JP7314494B2 - Pharmaceuticals containing prodrugs of amino acid derivatives - Google Patents

Description

The present invention relates to pharmaceuticals containing (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives and prodrugs of (1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives. More specifically, for example, subgroup II of metabotropic glutamate (mGlu) receptors effective for the treatment and prevention of mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, movement disorders associated with muscle stiffness, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, brain failure, cerebral edema, spinal cord disorders, head trauma, inflammation, immune-related diseases, etc. containing prodrugs of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives and (1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives, which are compounds that act as antagonists of the mGlu2 and mGlu3 receptors to which they belong. Regarding medicine. The present invention also relates to a medicament containing a prodrug that enhances the oral absorption of a compound (active form) acting as an antagonist of mGlu2 and mGlu3 receptors and increases the amount of exposure of the active form in vivo.

Metabotropic glutamate receptors are classified into three groups based on amino acid sequence homology, signaling mechanism and pharmacological properties. Among these, group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) are G protein-coupled receptors that bind adenyl cyclase and suppress forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) (Non-Patent Document 1). Group II metabotropic glutamate receptors are mainly present in the presynapses of the glutamate nervous system and function as autoreceptors, thereby suppressing excessive release of glutamate (Non-Patent Documents 2 and 3). Compounds that antagonize Group II metabotropic glutamate receptors are believed to be effective in the treatment or prevention of acute and chronic psychiatric and neurological disorders and include (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives and (1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]. Hexane-2,6-dicarboxylic acid derivatives are compounds with strong antagonistic effects on group II metabotropic glutamate receptors. For example, MGS0039 is disclosed as a compound. Its antagonist activity is 20 nM (mGlu2 receptor) and 24 nM (mGlu3 receptor), respectively, and in the rat forced swimming test, which is an animal model of depression, it has been reported to suppress immobility time from 1 mg/kg, as with existing antidepressants. Furthermore, in a mouse tail suspension test, it has been reported that it shortens the immobility time similarly to existing antidepressants (Non-Patent Document 4). Also, (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, which is a (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative, (1R,2R,3R,5R,6R) -2-Amino-3-[(3,4-difluorophenyl)methoxy]-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid and (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid have also been reported to have an antagonist activity of 500 nM or less against mGlu2 receptors (Patent document 1, Non-Patent Document 5).
However, (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-
Alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives and (1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives have poor oral absorption in monkeys. Therefore, it is possible that humans also have poor oral absorbability.
There are roughly two approaches for improving the membrane permeability such as oral absorbability of a compound. One is a method of changing the chemical structure of the compound itself, and the other is a method of devising a formulation without changing the chemical structure. Among the former is prodrug formation in which a small modifying group such as an alkyl group or an acyl group is attached to a reactive substituent such as a carboxy group or an amino group of a compound.
As the prodrug, a compound that exists stably as a prodrug prior to absorption, is improved in absorption by conversion into a prodrug, and is chemically or enzymatically converted into an active form rapidly in the small intestine, liver, and/or plasma during and/or after absorption is desired.
However, it is difficult to develop an ideal prodrug that satisfies all the above conditions. For example, prodrugs with ester linkages may be susceptible to hydrolysis reactions, which can greatly affect their chemical stability prior to absorption. A prodrug having an amide bond may significantly affect membrane permeability such as oral absorbability due to a large change in the physical properties of the compound. In addition, since the amide bond is difficult to hydrolyze, it may greatly affect the in vivo conversion of the compound to its active form and its concentration in plasma. Furthermore, the enzymes that control the biotransformation of prodrugs into active forms have substrate specificity. In particular, it is difficult to predict the pharmacokinetics of prodrugs, such as the inability of the enzyme to react due to steric hindrance of the substituents inserted to form prodrugs. For these reasons, it is not easy to estimate the membrane permeability such as oral absorption of a prodrug compound and the conversion to the active form to increase the plasma concentration of the active form. It has been reported that prodrugs of 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives, which act as antagonists of mGlu2 and mGlu3 receptors, have an ester bond at the 6-carboxylic acid or at both the 2- and 6-carboxylic acids (Patent Document 2, Patent Document 3, Patent Document 4, Patent Document 5, Non-Patent Document 6). However, there is no description or suggestion regarding increasing the plasma concentration of the active substance by a prodrug compound having an ester bond only at the 2-position carboxylic acid. In addition, there is no description or suggestion of enhancing the plasma concentration of the active by prodrugs of the active of the present invention.

WO03/061698 WO05/000791 WO2012/068041 WO2012/068067 WO2013/062680

Trends Pharmacol. Sci. , 14, 13-20, 1993. Neuropharmacol. , 40, 20-27, 2001. Eur. J. Pharmacol. , 356, 149-157, 1998. Neuropharmacol. , 2004, 46(4), 457-67. J. Med. Chem. , 2004, 47, 4570-4587. Bioorg. Med. Chem. , 2006, 14, 4193-4207.

The object of the present invention is, for example, mood disorders (including depression and bipolar disorder), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, motor disorders associated with muscle stiffness, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral failure, cerebral edema, spinal cord disorders, head trauma, inflammation, immune-related diseases, etc. A drug having therapeutic and preventive effects, which has high orally active group II metabotropic glutamic acid. An object of the present invention is to provide a medicine containing an active ingredient that antagonizes receptors.

The present inventors have extensively studied (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid ester derivatives and (1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid ester derivatives. prodrugs of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives and (1S,2R,3R,5R,6S)-2-amino-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives having It was found that it is converted into an active form in minutes and is useful as a medicine, especially an oral medicine. In addition, through animal experiments using the active substance and prodrug as test drugs, the present inventors have found that this type of prodrug increases the amount of exposure in vivo of the active substance, leading to the completion of the present invention.
The present invention will be described in detail below. Embodiments of the present invention (compounds contained in the medicament of the present invention are hereinafter referred to as "compounds of the present invention") include the following.
(1) Formula (IA)

［式（Ｉ-Ａ）中、
Ｒ¹は、Ｃ_1-6アルキル基、ヘテロアリール基（該ヘテロアリール基は、１個のハロゲン原子で置換されてもよい）、又は下記式（ＩＩＩＡ）を示し、

[In the formula (IA),
R ¹ represents a C _1-6 alkyl group, a heteroaryl group (the heteroaryl group may be substituted with one halogen atom), or the following formula (IIIA);

Ｒ^xは、水素原子、ハロゲン原子、Ｃ_1-6アルキル基、又はＣ_1-6アルコキシ基（該Ｃ_1-6アルキル基、及びＣ_1-6アルコキシ基は１～３個のハロゲン原子で置換されてもよい）を示
し、
Ｒ^yは、水素原子、フッ素原子、Ｃ_1-6アルキル基、又はＣ_1-6アルコキシ基（該Ｃ_1-6アル
キル基、及びＣ_1-6アルコキシ基は１～３個のハロゲン原子で置換されてもよい）を示し
、
Ｒ^1’は、水素原子、又はＣ_1-6アルキル基を示すか、
又は、Ｒ¹とＲ^1’が隣接する炭素原子と一緒になってＣ_3-8シクロアルカンを形成しても
よく、
Ｒ²は、Ｃ_3-6アルキル基（該Ｃ_3-6アルキル基は、１個のアミノ基で置換されてもよい）
、Ｃ_3-8シクロアルキル基（該Ｃ_3-8シクロアルキル基は、１～３個のＣ_1-6アルキル基で
置換されてもよい）、Ｃ_3-8シクロアルコキシ基（該Ｃ_3-8シクロアルコキシ基は、１～３個のＣ_1-6アルキル基で置換されてもよく、さらにＣ_3-8シクロアルコキシ基は、環中の異なる２個の炭素原子の間をＣ_1-5アルキレンで架橋されてもよい）、アダマンチル基（該
アダマンチル基は、１～３個のＣ_1-6アルキル基で置換されてもよい）、又はフェニル基
を示し、
Ｒ³は、水素原子又はＣ_1-6アルキル基を示し、
Ｒ⁴は、水素原子、又はフッ素原子を示す。]
で表される化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。
（２）Ｒ⁴が、フッ素原子である（１）に記載の化合物、又はその医薬上許容される塩を
有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。
（３）Ｒ²が、Ｃ_3-6アルキル基、Ｃ_3-8シクロアルキル基（該Ｃ_3-8シクロアルキル基は、１～３個のＣ_1-6アルキル基で置換されてもよい）、Ｃ_3-8シクロアルコキシ基（該Ｃ_3-8
シクロアルコキシ基は、１～３個のＣ_1-6アルキル基で置換されてもよく、さらにＣ_3-8シクロアルコキシ基は、環中の異なる２個の炭素原子の間をＣ_1-5アルキレンで架橋されて
もよい）、アダマンチル基（該アダマンチル基は、１～３個のＣ_1-6アルキル基で置換さ
れてもよい）、又はフェニル基である（２）に記載の化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。
（４）Ｒ¹がエチル基、４－フルオロフェニル基、３，４－ジフルオロフェニル基、４－
フルオロ－３－メトキシフェニル基、４－（トリフルオロメチル）フェニル基、３－フルオロフェニル基、４－メチルフェニル基、６－クロロピリジン－２－イル基、６－クロロピリジン－３－イル基、５－クロロピリジン－２－イル基、又は２－メチルプロピル基であり、
Ｒ^1’が、水素原子、又はメチル基を示すか、
又は、Ｒ¹とＲ^1’が隣接する炭素原子と一緒になってシクロペンタンを形成してもよく、Ｒ²が、下記式群（ＩＩＩＢ）のいずれかの構造を示し、

R ^x represents a hydrogen atom, a halogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group (the C _1-6 alkyl group and C _1-6 alkoxy group may be substituted with 1 to 3 halogen atoms);
R ^y represents a hydrogen atom, a fluorine atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group (the C _1-6 alkyl group and C _1-6 alkoxy group may be substituted with 1 to 3 halogen atoms);
R ^1' represents a hydrogen atom or a C _1-6 alkyl group;
or R ¹ and R ^1' together with adjacent carbon atoms may form a C _3-8 cycloalkane,
R ² is a C _3-6 alkyl group (the C _3-6 alkyl group may be substituted with one amino group)
, a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted by 1 to 3 C _1-6 alkyl groups), a C _3-8 cycloalkoxy group (the C _3-8 cycloalkoxy group may be substituted by 1 to 3 C _1-6 alkyl groups, and the C _3-8 cycloalkoxy group may be bridged by a C _1-5 alkylene between two different carbon atoms in the ring), an adamantyl group (the alkyl group may be a damantyl group optionally substituted with 1 to 3 C _1-6 alkyl groups), or a phenyl group,
R ³ represents a hydrogen atom or a C _1-6 alkyl group,
^R4 represents a hydrogen atom or a fluorine atom. ]
Mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, immune-related diseases.
(2) ^R4 contains a compound described in (1), which is a fluorine atom (1), or a mortgage (including depression, bipolar disorder), anxiety, cognitive impairment, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorders, Hanchin dancing Prevention or therapeutic drug selected from eating disorders, drug addiction, epilepsy, cerebral infarction, cerebral, cerebral edema, head trauma, inflammation, and immune -related diseases.
(3) R ² is a C _3-6 alkyl group, a C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with 1 to 3 C _1-6 alkyl groups), a C _3-8 cycloalkoxy group (the C _3-8
シクロアルコキシ基は、１～３個のＣ _1-6アルキル基で置換されてもよく、さらにＣ _3-8シクロアルコキシ基は、環中の異なる２個の炭素原子の間をＣ _1-5アルキレンで架橋されてもよい）、アダマンチル基（該アダマンチル基は、１～３個のＣ _1-6アルキル基で置換されてもよい）、又はフェニル基である（２）に記載の化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。
(4) R ¹ is an ethyl group, 4-fluorophenyl group, 3,4-difluorophenyl group, 4-
fluoro-3-methoxyphenyl group, 4-(trifluoromethyl)phenyl group, 3-fluorophenyl group, 4-methylphenyl group, 6-chloropyridin-2-yl group, 6-chloropyridin-3-yl group, 5-chloropyridin-2-yl group, or 2-methylpropyl group;
R ^1' represents a hydrogen atom or a methyl group;
Alternatively, R ¹ and R ^1′ together with the adjacent carbon atoms may form cyclopentane, and R ² represents any structure of formula group (IIIB):

Ｒ³が、水素原子又はＣ_1-6アルキル基である（２）又は（３）に記載の化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。
（５）Ｒ⁴が、水素原子である（１）に記載の化合物又はその医薬上許容される塩を有効
成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。
（６）Ｒ¹が、エチル基、４－フルオロフェニル基、３，４－ジフルオロフェニル基、４
－フルオロ－３－メトキシフェニル基、４－（トリフルオロメチル）フェニル基、３－フルオロフェニル基、４－メチルフェニル基、６－クロロピリジン－２－イル基、６－クロロピリジン－３－イル基、５－クロロピリジン－２－イル基、又は２－メチルプロピル基であり、
Ｒ^1’が、水素原子、又はメチル基を示すか、
又はＲ¹とＲ^1’が隣接する炭素原子と一緒になってシクロペンタンを形成してもよく、
Ｒ²が、下記式群（ＩＩＩＢ）のいずれかの構造を示し、

The group consisting of mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's chorea, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, and immune-related diseases, containing as active ingredients the compounds according to (2) or (3), wherein R ³ is a hydrogen atom or a C _1-6 alkyl group, or a pharmaceutically acceptable salt thereof. A prophylactic or therapeutic agent for a disease selected from
(5) A prophylactic or therapeutic drug for a disease selected from the group consisting of mood disorders (including depression and bipolar disorder), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune-related diseases, which contains as an active ingredient the compound according to (1), wherein R ⁴ is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
(6) R ¹ is an ethyl group, 4-fluorophenyl group, 3,4-difluorophenyl group, 4
-fluoro-3-methoxyphenyl group, 4-(trifluoromethyl)phenyl group, 3-fluorophenyl group, 4-methylphenyl group, 6-chloropyridin-2-yl group, 6-chloropyridin-3-yl group, 5-chloropyridin-2-yl group, or 2-methylpropyl group;
R ^1' represents a hydrogen atom or a methyl group;
or R ¹ and R ^1' may be taken together with adjacent carbon atoms to form cyclopentane,
R ² represents any structure of the following formula group (IIIB),

Ｒ³が、水素原子又はＣ_1-6アルキル基である（５）に記載の化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。
（７）Ｒ¹が、４－フルオロフェニル基又は３，４－ジフルオロフェニル基である（５）
又は（６）に記載の化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。
（８）Ｒ¹が、４－フルオロフェニル基であり、
Ｒ^1’が、水素原子であり、
Ｒ²が、下記式群（ＩＩＩｂ）のいずれかの構造を示す（５）～（７）のいずれか１つに
記載の化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。

Diseases selected from the group consisting of mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, and immune-related diseases, which contain the compound according to (5), wherein R ³ is a hydrogen atom or a C _1-6 alkyl group, or a pharmaceutically acceptable salt thereof, as an active ingredient. prophylactic or therapeutic agent.
(7) R ¹ is a 4-fluorophenyl group or a 3,4-difluorophenyl group (5)
Or a prophylactic or therapeutic drug for diseases selected from the group consisting of mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune-related diseases, which contain the compound according to (6) or a pharmaceutically acceptable salt thereof as an active ingredient.
(8) R ¹ is a 4-fluorophenyl group;
R ^1' is a hydrogen atom,
Mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, containing as an active ingredient the compound according to any one of (5) to (7), wherein R ² represents any one of the structures of the following formula group (IIIb), or a pharmaceutically acceptable salt thereof , an agent for the prevention or treatment of diseases selected from the group consisting of immune-related diseases.

（９）Ｒ³が、メチル基である（５）～（８）のいずれか１つに記載の化合物、又はその
医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。
（１０）式（Ｉ）

(9) Mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune-related diseases, containing as an active ingredient the compound according to any one of (5) to (8), wherein R ³ is a methyl group, or a pharmaceutically acceptable salt thereof. A prophylactic or therapeutic agent for the selected disease.
(10) Formula (I)

［式（Ｉ）中、
Ｒ¹は、エチル基、４－フルオロフェニル基、３，４－ジフルオロフェニル基を示し、
Ｒ²は、下記式群（ＩＩＩａ）のいずれかの構造を示し、

[in the formula (I),
R ¹ represents an ethyl group, a 4-fluorophenyl group or a 3,4-difluorophenyl group,
R ² represents any structure of the following formula group (IIIa),

Ｒ³は、水素原子又はＣ_1-6アルキル基を示す。］
で表される化合物、又はその医薬上許容される塩。
（１１）Ｒ²が、下記式群（ＩＩＩａ’）のいずれかの構造を示す（１０）に記載の化合
物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。

R ³ represents a hydrogen atom or a C _1-6 alkyl group. ]
A compound represented by or a pharmaceutically acceptable salt thereof.
(11) Mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune-related diseases, containing as active ingredients the compound according to (10), wherein R ² represents any of the structures of the following formula group (IIIa'), or a pharmaceutically acceptable salt thereof. A prophylactic or therapeutic agent for diseases selected from the group consisting of

（１２）Ｒ²が、下記式群（ＩＩＩｂ）のいずれかの構造を示す（１０）に記載の化合物
、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。

(12) Mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's chorea, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, and immune-related diseases, containing the compound according to (10), wherein R ² represents any of the structures of the following formula group (IIIb), or a pharmaceutically acceptable salt thereof, as an active ingredient. A prophylactic or therapeutic drug for diseases selected from the group consisting of:

（１３）Ｒ³が、メチル基である（１０）～（１２）のいずれか１つに記載の化合物、又
はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬。
（１４）以下に示す（１）に記載の化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬：
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］
デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛［（トリシクロ［３．３．１．１^3,7］デカン－１－カ
ルボニル）オキシ］メトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（３，４－ジフルオロフェニル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０
］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（３，４－ジフルオロフェニル）メトキシ］－６－フルオロ－２－（｛［（トリシクロ［３．３．１．１^3,7］デカン－
１－カルボニル）オキシ］メトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－２－（｛（１Ｒ）－１－［（｛［（１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）－３－プロポキシビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－２－（｛１－［（｛［（１Ｓ，２Ｒ，５Ｓ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）－３－プロポキシビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛１－［（｛［（１Ｓ，２Ｒ，４Ｓ）－１，７，７－トリメチルビシクロ［２．２．１］ヘプタン－２－イル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－プロポキシ－２－（｛１－［（｛［（１Ｓ，２Ｒ，４Ｓ）－１，７，７－トリメチルビシクロ［２．２．１］ヘプタン－２－イル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛１－［（｛［（１Ｒ，２Ｓ，４Ｒ）－１，７，７－トリメチルビシクロ［２．２．１］ヘプタン－２－イル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝
カルボニル）－３－｛［４－（トリフルオロメチル）フェニル］メトキシ｝ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（３－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］
デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（６－クロロピリジン－２－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（１Ｒ）－１－（４－フルオロ－３－メトキシフェニル）エトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル
）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（５－クロロピリジン－２－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（６－クロロピリジン－３－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－メチルフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デ
カン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－（３－メチルブトキシ）－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カ
ルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－（シクロペンチルオキシ）－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－
カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（３－フルオロ
フェニル）メトキシ］－２－（｛（１Ｒ）－１－［（｛［（１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（６－クロロピリジン－２－イル）メトキシ］－６－フルオロ－２－（｛（１Ｒ）－１－［（｛［（１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－２－（｛［（２，２－ジメチルプロパノイル）オキシ］メトキシ｝カルボニル）－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－２－｛［（ベンゾイルオキシ）メトキシ］カルボニル｝－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－２－（｛［（シクロヘキサンカルボニル）オキシ］メトキシ｝カルボニル）－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－２－アミノ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸。
（１５）以下に示す（１）に記載の化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬：
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］
デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛［（トリシクロ［３．３．１．１^3,7］デカン－１－カ
ルボニル）オキシ］メトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（３，４－ジフルオロフェニル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０
］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（３，４－ジフルオロフェニル）メトキシ］－６－フルオロ－２－（｛［（トリシクロ［３．３．１．１^3,7］デカン－
１－カルボニル）オキシ］メトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－２－（｛（１Ｒ）－１－［（｛［（１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）－３－プロポキシビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝
カルボニル）－３－｛［４－（トリフルオロメチル）フェニル］メトキシ｝ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（３－フルオロ
フェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］
デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（６－クロロピリジン－２－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（１Ｒ）－１－（４－フルオロ－３－メトキシフェニル）エトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル
）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（５－クロロピリジン－２－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（６－クロロピリジン－３－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－メチルフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デ
カン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－（３－メチルブトキシ）－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カ
ルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－（シクロペンチルオキシ）－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－
カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－２－アミノ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸。
（１６）以下に示す（１）～（４）又は（１０）～（１３）のいずれか１つに記載の化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬：
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］
デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸。

(13) Mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's chorea, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, and immune-related diseases, containing as an active ingredient the compound according to any one of (10) to (12), wherein R ³ is a methyl group, or a pharmaceutically acceptable salt thereof. A prophylactic or therapeutic drug for diseases selected from the group consisting of:
(14) A prophylactic or therapeutic agent for diseases selected from the group consisting of mood disorders (including depression and bipolar disorder), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, and immune-related diseases, containing as an active ingredient the compound according to (1) shown below, or a pharmaceutically acceptable salt thereof:
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]
Decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0
] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1 ^3,7 ]decane-
1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxy-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}
carbonyl)-3-{[4-(trifluoromethyl)phenyl]methoxy}bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]
Decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(1R)-1-(4-fluoro-3-methoxyphenyl)ethoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(5-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-3-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-methylphenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-(3-methylbutoxy)-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-(cyclopentyloxy)-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-
carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-2-({[(2,2-dimethylpropanoyl)oxy]methoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-2-{[(benzoyloxy)methoxy]carbonyl}-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-2-({[(cyclohexanecarbonyl)oxy]methoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic acid,
(1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid.
(15) A prophylactic or therapeutic drug for diseases selected from the group consisting of mood disorders (including depression and bipolar disorder), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, and immune-related diseases, containing as an active ingredient the compound according to (1) shown below, or a pharmaceutically acceptable salt thereof:
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]
Decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0
] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1 ^3,7 ]decane-
1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}
carbonyl)-3-{[4-(trifluoromethyl)phenyl]methoxy}bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]
Decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(1R)-1-(4-fluoro-3-methoxyphenyl)ethoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(5-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-3-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-methylphenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-(3-methylbutoxy)-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-(cyclopentyloxy)-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-
carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid.
(16) Mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, immune-related disorders, containing as an active ingredient a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (4) or (10) to (13) shown below. A prophylactic or therapeutic agent for a disease selected from the group consisting of:
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]
Decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid.

（１７）以下に示す（１）～（４）又は（１０）～（１３）のいずれか１つに記載の化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬：
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（３，４－ジフルオロフェニル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０
］ヘキサン－６－カルボン酸。

(17) Mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, immune-related disorders, containing as an active ingredient a compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (4) or (10) to (13) shown below. A prophylactic or therapeutic agent for a disease selected from the group consisting of:
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0
] Hexane-6-carboxylic acid.

（１８）以下に示す（１）～（４）又は（１０）～（１３）のいずれか１つに記載の化合物、又はその医薬上許容される塩を有効成分として含有する、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療薬：
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－２－（｛（１Ｒ）－１－［（｛［（１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）－３－プロポキシビシクロ［３．１．０］ヘキサン－６－カルボン酸。

(18) Mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, immune-related disorders, containing as an active ingredient the compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (4) or (10) to (13) shown below. A prophylactic or therapeutic agent for a disease selected from the group consisting of:
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid.

The prodrug of the amino acid derivative contained in the medicament of the present invention has improved membrane permeability such as oral absorbability, is rapidly converted into the active form (II)-A, (II)-1, (II)-2 or (II)-3 after absorption, and the active form exhibits affinity for group II metabotropic glutamate receptors and acts as an antagonist.

（式（ＩＩ）－Ａ中、Ｒ¹、Ｒ^1’及びＲ^４は前記の定義と同義である。）

(In Formula (II)-A, R ¹ , R ^1′ and R ⁴ have the same definitions as above.)

EMBODIMENT OF THE INVENTION Hereinafter, the form for implementing this invention is demonstrated concretely.

The terms used in this specification have the following meanings.
"C _1-6 alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms,
Examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group and neohexyl group.
"C _3-6 alkyl group" means a linear or branched alkyl group having 3 to 6 carbon atoms, and examples thereof include n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group, n-hexyl group, isohexyl group and neohexyl group.
"Heteroaryl group" means a monocyclic aromatic heterocyclic group, for example, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, pyridonyl group, thienyl group, pyrrolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, furyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, 1,3,4-thiadiazolyl group, 1,2, 3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group and the like can be mentioned.
A "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The “C _1-6 alkoxy group” is a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, isopropoxy, isobutoxy, tert-butoxy, sec-butoxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1,2-dimethylpropoxy, and the like. can be mentioned.
A " _C3-8 cycloalkyl group" is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
A " _C3-8 cycloalkoxy group" is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclooctyloxy group.
" _C3-8 cycloalkane" is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane.
"C _1-5 alkylene" includes methylene, ethylene, methylmethylene, trimethylene, methylethylene, dimethylmethylene, tetramethylene, ethylethylene, pentamethylene and the like.
When the above C _3-8 cycloalkoxy group is a C _3-8 cycloalkoxy group bridged by C _1-5 alkylene between two different carbon atoms in the ring, bicyclo[2.2.1]heptan-2-yl-oxy group and the like can be mentioned.

"Pharmaceutically acceptable salt" as used herein means a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or nitric acid, or acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycolic acid, glutamic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. acid, camphorsulfonic acid, or organic acids such as naphthalene-2-sulfonic acid; salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, and aluminum ion; Conversion of the educt to the salt in question can be carried out in a conventional manner.

Preferred embodiments of the compound of the present invention are shown below.
Compounds in which R ² is any structure of formula group (IIIB) below are preferred.

又は、別の態様として、Ｒ²が、下記式群（ＩＩＩａ）のいずれかの構造である化合物が
あげられる。

Alternatively, as another aspect, there are compounds in which R ² is any structure of the following formula group (IIIa).

下記式群（ＩＩＩａ’）のいずれかの構造である化合物がより好ましい。

A compound having any structure of the following formula group (IIIa') is more preferable.

さらに別の様態として、Ｒ²が、下記式群（ＩＩＩｂ）のいずれかの構造である化合物が
さらに好ましい。

As still another aspect, compounds in which R ² is any structure of the following formula group (IIIb) are more preferable.

Ｒ³が、水素原子又はメチル基の化合物が好ましく、メチル基である化合物がさらに好ま
しい。
Ｒ³がＣ_１－６アルキル基である場合、Ｒ³の立体が下記式（ＩＶａ）で示される立体が好ましい。

Compounds in which R ³ is a hydrogen atom or a methyl group are preferred, and compounds in which a methyl group is more preferred.
When R ³ is a C _1-6 alkyl group, the configuration of R ³ is preferably a configuration represented by the following formula (IVa).

Ｒ³がメチル基である場合、Ｒ³の立体が下記式（ＩＶｂ）で示される立体が好ましい。

When R ³ is a methyl group, the configuration of R ³ is preferably a configuration represented by the following formula (IVb).

本発明化合物中の好ましい化合物の例としては、下記の化合物若しくはその医薬上許容される塩があげられる：
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］
デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛［（トリシクロ［３．３．１．１^3,7］デカン－１－カ
ルボニル）オキシ］メトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（３，４－ジフルオロフェニル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０
］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（３，４－ジフルオロフェニル）メトキシ］－６－フルオロ－２－（｛［（トリシクロ［３．３．１．１^3,7］デカン－
１－カルボニル）オキシ］メトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－２－（｛（１Ｒ）－１－［（｛［（１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）－３－プロポキシビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－２－（｛１－［（｛［（１Ｓ，２Ｒ，５Ｓ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）－３－プロポキシビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛１－［（｛［（１Ｓ，２Ｒ，４Ｓ）－１，７，７－トリメチルビシクロ［２．２．１］ヘプタン－２－イル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－プロポキシ－２－（｛１－［（｛［（１Ｓ，２Ｒ，４Ｓ）－１，７，７－トリメチルビシクロ［２．２．１］ヘプタン－２－イル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛１－［（｛［（１Ｒ，２Ｓ，４Ｒ）－１，７，７－トリメチルビシクロ［２．２．１］ヘプタン－２－イル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝
カルボニル）－３－｛［４－（トリフルオロメチル）フェニル］メトキシ｝ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（３－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］
デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（６－クロロピリジン－２－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（１Ｒ）－１－（４－フルオロ－３－メトキシフェニル）エトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル
）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（５－クロロピリジン－２－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（６－クロロピリジン－３－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－メチルフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デ
カン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－（３－メチルブトキシ）－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カ
ルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－（シクロペンチルオキシ）－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－
カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（３－フルオロフェニル）メトキシ］－２－（｛（１Ｒ）－１－［（｛［（１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（６－クロロピリジン－２－イル）メトキシ］－６－フルオロ－２－（｛（１Ｒ）－１－［（｛［（１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－２－（｛［（２，２－ジメチルプロパノイル）オキシ］メトキシ｝カルボニル）－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－２－｛［（ベンゾイルオキシ）メトキシ］カルボニル｝－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－２－（｛［（シクロヘキサンカルボニル）オキシ］メトキシ｝カルボニル）－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－２－アミノ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸が挙げられる。
本発明化合物中のより好ましい化合物の例としては、下記の化合物若しくはその医薬上許容される塩があげられる：
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］
デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキ
サン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－（｛［（トリシクロ［３．３．１．１^3,7］デカン－１－カ
ルボニル）オキシ］メトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（３，４－ジフルオロフェニル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０
］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（３，４－ジフルオロフェニル）メトキシ］－６－フルオロ－２－（｛［（トリシクロ［３．３．１．１^3,7］デカン－
１－カルボニル）オキシ］メトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－２－（｛（１Ｒ）－１－［（｛［（１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル］オキシ｝カルボニル）オキシ］エトキシ｝カルボニル）－３－プロポキシビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝
カルボニル）－３－｛［４－（トリフルオロメチル）フェニル］メトキシ｝ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（３－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］
デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（６－クロロピリジン－２－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（１Ｒ）－１－（４－フルオロ－３－メトキシフェニル）エトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル
）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（５－クロロピリジン－２－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－［（６－クロロピリジン－３－イル）メトキシ］－６－フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．
０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－メチルフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デ
カン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－（３－メチルブトキシ）－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－カ
ルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－３－（シクロペンチルオキシ）－６－
フルオロ－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^3,7］デカン－１－
カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸、
（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－２－アミノ－３－［（４－フルオロフェニル）メトキシ］－２－（｛（１Ｓ）－１－［（トリシクロ［３．３．１．１^３，７］デカン－１－カルボニル）オキシ］エトキシ｝カルボニル）ビシクロ［３．１．０］ヘキサン－６－カルボン酸が挙げられる。

Examples of preferred compounds among the compounds of the present invention include the following compounds or pharmaceutically acceptable salts thereof:
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]
Decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0
] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1 ^3,7 ]decane-
1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxy-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}
carbonyl)-3-{[4-(trifluoromethyl)phenyl]methoxy}bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]
Decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(1R)-1-(4-fluoro-3-methoxyphenyl)ethoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(5-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-3-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-methylphenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-(3-methylbutoxy)-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-(cyclopentyloxy)-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-
carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-2-({[(2,2-dimethylpropanoyl)oxy]methoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-2-{[(benzoyloxy)methoxy]carbonyl}-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-2-({[(cyclohexanecarbonyl)oxy]methoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic acid,
(1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid.
Examples of more preferred compounds among the compounds of the present invention include the following compounds or pharmaceutically acceptable salts thereof:
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]
Decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0
] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1 ^3,7 ]decane-
1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}
carbonyl)-3-{[4-(trifluoromethyl)phenyl]methoxy}bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(3-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]
Decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(1R)-1-(4-fluoro-3-methoxyphenyl)ethoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(5-chloropyridin-2-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-[(6-chloropyridin-3-yl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.
0] hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-methylphenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-(3-methylbutoxy)-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1R,2R,3R,5R,6R)-2-amino-3-(cyclopentyloxy)-6-
fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-
carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid,
(1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid.

In addition, when the compounds of the present invention form hydrates or solvates, they are also included within the scope of the present invention. Also included within the scope of the invention are pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention.

The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures thereof in any ratio, racemates and the like.
The compounds of the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms or fluorine atoms are replaced with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolism and pharmacokinetic studies, biological analysis as receptor ligands, and the like.
The medicament of the present invention can be prepared as a pharmaceutical formulation by combining the compound of the present invention with one or more pharmaceutically acceptable carriers, excipients and diluents. Examples of the carriers, excipients and diluents include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, various oils such as soybean oil.
The medicament of the present invention is prepared by mixing the compound of the present invention with these carriers, excipients or diluents, and, if necessary, additives such as fillers, binders, disintegrants, pH adjusters and solubilizers generally used, and then preparing oral or parenteral medicaments such as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections and skin patches, particularly group II metabotropic glutamate receptor antagonists, by conventional formulation techniques. is prepared as a prodrug of
The medicament of the present invention can be administered orally or parenterally to adult patients at a dose of 0.01 to 500 mg of the compound of the present invention once a day or divided into several doses. Oral administration is preferred in terms of ease of use and efficacy. The dose and frequency of administration can be appropriately increased or decreased depending on the type of disease to be treated, the patient's age, body weight, symptoms, and the like.

Compounds (IA) and (I) of the present invention do not affect group II metabotropic glutamate receptors. However, it undergoes enzymatic or chemical hydrolysis in vivo and is converted to compounds (II)-A, (II)-1, (II)-2 or (II)-3, respectively, which are compounds with potent effects on group II metabotropic glutamate receptors. Therefore, the compounds of the present invention exhibit functions as drugs that act on group II metabotropic glutamate receptors.
That is, the compounds of the present invention can be used as prophylactic or therapeutic agents for diseases in which Group II metabotropic glutamate receptors are believed to be involved, such as mood disorders (including depression and bipolar disorder), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, movement disorders associated with muscle stiffness, sleep disorders, Huntington's disease, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral failure, cerebral edema, spinal cord disorders, head trauma, inflammation, and immune-related diseases. Acts as a prodrug that increases membrane permeability such as oral absorbability of the active form (II)-A, (II)-1, (II)-2 or (II)-3 that antagonizes metabotropic glutamate receptor II and increases the amount of exposure in vivo.

A representative method for preparing the compounds of the present invention represented by (IB) and (I) is shown in Scheme A below. The following methods are examples of methods for producing the compounds of the present invention, and are not intended to be limiting. In the examples of the production methods below, the compound may form a salt that does not interfere with the reaction. Also, the active forms represented by (II)-B and (II) can be obtained by the production methods described in WO03/061698 or WO2011/061935.
Scheme A

(The symbols in the formula are as defined above.)

Step 1: The compound (II)-B and the amino group of (II) are subjected to a general protection reaction with an allyloxycarbonyl group (see Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons, INC.) to lead to compound (1). For example, hydrocarbon solvents such as benzene, toluene, and hexane; halogen solvents such as dichloromethane, chloroform, and carbon tetrachloride; ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; amide solvents such as N,N-dimethylformamide and N-methyl-2-pyrrolidinone; Dimethylamino)pyridine, 2,6-di-t-butylpyridine and other organic bases, or in the presence or absence of inorganic salts such as potassium carbonate, sodium carbonate and sodium hydrogencarbonate, are reacted with allyl chloroformate to lead to compound (1).

Step 2: Compound (1) is reacted with allyl chloroformate in a halogen solvent such as dichloromethane, an ether solvent such as tetrahydrofuran, or an inert solvent such as dimethylsulfoxide in the presence of an organic base such as tributylamine, triethylamine, diisopropylethylamine, pyridine, or N-methylmorpholine, and then N,N-dimethyl-4-aminopyridine is added to give compound (2). The carboxy group of compound (1) can also be converted to compound (2) by reacting it with allyl alcohol in a general esterification reaction (see Comprehensive Organic Transformations Second Edition, 1999, John Wiley & Sons, INC.).

工程３：化合物（３）は、化合物（２）を式Ｌ－ＣＨ（Ｒ ³ ）－Ｏ－Ｃ（Ｏ）－Ｒ ² （式中Ｌは脱離基を示し、例えばハロゲン原子、ｐ－トルエンスルホニルオキシ基、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等を示す）と、ベンゼン、トルエン、ヘキサン、シクロヘキサンなどの炭化水素系溶媒、ジクロロメタン、クロロホルム、四塩化炭素などのハロゲン系溶媒、テトラヒドロフラン、ジエチルエーテル、１，２－ジメトキシエタンなどのエーテル系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン等のアミド系溶媒、ジメチルスルホキシド、水、又はこれらの混合溶媒等の不活性溶媒中、水素化ナトリウム、水素化カリウム、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸セシウム、炭酸水素セシウム、水酸化ナトリウム、水酸化カリウム等の無機塩基類、リチウムビス（トリメチルシリル）アミド、リチウムジイソプロピルアミド、ナトリウムアミド等の金属アミド類、トリエチルアミン、ピリジン、ジイソプロピルエチルアミン、４－（Ｎ，Ｎ－ジメチルアミノ）ピリジン、２，６－ジ－ｔｅｒｔ－ブチルピリジン等の有機塩基類、ｔｅｒｔ－ブトキシカリウム等の塩基の存在下、ヨウ化ナトリウムなどの適した活性化剤の存在下又は非存在下反応させることにより導くことができる。 Preferably, compound (3) can be obtained by reacting a compound represented by the formula Cl-CH( ^R )-O-C(O) ^-R2 or Br-CH( ^R3 )-O-C(O) ^-R2 at room temperature to 80°C for 2 hours to 1 day in a mixed solvent of chloroform and water in the presence of potassium carbonate and tetrabutylammonium hydrogensulfate.

Step 4: Compound (3) can be led to compound (I) of the present invention by subjecting compound (3) to a general deprotection reaction (see Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons, INC.). For example, in the presence of a zerovalent palladium catalyst such as tetrakistriphenylphosphine palladium (0) and a regenerating reagent for a metal catalyst such as 1,3-dimethylbarbituric acid, in an inert solvent such as a hydrocarbon solvent such as benzene, toluene, or hexane, a halogen solvent such as dichloromethane, chloroform, or carbon tetrachloride, an ether solvent such as tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane, or a mixed solvent thereof, the allyl group and allyloxycarbonyl group are deprotected to obtain the compound of the present invention. can lead to compound (I) which is Preferably, compounds (IB) and (I) of the present invention can be derived by reacting compound (3) in the presence of tetrakistriphenylphosphinepalladium (0) and 1,3-dimethylbarbituric acid in chloroform at room temperature to 50°C for 2 to 8 hours.

Scheme B below shows a representative method for producing the compound (II)-C, which is the active form of the compound (IC) of the present invention. The following methods are examples of methods for producing the compounds of the present invention, and are not intended to be limiting. In the examples of the production methods below, the compound may form a salt that does not interfere with the reaction.
Scheme B

(The symbols in the formula are as defined above.)

In the production method of the present invention, the compound (4) is subjected to a catalytic asymmetric Michael addition reaction, followed by a cyclization reaction involving de-ethoxycarbonylation, whereby the optically active compound (6) of the present invention can be obtained in two steps. Compound (6) can also be synthesized according to the following reports (Tetrahedron Asymmetry, 1997, 511-514, Chem. Eur. J., 2006, 12, 568-575, J. Org. Chem., 2008, 73, 3078-3087, Tetrahedron Asymmetry, 2 010, 1486-1493).

Step 5: Compound (5) can be obtained by subjecting compound (4) to an asymmetric Michael addition reaction. For example, in an inert solvent such as hydrocarbon solvents such as benzene, toluene, and hexane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and benzotrifluoride, ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane, amide solvents such as N,N-dimethylformamide and N-methyl-2-pyrrolidinone, dimethyl sulfoxide, and mixed solvents thereof, lithium aluminum hydride, (R)-(+)-1,1-bi-2-naphthol, After preparing a suspension containing an asymmetric catalyst in the presence or absence of an additive such as molecular sieves 4A, triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4-(N,N-dimethylamino)pyridine, 2,6-di-t-butylpyridine, potassium tert-butoxide and the like organic bases, or potassium carbonate, sodium carbonate, sodium hydrogencarbonate and other inorganic bases in the presence or absence of chloromethane. Reaction with diethyl ronate can lead to compound (5). Preferably, in the presence of lithium aluminum hydride, (R)-(+)-1,1-bi-2-naphthol, in tetrahydrofuran, the mixture is reacted at 0 to 70°C for 30 minutes to 1 day to prepare a suspension containing an asymmetric catalyst, and then diethyl chloromalonate and compound (4) are reacted at 0 to 70°C for 30 minutes to 1 day in the presence of molecular sieves 4A and sodium carbonate to lead to compound (5) of the present invention (Ange W. Chem., Int. Ed. Engl., 1996, 35, 104-106, Tetrahedron, 2002, 58, 2585-2588).

Step 6: Compound (5) can be led to compound (6) by subjecting it to a cyclization reaction involving removal of ethoxycarbonyl. For example, alcohol solvents such as methanol, ethanol, 2-propanol, tert-butyl alcohol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol; hydrocarbon solvents such as benzene, toluene and hexane; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and benzotrifluoride; In an inert solvent such as an amide solvent such as 2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof, in the presence or absence of an acid such as acetic acid, citric acid or formic acid, lithium chloride, sodium chloride, sodium cyanide, potassium cyanide, sodium bromide, lithium iodide, sodium iodide, lithium carbonate, potassium carbonate, sodium carbonate, sodium phosphate or other inorganic salts, or tetramethylammonium acetate or other inorganic salts or organic salts such as tetramethylammonium acetate can be reacted to yield compound (6). Preferably, compound (6) of the present invention can be obtained by reacting lithium chloride in the presence of acetic acid in an N-methyl-2-pyrrolidinone solvent at 0 to 180°C for 30 minutes to 1 day (J. Org. Chem., 1978, 43, 138-147, Org.

Step 7: Compound (7) can be obtained by reacting compound (6) with a silylating agent. For example, in an inert solvent such as hydrocarbon solvents such as benzene, toluene, and hexane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, and benzotrifluoride, ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane, amide solvents such as N,N-dimethylformamide and N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or mixed solvents thereof, sodium iodide, potassium iodide, tetrabutylammonium iodide, sodium bromide, bromine, etc. Organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclononene, and pyridine, metal amide bases such as lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide, alkali metal hydride bases such as sodium hydride and potassium hydride, and chlorotrimethylsilane, bromotrimethylsilane, and iodotrimethyl in the presence or absence of additives such as potassium chloride. Compound (7) can be obtained by reacting with a silylating agent such as silane or trimethylsilyl trifluoromethanesulfonate. Preferably, the compound (7) of the present invention can be obtained by reacting triethylamine and trimethylsilyl trifluoromethanesulfonate in a toluene solvent at -20 to 80°C for 30 minutes to 1 day (J.Med.Chem., 2000, 43, 4893-49
09, Bioorg. Med. Chem. , 2002, 10, 433-436).

Step 8: Compound (8) can be obtained by reacting compound (7) with an oxidizing agent.例えば、ベンゼン、トルエン、ヘキサンなどの炭化水素系溶媒、ジクロロメタン、クロロホルム、四塩化炭素、ベンゾトリフルオリドなどのハロゲン系溶媒、テトラヒドロフラン、ジエチルエーテル、１，２－ジメトキシエタンなどのエーテル系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン等のアミド系溶媒、ジメチルスルホキシド、アセトニトリル、水、又はこれらの混合溶媒等の不活性溶媒中、炭酸水素ナトリウム、炭酸水素カリウム、炭酸カリウム、炭酸ナトリウム、水酸化カルシウム、リン酸二水素カリウム、リン酸水素二カリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、ピリジン、酢酸等の添加剤存在下または非存在下にて、３－クロロ過安息香酸、過安息香酸、モノペルオキシフタル酸、モノペルオキシフタル酸マグネシウム塩、過酢酸等の過酸；メチルトリオキソレニウム又はトリス（セチルピリジニウム）ペルオキソタングストリン酸塩（ＰＣＷＰ）等の触媒存在下での過酸化水素；トリクロロアセトニトリル又はアセトニトリル等のニトリル化合物存在下での過酸化水素；トリクロロアセトニトリル又はアセトニトリル等のニトリル化合物及びアセトン等のケトン化合物存在下での過酸化水素；アセトン等のケトン化合物存在下でのオキソン（２ＫＨＳＯ ₅・ＫＨＳＯ ₄・Ｋ ₂ ＳＯ ₄ ）；ジメチルジオキシラン、ｔｅｒｔ－ブチルヒドロペルオキシド、四酸化オスミウムとＮ－メチルモルホリン－Ｎ－オキシド、四酢酸鉛、ヨードシルベンゼンと三フッ化ホウ素ジエチルエーテル錯体、塩化クロミル、オゾン等の酸化剤と反応させることにより、化合物（８）に導くことができる（Ｏｒｇａｎｉｃ Ｒｅａｃｔｉｏｎｓ，２００３，６２，１－３５６ 参照）。 Preferably, compound (8) of the present invention can be obtained by reacting methyltrioxorhenium and hydrogen peroxide in the presence of pyridine and acetic acid in an acetonitrile solvent at -20 to 80°C for 30 minutes to 1 day.

Step 9: Compound (9) can be obtained by reacting compound (8) with an alkylating agent.ベンゼン、トルエン、ヘキサン、シクロヘキサンなどの炭化水素系溶媒、ジクロロメタン、クロロホルム、四塩化炭素などのハロゲン系溶媒、テトラヒドロフラン、テトラヒドロピラン、ジエチルエーテル、１，２－ジメトキシエタンなどのエーテル系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン等のアミド系溶媒、ジメチルスルホキシド、水、又はこれらの混合溶媒等の不活性溶媒中、トリフルオロメタンスルホン酸、ビストリフルオロメタンフルオロメタンスルホンイミド、トリフルオロ酢酸、塩化水素、過塩素酸等のブレンステッド酸、又は三フッ化ホウ素・ジエチルエーテル錯体、塩化亜鉛、塩化スズ、トリフルオロメタンスルホン酸トリメチルシリル、トリフルオロメタンスルホン酸スカンジウム（ＩＩＩ）、トリフルオロメタンスルホン酸イッテルビウム（ＩＩＩ）等のルイス酸の存在下、式Ｒ ¹ Ｒ ⁵ ＣＨＯＣ（＝ＮＨ）ＣＣｌ ₃で表される化合物と反応させることにより導くことができる。 Formula ^R1R5CHOC (=NH ⁾ _CCl3
can be obtained by reacting an alcohol represented by the formula R ¹ R ⁵ CHOH with trichloroacetonitrile in the presence of a base according to the method described in the literature. (J. Chem. Soc., Perkin Trans. 1, 1985, 2247-225
0, Tetrahedron Lett. , 1996, 37, 1481-1484). Preferably, in a tetrahydropyran solvent in the presence of trifluoromethanesulfonic acid, with a compound represented by the formula R ¹ R ⁵ CHOC(=NH)CCl ₃ at -20 to 50°C for 30 minutes to 1
The reaction can lead to compound (9) (see J. Chem. Soc., Chem. Commun. 1981, 1240-1241, J. Chem. Soc., Perkin Trans. 1, 1985, 2247-2250).
また、ベンゼン、トルエン、ヘキサン、シクロヘキサンなどの炭化水素系溶媒、ジクロロメタン、クロロホルム、四塩化炭素などのハロゲン系溶媒、テトラヒドロフラン、テトラヒドロピラン、ジエチルエーテル、１，２－ジメトキシエタンなどのエーテル系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン等のアミド系溶媒、ジメチルスルホキシド、水、又はこれらの混合溶媒等の不活性溶媒中、水素化ナトリウム、水素化カリウム、炭酸カリウム、炭酸ナトリウム、炭酸セシウム、炭酸水素カリウム、炭酸水素ナトリウム、水酸化ナトリウム、水酸化カリウム、酸化銀（Ｉ）、炭酸銀（Ｉ）、トリフルオロメタンスルホン酸銀（Ｉ）等の無機塩基類、リチウムジイソプロピルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド等の金属アミド塩基類、トリエチルアミン、ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ジアザビシクロウンデセン、ジアザビシクロノネン、ピリジン、４－ジメチルアミノピリジン等の有機塩基類、又はカリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ペントキシド、カリウムｔｅｒｔ－ペントキシド等のアルコキシド塩基類存在下、テトラブチルアンモニウムヨージドなどの適した活性化剤の存在下又は非存在下、式Ｒ ¹ Ｒ ⁵ ＣＨ－Ｘで表される化合物と反応させることにより導くことができる。 Here, X represents a leaving group other than OC(=NH) _CCl3 , such as chlorine atom, bromine atom, iodine atom, p-toluenesulfonyloxy group, p-bromobenzenesulfonyloxy group, p-chlorobenzenesulfonyloxy group, p-nitrobenzenesulfonyloxy group, benzenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, and the like. Preferably, compound (9) can be obtained by reacting a compound represented by the formula ^R R ^CH -Cl at -20 to 50°C for 30 minutes to 1 day in the presence of silver (I) carbonate, silver (I) trifluoromethanesulfonate, and tetrabutylammonium iodide in a chloroform solvent.

Step 10: Compound (10) can be obtained by subjecting compound (9) to a dehydration condensation reaction with an optically active sulfinamide. For example, alcohol solvents such as methanol, ethanol, 2-propanol, tert-butyl alcohol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol; hydrocarbon solvents such as benzene, toluene and hexane; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and benzotrifluoride; Compound (13) can be obtained by reacting with (R)-2-methyl-2-sulfinamide in the presence of a Lewis acid such as titanium (IV) isopropoxide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide, and titanium (IV) butoxide in an amide solvent such as 2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof. Preferably, the compound (10) of the present invention can be derived by reacting with (R)-2-methyl-2-sulfinamide in the presence of titanium (IV) ethoxide in a tetrahydrofuran solvent at 0 to 80°C for 30 minutes to 1 day.

Step 11: Compound (10) is subjected to a cyano addition reaction to lead to compound (11) (see Chem. Rev., 2011, 111, 6947-6983). For example, alcohol solvents such as methanol, ethanol, 2-propanol, tert-butyl alcohol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol; hydrocarbon solvents such as benzene, toluene and hexane; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and benzotrifluoride; In an inert solvent such as an amide solvent such as 2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof, inorganic bases such as cesium fluoride, potassium fluoride, sodium fluoride, metal amide bases such as lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclononene, pyridine, 4 - by adding a cyanating agent such as trimethylsilyl cyanide, hydrogen cyanide, sodium cyanide, potassium cyanide, acetone cyanohydrin, diethyl cyanophosphonate, diethylaluminum cyanide, tert-butyldimethylsilyl cyanide, tributyltin cyanide and reacting in the presence or absence of an organic base such as dimethylaminopyridine or an alkoxide base such as potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, etc. , can lead to compound (11). Preferably, the compound (11) of the present invention can be derived by reacting it with trimethylsilyl cyanide at -20 to 80°C for 30 minutes to 1 day in the presence of cesium fluoride in a tetrahydrofuran solvent.

Step 12: Compound (11) can be led to compound (12) by reacting it with an acid catalyst. For example, alcohol solvents such as methanol, ethanol, 2-propanol, tert-butyl alcohol, 2,2,2-trifluoroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol; hydrocarbon solvents such as benzene, toluene, hexane and cyclohexane; halogen solvents such as dichloromethane, chloroform and carbon tetrachloride; In an inert solvent such as an amide solvent such as methyl-2-pyrrolidinone, dimethylsulfoxide, water, or a mixed solvent thereof, with a Lewis acid such as trifluoromethanesulfonic acid, bistrifluoromethanefluoromethanesulfonimide, trifluoroacetic acid, hydrogen chloride, Bronsted acid such as perchloric acid, boron trifluoride/diethyl ether complex, zinc chloride, tin chloride, trimethylsilyl trifluoromethanesulfonate, scandium trifluoromethanesulfonate (III), or ytterbium trifluoromethanesulfonate (III). The reaction can lead to compound (12). Preferably, compound (12) can be derived by reacting with a hydrogen chloride/ethanol solution in a tetrahydrofuran solvent at −20 to 50° C. for 30 minutes to 1 day.

Step 13: Compound (12) can be derived by reacting hydrogen peroxide with a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, ammonium hydroxide, sodium phosphate or an aqueous solution thereof in the presence of an inert solvent such as dimethylsulfoxide. Preferably, compound (II)-C can be obtained by reacting hydrogen peroxide with an aqueous sodium hydroxide solution in the presence of dimethylsulfoxide at 0 to 100°C for 30 minutes to 1 day (see Synthesis, 1989, 949-950, Bull. Chem. Soc. Jpn., 1981, 54, 793-799).

A representative method for preparing the compounds of the present invention represented by (IC) is shown in Scheme C below. The following methods are examples of methods for producing the compounds of the present invention, and are not intended to be limiting. In the examples of the production methods below, the compound may form a salt that does not interfere with the reaction.
Scheme C

(The symbols in the formula are as defined above.)

Step 14: The amino group of compound (II)-C is subjected to a general protection reaction with an allyloxycarbonyl group (Protective Groups in Organic Synthesis 4th edition, John Wiley & Sons, INC.), thereby leading to compound (13). For example, hydrocarbon solvents such as benzene, toluene, and hexane; halogen solvents such as dichloromethane, chloroform, and carbon tetrachloride; ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane; amide solvents such as N,N-dimethylformamide and N-methyl-2-pyrrolidinone; Dimethylamino)pyridine, 2,6-di-t-butylpyridine and other organic bases, or in the presence or absence of inorganic salts such as potassium carbonate, sodium carbonate and sodium hydrogencarbonate, are reacted with allyl chloroformate to lead to compound (13).

Step 15: Compound (13) is reacted with allyl chloroformate in a halogen solvent such as dichloromethane, an ether solvent such as tetrahydrofuran, or an inert solvent such as dimethylsulfoxide in the presence of an organic base such as tributylamine, triethylamine, diisopropylethylamine, pyridine, or N-methylmorpholine, and then N,N-dimethyl-4-aminopyridine is added to give compound (14). The carboxy group of compound (13) can also be converted to compound (14) by reacting it with allyl alcohol in a general esterification reaction (see Comprehensive Organic Transformations Second Edition, 1999, John Wiley & Sons, INC.).

工程１６：化合物（１５）は、化合物（１４）を式Ｌ－ＣＨ（Ｒ ³ ）－Ｏ－Ｃ（Ｏ）－Ｒ ² （式中Ｌは脱離基を示し、例えばハロゲン原子、ｐ－トルエンスルホニルオキシ基、メタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基等を示す）と、ベンゼン、トルエン、ヘキサン、シクロヘキサンなどの炭化水素系溶媒、ジクロロメタン、クロロホルム、四塩化炭素などのハロゲン系溶媒、テトラヒドロフラン、ジエチルエーテル、１，２－ジメトキシエタンなどのエーテル系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチル－２－ピロリジノン等のアミド系溶媒、ジメチルスルホキシド、水、又はこれらの混合溶媒等の不活性溶媒中、水素化ナトリウム、水素化カリウム、炭酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸セシウム、炭酸水素セシウム、水酸化ナトリウム、水酸化カリウム等の無機塩基類、リチウムビス（トリメチルシリル）アミド、リチウムジイソプロピルアミド、ナトリウムアミド等の金属アミド類、トリエチルアミン、ピリジン、ジイソプロピルエチルアミン、４－（Ｎ，Ｎ－ジメチルアミノ）ピリジン、２，６－ジ－ｔｅｒｔ－ブチルピリジン等の有機塩基類、ｔｅｒｔ－ブトキシカリウム等の塩基の存在下、ヨウ化ナトリウムなどの適した活性化剤の存在下又は非存在下反応させることにより導くことができる。 Preferably, compound (15) can be obtained by reacting with a compound represented by the formula Cl-CH(R ³ )-O-C(O)-R ² or Br-CH(R ³ )-O-C(O)-R ² at room temperature to 80°C for 2 hours to 1 day in a mixed solvent of chloroform and water in the presence of potassium carbonate and tetrabutylammonium hydrogensulfate.

Step 17: Compound (15) is subjected to a general deprotection reaction (Protective Groups
in Organic Synthesis 4th Edition, John Wiley & Sons, INC. Reference) can lead to the compound (IC) of the present invention. For example, in the presence of a zerovalent palladium catalyst such as tetrakistriphenylphosphine palladium (0) and a regenerating reagent for a metal catalyst such as 1,3-dimethylbarbituric acid, in an inert solvent such as a hydrocarbon solvent such as benzene, toluene, or hexane, a halogen solvent such as dichloromethane, chloroform, or carbon tetrachloride, an ether solvent such as tetrahydrofuran, diethyl ether, or 1,2-dimethoxyethane, or a mixed solvent thereof, the allyl group and allyloxycarbonyl group are deprotected to obtain the compound of the present invention. can lead to the compound (IC). Preferably, compound (15) is reacted in the presence of tetrakistriphenylphosphinepalladium (0) and 1,3-dimethylbarbituric acid in chloroform at room temperature to 50° C. for 2 to 8 hours to lead to compound (IC) of the present invention.

The present invention will be described in more detail below with reference to examples and test examples, but these do not limit the present invention and may be changed without departing from the scope of the present invention.

In the following examples, Reveleris Silica Flash Cartridge from Grace and YMC-DispoPack AT ODS-25 from YMC were used as "Grace" and "YMC C18", respectively, when purified by column chromatography.

In the following examples, Daicel columns and flow rates, analysis/prep times for resolving diastereomers using chiral column chromatography are shown below.
CHIRAL PAK IC-3: particle diameter 3 μm, inner diameter 4.6 mm, length 150 mm, flow rate 1.0 mL/min.
CHIRAK PAK ID-3: particle diameter 3 μm, inner diameter 4.6 mm, length 150 mm, flow rate 1.0 mL/min.
CHIRAK PAK AY-3: particle diameter 3 μm, inner diameter 4.6 mm, length 150 mm, flow rate 1.0 mL/min.
CHIRAL PAK IC: particle diameter 5 μm, inner diameter 20 mm, length 250 mm, flow rate 10 mL/min.
CHIRAL PAK ID: particle diameter 5 μm, inner diameter 20 mm, length 250 mm, flow rate 10 mL/min.

In the production examples and examples below, purification by preparative high performance liquid chromatography (HPLC) was performed under the following conditions.
Machine: Gilson Trilution LC
Column: YMC YMC-Actus Triant 5.0 μm 50×30 mm
Solvent: Liquid A: Water containing 0.1% trifluoroacetic acid, Liquid B: Acetonitrile containing 0.1% trifluoroacetic acid, or Liquid A: Water containing 0.1% formic acid, Liquid B: Acetonitrile containing 0.1% formic acid.
Flow rate: 40mL/min

Each equipment data described in the following examples was measured with the following measuring equipment.
MS spectrum: LCMS-IT-TOF (ESI/APCI dual source) (Shimadzu Corporation), 1290 Infinity and 6130 Quadrupole LC/MS (Agilent Technologies)
NMR spectrum [ ¹ H-NMR]: 600 MHz; JNM-ECA600 (JEOL Ltd.)
, 400 MHz; AVENCE III HD 400 (Bruker)
X-ray structure analysis: R-AXIS RAPID II (Rigaku)
Abbreviations in nuclear magnetic resonance (NMR) spectra used in the examples are shown below.
s: singlet, d: doublet, t: triplet, q: quartet, sxt: sixtet, dd: doublet doublet, ddd: doublet doublet do ublet), dt: doublet triplet, td: triplet doublet, qd: quartet doublet, m: multiplet, br: broad, J: coupling constant, Hz: hertz, CHLOROF ORM-d: deuterated chloroform, DMSO-d6: deuterated dimethyl sulfoxide, MeOH-d4: deuterated methanol

In the following reference examples and examples, compound names are ACD/Name 2015 (ACDLabs 2015, Advanced Chemistry Development
Inc. ).

In Reference Examples and Examples, the following terms and reagents are indicated as follows.
MgSO ₄ (magnesium sulfate), Na ₂ SO ₄ (anhydrous sodium sulfate), NaHCO ₃ (sodium hydrogen carbonate), NH ₄ Cl (ammonium chloride), DMF (N,N-dimethylformamide), EtOAc (ethyl acetate), CHCl ₃ (chloroform), THF (tetrahydrofuran), MeOH (methanol), EtOH (ethanol), IPA (isopropyl alcohol), H ₂ O (water), Pd (PPh ₃ ) ₄ [tetrakistriphenylphosphine palladium (0)], brine, HCl (hydrogen chloride).

Example 1 Synthesis of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

(1) (1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid

化合物（ＩＩ）－１（１．５ｇ、４．５８ｍｍｏｌ）（ＷＯ０３／０６１６９８ 参照）
の１，４－ｄｉｏｘａｎｅ溶液（９．２ｍＬ）に飽和ＮａＨＣＯ₃水溶液（１６ｍＬ、１
８．３２ｍｍｏｌ）を加え、室温で１０分撹拌した。そこへクロロギ酸アリル（０．９６ｍＬ、９．１７ｍｍｏｌ）を滴下し、室温で１８時間撹拌した。水、飽和ＮａＨＣＯ₃水
溶液を加えて溶液を塩基性にした後、ＥｔＯＡｃで洗浄した。続いて水層に２Ｍ塩酸を加えて溶液を酸性にし、ＥｔＯＡｃを用いて抽出後、Ｎａ₂ＳＯ₄で乾燥した。不溶物を濾別後、減圧下溶媒を留去することにより、表題化合物（１．９ｇ）を得た（褐色アモルファス）。
1H NMR (600 MHz, DMSO-d6) δ ppm 2.05 - 2.11 (1 H, m), 2.13 - 2.21 (1 H, m), 2.31 - 2.37 (1 H, m), 2.51 - 2.52 (1 H, m), 2.68 - 2.74 (1 H, m), 3.31 (1 H, s), 4.05 - 4.10 (1 H, m), 4.39 - 4.52 (3 H, m), 4.57 - 4.64 (1 H, m), 5.16 - 5.24 (1 H, m), 5.28 - 5.36 (1 H, m), 5.84 - 5.96 (1 H, m), 7.12 - 7.17 (2 H, m), 7.29 - 7.34 (2 H, m), 8.14 (1 H, s)
MS m/z : 434[M+Na]+

Compound (II)-1 (1.5 g, 4.58 mmol) (see WO03/061698)
1,4-dioxane solution (9.2 mL) of saturated aqueous NaHCO ₃ (16 mL, 1
8.32 mmol) was added and stirred at room temperature for 10 minutes. Allyl chloroformate (0.96 mL, 9.17 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 18 hours. The solution was basified by adding water, saturated aqueous NaHCO ₃ and washed with EtOAc. The aqueous layer was then acidified with 2M hydrochloric acid, extracted with EtOAc and dried over Na ₂ SO ₄ . After removing the insoluble matter by filtration, the solvent was distilled off under reduced pressure to obtain the title compound (1.9 g) (brown amorphous).
1H NMR (600 MHz, DMSO-d6) δ ppm 2.05 - 2.11 (1 H, m), 2.13 - 2.21 (1 H, m), 2.31 - 2.37 (1 H, m), 2.51 - 2.52 (1 H, m), 2.68 - 2.74 (1 H, m), 3.31 (1 H, s) , 4.05 - 4.10 (1 H, m), 4.39 - 4.52 (3 H, m), 4.57 - 4.64 (1 H, m), 5.16 - 5.24 (1 H, m), 5.28 - 5.36 (1 H, m), 5.84 - 5.96 (1 H, m), 7.12 - 7.17 (2 H , m), 7.29 - 7.34 (2 H, m), 8.14 (1 H, s)
MS m/z: 434[M+Na]+

(2) (1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-6-{[(prop-2-en-1-yl)oxy]carbonyl}-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2-carboxylic acid

（１）で得られた化合物（０．９５ｇ、２．３１ｍｍｏｌ）とＮ－メチルモルホリン（０．３８ｍＬ、３．４６ｍｍｏｌ）のＴＨＦ（１０ｍＬ）溶液に０℃でクロロギ酸アリル（０．３６ｍＬ，３．４６ｍｍｏｌ）を滴下して３０分撹拌した。そこへＮ，Ｎ－ジメチル－４－アミノピリジン（０．０７０ｇ、０．５８ｍｍｏｌ）を加え、室温まで戻して２時間半撹拌した。水、２Ｍ塩酸を加えて溶液を酸性にした後、ＥｔＯＡｃを用いて抽出した。Ｎａ₂ＳＯ₄で乾燥し、不溶物を濾別後、減圧下溶媒を留去することにより、表題化合物（１．０ｇ）を得た（茶色アモルファス）。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.20 - 2.28 (1 H, m), 2.35 - 2.47 (2 H, m), 2.91 - 3.07 (1 H, m), 3.83 - 3.92 (1 H, m), 4.43 - 4.69 (6 H, m), 5.11 - 5.37 (5 H, m), 5.83 - 5.96 (2 H, m), 6.95 - 7.03 (2 H, m), 7.20 - 7.24 (2 H, m)
MS m/z : 474[M+Na]+

Allyl chloroformate (0.36 mL, 3.46 mmol) was added dropwise to a solution of the compound obtained in (1) (0.95 g, 2.31 mmol) and N-methylmorpholine (0.38 mL, 3.46 mmol) in THF (10 mL) at 0° C. and stirred for 30 minutes. N,N-dimethyl-4-aminopyridine (0.070 g, 0.58 mmol) was added thereto, and the mixture was allowed to warm to room temperature and stirred for 2.5 hours. After adding water and 2M hydrochloric acid to acidify the solution, it was extracted with EtOAc. After drying with Na ₂ SO ₄ and removing insoluble matter by filtration, the title compound (1.0 g) was obtained by distilling off the solvent under reduced pressure (brown amorphous).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 2.20 - 2.28 (1 H, m), 2.35 - 2.47 (2 H, m), 2.91 - 3.07 (1 H, m), 3.83 - 3.92 (1 H, m), 4.43 - 4.69 (6 H, m), 5.11 - 5.37 (5 H, m), 5.83 - 5.96 (2 H, m), 6.95 - 7.03 (2 H, m), 7.20 - 7.24 (2 H, m)
MS m/z: 474[M+Na]+

(3) (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (Example 1)

（２）で得られた化合物（０．３０ｇ、０．６６ｍｍｏｌ）のＤＭＦ溶液（３．３ｍＬ）にＫ₂ＣＯ₃（０．０９６ｇ、０．７０ｍｍｏｌ）、１８－クラウン－６（０．１５ｍＬ、０．７０ｍｍｏｌ）を加えた。そこへ（１Ｒ）－１－クロロエチル （１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル カルボナート（ＷＯ２０１３／１８０２７１ 参照）（０．４２ｇ、１．５９ｍｍｏｌ）を加えて室温にて１８時間撹拌した。反応液を飽和ＮＨ₄Ｃｌ水溶液に滴下後、ＥｔＯＡｃを用いて抽出し、ｂｒ
ｉｎｅで洗浄した。Ｎａ₂ＳＯ₄で乾燥したのち、不溶物をろ過して減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｇｒａｃｅ １２ｇ、ｎ‐Ｈｅｘａｎｅ／ＥｔＯＡｃ＝９５／５～６０／４０）および（Ｇｒａｃｅ １２ｇ、ｎ‐Ｈｅｘａｎｅ／ＥｔＯＡｃ＝９５／５～８０／２０）にて精製し、無色油状物（０．３１ｇ）を得た。これをＣＨＣｌ₃（２．３ｍＬ）に溶解させ、１，３－ジメチルバルビツール酸
（０．０７２ｇ、０．４６ｍｍｏｌ）およびＰｄ（ＰＰｈ₃）₄（０．０１３ｇ、０．０１ｍｍｏｌ）を加えて室温で１時間撹拌した。反応液を減圧下濃縮し、逆相シリカゲルカラムクロマトグラフィー（ＹＭＣ Ｃ１８ １２ｇ， Ｈ₂Ｏ／ＭｅＣＮ＝９５／５～５／
９５）にて精製した。フラクションを濃縮して得られた残渣にＭｅＯＨを加え、室温で１
時間撹拌後、析出した結晶を濾取することにより、表題化合物（０．０９７ｇ）を得た（無色固体）。
1H NMR (600 MHz, DMSO-d6) δ ppm 0.69 - 0.90 (10 H, m), 0.92 - 1.08 (1 H, m), 1.32 - 1.46 (5 H, m), 1.62 (2 H, br d, J=11.6 Hz), 1.79 - 2.06 (5 H, m), 2.21 - 2.27 (1 H, m), 2.29 - 2.36 (1 H, m), 3.66 - 3.78 (1 H, m), 4.39 - 4.48 (2 H, m), 4.55 (1 H, br d, J=11.6 Hz), 6.64 - 6.73 (1 H, m), 7.09 - 7.22 (2 H, m), 7.22 - 7.36 (2 H, m)
MS m/z : 576[M+Na]+

K ₂ CO ₃ (0.096 g, 0.70 mmol) and 18-crown-6 (0.15 mL, 0.70 mmol) were added to a DMF solution (3.3 mL) of the compound (0.30 g, 0.66 mmol) obtained in (2). (1R)-1-Chloroethyl (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (see WO2013/180271) (0.42 g, 1.59 mmol) was added thereto and stirred at room temperature for 18 hours. The reaction mixture was added dropwise to a saturated NH ₄ Cl aqueous solution, extracted with EtOAc, and br
washed with ine. After drying with Na ₂ SO ₄ , the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (Grace 12 g, n-Hexane/EtOAc = 95/5 to 60/40) and (Grace 12 g, n-Hexane/EtOAc = 95/5 to 80/20) to give a colorless oil (0.31 g). This was dissolved in CHCl ₃ (2.3 mL), 1,3-dimethylbarbituric acid (0.072 g, 0.46 mmol) and Pd(PPh ₃ ) ₄ (0.013 g, 0.01 mmol) were added and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and subjected to reverse phase silica gel column chromatography (YMC C18 12 g, H ₂ O/MeCN=95/5-5/
95). MeOH was added to the residue obtained by concentrating the fractions and the mixture was stirred at room temperature for 1 hour.
After stirring for an hour, the precipitated crystals were collected by filtration to give the title compound (0.097 g) (colorless solid).
1H NMR (600 MHz, DMSO-d6) δ ppm 0.69 - 0.90 (10 H, m), 0.92 - 1.08 (1 H, m), 1.32 - 1.46 (5 H, m), 1.62 (2 H, br d, J=11.6 Hz), 1.79 - 2.06 (5 H, m), 2.21 - 2.27 (1 H, m), 2.29 - 2.36 (1 H, m), 3.66 - 3.78 (1 H, m), 4.39 - 4.48 (2 H, m), 4.55 (1 H, br d, J = 11.6 Hz), 6.64 - 6.73 (1 H, m), 7.09 - 7.22 (2 H, m ), 7.22 - 7.36 (2H, m)
MS m/z: 576[M+Na]+

Example 2 (1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

実施例１－（２）で得られた化合物（０．３０ｇ、０．６６ｍｍｏｌ）と（１Ｓ）－１－クロロエチル （１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル カルボナート（ＷＯ２０１３／１８０２７１ 参照）（０．４２ｇ、１．５９ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により表題化合物（０．０１８ｇ）を得た（無色固体）。
1H NMR (600 MHz, DMSO-d6) δ ppm 0.65 (3 H, d, J=7.0 Hz), 0.73 - 0.86 (7 H, m), 0.93-1.01 (2 H, m), 1.23 - 1.32 (1 H, m), 1.39 - 1.45 (4 H, m), 1.53 - 1.61 (2 H, m), 1.71 - 1.79 (1 H, m), 1.89 - 1.97 (2 H, m), 2.04 - 2.12 (1 H, m), 2.10 - 2.20 (1 H, m), 2.22 - 2.29 (1 H, m), 2.48 - 2.49 (2 H, m), 3.64-3.70 (1 H, m), 4.36 - 4.44 (2 H, m), 4.49 - 4.53 (1 H, m), 6.64 (1 H, q, J=5.4 Hz), 7.09 (2 H, s), 7.26 - 7.30 (2 H, m)
MS m/z : 576[M+Na]+

Using the compound (0.30 g, 0.66 mmol) obtained in Example 1-(2) and (1S)-1-chloroethyl (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (see WO2013/180271) (0.42 g, 1.59 mmol), the title compound (0.0 18 g) was obtained (colorless solid).
1H NMR (600 MHz, DMSO-d6) δ ppm 0.65 (3 H, d, J=7.0 Hz), 0.73 - 0.86 (7 H, m), 0.93-1.01 (2 H, m), 1.23 - 1.32 (1 H, m), 1.39 - 1.45 (4 H, m), 1.53 - 1.61 (2 H, m), 1.71 - 1.79 (1 H, m), 1.89 - 1.97 (2 H, m), 2.04 - 2.12 (1 H, m), 2.10 - 2.20 (1 H, m), 2.22 - 2.29 (1 H, m), 2.48 - 2.49 (2 H, m), 3.64-3. 70 (1 H, m), 4.36 - 4.44 (2 H, m), 4.49 - 4.53 (1 H, m), 6.64 (1 H, q, J=5.4 Hz), 7.09 (2 H, s), 7.26 - 7.30 (2 H, m)
MS m/z: 576[M+Na]+

Example 3 (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1R)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1
. 0] hexane-6-carboxylic acid

実施例１－（２）で得られた化合物（０．２０ｇ、０．４４ｍｍｏｌ）と（（１Ｓ）－１－クロロエチル トリシクロ［３．３．１．１^3,7］デカン－１－カルボキシラート（Ｗ
Ｏ２０１３／１８０２７１ 参照）（０．３２ｇ、１．３３ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により表題化合物（０．０９３ｇ）を得た（無色固体）。
1H NMR (600 MHz, DMSO-d6) δ ppm 1.40 - 1.45 (3 H, m), 1.55 (3 H, br d, J=11.6 Hz), 1.63 (3 H, br d, J=12.0 Hz), 1.68 - 1.80 (6 H, m), 1.86 - 1.91 (3 H, m), 2.00 - 2.05 (1 H, m), 2.12 (1 H, dd, J=7.8, 2.5 Hz), 2.19 - 2.25 (1 H, m), 2.27 - 2.33 (1 H, m), 2.51 - 2.53 (1 H, m), 3.71 - 3.76 (1 H, m), 4.43 - 4.51 (1 H, m), 4.54 (1 H, d, J=12.0 Hz), 6.86 (1 H, q, J=5.4 Hz), 7.12 - 7.17 (2 H, m), 7.29 - 7.33 (2 H, m)
MS m/z : 532[M-H]-

The compound (0.20 g, 0.44 mmol) obtained in Example 1-(2) and ((1S)-1-chloroethyl tricyclo[3.3.1.1 ^3,7 ]decane-1-carboxylate (W
02013/180271) (0.32 g, 1.33 mmol) to give the title compound (0.093 g) (colorless solid) in the same manner as in Example 1-(3).
1H NMR (600 MHz, DMSO-d6) δ ppm 1.40 - 1.45 (3 H, m), 1.55 (3 H, br d, J=11.6 Hz), 1.63 (3 H, br d, J=12.0 Hz), 1.68 - 1.80 (6 H, m), 1.86 - 1.91 (3 H, m), 2 .00 - 2.05 (1 H, m), 2.12 (1 H, dd, J=7.8, 2.5 Hz), 2.19 - 2.25 (1 H, m), 2.27 - 2.33 (1 H, m), 2.51 - 2.53 (1 H, m), 3.71 - 3.76 (1 H, m), 4.43 - 4.5 1 (1 H, m), 4.54 (1 H, d, J=12.0 Hz), 6.86 (1 H, q, J=5.4 Hz), 7.12 - 7.17 (2 H, m), 7.29 - 7.33 (2 H, m)
MS m/z : 532[MH]-

Example 4 (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1
. 0] hexane-6-carboxylic acid

実施例１－（２）で得られた化合物（０．２０ｇ、０．４４ｍｍｏｌ）と（１Ｒ）－１－クロロエチル トリシクロ［３．３．１．１^3,7］デカン－１－カルボキシラート（ＷＯ
２０１３／１８０２７１ 参照）（０．３２ｇ、１．３３ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により表題化合物（０．１５３ｇ）を得た（無色固体）。また、得られた化合物（実施例４）の絶対立体配置はＸ線構造解析により決定した。
1H NMR (600 MHz, DMSO-d6) δ ppm 1.40 (3 H, d, J=5.4 Hz), 1.57 - 1.71 (6 H, m), 1.74 - 1.80 (6 H, m), 1.88 - 2.00 (5 H, m), 2.18 - 2.26 (1 H, m), 2.29 - 2.38 (1
H, m), 2.40 - 2.48 (1 H, m), 3.70 - 3.77 (1 H, m), 4.45 (1 H, d, J=11.6 Hz), 4.56 (1 H, d, J=11.6 Hz), 6.76 (1 H, q, J=5.4 Hz), 7.13 - 7.18 (2 H, m), 7.27 - 7.32 (2 H, m)
MS m/z : 532[M-H]-

The compound (0.20 g, 0.44 mmol) obtained in Example 1-(2) and (1R)-1-chloroethyl tricyclo[3.3.1.1 ^3,7 ]decane-1-carboxylate (WO
2013/180271) (0.32 g, 1.33 mmol), the title compound (0.153 g) was obtained in the same manner as in Example 1-(3) (colorless solid). Also, the absolute configuration of the obtained compound (Example 4) was determined by X-ray structural analysis.
1H NMR (600 MHz, DMSO-d6) δ ppm 1.40 (3 H, d, J=5.4 Hz), 1.57 - 1.71 (6 H, m), 1.74 - 1.80 (6 H, m), 1.88 - 2.00 (5 H, m), 2.18 - 2.26 (1 H, m), 2.29 - 2.3 8 (1
H, m), 2.40 - 2.48 (1 H, m), 3.70 - 3.77 (1 H, m), 4.45 (1 H, d, J=11.6 Hz), 4.56 (1 H, d, J=11.6 Hz), 6.76 (1 H, q, J=5.4 Hz), 7.13 - 7.18 (2 H, m), 7 .27 - 7.32 (2H, m)
MS m/z : 532[MH]-

Example 5 (1R,2R,3R,5R,6R)-2-amino-2-[(1-{[(cyclohexyloxy)carbonyl]oxy}ethoxy)carbonyl]-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic acid

実施例１－（２）で得られた化合物（０．３０ｇ、０．６６ｍｍｏｌ）と１－クロロエチル シクロヘキシル カルボナート（０．２４ｍＬ、１．３３ｍｍｏｌ）を用い、実施例
１－（３）と同様の手法により表題化合物（０．０２３ｇ）を得た（無色固体）。
1H NMR (600 MHz, DMSO-d6) δ ppm 1.14 - 1.47 (10 H, m), 1.56 - 1.66 (2 H, m), 1.70 - 1.76 (1 H, m), 1.78 - 1.84 (1 H, m), 1.98 - 2.04 (1 H, m), 2.09 - 2.13 (1 H, m), 2.16 - 2.23 (1 H, m), 2.26 - 2.33 (1 H, m), 3.70 - 3.74 (1 H, m), 4.42 - 4.58 (3 H, m), 6.73 (1 H, q, J=5.4 Hz), 7.10 - 7.15 (2 H, m), 7.28 - 7.32 (2 H, m)
MS m/z : 520[M+Na]+

Using the compound (0.30 g, 0.66 mmol) obtained in Example 1-(2) and 1-chloroethyl cyclohexyl carbonate (0.24 mL, 1.33 mmol), the title compound (0.023 g) was obtained in the same manner as in Example 1-(3) (colorless solid).
1H NMR (600 MHz, DMSO-d6) δ ppm 1.14 - 1.47 (10 H, m), 1.56 - 1.66 (2 H, m), 1.70 - 1.76 (1 H, m), 1.78 - 1.84 (1 H, m), 1.98 - 2.04 (1 H, m), 2.09 - 2.13 (1 H, m), 2.16 - 2.23 (1 H, m), 2.26 - 2.33 (1 H, m), 3.70 - 3.74 (1 H, m), 4.42 - 4.58 (3 H, m), 6.73 (1 H, q, J=5.4 Hz), 7.10 - 7.15 (2 H, m), 7.28 - 7.32 (2H, m)
MS m/z : 520[M+Na]+

Example 6 (1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-{[(L-valyloxy)methoxy]carbonyl}bicyclo[3.1.0]hexane-6-carboxylic acid dihydrochloride

実施例１－（２）で得られた化合物（０．１５ｇ、０．３４ｍｍｏｌ）とクロロメチル Ｎ－（ｔｅｒｔ－ブトキシカルボニル）－Ｌ－バリナート（０．２７ｇ、１．０３ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により無色アモルファス（０．０９１ｇ）を得た。これをＣＨＣｌ₃（１．２ｍＬ）に溶解させ、室温にて４ＭＨＣｌ－ジオキサン溶
液（０．１２ｍＬ）を滴下して４時間撹拌した。析出した固体を濾取することにより、表題化合物（４０ｍｇ）を得た（淡黄色固体）。
1H NMR (600 MHz, MeOH-d4) δ ppm 1.01 (6 H, d, J=7.0 Hz), 2.20 - 2.27 (1 H, m), 2.42 - 2.53 (3 H, m), 2.58 - 2.64 (1 H, m), 3.69 (1 H, d, J=4.5 Hz), 4.16 - 4.20
(1 H, m), 4.56 (2 H, s), 6.01 (1 H, d, J=6.2 Hz), 6.13 (1 H, d, J=5.8 Hz), 7.09
- 7.14 (2 H, m), 7.35 - 7.39 (2 H, m), 7.91 (1 H, s)
MS m/z : 457[M+H]+

Using the compound (0.15 g, 0.34 mmol) obtained in Example 1-(2) and chloromethyl N-(tert-butoxycarbonyl)-L-valinate (0.27 g, 1.03 mmol), a colorless amorphous substance (0.091 g) was obtained in the same manner as in Example 1-(3). This was dissolved in CHCl ₃ (1.2 mL), 4M HCl-dioxane solution (0.12 mL) was added dropwise at room temperature, and the mixture was stirred for 4 hours. The precipitated solid was collected by filtration to obtain the title compound (40 mg) (pale yellow solid).
1H NMR (600 MHz, MeOH-d4) δ ppm 1.01 (6 H, d, J=7.0 Hz), 2.20 - 2.27 (1 H, m), 2.42 - 2.53 (3 H, m), 2.58 - 2.64 (1 H, m), 3.69 (1 H, d, J=4.5 Hz), 4.16 - 4 .20
(1 H, m), 4.56 (2 H, s), 6.01 (1 H, d, J=6.2 Hz), 6.13 (1 H, d, J=5.8 Hz), 7.09
- 7.14 (2 H, m), 7.35 - 7.39 (2 H, m), 7.91 (1 H, s)
MS m/z : 457[M+H]+

Example 7 (1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

実施例１－（２）で得られた化合物（０．１ｇ、０．２２ｍｍｏｌ）とクロロメチル トリシクロ［３．３．１．１^3,7］デカン－１－カルボキシラート（０．０５５ｇ、０．２
４ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により表題化合物（５２ｍｇ）を得た（無色固体）。
1H NMR (600 MHz, DMSO-d6) δ ppm 1.51 - 1.55 (3 H, m), 1.59 - 1.64 (3 H, m), 1.6
8 - 1.73 (6 H, m), 1.87 (3 H, br s), 1.95 - 2.00 (1 H, m), 2.09 (1 H, dd, J=7.6,
2.7 Hz), 2.13 - 2.19 (1 H, m), 2.29 (1 H, dd, J=13.2, 7.4 Hz), 2.47 (1 H, br d,
J=8.7 Hz), 2.52 - 2.57 (1 H, m), 3.70 - 3.75 (1 H, m), 4.46 (1 H, d, J=12.0 Hz), 4.57 (1 H, d, J=12.0 Hz), 5.75 (1 H, d, J=5.8 Hz), 5.83 (1 H, d, J=5.8 Hz), 7.15 (2 H, t, J=8.4 Hz), 7.30 (2 H, t, J=6.7 Hz)
MS m/z : 520[M+H]+

The compound (0.1 g, 0.22 mmol) obtained in Example 1-(2) and chloromethyl tricyclo[3.3.1.1 ^3,7 ]decane-1-carboxylate (0.055 g, 0.2
4 mmol) was used and the title compound (52 mg) was obtained by the same method as in Example 1-(3) (colorless solid).
1H NMR (600 MHz, DMSO-d6) δ ppm 1.51 - 1.55 (3 H, m), 1.59 - 1.64 (3 H, m), 1.6
8 - 1.73 (6 H, m), 1.87 (3 H, brs), 1.95 - 2.00 (1 H, m), 2.09 (1 H, dd, J = 7.6,
2.7 Hz), 2.13 - 2.19 (1 H, m), 2.29 (1 H, dd, J=13.2, 7.4 Hz), 2.47 (1 H, br d,
J=8.7 Hz), 2.52 - 2.57 (1 H, m), 3.70 - 3.75 (1 H, m), 4.46 (1 H, d, J=12.0 Hz), 4.57 (1 H, d, J=12.0 Hz), 5.75 (1 H, d, J=5.8 Hz), 5.83 (1 H, d, J=5. 8Hz), 7.15 (2H, t, J=8.4Hz), 7.30 (2H, t, J=6.7Hz)
MS m/z : 520[M+H]+

Example 8 Synthesis of (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

(1) (1R,2R,3R,5R,6R)-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid

実施例１－（１）と同様の手法により、化合物（ＩＩ）－２（１．５ｇ、３．９７ｍｍｏｌ）（ＷＯ０３／０６１６９８ 参照）から表題化合物（１．７ｇ）を得た（淡黄色アモ
ルファス）。
1H NMR (600 MHz, DMSO-d6) δ ppm 2.06 - 2.12 (1 H, m), 2.15 - 2.23 (1 H, m), 2.37 (1 H, dd, J=13.6, 7.4 Hz), 2.69 - 2.73 (1 H, m), 3.32 (2 H, br s), 4.00 - 4.10
(1 H, m), 4.38 - 4.53 (3 H, m), 4.57 - 4.63 (1 H, m), 5.15 - 5.24 (1 H, m), 5.27 - 5.36 (1 H, m), 5.82 - 5.96 (1 H, m), 7.09 - 7.16 (1 H, m), 7.29 - 7.42 (2 H,
m), 8.16 (1 H, s)
MS m/z : 452[M+Na]+

The title compound (1.7 g) was obtained (pale yellow amorphous) from compound (II)-2 (1.5 g, 3.97 mmol) (see WO03/061698) in the same manner as in Example 1-(1).
1H NMR (600 MHz, DMSO-d6) δ ppm 2.06 - 2.12 (1 H, m), 2.15 - 2.23 (1 H, m), 2.37 (1 H, dd, J=13.6, 7.4 Hz), 2.69 - 2.73 (1 H, m), 3.32 (2 H, br s), 4.00 - 4.10
(1 H, m), 4.38 - 4.53 (3 H, m), 4.57 - 4.63 (1 H, m), 5.15 - 5.24 (1 H, m), 5.27 - 5.36 (1 H, m), 5.82 - 5.96 (1 H, m), 7.09 - 7.16 (1 H, m), 7.29 - 7.42 (2 H,
m), 8.16 (1 H, s)
MS m/z: 452[M+Na]+

(2) (1R,2R,3R,5R,6R)-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-6-{[(prop-2-en-1-yl)oxy]carbonyl}-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2-carboxylic acid

（１）で得られた化合物（１．７ｇ、３．９６ｍｍｏｌ）を原料にして、実施例１－（２）と同様の手法により、表題化合物（１．８ｇ）を得た（茶色アモルファス）。
1H NMR (600 MHz, DMSO-d6) δ ppm 2.14 - 2.45 (3 H, m), 2.77 (1 H, br d, J=7.0 Hz), 4.06 - 4.20 (1 H, m), 4.39 - 4.72 (7 H, m), 5.14 - 5.36 (4 H, m), 5.84 - 5.97
(2 H, m), 7.01 - 7.45 (3 H, m), 8.20 (1 H, br s)
MS m/z : 492[M+Na]+

Using the compound (1.7 g, 3.96 mmol) obtained in (1) as a starting material, the title compound (1.8 g) was obtained (brown amorphous) in the same manner as in Example 1-(2).
1H NMR (600 MHz, DMSO-d6) δ ppm 2.14 - 2.45 (3 H, m), 2.77 (1 H, br d, J=7.0 Hz), 4.06 - 4.20 (1 H, m), 4.39 - 4.72 (7 H, m), 5.14 - 5.36 (4 H, m), 5.84 - 5 .97
(2 H, m), 7.01 - 7.45 (3 H, m), 8.20 (1 H, br s)
MS m/z: 492[M+Na]+

(3) (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (Example 8)

（２）で得られた化合物（０．３０ｇ、０．６４ｍｍｏｌ）と（１Ｒ）－１－クロロエチル （１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル カルボナート（０．４０ｇ、１．５３ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により表題化合物（１３５ｍｇ）を得た（無色固体）。
1H NMR (600 MHz, DMSO-d6) δ ppm 0.73 (3 H, d, J=7.0 Hz), 0.78 - 0.89 (7 H, m), 0.92 - 1.06 (2 H, m), 1.30 - 1.47 (5 H, m), 1.59 - 1.64 (2 H, m), 1.79 - 1.86 (1
H, m), 1.88 - 1.93 (1 H, m), 1.98 - 2.05 (2 H, m), 2.22 - 2.27 (1 H, m), 2.35 (1 H, dd, J=13.4, 7.6 Hz), 2.51 - 2.53 (1 H, m), 3.72 - 3.78 (1 H, m), 4.39 - 4.63 (3 H, m), 6.67 (1 H, q, J=5.4 Hz), 7.09 - 7.12 (1 H, m), 7.27 - 7.31 (1 H, m),
7.39 (1 H, dt, J=10.7, 8.5 Hz)
MS m/z : 594[M+Na]+

Using the compound (0.30 g, 0.64 mmol) obtained in (2) and (1R)-1-chloroethyl (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (0.40 g, 1.53 mmol), the title compound (135 mg) was obtained in the same manner as in Example 1-(3) (colorless solid).
1H NMR (600 MHz, DMSO-d6) δ ppm 0.73 (3 H, d, J=7.0 Hz), 0.78 - 0.89 (7 H, m), 0.92 - 1.06 (2 H, m), 1.30 - 1.47 (5 H, m), 1.59 - 1.64 (2 H, m), 1.79 - 1.8 6 (1
H, m), 1.88 - 1.93 (1 H, m), 1.98 - 2.05 (2 H, m), 2.22 - 2.27 (1 H, m), 2.35 (1 H, dd, J=13.4, 7.6 Hz), 2.51 - 2.53 (1 H, m), 3.72 - 3.78 (1 H, m), 4.39 - 4.63 (3 H, m), 6.67 (1 H, q, J=5.4 Hz), 7.09 - 7.12 (1 H, m), 7.27 - 7.31 (1 H, m),
7.39 (1H, dt, J=10.7, 8.5Hz)
MS m/z: 594[M+Na]+

Example 9 (1R,2R,3R,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

実施例８－（２）で得られた化合物（０．３０ｇ、０．６４ｍｍｏｌ）と（１Ｓ）－１－クロロエチル （１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル カルボナート（０．４０ｇ、１．５３ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により表題化合物（１９ｍｇ）を得た（無色固体）。
1H NMR (600 MHz, DMSO-d6) δ ppm 0.66 (3 H, d, J=6.6 Hz), 0.73 - 0.90 (7 H, m), 0.94 - 1.03 (2 H, m), 1.21 - 1.34 (2 H, m), 1.38 - 1.53 (4 H, m), 1.53 - 1.66 (2
H, m), 1.69 - 1.81 (1 H, m), 1.91 - 2.03 (2 H, m), 2.10 - 2.24 (2 H, m), 2.27 -
2.34 (1 H, m), 3.70 - 3.74 (1 H, m), 4.36 - 4.49 (2 H, m), 4.53 - 4.59 (1 H, m), 6.68 (1 H, q, J=5.0 Hz), 7.11 (1 H, br s), 7.30 - 7.38 (2 H, m)
MS m/z : 594[M+Na]+

Using the compound (0.30 g, 0.64 mmol) obtained in Example 8-(2) and (1S)-1-chloroethyl (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (0.40 g, 1.53 mmol), the title compound (19 mg) was obtained in the same manner as in Example 1-(3) (colorless solid).
1H NMR (600 MHz, DMSO-d6) δ ppm 0.66 (3 H, d, J=6.6 Hz), 0.73 - 0.90 (7 H, m), 0.94 - 1.03 (2 H, m), 1.21 - 1.34 (2 H, m), 1.38 - 1.53 (4 H, m), 1.53 - 1.6 6 (2
H, m), 1.69 - 1.81 (1 H, m), 1.91 - 2.03 (2 H, m), 2.10 - 2.24 (2 H, m), 2.27 -
2.34 (1 H, m), 3.70 - 3.74 (1 H, m), 4.36 - 4.49 (2 H, m), 4.53 - 4.59 (1 H, m), 6.68 (1 H, q, J=5.0 Hz), 7.11 (1 H, br s), 7.30 - 7.38 (2 H, m)
MS m/z: 594[M+Na]+

Example 10 (1R,2R,3R,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1R)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

実施例８－（２）で得られた化合物（０．２０ｇ、０．４２ｍｍｏｌ）と（１Ｓ）－１－クロロエチル トリシクロ［３．３．１．１^3,7］デカン－１－カルボキシラート（０．
３１ｇ、１．２８ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により表題化合物（１４９ｍｇ）を得た（無色固体）。
1H NMR (600 MHz, MeOH-d4) δ ppm 1.55 (3 H, d, J=5.4 Hz), 1.64 (3 H, br d, J=12.0 Hz), 1.74 (3 H, br d, J=12.0 Hz), 1.77 - 1.82 (6 H, m), 1.89 - 1.95 (3 H, m), 2.24 - 2.32 (2 H, m), 2.39 - 2.44 (1 H, m), 2.50 (1 H, dd, J=13.2, 7.4 Hz), 4.05
- 4.09 (1 H, m), 4.52 (2 H, s), 7.01 - 7.04 (1 H, m), 7.11 - 7.15 (1 H, m), 7.19 - 7.25 (1 H, m), 7.28 - 7.33 (1 H, m)
MS m/z : 550[M-H]-

The compound (0.20 g, 0.42 mmol) obtained in Example 8-(2) and (1S)-1-chloroethyl tricyclo[3.3.1.1 ^3,7 ]decane-1-carboxylate (0.20 g, 0.42 mmol)
31 g, 1.28 mmol) was used, and the title compound (149 mg) was obtained in the same manner as in Example 1-(3) (colorless solid).
1H NMR (600 MHz, MeOH-d4) δ ppm 1.55 (3 H, d, J=5.4 Hz), 1.64 (3 H, br d, J=12.0 Hz), 1.74 (3 H, br d, J=12.0 Hz), 1.77 - 1.82 (6 H, m), 1.89 - 1.95 (3 H, m), 2.24 - 2.32 (2 H, m), 2.39 - 2.44 (1 H, m), 2.50 (1 H, dd, J=13.2, 7.4 Hz), 4.05
- 4.09 (1 H, m), 4.52 (2 H, s), 7.01 - 7.04 (1 H, m), 7.11 - 7.15 (1 H, m), 7.19 - 7.25 (1 H, m), 7.28 - 7.33 (1 H, m)
MS m/z : 550[MH]-

Example 11 (1R,2R,3R,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

実施例８－（２）で得られた化合物（０．２０ｇ、０．４２ｍｍｏｌ）と（１Ｒ）－１－クロロエチル トリシクロ［３．３．１．１^3,7］デカン－１－カルボキシラート（０．
３１ｇ、１．２８ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により表題化合物（１２３ｍｇ）を得た（無色固体）。
1H NMR (600 MHz, MeOH-d4) δ ppm 1.48 (3 H, d, J=5.8 Hz), 1.70 - 1.80 (6 H, m), 1.90 (6 H, br s), 2.00 (3 H, br s), 2.18 - 2.21 (1 H, m), 2.25 - 2.29 (1 H, m), 2.42 - 2.48 (1 H, m), 2.52 - 2.58 (1 H, m), 4.06 - 4.11 (1 H, m), 4.49 - 4.56 (2
H, m), 6.92 (1 H, d, J=7.8 Hz), 7.10 - 7.14 (1 H, m), 7.21 - 7.28 (2 H, m)
MS m/z : 550[M-H]-

The compound (0.20 g, 0.42 mmol) obtained in Example 8-(2) and (1R)-1-chloroethyl tricyclo[3.3.1.1 ^3,7 ]decane-1-carboxylate (0.20 g, 0.42 mmol)
31 g, 1.28 mmol) was used to obtain the title compound (123 mg) (colorless solid) in the same manner as in Example 1-(3).
1H NMR (600 MHz, MeOH-d4) δ ppm 1.48 (3 H, d, J=5.8 Hz), 1.70 - 1.80 (6 H, m), 1.90 (6 H, br s), 2.00 (3 H, br s), 2.18 - 2.21 (1 H, m), 2.25 - 2.29 (1 H, m ), 2.42 - 2.48 (1 H, m), 2.52 - 2.58 (1 H, m), 4.06 - 4.11 (1 H, m), 4.49 - 4.56 (2
H, m), 6.92 (1 H, d, J=7.8 Hz), 7.10 - 7.14 (1 H, m), 7.21 - 7.28 (2 H, m)
MS m/z : 550[MH]-

Example 12 (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]methoxy}carbonyl)bicyclo[3.1.0]
Hexane-6-carboxylic acid

実施例８－（２）で得られた化合物（０．２０ｇ、０．４２ｍｍｏｌ）とクロロメチル トリシクロ［３．３．１．１^3,7］デカン－１－カルボキシラート（０．１９ｇ、０．８
５ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により表題化合物（６１ｍｇ）を得た（無色アモルファス）。
1H NMR (600 MHz, DMSO-d6) δ ppm 1.50 (3 H, br d, J=11.1 Hz), 1.60 (3 H, br d, J=12.0 Hz), 1.66 - 1.69 (6 H, m), 1.84 (3 H, br s), 1.94 - 1.99 (1 H, m), 2.05 - 2.12 (1 H, m), 2.12 - 2.17 (1 H, m), 2.30 (1 H, dd, J=13.6, 7.4 Hz), 3.68 - 3.74
(1 H, m), 4.45 (1 H, d, J=12.0 Hz), 4.56 (1 H, d, J=12.0 Hz), 5.73 (1 H, d, J=5.8 Hz), 5.84 (1 H, d, J=5.8 Hz), 7.08 - 7.11 (1 H, m), 7.26 - 7.31 (1 H, m), 7.34 - 7.41 (1 H, m)
MS m/z : 538[M+H]+

The compound (0.20 g, 0.42 mmol) obtained in Example 8-(2) and chloromethyl tricyclo[3.3.1.1 ^3,7 ]decane-1-carboxylate (0.19 g, 0.8
5 mmol), the title compound (61 mg) was obtained (colorless amorphous) in the same manner as in Example 1-(3).
1H NMR (600 MHz, DMSO-d6) δ ppm 1.50 (3 H, br d, J=11.1 Hz), 1.60 (3 H, br d, J=12.0 Hz), 1.66 - 1.69 (6 H, m), 1.84 (3 H, br s), 1.94 - 1.99 (1 H, m), 2.05 - 2.12 (1 H, m), 2.12 - 2.17 (1 H, m), 2.30 (1 H, dd, J=13.6, 7.4 Hz), 3.68 - 3.74
(1 H, m), 4.45 (1 H, d, J=12.0 Hz), 4.56 (1 H, d, J=12.0 Hz), 5.73 (1 H, d, J=5.8 Hz), 5.84 (1 H, d, J=5.8 Hz), 7.08 - 7.11 (1 H, m), 7.26 - 7.31 (1 H, m), 7.34 - 7.41 (1 H, m)
MS m/z : 538[M+H]+

Example 13 Synthesis of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid

（１）（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－６－フルオロ－２－（｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝アミノ）－３－プロポキシビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸

(1) (1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid

化合物（ＩＩ）－３（３．０ｇ、１１．４８ｍｍｏｌ）（ＷＯ０３／０６１６９８ 参照
）を原料にして、実施例１－（１）と同様の手法により、表題化合物（３．４ｇ）を得た（淡黄色アモルファス）。
1H NMR (600 MHz, DMSO-d6) δ ppm 0.80 (3 H, t, J=7.4 Hz), 1.40 (2 H, sxt, J=7.0 Hz), 2.02 - 2.07 (1 H, m), 2.07 - 2.15 (1 H, m), 2.32 (1 H, dd, J=14.0, 9.1 Hz),
2.63 - 2.70 (1 H, m), 3.26 - 3.37 (2 H, m), 3.47 - 3.55 (1 H, m), 3.86 - 3.93 (1 H, m), 4.46 (1 H, br d, J=4.5 Hz), 5.18 (1 H, d, J=9.9 Hz), 5.31 (1 H, d, J=16.9 Hz), 5.86 - 5.95 (1 H, m)
MS m/z : 368[M+Na]+

Compound (II)-3 (3.0 g, 11.48 mmol) (see WO03/061698) was used as a starting material and the title compound (3.4 g) was obtained (pale yellow amorphous) in the same manner as in Example 1-(1).
1H NMR (600 MHz, DMSO-d6) δ ppm 0.80 (3 H, t, J=7.4 Hz), 1.40 (2 H, sxt, J=7.0 Hz), 2.02 - 2.07 (1 H, m), 2.07 - 2.15 (1 H, m), 2.32 (1 H, dd, J=14.0, 9.1 Hz ),
2.63 - 2.70 (1 H, m), 3.26 - 3.37 (2 H, m), 3.47 - 3.55 (1 H, m), 3.86 - 3.93 (1 H, m), 4.46 (1 H, br d, J=4.5 Hz), 5.18 (1 H, d, J=9.9 Hz), 5.31 (1 H , d, J=16.9 Hz), 5.86 - 5.95 (1 H, m)
MS m/z : 368[M+Na]+

(2) (1R,2R,3R,5R,6R)-6-fluoro-6-{[(prop-2-en-1-yl)oxy]carbonyl}-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[3.1.0]hexane-2-carboxylic acid

（１）で得られた化合物（１．７ｇ、４．９５ｍｍｏｌ）を原料にして、実施例１－（２）と同様の手法により、表題化合物（１．８ｇ）を得た。
1H NMR (600 MHz, DMSO-d6) δ ppm 0.80 (3 H, t, J=7.4 Hz), 1.40 (2 H, sxt, J=7.4 Hz), 2.08 - 2.27 (2 H, m), 2.32 - 2.42 (1 H, m), 2.70 - 2.86 (1 H, m), 3.33 - 3.36 (2 H, m), 3.39 - 3.55 (1 H, m), 3.86 - 4.04 (1 H, m), 4.36 - 4.75 (4 H, m), 5
.08 - 5.39 (4 H, m), 5.82 - 5.97 (2 H, m)
MS m/z : 408[M+Na]+

Using the compound (1.7 g, 4.95 mmol) obtained in (1) as a starting material, the title compound (1.8 g) was obtained in the same manner as in Example 1-(2).
1H NMR (600 MHz, DMSO-d6) δ ppm 0.80 (3 H, t, J=7.4 Hz), 1.40 (2 H, sxt, J=7.4 Hz), 2.08 - 2.27 (2 H, m), 2.32 - 2.42 (1 H, m), 2.70 - 2.86 (1 H, m), 3.33 - 3.36 (2 H, m), 3.39 - 3.55 (1 H, m), 3.86 - 4.04 (1 H, m), 4.36 - 4.75 (4 H, m), 5
.08 - 5.39 (4H,m), 5.82 - 5.97 (2H,m)
MS m/z: 408[M+Na]+

(3) (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid (Example 13)

（２）で得られた化合物（０．３０ｇ、０．７８ｍｍｏｌ）と（１Ｒ）－１－クロロエチル （１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル カルボナート（０．４９ｇ、１．８７ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により表題化合物（４６ｍｇ）を得た（無色固体）。
1H NMR (600 MHz, DMSO-d6) δ ppm 0.74 (3 H, d, J=7.0 Hz), 0.78 - 0.89 (10 H, m),
0.95 - 1.07 (2 H, m), 1.32 - 1.48 (7 H, m), 1.59 - 1.64 (2 H, m), 1.80 - 1.86 (1 H, m), 1.90 - 2.00 (3 H, m), 2.15 - 2.20 (1 H, m), 2.33 (1 H, dd, J=13.2, 7.4 Hz), 3.30 (1 H, dt, J=9.1, 6.6 Hz), 3.43 (1 H, dt, J=9.1, 6.6 Hz), 3.56 - 3.64 (1 H, m), 4.41 - 4.47 (1 H, m), 6.65 - 6.68 (1 H, m)
MS m/z : 488[M+H]+

Using the compound (0.30 g, 0.78 mmol) obtained in (2) and (1R)-1-chloroethyl (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (0.49 g, 1.87 mmol), the title compound (46 mg) was obtained in the same manner as in Example 1-(3) (colorless solid).
1H NMR (600 MHz, DMSO-d6) δ ppm 0.74 (3 H, d, J=7.0 Hz), 0.78 - 0.89 (10 H, m),
0.95 - 1.07 (2 H, m), 1.32 - 1.48 (7 H, m), 1.59 - 1.64 (2 H, m), 1.80 - 1.86 (1 H, m), 1.90 - 2.00 (3 H, m), 2.15 - 2.20 (1 H, m), 2.33 (1 H, dd, J= 13.2, 7.4 Hz), 3.30 (1 H, dt, J=9.1, 6.6 Hz), 3.43 (1 H, dt, J=9.1, 6.6 Hz), 3.56 - 3.64 (1 H, m), 4.41 - 4.47 (1 H, m), 6.65 - 6.68 (1 H, m)
MS m/z : 488[M+H]+

Example 14 (1R,2R,3R,5R,6R)-2-Amino-6-fluoro-2-({(1S)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid

実施例１３－（２）で得られた化合物（０．３０ｇ、０．７８ｍｍｏｌ）と（１Ｓ）－１－クロロエチル （１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル カルボナート（０．４９ｇ、１．８７ｍｍｏｌ）を用い、実施例１－（３）と同様の手法により表題化合物（１００ｍｇ）を得た（無色固体）。
1H NMR (600 MHz, DMSO-d6) δ ppm 0.75 (3 H, d, J=7.0 Hz), 0.77 - 0.91 (10 H, m),
0.98 - 1.09 (2 H, m), 1.32 - 1.52 (7 H, m), 1.60 - 1.66 (2 H, m), 1.82 - 1.88 (1 H, m), 1.94 - 2.00 (2 H, m), 2.08 (1 H, dd, J=8.0, 2.5 Hz), 2.13 (1 H, ddd, J=13.2, 8.0, 5.8 Hz), 2.29 (1 H, dd, J=13.2, 7.4 Hz), 3.28 (1 H, dt, J=9.1, 6.6 Hz), 3.43 (1 H, dt, J=9.1, 6.6 Hz), 3.56 - 3.62 (1 H, m), 4.46 (1 H, td, J=10.8, 4.3 Hz), 6.67 (1 H, q, J=5.4 Hz)
MS m/z : 488[M+H]+

Using the compound (0.30 g, 0.78 mmol) obtained in Example 13-(2) and (1S)-1-chloroethyl (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (0.49 g, 1.87 mmol), the title compound (100 mg) was obtained in the same manner as in Example 1-(3) (colorless solid).
1H NMR (600 MHz, DMSO-d6) δ ppm 0.75 (3 H, d, J=7.0 Hz), 0.77 - 0.91 (10 H, m),
0.98 - 1.09 (2 H, m), 1.32 - 1.52 (7 H, m), 1.60 - 1.66 (2 H, m), 1.82 - 1.88 (1 H, m), 1.94 - 2.00 (2 H, m), 2.08 (1 H, dd, J=8.0, 2.5 Hz), 2.13 (1 H, ddd, J=13.2, 8.0, 5.8 Hz), 2.29 (1 H, dd, J=13.2, 7.4 Hz), 3.28 (1 H, dt, J=9.1, 6.6 Hz), 3.43 (1 H, dt, J=9.1, 6.6 Hz), 3.56 - 3.62 (1 H, m), 4 .46 (1H, td, J=10.8, 4.3Hz), 6.67 (1H, q, J=5.4Hz)
MS m/z : 488[M+H]+

Example 15 Synthesis of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid

(1) 1-chloroethyl (1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate

Ｄ－メントール（５．０ｇ、３１．９９ｍｍｏｌ）、ピリジン（２．６ｍＬ、３１．９９ｍｍｏｌ）のＣＨＣｌ₃溶液（３６ｍＬ）をアセトン‐ドライアイスバスにて－６０℃に
冷却し、カルボノクロリド酸 １－クロロエチル（３．６７ｍＬ、３３．５９ｍｍｏｌ）を１０分間で滴下した。－６０℃にて３０分撹拌後、氷浴にうつし、０℃まで昇温して水を加えた。有機層を分液後、ｂｒｉｎｅで洗浄しＭｇＳＯ₄で乾燥した。不溶物を濾別後
、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｇｒａｃｅ １２ｇ、ｎ‐Ｈｅｘａｎｅ／ＥｔＯＡｃ＝１００／０～９０／１０）にて精製することにより、表題化合物（７．７ｇ）を得た（無色油状物）。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.81 (3 H, dd, J=10.3, 7.0 Hz), 0.85 - 0.95 (7 H, m), 1.03 - 1.13 (2 H, m), 1.39 - 1.54 (2 H, m), 1.66 - 1.74 (2 H, m), 1.84 (3 H, dd, J=5.8, 2.1 Hz), 1.91 - 1.99 (1 H, m), 2.06 - 2.15 (1 H, m), 4.60 (1
H, qd, J=10.7, 4.3 Hz), 6.44 (1 H, qd, J=5.8, 1.7 Hz)

A CHCl ₃ solution (36 mL) of D-menthol (5.0 g, 31.99 mmol) and pyridine (2.6 mL, 31.99 mmol) was cooled to −60° C. in an acetone-dry ice bath, and 1-chloroethyl carbonochloridate (3.67 mL, 33.59 mmol) was added dropwise over 10 minutes. After stirring at -60°C for 30 minutes, the mixture was transferred to an ice bath, heated to 0°C, and water was added. After separating the organic layer, it was washed with brine and dried with MgSO ₄ . After removing the insoluble matter by filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (Grace 12 g, n-Hexane/EtOAc=100/0 to 90/10) to give the title compound (7.7 g) (colorless oil).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.81 (3 H, dd, J=10.3, 7.0 Hz), 0.85 - 0.95 (7 H, m), 1.03 - 1.13 (2 H, m), 1.39 - 1.54 (2 H, m), 1.66 - 1.74 (2 H, m), 1. 84 (3 H, dd, J=5.8, 2.1 Hz), 1.91 - 1.99 (1 H, m), 2.06 - 2.15 (1 H, m), 4.60 (1
H, qd, J=10.7, 4.3 Hz), 6.44 (1 H, qd, J=5.8, 1.7 Hz)

(2) 2-{1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethyl} 6-prop-2-en-1-yl (1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo [3.1.0] Hexane-2,6-dicarboxylate

実施例１３－（２）で得られた化合物（０．５６ｇ、１．４７ｍｍｏｌ）のＤＭＦ溶液（７ｍＬ）に（１）で得られた化合物（０．７７ｇ、２．９４ｍｍｏｌ）およびＫ₂ＣＯ₃（０．３０ｇ、２．２０ｍｍｏｌ）、ＮａＩ（０．４４ｇ、２．９４ｍｍｏｌ）を加え、５０℃にて３時間半撹拌した。反応液を室温まで冷却後、水を加えて分液した。水層からＥｔＯＡｃを用いて抽出後、有機層を合わせて５％ｂｒｉｎｅ、およびｂｒｉｎｅで洗浄した。ＭｇＳＯ₄で乾燥後、不溶物を濾別し減圧下溶媒を留去した。得られた残渣をシリカ
ゲルカラムクロマトグラフィー（Ｇｒａｃｅ １２ｇ、ｎ‐Ｈｅｘａｎｅ／ＥｔＯＡｃ＝１００／０～６０／４０）にて精製し、表題化合物（０．４０ｇ）をジアステレオマー混合物として得た（無色油状物）。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.77 - 0.95 (15 H, m), 1.50 - 1.58 (7 H, m), 1.66 - 1.71 (2 H, m), 1.93 - 2.02 (1 H, m), 2.08 - 2.16 (1 H, m), 2.20 - 2.27
(1 H, m), 2.31 - 2.38 (1 H, m), 2.40 - 2.48 (1 H, m), 2.90 - 3.03 (1 H, m), 3.29 - 3.34 (1 H, m), 3.46 - 3.53 (1 H, m), 3.73 - 3.78 (1 H, m), 4.53 - 4.71 (5 H,
m), 5.20 - 5.35 (5 H, m), 5.87 - 5.95 (2 H, m), 6.81 - 6.94 (1 H, m)

To a DMF solution (7 mL) of the compound (0.56 g, 1.47 mmol) obtained in Example 13-(2) were added the compound (0.77 g, 2.94 mmol) obtained in (1), K ₂ CO ₃ (0.30 g, 2.20 mmol), and NaI (0.44 g, 2.94 mmol), followed by stirring at 50° C. for 3.5 hours. After cooling the reaction solution to room temperature, water was added to separate the layers. After extracting the aqueous layer with EtOAc, the organic layers were combined and washed with 5% brine and brine. After drying with MgSO ₄ , the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (Grace 12 g, n-Hexane/EtOAc=100/0 to 60/40) to give the title compound (0.40 g) as a diastereomer mixture (colorless oil).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.77 - 0.95 (15 H, m), 1.50 - 1.58 (7 H, m), 1.66 - 1.71 (2 H, m), 1.93 - 2.02 (1 H, m), 2.08 - 2.16 (1 H, m), 2.20 - 2.2 7
(1 H, m), 2.31 - 2.38 (1 H, m), 2.40 - 2.48 (1 H, m), 2.90 - 3.03 (1 H, m), 3.29 - 3.34 (1 H, m), 3.46 - 3.53 (1 H, m), 3.73 - 3.78 (1 H, m), 4.53 - 4.71 (5H,
m), 5.20 - 5.35 (5 H, m), 5.87 - 5.95 (2 H, m), 6.81 - 6.94 (1 H, m)

(3) 2-{1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethyl} 6-prop-2-en-1-yl (1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo [3.1.0] Resolution of hexane-2,6-dicarboxylate

実施例１５（２）で得られた化合物をキラルカラムクロマトグラフィー（ＣＨＩＲＡＬＰＡＫ ＩＤ， ｎ‐Ｈｅｘａｎｅ／ＩＰＡ＝７：３）にて分取を行い、１ｓｔ ｐｅａｋ・実施例１５（３）‐Ａ（０．１４ｇ）および２ｎｄ ｐｅａｋ・実施例１５（３）‐Ｂ（０．２０ｇ）を得た（いずれも無色油状物）。
保持時間：実施例15(3)-A;3.22min., 実施例15(3)-B;5.72min.(CHIRAL PAK
ID-3, n‐Hexane/IPA=7:3)

The compound obtained in Example 15 (2) was separated by chiral column chromatography (CHIRALPAK ID, n-Hexane/IPA = 7:3) to obtain 1st peak-Example 15 (3)-A (0.14 g) and 2nd peak-Example 15 (3)-B (0.20 g) (both colorless oils).
Retention time: Example 15 (3)-A; 3.22 min., Example 15 (3)-B; 5.72 min. (CHIRAL PAK
ID-3, n-Hexane/IPA=7:3)

(4) (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({1-[
({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid (Examples 15-A, 15-B)

実施例１５（３）‐Ａ（０．１４ｇ、０．２３ｍｍｏｌ）のＣＨＣｌ₃溶液（２．３ｍＬ
）に１，３－ジメチルバルビツール酸（０．０３６ｇ、０．２３ｍｍｏｌ）およびＰｄ（ＰＰｈ₃）₄（０．００４ｇ、０．００３５ｍｍｏｌ）を加えて室温で２０分間撹拌した。反応液を減圧下濃縮し、得られた残渣にＭｅＣＮ（５ｍＬ）を加えて室温にて１時間半撹拌した。析出した結晶を濾取することにより、表題化合物・実施例１５－Ａ（０．０９０ｇ）を得た（無色固体）。同様にして実施例１５（３）‐Ｂ（０．２０ｇ、０．３３ｍｍｏｌ）から表題化合物・実施例１５－Ｂ（０．１３ｇ）を得た（無色固体）。
実施例１５－Ａ
1H NMR (400 MHz, DMSO-d6) δ ppm 0.74 - 0.91 (13 H, m), 0.95 - 1.12 (2 H, m), 1.33 - 1.51 (7 H, m), 1.60 - 1.68 (2 H, m), 1.79 - 1.90 (1 H, m), 1.94 - 2.05 (2 H, m), 2.06-2.19 (2 H, m), 2.27 - 2.36 (1 H, m),3.29 (1 H, dt, J=9.1, 6.7 Hz), 3.44 (3 H, dt, J=9.1, 6.7 Hz), 3.56 - 3.66 (1 H, m), 4.45 (1 H, td, J=10.9, 4.4 Hz), 6.74 (1 H, q, J=5.4 Hz)
MS m/z : 488[M+H]+
実施例１５－Ｂ
1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (3H, d, J=7.0 Hz),0.76-0.91 (10 H, m), 0.96 - 1.09 (2 H, m), 1.30 - 1.50 (7 H, m), 1.57-1.67 (2 H, m), 1.72 - 1.82 (1 H, m), 1.92 - 1.99 (3 H, m), 2.12-2.23 (1 H, m), 2.28 - 2.40 (1 H, m), 3.30 (1 H, dt, J=9.1, 6.5 Hz), 3.44 (1 H, dt, J=9.1, 6.5 Hz), 3.56 - 3.62 (1 H, m), 4.46 (1 H, td, J=10.9, 4.3 Hz), 6.69 (1 H, q, J=5.5 Hz)
MS m/z : 488[M+H]+

Example 15(3)-A (0.14 g, 0.23 mmol) in _CHCl3 (2.3 mL)
) was added with 1,3-dimethylbarbituric acid (0.036 g, 0.23 mmol) and Pd(PPh ₃ ) ₄ (0.004 g, 0.0035 mmol) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, MeCN (5 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 1.5 hours. By filtering the precipitated crystals, the title compound Example 15-A (0.090 g) was obtained (colorless solid). Similarly, the title compound Example 15-B (0.13 g) was obtained from Example 15(3)-B (0.20 g, 0.33 mmol) (colorless solid).
Example 15-A
1H NMR (400 MHz, DMSO-d6) δ ppm 0.74 - 0.91 (13 H, m), 0.95 - 1.12 (2 H, m), 1.33 - 1.51 (7 H, m), 1.60 - 1.68 (2 H, m), 1.79 - 1.90 (1 H, m), 1.94 - 2.05 (2 H, m), 2.06-2.19 (2 H, m), 2.27 - 2.36 (1 H, m), 3.29 (1 H, dt, J=9.1, 6.7 Hz), 3.44 (3 H, dt, J=9.1, 6.7 Hz), 3.56 - 3.66 (1 H, m), 4.45 (1 H, td) , J=10.9, 4.4 Hz), 6.74 (1 H, q, J=5.4 Hz)
MS m/z : 488[M+H]+
Example 15-B
1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (3H, d, J=7.0 Hz), 0.76-0.91 (10 H, m), 0.96 - 1.09 (2 H, m), 1.30 - 1.50 (7 H, m), 1.57-1.67 (2 H, m), 1.72 - 1.82 ( 1 H, m), 1.92 - 1.99 (3 H, m), 2.12-2.23 (1 H, m), 2.28 - 2.40 (1 H, m), 3.30 (1 H, dt, J=9.1, 6.5 Hz), 3.44 (1 H, dt, J=9.1, 6.5 Hz), 3.56 - 3.62 ( 1 H, m), 4.46 (1 H, td, J = 10.9, 4.3 Hz), 6.69 (1 H, q, J = 5.5 Hz)
MS m/z : 488[M+H]+

Example 16 Synthesis of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

(1) 2-{1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethyl} 6-prop-2-ene-
1-yl (1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

実施例１－（２）で得られた化合物（０．４１ｇ、０．９３ｍｍｏｌ）と実施例１５－（１）で得られた化合物（０．４８ｇ、１．８５ｍｍｏｌ）を原料にして、実施例１５－（２）と同様の手法により、表題化合物（０．４１ｇ）をジアステレオマー混合物として得た（無色油状物）。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.70 - 1.14 (12 H, m), 1.19 - 1.71 (7 H, m), 1.88 - 2.28 (2 H, m), 2.34 - 2.46 (2 H, m), 2.87 - 3.03 (1 H, m), 3.39 - 3.45 (1 H, m), 3.79 - 3.86 (1 H, m), 4.44 - 4.72 (7 H, m),5.00 - 5.10 (1 H, m), 5.20 - 5.36 (4 H, m), 5.85 - 5.95 (2 H, m), 6.84 - 6.95 (1 H, m), 6.99 - 7.06 (2 H,
m), 7.25 - 7.27 (2 H, m)
MS m/z : 700[M+Na]+

Using the compound (0.41 g, 0.93 mmol) obtained in Example 1-(2) and the compound (0.48 g, 1.85 mmol) obtained in Example 15-(1) as starting materials, the title compound (0.41 g) was obtained as a diastereomeric mixture (colorless oil) in the same manner as in Example 15-(2).
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.70 - 1.14 (12 H, m), 1.19 - 1.71 (7 H, m), 1.88 - 2.28 (2 H, m), 2.34 - 2.46 (2 H, m), 2.87 - 3.03 (1 H, m), 3.39 - 3.4 5 (1 H, m), 3.79 - 3.86 (1 H, m), 4.44 - 4.72 (7 H, m), 5.00 - 5.10 (1 H, m), 5.20 - 5.36 (4 H, m), 5.85 - 5.95 (2 H, m), 6.84 - 6.95 (1 H, m), 6.99 - 7 .06 (2H,
m), 7.25 - 7.27 (2H, m)
MS m/z : 700[M+Na]+

(2) 2-{1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethyl} 6-prop-2-en-1-yl (1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[ 3.1.0]Resolution of hexane-2,6-dicarboxylate

実施例１６（１）で得られた化合物をキラルカラムクロマトグラフィー（ＣＨＩＲＡＬＰＡＫ ＩＤ、ｎ‐Ｈｅｘａｎｅ／ＥｔＯＨ＝４：１）にて分取を行い、１ｓｔ ｐｅａｋ・実施例１６（２）‐Ａ（０．１１ｇ）および２ｎｄ ｐｅａｋ・実施例１６（２）‐Ｂ（０．１５ｇ）を得た（いずれも無色油状物）。
保持時間：実施例16(2)-A;2.92min., 実施例16(2)-B;4.30min.(CHIRAL PAK ID-3, n‐Hexane/EtOH=8:2)

The compound obtained in Example 16 (1) was separated by chiral column chromatography (CHIRALPAK ID, n-Hexane/EtOH=4:1) to obtain 1st peak/Example 16 (2)-A (0.11 g) and 2nd peak/Example 16 (2)-B (0.15 g) (both colorless oils).
Retention time: Example 16 (2)-A; 2.92 min., Example 16 (2)-B; 4.30 min. (CHIRAL PAK ID-3, n-Hexane/EtOH=8:2)

(3) (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,5S)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (Examples 16-A, 16-B)

（２）で得られた実施例１６（2）‐Ａ（０．１０ｇ、０．１５ｍｍｏｌ）および実施例
１６（2）‐Ｂ（０．１３ｇ、０．２０ｍｍｏｌ）をそれぞれ原料にして実施例１５－（4）と同様の手法により、表題化合物・実施例１６－Ａ（０．０５８ｇ）および実施例１６－Ｂ（０．０７６ｇ）を得た（いずれも無色固体）。
実施例１６－Ａ
1H NMR (400 MHz, DMSO-d6) δ ppm 0.75 (3 H, d, J= 6.9 Hz), 0.78-1.10 (7 H, m), 1.28 - 1.44 (2 H, m), 1.47 (3 H, d, J=5.5 Hz) 1.58 - 1.67 (2 H, m), 1.78 - 1.90 (2 H, m), 2.00-2.07 (2 H, m), 2.14 (1 H, dd, J=7.8, 2.8 Hz), 2.18-2.26 (1 H,m), 2.32 (1 H, dd, J=13.3, 7.4 Hz), 3.71 - 3.79 (1 H, m), 4.37 - 4.50 (2 H, m), 4.58
(1 H, d, J=12 Hz), 6.75 (1 H, q, J=5.5 Hz), 7.09-7.16 (2 H, m), 7.29-7.36 (2 H,
m)
MS m/z : 554[M+H]+
実施例１６－Ｂ
1H NMR (400 MHz, DMSO-d6) δ ppm 0.72 (3 H, d, J=7.0 Hz), 0.80 - 0.92 (7 H, m), 0.97 - 1.10 (2 H, m), 1.29 - 1.52 (4 H, m), 1.56 - 1.68 (2 H, m), 1.71-1.82 (1 H, m), 1.92 - 2.02 (3 H, m), 2.19 - 2.40 (2 H, m), 3.68 - 3.77 (1 H, m), 4.41 - 4.51 (2 H, m), 4.56 (1 H, d, J=12.0 Hz), 6.70 (1 H, q, J=5.4 Hz), 7.11-7.20 (2 H,
m), 7.27-7.34 (2 H, m)
MS m/z : 554[M+H]+

Using Example 16(2)-A (0.10 g, 0.15 mmol) and Example 16(2)-B (0.13 g, 0.20 mmol) obtained in (2) as starting materials, the title compound Example 16-A (0.058 g) and Example 16-B (0.076 g) were obtained (both colorless solids) in the same manner as in Example 15-(4).
Example 16-A
1H NMR (400 MHz, DMSO-d6) δ ppm 0.75 (3 H, d, J= 6.9 Hz), 0.78-1.10 (7 H, m), 1.28 - 1.44 (2 H, m), 1.47 (3 H, d, J=5.5 Hz) 1.58 - 1.67 (2 H, m), 1.78 - 1. 90 (2 H, m), 2.00-2.07 (2 H, m), 2.14 (1 H, dd, J=7.8, 2.8 Hz), 2.18-2.26 (1 H, m), 2.32 (1 H, dd, J=13.3, 7.4 Hz), 3.71 - 3.79 (1 H, m), 4.37 - 4.50 (2 H, m), 4.58
(1 H, d, J=12 Hz), 6.75 (1 H, q, J=5.5 Hz), 7.09-7.16 (2 H, m), 7.29-7.36 (2 H,
m)
MS m/z : 554[M+H]+
Example 16-B
1H NMR (400 MHz, DMSO-d6) δ ppm 0.72 (3 H, d, J=7.0 Hz), 0.80 - 0.92 (7 H, m), 0.97 - 1.10 (2 H, m), 1.29 - 1.52 (4 H, m), 1.56 - 1.68 (2 H, m), 1.71-1.82 (1 H, m), 1.92 - 2.02 (3 H, m), 2.19 - 2.40 (2 H, m), 3.68 - 3.77 (1 H, m), 4.41 - 4.51 (2 H, m), 4.56 (1 H, d, J=12.0 Hz), 6.70 (1 H, q, J=5.4 Hz), 7.1 1-7.20 (2H,
m), 7.27-7.34 (2H, m)
MS m/z : 554[M+H]+

Example 17 Synthesis of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

（１）１－クロロエチル （１Ｓ，２Ｒ，４Ｓ）－１，７，７－トリメチルビシクロ［２．２．１］ヘプタン－２－イル カルボナート

(1) 1-chloroethyl (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl carbonate

（－）－ボルネオール（５．０ｇ、３２．４１ｍｍｏｌ）を原料にして、実施例１５（１）と同様の手法により、表題化合物（８．２ｇ）を得た（無色油状物）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87 - 0.93 (9 H, m), 1.13 (1 H, ddd, J=13.9, 12.4, 3.5 Hz), 1.23 - 1.38 (2 H, m), 1.69 - 1.88 (5 H, m), 1.89 - 1.99 (1 H,
m), 2.35 - 2.46 (1 H, m), 4.85 - 4.92 (1 H, m), 6.43 (1 H, q, J=5.8 Hz)
MS m/z : 283[M+Na]+

Using (−)-borneol (5.0 g, 32.41 mmol) as a starting material, the title compound (8.2 g) was obtained (colorless oil) in the same manner as in Example 15(1).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87 - 0.93 (9 H, m), 1.13 (1 H, ddd, J=13.9, 12.4, 3.5 Hz), 1.23 - 1.38 (2 H, m), 1.69 - 1.88 (5 H, m), 1.89 - 1.99 (1 H ,
m), 2.35 - 2.46 (1H, m), 4.85 - 4.92 (1H, m), 6.43 (1H, q, J=5.8Hz)
MS m/z: 283[M+Na]+

(2) 6-prop-2-en-1-yl 2-{1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl} (1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl }amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

実施例１－（２）で得られた化合物（０．４０ｇ、０．８９ｍｍｏｌ）と実施例１７－（１）で得られた化合物（０．４６ｇ、１．７７ｍｍｏｌ）を原料にして、実施例１５－（２）と同様の手法により、表題化合物（０．４１ｇ）をジアステレオマー混合物として得た（無色油状物）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.83 - 0.97 (9 H, m), 1.01 - 1.14 (1 H, m), 1.20 - 1.40 (2 H, m), 1.52 (3 H, d, J=5.4 Hz), 1.62 - 1.78 (2 H, m), 1.86 - 1.96 (1 H, m), 2.23 - 2.47 (5 H, m), 2.94 - 3.05 (1 H, m), 3.84 (1 H, td, J=7.8,
4.8 Hz), 4.45 - 4.71 (6 H, m), 4.75 - 4.91 (1 H, m), 5.05 (1 H, s), 5.19 - 5.37
(4 H, m), 5.84 - 5.97 (2 H, m), 6.88 (1 H, q, J=5.5 Hz), 7.04 (2 H, m), 7.26 (2
H, m)

Using the compound (0.40 g, 0.89 mmol) obtained in Example 1-(2) and the compound (0.46 g, 1.77 mmol) obtained in Example 17-(1) as starting materials, the title compound (0.41 g) was obtained as a diastereomeric mixture (colorless oil) in the same manner as in Example 15-(2).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.83 - 0.97 (9 H, m), 1.01 - 1.14 (1 H, m), 1.20 - 1.40 (2 H, m), 1.52 (3 H, d, J=5.4 Hz), 1.62 - 1.78 (2 H, m), 1.86 - 1. 96 (1 H, m), 2.23 - 2.47 (5 H, m), 2.94 - 3.05 (1 H, m), 3.84 (1 H, td, J = 7.8,
4.8 Hz), 4.45 - 4.71 (6 H, m), 4.75 - 4.91 (1 H, m), 5.05 (1 H, s), 5.19 - 5.37
(4 H, m), 5.84 - 5.97 (2 H, m), 6.88 (1 H, q, J=5.5 Hz), 7.04 (2 H, m), 7.26 (2
H, m)

(3) 6-prop-2-en-1-yl 2-{1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl} (1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl }amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate resolution

実施例１７（２）で得られた化合物（０．４１ｇ、０．９３ｍｍｏｌ）をキラルカラムクロマトグラフィー（ＣＨＩＲＡＬＰＡＫ ＩＣ、ｎ‐Ｈｅｘａｎｅ／ＩＰＡ＝６：４）にて分取を行い、１ｓｔ ｐｅａｋ・実施例１７（３）‐Ａ（０．２０ｇ）および２ｎｄ ｐｅａｋ・実施例１７（３）‐Ｂ（０．１５ｇ）を得た（いずれも無色油状物）。
保持時間：実施例17(3)-A;4.57min., 実施例17(3)-B;5.84min.(CHIRAL PAK IC-3, n‐Hexane/IPA=6:4)

The compound (0.41 g, 0.93 mmol) obtained in Example 17 (2) was fractionated by chiral column chromatography (CHIRALPAK IC, n-Hexane/IPA = 6: 4) to obtain 1st peak Example 17 (3)-A (0.20 g) and 2nd peak Example 17 (3)-B (0.15 g) (both colorless oily things).
Retention time: Example 17 (3)-A; 4.57 min., Example 17 (3)-B; 5.84 min. (CHIRAL PAK IC-3, n-Hexane/IPA = 6: 4)

(4) (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (Example 17-A, 1 7-B)

実施例１７（３）で得られた実施例１７（３）‐Ａ（０．１８ｇ、０．２７ｍｍｏｌ）および実施例１７（３）‐Ｂ（０．１３ｇ、０．２０ｍｍｏｌ）をそれぞれ原料にして実施例１５－（４）と同様の手法により、表題化合物・実施例１７－Ａ（０．０９８ｇ）および実施例１７－Ｂ（０．０７２ｇ）を得た（いずれも無色固体）。
実施例１7－Ａ
1H NMR (400 MHz, DMSO-d6) δ ppm 0.78 - 0.86 (9 H, m), 0.97 (1 H, dd, J=13.9, 3.4 Hz), 1.13 - 1.21 (1 H, m), 1.23 - 1.32 (1 H, m), 1.43 (3 H, d, J=5.4 Hz), 1.63
- 1.81 (3 H, m), 1.97 - 2.05 (2 H, m), 2.20 - 2.37 (3 H, m), 3.69 - 3.77 (1 H, m), 4.45 (1 H, d, J=11.6 Hz), 4.55 (1 H, d, J=11.6 Hz), 4.70 - 4.75 (1 H, m), 6.69 (1 H, q, J=5.4 Hz), 7.12 - 7.18 (2 H, m), 7.26-7.32 (2 H,m)
MS m/z : 552[M+H]+
実施例１7－Ｂ
1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (3 H, s), 0.82 (6 H, s), 1.02 (1 H, dd, J=13.8, 3.4 Hz), 1.11 - 1.30 (2 H, m), 1.47 (3 H, d, J=5.5 Hz), 1.62- 1.78 (3 H, m), 1.99-2.07 (1 H,m), 2.10 - 2.34 (4 H, m), 3.69 - 3.76 (1 H, m), 4.46 (1 H, d, J=12.2 Hz), 4.55 (1 H, d, J=12.2 Hz), 4.64 - 4.72 (1 H, m), 6.75 (1 H, q, J=5.5 Hz), 7.08-7.16 (2 H,m), 7.29 - 7.34 (2 H, m)
MS m/z : 552[M+H]+

Example 17 (3)-A (0.18 g, 0.27 mmol) and Example 17 (3)-B (0.13 g, 0.20 mmol) obtained in Example 17 (3) were used as starting materials and the title compound Example 17-A (0.098 g) and Example 17-B (0.072 g) were obtained (both colorless solids) in the same manner as in Example 15-(4).
Example 17-A
1H NMR (400 MHz, DMSO-d6) δ ppm 0.78 - 0.86 (9 H, m), 0.97 (1 H, dd, J=13.9, 3.4 Hz), 1.13 - 1.21 (1 H, m), 1.23 - 1.32 (1 H, m), 1.43 (3 H, d, J=5.4 Hz), 1 .63
- 1.81 (3 H, m), 1.97 - 2.05 (2 H, m), 2.20 - 2.37 (3 H, m), 3.69 - 3.77 (1 H, m), 4.45 (1 H, d, J=11.6 Hz), 4.55 (1 H, d, J=11.6 Hz), 4.70 - 4.75 (1 H, m), 6.69 (1 H, q, J=5.4 Hz), 7.12 - 7.18 (2 H, m), 7.26-7.32 (2 H, m)
MS m/z : 552[M+H]+
Example 17-B
1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (3 H, s), 0.82 (6 H, s), 1.02 (1 H, dd, J=13.8, 3.4 Hz), 1.11 - 1.30 (2 H, m), 1.47 (3 H, d, J=5.5 Hz), 1.62- 1.78 ( 3 H, m), 1.99-2.07 (1 H, m), 2.10 - 2.34 (4 H, m), 3.69 - 3.76 (1 H, m), 4.46 (1 H, d, J=12.2 Hz), 4.55 (1 H, d, J=12.2 Hz), 4.64 - 4.72 (1 H, m), 6.7 5 (1 H, q, J=5.5 Hz), 7.08-7.16 (2 H, m), 7.29 - 7.34 (2 H, m)
MS m/z : 552[M+H]+

Example 18 Synthesis of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxy-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

（１）６－プロパ－２－エン－１－イル ２－｛１－［（｛［（１Ｓ，２Ｒ，４Ｓ）－１，７，７－トリメチルビシクロ［２．２．１］ヘプタン－２－イル］オキシ｝カルボニル）オキシ］エチル｝ （１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－６－フルオロ－２－（｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝アミノ）－３－プロポキシビシクロ［３．１．０］ヘキサン－２，６－ジカルボキシラート

(1) 6-prop-2-en-1-yl 2-{1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl} (1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[ 3.1.0]hexane-2,6-dicarboxylate

実施例１３－（２）で得られた化合物（０．４０ｇ、０．９４ｍｍｏｌ）と実施例１７－（１）で得られた化合物（０．４９ｇ、１．８９ｍｍｏｌ）を原料にして、実施例１５－（２）と同様の手法により、表題化合物（０．４４ｇ）をジアステレオマー混合物として得た（無色油状物）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.84 - 0.91 (12 H, m), 1.07 - 1.14 (1 H, m), 1.23 - 1.35 (2 H, m), 1.49 - 1.59 (6 H, m), 1.67 - 1.79 (2 H, m), 1.89 - 1.97 (1 H, m), 2.22 - 2.48 (4 H, m), 2.96 (1 H, br s), 3.27 - 3.34 (1 H, m), 3.44 -
3.53 (1 H, m), 3.72 - 3.79 (1 H, m), 4.51 - 4.71 (4 H, m), 4.82 - 4.87 (1 H, m), 5.16 - 5.36 (4 H, m), 5.84 - 5.96 (2 H, m), 6.84 - 6.91 (1 H, m)
MS m/z : 632[M+Na]+

Using the compound (0.40 g, 0.94 mmol) obtained in Example 13-(2) and the compound (0.49 g, 1.89 mmol) obtained in Example 17-(1) as starting materials, the title compound (0.44 g) was obtained as a diastereomeric mixture (colorless oil) in the same manner as in Example 15-(2).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.84 - 0.91 (12 H, m), 1.07 - 1.14 (1 H, m), 1.23 - 1.35 (2 H, m), 1.49 - 1.59 (6 H, m), 1.67 - 1.79 (2 H, m), 1.89 - 1.9 7 (1 H, m), 2.22 - 2.48 (4 H, m), 2.96 (1 H, br s), 3.27 - 3.34 (1 H, m), 3.44 -
3.53 (1 H, m), 3.72 - 3.79 (1 H, m), 4.51 - 4.71 (4 H, m), 4.82 - 4.87 (1 H, m), 5.16 - 5.36 (4 H, m), 5.84 - 5.96 (2 H, m), 6.84 - 6.91 (1 H, m)
MS m/z : 632[M+Na]+

(2) 6-prop-2-en-1-yl 2-{1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl} (1R,2R,3R,5R,6R)-6-fluoro-2-({[(
Resolution of prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[3.1.0]hexane-2,6-dicarboxylate

実施例１８（１）で得られた化合物をキラルカラムクロマトグラフィー（ＣＨＩＲＡＬＰＡＫ ＩＣ， ｎ‐Ｈｅｘａｎｅ／ＩＰＡ＝４０：６０）にて分取を行い、１ｓｔ ｐｅａｋ・実施例１８（２）‐Ａ（０．１７ｇ）および２ｎｄ ｐｅａｋ・実施例１８（２）‐Ｂ（０．１２ｇ）を得た（いずれも無色油状物）。
保持時間：実施例18(2)-A;3.42min., 実施例18(2)-B;4.26min.(CHIRAL PAK IC-3, n‐Hexane/IPA=2:3)

The compound obtained in Example 18 (1) was separated by chiral column chromatography (CHIRALPAK IC, n-Hexane/IPA = 40:60) to obtain 1st peak-Example 18 (2)-A (0.17 g) and 2nd peak-Example 18 (2)-B (0.12 g) (both colorless oils).
Retention time: Example 18 (2)-A; 3.42 min., Example 18 (2)-B; 4.26 min. (CHIRAL PAK IC-3, n-Hexane/IPA = 2: 3)

(3) (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxy-2-({1-[({[(1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (Examples 18-A, 18-B)

（２）で得られた実施例１８（２）‐Ａ（０．１６ｇ、０．２７ｍｍｏｌ）および実施例１８（２）‐Ｂ（０．１１ｇ、０．１９ｍｍｏｌ）をそれぞれ原料にして実施例１５－（４）と同様の手法により、表題化合物・実施例１８－Ａ（０．０８９ｇ）および実施例１８－Ｂ（０．０６４ｇ）を得た（いずれも無色固体）。
実施例１８－Ａ
1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 (3 H, s), 0.84 (6H, d, J=3.7 Hz), 0.95 (1
H, dd, J=13.8, 3.5 Hz), 1.10 - 1.19 (1 H, m), 1.22 - 1.31 (1 H, m), 1.47 (3 H, d, J=5.4 Hz), 1.62 - 1.80 (3 H, m), 2.02 - 2.08 (1 H, m), 2.11 - 2.36 (4 H, m), 3.70 - 3.77 (1 H, m), 4.48 (1H, d, J=12.0 Hz), 4.56 (1H, d, J=12.0 Hz), 4.68 - 4.77 (1 H, m), 6.74 (1 H, q, J=5.4 Hz), 7.09 - 7.18 (2 H, m), 7.29-7.36 (2 H,m)
MS m/z : 486[M+H]+
実施例１８－Ｂ
1H NMR (400 MHz, DMSO-d6) δ ppm 0.77 (3 H, s), 0.84 (6 H, d, J=7.8 Hz), 1.03 (1
H, dd, J=13.8, 3.4 Hz), 1.14-1.32 (2 H, m), 1.42 (3 H, d, J=5.3 Hz), 1.65 - 1.79 (3 H, m), 1.96 - 2.05 (2 H, m), 2.20 - 2.38 (3 H, m), 3.69 - 3.78 (1 H, m), 4.45 (1 H, d, J=11.6 Hz), 4.55 (1 H, d, J=11.6 Hz), 4.73 - 4.78 (1 H, m), 6.69 (1 H, q, J=5.3 Hz), 7.11-7.19 (2 H, m), 7.26 - 7.33 (2 H, m)
MS m/z : 486[M+H]+

Example 18 (2)-A (0.16 g, 0.27 mmol) and Example 18 (2)-B (0.11 g, 0.19 mmol) obtained in (2) were used as starting materials, respectively, and the title compound Example 18-A (0.089 g) and Example 18-B (0.064 g) were obtained (both colorless solids) in the same manner as in Example 15-(4).
Example 18-A
1H NMR (400 MHz, DMSO-d6) δ ppm 0.81 (3 H, s), 0.84 (6H, d, J=3.7 Hz), 0.95 (1
H, dd, J=13.8, 3.5 Hz), 1.10 - 1.19 (1 H, m), 1.22 - 1.31 (1 H, m), 1.47 (3 H, d, J=5.4 Hz), 1.62 - 1.80 (3 H, m), 2.02 - 2.08 (1 H, m), 2.11 - 2.36 (4 H, m), 3.70 - 3.77 (1 H, m), 4.48 (1 H, d, J=12.0 Hz), 4.56 (1 H, d, J=12.0 Hz), 4.68 - 4.77 (1 H, m), 6.74 (1 H, q, J=5.4 Hz), 7.09 - 7.18 (2 H, m), 7.29-7.36 (2H,m)
MS m/z : 486[M+H]+
Example 18-B
1H NMR (400 MHz, DMSO-d6) δ ppm 0.77 (3 H, s), 0.84 (6 H, d, J=7.8 Hz), 1.03 (1
H, dd, J=13.8, 3.4 Hz), 1.14-1.32 (2 H, m), 1.42 (3 H, d, J=5.3 Hz), 1.65 - 1.79 (3 H, m), 1.96 - 2.05 (2 H, m), 2.20 - 2.38 (3 H, m), 3.69 - 3.78 ( 1 H, m), 4.45 (1 H, d, J=11.6 Hz), 4.55 (1 H, d, J=11.6 Hz), 4.73 - 4.78 (1 H, m), 6.69 (1 H, q, J=5.3 Hz), 7.11-7.19 (2 H, m), 7.26 - 7.33 (2 H, m)
MS m/z : 486[M+H]+

Example 19 (1R,2R,3R,5R,6R)-2-Amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

(1) 1-chloroethyl (1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl carbonate

（＋）－ボルネオール（２．５ｇ、１６．２１ｍｍｏｌ）を原料にして、実施例１５（１）と同様の手法により、表題化合物（４．２ｇ）を得た（無色油状物）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87 - 0.93 (9 H, m), 1.13 (1 H, ddd, J=16.0, 12.4, 3.5 Hz), 1.23 - 1.38 (2 H, m), 1.69 - 1.83 (2 H, m), 1.83 - 1.88 (3 H,
m), 1.89 - 1.99 (1 H, m), 2.35 - 2.46 (1 H, m), 4.85 - 4.92 (1 H, m), 6.41 - 6.47 (1 H, m)
MS m/z : 283[M+Na]+

Using (+)-borneol (2.5 g, 16.21 mmol) as a raw material, the title compound (4.2 g) was obtained (colorless oil) in the same manner as in Example 15(1).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.87 - 0.93 (9 H, m), 1.13 (1 H, ddd, J=16.0, 12.4, 3.5 Hz), 1.23 - 1.38 (2 H, m), 1.69 - 1.83 (2 H, m), 1.83 - 1.88 (3 H ,
m), 1.89 - 1.99 (1 H, m), 2.35 - 2.46 (1 H, m), 4.85 - 4.92 (1 H, m), 6.41 - 6.47 (1 H, m)
MS m/z: 283[M+Na]+

(2) 6-prop-2-en-1-yl 2-{1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl} (1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl }amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

実施例１－（２）で得られた化合物（０．４０ｇ、０．８９ｍｍｏｌ）と実施例１９－（１）で得られた化合物（０．４６ｇ、１．７７ｍｍｏｌ）を原料にして、実施例１５－（２）と同様の手法により、表題化合物（０．３４ｇ）をジアステレオマー混合物として得た（無色油状物）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.83 - 0.90 (9 H, m), 1.05 - 1.13 (1 H, m), 1.20 - 1.35 (2 H, m), 1.47 - 1.55 (3 H, m), 1.66 - 1.79 (2 H, m), 1.87 - 1.96 (1 H, m), 2.22 - 2.29 (1 H, m), 2.30 - 2.46 (3 H, m), 2.90 - 3.04 (1 H, m), 3.81
- 3.88 (1 H, m), 4.45 - 4.71 (6 H, m), 4.80 - 4.87 (1 H, m), 5.03 - 5.14 (1 H, m), 5.15 - 5.36 (4 H, m), 5.84 - 5.96 (2 H, m), 6.89 (1 H, q, J=5.4 Hz), 7.03 (2
H, m), 7.23 - 7.30 (2 H, m)
MS m/z : 698[M+Na]+

Using the compound (0.40 g, 0.89 mmol) obtained in Example 1-(2) and the compound (0.46 g, 1.77 mmol) obtained in Example 19-(1) as starting materials, the title compound (0.34 g) was obtained as a diastereomeric mixture (colorless oil) in the same manner as in Example 15-(2).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.83 - 0.90 (9 H, m), 1.05 - 1.13 (1 H, m), 1.20 - 1.35 (2 H, m), 1.47 - 1.55 (3 H, m), 1.66 - 1.79 (2 H, m), 1.87 - 1.96 (1 H, m), 2.22 - 2.29 (1 H, m), 2.30 - 2.46 (3 H, m), 2.90 - 3.04 (1 H, m), 3.81
- 3.88 (1 H, m), 4.45 - 4.71 (6 H, m), 4.80 - 4.87 (1 H, m), 5.03 - 5.14 (1 H, m), 5.15 - 5.36 (4 H, m), 5.84 - 5.96 (2 H, m), 6.89 (1 H, q, J=5.4 Hz), 7.03 (2
H, m), 7.23 - 7.30 (2 H, m)
MS m/z : 698[M+Na]+

(3) 6-prop-2-en-1-yl 2-{1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl} (1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl }amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate resolution

実施例１９（２）で得られた化合物（０．３４ｇ、０．５０ｍｍｏｌ）をキラルカラムクロマトグラフィー（ＣＨＩＲＡＬＰＡＫ ＩＤ， ｎ‐Ｈｅｘａｎｅ／ＥｔＯＨ＝８４：１６）にて分取を行い、１ｓｔ ｐｅａｋ・実施例１９（３）‐Ａ（０．０８５ｇ、無色油状物）および２ｎｄ ｐｅａｋを含む成分を得た。２ｎｄ ｐｅａｋを含む成分について、さらにキラルカラムクロマトグラフィー（ＣＨＩＲＡＬＰＡＫ ＡＳ－Ｈ， ｎ‐Ｈｅｘａｎｅ／ＥｔＯＨ＝８０：２０）にて精製を行い、実施例１９（３）‐Ｂ（０．０９８ｇ）を得た（無色油状物）。
保持時間：実施例19(3)-A;3.51min., 実施例19(3)-B;4.25min.(CHIRAL PAK ID-3, n‐Hexane/EtOH=4:1)

The compound (0.34 g, 0.50 mmol) obtained in Example 19 (2) was fractionated by chiral column chromatography (CHIRALPAK ID, n-Hexane/EtOH = 84:16) to obtain a component containing 1st peak Example 19 (3)-A (0.085 g, colorless oil) and 2nd peak. The component containing the 2nd peak was further purified by chiral column chromatography (CHIRALPAK AS-H, n-Hexane/EtOH=80:20) to obtain Example 19(3)-B (0.098 g) (colorless oil).
Retention time: Example 19(3)-A; 3.51 min., Example 19(3)-B; 4.25 min. (CHIRAL PAK ID-3, n-Hexane/EtOH=4:1)

(4) (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (Example 19-A, 1 9-B)

実施例１９（３）で得られた実施例１９（３）‐Ａ（０．０７６ｇ、０．１１ｍｍｏｌ）および実施例１９（３）‐Ｂ（０．０８５ｇ、０．１３ｍｍｏｌ）をそれぞれ原料にして実施例１５－（４）と同様の手法により、表題化合物・実施例１９－Ａ（０．０４４ｇ）および実施例１９－Ｂ（０．０５６ｇ）を得た（いずれも無色固体）。
実施例１９－Ａ
1H NMR (400 MHz, DMSO-d6) δ ppm0.77 - 0.88 (12 H, m), 0.98 (1 H, dd, J=13.9, 3.4 Hz), 1.13 - 1.33 (2 H, m), 1.40 (2 H, sxt, 7.1 Hz), 1.49 (3 H, d, 5.4 Hz), 1.63 - 1.83 (3 H, m), 1.96 - 2.03 (2 H, m),2.15-2.23 (1 H,m), 2.25 - 2.38 (3 H, m), 3.26 - 3.33 (1 H, m), 3.39 - 3.47 (1 H, m), 3.54 - 3.64 (1 H, m), 4.70 - 4.76
(1 H, m), 6.66 - 6.71 (1 H, m)
MS m/z : 552[M+H]+
実施例１９－Ｂ
1H NMR (400 MHz, DMSO-d6) δ ppm 0.76 - 0.90 (12 H, m), 1.04 (1 H, dd, J=13.7, 3.3 Hz), 1.16 - 1.32 (2 H, m), 1.41 (2 H, sxt, J=7.1 Hz), 1.50 (3 H, d, J=5.4 Hz), 1.64 - 1.84 (3 H, m), 1.97 - 2.06 (1 H, m), 2.06 - 2.21 (2 H, m), 2.25 - 2.36 (2 H, m), 3.22 - 3.32 (1 H, m), 3.39 - 3.47 (1 H, m), 3.58 - 3.66 (1 H, m), 4.71
- 4.78 (1 H, m), 6.70 - 6.75 (1 H, m)
MS m/z : 552[M+H]+

Example 19 (3)-A (0.076 g, 0.11 mmol) and Example 19 (3)-B (0.085 g, 0.13 mmol) obtained in Example 19 (3) were used as starting materials and the title compound Example 19-A (0.044 g) and Example 19-B (0.056 g) were obtained (both colorless solids) in the same manner as in Example 15-(4).
Example 19-A
1H NMR (400 MHz, DMSO-d6) δ ppm 0.77 - 0.88 (12 H, m), 0.98 (1 H, dd, J=13.9, 3.4 Hz), 1.13 - 1.33 (2 H, m), 1.40 (2 H, sxt, 7.1 Hz), 1.49 (3 H, d, 5.4 Hz), 1.63 - 1.83 (3 H, m), 1.96 - 2.03 (2 H, m), 2.15 - 2.23 (1 H, m), 2.25 - 2.38 (3 H, m), 3.26 - 3.33 (1 H, m), 3.39 - 3.47 (1 H, m), 3.54 - 3.64 (1 H, m) , 4.70 - 4.76
(1 H, m), 6.66 - 6.71 (1 H, m)
MS m/z : 552[M+H]+
Example 19-B
1H NMR (400 MHz, DMSO-d6) δ ppm 0.76 - 0.90 (12 H, m), 1.04 (1 H, dd, J=13.7, 3.3 Hz), 1.16 - 1.32 (2 H, m), 1.41 (2 H, sxt, J=7.1 Hz), 1.50 (3 H, d, J=5.4 Hz), 1.64 - 1.84 (3 H, m), 1.97 - 2.06 (1 H, m), 2.06 - 2.21 (2 H, m), 2.25 - 2.36 (2 H, m), 3.22 - 3.32 (1 H, m), 3.39 - 3.47 (1 H, m), 3.58 - 3.66 ( 1H, m), 4.71
- 4.78 (1 H, m), 6.70 - 6.75 (1 H, m)
MS m/z : 552[M+H]+

Example 20 Synthesis of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxy-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

(1) 6-prop-2-en-1-yl 2-{1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl} (1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[ 3.1.0]hexane-2,6-dicarboxylate

実施例１３－（２）で得られた化合物（０．４０ｇ、０．９４ｍｍｏｌ）と実施例１９－（１）で得られた化合物（０．４９ｇ、１．８９ｍｍｏｌ）を原料にして、実施例１５－（２）と同様の手法により、表題化合物（０．２４ｇ）をジアステレオマー混合物として得た（無色アモルファス）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.84 - 0.92 (12 H, m), 1.03 - 1.13 (1 H, m), 1.22 - 1.35 (2 H, m), 1.47 - 1.57 (6 H, m), 1.67 - 1.79 (2 H, m), 1.90 - 1.97
(1 H, m), 2.21 - 2.48 (4 H, m), 2.91 - 3.01 (1 H, m), 3.27 - 3.33 (1 H, m), 3.47 - 3.53 (1 H, m), 3.72 - 3.78 (1 H, m), 4.50 - 4.71 (4 H, m), 4.83 - 4.88 (1 H,
m), 5.17 - 5.36 (4 H, m), 5.84 - 5.96 (2 H, m), 6.87 (1 H, q, J=5.3 Hz)
MS m/z : 610[M+H]+

Using the compound (0.40 g, 0.94 mmol) obtained in Example 13-(2) and the compound (0.49 g, 1.89 mmol) obtained in Example 19-(1) as starting materials, the title compound (0.24 g) was obtained as a diastereomer mixture (colorless amorphous) in the same manner as in Example 15-(2).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.84 - 0.92 (12 H, m), 1.03 - 1.13 (1 H, m), 1.22 - 1.35 (2 H, m), 1.47 - 1.57 (6 H, m), 1.67 - 1.79 (2 H, m), 1.90 - 1.9 7
(1 H, m), 2.21 - 2.48 (4 H, m), 2.91 - 3.01 (1 H, m), 3.27 - 3.33 (1 H, m), 3.47 - 3.53 (1 H, m), 3.72 - 3.78 (1 H, m), 4.50 - 4.71 (4 H, m), 4.83 - 4.88 (1H,
m), 5.17 - 5.36 (4H, m), 5.84 - 5.96 (2H, m), 6.87 (1H, q, J=5.3Hz)
MS m/z : 610[M+H]+

(2) 6-prop-2-en-1-yl 2-{1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl} (1R,2R,3R,5R,6R)-6-fluoro-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)-3-propoxybicyclo[ 3.1.0]Resolution of hexane-2,6-dicarboxylate

実施例２０（１）で得られた化合物（０．２４ｇ、０．４０ｍｍｏｌ）をキラルカラムクロマトグラフィー（ＣＨＩＲＡＬＰＡＫ ＩＤ， ｎ‐Ｈｅｘａｎｅ／ＥｔＯＨ＝８５：１５）にて分取を行い、１ｓｔ ｐｅａｋ・実施例２０（２）‐Ａ（０．０５６ｇ、無色油状物）および２ｎｄ ｐｅａｋ・実施例２０（２）‐Ｂ（０．１０ｇ、無色アモルファス）を得た。
保持時間：実施例20(2)-A;3.83min., 実施例20(2)-B;4.47min. (CHIRAL PAK ID-3, n‐Hexane/IPA=85:15)

The compound (0.24 g, 0.40 mmol) obtained in Example 20 (1) was fractionated by chiral column chromatography (CHIRALPAK ID, n-Hexane/EtOH = 85:15), and 1st peak Example 20 (2)-A (0.056 g, colorless oil) and 2nd peak Example 20 (2)-B (0.10 g, colorless amorphous).
Retention time: Example 20(2)-A; 3.83 min., Example 20(2)-B; 4.47 min. (CHIRAL PAK ID-3, n-Hexane/IPA=85:15)

(3) (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-propoxy-2-({1-[({[(1R,2S,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (Example 20)

（２）で得られた実施例２０（２）－A（０．０５６ｇ、０．０９２ｍｍｏｌ）を原料に
して実施例１５－（４）と同様の手法により、表題化合物・実施例２０（０．０１９ｇ）を得た（無色固体）。
1H NMR (400 MHz, DMSO-d6) δ ppm 0.77 - 0.89 (12 H, m), 1.00 (1 H, dd, J=13.9, 3.3 Hz), 1.13 - 1.23 (1 H, m), 1.24 - 1.33 (1 H, m), 1.36 - 1.47 (2 H, m), 1.50 (3 H, d, J=5.5 Hz), 1.66 - 1.83 (3 H, m), 1.97 - 2.22 (3 H, m), 2.26 - 2.36 (2 H,
m), 3.24 - 3.32 (1 H, m), 3.40 - 3.46 (1 H, m), 3.56 - 3.63 (1 H, m), 4.74 (1 H, m, J=9.6, 2.3 Hz), 6.72 (1 H, q, J=5.3 Hz)
MS m/z : 486[M+H]+

Example 20 (2)-A (0.056 g, 0.092 mmol) obtained in (2) was used as a starting material in the same manner as in Example 15-(4) to obtain the title compound Example 20 (0.019 g) (colorless solid).
1H NMR (400 MHz, DMSO-d6) δ ppm 0.77 - 0.89 (12 H, m), 1.00 (1 H, dd, J=13.9, 3.3 Hz), 1.13 - 1.23 (1 H, m), 1.24 - 1.33 (1 H, m), 1.36 - 1.47 (2 H, m), 1. 50 (3H, d, J=5.5Hz), 1.66 - 1.83 (3H, m), 1.97 - 2.22 (3H, m), 2.26 - 2.36 (2H,
m), 3.24 - 3.32 (1 H, m), 3.40 - 3.46 (1 H, m), 3.56 - 3.63 (1 H, m), 4.74 (1 H, m, J=9.6, 2.3 Hz), 6.72 (1 H, q, J=5.3 Hz)
MS m/z : 486[M+H]+

Example 21 Synthesis of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

(1) 1-chloroethyl (1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl carbonate

（＋）－フェンコール（５．０ｇ、３２．４１ｍｍｏｌ）を原料にして、実施例１５（１）と同様の手法により、表題化合物（６．２ｇ）を得た（無色油状物）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.86 (3 H, d, J=7.8 Hz), 1.10 - 1.17 (7 H,
m), 1.22 (1 H, dd, J=10.4, 1.5 Hz), 1.42 - 1.54 (1 H, m), 1.56 - 1.62 (1 H, m),
1.67 - 1.81 (3 H, m), 1.85 (3 H, d, J=5.7 Hz), 4.25 - 4.34 (1 H, m), 6.41 - 6.47 (1 H, m)
MS m/z : 283[M+Na]+

Using (+)-fenchol (5.0 g, 32.41 mmol) as a starting material, the title compound (6.2 g) was obtained (colorless oil) in the same manner as in Example 15(1).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.86 (3 H, d, J=7.8 Hz), 1.10 - 1.17 (7 H,
m), 1.22 (1 H, dd, J=10.4, 1.5 Hz), 1.42 - 1.54 (1 H, m), 1.56 - 1.62 (1 H, m),
1.67 - 1.81 (3 H, m), 1.85 (3 H, d, J=5.7 Hz), 4.25 - 4.34 (1 H, m), 6.41 - 6.47 (1 H, m)
MS m/z: 283[M+Na]+

(2) 6-prop-2-en-1-yl 2-{1-[({[(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl} (1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl }amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate

実施例１－（２）で得られた化合物のカリウム塩（０．４０ｇ、０．８１ｍｍｏｌ）と実施例２１－（１）で得られた化合物（０．４２ｇ、１．６３ｍｍｏｌ）を原料にして、実施例１５－（２）と同様の手法により、表題化合物（０．２９ｇ）をジアステレオマー混合物として得た（無色アモルファス）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.79 - 0.90 (3 H, m), 1.00 - 1.12 (7 H, m), 1.15 - 1.22 (1 H, m), 1.41 - 1.58 (5 H, m), 1.62 - 1.77 (3 H, m), 2.20 - 2.28 (1 H, m), 2.36 - 2.45 (2 H, m), 2.96 (1 H, br s), 3.79 - 3.85 (1 H, m), 4.20 - 4.26 (1 H, m), 4.44 - 4.71 (6 H, m), 5.04 (1 H, br s), 5.19 - 5.36 (4 H, m), 5.85
- 5.95 (2 H, m), 6.80 - 6.93 (1 H, m), 7.02 (2 H, t, J=8.7 Hz), 7.25 - 7.28 (2 H, m)
MS m/z : 676[M+H]+

Using the potassium salt (0.40 g, 0.81 mmol) of the compound obtained in Example 1-(2) and the compound (0.42 g, 1.63 mmol) obtained in Example 21-(1) as starting materials, the title compound (0.29 g) was obtained as a diastereomeric mixture (colorless amorphous) in the same manner as in Example 15-(2).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.79 - 0.90 (3 H, m), 1.00 - 1.12 (7 H, m), 1.15 - 1.22 (1 H, m), 1.41 - 1.58 (5 H, m), 1.62 - 1.77 (3 H, m), 2.20 - 2.28 (1 H, m), 2.36 - 2.45 (2 H, m), 2.96 (1 H, br s), 3.79 - 3.85 (1 H, m), 4.20 - 4.26 (1 H, m), 4.44 - 4.71 (6 H, m), 5.04 (1 H, br s), 5.19 - 5.36 (4 H , m), 5.85
- 5.95 (2 H, m), 6.80 - 6.93 (1 H, m), 7.02 (2 H, t, J=8.7 Hz), 7.25 - 7.28 (2 H, m)
MS m/z : 676[M+H]+

(3) 6-prop-2-en-1-yl 2-{1-[({[(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethyl} (1R,2R,3R,5R,6R)-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl }amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate resolution

実施例２１（２）で得られた化合物（０．１９ｇ、０．２８ｍｍｏｌ）をキラルカラムクロマトグラフィー（ＣＨＩＲＡＬＰＡＫ ＩＤ， ｎ‐Ｈｅｘａｎｅ／ＥｔＯＨ＝８５：１５）にて分取を行い、１ｓｔ ｐｅａｋ・実施例２１（３）‐Ａ（０．０６１ｇ）および２ｎｄ ｐｅａｋ・実施例２１（３）‐Ｂ（０．０４２ｇ）を得た（いずれも無色油状物）。
保持時間：実施例21(3)-A;3.43min., 実施例21(3)-B;4.60min.(CHIRAL PAK ID-3, n‐Hexane/EtOH=85:15)

The compound (0.19 g, 0.28 mmol) obtained in Example 21 (2) was fractionated by chiral column chromatography (CHIRALPAK ID, n-Hexane/EtOH=85:15) to obtain 1st peak Example 21 (3)-A (0.061 g) and 2nd peak Example 21 (3)-B (0.042 g) ( Both are colorless oils).
Retention time: Example 21 (3)-A; 3.43 min., Example 21 (3)-B; 4.60 min. (CHIRAL PAK ID-3, n-Hexane/EtOH=85:15)

(4) (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({1-[({[(1R,2R,4S)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (Example 21)

実施例２１（３）で得られた実施例２１（３）‐Ｂ（０．０４２ｇ、０．０６３ｍｍｏｌ）を原料にして、実施例１５－（４）と同様の手法により表題化合物・実施例２１（０．０２４ｇ）を得た（無色固体）。
1H NMR (400 MHz, DMSO-d6) δ ppm 0.77 (3 H, s), 0.97 - 1.21 (8 H, m), 1.37 - 1.48 (4 H, m), 1.52 - 1.66 (4 H, m), 1.70 (1 H, br d, J=3.3 Hz), 1.91 - 2.05 (3 H, m), 2.17 - 2.37 (2 H, m), 3.72 (1 H, m), 4.18 (1 H, d, J=1.6 Hz), 4.45 (1 H, d, J=11.6 Hz), 4.55 (1 H, d, J=11.9 Hz), 6.69 (1 H, q, J=5.5 Hz), 7.12 - 7.19 (2 H,
m), 7.26 - 7.32 (2 H, m)
MS m/z : 552[M+H]+

Example 21 (3)-B (0.042 g, 0.063 mmol) obtained in Example 21 (3) was used as a starting material, and the title compound Example 21 (0.024 g) was obtained in the same manner as in Example 15-(4) (colorless solid).
1H NMR (400 MHz, DMSO-d6) δ ppm 0.77 (3 H, s), 0.97 - 1.21 (8 H, m), 1.37 - 1.48 (4 H, m), 1.52 - 1.66 (4 H, m), 1.70 (1 H, br d, J=3.3 Hz), 1.91 - 2.05 (3 H, m), 2.17 - 2.37 (2 H, m), 3.72 (1 H, m), 4.18 (1 H, d, J=1.6 Hz), 4.45 (1 H, d, J=11.6 Hz), 4.55 (1 H, d, J=11.9 Hz), 6.69 (1 H, q, J=5.5 Hz), 7.12 - 7.19 (2H,
m), 7.26 - 7.32 (2H, m)
MS m/z : 552[M+H]+

Production of active forms (II)-4 to (II)-14

ＷＯ０３／０６１６９８またはＷＯ２０１１／０６１９３５記載の製造法に準じた手法で合成した活性体化合物（化合物番号（ＩＩ）－４～（ＩＩ）－１３）、及び実施例３８記載の製造法に準じた手法で合成した活性体化合物（化合物番号（ＩＩ）－１４）の構造式、化合物名及び機器データ（１H NMRおよび検出されたMSスペクトルデータ）を表Ａに示す。

Table A shows the structural formulas, compound names, and instrumental data (1H NMR and detected MS spectrum data) of the active compound (Compound Nos. (II)-4 to (II)-13) synthesized according to the production method described in WO03/061698 or WO2011/061935 and the active compound (Compound No. (II)-14) synthesized according to the production method described in Example 38.

The structural formulas, compound names and instrumental data (1H NMR and detected MS spectral data) of the compounds synthesized in the same manner as in Example 4 using the corresponding active forms described in [Table A] as starting materials are shown in Table B (Example Nos. 22 to 30).

Table C shows the structural formulas, compound names and instrumental data (1H NMR and detected MS spectral data) of the compounds synthesized in the same manner as in Example 1 using the corresponding active forms described in [Table A] as starting materials (Example Nos. 31 to 34).

Structural formulas of compounds synthesized by the same method as in Example 1, compound names and instrument data (1H
NMR and detected MS spectral data) are shown in Table D (Example Nos. 35-37). However, in the step corresponding to Example 1-(2), instead of (1R)-1-chloroethyl (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate, known compounds chloromethyl cyclohexanecarboxylate, chloromethyl benzoate, or chloromethyl 2,2-dimethylpropanoate were used. (1R,2R,3R,5R,6R)-2-amino-2-({(1S)-1-[(2,2-dimethylpropanoyl)oxy]ethoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic acid, (1R,2R,3R,5R,6R)-2-amino-2-{[(1S)-1-(benzoyloxy)ethyl Toxy]carbonyl}-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic acid and (1R,2R,3R,5R,6R)-2-amino-2-({(1S)-1-[(cyclohexanecarbonyl)oxy]ethoxy}carbonyl)-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylic acid can be similarly synthesized.

Example 38 Synthesis of (1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

(1) Synthesis of diethyl chloro[(1R)-3-oxocyclopentyl]propanedioate

水素化アルミニウムリチウム（２３０ｍｇ、６．０６１ｍｍｏｌ）のＴＨＦ溶液（２０ｍＬ）に、１～４℃で（Ｒ）－（＋）－１，１－ビ－２－ナフトール（３．７２ｇ、１３．０ｍｍｏｌ）のＴＨＦ溶液（２５ｍＬ）を加えた。室温で５０分間撹拌した後、モレキュラーシーブス４Ａ（１０．００ｇ）、炭酸ナトリウム（２８０ｍｇ、２．６４２ｍｍｏｌ）、及びジエチル ２－クロロプロパンジオアート（１３０．３５ｇ、６１２ｍｍｏｌ）を加えた。４０℃で３０分間撹拌した後、シクロペンタ－２－エン－１－オン（６０．００ｇ、７３０．８ｍｍｏｌ）を滴下し、４０℃で４時間撹拌した。室温で不溶物を濾別後、ろ液を減圧下濃縮し、表題化合物を含む混合物（２０２．３９ｇ）を得た（褐色オイル
）。表題化合物を含む混合物は、精製することなく次の反応に用いた。キラルカラムクロマトグラフィーによる分析により、光学純度は９０．８５％ｅｅであった。保持時間：（Ｒ）体；６．５８ ｍｉｎ、（Ｓ）体；１５．３８ ｍｉｎ（CHIRAL PAK ＡＹ－３, 流
速；１.０ｍL／ｍｉｎ、nHexane／EtOH=９０／１０)
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24 - 1.37 (6 H, m), 1.88 - 2.07 (1 H, m), 2.12 - 2.30 (2 H, m), 2.32 - 2.46 (2H, m), 2.47 - 2.58 (1 H, m), 3.16 - 3.32 (1 H, m), 4.22 - 4.40 (4 H, m)
MS m/z : 277 [M+H]+

To a THF solution (20 mL) of lithium aluminum hydride (230 mg, 6.061 mmol) was added a THF solution (25 mL) of (R)-(+)-1,1-bi-2-naphthol (3.72 g, 13.0 mmol) at 1-4°C. After stirring for 50 minutes at room temperature, molecular sieves 4A (10.00 g), sodium carbonate (280 mg, 2.642 mmol) and diethyl 2-chloropropanedioate (130.35 g, 612 mmol) were added. After stirring at 40°C for 30 minutes, cyclopent-2-en-1-one (60.00g, 730.8mmol) was added dropwise and stirred at 40°C for 4 hours. After filtering off the insoluble matter at room temperature, the filtrate was concentrated under reduced pressure to obtain a mixture (202.39 g) containing the title compound (brown oil). The mixture containing the title compound was used for the next reaction without purification. An analysis by chiral column chromatography gave an optical purity of 90.85% ee. Retention time: (R) body; 6.58 min, (S) body; 15.38 min (CHIRAL PAK AY-3, flow rate; 1.0 mL / min, nHexane / EtOH = 90/10)
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24 - 1.37 (6 H, m), 1.88 - 2.07 (1 H, m), 2.12 - 2.30 (2 H, m), 2.32 - 2.46 (2H, m), 2.47 - 2.58 (1 H, m), 3.16 - 3.32 (1 H, m), 4.22 - 4.40 (4 H, m)
MS m/z : 277 [M+H]+

(2) Synthesis of ethyl (1S,5R,6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate

実施例３８（１）で得られた化合物（２０２．３９ｇ、６１２ｍｍｏｌ）のＮ－メチル－２－ピロリジノン（６３０ｇ）溶液に７～１２℃で塩化リチウム（５１．８９ｇ，１．２２４ｍｏｌ）、酢酸（３６．７５ｇ，６１２ｍｍｏｌ）を加えた後、１２５℃で４時間撹拌した。反応液を室温に冷却してトルエン及び１０％食塩水を加えた後、分液し、有機層を１０％食塩水にて２回洗浄した。無水硫酸ナトリウムにて乾燥後ろ別した。減圧下溶媒を留去した後、ＩＰＡにより２回共沸した。ＩＰＡ（３０ｍＬ）を加え、５０℃に加熱した。混合溶液の加熱を止めた後、ｎ－ヘプタン（３０ｍＬ）を加え、撹拌しながら氷冷し、析出した固体をろ取した。固体を、氷冷したＩＰＡとｎ－ヘプタンの混合溶媒（１/１
、４５ｍＬ）で洗浄後、窒素を用いて通気乾燥することにより、表題化合物（５３．８７ｇ）を単一エナンチオマーとして得た（淡茶色固体）。キラルカラムクロマトグラフィーによる分析により、光学純度は＞９９％ｅｅであった。スペクトルデータは文献記載の方法で得られる化合物と同一であることを確認した（Ｊ．Ｍｅｄ．Ｃｈｅｍ．，２０００，４３，４８９３－４９０９ 参照）。保持時間：（１Ｓ，５Ｒ，６Ｓ）体；８．５２ ｍｉｎ、（１Ｒ，５Ｓ，６Ｒ）体；９．８７ ｍｉｎ（CHIRAL PAK ＡＹ－３, 流速；１.０ｍL／ｍｉｎ、n‐Hexane／EtOH=９０／１０)。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (3 H, t, J=7.1 Hz), 1.99 - 2.18 (4 H,
m), 2.19 - 2.26 (1 H, m), 2.27 - 2.31 (1 H, m), 2.49 - 2.54 (1 H, m), 4.16 (2 H, q, J=7.1 Hz)
MS m/z :169[M+H]+

A solution of the compound (202.39 g, 612 mmol) obtained in Example 38 (1) in N-methyl-2-pyrrolidinone (630 g) was added with lithium chloride (51.89 g, 1.224 mol) and acetic acid (36.75 g, 612 mmol) at 7 to 12°C, followed by stirring at 125°C for 4 hours. After cooling the reaction solution to room temperature and adding toluene and 10% saline, the mixture was separated and the organic layer was washed twice with 10% saline. After drying with anhydrous sodium sulfate, it was separated. After distilling off the solvent under reduced pressure, the residue was azeotropically distilled twice with IPA. IPA (30 mL) was added and heated to 50°C. After stopping the heating of the mixed solution, n-heptane (30 mL) was added, the mixture was ice-cooled with stirring, and the precipitated solid was collected by filtration. The solid was added to an ice-cooled mixed solvent of IPA and n-heptane (1/1
, 45 mL) and bubbling dry with nitrogen to give the title compound (53.87 g) as a single enantiomer (pale brown solid). The optical purity was >99% ee as analyzed by chiral column chromatography. It was confirmed that the spectral data are the same as the compound obtained by the method described in the literature (see J. Med. Chem., 2000, 43, 4893-4909). Retention time: (1S,5R,6S) form; 8.52 min, (1R,5S,6R) form; 9.87 min (CHIRAL PAK AY-3, flow rate; 1.0 mL/min, n-Hexane/EtOH=90/10).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (3 H, t, J=7.1 Hz), 1.99 - 2.18 (4 H,
m), 2.19 - 2.26 (1 H, m), 2.27 - 2.31 (1 H, m), 2.49 - 2.54 (1 H, m), 4.16 (2 H, q, J=7.1 Hz)
MS m/z:169[M+H]+

(3) Synthesis of ethyl (1S,5R,6S)-2-[(trimethylsilyl)oxy]bicyclo[3.1.0]hex-2-ene-6-carboxylate

実施例３８（２）で得られたエチル （１Ｓ，５Ｒ，６Ｓ）－２－オキソビシクロ［３．１．０］ヘキサン－６－カルボキシラート (５．０ ｇ、２９．７３ ｍｍｏｌ)のトル
エン（２３．１ ｍＬ）溶液に氷冷下トリエチルアミン（６．２２ ｍＬ、４４．５９ ｍｍｏｌ）およびトリメチルシリルトリフラート （７．９３ ｇ、３５．６７ ｍｍｏ
ｌ)を順次滴下し、１時間撹拌した。水（６０ ｍＬ）を加え３０分間撹拌した。有機層、水層を分層後、得られた有機層を飽和炭酸水素ナトリウム水溶液（２０ ｍＬ）、飽和食
塩水（２０ ｍＬ）にて順次洗浄した。無水硫酸ナトリウムにて乾燥後ろ過した。濾液を減圧下濃縮し、表題化合物（９．９１ ｇ、２８．７ ｍｍｏｌ)を得た。これ以上の精
製操作は行わずそのまま次反応へ用いた。
¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.22 (9 H, s), 1.21 - 1.27 (3 H, m), 2.08 - 2.19 (1 H, m), 2.20 - 2.28 (1 H, m), 2.28 - 2.41 (2 H, m), 2.52 - 2.66 (1 H, m), 4.11 (2 H, q, J = 7.2 Hz), 4.30 - 4.39 (1 H, m)

To a toluene (23.1 mL) solution of ethyl (1S,5R,6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate (5.0 g, 29.73 mmol) obtained in Example 38 (2) was added triethylamine (6.22 mL, 44.59 mmol) and trimethylsilyltriflate (7.93 g, 35.67 mmol) under ice cooling.
l) was added dropwise and stirred for 1 hour. Water (60 mL) was added and stirred for 30 minutes. After separating the organic layer and the aqueous layer, the obtained organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (20 mL) and saturated brine (20 mL) in that order. After drying with anhydrous sodium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (9.91 g, 28.7 mmol). The product was directly used in the next reaction without further purification.
¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.22 (9 H, s), 1.21 - 1.27 (3 H, m), 2.08 - 2.19 (1 H, m), 2.20 - 2.28 (1 H, m), 2.28 - 2.41 (2 H, m), 2.52 - 2.66 (1 H, m ), 4.11 (2 H, q, J = 7.2 Hz), 4.30 - 4.39 (1 H, m)

(4) Synthesis of ethyl (1S,3R,5R,6S)-3-hydroxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate

氷水で冷却したメチルトリオキソレニウム(ＶＩＩ) (３５．８ ｍｇ、 ０．１４４ ｍｍ
ｏｌ)のアセトニトリル（２８．７ ｍＬ）懸濁液に、酢酸（１７３ ｍｇ、２．８７ ｍｍｏｌ）、ピリジン（６８．２ ｍｇ、０．８６ ｍｍｏｌ）、３０％過酸化水素水（４．９９ ｍＬ、４８．９ ｍｍｏｌ）を順次滴下した。実施例３８（３）で得られたエチル
（１Ｓ，５Ｒ，６Ｓ）－２－［（トリメチルシリル）オキシ］ビシクロ［３．１．０］ヘキサ－２－エン－６－カルボキシラート（６．９１ ｇ、２８．７ ｍｍｏｌ）のアセトニトリル（５．０ ｍＬ）溶液を滴下した。室温にて１時間撹拌した。メチルトリオキソ
レニウム(ＶＩＩ) （１７．９ ｍｇ、０．０７１９ｍｍｏｌ）を加え室温にて１時間撹拌した。氷水下、炭酸ナトリウム (６０９ ｍｇ、５．７５ ｍｍｏｌ)の水溶液 (５．０
ｍＬ)、チオ硫酸ナトリウム五水和物 （１２．５ ｇ、５０．３ ｍｍｏｌ）の水溶液（５０ ｍＬ）を順次加え、１０分間撹拌した。酢酸エチル（１００ ｍＬ）にて２回抽出した。得られた有機層に無水硫酸ナトリウムを加えて室温で１４時間静置した。濾過後減圧下濃縮した。残渣にイソプロピルエ－テル（５０ ｍＬ）を加えて撹拌し、析出した固体を濾取した。表題化合物を（３．２６ ｇ）得た（無色固体）。
1H NMR (400 MHz, CHLOROFORM-d) δppm 1.22 - 1.33 (3 H, m), 1.94 - 2.11 (1 H, m),
2.20 - 2.27 (1 H, m), 2.33 - 2.39 (1 H, m), 2.48 - 2.56 (1 H, m), 2.61 - 2.69 (1 H, m), 3.90 - 4.02 (1 H, m), 4.12 - 4.22 (３ H, m)
MS m/z :185[M+H]+

Methyltrioxorhenium (VII) (35.8 mg, 0.144 mm) cooled with ice water
ol) in acetonitrile (28.7 mL), acetic acid (173 mg, 2.87 mmol), pyridine (68.2 mg, 0.86 mmol), and 30% hydrogen peroxide (4.99 mL, 48.9 mmol) were added dropwise in that order. A solution of ethyl (1S,5R,6S)-2-[(trimethylsilyl)oxy]bicyclo[3.1.0]hex-2-ene-6-carboxylate (6.91 g, 28.7 mmol) obtained in Example 38(3) in acetonitrile (5.0 mL) was added dropwise. Stir at room temperature for 1 hour. Methyltrioxorhenium (VII) (17.9 mg, 0.0719 mmol) was added and stirred at room temperature for 1 hour. Under ice water, an aqueous solution (5.0) of sodium carbonate (609 mg, 5.75 mmol)
mL) and an aqueous solution (50 mL) of sodium thiosulfate pentahydrate (12.5 g, 50.3 mmol) were sequentially added and stirred for 10 minutes. Extracted twice with ethyl acetate (100 mL). Anhydrous sodium sulfate was added to the obtained organic layer, and the mixture was allowed to stand at room temperature for 14 hours. After filtration, it was concentrated under reduced pressure. Isopropyl ether (50 mL) was added to the residue and the mixture was stirred, and the precipitated solid was collected by filtration. The title compound was obtained (3.26 g) (colorless solid).
1H NMR (400 MHz, CHLOROFORM-d) δppm 1.22 - 1.33 (3H, m), 1.94 - 2.11 (1H, m),
2.20 - 2.27 (1 H, m), 2.33 - 2.39 (1 H, m), 2.48 - 2.56 (1 H, m), 2.61 - 2.69 (1 H, m), 3.90 - 4.02 (1 H, m), 4.12 - 4.22 (3 H, m)
MS m/z:185[M+H]+

(5) Synthesis of ethyl (1S,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-oxobicyclo[3.1.0]hexane-6-carboxylate

実施例３８（４）で得られたエチル （１Ｓ，３Ｒ，５Ｒ，６Ｓ）－３－ヒドロキシ－２－オキソビシクロ［３．１．０］ヘキサン－６－カルボキシラート （０．５３ ｇ、２
．８８ ｍｍｏｌ）及び（４－フルオロフェニル）メチル ２，２，２－トリクロロエタンイミデート（１．２５ ｇ、４．６０ ｍｍｏｌ）のテトラヒドロピラン（３．０ ｍＬ）溶液に氷冷下、トリフルオロメタンスルホン酸（０．０６５ ｍＬ、０．５７５ ｍｍｏｌ）を滴下し、１時間撹拌した。反応液に水を加え、酢酸エチルにて抽出した後、飽和食塩水にて洗浄した。得られた有機層を無水硫酸ナトリウムにて乾燥し、濾過した。濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ ＳＮＡＰ Ｕｌｔｒａ ５０ ｇ, ヘキサン：酢酸エチル＝１００:０ ～ ３５：６５
）にて精製した。表題化合物を（０．５９ ｇ）を得た（無色油状物）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23 - 1.29 (3 H, m), 2.06 - 2.20 (2 H, m), 2.24 - 2.35 (1 H, m), 2.40 - 2.53 (2 H, m), 3.76 (1 H, t, J=8.3 Hz), 4.08 - 4.18 (2 H, m), 4.56 (1 H, d, J=11.6 Hz), 4.83 (1 H, d, J=11.7 Hz), 6.97 - 7.06 (2 H, m), 7.31 (2 H, t, J=6.1 Hz)
MS m/z :315 [M+Na]+

Ethyl (1S,3R,5R,6S)-3-hydroxy-2-oxobicyclo[3.1.0]hexane-6-carboxylate (0.53 g, 2
. 88 mmol) and (4-fluorophenyl)methyl 2,2,2-trichloroethaneimidate (1.25 g, 4.60 mmol) in tetrahydropyran (3.0 mL) under ice cooling, trifluoromethanesulfonic acid (0.065 mL, 0.575 mmol) was added dropwise and stirred for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and washed with saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (Biotage SNAP Ultra 50 g, hexane:ethyl acetate=100:0 to 35:65).
) for purification. The title compound was obtained (0.59 g) (colorless oil).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23 - 1.29 (3 H, m), 2.06 - 2.20 (2 H, m), 2.24 - 2.35 (1 H, m), 2.40 - 2.53 (2 H, m), 3.76 (1 H, t, J=8.3 Hz), 4.08 - 4. 18 (2 H, m), 4.56 (1 H, d, J=11.6 Hz), 4.83 (1 H, d, J=11.7 Hz), 6.97 - 7.06 (2 H, m), 7.31 (2 H, t, J=6.1 Hz)
MS m/z: 315 [M+Na]+

(6) Synthesis of ethyl (1S,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-{[(R)-2-methylpropane-2-sulfinyl]imino}bicyclo[3.1.0]hexane-6-carboxylate

実施例３８（５）で得られたエチル （１Ｓ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－２－オキソビシクロ［３．１．０］ヘキサン－６－カルボキシラート（１．００ ｇ、３．４２ ｍｍｏｌ）、（Ｒ）－（＋）－２－メチル－２－プロパンスルフィンアミド （０．８３ ｇ、６．８４ ｍｍｏｌ）のテトラヒドロフラン（６．８ ｍＬ)溶液に、室温下チタン(IV)エトキシド (２．１２ ｍＬ、１０．２６ ｍｍ
ｏｌ)を加え７０度にて２時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロ
ホルムにて抽出した。得られた有機層を無水硫酸マグネシウム乾燥し、濾過した。濾液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ
ＳＮＡＰ Ｕｌｔｒａ ５０ ｇ, ヘキサン：酢酸エチル＝１００:０ ～ ３０：７０）に
て精製した。表題化合物（０．８２９ ｇ）を得た（無色油状物）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.14 - 1.31 (12 H, m), 1.81 - 1.87 (1 H, m), 2.02 - 2.09 (1 H, m), 2.33 - 2.48 (2 H, m), 3.64 - 3.69 (1 H, m), 3.97 (1 H,
t, J=7.9 Hz), 4.08 - 4.17 (2 H, m), 4.49 - 4.62 (1 H, m), 4.92 (1 H, d, J=11.7 Hz), 6.99 - 7.05 (2 H, m), 7.24 - 7.30 (2 H, m)
MS m/z : 396 [M+H]+

Ethyl (1S,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-oxobicyclo[3.1.0]hexane-6-carboxylate (1.00 g, 3.42 mmol) obtained in Example 38 (5), (R)-(+)-2-methyl-2-propanesulfinamide (0.83 g, 6.84 mmol) in tetrahydrofuran (6.8 mL) solution to room temperature titanium (IV) ethoxide (2.12 mL, 10.26 mm
ol) was added and stirred at 70° C. for 2 hours. A saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (Biotage
SNAP Ultra 50 g, hexane:ethyl acetate=100:0 to 30:70). The title compound (0.829 g) was obtained (colorless oil).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.14 - 1.31 (12 H, m), 1.81 - 1.87 (1 H, m), 2.02 - 2.09 (1 H, m), 2.33 - 2.48 (2 H, m), 3.64 - 3.69 (1 H, m), 3.97 (1 H,
t, J=7.9 Hz), 4.08 - 4.17 (2 H, m), 4.49 - 4.62 (1 H, m), 4.92 (1 H, d, J=11.7 Hz), 6.99 - 7.05 (2 H, m), 7.24 - 7.30 (2 H, m)
MS m/z : 396 [M+H]+

(7) Synthesis of ethyl (1S,3R,5R,6S)-2-cyano-3-[(4-fluorophenyl)methoxy]-2-{[(R)-2-methylpropane-2-sulfinyl]amino}bicyclo[3.1.0]hexane-6-carboxylate

実施例３８（６）で得られたエチル （１Ｓ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－２－｛［（Ｒ）－２－メチルプロパン－２－スルフィニル］イミノ｝ビシクロ［３．１．０］ヘキサン－６－カルボキシラート（０．８３ｇ、２．０９
ｍｍｏｌ）のテトラヒドロフラン（４．２ ｍＬ）溶液に氷冷下フッ化セシウム（１．５９ｇ、１０．５ ｍｍｏｌ）、トリメチルシリルシアニド （０．６２３ ｇ、６．２
８ ｍｍｏｌ）を順次加え２時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムにて抽出した。有機層を分離後、減圧下濃縮した。残渣にヘキサン：酢酸エチル＝９：１の混合液を加え撹拌後、析出物を濾取し、表題化合物（０．７７ ｇ）を得た（無色固体）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (9 H, s), 1.24 (3 H, t, J=7.2 Hz), 1.69 (1 H, t, J=3.0 Hz), 2.06 - 2.17 (2 H, m), 2.25 - 2.33 (1 H, m), 2.51 (1 H, dd, J=6.6, 2.9 Hz), 3.48 - 3.59 (2 H, m), 4.06 - 4.16 (2 H, m), 4.52 - 4.63 (2 H, m), 7.05 (2 H, t, J=8.7 Hz), 7.31 - 7.37 (2 H, m)
MS m/z : 445 [M+Na]+

Ethyl (1S,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-{[(R)-2-methylpropane-2-sulfinyl]imino}bicyclo[3.1.0]hexane-6-carboxylate obtained in Example 38 (6) (0.83 g, 2.09
mmol) in tetrahydrofuran (4.2 mL), cesium fluoride (1.59 g, 10.5 mmol), trimethylsilyl cyanide (0.623 g, 6.2 g, 6.2
8 mmol) was sequentially added and stirred for 2 hours. A saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with chloroform. After separating the organic layer, it was concentrated under reduced pressure. A mixed solution of hexane:ethyl acetate=9:1 was added to the residue, and after stirring, the precipitate was collected by filtration to give the title compound (0.77 g) (colorless solid).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (9 H, s), 1.24 (3 H, t, J=7.2 Hz), 1.69 (1 H, t, J=3.0 Hz), 2.06 - 2.17 (2 H, m), 2.25 - 2.33 (1 H, m), 2.51 (1 H, dd, J=6.6, 2.9 Hz), 3.48 - 3.59 (2 H, m), 4.06 - 4.16 (2 H, m), 4.52 - 4.63 (2 H, m), 7.05 (2 H, t, J=8.7 Hz), 7.31 - 7.37 (2 H, m)
MS m/z : 445 [M+Na]+

(8) Synthesis of ethyl (1S,2S,3R,5R,6S)-2-amino-2-cyano-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylate

実施例３８（７）で得られたエチル （１Ｓ，３Ｒ，５Ｒ，６Ｓ）－２－シアノ－３－［（４－フルオロフェニル）メトキシ］－２－｛［（Ｒ）－２－メチルプロパン－２－スルフィニル］アミノ｝ビシクロ［３．１．０］ヘキサン－６－カルボキシラート（０．７７
ｇ、 １．８１ ｍｍｏｌ）のテトラヒドロフラン （１．８ ｍＬ）溶液に、氷冷下２
ｍｏｌ／Ｌ塩酸エタノール溶液（４．５ ｍＬ、 ９．００ ｍｍｏｌ）を加え、室温
にて４時間撹拌した。飽和炭酸水素ナトリウム水溶液を加えクロロホルムにて抽出した。水層、有機層を分離し、得られた有機層を減圧下濃縮した。残渣にイソプロピルエーテル
を加え撹拌することで表題化合物 （０．５１ ｇ）を得た（無色固体）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24 (3 H, t, J=7.2 Hz), 1.75 (1 H, t, J=3.1 Hz), 1.92 - 2.11 (4 H, m), 2.27 - 2.34 (2 H, m), 3.34 (1 H, dd, J=9.1, 6.7 Hz), 4.07 - 4.15 (2 H, m), 4.51 (1 H, d, J=11.9 Hz), 4.60 (1 H, d, J=12.0 Hz), 7.04 (2 H, t, J=8.7 Hz), 7.31 (2 H, dd, J=8.4, 5.5 Hz)
MS m/z : 319 [M+H]+

Ethyl (1S,3R,5R,6S)-2-cyano-3-[(4-fluorophenyl)methoxy]-2-{[(R)-2-methylpropane-2-sulfinyl]amino}bicyclo[3.1.0]hexane-6-carboxylate (0.77) obtained in Example 38 (7)
g, 1.81 mmol) in tetrahydrofuran (1.8 mL) under ice cooling.
A mol/L hydrochloric acid ethanol solution (4.5 mL, 9.00 mmol) was added, and the mixture was stirred at room temperature for 4 hours. A saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with chloroform. The aqueous layer and the organic layer were separated, and the resulting organic layer was concentrated under reduced pressure. Isopropyl ether was added to the residue and the mixture was stirred to give the title compound (0.51 g) (colorless solid).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24 (3 H, t, J=7.2 Hz), 1.75 (1 H, t, J=3.1 Hz), 1.92 - 2.11 (4 H, m), 2.27 - 2.34 (2 H, m), 3.34 (1 H, dd, J=9.1, 6.7 Hz), 4.07 - 4.15 (2 H, m), 4.51 (1 H, d, J=11.9 Hz), 4.60 (1 H, d, J=12.0 Hz), 7.04 (2 H, t, J=8.7 Hz), 7.31 (2 H, dd, J=8.4, 5.5 Hz)
MS m/z : 319 [M+H]+

(9) Synthesis of (1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (Compound No. II-15)

水酸化ナトリウム（１．４７ ｇ、７．３６ ｍｍｏｌ）の水 （５．９ ｍＬ）溶液に
、氷冷下３０％過酸化水素水（０．０８１ ｍＬ、０．７９ ｍｍｏｌ）および実施例３８（８）で得られたエチル （１Ｓ，２Ｓ，３Ｒ，５Ｒ，６Ｓ）－２－アミノ－２－シアノ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－６－カルボキシラート（０．１６ ｇ、０．５３ ｍｍｏｌ）のジメチルスルホキシド （０．５３ｍＬ）溶液を滴下した。室温に昇温し１時間撹拌した。１００℃に昇温し５時間撹拌した。室温にて１６時間撹拌した。４Ｍ塩酸にてｐH＝約１に調整し、１時間撹拌後、減
圧下濃縮した。残渣を分取HPLCにて精製し目的物を含む分画液を減圧下濃縮した。固化した残渣にEtOHを加え撹拌後、析出物を濾取し表題化合物（化合物番号ＩＩ－１５）を（０．０４６ ｇ）を得た（無色固体）。
1H NMR (400 MHz, DMSO-d6) δ ppm 1.65 - 1.73 (1 H, m), 1.73 - 1.81 (1 H, m), 1.85 (1 H, dd, J=7.2, 2.8 Hz), 2.05 - 2.20 (2 H, m), 3.42 - 3.71 (1 H, m), 4.32 (1 H, d, J=11.5 Hz), 4.48 (1 H, d, J=11.4 Hz), 7.07 - 7.18 (2 H, m), 7.34 (2 H, dd,
J=8.6, 5.7 Hz)
MS m/z : 310 [M+H]+

To a solution of sodium hydroxide (1.47 g, 7.36 mmol) in water (5.9 mL) was added 30% aqueous hydrogen peroxide (0.081 mL, 0.79 mmol) under ice cooling and ethyl (1S,2S,3R,5R,6S)-2-amino-2-cyano-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-6-carboxylate obtained in Example 38(8). A solution of (0.16 g, 0.53 mmol) in dimethylsulfoxide (0.53 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 1 hour. The temperature was raised to 100° C. and the mixture was stirred for 5 hours. Stir at room temperature for 16 hours. The pH was adjusted to about 1 with 4M hydrochloric acid, stirred for 1 hour, and concentrated under reduced pressure. The residue was purified by preparative HPLC, and the fraction containing the desired product was concentrated under reduced pressure. After EtOH was added to the solidified residue and stirred, the precipitate was collected by filtration to obtain the title compound (Compound No. II-15) (0.046 g) (colorless solid).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.65 - 1.73 (1 H, m), 1.73 - 1.81 (1 H, m), 1.85 (1 H, dd, J=7.2, 2.8 Hz), 2.05 - 2.20 (2 H, m), 3.42 - 3.71 (1 H, m), 4.32 (1 H, d, J=11.5 Hz), 4.48 (1 H, d, J=11.4 Hz), 7.07 - 7.18 (2 H, m), 7.34 (2 H, dd,
J=8.6, 5.7Hz)
MS m/z : 310 [M+H]+

(10) Synthesis of (1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid

実施例３８（９）で得られた（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－２－アミノ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸
（０．４９ ｍｇ、１．５８ ｍｍｏｌ）、１，４－ジオキサン（３．２ ｍＬ）および飽和炭酸水素ナトリウム水溶液（５．６ ｍＬ）の混合液に、室温にてクロロギ酸アリル
（０．３４ ｍＬ、３．１７ ｍｍｏｌ）を滴下し３時間撹拌した。水および酢酸エチルを加え１０分間撹拌後、有機層、水層を分離し、得られた水層に2M塩酸を加え、pH1に調
整し、酢酸エチルにて抽出し、無水硫酸ナトリウムにて乾燥後、濾過し、減圧下濃縮した。表題化合物を含む混合物（０．５３ ｇ）を得た（アモルファス）。これ以上の精製はせず次の反応に用いた。
MS m/z : 394 [M+H]+

Allyl chloroformate (0.34 mL, 3.17 mmol) was added dropwise and stirred for 3 hours. After adding water and ethyl acetate and stirring for 10 minutes, the organic layer and aqueous layer were separated, 2M hydrochloric acid was added to the resulting aqueous layer to adjust the pH to 1, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. A mixture (0.53 g) containing the title compound was obtained (amorphous). It was used for the next reaction without further purification.
MS m/z : 394 [M+H]+

(11) Synthesis of (1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-6-{[(prop-2-en-1-yl)oxy]carbonyl}-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2-carboxylic acid

実施例３８（１０）で得られた（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－２－（｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝アミノ）ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸（０．０５０ ｇ、０．１２ ｍｍｏｌ）のテトラヒドロフラン（０．６４ ｍＬ）溶液に、室温にて４－ジメチルアミノピリジン（３．８８ ｍｇ、０．０３２ ｍｍｏｌ）、４－メチルモルホリン（０．０２１ ｍＬ、０．１９ ｍｍｏｌ）、クロロギ酸アリル（０．０１５ ｍＬ、０．１４ ｍｍｏｌ）を順次加え、４時間撹拌した。飽和塩化アンモニウム水溶液を加え、クロロホルムにて抽出した。得られた有機層を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ ＳＮＡＰ Ｕｌｔｒａ ５０ ｇ, クロロホルム：メタノール＝１００:０ ～ ９０：１０）にて精製した。表題化合物を（０．
０１８ ｇ）を得た（褐色アモルファス）。
MS m/z : 434 [M+H]+

(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (0.050 g, 0.12 mmol) obtained in Example 38 (10) was dissolved in tetrahydrofuran (0.64 mL) at room temperature. Gin (3.88 mg, 0.032 mmol), 4-methylmorpholine (0.021 mL, 0.19 mmol) and allyl chloroformate (0.015 mL, 0.14 mmol) were sequentially added and stirred for 4 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with chloroform. The obtained organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage SNAP Ultra 50 g, chloroform:methanol=100:0 to 90:10). The title compound (0.
018 g) (brown amorphous).
MS m/z : 434 [M+H]+

(12) 6-prop-2-en-1-yl 2-[(1S)-1-{[(3R,5S)-tricyclo[3.3.1.13,7]decane-1-carbonyl]oxy}ethyl](1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0 ] Synthesis of hexane-2,6-dicarboxylate

実施例３８（１１）で得られた（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－６－｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝－２－（｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝アミノ）ビシクロ
［３．１．０］ヘキサン－２－カルボン酸（０．１４ ｇ、０．３３ ｍｍｏｌ）のジメチルスルホキシド（３．３ ｍＬ）溶液に、室温にて炭酸カリウム（０．０６７ｇ、０．４８ ｍｍｏｌ）を加え、１０分間撹拌後、（１Ｒ）－１－クロロエチル トリシクロ［３．３．１．１^３，７］デカン－１－カルボキシラート（０．１６ｇ、０．６５ ｍｍｏｌ）を加え１６時間撹拌した。酢酸エチルにて希釈し、飽和塩化アンモニウム水溶液、飽和食塩水で順次洗浄した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ ＳＮＡＰ Ｕｌｔｒａ １０ ｇ, ヘキサン：酢酸エチル＝９５：５ ～ ３０：７０）にて精製した。表題化合物を（０．１５ ｇ）を得た（淡黄色油状物）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (3 H, d, J=5.4 Hz), 1.55 (2 H, d, J=4.4 Hz), 1.62 - 1.75 (6 H, m), 1.82 - 1.91 (6 H, m), 1.95 - 2.18 (5 H, m), 2.23 -
2.33 (1 H, m), 2.57 (1 H, dd, J=6.9, 3.0 Hz), 4.39 - 4.62 (6 H, m), 5.15 - 5.36
(5 H, m), 5.83 - 5.95 (2 H, m), 6.91 (1 H, q, J=5.4 Hz), 6.99 - 7.06 (2 H, m), 7.20 - 7.25 (2 H, m)
MS m/z : 662 [M+Na]+

実施例３８（１１）で得られた（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－６－｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝－２－（｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝アミノ）ビシクロ［３．１．０］ヘキサン－２－カルボン酸（０．１４ ｇ、０．３３ ｍｍｏｌ）のジメチルスルホキシド（３．３ ｍＬ）溶液に、室温にて炭酸カリウム（０．０６７ｇ、０．４８ ｍｍｏｌ）を加え、１０分間撹拌後、（１Ｒ）－１－クロロエチル トリシクロ［３．３．１．１ ^３，７ ］デカン－１－カルボキシラート（０．１６ｇ、０．６５ ｍｍｏｌ）を加え１６時間撹拌した。 The mixture was diluted with ethyl acetate and washed successively with saturated aqueous ammonium chloride solution and saturated brine. The obtained residue was purified by silica gel column chromatography (Biotage SNAP Ultra 10 g, hexane:ethyl acetate=95:5 to 30:70). The title compound was obtained (0.15 g) (pale yellow oil).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (3 H, d, J=5.4 Hz), 1.55 (2 H, d, J=4.4 Hz), 1.62 - 1.75 (6 H, m), 1.82 - 1.91 (6 H, m), 1.95 - 2.18 (5 H, m), 2.23 -
2.33 (1 H, m), 2.57 (1 H, dd, J=6.9, 3.0 Hz), 4.39 - 4.62 (6 H, m), 5.15 - 5.36
(5 H, m), 5.83 - 5.95 (2 H, m), 6.91 (1 H, q, J=5.4 Hz), 6.99 - 7.06 (2 H, m), 7.20 - 7.25 (2 H, m)
MS m/z : 662 [M+Na]+

Example 38 Synthesis of (1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

実施例３８（１２）で得られた６－プロパ－２－エン－１－イル ２－［（１Ｓ）－１－｛［（３Ｒ，５Ｓ）－トリシクロ［３．３．１．１^３，７］デカン－１－カルボニル］オキシ｝エチル］ （１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－２－（｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝アミノ）ビシクロ［３．１．０］ヘキサン－２，６－ジカルボキシラート（０．１４ ｇ、０．２１ ｍｍｏｌ）のクロロホルム（０．７３ ｍＬ）溶液に１，３－ジメチルバルビツール酸（０．０３４ ｇ、０．２２ ｍｍｏｌ）および、テトラキス（トリフェニルホスフィン）パラジウム（０）（２．５ ｍｇ、０．００２ ｍｍｏｌ）を室温にて順次加え３時間撹拌した。反応混合物を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＹＭＣ Ｃ１８ １２ｇ，水：アセトニトリル＝９５：５～５：９５）にて精製した。表題化合物を含む画分を濃縮し、得られた残渣にイソプロピルエーテルを加え撹拌した。析出物を濾取し、表題化合物を（０．０２１ ｇ）を得た（無色固体）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (3 H, d, J=5.4 Hz), 1.64 - 1.76 (7 H,
m), 1.87 (6 H, s), 1.96 - 2.05 (5 H, m), 2.10 - 2.19 (1 H, m), 2.23 - 2.33 (1 H, m), 3.59 - 3.69 (1 H, m), 4.42 (2 H, s), 6.88 (1 H, q, J=5.4 Hz), 7.00 (2 H, t, J=8.1 Hz), 7.20 (2 H, t, J=6.4 Hz)
MS m/z : 514 [M-H]-

実施例３８（１２）で得られた６－プロパ－２－エン－１－イル ２－［（１Ｓ）－１－｛［（３Ｒ，５Ｓ）－トリシクロ［３．３．１．１ ^３，７ ］デカン－１－カルボニル］オキシ｝エチル］ （１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－２－（｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝アミノ）ビシクロ［３．１．０］ヘキサン－２，６－ジカルボキシラート（０．１４ ｇ、０．２１ ｍｍｏｌ）のクロロホルム（０．７３ ｍＬ）溶液に１，３－ジメチルバルビツール酸（０．０３４ ｇ、０．２２ ｍｍｏｌ）および、テトラキス（トリフェニルホスフィン）パラジウム（０）（２．５ ｍｇ、０．００２ ｍｍｏｌ）を室温にて順次加え３時間撹拌した。 The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (YMC C18 12 g, water:acetonitrile=95:5-5:95). Fractions containing the title compound were concentrated, and isopropyl ether was added to the resulting residue and stirred. The precipitate was collected by filtration to obtain the title compound (0.021 g) (colorless solid).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (3 H, d, J=5.4 Hz), 1.64 - 1.76 (7 H,
m), 1.87 (6 H, s), 1.96 - 2.05 (5 H, m), 2.10 - 2.19 (1 H, m), 2.23 - 2.33 (1 H, m), 3.59 - 3.69 (1 H, m), 4.42 (2 H, s), 6.88 (1 H, q, J = 5.4 Hz), 7 .00 (2H, t, J=8.1Hz), 7.20 (2H, t, J=6.4Hz)
MS m/z : 514 [MH]-

Example 39 Synthesis of (1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid

実施例３８（１１）で得られた（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－６－｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝－２－（｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝アミノ）ビシクロ［３．１．０］ヘキサン－２－カルボン酸（０．２０ ｇ、０．４６ ｍｍｏｌ）と（１Ｒ）－１－クロロエチル （１Ｒ，２Ｓ，５Ｒ）－５－メチル－２－（プロパン－２－イル）シクロヘキシル カルボナート（０．２９ ｇ、１．１１ ｍｍｏｌ）を用い、実施例３８（１２）および実施例３８（１３）と同様の手法により表題化合物・実施例番号３９（０．０１０ ｇ）を得た（無色固体）。
1H NMR (400 MHz, DMSO-d6) δ ppm 0.67 - 1.13 (13 H, m), 1.28 - 1.52 (3 H, m), 1.56 - 1.77 (4 H, m), 1.77 - 2.03 (4 H, m), 2.17 - 2.29 (2 H, m), 3.45 - 3.66 (1 H, m), 4.33 - 4.54 (3 H, m), 6.63 - 6.69 (1 H, m), 7.11 - 7.37 (4 H, m)
MS m/z : 534 [M-H]-

(1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-6-{[(prop-2-en-1-yl)oxy]carbonyl}-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2-carboxylic acid (0.20 g, 0.46 mmol) obtained in Example 38 (11) and (1R)- Using 1-chloroethyl (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl carbonate (0.29 g, 1.11 mmol), the title compound Example No. 39 (0.010 g) was obtained in the same manner as in Examples 38(12) and 38(13) (colorless solid).
1H NMR (400 MHz, DMSO-d6) δ ppm 0.67 - 1.13 (13 H, m), 1.28 - 1.52 (3 H, m), 1.56 - 1.77 (4 H, m), 1.77 - 2.03 (4 H, m), 2.17 - 2.29 (2 H, m), 3.45 - 3.66 (1 H, m), 4.33 - 4.54 (3 H, m), 6.63 - 6.69 (1 H, m), 7.11 - 7.37 (4 H, m)
MS m/z : 534 [MH]-

Reference Example 1 Synthesis of ((1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-6-({(1R)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-2-carboxylic acid

(1) Synthesis of (1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-5'-oxo-3'-{[(prop-2-en-1-yl)oxy]carbonyl}spiro[bicyclo[3.1.0]hexane-2,4'-[1,3]oxazolidine]-6-carboxylic acid

実施例３８（１０）で得られた１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－２－（｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝アミノ）ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸（０．０９６ ｇ、０．２４ ｍｍｏｌ）のトルエン（２．３ ｍＬ）溶液に、３７％ホルマリン（０．０６７２０ ｍＬ、０．８９６８ ｍｍｏｌ）、トルエンスルホン酸１水和物（２．３２ ｍｇ、０．０１２ ｍｍｏｌ）を加え、１２０℃にて４時間撹拌後、さらに室温にて１６時間撹拌した。反応混合物を減圧下濃縮し、表題化合物（０．１９ ｇ）を含む混合物を得た（淡黄色アモルファス）。精製せずに次反応に用いた。
MS m/z : 404 [M-H]-

To a toluene (2.3 mL) solution of 1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-2-({[(prop-2-en-1-yl)oxy]carbonyl}amino)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (0.096 g, 0.24 mmol) obtained in Example 38 (10), 37% formalin (0.0672 0 mL, 0.8968 mmol) and toluenesulfonic acid monohydrate (2.32 mg, 0.012 mmol) were added, and the mixture was stirred at 120°C for 4 hours and then at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give a mixture containing the title compound (0.19 g) (pale yellow amorphous). It was used for the next reaction without purification.
MS m/z : 404 [MH]-

(2) 3′-prop-2-en-1-yl 6-{(1R)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethyl} (1S,2R,3R,5R,6S)-3-[(4-fluorophenyl)methoxy]-5′-oxo-3′H-spiro[bicyclo[3.1.0]hexane-2,4′-[1,3]oxa Synthesis of zolidine]-3′,6-dicarboxylate

（１）で得られた（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－５’－オキソ－３’－｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝スピロ［ビシクロ［３．１．０］ヘキサン－２，４’－［１，３］オキサゾリジン］－６－カルボン酸（０．１９ ｇ、０．４７６ ｍｍｏｌ）のジメチルスルホキシド（１．６ ｍＬ）溶液に室温にて炭酸カリウム（０．７１４ ｍｍｏｌ）を加え、１０分間撹拌後、（１Ｒ）－１－クロロエチル トリシクロ［３．３．１．１^３，７］デカン－１－カルボキシラート（０．１６ｇ、０．６５ ｍｍｏｌ）を加え１６時間撹拌した。酢酸エチルにて希釈し、飽和塩化アンモニウム水溶液、飽和食塩水にて順次洗浄した。得られた残渣をシリカゲルカラムクロマトグラフィー（Ｂｉｏｔａｇｅ ＳＮＡＰ Ｕｌｔｒａ
１０ ｇ, ヘキサン：酢酸エチル＝９５：５ ～ ５０：５０）にて精製した。表題化合物
を含む混合物（０．０８８ ｇ）を得た（褐色油状物）。
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 - 1.47 (3 H, m), 1.63 - 2.10 (15 H, m), 2.17 - 2.45 (5 H, m), 4.01 - 4.21 (1 H, m), 4.21 - 4.39 (1 H, m), 4.45 - 4.62
(3 H, m), 5.12 - 5.36 (4 H, m), 5.84 - 5.94 (1 H, m), 6.75 - 6.89 (1 H, m), 6.90 - 7.08 (2 H, m), 7.11 - 7.24 (2 H, m)

（１）で得られた（１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－５'－オキソ－３'－｛［（プロパ－２－エン－１－イル）オキシ］カルボニル｝スピロ［ビシクロ［３．１．０］ヘキサン－２，４'－［１，３］オキサゾリジン］－６－カルボン酸（０．１９ ｇ、０．４７６ ｍｍｏｌ）のジメチルスルホキシド（１．６ ｍＬ）溶液に室温にて炭酸カリウム（０．７１４ ｍｍｏｌ）を加え、１０分間撹拌後、（１Ｒ）－１－クロロエチル トリシクロ［３．３．１．１ ^３，７ ］デカン－１－カルボキシラート（０．１６ｇ、０．６５ ｍｍｏｌ）を加え１６時間撹拌した。 The mixture was diluted with ethyl acetate and washed successively with saturated aqueous ammonium chloride solution and saturated brine. The resulting residue was subjected to silica gel column chromatography (Biotage SNAP Ultra
10 g, hexane:ethyl acetate=95:5 to 50:50). A mixture (0.088 g) containing the title compound was obtained (brown oil).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 - 1.47 (3 H, m), 1.63 - 2.10 (15 H, m), 2.17 - 2.45 (5 H, m), 4.01 - 4.21 (1 H, m), 4.21 - 4.39 (1 H, m), 4.45 - 4.6 2
(3 H, m), 5.12 - 5.36 (4 H, m), 5.84 - 5.94 (1 H, m), 6.75 - 6.89 (1 H, m), 6.90 - 7.08 (2 H, m), 7.11 - 7.24 (2 H, m)

(3) Synthesis of ((1S,2R,3R,5R,6S)-2-amino-3-[(4-fluorophenyl)methoxy]-6-({(1R)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-2-carboxylic acid

（２）で得られた３’－プロパ－２－エン－１－イル ６－｛（１Ｒ）－１－［（トリシクロ［３．３．１．１^３，７］デカン－１－カルボニル）オキシ］エチル｝ （１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－５’－オキソ－３’Ｈ－スピロ［ビシクロ［３．１．０］ヘキサン－２，４’－［１，３］オキサゾリジン］－３’，６－ジカルボキシラート（０．０８８ ｇ、０．１４ ｍｍｏｌ）のクロロホルム（１．４ ｍＬ）溶液に１，３－ジメチルバルビツール酸（０．２３ ｇ、０．１４ ｍｍｏｌ）および、テトラキス（トリフェニルホスフィン）パラジウム（０）（０．２ ｍｇ、０．０００１ ｍｍｏｌ）を室温にて順次加え３時間撹拌した。反応液を減圧下濃縮後、アセトニトリル（２．０ ｍL)を加え室温にて撹拌した。析出物を濾取、乾燥し、表題化合物を（０．０１４ ｇ）を得た（無色固体）。
1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (3 H, d, J=5.4 Hz), 1.61 - 2.02 (18 H, ｍ), 2.07 - 2.20 (2 H, m), 3.53 - 3.61 (1 H, m), 4.31 (1 H, d, J=11.5 Hz), 4.48 (1 H, d, J=11.6 Hz), 6.64 - 6.70 (1 H, m), 7.10 - 7.18 (2 H, m), 7.31 - 7.39 (2 H, m)
MS m/z : 516[M+H]+

（２）で得られた３'－プロパ－２－エン－１－イル ６－｛（１Ｒ）－１－［（トリシクロ［３．３．１．１ ^３，７ ］デカン－１－カルボニル）オキシ］エチル｝ （１Ｓ，２Ｒ，３Ｒ，５Ｒ，６Ｓ）－３－［（４－フルオロフェニル）メトキシ］－５'－オキソ－３'Ｈ－スピロ［ビシクロ［３．１．０］ヘキサン－２，４'－［１，３］オキサゾリジン］－３'，６－ジカルボキシラート（０．０８８ ｇ、０．１４ ｍｍｏｌ）のクロロホルム（１．４ ｍＬ）溶液に１，３－ジメチルバルビツール酸（０．２３ ｇ、０．１４ ｍｍｏｌ）および、テトラキス（トリフェニルホスフィン）パラジウム（０）（０．２ ｍｇ、０．０００１ ｍｍｏｌ）を室温にて順次加え３時間撹拌した。 After concentrating the reaction solution under reduced pressure, acetonitrile (2.0 mL) was added and the mixture was stirred at room temperature. The precipitate was collected by filtration and dried to give the title compound (0.014 g) (colorless solid).
1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (3 H, d, J=5.4 Hz), 1.61 - 2.02 (18 H, m), 2.07 - 2.20 (2 H, m), 3.53 - 3.61 (1 H, m), 4.31 (1 H, d, J=11.5 Hz), 4.48 (1 H, d, J=11.6 Hz), 6.64 - 6.70 (1 H, m), 7.10 - 7.18 (2 H, m), 7.31 - 7.39 (2 H, m)
MS m/z : 516[M+H]+

Test Example 1 [ ³⁵ S]GTPγS Binding Assay CHO cells stably expressing human metabotropic glutamate receptors mGluR2 and mGluR3 were placed in 10% dialyzed fetal bovine serum-containing Dulbecco's modified Eagle's medium [1% proline, 1 mM sodium pyruvate, 1 mM succinic acid, 1 mM disodium succinate, 100 units/mL penicillin, 100 μg/mL strain. 37°C, 5%
Cultured under _CO2 . Cells in a confluent state were washed with PBS(-), detached with a cell scraper, and centrifuged at 4° C. and 1000 rpm for 5 minutes to collect the cells. The resulting sediments were suspended in 20 mM HEPES buffer (pH 7.4) (mGluR2) or 20 mM HEPES buffer (pH 7.4) (mGluR3) containing 1 mM EDTA, homogenized with a Teflon (registered trademark) homogenizer, and then centrifuged at 4°C at 48,000 xg for 20 minutes to obtain sediments again. Further, the obtained sediment was washed by centrifugation twice and then homogenized with the above buffer to obtain a crude membrane fraction. The crude membrane fraction was added to the binding test buffer (final concentration; 20 mM HEPES, 100 mM NaCl, 10 mM MgCl ₂ , 10 μM GDP, 10 μg/mL saponin, 0.1 μM).
1% BSA) (mGluR2), (final concentration; 20 mM HEPES, 1 mM EDTA, 100 mM NaCl, 10 mM MgCl ₂ , 10 μM GDP, 10 μg/mL
saponin, 0.1% BSA) (mGluR3). Compounds (II)-1 to (II)-15 were added to the crude membrane fraction of 10 μg/assay of membrane protein and incubated at 30° C. for 20 minutes. After that, 20 (mGluR2) or 1 (mGluR3) μM glutamic acid and [ ³⁵ S]GTPγS (final concentration 0.15 nM) were added, and incubation was carried out at 30° C. for 1 hour. After incubation, the cells were suction filtered onto Whatman GF/C filters, and the filters were treated with ice-cold 20 mM HEPES buffer (pH 7.4) (mGluR2) or 20 mM buffer containing 1 mM EDTA.
Washed with 1000 μL of HEPES buffer (pH 7.4) (mGluR3). A scintillation cocktail was added to the resulting filter, and membrane-bound radioactivity was measured with a liquid scintillation counter. The residual radioactivity in the absence of glutamic acid was defined as non-specific binding, and the difference from the residual radioactivity in the presence of glutamic acid was defined as specific binding. Inhibition curves were obtained using non-linear analysis from the specific binding inhibition rate at various concentrations of compounds (II)-1 to (II)-15. The concentration (IC ₅₀ ) of compounds (II)-1 to (II)-15 at which the specific binding is inhibited by 50% was calculated from the inhibition curve. The results are shown in Table 1 below.

Test Example 2: Stability Test in Solution Stability of compound (IA) or (I) of the present invention in hydrochloric acid solution (pH 1.2) and 20 mM phosphate buffer (pH 6.5) was confirmed according to the following method.
The compound was dissolved in a hydrochloric acid solution (pH 1.2) containing hydrochloric acid and sodium chloride or a 20 mM phosphate buffer (pH 6.5) containing disodium hydrogen phosphate, sodium dihydrogen phosphate, and sodium chloride to prepare a solution with a concentration of about 50 μg/mL (near the saturated concentration if not dissolved). This solution was incubated at 37° C. for 1 hour, and the concentration of the compound before and after the incubation was quantified by high performance liquid chromatography to calculate the residual rate. When the solubility of the compound was low, the evaluation was not possible.
Table 2 below shows the residual ratios of representative compounds in hydrochloric acid solution (pH 1.2) and 20 mM phosphate buffer (pH 6.5).

ＮＡ；Ｎｏｔ ａｐｐｌｉｃａｂｌｅ ｂｅｃａｕｓｅ ｏｆ ｌｏｗ ｓｏｌｕｂｉｌｉｔｙ

以上より、本発明化合物は、胃及び小腸を想定した溶液での安定性が良く、消化管ではプロドラッグ体で存在することが想定できた。

NA: Not applicable because of low solubility

From the above, it can be assumed that the compound of the present invention has good stability in a solution intended for the stomach and small intestine, and exists as a prodrug in the gastrointestinal tract.

Test Example 3 Production rate test of compound (II)-A or (II) in liver S9 fraction The production rate of compound (II)-A or (II) in liver S9 fraction of compound (IA) or (I) of the present invention was confirmed according to the following method.
The compound of the present invention was added to sodium-potassium phosphate buffer (0.25 mol/L, pH 7.4) containing liver S9 fraction (human: XenoTech, LLC/H0620.S9/Lot.0810471, monkey: XenoTech, LLC/P2000.S9/Lot.0910273) and incubated for 15 minutes in the presence of coenzyme (37°C). The final concentration of the compound of the present invention and protein concentration in the reaction mixture were 1 μmol/L and 1 mg protein/mL, respectively. The incubated reaction mixture was added with twice the amount of dimethylsulfoxide to stop the reaction, and centrifuged (2150×g, 4° C., 10 minutes) to remove protein. The resulting supernatant was subjected to analysis by a liquid chromatography tandem mass spectrometry (LC-MS/MS) system.
Shimadzu Shim-pack XR-ODS (2.2 μm, 30 mm×3.0 mm I.D.) was used as the separation column, and a 0.1% formic acid/acetonitrile solution (flow rate: 1.3 mL/min) was used as the mobile phase, and the analyte was eluted in a linear gradient mode. Compound (IA) or (I) and compound (II)-A or (II) of the present invention were detected by Triple TOF equipped with a TurboIonSpray interface.
A 5600 system or a Triple Quad 5500 system (both manufactured by AB SCIEX) was used in positive or negative ion detection mode.
Table 3 below shows the production rate of compound (II)-A or (II) in the liver S9 fraction of the compound of the present invention.

本発明化合物（Ｉ－Ａ）、又は（Ｉ）は、化合物（ＩＩ）－Ａ、又は（ＩＩ）へ変換され、ヒト及びサルの肝臓でプロドラッグから活性体への変換が想定できた。

Compound (IA) or (I) of the present invention was converted to compound (II)-A or (II), and conversion from prodrug to active form in human and monkey livers could be envisioned.

Test Example 4 Measurement of Plasma Concentration of Compound (II)-A or (II) in Oral Administration to Monkeys After oral administration of compound (II)-A or (II) and compound (IA) or (I) of the present invention, the plasma concentration of compound (II)-A or (II) was measured according to the following method.
Compound (II)-A or (II) and invention compound (IA) or (I) were orally administered to male cynomolgus monkeys (fasted) at a dose of 1 mg/kg as compound (II) (base: 0.5% methylcellulose solution, administration volume: 5 mL/kg).
About 0.6 mL of blood was collected from the anterior flexural vein before oral administration, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after oral administration (anticoagulant: EDTA-2K). Plasma obtained by centrifugation (2000×g, 4° C., 15 minutes) was stored frozen at −30° C. until analysis. At the time of analysis, 200 μL of acetonitrile/methanol mixture containing an internal standard substance was added to 50 μL of plasma sample thawed under ice-cooling, stirred, and then centrifuged (3639×g, 4° C., 10 minutes) to remove proteins. The resulting supernatant was subjected to LC-MS/MS analysis. The lower limit of quantification for compound (II)-A or (II) was 1 ng/mL.
For representative compounds, the maximum plasma concentration (C _max ) and bioavailability (BA) of compound (II)-A or (II) upon oral administration to monkeys are shown in Table 45 below. In addition, BA
was calculated based on the plasma concentration of compound (II)-A or (II) when compound (II) was intravenously administered.

本発明化合物（Ｉ－Ａ）、又は（Ｉ）として経口投与することにより、化合物（ＩＩ）－Ａ、又は（ＩＩ）の曝露が飛躍的に向上し、優れたプロドラッグ効果を示した。

Oral administration of compound (IA) or (I) of the present invention dramatically improved the exposure of compound (II)-A or (II), demonstrating excellent prodrug effects.

According to the present invention, a medicament comprising compound (II)-A, or a prodrug of (II), having a strong action on group II metabotropic glutamate receptors, in particular diseases modulated by group II metabotropic glutamate receptor antagonists, such as mood disorders (including depression, bipolar disorder), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, movement disorders associated with muscle stiffness, sleep disorders, Huntington's chorea, eating disorders, drug dependence, epilepsy. , cerebral infarction, cerebral ischemia, cerebral insufficiency, cerebral edema, spinal cord injury, head injury, inflammation, immune-related diseases, etc., and is expected to contribute to the development of the pharmaceutical industry.

Claims (4)

Formula (I)
[in the formula (I),
R ¹ represents an ethyl group, a 4-fluorophenyl group, or a 3,4-difluorophenyl group,
R ² represents any structure of the following formula group (IIIb),
R ³ represents a methyl group. ]
で表される化合物、又はその医薬上許容される塩を有効成分として含有し、有効成分の投与量が１日当たり０．０１～５００ｍｇであり、 １種又は２種以上の医薬的に許容される担体、賦形剤及び希釈剤とを含む、気分障害（うつ病、双極性障害を含む）、不安障害、認知障害、発達障害、アルツハイマー病、パーキンソン病、睡眠障害、ハンチントン舞踏病、摂食障害、薬物依存症、てんかん、脳梗塞、脳虚血、脳浮腫、頭部外傷、炎症、免疫関連疾患からなる群から選択される疾患の予防又は治療に用いる経口又は非経口用医薬製剤。 The oral or parenteral pharmaceutical according to claim 1, wherein the active ingredient is (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid or a pharmaceutically acceptable salt thereof. formulation .
2. The oral or parenteral method according to claim 1, wherein the active ingredient is (1R,2R,3R,5R,6R)-2-amino-3-[(3,4-difluorophenyl)methoxy]-6-fluoro-2-({(1S)-1-[(tricyclo[3.3.1.1 ^3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid, or a pharmaceutically acceptable salt thereof. Oral pharmaceutical formulation .
The active ingredient is (1R,2R,3R,5R,6R)-2-amino-6-fluoro-2-({(1R)-1-[({[(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl]oxy}carbonyl)oxy]ethoxy}carbonyl)-3-propoxybicyclo[3.1.0]hexane-6-carboxylic acid, or a pharmaceutically acceptable salt thereof. Oral or parenteral pharmaceutical formulations of