JP2019073507A - Pharmaceutical containing prodrug of amino acid derivative - Google Patents

Abstract

To provide a prophylactic or therapeutic agent exhibiting good oral absorption in mood disorder (including depression and bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury, inflammation, immunity related disease, and the like.SOLUTION: A pharmaceutical contains, as an active ingredient, an amino acid derivative prodrug represented by general formula (I-A) being a prodrug of an amino acid derivative being a group 2 metabotropic glutamate receptor antagonist, or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

  The present invention relates to (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-alkoxybicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative, and (1S, 2R , 3R, 5R, 6S) -2-Amino-3-alkoxybicyclo [3.1.0] hexane-2,6-dicarboxylic acid related pharmaceutical containing medicaments. More specifically, 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 rigidity, sleep disorders, Huntington's chorea, feeding Metabotropic glutamate (mGlu) receptor effective for treatment and prevention of disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral failure, cerebral edema, spinal cord injury, head trauma, inflammation, immune related diseases, etc. (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-alkoxybicyclo [3.1.0], which are compounds acting as antagonists of the mGlu2 and mGlu3 receptors belonging to subgroup II of Hexane-2,6-dicarboxylic acid derivatives, and (1S, 2R, 3R, 5R, 6S) -2-amino-3-alkoxybicyclo [3.1.0] It relates to medicaments containing prodrugs of San-2,6-dicarboxylic acid derivatives. In addition, the present invention relates to a drug containing a prodrug which enhances the oral absorption of a compound (active form) acting as an antagonist of mGlu2 and mGlu3 receptors and increases the in vivo exposure of the active form.

Metabotropic glutamate receptors are classified into three groups based on amino acid sequence homology, signal transduction mechanism and pharmacological properties. Among them, group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) are G protein coupled receptors, which bind to adenyl cyclase and forskolin stimulate cyclic adenosine monophosphate (cAMP) Suppress accumulation (Non-Patent Document 1). In addition, group II metabotropic glutamate receptors are mainly present at the presynaptic synapse of the glutamatergic nervous system and function as autoreceptors, thereby suppressing excessive release of glutamate (Non-patent document 2, Non-patent document 3) ). Compounds that antagonize Group II metabotropic glutamate receptors are considered to be effective for the treatment or prevention of acute and chronic psychiatric and neurological diseases, and (1R, 2R, 3R, 5R, 6R) -2 -Amino-6-fluoro-3-alkoxybicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative, and (1S, 2R, 3R, 5R, 6S) -2-amino-3-alkoxybicyclo [1. 3.1.0] Hexane-2, 6-dicarboxylic acid derivatives are compounds having strong antagonism to group II metabotropic glutamate receptors. For example, MGS 0039 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 a depressed animal model, imitation time from 1 mg / kg like existing antidepressants It has been reported to suppress. Furthermore, in the mouse tail suspension test, it has been reported that the immobility time is shortened similarly to the existing antidepressants (Non-patent Document 4). In addition, (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-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid, (1R, 2R, 3R, 5R , 6R) -2-amino-3-[(3,4-difluorophenyl) methoxy] -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid, (1R, 2R, 3R, 5R And 6R) -2-amino-6-fluoro-3-propoxybicyclo [3.1.0] hexane-2,6-dicarboxylic acid also have antagonist activity of 500 nM or less for the mGlu2 receptor It has been reported (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 6,6-dicarboxylic acid derivatives have poor oral absorbability in monkeys. Therefore, oral absorption may be bad for humans.
There are roughly two approaches to improving membrane permeability such as oral absorption of compounds. One is a method of changing the chemical structure of the compound itself, and the other is a method of devising a pharmaceutical without changing the chemical structure. Among the former, there is prodrugization in which a small modifying group such as an alkyl group or an acyl group is bound to a reactive substituent such as a carboxy group or an amino group of the compound.
As the above-mentioned prodrug, it exists stably as a prodrug form before absorption, the absorption is improved by prodrugization, and when absorbed and / or after absorption, in the small intestine, liver and / or plasma, chemically or enzymatically It is desirable that the compound be rapidly converted to the active form.
However, it is difficult to develop an ideal prodrug which satisfies all the above conditions. For example, prodrugs with ester linkages can be susceptible to hydrolysis reactions, which can greatly affect the chemical stability prior to absorption. Prodrugs having an amide bond may greatly affect membrane permeability such as oral absorbability by largely changing the physical properties of the compound. In addition, since the amide bond is difficult to hydrolyze, the conversion of the compound to an in vivo active form and the plasma concentration may be greatly affected. Furthermore, the enzyme that controls the bioconversion of a prodrug to an active form has substrate specificity, and in particular, the body of the prodrug can not be reacted due to steric hindrance of the substituent inserted to make it into a prodrug, etc. It is difficult to predict the dynamics. For these reasons, it is by no means easy to increase the plasma concentration of the active form by estimating the membrane permeability and conversion to the active form such as oral absorption of a prodrugized compound. To date, the 6-position carboxylic acid or 2-position carboxylic acid and 6-position of 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative, a compound that acts as an antagonist of the mGlu2 and mGlu3 receptors It has been reported that the plasma concentration of an active form of a prodrug having an ester bond is increased in both of the 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 on raising the plasma concentration of the active form by a prodrug compound having an ester bond only at the 2-position carboxylic acid. In addition, there is no description or suggestion on raising the plasma concentration of the active substance by the prodrug of the active substance of the present invention.

WO 03/061698 WO05 / 000791 WO 2012/068041 WO 2012/068067 WO 2013/062680

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 disorder (including depression and bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, movement disorder associated with muscle rigidity, sleep disorder, Huntington's chorea, A drug with therapeutic and preventive effects such as eating disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral failure, cerebral edema, spinal cord injury, head trauma, inflammation, immune related diseases, etc. It is an object of the present invention to provide a medicament comprising an active ingredient that antagonizes highly active group II metabotropic glutamate receptors.

The present inventors have found that (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-alkoxybicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative and (1S 2,2R, 3R, 5R, 6S) -2-Amino-3-alkoxybicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivatives As a result of intensive investigations, antagonists for the group II metabotropic glutamate receptors (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-alkoxybicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative and (1S, 2R, 3R) having activity , 5R, 6S) -2-Amino-3-alkoxybicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative prodrug is used in the stomach and small intestine Stable in the stability test at boss was solution and is converted into the active substance in the S9 fraction of liver, they found that pharmaceutical, particularly useful as an oral medicine. In addition, the present inventors have found that this type of prodrug enhances the in vivo exposure amount of the active form through animal experiments using the active form and the prodrug as the test drug, and completed the present invention.
Hereinafter, the present invention will be described in detail. Embodiments of the present invention (hereinafter, compounds contained in the medicament of the present invention are referred to as “the compounds of the present invention”) include the following.
(1) Formula (I-A)

[In the formula (I-A),
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 is 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 the C _1-6 alkoxy group are substituted with 1 to 3 halogen atoms And may be
R ^y is 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 the C _1-6 alkoxy group are substituted with 1 to 3 halogen atoms And may be
R ^{1 ′} represents a hydrogen atom or a C _1-6 alkyl group,
Or R ¹ and R ^{1 ′} may be taken together with adjacent carbon atoms to 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)
, C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with 1 to 3 C _1-6 alkyl groups), C _3-8 cycloalkoxy group (said C _{3- The 8-} cycloalkoxy group may be substituted with 1 to 3 C _1-6 alkyl groups, and the C _3-8 cycloalkoxy group may be C _1-5 between two different carbon atoms in the ring. Alkylene bridged), an adamantyl group (the adamantyl group may be substituted by 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,
R ⁴ represents a hydrogen atom or a fluorine atom. ]
Mood disorder (including depression and bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, and sleep comprising as an active ingredient a compound represented by or a pharmaceutically acceptable salt thereof A drug for the prophylaxis or treatment of a disease selected from the group consisting of a disorder, Huntington's chorea, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune related diseases.
(2) A mood disorder (including depression and bipolar disorder), an anxiety disorder, which comprises, as an active ingredient, the compound according to (1), or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a fluorine atom. Cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington's chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, brain injury, head injury, inflammation, immune related diseases A preventive or therapeutic agent for a disease selected from the group.
(3) R ² is a C _3-6 alkyl group or 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
The cycloalkoxy group may be substituted with 1 to 3 C _1-6 alkyl groups, and further the C _3-8 cycloalkoxy group may be C _1-5 alkylene between two different carbon atoms in the ring Or adamantyl group (the adamantyl group may be substituted with 1 to 3 C _1-6 alkyl groups), or a compound according to (2) which is a phenyl group, or Mood disorder (including depression and bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington's chorea, feeding that contains pharmaceutically acceptable salt as an active ingredient A drug for the prophylaxis or treatment of a disease selected from the group consisting of disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, immune related diseases.
(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,
Whether R ^{1 ′} represents a hydrogen atom or a methyl group,
Alternatively, R ¹ and R ^{1 ′} may be taken together with adjacent carbon atoms to form cyclopentane, and R ² represents a structure of any of the following formula group (IIIB),

Mood disorder (depression, bipolar) containing as an active ingredient the compound 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 Disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's chorea, eating disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury , An agent for the prophylaxis or treatment of a disease selected from the group consisting of inflammation and immune related diseases.
(5) Mood disorder (including depression and bipolar disorder), anxiety disorder, and cognition containing the compound according to (1) or a pharmaceutically acceptable salt thereof according to (1), wherein R ⁴ is a hydrogen atom Disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington's chorea, eating disorder, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, immune related diseases A preventive or therapeutic agent for a disease selected from
(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 A 5-chloropyridin-2-yl group or a 2-methylpropyl group,
Whether 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 a structure of any of the following formula group (IIIB),

Mood disorder (including depression and bipolar disorder) containing as an active ingredient the compound according to (5) or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom or a C _1-6 alkyl group Anxiety disorder, Cognitive disorder, Developmental disorder, Alzheimer's disease, Parkinson's disease, Sleep disorder, Huntington's chorea, Eating disorder, Drug dependence, Epilepsy, Cerebral infarction, Cerebral ischemia, Brain edema, Head trauma, Inflammation, Immune A preventive or therapeutic agent for a disease selected from the group consisting of related diseases.
(7) R ¹ is a 4-fluorophenyl group or a 3,4-difluorophenyl group (5)
Or a mood disorder (including depression and bipolar disorder), an anxiety disorder, a cognitive disorder, a developmental disorder, Alzheimer's disease, and a parkinsonian comprising the compound according to (6) or a pharmaceutically acceptable salt thereof as an active ingredient Diseases, sleep disorders, Huntington's chorea, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cerebral edema, head trauma, inflammation, immunity or diseases selected from the group consisting of immune related diseases medicine.
(8) R ¹ is a 4-fluorophenyl group,
R ^{1 ′} is a hydrogen atom,
A mood comprising, as an active ingredient, the compound according to any one of (5) to (7), wherein R ² represents a structure of any one of the following formula group (IIIb), or a pharmaceutically acceptable salt thereof Disorder (including depression and bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia , A drug for the prophylaxis or treatment of a disease selected from the group consisting of brain edema, head trauma, inflammation and immune related diseases.

(9) A mood disorder (depression, bipolar disorder) comprising the compound according to any one of (5) to (8), wherein R ³ is a methyl group, or a pharmaceutically acceptable salt thereof as an active ingredient Sexual disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head An agent for the prophylaxis or treatment of a disease selected from the group consisting of trauma, inflammation and immune related diseases.
(10) Formula (I)

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

R ³ represents a hydrogen atom or a C _1-6 alkyl group. ]
Or a pharmaceutically acceptable salt thereof.
(11) A mood disorder (depression, which comprises the compound according to (10), wherein R ² represents a structure of any of the following formula group (IIIa ′), or a pharmaceutically acceptable salt thereof as an active ingredient: Anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's chorea, eating disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head An agent for the prophylaxis or treatment of a disease selected from the group consisting of head trauma, inflammation and immune related diseases.

(12) Mood disorder (depression, bipolar) wherein the compound according to (10), wherein R ² has a structure of any of the following formula group (IIIb), or a pharmaceutically acceptable salt thereof, as an active ingredient Sexual disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head An agent for the prophylaxis or treatment of a disease selected from the group consisting of trauma, inflammation and immune related diseases.

(13) A mood disorder (depression, bipolar disorder) comprising the compound according to any one of (10) to (12), wherein R ³ is a methyl group, or a pharmaceutically acceptable salt thereof as an active ingredient Sexual disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head An agent for the prophylaxis or treatment of a disease selected from the group consisting of trauma, inflammation and immune related diseases.
(14) A mood disorder (including depression and bipolar disorder), an anxiety disorder, a cognitive disorder, and a developmental disorder, which comprises the compound according to (1) shown below, or a pharmaceutically acceptable salt thereof as an active ingredient: Disease, Parkinson's disease, sleep disorder, Huntington's chorea, eating disorder, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, brain trauma, inflammation, immune related diseases Disease prevention or treatment:
(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 ^3,7,7 ] 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- (propane)] -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] heptane-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] Hpent-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] heptane-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 3.3.1.1 ^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) Mood disorder (including depression and bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, comprising the compound according to (1) shown below, or a pharmaceutically acceptable salt thereof as an active ingredient: Disease, Parkinson's disease, sleep disorder, Huntington's chorea, eating disorder, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, brain trauma, inflammation, immune related diseases Disease prevention or treatment:
(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 ^3,7,7 ] 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- (propane)] -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 3.3.1.1 ^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) A mood disorder (depression comprising the compound according to any one of (1) to (4) or (10) to (13) below, or a pharmaceutically acceptable salt thereof as an active ingredient Disease, bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington's chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema , A drug for the prophylaxis or treatment of a disease selected from the group consisting of head trauma, inflammation, immune related diseases:
(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) A mood disorder (depression comprising the compound according to any one of (1) to (4) or (10) to (13) below, or a pharmaceutically acceptable salt thereof as an active ingredient Disease, bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington's chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema , A drug for the prophylaxis or treatment of a disease selected from the group consisting of head trauma, inflammation, immune related diseases:
(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) A mood disorder (depression comprising the compound according to any one of (1) to (4) or (10) to (13) shown below, or a pharmaceutically acceptable salt thereof as an active ingredient Disease, bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington's chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema , A drug for the prophylaxis or treatment of a disease selected from the group consisting of head trauma, inflammation, immune related diseases:
(1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-2-({(1R) -1-[({[(1R, 2S, 5R) -5-methyl-2- (propane)] -2-yl) cyclohexyl] oxy} carbonyl) oxy] ethoxy} carbonyl) -3-propoxybicyclo [3.1.0] hexane-6-carboxylic acid.

Prodrugs of amino acid derivatives contained in the medicament of the present invention have improved membrane permeability such as oral absorbability, and are rapidly active after absorption (II) -A, (II) -1, (II) The activity is converted to -2 or (II) -3, and the active substance exhibits affinity for the group II metabotropic glutamate receptor and acts as an antagonist.

(In formula (II) -A, R ¹ , R ^{1 ′} and R ⁴ are as defined above.)

  Hereinafter, modes for carrying out the present invention will be specifically described.

The terms used in the present specification have the following meanings.
“C _1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms,
For example, 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, neohexyl group etc. can be mentioned.
The “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- Examples include butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl and the like.
"Heteroaryl group" means a monocyclic aromatic heterocyclic group, such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridinyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl Imidazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, etc. it can.
The "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The “C _1-6 alkoxy group” is a linear or branched C 1 to C ₆ alkoxy group, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and a pentyloxy group, Hexyloxy, isopropoxy, isobutoxy, tert-butoxy, sec-butoxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1,2-dimethylpropoxy and the like can be mentioned. .
The “C _3-8 cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group.
The “C _3-8 cycloalkoxy group” is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group or a cyclooctyloxy group.
The “C _3-8 cycloalkane” is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane.
_{Examples of} “C _1-5 alkylene” include methylene, ethylene, methylmethylene, trimethylene, methylethylene, dimethylmethylene, tetramethylene, ethylethylene, pentamethylene and the like.
If C _3-8 cycloalkoxy group of the is a C _3-8 cycloalkoxy group between two carbon atoms different in the ring are bridged with C _1-5 alkylene, bicyclo [2.2 .1] Heptan-2-yl-oxy group etc. can be mentioned.

  As used herein, the term "pharmaceutically acceptable salt" refers to salts with inorganic acids 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, Salt with an organic acid such as p-toluenesulfonic acid, camphorsulfonic acid or naphthalene-2-sulfonic acid, lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminum ion or the like Salts with multiple metal ions, ammonia, arginine, lysine, piperazine, choline, Triethanolamine, 4-phenylcyclohexylamine, 2-aminoethanol, salts with amines such as benzathine. The conversion of the free form into the salt can be carried out in a conventional manner.

Preferred embodiments of the compound of the present invention are listed below.
The compound whose R < ² > is a structure in any one of following formula group (IIIB) is preferable.

Or as another aspect, the compound whose R < ² > is a structure of either of following formula group (IIIa) is mention | raise | lifted.

Compounds having any structure of the following formula group (IIIa ′) are more preferred.

In still another embodiment, further preferred is a compound in which R ² is a structure of any of the following formula group (IIIb).

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

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

Examples of preferred compounds in the compound 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 ^3,7,7 ] 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- (propane)] -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] heptane-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] Hpent-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] heptane-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 3.3.1.1 ^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 in the compound 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 ^3,7,7 ] 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- (propane)] -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 3.3.1.1 ^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-1-1
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.

  When the compounds of the present invention form hydrates or solvates, they are also included in the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compound of the present invention are also included in the scope of the present invention.

The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of any ratio thereof, 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 substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful in, for example, metabolism and pharmacokinetics studies, biological analysis as ligands of receptors, and the like.
The medicament of the present invention may be prepared as a pharmaceutical preparation by combining the compound of the present invention and one or more pharmaceutically acceptable carriers, excipients and diluents. Examples of the carrier, excipient and diluent include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose And various oils such as water syrup, methyl cellulose, polyvinyl pyrrolidone, alkyl parahydroxy benzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like.
The medicament of the present invention comprises the compound of the present invention, and the carriers, excipients or diluents thereof, and, if necessary, commonly used fillers, binders, disintegrants, pH adjusters, solubilizers, etc. Orally or parenterally, such as tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, ointments, injections, skin patches, etc., according to conventional pharmaceutical techniques after mixing with It is prepared as a prodrug of a medicament, in particular a group II metabotropic glutamate receptor antagonist.
The medicament of the present invention can be orally or parenterally administered 0.01 to 500 mg of the compound of the present invention once or several times a day to an adult patient, but it is easy to use In terms of efficacy and efficacy, oral administration is preferred. The dose and the frequency of administration can be appropriately increased or decreased depending on the type of the disease to be treated, the age, weight, symptoms and the like of the patient.

The compounds of the present invention (IA) and (I) have no effect on group II metabotropic glutamate receptors. However, compounds (II) -A, (II) -1, (II) which are compounds which are enzymatically or chemically hydrolyzed in vivo and have a strong action on group II metabotropic glutamate receptors Converted to -2 or (II) -3, respectively. Accordingly, the compound of the present invention exerts a function as a drug acting on a group II metabotropic glutamate receptor.
That is, the compounds of the present invention can be used in mood disorders (including depression and bipolar disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, motor disorders associated with muscle rigidity, sleep disorders, Huntington's chorea, consumption Food disorder, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral failure, cerebral edema, spinal cord injury, head injury, inflammation, immune related diseases, etc., and group II metabotropic glutamate receptors are considered to be involved. Absorption of actives (II) -A, (II) -1, (II) -2 or (II) -3 which antagonize group II metabotropic glutamate receptors as a preventive or therapeutic agent for Act as a pro-drug to increase the membrane permeability and increase the in vivo exposure.

A representative preparation method of the compound of the present invention represented by (I-B) and (I) is shown in the following scheme A. The following method is an illustration of a method for producing the compound of the present invention and is not limited thereto. In the examples of the following production methods, the compound may form a salt that does not interfere with the reaction. Also, the active substances shown by (II) -B and (II) can be obtained by the production method described in WO 03/061698 or WO 2011/061535.
Scheme A

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

Step 1: For protecting the amino group of compounds (II) -B and (II) with a general allyloxycarbonyl group (see Protective Groups in Organic Synthesis 4th Edition, John Wiley & Sons, INC.) Compound (1) can be obtained by attaching. 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, N, N-dimethylformamide In an inert solvent such as an amide solvent such as N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof, triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4- (N, N- Reaction with allyl chloroformate in the presence or absence of organic bases such as dimethylamino) pyridine and 2,6-di-t-butylpyridine, or inorganic salts such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate Leads to the compound (1) by Can.

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

Step 3: The compound (3) is a compound of the formula L-CH (R ³ ) -O-C (O) -R ² (wherein L represents a leaving group, for example, a halogen atom, p-toluene) And sulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group and the like) and hydrocarbon solvents such as benzene, toluene, hexane and cyclohexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, tetrahydrofuran, diethyl Ethers, ether solvents such as 1,2-dimethoxyethane, amide solvents such as N, N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or inert solvents such as mixed solvents thereof , Sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, charcoal Inorganic bases such as cesium, cesium hydrogen carbonate, sodium hydroxide and potassium hydroxide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, metal amides such as sodium amide, triethylamine, pyridine, diisopropylethylamine, 4- (N, In the presence of a base such as N-dimethylamino) pyridine, an organic base such as 2,6-di-tert-butylpyridine, a base such as potassium tert-butoxide, in the presence or absence of a suitable activating agent such as sodium iodide It can lead by making it react below. Preferably, in the mixed solvent of chloroform and water, in the presence of potassium carbonate and tetrabutylammonium hydrogen sulfate, the formula Cl-CH (R ³ ) -O-C (O) -R ² or the formula Br-CH (R ³ Compound (3) can be obtained by reacting the compound represented by -O-C (O) -R ² at room temperature to 80 ° C for 2 hours to 1 day.

Step 4: The compound (3) is subjected to a general deprotection reaction (see Protective Groups in Organic Synthesis 4th Edition, John Wiley & Sons, INC.) To lead to the compound (I) of the present invention it can. For example, a hydrocarbon-based solvent such as benzene, toluene, or hexane, for example, in the presence of a zero-valent palladium catalyst such as tetrakistriphenylphosphine palladium (0) and a metal catalyst regeneration reagent such as 1,3-dimethylbarbituric acid Of allyl group and allyloxycarbonyl group in an inert solvent such as halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, or mixed solvents thereof Deprotection can lead to a compound (I) which is a compound of the present invention. Preferably, the compound of the present invention is produced 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. It can lead to (I-B) and (I).

An exemplary preparation method of the compound represented by (II) -C in the active form of the compound of the present invention represented by (IC) is shown in the following scheme B. The following method is an illustration of a method for producing the compound of the present invention and is not limited thereto. In the examples of the following production methods, 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 shown in the present invention, the compound (4) is subjected to a catalytic asymmetric Michael addition reaction and then subjected to a cyclization reaction involving deethoxycarbonyl to give an optically active compound of the present invention in two steps. It can lead to (6). Compound (6) can also be synthesized according to the following report (Tetrahedron Asymmetry, 1997, 511-514, Chem. Eur. J., 2006, 12, 568-575, J. Org. Chem., 2008. 73, 3078-3087, Tetrahedron Asymmetry, 2010, 1486-1493).

Step 5: Compound (4) can be subjected to asymmetric Michael addition reaction to give compound (5). For example, 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, N, Lithium aluminum hydride, (R)-(+)-1,1-bicarbonate in an inert solvent such as an amide solvent such as N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide or a mixed solvent thereof After preparing a suspension containing an asymmetric catalyst in the presence or absence of an additive such as -2-naphthol or molecular sieves 4A, triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4- ( N, N-Dimethylamino) pyridine, 2,6-di-t-butyl Compound by reacting with diethyl chloromalonate in the presence or absence of organic bases such as pyridine and potassium tert-butoxide, or inorganic bases such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate It can lead to (5). Preferably, the reaction is carried out in the presence of lithium aluminum hydride and (R)-(+)-1,1-bi-2-naphthol in tetrahydrofuran at 0 to 70 ° C. for 30 minutes to 1 day to include an asymmetric catalyst. After preparing the suspension, the compound (5) of the present invention is obtained by reacting diethyl chloromalonate with the compound (4) in the presence of molecular sieves 4A and sodium carbonate at 0 to 70 ° C. for 30 minutes to 1 day. (See Angew. Chem., Int. Ed. Engl., 1996, 35, 104-106, Tetrahedron, 2002, 58, 2585-2588).

Step 6: Compound (5) can be converted to compound (6) by subjecting it to a cyclization reaction involving deethoxycarbonyl. 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, benzene , Hydrocarbon solvents such as toluene and hexane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and benzotrifluoride, ether solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, N, N-dimethyl In the presence or absence of an acid such as acetic acid, citric acid or formic acid in an inert solvent such as an amide solvent such as formamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, water, or a mixed solvent thereof Lithium chloride, sodium chloride, sodium cyanide, potassium cyanide By reacting with an inorganic salt such as sodium bromide, lithium iodide, sodium iodide, lithium carbonate, potassium carbonate, sodium carbonate, sodium phosphate or an organic salt such as tetramethylammonium acetate, etc. Can lead to Preferably, the compound (6) of the present invention can be obtained by reacting lithium chloride with lithium chloride at 0 to 180 ° C. for 30 minutes to 1 day in N-methyl-2-pyrrolidinone solvent and in the presence of acetic acid (J Chem., 1978, 43, 138-147, Org. Process Res. Dev., 2012, 16, 129-140).

Step 7: Compound (6) can be converted to compound (7) by reacting with a silylating agent. For example, 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, N, Sodium iodide, potassium iodide, tetrabutylammonium iodide, odor in an inert solvent such as amide solvents such as N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof Organic bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclononene, pyridine, etc., lithium diisopropylamide, in the presence or absence of an additive such as sodium bromide or potassium bromide The Metal amide bases such as sodium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, alkali metal hydrides such as sodium hydride and potassium hydride, and chlorotrimethylsilane, bromotrimethylsilane, Compound (7) can be obtained by reaction with a silylating agent such as iodotrimethylsilane, trimethylsilyl trifluoromethanesulfonate and the like. Preferably, the compound (7) of the present invention can be obtained by reacting with triethylamine and trimethylsilyl trifluoromethanesulfonate in 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 (7) can be converted to compound (8) by reacting with an oxidizing agent. For example, 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, N, Sodium hydrogen carbonate, potassium hydrogen carbonate, potassium carbonate, sodium carbonate in an inert solvent such as amide solvents such as N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, acetonitrile, water, or a mixed solvent thereof 3-chloroperbenzoic acid in the presence or absence of additives such as calcium hydroxide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, pyridine, acetic acid and the like Acid, perbenzoic acid, monoperoxyphthalic acid Monoperoxyphthalic acid magnesium salt, peracids such as peracetic acid; hydrogen peroxide in the presence of a catalyst such as methyltrioxorhenium or tris (cetylpyridinium) peroxotungstophosphate (PCWP); nitriles such as trichloroacetonitrile or acetonitrile Hydrogen peroxide in the presence of a compound; hydrogen peroxide in the presence of a nitrile compound such as trichloroacetonitrile or acetonitrile and a ketone compound such as acetone; oxone ( ₂ KHSO ₅ · KHSO ₄ · K _{2 in the} presence of a ketone compound such as acetone SO ₄ ); Dimethyldioxirane, tert-butyl hydroperoxide, osmium tetraoxide and N-methylmorpholine-N-oxide, lead tetraacetate, iodosylbenzene and boron trifluoride diethyl etherate complex, chromyl chloride, ozone, etc. Agent and By response, it can be converted into the compound (8) (Organic Reactions, see 2003,62,1-356). Preferably, the compound (8) of the present invention is obtained by reacting with methyltrioxorhenium and hydrogen peroxide in the presence of pyridine, acetic acid in acetonitrile solvent at -20 to 80 ° C for 30 minutes to 1 day. it can.

Step 9: Compound (8) can be converted to compound (9) by reacting with an alkylating agent. Hydrocarbon solvents such as benzene, toluene, hexane and cyclohexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, tetrahydropyran, diethyl ether and 1,2-dimethoxyethane, N, N Trifluoromethanesulfonic acid, bistrifluoromethanefluoromethanesulfonimide, trifluoroacetic acid in an inert solvent such as an amide-based solvent such as dimethylformamide, N-methyl-2-pyrrolidinone, dimethylsulfoxide, water, or a mixed solvent thereof , Bronsted acids such as hydrogen chloride and perchloric acid, or boron trifluoride-diethyl ether complex, zinc chloride, tin chloride, trimethylsilyl trifluoromethanesulfonate, scandium trifluoromethanesulfonate (II ), The presence of trifluoromethanesulfonic acid ytterbium (III) a Lewis acid, such as can be derived by reacting the compound represented by the formula ^{R 1 R 5 CHOC (= NH} ) CCl 3. Formula R ¹ R ⁵ CHOC (= NH) CCl ₃
The compound represented by 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 a method described in the literature. (J. Chem. Soc., Perkin Trans. 1, 1985, 2247-225.
0, Tetrahedron Lett. , 1996, 37, 1481-1484). Preferably, a compound represented by the formula R ¹ R ⁵ CHOC (= NH) CCl ₃ in a tetrahydropyran solvent in the presence of trifluoromethanesulfonic acid, and at -20 to 50 ° C for 30 minutes to 1
Compound (9) can be obtained by reacting for 1 day (J. Chem. Soc., Chem. Commun. 1981, 1240-1241, J. Chem. Soc., Perkin Trans. 1, 1985, 2247-2250. reference).
In addition, hydrocarbon solvents such as benzene, toluene, hexane and cyclohexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, tetrahydropyran, diethyl ether and 1,2-dimethoxyethane, N Sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, in an inert solvent such as amide solvents such as N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof Inorganic bases such as cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium hydroxide, potassium hydroxide, silver (I) oxide, silver (I) carbonate, silver (I) trifluoromethanesulfonate, lithium diisopropylamide, lithium Hexamethyldisilage , Metal amide bases such as sodium hexamethyldisilazide, potassium hexamethyldisilazide, triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclononene, pyridine, 4-dimethylaminopyridine, etc. Or an alkoxide base such as potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, etc., in the presence or absence of a suitable activating agent such as tetrabutyl ammonium iodide, etc. It can be derived by reacting with a compound represented by ¹ R ⁵ CH-X. Here, X represents a leaving group other than OC (= NH) CCl ₃ , and examples thereof include a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyloxy group, a p-bromobenzenesulfonyloxy group, and a p-chlorobenzenesulfonyl group. And oxy, p-nitrobenzenesulfonyloxy, benzenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy and the like. Preferably, a compound represented by the formula R ¹ R ⁵ CH-Cl and a compound represented by the formula R ¹ R ⁵ CH-Cl in a chloroform solvent in the presence of silver carbonate (I), silver trifluoromethanesulfonate (I), and tetrabutylammonium iodide The reaction can be carried out at 30 ° C. for 30 minutes to 1 day to give a compound (9).

Step 10: A compound (10) can be obtained by subjecting the 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, benzene , Hydrocarbon solvents such as toluene and hexane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and benzotrifluoride, ether solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, N, N-dimethyl Titanium (IV) isopropoxide, titanium (IV) methoxide, titanium (IV) in an inert solvent such as formamide, an amide solvent such as N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof Ethoxide, titanium (IV) Pokishido, the presence of a Lewis acid such as titanium (IV) butoxide, by reaction with (R) -2-methyl-2-sulfinamide can be converted into the compound (13). Preferably, the compound of the present invention (10) is reacted with (R) -2-methyl-2-sulfinamide in tetrahydrofuran solvent in the presence of titanium (IV) ethoxide at 0 to 80 ° C. for 30 minutes to 1 day. Can lead to

Step 11: Compound (10) can be converted to compound (11) by subjecting it to a cyano addition reaction (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, benzene , Hydrocarbon solvents such as toluene and hexane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and benzotrifluoride, ether solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, N, N-dimethyl Inorganic bases such as cesium fluoride, potassium fluoride, sodium fluoride and the like in an inert solvent such as amide solvents such as formamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof lithium Diisopropylamide, lithium hexamethyldi Metal amide bases such as azide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclononene, pyridine, 4-dimethylaminopyridine Etc. or in the presence or absence of alkoxide bases such as potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide etc. trimethylsilyl cyanide, hydrogen cyanide, sodium cyanide, sodium cyanide, potassium cyanide, acetone cyanohydrin, diethyl To react by adding a cyanating agent such as cyanophosphonate, diethylaluminum cyanide, tert-butyldimethylsilyl cyanide, tributyltin cyanide, etc. Ri, can be converted into the compound (11). Preferably, the compound (11) of the present invention can be obtained by reacting with trimethylsilyl cyanide in the presence of cesium fluoride in tetrahydrofuran solvent at -20 to 80 ° C for 30 minutes to 1 day.

Step 12: Compound (12) can be leaded by reacting compound (11) 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, benzene Hydrocarbon solvents such as toluene, hexane and cyclohexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, tetrahydropyran, diethyl ether and 1,2-dimethoxyethane, N, N- Trifluoromethane sulfonic acid, bis trifluoromethane fluoro methane sulfone imide, trifluoroacetic acid, in an inert solvent such as an amide solvent such as dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof salt Hydrogen, Bronsted acid such as perchloric acid, or boron trifluoride-diethyl ether complex, zinc chloride, tin chloride, trimethylsilyl trifluoromethanesulfonate, scandium trifluoromethanesulfonate (III), ytterbium trifluoromethanesulfonate (III) Compound (12) can be obtained by reaction with a Lewis acid such as Preferably, the compound (12) can be obtained by reacting with a hydrogen chloride / ethanol solution at -20 to 50 ° C for 30 minutes to 1 day in a tetrahydrofuran solvent.

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

A representative method for producing the compound of the present invention represented by (IC) is shown in the following scheme C. The following method is an illustration of a method for producing the compound of the present invention and is not limited thereto. In the examples of the following production methods, 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 compound is obtained by subjecting the amino group of compound (II) -C to a general allyloxycarbonyl group-protecting reaction (see Protective Groups in Organic Synthesis Fourth Edition, John Wiley & Sons, INC.). It can lead to (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, N, N-dimethylformamide In an inert solvent such as an amide solvent such as N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof, triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine, 4- (N, N- Reaction with allyl chloroformate in the presence or absence of organic bases such as dimethylamino) pyridine and 2,6-di-t-butylpyridine, or inorganic salts such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate Leads to the compound (13) Door can be.

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

Step 16: The compound (15) is a compound of the formula L-CH (R ³ ) -O-C (O) -R ² (wherein L represents a leaving group, for example, a halogen atom, p-toluene) And sulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group and the like) and hydrocarbon solvents such as benzene, toluene, hexane and cyclohexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, tetrahydrofuran, diethyl Ethers, ether solvents such as 1,2-dimethoxyethane, amide solvents such as N, N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or inert solvents such as mixed solvents thereof , Sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate Inorganic bases such as cesium carbonate, cesium hydrogen carbonate, sodium hydroxide and potassium hydroxide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, metal amides such as sodium amide, triethylamine, pyridine, diisopropylethylamine, 4- ( Or N, N-dimethylamino) pyridine, an organic base such as 2,6-di-tert-butylpyridine, a base such as potassium tert-butoxy, or in the presence of a suitable activating agent such as sodium iodide or It can lead by making it react in absence. Preferably, in the mixed solvent of chloroform and water, in the presence of potassium carbonate and tetrabutylammonium hydrogen sulfate, the formula Cl-CH (R ³ ) -O-C (O) -R ² or the formula Br-CH (R ³ Compound (15) can be obtained by reacting with a compound represented by -O-C (O) -R ² at room temperature to 80 ° C for 2 hours to 1 day.

Step 17: General Deprotection Reaction of Compound (15) (Protective Groups
in Organic Synthesis 4th Edition, John Wiley & Sons, INC. The compound (I-C) of the present invention can be obtained by subjecting to (reference). For example, a hydrocarbon-based solvent such as benzene, toluene, or hexane, for example, in the presence of a zero-valent palladium catalyst such as tetrakistriphenylphosphine palladium (0) and a metal catalyst regeneration reagent such as 1,3-dimethylbarbituric acid Of allyl group and allyloxycarbonyl group in an inert solvent such as halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, or mixed solvents thereof Deprotection can lead to a compound (IC) which is a compound of the present invention. Preferably, the compound of the present invention is produced by reacting compound (15) in the presence of tetrakistriphenylphosphinepalladium (0) and 1,3-dimethylbarbituric acid in chloroform at room temperature to 50 ° C. for 2 to 8 hours. (I-C).

  Hereinafter, the present invention will be described in more detail by way of examples and test examples, but these do not limit the present invention, and may be changed within the scope of the present invention.

  In the following examples, Reveleris Silica Flash Cartridge for Grace Inc., and YMC-DispoPack AT ODS-25 Inc. for YMC Inc., were used for Grace Inc. when purified using column chromatography.

In the following examples, Daicel's column and flow rate, analysis / preparation time when 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 following production examples and examples, purification by preparative high performance liquid chromatography (HPLC) was performed under the following conditions.
Machine: Gilson Trilution LC
Column: YMC YMC-Actus Triant 5.0μm 50x30mm
Solvent: A solution; water containing 0.1% trifluoroacetic acid, B solution; Acetonitrile containing 0.1% trifluoroacetic acid, or A solution; water containing 0.1% formic acid, B solution; acetonitrile containing 0.1% formic acid Gradient: 0 minutes (liquid A / liquid B = 90/10), 11 minutes (liquid A / liquid B = 20/80), 12 to 13.5 minutes (liquid A / liquid B = 5/95)
Flow rate: 40 mL / min

Each device data described in the following examples were measured by the following measuring devices.
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-ECA 600 (Nippon Electron)
, 400 MHz; AVENCE III HD 400 (Bruker)
X-ray structural analysis: R-AXIS RAPID II (Rigaku)
The abbreviations in nuclear magnetic resonance (NMR) spectra used in the examples are indicated below.
s: singlet, d: doublet, t: triplet, q: quartet, sxt: sixt, dd: doublet doublet, dd: doublet doublet doublet (Doublet doublet doublet), dt: doublet triplet, td: triplet doublet, qd: quartet doublet, m: multiplet, br: broad, J: Coupling constant, Hz: Hertz, CHLOROFORM-d: deuterated chloroform , DMSO-d6: deuterated dimethyl sulfoxide, MeOH-d4: deuterated methanol

In the following reference examples and examples, the compound name is ACD / Name 2015 (ACDLabs 2015, Advanced Chemistry Development
Inc. It was named by.

In the 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 bicarbonate), NH ₄ Cl (ammonium chloride), DMF (N, N-dimethylformamide), EtOAc (ethyl acetate), CHCl 3 ₃ (chloroform), THF (tetrahydrofuran), MeOH (methanol), EtOH (ethanol), IPA (isopropyl alcohol), H ₂ O (water), Pd (PPh ₃ ) ₄ [tetrakistriphenylphosphine palladium (0)], brine (saturated brine), HCl (hydrogen chloride).

Example 1 (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({(1R) -1-[({[({ Synthesis of 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

Compound (II) -1 (1.5 g, 4.58 mmol) (see WO 03/061698)
Saturated aqueous NaHCO ₃ solution (16 mL, 1
8.32 mmol) was added and stirred at room temperature for 10 minutes. The allyl chloroformate (0.96 mL, 9.17 mmol) was dripped there, and it stirred at room temperature for 18 hours. The solution was basified by addition of water, saturated aqueous NaHCO ₃ solution and then washed with EtOAc. The aqueous layer was subsequently acidified with 2 M hydrochloric acid, extracted with EtOAc and dried over Na ₂ SO ₄ . The insoluble material was separated by filtration, and the solvent was evaporated under reduced pressure to give the title compound (1.9 g) (brown amorphous).
1 H 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

Allyl chloroformate (0.36 mL, 3) in 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. .46 mmol) was added dropwise and stirred for 30 minutes. The N, N- dimethyl 4-aminopyridine (0.070g, 0.58 mmol) was added there, and it returned to room temperature, and stirred for 2.5 hours. Water, 2 M hydrochloric acid was added to acidify the solution and then extracted with EtOAc. The extract was dried over Na ₂ SO ₄ , the insoluble matter was separated by filtration, and the solvent was evaporated under reduced pressure to give the title compound (1.0 g) (brown amorphous).
1 H 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 )

K ₂ CO ₃ (0.096 g, 0.70 mmol), 18-crown-6 (0.15 mL), in a DMF solution (3.3 mL) of the compound (0.30 g, 0.66 mmol) obtained in (2) 0.70 mmol) was added. Add (1R) -1-chloroethyl (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl carbonate (see WO2013 / 180271) (0.42 g, 1.59 mmol) there. Stir at room temperature for 18 hours. The reaction solution is added dropwise to a saturated aqueous NH ₄ Cl solution, and then extracted with EtOAc.
Washed with ine. After drying over Na ₂ SO ₄ , insolubles were filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Grace 12 g, n-Hexane / EtOAc = 95 / 5-60 / 40) and (Grace 12 g, n-Hexane / EtOAc = 95 / 5-80 / 20). , Colorless oil (0.31 g) was obtained. This is dissolved in CHCl ₃ (2.3 mL) and 1,3-dimethyl barbituric acid (0.072 g, 0.46 mmol) and Pd (PPh ₃ ) ₄ (0.013 g, 0.01 mmol) are added and room temperature The mixture was stirred for 1 hour. The reaction solution is concentrated under reduced pressure and reverse phase silica gel column chromatography (YMC C18 12 g, H ₂ O / MeCN = 95/5 to 5 /
It refine | purified in 95). To the residue obtained by concentrating the fractions, MeOH is added, and 1 at room temperature
After stirring for time, precipitated crystals were collected by filtration to give the title compound (0.097 g) (colorless solid).
1 H 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] +

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

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) The title compound (0.018 g) was obtained in the same manner as in Example 1- (3) using cyclohexyl carbonate (see WO 2013/180271) (0.42 g, 1.59 mmol) (colorless solid).
1 H 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

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
The title compound (0.093 g) was obtained in the same manner as in Example 1- (3) using O2013 / 180271) (0.32 g, 1.33 mmol) (colorless solid).
1 H NMR (600 MHz, DMSO-d6) δ ppm 1.40 to 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, m) d, J = 12.0 Hz), 6.86 (1 H, q, J = 5.4 Hz), 7.12 to 7.17 (2 H, m), 7.29 to 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

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)
The title compound (0.153 g) was obtained in the same manner as in Example 1- (3) using (2013/180271) (0.32 g, 1.33 mmol) (colorless solid). Further, the absolute configuration of the obtained compound (Example 4) was determined by X-ray structural analysis.
1 H 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 [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

The same procedure as in Example 1- (3), 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) Gave the title compound (0.023 g) (colorless solid).
1 H 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] +

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

Example 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 (0.091 g) was obtained in the same manner as in 1- (3). This was dissolved in CHCl ₃ (1.2 mL), and 4 M HCl in dioxane (0.12 mL) was added dropwise at room temperature and stirred for 4 hours. The precipitated solid was collected by filtration to give the title compound (40 mg) (light yellow solid).
1 H 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

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), 0.1. 2
The title compound (52 mg) was obtained in the same manner as in Example 1- (3) using 4 mmol) (colorless solid).
1 H 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] +

Example 8 (1R, 2R, 3R, 5R, 6R) -2-amino-3-[(3,4-difluorophenyl) methoxy] -6-fluoro-2-({(1R) -1-[({ Synthesis of [(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

The title compound (1.7 g) was obtained from compound (II) -2 (1.5 g, 3.97 mmol) (see WO 03/061698) in the same manner as in Example 1- (1) (light yellow amorphous) .
1 H 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

Using the compound (1.7 g, 3.96 mmol) obtained in (1) as a raw material, the title compound (1.8 g) was obtained in the same manner as in Example 1- (2) (brown amorphous).
1 H 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 (implementation Example 8)

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) The title compound (135 mg) was obtained in the same manner as in Example 1- (3) using .40 g (1.53 mmol) (colorless solid).
1 H 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] +

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

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) The title compound (19 mg) was obtained in the same manner as in Example 1- (3) using cyclohexyl carbonate (0.40 g, 1.53 mmol) (colorless solid).
1 H 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] +

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

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) .
The title compound (149 mg) was obtained in the same manner as in Example 1- (3) using 31 g (1.28 mmol) (colorless solid).
1 H 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

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 .
The title compound (123 mg) was obtained in the same manner as in Example 1- (3) using 31 g (1.28 mmol) (colorless solid).
1 H 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

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, 0.1. 8
The title compound (61 mg) was obtained in the same manner as in Example 1- (3) using 5 mmol) (colorless amorphous).
1 H 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 (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-2-({(1R) -1-[({[(1R, 2S, 5R) -5-methyl-2 Synthesis of (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-fluoro-2-({[(prop-2-en-1-yl) oxy] carbonyl} amino) -3-propoxybicyclo [3.1 .0] Hexane-2,6-dicarboxylic acid

The title compound (3.4 g) was obtained in the same manner as in Example 1- (1), using Compound (II) -3 (3.0 g, 11.48 mmol) (see WO 03/061698) as a starting material Pale yellow amorphous).
1 H 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-ene) -1-yl) oxy] carbonyl} amino) -3-propoxybicyclo [3.1.0] hexane-2-carboxylic acid

The compound (1.7 g, 4.95 mmol) obtained in (1) was used as a raw material, and the title compound (1.8 g) was obtained in the same manner as in Example 1- (2).
1 H 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] +

(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)

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) The title compound (46 mg) was obtained in the same manner as in Example 1- (3) using .49 g (1.87 mmol) (colorless solid).
1 H 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

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) The title compound (100 mg) was obtained in the same manner as in Example 1- (3) using cyclohexyl carbonate (0.49 g, 1.87 mmol) (colorless solid).
1 H 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] +

Example 15 (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-2-({1-[({[(1S, 2R, 5S) -5-methyl-2- (propane-) Synthesis of 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

A solution of D-menthol (5.0 g, 31.99 mmol) and pyridine (2.6 mL, 31.99 mmol) in CHCl ₃ (36 mL) was cooled to −60 ° C. with an acetone-dry ice bath, and carbonochlorid acid 1 -Chloroethyl (3.67 mL, 33.59 mmol) was added dropwise over 10 minutes. After stirring for 30 minutes at -60 ° C, the mixture was transferred to an ice bath, and the temperature was raised to 0 ° C and water was added. The organic layer was separated, washed with brine and dried over MgSO ₄ . After the insolubles were separated 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).
1 H 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-ene -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

The compound (0.77 g, 2.94 mmol) obtained in (1) in a DMF solution (7 mL) of the compound (0.56 g, 1.47 mmol) obtained in Example 13- (2) and K ₂ CO ₃ (0.30 g, 2.20 mmol) and NaI (0.44 g, 2.94 mmol) were added and stirred at 50 ° C. for 3 and a half hours. The reaction solution was cooled to room temperature and water was added to separate it. After extraction of the aqueous layer with EtOAc, the combined organic layers were washed with 5% brine and brine. After drying over MgSO ₄ , the insoluble matter was separated by filtration and the solvent was evaporated 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 object).
1 H 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)

(3) 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-2-({[(prop-2-en-1-yl) oxy] carbonyl} amino) -3-propoxybicyclo [3. 1.0] Resolution of hexane-2, 6-dicarboxylate

The compound obtained in Example 15 (2) is separated by chiral column chromatography (CHIRALPAK ID, n-Hexane / IPA = 7: 3), 1st peak · Example 15 (3) -A (0. 14 g) and 2nd peak. Example 15 (3) -B (0.20 g) were obtained (both are 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-[{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)

CHCl ₃ solution of Example 15 (3) -A (0.14g, 0.23mmol) (2.3mL
1) 1,3-Dimethylbarbituric acid (0.036 g, 0.23 mmol) and Pd (PPh ₃ ) ₄ (0.004 g, 0.0035 mmol) were added and stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, MeCN (5 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 1.5 hours. The precipitated crystals were collected by filtration to give the title compound Example 15-A (0.090 g) (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
1 H 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
1 H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (3 H, 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), 1.9-2-1.99 (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 (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({1-[({[(1S, 2R, Synthesis of 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

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 raw materials, The title compound (0.41 g) was obtained as a diastereomer mixture (colorless oil) by the same procedure as 15- (2).
1 H 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] +

(2) 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] Resolution of (carbonyl) amino) bicyclo [3.1.0] hexane-2,6-dicarboxylate

The compound obtained in Example 16 (1) is separated by chiral column chromatography (CHIRALPAK ID, n-Hexane / EtOH = 4: 1), and 1st peak · Example 16 (2) -A (0 .. 11 g) and 2nd peak. Example 16 (2) -B (0.15 g) were obtained (both are 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)

Example 15 starting from 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 raw materials In the same manner as in (4), the title compound Example 16-A (0.058 g) and Example 16-B (0.076 g) were obtained (both being colorless solids).
Example 16-A
1 H 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
1 H 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), 1.9 2-2.02 (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), 711-7.20 (2 H, 2 H, m)
m), 7.27-7.34 (2 H, m)
MS m / z: 554 [M + H] +

Example 17 (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({1-[({[(1S, 2R, Synthesis of 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-chloroethyl (1S, 2R, 4S) -1,7,7-trimethylbicyclo [2.2.1] heptan-2-yl carbonate

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).
1 H 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] +

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

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 raw materials, The title compound (0.41 g) was obtained as a diastereomer mixture (colorless oil) by the same procedure as 15- (2).
1 H 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] heptane-2-) [Il] oxy} carbonyl) oxy] ethyl} (1R, 2R, 3R, 5R, 6R) -6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({[(prop-2-ene-) Resolution of 1-yl) oxy] carbonyl} amino) bicyclo [3.1.0] hexane-2,6-dicarboxylate

The compound (0.41 g, 0.93 mmol) obtained in Example 17 (2) is separated by chiral column chromatography (CHIRALPAK IC, n-hexane / IPA = 6: 4) to give 1st peak Example 17 (3) -A (0.20 g) and 2nd peak. Example 17 (3) -B (0.15 g) were obtained (both are colorless oils).
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 (implementation Example 17-A, 17-B)

Starting from 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) as starting materials, respectively. The title compound Example 17-A (0.098 g) and Example 17-B (0.072 g) were obtained by a procedure similar to Example 15- (4) (both being colorless solids).
Example 17-A
1 H 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
1 H 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 to 1.30 (2 H, 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 18 (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-propoxy-2-({1-[({[(1S, 2R, 4S) -1,7,7 Synthesis of -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-[({[(1S, 2R, 4S) -1, 7, 7-trimethylbicyclo [2.2.1] heptane-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

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 diastereomer mixture (colorless oil) by the same procedure as 15- (2).
1 H 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 (2H, 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] +

(2) 6-prop-2-en-1-yl 2- {1-[({[(1S, 2R, 4S) -1, 7, 7-trimethylbicyclo [2.2.1] heptane-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

The compound obtained in Example 18 (1) was fractionated by chiral column chromatography (CHIRALPAK IC, n-Hexane / IPA = 40: 60), and 1st peak. 17 g) and 2nd peak. Example 18 (2) -B (0.12 g) were obtained (both are colorless oils).
Retention time: Example 18 (2)-A; 3.42 min., Example 18 (2)-B; 4.26 min.

(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) )

Example 15 using as raw materials each of Example 18 (2) -A (0.16 g, 0.27 mmol) and Example 18 (2) -B (0.11 g, 0.19 mmol) obtained in (2) In the same manner as in (4), the title compound Example 18-A (0.089 g) and Example 18-B (0.064 g) were obtained (both being colorless solids).
Example 18-A
1 H NMR (400 MHz, DMSO-d6) δ ppm 0.81 (3 H, s), 0.84 (6 H, d, J = 3.7 Hz), 0.95 (1
H, dd, J = 13.8, 3.5 Hz), 1.10 to 1.19 (1 H, m), 1.22 to 1.31 (1 H, m), 1.47 (3 H, d, J = 5.4 Hz), 1.62 to 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 (2 H, m) )
MS m / z: 486 [M + H] +
Example 18-B
1 H 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), 1.14-1.2 (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

Using (+)-borneol (2.5 g, 16.21 mmol) as a starting material, the title compound (4.2 g) was obtained in the same manner as in Example 15 (1) (colorless oil).
1 H 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] heptane-2-) [Il] oxy} carbonyl) oxy] ethyl} (1R, 2R, 3R, 5R, 6R) -6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({[(prop-2-ene-) 1-yl) oxy] carbonyl} amino) bicyclo [3.1.0] hexane-2,6-dicarboxylate

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 raw materials, The title compound (0.34 g) was obtained as a diastereomer mixture (colorless oil) according to a procedure similar to that of 15- (2).
1 H 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] heptane-2-) [Il] oxy} carbonyl) oxy] ethyl} (1R, 2R, 3R, 5R, 6R) -6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({[(prop-2-ene-) Resolution of 1-yl) oxy] carbonyl} amino) bicyclo [3.1.0] hexane-2,6-dicarboxylate

The compound (0.34 g, 0.50 mmol) obtained in Example 19 (2) is separated by chiral column chromatography (CHIRALPAK ID, n-Hexane / EtOH = 84: 16) to give 1st peak Example A component containing 19 (3) -A (0.085 g, colorless oil) and 2nd peak was obtained. 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 (implementation Example 19-A, 19-B)

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, respectively. The title compound Example 19-A (0.044 g) and Example 19-B (0.056 g) were obtained by a procedure similar to Example 15- (4) (both being colorless solids).
Example 19-A
1 H 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
1 H 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 20 (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-propoxy-2-({1-[({[(1R, 2S, 4R) -1,7,7 Synthesis of -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] heptane-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

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 raw materials The title compound (0.24 g) was obtained as a diastereomer mixture (colorless amorphous) by the same procedure as 15- (2).
1 H 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] +

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

The compound (0.24 g, 0.40 mmol) obtained in Example 20 (1) is separated by chiral column chromatography (CHIRALPAK ID, n-Hexane / EtOH = 85: 15) to give 1st peak Example 20 (2) -A (0.056 g, colorless oil) and 2nd peak. Example 20 (2) -B (0.10 g, colorless amorphous) were obtained.
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)

Using Example 20 (2) -A (0.056 g, 0.092 mmol) obtained in (2) as a raw material and following the same procedure as in Example 15- (4), the title compound Example 20 (0. 019 g) were obtained (colorless solid).
1 H 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 21 (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({1-[({[(1R, 2R, Synthesis of 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

The title compound (6.2 g) was obtained (colorless oil) in the same manner as in Example 15 (1), using (+)-phencole (5.0 g, 32.41 mmol) as a starting material.
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.86 (3 H, d, J = 7.8 Hz), 1.10-1.17 (7 H, 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] heptane-2-) [Il] oxy} carbonyl) oxy] ethyl} (1R, 2R, 3R, 5R, 6R) -6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({[(prop-2-ene-) 1-yl) oxy] carbonyl} amino) bicyclo [3.1.0] hexane-2,6-dicarboxylate

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 raw materials The title compound (0.29 g) was obtained as a diastereomer mixture (colorless amorphous) in the same manner as in Example 15- (2).
1 H 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] heptane-2-) [Il] oxy} carbonyl) oxy] ethyl} (1R, 2R, 3R, 5R, 6R) -6-fluoro-3-[(4-fluorophenyl) methoxy] -2-({[(prop-2-ene-) Resolution of 1-yl) oxy] carbonyl} amino) bicyclo [3.1.0] hexane-2,6-dicarboxylate

The compound (0.19 g, 0.28 mmol) obtained in Example 21 (2) is separated by chiral column chromatography (CHIRALPAK ID, n-Hexane / EtOH = 85: 15) to give 1st peak Example 21 (3) -A (0.061 g) and 2nd peak. Example 21 (3) -B (0.042 g) were obtained (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)

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 in the same manner as in Example 15- (4). (0.024 g) was obtained (colorless solid).
1 H 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] +

Production of Active Forms (II) -4 to (II) -14

Active compound (Compound No. (II) -4 to (II) -13) synthesized by the method according to the manufacturing method described in WO 03/061698 or WO 2011/061935 and the method according to the manufacturing method described in Example 38 The structural formula, compound name and instrumental data (1H NMR and detected MS spectral data) of the synthesized active compound (Compound No. (II) -14) are shown in Table A.

The structural formulas, compound names and instrumental data (1H NMR and detected MS spectral data) of the compounds synthesized by the same method as in Example 4 from the corresponding active substance described in [Table A] as a raw material are shown in Table B ((1) Example No. 22-30).

Table C shows the structural formulas, compound names and instrumental data (1H NMR and detected MS spectral data) of compounds synthesized by the same method as in Example 1 using the corresponding active substance described in [Table A] as a raw material. Example number 31-34).

Structural formula, compound name and instrumental data of compound synthesized by the same method as Example 1 (1H
The NMR and detected MS spectral data) are shown in Table D (example nos. 35-37). However, in the process corresponding to Example 1- (2), instead of (1R) -1-chloroethyl (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl carbonate, a known compound is used. It was carried out using certain chloromethyl cyclohexane carboxylate, chloromethyl benzoate or chloromethyl 2,2-dimethylpropanoate. (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) 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-[(cyclohexanecarbonyl) oxy] ethoxy} carbonyl) -6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane - - carboxylic acids can also be synthesized in the same manner.

Example 38 (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 synthesis

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

(R)-(+)-1,1-Bi-2-naphthol (3.72 g, 13.0 mmol) in THF solution (20 mL) of lithium aluminum hydride (230 mg, 6.061 mmol) at 1 to 4 ° C. A solution of THF (25 mL) was added. 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 (60.00 g, 730.8 mmol) was added dropwise and stirred at 40 ° C. for 4 hours. The insoluble material was separated by filtration at room temperature, and the filtrate was concentrated under reduced pressure to give 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. Analysis by chiral column chromatography gave an optical purity of 90.85% ee. Retention time: (R) form; 6.58 min, (S) form; 15.38 min (CHIRAL PAK AY-3, flow rate; 1.0 mL / min, nHexane / EtOH = 90/10)
1 H 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 (2 H, 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

Lithium chloride (51.89 g, 1.224 mol) at a temperature of 7 to 12 ° C. in a solution of the compound (202.39 g, 612 mmol) obtained in Example 38 (1) in N-methyl-2-pyrrolidinone (630 g), acetic acid After adding 36.75 g (612 mmol), the mixture was stirred at 125 ° C. for 4 hours. The reaction solution was cooled to room temperature, toluene and 10% brine were added, and then separated, and the organic layer was washed twice with 10% brine. After drying with anhydrous sodium sulfate, it was separated. After distilling off the solvent under reduced pressure, it was azeotroped twice with IPA. IPA (30 mL) was added and heated to 50.degree. After the heating of the mixed solution was stopped, n-heptane (30 mL) was added, the mixture was ice cooled with stirring, and the precipitated solid was collected by filtration. Ice-cold mixed solvent of IPA and n-heptane (1/1
, 45 mL) and then through-flow drying with nitrogen to give the title compound (53.87 g) as a single enantiomer (light brown solid). The optical purity was> 99% ee by analysis by chiral column chromatography. The spectral data were confirmed to be identical to the compounds obtained by the methods 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).
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (3 H, t, J = 7.1 Hz), 1.99-2.18 (4 H, 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] hexa-2-en-6-carboxylate

Example 38 (2) Ethyl (1S, 5R, 6S) -2-oxobicyclo [3.1.0] hexane-6-carboxylate (5.0 g, 29.73 mmol) in toluene 23.1 mL) triethylamine (6.22 mL, 44.59 mmol) and trimethylsilyl triflate (7.93 g, 35.67 mmo) under ice-cooling in the solution
l) was sequentially added dropwise and stirred for 1 hour. Water (60 mL) was added and stirred for 30 minutes. The organic layer and the aqueous layer were separated, and the obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL). After drying over anhydrous sodium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to give the title compound (9.91 g, 28.7 mmol). It was used for the next reaction without further purification operation.
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

Ice water cooled methyltrioxorhenium (VII) (35.8 mg, 0.144 mm)
Acetic acid (173 mg, 2.87 mmol), pyridine (68.2 mg, 0.86 mmol), 30% aqueous hydrogen peroxide (4.99 mL) in a suspension of ol) in acetonitrile (28.7 mL) , 48.9 mmol) was added dropwise sequentially. Ethyl (1S, 5R, 6S) -2-[(trimethylsilyl) oxy] bicyclo [3.1.0] hexa-2-en-6-carboxylate obtained in Example 38 (3) (6.91 g A solution of 28.7 mmol) 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 the mixture was stirred at room temperature for 1 hour. Aqueous solution of sodium carbonate (609 mg, 5.75 mmol) in ice water (5.0 mg)
An aqueous solution (50 mL) of sodium thiosulfate pentahydrate (12.5 g, 50.3 mmol) was successively added, and the mixture was stirred for 10 minutes. The mixture was extracted twice with ethyl acetate (100 mL). Anhydrous sodium sulfate was added to the obtained organic layer, and allowed to stand at room temperature for 14 hours. After filtration, it was concentrated under reduced pressure. To the residue was added isopropyl ether (50 mL) and the mixture was stirred, and the precipitated solid was collected by filtration. The title compound was obtained (3.26 g) (colorless solid).
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 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] +

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

Ethyl (1S, 3R, 5R, 6S) -3-hydroxy-2-oxobicyclo [3.1.0] hexane-6-carboxylate obtained in Example 38 (4) (0.53 g, 2
. Trifluoromethanesulfonic acid under ice-cooling to a solution of 88 mmol) and (4-fluorophenyl) methyl 2,2,2-trichloroethanimidate (1.25 g, 4.60 mmol) in tetrahydropyran (3.0 mL) (0.065 mL, 0.575 mmol) was added dropwise and stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and then washed with saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Biotage SNAP Ultra 50 g, hexane: ethyl acetate = 100: 0 to 35:65
It refine | purified in. The title compound (0.59 g) was obtained (colorless oil).
1 H 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) Ethyl (1S, 3R, 5R, 6S) -3-[(4-fluorophenyl) methoxy] -2-{[(R) -2-methylpropane-2-sulfinyl] imino} bicyclo [3.1 .0 Synthesis of Hexane-6-carboxylate

Ethyl (1S, 3R, 5R, 6S) -3-[(4-fluorophenyl) methoxy] -2-oxobicyclo [3.1.0] hexane-6-carboxylate obtained in Example 38 (5) (1.00 g, 3.42 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (0.83 g, 6.84 mmol) in tetrahydrofuran (6.8 mL) solution At room temperature, titanium (IV) ethoxide (2.12 mL, 10.26 mm)
ol) was added and stirred at 70 ° C. for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and extracted with chloroform. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (Biotage)
It refine | purified in SNAP Ultra 50g, hexane: ethyl acetate = 100: 0-30: 70). The title compound (0.829 g) was obtained (colorless oil).
1 H 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) Ethyl (1S, 3R, 5R, 6S) -2-cyano-3-[(4-fluorophenyl) methoxy] -2-{[(R) -2-methylpropane-2-sulfinyl] amino} bicyclo Synthesis of [3.1.0] hexane-6-carboxylate

Ethyl (1S, 3R, 5R, 6S) -3-[(4-fluorophenyl) methoxy] -2-{[(R) -2-methylpropane-2-sulfinyl] obtained in Example 38 (6) Imino} bicyclo [3.1.0] hexane-6-carboxylate (0.83 g, 2.09
Cesium fluoride (1.59 g, 10.5 mmol) and trimethylsilyl cyanide (0.623 g, 6.2) under ice-cooling in a solution of mmol) in tetrahydrofuran (4.2 mL)
8 mmol) were sequentially added and stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and extracted with chloroform. The organic layer was separated and concentrated under reduced pressure. A mixture of hexane: ethyl acetate = 9: 1 was added to the residue and stirred, and then the precipitate was collected by filtration to give the title compound (0.77 g) (colorless solid).
1 H 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) Ethyl (1S, 2S, 3R, 5R, 6S) -2-amino-2-cyano-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-6-carboxylate Synthesis

Ethyl (1S, 3R, 5R, 6S) -2-cyano-3-[(4-fluorophenyl) methoxy] -2-{[(R) -2-methylpropane- obtained in Example 38 (7) 2-sulfinyl] amino} bicyclo [3.1.0] hexane-6-carboxylate (0.77
g, 1.81 mmol) in tetrahydrofuran (1.8 mL) under ice-cooling 2
The mol / L hydrochloric acid ethanol solution (4.5 mL, 9.00 mmol) was added, and it stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added and extracted with chloroform. The aqueous layer and the organic layer were separated, and the obtained organic layer was concentrated under reduced pressure. The title compound (0.51 g) was obtained by adding isopropyl ether to the residue and stirring (colorless solid).
1 H 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) (1S, 2R, 3R, 5R, 6S) -2-amino-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (Compound No. II) -15) synthesis

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

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

(1S, 2R, 3R, 5R, 6S) -2-amino-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6 obtained in Example 38 (9) Allyl chloroformate (0.49 mg, 1.58 mmol) in a mixture of 1,4-dioxane (3.2 mL) and saturated aqueous sodium hydrogen carbonate (5.6 mL) at room temperature 0.34 mL, 3.17 mmol) was added dropwise and stirred for 3 hours. Water and ethyl acetate are added, and after stirring for 10 minutes, the organic layer and the aqueous layer are separated, 2 M hydrochloric acid is added to the obtained aqueous layer to adjust to pH 1, extracted with ethyl acetate, and 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) (1S, 2R, 3R, 5R, 6S) -3-[(4-fluorophenyl) methoxy] -6-{[(prop-2-en-1-yl) oxy] carbonyl} -2- ( Synthesis of {[(prop-2-en-1-yl) oxy] carbonyl} amino) bicyclo [3.1.0] hexane-2-carboxylic acid

(1S, 2R, 3R, 5R, 6S) -3-[(4-fluorophenyl) methoxy] -2-({[(prop-2-en-1-yl)) obtained in Example 38 (10) Oxy] carbonyl} amino) bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (0.050 g, 0.12 mmol) in tetrahydrofuran (0.64 mL) at room temperature Aminopyridine (3.88 mg, 0.032 mmol), 4-methylmorpholine (0.021 mL, 0.19 mmol), allyl chloroformate (0.015 mL, 0.14 mmol) were added sequentially, and 4 hours It stirred. Saturated aqueous ammonium chloride solution was added, and 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.
Obtained 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 Synthesis of [3.1.0] hexane-2,6-dicarboxylate

(1S, 2R, 3R, 5R, 6S) -3-[(4-fluorophenyl) methoxy] -6-{[(prop-2-en-1-yl) oxy obtained in Example 38 (11) ] Carbonyl} -2-({[(prop-2-en-1-yl) oxy] carbonyl} amino) bicyclo [3.1.0] hexane-2-carboxylic acid (0.14 g, 0.33 mmol) Potassium carbonate (0.067 g, 0.48 mmol) was added to a solution of dimethylsulfoxide (3.3 mL) at room temperature, and after stirring for 10 minutes, (1R) -1-chloroethyl tricyclo [3.3.1 .1 ^3,7 ] decane-1-carboxylate (0.16 g, 0.65 mmol) was added and stirred for 16 hours. The reaction solution 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 (0.15 g) was obtained (pale yellow oil).
1 H 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 (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 synthesis

6-prop-2-en-1-yl 2-[(1S) -1-{[(3R, 5S) -tricyclo [3.3.1.1 ^3,7] obtained in Example 38 (12) ] 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] hexane-2,6-dicarboxylate (0.14 g, 0.21 mmol) in chloroform (0.73 mL) in solution with 1,3-dimethyl Barbituric acid (0.034 g, 0.22 mmol) and tetrakis (triphenylphosphine) palladium (0) (2.5 mg, 0.002 mmol) were sequentially added at room temperature and stirred for 3 hours. 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 to 5:95). The fractions containing the title compound were concentrated, isopropyl ether was added to the obtained residue and the mixture was stirred. The precipitate was collected by filtration to give the title compound (0.021 g) (colorless solid).
1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (3 H, d, J = 5.4 Hz), 1.64 to 1.76 (7 H, 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 [MH]-

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

(1S, 2R, 3R, 5R, 6S) -3-[(4-fluorophenyl) methoxy] -6-{[(prop-2-en-1-yl) oxy obtained in Example 38 (11) ] Carbonyl} -2-({[(prop-2-en-1-yl) oxy] carbonyl} amino) bicyclo [3.1.0] hexane-2-carboxylic acid (0.20 g, 0.46 mmol ) And (1R) -1-chloroethyl (1R, 2S, 5R) -5-methyl-2- (propan-2-yl) cyclohexyl carbonate (0.29 g, 1.11 mmol) according to Example 38 12) and in the same manner as in Example 38 (13), the title compound Example No. 39 (0.010 g) was obtained (colorless solid).
1 H 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 ((1S, 2R, 3R, 5R, 6S) -2-amino-3-[(4-fluorophenyl) methoxy] -6-({(1R) -1-[(tricyclo [3.3. Synthesis of ^1.1,3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid

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

1S, 2R, 3R, 5R, 6S) -3-[(4-fluorophenyl) methoxy] -2-({[(prop-2-en-1-yl) oxy] oxy obtained in Example 38 (10) ] Carbonyl} amino) bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (0.096 g, 0.24 mmol) in toluene (2.3 mL) in 37% formalin (0.06720) 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) (light 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 '-[ Synthesis of 1,3] oxazolidine] -3 ', 6-dicarboxylate

(1S, 2R, 3R, 5R, 6S) -3-[(4-fluorophenyl) methoxy] -5'-oxo-3 '-{[(prop-2-ene-1-ene) obtained in (1) Dimethyl sulfoxide (0.19 g, 0.476 mmol) of dimethyl) oxy] carbonyl} spiro [bicyclo [3.1.0] hexane-2,4 '-[1,3] oxazolidine] -6-carboxylic acid (0.19 g, 0.476 mmol) After adding potassium carbonate (0.714 mmol) to the solution at room temperature and stirring for 10 minutes, (1R) -1-chloroethyl tricyclo [3.3.1.1 ^3,7 ] decane-1- Carboxylate (0.16 g, 0.65 mmol) was added and stirred for 16 hours. The reaction solution was diluted with ethyl acetate and washed successively with saturated aqueous ammonium chloride solution and saturated brine. The obtained residue is subjected to silica gel column chromatography (Biotage SNAP Ultra
It refine | purified in 10 g, hexane: ethyl acetate = 95: 5-50:50). A mixture (0.088 g) containing the title compound was obtained (brown oil).
1 H 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)

(3) ((1S, 2R, 3R, 5R, 6S) -2-amino-3-[(4-fluorophenyl) methoxy] -6-({(1R) -1-[(tricyclo [3.3. Synthesis of ^1.1,3,7 ] decane-1-carbonyl) oxy] ethoxy} carbonyl) bicyclo [3.1.0] hexane-2-carboxylic acid

3'-prop-2-en-1-yl 6-{(1R) -1-[(tricyclo [3.3.1.1 ^3,7 ] decane-1-carbonyl) oxy obtained in (2) Ethyl] (1S, 2R, 3R, 5R, 6S) -3-[(4-fluorophenyl) methoxy] -5'-oxo-3'H-spiro [bicyclo [3.1.0] hexane-2, A solution of 4 '-[1,3] oxazolidine] -3', 6-dicarboxylate (0.088 g, 0.14 mmol) in chloroform (1.4 mL) in 1,3-dimethyl barbituric acid (0) .23 g, 0.14 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.2 mg, 0.0001 mmol) were sequentially added at room temperature and stirred for 3 hours. The reaction mixture was concentrated 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).
1 H 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 to 6.70 (1 H, m), 7.10 to 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 Test Human metabotropic glutamate receptor mGluR2 and mGluR3 stable expression CHO cells were treated with 10% dialyzed fetal bovine serum-containing Dulbecco's modified Eagle's medium [1% proline, 1 mM sodium pyruvate, 1 mM succinic acid, 37 ° C, 5% using 1 mM disodium succinate, 100 units / mL penicillin, 100 μg / mL streptomycin, 400 (mGluR2) or 300 (mGluR3) μg / mL Hygromycin B, 2 mM L-glutamine (additional)
Incubated under CO ₂ . The confluent cells were washed with PBS (-), detached with a cell scraper and centrifuged at 4 ° C., 1000 rpm for 5 minutes to recover the cells. The obtained precipitate is suspended in 20 mM HEPES buffer (pH 7.4) (mGluR2) or 20 mM HEPES buffer (pH 7.4) (mGluR3) containing 1 mM EDTA, and the suspension is Teflon (registered trademark). ) After homogenization with a homogenizer, sedimentation was again obtained by centrifugation at 48,000 xg for 20 minutes at 4 ° C. Further, the obtained precipitate was washed twice by centrifugation and homogenized with the above buffer to obtain a crude membrane fraction. The crude membrane fraction was subjected to binding test buffer (final concentration; 20 mM HEPES, 100 mM NaCl, 10 mM MgCl ₂ , 10 μM GDP, 10 μg / mL saponin, 0.
1% BSA) (mGluR2), (final concentration; 20 mM HEPES, 1 mM EDTA, 100 mM NaCl, 10 mM MgCl ₂ , 10 μM GDP, 10 μg / mL
It was diluted with saponin, 0.1% BSA (mGluR3). Compounds (II) -1 to (II) -15 were added to a crude membrane fraction of 10 μg / assay of membrane protein, and incubation was carried out at 30 ° C. for 20 minutes. Thereafter, final concentrations of 20 (mGluR2) or 1 (mGluR3) μM glutamate and [ ³⁵ S] GTPγS (final concentration of 0.15 nM) were added, and incubation was performed at 30 ° C. for 1 hour. After incubation, filter by suction on a Whatman GF / C filter, and filter the above with ice-cold 20 mM HEPES buffer (pH 7.4) (mGluR2) or 20 mM containing 1 mM EDTA.
The cells were washed with 1000 μL of HEPES buffer (pH 7.4) (mGluR3). A scintillation cocktail was added to the resulting filter and the membrane bound radioactivity was measured with a liquid scintillation counter. The residual radioactivity in the absence of glutamate was regarded as nonspecific binding, and the difference from the residual radioactivity in the presence of glutamate as specific binding. Non-linear analysis was used to obtain inhibition curves from specific binding inhibition rates at various concentrations of compounds (II) -1 to (II) -15. The concentrations (IC ₅₀ ) of compounds (II) -1 to (II) -15 at which specific binding was suppressed by 50% were calculated from the inhibition curve. The results are shown in Table 1 below.

Test Example 2: Stability Test in Solution The stability of the compound (IA) of the present invention or (I) in a hydrochloric acid solution (pH 1.2) and 20 mM phosphate buffer (pH 6.5) was confirmed as follows. It went according to the method of.
Dissolve the compound in hydrochloric acid, hydrochloric acid solution containing sodium chloride (pH 1.2) or disodium hydrogen phosphate, sodium dihydrogen phosphate, 20 mM phosphate buffer solution containing sodium chloride (pH 6.5), about 50 μg / mL A solution of a concentration (in the case of non-dissolution, around the saturation concentration) was prepared. The solution was incubated at 37 ° C. for 1 hour, and the compound concentration before and after the incubation was quantified by high performance liquid chromatography to calculate the remaining rate. In addition, when the solubility of the compound was low, it was not evaluated.
The residual rates of representative compounds in hydrochloric acid solution (pH 1.2) and 20 mM phosphate buffer (pH 6.5) are shown in Table 2 below.

NA not applicable because of low solubility

From the above, it was possible to assume that the compound of the present invention has good stability in a solution supposing the stomach and small intestine, and exists in a prodrug form in the digestive tract.

Test Example 3: Production Rate Test of Compound (II) -A or (II) in Liver S9 Fraction Compound of the Present Invention (IA) or Compound (II) -A in Liver S9 Fraction of (I) The confirmation of the formation rate of (II) was performed according to the following method.
Sodium-potassium phosphate buffer (0.25 mol / L, pH 7) containing liver S9 fraction (human: XenoTech, LLC / H0620.S9 / Lot. 0810471, monkey: XenoTech, LLC / P2000. S9 / Lot. 0910273) The compound of the present invention was added to 4) and incubated for 15 minutes in the presence of coenzyme (37 ° C.). The final concentration and protein concentration of the compound of the present invention in the reaction mixture were 1 μmol / L and 1 mg protein / mL, respectively. The incubated reaction mixture was quenched with 2 volumes of dimethyl sulfoxide and centrifuged (2150 × g, 4 ° C., 10 minutes) to remove proteins. The resulting supernatant was subjected to analysis by a liquid chromatography tandem mass spectrometry (LC-MS / MS) system.
A separation column is Shimadzu Shim-pack XR-ODS (2.2 μm, 30 mm × 3.0 mm ID), and a mobile phase is a 0.1% formic acid / acetonitrile solution (flow rate: 1.3 mL / min). The analyte was eluted in linear gradient mode. The MS / MS detection of the compound of the present invention (IA) or (I) and the compound (II) -A or (II) is a Triple TOF equipped with a TurboIonSpray interface.
It carried out in positive ion or negative ion detection mode using 5600 system or Triple Quad 5500 system (all are AB SCIEX company make).
The production rate of compound (II) -A or (II) in the liver S9 fraction of the compound of the present invention is shown in Table 3 below.

The compound of the present invention (IA) or (I) was converted to compound (II) -A or (II), and conversion of a prodrug to an active form was possible in human and monkey liver.

Test Example 4 Measurement of Compound (II) -A or (II) Plasma Concentration in Oral Administration of Monkey Compound (II) -A or (II) and Compound (IA) or (I) of the Present Invention The measurement of the plasma concentration of compound (II) -A or (II) after oral administration was performed according to the following method.
Compound (II) -A or (II) and the invented 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).
Before oral administration, approximately 0.6 mL of blood was collected from the anterior flexion vein at 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. In the analysis, 200 μL of an acetonitrile / methanol mixed solution containing an internal standard substance is added to 50 μL of a plasma sample melted under ice-cooling and stirred, and then centrifuged (3639 × g, 4 ° C., 10 minutes) The protein was removed. The resulting supernatant was subjected to LC-MS / MS analysis. The lower limit of quantification of compound (II) -A or (II) was all 1 ng / mL.
The maximum plasma concentration (C _max ) and bioavailability (BA) of Compound (II) -A or (II) when orally administered to monkeys for representative compounds 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.

By orally administering the compound of the present invention (IA) or (I), the exposure of the compound (II) -A or (II) was dramatically improved, and an excellent prodrug effect was exhibited.

According to the present invention, a medicament comprising a prodrug of a compound (II) -A or (II) having a strong action on a group II metabotropic glutamate receptor, in particular, is modulated by a group II metabotropic glutamate receptor antagonist Diseases such as mood disorders (including depression and bipolar disorder), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, motor disorders associated with muscle rigidity, sleep disorders, Huntington's chorea, eating disorders, It has become possible to provide preventive or therapeutic agents for drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral failure, cerebral edema, spinal cord injury, head trauma, inflammation, immune related diseases etc. It is expected to contribute to

Claims (18)

Formula (I-A)
[In the formula (I-A),
R ¹ represents a C _1-6 alkyl group, a heteroaryl group (the heteroaryl group may be substituted with one halogen atom (or chlorine atom)), or the following formula (IIIA):
R ^x is 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 the C _1-6 alkoxy group are substituted with 1 to 3 halogen atoms And may be
R ^y is 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 the C _1-6 alkoxy group are substituted with 1 to 3 halogen atoms And may be
R ^{1 ′} represents a hydrogen atom or a C _1-6 alkyl group,
Or R ¹ and R ^{1 ′} may be taken together with adjacent carbon atoms to 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)
, C _3-8 cycloalkyl group (the C _3-8 cycloalkyl group may be substituted with 1 to 3 C _1-6 alkyl groups), C _3-8 cycloalkoxy group (said C _{3- The 8-} cycloalkoxy group may be substituted with 1 to 3 C _1-6 alkyl groups, and the C _3-8 cycloalkoxy group may be C _1-5 between two different carbon atoms in the ring. Alkylene bridged), an adamantyl group (the adamantyl group may be substituted by 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,
R ⁴ represents a hydrogen atom or a fluorine atom. ]
Mood disorder (including depression and bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, and sleep comprising as an active ingredient a compound represented by or a pharmaceutically acceptable salt thereof A drug for the prophylaxis or treatment of a disease selected from the group consisting of a disorder, Huntington's chorea, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune related diseases. A mood disorder (including depression and bipolar disorder), an anxiety disorder, a cognitive disorder, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R ⁴ is a fluorine atom. Select from the group consisting of developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's chorea, eating disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, immune related diseases Drugs for preventing or treating diseases. R ² is a C _3-6 alkyl group or a C _3-8 cycloalkyl group (wherein the C _3-8 cycloalkyl group is 1 to 3)
C 1 -C ₆ alkyl groups, C _3-8 cycloalkoxy groups (wherein the C _3-8 cycloalkoxy groups are substituted with 1 to 3 C _1-6 alkyl groups) The C _3-8 cycloalkoxy group may be further bridged by C _1-5 alkylene between two different carbon atoms in the ring, an adamantyl group (the adamantyl group is 1 to 3). The mood disorder (depression, bipolarity) comprising the compound according to claim 2, which is a C _1-6 alkyl group, optionally substituted, or a phenyl group, or a pharmaceutically acceptable salt thereof, as an active ingredient Disorders), anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's chorea, eating disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head injury , Inflammation, immune related diseases, disease of the disease selected from the group consisting of Preventive or therapeutic agent. 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, and R ^{1 ′} is a hydrogen atom, or Show methyl group,
Alternatively, R ¹ and R ^{1 ′} may be taken together with adjacent carbon atoms to form cyclopentane, and R ² represents a structure of any of the following formula group (IIIB),
A mood disorder (depression, bipolar disorder, etc.) comprising the compound according to claim 2 or 3 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R ³ is a hydrogen atom or a C _1-6 alkyl group 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 trauma, inflammation And a preventive or therapeutic agent for a disease selected from the group consisting of immune related diseases. A mood disorder (including depression and bipolar disorder), an anxiety disorder, a cognitive disorder, development comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R ⁴ is a hydrogen atom. Selected from the group consisting of disorders, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington's chorea, eating disorder, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, immune related diseases Drugs for the prevention or treatment of R ¹ represents an ethyl group, 4-fluorophenyl group, 3,4-difluorophenyl group, 4-fluoro-3-methoxyphenyl group, 4- (trifluoromethyl) phenyl group, 3-fluorophenyl group, 4-methyl A phenyl group, a 6-chloropyridin-2-yl group, a 6-chloropyridin-3-yl group, a 5-chloropyridin-2-yl group, or a 2-methylpropyl group;
Whether 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 a structure of any of the following formula group (IIIB),
A mood disorder (including depression and bipolar disorder) comprising the compound according to claim 5, or a pharmaceutically acceptable salt thereof, as an active ingredient, wherein R ³ is a hydrogen atom or a C _1-6 alkyl group. Anxiety disorder, Cognitive disorder, Developmental disorder, Alzheimer's disease, Parkinson's disease, Sleep disorder, Huntington's chorea, Eating disorder, Drug dependence, Epilepsy, Cerebral infarction, Cerebral ischemia, Brain edema, Head trauma, Inflammation, Immune A preventive or therapeutic agent for a disease selected from the group consisting of related diseases. The mood disorder (depression, which contains the compound according to claim 5 or 6 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R ¹ is a 4-fluorophenyl group or a 3,4-difluorophenyl group. Anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's chorea, eating disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head An agent for the prophylaxis or treatment of a disease selected from the group consisting of head trauma, inflammation and immune related diseases. R ¹ is a 4-fluorophenyl group,
R ^{1 ′} is a hydrogen atom,
A mood disorder comprising the compound according to any one of claims 5 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R ² represents a structure of any of the following formula group (IIIb): Depression, including bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, sleep disorder, Huntington's chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, brain An agent for the prophylaxis or treatment of a disease selected from the group consisting of edema, head trauma, inflammation and immune related diseases.
The mood disorder (including depression and bipolar disorder) comprising the compound according to any one of claims 5 to 8 wherein R ³ is a methyl group, or a pharmaceutically acceptable salt thereof as an active ingredient. Anxiety disorder, Cognitive disorder, Developmental disorder, Alzheimer's disease, Parkinson's disease, Sleep disorder, Huntington's chorea, Eating disorder, Drug dependence, Epilepsy, Cerebral infarction, Cerebral ischemia, Brain edema, Head trauma, Inflammation, Immune A preventive or therapeutic agent for a disease selected from the group consisting of related diseases. Formula (I)
[In the formula (I),
R ¹ represents an ethyl group, 4-fluorophenyl group or 3,4-difluorophenyl group,
R ² represents a structure of any of the following formula group (IIIa),
R ³ represents a hydrogen atom or a C _1-6 alkyl group. ]
Mood disorder (including depression and bipolar disorder), anxiety disorder, cognitive disorder, developmental disorder, Alzheimer's disease, Parkinson's disease, and sleep comprising as an active ingredient a compound represented by or a pharmaceutically acceptable salt thereof A drug for the prophylaxis or treatment of a disease selected from the group consisting of a disorder, Huntington's chorea, eating disorders, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, inflammation, and immune related diseases. A mood disorder (depression, bipolar disorder) comprising the compound according to claim 10, wherein R ² has a structure of any of the following formula group (IIIa ′), or a pharmaceutically acceptable salt thereof as an active ingredient: Anxiety disorders, cognitive disorders, developmental disorders, Alzheimer's disease, Parkinson's disease, sleep disorders, Huntington's chorea, eating disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, head trauma, An agent for the prophylaxis or treatment of a disease selected from the group consisting of inflammation and immune related diseases.
11. A mood disorder (depression, bipolar disorder or the like) comprising, as an active ingredient, the compound according to claim 10, wherein R ² has a structure of any of the following formula group (IIIb), or a pharmaceutically acceptable salt thereof: 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 trauma, inflammation And a preventive or therapeutic agent for a disease selected from the group consisting of immune related diseases.
The mood disorder (including depression and bipolar disorder) comprising the compound according to any one of claims 10 to 12 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein R ³ is a methyl group. Anxiety disorder, Cognitive disorder, Developmental disorder, Alzheimer's disease, Parkinson's disease, Sleep disorder, Huntington's chorea, Eating disorder, Drug dependence, Epilepsy, Cerebral infarction, Cerebral ischemia, Brain edema, Head trauma, Inflammation, Immune A preventive or therapeutic agent for a disease selected from the group consisting of related diseases. A mood disorder (including depression and bipolar disorder), an anxiety disorder, a cognitive disorder, a developmental disorder, Alzheimer's disease, which comprises the compound according to claim 1 shown below, or a pharmaceutically acceptable salt thereof as an active ingredient , Parkinson's disease, sleep disorder, Huntington's chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cerebral trauma, head injury, inflammation, immunity related disease selected from the group consisting of Or therapeutic agent:
(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 ^3,7,7 ] 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- (propane)] -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] heptane-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] Hpent-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] heptane-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 3.3.1.1 ^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. A mood disorder (including depression and bipolar disorder), an anxiety disorder, a cognitive disorder, a developmental disorder, Alzheimer's disease, which comprises the compound according to claim 1 shown below, or a pharmaceutically acceptable salt thereof as an active ingredient , Parkinson's disease, sleep disorder, Huntington's chorea, eating disorder, drug dependence, epilepsy, cerebral infarction, cerebral ischemia, cerebral edema, cerebral trauma, head injury, inflammation, immunity related disease selected from the group consisting of Or therapeutic agent:
(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 ^3,7,7 ] 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- (propane)] -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 3.3.1.
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. A mood disorder (including depression and bipolar disorder) comprising the compound according to any one of claims 1 to 4 or any one of claims 10 to 13 below, or a pharmaceutically acceptable salt thereof as an active ingredient 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 trauma, inflammation, Drugs for preventing or treating diseases selected from the group consisting of immune related diseases:
(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.
A mood disorder (including depression and bipolar disorder) comprising the compound according to any one of claims 1 to 4 or any one of claims 10 to 13 below, or a pharmaceutically acceptable salt thereof as an active ingredient 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 trauma, inflammation, Drugs for preventing or treating diseases selected from the group consisting of immune related diseases:
(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.
A mood disorder (including depression and bipolar disorder) comprising the compound according to any one of claims 1 to 4 or any one of claims 10 to 13 below, or a pharmaceutically acceptable salt thereof as an active ingredient 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 trauma, inflammation, Drugs for preventing or treating diseases selected from the group consisting of immune related diseases:
(1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-2-({(1R) -1-[({[(1R, 2S, 5R) -5-methyl-2- (propane)] -2-yl) cyclohexyl] oxy} carbonyl) oxy] ethoxy} carbonyl) -3-propoxybicyclo [3.1.0] hexane-6-carboxylic acid.