.639 min，MS (m/z) 332.9 (M + H ⁺)。 Example 130 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(6- methyl [1,2,4] triazolo [4,3-a ] pyridin -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (1R,5S,6r)-6-{[2-(5- methyl -2- pyridyl ) hydrazino ] carbonyl } -3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester to (1R, 5S, 6r) -3-{[(tertiary butyl) oxy] To a mixture of carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (300 mg, 1.32 mmol) in DMF (5 mL) was added 2-hydrazino-5-methylpyridine (162.58 mg, 1.32mmol), _Et3N (0.24mL, 1.45mmol) and HATU (551.79mg, 1.45mmol). The reaction mixture was stirred at 15°C for 16 hours to give a brown mixture. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA=6/1) to give the title compound (330 mg, 0.9928 mmol, 75.206% yield) as a yellow solid. LC-MS method 1 0.639 min, MS (m/z) 332.9 (M + H ⁺ ).

(1R,5S,6r)-6-(6- 甲基 [1,2,4] ***并 [4,3-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-{[2-(5-甲基-2-吡啶基)肼基]羰基}-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(270 mg，0.8100mmol)於MeCN (5 mL)中之混合物添加柏傑士試劑(387.13mg，1.62mmol)。在90℃下攪拌反應混合物12小時。TLC展示起始材料完全耗盡，且偵測到一個新樣點。真空濃縮反應混合物，得到殘餘物。藉由製備型TLC (SiO ₂，DCM:MeOH = 10:1)純化殘餘物，得到呈黃色固體狀之標題化合物(130mg，0.4135mmol，50.908%產率)。 LC-MS方法1 0.693 min，MS (m/z) 314.9 (M + H ⁺)。 (1R,5S,6r)-6-(6- Methyl [1,2,4] triazolo [4,3-a] pyridin -3- yl )-3- azabicyclo [3.1.0] hexyl Alkane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-{[2-(5-methyl-2-pyridyl)hydrazino]carbonyl}-3-azabicyclo[3.1. 0] A mixture of tert-butyl hexane-3-carboxylate (270 mg, 0.8100 mmol) in MeCN (5 mL) was added Bergers reagent (387.13 mg, 1.62 mmol). The reaction mixture was stirred at 90°C for 12 hours. TLC showed complete consumption of starting material and one new spot was detected. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10:1 ) to give the title compound (130 mg, 0.4135 mmol, 50.908% yield) as a yellow solid. LC-MS method 1 0.693 min, MS (m/z) 314.9 (M + H ⁺ ).

3-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-6- 甲基 [1,2,4] ***并 [4,3-a] 吡啶 TFA 鹽向(1R,5S,6r)-6-(6-甲基[1,2,4]***并[4,3-a]吡啶-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(130 mg，0.4100mmol)於DCM (4mL)中之溶液添加TFA (1 mL，13.46mmol)。在15℃下攪拌反應混合物2小時，得到黃色混合物。TLC (DCM:MeOH = 10:1)展示起始材料完全耗盡。真空濃縮反應混合物，得到呈黃色油狀之標題化合物(135mg，0.4112mmol，99.446%產率)。 3-[(1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl ]-6- methyl [1,2,4] triazolo [4,3-a] pyridine TFA salt to (1R,5S,6r)-6-(6-methyl[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3-azabicyclo[3.1. 0] A solution of tert-butyl hexane-3-carboxylate (130 mg, 0.4100 mmol) in DCM (4 mL) was added TFA (1 mL, 13.46 mmol). The reaction mixture was stirred at 15°C for 2 hours to give a yellow mixture. TLC (DCM:MeOH=10:1) showed complete consumption of starting material. The reaction mixture was concentrated in vacuo to afford the title compound (135 mg, 0.4112 mmol, 99.446% yield) as a yellow oil.

(5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(6- 甲基 [1,2,4] ***并 [4,3-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-6-甲基[1,2,4]***并[4,3-a]吡啶TFA鹽(130 mg，0.4000mmol)於DMF (3.0297mL)中之混合物添加5-異丙基-1H-吡唑-3-羧酸(61.05mg，0.4000mmol)、DIPEA (0.2mL，1.19mmol)及HATU (180.57mg，0.4800mmol)。在15℃下攪拌反應混合物12小時，得到褐色混合物。LCMS展示起始材料完全耗盡。藉由製備型HPLC (HCl)純化反應混合物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(25.34mg，0.0698mmol，17.624%產率)。 LC-MS方法1: 350.9 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (dd, J=6.9, 1.2 Hz, 6 H), 2.37 (d, J=3.6 Hz, 1 H), 2.40 (s, 3 H), 2.44 (br d, J=1.9 Hz, 1 H), 2.47 (dd, J=3.4, 1.6 Hz, 1 H), 2.93 - 3.03 (m, 1 H), 3.62 (br s, 1 H), 3.66 (br d, J=3.5 Hz, 1 H), 4.00 (br dd, J=11.9, 4.2 Hz, 1 H), 4.21 (d, J=12.4 Hz, 1 H), 4.53 (br d, J=11.8 Hz, 1 H), 6.45 (s, 1 H), 7.78 (d, J=9.5 Hz, 1 H), 7.91 (d, J=9.3 Hz, 1 H), 8.86 (s, 1 H)。 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(6- methyl [1,2,4] triazolo [4,3-a] pyridine -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6- To a mixture of 6-methyl[1,2,4]triazolo[4,3-a]pyridine TFA salt (130 mg, 0.4000 mmol) in DMF (3.0297 mL) was added 5-isopropyl- 1H-Pyrazole-3-carboxylic acid (61.05 mg, 0.4000 mmol), DIPEA (0.2 mL, 1.19 mmol) and HATU (180.57 mg, 0.4800 mmol). The reaction mixture was stirred at 15°C for 12 hours to give a brown mixture. LCMS showed complete consumption of starting material. The reaction mixture was purified by preparative HPLC (HCl). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to afford the title compound (25.34 mg, 0.0698 mmol, 17.624% yield) as a white solid. LC-MS method 1: 350.9 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (dd, J =6.9, 1.2 Hz, 6 H), 2.37 (d, J =3.6 Hz, 1 H), 2.40 (s, 3 H), 2.44 (br d, J =1.9 Hz, 1 H), 2.47 (dd, J =3.4, 1.6 Hz, 1 H), 2.93 - 3.03 (m, 1 H) , 3.62 (br s, 1 H), 3.66 (br d, J =3.5 Hz, 1 H), 4.00 (br dd, J =11.9, 4.2 Hz, 1 H), 4.21 (d, J =12.4 Hz, 1 H), 4.53 (br d, J =11.8 Hz, 1 H), 6.45 (s, 1 H), 7.78 (d, J =9.5 Hz, 1 H), 7.91 (d, J =9.3 Hz, 1 H) , 8.86 (s, 1 H).

實例 131    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(6- 甲氧基 [1,2,4] ***并 [4,3-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 2- 肼基 -5- 甲氧基吡啶2-氯-5-甲氧基吡啶(1.5.g，7.98mmol)及水合肼(20.g，379.54mmol)經合併且緩慢地加熱至140℃。在140℃下攪拌反應混合物16小時。LCMS展示發現所要峰值。在減壓下濃縮混合物，獲得殘餘物。藉由孔比快速(Combi Flash)用矽膠(MeOH/DCM=1/10)純化殘餘物，得到呈黃色油狀之標題化合物(650mg，4.6709mmol，58.548%產率)。 LC-MS方法1 0.192min，MS (m/z) 140.0 (M + H ⁺)。 Example 131 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(6- methoxy [1,2,4] triazolo [4,3- a] pyridin -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone 2- hydrazino -5- methoxypyridine 2-chloro-5-methoxypyridine (1.5 g, 7.98mmol) and hydrazine hydrate (20.g, 379.54mmol) were combined and heated slowly to 140°C. The reaction mixture was stirred at 140°C for 16 hours. LCMS showed that the desired peak was found. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by Combi Flash on silica gel (MeOH/DCM = 1/10) to give the title compound (650 mg, 4.6709 mmol, 58.548% yield) as a yellow oil. LC-MS method 1 0.192min, MS (m/z) 140.0 (M + H ⁺ ).

(1R,5S,6r)-6-{[2-(5- 甲氧基 -2- 吡啶基 ) 肼基 ] 羰基 }-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(979.85mg，4.31mmol)及HATU (2.46g，6.47mmol)於DCM (20mL)中之混合物添加Et ₃N (1.43mL，8.62mmol)，且在20℃下攪拌所得混合物10 min。隨後添加2-肼基-5-甲氧基吡啶(600 mg，4.31mmol)。在20℃下於N ₂下攪拌所得混合物16小時，得到褐色混合物。用H ₂O (20 mL)稀釋反應混合物且用EtOAc (30 mL×3)萃取。用鹽水(20 mL)洗滌有機層，經Na ₂SO ₄乾燥且真空濃縮，得到褐色油狀物。藉由製備型TLC (PE/EA=1/1)純化粗物質油，得到呈黃色固體狀之標題化合物(400 mg，1.1481mmol，26.628%產率)。 LC-MS方法1: 349.1 [M+H ⁺]。 (1R,5S,6r)-6-{[2-(5- Methoxy -2- pyridyl ) hydrazino ] carbonyl }-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tris (1R,5S,6r)-3-{[(tertiary butyl)oxy]carbonyl } -3-azabicyclo[3.1.0]hexane-6-carboxylic acid (979.85mg, 4.31 mmol) and HATU (2.46 g, 6.47 mmol) in DCM (20 mL) was added _Et3N (1.43 mL, 8.62 mmol), and the resulting mixture was stirred at 20 °C for 10 min. Then 2-hydrazino-5-methoxypyridine (600 mg, 4.31 mmol) was added. The resulting mixture was stirred at 20 °C under _N2 for 16 h to give a brown mixture. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give a brown oil. The crude oil was purified by prep-TLC (PE/EA=1/1) to give the title compound (400 mg, 1.1481 mmol, 26.628% yield) as a yellow solid. LC-MS method 1: 349.1 [M+H ⁺ ].

(1R,5S,6r)-6-(6- 甲氧基 [1,2,4] ***并 [4,3-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-{[2-(5-甲氧基-2-吡啶基)肼基]羰基}-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(380 mg，1.09mmol)於MeCN (20 mL)中之溶液添加柏傑士試劑(649.78mg，2.73mmol)。在95℃下於N ₂下攪拌混合物16小時。用H ₂O (20 mL)稀釋反應混合物且用EtOAc (30 mL × 3)萃取。合併之有機層經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到殘餘物。藉由孔比快速用矽膠(EtOAc/PE=1/1)純化殘餘物，得到呈黃色固體狀之標題化合物(120mg，0.3133mmol，28.723%產率)。 LC-MS方法1: 331.0 [M+H ⁺]。 (1R,5S,6r)-6-(6- Methoxy [1,2,4] triazolo [4,3-a] pyridin -3- yl )-3- azabicyclo [3.1.0] Hexane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-{[2-(5-methoxy-2-pyridyl)hydrazino]carbonyl}-3-azabicyclo[ 3.1.0] To a solution of tert-butyl hexane-3-carboxylate (380 mg, 1.09 mmol) in MeCN (20 mL) was added Burgess reagent (649.78 mg, 2.73 mmol). The mixture was stirred at 95 °C under _N2 for 16 h. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified on silica gel (EtOAc/PE = 1/1) by porosity flash to give the title compound (120 mg, 0.3133 mmol, 28.723% yield) as a yellow solid. LC-MS method 1: 331.0 [M+H ⁺ ].

3-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-6- 甲氧基 [1,2,4] ***并 [4,3-a] 吡啶 TFA 鹽在20℃下向(1R,5S,6r)-6-(6-甲氧基[1,2,4]***并[4,3-a]吡啶-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(100 mg，0.30 mmol)於DCM (3mL)中之溶液添加TFA (0.13mL，1.82mmol)。在20℃下攪拌混合物16小時。濃縮反應混合物，得到呈黃色油狀之標題化合物(100 mg，0.4343mmol，143.48%產率)。 LC-MS方法1: 230.95 [M+H ⁺]。 3-[(1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl ]-6- methoxy [1,2,4] triazolo [4,3-a] Pyridine TFA salt was converted to (1R,5S,6r)-6-(6-methoxy[1,2,4]triazolo[4,3-a]pyridin-3-yl)-3- To a solution of tert-butyl azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 0.30 mmol) in DCM (3 mL) was added TFA (0.13 mL, 1.82 mmol). The mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated to afford the title compound (100 mg, 0.4343 mmol, 143.48% yield) as a yellow oil. LC-MS method 1: 230.95 [M+H ⁺ ].

(5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(6- 甲氧基 [1,2,4] ***并 [4,3-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-異丙基-1H-吡唑-3-羧酸(65 mg，0.42 mmol)於DCM (3 mL)中之混合物添加HATU (241.77mg，0.6300mmol)及Et ₃N (0.14mL，0.8400mmol)，且在20℃下於N ₂下攪拌混合物10 min。隨後，添加於DCM (2 mL)中之3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-6-甲氧基[1,2,4]***并[4,3-a]吡啶TFA鹽(97.08mg，0.4200mmol)。在20℃下攪拌所得混合物16小時，得到褐色混合物。用H ₂O (20 mL)稀釋反應物且用DCM (20 mL)萃取。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到褐色油狀物。藉由製備型HPLC (FA)純化褐色油狀物且凍乾所獲得流體，得到呈淡黃色固體狀之標題化合物(40.47mg，0.1054mmol，24.997%產率)。 LC-MS方法1: 367.0 [M+H ⁺]。 ¹H NMR (400MHz, 氯仿-d) δ = 8.11 (s, 1H), 7.65 (d, J=10.0 Hz, 1H), 7.39 (s, 1H), 7.06 (dd, J=2.0, 10.0 Hz, 1H), 6.57 (s, 1H), 4.55 (d, J=11.5 Hz, 1H), 4.44 (d, J=12.5 Hz, 1H), 4.10 (dd, J=3.8, 11.8 Hz, 1H), 3.89 (s, 3H), 3.84 - 3.73 (m, 1H), 3.07 (td, J=7.2, 13.8 Hz, 1H), 2.82 - 2.74 (m, 1H), 2.31 - 2.29 (m, 1H), 1.89 (br s, 1H), 1.33 (d, J=6.8 Hz, 6H) (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(6- methoxy [1,2,4] triazolo [4,3-a] Pyridin -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 5-isopropyl-1H-pyrazole-3-carboxylic acid (65 mg, 0.42 mmol) in DCM (3 mL) was added HATU (241.77 mg, 0.6300 mmol) and _Et3N (0.14 mL, 0.8400 mmol), and the mixture was stirred at 20 °C under _N2 for 10 min. Subsequently, 3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-6-methoxy[1,2,4 ] Triazolo[4,3-a]pyridine TFA salt (97.08 mg, 0.4200 mmol). The resulting mixture was stirred at 20°C for 16 hours to give a brown mixture. The reaction was diluted with H ₂ O (20 mL) and extracted with DCM (20 mL). The combined organic layers were separated, then dried over _Na2SO4 and concentrated _in vacuo to give a brown oil. The brown oil was purified by preparative HPLC (FA) and the obtained fluid was lyophilized to give the title compound (40.47 mg, 0.1054 mmol, 24.997% yield) as a pale yellow solid. LC-MS method 1: 367.0 [M+H ⁺ ]. ¹ H NMR (400MHz, chloroform-d) δ = 8.11 (s, 1H), 7.65 (d, J =10.0 Hz, 1H), 7.39 (s, 1H), 7.06 (dd, J =2.0, 10.0 Hz, 1H ), 6.57 (s, 1H), 4.55 (d, J =11.5 Hz, 1H), 4.44 (d, J =12.5 Hz, 1H), 4.10 (dd, J =3.8, 11.8 Hz, 1H), 3.89 (s , 3H), 3.84 - 3.73 (m, 1H), 3.07 (td, J =7.2, 13.8 Hz, 1H), 2.82 - 2.74 (m, 1H), 2.31 - 2.29 (m, 1H), 1.89 (br s, 1H), 1.33 (d, J =6.8 Hz, 6H)

實例 132    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-([1,2,3] ***并 [1,5-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-([1,2,3] ***并 [1,5-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-異丙基-1H-吡唑-3-羧酸(25.64mg，0.1700mmol)於DMF (1.2489mL)中之溶液添加HATU (47.82mg，0.2500mmol)及DIPEA (64.5 mg，0.50 mmol)。在15℃下攪拌反應混合物30 min。隨後添加3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-l[1,2,3]***并[1,5-a]吡啶TFA鹽(33.3mg，0.1700mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (NH ₃)純化反應混合物，得到呈白色粉末狀之標題化合物(18.6mg，0.0553mmol，33.249%產率)。 LC-MS方法1: 336.9 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 8.64 (d, J=7.2 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.19 (dd, J=6.8, 8.3 Hz, 1H), 6.94 (dt, J=1.0, 6.9 Hz, 1H), 6.52 (s, 1H), 4.42 (br d, J=11.3 Hz, 1H), 4.35 (d, J=12.8 Hz, 1H), 4.05 (dd, J=4.4, 11.1 Hz, 1H), 3.77 (dd, J=4.4, 12.6 Hz, 1H), 3.09 - 2.98 (m, 1H), 2.49 (td, J=3.8, 7.4 Hz, 1H), 2.30 (td, J=3.8, 7.4 Hz, 1H), 1.96 (t, J=3.4 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H)。 Example 132 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-([1,2,3] triazolo [1,5-a] pyridine -3 -yl ) -3- azabicyclo [3.1.0] hex -3- yl ] methanone (5- isopropyl- 1H- pyrazol -3- yl )[(1R,5S,6r)-6-( [1,2,3] triazolo [1,5-a] pyridin - 3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 5-isopropyl-1H - A solution of pyrazole-3-carboxylic acid (25.64 mg, 0.1700 mmol) in DMF (1.2489 mL) was added with HATU (47.82 mg, 0.2500 mmol) and DIPEA (64.5 mg, 0.50 mmol). The reaction mixture was stirred at 15 °C for 30 min. Then add 3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-l[1,2,3]triazolo[1,5-a]pyridine TFA Salt (33.3 mg, 0.1700 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC (NH ₃ ) to afford the title compound (18.6 mg, 0.0553 mmol, 33.249% yield) as a white powder. LC-MS method 1: 336.9 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 8.64 (d, J =7.2 Hz, 1H), 7.67 (d, J =8.8 Hz, 1H), 7.19 (dd, J =6.8, 8.3 Hz, 1H), 6.94 (dt, J =1.0, 6.9 Hz, 1H), 6.52 (s, 1H), 4.42 (br d, J =11.3 Hz, 1H), 4.35 (d , J =12.8 Hz, 1H), 4.05 (dd, J =4.4, 11.1 Hz, 1H), 3.77 (dd, J =4.4, 12.6 Hz, 1H), 3.09 - 2.98 (m, 1H), 2.49 (td, J =3.8, 7.4 Hz, 1H), 2.30 (td, J =3.8, 7.4 Hz, 1H), 1.96 (t, J =3.4 Hz, 1H), 1.31 (d, J =6.8 Hz, 6H).

實例 133    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5- 甲基 [1,2,3] ***并 [1,5-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 溴基 (4- 甲基 -2- 吡啶基 ) 鎂在15℃下向2-溴-4-甲基吡啶(0.67mL，6.33mmol)於THF (10mL)中之溶液添加氯基(異丙基)鎂(3.2mL，6.33mmol)。在0℃下攪拌反應混合物4小時，得到呈混合物之標題化合物。反應混合物在無進一步純化之情況下用於下一步驟。 Example 133 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(5- methyl [1,2,3] triazolo [1,5-a ] pyridin -3- yl )-3- azabicyclo [ 3.1.0] hex -3- yl ] methanonebromo (4- methyl -2- pyridyl ) magnesium to 2-bromo-4 at 15°C - A solution of picoline (0.67 mL, 6.33 mmol) in THF (10 mL) was added with chloro(isopropyl)magnesium (3.2 mL, 6.33 mmol). The reaction mixture was stirred at 0°C for 4 hours to afford the title compound as a mixture. The reaction mixture was used in the next step without further purification.

(1R,5S,6r)-6-[ 羥基 (4- 甲基 -2- 吡啶基 ) 甲基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在0℃下向(1R,5S,6r)-6-甲醯基-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(300 mg，1.42mmol)於THF (3mL)中之溶液添加溴基(4-甲基-2-吡啶基)鎂(418.2mg，2.13mmol)。在0℃下攪拌反應混合物2小時，得到淺黃色混合物。TLC (EA)展示新樣點。用H ₂O (30 mL)淬滅反應混合物且用EtOAc (30 mL×2)萃取。用鹽水(30 mL×2)洗滌有機層，經無水Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到殘餘物。藉由矽膠管柱(PE/EA=1:0至1:2)純化殘餘物，得到呈淺黃色膠質之標題化合物(400mg，1.3141mmol，92.542%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ = 8.31 (d, J = 5.2 Hz, 1H), 7.30 (s, 1H), 7.08 (d, J = 5.2 Hz, 1H), 5.36 (d, J = 4.8 Hz, 1H), 4.50-4.40 (m, 1H), 3.45-3.35 (m, 4H), 2.32 (s, 3H), 1.65-1.50 (m, 2H), 1.34 (s, 9H), 0.85-0.80 (m, 1H)。 (1R,5S,6r)-6-[ Hydroxy (4- methyl -2- pyridyl ) methyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester in 0 (1R,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester (300 mg, 1.42mmol) in THF (3mL) at °C To the solution in was added bromo(4-methyl-2-pyridyl)magnesium (418.2 mg, 2.13 mmol). The reaction mixture was stirred at 0 °C for 2 hours to obtain a pale yellow mixture. TLC (EA) showed new samples. The reaction mixture was quenched with H ₂ O (30 mL) and extracted with EtOAc (30 mL×2). The organic layer was washed with brine (30 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (PE/EA=1:0 to 1:2) to obtain the title compound (400 mg, 1.3141 mmol, 92.542% yield) as light yellow gum. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.31 (d, J = 5.2 Hz, 1H), 7.30 (s, 1H), 7.08 (d, J = 5.2 Hz, 1H), 5.36 (d, J = 4.8 Hz, 1H), 4.50-4.40 (m, 1H), 3.45-3.35 (m, 4H), 2.32 (s, 3H), 1.65-1.50 (m, 2H), 1.34 (s, 9H), 0.85-0.80 (m, 1H).

(1R,5S,6r)-6-[(4- 甲基 -2- 吡啶基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在15℃下向(1R,5S,6r)-6-[羥基(4-甲基-2-吡啶基)甲基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(300 mg，0.9900mmol)於DCM (6mL)中之溶液添加DMP (418.04mg，0.9900mmol)。在15℃下攪拌反應混合物20 min，得到白色混合物。TLC (PE/EA=1:1)展示新樣點。用NaHCO ₃(30 mL)淬滅合併之反應混合物且用EtOAc (30 mL×2)萃取。用鹽水(30 mL×2)洗滌有機層，經無水Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈淡黃色固體狀之粗產物。藉由二氧化矽管柱(PE/EA=1:1)純化粗產物，得到呈白色固體狀之標題化合物(300 mg，0.9922mmol，100.66%產率)。 ¹H NMR (400MHz, DMSO-d ₆) δ = 8.60 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 7.51 (d, J = 4.8 Hz, 1H), 4.50-4.40 (m, 1H), 3.57 (d, J = 11.2 Hz, 2H), 3.45-3.35 (m, 2H), 3.25-3.20 (m, 1H), 2.40 (s, 3H), 2.20 (brs, 2H), 1.40 (s, 9H)。 (1R,5S,6r)-6-[(4- Methyl -2- pyridyl ) carbonyl ]-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl ester at 15°C To (1R, 5S, 6r)-6-[hydroxyl (4-methyl-2-pyridyl) methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tertiary butyl ester ( To a solution of 300 mg, 0.9900 mmol) in DCM (6 mL) was added DMP (418.04 mg, 0.9900 mmol). The reaction mixture was stirred at 15 °C for 20 min to give a white mixture. TLC (PE/EA=1:1) showed new samples. The combined reaction mixture was quenched with NaHCO ₃ (30 mL) and extracted with EtOAc (30 mL×2). The organic layer was washed with brine (30 mL x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude product as light yellow solid. The crude product was purified by silica column (PE/EA=1:1) to give the title compound (300 mg, 0.9922 mmol, 100.66% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.60 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 7.51 (d, J = 4.8 Hz, 1H), 4.50-4.40 (m, 1H), 3.57 (d, J = 11.2 Hz, 2H), 3.45-3.35 (m, 2H), 3.25-3.20 (m, 1H), 2.40 (s, 3H), 2.20 (brs, 2H), 1.40 (s , 9H).

(1R,5S,6r)-6-(5- 甲基 [1,2,3] ***并 [1,5-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯向(1R,5S,6r)-6-[(4-甲基-2-吡啶基)羰基]-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(150 mg，0.5000mmol)於EtOH (3mL)中之溶液添加水合肼(37.25mg，0.7400mmol)。在60℃下攪拌反應混合物6小時，得到無色混合物。隨後添加乙酸銅(4.94mg，0.0200mmol)及乙酸乙酯(14.304mL)。隨後在20℃下攪拌反應混合物1小時，得到無色混合物。濃縮反應混合物，得到殘餘物。藉由製備型TLC (PE/EA=1:1)純化殘餘物，得到呈無色油狀之標題化合物(50mg，0.1590mmol，32.06%產率)。 ¹H NMR (400MHz, 氯仿-d) δ = 8.51 (d, J = 7.2 Hz, 1H), 7.43 (s, 1H), 6.75 (dd, J = 7.2, 1.6 Hz, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.45-3.35 (m, 2H), 2.43 (s, 3H), 2.35-2.35 (m, 1H), 2.20-2.10 (m, 1H), 1.95-1.90 (m, 1H), 1.48 (s, 9H)。 (1R,5S,6r)-6-(5- Methyl [1,2,3] triazolo [1,5-a] pyridin -3- yl )-3- azabicyclo [3.1.0] hexyl Alkane -3- carboxylic acid tertiary butyl ester to (1R,5S,6r)-6-[(4-methyl-2-pyridyl)carbonyl]-3-azabicyclo[3.1.0]hexane-3 - To a solution of tert-butylcarboxylate (150 mg, 0.5000 mmol) in EtOH (3 mL) was added hydrazine hydrate (37.25 mg, 0.7400 mmol). The reaction mixture was stirred at 60°C for 6 hours to obtain a colorless mixture. Then copper acetate (4.94 mg, 0.0200 mmol) and ethyl acetate (14.304 mL) were added. The reaction mixture was then stirred at 20° C. for 1 hour to give a colorless mixture. The reaction mixture was concentrated to give a residue. The residue was purified by prep-TLC (PE/EA=1:1) to give the title compound (50 mg, 0.1590 mmol, 32.06% yield) as a colorless oil. ¹ H NMR (400MHz, chloroform-d) δ = 8.51 (d, J = 7.2 Hz, 1H), 7.43 (s, 1H), 6.75 (dd, J = 7.2, 1.6 Hz, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.45-3.35 (m, 2H), 2.43 (s, 3H), 2.35-2.35 (m, 1H), 2.20-2.10 (m, 1H), 1.95-1.90 (m, 1H), 1.48 (s, 9H).

3-[(1R,5S,6r)-3- 氮雜雙環 [3.1.0] 己 -6- 基 ]-5- 甲基 [1,2,3] ***并 [1,5-a] 吡啶 TFA 鹽向(1R,5S,6r)-6-(5-甲基[1,2,3]***并[1,5-a]吡啶-3-基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯於DCM (5mL)中之溶液添加TFA (0.01mL，0.1600mmol)。在20℃下攪拌反應混合物16小時，得到無色混合物。LCMS展示所要MS。自反應混合物移除溶劑，得到標題化合物。產物直接用於下一步驟。 LC-MS方法1 0.398 min，MS (m/z) 214.9 (M + H ⁺)。 3-[(1R,5S,6r)-3- Azabicyclo [3.1.0] hex -6- yl ]-5- methyl [1,2,3] triazolo [1,5-a] pyridine TFA salt to (1R,5S,6r)-6-(5-methyl[1,2,3]triazolo[1,5-a]pyridin-3-yl)-3-azabicyclo[3.1. 0] A solution of tert-butyl hexane-3-carboxylate in DCM (5 mL) was added with TFA (0.01 mL, 0.1600 mmol). The reaction mixture was stirred at 20°C for 16 hours to give a colorless mixture. LCMS showed desired MS. The solvent was removed from the reaction mixture to afford the title compound. The product was used directly in the next step. LC-MS method 1 0.398 min, MS (m/z) 214.9 (M + H ⁺ ).

(5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(5- 甲基 [1,2,3] ***并 [1,5-a] 吡啶 -3- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-異丙基-1H-吡唑-3-羧酸(24.46mg，0.1600mmol)於DMF (1.1917mL)中之溶液添加HATU (45.63mg，0.2400mmol)。在15℃下攪拌反應混合物30 min。隨後添加3-[(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基]-5-甲基[1,2,3]***并[1,5-a]吡啶TFA鹽(34 mg，0.1600mmol)及DIPEA (61.52 mg，0.476 mmol)。在15℃下攪拌反應混合物0.5小時，得到黃色混合物。LCMS展示所要MS。藉由製備型HPLC (NH ₃)純化反應混合物，得到呈白色粉末狀之標題化合物(22.4mg，0.0639mmol，40.285%產率)。 LC-MS方法1: 350.9 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 8.52 (d, J=7.2 Hz, 1H), 7.41 (s, 1H), 6.76 (dd, J=1.6, 7.2 Hz, 1H), 6.51 (s, 1H), 4.40 (br d, J=10.8 Hz, 1H), 4.34 (d, J=12.4 Hz, 1H), 4.03 (dd, J=4.4, 11.2 Hz, 1H), 3.76 (dd, J=4.4, 12.4 Hz, 1H), 3.04 (spt, J=6.9 Hz, 1H), 2.47 - 2.44 (m, 1H), 2.42 (s, 3H), 2.26 (td, J=3.8, 7.4 Hz, 1H), 1.91 (t, J=3.4 Hz, 1H), 1.31 (d, J=7.2 Hz, 6H) (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(5- methyl [1,2,3] triazolo [1,5-a] pyridine -3- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone to 5-isopropyl-1H-pyrazole-3-carboxylic acid (24.46mg, 0.1600mmol) in DMF ( 1.1917 mL) of the solution was added HATU (45.63 mg, 0.2400 mmol). The reaction mixture was stirred at 15 °C for 30 min. Then add 3-[(1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl]-5-methyl[1,2,3]triazolo[1,5-a ] Pyridine TFA salt (34 mg, 0.1600 mmol) and DIPEA (61.52 mg, 0.476 mmol). The reaction mixture was stirred at 15°C for 0.5 hours to give a yellow mixture. LCMS showed desired MS. The reaction mixture was purified by preparative HPLC (NH ₃ ) to afford the title compound (22.4 mg, 0.0639 mmol, 40.285% yield) as a white powder. LC-MS method 1: 350.9 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 8.52 (d, J =7.2 Hz, 1H), 7.41 (s, 1H), 6.76 (dd, J = 1.6, 7.2 Hz, 1H), 6.51 (s, 1H), 4.40 (br d, J =10.8 Hz, 1H), 4.34 (d, J =12.4 Hz, 1H), 4.03 (dd, J =4.4, 11.2 Hz , 1H), 3.76 (dd, J =4.4, 12.4 Hz, 1H), 3.04 (spt, J =6.9 Hz, 1H), 2.47 - 2.44 (m, 1H), 2.42 (s, 3H), 2.26 (td, J =3.8, 7.4 Hz, 1H), 1.91 (t, J =3.4 Hz, 1H), 1.31 (d, J =7.2 Hz, 6H)

實例 134    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(1H- 四唑 -5- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(1H- 四唑 -5- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-異丙基-1H-吡唑-3-羧酸(90 mg，0.5800mmol)於DMF (6mL)中之溶液添加N-乙基-N-異丙基丙-2-胺(0.4mL，2.34mmol)及HATU (266.2mg，0.7000mmol)。在攪拌30 min之後，添加(1R,5S,6r)-6-(1H-四唑-5-基)-3-氮雜雙環[3.1.0]己烷TFA鹽(79.42mg，0.5300mmol)且在15℃下攪拌反應混合物16小時，得到紅色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (FA)純化粗物質，得到呈白色固體狀之標題化合物(13.3mg，0.0463mmol，7.9295%產率)。 LC-MS 方法 1: 288.0 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d ₆) δ 6.41 (s, 1H), 4.42 (br d, J=12.05 Hz, 1H), 4.05 (d, J=12.30 Hz, 1H), 3.90 (dd, J=3.89, 11.92 Hz, 1H), 3.57 (br dd, J=4.02, 12.30 Hz, 1H), 2.96 (td, J=6.96, 13.68 Hz, 1H), 2.26-2.35 (m, 1H), 2.21 (m, 1H), 1.97 (t, J=3.26 Hz, 1H), 1.22 (d, J=7.03 Hz, 7H) Example 134 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(1H- tetrazol -5- yl )-3- azabicyclo [3.1.0] Hex -3- yl ] methanone (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(1H- tetrazol -5- yl )-3- aza Bicyclo [3.1.0] hex -3- yl ] methanone To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (90 mg, 0.5800 mmol) in DMF (6 mL) was added N-ethyl -N-Isopropylpropan-2-amine (0.4 mL, 2.34 mmol) and HATU (266.2 mg, 0.7000 mmol). After stirring for 30 min, (1R,5S,6r)-6-(1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane TFA salt (79.42 mg, 0.5300 mmol) was added and The reaction mixture was stirred at 15°C for 16 hours to obtain a red solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC (FA) to afford the title compound (13.3 mg, 0.0463 mmol, 7.9295% yield) as a white solid. LC-MS method 1 : 288.0 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.41 (s, 1H), 4.42 (br d, J =12.05 Hz, 1H), 4.05 (d, J =12.30 Hz, 1H), 3.90 (dd, J =3.89, 11.92 Hz, 1H), 3.57 (br dd, J =4.02, 12.30 Hz, 1H), 2.96 (td, J =6.96, 13.68 Hz, 1H) , 2.26-2.35 (m, 1H), 2.21 (m, 1H), 1.97 (t, J =3.26 Hz, 1H), 1.22 (d, J =7.03 Hz, 7H)

實例 135    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(1- 苯基 -1H- 四唑 -5- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (1R,5S,6r)-6-( 苯胺甲醯基 )-3- 氮雜雙環 [3.1.0] 己烷 -3- 羧酸三級丁酯在10℃下攪拌(1R,5S,6r)-3-{[(三級丁基)氧基]羰基}-3-氮雜雙環[3.1.0]己烷-6-羧酸(500 mg，2.2mmol)、HOBt (356.74mg，2.64mmol)、苯胺(0.45mL，2.64mmol)及EDCI (506.12mg，2.64mmol)於DCM (5mL)中之溶液30 min。隨後將其冷卻至0℃且逐滴添加苯胺(0.3mL，3.3mmol)，攪拌16小時，得到白色懸浮液。TLC (DCM/MeOH =10/1 Rf =0.1)展示偵測到新樣點。添加H ₂O (10 mL)且用EtOAc (10 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到白色固體。藉由矽膠層析(PE/EA=10/1至3/1)來純化粗物質，得到呈白色固體狀之標題化合物(590mg，1.9513mmol，88.688%產率)。 LC-MS方法1 0.858 min，MS (m/z) 303.0 (M + H ⁺)。 Example 135 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(1- phenyl -1H- tetrazol -5- yl )-3- azabicyclo [3.1.0] Hex -3- yl ] methanone (1R,5S,6r)-6-( anilinoyl )-3- azabicyclo [3.1.0] hexane -3- carboxylic acid tertiary butyl (1R,5S,6r)-3-{[(tertiary butyl)oxy ] carbonyl}-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (500 mg , 2.2mmol), HOBt (356.74mg, 2.64mmol), aniline (0.45mL, 2.64mmol) and EDCI (506.12mg, 2.64mmol) in DCM (5mL) for 30 min. It was then cooled to 0 °C and aniline (0.3 mL, 3.3 mmol) was added dropwise and stirred for 16 hours to give a white suspension. TLC (DCM/MeOH=10/1 Rf=0.1) showed detection of a new spot. H ₂ O (10 mL) was added and it was extracted with EtOAc (10 mL×2). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo to give a white solid. The crude material was purified by silica gel chromatography (PE/EA = 10/1 to 3/1 ) to afford the title compound (590 mg, 1.9513 mmol, 88.688% yield) as a white solid. LC-MS method 1 0.858 min, MS (m/z) 303.0 (M + H ⁺ ).

(1R,5S,6r)-N- 苯基 -3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺氫氯化物在10℃下攪拌(1R,5S,6r)-6-(苯胺甲醯基)-3-氮雜雙環[3.1.0]己烷-3-羧酸三級丁酯(640 mg，2.12mmol)於HCl/二㗁烷(6 mL，2.12mmol)中之溶液3小時，得到黃色溶液。在真空中蒸發反應混合物，得到呈白色固體狀之標題化合物(500 mg，2.0946mmol，98.96%產率)。 LC-MS方法1 0.285 min，MS (m/z) 203.0 (M + H ⁺)。 (1R,5S,6r)-N- phenyl -3- azabicyclo [3.1.0] hexane -6- formamide hydrochloride was stirred at 10°C (1R,5S,6r)-6-( A solution of tert-butyl anilinoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (640 mg, 2.12mmol) in HCl/dioxane (6 mL, 2.12mmol) After 3 hours, a yellow solution was obtained. The reaction mixture was evaporated in vacuo to afford the title compound (500 mg, 2.0946 mmol, 98.96% yield) as a white solid. LC-MS method 1 0.285 min, MS (m/z) 203.0 (M + H ⁺ ).

(1R,5S,6r)-3- 苯甲基 -N- 苯基 -3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向(1R,5S,6r)-N-苯基-3-氮雜雙環[3.1.0]己烷-6-甲醯胺氫氯化物(500 mg，2.09mmol)及苯甲醛(0.25mL，2.51mmol)於DCM (15mL)及MeOH (5mL)中之溶液添加三乙胺(0.29mL，2.09mmol)。在攪拌5 min之後，添加三乙醯氧基硼氫化鈉(887.86mg，4.19mmol)。在10℃下攪拌反應混合物16小時，得到黃色溶液。TLC (DCM/MeOH =10/1 Rf =0.6)展示偵測到新樣點。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(DCM/MeOH=10/1至3/1)來純化粗物質，得到呈白色固體狀之標題化合物(600 mg，2.0522mmol，97.976%產率)。 LC-MS方法1 0.692 min，MS (m/z) 293.2 (M + H ⁺)。 (1R,5S,6r)-3- Benzyl -N- phenyl -3- azabicyclo [3.1.0] hexane -6- formamide to (1R,5S,6r)-N-phenyl -3-Azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (500 mg, 2.09 mmol) and benzaldehyde (0.25 mL, 2.51 mmol) in DCM (15 mL) and MeOH (5 mL) The solution was added triethylamine (0.29 mL, 2.09 mmol). After stirring for 5 min, sodium triacetoxyborohydride (887.86 mg, 4.19 mmol) was added. The reaction mixture was stirred at 10 °C for 16 hours to obtain a yellow solution. TLC (DCM/MeOH=10/1 Rf=0.6) showed detection of a new spot. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (DCM/MeOH = 10/1 to 3/1 ) to afford the title compound (600 mg, 2.0522 mmol, 97.976% yield) as a white solid. LC-MS method 1 0.692 min, MS (m/z) 293.2 (M + H ⁺ ).

(1R,5S,6r)-3- 苯甲基 -6-(1- 苯基 -1H- 四唑 -5- 基 )-3- 氮雜雙環 [3.1.0] 己烷向(1R,5S,6r)-3-苯甲基-N-苯基-3-氮雜雙環[3.1.0]己烷-6-甲醯胺(330 mg，1.13mmol)於DCM (10 mL)中之溶液添加Tf ₂O (0.39mL，2.26mmol)。在攪拌5 min之後，添加TMSN ₃(0.59mL，4.51mmol)且攪拌反應物16小時，得到黃色溶液。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色固體狀之標題化合物(298mg，0.9389mmol，83.184%產率)。 LC-MS方法1 0.712 min，MS (m/z) 318.1 (M + H ⁺)。 (1R,5S,6r)-3- Benzyl -6-(1- phenyl -1H- tetrazol -5- yl )-3- azabicyclo [3.1.0] hexane to (1R,5S, 6r) A solution of -3-benzyl-N-phenyl-3-azabicyclo[3.1.0]hexane-6-carboxamide (330 mg, 1.13 mmol) in DCM (10 mL) was added with Tf ₂ O (0.39 mL, 2.26 mmol). After stirring for 5 min, _TMSN3 (0.59 mL, 4.51 mmol) was added and the reaction was stirred for 16 h to give a yellow solution. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (298 mg, 0.9389 mmol, 83.184% yield) as a yellow solid. LC-MS method 1 0.712 min, MS (m/z) 318.1 (M + H ⁺ ).

(1R,5S,6r)-6-(1- 苯基 -1H- 四唑 -5- 基 )-3- 氮雜雙環 [3.1.0] 己烷向(1R,5S,6r)-3-苯甲基-6-(1-苯基-1H-四唑-5-基)-3-氮雜雙環[3.1.0]己烷(500 mg，1.58mmol)於MeOH (15 mL)中之溶液添加Pd/C (50.0 mg)。在10℃下於H ₂氛圍下將其攪拌3小時，得到黃色固體。經由矽藻土墊將其過濾且真空濃縮濾液，得到呈白色固體狀之標題化合物(400 mg，1.76mmol，111.72%產率)。 LC-MS方法1 0.538 min，MS (m/z) 228.0 (M + H ⁺)。 (1R,5S,6r)-6-(1- phenyl -1H- tetrazol -5- yl )-3- azabicyclo [3.1.0] hexane to (1R,5S,6r)-3-benzene A solution of methyl-6-(1-phenyl-1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane (500 mg, 1.58 mmol) in MeOH (15 mL) was added Pd/C (50.0 mg). It was stirred at 10 °C under _H2 atmosphere for 3 h to give a yellow solid. It was filtered through a pad of celite and the filtrate was concentrated in vacuo to afford the title compound (400 mg, 1.76 mmol, 111.72% yield) as a white solid. LC-MS method 1 0.538 min, MS (m/z) 228.0 (M + H ⁺ ).

(5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6-(1- 苯基 -1H- 四唑 -5- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮在10℃下攪拌5-異丙基-1H-吡唑-3-羧酸(50 mg，0.3200mmol)、N-乙基-N-異丙基丙-2-胺(0.17mL，0.9700mmol)及HATU (74.61mg，0.3900mmol)於DMF (2mL)中之溶液30 min。隨後添加(1R,5S,6r)-6-(1-苯基-1H-四唑-5-基)-3-氮雜雙環[3.1.0]己烷(66.34mg，0.2900mmol)，且攪拌反應混合物16小時，得到黃色溶液。添加H ₂O (10 mL)且用EtOAc (10 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由矽膠層析(DCM/EA=3/1至1/2)來純化粗物質，得到呈白色固體狀之標題化合物(21.25mg，0.0584mmol，3.5987%產率)。 LC-MS方法1: 364.1 [M+H ⁺] ¹H NMR (400 MHz, DMSO-d ₆) δ 12.94 (br s, 1H), 7.64-7.72 (m, 5H), 6.35 (s, 1H), 4.38 (br d, J=12.30 Hz, 1H), 3.90-3.98 (m, 2H), 3.58 (br dd, J=4.27, 12.55 Hz, 1H), 2.91-2.97 (m, 1H), 2.35 (br dd, J=3.76, 7.78 Hz, 1H), 1.79 (br s, 1H), 1.20 (d, J=6.78 Hz, 6H) (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6-(1- phenyl -1H- tetrazol -5- yl )-3- azabicyclo [3.1 .0] hex -3- yl ] methanone was stirred at 10°C with 5-isopropyl-1H-pyrazole-3-carboxylic acid (50 mg, 0.3200mmol), N-ethyl-N-isopropylpropyl - A solution of 2-amine (0.17 mL, 0.9700 mmol) and HATU (74.61 mg, 0.3900 mmol) in DMF (2 mL) for 30 min. Then (1R,5S,6r)-6-(1-phenyl-1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hexane (66.34 mg, 0.2900 mmol) was added and stirred The reaction mixture was reacted for 16 hours to obtain a yellow solution. H ₂ O (10 mL) was added and it was extracted with EtOAc (10 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by silica gel chromatography (DCM/EA = 3/1 to 1/2) to afford the title compound (21.25 mg, 0.0584 mmol, 3.5987% yield) as a white solid. LC-MS method 1: 364.1 [M+H ⁺ ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.94 (br s, 1H), 7.64-7.72 (m, 5H), 6.35 (s, 1H), 4.38 (br d, J =12.30 Hz, 1H), 3.90-3.98 (m, 2H), 3.58 (br dd, J =4.27, 12.55 Hz, 1H), 2.91-2.97 (m, 1H), 2.35 (br dd , J =3.76, 7.78 Hz, 1H), 1.79 (br s, 1H), 1.20 (d, J =6.78 Hz, 6H)

實例 136    (1R,5S,6r)-N-( 丙 -2- 基 )-3-[5-( 丙 -2- 基 )-1H- 吡唑 -3- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-3-[(5- 異丙基 -1H- 吡唑 -3- 基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 羧酸向(1R,5S,6r)-3-[(5-異丙基-1H-吡唑-3-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-羧酸乙酯(400 mg，1.37mmol)於THF (5mL)及H ₂O (1 mL，1.37mmol)中之溶液添加LiOH·H ₂O (172.82mg，4.12mmol)。在25℃下攪拌混合物3小時，得到褐色懸浮液。將反應物傾入H ₂O (20 mL)中且用1 N HCl酸化至pH=3至4且用EtOAc (100 mL × 3)萃取。合併之有機層經Na ₂SO ₄乾燥，過濾且在減壓下濃縮，得到呈白色固體之標題化合物(310mg，1.1774mmol，85.76%產率)。 Example 136 (1R, 5S, 6r)-N-( prop -2- yl )-3-[5-( prop -2- yl )-1H- pyrazole -3- carbonyl ]-3- azabicyclo [3.1 .0] Hexane -6- formamide (1R,5S,6r)-3-[(5- isopropyl -1H- pyrazol -3- yl ) carbonyl ]-3- azabicyclo [3.1.0 ] Hexane -6- carboxylic acid to (1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0]hexane To a solution of ethyl alkane-6-carboxylate (400 mg, 1.37 mmol) in THF (5 mL) and H ₂ O (1 mL, 1.37 mmol) was added LiOH·H ₂ O (172.82 mg, 4.12 mmol). The mixture was stirred at 25°C for 3 hours to give a brown suspension. The reaction was poured into H ₂ O (20 mL) and acidified with 1 N HCl to pH=3-4 and extracted with EtOAc (100 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford the title compound (310 mg, 1.1774 mmol, 85.76% yield) as a white solid.

(1R,5S,6r)-N-( 丙 -2- 基 )-3-[5-( 丙 -2- 基 )-1H- 吡唑 -3- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向(1R,5S,6r)-3-[(5-異丙基-1H-吡唑-3-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-羧酸(50 mg，0.19 mmol)於DMF (1.5mL)中之混合物添加異丙基胺(16.55mg，0.1900mmol)、HATU (86.6mg，0.2300mmol)及DIPEA (0.06mL，0.3800mmol)。在100℃下攪拌混合物16小時，得到褐色混合物。LCMS展示起始材料完全耗盡。過濾反應混合物，且藉由製備型HPLC (FA)純化濾液。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色粉末狀之標題化合物(6.83mg，0.0205mmol，10.819%產率)。 ¹H NMR (400 MHz, 氯仿-d) δ ppm 6.45 (s, 1 H), 4.09 - 4.19 (m, 2 H), 3.95 (br dd, J = 11.1, 4.3 Hz, 1 H), 3.69 (br dd, J = 12.5, 4.3 Hz, 2 H), 3.10 (dt, J = 13.9, 7.1 Hz, 1 H), 3.03 (s, 3 H), 2.23 - 2.31 (m, 1 H), 2.09 - 2.17 (m, 1 H), 1.60 (br s, 1 H), 1.40 (s, 9 H), 1.33 (d, J = 6.9 Hz, 6 H) (1R,5S,6r)-N-(prop -2- yl )-3-[5-( prop -2- yl )-1H- pyrazole -3- carbonyl ] -3- azabicyclo [3.1.0 ] Hexane -6- formamide to (1R,5S,6r)-3-[(5-isopropyl-1H-pyrazol-3-yl)carbonyl]-3-azabicyclo[3.1.0] To a mixture of hexane-6-carboxylic acid (50 mg, 0.19 mmol) in DMF (1.5 mL) was added isopropylamine (16.55 mg, 0.1900 mmol), HATU (86.6 mg, 0.2300 mmol) and DIPEA (0.06 mL, 0.3800 mmol). The mixture was stirred at 100°C for 16 hours to give a brown mixture. LCMS showed complete consumption of starting material. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (FA). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (6.83 mg, 0.0205 mmol, 10.819% yield) as a white powder. ¹ H NMR (400 MHz, chloroform-d) δ ppm 6.45 (s, 1 H), 4.09 - 4.19 (m, 2 H), 3.95 (br dd, J = 11.1, 4.3 Hz, 1 H), 3.69 (br dd, J = 12.5, 4.3 Hz, 2 H), 3.10 (dt, J = 13.9, 7.1 Hz, 1 H), 3.03 (s, 3 H), 2.23 - 2.31 (m, 1 H), 2.09 - 2.17 ( m, 1 H), 1.60 (br s, 1 H), 1.40 (s, 9 H), 1.33 (d, J = 6.9 Hz, 6 H)

實例 137    (1R,5S,6r)-N- 三級丁基 -N- 甲基 -3-[5-( 丙 -2- 基 )-1H- 吡唑 -3- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-N- 三級丁基 -N- 甲基 -3-[5-( 丙 -2- 基 )-1H- 吡唑 -3- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向(1R,5S,6r)-3-[(5-異丙基-1H-吡唑-3-基)羰基]-3-氮雜雙環[3.1.0]己烷-6-羧酸(100 mg，0.3800mmol)於DMF (2mL)中之混合物添加三級丁基甲胺(22.45mg，0.3800mmol)、HATU (173.19mg，0.4600mmol)及DIPEA (0.13mL，0.7600mmol)。在30℃下攪拌混合物16小時，得到黃色懸浮液。LCMS展示起始材料完全耗盡。過濾懸浮液且用EtOAc (3 mL)洗滌濾餅。真空乾燥濾餅，得到呈白色固體狀之標題化合物(72.08mg，0.2368mmol，62.347%產率)。 ¹H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (s, 1 H), 12.94 (s, 1 H), 7.87 (d, J = 7.5 Hz, 1 H), 6.45 - 6.52 (m, 1 H), 6.50 (d, J = 1.6 Hz, 1 H), 6.35 (d, J = 1.9 Hz, 1 H), 4.29 (d, J = 12.0 Hz, 1 H), 3.86 - 3.97 (m, 1 H), 3.72 - 3.84 (m, 2 H), 3.39 - 3.49 (m, 1 H), 2.89 - 3.05 (m, 1 H), 1.90 - 1.96 (m, 1 H), 1.85 (dt, J = 7.4, 3.6 Hz, 1 H), 1.30 (t, J = 3.1 Hz, 1 H), 1.18 - 1.23 (m, 6 H), 1.02 (dd, J = 6.5, 4.6 Hz, 6 H) Example 137 (1R,5S,6r)-N- tertiary butyl -N- methyl -3-[5-( propan -2- yl )-1H- pyrazole -3- carbonyl ]-3- azabicyclo [3.1.0] Hexane -6- formamide (1R,5S,6r)-N- tertiary butyl -N- methyl - 3-[5-( propan -2- yl )-1H- pyrazole -3- carbonyl ]-3- azabicyclo [3.1.0] hexane -6- formamide to (1R,5S,6r)-3-[(5-isopropyl-1H-pyrazole-3- yl)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (100 mg, 0.3800 mmol) in DMF (2 mL) was added tertiary butylmethylamine (22.45 mg, 0.3800 mmol), HATU (173.19 mg, 0.4600 mmol) and DIPEA (0.13 mL, 0.7600 mmol). The mixture was stirred at 30°C for 16 hours to give a yellow suspension. LCMS showed complete consumption of starting material. The suspension was filtered and the filter cake was washed with EtOAc (3 mL). The filter cake was dried in vacuo to afford the title compound (72.08 mg, 0.2368 mmol, 62.347% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (s, 1 H), 12.94 (s, 1 H), 7.87 (d, J = 7.5 Hz, 1 H), 6.45 - 6.52 (m, 1 H ), 6.50 (d, J = 1.6 Hz, 1 H), 6.35 (d, J = 1.9 Hz, 1 H), 4.29 (d, J = 12.0 Hz, 1 H), 3.86 - 3.97 (m, 1 H) , 3.72 - 3.84 (m, 2H), 3.39 - 3.49 (m, 1H), 2.89 - 3.05 (m, 1H), 1.90 - 1.96 (m, 1H), 1.85 (dt, J = 7.4, 3.6 Hz, 1 H), 1.30 (t, J = 3.1 Hz, 1 H), 1.18 - 1.23 (m, 6 H), 1.02 (dd, J = 6.5, 4.6 Hz, 6 H)

實例 138    (1R,5S,6r)-N- 甲基 -N-(1- 甲基環丙基 )-3-[5-( 丙 -2- 基 )-1H- 吡唑 -3- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-N- 甲基 -N-(1- 甲基環丙基 )-3-[5-( 丙 -2- 基 )-1H- 吡唑 -3- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向(1R,5S,6r)-N-甲基-N-(1-甲基環丙基)-3-氮雜雙環[3.1.0]己烷-6-甲醯胺氫氯化物(80 mg，0.4100mmol)於DMF (3.2mL)中之溶液添加5-異丙基-1H-吡唑-3-羧酸(63.49mg，0.4100mmol)、HATU (203.43mg，0.5400mmol)及Et ₃N (0.2mL，1.24mmol)。在20℃下攪拌混合物16小時。TLC (PE/EA=0/1)展示新樣點(Rf=0.5)且反應完成。用H ₂O (10 mL)稀釋混合物且用EA (10mL×2)萃取。用H ₂O (5 mL)及NH ₄Cl (5 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥且真空濃縮，得到粗物質油。藉由製備型TLC (PE/EA=0/1)純化粗物質油，得到粗產物。藉由製備型HPLC (FA)純化粗產物，得到呈白色粉末狀之標題化合物(20.8mg，0.0630mmol，15.287%產率)。 LC-MS方法1: 341.0 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 6.44 (br s, 1H), 4.13 (br s, 1H), 4.04 (d, J=12.8 Hz, 1H), 3.94 (dd, J=4.0, 11.3 Hz, 1H), 3.68 (dd, J=4.1, 12.8 Hz, 1H), 3.01 - 2.92 (m, 1H), 2.84 (s, 3H), 2.03 - 1.87 (m, 1H), 1.28 (s, 3H), 1.24 (d, J=6.9 Hz, 6H), 1.21 - 1.14 (m, 1H), 0.98 - 0.66 (m, 3H), 0.58 (br s, 1H) Example 138 (1R, 5S, 6r)-N- methyl -N-(1- methylcyclopropyl )-3-[5-( prop -2- yl )-1H- pyrazole -3- carbonyl ]- 3- Azabicyclo [3.1.0] hexane -6- formamide (1R,5S,6r)-N- methyl- N-(1- methylcyclopropyl )-3-[5-( propane -2- yl )-1H- pyrazole -3- carbonyl ]-3- azabicyclo [3.1.0] hexane -6- carboxamide to (1R,5S,6r)-N-methyl-N- A solution of (1-methylcyclopropyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrochloride (80 mg, 0.4100 mmol) in DMF (3.2 mL) was added 5- Isopropyl-1H-pyrazole-3-carboxylic acid (63.49mg, 0.4100mmol), HATU (203.43mg, 0.5400mmol) and _Et3N (0.2mL, 1.24mmol). The mixture was stirred at 20°C for 16 hours. TLC (PE/EA=0/1) showed a fresh spot (Rf=0.5) and the reaction was complete. The mixture was diluted with H ₂ O (10 mL) and extracted with EA (10 mL×2). The combined organic layers were washed with H ₂ O (5 mL) and NH ₄ Cl (5 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give a crude oil. The crude oil was purified by preparative TLC (PE/EA=0/1) to give the crude product. The crude product was purified by preparative HPLC (FA) to afford the title compound (20.8 mg, 0.0630 mmol, 15.287% yield) as a white powder. LC-MS method 1: 341.0 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 6.44 (br s, 1H), 4.13 (br s, 1H), 4.04 (d, J =12.8 Hz, 1H), 3.94 (dd, J =4.0, 11.3 Hz, 1H), 3.68 (dd, J =4.1, 12.8 Hz, 1H), 3.01 - 2.92 (m, 1H), 2.84 (s, 3H), 2.03 - 1.87 (m, 1H), 1.28 (s, 3H), 1.24 (d, J =6.9 Hz, 6H), 1.21 - 1.14 (m, 1H), 0.98 - 0.66 (m, 3H), 0.58 (br s, 1H)

實例 139    [(1R,5S,6r)-6-(2,2- 二甲基 -2,3- 二氫 -1H- 吲哚 -1- 羰基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][5-( 丙 -2- 基 )-1H- 吡唑 -3- 基 ] 甲酮 [(1R,5S,6r)-6-(2,2- 二甲基 -2,3- 二氫 -1H- 吲哚 -1- 羰基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ][5-( 丙 -2- 基 )-1H- 吡唑 -3- 基 ] 甲酮向5-異丙基-1H-吡唑-3-羧酸及EDCI (55.95mg，0.2900mmol)於吡啶(3mL)中之溶液添加(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基(2,2-二甲基-2,3,3a,7a-四氫-1H-吲哚-1-基)甲酮TFA鹽(49.88mg，0.1900mmol)，且在20℃下於N ₂下攪拌反應混合物16小時。LCMS展示發現所要峰值。用H ₂O (30mL)稀釋反應物且用EtOAc (20mL×3)萃取。分離合併之有機層，隨後經Na ₂SO ₄乾燥且真空濃縮，得到褐色油狀物。藉由製備型HPLC (NH ₃)純化褐色油狀物且合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(36.39mg，0.0927mmol，47.647%產率)。 LC-MS方法1: 393.1 [M+H ⁺]。 ¹H NMR (400MHz, 氯仿-d) δ = 7.23 - 6.89 (m, 4H), 6.50 (s, 1H), 4.34 (br d, J=11.5 Hz, 1H), 4.29 - 4.20 (m, 1H), 4.05 (dd, J=4.3, 11.6 Hz, 1H), 3.81 (dd, J=4.4, 12.9 Hz, 1H), 3.13 - 2.87 (m, 3H), 2.54 (td, J=3.7, 7.3 Hz, 1H), 2.32 (td, J=3.7, 7.2 Hz, 1H), 1.93 (br s, 1H), 1.61 (s, 3H), 1.53 (br s, 3H), 1.30 (d, J=7.0 Hz, 6H) Example 139 [(1R,5S,6r)-6-(2,2- Dimethyl -2,3- dihydro -1H- indole -1- carbonyl )-3- azabicyclo [3.1.0] hexyl -3- yl ][5-( propan -2- yl )-1H- pyrazol -3 - yl ] methanone [(1R,5S,6r)-6-(2,2- dimethyl -2,3 -Dihydro - 1H- indole -1- carbonyl )-3- azabicyclo [3.1.0] hex -3- yl ][5-( propan -2- yl )-1H- pyrazol -3- yl ] Methanone To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid and EDCI (55.95 mg, 0.2900 mmol) in pyridine (3 mL) was added (1R,5S,6r)-3-azabicyclo[ 3.1.0] Hex-6-yl(2,2-dimethyl-2,3,3a,7a-tetrahydro-1H-indol-1-yl)methanone TFA salt (49.88 mg, 0.1900 mmol), And the reaction mixture was stirred at 20 °C under _N2 for 16 h. LCMS showed that the desired peak was found. The reaction was diluted with H ₂ O (30 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were separated, then dried over _Na2SO4 and concentrated _in vacuo to give a brown oil. The brown oil was purified by preparative HPLC (NH ₃ ) and the resulting fluids were combined, concentrated to remove most of the CH ₃ CN and lyophilized to give the title compound (36.39 mg, 0.0927 mmol, 47.647% Yield). LC-MS method 1: 393.1 [M+H ⁺ ]. ¹ H NMR (400MHz, chloroform-d) δ = 7.23 - 6.89 (m, 4H), 6.50 (s, 1H), 4.34 (br d, J =11.5 Hz, 1H), 4.29 - 4.20 (m, 1H), 4.05 (dd, J =4.3, 11.6 Hz, 1H), 3.81 (dd, J =4.4, 12.9 Hz, 1H), 3.13 - 2.87 (m, 3H), 2.54 (td, J =3.7, 7.3 Hz, 1H) , 2.32 (td, J =3.7, 7.2 Hz, 1H), 1.93 (br s, 1H), 1.61 (s, 3H), 1.53 (br s, 3H), 1.30 (d, J =7.0 Hz, 6H)

實例 140    (5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[(4- 甲基 -2- 噻吩基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 ){(1R,5S,6r)-6-[(4- 甲基 -2- 噻吩基 ) 羰基 ]-3- 氮雜雙環 [3.1.0] 己 -3- 基 } 甲酮向(1R,5S,6r)-3-氮雜雙環[3.1.0]己-6-基(4-甲基-2-噻吩基)甲酮TFA鹽(60 mg，0.2900mmol)於DMF (2mL)中之溶液添加HATU (165.98mg，0.4300mmol)及Et ₃N (0.07mL，0.5800mmol)，且在20℃下於N ₂下攪拌混合物10 min。隨後，添加於DMF (1mL)中之5-異丙基-1H-吡唑-3-羧酸(44.62mg，0.2900mmol)，且在20℃下攪拌所得混合物16小時，得到黃色混合物。將反應混合物傾入H ₂O (5 mL)中且用EA (5 mL × 3)萃取。用鹽水(10 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥，過濾且在減壓下濃縮。藉由製備型HPLC (NH ₃)純化粗產物且凍乾，得到呈白色固體狀之標題化合物(90mg，0.2621mmol，90.535%產率)。 LC-MS方法1: 344.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 10.33 (br s, 1H), 7.60 (d, J=0.8 Hz, 1H), 7.26 (s, 1H), 6.53 (s, 1H), 4.37 (br d, J=11.5 Hz, 1H), 4.26 (d, J=13.1 Hz, 1H), 4.02 (dd, J=4.1, 11.7 Hz, 1H), 3.74 (dd, J=4.1, 12.9 Hz, 1H), 3.04 (td, J=6.8, 13.7 Hz, 1H), 2.49 (td, J=3.5, 7.2 Hz, 1H), 2.38 (td, J=3.6, 7.3 Hz, 1H), 2.34 - 2.31 (m, 1H), 2.30 (s, 3H), 1.32 (d, J=6.8 Hz, 6H) Example 140 (5- isopropyl -1H- pyrazol -3- yl ){(1R,5S,6r)-6-[(4- methyl -2- thienyl ) carbonyl ]-3- azabicyclo [ 3.1.0] Hex -3- yl } methanone (5- isopropyl -1H- pyrazol -3- yl ){(1R,5S,6r)-6-[(4- methyl -2- thienyl ) carbonyl ]-3- azabicyclo [3.1.0] hex -3- yl } methanone to (1R,5S,6r)-3-azabicyclo[3.1.0]hex-6-yl(4-methanone To a solution of 2-thienyl)methanone TFA salt (60 mg, 0.2900 mmol) in DMF (2 mL) was added HATU (165.98 mg, 0.4300 mmol) and Et ₃ N (0.07 mL, 0.5800 mmol), and at 20 The mixture was stirred at °C for 10 min under _N2 . Then, 5-isopropyl-1H-pyrazole-3-carboxylic acid (44.62 mg, 0.2900 mmol) in DMF (1 mL) was added, and the resulting mixture was stirred at 20 °C for 16 hours to give a yellow mixture. The reaction mixture was poured into H ₂ O (5 mL) and extracted with EA (5 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC ( _NH3 ) and lyophilized to afford the title compound (90 mg, 0.2621 mmol, 90.535% yield) as a white solid. LC-MS method 1: 344.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 10.33 (br s, 1H), 7.60 (d, J =0.8 Hz, 1H), 7.26 (s, 1H ), 6.53 (s, 1H), 4.37 (br d, J =11.5 Hz, 1H), 4.26 (d, J =13.1 Hz, 1H), 4.02 (dd, J =4.1, 11.7 Hz, 1H), 3.74 ( dd, J =4.1, 12.9 Hz, 1H), 3.04 (td, J =6.8, 13.7 Hz, 1H), 2.49 (td, J =3.5, 7.2 Hz, 1H), 2.38 (td, J =3.6, 7.3 Hz , 1H), 2.34 - 2.31 (m, 1H), 2.30 (s, 3H), 1.32 (d, J =6.8 Hz, 6H)

實例 141    [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮 [(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -3- 基 ](5- 異丙基 -1H- 吡唑 -3- 基 ) 甲酮向5-異丙基-1H-吡唑-3-羧酸(38.5mg，0.2500mmol)於DMF (1.5mL)中之溶液添加HATU (112.84mg，0.3000mmol)、DIPEA (0.13mL，0.7900mmol)及(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己烷TFA鹽(70 mg，0.2300mmol)。在20℃下攪拌混合物12小時，得到褐色溶液。將混合物傾入H ₂O (15 mL)中且用EtOAc (15 mL × 5)萃取。用鹽水(50 mL)洗滌合併之有機層，經Na ₂SO ₄乾燥且濃縮至乾燥。藉由製備型TLC (PE:EtOAc=1:1)純化殘餘物，得到白色固體。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(3.63mg，0.0110mmol，4.8386%產率)。 LC-MS方法1: 331.0 [M+H ⁺] ¹H NMR (400 MHz, 氯仿 -d) δ ppm 6.50 (1 H, s), 4.09 - 4.18 (1 H, m), 4.01 (1 H, br d, J=11.54 Hz), 3.81 - 3.95 (2 H, m), 3.03 (1 H, dt, J=13.93, 7.09 Hz), 2.68 (2 H, s), 2.22 (1 H, dd, J=8.16, 5.40 Hz), 2.06 (1 H, dd, J=7.91, 4.14 Hz), 1.38 (6 H, d, J=2.26 Hz), 1.31 (6 H, d, J=7.03 Hz), 1.17 (3 H, s) Example 141 [(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-6- methyl -3- aza Bicyclo [3.1.0] hex -3- yl ](5- isopropyl - 1H- pyrazol -3- yl ) methanone [(1R,5S,6r)-6-(5,5- dimethyl- 4,5- dihydro -1,2- oxazol -3- yl )-6- methyl -3- azabicyclo [3.1.0] hex -3- yl ](5- isopropyl -1H- pyridine Azol -3- yl ) methanone To a solution of 5-isopropyl-1H-pyrazole-3-carboxylic acid (38.5 mg, 0.2500 mmol) in DMF (1.5 mL) was added HATU (112.84 mg, 0.3000 mmol), DIPEA (0.13mL, 0.7900mmol) and (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methanol Ethyl-3-azabicyclo[3.1.0]hexane TFA salt (70 mg, 0.2300 mmol). The mixture was stirred at 20 °C for 12 hours to obtain a brown solution. The mixture was poured into H ₂ O (15 mL) and extracted with EtOAc (15 mL×5). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated to dryness. The residue was purified by prep-TLC (PE:EtOAc=1:1) to give a white solid. The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to afford the title compound (3.63 mg, 0.0110 mmol, 4.8386% yield) as a white solid. LC-MS method 1: 331.0 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform -d ) δ ppm 6.50 (1 H, s), 4.09 - 4.18 (1 H, m), 4.01 (1 H, br d, J =11.54 Hz), 3.81 - 3.95 (2 H, m), 3.03 (1 H, dt, J =13.93, 7.09 Hz), 2.68 (2 H, s), 2.22 (1 H, dt, J = 8.16, 5.40 Hz), 2.06 (1 H, dd, J =7.91, 4.14 Hz), 1.38 (6 H, d, J =2.26 Hz), 1.31 (6 H, d, J =7.03 Hz), 1.17 (3 H, s)

實例 142    [5-(1- 環丙基乙基 )-1H- 吡唑 -3- 基 ][(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 [5-(1- 環丙基乙基 )-1H- 吡唑 -3- 基 ][(1R,5S,6r)-6-(5,5- 二甲基 -4,5- 二氫 -1,2- 㗁唑 -3- 基 )-6- 甲基 -3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己烷TFA鹽(40 mg，0.2200mmol)及HATU (110.32mg，0.2900mmol)於DMF (1mL)中之經攪拌溶液添加DIPEA (0.23mL，1.33mmol)。在攪拌30 min之後，添加5-(1-環丙基乙基)-1H-吡唑-3-羧酸(68.44mg，0.2200mmol)。在20℃下攪拌反應混合物16小時，得到黃色溶液。LCMS展示新峰值給出所要ms。添加H ₂O (30 mL)且用EtOAc (30 mL×2)對其進行萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到黃色油狀物。藉由製備型HPLC (NH ₃)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(16.69mg，0.0468mmol，21.093%產率)。 LC-MS方法1: 357.2 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ 6.58 (s, 1H), 4.11-4.17 (m, 1H), 4.00-4.08 (m, 1H), 3.82-3.92 (m, 2H), 2.67 (s, 2H), 2.21 (dd, J=5.40, 7.91 Hz, 1H), 2.13 (dd, J=7.03, 9.03 Hz, 1H), 2.04 (dd, J=5.02, 7.03 Hz, 1H), 1.36-1.40 (m, 9H), 1.17 (d, J=0.75 Hz, 3H), 0.88-0.97 (m, 1H), 0.58 (br d, J=7.28 Hz, 2H), 0.20-0.31 (m, 2H) Example 142 [5-(1- cyclopropylethyl )-1H- pyrazol -3- yl ][(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro -1,2- oxazol -3- yl )-6- methyl -3- azabicyclo [3.1.0] hex -3- yl ] methanone [5-(1- cyclopropylethyl )-1H -pyrazol -3- yl ][(1R,5S,6r)-6-(5,5- dimethyl -4,5- dihydro - 1,2- oxazol -3- yl )-6 - methanol Base -3- azabicyclo [3.1.0] hex -3- yl ] methanone to (1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2 -Zazol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hexane TFA salt (40 mg, 0.2200 mmol) and HATU (110.32 mg, 0.2900 mmol) in DMF (1 mL) To the stirred solution was added DIPEA (0.23 mL, 1.33 mmol). After stirring for 30 min, 5-(1-cyclopropylethyl)-1H-pyrazole-3-carboxylic acid (68.44 mg, 0.2200 mmol) was added. The reaction mixture was stirred at 20 °C for 16 hours to give a yellow solution. LCMS showed new peaks giving desired ms. H ₂ O (30 mL) was added and it was extracted with EtOAc (30 mL×2). _The combined organic layers were dried over _Na2SO4 and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC ( _NH3 ). The obtained fluid was concentrated in vacuo to remove most of _CH3CN and lyophilized to give the title compound (16.69 mg, 0.0468 mmol, 21.093% yield) as a white solid. LC-MS method 1: 357.2 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ 6.58 (s, 1H), 4.11-4.17 (m, 1H), 4.00-4.08 (m, 1H), 3.82-3.92 (m, 2H), 2.67 (s, 2H), 2.21 (dd, J=5.40, 7.91 Hz, 1H), 2.13 (dd, J=7.03, 9.03 Hz, 1H), 2.04 (dd, J= 5.02, 7.03 Hz, 1H), 1.36-1.40 (m, 9H), 1.17 (d, J=0.75 Hz, 3H), 0.88-0.97 (m, 1H), 0.58 (br d, J=7.28 Hz, 2H) , 0.20-0.31 (m, 2H)

實例 143    (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6- 甲基 -6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 異丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6- 甲基 -6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向100 mL圓底燒瓶裝入5-異丙基-1H-吡唑-3-羧酸(50.34mg，0.3300mmol)、HATU (149.78mg，0.3900mmol)、N-乙基-N-異丙基丙-2-胺(0.17mL，0.9800mmol)及DMF (1.6108mL)。在攪拌30 min之後，添加6-[(1R,5S,6r)-6-甲基-3-氮雜雙環[3.1.0]己-6-基]-4-氧雜-5-氮雜螺[2.4]庚-5-烯TFA鹽(100 mg，0.3300mmol)。在10℃下攪拌反應混合物1小時，得到黃色溶液。用H ₂O (20 mL)稀釋反應混合物且用EtOAc (30 mL×2)萃取。合併之有機層經Na ₂SO ₄乾燥且真空濃縮，得到呈黃色油狀之殘餘物。藉由製備型HPLC (NH ₃)純化粗物質。真空濃縮所獲得流體以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(48.63mg，0.1481mmol，45.353%產率)。 LC-MS方法1: 329.2 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 6.50 (s, 1H), 4.19 - 4.10 (m, 1H), 4.03 (br d, J=11.9 Hz, 1H), 3.94 - 3.84 (m, 2H), 3.06 - 2.98 (m, 3H), 2.26 (m, 1H), 2.16 - 2.07 (m, 1H), 1.30 (d, J=7.2 Hz, 6H), 1.20 (s, 3H), 1.15 - 1.10 (m, 2H), 0.74 - 0.69 (m, 2H) Example 143 (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6- methyl -6-(4- oxa -5- azaspiro [2.4 ] hept- 5- en -6- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (5- isopropyl -1H- pyrazol -3- yl )[(1R,5S,6r )-6- methyl - 6-(4- oxa- 5- azaspiro [2.4] hept -5- en -6- yl )-3- azabicyclo [3.1.0] hex -3- yl ] Methanone Into a 100 mL round bottom flask was charged 5-isopropyl-1H-pyrazole-3-carboxylic acid (50.34 mg, 0.3300 mmol), HATU (149.78 mg, 0.3900 mmol), N-ethyl-N-iso Propylpropan-2-amine (0.17 mL, 0.9800 mmol) and DMF (1.6108 mL). After stirring for 30 min, 6-[(1R,5S,6r)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro [2.4] Hept-5-ene TFA salt (100 mg, 0.3300 mmol). The reaction mixture was stirred at 10 °C for 1 hour to give a yellow solution. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were dried over _Na2SO4 and concentrated _in vacuo to give a residue as a yellow oil. The crude material was purified by preparative HPLC ( _NH3 ). The obtained fluid was concentrated in vacuo to remove most of the _CH3CN and lyophilized to give the title compound (48.63 mg, 0.1481 mmol, 45.353% yield) as a white solid. LC-MS method 1: 329.2 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 6.50 (s, 1H), 4.19 - 4.10 (m, 1H), 4.03 (br d, J =11.9 Hz , 1H), 3.94 - 3.84 (m, 2H), 3.06 - 2.98 (m, 3H), 2.26 (m, 1H), 2.16 - 2.07 (m, 1H), 1.30 (d, J =7.2 Hz, 6H), 1.20 (s, 3H), 1.15 - 1.10 (m, 2H), 0.74 - 0.69 (m, 2H)

實例 144    (5- 環丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6- 甲基 -6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮 (5- 環丙基 -1H- 吡唑 -3- 基 )[(1R,5S,6r)-6- 甲基 -6-(4- 氧雜 -5- 氮雜螺 [2.4] 庚 -5- 烯 -6- 基 )-3- 氮雜雙環 [3.1.0] 己 -3- 基 ] 甲酮向5-環丙基-1H-吡唑-3-羧酸(21.86mg，0.1400mmol)於吡啶(1.5mL)中之溶液添加EDCI (62.59mg，0.3300mmol)及6-[(1R,5S,6r)-6-甲基-3-氮雜雙環[3.1.0]己-6-基]-4-氧雜-5-氮雜螺[2.4]庚-5-烯TFA鹽(40 mg，0.1300mmol)。在25℃下攪拌混合物2小時，得到黃色溶液。LCMS展示所要MS作為主峰。直接濃縮反應混合物。藉由製備型HPLC (NH ₃)純化殘餘物，得到呈黃色固體狀之標題化合物(11.2mg，0.0343mmol，26.275%產率)。 LC-MS方法1: 327.1 [M+H ⁺] ¹H NMR (400 MHz, 氯仿-d) δ ppm 6.35 (1 H, s), 4.07 - 4.16 (1 H, m), 3.95 - 4.02 (1 H, m), 3.83 - 3.95 (2 H, m), 3.01 (2 H, s), 2.27 (1 H, dd, J=8.16, 5.40 Hz), 2.12 (1 H, dd, J=7.40, 4.64 Hz), 1.88 - 1.95 (1 H, m), 1.18 - 1.22 (3 H, m), 1.11 - 1.17 (2 H, m), 0.95 - 1.02 (2 H, m), 0.71 - 0.79 (4 H, m) Example 144 (5- cyclopropyl -1H- pyrazol -3- yl )[(1R,5S,6r)-6- methyl -6-(4- oxa- 5- azaspiro [2.4 ] hept- 5- en -6- yl )-3- azabicyclo [3.1.0] hex -3- yl ] methanone (5 -cyclopropyl -1H- pyrazol -3- yl )[(1R,5S,6r )-6- methyl - 6-(4- oxa- 5- azaspiro [2.4] hept -5- en -6- yl )-3- azabicyclo [3.1.0] hex -3- yl ] Methanone To a solution of 5-cyclopropyl-1H-pyrazole-3-carboxylic acid (21.86 mg, 0.1400 mmol) in pyridine (1.5 mL) was added EDCI (62.59 mg, 0.3300 mmol) and 6-[(1R, 5S,6r)-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]-4-oxa-5-azaspiro[2.4]hept-5-ene TFA salt (40 mg , 0.1300 mmol). The mixture was stirred at 25°C for 2 hours to give a yellow solution. LCMS showed the desired MS as the main peak. The reaction mixture was directly concentrated. The residue was purified by preparative HPLC ( _NH3 ) to afford the title compound (11.2 mg, 0.0343 mmol, 26.275% yield) as a yellow solid. LC-MS method 1: 327.1 [M+H ⁺ ] ¹ H NMR (400 MHz, chloroform-d) δ ppm 6.35 (1 H, s), 4.07 - 4.16 (1 H, m), 3.95 - 4.02 (1 H , m), 3.83 - 3.95 (2 H, m), 3.01 (2 H, s), 2.27 (1 H, dd, J=8.16, 5.40 Hz), 2.12 (1 H, dd, J=7.40, 4.64 Hz ), 1.88 - 1.95 (1 H, m), 1.18 - 1.22 (3 H, m), 1.11 - 1.17 (2 H, m), 0.95 - 1.02 (2 H, m), 0.71 - 0.79 (4 H, m )

實例 145    (1R,5S,6r)-N- 三級丁基 -6- 甲基 -3-[5-( 丙 -2- 基 )-1H- 吡唑 -3- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺 (1R,5S,6r)-N- 三級丁基 -6- 甲基 -3-[5-( 丙 -2- 基 )-1H- 吡唑 -3- 羰基 ]-3- 氮雜雙環 [3.1.0] 己烷 -6- 甲醯胺向5-異丙基-1H-吡唑-3-羧酸(15.71 mg，0.10 mmol)於DMF (0.50 mL)中之溶液添加HATU (50.64 mg，0.13 mmol)及Et ₃N (0.04 mL，0.31 mmol)。在20至25℃下攪拌混合物0.5小時。隨後向混合物添加(1R,5S,6r)-6-甲基-N-(三級丁基)-3-氮雜雙環[3.1.0]己烷-6-甲醯胺TFA鹽(20 mg，0.10 mmol)。在20至25℃下攪拌所得混合物2小時。LCMS展示所要MS (作為主峰)。藉由製備型HPLC (NH ₃)純化殘餘物。合併所獲得流體，濃縮以移除大部分CH ₃CN且凍乾，得到呈白色固體狀之標題化合物(6.94 mg，0.0209 mmol，20.489%產率)。 LC-MS方法1: 333.3 [M+H ⁺] ¹H NMR (400MHz, 氯仿-d) δ = 6.49 (s, 1H), 5.59 (s, 1H), 4.13 (dd, J=5.7, 11.9 Hz, 1H), 3.95 - 3.86 (m, 2H), 3.79 - 3.71 (m, 1H), 3.03 (td, J=6.9, 13.8 Hz, 1H), 2.33 (dd, J=5.4, 8.1 Hz, 1H), 2.18 (dd, J=5.4, 8.0 Hz, 1H), 1.36 (s, 9H), 1.31 (d, J=6.9 Hz, 6H), 1.14 (s, 3H) Example 145 (1R, 5S, 6r)-N- tertiary butyl -6- methyl -3-[5-( propan -2- yl )-1H- pyrazole -3- carbonyl ]-3- azabicyclo [3.1.0] Hexane -6- formamide (1R,5S,6r)-N- tertiary butyl- 6- methyl -3- [5-( propan -2- yl )-1H- pyrazole -3- carbonyl ]-3- azabicyclo [3.1.0] hexane -6- formamide to 5-isopropyl-1H-pyrazole-3-carboxylic acid (15.71 mg, 0.10 mmol) in DMF ( 0.50 mL) was added HATU (50.64 mg, 0.13 mmol) and _Et3N (0.04 mL, 0.31 mmol). The mixture was stirred at 20 to 25°C for 0.5 hours. Then (1R,5S,6r)-6-methyl-N-(tertiary butyl)-3-azabicyclo[3.1.0]hexane-6-carboxamide TFA salt (20 mg, 0.10 mmol). The resulting mixture was stirred at 20 to 25°C for 2 hours. LCMS showed desired MS (as main peak). The residue was purified by preparative HPLC ( _NH3 ). The resulting fluids were combined, concentrated to remove most of _CH3CN and lyophilized to give the title compound (6.94 mg, 0.0209 mmol, 20.489% yield) as a white solid. LC-MS method 1: 333.3 [M+H ⁺ ] ¹ H NMR (400MHz, chloroform-d) δ = 6.49 (s, 1H), 5.59 (s, 1H), 4.13 (dd, J =5.7, 11.9 Hz, 1H), 3.95 - 3.86 (m, 2H), 3.79 - 3.71 (m, 1H), 3.03 (td, J =6.9, 13.8 Hz, 1H), 2.33 (dd, J =5.4, 8.1 Hz, 1H), 2.18 (dd, J =5.4, 8.0 Hz, 1H), 1.36 (s, 9H), 1.31 (d, J =6.9 Hz, 6H), 1.14 (s, 3H)

生物實例 1 ： 生物化學 KDM5A 抑制分析使用384孔白色格雷內爾784075(格雷內爾(Greiner))，代表性化合物使用HTRF®技術(浠思生物測定(Cisbio Bioassays))表徵其對KDM5A之抑制。簡要地，測試化合物、參考化合物及DMSO控制(典型化合物濃度範圍1pM至10µM，DMSO之最終分析濃度(FAC*) 0.5%)藉由Echo®聲學分配平台(萊伯塞(Labcyte))來添加至384孔培養盤。向孔添加於分析緩衝液(50 mM MES，50 mM NaCl，1 mM TCEP，0.01% v/v 吐溫(Tween) 20，0.03% BSA，pH 6.5)中之五(5) μl之KDM5A蛋白(藉由自然化學生物學(Nat Chem Biol) 12, 531-538 (2016)中所描述之方法產生) (5-20 nM FAC*)且在25攝氏度下將培養盤培養10至20分鐘。隨後，向孔添加於分析緩衝液中之5 μl之α-酮基戊二酸(100 μM FAC*)、生物素標記之H3K4-Me3受質(安肽生技(Anaspec)目錄號#AS-64357-1；200 nM FAC*)、Fe(II)SO ₄(100 μM FAC*)及抗壞血酸(2 mM FAC*)且在室溫下將培養盤培養20分鐘。藉由添加於HTRF偵測緩衝液(浠思生物測定目錄號#62SDBRDF)中之10 μl之抗H3K4-Me2-Eu(K) (浠思生物測定目錄號#61KA2KAH；0.75 nM FAC**) + 抗生蛋白鏈菌素XL665 (浠思生物測定目錄號#610SAXLB；25 nM FAC**)來中止反應。在340 nm激勵及在620 nm及665 nm下之雙重發射之量測之前在室溫下培養混合物30分鐘。 *FAC：基於10 μl之分析緩衝液而計算之最終分析濃度 **FAC：基於20 μl之偵測緩衝液而計算之最終分析濃度 分析個別分析培養盤之原始資料(來自各孔之665 nm及620 nm讀數)。使用以下計算來計算發射之比率： 比率 = (665 nm發射 / 620 nm發射) × 10000。 使用DMSO控制(最大回應或0%抑制)及1 μM參考控制化合物(最小回應或100%抑制)，使用最小與最大控制孔之中值及以下計算來計算各孔之百分率抑制值： %抑制 = (孔比率 -最大控制比率) / (最小控制比率 - 最大控制比率) × 100。 使用四參數曲線擬合，自針對化合物濃度繪製之%抑制之曲線圖計算化合物IC ₅₀值。 [結果] Biological Example 1 : Biochemical KDM5A Inhibition Assay Using 384-well white Grenell 784075 (Greiner), representative compounds were characterized for their inhibition of KDM5A using HTRF® technology (Cisbio Bioassays). Briefly, test compounds, reference compounds, and DMSO controls (typical compound concentrations ranging from 1 pM to 10 µM, final assay concentration (FAC*) 0.5% in DMSO) were added to 384-well culture plate. Five (5) μl of KDM5A protein ( produced by the method described in Nat Chem Biol 12, 531-538 (2016) (5-20 nM FAC*) and incubating the plate at 25°C for 10-20 minutes. Subsequently, 5 μl of α-ketoglutaric acid (100 μM FAC*), biotin-labeled H3K4-Me3 substrate (Anaspec cat #AS- 64357-1; 200 nM FAC*), Fe(II)SO ₄ (100 μM FAC*) and ascorbic acid (2 mM FAC*) and the plates were incubated at room temperature for 20 min. By adding 10 μΐ of anti-H3K4-Me2-Eu(K) (Catalog #61KA2KAH; 0.75 nM FAC**) in HTRF Detection Buffer (Catalog #62SDBRDF) + Streptavidin XL665 (Xisi Bioassay Cat #610SAXLB; 25 nM FAC**) was used to stop the reaction. The mixture was incubated at room temperature for 30 minutes before excitation at 340 nm and measurement of dual emission at 620 nm and 665 nm. *FAC: Calculated final assay concentration based on 10 μl of assay buffer **FAC: Calculated final assay concentration based on 20 μl of detection buffer Raw data from individual assay plates (665 nm and 620 nm readout). The ratio of emissions was calculated using the following calculation: Ratio = (665 nm emission/620 nm emission) x 10000. Using the DMSO control (maximum response or 0% inhibition) and 1 μM reference control compound (minimum response or 100% inhibition), calculate the percent inhibition for each well using the median of the minimum and maximum control wells and the following calculation: % inhibition = (hole ratio - maximum control ratio) / (minimum control ratio - maximum control ratio) × 100. Compound _IC50 values were calculated from plots of % inhibition plotted against compound concentrations using four parameter curve fitting. [result]

本發明化合物呈現強KDM5抑制活性。在下表中展示代表性本發明化合物之IC ₅₀值(μM)。比較化合物(R)-N-(1-(3-異丙基-1H-吡唑-5-羰基)吡咯啶-3-基)環丙烷甲醯胺(PTL 1 (國際公開案第WO2016057924號之手冊)中所描述之實例29之化合物)之IC ₅₀值(μM)為0.02 μM。且比較化合物(5-異丙基-1H-吡唑-3-基)((1R,5S,6r)-6-(5-甲基-4-苯基異㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基)甲酮(PTL 3 (國際公開案第WO2021010492號之手冊)中描述之實例134的化合物)之IC ₅₀值(μM)為0.03 μM。 實例編號 IC ₅₀值(µM)    實例編號 IC ₅₀值(µM) 實例1 0.02    實例82 0.03 實例9 0.4    實例84 0.03 實例12 0.06    實例85 0.02 實例22 0.4    實例87 0.04 實例24 0.2    實例88 0.07 實例27 1.0    實例90 0.05 實例33 0.03    實例93 0.2 實例40 0.2    實例96 0.03 實例51 0.02    實例103 0.2 實例55 0.02    實例104 0.04 實例56 0.2    實例106 0.04 實例59 0.02    實例110 0.05 實例60 0.2    實例119 0.3 實例62 0.01    實例121 0.04 實例63 0.01    實例124 0.04 實例65 0.02    實例131 0.01 實例66 0.03    實例132 0.04 實例69 0.2    實例134 0.004 實例75 0.4    實例136 0.05 實例76 0.06    實例138 0.8 實例77 0.02    實例144 0.02 實例81 0.06    實例145 0.09 The compounds of the present invention exhibit strong KDM5 inhibitory activity. _IC50 values (μΜ) for representative compounds of the invention are shown in the table below. Comparative compound (R)-N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropanecarboxamide (PTL 1 (International Publication No. WO2016057924 No. The _IC50 value (μM) of the compound of Example 29 described in the manual) was 0.02 μM. And compare compound (5-isopropyl-1H-pyrazol-3-yl) ((1R,5S,6r)-6-(5-methyl-4-phenylisozazol-3-yl)-3 - The IC ₅₀ value (μM) of azabicyclo[3.1.0]hex-3-yl)methanone (compound of Example 134 described in PTL 3 (Handbook of International Publication No. WO2021010492)) was 0.03 μM. instance number _IC50 value (µM) instance number _IC50 value (µM) Example 1 0.02 Example 82 0.03 Example 9 0.4 Example 84 0.03 Example 12 0.06 Example 85 0.02 Example 22 0.4 Example 87 0.04 Example 24 0.2 Example 88 0.07 Example 27 1.0 Example 90 0.05 Example 33 0.03 Example 93 0.2 Example 40 0.2 Example 96 0.03 Example 51 0.02 Example 103 0.2 Example 55 0.02 Example 104 0.04 Example 56 0.2 Example 106 0.04 Example 59 0.02 Example 110 0.05 Example 60 0.2 Example 119 0.3 Example 62 0.01 Example 121 0.04 Example 63 0.01 Example 124 0.04 Example 65 0.02 Example 131 0.01 Example 66 0.03 Example 132 0.04 Example 69 0.2 Example 134 0.004 Example 75 0.4 Example 136 0.05 Example 76 0.06 Example 138 0.8 Example 77 0.02 Example 144 0.02 Example 81 0.06 Example 145 0.09

生物實例 2 ： 人類肝臟微粒體中之代謝穩定性在96孔培養盤中一式兩份進行人類肝臟微粒體(BD基因測試公司(BD Gentest Corporation)，目錄號#452161)培養。各孔含有40 μL之0.1 M磷酸鉀緩衝液(pH 7.4)、4.125 mM MgCl ₂、0.625 mg/mL肝臟微粒體及測試化合物(1.25 μM)。在37℃下之5-min預培養之後，添加於0.1M磷酸鉀緩衝液中之10 uL之5.0 mM NADPH以引發酶反應。最終組分濃度為0.1M磷酸鉀緩衝液(pH 7.4)、1.0 mM NADPH、3.3 mM MgCl ₂、0.5 mg/mL肝臟微粒體及測試化合物(1.0 μM)。藉由添加含有內標物之200 μL之冰冷乙腈來在0及60 min處終止反應。 LC-MS/MS分析如以下所指定來進行。 LC 系統 ACQUITY UPLC H類加系統(ACQUITY UPLC H-Class PLUS System) (沃特斯(Waters)) 管柱 ACQUITY UPLC BEH C18管柱2.1 mm ID × 50 mm (沃特斯) 溶離條件 管柱溫度：25℃ 行動相： A：水(0.1%甲酸) B：乙腈(0.1%甲酸) 梯度程序： 時間 (min)      0      1.20         1.40         1.41         1.50 行動相 B (%) 10    90            90            10            10 流速：0.6mL/min MS 系統 API4000 (AB Sciex) 條件 電噴霧電離、陽離子模式、多反應監測模式 根據下文描述之公式而自在反應開始之後0及60 min收集之樣本之峰面積比率(測試化合物/內標物)計算測試化合物的在60 min處之剩餘(%)。 在60 min處之剩餘(%) = 在60 min處收集之樣本之峰面積比率 / 在0min處收集之樣本之峰面積比率 × 100 Biological Example 2 : Metabolic Stability in Human Liver Microsomes Human liver microsomes (BD Gentest Corporation, Cat #452161 ) were cultured in duplicate in 96-well culture dishes. Each well contained 40 μL of 0.1 M potassium phosphate buffer (pH 7.4), 4.125 mM MgCl ₂ , 0.625 mg/mL liver microsomes, and test compound (1.25 μM). After a 5-min preincubation at 37°C, 10 uL of 5.0 mM NADPH in 0.1 M potassium phosphate buffer was added to initiate the enzyme reaction. Final component concentrations were 0.1 M potassium phosphate buffer (pH 7.4), 1.0 mM NADPH, 3.3 mM _MgCl2 , 0.5 mg/mL liver microsomes, and test compound (1.0 μΜ). Reactions were stopped at 0 and 60 min by the addition of 200 μL of ice-cold acetonitrile containing an internal standard. LC-MS/MS analysis was performed as specified below. LC system ACQUITY UPLC H-Class PLUS System (Waters) String ACQUITY UPLC BEH C18 Column 2.1 mm ID × 50 mm (Waters) Dissolution conditions Column temperature: 25°C Mobile phase: A: Water (0.1% formic acid) B: Acetonitrile (0.1% formic acid) Gradient program: Time (min) 0 1.20 1.40 1.41 1.50 Mobile phase B (%) 10 90 90 10 10 Flow rate: 0.6mL/min MS system API4000 (AB Sciex) condition Electrospray ionization, positive ion mode, multiple reaction monitoring mode The remaining (%) of the test compound at 60 min was calculated from the peak area ratio (test compound/internal standard substance) of samples collected at 0 and 60 min after the start of the reaction according to the formula described below. Remaining at 60 min (%) = peak area ratio of samples collected at 60 min/ peak area ratio of samples collected at 0 min × 100

[結果] 本發明化合物為對肝臟代謝穩定的。在下表中展示代表性本發明化合物在人類肝臟微粒體中之代謝穩定性。 實例編號 人類肝臟微粒體中之代謝穩定性(在60 min處之剩餘%) 實例1 95 實例9 93 實例12 100 實例24 101 實例27 97 實例33 103 實例40 103 實例51 95 實例59 100 實例60 102 實例62 83 實例65 93 實例66 89 實例69 89 實例75 102 實例81 100 實例82 104 實例84 92 實例85 98 實例87 99 實例88 95 實例90 100 實例93 86 實例96 83 實例110 85 實例119 102 實例121 114 實例124 97 實例131 84 實例136 97 實例144 101 實例145 99 [Results] The compounds of the present invention were stable to liver metabolism. The metabolic stability of representative compounds of the invention in human liver microsomes is shown in the table below. instance number Metabolic stability in human liver microsomes (% remaining at 60 min) Example 1 95 Example 9 93 Example 12 100 Example 24 101 Example 27 97 Example 33 103 Example 40 103 Example 51 95 Example 59 100 Example 60 102 Example 62 83 Example 65 93 Example 66 89 Example 69 89 Example 75 102 Example 81 100 Example 82 104 Example 84 92 Example 85 98 Example 87 99 Example 88 95 Example 90 100 Example 93 86 Example 96 83 Example 110 85 Example 119 102 Example 121 114 Example 124 97 Example 131 84 Example 136 97 Example 144 101 Example 145 99

生物實例 3 ： 小鼠中之大腦濃度測試化合物在1或3 mg/kg下經口投與至小鼠(C57BL/6)。在投與之後2小時收集大腦樣本且用3倍體積之蒸餾水進行均質化。 LC-MS/MS分析如以下所指定來進行。標準校準樣本使用相同基質(matrix)來製備且以相同方式進行分析。 萃取工序 混合40 µL之樣本與含有內標物的40 µL之乙腈及160 µL之乙腈/乙醇(7:3)，且攪拌混合物。將所有者轉移至去蛋白作用過濾器板以供抽濾且將濾液注入至LC系統。 LC 系統 日珥(Prominence) UFLC _XR(島津公司(Shimadzu Corporation)) 管柱 Shim-pack XR-ODSII 2.0 mm ID × 75 mm (島津公司) 溶離條件 管柱溫度：40℃ 行動相： A：0.2%甲酸 5 mM乙酸銨水溶液 B：乙腈 梯度程序： 時間 (min)      0      1.5   3.0   3.1   4 行動相 B (%) 10    90    90    10    10 流速：0.5 mL/min MS 系統 API4000 (AB Sciex) 條件 電噴霧電離、陽離子模式、多反應監測模式 分析標準校準樣本以自峰面積比率(測試化合物/內標物)計算回歸方程式。峰面積比率針對量測樣本而經判定且經指定至回歸方程式以計算分析值。 Biological Example 3 : Brain Concentration in Mice Test compounds were orally administered to mice (C57BL/6) at 1 or 3 mg/kg. Brain samples were collected 2 hours after administration and homogenized with 3 volumes of distilled water. LC-MS/MS analysis was performed as specified below. Standard calibration samples were prepared using the same matrix and analyzed in the same manner. Extraction process Mix 40 µL of sample with 40 µL of acetonitrile containing internal standard and 160 µL of acetonitrile/ethanol (7:3) and stir the mixture. The owner was transferred to a deproteinization filter plate for suction filtration and the filtrate was injected into the LC system. LC system Prominence UFLC _XR (Shimadzu Corporation) String Shim-pack XR-ODSII 2.0 mm ID × 75 mm (Shimadzu Corporation) Dissolution conditions Column temperature: 40°C Mobile phase: A: 0.2% formic acid 5 mM ammonium acetate aqueous solution B: Acetonitrile gradient program: Time (min) 0 1.5 3.0 3.1 4 Mobile phase B (%) 10 90 90 10 10 Flow rate: 0.5 mL/ min MS system API4000 (AB Sciex) condition Electrospray ionization, positive ion mode, multiple reaction monitoring mode Standard calibration samples were analyzed to calculate regression equations from peak area ratios (test compound/internal standard). The peak area ratios are determined for the measurement samples and assigned to the regression equation to calculate the analysis value.

[結果] 本發明化合物之未結合大腦濃度為高。在下表中展示代表性本發明化合物之在1 mg/kg下在2小時處之未結合大腦濃度。藉由來自3 mg/kg資料之比例計算值來獲得具有*之值。比較化合物(R)-N-(1-(3-異丙基-1H-吡唑-5-羰基)吡咯啶-3-基)環丙烷甲醯胺(PTL 1(國際公開案第WO2016057924號之手冊)中所描述之實例29之化合物)之在2小時處之未結合大腦濃度為2.5 ng/g。在投與之後2小時，在大腦中不可偵測到比較化合物(5-異丙基-1H-吡唑-3-基)((1R,5S,6r)-6-(5-甲基-4-苯基異㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基)甲酮(PTL 3 (國際公開案第WO2021010492號之手冊)中描述之實例134之化合物)。 實例編號 在1 mg/kg下在2小時處之未結合大腦濃度(ng/g) 實例1 93.7* 實例12 10.8 實例33 62.1 實例51 55.3 實例81 21.9 實例82 57.4 實例85 76.7 實例88 39.5* [Results] The unbound brain concentration of the compound of the present invention was high. Unbound brain concentrations at 1 mg/kg at 2 hours for representative compounds of the invention are shown in the table below. Values with * were obtained by ratio calculations from the 3 mg/kg data. Comparative compound (R)-N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropanecarboxamide (PTL 1 (International Publication No. WO2016057924 No. The unbound brain concentration at 2 hours of the compound of Example 29 described in the manual) was 2.5 ng/g. The comparative compound (5-isopropyl-1H-pyrazol-3-yl)((1R,5S,6r)-6-(5-methyl-4 The compound of Example 134 described in -Phenylisozazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl)methanone (PTL 3 (Handbook of International Publication No. WO2021010492) ). instance number Unbound brain concentration (ng/g) at 2 hours at 1 mg/kg Example 1 93.7* Example 12 10.8 Example 33 62.1 Example 51 55.3 Example 81 21.9 Example 82 57.4 Example 85 76.7 Example 88 39.5*

調配物實例 1 ：含有5 mg之[(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮之錠劑 以下組分可根據標準方法來混合及壓縮為錠劑以獲得各自含有5 mg之活性組分之10,000個錠劑。 •  [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮：50 g •  羧甲基纖維素鈣(崩散劑)：20 g •  硬脂酸鎂(潤滑劑)：10 g •  微晶纖維素：920 g Formulation Example 1 : Containing 5 mg of [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3- Tablets of azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone The following components can be mixed and compressed into tablets according to standard methods. 10,000 lozenges each containing 5 mg of active ingredient are obtained. • [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0] Hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone: 50 g Carmellose calcium (disintegrant): 20 g Magnesium stearate (lubricant) : 10 g • Microcrystalline Cellulose: 920 g

調配物實例 2 ：含有5 mg之[(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](1-異丙基-1H-咪唑-4-基)甲酮之錠劑 以下組分可根據標準方法來混合及壓縮為錠劑以獲得各自含有5 mg之活性組分之10,000個錠劑。 •  [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](1-異丙基-1H-咪唑-4-基)甲酮：50 g •  羧甲基纖維素鈣(崩散劑)：20 g •  硬脂酸鎂(潤滑劑)：10 g •  微晶纖維素：920 g Formulation Example 2 : Containing 5 mg of [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3- Tablets of azabicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone The following components can be mixed and compressed into tablets according to standard methods to obtain 10,000 lozenges each containing 5 mg of active ingredient. • [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0] Hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone: 50 g Carmellose calcium (disintegrant): 20 g Magnesium stearate (lubricant): 10 g • Microcrystalline cellulose: 920 g

調配物實例 3 ：含有20 mg之[(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮之注射劑 以下組分可根據標準方法來混合，且溶液可隨後根據標準方法來滅菌，以5-mL等分試樣劃分至安瓿中且根據標準方法來凍乾以獲得各自含有20 mg之活性組分之10,000個安瓿。 •  [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮：200 g •  甘露醇：20 g •  蒸餾水：50 L [工業實用性] Formulation Example 3 : Containing 20 mg of [(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3- Injection of azabicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone The following components can be mixed according to the standard method, and the solution can then be mixed according to the standard method Sterilized by method, divided into ampoules in 5-mL aliquots and lyophilized according to standard methods to obtain 10,000 ampoules each containing 20 mg of active ingredient. • [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0] Hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone: 200 g Mannitol: 20 g Distilled water: 50 L [Industrial applicability]

本發明化合物具有KDM5抑制活性，且因此可用作對癌症、亨廷頓氏病、阿茲海默症及其類似者之預防劑及/或治療劑。The compound of the present invention has KDM5 inhibitory activity, and thus is useful as a preventive and/or therapeutic agent for cancer, Huntington's disease, Alzheimer's disease and the like.

Claims (22)

一種醫藥組合物，其包含由通式(I)表示之化合物： 其中R ¹表示Cyc1、-CO-Cyc2或-CONR ¹⁰R ¹¹； Cyc1表示5至9員芳族雜環或5員非芳族雜環，其中各者可經1至5個R ¹²取代； R ¹²表示(1) C1-4烷基、(2) C3-7環烷基、(3) C1-4鹵烷基、(4) C1-4烷氧基、(5)可經1至3個R ¹⁷取代之苯基、(6)經苯基取代之C1-4烷基、(7)二甲基胺基、(8)吡啶基或(9) 1-(環丙基甲基)吡唑-3-基； 複數個R ¹²可相同或不同； 兩個R ¹²以及附接至此等R ¹²之原子可形成C3-5環烷烴，其中C3-5環烷烴之碳原子可經選自1至2個N、O及S之雜原子置換； R ¹⁷表示C1-4烷基、C1-4烷氧基或鹵素； 複數個R ¹⁷可相同或不同； Cyc2表示C3-12單或雙環碳環或5至9員單或雙環雜環，其中各者可經1至5個R ¹³取代； R ¹³表示C1-4烷基、C1-4烷氧基或鹵素； 複數個R ¹³可相同或不同； R ¹⁰表示 其中R ¹⁸及R ¹⁹獨立地表示C1-4烷基； R ¹⁸及R ¹⁹以及附接至R ¹⁸及R ¹⁹之碳原子可形成C3-5環烷烴； R ²⁰表示氫原子、C1-4烷基、C1-4鹵烷基或腈； (在基團中，箭頭指示結合至-CON＜之氮原子)； R ¹¹表示氫原子、C1-4烷基或1至9個氘化C1-4烷基； R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷及R ⁸獨立地表示氫原子、C1-4烷基、鹵素或C1-4烷氧基； R ⁹表示可經1至3個R ¹⁴取代之咪唑或可經1至3個R ¹⁵取代之吡唑； R ¹⁴表示(1) C1-8烷基、(2)可經C1-4烷基取代之C3-7環烷基、(3) C1-8鹵烷基、(4)經可經1至3個R ¹⁶取代之Cyc3取代的C1-8烷基或(5)經苯氧基取代之C1-8烷基； Cyc3表示苯基、C3-7環烷基、吡啶基、噻唑基或四氫哌喃基； R ¹⁶表示C1-4烷基、鹵素、C1-4烷氧基或氰基； 複數個R ¹⁴可相同或不同； 複數個R ¹⁶可相同或不同； R ¹⁵表示(1) C1-8烷基、(2)可經C1-4烷基取代之C3-7環烷基、(3) C1-8鹵烷基、(4)經可經1至3個R ²¹取代之Cyc4取代的C1-8烷基或(5)經苯氧基取代之C1-8烷基； Cyc4表示苯基、C3-7環烷基、吡啶基、噻唑基或四氫哌喃基； R ²¹表示C1-4烷基、鹵素、C1-4烷氧基或氰基； 複數個R ¹⁵可相同或不同； 複數個R ²¹可相同或不同； 各氫原子可為氘原子或氚原子； 其限制條件為排除((1R,5S,6r)-6-(環丙烷羰基)-3-氮雜雙環[3.1.0]己-3-基)(5-異丙基-1H-吡唑-3-基)甲酮、(5-異丙基-1H-吡唑-3-基)-[(1R,5S)-6-[(2R)-2-甲基吡咯啶-1-羰基]-3-氮雜雙環[3.1.0]己-3-基]甲酮、(5-異丙基-1H-吡唑-3-基)-[(1S,5R)-6-[(2S)-2-甲基吡咯啶-1-羰基]-3-氮雜雙環[3.1.0]己-3-基]甲酮、[(1S,5R)-6-(2,2-二甲基吡咯啶-1-羰基)-3-氮雜雙環[3.1.0]己-3-基]-(5-異丙基-1H-吡唑-3-基)甲酮及(5-異丙基-1H-吡唑-3-基)-[(1S,5R)-6-(5-甲基-4-苯基-異㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； 或其鹽及醫藥學上可接受之載劑。 A pharmaceutical composition comprising a compound represented by general formula (I): Wherein R ¹ represents Cyc1, -CO-Cyc2 or -CONR ¹⁰ R ¹¹ ; Cyc1 represents 5 to 9 members of aromatic heterocycle or 5 members of non-aromatic heterocycle, each of which can be substituted by 1 to 5 R ¹² ; R ¹² represents (1) C1-4 alkyl, (2) C3-7 cycloalkyl, (3) C1-4 haloalkyl, (4) C1-4 alkoxy, (5) can be through 1 to 3 R ¹⁷ substituted phenyl, (6) C1-4 alkyl substituted by phenyl, (7) dimethylamino, (8) pyridyl or (9) 1-(cyclopropylmethyl) pyrazole -3-base; a plurality of R ¹² can be the same or different; two R ¹² and the atoms attached to these R ¹² can form a C3-5 cycloalkane, wherein the carbon atoms of the C3-5 cycloalkane can be selected from 1 to 2 N, O and S heteroatom replacement; R ¹⁷ represents C1-4 alkyl, C1-4 alkoxy or halogen; multiple R ¹⁷ can be the same or different; Cyc2 represents C3-12 single or bicyclic carbocycle or 5 to 9 membered mono- or bicyclic heterocycles, each of which can be substituted by 1 to 5 R ¹³ ; R ¹³ represents C1-4 alkyl, C1-4 alkoxy or halogen; a plurality of R ¹³ can be the same or different; R ¹⁰ means Wherein R ¹⁸ and R ¹⁹ independently represent C1-4 alkyl; R ¹⁸ and R ¹⁹ and carbon atoms attached to R ¹⁸ and R ¹⁹ can form C3-5 cycloalkane; R ²⁰ represents hydrogen atom, C1-4 alkane group, C1-4 haloalkyl or nitrile; (in the group, the arrow indicates the nitrogen atom bound to -CON<); R ¹¹ represents a hydrogen atom, C1-4 alkyl or 1 to 9 deuterated C1-4 Alkyl group; R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ independently represent a hydrogen atom, C1-4 alkyl, halogen or C1-4 alkoxy; R ⁹ represents that 1 Up to 3 R ¹⁴ substituted imidazoles or 1 to 3 R ¹⁵ substituted pyrazoles; R ¹⁴ represents (1) C1-8 alkyl, (2) C3-7 ring which may be substituted by C1-4 alkyl Alkyl, (3) C1-8 haloalkyl, (4) C1-8 alkyl substituted by Cyc3 which may be substituted by 1 to 3 R ¹⁶ or (5) C1-8 alkyl substituted by phenoxy ; Cyc3 represents phenyl, C3-7 cycloalkyl, pyridyl, thiazolyl or tetrahydropyranyl; R ¹⁶ represents C1-4 alkyl, halogen, C1-4 alkoxy or cyano; plural R ¹⁴ Can be the same or different; Multiple R ¹⁶ can be the same or different; R ¹⁵ represents (1) C1-8 alkyl, (2) C3-7 cycloalkyl which may be substituted by C1-4 alkyl, (3) C1- 8 haloalkyl, (4) C1-8 alkyl substituted by Cyc4 which may be substituted by 1 to 3 R ²¹ or (5) C1-8 alkyl substituted by phenoxy; Cyc4 represents phenyl, C3- 7 cycloalkyl, pyridyl, thiazolyl or tetrahydropyranyl; R ²¹ represents C1-4 alkyl, halogen, C1-4 alkoxy or cyano; multiple R ¹⁵ can be the same or different; multiple R ²¹ can be the same or different; each hydrogen atom can be a deuterium atom or a tritium atom; the restriction is to exclude ((1R,5S,6r)-6-(cyclopropanecarbonyl)-3-azabicyclo[3.1.0]hexyl -3-yl)(5-isopropyl-1H-pyrazol-3-yl)methanone, (5-isopropyl-1H-pyrazol-3-yl)-[(1R,5S)-6- [(2R)-2-methylpyrrolidine-1-carbonyl]-3-azabicyclo[3.1.0]hex-3-yl]methanone, (5-isopropyl-1H-pyrazole-3- base)-[(1S,5R)-6-[(2S)-2-methylpyrrolidin-1-carbonyl]-3-azabicyclo[3.1.0]hex-3-yl]methanone, [( 1S,5R)-6-(2,2-Dimethylpyrrolidine-1-carbonyl)-3-azabicyclo[3.1.0]hex-3-yl]-(5-isopropyl-1H-pyridine Azol-3-yl)methanone and (5-isopropyl-1H-pyrazol-3-yl)-[(1S,5R)-6-(5-methyl-4-phenyl-isoxazole- 3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; or a salt thereof and a pharmaceutically acceptable carrier. 如請求項1之醫藥組合物，其中R ¹表示Cyc1，且Cyc1表示可經1至5個R ¹²取代之5員非芳族雜環。 The pharmaceutical composition according to claim 1, wherein R ¹ represents Cyc1, and Cyc1 represents a 5-membered non-aromatic heterocyclic ring which may be substituted by 1 to 5 R ¹² . 如請求項2之醫藥組合物，其中5員非芳族雜環表示4,5-二氫異㗁唑或4,5-二氫-1,2,4-㗁二唑。The pharmaceutical composition according to claim 2, wherein the 5-membered non-aromatic heterocycle represents 4,5-dihydroisoxazole or 4,5-dihydro-1,2,4-oxadiazole. 如請求項1至3中任一項之醫藥組合物，其中R ⁹表示可經1至3個R ¹⁴取代之咪唑。 The pharmaceutical composition according to any one of claims 1 to 3, wherein R ⁹ represents imidazole which may be substituted by 1 to 3 R ¹⁴ . 如請求項1至4中任一項之醫藥組合物，其中該由該通式(I)表示之化合物或其鹽為由通式(I-1)表示之化合物 其中R ^12-1及R ^12-2獨立地表示C1-4烷基； R ^12-1及R ^12-2以及鍵結至該R ^12-1及R ^12-2之原子可形成C3-5環烷烴； R ^14-1表示可經C1-4烷基取代之C1-4烷基或C3-5環烷基； 其他符號表示如請求項1中所述相同含義； 或其鹽。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the compound represented by the general formula (I) or a salt thereof is a compound represented by the general formula (I-1) Wherein R ^12-1 and R ^12-2 independently represent C1-4 alkyl; R ^12-1 and R ^12-2 and atoms bonded to the R ^12-1 and R ^12-2 can form a C3-5 ring Alkane; R ^14-1 represents C1-4 alkyl or C3-5 cycloalkyl which may be substituted by C1-4 alkyl; other symbols represent the same meaning as described in Claim 1; or a salt thereof. 如請求項1之醫藥組合物，其中該由通式(I)表示之化合物或其鹽係選自由以下各者組成之群的化合物： (1) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](1-異丙基-1H-咪唑-4-基)甲酮； (2) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基][1-(1-甲基環丙基)-1H-咪唑-4-基]甲酮； (3) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基]甲酮； (4) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (5) {1-[(2S)-丁-2-基]-1H-咪唑-4-基}[(1R,5S,6S)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (6) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基](1-異丙基-1H-咪唑-4-基)甲酮； (7) (1-異丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (8) (1-環丙基-1H-咪唑-4-基)[(1R,5S,6r)-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮；及 (9) [1-(1-甲基環丙基)-1H-咪唑-4-基][(1R,5S,6r)-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； 或其鹽。 The pharmaceutical composition according to claim 1, wherein the compound represented by general formula (I) or its salt is a compound selected from the group consisting of: (1) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1. 0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone; (2) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1. 0]hex-3-yl][1-(1-methylcyclopropyl)-1H-imidazol-4-yl]methanone; (3) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(5,5-dimethyl-4,5-dihydro-1,2-㗁Azol-3-yl)-6-methyl-3-azabicyclo[3.1.0]hex-3-yl]methanone; (4) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept- 5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (5) {1-[(2S)-But-2-yl]-1H-imidazol-4-yl}[(1R,5S,6S)-6-(5,5-Dimethyl-4,5- Dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (6) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-nitrogen Heterobicyclo[3.1.0]hex-3-yl](1-isopropyl-1H-imidazol-4-yl)methanone; (7) (1-isopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]hept- 5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (8) (1-cyclopropyl-1H-imidazol-4-yl)[(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]hept-5-ene-6 -yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; and (9) [1-(1-methylcyclopropyl)-1H-imidazol-4-yl][(1R,5S,6r)-6-(4-oxa-5-azaspiro[2.4]heptane -5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; or its salt. 如請求項1至3中任一項之醫藥組合物，其中R ⁹表示可經1至3個R ¹⁵取代之吡唑。 The pharmaceutical composition according to any one of claims 1 to 3, wherein R ⁹ represents pyrazole which may be substituted by 1 to 3 R ¹⁵ . 如請求項1之醫藥組合物，其中該由該通式(I)表示之化合物或其鹽為由通式(I-2)表示之化合物 其中所有符號表示如請求項1或請求項5中所述相同含義； 或其鹽。 The pharmaceutical composition according to claim 1, wherein the compound represented by the general formula (I) or its salt is a compound represented by the general formula (I-2) Wherein, all the symbols represent the same meanings as described in claim item 1 or claim item 5; or their salts. 如請求項1之醫藥組合物，其中該由通式(I)表示之化合物或其鹽係選自由以下各者組成之群的化合物： (1) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮； (2) (5-異丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-(2-氧雜-3-氮雜雙環[3.1.0]己-3-烯-4-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (3) [5-(1-環丙基乙基)-1H-吡唑-3-基][(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； (4) [(1R,5S,6r)-6-(5,5-二甲基-4,5-二氫-1,2-㗁唑-3-基)-6-甲基-3-氮雜雙環[3.1.0]己-3-基](5-異丙基-1H-吡唑-3-基)甲酮；及 (5) (5-環丙基-1H-吡唑-3-基)[(1R,5S,6r)-6-甲基-6-(4-氧雜-5-氮雜螺[2.4]庚-5-烯-6-基)-3-氮雜雙環[3.1.0]己-3-基]甲酮； 或其鹽。 The pharmaceutical composition according to claim 1, wherein the compound represented by general formula (I) or its salt is a compound selected from the group consisting of: (1) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-3-azabicyclo[3.1. 0] Hex-3-yl] (5-isopropyl-1H-pyrazol-3-yl)methanone; (2) (5-isopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-(2-oxa-3-azabicyclo[3.1.0]hexa-3- En-4-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (3) [5-(1-cyclopropylethyl)-1H-pyrazol-3-yl][(1R,5S,6r)-6-(5,5-dimethyl-4,5-di Hydrogen-1,2-oxazol-3-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; (4) [(1R,5S,6r)-6-(5,5-Dimethyl-4,5-dihydro-1,2-oxazol-3-yl)-6-methyl-3-nitrogen Heterobicyclo[3.1.0]hex-3-yl](5-isopropyl-1H-pyrazol-3-yl)methanone; and (5) (5-cyclopropyl-1H-pyrazol-3-yl)[(1R,5S,6r)-6-methyl-6-(4-oxa-5-azaspiro[2.4]heptane -5-en-6-yl)-3-azabicyclo[3.1.0]hex-3-yl]methanone; or its salt. 如請求項1之醫藥組合物，其中R ¹表示-CONR ¹⁰R ¹¹。 The pharmaceutical composition according to claim 1, wherein R ¹ represents -CONR ¹⁰ R ¹¹ . 如請求項10之醫藥組合物，其中R ¹⁰表示異丙基、三級丁基、1,1,1-三氟-2-甲基丙-2-基、1-甲基環丙基、1-(三氟甲基)環丙基或1-氰基環丙基。 Such as the pharmaceutical composition of claim item 10, wherein R ¹⁰ represents isopropyl, tertiary butyl, 1,1,1-trifluoro-2-methylprop-2-yl, 1-methylcyclopropyl, 1 -(trifluoromethyl)cyclopropyl or 1-cyanocyclopropyl. 如請求項10或11之醫藥組合物，其中R ⁹表示可經1至3個R ¹⁴取代之咪唑。 The pharmaceutical composition according to claim 10 or 11, wherein R ⁹ represents imidazole which may be substituted by 1 to 3 R ¹⁴ . 如請求項1之醫藥組合物，其中該由該通式(I)表示之化合物或其鹽為由通式(I-3)表示之化合物 其中R ^10-1表示異丙基、三級丁基、1,1,1-三氟-2-甲基丙-2-基、1-甲基環丙基、1-(三氟甲基)環丙基或1-氰基環丙基； 其他符號表示如請求項1或請求項5中所述相同含義； 或其鹽。 The pharmaceutical composition according to claim 1, wherein the compound represented by the general formula (I) or its salt is a compound represented by the general formula (I-3) Where R ^10-1 represents isopropyl, tertiary butyl, 1,1,1-trifluoro-2-methylprop-2-yl, 1-methylcyclopropyl, 1-(trifluoromethyl) Cyclopropyl or 1-cyanocyclopropyl; Other symbols represent the same meaning as described in Claim 1 or Claim 5; or a salt thereof. 如請求項1之醫藥組合物，其中該由通式(I)表示之化合物或其鹽係選自由以下各者組成之群的化合物： (1) (1R,5S,6r)-N-三級丁基-6-甲基-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (2) (1R,5S,6r)-N-三級丁基-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (3) (1R,5S,6r)-N-(丙-2-基)-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺；及 (4) (1R,5S,6r)-N-(1-氰基環丙基)-3-[1-(丙-2-基)-1H-咪唑-4-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； 或其鹽。 The pharmaceutical composition according to claim 1, wherein the compound represented by general formula (I) or its salt is a compound selected from the group consisting of: (1) (1R,5S,6r)-N-tertiary butyl-6-methyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo [3.1.0] Hexane-6-formamide; (2) (1R,5S,6r)-N-tertiary butyl-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1.0] Hexane-6-formamide; (3) (1R,5S,6r)-N-(prop-2-yl)-3-[1-(prop-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo[3.1 .0] hexane-6-carboxamide; and (4) (1R,5S,6r)-N-(1-cyanocyclopropyl)-3-[1-(propan-2-yl)-1H-imidazole-4-carbonyl]-3-azabicyclo [3.1.0] Hexane-6-formamide; or its salt. 如請求項10或11之醫藥組合物，其中R ⁹表示可經1至3個R ¹⁵取代之吡唑。 The pharmaceutical composition according to claim 10 or 11, wherein R ⁹ represents pyrazole which may be substituted by 1 to 3 R ¹⁵ . 如請求項1之醫藥組合物，其中該由該通式(I)表示之化合物或其鹽為由通式(I-4)表示之化合物 其中所有符號表示如請求項1或請求項13中所述相同含義； 或其鹽。 The pharmaceutical composition according to claim 1, wherein the compound represented by the general formula (I) or its salt is a compound represented by the general formula (I-4) Wherein, all the symbols represent the same meanings as described in claim item 1 or claim item 13; or their salts. 如請求項1之醫藥組合物，其中該由通式(I)表示之化合物或其鹽係選自由以下各者組成之群的化合物： (1) (1R,5S,6r)-N-(丙-2-基)-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (2) (1R,5S,6r)-N-三級丁基-6-甲基-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； (3) (1R,5S,6r)-N-三級丁基-N-甲基-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺；及 (4) (1R,5S,6r)-N-甲基-N-(1-甲基環丙基)-3-[5-(丙-2-基)-1H-吡唑-3-羰基]-3-氮雜雙環[3.1.0]己烷-6-甲醯胺； 或其鹽。 The pharmaceutical composition according to claim 1, wherein the compound represented by general formula (I) or its salt is a compound selected from the group consisting of: (1) (1R,5S,6r)-N-(prop-2-yl)-3-[5-(prop-2-yl)-1H-pyrazole-3-carbonyl]-3-azabicyclo[ 3.1.0] hexane-6-formamide; (2) (1R,5S,6r)-N-tertiary butyl-6-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-aza Bicyclo[3.1.0]hexane-6-carboxamide; (3) (1R,5S,6r)-N-tertiary butyl-N-methyl-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl]-3-aza Bicyclo[3.1.0]hexane-6-carboxamide; and (4) (1R,5S,6r)-N-methyl-N-(1-methylcyclopropyl)-3-[5-(propan-2-yl)-1H-pyrazole-3-carbonyl] -3-Azabicyclo[3.1.0]hexane-6-carboxamide; or its salt. 如請求項1之醫藥組合物，其為KDM5抑制劑。The pharmaceutical composition according to claim 1, which is a KDM5 inhibitor. 如請求項1之醫藥組合物，其為針對KDM5相關疾病之預防劑及/或治療劑。The pharmaceutical composition according to claim 1, which is a preventive and/or therapeutic agent for KDM5-related diseases. 如請求項19之醫藥組合物，其中該KDM5相關疾病為癌症或阿茲海默症(Alzheimer disease)。The pharmaceutical composition according to claim 19, wherein the KDM5-related disease is cancer or Alzheimer's disease. 一種如請求項1至17中任一項之醫藥組合物的用途，其用於製造用於治療KDM5相關疾病之藥物。A use of the pharmaceutical composition according to any one of claims 1 to 17, which is used for the manufacture of medicines for treating KDM5-related diseases. 如請求項21之用途，其中該KDM5相關疾病為癌症或阿茲海默症。The use according to claim 21, wherein the KDM5-related disease is cancer or Alzheimer's disease.