RU2780892C2 - Heterocyclic compound - Google Patents

Abstract

FIELD: organic chemistry; pharmaceutics.

SUBSTANCE: group of inventions relates to the field of organic chemistry and pharmaceutics; it is intended for use in the treatment of neurodegenerative diseases. A new compound of the formula (I) is presented, where A is C_3-10 cycloalkyl group substituted with 1-3 substitutes selected from (a) phenoxy group optionally substituted with 1-4 substitutes selected from (i) halogen atom, and (ii) optionally halogenated C_1-6 alkyl group, (b) phenoxy-C_1-6 alkyl group optionally substituted with 1-4 substitutes selected from (i) halogen atom, and (ii) optionally halogenated C_1-6 alkyl group, (c) benzyloxy group optionally substituted with 1-4 substitutes selected from (i) halogen atom, and (ii) optionally halogenated C_1-6 alkyl group, and (d) benzyloxy-C_1-6 alkyl group optionally substituted with 1-4 substitutes selected from (i) halogen atom, and (ii) optionally halogenated C_1-6 alkyl group, and optionally additionally substituted with 1-3 C_1-6 alkyl groups; L is a bond or C_1-3 alkylene group; ring D is 4- or 5-element nitrogen-containing heterocycle; n is equal to 1 or 2; X is -O- or -CH₂-; and both R^a and R^b are hydrogen atoms; or its pharmaceutically acceptable salt. In addition, specific compounds-derivatives of the formula (I), a drug, which is a monoacylglycerolipase inhibitor, containing the specified compound, as well as a method for inhibition of monoacylglycerolipase in a mammal, including administration to a mammal of effective amount of the compound or salt according to cl. 1, are described.

EFFECT: group of inventions provides effective inhibition of monoacylglycerolipase in a mammal.

9 cl, 5 tbl, 67 ex

Description

FIELD OF TECHNOLOGY

[0001]

The present invention relates to a heterocyclic compound having an inhibitory effect on monoacylglycerol lipase (sometimes referred to as "MAGL" in the present description), a drug containing the same, and the like.

[0002]

(prior art)

Arachidonic acid (sometimes referred to herein as "AA") and its in vivo product, an eicosanoid, have been reported to cause inflammation in the central and peripheral nervous system [Non-Patent Document 1: Science, vol. 294, pages 1871-1875, 2001]. An inhibitor that suppresses the arachidonic acid production pathway and the eicosanoid production pathway is promising as a therapeutic drug for inflammatory diseases, and non-steroidal anti-inflammatory drugs such as a cyclooxygenase inhibitor and the like are used as therapeutic drugs for inflammatory pain. However, when a cyclooxygenase inhibitor is used for a long time, digestive tract disorders sometimes develop as side effects, which creates a problem. In addition, circulatory problems such as myocardial infarction, cerebral infarction and the like have also created problems in recent years.

[0003]

It is assumed that brain inflammation accompanied by glial cell activation is a pathological change characteristic of neurodegenerative diseases (eg, Alzheimer's disease, etc.) [Non-Patent Document 2: Molecular Neurobiology (Mol. Neurobiol), vol. 41, pages 115-128, 2010]. It has been reported that anti-inflammatory drugs inhibit glial cell activation and inhibit neurodegenerative progression in an animal model of tau overexpression (human tau transgenic mouse, etc.), which is a pathological characteristic of Alzheimer's disease [Non-Patent Document 3: Neuron, vol. 53, pages 337-351, 2007]. In addition, the effectiveness of suppressing brain inflammation for the treatment of neurodegenerative diseases such as Alzheimer's disease and the like has been proposed [Non-Patent Document 4: Nature Reviews Neurology (Nat. Rev. Neurol.), vol. 6, pages 193-201, 2010], and a therapeutic drug that suppresses brain inflammation is promising as a therapeutic or prophylactic drug in neurodegenerative diseases.

[0004]

Monoacylglycerol lipase (MAGL) is an enzyme that hydrolyzes monoacylglycerol into fatty acid and glycerol. In the central nervous system, the substrate of MAGL is 2-arachidonoylglycerol (also referred to as 2-AG in the present specification), which is degraded into arachidonic acid and glycerol [Non-Patent Document 5: Chemistry and Physics of Lipids (Chem phys Lipids) vol. 121, pages 149-158, 2002]. In recent years, suppression of arachidonic acid and eicosanoid production, suppression of glial cell activation, suppression of inflammatory cytokine production, and reduction of the effect on Aβ plaque accumulation, which is the pathological diagnosis of Alzheimer's disease, have been reported in a cross-bred animal deficient in MAGL and amyloid β (herein also referred to as Aβ) with an overexpressing animal model (APP/PS1 double transgenic mouse, etc.) [Non-Patent Document 6: Cell Report (Cell Rep.), vol. 1, pages 617-623, 2012], and an inhibitor, etc., which inhibit the action of MAGL, are promising as a therapeutic or prophylactic drug in Alzheimer's disease.

[0005]

In addition, cannabinoid receptor 1 (herein referred to as CB1) and cannabinoid receptor 2 (herein referred to as CB2) have been identified as receptors for 2-AG, which is a substrate of MAGL [Non-Patent Document 7: Biochemical Pharmacology (Biochem. Pharmcol .) vol. 50, 83-90, 1995]. CB1 is mainly expressed in the region of the brain [non-patent document 8: Molecular Pharmacology (Mol. Pharmacol.), vol. 34, pages 605-613, 1988], and CB2 is expressed in immunocytes and glial macrophages in the brain region [non-patent document 9: Neuroscience Letters (Neurosci. Lett.), vol. 396, pages 113-116, 2006]. In recent years, it has been reported that a CB1 receptor agonist improves cognition [Non-Patent Document 10: Journal of Alzheimer's Disease (J. Alzheimers. Dis.), vol. 30, pages 439-459, 2012], and 2-AG, which is a substrate of MAGL, exhibits a protective effect against neuronal cell death due to Aβ [Non-Patent Document 11: Neuroscience, vol. 178, pages 159-168, 2011]. Therefore, a MAGL inhibitor that inhibits 2-AG degradation is promising as a therapeutic or prophylactic drug, which has the effect of not only relieving symptoms, but also suppressing disease progression by suppressing inflammation in the brain, nerve cell death, Aβ accumulation, and similar to that seen in Alzheimer's disease.

[0006]

Parkinson's disease, which is one of the neurodegenerative diseases, is a disease associated with movement disorders caused by degeneration of midbrain dopamine nerve cells, in which glial cell activation is reported [Non-Patent Document 12: Annals of Neurology (Ann. Neurol.) vol. 57, pages 168-175, 2005]. Although 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is known to induce cell death of the substantia nigra dopamine neuron, it has been shown to have a protective effect against neuronal cell death in MAGL-deficient mice [non-patent paper 13: Science, vol. 334, pages 809-813, 2011]. Therefore, inhibitors, etc., which inhibit the action of MAGL are promising as new therapeutic drugs for Parkinson's disease.

[0007]

Amyotrophic lateral sclerosis (herein referred to as ALS) is a disease associated with motor neuron degeneration, and there is currently no effective treatment. Glial cell activation in ALS has been reported [Non-Patent Document 14: Neurobiology of Disease (Neurobiol. Dis.) vol. 15, pages 601-609, 2004]. It has also been reported that CB2 activation suppresses disease progression in superoxide dismutase overexpressing mouse mutant, which is an animal model of ALS [Non-Patent Document 15: European Journal of Pharmacology (Eur. J. Pharmacol.), vol. 542, pages 100-105, 2006]. In addition, brain inflammation in MAGL-deficient mice has been reported to be suppressed by a decrease in arachidonic acid, which is a product of MAGL in vivo [Non-Patent Document 13: Science, vol. 334, pages 809-813, 2011]. Therefore, the MAGL inhibitor is promising as a new therapeutic drug for the treatment of ALS.

[0008]

Huntington's disease, which is one of the neurodegenerative diseases, is a disease in which neurological function is lost as a result of nerve cell death and brain inflammation due to polyglutamine aggregation. It has been reported that CB2 activation suppresses brain inflammation and exhibits a neuroprotective effect in the R6/2 mouse, which is an animal model of Huntington's disease [Non-Patent Document 16: Brain, vol. 132, pages 3152-3164, 2009]. In addition, it has been reported that brain inflammation is suppressed by a decrease in arachidonic acid, which is a product of MAGL, in MAGL-deficient mice [Non-Patent Document 13: Science, vol. 334, pages 809-813, 2011]. Therefore, the MAGL inhibitor is promising as a new therapeutic drug for the treatment of Huntington's disease.

[0009]

It has been reported that 2-AG, which is a substrate of MAGL, suppresses the progression of a disease state in an autoimmune encephalomyelitis model, that is, an animal model of multiple sclerosis, which is one of the central diseases of demyelination [Non-Patent Document 17: Brain Research (Brain Res.), vol. 1390, pages 126-141, 2011]. In addition, it has been reported that brain inflammation is suppressed by a decrease in arachidonic acid, which is a product of MAGL, in MAGL-deficient mice [Non-Patent Document 13: Science, vol. 334, pages 809-813, 2011]. Therefore, the MAGL inhibitor is promising as a new therapeutic drug for the treatment of multiple sclerosis.

[0010]

Traumatic brain injury (TBI) is a pathological condition that has an extremely detrimental effect on people's health, and there is currently no effective treatment. It has been reported that 2-AG, which is a substrate of MAGL, has a protective effect against nerve cell death in an animal model of closed skull trauma [Non-Patent Document 18: Nature, vol. 413, pages 527-531, 2001]. Therefore, the MAGL inhibitor is promising as a new therapeutic or prophylactic drug for traumatic brain injury.

[0011]

Glaucoma most commonly causes vision loss and is considered a major social problem. It has been reported that 2-AG, which is a substrate of MAGL, activates water outflow in an intraocular perfusion model [Non-Patent Document 19: Experimental Eye Research (Exp. Eye Res.), vol. 87, pages 106-114, 2008]. Therefore, the MAGL inhibitor is promising as a new therapeutic or prophylactic drug for the treatment of glaucoma.

[0012]

Anxiety disorder is a mental illness that is very common and greatly affects the quality of life. It has been reported that 2-AG, which is a substrate of MAGL, exhibits an anti-anxiety effect in the elevated plus maze test, which is an effective anxiety disorder test system [Non-Patent Document 20: Behavioral Brain Research (Behav. Brain Res.), vol. 252, pages 10-17, 2013]. Therefore, the MAGL inhibitor is promising as a new therapeutic drug for the treatment of anxiety disorders.

[0013]

2-AG, which is a substrate of MAGL, showed an antinociceptive effect in the formalin test [Non-Patent Document 21: British Journal of Pharmacology, vol. 150, pages 693-701, 2007]. In addition, it has been reported that 2-AG shows an effect in the mechanical hyperalgesia test, which is a model of carcinomatous pain [Non-Patent Document 22: Pharmacological Research (Pharmacol. Res.), vol. 64, pages 60-67, 2011]. Therefore, the MAGL inhibitor is promising as a new therapeutic drug for inflammatory pain and nerve pain.

[0014]

Epilepsy greatly affects daily life. It is known that brain inflammation has been induced in the hippocampus of patients with temporal lobe epilepsy, and brain inflammation accompanied by glial cell activation is involved in seizure [Non-Patent Document 23: Nature Medicine (Nature Med.), vol. 16, pages 413-419, 2010]. 2-AG, which is a substrate of MAGL, has an inhibitory effect on pentylenetetrazole-induced seizure, which is a model of acute convulsions [Non-Patent Document 24: Neurochemical Research (Neurochem. Res.), vol. 36, pages 1520-1525, 2011]. Therefore, the MAGL inhibitor is promising as a new therapeutic drug for the treatment of epilepsy.

[0015]

Depression is a disease that is very common in modern society and greatly affects the quality of life. It has been reported that 2-AG, which is a substrate of MAGL, exhibits an antidepressant effect on a chronic stress model, which is an effective depression test system [Non-Patent Document 25: Neuropsychopharmacology, vol. 39, pages 1763-1776, 2014]. Therefore, the MAGL inhibitor is promising as a new therapeutic drug for the treatment of depression.

[0016]

Migraine is a disease that is very common in modern society and greatly affects the quality of life. One of the factors in the development of migraine is inflammation of the brain. It has been reported that CB2 activation has an analgesic effect in nitroglycerin administered rats, which is an effective test system for treating migraine [Non-Patent Document 26: Journal of Headache and Pain, vol. 15, no. 14, 2014]. Therefore, the MAGL inhibitor is promising as a new therapeutic drug for the treatment of migraine.

[0017]

Cerebral edema is a disease that develops in connection with various encephalopathies. One of the causes of cerebral edema is the destruction of the blood-brain barrier. It is known that arachidonic acid and eicosanoids destroy the blood-brain barrier [Non-Patent Document 27: Brain Research, vol. 1298, pages 13-23, 2009]. An inhibitor that inhibits the action of MAGL reduces the production of MAGL arachidonic acid. Therefore, the MAGL inhibitor is promising as a new therapeutic drug for the treatment of cerebral edema.

[0018]

Cerebral ischemia is one of the factors causing the occurrence of cerebral infarction. 2-AG, which is a substrate of MAGL, has been reported to have a protective effect on the brain in a test system effective for treating cerebral ischemia [Non-Patent Document 28: Brain Research, vol. 1474, pages 91-99, 2012]. Therefore, the MAGL inhibitor is promising as a new therapeutic drug for the treatment of cerebral ischemia.

[0019]

The following compounds are known as heterocyclic compounds. Patent Document 1 describes that the compound is represented by the following formula (I):

[0020]

[0021]

where each character is as defined in Patent Document 1,

is a MAGL inhibitor and is useful for treating pain and the like.

Patent Document 2 describes that the compound is represented by the following formula (I):

[0022]

[0023]

where each character is as defined in Patent Document 2,

is a MAGL inhibitor and is useful for treating pain and the like.

Patent Document 3 describes that the compound is represented by the following formula (I):

[0024]

[0025]

where each character is as defined in Patent Document 3,

is a MAGL inhibitor and is useful for treating pain and the like.

Patent Document 4 describes that the compound is represented by the following formula (I):

[0026]

[0027]

where each character is as defined in Patent Document 4,

is a MAGL inhibitor and is useful for treating pain and the like.

Patent Document 5 describes that the compound is represented by the following formula:

[0028]

[0029]

where each character is as defined in Patent Document 5,

useful as a MAGL inhibitor.

Patent Document 6 describes that the compound is represented by the following formula:

[0030]

[0031]

where each symbol is as defined in Patent Document 6, and the compound is represented by the following formula:

[0032]

[0033]

where each character is as defined in Patent Document 6,

useful as a MAGL inhibitor.

Patent Document 7 describes that the compound is represented by the following formula:

[0034]

[0035]

where each character is as defined in Patent Document 7,

useful as a MAGL inhibitor.

Patent Document 8 describes that the compound is represented by the following formula (I):

[0036]

[0037]

where each character is as defined in Patent Document 8,

is an inhibitor of MAGL and is suitable for the treatment, improvement or prevention of metabolic diseases (obesity, diabetes).

Patent Document 9 describes that the compound is represented by the following formula (I):

[0038]

[0039]

where each character is as defined in Patent Document 9,

is an inhibitor of MAGL and is suitable for the treatment, improvement or prevention of metabolic diseases (obesity, diabetes).

[0040]

Patent Document 10 describes that the compound is represented by the following formula (I):

[0041]

[0042]

where each character is as defined in Patent Document 10,

is a MAGL inhibitor and is useful in the treatment, amelioration or prevention of neurodegenerative diseases, anxiety disorders, pain and epilepsy.

Patent Document 11 describes that the compound is represented by the following formula (I):

[0043]

[0044]

where each character is as defined in Patent Document 11,

is an inhibitor of MAGL and is useful in the prevention or treatment of neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, glaucoma, multiple sclerosis, etc.), anxiety disorder, pain (e.g. , inflammatory pain, cancer pain, nerve pain, etc.), epilepsy, depression, and the like.

Patent Document 12 describes that the compound is represented by the following formula (I):

[0045]

[0046]

where each character is as defined in Patent Document 12,

is an inhibitor of MAGL and is useful in the prevention or treatment of neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, glaucoma, multiple sclerosis, etc.), anxiety disorder, pain (e.g. , inflammatory pain, cancer pain, nerve pain, etc.), epilepsy, depression, and the like.

Patent Document 13 describes that the compound is represented by the following formula (I):

[0047]

[0048]

where each character is as defined in Patent Document 13,

is an inhibitor of MAGL and is useful in the prevention or treatment of neurodegenerative diseases (e.g. Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, glaucoma, multiple sclerosis, etc.), anxiety disorder, pain (e.g. , inflammatory pain, cancer pain, nerve pain, etc.), epilepsy, depression, and the like.

List of documents

patent document

[0049]

Patent Document 1: WO 2010/124122

Patent Document 2: WO 2010/124082

Patent Document 3: WO 2010/124086

Patent Document 4: WO 2010/124121

Patent Document 5: WO 2012/030907

Patent Document 6: WO 2012/044613

Patent Document 7: WO 2012/054716

Patent Document 8: WO 2013/049289

Patent Document 9: WO 2013/049293

Patent Document 10: WO 2015/099196

Patent Document 11: WO 2016/158956

Patent document 12: WO 2017/171100

Patent document 13: WO 2017/170830

non-patent document

[0050]

Non-Patent Document 1: Science, vol. 294, pages 1871-1875, 2001

Non-Patent Document 2: Molecular Neurobiology (Mol. Neurobiol), vol. 41, pages 115-128, 2010

Non-Patent Document 3: Neuron, vol. 53, pages 337-351, 2007

Non-Patent Document 4: Nature Reviews Neurology (Nat. Rev. Neurol.), vol. 6, pages 193-201, 2010

Non-Patent Document 5: Chemistry and Physics of Lipids (Chem phys Lipids) vol. 121, pages 149-158, 2002

Non-Patent Document 6: Cell Report (Cell Rep.), vol. 1, page 617-623, 2012

Non-Patent Document 7: Biochemical Pharmacology (Biochem. Pharmcol.) vol. 50, 83-90, 1995

Non-Patent Document 8: Molecular Pharmacology (Mol. Pharmacol.), vol. 34, pages 605-613, 1988

Non-Patent Document 9: Neuroscience Letters (Neurosci. Lett.), vol. 396, pages 113-116, 2006

Non-Patent Document 10: Journal of Alzheimer's Disease (J. Alzheimers. Dis.), vol. 30, pages 439-459, 2012

Non-Patent Document 11: Neuroscience, vol. 178, pages 159-168, 2011

Non-Patent Document 12: Annals of Neurology (Ann. Neurol.) vol. 57, pages 168-175, 2005

Non-Patent Document 13: Science, vol. 334, pages 809-813, 2011

Non-Patent Document 14: Neurobiology of Disease (Neurobiol. Dis.) vol. 15, pages 601-609, 2004

Non-Patent Document 15: European Journal of Pharmacology (Eur. J. Pharmacol.), vol. 542, pages 100-105, 2006

Non-Patent Document 16: Brain, vol. 132, pages 3152-3164, 2009

Non-Patent Document 17: Brain Research (Brain Res.), vol. 1390, pages 126-141, 2011

Non-Patent Document 18: Nature, vol. 413, pages 527-531, 2001

Non-Patent Document 19: Experimental Eye Research (Exp. Eye Res.), vol. 87, pages 106-114, 2008

Non-Patent Document 20: Behavioral Brain Research (Behav. Brain Res.), vol. 252, pages 10-17, 2013

Non-Patent Document 21: British Journal of Pharmacology, vol. 150, pages 693-701, 2007

Non-Patent Document 22: Pharmacological Research (Pharmacol. Res.), vol. 64, pages 60-67, 2011

Non-Patent Document 23: Nature Medicine (Nature Med.), vol. 16, pages 413-419, 2010

Non-Patent Document 24: Neurochemical Research (Neurochem. Res.), vol. 36, pages 1520-1525, 2011

Non-Patent Document 25: Neuropsychopharmacology, vol. 39, pages 1763-1776, 2014

Non-Patent Document 26: Journal of Headache and Pain, vol. 15, no. 14, 2014

Non-Patent Document 27: Brain Research, vol. 1298, pages 13-23, 2009

Non-Patent Document 28: Brain Research, vol. 1474, pages 91-99, 2012

The essence of the invention

Problems to be Solved by the Invention

[0051]

It is an object of the present invention to provide a compound having an inhibitory effect on MAGL that is expected to be useful as an agent for the prevention or treatment of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, glaucoma, multiple sclerosis, etc.), anxiety disorder, pain (eg, inflammatory pain, cancer pain, neurogenic pain, etc.), epilepsy, depression, and the like.

Ways to solve problems

[0052]

The inventors of the present invention have conducted intensive studies in an attempt to solve the above problems, and found that the compound represented by the following formula (I) has an inhibitory effect on MAGL, and therefore it is expected to be useful as an agent for the prevention or treatment of neurodegenerative diseases ( e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, glaucoma, multiple sclerosis, etc.), anxiety disorder, pain (e.g., inflammatory pain, cancer pain, neurogenic pain, etc.) .), epilepsy, depression and the like, which led to the completion of the present invention.

[0053]

Accordingly, the present invention provides the following.

[1] The compound represented by formula (I):

[0054]

[0055]

where

A is an optionally substituted saturated cyclic group,

L represents a bond or a C _1-3 alkylene group optionally substituted with a halogen atom(s),

Ring D is a ring optionally further substituted with C _1-6 alkyl group(s) optionally substituted with halogen atom(s),

n is 1 or 2,

X is -O-, -CR ¹ R ² - or -NR ³ -,

R ^a and R ^b are each independently a hydrogen atom or a C _1-6 alkyl group optionally substituted with halogen atom(s), and

R ¹ , R ² and R ³ each independently represents a hydrogen atom or a substituent,

or a salt thereof (hereinafter sometimes referred to as compound (I)).

[0056]

[2] A compound or salt of the above [1], where

A is a C _3-10 cycloalkyl group

substituted with 1-3 substituents selected from

(a) C _6-14 aryloxy optionally substituted with 1-4 substituents selected from

(i) a halogen atom and

(ii) an optionally halogenated C _1-6 alkyl group,

(b) C _6-14 aryloxy-C _1-6 alkyl group optionally substituted with 1-4 substituents selected from

(i) a halogen atom and

(ii) an optionally halogenated C _1-6 alkyl group,

(c) C _7-16 aralkyloxy optionally substituted with 1-4 substituents selected from

(i) a halogen atom and

(ii) an optionally halogenated C _1-6 alkyl group, and

(d) C _7-16 aralkyloxy-C _1-6 alkyl group optionally substituted with 1-4 substituents selected from

(i) a halogen atom and

(ii) an optionally halogenated C _1-6 alkyl group, and

optionally further substituted with 1-3 C _1-6 alkyl groups;

L is a bond or a C _1-3 alkylene group;

ring D is a 4- or 5-membered nitrogen-containing heterocycle;

n is 1 or 2;

X represents -O- or -CH ₂ -; and

both R ^a and R ^b are hydrogen atoms.

[0057]

[3] A compound or salt of the above [1], where

A is a cyclobutyl group substituted with one substituent selected from

(a) a phenoxy group substituted with 3 halogen atoms, and

(b) a phenoxymethyl group substituted with 3 halogen atoms;

L is a bond;

ring D is an azetidine ring;

n is 1;

X is -O-; and

both R ^a and R ^b are hydrogen atoms.

[0058]

[4] cis-3-((2,3,4-Trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate or a salt thereof.

[5] cis-3-((2,4,6-Trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate or a salt thereof.

[6] cis-3-(2,4,6-Trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate or a salt thereof.

[0059]

[7] A drug containing a compound or salt of the above [1].

[8] The drug of the above [7], which is a monoacylglycerol lipase inhibitor.

[9] The drug of the above [7], which is an agent for the prevention or treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, anxiety disorder, pain, epilepsy or depression.

[0060]

[10] A method for inhibiting monoacylglycerol lipase in a mammal, comprising administering to the mammal an effective amount of a compound or salt of the above [1].

[11] A method for preventing or treating Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, anxiety disorder, pain, epilepsy or depression in a mammal, comprising administering to the mammal an effective amount of a compound or salt of the above [1].

[0061]

[12] A compound or salt of the above [1] for use in the prevention or treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, anxiety disorder, pain, epilepsy or depression.

[13] The use of a compound or salt of the above [1] for the manufacture of an agent for use in the prevention or treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, anxiety disorder, pain, epilepsy or depression.

Invention Effect

[0062]

According to the present invention, a compound having an excellent inhibitory effect on MAGL, which is expected to be useful as an agent for the prevention or treatment of neurodegenerative diseases (for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, glaucoma , multiple sclerosis, etc.), anxiety disorder, pain (eg, inflammatory pain, cancer pain, neurogenic pain, etc.), epilepsy, depression, and the like.

[0063]

(Detailed description of the essence of the invention)

The present invention is explained in detail as follows.

[0064]

The definition of each substituent used in this description is described in detail below. Unless otherwise indicated, each substituent has the following definition.

As used herein, examples of the "halogen atom" include fluorine, chlorine, bromine, and iodine.

In this specification, examples of "C _1-6 alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1.1 -dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.

In this specification, examples of the "optionally halogenated C _1-6 alkyl group" include a C _1-6 alkyl group optionally having 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl.

In this description, examples of "C _2-6 alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl , 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.

In this description, examples of "C _2-6 alkynyl group" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl , 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.

In this specification, examples of the "C _3-10 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl .

In this specification, examples of the "optionally halogenated C _3-10 cycloalkyl group" include a C _3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In this specification, examples of the "C _3-10 cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

In this description, examples of "C _6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.

In this specification, examples of the "C _7-16 aralkyl group" include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0065]

As used herein, examples of "C _1-6 alkoxy groups" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

As used herein, examples of the "optionally halogenated C _1-6 alkoxy group" include a C _1-6 alkoxy group optionally having 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.

In this specification, examples of "C _3-10 cycloalkyloxy groups" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

As used herein, examples of "C _1-6 alkylthio groups" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, t-butylthio, pentylthio, and hexylthio.

As used herein, examples of the "optionally halogenated C _1-6 alkylthio group" include a C _1-6 alkylthio group optionally having 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

As used herein, examples of the "C _1-6 alkyl carbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl.

In this specification, examples of the "optionally halogenated C _1-6 alkyl carbonyl group" include a C _1-6 alkyl carbonyl group optionally having 1 to 7, preferably 1 to 5 halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

As used herein, examples of the "C _1-6 alkoxycarbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

In this description, examples of "C _6-14 aryl-carbonyl group" include benzoyl, 1-naphthoyl and 2-naphthoyl.

In this specification, examples of the "C _7-16 aralkyl carbonyl group" include phenylacetyl and phenylpropionyl.

As used herein, examples of the "5-14 membered aromatic heterocyclylcarbonyl group" include nicotinoyl, isonicotinoyl, thenoyl, and furoyl.

In this specification, examples of the "3-14 membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0066]

As used herein, examples of the "mono- or di-C _1-6 alkyl-carbamoyl group" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

In this description, examples of "mono - or di-C _7-16 -aryl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl.

In this specification, examples of the "C _1-6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and t-butylsulfonyl.

In this specification, examples of the "optionally halogenated C _1-6 alkylsulfonyl group" include a C _1-6 alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl.

In this specification, examples of the "C _6-14 arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0067]

As used herein, examples of a "substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group. , an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group.

In this specification, examples of a "hydrocarbon group" (including a "hydrocarbon group" from an "optionally substituted hydrocarbon group") include a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-10 cycloalkyl group , a C _3-10 cycloalkenyl group, a C _6-14 aryl group, and a C _7-16 aralkyl group.

[0068]

As used herein, examples of an "optionally substituted hydrocarbon group" include a hydrocarbon group optionally having a substituent(s) selected from the following substituent group A.

[Substituent Group A]

(1) a halogen atom,

(2) nitro group,

(3) cyano group,

(4) oxo group,

(5) hydroxy group,

(6) an optionally halogenated C _1-6 alkoxy group,

(7) C _6-14 aryloxy (eg phenoxy, naphthoxy),

(8) C _7-16 aralkyloxy (e.g. benzyloxy),

(9) 5-14 membered aromatic heterocyclyloxy group (e.g. pyridyloxy),

(10) 3-14 membered non-aromatic heterocyclyloxy group (e.g. morpholinyloxy, piperidinyloxy),

(11) C _1-6 alkyl-carbonyloxy group (for example, acetoxy, propanoyloxy),

(12) C _6-14 aryl-carbonyloxy group (for example, benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),

(13) C _1-6 alkoxy-carbonyloxy group (for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

(14) mono- or di-C _1-6 alkyl-carbamoyloxy group (for example, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),

(15) C _6-14 aryl-carbamoyloxy group (for example, phenylcarbamoyloxy, naphthylcarbamoyloxy),

(16) 5-14 membered aromatic heterocyclylcarbonyloxy group (e.g. nicotinoyloxy),

(17) 3-14 membered non-aromatic heterocyclylcarbonyloxy group (e.g. morpholinylcarbonyloxy, piperidinylcarbonyloxy),

(18) an optionally halogenated C _1-6 alkylsulfonyloxy group (eg methylsulfonyloxy, trifluoromethylsulfonyloxy),

(19) a C _6-14 arylsulfonyloxy group optionally substituted with a C _1-6 alkyl group (eg phenylsulfonyloxy, toluenesulfonyloxy),

(20) an optionally halogenated C _1-6 alkylthio group,

(21) 5-14 membered aromatic heterocyclic group,

(22) 3-14 membered non-aromatic heterocyclic group,

(23) formyl group,

(24) carboxy group,

(25) an optionally halogenated C _1-6 alkyl carbonyl group,

(26) C _6-14 aryl carbonyl group,

(27) 5-14 membered aromatic heterocyclylcarbonyl group,

(28) 3-14 membered non-aromatic heterocyclylcarbonyl group,

(29) C _1-6 alkoxy carbonyl group,

(30) C _6-14 aryloxycarbonyl group (eg phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl),

(31) C _7-16 aralkyloxy-carbonyl group (for example, benzyloxycarbonyl, phenethyloxycarbonyl),

(32) carbamoyl group,

(33) thiocarbamoyl group,

(34) mono- or di-C _1-6 alkyl carbamoyl group,

(35) C _6-14 aryl-carbamoyl group (eg phenylcarbamoyl),

(36) 5-14 membered aromatic heterocyclylcarbamoyl group (e.g. pyridylcarbamoyl, thienylcarbamoyl),

(37) 3-14 membered non-aromatic heterocyclylcarbamoyl group (e.g. morpholinylcarbamoyl, piperidinylcarbamoyl),

(38) an optionally halogenated C _1-6 alkylsulfonyl group,

(39) C _6-14 arylsulfonyl group,

(40) 5-14 membered aromatic heterocyclylsulfonyl group (eg pyridylsulfonyl, thienylsulfonyl),

(41) an optionally halogenated C _1-6 alkylsulfinyl group,

(42) C _6-14 arylsulfinyl group (eg phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl),

(43) 5-14 membered aromatic heterocyclylsulfinyl group (eg pyridylsulfinyl, thienylsulfinyl),

(44) amino group,

(45) a mono- or di-C _1-6 alkylamino group (eg methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),

(46) a mono- or di-C _6-14 arylamino group (eg phenylamino),

(47) 5-14 membered aromatic heterocyclylamino group (e.g. pyridylamino),

(48) C _7-16 aralkylamino (e.g. benzylamino),

(49) formylamino group,

(50) C _1-6 alkyl-carbonylamino group (for example, acetylamino, propanoylamino, butanoylamino),

(51) (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino group (for example, N-acetyl-N-methylamino),

(52) C _6-14 aryl-carbonylamino group (for example, phenylcarbonylamino, naphthylcarbonylamino),

(53) C _1-6 alkoxycarbonylamino (for example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, t-butoxycarbonylamino),

(54) C _7-16 aralkyloxy-carbonylamino group (for example, benzyloxycarbonylamino),

(55) C _1-6 alkylsulfonylamino (for example, methylsulfonylamino, ethylsulfonylamino),

(56) a C _6-14 arylsulfonylamino group optionally substituted with a C _1-6 alkyl group (eg phenylsulfonylamino, toluenesulfonylamino),

(57) an optionally halogenated C _1-6 alkyl group,

(58) C _2-6 alkenyl group,

(59) C _2-6 alkynyl group,

(60) C _3-10 cycloalkyl group,

(61) C _3-10 cycloalkenyl group and

(62) C _6-14 aryl group.

[0069]

The number of the above substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, the respective substituents may be the same or different.

In this specification, examples of a "heterocyclic group" (including a "heterocyclic group" in an "optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7 to 10-membered bridged heterocyclic group, each of which contains as a ring atom, in addition to a carbon atom, from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

[0070]

In this specification, examples of an "aromatic heterocyclic group" (including a "5-14 membered aromatic heterocyclic group") include a 5-14 membered (preferably 5-10 membered) aromatic heterocyclic group having, as a ring atom, in addition to a carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

Preferred examples of "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2 ,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and

8-14-членные конденсированные полициклические (предпочтительно би или трициклические) ароматические гетероциклические группы, такие как бензотиофенил, бензофуранил, бензимидазоил, бензоксазолил, бензизоксазолил, бензотиазолил, бензизотиазолил, бензотриазолил, имидазопиридинил, тиенопиридинил, фуропиридинил, пирролопиридинил, пиразолопиридинил, оксазолопиридинил, тиазолoпиридинил, имидазопиразинил , имидазопиримидинил, тиенопиримидинил, фуропиримидинил, пирролопиримидинил, пиразолопиримидинил, оксазолопиримидинил, тиазолoпиримидинил, пиразолотриазинил, нафто[2,3-b] тиенил, феноксантинил, индолил, изоиндолил, 1H-индазолил, пуринил, изохинолил, хинолил, фталазинил, нафтиридинил, хиноксалинил, хиназолинил , cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like

[0071]

In this specification, examples of a "non-aromatic heterocyclic group" (including a "3-14 membered non-aromatic heterocyclic group") include a 3-14-membered (preferably 4-10-membered) non-aromatic heterocyclic group containing, as a ring atom, other than a carbon atom , from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.

Preferred examples of "non-aromatic heterocyclic group" include 3-8 membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolidinyl, , тиазолинил, тиазолидинил, тетрагидроизотиазолил, тетрагидрооксазолил, тетрагидроизоксазолил, пиперидинил, пиперазинил, тетрагидропиридинил, дигидропиридинил, дигидротиопиранил, тетрагидропиримидинил, тетрагидропиридазинил, дигидропиранил, тетрагидропиранил, тетрагидротиопиранил, морфолинил, тиоморфолинил, азепанил, диазепанил, азепинил, оксепанил, азоканил, диазоканил и.т. P; and

9-14 membered fused polycyclic (preferably bi or tricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolisinyl, indolinyl, isoindolinyl , tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydro- octaneoxynylthineazinyl, and the like

[0072]

In this specification, preferred examples of the "7-10 membered bridging heterocyclic group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl.

In this specification, examples of a "nitrogen-containing heterocyclic group" include a "heterocyclic group" containing at least one nitrogen atom as a ring atom.

In this specification, examples of "optionally substituted heterocyclic group" include a heterocyclic group optionally having a substituent(s) selected from the aforementioned "substituent group A".

The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is two or more, the respective substituents may be the same or different.

[0073]

As used herein, examples of an "acyl group" include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which optionally has "1 or 2 substituents selected from a C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _3-10 cycloalkenyl group, C _6-14 aryl group, C _7-16 aralkyl group, 5-14 membered aromatic heterocyclic group, and 3-14 membered non-aromatic heterocyclic group groups each optionally having 1 to 3 substituents selected from a halogen atom, an optionally halogenated C _1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group."

Examples of the "acyl group" also include a hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclylsulfinyl group.

Here, a hydrocarbon-sulfonyl group means a sulfonyl group linked to a hydrocarbon group, a heterocyclylsulfonyl group means a sulfonyl group linked to a heterocyclic group, a hydrocarbon-sulfinyl group means a sulfinyl group linked to a hydrocarbon group, a heterocyclylsulfinyl group means a sulfinyl group linked to a heterocyclic group.

Preferred examples of an "acyl group" include a formyl group, a carboxy group, a C _1-6 alkyl carbonyl group, a C _2-6 alkenyl carbonyl group (e.g., crotonoyl), a C _3-10 cycloalkyl carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C _3-10 cycloalkenyl carbonyl group (e.g. 2-cyclohexenecarbonyl), C _6-14 aryl carbonyl group, C _7-16 aralkyl carbonyl group, 5-14 membered aromatic heterocyclylcarbonyl group, 3- 14-membered non-aromatic heterocyclylcarbonyl group, C _1-6 alkoxy carbonyl group, C _6-14 aryloxy carbonyl group (e.g. phenyloxycarbonyl, naphthyloxycarbonyl), C _7-16 aralkyloxy carbonyl group (e.g. benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group , mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _2-6 alkenyl-carbamoyl group (for example, diallylcarbamoyl), mono- or di-C _3-10 cycloalkyl-carbamoyl group (for example, cyclopropylcarbamoyl), mono- or di-C _6-14 aryl-carbamoyl group (eg phenylcarbamoyl), mono- or di-C _7-16 aralkyl-carbamoyl group, 5-14 membered aromatic heterocyclylcarbamoyl group (eg pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C _1-6 alkyl-thiocarbamoyl group (for example, methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _2-6 alkenyl-thiocarbamoyl group (for example, diallylthiocarbamoyl), mono - or di-C _3-10 cycloalkylthiocarbamoyl group (eg cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl group (eg phenylthiocarbamoyl), mono- or di-C _7-16 aralkyl- thiocarbamoyl group (for example, benzylthiocarbamoyl, phenethylthiocarbamoyl), 5-14 membered aromatic heterocyclylthiocarbamoyl group (for example, pyridylthiocarbamoyl), sulfino group, C _1-6 alkylsulfinyl group (for example, methylsulfinyl, ethylsulfinyl), sulfo group, C _1-6 alkylsulfonyl group, C _6-14 ari a lsulfonyl group, a phosphono group and a mono- or di-C _1-6 alkylphosphono group (eg dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0074]

In this specification, examples of the "optionally substituted amino group" include an amino group optionally having "1 or 2 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl carbonyl group, C _6-14 aryl carbonyl group, C _7-16 aralkyl carbonyl group, 5-14 membered aromatic heterocyclylcarbonyl group, 3-14 membered non-aromatic heterocyclylcarbonyl group group, C _1-6 alkoxy-carbonyl group, 5-14 membered aromatic heterocyclic group, carbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _7-16 aralkyl-carbamoyl group , a C _1-6 alkylsulfonyl group, and a C _6-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".

Preferred examples of an optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C _1-6 alkyl) amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C _2-6 an alkenylamino group (eg diallylamino), a mono- or di-C _3-10 cycloalkylamino group (eg cyclopropylamino, cyclohexylamino), a mono- or di-C _6-14 arylamino group (eg phenylamino), a mono- or di-C _7-16 an aralkylamino group (eg benzylamino, dibenzylamino), a mono- or di-(optionally halogenated C _1-6 alkyl)-carbonylamino group (eg acetylamino, propionylamino), a mono- or di-C _6-14 aryl-carbonylamino group (eg benzoylamino) , mono- or di-C _7-16 aralkyl-carbonylamino group (for example, benzylcarbonylamino), mono- or di-5-14-membered aromatic heterocyclylcarbonylamino group (for example, nicotinoylamino, isonicotinoylamino), mono- or di-3-14-membered non-aromatic heterocycles l-carbonylamino group (for example, piperidinylcarbonylamino), mono- or di-C _1-6 alkoxy-carbonylamino group (for example, tert-butoxycarbonylamino), 5-14-membered aromatic heterocyclylamino group (for example, pyridylamino), carbamoylamino group, (mono- or di-C _{1 -6} alkyl-carbamoyl)amino group (for example, methylcarbamoylamino), (mono- or di-C _7-16 aralkyl-carbamoyl)amino group (for example, benzylcarbamoylamino), C _1-6 alkylsulfonylamino group (for example, methylsulfonylamino, ethylsulfonylamino), C _{6- 14} arylsulfonylamino (for example, phenylsulfonylamino), (C _1-6 alkyl) (C _1-6 alkyl-carbonyl) amino (for example, N-acetyl-N-methylamino) and (C _1-6 alkyl) (C _6-14 aryl -carbonyl)amino group (eg N-benzoyl-N-methylamino).

[0075]

In this specification, examples of the "optionally substituted carbamoyl group" include a carbamoyl group optionally having "1 or 2 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl carbonyl group, C _6-14 aryl carbonyl group, C _7-16 aralkyl carbonyl group, 5-14 membered aromatic heterocyclylcarbonyl group, 3-14 membered a non-aromatic heterocyclylcarbonyl group, a C _1-6 alkoxy-carbonyl group, a 5-14 membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C _1-6 alkyl-carbamoyl group, and a mono- or di-C _7-16 aralkyl- a carbamoyl group, each optionally having 1 to 3 substituents selected from substituent group A".

Preferred examples of an optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C _1-6 alkyl carbamoyl group, a mono- or di-C _2-6 alkenyl carbamoyl group (e.g., diallylcarbamoyl), a mono- or di-C _{3 -10} cycloalkyl-carbamoyl group (for example, cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C _6-14 aryl-carbamoyl group (for example, phenylcarbamoyl), mono- or di-C _7-16 aralkyl-carbamoyl group, mono- or di-C _1-6 alkyl-carbonyl-carbamoyl group (for example, acetylcarbamoyl, propionylcarbamoyl), mono- or di-C _6-14 aryl-carbonyl-carbamoyl group (for example, benzoylcarbamoyl) and 5-14-membered aromatic heterocyclylcarbamoyl group ( e.g. pyridylcarbamoyl).

[0076]

In this specification, examples of the "optionally substituted thiocarbamoyl group" include a thiocarbamoyl group optionally having "1 or 2 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl carbonyl group, C _6-14 aryl carbonyl group, C _7-16 aralkyl carbonyl group, 5-14 membered aromatic heterocyclylcarbonyl group, 3-14 membered a non-aromatic heterocyclylcarbonyl group, a C _1-6 alkoxy-carbonyl group, a 5-14 membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C _1-6 alkyl-carbamoyl group, and a mono- or di-C _7-16 aralkyl- a carbamoyl group, each optionally having 1 to 3 substituents selected from substituent group A".

Preferred examples of an optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C _1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C _{2 -6} alkenyl-thiocarbamoyl group (e.g. diallylthiocarbamoyl), mono- or di-C _3-10 cycloalkyl-thiocarbamoyl group (e.g. cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C _6-14 aryl-thiocarbamoyl group (e.g. phenylthiocarbamoyl ), mono- or di-C _7-16 aralkyl-thiocarbamoyl group (for example, benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C _1-6 alkyl-carbonyl-thiocarbamoyl group (for example, acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di -C _6-14 aryl-carbonyl-thiocarbamoyl group (eg benzoylthiocarbamoyl) and 5-14 membered aromatic heterocyclylthiocarbamoyl group (eg pyridylthiocarbamoyl).

[0077]

In this specification, examples of the "optionally substituted sulfamoyl group" include a sulfamoyl group optionally having "1 or 2 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl carbonyl group, C _6-14 aryl carbonyl group, C _7-16 aralkyl carbonyl group, 5-14 membered aromatic heterocyclylcarbonyl group, 3-14 membered a non-aromatic heterocyclylcarbonyl group, a C _1-6 alkoxy-carbonyl group, a 5-14 membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C _1-6 alkyl-carbamoyl group, and a mono- or di-C _7-16 aralkyl- a carbamoyl group, each optionally having 1 to 3 substituents selected from substituent group A".

Preferred examples of an optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C _1-6 alkyl sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C _{2 -6} alkenylsulfamoyl group (e.g. diallyl sulfamoyl), mono- or di-C _3-10 cycloalkyl sulfamoyl group (e.g. cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C _6-14 aryl sulfamoyl group (e.g. phenylsulfamoyl ), mono- or di-C _7-16 aralkyl sulfamoyl group (eg benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C _1-6 alkyl-carbonyl sulfamoyl group (eg acetylsulfamoyl, propionylsulfamoyl), mono- or di -C _6-14 aryl-carbonyl-sulfamoyl group (eg benzoylsulfamoyl) and 5-14 membered aromatic heterocyclylsulfamoyl group (eg pyridylsulfamoyl).

[0078]

As used herein, examples of the "optionally substituted hydroxy group" include a hydroxy group optionally having "a substituent selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _{7- 16} aralkyl group, C _1-6 alkyl carbonyl group, C _6-14 aryl carbonyl group, C _7-16 aralkyl carbonyl group, 5-14 membered aromatic heterocyclylcarbonyl group, 3-14 membered non-aromatic heterocyclylcarbonyl group, C _1-6 alkoxy-carbonyl group, 5-14 membered aromatic heterocyclic group, carbamoyl group, mono- or di-C _1-6 alkyl-carbamoyl group, mono- or di-C _7-16 aralkyl-carbamoyl group, C _{1 -6} alkylsulfonyl group and C _6-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from substituent group A'.

Preferred examples of optionally substituted hydroxy include hydroxy, C _1-6 alkoxy, C _2-6 alkenyloxy (e.g. alllyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C _3-10 cycloalkyloxy (e.g. cyclohexyloxy), C _{6 -14} aryloxy (eg phenoxy, naphthyloxy), C _7-16 aralkyloxy (eg benzyloxy, phenethyloxy), C _1-6 alkylcarbonyloxy (eg acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C _6-14 aryl -carbonyloxy group (for example, benzoyloxy), C _7-16 aralkyl-carbonyloxy group (for example, benzylcarbonyloxy), 5-14-membered aromatic heterocyclylcarbonyloxy group (for example, nicotinoyloxy), 3-14-membered non-aromatic heterocyclylcarbonyloxy group (for example, piperidinylcarbonyloxy), C _{1- 6} alkoxy-carbonyloxy group (for example, tert-butoxycarbonyloxy), 5-14 membered aromatic heterocyclyloxy group (for example, pyridyloxy), carbamoyloxy group, C _1-6 alkyl-carbamoyloxy group (on eg methylcarbamoyloxy), a C _7-16 aralkyl carbamoyloxy group (eg benzylcarbamoyloxy), a C _1-6 alkylsulfonyloxy group (eg methylsulfonyloxy, ethylsulfonyloxy) and a C _6-14 arylsulfonyloxy group (eg phenylsulfonyloxy).

[0079]

In this specification, examples of the "optionally substituted sulfanyl group" include a sulfanyl group optionally having "a substituent selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group, C _7-16 aralkyl group, C _1-6 alkyl carbonyl group, C _6-14 aryl carbonyl group, and 5-14 membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from substituent group A" , and a halogenated sulfanyl group.

Preferred examples of an optionally substituted sulfanyl group include a sulfanyl (-SH) group, a C _1-6 alkylthio group, a C _2-6 alkenylthio group (e.g. allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C _3-10 cycloalkylthio group (e.g. , cyclohexylthio), C _6-14 arylthio (e.g. phenylthio, naphthylthio), C _7-16 aralkylthio (e.g. benzylthio, phenethylthio), C _1-6 alkyl carbonylthio (e.g. acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio) , a C _6-14 aryl carbonylthio group (eg benzoylthio), a 5-14 membered aromatic heterocyclylthio group (eg pyridylthio) and a halogenated thio group (eg pentafluorothio).

[0080]

In this specification, examples of the "optionally substituted silyl group" include a silyl group optionally having "1-3 substituents selected from C _1-6 alkyl group, C _2-6 alkenyl group, C _3-10 cycloalkyl group, C _6-14 aryl group and C _7-16 aralkyl group, each of which optionally has from 1 to 3 substituents selected from substituent group A".

Preferred examples of an optionally substituted silyl group include a tri-C _1-6 alkylsilyl group (eg trimethylsilyl, t-butyl(dimethyl)silyl).

[0081]

In the present description, examples of "heterocycle" include an aromatic heterocycle and a non-aromatic heterocycle, each of which contains, as a ring atom, in addition to a carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.

[0082]

In the present description, examples of "aromatic heterocycle" include 5-14-membered (preferably 5-10-membered) aromatic heterocycle containing, as a ring atom, in addition to a carbon atom, from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferred examples of "aromatic heterocycle" include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4 -oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine, etc.; and

8-14 membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiasol, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, thiazolopyridine, thiazolopyridine, , imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiine, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine , quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine and the like.

[0083]

In the present specification, examples of a "non-aromatic heterocycle" include a 3-14-membered (preferably 4-10-membered) non-aromatic heterocycle containing, as a ring atom, in addition to a carbon atom, from 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Preferred examples of "non-aromatic heterocycle" include 3-8 membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane and the like, oxepane; and

9-14 membered fused polycyclic (preferably bi or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazol, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolysine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline and the like.

In this description, examples of "nitrogen-containing heterocyclyl" include "heterocycle" containing at least one nitrogen atom as a ring atom.

[0084]

The definition of each symbol in formula (I) is explained in detail below.

[0085]

A is an optionally substituted saturated cyclic group.

Examples of the "saturated cyclic group" of the "optionally substituted saturated cyclic group" represented by A include a C _3-10 cycloalkyl group and a saturated heterocyclic group. Examples of "saturated heterocyclic group" include saturated groups from "non-aromatic heterocyclic group" and specific examples thereof include 3-8 membered saturated monocyclic non-aromatic heterocyclic groups such as aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, imidazolidinyl .

[0086]

The "saturated cyclic group" of the "optionally substituted saturated cyclic group" represented by A is a C _3-10 cycloalkyl group, more preferably a C _3-6 cycloalkyl group (eg cyclobutyl, cyclohexyl), even more preferably a cyclic group or a cyclohexyl group, in particular a cyclobutyl group.

[0087]

The "saturated cyclic group" of the "optionally substituted saturated cyclic group" represented by A is optionally substituted with, for example, substituent(s) selected from the above substituents of group A. The number of substituents is, for example, 1 to 3. When the number of substituents is 2 or moreover, the respective substituents may be the same or different. In addition, the substituent group A is optionally further substituted with substituent(s) selected from the above substituent group A. The number of substituents is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0088]

Preferred examples of a substituent include

(a) an optionally substituted C _6-14 aryloxy group (eg phenoxy),

(b) an optionally substituted C _6-14 aryloxy-C _1-6 alkyl group (preferably a C _6-14 aryloxymethyl group (eg phenoxymethyl)),

(c) an optionally substituted C _7-16 aralkyloxy group (eg benzyloxy),

(d) an optionally substituted C _7-16 aralkyloxy-C _1-6 alkyl group (preferably a C _7-16 aralkyloxymethyl group (eg, benzyloxymethyl)), and

(e) a C _1-6 alkyl group (eg methyl).

More preferred examples of a substituent include

(a) an optionally substituted C _6-14 aryloxy group (eg phenoxy),

(b) an optionally substituted C _6-14 aryloxy-C _1-6 alkyl group (preferably a C _6-14 aryloxymethyl group (eg phenoxymethyl)), and

(c) a C _1-6 alkyl group (eg methyl).

Specific preferred examples of a substituent include

(a) an optionally substituted C _6-14 aryloxy group (eg phenoxy), and

(b) an optionally substituted C _6-14 aryloxy-C _1-6 alkyl group (preferably a C _6-14 aryloxymethyl group (eg phenoxymethyl)).

[0089]

Preferred examples of the substituent "optionally substituted C _6-14 aryloxy", "optionally substituted C _6-14 aryloxy-C _1-6 alkyl", "optionally substituted C _7-16 aralkyloxy" and "optionally substituted C _7-16 aralkyloxy-C _1-6 alkyl group" contain a halogen atom (eg fluorine atom, chlorine atom) and an optionally halogenated C _1-6 alkyl group (eg methyl, trifluoromethyl).

[0090]

A is preferably an optionally substituted C _3-10 cycloalkyl group (preferably a C _3-6 cycloalkyl group (eg cyclobutyl, cyclohexyl), particularly preferably cyclobutyl).

[0091]

A is more preferably a C _3-10 cycloalkyl group (preferably a C _3-6 cycloalkyl group (eg cyclobutyl, cyclohexyl), particularly preferably cyclobutyl)

substituted with 1-3 (preferably 1) substituents selected from

(a) an optionally substituted C _6-14 aryloxy group (eg phenoxy),

(b) an optionally substituted C _6-14 aryloxy-C _1-6 alkyl group (preferably a C _6-14 aryloxymethyl group (eg phenoxymethyl)),

(c) an optionally substituted C _7-16 aralkyloxy group (eg, benzyloxy), and

(d) an optionally substituted C _7-16 aralkyloxy-C _1-6 alkyl group (preferably a C _7-16 aralkyloxymethyl group (eg, benzyloxymethyl)), and

optionally further substituted with 1-3 (preferably 1) substituents selected from

(e) a C _1-6 alkyl group (eg methyl).

[0092]

A is even more preferably a C _3-10 cycloalkyl group (preferably a C _3-6 cycloalkyl group (eg cyclobutyl, cyclohexyl), particularly preferably cyclobutyl)

substituted with 1-3 (preferably 1) substituents selected from

(a) C _6-14 aryloxy (eg phenoxy) optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl),

(b) C _6-14 aryloxy-C _1-6 alkyl group (preferably C _6-14 aryloxymethyl group (eg phenoxymethyl)), optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl),

(c) C _7-16 aralkyloxy (e.g. benzyloxy) optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl), and

(d) C _7-16 aralkyloxy-C _1-6 alkyl group (preferably C _7-16 aralkyloxymethyl group (eg benzyloxymethyl)), optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl), and

optionally further substituted with 1 to 3 (preferably 1) C _1-6 alkyl groups (eg methyl).

[0093]

A is even more preferably

(1) cyclobutyl group

substituted with 1-3 (preferably 1) substituents selected from

(a) a phenoxy group optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl),

(b) a phenoxymethyl group optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl),

(c) a benzyloxy group optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl), and

(d) a benzyloxymethyl group optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl), and

optionally further substituted with 1 to 3 (preferably 1) C _1-6 alkyl groups (eg methyl), or

(2) a cyclohexyl group substituted with 1-3 (preferably 1) substituents selected from

(a) a phenoxy group optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, a fluorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg trifluoromethyl).

[0094]

A is even more preferably a cyclobutyl group

substituted with one substituent selected from

(a) a phenoxy group substituted with 2 or 3 substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) a C _1-6 alkyl group (eg methyl), and

(b) a phenoxymethyl group substituted with 2 or 3 substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) a C _1-6 alkyl group (eg methyl), and

optionally further substituted with 1 to 3 (preferably 1) C _1-6 alkyl groups (eg methyl).

[0095]

A is particularly preferably a cyclobutyl group substituted with one substituent selected from

(a) a phenoxy group substituted with 3 halogen atoms (eg a fluorine atom), and

(b) a phenoxymethyl group substituted with 3 halogen atoms (eg a fluorine atom).

[0096]

In another embodiment of the invention, when A is a substituted cyclobutyl group, one substituent Y is selected from

(a) an optionally substituted C _6-14 aryloxy group (eg phenoxy),

(b) an optionally substituted C _6-14 aryloxy-C _1-6 alkyl group (preferably a C _6-14 aryloxymethyl group (eg phenoxymethyl)),

(c) an optionally substituted C _7-16 aralkyloxy group (eg, benzyloxy), and

(d) an optionally substituted C _7-16 aralkyloxy-C _1-6 alkyl group (preferably a C _7-16 aralkyloxymethyl group (eg benzyloxymethyl)),

preferably substituted at the 3-position on the cyclobutane ring as shown in the following partial structure.

[0097]

[0098]

In this case, the cyclobutyl group is optionally further substituted with 1-3 (preferably 1) substituents selected from

(e) a C _1-6 alkyl group (eg methyl).

The above partial structure is preferably

[0099]

.

.

[0100]

[0101]

L represents a bond or a C _1-3 alkylene group optionally substituted with a halogen atom(s).

[0102]

Examples of the "C _1-3 alkylene group" of the "optionally substituted C _1-3 alkylene group" represented by L include -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH(C ₂ H ₅ )-, -CH ₂ -CH(CH ₃ )-, -CH(CH ₃ )-CH ₂ - and the like.

[0103]

L is preferably a bond or a C _1-3 alkylene group (eg -CH ₂ -).

L is preferably a bond.

[0104]

Ring D is a ring optionally further substituted with C _1-6 alkyl group(s) optionally substituted with halogen atom(s).

[0105]

Examples of the “ring” of “ring optionally further substituted with C _1-6 alkyl group(s) optionally substituted with halogen atom(s)” are represented by ring D including a 4- or 5-membered nitrogen-containing heterocycle and the like. Examples of "4- or 5-membered nitrogen-containing heterocycle" include 4- or 5-membered rings containing at least one nitrogen atom as a ring-forming atom from "heterocycles", and specific examples thereof include azetidine, pyrrolidine, and the like. .

[0106]

The “ring” of “ring optionally further substituted with C _1-6 alkyl group(s) optionally substituted with halogen atom(s)” represented by ring D is preferably a 4- or 5-membered nitrogen-containing heterocycle (e.g., azetidine, pyrrolidine ), more preferably an azetidine ring or a pyrrolidine ring, particularly preferably an azetidine ring.

[0107]

Ring D is preferably a 4- or 5-membered nitrogen-containing heterocycle (eg, azetidine, pyrrolidine) optionally further substituted with C _1-6 alkyl group(s) optionally substituted with halogen atom(s).

Ring D is more preferably a 4- or 5-membered nitrogen-containing heterocycle (eg, azetidine, pyrrolidine).

Ring D is even more preferably an azetidine ring or a pyrrolidine ring.

Ring D is particularly preferably an azetidine ring.

[0108]

n is 1 or 2.

n is preferably 1.

[0109]

X represents -O-, -CR ¹ R ² - or -NR ³ -.

R ¹ , R ² and R ³ are each independently a hydrogen atom or a substituent. Examples of "substituent" include substituent(s) selected from substituent group A.

[0110]

X is preferably -O- or -CR ¹ R ² -.

Both R ¹ and R ² preferably represent hydrogen atoms.

X is more preferably -O- or -CH ₂ -.

X is even more preferably -O-.

[0111]

R ^a and R ^b are each independently a hydrogen atom or a C _1-6 alkyl group optionally substituted with a halogen atom(s).

Both R ^a and R ^b are preferably hydrogen atoms.

[0112]

The ring combination D, n, X, R ^a and R ^b is preferably

Ring D is a 4- or 5-membered nitrogen-containing heterocycle (eg, azetidine, pyrrolidine);

n is 1 or 2;

X represents -O- or -CH ₂ -; and

both R ^a and R ^b are hydrogen atoms,

more preferably

ring D is an azetidine ring or a pyrrolidine ring;

n is 1 or 2;

X represents -O- or -CH ₂ -; and

both R ^a and R ^b are hydrogen atoms,

particularly preferred

ring D is an azetidine ring;

n is 1;

X is -O-; and

both R ^a and R ^b are hydrogen atoms.

[0113]

Preferred examples of compound (I) include the following compounds.

[0114]

[Connection A]

Compound (I), where

A is a C _3-10 cycloalkyl group (preferably a C _3-6 cycloalkyl group (eg cyclobutyl, cyclohexyl), more specifically preferably cyclobutyl)

substituted with 1-3 (preferably 1) substituents selected from

(a) an optionally substituted C _6-14 aryloxy group (eg phenoxy),

(b) an optionally substituted C _6-14 aryloxy-C _1-6 alkyl group (preferably a C _6-14 aryloxymethyl group (eg phenoxymethyl)),

(c) an optionally substituted C _7-16 aralkyloxy group (eg, benzyloxy), and

(d) an optionally substituted C _7-16 aralkyloxy-C _1-6 alkyl group (preferably a C _7-16 aralkyloxymethyl group (eg, benzyloxymethyl)), and

optionally further substituted with 1-3 (preferably 1) substituents selected from

(e) a C _1-6 alkyl group (eg methyl);

L represents a bond or a C _1-3 alkylene group optionally substituted with a halogen atom(s);

Ring D is a 4 or 5-membered nitrogen-containing heterocycle (eg, azetidine, pyrrolidine) optionally further substituted with C _1-6 alkyl group(s) optionally substituted with halogen atom(s);

n is 1 or 2;

X is -O- or -CR ¹ R ² -;

R ¹ and R ² are each independently a hydrogen atom or a substituent; and

R ^a and R ^b are each independently a hydrogen atom or a C _1-6 alkyl group optionally substituted with a halogen atom(s).

[0115]

[Connection B]

Compound (I), where

A is a C _3-10 cycloalkyl group (preferably a C _3-6 cycloalkyl group (eg cyclobutyl, cyclohexyl), more specifically preferably cyclobutyl)

substituted with 1-3 (preferably 1) substituents selected from

(a) C _6-14 aryloxy (eg phenoxy) optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl),

(b) C _6-14 aryloxy-C _1-6 alkyl group (preferably C _6-14 aryloxymethyl group (eg phenoxymethyl)), optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl),

(c) C _7-16 aralkyloxy (e.g. benzyloxy) optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl), and

(d) C _7-16 aralkyloxy-C _1-6 alkyl group (preferably C _7-16 aralkyloxymethyl group (eg benzyloxymethyl)), optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl), and

optionally further substituted with 1 to 3 (preferably 1) C _1-6 alkyl groups (eg methyl);

L is a bond or a C _1-3 alkylene group (eg -CH ₂ -);

Ring D is a 4- or 5-membered nitrogen-containing heterocycle (eg, azetidine, pyrrolidine);

n is 1 or 2;

X represents -O- or -CH ₂ -; and

both R ^a and R ^b are hydrogen atoms.

[0116]

[Connection C]

Compound (I), where

A represents

(1) cyclobutyl group

substituted with 1-3 (preferably 1) substituents selected from

(a) a phenoxy group optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl),

(b) a phenoxymethyl group optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl),

(c) a benzyloxy group optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl), and

(d) a benzyloxymethyl group optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg methyl, trifluoromethyl), and

optionally further substituted with 1 to 3 (preferably 1) C _1-6 alkyl groups (eg methyl), or

(2) a cyclohexyl group substituted with 1-3 (preferably 1) substituents selected from

(a) a phenoxy group optionally substituted with 1-4 (preferably 1-3, more preferably 2-3) substituents selected from

(i) a halogen atom (eg, a fluorine atom), and

(ii) an optionally substituted C _1-6 alkyl group (eg trifluoromethyl);

L is a bond or a C _1-3 alkylene group (eg -CH ₂ -);

ring D is an azetidine ring or a pyrrolidine ring;

n is 1 or 2;

X represents -O- or -CH ₂ -; and

both R ^a and R ^b are hydrogen atoms.

[0117]

[Connection D]

Compound (I), where

A is a cyclobutyl group,

substituted with one substituent selected from

(a) a phenoxy group substituted with 2 or 3 substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) a C _1-6 alkyl group (eg methyl), and

(b) a phenoxymethyl group substituted with 2 or 3 substituents selected from

(i) a halogen atom (eg, fluorine atom, chlorine atom), and

(ii) a C _1-6 alkyl group (eg methyl), and

optionally further substituted with 1 to 3 (preferably 1) C _1-6 alkyl groups (eg methyl);

L is a bond;

ring D is an azetidine ring;

n is 1;

X is -O-; and

both R ^a and R ^b are hydrogen atoms.

[0118]

[Connection E]

Compound (I), where

A is a cyclobutyl group substituted with one substituent selected from

(a) a phenoxy group substituted with 3 halogen atoms (eg a fluorine atom), and

(b) a phenoxymethyl group substituted with 3 halogen atoms (eg a fluorine atom);

L is a bond;

ring D is an azetidine ring;

n is 1;

X is -O-; and

both R ^a and R ^b are hydrogen atoms.

[0119]

Specific examples of compound (I) include the compounds of Examples 1 to 64.

Among them,

cis-3-((2,3,4-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate (Example 16) or a salt thereof;

cis-3-((2,4,6-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate (Example 18) or a salt thereof; and

cis-3-(2,4,6-trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate (Example 46) or a salt thereof

are preferred.

[0120]

When the compound (I) is a salt, examples of the salt include metal salts, ammonium salts, organic base salts, inorganic acid salts, organic acid salts, and basic or acidic amino acid salts. Preferred examples of the metal salt include alkali metal salts such as sodium salts, potassium salts and the like; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts and the like; and aluminum salts. Preferred examples of the organic base salt include those with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like. Preferred examples of the inorganic acid salt include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of organic acid salts include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid and the like. Preferred examples of salts with a basic amino acid include salts with arginine, lysine, ornithine, and the like. Preferred examples of salts with an acidic amino acid include salts with aspartic acid, glutamic acid, and the like. Among them, a pharmaceutically acceptable salt is preferred. For example, when the compound has an acidic functional group, examples of the salt include inorganic salts such as alkali metal salts (for example, sodium salt, potassium salt, etc.), alkaline earth metal salts (for example, calcium salt, magnesium salt, etc. .). and the like, ammonium salt, etc., and when the compound has a basic functional group, examples of the salt include salts with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like, and salts with an organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

When the compound (I) contains isomers such as tautomers, optical isomers, stereoisomers, positional isomers and rotational isomers, any isomer or mixture is also included in the compound of the present invention. In addition, when the compound (I) contains an optical isomer, that optical isomer separated from the racemate is included in the compound (I).

Compound (I) can be obtained in crystalline form. Any single crystal form or crystalline mixture can be included in the compound (I).

Compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. As used herein, a co-crystal or co-crystal salt means a crystalline material composed of two or more unique solid particles at room temperature, each of which has distinct physical characteristics such as structure, melting point and heats of fusion, hygroscopicity, solubility, and stability. The co-crystal or co-crystal salt can be obtained according to the co-crystallization process known per se.

Compound (I) may be a solvate (eg, hydrate) or a non-solvate, and both are included in compound (I).

Compounds labeled or substituted with isotopes (eg ² H, ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²⁵ I, etc.) are also included in compound (I). The compound labeled or substituted with isotopes can be used, for example, as a tracer used for positron emission tomography (PET) (PET tracer), and is expected to be useful in the field of medical diagnosis and the like.

[0121]

The method for preparing the compound of the present invention is explained below.

[0122]

The starting material compound and the reagent used, as well as the compound obtained in each step in the following production method, may each be in the form of a salt, and examples of such a salt include salts similar to those of the compound of this invention and the like.

[0123]

When the compound obtained in each step is in free form, it can be converted to the desired salt according to a method known per se. When the compound obtained in each step is a salt, it may be converted to the desired free form or other salt according to a method known per se.

[0124]

The compound obtained in each step can be used directly as the mixture used or as the crude product for the next reaction. Alternatively, the compound obtained in each step may be isolated and purified from the reaction mixture according to a method known per se, for example, isolation methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography, and the like

[0125]

When the starting compound and the reagent used in each step are commercially available, the commercially available product can also be used directly.

[0126]

In the reaction in each step, although the reaction time varies depending on the reagent and solvent used, it is usually 1 minute - 48 hours, preferably 10 minutes - 8 hours, unless otherwise indicated.

[0127]

In the reaction in each step, although the reaction temperature varies depending on the type of reagent and solvent used, it is usually -78°C - 300°C, preferably -78°C - 150°C, unless otherwise indicated.

[0128]

In the reaction at each stage, although the pressure varies depending on the type of reagent and solvent used, it is usually 1-20 atm, preferably 1-3 atm, unless otherwise indicated.

[0129]

A microwave synthesizer such as the Biotage Initiator and the like can be used for the reaction at each step. Although the reaction temperature varies depending on the type of reagent and solvent used, typically room temperature is -300°C, preferably 50°C - 250°C, unless otherwise indicated. Although the reaction time varies depending on the type of reagent and solvent used, it is usually 1 minute - 48 hours, preferably 1 minute - 8 hours, unless otherwise indicated.

[0130]

In the reaction at each stage, the reagent is used in an amount of 0.5 equivalents - 20 equivalents, preferably 0.8 equivalents - 5 equivalents relative to the substrate, unless otherwise indicated. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent - 1 equivalent, preferably 0.01 equivalent - 0.2 equivalent relative to the substrate. When a reagent is used as a reaction solvent, the reagent is used in the amount of the solvent.

[0131]

Unless otherwise indicated, the reaction in each step is carried out without solvent or by dissolving or suspending the starting compound in a suitable solvent. Examples of the solvent include those described in the Examples and the following solvents.

alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol and the like;

ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane and the like;

aromatic hydrocarbons: chlorobenzene, toluene, xylene and the like;

saturated hydrocarbons: cyclohexane, hexane and the like;

amides: N, N-dimethylformamide, N-methylpyrrolidone and the like;

halogenated hydrocarbons: dichloromethane, carbon tetrachloride and the like;

nitriles: acetonitrile and the like;

sulfoxides: dimethyl sulfoxide and the like;

aromatic organic bases: pyridine and the like;

anhydrides: acetic anhydride and the like;

organic acids: formic acid, acetic acid, trifluoroacetic acid and the like;

inorganic acids: hydrochloric acid, sulfuric acid and the like;

esters: ethyl acetate and the like;

ketones: acetone, methyl ethyl ketone and the like;

water.

The above solvent can be used in a mixture of two or more kinds thereof in an appropriate ratio.

[0132]

When a base is used for the reaction in each step, examples thereof include those described in Examples and the following bases.

inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate and the like;

organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine and the like;

metal alkoxides: sodium ethoxide, potassium t-butoxide and the like;

alkali metal hydrides: sodium hydride and the like;

metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like;

lithium organic compounds: n-butyllithium and the like.

[0133]

When an acid or an acid catalyst is used for the reaction in each step, examples thereof include those described in the examples and the following acids and acid catalysts.

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like;

organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid and the like;

Lewis acid: boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous ferric chloride and the like.

[0134]

Unless otherwise indicated, the reaction of each step is carried out according to a method known per se, for example, the method described in Jikken Kagaku Kouza, 5th ed., vol. 13-19 (the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza Volume 14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry, 2nd revised edition (L. F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, revised edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective vol. I-VII (John Wiley & Sons Inc); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Volume 1 - Volume 14 (Elsevier Japan); Strategic Applications of Named Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989 or the like, or in the manner described in the examples.

[0135]

At each step, the reaction of introducing a protecting group or deprotecting a functional group is carried out in accordance with a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 4th ed.", Wiley-Interscience, Inc., 2007 ( Theodora W. Greene, Peter G. M. Wuts); "Protecting Groups 3rd ed." Thieme, 2004 (P.J. Kocienski), or the like, or in the manner described in the examples.

Examples of a protecting group for an alcohol hydroxy group and the like, a phenolic hydroxy group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; carboxylate ester type protecting groups such as acetic ester and the like; sulfonate ester type protecting groups such as methanesulfonate ether and the like; carbonate ester type protecting groups such as tert-butyl carbonate and the like, and the like

Examples of a protecting group for an aldehyde carbonyl group include acetal-type protecting groups such as dimethyl acetal and the like; acetal-type cyclic protecting groups such as 1,3-dioxane and the like, and the like

Examples of a protecting group for a ketone carbonyl group include ketal-type protecting groups such as dimethylketal and the like; ketal ring-type protecting groups such as 1,3-dioxane and the like; oxime-type protecting groups such as O-methyl oxime and the like; hydrazone type protecting groups such as N,N-dimethylhydrazone and the like, and the like

Examples of a protecting group for a carboxy group include ester-type protecting groups such as methyl ester and the like; amide-type protecting groups such as N, N-dimethylamide and the like, and the like

Examples of a protecting group for a thiol include ether-type protecting groups such as benzylthioether and the like; ester type protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like, and the like

Examples of a protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and the like include carbamate-type protecting groups such as benzyl carbamate and the like; amide-type protecting groups such as acetamide and the like; alkylamine type protecting groups such as N-triphenylmethylamine and the like; sulfonamide-type protecting groups such as methanesulfonamide and the like, and the like.

The protecting groups may be removed according to a method known per se, for example using an acid, base, ultraviolet, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide, trimethylsilyl bromide ) and the like, recovery method and the like.

[0136]

When the reduction reaction is carried out in each step, examples of the reducing agent used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, tetramethylammonium triacetoxyborohydride and the like; boranes such as borane-tetrahydrofuran complex and the like; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane and the like When a carbon-carbon double bond or a triple bond is reduced, a method using a catalyst such as palladium-carbon, Lindlar's catalyst and the like can be used.

[0137]

When the oxidation reaction is carried out in each step, examples of the oxidizing agent to be used include peroxides such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, t-butyl hydroperoxide and the like; perchlorates such as tetrabutylammonium perchlorate and the like; chlorates such as sodium chlorate and the like; chlorites such as sodium chlorite and the like; periodates such as sodium periodate and the like; hypervalent iodine reagents such as iodosylbenzene and the like; reagents containing manganese, such as manganese dioxide, potassium permanganate and the like; lead products such as lead tetraacetate and the like; reagents containing chromium, such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent and the like; halogen compounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like

[0138]

When a radical cyclization reaction is carried out in each step, examples of the radical reaction initiator used include azo compounds such as azobisisobutyronitrile (AIBN) and the like; water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA) and the like; triethylboron in the presence of air or oxygen; benzoyl peroxide and the like. Examples of the radical reagent used include tributylstannan, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, and the like.

[0139]

When the Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidenephosphoranes and the like. Alkylidene phosphoranes can be prepared according to a method known per se, for example by reacting a phosphonium salt with a strong base.

[0140]

When the Horner-Emmons reaction is carried out in each step, examples of the reagents used include phosphonoacetates such as methyl dimethyl phosphonoacetate, ethyl diethyl phosphonoacetate and the like; and bases such as alkali metal hydrides, organolithium compounds and the like.

[0141]

When a Friedel-Crafts reaction is carried out in each step, a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (eg, alkyl halide, alcohol, olefin) is used as the reactant. Alternatively, an organic acid or an inorganic acid and an anhydride such as acetic anhydride and the like can also be used instead of a Lewis acid, and it can also be used instead of an acid chloride.

[0142]

When an aromatic nucleophilic substitution reaction is carried out in each step, a nucleophile (eg, amine, imidazole, etc.) and a base (eg, organic base, etc.) are used as a reactant.

[0143]

When a nucleophilic addition reaction is carried out with a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) with a carbanion or a nucleophilic substitution reaction with a carbanion, and examples of bases to be used to form a carbanion include organolithium compounds, metal alkoxides, inorganic bases, organic foundations and the like.

[0144]

When the Grignard reaction is carried out in each step, examples of the Grignard reagent used include aryl magnesium halides such as phenyl magnesium bromide and the like; and alkyl magnesium halides such as methyl magnesium bromide and the like. The Grignard reagent can be prepared according to a method known per se, for example by reacting an alkyl halide or an aryl halide with magnesium metal in ether or tetrahydrofuran as solvent.

[0145]

When the Knoevenagel condensation reaction is carried out in each step, a compound having an activated methylene group with two electron withdrawing groups (for example, malonic acid, diethylmalonate, malononitrile, etc.) and a base (for example, an organic base, a metal alkoxide, an inorganic base).

[0146]

When the Vilsmeier-Haack reaction is carried out in each step, phosphoryl chloride and an amide derivative (eg N,N-dimethylformamide, etc.) are used as a reactant.

[0147]

When an azidation reaction of an alcohol, an alkyl halide or a sulfonate is carried out in each step, examples of the azidating agent to be used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide and the like. For example, for the alcohol azidation reaction, a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), a method using trimethylsilyl azide and a Lewis acid, and the like are used.

[0148]

When the reductive amination reaction is carried out in the next step, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde and the like, and ketones such as cyclohexanone and the like. When the substrate is a carbonyl compound, examples of the amine to be used include ammonia, primary amines such as methylamine and the like; secondary amines such as dimethylamine and the like.

[0149]

When the Mitsunobu reaction is carried out in the next step, azodicarboxylate (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as a reactant.

[0150]

When an esterification reaction, an amidation reaction or a urea formation reaction is carried out in the next step, examples of the reagents used include acyl halides such as acid chlorides, acid bromides and the like; activated carboxylic acids such as anhydrides, activated esters, sulfates and the like. Examples of the carboxylic acid activating agent include carbodiimide condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM) and the like; carbonate condensing agents such as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mukaiyam's reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate and the like; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphorate (HATU); sulphuric acid; their combinations and the like. When a carbodiimide condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the like can be added to the reaction system.

[0151]

When coupling reactions are carried out in each step, examples of metal catalysts used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II) , tris(dibenzylidenacetone)dipalladium(0), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride and the like; nickel compounds such as tetrakis(triphenylphosphine)nickel(0) and the like; rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride and the like; cobalt compounds; copper compounds such as copper oxide, copper (I) iodide and the like; platinum compounds and the like. In addition, a base may be added to the reaction system, and examples thereof include inorganic bases and the like.

[0152]

When the thiocarbonylation reaction is carried out in each step, phosphorus pentasulfide is usually used as the thiocarbonylating agent. Alternatively, a reagent having a 1,3,2,4-dithiadiphosphetan-2,4-disulfide structure (e.g., 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetan-2,4-disulfide (Lausson's reagent), etc.) can also be used instead of phosphorus pentasulfide.

[0153]

When the halogenation reaction is carried out in each step, examples of the halogenating agent to be used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride and the like. In addition, the reaction can be accelerated by exposing the reaction system to a radical reaction initiator such as heat, light, benzoyl peroxide, azobisisobutyronitrile and the like.

[0154]

When the hydroxy group halogenation reaction is carried out in each step, examples of the halogenating agent to be used include hydrohalic acids and inorganic acid halides, in particular, hydrochloric acid, thionyl chloride, phosphorus oxychloride and the like for chlorination, 48% hydrobromic acid and the like for bromination. . In addition, a method for producing an alkyl halide by reacting an alcohol with triphenylphosphine and carbon tetrachloride or carbon tetrabromide or the like can be used. Alternatively, a two-step process for producing an alkyl halide can also be used, comprising converting an alcohol to the corresponding sulfonate, followed by reacting the sulfonate with lithium bromide, lithium chloride, or sodium iodide.

[0155]

When the Arbuzov reaction is carried out in each step, examples of the reagents used include alkyl halides such as ethyl bromoacetate and the like; and phosphites such as triethyl phosphite, tri(isopropyl) phosphite, and the like.

[0156]

When the sulfonate esterification reaction is carried out in each step, examples of the sulfonating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0157]

When the hydrolysis reaction is carried out in each step, an acid or a base is used as a reactant. For the acid hydrolysis reaction of the t-butyl ester, formic acid, triethylsilane, and the like can be added to the cation of the t-butyl reduction trap, which is a by-product.

[0158]

When the dehydration reaction is carried out in each step, examples of the dehydrating agent used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[0159]

When the carbonylation reaction is carried out in each step, examples of the reagent used include triphosgene, 1,1'-carbonylbis-1H-imidazole, diphosgene, phenyl chloroformate and the like.

[0160]

Compound (I) can be synthesized according to the following schemes. Each symbol in schema formulas is as defined above unless otherwise noted. P ¹ is an "amino protecting group". Examples of the "amino protecting group" include t-butoxycarbonyl group and the like, in addition to those exemplified by the above-mentioned amino protecting group. R ⁴ is an optionally substituted C _1-6 alkyl group (eg methyl).

[0161]

Compound (I) can be obtained by subjecting compound (2) and compound (3) to a carbonylation reaction.

[0162]

[0163]

In addition, if desired, the compound (I) can be synthesized by carrying out a deprotection reaction, an acylation reaction, an alkylation reaction, a Mitsunobu reaction, a hydrogenation reaction, an oxidation reaction, a reduction reaction, a carbon chain extension reaction, a halogenation reaction, a substituent exchange reaction, a coupling reaction , nucleophilic addition reactions of carbon anion, Grignard reaction, deoxofluorination reaction and the like alone and one or two or more of them in combination.

[0164]

Among the compound (3) used in the Reaction Scheme 1, the compound (3-1), which is the compound (3), where X is -O-, can be obtained from the compound (4) according to the following method.

[0165]

[0166]

Compound (5) can be obtained by subjecting compound (4) to a nucleophilic substitution reaction. Examples of the nucleophile include sodium nitrite and the like.

Compound (7) can be obtained by subjecting compound (5) to an aldol reaction with compound (6) in the presence of a base. Examples of the base include triethylamine and the like.

Compound (8) can be obtained by subjecting compound (7) to a reduction reaction.

Compound (9) can be obtained by subjecting compound (8) to a cyclization reaction using a carbonylation reaction in the presence of a base. Examples of the base include triethylamine and the like.

Compound (3-1) can be obtained by subjecting compound (9) to a deprotection reaction.

[0167]

Among the compound (3) used in the Reaction Scheme 1, the compound (3-2), which is the compound (3), where X is -CH ₂ -, can be obtained from the compound (5) according to the following method.

[0168]

[0169]

Compound (11) can be obtained by subjecting compound (5) to a Michael reaction with compound (10) in the presence of a base. Examples of the base include DBU, potassium carbonate and the like.

Compound (12) can be obtained by subjecting compound (11) to a reduction reaction. As the reaction condition, the combined use of sodium borohydride and nickel(II) chloride hexahydrate, the use of Raney nickel under a hydrogen atmosphere, and the like can be used.

Compound (13) can be obtained by subjecting compound (12) to a cyclization reaction in the presence of a base. Examples of the base include potassium carbonate and the like.

Compound (3-2) can be obtained by subjecting compound (13) to a deprotection reaction.

[0170]

Among the compound (3) used in the Reaction Scheme 1, the compound (3-3), which is the compound (3), where X is -NR ³ -, can be obtained from the compound (7) according to the following method. R ⁵ is methyl, p-methylphenyl or trifluoromethyl.

[0171]

[0172]

Compound (14) can be obtained by subjecting compound (7) to sulfonate esterification in the presence of a base. Examples of the base include triethylamine, pyridine and the like.

Compound (16) can be obtained by subjecting compound (7) to a Mitsunobu reaction with compound (15). Compound (16) can also be obtained by subjecting compound (14) to an alkylation reaction with compound (15) in the presence of a base. Examples of the base include the above organic bases, inorganic bases, metal alkoxides, alkali metal hydrides and metal amides.

Compound (18) can be obtained by subjecting compound (14) to an alkylation reaction with compound (17) in the presence of a base. Examples of the base include the bases exemplified in the above alkylation reaction. Compound (18) can also be obtained by subjecting compound (16) to a deprotection reaction in the presence of a base and a nucleophile. Examples of the nucleophile used include thioglycolic acid, thiophenol and the like. Examples of the base include triethylamine, lithium hydroxide, potassium carbonate and the like.

Compound (20) can be obtained by subjecting compound (19) to a cyclization reaction. The cyclization reaction can be carried out using a base. Examples of the base used include triethylamine and the like.

[0173]

Compounds (2), (4), (6), (10), (15) and (17) which are used as starting materials in each scheme may be commercially available products or may be prepared according to known per se way.

[0174]

The starting compound and/or an intermediate in the preparation of compound (I) may form a salt. The salt is not particularly limited as long as the reaction can be performed. Examples thereof include salts like salts optionally formed by compound (I) and the like.

As for the configurational isomers (E, Z forms) of the compound (I), they can be isolated and purified when isomerization occurs, for example, according to conventional separation methods such as extraction, recrystallization, distillation, chromatography and the like, for obtain a pure compound. In addition, the corresponding pure isomer can also be obtained by double bond isomerization using heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical catalyst, light irradiation, a strong base catalyst, and the like according to the method described in Shin Jikken Kagaku Kouza 14 (The Chemical Society of Japan ed.), pages 251 to 253, 4th Edition Jikken Kagaku Kouza 19 (The Chemical Society of Japan ed.), pages 273 to 274, or in a similar manner.

[0175]

Compound (I) contains a stereoisomer depending on the type of substituent, and each stereoisomer and mixture thereof are included in the present invention.

Compound (I) may be a hydrate or non-hydrate.

When the target product is obtained in the free form from the above reaction, it can be converted into a salt according to the conventional method, or when the target product is obtained as a salt, it can be converted into the free form or another salt according to the conventional method. Compound (I) thus obtained can also be isolated and purified from the reaction mixture according to a known method such as transfer, concentration, solvent extraction, distillation, crystallization, recrystallization, chromatography and the like.

When the compound (I) contains a configurational isomer, a diastereomer, a conformer, and the like, each of them can be isolated according to the aforementioned separation and purification methods when desired. In addition, when the compound (I) is racemic, the d-form and the l-form can be isolated according to conventional optical resolution.

[0176]

Compound (I) thus obtained, other intermediates of its reaction and its starting compounds can be isolated and purified from the reaction mixture according to a method known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography , thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC), medium pressure preparative liquid chromatography (medium pressure preparative LC) and the like.

[0177]

The salt of the compound (I) can be obtained according to a method known per se. For example, when the compound (I) is a basic compound, it can be obtained by adding an inorganic acid or an organic acid, or when the compound (I) is an acidic compound, by adding an organic base or an inorganic base.

When the compound (I) contains an optical isomer, each optical isomer and mixture thereof are included within the scope of the present invention, and if desired, these isomers may be subjected to optical resolution or may be obtained, respectively, in accordance with a method known per se.

[0178]

When the compound (I) contains a configurational isomer, a diastereomer, a conformer, and the like, each of them can be isolated according to the aforementioned separation and purification methods when desired. In addition, when the compound (I) is racemic, the S-form and R-form can be isolated according to conventionally accepted optical resolution.

When compound (I) contains a stereoisomer, each isomer and mixture thereof are included in the present invention.

[0179]

The compound of this invention is expected to be useful in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, etc.) as an agent for the prevention or treatment of diseases, for example,

(1) mental illness [for example, depression, major depression, bipolar depression, dysthymic disorder, emotional disorder (seasonal affective disorder and the like), recurrent depression, postpartum depression, stress disorder, depression symptom, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive disorder, post-traumatic stress disorder, post-traumatic stress disorder, Tourette syndrome, autism, fragile X syndrome, Rett syndrome, adjustment disorder, bipolar disorder, neurosis, schizophrenia (e.g. , positive symptom, negative symptom, cognitive impairment), chronic fatigue syndrome, anxiety neurosis, obsessive-compulsive disorder, panic disorder, epilepsy, anxiety disorder, anxiety, anxious mental state, emotional anomaly, cyclothymia, erethism nervosa, weakness, addiction, low sex drive, attention deficit hyperactivity disorder (ADHD), psychotic major depression, treatment-resistant depression, depressive disorder, catalepsy, hebephrenic schizophrenia, paranoid schizophrenia],

(2) neurodegenerative diseases [eg, Alzheimer's disease, Alzheimer's type dementia, Parkinson's disease, Huntington's disease, multi-infarct dementia, frontotemporal dementia, Parkinson's-type dementia, progressive supranuclear palsy, Pick syndrome, Niemann-Pick syndrome, corticobasal degeneration, Down's disease, vascular dementia, postencephalitic parkinsonism, Lewy body dementia, HIV dementia, amyotrophic lateral sclerosis (ALS), motor neurogenesis disease (MND), Creutzfeldt-Jakob disease or prion disease, cerebral palsy, progressive supranuclear palsy, craniocerebral brain injury, glaucoma, multiple sclerosis, neuromyelitis optic nerve (NMO), postoperative cognitive dysfunction (POCD), postoperative delirium (POD), delirium],

(3) age-related cognitive memory disorders [eg, age-related memory disorders, senile dementia],

(4) sleep disorders [eg, congenital sleep disorders (eg, psychophysiological insomnia and the like), acquired sleep disorder, circadian rhythm disorders (eg, jet lag syndrome), shift work sleep disorders, irregular wakefulness during sleep, delayed onset sleep phase syndrome, sleep phase advance syndrome, 24-hour wakefulness without sleep, etc.), parasomnia, sleep disorders associated with a congenital medical or psychiatric disorder (for example, chronic obstructive pulmonary disease, Alzheimer's disease, Parkinson's disease, cerebrovascular dementia, schizophrenia, depression, anxiety neurosis), stress insomnia, insomnia, insomnia neurosis, sleep apnea syndrome],

(5) respiratory depression caused by anesthetics, traumatic disease or neurodegenerative disease and the like,

(6) traumatic brain injury, cerebral apoplexy, anorexia nervosa, eating disorder, anorexia nervosa, hyperorexia, other eating disorder, alcohol dependence, alcohol addiction, alcohol amnesia, alcohol paranoia, alcohol addiction, alcohol withdrawal, alcohol insanity, alcohol poisoning, alcoholic jealousy, alcoholic mania, alcohol-dependent mental disorder, alcoholic insanity, pharmacophilia, pharmacophobia, drug addiction, drug withdrawal, stress headache, catatonic headache, diabetic neuropathy, obesity, diabetes, muscle spasm, Meniere's disease, autonomic ataxia, alopecia, glaucoma, hypertension, heart disease, tachycardia, congestive heart failure, hyperventilation, bronchial asthma, sleep apnea, sudden infant death syndrome, inflammatory disease, allergic disease, impotence, menopausal disorder, infertility, neoplasms (eg, cancer, liver neoplasms, colon neoplasms, breast neoplasms, prostate neoplasms, neuroblastoma, bone neoplasms, oral cavity neoplasms, mastocytoma, cholangiocarcinoma, Lewis lung carcinoma, etc.), immunodeficiency syndrome caused by HIV infection, stress-induced immunodeficiency syndrome, cerebrospinal meningitis, acromegaly, urinary incontinence, metabolic syndrome, osteoporosis, gastric ulcer, irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, stress gastrointestinal disorder, stress vomiting, diarrhea, constipation, postoperative ulcers, rheumatoid arthritis, osteoarthritis, functional dyspepsia, hyperalgesia, insulin resistance, boxer dementia, nausea, vomiting, neoplasm metastasis, brain injury, seizure, changes in body weight, weight gain, loss in esa, colitis, alcoholism, hypothermia, fatty liver, atherosclerosis, infection, muscle spasticity, hypertension, stroke, malignant migratory partial seizures in infancy, diabetes mellitus, type 2 diabetes mellitus, dyslipidemia, visceral obesity, ocular hypotension, anorexia, fibrosis, infarction myocardial infarction, cachexia, induced psychotic disorder, ataxia, AIDS wasting syndrome, cirrhotic cardiomyopathy, uremic pruritus, neurobehavioral manifestations, tubulointerstitial nephritis and uveitis syndrome, interstitial cystitis, retinitis pigmentosa, autoimmune diseases, coronary artery disease, aspirin-induced asthma, platelet pool deficiency , diabetic embryopathy, Artus urticaria, asthma, toxic oil syndrome, otitis media and the like,

(7) pain (eg, inflammatory pain, cancer pain, neuropathic pain, acute pain, pain associated with peripheral neuropathy, central pain, fibromyalgia, sickle cell vascular crises, multiple sclerosis-mediated spasticity or pain, functional pain in chest, complex regional pain syndrome, etc.),

(8) migraines,

(9) cerebral edema,

(10) cerebral ischemia, ischemia and the like.

[0180]

Since the compound of the present invention has an excellent inhibitory effect on MAGL, an excellent prophylactic or therapeutic effect for the aforementioned diseases can be expected.

[0181]

Since the compound of the present invention has an excellent inhibitory effect on MAGL, an excellent preventive or therapeutic effect can be expected in neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, glaucoma, multiple sclerosis, etc.). etc.), anxiety disorder, pain (eg, inflammatory pain, cancer pain, neurogenic pain, etc.), epilepsy, depression, and the like, in particular Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis , anxiety disorder, pain, epilepsy or depression.

[0182]

Compound (I) can be used as a prodrug.

[0183]

Compound (I) prodrug means a compound that is converted to compound (I) by reaction by enzyme, gastric acid, etc. under physiological conditions in a living body, that is, a compound that is converted to compound (I) by oxidation, reduction, hydrolysis, etc. by an enzyme; a compound which is converted to compound (I) by hydrolysis, etc. by gastric acid, etc.

[0184]

A prodrug for compound (I) may be a compound obtained by subjecting an amino group in compound (I) to acylation, alkylation or phosphorylation (for example, a compound obtained by subjecting an amino group to compound (I) to eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2 -oxo-1,3-dioxolen-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butyation, etc.); a compound obtained by subjecting a hydroxy group in compound (I) to acylation, alkylation, phosphorylation or boronation (for example, a compound obtained by subjecting a hydroxy group in compound (I) to acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation, etc.) d.); a compound obtained by subjecting a carboxyl group in compound (I) to esterification or amidation (for example, a compound obtained by subjecting a carboxyl group to compound (I) to ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-esterification, cyclohexyloxycarbonylethyl esterification or methylamidation, etc.) and the like. Any of these compounds can be obtained from compound (I) in a manner known per se. The prodrug of compound (I) may be a compound that is converted to compound (I) under physiological conditions, as described in Development of Pharmaceutical Products, vol. 7, Molecule Design, 163-198, Hirokawa Shoten (1990).

[0185]

The compound of the present invention has excellent in vivo kinetics (e.g., plasma half-life, intracerebral tolerance, metabolic stability), exhibits low toxicity (e.g., higher drug quality in terms of acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity). toxicity, cardiotoxicity, drug interactions, carcinogenicity, etc.). The compound of the present invention is directly used as a drug or pharmaceutical composition mixed with a pharmaceutically acceptable carrier or the like for safe oral or parenteral administration to mammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits). , cats, dogs, sheep and goats). Examples of "parenteral" include intravenous, intramuscular, subcutaneous, intraorganic, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal, and intratumoral administration, administration in the vicinity of a tumor, etc., and direct administration to a lesion.

[0186]

Although the dosage of the compound of the present invention varies depending on the route of administration, symptom and the like, when, for example, the compound is administered orally to an Alzheimer's disease patient (adult, body weight, for example, 40-80 kg, for example, 60 kg), it is eg 0.001-1000 mg/kg body weight/day, preferably 0.01-100 mg/kg body weight/day, more preferably 0.1-10 mg/kg body weight/day. This amount can be administered from 1 to 3 servings per day.

[0187]

The drug containing the compound of the present invention can be used alone or as a pharmaceutical composition containing the compound of the present invention and a pharmaceutically acceptable carrier according to a method known per se, as well as a method for preparing a pharmaceutical preparation (for example, the method described in Japanese pharmacopoeia, etc.). The drug containing the compound of the present invention can be safely administered in the form of, for example, tablets (including sugar-coated tablet, film-coated tablet, sublingual tablet, oral disintegration tablet, buccal and the like), pills, powder, granules, capsule (including soft capsule, microcapsule), trochet, syrup, liquid, emulsion, suspension, controlled release formulation (eg, immediate release formulation, delayed release formulation, sustained release microcapsule), aerosol, film (eg, orally disintegrating film, adhesive film to the oral mucosa), injection (for example, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip infusion, transdermal absorption type preparation, ointment, lotion, adhesive preparation, suppository (for example, rectal suppository, vaginal suppository), pellet, nasal drug, lung drug (inhalant), eye drops and the like, orally or parenterally (for example, intravenously, intramuscularly, subcutaneously, intraorganically, intranasally, intradermally, instillation, intracerebral, intrarectal, intravaginally, intraperitoneally and injected into the lesion).

[0188]

As the aforementioned "pharmaceutically acceptable carrier", various organic or inorganic carriers commonly used as preparation materials (starting materials) can be used. For example, a filler, lubricant, binder, disintegrant, and the like are used for solid preparations, and a solvent, solubilizing agent, suspending agent, isotonic agent, buffer, soothing agent, and the like are used for liquid preparations. Where necessary, preparation additives such as a preservative, antioxidant, coloring agent, sweetener, and the like may also be used.

Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like.

Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silicon dioxide and the like.

Examples of the binder include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.

Examples of the disintegrant include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like.

Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.

Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl amino propionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; etc.

Examples of the isotonicity agent include glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol and the like.

Examples of the buffer include buffer solutions such as phosphates, acetates, carbonates, citrates, and the like.

Examples of the soothing agent include benzyl alcohol and the like.

Examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid and the like.

Examples of the antioxidant include sulfite, ascorbic acid, α-tocopherol and the like.

[0189]

Although the pharmaceutical composition varies depending on the dosage form, the route of administration, the carrier and the like, it can be obtained in accordance with the usual method by adding the compound of the present invention in a proportion of usually 0.01-100% (w/w), preferably, 0.1-95% (wt./mass.) of the total amount of the drug.

[0190]

The compound of the present invention can be used in combination with other active ingredients (hereinafter, it will be abbreviated as concomitant drug).

[0191]

Examples of a concomitant drug include the following. benzodiazepine (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel inhibitor (pregabalin, etc.), tricyclic or tetracyclic antidepressant (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride) selective serotonin reuptake inhibitor (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitor (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.). ), norepinephrine reuptake inhibitor (reboxetine mesylate, etc.), norepinephrine-dopamine reuptake inhibitor (bupropion hydrochloride, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, septipilin maleate, 5-HT agonist _1A (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT ₃ antagonist (cyamemazy n, etc.), non-selective cardiac β-inhibitor (propranolol hydrochloride, oxprenolol hydrochloride, etc.), histamine H1 antagonist ₍ hydroxyzine hydrochloride, etc.), therapeutic drug for schizophrenia (chlorpromazine, haloperidol , sulpiride, clozapine, trifluoperazine hydrochloride, fluphenazine hydrochloride, olanzapine, quetiapine fumarate, risperidone, aripiprazole, etc.), CRF antagonist, other anti-anxiety drug (meprobamate, etc.), tachykinin antagonist (MK-869, saridutant etc.), a drug acting on the metabotropic glutamate receptor, CCK antagonist, β3 adrenaline antagonist (amibegron hydrochloride, etc.), GAT-1 inhibitor (tiagabine hydrochloride, etc.), N-calcium channel inhibitor type, carbonic anhydrase II inhibitor, NMDA glycine group agonist, NMDA antagonist (memantine, etc.), peripheral benzodiazepine receptor agonist, vasopressin antagonist, vasopressin V1b antagonist, vasopressin V1a antagonist, phosphodiesterase inhibitor, opioid antagonist, opioid agonist, uridine, nicotinic acid receptor agonist, thyroid hormone (T3, T4), TSH, TRH, MAO inhibitor (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), 5-HT2A _antagonist , reverse 5-HT2A agonist, COMT inhibitor (entacapone, etc.), therapeutic drug for bipolar disorder (lithium carbonate, sodium valproate, lamotrigine, riluzole, _felbamate , etc.), cannabinoid CB1 antagonist (rimonabant, etc.) FAAH inhibitor, sodium channel inhibitor, ADHD drug (methylphenidate hydrochloride), methamphetamine hydrochloride, etc.), alcoholism therapeutic drug, autism therapeutic drug, chronic fatigue syndrome therapeutic drug, spasm therapeutic drug, Fibromyalgia syndrome therapeutic drug, headache therapeutic drug, insomnia therapeutic drug (etizolam, zopiclone, triazolam, zolpidem, ramelteon, indiplon, etc.), internist therapeutic drug for smoking, therapeutic drug for myasthenia gravis, therapeutic drug for cerebral infarction, therapeutic drug for mania, drug for hypersomnia, therapeutic drug for pain, therapeutic drug for dysthymia, therapeutic drug for autonomic ataxia, therapeutic drug for sexual dysfunction in men and women, migraine therapeutic drug, pathological gambler therapeutic drug, restless leg syndrome therapeutic drug, drug addiction therapeutic drug, alcohol syndrome therapeutic drug, irritable bowel syndrome drug, Alzheimer's drug (donepezil, galantamine , memantine, rivastigmine, etc.), a therapeutic drug for the treatment of Parkinson's disease (levodopa, carbidopa, benserazide, selegiline, zonisamide, entacapone, amantadine, talipexol, pramipexole, apomorphine, cabergo lyn, bromocriptine, istradephylline, trihexyphenidyl, promethazine, pergolide, etc.), therapeutic drug for Huntington's disease (chlorpromazine, hydrochloride, haloperidol, reserpine, etc.), therapeutic drug for ALS (riluzole, etc.). neurotrophic factor, etc.), a therapeutic drug for multiple sclerosis (molecular target drug such as fingolimod, interferon beta 1b, natalizumab and the like, etc.), an antiepileptic drug (phenytoin, carbamazepine , phenobarbital, primidone, zonisamide, sodium valproate, ethosuximide, diazepam, nitrazepam, clonazepam, clobazam, gabapentin, topiramate, lamotrigine, levetiracetam, styripentol, rufinamide, etc.), therapeutic drug for lipid disorders, such as cholesterol lowering drug (a number of statins (pravastatin sodium, atrovastatin, simvastatin, rosuvastatin, etc.), fibrate (clofibrate, etc.), squalene synthetase inhibitor), therapeutic drug drug for abnormal behavior or suppression of dromomania due to dementia (sedatives, anti-anxiety drug, etc.), apoptosis inhibitor, anti-obesity drug, diabetes drug, hypertension drug, hypotension drug, drug rheumatism drug (DMARD), anti-cancer drug, parathyroid drug (PTH), calcium receptor antagonist, sex hormone or derivative (progesterone, estradiol, estradiol benzoate, etc.), neuronal differentiation stimulant, regeneration stimulator nerves, non-steroidal anti-inflammatory drug (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroid (dexamethasone, cortisone acetate, etc.), anti-cytokine drug (TNF inhibitor, MAP kinase inhibitor etc.), antibody drug, nucleic acid or nucleic derivative a new acid, an aptamer drug, and the like.

[0192]

By combining the compound of the present invention and the concomitant drug, an excellent effect such as

(1) the dose can be reduced compared to a single administration of the compound of the present invention or a concomitant drug,

(2) the drug to be combined with the compound of the present invention can be selected according to the pathological condition of the patients (mild case, severe case, and the like),

(3) the treatment period can be set to be longer by selecting a concomitant drug having a different action and mechanism from the compound of the present invention,

(4) a long-term therapeutic effect can be achieved by selecting a concomitant drug having a different action and mechanism from the compound of the present invention,

(5) a synergistic effect can be achieved by the combined use of the compound of the present invention and a concomitant drug and the like.

[0193]

Hereinafter, the compound of the present invention and the concomitant drug used in combination are referred to as the "combination agent of the present invention".

When using the combination agent of the present invention, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or its pharmaceutical composition and the concomitant drug or its pharmaceutical composition may be administered to the subject of administration at the same time or may be administered at different times. The dosage of the concomitant drug may be determined according to the clinically used dose, and may be appropriately selected depending on the administration subject, route of administration, disease, combination, and the like.

The administration method of the concomitant drug of the present invention is not particularly limited, and it is sufficient that the compound of the present invention and the concomitant drug be combined upon administration. Examples of such an administration mode include the following methods:

(1) administration of one preparation obtained by simultaneously processing the compound of the present invention and the concomitant drug, (2) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which were obtained separately, by the same administration route, (3 ) administering two kinds of preparations of the compound of the present invention and a concomitant drug that were prepared separately by the same staggered administration route, (4) simultaneous administration of two kinds of preparations of the compound of the present invention and a concomitant drug that were prepared separately , different routes of administration, (5) the administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which were obtained separately, by different routes of administration in a checkerboard pattern (for example, administration in the order of the compound of the present invention and the concomitant medicinal product or vice versa) and the like.

[0194]

The combination agent of the present invention exhibits low toxicity. For example, the compound of the present invention and/or the aforementioned concomitant drug can be combined with a pharmacologically acceptable carrier according to a known method to prepare a pharmaceutical composition such as tablets (including sugar-coated tablet and film-coated tablet), powders, granules. , capsules (including softgels), liquids, injections, suppositories, sustained release agents, etc. These compositions can be safely administered orally or non-orally (eg, topically, rectally, intravenously, etc.). The injection can be administered intravenously, intramuscularly, subcutaneously or by intraorganic administration or directly into the lesion.

Examples of pharmacologically acceptable carriers used to prepare the combination agent of the present invention include those similar to those mentioned above.

[0195]

The mixing ratio of the compound of the present invention with the concomitant drug in the combined agent of the present invention can be appropriately selected depending on the administration subject, administration route, diseases, and the like.

For example, the content of the compound of the present invention in the combination agent of the present invention differs depending on the form of the preparation and is usually from about 0.01 to about 100 wt%, preferably from about 0.1 to about 50 wt%, even more preferably , from about 0.5 to about 20% of the mass. per drug. The content of the concomitant drug in the combination agent of the present invention varies depending on the form of the drug and is usually from about 0.01 to about 100 wt.%, preferably from about 0.1 to about 50 wt.%, even more preferably, from about 0.5 to about 20% of the mass. per drug.

Examples

[0196]

The present invention is explained in detail below with reference to Examples, Experimental Examples and Preparation Examples, which should not be construed as limiting, and the invention may be modified within the scope of the present invention.

In the following examples, "room temperature" usually means from about 10°C to about 35°C. Ratios given for mixed solvents are by volume unless otherwise noted. % means % wt., unless otherwise indicated.

Column chromatography elution in the examples was carried out under TLC (thin layer chromatography) monitoring unless otherwise indicated. In TLC observation, 60 F ₂₅₄ TLC plates manufactured by Merck were used, a solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used for detection. In silica gel column chromatography, NH refers to the use of aminopropylsilane bonded silica gel and diol refers to the use of 3-(2,3-dihydroxypropoxy)propylsilane bonded silica gel. In preparative HPLC (high performance liquid chromatography), the indication C18 indicates the use of octadecyl-bound silica gel. The ratio for the eluting solvent is, unless otherwise indicated, a mixing ratio by volume.

For analysis ^{of 1} H NMR used software ACD/SpecManager (trade name) and the like. Peaks of a hydroxyl group, an amino group, and the like having a very soft proton peak are sometimes not described.

MS was measured by LC/MS. The ESI method or the APCI method was used as the ionization method. The data indicates the actual measured value (found). Although a molecular ion peak is usually observed, a fragment ion is sometimes observed. In the case of a salt, a molecular ion peak or a free-form fragment ion peak is usually observed.

The X-ray powder diffraction pattern was measured using characteristic Cu-Kα radiation from Rigaku Ultima IV and described characteristic peaks.

The following conventions are used in the examples.

m.p.: melting point

MS: mass spectrum

M: molar concentration

CDCl ₃ : deuterochloroform

DMSO-d ₆ : deuterodimethyl sulfoxide

¹ H NMR: proton nuclear magnetic resonance

LC/MS: liquid chromatography-mass spectrometry

ESI: Electrospray Ionization

APCI: Atmospheric Pressure Chemical Ionization

DIAD: diisopropyl azodicarboxylate

DMSO: dimethyl sulfoxide

DMA: N,N-dimethylacetamide

DMAP: N,N-dimethyl-4-aminopyridine

DMF: N,N-dimethylformamide

TBAF: tetrabutylammonium fluoride

TEA: triethylamine

THF: tetrahydrofuran

[0197]

Example 1

cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0198]

A) tert-butyl ((cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutyl)oxy)dimethylsilane

To a mixture of cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutanol (500 mg), 1,2-difluoro-4-(trifluoromethyl)benzene (0.383 ml) and THF (10 ml), potassium (333 mg) at 0°C. The mixture was stirred under argon atmosphere at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solution was passed through NH silica gel, eluted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (900 mg) as a crude product.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.05 (6H, s), 0.86 (9H, s), 1.90-2.04 (2H, m), 2.87-3, 00 (2H, m), 3.98-4.11 (1H, m), 4.41-4.54 (1H, m), 7.18 (1H, t, J=8.4 Hz), 7 .50 (1H, d, J=8.5 Hz), 7.67 (1H, dd, J=11.3, 2.1 Hz).

[0199]

B) cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutanol

To a mixture of tert-butyl ((cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutyl)oxy)dimethylsilane (crude product, 900 mg) and THF (10 ml) was added TBAF (1 M THF solution, 3 .7 ml). The mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solution was passed through NH silica gel, eluted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (486 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.89-2.02 (2H, m), 2.81-2.92 (2H, m), 3.79-3.93 (1H, m ), 4.37-4.49 (1H, m), 5.24 (1H, d, J=6.8 Hz), 7.19 (1H, t, J=8.5 Hz), 7.50 (1H, d, J=8.7 Hz), 7.67 (1H, dd, J=11.3, 2.1 Hz).

[0200]

C) tert-butyl-3-(hydroxymethyl)-3-nitroazetidine-1-carboxylate

Formaldehyde (37% aqueous solution, 73 ml) was added to a mixture of tert-butyl 3-nitroazetidine-1-carboxylate (90 g) and acetonitrile (1.25 L) and then TEA (60 ml) was added dropwise thereto at room temperature, and the reaction mixture was stirred at room temperature for 16 hours, the Reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (85 mg).

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.45 (9H, s), 2.68 (1H, br. s), 4.11 (2H, d, J=10.4 Hz), 4.19 -4.21(2H, m), 4.39-4.46(2H, m).

[0201]

D) tert-butyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of tert-butyl 3-(hydroxymethyl)-3-nitroazetidine-1-carboxylate (85 g), Raney nickel (9 g) and methanol (1.5 L) was hydrogenated at 60 psi. inch at room temperature for 16 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain an intermediate compound (68 g). Triphosgene (40 g) was added to a mixture of the resulting intermediate (68 g), TEA (100 ml) and THF (1.5 L) at 0°C and the reaction mixture was stirred at 0°C for 30 min. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (58 g).

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.43 (9H, s), 4.03 (2H, d, J=10.1 Hz), 4.13 (2H, d, J=9.5 Hz ), 4.53 (2H, s), 6.52 (1H, br. s).

[0202]

E) 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate

To a mixture of tert-butyl 6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate (58 g) and ethyl acetate (1.2 L) was added tosylic acid hydrate (58 g) at room temperature , and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, tosylic acid hydrate (14.5 g) was added thereto, and the mixture was heated at reflux for an additional 2 hours. The reaction mixture was cooled to room temperature, and the solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (62 g).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.29 (3H, s), 4.05-4.15 (4H, m), 4.54 (2H, s), 7.13 (2H, d, J=7.8 Hz), 7.50 (2H, d, J=7.8 Hz), 8.51-8.54 (3H, m).

[0203]

F) cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (202 mg) was added to a mixture of cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutanol (486 mg), TEA (1.08 ml) and acetonitrile (16 ml). The reaction mixture was stirred at 0°C for 30 min and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (583 mg) was added thereto. The mixture was stirred at the same temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solution was passed through NH silica gel, eluted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (605 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.06-2.21 (2H, m), 2.93-3.07 (2H, m), 3.92-4.17 (4H, m ), 4.47(2H, s), 4.54-4.71(2H, m), 7.20(1H, t, J=8.5Hz), 7.51(1H, d, J= 7.7 Hz), 7.69 (1H, dd, J=11.4, 2.0 Hz), 8.40 (1H, s).

[0204]

Example 2

cis-3-(benzyloxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (191 mg) was added to a mixture of cis-3-(benzyloxy)cyclobutanol (328 mg), TEA (1.03 ml) and acetonitrile (15 ml). The reaction mixture was stirred at 0°C for 30 min and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (553 mg) was added thereto. The mixture was stirred at the same temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solution was passed through NH silica gel, eluted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from diisopropyl ether to give the title compound (436 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.80-1.95 (2H, m), 2.59-2.72 (2H, m), 3.65-3.78 (1H, m ), 3.89-4.16(4H, m), 4.36(2H, s), 4.43-4.45(3H, m), 7.24-7.40(5H, m), 8.39 (1H, s).

[0205]

Example 3

cis-3-((3-chloro-4-methylbenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0206]

A) tert-butyl ((cis-3-((3-chloro-4-methylbenzyl)oxy)cyclobutyl)oxy)dimethylsilane

To a mixture of cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutanol (500 mg) and DMF (9.3 ml) was added sodium hydride (60%, 109 mg) at 0°C. The reaction mixture was stirred at the same temperature for 10 minutes, and a mixture of 4-(bromomethyl)-2-chloro-1-methylbenzene (597 mg) and DMF (3.1 ml) was added thereto. The mixture was stirred under argon at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (782 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.00 (6H, s), 0.83 (9H, s), 1.67-1.81 (2H, m), 2.30 (3H, s), 2.52-2.64 (2H, m), 3.55 (1H, fifth, J=7.0 Hz), 3.88 (1H, fifth, J=7.1 Hz), 4, 29 (2H, s), 7.16 (1H, dd, J=7.9, 1.5 Hz), 7.26-7.37 (2H, m).

[0207]

B) cis-3-((3-chloro-4-methylbenzyl)oxy)cyclobutanol

To a mixture of tert-butyl ((cis-3-((3-chloro-4-methylbenzyl)oxy)cyclobutyl)oxy)dimethylsilane (782 mg) and THF (12 ml) was added TBAF (1 M THF solution, 4.6 ml ). The mixture was stirred at room temperature for 64 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (461 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.65-1.80 (2H, m), 2.31 (3H, s), 2.45-2.58 (2H, m), 3, 46-3.59(1H, m), 3.60-3.74(1H, m), 4.30(2H, s), 4.99(1H, d, J=6.6Hz), 7 .13-7.20 (1H, m), 7.27-7.36 (2H, m).

[0208]

C) cis-3-((3-chloro-4-methylbenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (211 mg) was added to a mixture of cis-3-((3-chloro-4-methylbenzyl)oxy)cyclobutanol (461 mg), TEA (1.13 ml) and acetonitrile (10 ml) at 0°C. The reaction mixture was stirred at the same temperature for 20 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (641 mg) was added thereto. The mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (575 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.88 (2H, dtd, J=9.8, 7.3, 2.9 Hz), 2.31 (3H, s), 2.65 ( 2H, dtd, J=9.7, 6.6, 2.9 Hz), 3.71 (1H, fifth, J=6.8 Hz), 3.89-4.01 (2H, m), 4 .08 (2H, d, J=8.7 Hz), 4.33 (2H, s), 4.40-4.57 (3H, m), 7.18 (1H, dd, J=7.6 , 1.4 Hz), 7.32 (1H, d, J=7.7 Hz), 7.35 (1H, d, J=1.5 Hz), 8.38 (1H, s).

[0209]

Example 4

cis-3-((4-chloro-3-methylbenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0210]

A) tert-butyl ((cis-3-((4-chloro-3-methylbenzyl)oxy)cyclobutyl)oxy)dimethylsilane

To a mixture of cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutanol (500 mg) and DMF (9.3 ml) was added sodium hydride (60%, 109 mg) under argon at 0°C. The reaction mixture was stirred at the same temperature for 10 min, and a mixture of 4-(bromomethyl)-1-chloro-2-methylbenzene (597 mg) and DMF (3.1 ml) was added thereto at 0°C. The mixture was stirred under argon at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (833 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.01 (6H, s), 0.85 (9H, s), 1.67-1.83 (2H, m), 2.32 (3H, s), 2.59 (2H, dtd, J=9.0, 6.4, 2.9 Hz), 3.57 (1H, fifth, J=7.0 Hz), 3.89 (1H, fifth , J=7.1 Hz), 4.30 (2H, s), 7.15 (1H, dd, J=8.2, 1.8 Hz), 7.28 (1H, s), 7.36 (1H, d, J=8.1 Hz).

[0211]

B) cis-3-((4-chloro-3-methylbenzyl)oxy)cyclobutanol

To a mixture of tert-butyl ((cis-3-((4-chloro-3-methylbenzyl)oxy)cyclobutyl)oxy)dimethylsilane (833 mg) and THF (12 ml) was added TBAF (1 M THF solution, 4.9 ml ). The mixture was stirred at room temperature for 64 hours. The mixture was diluted with ethyl acetate, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (511 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.64-1.80 (2H, m), 2.32 (3H, s), 2.47-2.59 (2H, m), 3, 47-3.59(1H, m), 3.60-3.75(1H, m), 4.29(2H, s), 4.99(1H, d, J=6.6Hz), 7 .14 (1H, dd, J=8.1, 1.7 Hz), 7.28 (1H, s), 7.36 (1H, d, J=8.1 Hz).

[0212]

C) cis-3-((4-chloro-3-methylbenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (234 mg) was added to a mixture of cis-3-((4-chloro-3-methylbenzyl)oxy)cyclobutanol (511 mg), TEA (1.26 ml) and acetonitrile (11 ml) at 0°C. The reaction mixture was stirred at the same temperature for 20 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (711 mg) was added thereto. The mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (651 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.80-1.95 (2H, m), 2.32 (3H, s), 2.65 (2H, dtd, J=9.7.6 .6, 3.0 Hz), 3.71 (1H, fifth, J=6.8 Hz), 3.91-4.01 (2H, m), 4.08 (2H, d, J=9, 3 Hz), 4.32 (2H, s), 4.42-4.57 (3H, m), 7.16 (1H, dd, J=8.1, 1.7 Hz), 7.29 ( 1H, d, J=1.5 Hz), 7.37 (1H, d, J=8.1 Hz), 8.38 (1H, s).

[0213]

Example 5

cis-3-((2,3-difluoro-4-methylbenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0214]

A) tert-butyl ((cis-3-((2,3-difluoro-4-methylbenzyl)oxy)cyclobutyl)oxy)dimethylsilane

To a mixture of cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutanol (400 mg) and DMF (5 ml) was added sodium hydride (60%, 87 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 minutes, and 1-(bromomethyl)-2,3-difluoro-4-methylbenzene (481 mg) was added thereto at room temperature. The mixture was stirred overnight under argon at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (636 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.00-0.02 (6H, m), 0.84 (9H, s), 1.65-1.81 (2H, m), 2, 27 (3H, d, J=2.1 Hz), 2.54-2.66 (2H, m), 3.58 (1H, fifth, J=7.0 Hz), 3.89 (1H, fifth , J=7.1 Hz), 4.38(2H, d, J=7.1 Hz), 7.01-7.18(2H, m).

[0215]

B) cis-3-((2,3-difluoro-4-methylbenzyl)oxy)cyclobutanol

To a mixture of tert-butyl ((cis-3-((2,3-difluoro-4-methylbenzyl)oxy)cyclobutyl)oxy)dimethylsilane (636 mg) and THF (10 ml) was added TBAF (1 M THF solution, 2 8 ml) at room temperature. The mixture was stirred at the same temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (302 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.63-1.79 (2H, m), 2.27 (3H, d, J=2.1 Hz), 2.51-2.58 (2H , m), 3.54 (1H, fifth, J=7.1 Hz), 3.61-3.74 (1H, m), 4.38 (2H, d, J=1.1 Hz), 5 .00 (1H, d, J=6.8 Hz), 6.88-7.29 (2H, m).

[0216]

C) cis-3-((2,3-difluoro-4-methylbenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (137 mg) was added to a mixture of 3-((2,3-difluoro-4-methylbenzyl)oxy)cyclobutanol (302 mg), TEA (0.74 ml) and acetonitrile (10 ml) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (417 mg) was added thereto at 0°C. The mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (300 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.77-1.92 (2H, m), 2.27 (3H, d, J=2.1 Hz), 2.59-2.71 ( 2H, m), 3.60-3.81(1H, m), 3.89-4.02(2H, m), 4.02-4.13(2H, m), 4.41(2H, s), 4.45-4.54(3H, m), 6.96-7.20(2H, m), 8.38(1H, s).

[0217]

Example 6

cis-3-((2,3,4-trifluorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0218]

A) tert-butyl(dimethyl)((cis-3-((2,3,4-trifluorobenzyl)oxy)cyclobutyl)oxy)silane

To a mixture of cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutanol (400 mg) and DMF (6.0 ml) was added sodium hydride (60%, 95.0 mg) at 0°C. The reaction mixture was stirred at the same temperature for 10 min, and 1-(bromomethyl)-2,3,4-trifluorobenzene (534 mg) was added thereto at 0°C. The mixture was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (716 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.01 (6H, s), 0.84 (9H, s), 1.64-1.90 (2H, m), 2.53-2, 67 (2H, m), 3.59 (1H, fifth, J=7.1 Hz), 3.90 (1H, fifth, J=7.1 Hz), 4.40 (2H, s), 7, 23-7.40 (2H, m).

[0219]

B) cis-3-((2,3,4-trifluorobenzyl)oxy)cyclobutanol

TBAF (1 M THF solution , 3.1 ml) at 0°C. The mixture was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (413 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.64-1.79 (2H, m), 2.51-2.60 (2H, m), 3.50-3.61 (1H, m ), 3.61-3.78(1H, m), 4.40(2H, s), 5.02(1H, d, J=6.4Hz), 7.23-7.38(2H, m).

[0220]

C) cis-3-((2,3,4-trifluorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-((2,3,4-trifluorobenzyl)oxy)cyclobutanol (250 mg), TEA (0.898 ml) and acetonitrile (5.0 ml) was added triphosgene (112 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (340 mg) was added thereto at 0°C. The mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) and crystallized from ethyl acetate/hexane to give the title compound (176 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.76-1.98 (2H, m), 2.57-2.79 (2H, m), 3.74 (1H, quint, J=6 .8 Hz), 3.87-4.21(4H, m), 4.36-4.61(5H, m), 7.21-7.43(2H, m), 8.39(1H, With).

[0221]

Example 7

cis-3-((2,4,5-trifluorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0222]

A) tert-butyl(dimethyl)((cis-3-((2,4,5-trifluorobenzyl)oxy)cyclobutyl)oxy)silane

To a mixture of cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutanol (500 mg) and DMF (5 ml) was added sodium hydride (60%, 109 mg) at 0°C. The reaction mixture was stirred at room temperature for 30 min, and 1-(bromomethyl)-2,4,5-trifluorobenzene (0.358 ml) was added thereto at 0°C. The mixture was stirred under argon atmosphere at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (428 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.01 (6H, s), 0.85 (9H, s), 1.69-1.80 (2H, m), 2.54-2, 65(2H, m), 3.54-3.65(1H, m), 3.84-3.95(1H, m), 4.35(2H, s), 7.47-7.59( 2H, m).

[0223]

B) cis-3-((2,4,5-trifluorobenzyl)oxy)cyclobutanol

TBAF (1 M THF solution, 1 .5 ml) at room temperature. The mixture was stirred at the same temperature for 1 hour. A saturated sodium chloride aqueous solution was added to this mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (126 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.65-1.79 (2H, m), 2.51-2.59 (2H, m), 3.56 (1H, quint, J=7 .0 Hz), 3.62-3.75 (1H, m), 4.35 (2H, s), 5.01 (1H, d, J=6.6 Hz), 7.52 (2H, ddt , J=10.8, 9.5, 6.7 Hz).

[0224]

C) cis-3-((2,4,5-trifluorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (56.4 mg) was added to a mixture of cis-3-((2,4,5-trifluorobenzyl)oxy)cyclobutanol (126 mg), TEA (0.333 ml), and acetonitrile (3 ml) at 0°C. The reaction mixture was stirred at the same temperature for 20 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (163 mg) was added thereto at 0°C. The mixture was stirred at room temperature for 3 hours. To this mixture was added water at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (77.3 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.81-1.94 (2H, m), 2.60-2.72 (2H, m), 3.74 (1H, quint, J=6 .8 Hz), 3.92-4.14(4H, m), 4.34-4.55(5H, m), 7.48-7.61(2H, m), 8.39(1H, With).

[0225]

Example 8

cis-3-((2,4,6-trifluorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0226]

A) tert-butyl(dimethyl)((cis-3-((2,4,6-trifluorobenzyl)oxy)cyclobutyl)oxy)silane

To a mixture of cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutanol (400 mg) and DMF (7.4 ml) was added sodium hydride (60%, 87 mg) at 0°C. The reaction mixture was stirred at the same temperature for 10 min, and a mixture of 2-(bromomethyl)-1,3,5-trifluorobenzene (489 mg) and DMF (2.5 ml) was added thereto at 0°C. The mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (682 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.00 (6H, s), 0.84 (9H, s), 1.63-1.77 (2H, m), 2.52-2, 65 (2H, m), 3.57 (1H, fifth, J=6.9 Hz), 3.90 (1H, fifth, J=7.1 Hz), 4.36 (2H, s), 7, 13-7.27 (2H, m).

[0227]

B) cis-3-((2,4,6-trifluorobenzyl)oxy)cyclobutanol

TBAF (1 M THF solution , 3.9 ml). The mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (397 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.60-1.75 (2H, m), 2.44-2.57 (2H, m), 3.53 (1H, quint, J=7 .0 Hz), 3.60-3.75 (1H, m), 4.35 (2H, s), 5.00 (1H, d, J=6.8 Hz), 7.13-7.27 (2H, m).

[0228]

C) cis-3-((2,4,6-trifluorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (178 mg) was added to a mixture of cis-3-((2,4,6-trifluorobenzyl)oxy)cyclobutanol (397 mg), TEA (0.953 ml) and acetonitrile (8.5 ml) at 0°C. The reaction mixture was stirred at the same temperature for 20 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (539 mg) was added thereto. The mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from diisopropyl ether to give the title compound (218 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.71-1.91 (2H, m), 2.56-2.78 (2H, m), 3.71 (1H, quint, J=6 .8 Hz), 3.89-4.01(2H, m), 4.02-4.15(2H, m), 4.39(2H, s), 4.43-4.56(3H, m), 7.15-7.28 (2H, m), 8.38 (1H, s).

[0229]

Example 9

cis-3-((3,4-dichlorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0230]

A) tert-butyl ((cis-3-((3,4-dichlorobenzyl)oxy)cyclobutyl)oxy)dimethylsilane

To a mixture of cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutanol (270 mg) and DMF (3 ml) was added sodium hydride (60%, 58.7 mg) at 0°C. The reaction mixture was stirred at room temperature for 30 min, and 4-(bromomethyl)-1,2-dichlorobenzene (0.213 ml) was added thereto at 0°C. The mixture was stirred under argon atmosphere at room temperature for 3 hours. To this mixture was added water at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (240 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.01 (6H, s), 0.85 (9H, s), 1.71-1.83 (2H, m), 2.54-2, 65(2H, m), 3.53-3.64(1H, m), 3.90(1H, fifth, J=7.1Hz), 4.35(2H, s), 7.31(1H , dd, J=8.3, 1.9 Hz), 7.57 (1H, d, J=1.9 Hz), 7.60 (1H, d, J=8.3 Hz).

[0231]

B) cis-3-((3,4-dichlorobenzyl)oxy)cyclobutanol

To a mixture of tert-butyl ((cis-3-((3,4-dichlorobenzyl)oxy)cyclobutyl)oxy)dimethylsilane (240 mg) and THF (3 ml) was added TBAF (1 M THF solution, 0.66 ml) at room temperature. The mixture was stirred at the same temperature for 1 hour. Water was added to this mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (100 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.67-1.80 (2H, m), 2.51-2.59 (2H, m), 3.49-3.61 (1H, m ), 3.61-3.75(1H, m), 4.35(2H, s), 4.97-5.03(1H, m), 7.31(1H, dd, J=8.3 , 1.9 Hz), 7.56 (1H, d, J=1.9 Hz), 7.60 (1H, d, J=8.1 Hz).

[0232]

C) cis-3-((3,4-dichlorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (42.0 mg) was added to a mixture of cis-3-((3,4-dichlorobenzyl)oxy)cyclobutanol (100 mg), TEA (0.186 ml) and acetonitrile (2 ml) at 0°C. The reaction mixture was stirred at the same temperature for 10 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (122 mg) was added thereto at 0°C. The mixture was stirred at 0° C. for 2 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and then purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). A saturated aqueous sodium hydrogen carbonate solution was added to the resulting fraction, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (18.5 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.89 (2H, dtd, J=9.8, 7.3, 2.9 Hz), 2.60-2.71 (2H, m), 3.73 (1H, fifth, J=6.9 Hz), 3.92-4.14 (4H, m), 4.35-4.56 (5H, m), 7.32 (1H, dd, J=8.3, 1.9 Hz), 7.56-7.64(2H, m), 8.39(1H, s).

[0233]

Example 10

cis-3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0234]

A) cis-3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)cyclobutanol

To a mixture of cis-3-((tert-butyl(diphenyl)silyl)oxy)cyclobutanol (352 mg) and DMF (4.0 ml) was added sodium hydride (60%, 51.8 mg) at 0°C. The reaction mixture was stirred at the same temperature for 10 min, and a mixture of 1-(bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene (277 mg) and DMF (1.5 ml) was added thereto at 0°C. The mixture was stirred at room temperature for 3 days. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give intermediate (315 mg) as a crude product. To a mixture of the obtained intermediate (crude product, 310 mg) and THF (4.0 ml) was added TBAF (1 M THF solution, 0.27 ml) at room temperature. The mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (132 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.70 (1H, d, J=6.4 Hz), 1.88-2.03 (2H, m), 2.69-2.85 (2H, m), 3.67 (1H, fifth, J=6.9 Hz), 3.96 (1H, sixth, J=7.0 Hz), 4.52 (2H, s), 7.31 (1H, d, J=9.8 Hz), 7.42(1H, d, J=7.9 Hz), 7.52-7.64(1H, m).

[0235]

B) cis-3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)cyclobutanol (131 mg), TEA (0.275 ml) and acetonitrile (3.5 ml) was added triphosgene (51.3 mg) at 0 °C The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (156 mg) was added thereto at 0°C. The mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) and crystallized from ethyl acetate/hexane to give the title compound (73.6 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.82-2.03 (2H, m), 2.61-2.78 (2H, m), 3.78 (1H, quint, J=6 .9 Hz), 3.90-4.19(4H, m), 4.41-4.61(5H, m), 7.57-7.77(3H, m), 8.39(1H, With).

[0236]

Example 11

cis-3-((3-chloro-4-(trifluoromethyl)benzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0237]

A) tert-butyl ((cis-3-((3-chloro-4-(trifluoromethyl)benzyl)oxy)cyclobutyl)oxy)dimethylsilane

To a mixture of cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutanol (416 mg) and DMF (7.7 ml) was added sodium hydride (60%, 90 mg) at 0°C. The reaction mixture was stirred at the same temperature for 10 min, and a mixture of 3-chloro-4-(trifluoromethyl)benzylmethanesulfonate (653 mg) and DMF (2.6 ml) was added thereto at 0°C. The mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (549 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.02 (6H, s), 0.85 (9H, s), 1.72-1.86 (2H, m), 2.55-2, 68 (2H, m), 3.62 (1H, fifth, J=7.0 Hz), 3.91 (1H, fifth, J=7.1 Hz), 4.45 (2H, s), 7, 49 (1H, d, J=8.1 Hz), 7.64 (1H, s), 7.83 (1H, d, J=8.1 Hz).

[0238]

B) cis-3-((3-chloro-4-(trifluoromethyl)benzyl)oxy)cyclobutanol

TBAF (1 M THF solution , 2.8 ml). The mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (293 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.67-1.83 (2H, m), 2.50-2.61 (2H, m), 3.52-3.76 (2H, m ), 4.45 (2H, s), 5.03 (1H, d, J=6.6 Hz), 7.49 (1H, dd, J=8.1, 0.8 Hz), 7.64 (1H, s), 7.83 (1H, d, J=8.1 Hz).

[0239]

C) cis-3-((3-chloro-4-(trifluoromethyl)benzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-((3-chloro-4-(trifluoromethyl)benzyl)oxy)cyclobutanol (293 mg), TEA (0.582 ml) and acetonitrile (5.2 ml) was added triphosgene (108 mg) at 0°C . The reaction mixture was stirred at the same temperature for 20 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (329 mg) was added thereto. The mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and crystallized from ethyl acetate/hexane to give the title compound (46.0 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.83-2.03 (2H, m), 2.60-2.79 (2H, m), 3.76 (1H, quint, J=6 .9 Hz), 3.89-4.02 (2H, m), 4.09 (2H, d, J=8.7 Hz), 4.39-4.59 (5H, m), 7.50 (1H, d, J=7.9 Hz), 7.66 (1H, s), 7.84 (1H, d, J=8.3 Hz), 8.39 (1H, s).

[0240]

Example 12

cis-3-((2-fluoro-4-methylphenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0241]

A) (cis-3-(benzyloxy)cyclobutyl)methyl-4-methylbenzenesulfonate

To a mixture of (cis-3-(benzyloxy)cyclobutyl)methanol (1.78 g), 4-methylbenzenesulfonyl chloride (1.94 g) and acetonitrile (20 ml) was added TEA (1.93 ml) dropwise at 0°C and trimethylamine hydrochloride (88 mg) was added thereto. The mixture was stirred at the same temperature for 40 minutes and partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.97 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.46-1.63 (2H, m), 2.02-2.28 (3H, m), 2.42 (3H, s), 3, 86 (1H, fifth, J=7.2 Hz), 3.99 (2H, d, J=6.0 Hz), 4.31 (2H, s), 7.21-7.39 (5H, m ), 7.48 (2H, d, J=7.9 Hz), 7.70-7.85 (2H, m).

[0242]

B) 1-((cis-3-(benzyloxy)cyclobutyl)methoxy)-2-fluoro-4-methylbenzene

A mixture of (cis-3-(benzyloxy)cyclobutyl)methyl-4-methylbenzenesulfonate (300 mg), 2-fluoro-4-methylphenol (131 mg), potassium carbonate (239 mg) and DMF (3.0 ml) was stirred at 80 °C for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solution was passed through NH silica gel, eluted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (260 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.67-1.80 (2H, m), 2.15-2.39 (6H, m), 3.88-3.99 (3H, m ), 4.37(2H, s), 6.86-6.93(1H, m), 6.97-7.06(2H, m), 7.23-7.39(5H, m).

[0243]

C) cis-3-((2-fluoro-4-methylphenoxy)methyl)cyclobutanol

A mixture of 1-((cis-3-(benzyloxy)cyclobutyl)methoxy)-2-fluoro-4-methylbenzene (260 mg), palladium/charcoal (Pd 10%, 50% moisture, 184 mg) and methanol (20 ml) stirred under atmospheric pressure of a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was passed through NH silica gel and eluted with ethyl acetate to give the title compound (182 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.55-1.69 (2H, m), 2.01-2.18 (1H, m), 2.23 (3H, s), 2, 24-2.35 (2H, m), 3.90-4.07 (3H, m), 5.00 (1H, d, J=6.4 Hz), 6.86-6.93 (1H, m), 6.96-7.05 (2H, m).

[0244]

D) cis-3-((2-fluoro-4-methylphenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (90 mg) was added to a mixture of cis-3-((2-fluoro-4-methylphenoxy)methyl)cyclobutanol (182 mg), TEA (0.483 ml) and acetonitrile (9 ml). The reaction mixture was stirred at 0°C for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (260 mg) was added thereto. The mixture was stirred at the same temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solution was passed through NH silica gel and eluted with ethyl acetate. The solution was concentrated and the residue was crystallized from ethyl acetate/hexane (3/1) to give the title compound (238 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.75-1.93 (2H, m), 2.23 (3H, s), 2.26-2.47 (3H, m), 3, 90-4.14(6H, m), 4.47(2H, s), 4.70-4.85(1H, m), 6.86-6.95(1H, m), 6.97- 7.06 (2H, m), 8.34-8.42 (1H, m).

[0245]

Example 13

cis-3-((4-fluoro-2-methylphenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0246]

A) 1-((cis-3-(benzyloxy)cyclobutyl)methoxy)-4-fluoro-2-methylbenzene

To a mixture of 4-fluoro-2-methylphenol (120 mg), potassium carbonate (263 mg) and DMA (5 ml) was added (cis-3-(benzyloxy)cyclobutyl)methyl-4-methylbenzenesulfonate (300 mg) at room temperature. The mixture was stirred at 80° C. for 3 hours. Water was added to this mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (215 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.67-1.88 (2H, m), 2.15 (3H, s), 2.19-2.41 (3H, m), 3, 79-4.01(3H, m), 4.38(2H, s), 6.79-7.07(3H, m), 7.18-7.46(5H, m).

[0247]

B) cis-3-((4-fluoro-2-methylphenoxy)methyl)cyclobutanol

Mixture of 1-((cis-3-(benzyloxy)cyclobutyl)methoxy)-4-fluoro-2-methylbenzene (215 mg), palladium/charcoal (Pd 10%, 50% moisture, 100 mg) and methanol (20 ml) stirred overnight under atmospheric pressure of a hydrogen atmosphere at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (145 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.57-1.74 (2H, m), 2.03-2.14 (1H, m), 2.15 (3H, s), 2, 23-2.35 (2H, m), 3.87 (2H, d, J=6.0 Hz), 3.91-4.05 (1H, m), 5.00 (1H, br. s) , 6.72-7.13 (3H, m).

[0248]

C) cis-3-((4-fluoro-2-methylphenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-((4-fluoro-2-methylphenoxy)methyl)cyclobutanol (145 mg), TEA (0.38 ml) and acetonitrile (5 ml) was added triphosgene (71.6 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (217 mg) was added thereto. The mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (125 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.80-1.98 (2H, m), 2.17 (3H, s), 2.26-2.45 (3H, m), 3, 91 (2H, d, J=5.1 Hz), 3.94-4.02 (2H, m), 4.03-4.12 (2H, m), 4.47 (2H, s), 4 .66-4.88(1H, m), 6.80-7.10(3H, m), 8.38(1H, s).

[0249]

Example 14

cis-3-((2-chloro-4-fluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0250]

A) ethyl cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutanecarboxylate

To a mixture of 2,6-dimethylpyridine (9.44 ml), ethyl cis-3-hydroxycyclobutanecarboxylate (5.84 g) and DMF (50 ml) was added tert-butyl (dimethyl)silyl trifluoromethanesulfonate (11 ml) at 0°C. The mixture was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.4 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.02 (6H, s), 0.85 (9H, s), 1.17 (3H, t, J=7.1 Hz), 1.89 -2.02(2H, m), 2.37-2.47(2H, m), 2.53-2.65(1H, m), 4.05(2H, q, J=7.2Hz ), 4.11-4.22 (1H, m).

[0251]

B) (cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutyl)methanol

To a mixture of ethyl cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutanecarboxylate (10.4 g) and THF (100 ml) was added lithium aluminum hydride (1.69 g) at 0°C. The mixture was stirred at the same temperature for 30 minutes. To this mixture was added 10 aqueous sodium sulfate at 0°C, and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.66 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.01 (6H, s), 0.85 (9H, s), 1.48-1.62 (2H, m), 1.71-1, 86 (1H, m), 2.11-2.24 (2H, m), 3.27-3.38 (2H, m), 4.03-4.15 (1H, m), 4.42 ( 1H, t, J=5.5 Hz).

[0252]

C) (cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutyl)methyl-4-methylbenzenesulfonate

4-Methylbenzenesulfonyl chloride (3.01 d) and trimethylamine hydrochloride (144 mg) at 0°C. The mixture was stirred at the same temperature for 10 minutes and then at room temperature for 1 hour. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.12 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ -0.02 (6H, s), 0.82 (9H, s), 1.40-1.54 (2H, m), 1.92-2 .07 (1H, m), 2.10-2.29 (2H, m), 2.42 (3H, s), 3.97 (2H, d, J=6.4 Hz), 4.08 ( 1H, fifth, J=7.3 Hz), 7.48 (2H, d, J=7.9 Hz), 7.73-7.84 (2H, m).

[0253]

D) tert-butyl ((cis-3-((2-chloro-4-fluorophenoxy)methyl)cyclobutyl)oxy)dimethylsilane

Mixture of (cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutyl)methyl-4-methylbenzenesulfonate (678 mg), 2-chloro-4-fluorophenol (349 mg), potassium carbonate (379 mg) and DMF (5.0 ml) was stirred overnight at 80°C. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (338 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.00 (6H, s), 0.83 (9H, s), 1.65-1.80 (2H, m), 2.05-2, 20 (1H, m), 2.24-2.40 (2H, m), 3.97 (2H, d, J=6.0 Hz), 4.15 (1H, fifth, J=7.3 Hz ), 7.07-7.18(2H, m), 7.33-7.45(1H, m).

[0254]

E) cis-3-((2-chloro-4-fluorophenoxy)methyl)cyclobutanol

To a mixture of t-butyl ((cis-3-((2-chloro-4-fluorophenoxy)methyl)cyclobutyl)oxy)dimethylsilane (337 mg) and THF (4.0 ml) was added TBAF (1 M THF solution, 1. 5 ml) at room temperature. The mixture was stirred at the same temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (214 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.58-1.74 (2H, m), 2.04-2.21 (1H, m), 2.22-2.39 (2H, m ), 3.87-4.09 (3H, m), 5.01 (1H, d, J=6.4 Hz), 7.07-7.26 (2H, m), 7.31-7, 52 (1H, m).

[0255]

F) cis-3-((2-chloro-4-fluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (96.0 mg) was added to a mixture of cis-3-((2-chloro-4-fluorophenoxy)methyl)cyclobutanol (213 mg), TEA (0.770 ml) and acetonitrile (4.0 ml) at 0°C. The reaction mixture was stirred at the same temperature for 20 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (291 mg) was added thereto. The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane. The resulting solid was purified by HPLC (C18, mobile phase: water/acetonitrile (containing 10 mM NH ₄ HCO ₃ )). The resulting fraction was partially concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (235 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.81-2.01 (2H, m), 2.24-2.46 (3H, m), 3.89-4.15 (6H, m ), 4.47(2H, s), 4.69-4.88(1H, m), 7.03-7.24(2H, m), 7.34-7.56(1H, m), 8.39 (1H, s).

[0256]

Example 15

cis-3-((4-chloro-2-fluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0257]

A) ethyl cis-3-((tert-butyl(diphenyl)silyl)oxy)cyclobutanecarboxylate

To a mixture of ethyl cis-3-hydroxycyclobutanecarboxylate (500 mg), imidazole (283 mg), DMAP (21.2 mg) and DMF (12 ml) was added tert-butyl(diphenyl)chlorosilane (1.05 g). The mixture was stirred at room temperature for 5 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.23 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.98 (9H, s), 1.12-1.22 (3H, m), 2.05-2.18 (2H, m), 2, 27-2.41(2H, m), 2.52-2.59(1H, m), 3.94-4.09(2H, m), 4.10-4.22(1H, m), 7.36-7.52(6H, m), 7.53-7.66(4H, m).

[0258]

B) (cis-3-((tert-butyl(diphenyl)silyl)oxy)cyclobutyl)methanol

To a mixture of ethyl cis-3-((tert-butyl(diphenyl)silyl)oxy)cyclobutanecarboxylate (4.3 g) and THF (50 ml) was added dropwise a mixture of lithium aluminum hydride (469 mg) and THF (50 ml) at 0 °C The mixture was stirred at the same temperature for 15 minutes. To this mixture was added 10 aqueous sodium sulfate, and the mixture was stirred for 15 minutes. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.54 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.97 (9H, s), 1.64-1.82 (3H, m), 2.06-2.17 (2H, m), 3, 31-3.36 (2H, m), 4.04-4.16 (1H, m), 4.43 (1H, t, J=5.4 Hz), 7.31-7.51 (6H, m), 7.55-7.67 (4H, m).

[0259]

C) (cis-3-((tert-butyl(diphenyl)silyl)oxy)cyclobutyl)methyl-4-methylbenzenesulfonate

TEA (0.551 ml) and trimethylamine hydrochloride (25.3 mg) at 0°C. The mixture was stirred at the same temperature for 1 hour. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.29 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.95 (9H, s), 1.54-1.73 (2H, m), 1.82-1.97 (1H, m), 2, 03-2.21(2H, m), 2.39(1H, s), 2.42(3H, s), 3.98(2H, d, J=6.0Hz), 7.37-7 .51 (8H, m), 7.53-7.62 (4H, m), 7.77 (2H, d, J=8.3 Hz).

[0260]

D) tert-butyl ((cis-3-((4-chloro-2-fluorophenoxy)methyl)cyclobutyl)oxy)diphenylsilane

Mixture of (cis-3-((tert-butyl(diphenyl)silyl)oxy)cyclobutyl)methyl-4-methylbenzenesulfonate (500 mg), 4-chloro-2-fluorophenol (178 mg), potassium carbonate (210 mg) and DMF (4.0 ml) was stirred at 80° C. for 4 hours. Water was added to this mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (439 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.98 (9H, s), 1.74-1.94 (2H, m), 2.01-2.15 (1H, m), 2, 17-2.35 (2H, m), 4.00 (2H, d, J=6.0 Hz), 4.17 (1H, fifth, J=7.2 Hz), 7.08-7.24 (2H, m), 7.35-7.52 (7H, m), 7.56-7.71 (4H, m).

[0261]

E) cis-3-((4-chloro-2-fluorophenoxy)methyl)cyclobutanol

To a mixture of tert-butyl ((cis-3-((4-chloro-2-fluorophenoxy)methyl)cyclobutyl)oxy)diphenylsilane (430 mg) and THF (4.0 ml) was added TBAF (1 M THF solution, 0. 41 ml) at room temperature. The mixture was stirred at the same temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (202 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.52-1.72 (2H, m), 2.02-2.20 (1H, m), 2.22-2.40 (2H, m ), 3.89-4.08 (3H, m), 5.03 (1H, d, J=6.4 Hz), 7.10-7.23 (2H, m), 7.35-7, 46 (1H, m).

[0262]

F) cis-3-((4-chloro-2-fluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-((4-chloro-2-fluorophenoxy)methyl)cyclobutanol (200 mg), TEA (0.723 ml) and acetonitrile (4.0 ml) was added triphosgene (90.0 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (273 mg) was added thereto. The mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane. The resulting solid was purified by HPLC (column: CHIRALPAK AD, 50 mm ID x 500 ml, manufactured by Daicel Corporation, mobile phase: hexane/ethanol (400/600 (v/v)) and crystallized from ethyl acetate/hexane to obtain the title compound (170 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.76-1.94 (2H, m), 2.22-2.46 (3H, m), 3.88-4.23 (6H, m ), 4.47(2H, s), 4.66-4.91(1H, m), 7.11-7.27(2H, m), 7.37-7.50(1H, m), 8.39 (1H, s).

[0263]

Example 16

cis-3-((2,3,4-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0264]

A) tert-butyl(dimethyl)((cis-3-((2,3,4-trifluorophenoxy)methyl)cyclobutyl)oxy)silane

Mixture of (cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutyl)methyl-4-methylbenzenesulfonate (53.3 g), 2,3,4-trifluorophenol (22.6 g), cesium carbonate (70 .3 g) and DMF (290 ml) were stirred overnight at room temperature. To this mixture was added a solution of 2,3,4-trifluorophenol (8.52 g) in DMF (50 ml) at room temperature, and the mixture was stirred for 3 days. The mixture was diluted with water and extracted with toluene/ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (45.6 g).

¹ H NMR (300 MHz, CDCl ₃ ) δ 0.05 (6H, s), 0.88 (9H, s), 1.70-1.89 (2H, m), 2.09-2.30 ( 1H, m), 2.37-2.52 (2H, m), 3.97 (2H, d, J=6.4 Hz), 4.12-4.25 (1H, m), 6.56 -6.73 (1H, m), 6.77-6.96 (1H, m).

[0265]

B) cis-3-((2,3,4-trifluorophenoxy)methyl)cyclobutanol

TBAF hydrate (42, 2 g) at 0° C. and the reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated and washed with water and saturated aqueous sodium chloride. The aqueous layer was re-extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride solution. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (31.2 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.52-1.72 (2H, m), 2.03-2.21 (1H, m), 2.24-2.38 (2H, m ), 3.91-4.09 (3H, m), 5.04 (1H, d, J=6.4 Hz), 6.94-7.10 (1H, m), 7.13-7, 35 (1H, m).

[0266]

C) cis-3-((2,3,4-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (1.01 g) was added to a mixture of cis-3-((2,3,4-trifluorophenoxy)methyl)cyclobutanol (2.25 g), TEA (6.73 ml) and acetonitrile (24 ml) at 0° C and the reaction mixture was stirred at the same temperature for 1 hour. To this mixture was added 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (2.91 g) at 0°C and the reaction mixture heated to room temperature. The mixture was stirred at room temperature for 16 hours, diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) and crystallized from ethyl acetate/hexane. The resulting solid was recrystallized from ethanol/water/heptane to give the title compound (2.54 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.78-2.00 (2H, m), 2.24-2.47 (3H, m), 3.91-4.20 (6H, m ), 4.47(2H, s), 4.72-4.87(1H, m), 6.96-7.09(1H, m), 7.19-7.32(1H, m), 8.39 (1H, s).

T. pl. 145°C

X-ray powder diffraction pattern of the crystal (2θ diffraction angle): 9.8°, 13.6°, 14.4°, 15.2°, 18.2°, 19.6°, 22.0°, 24.3°, 25 .4° and 29.1°

[0267]

Example 17

cis-3-((2,4,5-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0268]

A) 1-((cis-3-(benzyloxy)cyclobutyl)methoxy)-2,4,5-trifluorobenzene

To a mixture of 2,4,5-trifluorophenol (282 mg), potassium carbonate (527 mg) and DMF (6 ml) was added (cis-3-(benzyloxy)cyclobutyl)methyl-4-methylbenzenesulfonate (600 mg) at room temperature. The mixture was stirred at 80° C. for 3 hours. Water was added to this mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (455 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.67-1.80 (2H, m), 2.16-2.40 (3H, m), 3.94 (1H, quint, J=7 .3 Hz), 4.02 (2H, d, J=6.0 Hz), 4.37 (2H, s), 7.23-7.45 (6H, m), 7.57 (1H, td , J=10.9, 7.9 Hz).

[0269]

B) cis-3-((2,4,5-trifluorophenoxy)methyl)cyclobutanol

A mixture of 1-((cis-3-(benzyloxy)cyclobutyl)methoxy)-2,4,5-trifluorobenzene (455 mg), palladium/charcoal (Pd 10%, 50% moisture, 100 mg) and methanol (5 ml) stirred overnight under atmospheric pressure of a hydrogen atmosphere at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To this residue were added palladium/carbon (Pd 10%, 50% moisture, 100 mg) and methanol (5 ml) and the mixture was stirred under atmospheric pressure of hydrogen atmosphere at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to give the title compound (307 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.56-1.68 (2H, m), 2.02-2.19 (1H, m), 2.24-2.35 (2H, m ), 3.94-4.02 (3H, m), 5.03 (1H, br. s), 7.38 (1H, dt, J=12.4, 8.0 Hz), 7.56 ( 1H, td, J=11.0, 7.9 Hz).

[0270]

C) cis-3-((2,4,5-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-((2,4,5-trifluorophenoxy)methyl)cyclobutanol (307 mg), TEA (0.737 ml) and acetonitrile (6 ml) was added triphosgene (157 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (397 mg) was added thereto. The mixture was stirred at room temperature for 4 hours. To this mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (219 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.78-1.92 (2H, m), 2.27-2.47 (3H, m), 3.94-4.13 (6H, m ), 4.47 (2H, s), 4.72-4.85 (1H, m), 7.39 (1H, dt, J=12.3, 8.0 Hz), 7.58 (1H, td, J=10.9, 7.5 Hz), 8.39 (1H, s).

[0271]

Example 18

cis-3-((2,4,6-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0272]

A) 2-((cis-3-(benzyloxy)cyclobutyl)methoxy)-1,3,5-trifluorobenzene

Potassium carbonate (209 mg) was added to a mixture of (cis-3-(benzyloxy)cyclobutyl)methyl-4-methylbenzenesulfonate (350 mg), 2,4,6-trifluorophenol (180 mg) and DMF (4.0 ml) at room temperature. temperature. The mixture was stirred overnight at 80 ºC. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (298 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.63-1.84 (2H, m), 2.07-2.24 (1H, m), 2.24-2.41 (2H, m ), 3.86-3.97(1H, m), 4.01(2H, d, J=6.0Hz), 4.36(2H, s), 7.17-7.40(7H, m).

[0273]

B) cis-3-((2,4,6-trifluorophenoxy)methyl)cyclobutanol

A mixture of 2-((cis-3-(benzyloxy)cyclobutyl)methoxy)-1,3,5-trifluorobenzene (294 mg), palladium hydroxide/charcoal (Pd 20%, 50% moisture, 30.0 mg) and ethyl acetate ( 4.0 ml) was stirred under atmospheric pressure of hydrogen atmosphere at room temperature for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (211 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.52-1.73 (2H, m), 1.96-2.15 (1H, m), 2.17-2.35 (2H, m ), 3.89-4.07(3H, m), 4.99(1H, d, J=6.4Hz), 7.02-7.40(2H, m).

[0274]

C) cis-3-((2,4,6-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-((2,4,6-trifluorophenoxy)methyl)cyclobutanol (209 mg), TEA (0.751 ml) and acetonitrile (4.0 ml) was added triphosgene (93.0 mg) at 0°C. The reaction mixture was stirred at the same temperature for 20 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (284 mg) was added thereto. The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (266 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.75-2.02 (2H, m), 2.17-2.46 (3H, m), 3.89-4.20 (6H, m ), 4.47(2H, s), 4.76(1H, fifth, J=7.3Hz), 7.16-7.37(2H, m), 8.38(1H, s).

T. pl. 111°C

X-ray powder diffraction pattern of the crystal (diffraction angle 2θ): 3.7°, 7.4°, 14.8°, 18.1°, 20.6°, 22.3° and 24.4°

[0275]

Example 19

cis-3-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0276]

A) cis-3-(ethoxycarbonyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (233 mg) was added to a mixture of ethyl cis-3-hydroxycyclobutanecarboxylate (324 mg), TEA (1.04 ml) and acetonitrile (19 ml) at 0°C. The reaction mixture was stirred at the same temperature for 10 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (562 mg) was added thereto at 0°C. The mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (370 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.17 (3H, t, J=7.1 Hz), 2.04-2.18 (2H, m), 2.44-2.57 ( 2H, m), 2.69-2.84(1H, m), 3.90-4.15(6H, m), 4.47(2H, s), 4.78(1H, quint, J= 7.6 Hz), 8.39 (1H, s).

[0277]

B) cis-3-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of lithium aluminum hydride (70.6 mg) and THF (6.2 ml) was added dropwise a mixture of cis-3-(ethoxycarbonyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2- carboxylate (370 mg) and THF (6.2 ml) at 0°C. The mixture was stirred under an argon atmosphere at the same temperature for 30 minutes. To this mixture, water, 15% aqueous sodium hydroxide solution and water were added successively at 0°C, and the mixture was stirred at room temperature for 30 minutes. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give intermediate (67.7 mg) as a crude product. To a mixture of the resulting intermediate (crude, 67.7 mg), 2-fluoro-4-(trifluoromethyl)phenol (47.6 mg) and THF (5.3 ml) was added triphenylphosphine (on polymer support, 3 mmol/g , 440 mg) and bis(2-methoxyethyl)(E)-diazene-1,2-dicarboxylate (124 mg). The mixture was stirred at room temperature for 3 hours. The insoluble matter was removed by filtration, and the filtrate was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (28.5 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.79-1.95 (2H, m), 2.27-2.46 (3H, m), 3.90-4.02 (2H, m ), 4.03-4.19(4H, m), 4.47(2H, s), 4.72-4.87(1H, m), 7.30-7.40(1H, m), 7.53 (1H, d, J=8.9 Hz), 7.67 (1H, dd, J=11.2, 2.0 Hz), 8.39 (1H, s).

[0278]

Example 20

cis-3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0279]

A) cis-3-((((4-methylphenyl)sulfonyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

4-methylbenzenesulfonyl chloride (60 .6 mg). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and dried over anhydrous sodium sulfate. The solution was passed through NH silica gel, eluted with ethyl acetate, and concentrated under reduced pressure to give the title compound (109 mg) as a crude product.

MS: [M+H] ⁺ 411.2

[0280]

B) cis-3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Cis-3-((((4-methylphenyl)sulfonyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate mixture (crude product, 109 mg), 2-chloro-4-(trifluoromethyl)phenol (78 mg), potassium carbonate (110 mg) and DMF (3 ml) were stirred at 80°C for 1 h. The mixture was diluted with ethyl acetate at room temperature, washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solution was passed through NH silica gel, eluted with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from diisopropyl ether to give the title compound (19.4 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.85-2.02 (2H, m), 2.30-2.54(3H, m), 3.91-4.19 (6H, m ), 4.47 (2H, s), 4.71-4.87 (1H, m), 7.32 (1H, d, J=8.7 Hz), 7.68 (1H, dd, J= 8.9, 2.1 Hz), 7.84 (1H, d, J=1.9 Hz), 8.39 (1H, s).

[0281]

Example 21

trans-3-((2,3,4-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0282]

A) (trans-3-(benzyloxy)cyclobutyl)methyl-4-methylbenzenesulfonate

To a mixture of (trans-3-(benzyloxy)cyclobutyl)methanol (236 mg), TEA (0.256 ml) and acetonitrile (4.0 ml) was added 4-methylbenzenesulfonyl chloride (281 mg) and trimethylamine hydrochloride (11.7 mg) at 0 °C The mixture was stirred at the same temperature for 45 minutes. Water was added to this mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (425 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.99-2.24 (4H, m), 2.45 (3H, s), 2.48-2.64 (1H, m), 4.02 ( 2H, d, J=6.8 Hz), 4.05-4.16(1H, m), 4.36(2H, s), 7.27-7.44(7H, m), 7.72 -7.84 (2H, m).

[0283]

B) 1-((trans-3-(benzyloxy)cyclobutyl)methoxy)-2,3,4-trifluorobenzene

A mixture of (trans-3-(benzyloxy)cyclobutyl)methyl-4-methylbenzenesulfonate (417 mg), 2,3,4-trifluorophenol (214 mg), potassium carbonate (250 mg) and DMF (4.0 ml) was stirred at 80 °C for 8 h. To this reaction mixture were added 2,3,4-trifluorophenol (428 mg) and potassium carbonate (499 mg) and the mixture was stirred at 100°C for 6 h and then at 80°C for over 14 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate/toluene. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (352 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.12 (4H, t, J=6.6 Hz), 2.61 (1H, dt, J=13.5, 6.6 Hz), 4 .08 (2H, d, J=6.8 Hz), 4.21 (1H, fifth, J=6.7 Hz), 4.36 (2H, s), 7.04 (1H, tdd, J= 9.2, 4.9, 2.6 Hz), 7.18-7.43 (6H, m).

[0284]

C) trans-3-((2,3,4-trifluorophenoxy)methyl)cyclobutanol

A mixture of 1-((trans-3-(benzyloxy)cyclobutyl)methoxy)-2,3,4-trifluorobenzene (346 mg), palladium hydroxide/charcoal (Pd 20%, 50% moisture, 35.0 mg) and ethyl acetate ( 5.0 ml) was stirred overnight under atmospheric pressure of a hydrogen atmosphere at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (212 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.92-2.16 (4H, m), 4.05 (2H, d, J=7.2 Hz), 4.27 (1H, sixth, J=6.8 Hz), 5.03(1H, d, J=6.0 Hz), 6.97-7.10(1H, m), 7.18-7.34(1H, m).

[0285]

D) trans-3-((2,3,4-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of trans-3-((2,3,4-trifluorophenoxy)methyl)cyclobutanol (100 mg), TEA (0.299 ml) and acetonitrile (4.0 ml) was added triphosgene (44.7 mg) at 0°C. The reaction mixture was stirred at the same temperature for 20 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (136 mg) was added thereto at 0°C. The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate), and crystallized from ethyl acetate/diisopropyl ether to give the title compound (130 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.13-2.31 (4H, m), 2.58-2.77 (1H, m), 3.92-4.22 (6H, m ), 4.48 (2H, s), 5.02 (1H, fifth, J=7.1 Hz), 6.98-7.12 (1H, m), 7.19-7.34 (1H, m), 8.40 (1H, s).

[0286]

Example 22

trans-3-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0287]

A) trans-3-(ethoxycarbonyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

Triphosgene (233 mg) was added to a mixture of ethyl trans-3-hydroxycyclobutanecarboxylate (329 mg), TEA (1.04 ml) and acetonitrile (19 ml) at 0°C. The reaction mixture was stirred at the same temperature for 10 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (562 mg) was added thereto at 0°C. The mixture was stirred at room temperature for 16 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (330 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.07-1.27 (3H, m), 2.19-2.36 (2H, m), 2.38-2.48 (2H, m ), 2.98-3.13(1H, m), 3.88-4.19(6H, m), 4.47(2H, s), 4.96(1H, quint, J=7.1 Hz), 8.40 (1H, s).

[0288]

B) trans-3-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of lithium aluminum hydride (63.0 mg) and THF (5.5 ml) was added dropwise a mixture of trans-3-(ethoxycarbonyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2- carboxylate (330 mg) and THF (5.5 ml) at 0°C. The mixture was stirred under argon at 0° C. for 30 min. Water, 15% aqueous sodium hydroxide solution and water were added to this mixture successively at 0°C, and the mixture was stirred at room temperature for 30 minutes. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give intermediate (49.3 mg) as a crude product. To a mixture of the resulting intermediate (crude, 49.3 mg), 2-fluoro-4-(trifluoromethyl)phenol (34.6 mg) and THF (3.9 ml) was added triphenylphosphine (on polymer support, 3 mmol/g , 320 mg) and bis(2-methoxyethyl)(E)-diazene-1,2-dicarboxylate (90 mg). The mixture was stirred at room temperature for 3 hours. The insoluble matter was removed by filtration and the filtrate was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and crystallized from ethyl acetate/diisopropyl ether to give the title compound (5.4 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.17-2.31 (4H, m), 2.59-2.78 (1H, m), 3.92-4.03 (2H, m ), 4.05-4.14 (2H, m), 4.19 (2H, d, J=6.8 Hz), 4.48 (2H, s), 5.04 (1H, fifth, J= 6.9 Hz), 7.31-7.43 (1H, m), 7.54 (1H, d, J=8.5 Hz), 7.61-7.73 (1H, m), 8, 40 (1H, s).

[0289]

Example 23

(cis-3-(2,4,6-trifluorophenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0290]

A) ethyl 3-(2,4,6-trifluorophenoxy)cyclobutanecarboxylate

A mixture of ethyl 3-((methylsulfonyl)oxy)cyclobutanecarboxylate (1.5 g), sodium iodide (2.53 g) and acetone (15 ml) was irradiated with microwave radiation at 130°C for 2 hours. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Diisopropyl ether was added to this residue, the insoluble matter was removed by filtration, and the filtrate was concentrated. DMF (7 ml) was added to this residue, and a mixture of 2,4,6-trifluorophenol (999 mg), potassium carbonate (2.05 g) and DMF (7 ml) was added thereto at room temperature. The mixture was stirred at 80° C. for 3 hours. Water was added to this mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.04 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.18 (3H, t, J=7.2 Hz), 2.19-3.17 (5H, m), 4.03-4.13 ( 2H, m), 4.48-4.80(1H, m), 7.19-7.34(2H, m).

[0291]

B) (3-(2,4,6-trifluorophenoxy)cyclobutyl)methanol

To a mixture of lithium aluminum hydride (215 mg) and THF (10 ml) was added dropwise a mixture of ethyl 3-(2,4,6-trifluorophenoxy)cyclobutanecarboxylate (1.04 g) and THF (10 ml) at 0°C. The mixture was stirred under an argon atmosphere at the same temperature for 2 hours. To this mixture, 10% sodium potassium tartrate aqueous solution and ethyl acetate were added at 0°C, and the insoluble matter was removed by filtration. The organic layer of the filtrate was removed and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (566 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.81-1.93 (1H, m), 2.05-2.40 (4H, m), 3.33-3.43 (2H, m ), 4.41-4.75(2H, m), 7.17-7.31(2H, m).

[0292]

C) (3-(2,4,6-trifluorophenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of (3-(2,4,6-trifluorophenoxy)cyclobutyl)methanol (251 mg), TEA (0.497 ml) and acetonitrile (6 ml) was added triphosgene (112 mg) at 0°C. The reaction mixture was stirred at the same temperature for 20 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (325 mg) was added thereto at 0°C. The mixture was stirred at the same temperature for 1 hour. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (160 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.82-1.94 (1H, m), 2.01-2.19 (2H, m), 2.19-2.38 (2H, m ), 3.94-4.01(4H, m), 4.05-4.13(2H, m), 4.42-4.56(2H, m), 4.73(1H, quint, J =6.5 Hz), 7.18-7.32 (2H, m), 8.39 (1H, d, J=2.6 Hz).

[0293]

D) (cis-3-(2,4,6-trifluorophenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

(3-(2,4,6-Trifluorophenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate (150 mg) was separated by HPLC (column: CHIRALCEL OJ (trade brand), 50 mm ID×500 ml, manufactured by Daicel Corporation, mobile phase: hexane/ethanol=45/55), and the fraction having the shorter retention time was concentrated. The residue was recrystallized from ethyl acetate/hexane to give the title compound (26.8 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.80-1.95 (2H, m), 1.98-2.16 (1H, m), 2.27-2.39 (2H, m ), 3.92-4.03(4H, m), 4.03-4.13(2H, m), 4.45-4.56(3H, m), 7.18-7.33(2H , m), 8.40 (1H, s).

[0294]

Example 24

(cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutyl)methyl 6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0295]

A) ethyl cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutanecarboxylate

To a mixture of ethyl cis-3-hydroxycyclobutanecarboxylate (1 g) and DMF (10 ml) was added sodium hydride (60%, 305 mg) at 0°C. The reaction mixture was stirred under argon atmosphere at room temperature for 30 min, and a mixture of 1,2-difluoro-4-(trifluoromethyl)benzene (1.26 g) and DMF (10 ml) was added dropwise thereto at 0°C. The mixture was stirred under argon atmosphere at room temperature for 4 hours. To this mixture was added water at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (386 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.19 (3H, t, J=7.2 Hz), 2.18-2.33 (2H, m), 2.72-2.95 ( 3H, m), 4.09 (2H, q, J=7.1 Hz), 4.77-4.89 (1H, m), 7.21 (1H, t, J=8.5 Hz), 7.51 (1H, d, J=8.7 Hz), 7.69 (1H, dd, J=11.5, 2.1 Hz).

[0296]

B) (cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutyl)methanol

To a mixture of lithium aluminum hydride (52.6 mg) and THF (4 ml) was added dropwise a mixture of ethyl cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutanecarboxylate (386 mg) and THF (4 ml) at 0 °C The mixture was stirred under argon atmosphere at room temperature for 2 hours. To this mixture was added 10% aqueous sodium potassium tartrate solution and ethyl acetate at room temperature, and the insoluble matter was removed by filtration. The organic layer of the filtrate was removed and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (367 mg) as a crude product.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.80-1.94 (2H, m), 2.01-2.16 (1H, m), 2.43-2.56 (2H, m ), 3.40 (2H, t, J=5.5 Hz), 4.58 (1H, t, J=5.4 Hz), 4.75 (1H, fifth, J=7.2 Hz), 7.20 (1H, t, J=8.5 Hz), 7.50 (1H, dd, J=8.6, 0.8 Hz), 7.66 (1H, dd, J=11.4, 2.0 Hz).

[0297]

C) (cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of (cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutyl)methanol (215 mg), TEA (0.374 ml) and acetonitrile (5 ml) was added triphosgene (85 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (244 mg) was added thereto. The mixture was stirred at room temperature for 3 hours. To this mixture was added water at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (45.4 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.80-1.95 (2H, m), 2.19-2.35 (1H, m), 2.53-2.68 (2H, m ), 3.93-4.14(6H, m), 4.47(2H, s), 4.77(1H, fifth, J=7.1Hz), 7.20(1H, t, J= 8.5 Hz), 7.50 (1H, d, J=8.7 Hz), 7.67 (1H, dd, J=11.4, 2.0 Hz), 8.39 (1H, s) .

[0298]

Example 25

(trans-3-(2,4,6-trifluorophenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

(3-(2,4,6-Trifluorophenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate (150 mg) was separated by HPLC (column: CHIRALCEL OJ (trade brand), 50 mm ID×500 ml, manufactured by Daicel Corporation, mobile phase: hexane/ethanol=45/55), and the fraction having a longer retention time was concentrated. The residue was recrystallized from ethyl acetate/hexane to give the title compound (66.2 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.07-2.19 (2H, m), 2.19-2.32 (2H, m), 3.35-3.39 (1H, m ), 3.92-4.02(4H, m), 4.05-4.12(2H, m), 4.47(2H, s), 4.73(1H, quint, J=6.5 Hz), 7.18-7.34(2H, m), 8.39(1H, s).

[0299]

Example 26

(cis-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutyl)methyl 6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0300]

A) ethyl cis-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutanecarboxylate

To a mixture of ethyl cis-3-hydroxycyclobutanecarboxylate (1 g) and THF (20 ml) was added sodium hydride (60%, 305 mg) at 0°C. The reaction mixture was stirred at room temperature for 30 min, and 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (0.950 ml) was added thereto at 0°C. The mixture was stirred under argon at room temperature for 2 hours. To this mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (352 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.19 (3H, t, J=7.1 Hz), 2.19-2.30 (2H, m), 2.74-2.95 ( 3H, m), 4.09 (2H, q, J=7.1 Hz), 4.81-4.91 (1H, m), 7.17 (1H, d, J=8.7 Hz), 7.66 (1H, dd, J=8.7, 1.5 Hz), 7.84 (1H, d, J=1.7 Hz).

[0301]

B) (cis-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutyl)methanol

To a mixture of ethyl cis-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutanecarboxylate (352 mg) and THF (4 ml) was added a mixture of lithium aluminum hydride (62.1 mg) and THF (4 ml) at 0°C . The mixture was stirred under argon atmosphere at room temperature for 4 hours. To this mixture was added 10% aqueous sodium potassium tartrate solution and ethyl acetate at 0°C, and the insoluble matter was removed by filtration. The organic layer of the filtrate was removed and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (195 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.80-1.93 (2H, m), 2.01-2.17 (1H, m), 2.44-2.56 (2H, m ), 3.41 (2H, t, J=5.4 Hz), 4.59 (1H, t, J=5.5 Hz), 4.76 (1H, fifth, J=7.2 Hz), 7.17 (1H, d, J=8.5 Hz), 7.64 (1H, dd, J=8.7, 1.7 Hz), 7.82 (1H, d, J=2.1 Hz ).

[0302]

C) (cis-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of (cis-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutyl)methanol (195 mg), 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (230 mg), TEA (0.320 ml) and THF (12 ml) were added triphosgene (72.2 mg) at 0°C. The mixture was stirred at 0° C. for 2 hours. Water was added to this mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and then purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). A saturated aqueous sodium hydrogen carbonate solution was added to the resulting fraction, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (13.2 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.05-2.12 (2H, m), 2.28-2.44 (1H, m), 2.58-2.71 (2H, m), 4.09-4.13(4H, m), 4.20-4.26(2H, m), 4.54(2H, s), 4.61-4.73(1H, m), 6, 73 (1H, s), 6.81 (1H, d, J=8.5 Hz), 7.44 (1H, dd, J=8.6, 1.6 Hz), 7.63 (1H, d , J=2.1 Hz).

[0303]

Example 27

(trans-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0304]

A) ethyl trans-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutanecarboxylate

Potassium carbonate (695 mg) at room temperature. The mixture was stirred at 80° C. for 16 hours. Water was added to this mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (473 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.22 (3H, t, J=7.1 Hz), 2.36-2.48 (2H, m), 2.68-2.79 ( 2H, m), 3.14-3.26 (1H, m), 4.13 (2H, q, J=7.1 Hz), 5.02 (1H, fifth, J=6.6 Hz), 7.11 (1H, d, J=8.7 Hz), 7.61-7.68 (1H, m), 7.85 (1H, d, J=1.7 Hz).

[0305]

B) (trans-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutyl)methanol

To a mixture of ethyl trans-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutanecarboxylate (473 mg) and THF (5 ml) was added a mixture of lithium aluminum hydride (61.2 mg) and THF (5 ml) at 0°C . The mixture was stirred under argon atmosphere at room temperature for 1 hour. To this mixture was added 10% aqueous sodium potassium tartrate solution and ethyl acetate at 0°C. The insoluble matter was removed by filtration, the organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (277 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.10-2.24 (2H, m), 2.28-2.45 (3H, m), 3.48 (2H, t, J=5 .8 Hz), 4.69 (1H, t, J=5.3 Hz), 4.94 (1H, fifth, J=6.5 Hz), 7.08 (1H, d, J=8.5 Hz), 7.61-7.68 (1H, m), 7.83 (1H, d, J=1.7 Hz).

[0306]

C) (trans-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (296 mg), (trans-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutyl)methanol (277 mg), TEA (0.454 ml) and THF (6 ml) were added triphosgene (103 mg) at 0°C. The mixture was stirred at room temperature for 2 hours. To this mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/diisopropyl ether/hexane to give the title compound (29.7 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.19-2.29 (2H, m), 2.31-2.40 (2H, m), 2.54-2.66 (1H, m ), 3.97-4.17(6H, m), 4.49(2H, s), 5.00(1H, fifth, J=6.6Hz), 7.10(1H, d, J= 8.7 Hz), 7.66 (1H, dd, J=8.7, 1.7 Hz), 7.84 (1H, d, J=1.9 Hz), 8.42 (1H, s) .

[0307]

Example 28

cis-3-(((3-chloro-4-methylbenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0308]

A) cis-3-(((3-chloro-4-methylbenzyl)oxy)methyl)cyclobutanol

To a mixture of (cis-3-((tert-butyl(diphenyl)silyl)oxy)cyclobutyl)methanol (395 mg) and DMF (5 ml) was added sodium hydride (60%, 60.3 mg) at 0°C. The reaction mixture was stirred at the same temperature for 15 minutes, and a mixture of 4-(bromomethyl)-2-chloro-1-methylbenzene (280 mg) and DMF (2 ml) was added thereto. The mixture was stirred at room temperature for 2 hours. To this mixture was added water at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give intermediate (317 mg) as a crude product. To a mixture of the obtained intermediate (crude product, 316 mg) and THF (6.6 ml) was added TBAF (1 M THF solution, 0.79 ml) at 0°C. The reaction mixture was stirred overnight at room temperature and TBAF (1 M THF solution, 0.33 ml) was added thereto at 0°C. The mixture was stirred at room temperature for 3 hours. To this mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (83.9 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.42-1.58 (2H, m), 1.80-1.99 (1H, m), 2.10-2.28 (2H, m ), 2.31 (3H, s), 3.34 (2H, d, J=6.2 Hz), 3.85-3.99 (1H, m), 4.41 (2H, s), 4 .92 (1H, d, J=6.6 Hz), 7.17 (1H, dd, J=7.6, 1.4 Hz), 7.28-7.41 (2H, m).

[0309]

B) cis-3-(((3-chloro-4-methylbenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-(((3-chloro-4-methylbenzyl)oxy)methyl)cyclobutanol (83 mg), TEA (0.192 ml) and acetonitrile (3.5 ml) was added triphosgene (43.0 mg) at 0 °C The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (104 mg) was added thereto at 0°C. The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (69.9 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.65-1.82 (2H, m), 2.11 (1H, d, J=6.8 Hz), 2.25-2.40 ( 5H, m), 3.38 (2H, d, J=5.9 Hz), 3.87-4.15 (4H, m), 4.44 (4H, d, J=10.0 Hz), 4.72(1H, t, J=7.5Hz), 7.13-7.22(1H, m), 7.28-7.38(2H, m), 8.37(1H, s) .

[0310]

Example 29

cis-3-(((4-chloro-3-methylbenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0311]

A) cis-3-(((4-chloro-3-methylbenzyl)oxy)methyl)cyclobutanol

To a mixture of (cis-3-((tert-butyl(diphenyl)silyl)oxy)cyclobutyl)methanol (0.8 g) and DMF (20 ml) was added sodium hydride (60%, 122 mg) at 0°C. The reaction mixture was stirred at the same temperature for 15 minutes, and a mixture of 4-(bromomethyl)-1-chloro-2-methylbenzene (567 mg) and DMF (2 ml) was added thereto. The mixture was stirred at room temperature for 2 hours. To this mixture was added water at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give intermediate (770 mg) as a crude product. To a mixture of the obtained intermediate (crude product, 769 mg) and THF (16 ml) was added TBAF (1 M THF solution, 2.4 ml) at 0°C. The reaction mixture was stirred overnight at room temperature and TBAF (1 M THF solution, 0.80 ml) was added thereto. The mixture was stirred at room temperature for 3 hours. To this mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (241 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.41-1.61 (2H, m), 1.81-2.02 (1H, m), 2.10-2.27 (2H, m) , 2.32(3H, s), 3.35(2H, d, J=6.2 Hz), 3.81-4.02(1H, m), 4.40(2H, s), 4, 92 (1H, d, J=6.6 Hz), 7.15 (1H, dd, J=8.1, 1.7 Hz), 7.28 (1H, d, J=1.1 Hz), 7.37 (1H, d, J=8.1 Hz).

[0312]

B) cis-3-(((4-chloro-3-methylbenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-(((4-chloro-3-methylbenzyl)oxy)methyl)cyclobutanol (241 mg), TEA (0.558 ml) and acetonitrile (10 ml) was added triphosgene (125 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (301 mg) was added thereto at 0°C. The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (291 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.65-1.84 (2H, m), 2.03-2.20 (1H, m), 2.24-2.40 (5H, m ), 3.38 (2H, d, J=5.9 Hz), 3.87-4.15 (4H, m), 4.42 (2H, s), 4.46 (2H, s), 4 .72 (1H, t, J=7.6 Hz), 7.15 (1H, dd, J=8.2, 1.6 Hz), 7.28 (1H, s), 7.38 (1H, d, J=8.1 Hz), 8.37 (1H, s).

[0313]

Example 30

cis-3-(((2-chloro-4-fluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0314]

A) tert-butyl ((cis-3-(((2-chloro-4-fluorobenzyl)oxy)methyl)cyclobutyl)oxy)dimethylsilane

To a mixture of (cis-3-((tert-butyl(dimethyl)silyl)oxy)cyclobutyl)methanol (400 mg) and DMF (4.0 ml) was added sodium hydride (60%, 89.0 mg) at 0°C . The reaction mixture was stirred at the same temperature for 10 min, and 1-(bromomethyl)-2-chloro-4-fluorobenzene (496 mg) was added thereto at 0°C. The mixture was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (602 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.01 (6H, s), 0.84 (9H, s), 1.49-1.73 (2H, m), 1.86-2, 13 (1H, m), 2.19-2.38 (2H, m), 3.43 (2H, d, J=6.0 Hz), 4.12 (1H, fifth, J=7.3 Hz ), 4.49(2H, s), 7.16-7.33(1H, m), 7.39-7.55(2H, m).

[0315]

B) cis-3-(((2-chloro-4-fluorobenzyl)oxy)methyl)cyclobutanol

TBAF (1 M THF solution , 2.0 ml) at room temperature. The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (364 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.46-1.63 (2H, m), 1.85-2.03 (1H, m), 2.16-2.31 (2H, m ), 3.42 (2H, d, J=6.4 Hz), 3.78-3.99 (1H, m), 4.49 (2H, s), 4.94 (1H, d, J= 6.4 Hz), 7.24 (1H, td, J=8.5, 2.6 Hz), 7.44 (1H, dd, J=8.7, 2.6 Hz), 7.52 ( 1H, dd, J=8.7, 6.4 Hz).

[0316]

C) cis-3-(((2-chloro-4-fluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-(((2-chloro-4-fluorobenzyl)oxy)methyl)cyclobutanol (240 mg), TEA (0.818 ml) and acetonitrile (4.0 ml) was added triphosgene (102 mg) at 0°C . The reaction mixture was stirred at the same temperature for 20 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (309 mg) was added thereto. The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (301 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.68-1.85 (2H, m), 2.06-2.23 (1H, m), 2.26-2.42 (2H, m ), 3.46 (2H, d, J=6.0 Hz), 3.89-4.18 (4H, m), 4.49 (4H, d, J=12.1 Hz), 4.73 (1H, fifth, J=7.5 Hz), 7.24 (1H, td, J=8.5, 2.6 Hz), 7.40-7.61 (2H, m), 8.38 ( 1H, s).

[0317]

Example 31

cis-3-(((2,3,4-trifluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0318]

A) cis-3-(((2,3,4-trifluorobenzyl)oxy)methyl)cyclobutanol

To a mixture of (cis-3-((tert-butyl(diphenyl)silyl)oxy)cyclobutyl)methanol (1.01 g) and DMF (15 ml) was added sodium hydride (60%, 154 mg) at 0°C. The reaction mixture was stirred at the same temperature for 15 minutes, and 1-(bromomethyl)-2,3,4-trifluorobenzene (734 mg) was added thereto. The mixture was stirred at room temperature for 2 hours. To this mixture was added water at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give intermediate (1.08 g) as a crude product. To a mixture of the obtained intermediate (crude product, 1.08 g) and THF (22 ml) was added TBAF (1 M THF solution, 3.3 ml) at 0°C. The mixture was stirred overnight at room temperature. Water was added to this mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (291 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.39-1.60 (2H, m), 1.77-2.00 (1H, m), 2.14-2.33 (2H, m ), 3.38 (2H, d, J=6.2 Hz), 3.79-3.98 (1H, m), 4.50 (2H, s), 4.92 (1H, d, J= 6.6 Hz), 7.13-7.45 (2H, m).

[0319]

B) cis-3-(((2,3,4-trifluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-(((2,3,4-trifluorobenzyl)oxy)methyl)cyclobutanol (290 mg), TEA (0.657 ml) and acetonitrile (12 ml) was added triphosgene (147 mg) at 0°C. The reaction mixture was stirred at room temperature for 30 min and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (354 mg) was added to it at 0°C. The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (351 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.64-1.83 (2H, m), 1.99-2.19 (1H, m), 2.21-2.43 (2H, m ), 3.37-3.52(2H, m), 3.83-4.19(4H, m), 4.36-4.58(4H, m), 4.72(1H, quint, J = 7.5 Hz), 7.17-7.42 (2H, m), 8.38 (1H, s).

[0320]

Example 32

cis-3-(((2,4,5-trifluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0321]

A) tert-butyl(diphenyl)((cis-3-(((2,4,5-trifluorobenzyl)oxy)methyl)cyclobutyl)oxy)silane

To a mixture of (cis-3-((tert-butyl(diphenyl)silyl)oxy)cyclobutyl)methanol (1.00 g) and DMF (15 ml) was added sodium hydride (60%, 129 mg) at 0°C. The reaction mixture was stirred at the same temperature for 15 minutes, and 1-(bromomethyl)-2,4,5-trifluorobenzene (793 mg) was added thereto. The mixture was stirred at room temperature for 3 hours. To this mixture was added water at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (981 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.97 (9H, s), 1.61-1.80 (2H, m), 1.81-1.97 (1H, m), 2, 07-2.25 (2H, m), 3.40 (2H, d, J=6.0 Hz), 4.06-4.19 (1H, m), 4.45 (2H, s), 7 .36-7.67 (12H, m).

[0322]

B) cis-3-(((2,4,5-trifluorobenzyl)oxy)methyl)cyclobutanol

TBAF (1 M THF solution, 3.0 ml) at room temperature. The mixture was stirred at room temperature for 4 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (296 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.40-1.59 (2H, m), 1.85-1.98 (1H, m), 2.13-2.31 (2H, m ), 3.39 (2H, d, J=6.2 Hz), 3.82-3.98 (1H, m), 4.45 (2H, s), 4.92 (1H, d, J= 6.6 Hz), 7.38-7.64 (2H, m).

[0323]

C) cis-3-(((2,4,5-trifluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-(((2,4,5-trifluorobenzyl)oxy)methyl)cyclobutanol (301 mg), TEA (0.68 ml) and acetonitrile (5 ml) was added triphosgene (127 mg) at 0°C . The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (385 mg) was added thereto. The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (105 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.65-1.81 (2H, m), 2.02-2.20 (1H, m), 2.26-2.37 (2H, m ), 3.42 (2H, d, J=5.9 Hz), 3.90-4.00 (2H, m), 4.02-4.12 (2H, m), 4.46 (2H, s), 4.47(2H, s), 4.72(1H, fifth, J=7.4Hz), 7.35-7.71(2H, m), 8.37(1H, s).

[0324]

Example 33

cis-3-(((2,4,6-trifluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0325]

A) cis-3-(((2,4,6-trifluorobenzyl)oxy)methyl)cyclobutanol

To a mixture of (cis-3-((tert-butyl(diphenyl)silyl)oxy)cyclobutyl)methanol (804 mg) and DMF (10 ml) was added sodium hydride (60%, 123 mg) at 0°C. The reaction mixture was stirred at the same temperature for 15 minutes, and a mixture of 2-(bromomethyl)-1,3,5-trifluorobenzene (584 mg) and DMF (2 ml) was added thereto. The mixture was stirred at room temperature for 2 hours. To this mixture was added water at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give intermediate (1.11 g) as a crude product. To a mixture of the obtained intermediate (crude product, 1.1 g) and THF (11 ml) was added TBAF (1 M THF solution, 4.5 ml) at 0°C. The mixture was stirred overnight at room temperature. Water was added to this mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (82 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.29-1.56 (2H, m), 1.77-1.95 (1H, m), 2.12-2.30 (2H, m ), 3.35 (2H, d, J=6.2 Hz), 3.79-4.05 (1H, m), 4.44 (2H, s), 4.90 (1H, d, J= 6.6 Hz), 7.21 (2H, dd, J=9.3, 8.0 Hz).

[0326]

B) cis-3-(((2,4,6-trifluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of cis-3-(((2,4,6-trifluorobenzyl)oxy)methyl)cyclobutanol (352 mg), TEA (0.797 ml) and acetonitrile (14 ml) was added triphosgene (178 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (429 mg) was added thereto at 0°C. The mixture was stirred overnight at room temperature. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/hexane to give the title compound (409 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.59-1.78 (2H, m), 2.01-2.17 (1H, m), 2.22-2.36 (2H, m ), 3.39 (2H, d, J=6.0 Hz), 3.90-3.98 (2H, m), 4.01-4.13 (2H, m), 4.42-4, 50(4H, m), 4.70(1H, fifth, J=7.6Hz), 7.11-7.34(2H, m), 8.37(1H, s).

[0327]

Example 39

trans-3-(2,3,4-trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0328]

A) 1-((trans-3-(benzyloxy)cyclobutyl)oxy)-2,3,4-trifluorobenzene

DIAD (40% toluene solution, 1, 14 ml) at room temperature. The mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (426 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.28-2.41 (2H, m), 2.46 (2H, dd, J=6.8, 4.5 Hz), 4.28 ( 1H, tt, J=7.0, 4.7 Hz), 4.40(2H, s), 4.94(1H, tt, J=6.9, 4.2 Hz), 6.84(1H , tdd, J=9.2, 4.5, 2.6 Hz), 7.12-7.48 (6H, m).

[0329]

B) trans-3-(2,3,4-trifluorophenoxy)cyclobutanol

A mixture of 1-((trans-3-(benzyloxy)cyclobutyl)oxy)-2,3,4-trifluorobenzene (417 mg), palladium hydroxide/charcoal (Pd 20%, 50% moisture, 40.0 mg) and ethyl acetate ( 6.0 ml) was stirred overnight under atmospheric pressure of a hydrogen atmosphere at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (287 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.19-2.41 (4H, m), 4.28-4.44 (1H, m), 4.85-4.97 (1H, m ), 5.20 (1H, d, J=5.3 Hz), 6.80 (1H, tdd, J=9.2, 4.8, 2.6 Hz), 7.12-7.31 ( 1H, m).

[0330]

C) trans-3-(2,3,4-trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of trans-3-(2,3,4-trifluorophenoxy)cyclobutanol (280 mg), TEA (0.892 ml) and THF (6.0 ml) was added triphosgene (133 mg) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (385 mg) was added thereto at 0°C. The mixture was stirred at room temperature for 2 days. The mixture was passed through NH silica gel, eluted with ethyl acetate/methanol (10/1), and crystallized from ethyl acetate/diisopropyl ether to give the title compound (405 mg).

¹ H NMR (300 MHz, CDCl ₃ ) δ 2.44-2.77 (4H, m), 4.05-4.28 (4H, m), 4.56 (2H, s), 4.78- 4.93(1H, m), 5.19(1H, tt, J=7.2, 4.5Hz), 6.02(1H, s), 6.33-6.58(1H, m) , 6.71-6.96 (1H, m).

[0331]

Example 44

cis-3-(2-chloro-4-fluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0332]

A) trans-3-(benzyloxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

A mixture of trans-3-(benzyloxy)cyclobutanol (9.65 g), TEA (37.6 ml) and THF (120 ml) was cooled to -10°C in an ice bath with salt. While maintaining the internal temperature of the reaction mixture at 5° C. or lower, a mixture of triphosgene (5.62 g) and THF (40 ml) was added dropwise thereto over 30 minutes. THF (50 ml) was added to the reaction mixture, the mixture was stirred at -10°C for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (16.3 g) was added thereto in small portions . The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/diisopropyl ether to give the title compound (15.6 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.15-2.41 (4H, m), 3.91-4.13 (4H, m), 4.15-4.27 (1H, m ), 4.37(2H, s), 4.47(2H, s), 4.87-5.02(1H, m), 7.21-7.46(5H, m), 8.39( 1H, s).

[0333]

B) trans-3-hydroxycyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of trans-3-(benzyloxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate (7.50 g), ethyl acetate (50 ml) and methanol (50 ml) palladium/charcoal hydroxide (Pd 20%, 50% moisture, 750 mg) was added under nitrogen at room temperature. The reaction mixture was stirred under atmospheric pressure of hydrogen atmosphere at room temperature for 4 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (5.47 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.07-2.27 (4H, m), 3.91-4.15 (4H, m), 4.22-4.36 (1H, m ), 4.47 (2H, s), 4.85-4.99 (1H, m), 5.11 (1H, d, J=5.3 Hz), 8.40 (1H, s).

[0334]

C) cis-3-(2-chloro-4-fluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of trans-3-hydroxycyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate (250 mg), 2-chloro-4-fluorophenol (0.165 ml), triphenylphosphine (on a polymer support, 3 mmol/g, 1.03 g) and THF (5.0 ml) were added DIAD (0.305 ml) at room temperature. The mixture was stirred at 60° C. for 3 hours. The reaction mixture was passed through NH silica gel and eluted with ethyl acetate/methanol (10/1) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), crystallized from ethyl acetate/diisopropyl ether, washed with ethyl acetate/diisopropyl ether (1/10), and dried under reduced pressure at 80°C for 2 h to give the title compound (245 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.99-2.20 (2H, m), 2.90-3.06 (2H, m), 3.88-4.22 (4H, m ), 4.40-4.53 (3H, m), 4.63 (1H, fifth, J=7.1 Hz), 6.94-7.07 (1H, m), 7.15 (1H, td, J=8.6, 3.0 Hz), 7.44 (1H, dd, J=8.3, 3.0 Hz), 8.39 (1H, s).

[0335]

Example 46

cis-3-(2,4,6-trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of trans-3-hydroxycyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate (250 mg), 2,4,6-trifluorophenol (229 mg), triphenylphosphine (on a polymer support, 3 mmol/g, 1.03 g) and THF (5.0 ml) were added DIAD (0.305 ml) at room temperature. The mixture was stirred at the same temperature for 1 hour and then at 60° C. for 1 hour. The reaction mixture was passed through NH silica gel and eluted with ethyl acetate/methanol (9/1) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/diisopropyl ether to give the title compound (327 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.05-2.25 (2H, m), 2.67-2.86 (2H, m), 3.90-4.19 (4H, m ), 4.34 (1H, fifth, J=6.9 Hz), 4.43-4.56 (3H, m), 7.20-7.40 (2H, m), 8.40 (1H, With).

T. pl. 160°C

X-ray powder diffraction pattern of the crystal (diffraction angle 2θ): 4.1°, 8.2°, 12.3°, 16.4°, 18.6°, 21.5°, 23.4° and 24.7°

[0336]

Example 50

cis-3-(4-fluoro-3-methylphenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of trans-3-hydroxycyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate (250 mg), 4-fluoro-3-methylphenol (0.172 ml), triphenylphosphine (on a polymer support, 3 mmol/g, 1.03 g) and THF (5.0 ml) were added DIAD (0.305 ml) at room temperature. The mixture was stirred at the same temperature for 1 hour and then at 60° C. for 1 hour. The reaction mixture was passed through NH silica gel and eluted with ethyl acetate/methanol (9/1) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and crystallized from ethyl acetate/diisopropyl ether to give a crude product (257 mg). The resulting crude product (243 mg) was recrystallized from ethanol/water to give the title compound (216 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.92-2.11 (2H, m), 2.19 (3H, d, J=1.9 Hz), 2.83-3.05 (2H , m), 3.92-4.21 (4H, m), 4.36 (1H, fifth, J=6.7 Hz), 4.47 (2H, s), 4.61 (1H, fifth, J=7.2Hz), 6.66(1H, dt, J=8.7, 3.6Hz), 6.76(1H, dd, J=6.5, 2.9Hz), 7, 02 (1H, t, J=9.2 Hz), 8.40 (1H, s).

[0337]

Example 63

cis-3-(2-chloro-4-fluorophenoxy)-3-methylcyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

[0338]

A) 1-((3-(benzyloxy)-1-methylcyclobutyl)oxy)-4-fluoro-2-nitrobenzene

To a mixture of 3-(benzyloxy)-1-methylcyclobutanol (0.89 g) and DMF (10 ml) was added sodium hydride (60%, 204 mg) under argon at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and 1,4-difluoro-2-nitrobenzene (0.552 ml) was added thereto at 0°C. The mixture was stirred under argon at room temperature for 1 h, 60° C. for 3 h and then overnight at room temperature. 0.1 M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then purified by NH silica gel column chromatography (ethyl acetate/hexane) to give the title compound (629 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.45 (3H, s), 2.17-2.27 (2H, m), 2.61-2.70 (2H, m), 3, 89 (1H, fifth, J=6.9 Hz), 4.39 (2H, s), 7.17 (1H, dd, J=9.4, 4.5 Hz), 7.24-7.39 (5H, m), 7.43-7.52 (1H, m), 7.86 (1H, dd, J=7.9, 3.2 Hz).

[0339]

B) 2-((3-(benzyloxy)-1-methylcyclobutyl)oxy)-5-fluoroaniline

1-((3-(Benzyloxy)-1-methylcyclobutyl)oxy)-4-fluoro-2-nitrobenzene mixture (629 mg), palladium/charcoal (ethylenediamine complex, Pd 3.5-6.5%, 202 mg) and methanol (12 ml) was stirred overnight under atmospheric pressure of a hydrogen atmosphere at room temperature. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (483 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.33-1.41 (3H, m), 2.14-2.24 (2H, m), 2.42-2.48 (2H, m ), 3.81(1H, fifth, J=6.9Hz), 4.36(2H, s), 4.97(2H, s), 6.19(1H, td, J=8.6, 3.1 Hz), 6.43 (1H, dd, J=10.9, 3.1 Hz), 6.61 (1H, dd, J=8.7, 5.7 Hz), 7.24- 7.37 (5H, m).

[0340]

C) 1-((3-(benzyloxy)-1-methylcyclobutyl)oxy)-2-chloro-4-fluorobenzene

To a mixture of 2-((3-(benzyloxy)-1-methylcyclobutyl)oxy)-5-fluoroaniline (483 mg) and hydrochloric acid (6 M, 10 ml) was added a mixture of sodium nitrite (133 mg) and water (1 ml) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and copper(I) chloride (190 mg) was added thereto at 0°C. The mixture was stirred at the same temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (209 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.42 (3H, s), 2.15-2.27 (2H, m), 2.55-2.65 (2H, m), 3, 87 (1H, fifth, J=6.9 Hz), 4.38 (2H, s), 6.98-7.05 (1H, m), 7.09-7.17 (1H, m), 7 .25-7.38 (5H, m), 7.44 (1H, dd, J=8.5, 3.0 Hz).

[0341]

D) cis-3-(2-chloro-4-fluorophenoxy)-3-methylcyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

To a mixture of sodium iodide (187 mg) and acetonitrile (2 ml) was added chlorotrimethylsilane (0.159 ml) at 0°C. The mixture was stirred at the same temperature for 30 minutes, and a mixture of 1-((3-(benzyloxy)-1-methylcyclobutyl)oxy)-2-chloro-4-fluorobenzene (200 mg) and acetonitrile (2 ml) was added thereto. at 0°C. The mixture was stirred at 0°C for 1 h and then at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give intermediate (93 mg). Triphosgene (64.8 mg) was added to a mixture of the resulting intermediate (93 mg), TEA (0.287 ml) and acetonitrile (2 ml) at 0°C. The reaction mixture was stirred at the same temperature for 30 min, and 7-oxa-2,5-diazaspiro[3.4]octane-6-ontosylate (187 mg) was added thereto at 0°C. The mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane). The residue was purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). A saturated aqueous sodium hydrogen carbonate solution was added to the resulting fraction, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (74.7 mg).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.45 (3H, s), 2.24-2.37 (2H, m), 2.65-2.76 (2H, m), 3, 91-4.01 (2H, m), 4.01-4.13 (2H, m), 4.46 (2H, s), 4.68 (1H, fifth, J=7.1 Hz), 6 .97-7.05(1H, m), 7.08-7.17(1H, m), 7.45(1H, dd, J=8.4, 3.1 Hz), 8.37(1H , With).

[0342]

Example compounds are shown in Table 1 below. MC in the tables means the actual measured value. Compounds of Examples 34-38, 40-43, 45, 47-49, 51-62 and 64 in the following tables were obtained in accordance with the methods described in the above examples, or methods similar to them.

[0343]

Table 1-1

Example No. IUPAC name Structural formula MS one cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

402.9 2 cis-3-(benzyloxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

331.1 3 cis-3-((3-chloro-4-methylbenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

379.0 four cis-3-((4-chloro-3-methylbenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

378.9 5 cis-3-((2,3-difluoro-4-methylbenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

380.9 6 cis-3-({2,3,4-trifluorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

384.9 7 cis-3-((2,4,5-trifluorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

385.0 eight cis-3-((2,4,6-trifluorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

384.9

[0344]

Table 1-2

Example No. IUPAC name Structural formula MS 9 cis-3-((3,4-dichlorobenzyl)oxy)cyclobutyl 6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

398.8 ten cis-3-((2~fluoro-4-(trifluoromethyl)benzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

416.9 eleven cis-3-((3-chloro-4-(trifluoromethyl)benzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

432.8 12 cis-3-((2-fluoro-4-methylphenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

363.0 13 cis-3-((4-fluoro-2-methylphenoxy)methyl)cyclobutyl 6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

363.0 fourteen cis-3-((2-chloro-4-fluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

382.9 fifteen cis-3-((4-chloro-2-fluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

382.9 16 cis-3-((2,3,4-trifluorophenoxy)methyl)cyclobutyl 6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

385.0

[0345]

Table 1-3

Example No. IUPAC name Structural formula MS 17 cis-3-((2,4,5-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

384.9 eighteen cis-3-((2,4,6-trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

384.9 19 cis-3-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

417.0 twenty cis-3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)cyclobutyl 6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

432.9 21 trans-3-((2,3,4-trifluorophenoxy)methyl)cyclobutyl 6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

385.0 22 trans-3-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

416.9 23 (cis-3-(2,4,6-trifluorophenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

384.9 24 (cis-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

416.9

[0346]

Table 1-4

Example No. IUPAC name Structural formula MS 25 (trans-3-(2,4,6-trifluorophenoxy)cyclobutyl)methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

384.9 26 (cis-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutyl)methyl 6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

432.8 27 (trans-3-(2-chloro-4-(trifluoromethyl)phenoxy)cyclobutyl(methyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

432.9 28 cis-3-(((3-chloro-4-methylbenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

392.9 29 cis-3-(((4-chloro-3-methylbenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

392.9 thirty cis-3-(((2-chloro-4-fluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

397.0 31 cis-3-(((2,3,4-trifluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

398.9 32 cis-3-(((2,4,5-trifluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

398.9

[0347]

Table 1-5

Example No. IUPAC name Structural formula MS 33 cis-3-(((2,4,6-trifluorobenzyl)oxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

398.9 34 trans-3-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

403.1 35 cis-3-((2,3,4-trifluorophenoxy)methyl)cyclobutyl-2-oxo-3-oxa-1,7-diazaspiro[4.4]nonane-7-carboxylate (optical isomer)

399.0 36 cis-3-(((2-fluoro-4-(trifluoromethyl)benzyl)oxy)methyl)cyclobutyl 6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

431.0 37 trans-4-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclohexyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

431.0 38 cis-4-(2-fluoro-4-(trifluoromethyl)phenoxy)cyclohexyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

430.9 39 trans-3-(2,3,4-trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

371.0 40 cis-3-((2,4-difluorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

367.1

[0348]

Table 1-6

Example No. IUPAC name Structural formula MS 41 cis-3-((3,4-difluorobenzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

367.0 42 trans-3-(benzyloxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

331.0 43 trans-3-(2,4,6-trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

370.9 44 cis-3-(2-chloro-4-fluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

368.9 45 cis-3-(3-fluoro-4-methylphenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

348.9 46 cis-3-(2,4,6-trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

370.9 47 cis-3-(4-chlorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

351.0 48 cis-3-(4-(trifluoromethyl)phenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

385.1

[0349]

Table 1-7

Example No. IUPAC name Structural formula MS 49 cis-3-(3-chlorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

351.1 fifty cis-3-(4-fluoro-3-methylphenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

349.1 51 cis-3-(2,3,4-trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

371.0 52 cis-3-(2-chlorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

351.0 53 cis-3-(4-methylphenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

331.1 54 cis-3-(4-chloro-2-fluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

369.0 55 cis-3-(4-fluoro-2-methylphenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

349.1 56 cis-3-(2-fluoro-4-methylphenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

349.0

[0350]

Table 1-8

Example No. IUPAC name Structural formula MS 57 cis-3-(2,4,5-trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

371.0 58 cis-3-(benzyloxy)-1-methylcyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

345.1 59 trans-3-(benzyloxy)-1-methylcyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

345.1 60 cis-1-methyl-3-(2,4,6-trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

385.0 61 trans-1-methyl-3-(2,4,6-trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

385.0 62 trans-3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

417.0 63 cis-3-(2-chloro-4-fluorophenoxy)-3-methylcyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate

383.0 64 cis-3-((2,3,4-trifluorophenoxy)methyl)cyclobutyl 6-oxo-2,5-diazaspiro[3.4]octane-2-carboxylate

385.0

[0351]

Comparative Example 1

(1r,3r)-3-(benzyloxy)cyclobutan-1-ol (identical to trans-3-(benzyloxy)cyclobutanol)

[0352]

A) (1r,3r)-3-(benzyloxy)cyclobutyl-4-nitrobenzoate

To a mixture of 3-(benzyloxy)cyclobutanone (24.7 g) and methanol (300 ml) was added sodium borohydride (5.30 g) in small portions at 0° C. and the mixture was stirred at 23° C. for 2 h. The methanol was evaporated under reduced pressure and the residue was diluted with 0.5 M hydrochloric acid (200 ml). The mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a crude product (21.8 g). This crude product was separated by HPLC (column: CHIRALPAK AD (trade name), 50 mm ID x 500 ml, manufactured by Daicel Corporation, mobile phase: hexane/ethanol (900/100 (v/v))) to obtain (1s, 3s)-3-(benzyloxy)cyclobutan-1-ol (17.7 g). To the resulting mixture of (1s,3s)-3-(benzyloxy)cyclobutan-1-ol (10.0 g), 4-nitrobenzoic acid (14.07 g), triphenylphosphine (22.07 g) and THF (125 ml) DIAD (18.91 g) was added dropwise at 0° C. and the mixture was warmed to room temperature. The mixture was stirred overnight at room temperature, diluted with toluene, and concentrated under reduced pressure to about 100 ml. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (18.45 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ2.42-2.49 (4H, m), 4.34 (1H, quin, J=5.8 Hz), 4.42 (2H, s), 5.21-5.40(1H, m), 7.18-7.42(5H, m), 8.15-8.27(2H, m), 8.30-8.46(2H, m ).

[0353]

B) (1r,3r)-3-(benzyloxy)cyclobutan-1-ol

To a mixture of (1r,3r)-3-(benzyloxy)cyclobutyl-4-nitrobenzoate (18.37 g) and THF (100 ml)/methanol (20.0 ml) was added 2M aqueous sodium hydroxide solution (84 ml) dropwise at 0°C, and the mixture was stirred over night at room temperature. The organic solvent was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (9.65 g).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ1.95-2.08 (2H, m), 2.12-2.25 (2H, m), 4.09-4.20 (1H, m) , 4.27 (1H, tk, J=7.1, 4.9 Hz), 4.33 (2H, s), 4.98 (1H, d, J=5.3 Hz), 7.21- 7.42 (5H, m).

[0354]

Experimental Example 1 Cloning of Human MGLL Encoding MAGL Protein and Construction of Expression Plasmid

Human MGLL cDNA was obtained by PCR using a human ORF clone (DNA form; clone ID: 100004585) as a template. Two types of primers were used for PCR:

5'-CCACCATCATCACGGATCCATGCCAGAGGAAAGTTCCCCCA-3'

[SEQ ID NO: 1]

and

5'-TGGTGCTCGAGTGCGGCCGCTCAGGGTGGGGACGCAGTTC-3'

[SEQ ID NO: 2]

and PrimeSTAR MAX DNA polymerase (Takara Bio Inc.) and (1) the reaction was carried out at 98°C for 1 min, (2) 25 reaction cycles at 98°C for 10 s and 68°C for 10 s for one cycle, and (3) the reaction was carried out at 72°C for 1 min. The resulting PCR product was digested with Bam HI and Not I (Takara Bio Inc.), inserted into the Bam HI/Not I site of pET21HH (V) (pET21a (Novagen) inserted with His x6 and TEV protease recognition sequence) using Ligation High (Toyobo Co., Ltd.) and introduced into ECOS ^TM JM109 (Nippon Gene Co., Ltd.), whereby the expression plasmid pET21HH(V)/His-hMGLLv2 for Escherichia coli was constructed.

[0355]

Experimental Example 2: Preparation of recombinant polyhistidine labeled human MAGL protein.

The recombinant His-hMAGL protein was obtained by transforming ECOS ^TM Competent E. coli BL21(DE3) (Nippon Gene Co., Ltd.) with the plasmid pET21HH(V)/His-hMGLLv2 obtained above. Escherichia coli obtained by transformation was inoculated into 10 ml LB medium (1% peptone, 0.5% yeast extract, 0.5% sodium chloride, 0.01% ampicillin) and cultured at 30°C for 16 hours. culture medium (5 ml) was transferred to a 2 L Sakaguchi flask containing 1 L of basic fermentation medium (1.05% M9 MEDIUM BROTH (AMRESCO LLC), 0.5% yeast extract, 1.5% sorbitol, 1.5% casamino acid, 0.024% magnesium sulfate, 0.01% defoamer PE-L (Wako Pure Chemical Industries, Ltd.), 0.01% ampicillin) and started shaking the culture at 37°C and 150 rpm. When the turbidity of the culture medium reached about 500 Klett units, the culture temperature was lowered to 16°C, isopropyl-β-D-thiogalactopyranoside (IPTG) was added to a final concentration of 1 mM, and the mixture was additionally cultured for 19 hours. After completion of the culture, the culture medium was centrifuged ( 4°C, 6000 rpm, 10 min) to obtain His-hMAGL-expressed Escherichia coli. His-hMAGL-expressed Escherichia coli was then suspended in 50 mM Tris-HCl (pH 8.0, 100 ml) containing 1% Triton X-100, 20 mM imidazole, 3 mM DTT, 5 U/ml benzonase (Merck) and 150 mM NaCl, and the suspension was sufficiently cooled and sonicated at AMPLITUDE=60%, 15 s/on, 30 s/off. for 3 min using a 3/4” BRANSON Digital Sonifier 450 hard type crushed horn (Central Scientific Commerce, Inc.). In addition, the homogenate was centrifuged (4°C, 6000 rpm, 20 min) and the supernatant was obtained. An AKTA explorer 10s (GE Healthcare Japan Corporation) at 4°C was used as a cleaning apparatus. To the resulting supernatant was added 5 M NaCl to a final salt concentration of 0.3 M, and the mixture was passed through and adsorbed onto 5 ml Ni-NTA Superflow (QIAGEN) cartridges pre-equilibrated with buffer A (50 mM Tris-HCl (pH 8.0) containing 0.05% Triton X-100, 1 mM DTT, 300 mM NaCl). The column was washed sufficiently with buffer A containing 20 mM imidazole and His-hMAGL was eluted with buffer A containing imidazole at a final concentration of 250 mM. The eluate was then gel-filtered using a HiLoad 16/600 Superdex 200 pg (GE Healthcare Japan Corporation) equilibrated with 50 mM Tris-HCl pH 8.0 containing 10% glycerol, 0.05% Triton X-100, 1 mM DTT and 150 mm NaCl. The eluted fraction was concentrated with Amicon Ultra-15 10K (Merck Millipore) to give purified His-hMAGL protein. Protein concentration was measured with a BCA protein assay kit (Thermo Fisher Scientific) using BSA as a standard.

[0356]

Experimental Example 3 Measurement of Inhibitory Activity of MAGL

His-hMAGL prepared above was diluted with enzyme reaction buffer (10 mM Tris-HCl, pH 7.5, 1 mM EDTA, 0.025% (w/v) Triton X-100, 0.01% BSA) to concentration 7.5 ng/ml. To each well of a 384-well assay plate (Greiner 781280) was added a solution (5 µl) of the test compound dissolved in dimethyl sulfoxide (DMSO), which was diluted with the above enzyme reaction buffer, then His-hMAGL solution (5 µl) diluted to a concentration of 7 .5 ng/ml and the mixture was incubated at room temperature for 60 minutes. Thereafter, 5 μl of 150 μM 2-arachidonylglycerol (Tocris Bioscience) was added to each well, and the mixture was incubated at room temperature for 10 minutes. Then, 10 µl of 2% formic acid (Wako Pure Chemical Industries, Ltd.) was added to stop the reaction. In addition, acetonitrile (50 μl) containing 3 μM arachidonic acid-d8 (Cayman Chemical Company) was added and the mixture was stirred.

The amount of arachidonic acid in the resulting enzyme reaction mixture was calculated by measuring with RapidFire-mass spectrometry and correcting for the amount of arachidonic acid-d8. Online high throughput solid phase extraction was performed using a RapidFire 300 ^TM system (Agilent Technologies, Inc.). Samples were loaded onto a SPE C4 cartridge (Agilent Technologies, Inc.) and desalted with 0.2% (v/v) acetic acid (Wako Pure Chemical Industries, Ltd.) in ultrapure water/acetonitrile (70/30, v/v). v/v) at a flow rate of 1.5 ml/min, eluted at a flow rate of 0.5 ml/min with 0.2% (v/v) acetic acid dissolved in acetonitrile/ultrapure water (90/10, v/v). /v) and introduced into the mass spectrometric part. The injection needle was flushed with ultrapure water (500 milliseconds) and acetonitrile (500 milliseconds) to minimize carryover. The suction time (5 μl injection cycle), load/purge time, elution time, and reequilibration time were adjusted to 300, 3000, 4250, and 1000 milliseconds, respectively, and the total cycle time was adjusted to about 10.0 seconds. The RapidFire300 system was controlled with RapidFire UI version 3.6 software (Agilent Technologies, Inc.).

Mass spectrometry of the resulting product was performed using an API4000 ^TM triple quadrupole mass spectrometer (AB SCIEX) equipped with an electrospray ion source (TurboIon Spray ^TM ) in negative selective reaction control (SRM) mode. SRM conditions are shown below. The instrument parameters were optimized as follows: capillary temperature 600°C, ion spray voltage -4.5 kV, collision gas 8, gas curtain 15 psi. in., ion source gas 1 60 psi in., ion source gas 2 60 psi The mass spectrometer was controlled using Analyst ^TM software version 1.5.1 (AB SCIEX). Peak area integration was analyzed using RapidFire integrator software version 3.6 (Agilent Technologies, Inc.).

The MAGL inhibition rate (%) was calculated according to the following calculation formula.

(1-(amount of arachidonic acid produced from the test compound of the added group - amount of arachidonic acid produced from the group without enzymes) ÷ (amount of arachidonic acid produced from the group without test compound - amount of arachidonic acid produced from the group without enzymes) )×100

The results are illustrated in the following Table. 2.

[0357]

Table 2-1

Example % inhibition (10 µM) one 100 2 101 3 101 four 100 5 99 6 101 7 100 eight 100 9 99 ten 99 eleven 100 12 101 13 102 fourteen 98 fifteen 103 16 100 17 101 eighteen 102 19 98 twenty 100 21 100 22 103 23 100 24 103 25 100 26 100 27 100 28 100 29 100 thirty 100 31 100 32 100

[0358]

Table 2-2

Example % inhibition (10 µM) 33 101 34 99 35 100 36 100 37 101 38 102 39 100 40 100 41 99 42 99 43 102 44 103 45 98 46 102 47 100 48 100 49 100 fifty 99 51 99 52 100 53 101 54 100 55 100 56 101 57 100 58 93 59 99 60 98 61 100 62 99 63 100 64 101

[0359]

As can be seen from Table 2, the compound of the present invention has inhibitory activity against MAGL.

[0360]

Experimental Example 4: Measurement of intracerebral concentrations of 2-AG and arachidonic acid

As mice, 8-week-old male C57BL/6J mice (CLEA Japan, Inc.) were used (6 mice per group). Solutions for administration were prepared by suspending test compounds (compound 1 (compound of Example 16), compound 2 (compound of Example 18) and compound 3 (compound of Example 46)) in 0.5% methylcellulose solution (Wako Pure Chemical Industries, Ltd.). The dose of the test compound was 1 mg/kg body weight/10 ml. Test compounds were administered via a gastric tube at a dose of 1 mg/kg body weight. The brain was isolated after administration of the test compound (the release time after administration of the test compound is illustrated in Table 3), and the cerebral hemisphere was extracted. The resulting cerebral hemisphere was frozen on dry ice and the weight of the frozen tissue was measured.

[0361]

Brain tissue was homogenized with 4x (by volume) isopropanol (IPA) and diluted twice with IPA. To the diluted sample (200 µl) was added an internal standard solution (5 µl) ([5,6,8,9,11,12,14,15-D8]-(5Z,8Z,11Z,14Z)5,8,11 ,14-eicosatetraenoic acid (AA-d ₈ , 0.5 nmol/ml IPA) and [5,6,8,9,11,12,14,15-D8]-(5Z,8Z,11Z,14Z)- 5,8,11,14-eicosatetraenoyl-2-glycerol ester (2-AG-d ₈ , 0.5 nmol/ml IPA)), and the mixture was centrifuged at 15,000 rpm for 5 minutes. The supernatant was injected into a liquid chromatograph - mass spectrometer for quantitative analysis.

For liquid chromatography, a Shimadzu LC20A system (Shimadzu Corporation) was used. Separation was performed by gradient elution with mobile phase A (10 mmol/l HCOONH ₄ /HCOOH (100:0.2, v/v)) and mobile phase B (ethanol/IPA (3:2, v/v). )) using a Shim-pack XR-ODS (2.2 µm, 2.0 x 30 mm, Shimadzu Corporation) at a column temperature of 50°C, with a flow rate of 0.5 ml/min. Gradient conditions are shown below: 0-1 min, 1% B; 1-1.2 min, 1-55% B; 1.2-2.7 min, 55-75% B; 2.7-3.5 min, 75-99% B; 3.5-6 min, 99% B; 6-8 min, 1% B.

An API5000 (AB SCIEX) was used as a mass spectrometer. The eluate from liquid chromatography was directly ionized by the turbospray ionization method, where (5Z,8Z,11Z,14Z)5,8,11,14-eicosatetraenoic acid (AA) and AA-d ₈ were measured in negative ionization mode, and (5Z,8Z, 11Z,14Z)5,8,11,14-eicosatetraenoyl-2-glycerol ester (2-AG) and 2-AG-d ₈ were measured in positive ionization mode. Mass spectrometer detection conditions are illustrated in Table 4.

The solution for the calibration curve was prepared to a concentration of 2, 5, 10, 20, 50, 100, 200, 500, 1000 nmol/ml acetonitrile. These solutions (10 μl) were mixed with 200 μl of IPA and 5 μl of internal standard solution, and the mixture was centrifuged at 15000 rpm for 5 min, and the supernatant was injected into a liquid chromatograph-mass spectrometer. Linear regression with 1/x ² weighting was used to fit the standard curve, and the quantification was validated with an accuracy of 100±20% and R ² >0.99.

The results are presented in Table 5.

[0362]

As can be seen from Table 5, compounds 1, 2 and 3 migrated to the brain when administered orally to C57BL/6J mice, and these compounds increased the intracerebral concentration of 2-AG and simultaneously reduced the intracerebral concentration of arachidonic acid compared to the control.

[0363]

Table 3

Test compound release time after test compound administration (hours) connection 1 one compound 2 one compound 3 one

[0364]

Table 4

mass spectrometer parameter

target molecule Polarity Q1 Q3 retention time (ms) DP(V) EP(V) CE(V) CXP(V) arachidonic acid - 303.2 205.2 25 -90 -eleven -17 -fifteen arachidonic acid-d8 - 311.4 267.4 25 -175 -ten -22 -17 2-arachidonylglycerol + 379.3 95 25 181 ten 91 fourteen 2-arachidonylglycerol-d8 + 387.4 294.2 25 161 ten 23 eighteen

DP︰ decomposition potential

EP︰ input potential

CE: splitting energy

CXP: Collision cell output voltage

[0365]

Table 5

2-AG concentration (nmol/g) arachidonic acid concentration (nmol/g) control 13.5 203.1 connection 1 82.3 119.8 compound 2 128.7 84.3 connection 3 79.0 138.0

[0366]

Preparation examples

Medicines containing the compound of this invention as an active ingredient can be obtained, for example, in the form of the following preparations.

1. capsule

(1) the compound obtained in Example 1 10 mg

(2) lactose 90 mg

(3) microcrystalline cellulose 70 mg

(4) magnesium stearate 10 mg

1 capsule 180 mg

The total of the above (1), (2) and (3) and 5 mg (4) are mixed and granulated, and 5 mg of the remaining (4) is added. The whole mixture is sealed in a gelatin capsule.

[0367]

2. tablet

(1) the compound obtained in Example 1 10 mg

(2) lactose 35 mg

(3) corn starch 150 mg

(4) microcrystalline cellulose 30 mg

(5) magnesium stearate 5 mg

1 tablet 230 mg

The total amount of the above (1), (2) and (3), 20 mg (4) and 2.5 mg (5) are mixed and granulated, and 10 mg of the remaining (4) and 2.5 mg of the remaining (5) are added to mixture for compression in the form of a tablet.

Industrial Applicability

[0368]

According to the present invention, a compound having an inhibitory action against MAGL, which is expected to be useful as an agent for the prevention or treatment of neurodegenerative diseases (for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, glaucoma , multiple sclerosis, etc.), anxiety disorder, pain (eg, inflammatory pain, cancer pain, neurogenic pain, etc.), epilepsy, depression, and the like.

[0369]

This application is based on Patent Application No. 2017-190838 filed September 29, 2017 in Japan, the contents of which are incorporated herein in their entirety.

Claims (39)

1. The compound represented by formula (I):

where A is a C _3-10 cycloalkyl group substituted with 1-3 substituents selected from (a) a phenoxy group optionally substituted with 1-4 substituents selected from (i) a halogen atom and (ii) an optionally halogenated C _1-6 alkyl group, (b) a phenoxy-C _1-6 alkyl group optionally substituted with 1-4 substituents selected from (i) a halogen atom and (ii) an optionally halogenated C _1-6 alkyl group, (c) a benzyloxy group optionally substituted with 1-4 substituents selected from (i) a halogen atom and (ii) an optionally halogenated C _1-6 alkyl group, and (d) a benzyloxy-C _1-6 alkyl group optionally substituted with 1-4 substituents selected from (i) a halogen atom and (ii) an optionally halogenated C _1-6 alkyl group, and optionally further substituted with 1-3 C _1-6 alkyl groups; L is a bond or a C _1-3 alkylene group; ring D is a 4- or 5-membered nitrogen-containing heterocycle; n is 1 or 2; X represents -O- or -CH ₂ -; and both R ^a and R ^b are hydrogen atoms; or a pharmaceutically acceptable salt thereof. 2. A compound or pharmaceutically acceptable salt according to claim 1, where A is a cyclobutyl group substituted with one substituent selected from (a) a phenoxy group substituted with 3 halogen atoms, and (b) a phenoxymethyl group substituted with 3 halogen atoms; L is a bond; ring D is an azetidine ring; n is 1; X is -O-; and both R ^a and R ^b are hydrogen atoms. 3. cis-3-((2,3,4-Trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate or a pharmaceutically acceptable salt thereof. 4. cis-3-((2,4,6-Trifluorophenoxy)methyl)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate or a pharmaceutically acceptable salt thereof. 5. cis-3-(2,4,6-Trifluorophenoxy)cyclobutyl-6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carboxylate, or a pharmaceutically acceptable salt thereof. 6. A drug that is a monoacylglycerol lipase inhibitor containing a compound or salt according to claim 1. 7. The drug according to claim 6, characterized in that it is an agent for the prevention or treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, anxiety disorder, pain, epilepsy or depression. 8. A method for inhibiting monoacylglycerol lipase in a mammal, comprising administering to the mammal an effective amount of a compound or salt according to claim 1. 9. A compound or salt according to claim 1 for use in the prevention or treatment of Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, anxiety disorder, pain, epilepsy, or depression.