WO2011142359A1 - Spiro compound and drug for activating adiponectin receptor - Google Patents

Abstract

Provided is a novel drug which has adiponectin receptor affinity and agonist effects, and which is useful in the prevention or treatment of metabolic syndrome, particularly metabolic syndrome accompanied by obesity and diabetes, and arteriosclerosis, etc. A novel spiro compound represented by formula (I) (where Z¹, X, L¹, L², E, R⁶, R⁷, m, n, and T are as defined in the text), tautomers of the compound, or pharmaceutically acceptable salts thereof are provided.

Description

Spiro compounds and adiponectin receptor activators

The present invention relates to a preventive / therapeutic / ameliorating agent for diseases in which an adiponectin receptor activation action is effective, characterized by having affinity for an adiponectin receptor and / or an agonistic action. Furthermore, the present invention relates to a metabolic syndrome containing a drug having an adiponectin receptor agonistic action as an active ingredient, particularly a metabolic syndrome associated with obesity or diabetes, and a prophylactic or therapeutic agent for arteriosclerosis.

Adiponectin is a kind of adipocytokine that is a physiologically active substance secreted from adipocytes. Various possibilities have been suggested for the role of adiponectin, but the most important role is to prevent tissues from acquiring insulin resistance and to act as a protective factor for diabetes. It has been reported that the resistance index is inversely correlated with the blood adiponectin concentration (see, for example, Non-Patent Document 1).
In addition, as its detailed action, by directly stimulating sugar uptake in adipose tissue and muscle tissue, increasing fatty acid oxidation in liver and muscle tissue, reducing intracellular fatty acid and triglyceride content, The possibility of improving insulin resistance is considered (for example, see Non-Patent Documents 2, 3, and 4). Considering such effects, adiponectin may improve obesity through improvement of insulin resistance, and it has been reported that the degree of obesity actually decreases in inverse proportion to the blood adiponectin concentration (for example, Non-patent document 5). Furthermore, adiponectin may be effective in treating metabolic syndrome, which is a complex pathological condition involving them, by improving diabetes and obesity.

It has been clarified that the action of adiponectin is mediated by an adiponectin receptor (hereinafter sometimes referred to as AdipoR). In addition, AdipoR has two subtypes, AdipoR1 and AdipoR2, AdipoR1 is distributed in systemic tissues, and its stimulation mainly shows AMP kinase activation (gluconeogenesis suppression) action, while AdipoR2 is the main It is reported that the stimulation is mainly exerted on the action of enhancing β-oxidation of fatty acids through the activation of PPARα. AMP kinase is a kinase whose substrate is an enzyme important for glycolipid metabolism such as ACC and HMG-CoA, and regulates various metabolic pathways such as sugar transport, glycolysis, and lipid metabolism. Β-oxidation of activated AMP kinase and activated fatty acid enhances metabolic pathways such as fatty acid degradation and glycolysis, and exerts an insulin resistance improving action by suppressing lipid biosynthesis and the like.
In addition, adiponectin has been reported to reduce glycogen content by reducing liver glycogen synthase activity. In addition, it has been reported that adiponectin exerts a protective action against inflammation, coronary artery disease, nonalcoholic steatohepatitis, liver fibrosis or malignant tumor (for example, Non-Patent Documents 6 and 7, and 8).

As described above, a compound having an affinity for an adiponectin receptor and / or an agonistic action exhibits an adiponectin-like action, whereby a disease in which the adiponectin receptor activating action is effective, such as diabetes, obesity, metabolic It may be effective in the prevention, treatment and improvement of syndrome, arteriosclerosis, coronary artery disease, nonalcoholic steatohepatitis, liver fibrosis or malignant tumors, especially diabetes.

As a low molecular weight compound exhibiting an adiponectin receptor agonist activity, a report from Rigel has been made (see Patent Documents 1 to 4), but further drug development is desired.

International Publication No. 2008/083124 International Publication No. 2009/066511 International Publication No. 2009/076631 International Publication No. 2009/132136

It is an object of the present invention to provide a novel pharmaceutical having excellent adiponectin receptor affinity and agonistic activity and useful for the prevention or treatment of metabolic syndrome, particularly metabolic syndrome associated with obesity and diabetes, and arteriosclerosis. And

As a result of intensive studies on the above problems, the present inventors have found that the compound represented by the general formula (I) exhibits an excellent adiponectin receptor agonistic action, and completed the present invention.
That is, the present invention relates to the following.
(1)
Formula (I)

[In the formula (I),
E means an oxygen atom or a sulfur atom,
L 1 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
L 2 represents a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
X represents a C 3-11 cycloalkylene group, a C 3-11 cycloalkenylene group (the C 3-11 cycloalkylene group and the C 3-11 cycloalkenylene group are unsubstituted or a C 1-3 alkyl group) Substituted with one or more substituents independently selected from the group consisting of C 2-3 alkenyl groups, —OR 16 and cyano groups.), C 6-10 arylene groups or 5- to 10-membered heteroarylenes A group (the C 6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted or a halogen atom, a nitro group, a cyano group, a C 1-3 alkyl group (the C 1-3 alkyl group is or an unsubstituted, substituted by one or more substituents independently selected from the group consisting of a halogen atom and -OR 16.), C 2-3 alkenyl, C 2-3 Rukiniru group, -OR 16, -O (C 2-3 alkenyl group), - O (C 3-4 cycloalkyl group), - N (R 16) C (= O) OR 17, -N (R 16) C (═O) R 17 , —N (R 16 ) C (═O) H, —N (R 16 ) R 17 , —NH 2 , —N (R 16 ) S (═O) 2 R 17 , — C (═O) NR 16 R 17 , —C (═O) NH 2 , —C (═O) R 16 , —S (═O) 2 R 17 , —S (═O) 2 NR 16 R 17 , Substituted with one or more substituents independently selected from the group consisting of —S (═O) 2 NH 2 ;
Z 1 represents the formulas (II-1) to (II-8)

(Where
J ¹ each independently represents an oxygen atom or a sulfur atom;
G ¹ means a single bond, an oxygen atom or a sulfur atom,
R ¹ and R ³ are
R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or one selected independently from substituent group A ₃ ) Substituted with the above substituents), a C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5-10 membered heteroaryl (wherein the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or independently of the group consisting of substituent groups A ₂ and C _4-6 alkyl groups) The C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group may be unsubstituted or substituted with one or more selected substituents). Substituent Which is substituted by one or more substituents independently selected from the group consisting of A ₁ and C _4-6 alkyl groups.) Means, R ³ means a hydrogen atom or a C _1-3 alkyl group Or
Or R ¹ and R ³ together with the nitrogen atom to which they are attached are 4- to 11-membered heterocycloalkyl groups (the 4- to 11-membered heterocycloalkyl groups are unsubstituted or substituted) Substituted with one or more substituents independently selected from the group consisting of group A ₁ and a C _4-6 alkyl group;
R ² represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₃ ). A C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( The C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups. The C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group may be unsubstituted or substituted with the substituent groups A ₁ and C _4-6 alkyl. A group of groups Substituted by one or more substituents independently selected),
R ⁴ and R ⁵ each independently represents a hydrogen atom or a C _1-3 alkyl group. )
Means either
m means an integer of 1 or 2,
R ⁶ independently represents a hydrogen atom, a C _1-3 alkyl group or a cyclopropyl group, or two R ⁶ existing on the same carbon atom are bonded to the carbon atom to which they are bonded. Together with C to form a C _3-6 cycloalkane,
n means an integer of 0 to 4,
Each R ⁷ independently represents a C _1-3 alkyl group;
T represents the formulas (VI-1) to (VI-3)

(Where
L ⁴ represents a C _1-3 alkylene group,
L ⁵ represents a single bond, an oxygen atom, a sulfur atom, S (═O), S (═O) ₂ , C═O or C═NOR ¹² ;
R ⁸ represents a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or substituted with the substituent groups A ₂ and C _4. Substituted with one or more substituents independently selected from the group consisting of _-6 alkyl groups).
J ² means an oxygen atom or a sulfur atom,
G ² means an oxygen atom, a sulfur atom or NR ¹¹ ,
R ⁹ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₄ ). , A C _6-10 aryl group (the C _6-10 aryl group is one or more substituents which are unsubstituted or independently selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups) A C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is a C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered) Heteroaryl is unsubstituted or substituted by one or more substituents independently selected from the group consisting of substituent groups A ₂ and C _4-6 alkyl groups. well, and the _{C 3-11} cycloalkyl Group is substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted.), Or, a C _1-3 alkyl group (the C _1-3 alkyl group Is a C _6-10 aryl group or a C _3-11 cycloalkyl group (the C _6-10 aryl group and the C _3-11 cycloalkyl group are unsubstituted or substituted with the substituent groups A ₂ and C _4-6. Substituted with one or more substituents independently selected from the group consisting of alkyl groups).
R ¹⁰ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ ). A C _6-10 aryl group, a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or substituted with the substituent groups A ₂ and C _4-6 alkyl, Substituted with one or more substituents independently selected from the group consisting of groups), a C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5- 10-membered heteroaryl (wherein the C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups independently Substituted by substituents It is.) And may be a condensed ring, and the C _3-11 cycloalkyl group, optionally substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted Or a C _1-3 alkyl group (the C _1-3 alkyl group is a C _3-11 cycloalkyl group (the C _3-11 cycloalkyl group is unsubstituted or substituted by the substituent group A ₂₎ . Substituted with one or more independently selected substituents)). )
Means either
Substituent group A ₁ is a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₃ ). .) and means a substituent group consisting of substituent group a _3,
Substituent group A ₃ is
A C _3-11 cycloalkyl group, a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of substituent groups A ₂ and C _4-6 alkyl groups The C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group may be unsubstituted or substituted with the substituent group A ₂ and the C _4-6 alkyl group. which is substituted by one or more substituents independently selected from the group consisting _{of.), C 6-10} aryl group, 5-10-membered heteroaryl group (the _{C 6-10} aryl group and 5 to 1 Membered heteroaryl group, 4-11-membered heterocycloalkyl alkane (said 4-11 membered heterocycloalkyl cycloalkane is substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted And the C _6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or a group consisting of the substituent group A ₂ and the C _4-6 alkyl group. Substituted with one or more substituents selected more independently.), —C (═O) OR ¹³ , —C (═O) NR ¹² R ¹³ , —C (═O) R ¹³ , — C (= NOR ¹² ) R ¹³ , —S (═O) R ¹³ , —S (═O) ₂ R ¹³ , —OR ¹³ , —SR ¹³ , —N (R ¹² ) C (═O) OR ¹³ , ^{-N (R 12) C (=} O) R 13, -N (R 12) R 13, C Gen atom, a cyano group, a nitro group, means a formyl ^{group, -C (= NOR 12) H} , -N (R 12) C (= O) H, or a substituent group consisting of a hydroxyl group,
Substituent group A ₂ is
Means a substituent group composed of a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms) and a substituent group A ₄ ,
Substituent group A ₄ is
Halogen atom, nitro group, cyano group, —OR ¹⁴ , —SR ¹⁴ , —C (═O) OR ¹⁴ , —C (═O) NR ¹⁴ R ¹⁵ , —C (═O) R ¹⁵ , —C (= NOR ¹⁵ ) R ¹⁴ , -C (= NOR ¹⁵ ) H, -S (= O) R ¹⁴ , -S (= O) ₂ R ¹⁴ , -N (R ¹⁵ ) C (= O) OR ¹⁴ , -N (R ¹⁵ ) C (═O) R ¹⁴ , or —N (R ¹⁵ ) C (═O) H means a substituent group composed of,
Each of R ¹¹ independently represents a hydrogen atom or a C _1-6 alkyl group;
Each R ¹² independently represents a hydrogen atom or a C _1-3 alkyl group;
Each R ¹³ is independently
A C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ ),
C _3-11 cycloalkyl group, _4-11 membered heterocycloalkyl group, C _6-10 aryl group, or 5-10 membered heteroaryl group (the C _3-11 cycloalkyl group, _4-11 membered heterocycloalkyl group) , The C _6-10 aryl group and the 5- to 10-membered heteroaryl group are one or more substituents which are unsubstituted or independently selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups Is replaced by
R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁵ represents a hydrogen atom or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁶ represents a hydrogen atom or a C _1-3 alkyl group,
R ¹⁷ means a C _1-3 alkyl group. ]
Or a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(2)
Formula (I)

[In the formula (I),
E means an oxygen atom or a sulfur atom,
L 1 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
L 2 represents a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
X represents a C 3-11 cycloalkylene group, a C 3-11 cycloalkenylene group (the C 3-11 cycloalkylene group and the C 3-11 cycloalkenylene group are unsubstituted or a C 1-3 alkyl group) Substituted with one or more substituents independently selected from the group consisting of C 2-3 alkenyl groups, —OR 16 and cyano groups.), C 6-10 arylene groups or 5- to 10-membered heteroarylenes A group (the C 6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted or a halogen atom, a nitro group, a cyano group, a C 1-3 alkyl group (the C 1-3 alkyl group is or an unsubstituted, substituted by one or more substituents independently selected from the group consisting of a halogen atom and -OR 16.), C 2-3 alkenyl, C 2-3 Rukiniru group, -OR 16, -O (C 2-3 alkenyl group), - O (C 3-4 cycloalkyl group), - N (R 16) C (= O) OR 17, -N (R 16) C (═O) R 17 , —N (R 16 ) C (═O) H, —N (R 16 ) R 17 , —NH 2 , —N (R 16 ) S (═O) 2 R 17 , — C (═O) NR 16 R 17 , —C (═O) NH 2 , —C (═O) R 16 , —S (═O) 2 R 17 , —S (═O) 2 NR 16 R 17 , Substituted with one or more substituents independently selected from the group consisting of —S (═O) 2 NH 2 ;
Z 1 represents the formulas (II-1) to (II-8)

(Where
J ¹ each independently represents an oxygen atom or a sulfur atom;
G ¹ means a single bond, an oxygen atom or a sulfur atom,
R ¹ and R ³ are
R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or one selected independently from substituent group A ₃ ) Substituted with the above substituents), a C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5- to 10-membered heteroaryl (the C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ The C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group may be unsubstituted or independently selected from the substituent group A ₁ One or more Which is substituted by substituents.) I mean, or R ³ means a hydrogen atom or a C _1-3 alkyl group,
Or R ¹ and R ³ together with the nitrogen atom to which they are attached are 4- to 11-membered heterocycloalkyl groups (the 4- to 11-membered heterocycloalkyl groups are unsubstituted or substituted) which is substituted by one or more substituents independently selected from the group a _1.) means,
R ² represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₃ ). A C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( The C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ). And the C _3-11 cycloalkyl group and the _4- to 11-membered heterocycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₁ ) And,
R ⁴ and R ⁵ each independently represents a hydrogen atom or a C _1-3 alkyl group. )
Means either
m means an integer of 1 or 2,
R ⁶ independently represents a hydrogen atom, a C _1-3 alkyl group or a cyclopropyl group, or two R ⁶ existing on the same carbon atom are bonded to the carbon atom to which they are bonded. Together with C to form a C _3-6 cycloalkane,
n means an integer of 0 to 4,
Each R ⁷ independently represents a C _1-3 alkyl group;
T represents the formulas (VI-1) to (VI-3)

(Where
L ⁴ represents a C _1-3 alkylene group,
L ⁵ represents a single bond, an oxygen atom, a sulfur atom, S (═O), S (═O) ₂ , C═O or C═NOR ¹² ;
R ⁸ represents a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or independently of the substituent group A ₂₎ Substituted with one or more substituents selected from
J ² means an oxygen atom or a sulfur atom,
G ² means an oxygen atom, a sulfur atom or NR ¹¹ ,
R ⁹ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₄ ). A C _6-10 aryl group (the C _6-10 aryl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ), C _{3 -11} cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5- to 10-membered heteroaryl (the C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted) Substituted with one or more substituents independently selected from group A ₂ ) and the C _3-11 cycloalkyl group may be unsubstituted or substituted. one or more independently selected from the group & A ₂ Which is substituted by a substituent.), _{Or, a C 1-3} alkyl group (the _{C 1-3} alkyl _{group, C 6-10} aryl group or _{C 3-11} cycloalkyl group (the _{C 6-10} aryl The group and the C _3-11 cycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ). And
R ¹⁰ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ ). , C _6-10 aryl group, 5- to 10-membered heteroaryl group (the C _6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or independently selected from substituent group A ₂ Substituted with one or more substituents), a C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5- to 10-membered heteroaryl (the C _6-10 Aryl and 5- to 10-membered heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from substituent group A ₂ ) and The C _3-11 cycloalkyl group is , Unsubstituted or substituted with one or more substituents independently selected from substituent group A ₂ ), or a C _1-3 alkyl group (the C _1-3 alkyl group is C ₃ Substituted with an _-11 cycloalkyl group (the C _3-11 cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ). Means). )
Means either
Substituent group A ₁ is a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₃ ). .) and means a substituent group consisting of substituent group a _3,
Substituent group A ₃ is
A C _3-11 cycloalkyl group, a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ . And the C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from substituent group A _{2 .), C 6-10} aryl group, 5-10-membered heteroaryl group (the _{C 6-10} aryl and 5-10 membered heteroaryl group, 4-11-membered heterocycloalkyl alkane (said 4-11 Heterocycloalkane may be condensed with unsubstituted or substituted with or independently from the substituent group A ₂ is substituted by one or more substituents selected.), And the C _6-10 aryl The group and the 5- to 10-membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ )), —C (═O) OR ¹³ , -C (= O) NR ¹² R ¹³ , -C (= O) R ¹³ , -C (= NOR ¹² ) R ¹³ , -S (= O) R ¹³ , -S (= O) ₂ R ¹³ ,- OR ¹³ , —SR ¹³ , —N (R ¹² ) C (═O) OR ¹³ , —N (R ¹² ) C (═O) R ¹³ , —N (R ¹² ) R ¹³ , halogen atom, cyano group, A nitro group, a formyl group, —C (═NOR ¹² ) H, —N (R ¹² ) C (═O) H, Or a group of substituents composed of hydroxyl groups,
Substituent group A ₂ is
Means a substituent group composed of a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms) and a substituent group A ₄ ,
Substituent group A ₄ is
Halogen atom, nitro group, cyano group, —OR ¹⁴ , —SR ¹⁴ , —C (═O) OR ¹⁴ , —C (═O) NR ¹⁴ R ¹⁵ , —C (═O) R ¹⁵ , —C (= NOR ¹⁵ ) R ¹⁴ , -C (= NOR ¹⁵ ) H, -S (= O) R ¹⁴ , -S (= O) ₂ R ¹⁴ , -N (R ¹⁵ ) C (= O) OR ¹⁴ , -N (R ¹⁵ ) C (═O) R ¹⁴ , or —N (R ¹⁵ ) C (═O) H means a substituent group composed of,
Each of R ¹¹ independently represents a hydrogen atom or a C _1-6 alkyl group;
Each R ¹² independently represents a hydrogen atom or a C _1-3 alkyl group;
Each R ¹³ is independently
A C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ ),
C _3-11 cycloalkyl group, _4-11 membered heterocycloalkyl group, C _6-10 aryl group, or 5-10 membered heteroaryl group (the C _3-11 cycloalkyl group, _4-11 membered heterocycloalkyl group) , C _6-10 aryl and 5-10-membered heteroaryl group is substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted.) means ,
R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁵ represents a hydrogen atom or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ¹⁶ represents a hydrogen atom or a C _1-3 alkyl group,
R ¹⁷ means a C _1-3 alkyl group. ]
A spiro compound according to the above (1), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(3)
X is a C _3-11 cycloalkylene group or a C _3-11 cycloalkenylene group (the C _3-11 cycloalkylene group and the C _3-11 cycloalkenylene group are unsubstituted or a C _1-3 alkyl group) Substituted with one or more substituents independently selected from the group consisting of C ₂ , C _2-3 alkenyl groups, —OR ¹⁶ and cyano groups.)
The spiro compound according to the above (2), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(4)
X is a C _6-10 arylene group or a 5- to 10-membered heteroarylene group (the C _6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted, halogen atoms, nitro groups, cyano groups, A C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a halogen atom and —OR ¹⁶ ). ), C _2-3 alkenyl group, C _2-3 alkynyl group, —OR ¹⁶ , —O (C _2-3 alkenyl group), —O (C _3-4 cycloalkyl group), —N (R ¹⁶ ) C (═O) OR ¹⁷ , —N (R ¹⁶ ) C (═O) R ¹⁷ , —N (R ¹⁶ ) C (═O) H, —N (R ¹⁶ ) R ¹⁷ , —NH ₂ , —N ( _{^{R 16) S (= O)}} 2 R 17, -C (= O) NR 16 R 1 _{^{, -C (= O) NH 2}} , -C (= O) R 16, -S (= O) 2 R 17, -S (= O) 2 NR 16 R 17, -S (= O) 2 NH 2 Substituted with one or more substituents independently selected from the group consisting of
The spiro compound according to the above (2), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(5)
L ¹ is a C _1-3 alkylene group, C _2-3 alkenylene group or C _2-3 alkynylene group (the C _1-3 alkylene group, C _2-3 alkenylene group and C _2-3 alkynylene group are unsubstituted) Or substituted by a cyclopropyl group.)
The spiro compound according to the above (4), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(6)
Z ¹ is represented by formulas (II-1) to (II-8)

(Where
J ¹ each independently represents an oxygen atom or a sulfur atom;
G ¹ means a single bond, an oxygen atom or a sulfur atom,
R ¹ and R ³ are
R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-5 alkyl group (wherein the C _1-5 alkyl group is unsubstituted or independently selected from Substituent Group A ₃ Substituted by the above substituents, provided that when m is 1 and both R ⁶ are hydrogen atoms, the C _1-5 alkyl group is independently selected from the substituent group A ₃ A C _6-9 alkyl group (wherein the C _6-9 alkyl group is unsubstituted or independently selected from Substituent Group A ₃ ). Substituted with the above substituents), a C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5-10 membered hetero ants (Wherein the C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ) and fused rings And the C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group may be unsubstituted or substituted by one or more substituents independently selected from the substituent group A ₁ Substituted, and R ³ represents a hydrogen atom or a C _1-3 alkyl group,
Or R ¹ and R ³ together with the nitrogen atom to which they are attached are 4- to 11-membered heterocycloalkyl groups (the 4- to 11-membered heterocycloalkyl groups are unsubstituted or substituted) which is substituted by one or more substituents independently selected from the group a _1.) means,
R ² represents a C _1-5 alkyl group (the C _1-5 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A _3, provided that , M means 1 and two R ⁶ both represent a hydrogen atom, the C _1-5 alkyl group is substituted with one or more substituents independently selected from the substituent group A _3. A C _6-9 alkyl group (the C _6-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₃ ). A C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( the _{C 6-10} aryl and 5-10 Heteroaryl may be condensed one or more are replaced by a substituent.) And selected as or independently from Substituent group A ₂ unsubstituted, and the C _3-11 cycloalkyl groups and 4-11 membered heterocycloalkyl group is substituted by one or more substituents selected as or independently from substituent group a ₁ unsubstituted.) I mean,
R ⁴ and R ⁵ each independently represents a hydrogen atom or a C _1-3 alkyl group. )
The spiro compound according to (5), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(7)
L ¹ is a C _1-3 alkylene group,
L ² is a single bond,
Z ¹ represents the formula (II-1), (II-4) or (II-7)

(Wherein R ¹ , R ² , R ³ , R ⁴ , J ¹ and G ¹ have the same meaning as defined in (2) above), (2) or (3) Or a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(8)
L ¹ is a C _1-3 alkylene group,
L ² is a single bond,
Z ¹ represents the formula (II-1), (II-4) or (II-7)

(Wherein R ¹ , R ² , R ³ , R ⁴ , J ¹ and G ¹ have the same meaning as defined in (6) above), and the spiro described in (6) above A compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(9)
The spiro compound according to any one of (2) to (8) above, wherein E is an oxygen atom, m is 1, and n is 0, a tautomer of the compound, or a pharmaceutically acceptable salt thereof An acceptable salt.

(10)
The spiro compound according to any one of (2) to (8) above, wherein E is an oxygen atom, m is 2, and n is 0, a tautomer of the compound, or a pharmaceutically acceptable salt thereof An acceptable salt.

(11)
T is the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ have the same meaning as defined in (2) above). The spiro compound according to any one of (2) to (10) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(12)
Z ¹ is
Formula (II-1), (II-4) or (II-7)

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)) Or R ³ represents a hydrogen atom,
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and a 5- to 10-membered heteroaryl group) is 4-11 membered heterocycloalkyl alkanes (the 4-11 membered heterocycloalkyl alkanes are substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted.) and The C _6-10 aryl group and the 5- to 10-membered heteroaryl group may be condensed or substituted with one or more substituents independently selected from substituent group A ₂ And the C _1-6 alkyl group is substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group. means may be.), ^{R 3} Means a hydrogen atom,
R ¹ is a 4- to 11-membered nitrogen-containing heterocycloalkyl group (the 4- to 11-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Unsubstituted or independently from the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH ₃ Substituted with one or more selected substituents) or substituted with either a cyano group) or substituted with either —C (═O) O (C _1-6 alkyl). R ³ represents a hydrogen atom, or
R ¹ and R ³ together with the nitrogen atom to which they are bonded are 4- to 11-membered nitrogen-containing heterocycloalkyl groups (the 4- to 11-membered nitrogen-containing heterocycloalkyl groups are represented by substituent group A ₁ Substituted with one or more independently selected substituents),
R ² is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is substituted with a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). .)
R ⁴ represents a hydrogen atom,
J ¹ means an oxygen atom,
G ¹ means a single bond or an oxygen atom. )
The spiro compound according to any one of (2) to (11) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(13)
Z ¹ is
Formula (II-1), (II-4) or (II-7)

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)) Or R ³ represents a hydrogen atom,
R ¹ is a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Unsubstituted or independently from the group consisting of —C (═O) OCH ₃ , a cyano group, a nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , a chlorine atom, —CF ₃ and —CH ₃ Substituted with one or more selected substituents)), substituted with), and R ³ represents a hydrogen atom, or R ¹ and R ³ are , 1 they are bonded to together with the nitrogen atom a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is independently selected from substituent group a ₁ Substituted with one or more substituents.
R ² is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is substituted with a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). .)
R ⁴ represents a hydrogen atom,
J ¹ means an oxygen atom,
G ¹ means a single bond or an oxygen atom. )
The spiro compound according to any one of the above (2) to (12), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(14)
Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and a 5- to 10-membered heteroaryl group) Is a 4- to 7-membered oxygenated heterocycloalkane (the 4- to 7-membered oxygenated heterocycloalkane is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂₎ And the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or independently selected from substituent group A ₂ The C _1-6 alkyl group is substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group. Meaning R) ³ means a hydrogen atom,
R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ represents a hydrogen atom, or R ¹ and R ³ together with the nitrogen atom to which they are bonded are an azetidinyl group (the azetidinyl group is independently of the substituent group A ₁ Substituted with one or more selected substituents),
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of the above (2) to (12), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(15)
T is the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ each independently represents a C _6-10 aryl group or a 5-10 membered nitrogen-containing group) A heteroaryl group (a C _6-10 aryl group and a 5-10 membered nitrogen-containing heteroaryl group are unsubstituted or a fluorine atom, a C _1-3 alkyl group (the C _1-3 alkyl group includes one or more Or substituted with one or more substituents independently selected from the group consisting of a cyano group.)) And (2) above. The spiro compound according to any one of (1) to (14), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(16)
T is the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ are each independently a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are , Unsubstituted or independently selected from the group consisting of a fluorine atom, a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group The spiro compound according to any one of (2) to (15) above, which is substituted by one or more substituents, and a tautomer of the compound, Or a pharmaceutically acceptable salt thereof.

(17)
T is the formula (VI-1) or (VI-2)

(In the formula, L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group (the phenyl group represents one or two Or a C _1-3 alkyl group (the C _1-3 alkyl group is substituted with one or more fluorine atoms) or a cyano group). The spiro compound according to any one of (2) to (16) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(18)
T is the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ each independently represents a phenyl group (the phenyl group represents one or more fluorine atoms) Substituted by an atom, and the phenyl group is substituted by either a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms) or a cyano group The spiro compound according to any one of the above (2) to (16), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(19)
Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a phenyl group, 5-10 A member heteroaryl group (the phenyl group and the 5-10 membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or one or more Substituted with one or more substituents independently selected from the group consisting of halogen atoms and cyano groups), —C (═O) OR ¹³ , —C ( ═O) substituted with one or more substituents independently selected from the group consisting of R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , a halogen atom and a cyano group.
R ¹² represents a hydrogen atom,
R ¹³ represents a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a C _6-10 aryl group, or 5 to 10 members. A heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or Substituted with one or more substituents independently selected from the group consisting of a halogen atom, a cyano group, and —OR ¹⁴ ),
R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of (2) to (13) or (15) to (18), a tautomer of the compound, or a pharmaceutically acceptable salt thereof .

(20)
Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group, a pyridyl group, a furyl group or an isoxazolyl group (the phenyl group, the pyridyl group, the furyl group and the isoxazolyl group are 4 to 7-membered). It may be condensed with an oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group, furyl group and isoxazolyl group may be unsubstituted, halogen atom, cyano group, C _1-3 alkyl group (the C _{1-3 1-3} alkyl groups are substituted by one or more fluorine atoms.) And one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl). And R ³ is a hydrogen atom, or R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group). , Pyridyl group or furyl group (the phenyl group, pyridyl group and furyl group may be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group and furyl group are unsubstituted. Or one or more independently selected from the group consisting of a halogen atom, a cyano group and a C _1-3 alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms) And the C _1-3 alkyl group is one or more independently selected from the group consisting of a hydroxyl group, a halogen atom, and a cyano group. Substituted with a substituent group), R ³ represents a hydrogen atom,
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of (2) to (12) or (14) to (18), a tautomer of the compound, or a pharmaceutically acceptable salt thereof .

(21)
Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are piperidyl, piperazinyl, homopiperidyl or homopiperazinyl (the piperidyl, piperazinyl, homopiperidyl and homopiperazinyl groups are -C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , substituted by one or more substituents independently selected from the group consisting of a halogen atom and a cyano group Means)
R ¹² represents a hydrogen atom,
R ¹³ is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a phenyl group or a pyridyl group (the phenyl group and pyridyl group). The group may be unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom, a cyano group, and Substituted with one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl).
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to (19) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(22)
Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are piperidyl, piperazinyl, homopiperidyl or homopiperazinyl (the piperidyl, piperazinyl, homopiperidyl and homopiperazinyl groups are phenyl groups , Pyridyl group, oxadiazolyl group, benzimidazolyl group, benzisoxazolyl group or quinolyl group (the phenyl group, pyridyl group, oxadiazolyl group, benzimidazolyl group, benzisoxazolyl group and quinolyl group are unsubstituted) Or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), independently selected from the group consisting of a halogen atom and a cyano group Substituted with one or more substituents). Taste,
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to (19) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(23)
Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are azetidinyl groups (the azetidinyl group is unsubstituted or —C (═O) OR ¹³ , —C (═O) Substituted with one or more substituents independently selected from the group consisting of R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , a halogen atom and a cyano group.
R ¹² represents a hydrogen atom,
R ¹³ represents a C _1-6 alkyl group, a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted). Or substituted with one or more substituents independently selected from the group consisting of a halogen atom, a cyano group, and —O (C _1-3 alkyl). Means either)
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to any one of (2) to (12) and (14), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(24)
L ¹ is a C _1-3 alkylene group,
L ² is a single bond,
E is an oxygen atom,
m is an integer of 1 or 2,
R ⁶ is a hydrogen atom,
n is 0,
T is the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ have the same meaning as defined in (1) above). The spiro compound according to (1) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(25)
Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ is either a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are substituted with a C _4-6 alkyl group)). Or R ³ represents a hydrogen atom, or
R ¹ represents a piperidyl group (the piperidyl group is substituted by a C _4-6 alkyl group), R ³ represents a hydrogen atom, or R ¹ and R ³ are bonded to each other. A piperidyl group together with the nitrogen atom in which the piperidyl group is independently selected from the group consisting of —C (═O) R ¹³ , —OR ¹³ and —NR ¹² R ¹³ Substituted by a group)
R ¹² represents a hydrogen atom,
R ¹³ represents either a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or substituted by a C _4-6 alkyl group);
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. )
The spiro compound according to (1) or (24), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(26)
Z ¹ is
Formula (II-1) or (II-4)

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)) Or R ³ represents a hydrogen atom,
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and a 5- to 10-membered heteroaryl group) May be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a halogen atom, a cyano group, C _1-3 alkyl groups (the C _1-3 alkyl groups are unsubstituted or substituted by one or more fluorine atoms), —O (C _1-3 alkyl) and C _4-6 alkyl groups And the C _1-6 alkyl group is substituted with a hydroxyl group, a halogen atom or a cyano group, and is substituted with one or more substituents independently selected from the group consisting of Chosen independently from the group May be substituted with one or more substituents.) Means, or R ³ means a hydrogen atom,
R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ represents a hydrogen atom, or R ¹ and R ³ together with the nitrogen atom to which they are bonded are an azetidinyl group or a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the azetidinyl group). And a 5- to 7-membered nitrogen-containing heterocycloalkyl group is a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and the 5-10-membered heteroaryl group are unsubstituted or a C _1-3 alkyl group) (The C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups Replaced One or more independently selected from the group consisting of —C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , a halogen atom and a cyano group. Substituted with a substituent of
R ¹² represents a hydrogen atom,
R ¹³ is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a phenyl group or a pyridyl group (the phenyl group and pyridyl group). The group may be unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom, a cyano group, and Substituted with one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl).
R ⁴ represents a hydrogen atom,
J ¹ is, means an oxygen atom. The spiro compound according to (1) or (24), a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(27)
T is the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ are each independently a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are , Unsubstituted or independently selected from the group consisting of a fluorine atom, a C _1-3 alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group The spiro compound according to any one of (1), (24) to (26) above, which is substituted by one or more substituents) Mutant, or a pharmaceutically acceptable salt thereof.

(28)
T is the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group (the phenyl group is a C _4-6 alkyl group) The spiro compound according to any one of (1), (24) to (26), a tautomer of the compound, or Its pharmaceutically acceptable salt.

(29)
The spiro compound according to any one of (2) to (23), wherein R ⁶ is a hydrogen atom, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(30)
The spiro compound according to any one of (1) to (3), (7), (9) to (29), wherein X is cyclohexylene, a tautomer of the compound, or a pharmaceutically acceptable salt thereof An acceptable salt.

(31)
Any one of the above (1) or (2), (4) to (6), and (8) to (29), wherein X is a phenylene group, pyridinediyl group, pyrazinediyl group, thiophenediyl group, or thiazolediyl group Or a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

(32)
An adiponectin receptor activator comprising the spiro compound according to any one of (1) to (31) above, a tautomer of the compound, or a pharmaceutically acceptable salt thereof as an active ingredient.

(33)
A prophylactic / therapeutic / ameliorating agent for a disease having an effective adiponectin receptor activating action, comprising the adiponectin receptor activating drug according to (32) as an active ingredient.

(34)
A preventive or therapeutic agent for metabolic syndrome and arteriosclerosis comprising the adiponectin receptor activator according to (32) above as an active ingredient.

(35)
The pharmaceutical which contains the spiro compound of any one of said (1) thru | or (31), the tautomer of this compound, or its pharmaceutically acceptable salt as an active ingredient.

Hereinafter, the present invention will be described in more detail.
In this specification, “n-” is normal, “s-” and “sec-” are secondary, “t-” and “tert-” are tertiary, “o-” is ortho, “m-” Means meta, “p-” means para, “rac-” means racemate, “Ph” means phenyl, “Py” means pyridyl, “Me” means methyl, “Et” means ethyl, “Pr” means propyl , “Bu” means butyl, “Boc” means tert-butoxycarbonyl, “Ms” means methanesulfonyl, “Ts” means p-toluenesulfonyl, and “Tf” means trifluoromethanesulfonyl.

“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, “4 to 11-membered heterocycloalkane” means
1) 4 to 11 atoms constituting the ring,
2) The atoms constituting the ring contain at least one heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom,
3) the ring is saturated or partially unsaturated,
4) The ring may contain 1 to 3 carbonyl groups or thiocarbonyl groups,
5) When a sulfur atom is contained in the atoms constituting the ring, the sulfur atom may be a sulfinyl group or a sulfone group. 6) An aromatic heterocyclic ring is meant. Specific examples of this “4 to 11-membered heterocycloalkane” include, for example:

Etc.

“The 4-11 membered heterocycloalkyl group” means a monovalent substituent obtained by removing one hydrogen atom from the “4-11 membered heterocycloalkane”.

“4- to 11-membered oxygen-containing heterocycloalkyl group” refers to the above-mentioned definition of “4- to 11-membered heterocycloalkyl group” in which the hetero atom contained in the atoms constituting the ring is one kind of oxygen atom. Means.
Specific examples of the group include, for example,

Etc.

“The 4 to 7-membered oxygen-containing heterocycloalkyl group” means the above-mentioned definition “4 to 11-membered oxygen-containing heterocycloalkyl group” having 4 to 7 atoms constituting the ring.

“4- to 11-membered nitrogen-containing heterocycloalkyl group” is defined as “4- to 11-membered heterocycloalkyl group” in which a hetero atom contained in a ring atom is one kind of nitrogen atom Means.
Specific examples of the group include, for example,

Etc.

“The 5- to 7-membered nitrogen-containing heterocycloalkyl group” means the above-mentioned definition “the 4- to 11-membered nitrogen-containing heterocycloalkyl group” having 5 to 7 atoms constituting the ring.

The “4 to 11-membered oxygen-containing nitrogen-containing heterocycloalkyl group” means that the hetero atoms contained in the atoms constituting the ring in the above-mentioned definition “4 to 11-membered heterocycloalkyl group” are oxygen atoms and nitrogen atoms. Means two types.
Specific examples of the group include, for example,

Etc.

The “4- to 11-membered sulfur-containing nitrogen-containing heterocycloalkyl group” means that the hetero atom contained in the atoms constituting the ring in the above-mentioned definition “the 4- to 11-membered heterocycloalkyl group” is a sulfur atom and a nitrogen atom. Means two types. The “4- to 11-membered sulfur-containing nitrogen-containing heterocycloalkyl group” also includes a monooxide and a dioxide of a sulfur atom.
Specific examples of the group include, for example,

Etc.

"5-10 membered heteroaryl"
1) There are 5 to 10 atoms constituting the ring,
2) The atoms constituting the ring contain at least one heteroatom selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom,
3) A monocyclic or bicyclic aromatic heterocycle.
Specific examples of this “5- to 10-membered heteroaryl” include, for example, pyrrole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, tetrazole, benzotriazole, pyrazole, imidazole, benzimidazole, indole, isoindole, and India. Lysine, purine, indazole, quinoline, isoquinoline, quinolidine, phthalazine, quinoxaline, quinazoline, cinnoline, pteridine, imidazo [1,5-a] [1,3,5] triazine, pyrazino [2,3-d] pyridazine, imidazo [4,5-b] pyridine, imidazo [1,2-a] pyrimidine, pyrazolo [1,5-a] pyrimidine, furan, pyran, benzofuran, isobenzofuran, thiophene, benzothiophene, thiazole, isothiazole, benzothiazole , Benzothiadiazole, isoxazole Oxazole, benzoxazole, oxadiazole, pyrazolo [3,4-d] oxazole, imidazo [4,5-d] thiazole, thieno [3,2-b] furan, thieno [2,3-c] pyrazole, [ 1,4] dioxino [2,3-b] pyridine and the like.
Further, when the “5- to 10-membered heteroaryl” has a C═N double bond, the N-oxide form thereof is also included.

“5- to 10-membered heteroaryl group”
A monovalent substituent obtained by removing one hydrogen atom from the above-mentioned definition “5- to 10-membered heteroaryl”.

“C _6-10 aryl” means
1) There are 6 to 10 atoms constituting the ring,
2) It means a monocyclic or bicyclic aromatic hydrocarbon ring in which all atoms constituting the ring are carbon atoms.
Specific examples of “C _6-10 aryl” include benzene, pentalene, naphthalene, azulene and the like.

The “C _6-10 aryl group” means a monovalent substituent obtained by removing one hydrogen atom from the above-defined “C _6-10 aryl”.

In the present specification, the “C _1-3 alkyl group” means a methyl group, an ethyl group, a propyl group or an isopropyl group.

“C _1-6 alkyl group” means
A monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 1 to 6 carbon atoms.
Specific examples of the group include, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, neopentyl group, t-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1, Examples include 1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, and the like.

“C _1-9 alkyl group” means
A monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 1 to 9 carbon atoms.

“C _1-5 alkyl group” means
A monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 1 to 5 carbon atoms.
“C _4-6 alkyl group” means
A monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 4 to 6 carbon atoms.

“C _6-9 alkyl group” means
A monovalent substituent obtained by removing one hydrogen atom from a linear or branched saturated hydrocarbon having 6 to 9 carbon atoms.

“C _3-6 cycloalkane” means
1) 3-6 atoms constituting the ring,
2) An aromatic hydrocarbon ring of “monocyclic system” or “bridged ring system” in which all atoms constituting the ring are carbon atoms.
Specific examples of the “C _3-6 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.

“C _3-11 cycloalkane” means
1) 3 to 11 atoms constituting the ring,
2) The atoms constituting the ring are all carbon atoms. 3) “Monocyclic system”, “fused ring system”, “bridged ring system” or “spiro ring system” aliphatic hydrocarbon ring.
Specific examples of this “C _3-11 cycloalkane” include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, adamantane, bicyclo [3.1.0] octane, bicyclo [2.2. 1] heptane, spiro [5.5] undecane, etc.

The “C _3-11 cycloalkyl group” means a monovalent substituent obtained by removing one hydrogen atom from the above-mentioned definition “C _3-11 cycloalkane”.

The “C _3-4 cycloalkyl group” means the above-defined “C _3-11 cycloalkyl group” having 3 to 4 atoms constituting the ring.

The “C _2-3 alkenyl group” refers to an ethenyl group, a prop-1-en-1-yl group, a prop-2-en-1-yl group, or a prop-1-en-2-yl group.

“C _2-6 alkenyl group” means
1) 2 to 6 carbon atoms,
2) A monovalent substituent obtained by removing one hydrogen atom from a linear or branched unsaturated hydrocarbon having one or more double bonds.
Specific examples of the group include, for example, ethenyl group, prop-1-en-1-yl group, prop-2-en-1-yl group, prop-1-en-2-yl group, butane -1-en-1-yl group, but-2-en-1-yl group, but-3-en-1-yl group, penta-1-en-1-yl group, penta-4-en-1 -Yl group, hexa-1-en-1-yl group, hexa-5-en-1-yl group, 4-methylpent-3-en-1-yl group penta-2,4-dien-1-yl group Etc.

“C _3-11 cycloalkene” means
1) 3 to 11 atoms constituting the ring,
2) The atoms constituting the ring are all carbon atoms,
3) means a “monocyclic”, “fused ring”, “bridged ring” or “spiro ring” aliphatic hydrocarbon ring having one or more double bonds.
Specific examples of this “C _3-11 cycloalkene” include, for example, cyclopropene, cyclobutene, cyclopentene, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptene, cyclooctene, 1 , 4-cyclooctadiene, 1,2,3,3a, 4,6a-hexahydropentalene, (1R, 4S) -bicyclo [2.2.1] hept-2-ene, spiro [5.5] undec-2- En.

The “C _3-11 cycloalkenyl group” means a monovalent substituent obtained by removing one hydrogen atom from the above definition “C _3-11 cycloalkene”.

The “C _2-3 alkynyl group” means an ethynyl group, a prop-1-in-1-yl group, or a prop-2-in-1-yl group.

The “C _1-3 alkylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the definition “C _1-3 alkyl group”.
Specific examples of the group include methylene group, ethylene group, propane-1,3-diyl group, propane-2,2-diyl group and the like.

The “C _1-6 alkylene group” means a divalent substituent in which one hydrogen atom at any position is removed from the above-defined “C _1-6 alkyl group”.
Specific examples of the group include methylene group, ethylene group, propane-1,3-diyl group, propane-2,2-diyl group, 2,2-dimethyl-propane-1,3-diyl group, Hexane-1,6-diyl group, 3-methylbutane-1,2-diyl group and the like can be mentioned.

The “C _3-11 cycloalkylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the above-defined “C _3-11 cycloalkyl group”.
Specific examples of the group include cyclopropane-1,1-diyl group, cyclopropane-1,2-diyl group, cyclopentane-1,3-diyl group, cyclohexane-1,4-diyl group, Cyclohexane-1,1-diyl group, bicyclo [2.2.1] heptane-2,5-diyl group, bicyclo [3.3.0] octane-2,5-diyl group, spiro [5.5] undecane-3,9-diyl Groups and the like.

The “C _3-11 cycloalkenylene group” means a divalent substituent obtained by further removing one hydrogen atom at any position from the above-defined “C _3-11 cycloalkenyl group”.

The “C _6-10 arylene group” means a divalent substituent in which one hydrogen atom at an arbitrary position is removed from the above-defined “C _6-10 aryl group”.
Specific examples of the group include a phenylene group and a naphthalene-2,6-diyl group.

The “5- to 10-membered heteroarylene group” means a divalent substituent obtained by further removing one hydrogen atom at any position from the above-defined “5- to 10-membered heteroaryl group”.
Specific examples of the group include a pyridine-2,5-diyl group, a pyrimidine-2,4-diyl group, and a pyridazine-3,6-diyl group.

The “C _2-3 alkenylene group” means a divalent substituent obtained by further removing one hydrogen atom at an arbitrary position from the definition “C _2-3 alkenyl group”.

The “C _2-3 alkynylene group” means a divalent substituent obtained by removing one hydrogen atom at any position from the above-defined “C _2-3 alkynyl group”.

Next, preferred structures of each substituent in the present invention are listed.

E is preferably an oxygen atom.

L ¹ is preferably a C _1-3 alkylene group, a C _2-3 alkenylene group or a C _2-3 alkynylene group (the C _1-3 alkylene group, C _2-3 alkenylene group and C _2-3 alkynylene group are It is unsubstituted or substituted by a cyclopropyl group.), More preferably a C _1-3 alkylene group, and still more preferably a methylene group.

L ² is preferably a single bond or a C _1-3 alkylene group, more preferably a single bond or a methylene group, and still more preferably a single bond.

Preferable examples of X include a C _3-11 cycloalkylene group, more preferably a cyclohexanediyl group, and still more preferably a cyclohexane-1,4-diyl group.
Other preferable examples of X include a C _6-10 arylene group (the C _6-10 arylene group is unsubstituted or substituted with a methoxy group) or a 5- to 10-membered heteroarylene group. More preferably, it is a phenylene group, a thiophenediyl group or a pyridinediyl group, and more preferably a phenylene group.

R ⁴ is preferably a hydrogen atom.

R ⁶ is preferably each independently a hydrogen atom or a C _1-3 alkyl group, more preferably a hydrogen atom or a methyl group, and still more preferably a hydrogen atom.

R ⁷ is preferably each independently a methyl group.

As preferred examples of T, formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ represents a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or C 1 independently selected from the group consisting of a _1-6 alkyl group, a fluorine atom, a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group. R ¹⁰ is a phenyl group, a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or a C _1-6 alkyl group, a fluorine atom, a C atom). _1-3 alkyl group (the C _1-3 alkyl group is substituted with one or more fluorine atoms) and one or more substituents independently selected from the group consisting of cyano groups .) or _{C 6-10} It means a C _3-11 cycloalkyl group which is fused with the reel.) Is either.

Preferred examples of Z ¹ include those of formula (III-1), (III-2) or (III-3)

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 11-membered heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). ), R ³ represents a hydrogen atom, and G ¹ represents a single bond or an oxygen atom. ) More preferably, the formula (III-1), (III-2) or (III-3)

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)) .), R ³ represents a hydrogen atom, and G ¹ represents a single bond or an oxygen atom. )

Other preferred examples of Z ¹ include compounds of the formula (III-1), (III-2) or (III-3)

(Wherein R ¹ and R ³ are
R ¹ is a 4- to 11-membered heterocycloalkyl group (the 4- to 11-membered heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is unsubstituted) Or independently selected from the group consisting of —C (═O) OCH ₃ , a cyano group, a nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , a chlorine atom, —CF ₃ and —CH _3. substituted with are substituted.) by one or more substituents.) is substituted with.) means, R ³ is a hydrogen atom, means G ¹ is a single bond or an oxygen atom To do. ) More preferably, the formula (III-1), (III-2) or (III-3)

(Wherein R ¹ and R ³ are
R ¹ is a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Unsubstituted or independently from the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH ₃ Substituted with one or more selected substituents)), substituted with), R ³ represents a hydrogen atom, and G ¹ represents a single bond or an oxygen atom. Means. ) More specific examples of the 5- to 7-membered nitrogen-containing heterocycloalkyl group include a piperidyl group, a piperazinyl group, a homopiperidyl group, and a homopiperazinyl group.

Other preferred examples of Z ¹ include compounds of the formula (III-1) or (III-2)

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are 4- to 11-membered heterocycloalkyl groups (the 4- to 11-membered heterocycloalkyl group is a C _1-6 alkyl group, phenyl A 5- to 10-membered heteroaryl group (the phenyl group and 5- to 10-membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted); Or substituted with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group.), —C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , substituted with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group. R ¹² represents a hydrogen atom Means that R ¹³ is a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or C _1-3 alkyl) One or more substituents independently selected from the group consisting of a group (the C _1-3 alkyl group is substituted by one or more fluorine atoms), a C _1-6 alkyl group, a halogen atom and a cyano group; Substituted by a group). ) More preferably, the formula (III-1) or (III-2)

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are an azetidinyl group, a 5- to 7-membered nitrogen-containing heterocycloalkyl group, or a 4- to 11-membered oxygen-containing nitrogen-containing heterocycloalkyl group (the azetidinyl A 5- to 7-membered nitrogen-containing heterocycloalkyl group and a 4- to 11-membered oxygen-containing nitrogen-containing heterocycloalkyl group include a C _1-6 alkyl group, a phenyl group, and a 5-10-membered heteroaryl group (the phenyl group and A 5-10 membered heteroaryl group is unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms). Substituted with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group.), —C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , -NR ¹² R ¹³ is substituted with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group.), R ¹² is a hydrogen atom, and R ¹³ is C _{6. A -10} aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group Is substituted by one or more fluorine atoms), and is substituted by one or more substituents independently selected from the group consisting of C _1-6 alkyl groups, halogen atoms and cyano groups. It means either. ) More preferably, the formula (III-1) or (III-2)

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are an azetidinyl group or a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the azetidinyl group and a 5- to 7-membered nitrogen-containing heterocycloalkyl group are A C _1-6 alkyl group, a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and the 5-10-membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 The alkyl group is unsubstituted or substituted by one or more fluorine atoms), and is substituted by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups. , —C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , one or more substituents independently selected from the group consisting of a halogen atom and a cyano group Replace Is.) ^{Means, R 12} is, represents a hydrogen ^{atom, R 13} _{is C 1-3} alkyl group (the _{C 1-3} alkyl group is either unsubstituted or one or more fluorine atoms A C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or substituted by C _1-3 One or more selected from the group consisting of an alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms), a C _1-6 alkyl group, a halogen atom and a cyano group; It is substituted by a substituent. ) Specific examples of particularly preferred 5- to 7-membered nitrogen-containing heterocycloalkyl groups include piperidyl group, piperazinyl group, homopiperidyl group and homopiperazinyl group.

Other preferred examples of Z ¹ include compounds of the formula (III-1) or (III-2)

(Wherein R ¹ and R ³ are
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and a 5- to 10-membered heteroaryl group) May be condensed with a _4- to 7-membered oxygen-containing heterocycloalkane, and the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a C _4-6 alkyl group, A halogen atom, a cyano group, a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms) and —O (C _1-3 alkyl) Substituted with one or more substituents independently selected from the group consisting of: and the C _1-6 alkyl group is independent of the group consisting of a hydroxyl group, a halogen atom and a cyano group. One or more selected May be substituted with a substituent.) Means, R ³ means a hydrogen atom. ) More preferably, the formula (III-1) or (III-2)

(Wherein R ¹ and R ³ are
R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group, a pyridyl group, a furyl group, or an isoxazolyl group (the phenyl group, the pyridyl group, the furyl group, and the isoxazolyl group are 4 to 7 members) It may be condensed with an oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group, furyl group and isoxazolyl group are unsubstituted or a C _4-6 alkyl group, a halogen atom, a cyano group, C _1- Independently selected from the group consisting of ₃ alkyl groups (wherein the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms) and —O (C _1-3 alkyl) which is substituted by one or more substituents. is substituted by any of the), and the C _1-3 alkyl group, Germany from the group consisting hydroxyl, a halogen atom, and a cyano group To one or more substituents selected may be substituted.) Means, R ³ means a hydrogen atom. )

Other preferred examples of Z ¹ include compounds of the formula (III-1) or (III-2)

(Wherein R ¹ and R ³ are
R ¹ represents a 4-11 membered heterocycloalkyl group (the 4-11 membered heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)); R ³ represents a hydrogen atom. ) More preferably, the formula (III-1) or (III-2)

(Wherein R ¹ and R ³ are
R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ means a hydrogen atom. ) More specific examples of the 4-11 membered nitrogen-containing heterocycloalkyl group include azetidinyl group, pyrrolidinyl group, piperidyl group, piperazinyl group, homopiperidyl group and homopiperazinyl group.

Examples of preferred compounds of the spiro compound of the present invention include the structures shown below.
(1) Formula (I)

[In the formula (I),
E means an oxygen atom,
L ¹ means a C _1-3 alkylene group, a C _2-3 alkenylene group or a C _2-3 alkynylene group,
L ² represents a single bond or a C _1-3 alkylene group,
X represents a C _3-11 cycloalkylene group, a C _6-10 arylene group (the C _6-10 arylene group is unsubstituted or substituted with a methoxy group) or a 5- to 10-membered heteroarylene group. Means
Z ¹ is
Formula (III-1), (III-2) or (III-3)

(Wherein R ¹ and R ³ are
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a _4- to 7-membered oxygen-containing heterocycloalkyl group, a C _6-10 aryl group, a 5- to 10-membered heteroaryl group (the C _{6- The 10} aryl group and the 5- to 10-membered heteroaryl group may be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted. Or a C _4-6 alkyl group, a halogen atom, a cyano group, a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms). ) And —O (C _1-3 alkyl) is substituted by one or more substituents independently selected from the group consisting of :) or —NHC (═O) O (C _1-6 alkyl) It is substituted with one, and the C _1- Alkyl group means a hydroxyl group, with one or more substituents independently selected from the group consisting of a halogen atom and a cyano group may be substituted.), R ³ means a hydrogen atom or,
R ¹ is a 4- to 11-membered nitrogen-containing heterocycloalkyl group (the 4- to 11-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Unsubstituted or independently from the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH ₃ Substituted with one or more selected substituents) or substituted with either a cyano group) or substituted with either —C (═O) O (C _1-6 alkyl). R ³ represents a hydrogen atom, or
R ¹ and R ³ together with the nitrogen atom to which they are attached are a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogenated heterocycloalkyl group is a C _1-6 alkyl group). A phenyl group, a 5-10 membered heteroaryl group (the phenyl group and the 5-10 membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted) Or substituted with one or more substituents independently selected from the group consisting of halogen atoms and cyano groups), —C (═O And substituted with one or more substituents independently selected from the group consisting of OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , a halogen atom and a cyano group. And R ¹² is Represents a hydrogen atom, and R ¹³ represents a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or C _1-3 alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms), a C _1-6 alkyl group, a halogen atom and a cyano group independently selected from the group Substituted with one or more substituents)
G ¹ means a single bond or an oxygen atom. )
m means 1;
R ⁶ represents a hydrogen atom,
n means 0,
T represents the formula (VI-1) or (VI-2)

(Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ represents a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or C 1 independently selected from the group consisting of a _1-6 alkyl group, a fluorine atom, a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group. R ¹⁰ is a phenyl group, a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or a C _1-6 alkyl group, a fluorine atom, a C atom). _1-3 alkyl group (the C _1-3 alkyl group is substituted with one or more fluorine atoms) and one or more substituents independently selected from the group consisting of cyano groups .) or _{C 6-10} Means a C _3-11 cycloalkyl group which is fused with the reel.) Means. ]
A spiro compound represented by:
(2) The spiro compound according to (1), wherein L ¹ is a C _1-3 alkylene group.
(3) The spiro compound according to (1), wherein L ¹ is a methylene group.
(4) The spiro compound according to any one of (1) to (3), wherein L ² is a single bond or a methylene group.
(5) The spiro compound according to any one of (1) to (3), wherein L ² is a single bond.
(6) The spiro compound according to any one of (1) to (5), wherein X is a cyclohexanediyl group.
(7) The spiro compound according to any one of (1) to (5), wherein X is a cyclohexane-1,4-diyl group.
(8) The spiro compound according to any one of (1) to (5), wherein X is a pyridinediyl group.
(9) The spiro compound according to any one of (1) to (5), wherein X is a thiophenediyl group.
(10) The spiro compound according to any one of (1) to (5), wherein X is a phenylene group.
(11) The spiro compound according to any one of (1) to (10), wherein R ⁶ is a hydrogen atom or a methyl group.
(12) The spiro compound according to any one of (1) to (10), wherein R ⁶ is a hydrogen atom.
(13) The spiro compound according to any one of (1) to (12), wherein T is any one of the structures shown below.

(14) Z ¹ is represented by the formula (III-1), (III-2) or (III-3)

(Wherein R ¹ and R ³ are
R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)) .), R ³ represents a hydrogen atom, and G ¹ represents a single bond or an oxygen atom. The spiro compound according to any one of (1) to (13), wherein
(15) The spiro compound according to (14), wherein Z ¹ is any of the structures shown below.

(16) Z ¹ is represented by the formula (III-1), (III-2) or (III-3)

(Wherein R ¹ and R ³ are
R ¹ is a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Unsubstituted or independently from the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH ₃ Substituted with one or more selected substituents)), substituted with), R ³ represents a hydrogen atom, and G ¹ represents a single bond or an oxygen atom. Means. The spiro compound according to any one of (1) to (13), wherein
(17) The spiro compound according to the above (16), wherein the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a piperidyl group, piperazinyl group, homopiperidyl group or homopiperazinyl group.
(18) The spiro compound according to (16), wherein Z ¹ is any of the structures shown below.

(19) Z ¹ is represented by formula (III-1) or (III-2)

(Wherein R ¹ and R ³ are
R ¹ and R ³ together with the nitrogen atom to which they are attached are an azetidinyl group or a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the azetidinyl group and a 5- to 7-membered nitrogen-containing heterocycloalkyl group are A C _1-6 alkyl group, a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and the 5-10-membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 The alkyl group is unsubstituted or substituted by one or more fluorine atoms), and is substituted by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups. , —C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , one or more substituents independently selected from the group consisting of a halogen atom and a cyano group Replace Is.) ^{Means, R 12} is, represents a hydrogen ^{atom, R 13} _{is C 1-3} alkyl group (the _{C 1-3} alkyl group is either unsubstituted or one or more fluorine atoms A C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or substituted by C _1-3 One or more selected from the group consisting of an alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms), a C _1-6 alkyl group, a halogen atom and a cyano group; It is substituted by a substituent. The spiro compound according to any one of (1) to (13), which is any one of
(20) The spiro compound according to the above (19), wherein the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a pyrrolidinyl group, piperidyl group, piperazinyl group, homopiperidyl group or homopiperazinyl group.
(21) The spiro compound according to (19), wherein Z ¹ is any one of the structures shown below.

(22) Z ¹ is represented by formula (III-1) or (III-2)

(Wherein R ¹ and R ³ are
R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and a 5- to 10-membered heteroaryl group) May be condensed with a _4- to 7-membered oxygen-containing heterocycloalkane, and the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a C _4-6 alkyl group, A halogen atom, a cyano group, a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms) and —O (C _1-3 alkyl) Substituted with one or more substituents independently selected from the group consisting of: and the C _1-6 alkyl group is independent of the group consisting of a hydroxyl group, a halogen atom and a cyano group. One or more selected May be substituted with a substituent.) Means, R ³ means a hydrogen atom. The spiro compound according to any one of (1) to (13), wherein
(23) R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group, a pyridyl group, a furyl group, or an isoxazolyl group (the phenyl group, pyridyl group, furyl group, and isoxazolyl group are 4 May be condensed with a ˜7-membered oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group, furyl group and isoxazolyl group are unsubstituted or a C _4-6 alkyl group, a halogen atom, a cyano group, Independently of the group consisting of C _1-3 alkyl group (wherein the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms) and —O (C _1-3 alkyl). is substituted by one or more substituents selected Te. which is substituted by one of), and the C _1-3 alkyl group, comprising a hydroxyl group, a halogen atom, and a cyano group May be substituted with one or more substituents selected more independently.) Is the (22) spiro compound as claimed.
(24) The spiro compound according to (22), wherein Z ¹ is any one of the structures shown below.

(25) Z ¹ is represented by the formula (III-1) or (III-2)

(Wherein R ¹ and R ³ are
R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ means a hydrogen atom. The spiro compound according to any one of (1) to (13), wherein
(26) The spiro compound according to the above (25), wherein the 4-11 membered nitrogen-containing heterocycloalkyl group is an azetidinyl group, a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a homopiperidyl group or a homopiperazinyl group.
(27) The spiro compound according to (25), wherein Z ¹ is any one of the structures shown below.

In the present invention, the compound represented by the formula (I) of the present invention exists, for example, via the tautomerism and geometric isomerism, both inside and outside the ring, in addition to a mixture thereof, It also exists as a mixture of isomers. Further, when an asymmetric center is present, or when an asymmetric center is formed as a result of isomerization, it includes the presence of each optical isomer and a mixture in an arbitrary ratio. In addition, in the case of a compound having two or more asymmetric centers, diastereomers by respective optical isomerism also exist. The compounds of the present invention also include those containing all these types in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and optically active forms can be obtained by organic chemistry techniques well known for this purpose. it can.

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can exist as any crystal form depending on the production conditions, and can exist as any hydrate. Forms and hydrates and mixtures thereof are also included within the scope of the present invention. Moreover, although it may exist as a solvate containing organic solvents, such as acetone, ethanol, and tetrahydrofuran, all of these forms are contained in the scope of the present invention.

The compound represented by the formula (I) of the present invention can be converted into a pharmaceutically acceptable salt as needed, or can be liberated from the produced salt. Examples of the pharmaceutically acceptable salt of the present invention include salts with alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (magnesium, calcium, etc.), ammonium, organic bases and amino acids. It is done. In addition, inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) Other salts are also possible.

The prophylactic / therapeutic / ameliorating agent for “disease with an effective adiponectin receptor activation effect” containing the “adiponectin receptor activator” of the present invention as an active ingredient is usually a tablet, capsule, powder, granule, It can be administered as an oral preparation such as a pill or syrup, a rectal administration agent, a transdermal absorption agent or an injection. The agent can be administered as a single therapeutic agent or as a mixture with other therapeutic agents. They may be administered alone, but are generally administered in the form of a pharmaceutical composition. These preparations can be produced by a conventional method with addition of pharmacologically and pharmaceutically acceptable additives. That is, additives such as ordinary excipients, lubricants, binders, disintegrants, wetting agents, plasticizers, and coating agents can be used for oral preparations. Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or provided as dry syrups prepared with water or other suitable solvent prior to use. Good. The liquid preparation may contain conventional additives such as suspending agents, fragrances, diluents or emulsifiers. When administered rectally, it can be administered as a suppository. Suppositories are based on suitable substances such as cacao butter, lauric fat, macrogol, glycerogelatin, witepsol, sodium stearate or mixtures thereof, and emulsifiers, suspending agents, preservatives, etc. as necessary Can be added. Injections include aqueous or injectable distilled water, physiological saline, 5% glucose solution, propylene glycol and other solubilizers or solubilizers, pH adjusters, isotonic agents, Pharmaceutical ingredients such as stabilizers are used.

When the drug of the present invention is administered to humans, the dosage is determined depending on the age, condition, etc. of the patient. In general, in the case of adults, injection is about 0.1 to 1000 mg / human / day for oral administration or rectal administration. The dosage is about 0.05 mg to 500 mg / human / day. These numerical values are merely examples, and the dosage is determined according to the symptoms of the patient.

As a scene where the present invention is used, there is a scene where improvement of a disease state can be expected by using a compound having an adiponectin receptor activating action. Specifically, prevention and treatment of metabolic syndrome, particularly metabolic syndrome with obesity, diabetes, hypertension, etc., and arteriosclerosis; prevention and treatment of cardiovascular diseases such as myocardial infarction and myocardial hypertrophy; non-alcoholic fatty Prevention and treatment of liver diseases such as hepatitis and liver fibrosis; prevention and treatment of malignant tumors such as gastric cancer, rectal cancer, breast cancer and myeloblastic leukemia; other systemic lupus erythematosus due to anti-inflammatory action, renal failure, A scene of performing prevention / treatment of acute lung injury is assumed, but is not limited thereto.

The compound of the present invention can be synthesized by the method shown below, but the following production method is an example of a general production method and does not limit the production method.

The compound of the present invention can usually be purified by column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC), etc., and if necessary, it has a high purity by recrystallization or washing with a solvent. Can be obtained.

Examples of the base in the description of the general production method of the compound of the present invention include sodium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium t-butoxide, Alkali metal salts such as sodium t-butoxide, sodium amide, sodium hydride, lithium hydride, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, n-butyllithium, pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, And amines such as N-methylpiperidine and bis (trimethylsilyl) amine.
The solvent in the description of the general production method of the compound of the present invention is not particularly limited as long as it is stable under the reaction conditions and is inert and does not hinder the reaction. For example, a sulfoxide solvent represented by dimethyl sulfoxide; an amide solvent represented by N, N-dimethylformamide or N, N-dimethylacetamide; diethyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane or cyclopentyl methyl ether Ether solvents represented by: halogen solvents represented by dichloromethane, chloroform or 1,2-dichloroethane; nitrile solvents represented by acetonitrile or propionitrile; aromatic hydrocarbon systems represented by benzene or toluene Solvent; hydrocarbon solvent represented by n-hexane, n-heptane or cyclohexane; ester solvent represented by ethyl acetate or n-butyl acetate; methanol, ethanol, 1-propanol, Alcohol solvents represented by 2-propanol or ethylene glycol; or water. In addition, the reaction can be carried out under a condition in which the above solvents are arbitrarily mixed or in the absence of a solvent.

The reaction temperature in the general production method of the compound of the present invention can be selected from −78 ° C. within the range of the boiling point of the solvent used for the reaction. It can be carried out under irradiation or the like.

In the following general production method of the compound of the present invention, the general formulas of intermediates and final products in each step are shown, and these intermediates and final products also include their precursors. Here, a precursor means a compound that can be derived into a target product by performing deprotection, hydrolysis, reduction, oxidation, alkylation, etc., if necessary. Protected with various protecting groups. Protection and deprotection are generally known protection reactions / deprotection reactions [eg, Protective Groups in Organic Synthesis, Fourth Fourth Edition, TW Greene ), By John Wiley & Sons Inc. (2006), etc.].

Among the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-1) can be produced, for example, by the following method.

[Wherein P ¹ represents an amino-protecting group, P ² represents a carboxyl-protecting group, V ^1a , V ^1b and V ² each independently represent a leaving group, Same as definition. ]

(Step 1) This step is a so-called Corey-Chaykovsky reaction in which the compound (2) is produced by converting the carbonyl group of the compound (1) into an epoxide by reaction with sulfur ylide. . The compound (1) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
The reaction in this step is performed by reacting a sulfur ylide generated by reacting a base with a sulfonium ion such as trimethylsulfonium iodide or a sulfoxonium ion such as trimethylsulfoxonium iodide and the compound (1). Can be done. The amount of trimethylsulfonium iodide, trimethylsulfoxonium iodide, etc. used in this step is usually 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1).
Examples of the base used in this step include sodium hydroxide, potassium hydroxide, sodium hydride, lithium hexamethyldisilazide and the like, preferably sodium hydroxide. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (1).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, acetonitrile, methanol, ethanol, tert-butanol, water, dimethyl sulfoxide, N, N-dimethylformamide, and the like. Methanol, acetonitrile, water.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 120 hours.

(Step 2) This step is a method for producing an amino alcohol compound (4) by reacting the epoxide moiety of the compound (2) obtained in the step 1 with the amino group of the compound (3). The compound (3) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, methanol, ethanol, water, and the like, preferably methanol and water.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 120 hours.

(Step 3) In this step, compound (6) is produced by reacting compound (4) obtained in step 2 above with the carbonylating agent or thiocarbonylating agent represented by compound (5). It is a method to do. Examples of the compound (5) used include 1,1′-carbonyldiimidazole, p-nitrophenyl chloroformate, 1,1′-thiocarbonyldiimidazole, triphosgene, thiophosgene, and preferably 1,1′-carbonyl. Carbonyldiimidazole, p-nitrophenyl chloroformate, 1,1'-thiocarbonyldiimidazole. The amount of the compound (5) is usually 1 to 20 equivalents, preferably 1 to 6 equivalents, relative to 1 equivalent of the compound (4).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform and the like, and preferably 1,4-dioxane and chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 120 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 72 hours.

(Step 4) This step is a method for producing the compound (7) by hydrolyzing the ester group of the compound (6) obtained in the step 3 with a base.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (6).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 5) In this step, compound (9) is produced by reacting the carboxyl group of compound (7) obtained in step 4 with the amine moiety of compound (8) to produce an amide bond. Is the method. The compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (7) or a reactive derivative thereof. Examples of the reactive derivative of the compound (7) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds).・ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (7) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark). The amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (7).
In addition, the amount of compound (8) to be used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (7).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

(Step 6) This step is a method for producing the compound (10) by removing the amino-protecting group of the compound (9) obtained in the step 5. The reaction in this step is a reaction for removing the protecting group of the amino group, and is a method described in the literature [for example, Protective Groups In Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.], a method according to it, or a combination of these and ordinary methods Can do.

(Step 7) This step is a method for producing compound (I-1) or a precursor thereof by reacting compound (10) obtained in step 6 with compound (11) in the presence of a base. is there. The compound (11) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.
Examples of the base used in this step include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
In the compound (11) used in this step, when the carbon atom to which V ² is bonded is substituted with 1 to 2 hydrogen atoms, V ² and one hydrogen atom are combined to form carbonyl Compound (I-1) can also be produced by reductive amination with a base aldehyde compound or ketone compound.
Examples of the reducing agent used in this step include sodium triacetoxyborohydride, zinc chloride-sodium cyanoborohydride complex, and the like, preferably sodium triacetoxyborohydride. The amount of the reducing agent is usually 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.

Of the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-2) can be produced, for example, by the following method.

[Wherein V ³ represents a leaving group, and other symbols are the same as defined above. ]

(Step 8) In this step, compound (I-2) or a precursor thereof is reacted with the amine moiety of compound (10) obtained in step 6 above and compound (12) or compound (13). It is a method of manufacturing. The compound (12) or compound (13) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

Of the compounds encompassed by the compound (I) according to the present invention, the compound represented by the formula (I-3) can be produced, for example, by the following method.

[Wherein, V ^4a represents a halogen atom or a halogen atom equivalent, and R ^10a represents a C _6-10 aryl group, a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and a 5- to 10-membered heteroaryl group Is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A _{2. The} other symbols are the same as defined above. ]

(Step 9) In this step, compound (I-3) or a precursor thereof is produced by reacting compound (10) obtained in step 6 with compound (14) in the presence of a transition metal catalyst. This is the so-called Buchwald-Hartwig reaction. The compound (14) used in this step can be obtained as a compound synthesized by using various organic synthesis techniques known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The reaction in this step is carried out according to a method described in the literature (for example, Angew. Chem. Int. Ed., 1998, 37, 2046-2067, Accounts of Chemical Research ( Acc. Chem. Res.), 1998, Vol. 31, pp. 805-818).
Examples of the transition metal catalyst combination used in this step include palladium acetate and tris (dibenzylideneacetone) palladium as the transition metal complex, and 2,2′-bis (diphenylphosphino) as the ligand. ) -1,1'-binaphthalene and the like. Examples of the base include cesium carbonate, potassium phosphate, sodium tert-butoxide and the like. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone and the like, preferably toluene, 1,4-dioxane.
The reaction temperature is usually 20 ° C. to the reflux temperature of the reaction solvent, preferably 50 to 180 ° C.
The reaction time is usually 0.1 to 48 hours, preferably 0.1 to 24 hours.

In this step, compound (I-3) can also be produced without using a transition metal catalyst. In this case, examples of the base used in this step include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.

Of the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-4) can be produced, for example, by the following method.

[Wherein, V ^4b represents a leaving group, R ^10b represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or independently selected from substituent group A ₄ ) Substituted with one or more substituents), a C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5- to 10-membered heteroaryl (the C _6-10 Aryl and 5- to 10-membered heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from substituent group A ₂ ) and A C _3-11 cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ), or a C _1-3 alkyl group C _1-3 alkyl group is C _3-11 cycloalkyl A group (the C _3-11 cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ )). The other symbols are the same as defined above. ]

(Step 10) This step is a method for producing compound (I-4) or a precursor thereof by reacting compound (10) obtained in step 6 with compound (15) in the presence of a base. is there.
Examples of the base used in this step include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
In the compound (15) used in this step, when the carbon atom to which V ^4b is bonded is substituted with 1 to 2 hydrogen atoms, V ^4b and one hydrogen atom are combined to form carbonyl. Compound (I-4) can also be produced by reductive amination with a base aldehyde compound or ketone compound.
Examples of the reducing agent used in this step include sodium triacetoxyborohydride, zinc chloride-sodium cyanoborohydride complex, 2-picoline borane complex, and the like, preferably sodium triacetoxyborohydride. The amount of the reducing agent is usually 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (10).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.

The compound represented by the formula (I-1) can also be produced from the compound (6) by the following method.

[Wherein the symbols are as defined above. ]

(Step 11) This step is a method for producing the compound (16) by removing the amino-protecting group of the compound (6) obtained in the step 3. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.

(Step 12) This step is a method for producing the compound (17) by reacting the compound (16) obtained in the step 11 with the compound (11) in the presence of a base. The compound (11) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.
Examples of the base used in this step include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
In the compound (11) used in this step, when the carbon atom to which V ² is bonded is substituted with 1 to 2 hydrogen atoms, V ² and one hydrogen atom are combined to form carbonyl Compound (17) can also be produced by reductive amination with a base aldehyde compound or ketone compound.
Examples of the reducing agent used in this step include sodium triacetoxyborohydride, zinc chloride-sodium cyanoborohydride complex, 2-picoline borane complex, and the like, preferably sodium triacetoxyborohydride. The amount of the reducing agent is usually 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.

(Step 13) This step is a method for producing the compound (18) by hydrolyzing the ester group of the compound (17) obtained in the step 12 with a base.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (17).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 14) In this step, an amide bond is formed by reacting the carboxyl group of compound (18) obtained in step 13 with the amine moiety of compound (8) to produce compound (I-1) or It is a method for producing these precursors. The compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (18) or a reactive derivative thereof. Examples of the reactive derivative of the compound (18) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds).・ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (18) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

The compound represented by the formula (I-2) can also be produced from the compound (16) by the following method.

[Wherein the symbols are as defined above. ]

(Step 15) This step is a method for producing a compound (19) by reacting the amine moiety of the compound (16) obtained in the step 11 with the compound (12) or the compound (13). The compound (12) or compound (13) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

(Step 16) This step is a method for producing the compound (20) by hydrolyzing the ester group of the compound (19) obtained in the step 15 with a base.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (19).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 17) In this step, an amide bond is produced by reacting the carboxyl group of the compound (20) obtained in the above step 16 with the amine moiety of the compound (8) to produce the compound (I-2) or It is a method for producing these precursors. The compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (20) or a reactive derivative thereof. Examples of the reactive derivative of the compound (20) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organics).・ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (20) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark). The amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (20).
In addition, the amount of compound (8) to be used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (20).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

The compound represented by the formula (I-3) can also be produced from the compound (16) by the following method.

[Wherein the symbols are as defined above. ]

(Step 18) This step is a method for producing the compound (21) by reacting the compound (16) obtained in the step 11 with the compound (14) in the presence of a transition metal catalyst, so-called Buchwald- It is a Buchwald-Hartwig reaction. The compound (14) used in this step can be obtained as a compound synthesized by using various organic synthesis techniques known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The reaction in this step is carried out according to a method described in the literature (for example, Angew. Chem. Int. Ed., 1998, 37, 2046-2067, Accounts of Chemical Research ( Acc. Chem. Res.), 1998, Vol. 31, pp. 805-818).
Examples of the transition metal catalyst combination used in this step include palladium acetate and tris (dibenzylideneacetone) palladium as the transition metal complex, and 2,2′-bis (diphenylphosphino) as the ligand. ) -1,1'-binaphthalene and the like. Examples of the base include cesium carbonate, potassium phosphate, sodium tert-butoxide and the like. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include toluene, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N-methylpyrrolidone and the like, preferably toluene, 1,4-dioxane.
The reaction temperature is usually 20 ° C to the reflux temperature of the reaction solvent, preferably 50 ° C to 180 ° C.
The reaction time is usually 0.1 to 48 hours, preferably 0.1 to 24 hours.

In this step, compound (21) can also be produced without using a transition metal catalyst. In this case, examples of the base used in this step include potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.

(Step 19) This step is a method for producing the compound (22) by hydrolyzing the ester group of the compound (21) obtained in the step 18.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (21).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 20) In this step, an amide bond is produced by reacting the carboxyl group of compound (22) obtained in step 15 with the amine moiety of compound (8) to produce compound (I-3) or It is a method for producing these precursors. The compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (22) or a reactive derivative thereof. Examples of the reactive derivative of the compound (22) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds).・ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (22) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark). The amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (22).
The amount of compound (8) to be used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (22).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

The compound represented by the formula (I-4) can also be produced from the compound (16) by the following method.

[Wherein the symbols are as defined above. ]

(Step 21) This step is a method for producing a compound (23) by reacting the compound (16) obtained in the step 11 with a compound (15) in the presence of a base.
Examples of the base used in this step include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine, and preferably potassium carbonate. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide and the like, preferably tetrahydrofuran, N, N-dimethyl. Formamide.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.
In the compound (13) used in this step, when the carbon atom to which V ^4b is bonded is substituted with 1 to 2 hydrogen atoms, V ^4b and one hydrogen atom are combined to form carbonyl. Compound (23) can also be produced by reductive amination with a base aldehyde compound or ketone compound. Examples of the reducing agent used in this step include sodium triacetoxyborohydride, zinc chloride-sodium cyanoborohydride complex, 2-picoline borane complex, and the like, preferably sodium triacetoxyborohydride. The amount of the reducing agent is usually 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (16).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include chloroform, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, acetic acid, and the like, preferably chloroform and methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 30 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 48 hours.

(Step 22) This step is a method for producing the compound (24) by hydrolyzing the ester group of the compound (23) obtained in the step 21.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is usually 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (23).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 23) In this step, an amide bond is formed by reacting the carboxyl group of the compound (24) obtained in the above step 22 with the amine moiety of the compound (8) to produce the compound (I-4) or It is a method for producing these precursors. The compound (8) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The amide bond forming reaction in this step is performed using a carboxylic acid represented by compound (24) or a reactive derivative thereof. Examples of the reactive derivative of the compound (24) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds).・ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (24) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

Of the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-5) can be produced, for example, by the following method.

[Wherein the symbols are as defined above. ]

(Step 24) This step is a step wherein the compound (I-1), compound (I-2), compound (I-3) or compound (I-3) obtained in the step 7, 8, 9, 10, 14, 17, 20, or 23 is used. In this method, compound (I-5) is produced by converting a carbonyl group of compound (I-4) into a thiocarbonyl group. The reaction in this step can be carried out by using a Lawesson reagent or diphosphorus pentasulfide.
The amount of Lawesson's reagent or diphosphorus pentasulfide used in this step is 1 to 100 equivalents, preferably 1 to 1 with respect to 1 equivalent of any of compounds (I-1) to (I-4). 10 equivalents.
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran.
The reaction temperature is usually 20 to 200 ° C., preferably 50 ° C. to the reflux temperature of the reaction solvent.
The reaction time is usually 0.1 to 48 hours, preferably 1 to 24 hours.

Of the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-6) can be produced, for example, by the following method.

[Wherein V ⁵ represents a leaving group, and other symbols are the same as defined above. ]

(Step 25) In this step, an anion is generated at the α-position of the ester group of the compound (25) in the presence of a base, and this is allowed to act on the carbonyl group of the compound (1), whereby the compound (26) is produced. It is a manufacturing method. Compound (1) and compound (25) used in this step can be obtained from commercially available compounds, known compounds, or compounds synthesized by various organic synthesis techniques known to those skilled in the art from readily available compounds. Examples of the base used in this step include lithium diisopropylamide and lithium hexamethyldisilazide.
The amount of the base used in this step is usually 0.9 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (25).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran.
The reaction temperature is usually −78 to 100 ° C., preferably −78 to 30 ° C.
The reaction time is usually 0.1 to 48 hours, preferably 1 to 24 hours.

(Step 26) This step is a method for producing the compound (27) by hydrolyzing the ester group of the compound (26) obtained in the step 25.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (26).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 27) This step is a method for producing the compound (28) by converting the carboxyl group of the compound (27) obtained in the step 26 into an isocyanate by a rearrangement reaction and cyclizing it as it is in the molecule. is there. The reaction in this step is performed according to a method described in the literature (for example, Comprehensive Organic Transformations 2nd Edition (Comprehensive Organic Transformations, Second Edition), by Richard ・ C. Larock, John Wiley & Sands Incorporated (John Wiley & Sons Inc. (1999) pp. 868-869, etc.), a method according to them, or a combination of these and conventional methods.

(Step 28) This step is a method for producing a compound (30) by reacting the compound (28) obtained in the step 27 with a compound part (29) in the presence of a base. The compound (29) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.
Examples of the base used in this step include sodium hydride, potassium hydride, potassium t-butoxide, cesium fluoride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and the like. Is sodium hydride, potassium t-butoxide. The amount of the base is generally 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (28).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tert -Butanol and the like, and tetrahydrofuran, N, N-dimethylformamide are preferable.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.

The conversion from the compound (30) to the compound represented by the formula (I-6) is performed by the above steps 4 to 7, 8, 9, 10, 11 to 14, 15 to 17, 18 to 20, 21 to 23, And 24 can be carried out by a method combining any of the methods similar to those described above, a method according to this, or a method combining these with conventional methods.

Of the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-7) can be produced, for example, by the following method.

[Wherein the symbols are as defined above. ]

(Step 29) In this step, an anion is generated at the α-position of the cyano group of the compound (31) in the presence of a base, and this is allowed to act on the carbonyl group of the compound (1), whereby the compound (32) It is a manufacturing method. Compound (1) and compound (31) used in this step can be obtained as commercially available compounds, known compounds, or compounds synthesized from readily available compounds using various organic synthesis methods known to those skilled in the art. Examples of the base used in this step include lithium diisopropylamide and lithium hexamethyldisilazide.
The amount of the base used in this step is usually 0.9 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of compound (31).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran.
The reaction temperature is usually −78 to 100 ° C., preferably −78 to 30 ° C.
The reaction time is usually 0.1 to 48 hours, preferably 1 to 24 hours.

(Step 30) This step is a method for producing a compound (33) by reducing the cyano group of the compound (32) obtained in the step 29 and converting it to an aminomethyl group in the presence of a base. The reaction in this step is performed according to a method described in the literature (for example, Comprehensive Organic Transformations 2nd Edition (Comprehensive Organic Transformations, Second Edition), by Richard ・ C. Larock, John Wiley & Sands Incorporated (John Wiley & Sons Inc. (1999) pp. 875-878, etc.), a method based thereon, or a combination of these and conventional methods.

(Step 31) In this step, compound (34) is produced by reacting compound (33) obtained in step 30 with the carbonylating agent or thiocarbonylating agent represented by compound (5). It is a method to do. Examples of the compound (5) used include 1,1′-carbonyldiimidazole, p-nitrophenyl chloroformate, 1,1′-thiocarbonyldiimidazole, triphosgene, thiophosgene and the like. The amount of the compound (5) is usually 1 to 20 equivalents, preferably 1 to 6 equivalents, relative to 1 equivalent of the compound (33).
The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform and the like, and preferably 1,4-dioxane and chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 120 ° C.
The reaction time is usually 0.1 to 100 hours, preferably 0.1 to 72 hours.

(Step 32) This step is a method for producing a compound (35) by reacting the compound (34) obtained in the step 31 with a compound part (29) in the presence of a base. The compound (29) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. Examples of the base used in this step include sodium hydride and potassium t-butoxide.
Examples of the base used in this step include sodium hydride, potassium hydride, potassium t-butoxide, cesium fluoride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and the like. Is sodium hydride, potassium t-butoxide. The amount of the base is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (34).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction. For example, acetonitrile, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tert -Butanol and the like, and tetrahydrofuran, N, N-dimethylformamide are preferable.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 48 hours.

The conversion from the compound (35) to the compound represented by the formula (I-7) is performed by the above steps 4 to 7, 8, 9, 10, 11 to 14, 15 to 17, 18 to 20, 21 to 23, And 24 can be carried out by a method combining any of the methods similar to those described above, a method according to this, or a method combining these with conventional methods.

Of the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-8) can be produced, for example, by the following method.

Wherein, P ¹ and P ³ is an amino-protecting group, P ² represents a protecting group of carboxyl group, V ⁶ represents a leaving group, and other symbols are as defined above. ]

(Step 33) This step is a method for producing a compound (37) by hydrolyzing the ester group of the compound (36) obtained in the step 3, 28 or 32.
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (36).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 34) In this step, a hydrazide bond is generated by reacting the carboxyl group of the compound (37) obtained in Step 33 with the amine moiety of the compound (38) to produce the compound (39). Is the method. The compound (37) used in this step can be obtained as a compound synthesized using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The hydrazide bond forming reaction in this step is performed using a carboxylic acid represented by compound (37) or a reactive derivative thereof. Examples of the reactive derivative of compound (37) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in literature (for example, comprehensive organic・ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (37) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyldisulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark). The amount of the condensing agent is 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (37).
The amount of compound (38) to be used is 0.5 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (37).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

(Step 35) In this step, compound (40) is obtained by selectively removing the group (P ³ : amino-protecting group) protecting the hydrazide group of compound (39) obtained in Step 34. It is a method of manufacturing. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method based thereon or a combination of these with conventional methods it can.

(Step 36) This step is a method for producing the compound (42) by reacting the hydrazide moiety of the compound (40) obtained in the step 35 with the compound (41). The compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

(Step 37) This step is a method for producing the compound (43) by removing the amino-protecting group of the compound (42) obtained in the step 36. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.

The conversion from the compound (43) to the compound represented by the formula (I-8) was carried out in the same manner as in Step 7, 8, 9 or 10 above, a method analogous thereto or a combination thereof with a conventional method. It can be done by the method.

The compound represented by the formula (I-8) can also be produced, for example, by the following method.

Wherein, P ¹ and P ³ is an amino-protecting group, P ² represents a protecting group of carboxyl group, V ⁶ represents a leaving group, and other symbols are as defined above. ]

(Step 38) This step is a method for producing the compound (44) by removing the amino-protecting group (P ¹ ) of the compound (36) obtained in the step 3, 28 or 32. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method based thereon or a combination of these with conventional methods it can.

The conversion from the compound (44) to the compound (45) can be carried out by the same method as in the above-mentioned step 12, 15, 18 or 23, a method according to this, or a method combining these with conventional methods.

(Step 39) This step is a method for producing a compound (46) by hydrolyzing the ester group of the compound (45).
Examples of the base used in this step include sodium hydroxide and potassium hydroxide. The amount of the base is generally 1 to 100 equivalents, preferably 1 to 10 equivalents, relative to 1 equivalent of compound (45).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, and preferably methanol.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 180 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 24 hours.

(Step 40) In this step, a hydrazide bond is generated by reacting the carboxyl group of compound (46) obtained in Step 39 with the amine moiety of compound (38) to produce compound (47). Is the method. The compound (38) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds. The hydrazide bond forming reaction in this step is performed using a carboxylic acid represented by compound (46) or a reactive derivative thereof. Examples of the reactive derivative of the compound (46) include mixed acid anhydrides, active esters, active amides, acid halides, etc., and these include, for example, methods described in the literature (for example, comprehensive organic compounds).・ Transformations 2nd edition (Comprehensive Organic Transformations, Second Edition), by Richard C. Larock, John Wiley & Sons Inc. (1999) 1941-1949). In the above reaction, when the carboxylic acid represented by the compound (46) is used, for example, 1,1′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide, diphenylphosphoryl azide, dipyridyl disulfide-triphenylphosphine, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, The reaction can be carried out in the presence of a condensing agent such as PyBOP (registered trademark) or PyBroP (registered trademark).
The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, chloroform, acetonitrile, N, N-dimethylformamide, and preferably chloroform.
The reaction temperature is usually 0 ° C. to the reflux temperature of the reaction solvent, preferably 0 to 60 ° C.
The reaction time is usually 0.1 to 240 hours, preferably 0.1 to 100 hours.

(Step 41) In this step, compound (48) is produced by removing the group (P ³ : protecting group for amino group) protecting the hydrazide group of compound (47) obtained in Step 40. Is the method. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth Edition, Green Edition) (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method based thereon or a combination of these with conventional methods it can.

(Step 42) This step is a method for producing compound (I-8) or a precursor thereof by reacting the hydrazide moiety of compound (48) obtained in step 41 with compound (41). is there. The compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

Of the compounds included in the compound (I) according to the present invention, the compound represented by the formula (I-9) can be produced, for example, by the following method.

[Wherein P ¹ represents an amino-protecting group, V ⁷ represents a leaving group, and other symbols are the same as defined above. ]

(Step 43) This step is a method for producing compound (51) by reacting the hydrazide moiety of compound (40) obtained in step 35 with compound (49) or compound (50). The compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.

(Step 44) This step is a method for producing the compound (52) by removing the amino-protecting group of the compound (51) obtained in the step 43. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.

The conversion from the compound (52) to the compound represented by the formula (I-8) was carried out in the same manner as in Step 7, 8, 9 or 10 above, a method analogous thereto or a combination thereof with a conventional method. It can be done by the method.

The compound represented by the above formula (I-9) can also be produced, for example, by the following method.

[Wherein V ⁷ represents a leaving group, and other symbols are the same as defined above. ]

(Step 45) This step comprises reacting the hydrazide moiety of compound (48) obtained in step 41 with compound (49) or compound (50) to give compound (I-9) or a precursor thereof. It is a method of manufacturing. The compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.

Among the compounds included in the compound (I) according to the present invention, compounds represented by the formula (I-10), the formula (I-11), the formula (I-12) and the formula (I-13) Can be produced, for example, by the following method.

[Wherein V ⁸ and V ⁹ represent a leaving group, and other symbols are the same as defined above. ]

(Step 46) This step is a method for producing a compound (53) by converting the carboxyl group of the compound (46) obtained in the step 39 into an amino group by a rearrangement reaction. Rearrangement reactions that can be used in this process include rearrangement reactions via acyl azides (so-called Curtius rearrangement and Schmidt rearrangement), rearrangement reactions via primary amides (so-called Hofmann rearrangement) and hydroxams. Examples include a rearrangement reaction via an acid (so-called Lossen rearrangement). These reactions are described in literature (eg Comprehensive Organic Transformations, Second Edition, Richard C. Larock, John Wiley and Sons). Incorporated (John Wiley & Sons Inc. (1999) pp. 868-869, etc.), a method according to it, or a combination of these and conventional methods.

(Step 47) This step is a method for producing compound (I-10) or a precursor thereof by reacting the amine moiety of compound (53) obtained in step 46 with compound (41). is there. The compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

(Step 48) In this step, compound (I-11) or a precursor thereof is reacted with the amine moiety of compound (53) obtained in step 46 and compound (49) or compound (50). It is a method of manufacturing. The compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.

(Step 49) This step is a method for producing compound (I-12) or a precursor thereof by reacting the amine moiety of compound (53) obtained in step 46 with compound (54). is there. The compound (54) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized by various organic synthesis methods known to those skilled in the art from a readily available compound.

(Step 50) This step is a method for producing compound (I-13) or a precursor thereof by reacting the amine moiety of compound (53) obtained in step 46 with compound (55). is there. The compound (55) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized from various readily available organic synthesis methods known to those skilled in the art.

The compound represented by the above formula (I-10) can also be produced, for example, by the following method.

[Wherein the symbols are as defined above. ]

(Step 51) This step is a method for producing a compound (56) by converting the carboxyl group of the compound (37) obtained in the step 33 to an amino group by a rearrangement reaction. Rearrangement reactions that can be used in this process include rearrangement reactions via acyl azides (so-called Curtius rearrangement and Schmidt rearrangement), rearrangement reactions via primary amides (so-called Hofmann rearrangement) and hydroxams. Examples include a rearrangement reaction via an acid (so-called Lossen rearrangement). These reactions are described in literature (eg Comprehensive Organic Transformations, Second Edition, Richard C. Larock, John Wiley and Sons). Incorporated (John Wiley & Sons Inc. (1999) pp. 868-869, etc.), a method according to it, or a combination of these and conventional methods.

(Step 52) This step is a method for producing a compound (57) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (41). The compound (41) used in this step can be obtained as a compound synthesized by using various organic synthesis methods known to those skilled in the art from commercially available compounds, known compounds, or readily available compounds.

(Step 53) This step is a method for producing the compound (58) by removing the amino-protecting group of the compound (57) obtained in the step 52. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.

The conversion from compound (58) to the compound represented by formula (I-10) was carried out in the same manner as in Steps 7, 8, 9 or 10 above, a method analogous thereto, or a combination of these and conventional methods. It can be done by the method.

The compound represented by the formula (I-11) can also be produced, for example, by the following method.

[Wherein the symbols are as defined above. ]

(Step 54) This step is a method for producing the compound (59) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (49) or the compound (50). The compound (49) or compound (50) used in this step can be obtained as a compound synthesized from a commercially available compound, a known compound, or an easily available compound using various organic synthesis methods known to those skilled in the art.

(Step 55) This step is a method for producing the compound (60) by removing the amino-protecting group of the compound (59) obtained in the step 54. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.

The conversion from the compound (60) to the compound represented by the formula (I-11) was carried out in the same manner as in the above-mentioned Step 7, 8, 9 or 10, a method analogous thereto, or a combination thereof with a conventional method. It can be done by the method.

The compound represented by the formula (I-12) can also be produced, for example, by the following method.

[Wherein the symbols are as defined above. ]

(Step 56) This step is a method for producing the compound (61) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (54). The compound (54) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized by various organic synthesis methods known to those skilled in the art from a readily available compound.

(Step 57) This step is a method for producing the compound (62) by removing the amino-protecting group of the compound (61) obtained in the step 56. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.

The conversion from the compound (62) to the compound represented by the formula (I-12) was carried out in the same manner as in Step 7, 8, 9 or 10 above, a method analogous thereto or a combination thereof with a conventional method. It can be done by the method.

Further, the compound represented by the formula (I-13) can also be produced, for example, by the following method.

[Wherein the symbols are as defined above. ]

(Step 58) This step is a method for producing a compound (63) by reacting the amine moiety of the compound (56) obtained in the step 51 with the compound (55). The compound (55) used in this step can be obtained from a commercially available compound, a known compound, or a compound synthesized from various readily available organic synthesis methods known to those skilled in the art.

(Step 59) This step is a method for producing the compound (64) by removing the amino-protecting group of the compound (63) obtained in the step 58. The reaction in this step is a reaction for removing the protecting group of the amino group, and a method described in the literature (for example, Protective Groups in Organic Synthesis, Fourth edition), Green (TWGreene), John Wiley & Sons Inc. (2006), etc.), a method according to it, or a combination of these and ordinary methods Can do.

The conversion from the compound (64) to the compound represented by the formula (I-13) was carried out in the same manner as in Step 7, 8, 9 or 10 above, a method analogous thereto or a combination thereof with a conventional method. It can be done by the method.

The present invention will be described in more detail with reference synthesis examples, synthesis examples, test examples, and formulation examples below, but the present invention is not limited to these examples.
The NMR (nuclear magnetic resonance) spectrum was measured at room temperature using a 300 MHz (JNM-ECP300; manufactured by JEOL or JNM-ECX300; manufactured by JEOL) type spectrometer. The chemical shift value in this specification uses tetramethylsilane as an internal standard substance when any of deuterated chloroform (CDCl ₃ ), deuterated dimethyl sulfoxide (DMSO-d ₆ ), and deuterated methanol (CD ₃ OD) is used. All δ values are shown in ppm (parts per million). In the description of the NMR spectrum, s is a singlet, d is a doublet, dd is a doublet of doublet, dt is a doublet of triplet, dq is a doublet of quartet, ddd is a doublet of doublet of Doublet, t is triplet, tt is triplet of triplet, q is quartet, sep is septet, quint is quintet, m is multiplet, br is broad, J is coupling constant, and Hz is hertz.
The LC-MS (liquid chromatograph-mass spectrometry) spectrum was measured using the following conditions and apparatus.
Condition 1:
Device: Waters micromass ZQ
Column: Waters SunFire C18 (3.5 μm, 4.6 × 30 mm)
Column temperature: 40 ° C
Eluent composition: acetonitrile / 0.1 mass% formic acid aqueous solution (volume ratio: 10/90 → 85/15)

Condition 2
Device: Waters micromass ZQ
Column: Waters SunFire C18 (3.5 μm, 2.1 × 20 mm)
Column temperature: 40 ° C
Eluent composition: acetonitrile / 0.1 mass% formic acid aqueous solution (volume ratio: 15/85 → 85/15)

When purified by HPLC, the following conditions and equipment were used.
Device: Waters micromass ZQ
Column: WatersSunFireC18 (5.0 μm, 19 × 100 mm)
Column temperature: 23 ± 2 ° C
Eluent composition: acetonitrile / 0.1 wt% formic acid aqueous solution (volume ratio: 20/80 → 95/5)
Flow rate: 20 mL / min

In addition, when there exists description regarding the mixing ratio of a mixed solvent in an Example, when there is no description in particular, a mixing ratio means a volume ratio.

Reference Example 1-1
Preparation of 1-oxa-6-azaspiro [2.5] octane-6-carboxylate t-butyl 1- (t-butoxycarbonyl) -4-piperidone (purchased from Wako Pure Chemical Industries, Ltd.) (5.1 g 26 mmol) was dissolved in acetonitrile (50 mL), trimethylsulfoxonium iodide (6.6 g, 30 mmol) and potassium hydroxide (2.1 g, 38 mmol) were added, and the mixture was vigorously stirred at room temperature for 3 days. After completion of the reaction, insoluble matters in the obtained reaction mixture were removed, hexane / ethyl acetate (2/1, 75 mL) and water (25 mL) were added, and the mixture was shaken and allowed to stand to separate the supernatant. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give t-butyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate (4.3 g, yield 78%). Was obtained as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41-1.50 (2H, m), 1.48 (9H, s), 1.80 (2H, ddd, J = 13.1, 9 .. 4, 3.3 Hz), 2.69 (2H, s), 3.43 (2H, ddd, J = 13.1, 9.4, 3.3 Hz), 3.63-3.80 (2H, m ).

Reference Example 1-2
Production of t-butyl 3- [4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Obtained in Reference Example 1-1 1-oxa-6-azaspiro [2.5] octane-6-carboxylate t-butyl (17 g, 80 mmol) and methyl 4-aminomethylbenzoate (purchased from Aldrich) (17 g, 86 mmol) 340 mL), water (30 mL) and 1M aqueous sodium hydroxide solution (86 mL, 86 mol) were added, and the mixture was stirred at room temperature for 3 days, and methanol was evaporated under reduced pressure. Water (200 mL) was added to the resulting reaction mixture, and the mixture was extracted with chloroform (340 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give t-butyl 4-hydroxy-4-{[4- (methoxycarbonyl) benzylamino] methyl} piperidine-1-carboxylate (37 g, yield). (Quantitative) was obtained as a yellow oil. Used in the next reaction without purification.
The obtained 4-hydroxy-4-{[4- (methoxycarbonyl) benzylamino] methyl} piperidine-1-carboxylate t-butyl (34 g, 75 mmol) was dissolved in 1,4-dioxane (300 mL). , 1′-carbonyldiimidazole (46 g, 300 mmol) was added and stirred at 90 ° C. for 2 days. The reaction mixture was cooled and concentrated under reduced pressure, ethyl acetate (100 mL) and water (20 mL) were added under ice cooling, and the mixture was concentrated under reduced pressure. Ethyl acetate (300 mL) and water (200 mL) were added thereto, the organic layer was separated, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: chloroform / ethyl acetate = 10/1], and chloroform / ethyl acetate. / Recrystallization from hexane to give t-butyl 3- [4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (11 g 29%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.54-1.67 (2H, m), 1.86 (2H, d, J = 13.0 Hz), 3 .13 (2H, s), 3.28 (2H, t, J = 11.6 Hz), 3.81 (2H, d, J = 11.6 Hz), 3.92 (3H, s), 4.49 (2H, s), 7.34 (2H, d, J = 8.2 Hz), 8.04 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.14 minutes; m / z 426.9 [M + Na] ⁺ (ESI positive ion mode), m / z 448.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 1-3
Preparation of 4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid methyl hydrochloride 3- [obtained in Reference Example 1-2 4- (Methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (5.0 g, 12 mmol) dissolved in methanol (70 mL) 4M hydrogen chloride-dioxane solution (31 mL, 120 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The precipitated solid was collected by filtration, dried at 50 ° C. under reduced pressure, and methyl 4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate hydrochloride The salt (4.0 g, 95% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.85-2.07 (4H, m), 2.97-3.25 (4H, m), 3.31 (2H, s), 3 .84 (3H, s), 4.44 (2H, s), 7.41 (2H, d, J = 8.2 Hz), 7.95 (2H, d, J = 7.8 Hz), 8.82 (2H, brs).

LC / MS [Condition 1]: Retention time 0.88 minutes; m / z 305.0 [M + H] ⁺ (ESI positive ion mode)

Example 1
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate (Compound No. 1 ) obtained in reference example 1-3, 4 - [(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate hydrochloride (4 (0.0 g, 11 mmol) in N, N-dimethylformamide (40 mL), triethylamine (4.9 mL, 35 mmol), 4- (trifluoromethyl) benzyl bromide (purchased from Tokyo Chemical Industry Co., Ltd.) (3. 4 g, 14 mmol) was added at room temperature, followed by stirring for 3 hours. The reaction mixture was added dropwise to water (200 mL), and the precipitated solid was collected by filtration and washed with water. The obtained solid was dried at 50 ° C. under reduced pressure to give 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Methyl 3-yl} methyl) benzoate (5.2 g, 95% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.73 (2H, ddd, J = 14.0, 7.2, 7.4 Hz), 1.92 (2H, dt, J = 12.9, 4 .7 Hz), 2.62-2.47 (4H, m), 3.13 (2H, s), 3.56 (2H, s), 3.92 (3H, s), 4.48 (2H, s), 7.33 (2H, d, J = 8.3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.3 Hz), 8. 03 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 3.25 minutes; m / z 462.9 [M + H] ⁺ (ESI positive ion mode), m / z 507.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 2-1
Preparation of methyl (1r, 4r) -4- (aminomethyl) cyclohexanecarboxylic acid hydrochloride trans-4-aminomethyl-1-cyclohexanecarboxylic acid (purchased from Tokyo Chemical Industry Co., Ltd.) (3.9 g, 25 mmol) Dissolved in methanol (60 mL), 1M hydrogen chloride-methanol (39 mL, 75 mmol) was added, and the mixture was stirred at room temperature for 7 hr. After completion of the reaction, the reaction solvent was distilled off under reduced pressure. The precipitated solid was dissolved in chloroform, cyclopentyl methyl ether (20 mL) was added, and the precipitated solid was again collected by filtration to give (1r, 4r) -4- (aminomethyl) cyclohexanecarboxylic acid methyl hydrochloride ( 5.5 g, quantitative) was obtained as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.08 (2H, q, J = 11.9 Hz), 1.48 (2H, q, J = 12.7 Hz), 1.68-1.87 ( 1H, m), 1.88-2.12 (4H, m), 2.26 (1H, tt, J = 12.3, 3.3 Hz), 2.76-2.95 (2H, brm), 3.66 (3H, s), 8.36 (2H, brs).

Reference Example 2-2
Production of t-butyl 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate T-Butyl 1-oxa-6-azaspiro [2.5] octane-6-carboxylate (3.2 g, 15 mmol) obtained in Reference Example 1-1, obtained in Reference Example 2-1 (1r , 4r) -4- (aminomethyl) cyclohexanecarboxylic acid methyl hydrochloride (3.4 g, 17 mmol) was dissolved in a methanol-water mixed solvent (1: 1, 96 mL), and 1M aqueous sodium hydroxide solution (15 mL, 15 mmol) was dissolved. And stirred for 6 days at room temperature. After completion of the reaction, methanol was distilled off under reduced pressure, chloroform (80 mL) and water (20 mL) were added, and the mixture was shaken and allowed to stand to separate the organic layer. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-hydroxy-4-({[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methylamino} methyl as a reaction intermediate. ) Piperidine-1-carboxylate t-butyl was obtained as a pale yellow oil. The resulting 4-hydroxy-4-({[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methylamino} methyl) piperidine-1-carboxylate was converted to 1,4-dioxane (20 mL). After dissolution, 1,1′-carbonyldiimidazole (1.1 g, 66 mmol) was added, and the mixture was stirred at 90 ° C. for 2 days. After completion of the reaction, the reaction solvent was distilled off under reduced pressure, water (50 mL), 1M hydrochloric acid (100 mL) and chloroform (200 mL) were added to the residue, shaken and allowed to stand, and the organic layer was separated. . The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3 , 8-diazaspiro [4.5] decane-8-carboxylate t-butyl (3.3 g, yield 54%) was obtained as a pale yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.9 Hz), 1.42 (2H, dq, J = 3.6, 12.9 Hz), 1.46 (9H, s), 1.52-1.62 (1H, m), 1.66 (2H, ddd, J = 11.9, 12.2, 4.6 Hz), 1.77 (2H , Brd, J = 13.2 Hz), 1.88 (2H, brd, J = 13.2 Hz), 2.02 (2H, brd, J = 13.5 Hz), 2.26 (1H, tt, J = 12.2, 3.3 Hz), 3.10 (2H, d, J = 7.3 Hz), 3.26 (2H, s), 3.27 (2H, brt, J = 11.6 Hz), 3. 67 (3H, s), 3.75-3.97 (2H, brm).

Reference Example 2-3
Preparation of (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane obtained in Reference Example 2-2 Dissolve t-butyl -8-carboxylate (1.9 g, 4.5 mmol) in 1,4-dioxane (40 mL), add 1M aqueous sodium hydroxide solution (6.8 mL, 6.8 mmol), and bring to room temperature. Stir for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to distill off 1,4-dioxane. Then, 1M hydrochloric acid (6.8 mL) and ethyl acetate (40 mL) were added to the residual reaction mixture, and the organic layer was separated. The obtained organic layer was concentrated to dryness under reduced pressure to give (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl] methyl} cyclohexanecarboxylic acid (1.9 g, quantitative) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.9 Hz), 1.42 (2H, dq, J = 3.6, 12.9 Hz), 1.46 (9H, s), 1.52-1.62 (1H, m), 1.66 (2H, ddd, J = 11.9, 12.2, 4.6 Hz), 1.77 (2H , Brd, J = 13.2 Hz), 1.88 (2H, brd, J = 13.2 Hz), 2.02 (2H, brd, J = 13.5 Hz), 2.26 (1H, tt, J = 12.2, 3.3 Hz), 3.10 (2H, d, J = 7.3 Hz), 3.26 (2H, s), 3.27 (2H, brt, J = 11.6 Hz), 3. 75-3.97 (2H, brm).

LC / MS [Condition 1]: Retention time 3.65 minutes; m / z 395 [MH] ⁻ (ESI negative ion mode)

Example 2
2-oxo-3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3,8-diazaspiro [4.5] decane- Production of t-butyl 8-carboxylate (Compound No. 2) (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxaxamine obtained in Reference Example 2-3 -3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (700 mg, 1.7 mmol) was dissolved in chloroform (14 mL) and tetrahydrofurfurylamine (0.26 mL, 2.5 mmol) was dissolved. , 1-hydroxybenzotriazole (230 mg, 1.7 mol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4 0 mg, 2.5 mmol) and the mixture was stirred at room temperature for 4 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove chloroform, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the organic layer. The organic layer was concentrated to dryness under reduced pressure to give 2-oxo-3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3, T-butyl 8-diazaspiro [4.5] decane-8-carboxylate (870 mg, quantitative) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, m), 1.46 (9H, s), 1.43-1.79 (7H), 1.87-2.09 (9H , M), 3.08 (2H, d, J = 5.4 Hz), 3.08-3.16 (1H, m), 3.26 (2H, s), 3.26-3.32 (2H M), 3.54-3.62 (1H, m), 3.72-3.78 (1H, m), 3.82-3.98 (4H, m).

Example 3
(1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexane Preparation of carboxamide hydrochloride (Compound No. 3) 2-oxo-3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl obtained in Example 2 ] 1-Oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (1.2 g, 2.4 mmol) was dissolved in methanol (20 mL), and 4M hydrogen chloride- Dioxane solution (3.0 mL, 12 mmol) was added and stirred at 50 ° C. for 1 day. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N— [(Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride (1.0 g, quantitative) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.82-0.93 (2H, m), 1.27-1.39 (2H, m), 1.44-1.52 (2H, m), 1.64-1.88 (7H), 1.99-2.13 (5H, m), 2.97 (2H, d, J = 6.6 Hz), 3.08-3.16 ( 6H, m), 3.40 (2H, s), 3.45-3.62 (3H, m), 7.81 (1H, brs), 9.23-9.32 (2H, brm).

Example 4
(1r, 4r) -4-{[2-oxo-8- (pyridin-3-ylmethyl) -1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- [ Preparation of (tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 4) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [3] obtained in Example 3 4.5] Decan-3-yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride (50 mg, 0.13 mmol) dissolved in N, N-dimethylformamide (1.0 mL) At room temperature, triethylamine (0.055 mL, 0.33 mmol) and 3- (bromomethyl) pyridine hydrobromide (49 mg, 0.17 mmol) were added. And the mixture was stirred at room temperature for 1 day. After completion of the reaction, ethyl acetate was added, washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 30/1], and (1r, 4r) -4-{[2-oxo-8 -(Pyridin-3-ylmethyl) -1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (2.9 mg Yield 4%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00-1.04 (2H, m), 1.47-1.58 (4H, m), 1.69-1.79 (5H, m) , 1.87-2.05 (7H, m), 2.57 (4H, brm), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.54 (2H, s), 3.56-3.62 (1H, m), 3.73-3.78 (1H, m), 3.84-3.86 (1H, m), 3.92-3 .94 (1H, m), 5.81 (1H, brs), 7.25 (1H, dd, J = 7.7, 5.1 Hz), 7.64 (1H, d, J = 7.7 Hz) 8.51 (1H, d, J = 5.1 Hz), 8.56 (1H, s).

Example 5
(1r, 4r) -4-({8- [2- (ethylthio) ethyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N— Preparation of [(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 5) Substantially Examples except that 2-bromoethylethyl sulfide was used instead of 3- (bromomethyl) pyridine hydrobromide The reaction was performed in the same manner as in 4 to obtain the title compound (3.1 mg, yield 7%) as a colorless powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.96-1.08 (2H, m), 1.27 (3H, t, J = 7.2 Hz) 1.43-1.60 (4H, m ), 1.75-2.08 (12H, m), 2.53-2.65 (8H, m), 2.57 (2H, q, J = 7.2 Hz), 3.09 (2H, d) , J = 7.8 Hz), 3.07-3.15 (1H, m), 3.25 (2H, s), 3.55-3.63 (1H, m), 3.71-3.98 (3H, m), 5.81 (1H, brs).

Reference Example 6-1
Preparation of (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylic acid methyl hydrochloride In Reference Example 2-2 The resulting 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t -Butyl (2.4 g, 5.8 mmol) was dissolved in methanol (30 mL), 4 M hydrogen chloride-dioxane solution (15 mL, 58 mmol) was added at 0 ° C., and the mixture was warmed to room temperature and stirred for 1 day. Thereafter, the solution was concentrated to dryness under reduced pressure, and (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylate methyl hydrochloric acid The salt (2.1 g, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 12.3 Hz), 1.42 (2H, q, J = 12.7 Hz), 1.51-1.66 ( 1H, m), 1.76 (2H, d, J = 11.5 Hz), 1.97-2.15 (4H, m), 2.19-2.41 (3H, m), 3.11 ( 2H, d, J = 7.4 Hz), 3.21-3.40 (4H, m), 3.41-3.55 (2H, m), 3.67 (3H, s), 9.75 ( 2H, brs).

LC / MS [Condition 1]: Retention time 0.82 minutes; m / z 311.0 [M + H] ⁺ (ESI positive ion mode)

Reference Example 6-2
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Preparation of methyl carboxylate (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) obtained in Reference Synthesis Example 6-1 Methyl] cyclohexanecarboxylic acid methyl hydrochloride (2.1 g, 5.9 mmol) was dissolved in N, N-dimethylformamide (22 mL) and then 4- (trifluoromethyl) benzyl bromide (1.6 g, 6) at room temperature. 0.5 mmol) and triethylamine (2.5 mL, 18 mmol) were added, and the mixture was stirred at room temperature for 1 day. Thereafter, 80 mL of water was added, and the precipitated solid was collected by filtration, and (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Diazaspiro [4.5] decan-3-yl} methyl) methyl cyclohexanecarboxylate (2.6 g, 94% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.93-1.11 (2H, m), 1.33-1.49 (2H, m), 1.50-1.66 (1H, m) , 1.70-1.86 (4H, m), 1.88-2.08 (4H, m), 2.25 (1H, tt, J = 12.1, 3.5 Hz), 2.57 ( 4H, brs), 3.09 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.58 (2H, brs), 3.66 (3H, s), 7.33 -7.72 (4H, brm).

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 469.2 [M + H] ⁺ (ESI positive ion mode), m / z 512.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 6-3
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Preparation of carboxylic acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro obtained in Reference Example 6-2 [4.5] Methyl [decane-3-yl} methyl) cyclohexanecarboxylate (2.6 g, 5.6 mmol) was dissolved in methanol (28 mL), and then 1 M aqueous sodium hydroxide solution (8.4 mL, 84 mmol) at room temperature. ) And stirred at 60 ° C. for 1 hour. Then, it concentrated under pressure reduction, methanol was distilled off, and water (25 mL) was added. 1M hydrochloric acid was added until the pH reached 6, and the precipitated solid was collected by filtration to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, 8-Diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (2.3 g, 90% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.94-1.13 (2H, m), 1.33-1.51 (2H, m), 1.51-1.68 (1H, m) , 1.72-2.14 (8H, m), 2.20-2.35 (1H, m), 2.61 (4H, brs), 3.10 (2H, d, J = 7.4 Hz) 3.27 (2H, s), 3.61 (2H, brs), 7.45 (2H, d, J = 7.4 Hz), 7.59 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 454.8 [M + H] ⁺ (ESI positive ion mode), m / z 452.9 [MH] ⁻ (ESI negative ion mode)

Example 6
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} (Methyl) cyclohexanecarboxamido] piperidine-1-carboxylate t-butyl (Compound No. 6) (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (92 mg, 0.20 mmol) and 4-aminopiperidine-1-carboxylic acid After dissolving t-butyl (45 mg, 0.22 mmol) and 1-hydroxybenzotriazole (27 mg, 0.20 mol) in chloroform (1.0 ml), at room temperature, - ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (46 mg, 0.22 mmol) and the mixture was stirred at room temperature for 3 days. Thereafter, the reaction mixture was concentrated under reduced pressure to distill off chloroform, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1- Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide] piperidine-1-carboxylate (120 mg, 89% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, qd, J = 13.1, 3.3 Hz), 1.27 (2H, qd, J = 11.9, 4.1 Hz), 1.39-1.67 (13H, m), 1.70-2.06 (10H, m), 2.56 (4H, brs), 2.84 (2H, t, J = 11.9 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.81-3.98 (1H, m), 3.97- 4.12 (2H, brm), 5.42 (1H, d, J = 7.4 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8) .2 Hz).

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 636.9 [M + H] ⁺ (ESI positive ion mode)), m / z 681.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 7
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (Compound No. 7) 4-[(1r, 4r) -4-({2-oxo-8- [4] obtained in Example 6 -(Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide] piperidine-1-carboxylate (49 mg, 0.077 mmol) Was dissolved in methanol (0.50 mL), 4M hydrogen chloride-dioxane solution (0.19 mL, 0.77 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 day. Then, it was concentrated to dryness under reduced pressure to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Decan-3-yl} methyl) -N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (47 mg, quantitative) was obtained as a white powder.

LC / MS [Condition 1]: Retention time 1.10 minutes; m / z 536.8 [M + H] ⁺ (ESI positive ion mode), m / z 581.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 8
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexanecarboxamide] piperidine-1-carboxylate (Compound No. 8) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) obtained in Example 7 )] Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (20 mg, 0.033 mmol) Dissolve in ethyl (1.0 mL), add triethylamine (0.023 mL, 0.17 mmol) and methyl chloroformate (0.038 mL, 0.050 mmol) at room temperature, And the mixture was stirred for 1 day with warm. Thereafter, water is added to separate the organic layer. The organic layer is dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure to give 4-[(1r, 4r) -4-({2-oxo-8- [ 4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamido] piperidine-1-carboxylate (4.3 mg, yield 22 %) As a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, qd, J = 12.7, 2.5 Hz), 1.20-1.38 (2H, m), 1.39-1. 67 (3H, m), 1.70-2.06 (11H, m), 2.56 (4H, brs), 2.90 (2H, t, J = 11.9 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.69 (3H, s), 3.82-4.00 (1H, m), 4 .00-4.24 (2H, m), 5.46 (1H, d, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [condition 1]: retention time 3.16 minutes; m / z 595.0 [M + H] ⁺ (ESI positive ion mode),

Example 9
(1r, 4r) -N- [1- (cyanomethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 9) (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (15 mg, .0. 024 mmol) was suspended in ethyl acetate (1.0 mL) and triethylamine (0.017 mL, 0.12 mmol) and bromoacetonitrile (0.020 mL, 0.029 m) at room temperature. ol) were added and stirred at room temperature for 1 day. Thereafter, the reaction mixture was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 10/1] (1r, 4r) -N- [1- (cyanomethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] decan-3-yl} methyl) cyclohexanecarboxamide (1.8 mg, 13% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 12.7 Hz), 1.38-1.67 (6H, m), 1.71-1.84 (4H, m), 1.84-2.06 (6H, m), 2.45 (2H, td, J = 11.2, 2.5 Hz), 2.61 (4H, brs), 2.72-2. 82 (2H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.50 (2H, s), 3.57 (2H, s), 3 .72-3.90 (1H, m), 5.30 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 575.9 [M + H] ⁺ (ESI positive ion mode), m / z 620.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 10
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 10) (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (41 mg, 0.090 mmol) and tetrahydrofurfurylamine (0.0090 mL, 0 .090 mmol) and 1-hydroxybenzotriazole (12 mg, 0.090 mol) in chloroform (1.0 ml), and then at room temperature. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (21 mg, 0.11 mmol) and the mixture was stirred at room temperature for 1 day. Thereafter, the reaction mixture was concentrated under reduced pressure to distill off chloroform, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3 , 8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (41 mg, 85% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, qd, J = 11.5, 2.0 Hz), 1.40-1.66 (4H, m), 1.71-1. 85 (4H, m), 1.86-2.10 (8H, m), 2.56 (4H, brs), 3.05-3.16 (3H, m), 3.25 (2H, s) , 3.52-3.63 (3H, m), 3.69-3.80 (1H, m), 3.88-3.80 (1H, m), 3.99-3.89 (1H, m), 5.81 (1H, s), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.98 minutes; m / z 537.8 [M + H] ⁺ (ESI positive ion mode), m / z 582.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 11
(1r, 4r) -N- (1-methoxybutan-2-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Decan-3-yl} methyl) cyclohexane carboxamide (Compound No. 11) Substantially Example 10 except that 2-amino-1-methoxybutane was used instead of tetrahydrofurfurylamine. The title compound (20 mg, yield 78%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.90 (3H, t, J = 7.8 Hz), 1.02 (2H, q, J = 12.7 Hz), 1.40-1.67 ( 5H, m), 1.71-1.84 (4H, m), 1.86-2.08 (5H, m), 2.56 (4H, brs), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.31-3.44 (5H, m), 3.57 (2H, s), 3.89-4.01 (1H, m), 5 .60 (1H, d, J = 9.0 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 539.8 [M + H] ⁺ (ESI positive ion mode), m / z 584.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 12
2-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of t-butyl methyl) cyclohexanecarbonyl] hydrazinecarboxylate (Compound No. 12) The compound (140 mg, yield 95%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 12.7 Hz), 1.42-1.64 (12H, m), 1.72-1.84 (4H, m), 1.89-2.01 (4H, m), 2.02-2.16 (1H, m), 2.56 (4H, brs), 3.10 (2H, d, J = 7. 4Hz), 3.25 (2H, s), 3.57 (2H, s), 6.44 (1H, s), 7.18 (1H, s), 7.44 (2H, d, J = 8) .2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 568.8 [M + H] ⁺ (ESI positive ion mode), m / z 567.0 [MH] ⁻ (ESI negative ion mode)

Example 13
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Preparation of carbohydrazide dihydrochloride (Compound No. 13) 2-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl]-] obtained in Example 12 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarbonyl] hydrazine carboxylate t-butyl (63 mg, 0.11 mmol) was dissolved in methanol (0.50 mL) at room temperature. 4M hydrogen chloride-dioxane solution (0.28 mL, 1.1 mmol) was added and stirred at room temperature for 1 day. Then, it was concentrated to dryness under reduced pressure to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Decan-3-yl} methyl) cyclohexanecarbohydrazide dihydrochloride (60 mg, quantitative) was obtained as a white powder.

LC / MS [Condition 1]: Retention time 3.24 minutes; m / z 468.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 14
Preparation of 2- (tetrahydrofuran-2-yl) acetic acid Ethyl 2- (tetrahydrofuran-2-yl) acetate (purchased from Tokyo Chemical Industry Co., Ltd.) (0.94 g, 6.0 mmol) in methanol (6.0 mL) Dissolved, 1M aqueous sodium hydroxide solution (9.0 mL, 9.0 mmol) was added and stirred at room temperature for 3.5 hours. The reaction mixture was neutralized with 1M hydrochloric acid (9.0 mL), and methanol was distilled off under reduced pressure. Water (10 mL) and chloroform (10 mL) were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2- (tetrahydrofuran-2-yl) acetic acid (0.55 g, yield 70%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58 (1H, dq, J = 12.3, 7.8 Hz), 2.02-1.84 (2H, m), 2.11 (1H, dtt, J = 11.9, 7.4, 6.1 Hz), 2.56 (1H, dd, J = 15.6, 5.7 Hz), 2.62 (1H, dd, J = 15.6, 7.4 Hz), 3.80 (1H, dt, J = 8.6, 7.0 Hz), 3.92 (1H, dt, J = 8.2, 7.0 Hz), 4.26 (1H, tt) , J = 6.5, 6.5 Hz).

LC / MS [Condition 1]: retention time 0.73 min; m / z 130.9 [M + H] ⁺ (ESI positive ion mode)

Example 14
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N ′-[2- (tetrahydrofuran-2-yl) acetyl] cyclohexanecarbohydrazide (Compound No. 14) (1r, 4r) -4-({2-oxo-8- [ 4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarbohydrazide dihydrochloride (42 mg, 0.077 mmol) and Reference Example 14 The obtained 2- (tetrahydrofuran-2-yl) acetic acid (15 mg, 0.12 mmol) and 1-hydroxybenzotriazole (10 mg, 0.077 mmol) were mixed with chloroform. Dissolve in chloroform (1.0 mL), add triethylamine (0.054 mL, 0.39 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (16 mg, 0.085 mmol) at room temperature. Stir at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure to distill off chloroform, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to separate the organic layer. Thereafter, the organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa. −3,8-diazaspiro [4.5] decan-3-yl} methyl) -N ′-[2- (tetrahydrofuran-2-yl) acetyl] cyclohexanecarbohydrazide (25 mg, 55% yield) as a white powder Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 12.7 Hz), 1.43-1.67 (4H, m), 1.71-1.85 (4H, m), 2.17-1.86 (8H, m), 2.41-2.62 (6H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.81 (1H, q, J = 6.5 Hz), 3.96 (1H, q, J = 7.0 Hz), 4.10-4.22 ( 1H, m), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 8.05 (1H, d, J = 4.5 Hz), 9.08 (1H, d, J = 4.5 Hz).

LC / MS [Condition 1]: Retention time 2.81 minutes; m / z 580.9 [M + H] ⁺ (ESI positive ion mode), m / z 579.1 [MH] ⁻ (ESI negative ion mode)

Example 16
3-{[(1r, 4r) -4- (piperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Production of decan-2-one (Compound No. 16) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl]-) obtained in Reference Example 6-3 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (66 mg, 0.15 mmol) and piperidine (0.016 mL, 0.16 mmol), and 1-hydroxybenzotriazole (20 mg, 0.15 mol) was dissolved in chloroform (1.0 ml) and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide salt at room temperature. Salt (31 mg, 0.16 mmol) and the mixture was stirred at room temperature for 3 days. Thereafter, the reaction mixture was concentrated under reduced pressure to distill off chloroform, and ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 10/1], 3-{[(1r, 4r) -4- (piperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-2-one (44 mg, 57% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.46-1.70 (9H, m), 1.70-1.86 (6H, m), 1.88-2.00 (2H, m), 2.38-2.51 (1H, m), 2.56 (4H, brs), 3.10 (2H, d, J = 7. 4 Hz), 3.25 (2H, s), 3.41 (2H, t, J = 5.1 Hz), 3.49-3.62 (4H, m), 7.43 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 521.9 [M + H] ⁺ (ESI positive ion mode), m / z 566.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 17-1
(1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} of methyl cyclohexanecarboxylate (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylic acid obtained in Preparation Reference Example 6-1 Methyl hydrochloride (910 mg, 2.6 mmol) was dissolved in N, N-dimethylformamide (10 mL), and then 4-cyanobenzyl bromide (570 mg, 2.9 mmol), triethylamine (1.1 mL, 7.9 mmol) at room temperature. ) And stirred at room temperature for 1 day. Thereafter, 100 mL of water was added, and the precipitated solid was collected by filtration, and (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4 .5] Decan-3-yl] methyl} cyclohexanecarboxylate (1.0 g, 92% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 12.3 Hz), 1.41 (2H, q, J = 12.3 Hz), 1.49-1.66 ( 1H, m), 1.70-1.85 (4H, m), 1.88-2.07 (4H, m), 2.25 (1H, tt, J = 12.3, 4.5 Hz), 2.50-2.61 (4H, brm), 3.09 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.57 (2H, s), 3.66 ( 3H, s), 7.44 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.61 minutes; m / z 425.9 [M + H] ⁺ (ESI positive ion mode), m / z 470.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 17-2
Preparation of (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3 obtained in Reference Example 17-1 -Il] methyl} methyl cyclohexanecarboxylate (1.0 g, 2.4 mmol) was dissolved in methanol (10 mL), 1 M aqueous sodium hydroxide solution (3.6 mL, 3.6 mmol) was added at room temperature, and Stir for 3 hours. The reaction mixture was concentrated under reduced pressure to distill off methanol, and water (4.0 mL) was added. 1M hydrochloric acid was added until the pH reached 6, and the precipitated solid was collected by filtration to give (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro. [4.5] Decan-3-yl] methyl} cyclohexanecarboxylic acid (1.0 g, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.92 (2H, q, J = 13.1 Hz), 1.27 (2H, q, J = 12.7 Hz), 1.42-2. 20 (10H, m), 2.30-2.59 (6H, brm), 2.97 (2H, d, J = 7.0 Hz), 3.34 (2H, s), 7.33-8. 12 (4H, m), 12.02 (1H, s).

LC / MS [Condition 1]: Retention time 1.04 minutes; m / z 411.9 [M + H] ⁺ (ESI positive ion mode)

Example 17
4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide ) Production of t-butyl piperidine-1-carboxylate (Compound No. 17) (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-] obtained in Reference Example 17-2 1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (110 mg, 0.26 mmol) and t-butyl 4-aminopiperidine-1-carboxylate (58 mg, 0 .29 mmol) and 1-hydroxybenzotriazole (35 mg, 0.26 mol) in N, N-dimethylformamide (1.0 ml), 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (55 mg, 0.29 mmol) was stirred for 1 day after the addition of. Then, chloroform and saturated sodium hydrogencarbonate aqueous solution were added to the reaction mixture, and the organic layer was isolate | separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3 , 8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide) t-butyl piperidine-1-carboxylate (70 mg, 45% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 11.5 Hz), 1.19-1.36 (2H, m), 1.38-1.68 (13H, m), 1.69-2.06 (10H, m), 2.56 (4H, brs), 2.84 (2H, t, J = 12.9 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.82-4.13 (3H, m), 5.29 (1 H, d, J = 8.2 Hz) 7.44 (2H, d, J = 7.4 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [condition 1]: retention time 3.16 minutes; m / z 594.0 [M + H] ⁺ (ESI positive ion mode), m / z 638.2 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 18
(1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- (piperidine Preparation of 4-yl) cyclohexanecarboxamide dihydrochloride 4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-] obtained in Example 17 3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide) piperidine-1-carboxylate t-butyl (64 mg, 0.11 mmol) dissolved in methanol and 4M hydrogen chloride at room temperature Add dioxane solution (0.28 mL, 1.1 mmol) and stir at 60 ° C. for 1 hour. Then, it was concentrated to dryness under reduced pressure, and (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl ] Methyl} -N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (64 mg, quantitative) was obtained as a green solid.

LC / MS [Condition 1]: retention time 0.53 minutes; m / z 493.9 [M + H] ⁺ (ESI positive ion mode), m / z 528.1 [M + Cl] ⁻ (ESI negative ion mode)

Example 18
4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide ) Preparation of methyl piperidine-1-carboxylate (Compound No. 18) (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-] obtained in Reference Example 18 3,8-Diazaspiro [4.5] decan-3-yl] methyl} -N- (piperidin-4-yl) cyclohexanecarboxamide dihydrochloride (17 mg, 0.030 mmol) was added to N, N-dimethylformamide (0. 50 mL), and triethylamine (0.021 mL, 0.15 mmol) and methyl chloroformate (0.0040 mL, 0.045 mmol) were added at room temperature. And the mixture was stirred in 3 hours. Chloroform and water were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3, Methyl 8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide) piperidine-1-carboxylate (6.2 mg, 36% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 11.9 Hz), 1.18-1.37 (2H, m), 1.37-1.66 (3H, m), 1.69-1.83 (4H, m), 1.83 to 2.05 (7H, m), 2.55 (4H, brs), 2.89 (2H, t, J = 1.11. 9 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.56 (2H, s), 3.68 (3H, s), 3.83-3 .99 (1H, m), 4.08 (2H, brs), 5.30 (1H, d, J = 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.60 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.69 minutes; m / z 551.9 [M + H] ⁺ (ESI positive ion mode)

Example 19
(1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- [1 Preparation of — (cyanomethyl) piperidin-4-yl] cyclohexanecarboxamide (Compound No. 19) The reaction was conducted in substantially the same manner as in Example 18 except that bromoacetonitrile was used instead of methyl chloroformate to give the title compound ( 2.4 mg, 13% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 13.1 Hz), 1.38-1.65 (5H, m), 1.70-1.84 (4H, m), 1.84-2.06 (7H, m), 2.45 (2H, t, J = 11.0 Hz), 2.56 (4H, brs), 2.71-2.82 (2H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.50 (2H, s), 3.56 (2H, s), 3.74-3 .89 (1H, m), 5.27 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.60 (2H, d, J = 7. 8 Hz).

LC / MS [Condition 1]: Retention time 1.08 minutes; m / z 532.7 [M + H] ⁺ (ESI positive ion mode), m / z 567.0 [M + Cl] ⁻ (ESI negative ion mode)

Example 20
(1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 20) Substantially the same as Example 17 except that tetrahydrofurfurylamine was used in place of t-butyl 4-aminopiperidine-1-carboxylate Reaction was performed to obtain the title compound (13 mg, yield 32%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 11.6 Hz), 1.66-1.39 (4H, m), 1.71-2.10 (12H, m), 2.49-2.61 (4H, brm), 3.03-3.17 (3H, m), 3.25 (2H, s), 3.53-3.64 (3H, m) , 3.70-3.79 (1H, m), 3.80-3.89 (1H, m), 3.89-3.99 (1H, m), 5.79 (1H, t, J = 5.3 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 1.42 minutes; m / z 494.9 [M + H] ⁺ (ESI positive ion mode), m / z 539.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 21
Production of 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid Example 1 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid obtained in Methyl (5.2 g, 11 mmol) was dissolved in a mixed solvent of methanol-tetrahydrofuran (25 mL-25 mL), 1M aqueous sodium hydroxide solution (56 mL, 56 mmol) was added, and the mixture was stirred at 60 ° C. for 30 min. The reaction mixture was cooled, 1,4-dioxane (100 mL) was added, and the mixture was concentrated under reduced pressure. Water (20 mL) and 1M hydrochloric acid (56 mL, 56 mmol) were added to the obtained pale yellow liquid. The precipitated solid was collected by filtration and dried at 50 ° C. under reduced pressure to give 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Decan-3-yl} methyl) benzoic acid (4.7 g, 94% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.67-1.85 (4H, m), 2.36-2.46 (4H, m), 3.20 (2H, s), 3 .56 (2H, s), 4.41 (2H, s), 7.36 (2H, d, J = 8.2 Hz), 7.51 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz), 7.92 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.89 minutes; m / z 448.8 [M + H] ⁺ (ESI positive ion mode), m / z 446.9 [MH] ⁻ (ESI negative ion mode)

Example 21
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine- Production of t-butyl 1-carboxylate (Compound No. 21) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 obtained in Reference Example 21 -Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (500 mg, 1.1 mmol), t-butyl 4-aminopiperidine-1-carboxylate (250 mg, 1.2 mmol), and 1-hydroxy 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide salt is dissolved in chloroform (6.0 ml) after dissolving benzotriazole (150 mg, 1.1 mol) at room temperature. It was stirred for 1 day after the addition of salt (230mg, 1.2mmol). Thereafter, the reaction mixture was concentrated under reduced pressure to distill off chloroform, and ethyl acetate (20 mL) and saturated aqueous sodium hydrogen carbonate solution were added to the residue to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine-1-carboxylate (680 mg, 97% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.51-1.33 (11H, m), 1.65-1.78 (2H, m), 1.84-1.95 (2H, m) 1.97-2.07 (2H, m), 2.44-2.59 (4H, brm), 2.91 (2H, t, J = 12.1 Hz), 3.11 (2H, s) , 3.55 (2H, s), 4.02-4.21 (3H, m), 4.46 (2H, s), 6.00 (1H, d, J = 7.8 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.55 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 3.46 minutes; m / z 631.0 [M + H] ⁺ (ESI positive ion mode), m / z 675.2 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 22
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidine-4 Preparation of 4- yl) benzamide dihydrochloride 4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro obtained in Example 21 [4.5] decan-3-yl} methyl) benzamide] piperidine-1-carboxylate t-butyl (680 mg, 1.1 mmol) was dissolved in methanol (5.0 mL) and 4 M hydrogen chloride-dioxane at room temperature. The solution (2.7 mL, 11 mmol) was added and stirred at room temperature for 1 day. Thereafter, the solution was concentrated to dryness under reduced pressure to give 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl}. Methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (650 mg, quantitative) was obtained as a white powder.

LC / MS [Condition 1]: retention time 0.94 min; m / z 530.9 [M + H] ⁺ (ESI positive ion mode), m / z 575.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 22
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine- Preparation of methyl 1-carboxylate (Compound No. 22) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro obtained in Reference Example 22 [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (213 mg, 0.35 mmol) was dissolved in N, N-dimethylformamide (1.0 mL), Triethylamine (0.25 mL, 1.8 mmol) and methyl chloroformate (0.054 mL, 0.71 mmol) were added at room temperature, and the mixture was stirred at room temperature for 1 day. Thereafter, ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine-1-carboxylate (150 mg, 71% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.33-1.51 (2H, m), 1.65-1.79 (2H, m), 1.84-1.96 (2H, brm) 1.99-2.10 (2H, brm), 2.42-2.61 (4H, brm), 2.97 (2H, t, J = 11.9 Hz), 3.11 (2H, s) , 3.55 (2H, s), 3.70 (3H, s), 4.04-4.27 (3H, m), 4.46 (2H, s), 5.97 (1H, d, J = 7.8 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.55 (2H, d, J = 8.2 Hz) , 7.73 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.20 minutes; m / z 588.9 [M + H] ⁺ (ESI positive ion mode), m / z 633.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 23
N- [1- (cyanomethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 23) The reaction was conducted in substantially the same manner as in Example 22 except that bromoacetonitrile was used instead of methyl chloroformate to give the title compound (30 mg, yield). 80%) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 569.9 [M + H] ⁺ (ESI positive ion mode), m / z 614.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 24
N- (1-acetylpiperidin-4-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) benzamide (Compound No. 24) The reaction was conducted in substantially the same manner as in Example 22 except that acetyl chloride was used in place of methyl chloroformate to give the title compound (31 mg, yield 82 %) As a white solid.

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 572.8 [M + H] ⁺ (ESI positive ion mode), m / z 616.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 25
N- [1- (methylsulfonyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-3-yl} methyl) benzamide (Compound No. 25) The reaction was conducted in substantially the same manner as in Example 22 except that methanesulfonyl chloride was used in place of methyl chloroformate to give the title compound (30 mg Yield 75%) as a white solid.

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 608.8 [M + H] ⁺ (ESI positive ion mode), m / z 652.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 26
N- [1- (4-Chlorobenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 26) The reaction was carried out in substantially the same manner as in Example 22 except that 4-chlorobenzyl bromide was used instead of methyl chloroformate. The title compound (18 mg, 41% yield) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 654.9 [M + H] ⁺ (ESI positive ion mode), m / z 699.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 27
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- {1- [ Preparation of 4- (trifluoromethyl) benzyl] piperidin-4-yl} benzamide (Compound No. 27) Substantially Example 22 except that 4- (trifluoromethyl) benzyl bromide was used instead of methyl chloroformate. The title compound (27 mg, yield 60%) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 689.0 [M + H] ⁺ (ESI positive ion mode), m / z 733.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 28
N- [1- (3-Methylbenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 28) The reaction was carried out in substantially the same manner as in Example 22 except that α-bromo-m-xylene was used instead of methyl chloroformate. To give the title compound (22 mg, 51% yield) as a white solid.

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 635.0 [M + H] ⁺ (ESI positive ion mode), m / z 679.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 29
N- (1-ethylpiperidin-4-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) benzamide (Compound No. 29) The reaction was conducted in substantially the same manner as in Example 22 except that bromoethane was used in place of methyl chloroformate to give the title compound (7.4 mg, yield). 20%) as a white solid.

LC / MS [Condition 1]: Retention time 1.16 minutes; m / z 558.9 [M + H] ⁺ (ESI positive ion mode)

Example 30
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- {1- [ Preparation of 4- (trifluoromethoxy) benzyl] piperidin-4-yl} benzamide (Compound No. 30) Substantially the same as in Example 22 except that 4- (trifluoromethoxy) benzyl bromide was used instead of methyl chloroformate. The reaction was performed in the same manner to obtain the title compound (30 mg, yield 66%) as a white solid.

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 705.3 [M + H] ⁺ (ESI positive ion mode), m / z 749.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 31
N- {1- [2- (diethylamino) -2-oxoethyl] piperidin-4-yl} -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (Compound No. 31) 4-({2-oxo-8- [4- (trifluoromethyl)) obtained in Reference Example 22 [Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (40 mg, 0.066 mmol) was added to N, N -Dissolved in dimethylformamide (4.0 mL), triethylamine (0.046 mL, 0.33 mmol), and N, N-diethylchloroacetamide (0.018 mL, 0.13 mm) at room temperature l) and the mixture was stirred for 1 day at 40 ° C.. The reaction mixture was concentrated under reduced pressure to distill off N, N-dimethylformamide. The obtained residue was purified by HPLC, and N- {1- [2- (diethylamino) -2-oxoethyl] piperidin-4-yl} -4-({2-oxo-8- [4- (tri Fluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (17 mg, 40% yield) was obtained as a yellow solid.

LC / MS [Condition 1]: Retention time 2.73 minutes; m / z 643.9 [M + H] ⁺ (ESI positive ion mode), m / z 688.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 32
N- {1- [4- (methylthio) benzyl] piperidin-4-yl} -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro Preparation of [4.5] decan-3-yl} methyl) benzamide (Compound No. 32) Substantially the same as in Example 31 except that 4- (methylthio) benzyl bromide was used instead of N, N-diethylchloroacetamide. The reaction was performed in the same manner to obtain the title compound (13 mg, yield 30%) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.20 minutes; m / z 666.9 [M + H] ⁺ (ESI positive ion mode), m / z 710.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 33
N- [1- (Naphthalen-2-ylmethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 33) Substantially the same as Example 31 except that 2- (bromomethyl) naphthalene was used instead of N, N-diethylchloroacetamide. Reaction was performed to obtain the title compound (16 mg, yield 36%) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.34 minutes; m / z 671.1 [M + H] ⁺ (ESI positive ion mode), m / z 715.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 34
N- [1- (3-nitrobenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 34) The reaction was carried out in substantially the same manner as in Example 31 except that 3-nitrobenzyl bromide was used instead of N, N-diethylchloroacetamide Performed to give the title compound (14 mg, 32% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 666.0 [M + H] ⁺ (ESI positive ion mode), m / z 710.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 35
N- [1- (3-Chlorobenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 35) The reaction was carried out in substantially the same manner as in Example 31 except that 3-chlorobenzyl bromide was used instead of N, N-diethylchloroacetamide. Performed to give the title compound (13 mg, 30% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 654.9 [M + H] ⁺ (ESI positive ion mode), m / z 699.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 36
N- [1- (3-methoxybenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 36) The reaction was carried out in substantially the same manner as in Example 31 except that 3-methoxybenzyl bromide was used instead of N, N-diethylchloroacetamide. Performed to give the title compound (14 mg, 33% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 650.9 [M + H] ⁺ (ESI positive ion mode), m / z 695.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 37
N- [1- (3-cyanobenzyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 37) Reaction was substantially the same as Example 31 except that 3-bromomethylbenzonitrile was used instead of N, N-diethylchloroacetamide. To give the title compound (12 mg, 28% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 646.0 [M + H] ⁺ (ESI positive ion mode), m / z 690.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 38
4- (4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of piperidin-1-yl) ethyl butanoate (Compound No. 38) The reaction was carried out in substantially the same manner as in Example 31 except that ethyl 4-bromobutyrate was used in place of N, N-diethylchloroacetamide. The title compound (63 mg, 61% yield) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 2.79 minutes; m / z 645.0 [M + H] ⁺ (ESI positive ion mode), m / z 689.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 39
3-({4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of benzamido] piperidin-1-yl} methyl) methyl benzoate (Compound No. 39) Essentially the same as Example 31 except that methyl 3- (bromomethyl) benzoate was used in place of N, N-diethylchloroacetamide. The reaction was performed in the same manner to obtain the title compound (73 mg, yield 67%) as a white solid.

LC / MS [Condition 1]: Retention time 2.98 minutes; m / z 679.1 [M + H] ⁺ (ESI positive ion mode), m / z 723.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 40
4-({4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamido] piperidin-1-yl} methyl) Preparation of Methyl Benzoate (Compound No. 40) Substantially as in Example 31 except that methyl 4- (bromomethyl) benzoate is used in place of N, N-diethylchloroacetamide. The reaction was performed in the same manner to obtain the title compound (84 mg, yield 77%) as a yellow solid.

LC / MS [Condition 1]: Retention time 2.98 minutes; m / z 679.1 [M + H] ⁺ (ESI positive ion mode), m / z 723.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 41
4-({4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of benzamido] piperidin-1-yl} methyl) benzoic acid (Compound No. 41) 4-({4- [4-({2-oxo-8- [4- (trifluoro )] obtained in Example 40 Methyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamido] piperidin-1-yl} methyl) methyl benzoate (33 mg, 0.048 mmol) in methanol After dissolution, 1 M aqueous sodium hydroxide solution (0.088 mM, 0.48 mmol) was added at room temperature, and the mixture was stirred at 60 ° C. for 10 hr. The reaction mixture was concentrated under reduced pressure to distill off methanol, and 1M hydrochloric acid was added until pH 7 was reached. Thereafter, chloroform was added to separate the organic layer, and the obtained organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give 4-({4- [4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamido] piperidin-1-yl} methyl) benzoic acid (5.2 mg, Yield 16%) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 2.61 minutes; m / z 665.1 [M + H] ⁺ (ESI positive ion mode), m / z 663.1 [MH] ⁻ (ESI negative ion mode)

Example 42
N- (1- (2-ethylbutyl) piperidin-4-yl) -4-((2-oxo-8- (4- (trifluoromethyl) benzyl) -1-oxa-3,8-diazaspiro [4. 5] Preparation of Decan-3-yl) methyl) benzamide (Compound No. 42) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa obtained in Reference Example 22 -3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (38 mg, 0.063 mmol) dissolved in methanol and acetic acid at room temperature (0.011 mL, 0.19 mmol) and 2-ethylbutyraldehyde (0.045 mL, 0.38 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Then, sodium triacetoxyborohydride (70 mg, 0.32 mmol) was added to the reaction mixture and stirred for 3 days. Thereafter, chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to distill off chloroform. The obtained residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: hexane / ethyl acetate = 1/4], and N- [1- (2-ethylbutyl) piperidine- 4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide ( 24 mg, 62% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.86 (6H, t, J = 7.4 Hz), 1.21-1.45 (5H, m), 1.47-1.62 (2H, m), 1.65-1.78 (2H, m), 1.83-2.19 (8H, m), 2.45-2.60 (4H, brm), 2.80 (2H, d, J = 11.9 Hz), 3.11 (2H, s), 3.55 (2H, s), 3.90-4.06 (1H, m), 4.45 (2H, s), 5.97. (1H, d, J = 7.8 Hz), 7.32 (2H, d, J = 8.6 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.73 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 615.0 [M + H] ⁺ (ESI positive ion mode), m / z 659.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 43
N- [1- (cyclohexylmethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) benzamide (Compound No. 43) The reaction was conducted in substantially the same manner as in Example 42 except that cyclohexanecarboxaldehyde was used instead of 2-ethylbutyraldehyde to give the title compound ( 2.8 mg, 11% yield) was obtained as a yellow solid.

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 627.0 [M + H] ⁺ (ESI positive ion mode), m / z 671.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 44
N- (2-morpholinoethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 44) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4] obtained in Reference Example 21 .5] decan-3-yl} methyl) benzoic acid (40 mg, 0.089 mmol), 4- (2-aminoethyl) morpholine (0.023 mL, 0.18 mmol), and 1-hydroxybenzotriazole (12 mg, 0.089 mol) was dissolved in N, N-dimethylformamide (4.0 mL) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.0 2 mL, 0.18 mmol) was added, which was stirred for 1 day at 40 ° C.. The reaction mixture was concentrated under reduced pressure to distill off N, N-dimethylformamide, chloroform and saturated aqueous sodium hydrogen carbonate solution were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to distill off chloroform, and the residue was purified by HPLC, and N- (2-morpholinoethyl) -4-({2-oxo -8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (38 mg, 95% yield) was obtained as a yellow solid. It was.

LC / MS [Condition 1]: Retention time 1.04 minutes; m / z 561.2 [M + H] ⁺ (ESI positive ion mode), m / z 605.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 45
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [3- ( Preparation of 2-oxopyrrolidin-1-yl) propyl] benzamide (Compound No. 45) Substantially except that 1- (3-aminopropyl) -2-pyrrolidone is used instead of 4- (2-aminoethyl) morpholine Was reacted in the same manner as in Example 44 to give the title compound (41 mg, quantitative) as a brown oil.

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 572.9 [M + H] ⁺ (ESI positive ion mode), m / z 617.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 46
N- (1-methoxybutan-2-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) benzamide (Compound No. 46) The reaction was carried out in substantially the same manner as in Example 44, except that 2-amino-1-methoxybutane was used instead of 4- (2-aminoethyl) morpholine. Performed to give the title compound (35 mg, quantitative) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 533.9 [M + H] ⁺ (ESI positive ion mode), m / z 578.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 47
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] benzamide (Compound No. 47) The reaction was conducted in substantially the same manner as in Example 44 except that tetrahydrofurfurylamine was used in place of 4- (2-aminoethyl) morpholine. (35 mg, quantitative) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 531.8 [M + H] ⁺ (ESI positive ion mode), m / z 575.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 48
N-cyclooctyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide ( Preparation of Compound No. 48) The reaction was conducted in substantially the same manner as in Example 44 except that cyclooctylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (37 mg, quantitative) as yellow Obtained as a solid.

LC / MS [Condition 1]: Retention time 3.62 minutes; m / z 557.9 [M + H] ⁺ (ESI positive ion mode), m / z 602.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 49
(S) -N- (1-hydroxy-4-methylpentan-2-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl} methyl) benzamide (Compound No. 49) Substantially carried out except that L-(+)-leucinol was used instead of 4- (2-aminoethyl) morpholine The reaction was carried out in the same manner as in Example 44 to obtain the title compound (33 mg, yield 94%) as a white solid.

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 547.8 [M + H] ⁺ (ESI positive ion mode), m / z 592.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 50
N- (1-adamantylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 50) The reaction was conducted in substantially the same manner as in Example 44 except that 1-adamantanemethylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (39 mg , Quantitative) was obtained as a yellow solid.

LC / MS [Condition 1]: Retention time 3.78 minutes; m / z 595.8 [M + H] ⁺ (ESI positive ion mode), m / z 640.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 51
t-butyl 5- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of pentylcarbamate (Compound No. 51) Substantially the same as Example 44, except that N- (t-butoxycarbonyl) -1,5-diaminopentane was used instead of 4- (2-aminoethyl) morpholine. The title compound (41 mg, quantitative) was obtained as a brown oil.

LC / MS [Condition 1]: Retention time 3.44 minutes; m / z 632.8 [M + H] ⁺ (ESI positive ion mode), m / z 677.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 52
t-butyl 6- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of hexyl carbamate (Compound No. 52) Substantially the same as Example 44, except that N- (t-butoxycarbonyl) -1,6-diaminohexane was used instead of 4- (2-aminoethyl) morpholine. The title compound (43 mg, quantitative) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.54 minutes; m / z 646.9 [M + H] ⁺ (ESI positive ion mode), m / z 691.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 53
3- [4- (Thiomorpholine-4-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (compound Preparation of No. 53) The reaction was carried out in substantially the same manner as in Example 44 except that thiomorpholine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (35 mg, quantitative) as a white solid. Obtained.

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 533.7 [M + H] ⁺ (ESI positive ion mode), m / z 578.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 54
3- {4- [4- (Pyrrolidin-1-yl) piperidin-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-2-one (Compound No. 54) Reaction substantially in the same manner as in Example 44 except that 4- (pyrrolidin-1-yl) piperidine was used instead of 4- (2-aminoethyl) morpholine To give the title compound (28 mg, 72% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 1.12 minutes; m / z 584.7 [M + H] ⁺ (ESI positive ion mode), m / z 629.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 55
3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of (Compound No. 55) The reaction was conducted in substantially the same manner as in Example 44 except that 4-benzoylpiperidine hydrochloride and triethylamine were used instead of 4- (2-aminoethyl) morpholine to give the title compound (41 mg , Quantitative) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 619.8 [M + H] ⁺ (ESI positive ion mode), m / z 664.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 56
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 56) The reaction was carried out in substantially the same manner as in Example 44, except that piperonylamine was used instead of 4- (2-aminoethyl) morpholine. To give the title compound (38 mg, quantitative) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 581.8 [M + H] ⁺ (ESI positive ion mode), m / z 625.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 57
N- (2,3-dihydro-1H-inden-1-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 57) Reaction substantially in the same manner as in Example 44 except that 1-aminoindane was used instead of 4- (2-aminoethyl) morpholine To give the title compound (37 mg, quantitative) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.50 minutes; m / z 563.8 [M + H] ⁺ (ESI positive ion mode), m / z 607.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 58
N- (Naphthalen-1-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Preparation of methyl) benzamide (Compound No. 58) The reaction was conducted in substantially the same manner as in Example 44 except that 1-naphthylmethylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound ( 38 mg, quantitative) was obtained as a yellow solid.

LC / MS [Condition 1]: Retention time 3.56 min; m / z 587.8 [M + H] ⁺ (ESI positive ion mode), m / z 632.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 59
N- (2,3-dihydro-1H-inden-2-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 59) Reaction substantially in the same manner as in Example 44 except that 2-aminoindane was used instead of 4- (2-aminoethyl) morpholine To give the title compound (10 mg, 27% yield) as a yellow solid.

LC / MS [Condition 1]: Retention time 3.50 minutes; m / z 563.8 [M + H] ⁺ (ESI positive ion mode), m / z 607.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 60
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-phenethylbenzamide (compound Preparation of No. 60) The reaction was conducted in substantially the same manner as in Example 44 except that phenethylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (30 mg, yield 81%) as a white solid Got as.

LC / MS [Condition 1]: Retention time 3.40 minutes; m / z 551.8 [M + H] ⁺ (ESI positive ion mode), m / z 596.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 61
N-isopropyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (compound Preparation of No. 61) The reaction was conducted in substantially the same manner as in Example 44 except that isopropylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (39 mg, yield 88%) as white Obtained as a solid.

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 489.7 [M + H] ⁺ (ESI positive ion mode), m / z 533.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 62
N-cyclohexyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (compound Preparation of No. 62) The reaction was carried out in substantially the same manner as in Example 44 except that cyclohexylamine was used instead of 4- (2-aminoethyl) morpholine to give the title compound (47 mg, quantitative) as a white solid. Obtained.

LC / MS [Condition 1]: Retention time 3.42 minutes; m / z 529.7 [M + H] ⁺ (ESI positive ion mode), m / z 573.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 63
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [1- ( Preparation of Pyridin-4-yl) piperidin-4-yl] benzamide (Compound No. 63) Essentially except that 4- (4-aminopiperidino) pyridine was used in place of 4- (2-aminoethyl) morpholine The reaction was conducted in the same manner as for 44 to give the title compound (51 mg, yield 79%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.49-1.65 (2H, m), 1.65-1.78 (2H, m), 1.85-1.96 (2H, brm) 2.10-2.21 (2H, brm), 2.62-2.42 (4H, brm), 2.98-3.15 (4H, m), 3.55 (2H, s), 3 .86-3.97 (2H, brm), 4.18-4.33 (1H, m), 4.46 (2H, s), 6.01 (1H, d, J = 7.8 Hz), 6 .69 (2H, dd, J = 5.3, 1.6 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7. 56 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz), 8.28 (2H, dd, J = 5.3, 1.6 Hz).

Reference Example 64
Preparation of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride Nicotinaldehyde (purchased from Tokyo Chemical Industry Co., Ltd.) (1.3 g, 12 mmol) was dissolved in chloroform (50 ml) at room temperature. 4- (t-Butoxycarbonylamino) piperidine (purchased from Sigma-Aldrich) (2.4 g, 12 mmol) was added, and the mixture was stirred for 2 minutes. Sodium triacetoxyborohydride (3.2 g, 15 mmol) was slowly added to the reaction mixture, and then stirred at room temperature for 4 hours. After adding 1M aqueous sodium hydroxide solution to the reaction mixture, the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give 1- (pyridin-3-ylmethyl) -4- (t-butoxycarbonylamino) piperidine as a white solid Got as. Without further purification, this compound was dissolved in methanol (5.0 ml), a 4M hydrogen chloride-dioxane solution (25 ml) was added at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, methanol and ethyl acetate were added to the obtained residue, and the mixture was allowed to stand overnight. The precipitated solid was collected by filtration and dried at 50 ° C. under reduced pressure for 1 hour to give 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride (2.9 g, yield 81%) as a white solid Got as.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 2.03-2.22 (2H, m), 2.28 (2H, d, J = 13.0 Hz), 3.25-3.45 (2H M), 3.49-3.62 (1H, m), 3.67 (2H, d, J = 12.6 Hz), 4.68 (2H, s), 8.19 (1H, dd, J = 8.2, 5.8 Hz), 8.94 (1H, dt, J = 8.2, 1.7 Hz), 8.98 (1H, d, J = 5.8 Hz), 9.26 (1H, d, J = 1.7 Hz).

Example 64
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [1- ( Preparation of Pyridin-3-ylmethyl) piperidin-4-yl] benzamide (Compound No. 64) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa obtained in Reference Example 21 -3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (23 mg, 0.051 mmol), 4-amino-1- (pyridin-3-ylmethyl) obtained in Reference Example 64 Piperidine trihydrochloride (18 mg, 0.062 mmol) and triethylamine (0.035 mL, 0.26 mmol) are suspended in chloroform (1.5 mL) and 1-hydroxybenzotriazole ( .8Mg, stirred 16 hours at room temperature After addition of 0.051 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (14 mg, 0.076 mmol). Chloroform (1.0 mL) and saturated aqueous sodium hydrogen carbonate solution (2.0 mL) were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform (2.0 mL). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: ethyl acetate] The title compound (25 mg, 80% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.56 (2H, dq, J = 3.9, 11.6 Hz), 1.66-1.79 (2H, m), 1.85-1. 96 (2H, m), 2.21 (2H, dt, J = 2.8, 11.6 Hz), 2.43-2.62 (4H, m), 2.85 (2H, d, J = 11 .8 Hz), 3.11 (2H, s), 3.54 (4 H, d, J = 5.8 Hz), 3.93-4.10 (1 H, m), 4.46 (2 H, s), 6.01 (1H, d, J = 7.4 Hz), 7.26 (3H, dd, J = 7.4, 5.0 Hz), 7.33 (2H, d, J = 8.3 Hz), 7 .42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.0 Hz), 7.66 (1H, dt, J = 7.7, 1.9 Hz), 7. 74 (2H, d, J 8.3Hz), 8.51 (1H, dd, J = 4.7,1.7Hz), 8.56 (1H, d, J = 1.9Hz).

LC / MS [Condition 1]: Retention time 1.19 minutes; m / z 621.8 [M + H] ⁺ (ESI positive ion mode), m / z 620.0 [MH] ⁻ (ESI negative ion mode)

Example 65
N- [3- (dimethylamino) propyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) Preparation of benzamidoformate (Compound No. 65) Substantially except that N, N-dimethylpropanediamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of 4- (2-aminoethyl) morpholine The reaction was carried out as in Example 44 to give the title compound (43 mg, 79% yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.78-1.99 (4H, m), 2.11 (2H, tt, J = 6.1, 6.5 Hz), 2.57-2. 74 (4H, m), 2.76 (6H, s), 3.09 (2H, t, J = 6.8 Hz), 3.15 (2H, s), 3.58 (2H, q, J = 6.1 Hz), 3.69 (2H, s), 4.45 (2H, s), 7.34 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J = 7. 2 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.93 (2H, d, J = 8.5 Hz), 8.19 (1H, t, J = 5.5 Hz), 8. 40 (2H, s).

LC / MS [Condition 1]: Retention time 1.07 minutes; m / z 532.8 [M + H] ⁺ (ESI positive ion mode), m / z 577.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 66
3- [4- (morpholine-4-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-oneformate ( Preparation of Compound No. 66) The reaction was conducted in substantially the same manner as in Example 44 except that morpholine (purchased from Junsei Kagaku) was used instead of 4- (2-aminoethyl) morpholine to give the title compound ( 38 mg, yield 76%) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.83-1.99 (4H, m), 2.61-2.90 (4H, m), 3.16 (2H, s), 3.24 -3.95 (10H, brm), 4.44 (2H, s), 7.31 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7 .47 (3H, d, J = 8.2 Hz), 7.60 (2H, d, J = 8.2 Hz), 8.22 (1H, s).

LC / MS [Condition 1]: Retention time 2.91 minutes; m / z 517.8 [M + H] ⁺ (ESI positive ion mode), m / z 561.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 67
N-benzyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide formate Production of (Compound No. 67) The reaction was carried out in substantially the same manner as in Example 44 except that benzylamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of 4- (2-aminoethyl) morpholine. The title compound (10 mg, 21% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.64-1.90 (3H, brm), 2.33 to 2.56 (2H, brm), 3.21 (2H, s), 3 .75-3.38 (5H, m), 4.39 (2H, s), 4.46 (2H, d, J = 5.8 Hz), 7.18-7.33 (5H, m), 7 .34 (2H, d, J = 8.2 Hz), 7.47-7.61 (2H, m), 7.63-7.76 (2H, m), 7.88 (3H, d, J = 8.2 Hz), 9.04 (1H, t, J = 5.5 Hz).

LC / MS [Condition 1]: Retention time 3.37 minutes; m / z 537.8 [M + H] ⁺ (ESI positive ion mode), m / z 535.9 [MH] ⁻ (ESI negative ion mode)

Example 68
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (pyridine-3 -Preparation of ylmethyl) benzamide (Compound No. 68) Except for using 4-picolylamine (purchased from Tokyo Chemical Industry Co., Ltd.) instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The reaction was carried out substantially in the same manner as in Example 64 to obtain the title compound (17 mg, yield 70%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65-1.78 (2H, m), 1.84-1.96 (2H, m), 2.42-2.62 (4H, brm) , 3.12 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.67 (2H, d, J = 6.1 Hz), 6.54 (1H, t , J = 5.5 Hz), 7.29 (1H, dd, J = 8.2, 5.1 Hz), 7.34 (2H, d, J = 8.5 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.72 (1H, dt, J = 7.8, 2.0 Hz), 7.79 (2H, d, J = 8.2 Hz), 8.55 (1H, dd, J = 4.8, 1.7 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 1.21 minutes; m / z 536.9 [MH] ⁻ (ESI negative ion mode)

Example 69
4-([4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamido] methyl ) Preparation of methyl benzoate (Compound No. 69) 4- (Aminomethyl) benzoic acid methyl hydrochloride instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The reaction was carried out substantially in the same manner as in Example 64 except that was used to obtain the title compound (140 mg, quantitative) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72 (2H, ddd, J = 13.6, 6.8, 7.2 Hz), 1.90 (2H, dt, J = 13.3, ₃ ) .4 Hz), 2.42-2.60 (4H, m), 3.12 (2H, s), 3.55 (2H, s), 3.91 (3H, s), 4.46 (2H, s), 4.71 (2H, d, J = 6.1 Hz), 6.52 (1H, t, J = 5.8 Hz), 7.34 (2H, d, J = 8.2 Hz), 7. 42 (4H, d, J = 8.5 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.80 (2H, d, J = 8.5 Hz), 8.02 (2H, d , J = 8.4 Hz).

LC / MS [Condition 1]: Retention time 3.41 minutes; m / z 595.81 [M + H] ⁺ (ESI positive ion mode), m / z 593.9 [MH] ⁻ (ESI negative ion mode)

Example 70
t-butyl 2- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of ethyl carbamate (Compound No. 70) Instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride, t-butyl 2-aminoethylcarbamate (purchased from Tokyo Chemical Industry Co., Ltd.) The reaction was carried out substantially in the same manner as in Example 64 except for using, and the title compound (11 mg, yield 43%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.43 (9H, s), 1.71 (2H, ddd, J = 14.0, 6.5, 5.8 Hz), 1.84-1. 97 (2H, m), 2.42-2.61 (4H, m), 3.11 (2H, s), 3.41 (2H, q, J = 5.5 Hz), 3.55-3. 57 (4H, m), 4.46 (2H, s), 4.96 (1H, brs), 7.32 (3H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.81 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.27 minutes; m / z 590.9 [M + H] ⁺ (ESI positive ion mode), m / z 634.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 71
t-butyl 4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of butyl carbamate (Compound No. 71) Instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride, t-butyl 4-aminobutylcarbamate (purchased from Tokyo Chemical Industry Co., Ltd.) The reaction was carried out substantially in the same manner as in Example 64 except for using, and the title compound (25 mg, yield 80%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.54-1.67 (4H, m), 1.72 (2H, ddd, J = 14.0, 7. 2,6.8 Hz), 1.91 (2H, dt, J = 13.0, 4.1 Hz), 2.46-2.59 (4H, m), 3.12 (2H, s), 3. 17 (2H, q, J = 6.1 Hz), 3.50 (2H, q, J = 6.5 Hz), 3.55 (2H, s), 4.46 (2H, s), 4.65 ( 1H, brs), 6.57 (1H, brs), 7.32 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 3.41 min; m / z 618.9 [M + H] ⁺ (ESI positive ion mode), m / z 663.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 72
N-butyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (compound Preparation of No. 72) Substantially the same as Example 64 except that butylamine (purchased from Wako Pure Chemical Industries, Ltd.) was used instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The title compound (17 mg, 76% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.96 (3H, t, J = 7.2 Hz), 1.43 (2H, tt, J = 10.0, 5.0 Hz), 1.66— 1.54 (2H, m), 1.72 (2H, ddd, J = 13.8, 7.0, 6.5 Hz), 1.91 (2H, dt, J = 13.3, 3.7 Hz) , 2.44-2.62 (4H, m), 3.12 (2H, s), 3.46 (2H, q, J = 6.5 Hz), 3.55 (2H, s), 4.46 (2H, s), 6.10 (1H, t, J = 5.8 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz) 7.56 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.31 min; m / z 503.9 [M + H] ⁺ (ESI positive ion mode), m / z 547.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 73
N- (2-methoxyethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 73) Other than using 2-methoxyethylamine (purchased from Wako Pure Chemical Industries, Ltd.) instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The reaction was carried out substantially in the same manner as in Example 64 to obtain the title compound (15 mg, yield 64%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72 (2H, ddd, J = 14.3, 6.9, 6.1 Hz), 1.91 (2H, d, J = 12.7 Hz), 2.45-2.62 (4H, m), 3.12 (2H, s), 3.39 (3H, s), 3.55 (2H, s), 3.57 (2H, t, J = 5.0 Hz), 3.66 (2H, q, J = 5.2 Hz), 4.47 (2H, s), 6.51 (1H, brs), 7.33 (2H, d, J = 8. 3 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.56 (2H, d, J = 8.3 Hz), 7.77 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 2.95 minutes; m / z 505.8 [M + H] ⁺ (ESI positive ion mode), m / z 503.9 [MH] ⁻ (ESI negative ion mode)

Example 74
3- [4- (Piperidin-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 74) The reaction was carried out in substantially the same manner as in Example 64 except that piperidine (purchased from Junsei Kagaku) was used instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride. The title compound (12 mg, 52% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.80-1.43 (8H, m), 1.92 (2H, dt, J = 12.9, 4.1 Hz), 2.44-2. 61 (4H, m), 3.13 (2H, s), 3.25-3.43 (2H, brm), 3.56 (2H, s), 3.63-3.79 (2H, brm) 4.44 (2H, s), 7.29 (2H, d, J = 8.0 Hz), 7.38 (2H, d, J = 8.0 Hz), 7.43 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 3.29 minutes; m / z 515.8 [M + H] ⁺ (ESI positive ion mode), m / z 559.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 75
(1r, 4r) -4-{[4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) benzamido] methyl} methyl cyclohexanecarboxylate (Compound No. 75) Trans-4 obtained in Reference Example 2-1 instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride Reaction was carried out in substantially the same manner as in Example 64 except that methyl aminomethylcyclohexanecarboxylate hydrochloride was used to obtain the title compound as a white solid (20 mg, yield 75%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 3.4, 12.3 Hz), 1.44 (2H, dq, J = 3.4, 13.0 Hz), 1.52-1.79 (3H, m), 1.84-1.96 (4H, m), 1.98-2.08 (2H, m), 2.26 (1H, tt, J = 11 .9, 3.7 Hz), 2.62-2.43 (4H, m), 3.12 (2H, s), 3.33 (2H, t, J = 6.5 Hz), 3.55 (2H , S), 3.66 (3H, s), 4.46 (2H, s), 6.16 (1H, t, J = 5.8 Hz), 7.33 (2H, d, J = 8.2 Hz). ), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.75 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.37 minutes; m / z 601.9 [M + H] ⁺ (ESI positive ion mode), m / z 600.0 [MH] ⁻ (ESI negative ion mode)

Example 76
1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperidine- Preparation of methyl 4-carboxylate (Compound No. 76) Instead of using 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride, methyl isonipecotate (purchased from Tokyo Chemical Industry Co., Ltd.) was used. The reaction was carried out substantially in the same manner as in Example 64 to give the title compound (20 mg, yield 75%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.59-2.12 (8H, m), 2.46-2.58 (4H, m), 2.60 (1H, tt, J = 10. 6, 4.3 Hz), 2.98-3.17 (2H, m), 3.13 (2H, s), 3.56 (2H, s), 3.69-3.73 (1 H, m) 3.71 (3H, s), 4.61-4.38 (1H, m), 4.45 (2H, s), 7.30 (2H, d, J = 7.9 Hz), 7.39. (2H, d, J = 8.3 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: Retention time 3.21 minutes; m / z 573.8 [M + H] ⁺ (ESI positive ion mode), m / z 617.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 77
2- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamido] acetic acid ethyl Preparation of (Compound No. 77) Substantially except that glycine ethyl ester hydrochloride (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride The reaction was carried out in the same manner as in Example 64 to obtain the title compound as a white solid (20 mg, yield 75%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.32 (3H, t, J = 7.4 Hz), 1.65-1.79 (2H, m), 1.92 (2H, dt, J = 12.7, 3.7 Hz), 2.45-2.62 (4H, m), 3.12 (2H, s), 3.55 (2H, s), 4.24 (2H, d, J = 4.9 Hz), 4.27 (2H, q, J = 7.0 Hz), 4.47 (2H, s), 6.62 (1H, t, J = 4.9 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.80 (2H, d, J = 8) .2 Hz).

LC / MS [Condition 1]: Retention time 3.07 minutes; m / z 533.7 [M + H] ⁺ (ESI positive ion mode), m / z 532.0 [MH] ⁻ (ESI negative ion mode)

Example 78
(1r, 4r) -N- (2-Isopropoxyethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 78) The reaction was carried out in substantially the same manner as in Example 10 except that 2-aminoethylisopropyl ether was used instead of tetrahydrofurfurylamine. The compound (32 mg, 88% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.3 Hz), 1.16 (6H, d, J = 6.1 Hz), 2.08- 1.39 (12H, m), 2.50-2.61 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.38 ( 4H, s), 3.41 (2H, q, J = 4.9 Hz), 3.44-3.51 (2H, m), 3.52-3.63 (3H, m), 5.85 ( 1H, t, J = 4.9 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 539.8 [M + H] ⁺ (ESI positive ion mode), m / z 584.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 79
(1r, 4r) -N- (furan-2-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 79) The reaction was conducted in substantially the same manner as in Example 10 except that furfurylamine was used instead of tetrahydrofurfurylamine to give the title compound (35 mg, (96% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 12.7 Hz), 1.50 (2H, dq, J = 3.3, 12.3 Hz), 1.60-1.68 (1H, m), 1.70-1.85 (4H, m), 1.86-1.98 (4H, m), 2.04 (1H, tt, J = 11 .9, 3.7 Hz), 2.48-2.61 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H) , S), 4.43 (2H, d, J = 5.7 Hz), 5.73 (1H, t, J = 5.1 Hz), 6.21 (1H, d, J = 3.3 Hz), 6 .32 (1H, dd, J = 3.3, 1.6 Hz), 7.35-7.35 (1H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 ( 2H, d, J = 8. Hz).

LC / MS [Condition 1]: Retention time 3.21 minutes; m / z 533.8 [M + H] ⁺ (ESI positive ion mode), m / z 578.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 80
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- (tetrahydro-2H-pyran-4-yl) cyclohexanecarboxamide (Compound No. 80) Substantially Example 10 except that 4-amino-tetrahydro-2H-pyran hydrochloride was used instead of tetrahydrofurfurylamine The title compound (31 mg, yield 84%) was obtained as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 12.7 Hz), 1.35 to 2.06 (16H, m), 2.49-1. 62 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.46 (2H, td, J = 11.7, 2.0 Hz), 3.57 (2H, s), 3.88-4.06 (3H, m), 5.32 (1H, d, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz) ), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.97 minutes; m / z 537.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 81
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N-[(tetrahydro-2H-pyran-4-yl) methyl] cyclohexanecarboxamide (Compound No. 81) Substantially Example 10 except that 4- (aminomethyl) tetrahydropyran was used in place of tetrahydrofurfurylamine. The title compound (31 mg, 84% yield) was obtained as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, tdd, J = 13.1, 13.1, 3.0 Hz), 1.30 (2H, tdd, J = 11.9, 11) .9, 5.3 Hz), 1.41-1.99 (14H, m), 2.02 (1H, tt, J = 11.1, 4.1 Hz), 2.47-2.62 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.15 (2H, t, J = 6.5 Hz), 3.26 (2H, s), 3.36 (2H, td, J = 11.8, 2.2 Hz), 3.57 (2H, s), 3.92-4.01 (2H, m), 5.55 (1 H, t, J = 5.7 Hz), 7. 44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.07 minutes; m / z 551.8 [M + H] ⁺ (ESI positive ion mode), m / z 596.0 [MH] ⁻ (ESI negative ion mode)

Example 82
t-butyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenylcarbamate (compound No. 82) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 obtained in Reference Example 21 -Il} methyl) benzoic acid (190 mg, 0.42 mmol) was suspended in t-butyl alcohol (2.0 mL) and triethylamine (0.15 mL, 1.0 mmol) and diphenylphosphoryl azide (0.14 mL, 0.63 mmol). ) And stirred at room temperature for 30 minutes, and then stirred at 80 ° C. for 6 hours. The reaction mixture was cooled to room temperature, ethyl acetate (5.0 mL) and water (5.0 mL) were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 2/1 to 1/1], and the title compound (160 mg, Yield 64%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.52 (9H, s), 1.69 (2H, ddd, J = 14.7, 7.2, 7.5 Hz), 1.89 (2H, dt, J = 13.0, 3.7 Hz), 2.43-2.59 (4H, m), 3.09 (2H, s), 3.55 (2H, s), 4.36 (2H, s), 6.49 (1H, brs), 7.19 (2H, d, J = 8.5 Hz), 7.34 (2H, d, J = 8.5 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.55 minutes; m / z 519.8 [M + H] ⁺ (ESI positive ion mode), m / z 518.0 [MH] ⁻ (ESI negative ion mode)

Example 83
t-butyl 3- {3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) phenyl] ureido} propylcarbamate (Compound No. 83) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 obtained in Reference Example 21 -Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (43 mg, 0.096 mmol) suspended in toluene (1.0 mL), triethylamine (0.033 mL, 0.24 mmol) and diphenylphosphoryl azide ( 0.031 mL, 0.14 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, and then stirred at 80 ° C. for 4 hours. N- (t-butoxycarbonyl) -1,3-diaminopropane (purchased from Tokyo Chemical Industry Co., Ltd.) (33 mg, 0.19 mmol) was added as it was, and the mixture was stirred at 80 ° C. for 4 hours. The reaction mixture was cooled to room temperature, ethyl acetate (3.0) mL and water (3.0) mL were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3.0) mL. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia, developing solvent: ethyl acetate] to give the title compound (23 mg, yield 39%) as a colorless oil. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.59-1.77 (4H, m), 1.89 (2H, dt, J = 13.0, 3. 4Hz), 2.43-2.60 (4H, m), 3.11 (2H, s), 3.21 (2H, q, J = 6.5 Hz), 3.29 (2H, q, J = 5.8 Hz), 3.54 (2H, s), 4.36 (2H, s), 4.87 (1H, t, J = 6.5 Hz), 5.58 (1H, t, J = 6. 5 Hz), 6.71 (1H, brs), 7.16 (2H, d, J = 8.2 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.56 (2H, d, J = 8.5 Hz).

LC / MS [Condition 1]: Retention time 3.43 minutes; m / z 619.9 [M + H] ⁺ (ESI positive ion mode), m / z 618.0 [MH] ⁻ (ESI negative ion mode)

Example 84
1- (1-Benzylpiperidin-4-yl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) phenyl] urea (Compound No. 84) N- (t-butoxycarbonyl) -1,3-diaminopropane instead of 4-amino-1-benzylpiperidine (Tokyo Chemical Industry ( The title compound (7.0 mg, yield 11%) was obtained as a white solid in substantially the same manner as in Example 83, except that the product purchased from KK was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (2H, dq, J = 3.7, 11.6 Hz), 1.79-1.58 (2H, m), 1.83-2. 02 (4H, m), 2.13 (2H, t, J = 10.9 Hz), 2.42-2.59 (4H, m), 2.81 (2H, d, J = 11.6 Hz), 3.12 (2H, s), 3.49 (2H, s), 3.54 (2H, s), 3.61-3.80 (1H, m), 4.36 (2H, s), 4 .68 (1H, d, J = 7.8 Hz), 6.43 (1H, s), 7.16 (2H, d, J = 8.5 Hz), 7.22-7.35 (7H, m) , 7.41 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.27 minutes; m / z 635.9 [M + H] ⁺ (ESI positive ion mode), m / z 634.0 [MH] ⁻ (ESI negative ion mode)

Example 85
1-Benzylpiperidin-4-yl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) Preparation of phenyl carbamate (Compound No. 85) Other than using 4-hydroxy-1-benzylpiperidine (purchased from Tokyo Chemical Industry Co., Ltd.) instead of N- (t-butoxycarbonyl) -1,3-diaminopropane Was reacted in substantially the same manner as in Example 83 to give the title compound (4.9 mg, yield 8%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.03-1.61 (8H, m), 2.28 (2H, t, J = 9.6 Hz), 2.44-2.59 (4H, m), 2.66-2.78 (2H, m), 3.10 (2H, s), 3.52 (2H, s), 3.55 (2H, s), 4.37 (2H, s) ), 4.72-4.85 (1H, m), 6.60 (1H, s), 7.20 (2H, d, J = 8.3 Hz), 7.24-7.40 (7H, m ), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 3.13 minutes; m / z 637.02 [M + H] ⁺ (ESI positive ion mode), m / z 635.07 [MH] ⁻ (ESI negative ion mode)

Example 86
3- (t-Butoxycarbonylamino) propyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) Phenylcarbamate (Compound No. 86) Preparation of t-butyl N- (3-hydroxypropyl) carbamate instead of N- (t-butoxycarbonyl) -1,3-diaminopropane (Tokyo Chemical Industry Co., Ltd.) The title compound (16 mg, 27% yield) was obtained as a colorless oil substantially in the same manner as in Example 83 except that the above compound was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.59-1.95 (6H, m), 2.43-2.63 (4H, m), 3.10 (2H, s), 3.24 (2H, q, J = 6.0 Hz), 3.55 (2H, s), 4.23 (2H, t, J = 6.3 Hz) 4.37 (2H, s), 4.68 (1H, brs), 6.75 (1H, brs), 7.23 (2H, d, J = 8.2 Hz), 7.37 (2H, d, J = 8.2 Hz) , 7.42 (2H, d, J = 8.5 Hz), 7.56 (2H, d, J = 8.5 Hz).

LC / MS [Condition 1]: Retention time 3.55 minutes; m / z 621.0 [M + H] ⁺ (ESI positive ion mode), m / z 619.0 [MH] ⁻ (ESI negative ion mode)

Example 87
1-cyclohexyl-3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of phenyl] urea (Compound No. 87) Substantially Examples except that cyclohexylamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of N- (t-butoxycarbonyl) -1,3-diaminopropane The reaction was conducted in the same manner as in 83 to give the title compound (17 mg, yield 34%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06-1.47 (6H, m), 1.64-1.81 (4H, m), 1.83 to 2.03 (4H, m) , 2.42-2.61 (4H, m), 3.13 (2H, s), 3.55 (2H, s), 3.58-3.73 (1H, m), 4.36 (2H , S), 4.72 (1H, d, J = 7.7 Hz), 6.47 (1H, s), 7.16 (2H, d, J = 8.3 Hz), 7.29 (2H, d) , J = 8.5 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 3.41 min; m / z 544.9 [M + H] ⁺ (ESI positive ion mode), m / z 543.0 [M−H] ⁻ (ESI negative ion mode)

Example 88
Cyclohexyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenylcarbamate (Compound No. 88 )Manufacturing of
　 The title compound was reacted in substantially the same manner as in Example 83 except that cyclohexanol (purchased from Kanto Chemical Co., Inc.) was used instead of N- (t-butoxycarbonyl) -1,3-diaminopropane. (3.0 mg, 6% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.81-1.35 (10H, m), 1.83-2.00 (4H, m), 2.42-2.62 (4H, m) 3.10 (2H, s), 3.55 (2H, s), 4.37 (2H, s), 4.69-4.80 (1H, m), 6.56 (1H, s), 7.20 (2H, d, J = 8.5 Hz), 7.37 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H , D, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.67 minutes; m / z 545.8 [M + H] ⁺ (ESI positive ion mode), m / z 544.0 [MH] ⁻ (ESI negative ion mode)

Example 89
1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] -3 -Preparation of [(tetrahydrofuran-2-yl) methyl] urea (Compound No. 89) Tetrahydrofurfurylamine instead of N- (t-butoxycarbonyl) -1,3-diaminopropane (purchased from Tokyo Chemical Industry Co., Ltd.) The title compound (20 mg, 38% yield) was obtained as a colorless oil by substantially reacting in the same manner as in Example 83 except that was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.59-1.77 (3H, m), 1.84 to 2.04 (5H, m), 2.40-2.62 (4H, m) , 3.11 (2H, s), 3.15 (1H, ddd, J = 14.3, 6.5, 5.3 Hz), 3.56 (2H, s), 3.58 (1H, ddd, J = 14.7, 7.0, 2.9 Hz), 3.78 (1H, dt, J = 8.2, 7.0 Hz), 3.88 (1H, dt, J = 8.2, 6. 5 Hz), 3.98-4.08 (1 H, m), 4.36 (2 H, s), 5.23 (1 H, t, J = 5.3 Hz), 7.17 (2 H, d, J = 8.2 Hz), 7.30 (1H, brs), 7.32 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2H ).

LC / MS [Condition 1]: Retention time 3.17 minutes; m / z 546.8 [M + H] ⁺ (ESI positive ion mode), m / z 545.0 [MH] ⁻ (ESI negative ion mode)

Example 90
(Tetrahydrofuran-2-yl) methyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) Preparation of phenyl carbamate (Compound No. 90) Substantially except that tetrahydrofurfuryl alcohol (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of N- (t-butoxycarbonyl) -1,3-diaminopropane. The reaction was carried out in the same manner as in Example 83 to obtain the title compound (30 mg, yield 96%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.57-1.76 (3H, m), 1.84-2.10 (5H, m), 2.45-2.60 (4H, m) , 3.10 (2H, s), 3.54 (2H, s), 3.82 (1H, dt, J = 8.2, 7.0 Hz), 3.91 (1H, dt, J = 8. 6, 6.5 Hz), 4.05 (1H, dd, J = 11.1, 7.4 Hz), 4.21-4.10 (1H, m), 4.29 (1H, dd, J = 11) .1, 2.9 Hz), 4.37 (2 H, s), 6.78 (1 H, s), 7.20 (2 H, d, J = 8.2 Hz), 7.36 (2 H, d, J = 8.6 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.25 minutes; m / z 547.7 [M + H] ⁺ (ESI positive ion mode), m / z 545.9 [MH] ⁻ (ESI negative ion mode)

Example 91
1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexyl] -3-[(tetrahydrofuran-2-yl) methyl] urea (Compound No. 91) Tetrahydrofurfurylamine (Tokyo Chemical Industry Co., Ltd.) instead of N- (t-butoxycarbonyl) -1,3-diaminopropane 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) ) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-] obtained in Reference Example 6-3 instead of benzoic acid Diazaspiro [4. Except using] decan-3-yl} methyl) cyclohexanecarboxylic acid The reaction was carried out in the same manner as substantially Example 83 to give the title compound (39 mg, 71% yield) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.97-1.19 (4H, m), 1.50-2.08 (13H, m), 2.46-2.63 (4H, m) 3.03 (1H, ddd, J = 14.3, 7.0, 5.3 Hz), 3.08 (2H, d, J = 7.0 Hz), 3.27 (2H, s), 3. 41-3.52 (2H, m), 3.57 (2H, s), 3.74 (1H, dt, J = 8.2, 7.0 Hz), 3.83 (1H, dt, J = 7 .8, 6.5 Hz), 3.91-4.01 (1H, m), 4.53-4.72 (2H, brm), 7.44 (2H, d, J = 8.2 Hz), 7 .57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 552.8 [M + H] ⁺ (ESI positive ion mode), m / z 597.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 92
(Tetrahydrofuran-2-yl) methyl (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane Preparation of -3-yl} methyl) cyclohexyl carbamate (Compound No. 92) Tetrahydrofurfuryl alcohol (purchased from Tokyo Chemical Industry Co., Ltd.) instead of N- (t-butoxycarbonyl) -1,3-diaminopropane, Reference example instead of 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] deca N-3-yl} methyl) cyclohexanecarboxylic acid was used except that the reaction was carried out in substantially the same manner as in Example 83 to obtain the title compound (24 mg, yield 41%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00-1.19 (4H, m), 1.48-2.09 (13H, m), 2.48-2.64 (4H, m) , 3.08 (2H, d, J = 7.0 Hz), 3.26 (2H, s), 3.35-3.48 (1H, m), 3.57 (2H, s), 3.80 (1H, dt, J = 7.8, 6.5 Hz), 3.85-3.95 (2H, m), 4.14-4.03 (1H, m), 4.18 (1H, dd, J = 11.1, 3.3 Hz), 4.63 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.07 minutes; m / z 553.4 [M + H] ⁺ (ESI positive ion mode), m / z 597.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 93
Preparation of 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one dihydrochloride In Example 82 The resulting t-butyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl Carbamate (160 mg, 0.31 mmol) was dissolved in 1,4-dioxane (4.0 mL), 4M hydrogen chloride-dioxane solution (3.0 ml) and methanol (4.0 mL) were added, and the mixture was stirred at 50 ° C. for 3 hours. It was. This was concentrated to dryness under reduced pressure, and 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Dihydrochloride (200 mg, quantitative) was obtained as a yellow solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 2.13-2.29 (4H, m), 3.42-3.31 (2H, m), 3.37 (2H, brs), 3. 49 (2H, d, J = 12.7 Hz), 4.49 (4H, s), 7.42 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 8.2 Hz) ), 7.77-7.87 (4H, m).

LC / MS [Condition 1]: Retention time 1.06 minutes; m / z 419.4 [M + H] ⁺ (ESI positive ion mode)

Example 93
N- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] cyclohexanecarboxamide Production of (Compound No. 93) 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 93 Decan-2-one dihydrochloride (23 mg, 0.047 mmol), triethylamine (0.015 mL, 0.11 mmol) was dissolved in dichloromethane (2.0 mL), and cyclohexanecarbonyl chloride (0.010 mL, 0.074 mmol) was dissolved. In addition, the mixture was stirred at 40 ° C for 4 hours. Chloroform (4.0 mL) and saturated aqueous sodium hydrogen carbonate solution (4.0 mL) were added to the reaction mixture, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia, developing solvent: ethyl acetate] to give the title compound (4.5 mg, yield 77%) as a colorless oil. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.21-2.01 (14H, m), 2.23 (1H, tt, J = 11.6, 3.3 Hz), 2.43-2. 62 (4H, m), 3.10 (2H, s), 3.55 (2H, s), 4.38 (2H, s), 7.15 (1H, s), 7.22 (2H, d , J = 8.3 Hz), 7.42 (2H, d, J = 7.9 Hz), 7.51 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 7. 9 Hz).

LC / MS [Condition 1]: Retention time 3.51 minutes; m / z 529.8 [M + H] ⁺ (ESI positive ion mode), m / z 529.7 [MH] ⁻ (ESI negative ion mode)

Example 94
t-butyl 4-oxo-4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) phenylamino] butylcarbamate (Compound No. 94) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] 4- (t-Butoxycarbonylamino) butylcarboxylic acid (purchased from Aldrich Co.) instead of decane-3-yl} methyl) benzoic acid, 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane--obtained in Reference Example 93 instead of the salt The reaction was carried out substantially in the same manner as in Example 64 except that 2-one dihydrochloride was used to give the title compound (16 mg, yield 61%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.77-1.64 (2H, m), 1.82-1.95 (4H, m), 2.38 (2H, t, J = 6.3 Hz), 2.44-2.61 (4H, m), 3.08 (2H, s), 3.26 (2H, q, J = 5.9 Hz), 3 .55 (2H, s), 4.38 (2H, s), 4.79 (1H, t, J = 5.3 Hz), 7.22 (2H, d, J = 8.3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 7.9 Hz), 7.62 (2H, d, J = 8.3 Hz), 9.00 (1H, s) .

LC / MS [Condition 1]: Retention time 3.39 minutes; m / z 604.9 [M + H] ⁺ (ESI positive ion mode), m / z 603.0 [MH] ⁻ (ESI negative ion mode)

Example 95
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenylcarbamoyl] piperidine Preparation of t-butyl-1-carboxylate (Compound No. 95) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Decan-3-yl} methyl) benzoic acid instead of 1- (t-butoxycarbonyl) piperidine-4-carboxylic acid (purchased from Sigma-Aldrich Japan), 4-amino-1- (pyridine-3- 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazas obtained in Reference Example 93 instead of (ylmethyl) piperidine trihydrochloride B [4.5] Except for using an decan-2-one dihydrochloride The reaction was carried out in the same manner as substantially Example 64 to give the title compound (17 mg, 93% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.64-1.82 (4H, m), 1.83-1.95 (4H, m), 2.39 (1H, tt, J = 11.5, 3.7 Hz), 2.46-2.58 (4H, m), 2.79 (2H, t, J = 11.9 Hz), 3.11 (2H, s), 3.54 (2H, s), 4.19 (2H, d, J = 11.9 Hz), 4.38 (2H, s), 7.22 (2H, d, J = 8.6 Hz) 7.29 (1H, s), 7.42 (2H, d, J = 7.8 Hz), 7.50 (2H, d, J = 8.6 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 3.57 minutes; m / z 630.9 [M + H] ⁺ (ESI positive ion mode), m / z 629.1 [MH] ⁻ (ESI negative ion mode)

Reference Example 96-1
t-butyl (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexyl carbamate 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [6] obtained in Reference Example 6-3 instead of the acid 4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid was used except that the reaction was carried out in substantially the same manner as in Example 82 to give the title compound (8.0 mg, yield 10%) as a white solid Got as.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.98-1.17 (4H, m), 1.44 (9H, s), 1.63-1.48 (1H, m), 1.68 -1.83 (4H, m), 1.87-2.08 (4H, m), 2.48-2.59 (4H, m), 3.07 (2H, d, J = 7.0Hz) , 3.26 (2H, s), 3.30-3.43 (1H, m), 3.57 (2H, s), 4.36 (1H, brs), 7.44 (2H, d, J = 7.8 Hz), 7.58 (2H, t, J = 8.0 Hz).

LC / MS [condition 1]: retention time 3.48 minutes; m / z 525.8 [M + H] ⁺ (ESI positive ion mode), m / z 570.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 96-2
3-{[(1r, 4r) -4-aminocyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of dihydrochloride t-butyl (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, obtained in Reference Example 96-1 8-Diazaspiro [4.5] decan-3-yl} methyl) cyclohexyl carbamate is converted to t-butyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 The reaction was carried out in substantially the same manner as in Reference Example 93 except that it was used in place of -diazaspiro [4.5] decan-3-yl} methyl) phenylcarbamate, and the title compound (5.0 mg, quantitative) was obtained lightly. As yellow liquid It was.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 1.12 (2H, q, J = 12.7 Hz), 1.26-1.51 (3H, m), 1.57-1.77 (1H M), 1.84 (2H, d, J = 12.3 Hz), 2.06 (2H, d, J = 11.1 Hz), 2.14-2.33 (4H, m), 2.97. −3.12 (1H, m), 3.12 (2H, d, J = 7.4 Hz), 3.72−3.35 (4H, m), 4.49 (2H, s), 7.81 (4H, s).

LC / MS [Condition 1]: Retention time 0.88 min; m / z 426.0 [M + H] ⁺ (ESI positive ion mode)

Example 96
N-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexyl] -2- (tetrahydrofuran-2-yl) acetamide (Compound No. 96) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 2-diatetraspiro [4.5] decan-3-yl} methyl) benzoic acid instead of 2- (tetrahydrofuran-2-yl) acetic acid, 4-amino-1- (pyridin-3-ylmethyl) obtained in Reference Example 14 ) 3-{[(1r, 4r) -4-Aminocyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1- obtained in Reference Example 96-2 instead of piperidine trihydrochloride Oxa The reaction was carried out in substantially the same manner as in Example 64 except that 3,8-diazaspiro [4.5] decan-2-one dihydrochloride was used to give the title compound (4.7 mg, yield 87%). Obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02-1.21 (4H, m), 1.45-2.15 (13H, m), 2.36 (1H, dd, J = 15. 1,7.8 Hz), 2.46 (1H, dd, J = 15.1, 3.7 Hz), 2.46-2.73 (4H, m), 3.08 (2H, d, J = 7) .0Hz), 3.27 (2H, s), 3.57 (2H, s), 3.63-3.81 (1H, m), 3.77 (1H, dt, J = 7.4, 7 .4 Hz), 3.88 (1 H, dt, J = 8.6, 7.0 Hz), 4.05-4.15 (1 H, m), 6.30 (1 H, d, J = 8.2 Hz) 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.05 minutes; m / z 537.8 [M + H] ⁺ (ESI positive ion mode), m / z 582.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 97
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarbothioamide (Compound No. 97) (1r, 4r) -4-({2-oxo-8- [4- ( Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (21 mg, 0.038 mol) ) Was dissolved in toluene (2.0 mL), Lawesson's reagent (18 mg, 0.045 mol) was added, and the mixture was stirred at 110 ° C. for 2 hours. After cooling, ethyl acetate (5.0 mL) and saturated aqueous sodium hydrogen carbonate solution (3.0 mL) were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (5.0 mL), and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia, developing solvent: hexane / ethyl acetate = 1/1] to give the title compound (2.4 mg, 17% yield). ) Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07 (2H, dq, J = 3.3, 12.7 Hz), 1.62-2.08 (15H, m), 2.43 (1H, tt, J = 12.3, 3.3 Hz), 2.49-2.68 (4H, m), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.45 (1H, ddd, J = 14.3, 9.0, 3.7 Hz), 3.57 (2H, s), 3.78 (1H, dt, J = 8.2, 6.5 Hz) 3.89 (1H, dt, J = 8.6, 6.5 Hz), 4.04-4.14 (2H, m), 7.44 (2H, d, J = 7.8 Hz), 7. 57 (2H, d, J = 7.8 Hz), 7.58 (1 H, s).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 553.8 [M + H] ⁺ (ESI positive ion mode), m / z 551.9 [MH] ⁻ (ESI negative ion mode)

Reference Example 98
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexane Preparation of carboxamide hydrochloride 3-{[(1r, 4r) -4- (1-benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3 obtained in Example 123 , 8-diazaspiro [4.5] decane-8-carboxylate t-butyl (0.35 g, 0.62 mmol) dissolved in a mixed solvent of 1,4-dioxane (7.0 mL) and methanol (4.0 mL) 4M hydrogen chloride-dioxane solution (0.62 mL, 2.5 mmol) was added at room temperature, and the mixture was allowed to stand at room temperature for 1 day, and then concentrated to dryness under reduced pressure. Acetone (5.0 mL) was added to the residue and allowed to stand for 3 days, then concentrated to dryness under reduced pressure to give (1r, 4r) -N- (1-benzylpiperidin-4-yl) -4- [ -Oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxamide hydrochloride (0.35 g, quantitative yield) was obtained as a white solid.

Example 98
(1r, 4r) -4-[(8-Benzyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N- (1-benzylpiperidine-4 Preparation of —yl) cyclohexanecarboxamide (Compound No. 98) (1r, 4r) -N- (1-benzylpiperidin-4-yl) -4-[(2-oxo-1-oxa) obtained in Reference Example 98 −3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxamide hydrochloride (20 mg, 0.037 mmol) was suspended in N, N-dimethylformamide (0.40 mL) and triethylamine (0. 021 mL, 0.15 mmol) and benzyl bromide (0.0050 mL, 0.041 mmol) were added, and the mixture was stirred at room temperature for 3 days. Water (1.0 mL) and chloroform (2.0 mL) were added to the reaction mixture, and the organic layer was separated and washed with water (1.0 mL). The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020, manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 1/1] to give the title compound. (15 mg, 72% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.7, 11.9 Hz), 1.34-1.56 (5H, m), 1.69-2. 03 (11H, m), 2.11 (2H, t, J = 11.6 Hz), 2.46-2.65 (4H, m), 2.80 (2H, d, J = 11.6 Hz), 3.08 (2H, d, J = 7.2 Hz), 3.24 (2H, s), 3.49 (2H, s), 3.53 (2H, s), 3.69-3.87 ( 1H, m), 5.28 (1H, d, J = 7.8 Hz), 7.37-7.22 (10H, m).

LC / MS [Condition 1]: Retention time 1.15 minutes; m / z 559.1 [M + H] ⁺ (ESI positive ion mode), m / z 603.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 99
3-{[(1r, 4r) -4- (1-Benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- Production of benzyl carboxylate (Compound No. 99) The compound (15 mg, 68% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.0, 12.2 Hz), 1.95-1.33 (15H, m), 1.97 (1H, tt, J = 12.9, 3.3 Hz), 2.10 (2H, t, J = 111.2 Hz), 2.80 (2H, d, J = 11.6 Hz), 3.10 (2H, d , J = 7.3 Hz), 3.25 (2H, s), 3.33 (2H, t, J = 11.6 Hz), 3.48 (2H, s), 3.70-3.86 (1H) M), 3.87-4.06 (2H, m), 5.13 (2H, s), 5.29 (1H, d, J = 7.6 Hz), 7.31-7.36 (10H) , M).

LC / MS [Condition 1]: Retention time 3.35 minutes; m / z 603.0 [M + H] ⁺ (ESI positive ion mode), m / z 647.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 100
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] Decan-3-yl] methyl} cyclohexanecarboxamide (Compound No. 100) The reaction was conducted in substantially the same manner as in Example 98 except that 4-cyanobenzyl bromide was used instead of benzyl bromide to give the title compound (11 mg Yield 51%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.6, 12.6 Hz), 1.35 to 2.03 (16H, m), 2.11 (2H, t, J = 10.9 Hz), 2.48-2.63 (4H, m), 2.81 (2H, d, J = 11.9 Hz), 3.09 (2H, d, J = 7.3 Hz) ), 3.25 (2H, s), 3.49 (2H, s), 3.57 (2H, s), 3.70-3.86 (1H, m), 5.27 (1H, d, J = 7.9 Hz), 7.37-7.23 (5H, m), 7.44 (2H, d, J = 8.3 Hz), 7.61 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 1.07 minutes; m / z 583.9 [M + H] ⁺ (ESI positive ion mode), m / z 628.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 101
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-({8-[(3,5-dimethylisoxazol-4-yl) methyl] -2-oxo-1-oxa Preparation of —3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 101) 4- (chloromethyl) -3,5-dimethylisoxazole (Aldrich) instead of benzyl bromide The title compound (18 mg, yield 85%) was obtained as a white solid in substantially the same manner as in Example 98 except that the product (purchased from KK) was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 13.2 Hz), 1.80-1.91 (16H, m), 2.11 (2H, t, J = 11.2 Hz), 2.24 (3 H, s), 2.33 (3 H, s), 2.40-2.60 (4 H, m), 2.80 (2 H, d, J = 10.6 Hz) 3.09 (2H, d, J = 7.3 Hz), 3.24 (4H, s), 3.49 (2H, s), 3.71-3.87 (1H, m), 5.29 (1H, d, J = 8.3 Hz), 7.43-7.23 (5H, m).

LC / MS [Condition 1]: Retention time 0.69 minutes; m / z 578.0 [M + H] ⁺ (ESI positive ion mode), m / z 622.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 102
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-{[8- (3-methoxybenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] Decan-3-yl] methyl} cyclohexanecarboxamide (Compound No. 102) The reaction was conducted in substantially the same manner as in Example 98 except that 3-methoxybenzyl bromide was used instead of benzyl bromide to give the title compound (13 mg Yield 61%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.0, 11.9 Hz), 2.03-1.33 (16H, m), 2.11 (2H, t, J = 10.9 Hz), 2.47-2.63 (4H, m), 2.80 (2H, d, J = 10.9 Hz), 3.09 (2H, d, J = 7.3 Hz) ), 3.24 (2H, s), 3.49 (2H, s), 3.50 (2H, s), 3.71-3.85 (1H, m), 3.81 (3H, s) 5.28 (1H, d, J = 7.3 Hz), 6.80 (1H, dd, J = 7.6, 3.0 Hz), 6.85-6.94 (2H, m), 7. 19-7.37 (6H, m).

LC / MS [Condition 1]: Retention time 1.25 minutes; m / z 589.0 [M + H] ⁺ (ESI positive ion mode), m / z 633.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 103
4-[(3-{[(1r, 4r) -4- (1-benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] Decan-8-yl) methyl] Preparation of methylbenzoate (Compound No. 103) The title compound (30 mg, 65% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 12.2 Hz), 1.33-2.03 (16H, m), 2.11 (2H, t, J = 11.1 Hz), 2.48-2.62 (4 H, m), 2.80 (2 H, d, J = 11.6 Hz), 3.09 (2 H, d, J = 7.3 Hz), 3. 25 (2H, s), 3.49 (2H, s), 3.57 (2H, s), 3.70-3.85 (1H, m), 3.91 (3H, s), 5.29 (1H, d, J = 7.6 Hz), 7.35-7.22 (5H, m), 7.39 (2H, d, J = 8.3 Hz), 7.99 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 1.09 minutes; m / z 617.0 [M + H] ⁺ (ESI positive ion mode), m / z 661.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 104
4-[(3-{[(1r, 4r) -4- (1-benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] Preparation of decan-8-yl) methyl] benzoic acid (Compound No. 104) 4-[(3-{[(1r, 4r)] obtained in Example 103 instead of 2- (tetrahydrofuran-2-yl) ethyl acetate -4- (1-Benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl) methyl] methyl benzoate is used Except for the above, the reaction was carried out in substantially the same manner as in Reference Example 14 to obtain the title compound (1.2 mg, yield 5%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.98 (2H, q, J = 13.1 Hz), 1.43 (2H, q, J = 13.5 Hz), 1.46-1.65 ( 1H, m), 1.77-1.93 (13H, m), 2.33 (2H, t, J = 11.1 Hz), 2.55-2.81 (4H, m), 3.07 ( 2H, d, J = 7.0 Hz), 3.13 (2H, d, J = 11.5 Hz), 3.25 (2H, s), 3.70 (2H, s), 3.76-3. 93 (1H, m), 3.78 (2H, s), 5.70 (1H, d, J = 7.8 Hz), 7.30-7.43 (7H, m), 8.02 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 0.93 minutes; m / z 602, 6 [M + H] ⁺ (ESI positive ion mode), m / z 601.1 [MH] ⁻ (ESI negative ion mode)

Example 105
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Production of methyl carboxylate (Compound No. 105) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3 obtained in Reference Example 6-1 -Yl) methyl] cyclohexanecarboxylic acid methyl hydrochloride is desalted to give (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) Methyl] methyl cyclohexanecarboxylate was obtained. Under a nitrogen atmosphere, the resulting methyl (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylate (100 mg, 0.32 mmol), palladium acetate (7.2 mg, 0.032 mmol), 2,2′-bis (diphenylphosphino) -1,1′-binaphthalene (20 mg, 0.032 mmol), cesium carbonate (210 mg, 0.32 mmol). 64 mmol) and 4-bromobenzotrifluoride (72 mg, 0.32 mmol) were dissolved in 1,4-dioxane (3.0 mL), and the mixture was stirred at 100 ° C. for 19 hours under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate and water were added and stirred for 20 minutes. Insolubles were removed by celite filtration, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After concentrating to dryness under reduced pressure, the resulting residue was purified by silica gel column chromatography [Polipack NH 60 μm, developed by Moritex, developing solvent: hexane / ethyl acetate], and the title compound (110 mg, 77% yield) was white. Obtained as a solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.94-1.13 (2H, m), 1.32-1.51 (2H, m), 1.52-1.66 (1H, m) , 1.73-1.91 (4H, m), 1.95-2.11 (4H, m), 2.18-2.34 (1H, m), 3.12 (2H, d, J = 7.4 Hz), 3.29 (2H, s), 3.31-3.44 (2H, m), 3.52-3.72 (2H, m), 3.67 (3H, s), 6 .94 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz).

LC / MS [Condition 2]: Retention time 4.51 minutes; m / z 455.0 [M + H] ⁺ (ESI positive ion mode)

Reference Example 106
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Preparation of carboxylic acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4. 5] Decan-3-yl} methyl) methyl cyclohexanecarboxylate (110 mg, 0.25 mmol) was dissolved in a mixed solvent of methanol (1.5 mL) and tetrahydrofuran (1.5 mL), and 5 M aqueous sodium hydroxide solution (0. 60 mL) was added and stirred at room temperature for 9 hours. After cooling to 0 ° C., the pH was adjusted to 4 by adding 5M hydrochloric acid. The precipitated white solid was collected by filtration and dried under reduced pressure at 50 ° C. for 1 hour to obtain the tetrahydrofuran-methanol hydrate (110 mg) of the title compound.

Example 106
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Production of N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 106) (1r, 4r) -4-({2-oxo-8- [4- (trifluoro) obtained in Reference Example 106 Methyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (50 mg, 0.11 mmol), tetrahydrofurfurylamine (23 mg, 0.23 mmol), 1 -Hydroxybenzotriazole (23 mg, 0.17 mmol) dissolved in chloroform, then triethylamine (12 mg, 0.11 mm l) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (33 mg, 0.17 mmol) was added and stirred at room temperature for 11 hours. Water was added to separate the organic layer, which was washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack NH 60 μm, manufactured by Moritex, developing solvent: chloroform / ethyl acetate = 3/1 to chloroform / methanol = 10/1] to give the title compound (39 mg, yield 65 %) As a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.7 Hz), 1.40-1.67 (3H, m), 1.72-2.12 (13H, m), 3.03-3.18 (1H, m), 3.12 (2H, d, J = 7.4 Hz), 3.29 (2H, s), 3.32-3.44 (2H, m), 3.53-3.65 (3H, m), 3.70-4.01 (3H, m), 5.75-5.89 (1H, brm), 6.94 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz).

Example 107
(1r, 4r) -N-cyclohexyl-4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) cyclohexanecarboxamide (Compound No. 107) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-) obtained in Reference Example 106 3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (10 mg, 0.023 mmol), cyclohexylamine (2.3 mg, 0.023 mmol), 1-hydroxybenzotriazole (5.7 mg) , 0.030 mmol) in chloroform, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 5.7 mg, 0.030 mmol) was added and stirred at room temperature for 3 days. Water was added to separate the organic layer, which was washed with saturated sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The resulting residue was purified by preparative thin layer chromatography [Merck PLC glass plate silica gel _{60F 254,} developing solvent: ethyl acetate 100%] to give the title compound (7.6 mg, 63% yield) Obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.91-2.11 (24H, m), 3.12 (2H, d, J = 7.2 Hz), 3.29 (2H, s), 3 .38 (2H, t, J = 11.6 Hz), 3.59 (2H, d, J = 13.5 Hz), 3.68-3.83 (1H, m), 5.28 (1H, d, J = 7.4 Hz), 6.94 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz).

Reference Example 108-1
Preparation of t-butyl 3- [3- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 3- (Aminomethyl) methyl benzoate Hydrochloric acid salt (950 mg, 0.47 mmol) was dissolved in water (1.0 mL), 5M aqueous sodium hydroxide solution (0.094 mL, 0.47 mmol) and 1-oxa-6 obtained in Reference Example 1-1 -A solution of t-butyl azaspiro [2.5] octane-6-carboxylate (100 mg, 0.47 mmol) in methanol (1.0 mL) was added and stirred at room temperature for 10 days. The mixture was concentrated under reduced pressure to distill off methanol. Chloroform was added to the residual reaction mixture to separate the organic layer, which was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack SI 60 μm manufactured by Moritex, developing solvent: hexane / ethyl acetate], and 3-{[(4-hydroxypiperidin-4-yl) methylamino] methyl} benzoic acid Methyl acid (96 mg, 54% yield) was obtained as a colorless oil. This was dissolved in chloroform (2.0 mL), 1,1′-carbonyldiimidazole (82 mg, 0.51 mmol) was added, and the mixture was stirred at 50 ° C. for 3 hr. Further, 1,1′-carbonyldiimidazole (82 mg, 0.51 mmol) was added, followed by stirring at 50 ° C. for 3 hours. Water was added and the mixture was stirred at room temperature for 10 minutes. After the foaming had subsided, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack SI 60 μm, developed by Mortex, developing solvent: hexane / ethyl acetate] to obtain the title compound (55 mg, yield 29%).

Reference Example 108-2
Reference Example for Production of Methyl 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoate 3- [3- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (50 mg, 0 .12 mmol) was dissolved in methanol (0.10 mL), 4M hydrogen chloride-dioxane solution (1.5 mL) was added, and the mixture was stirred at room temperature for 40 min. The reaction mixture was concentrated to dryness under reduced pressure and further azeotroped with methanol three times to give 3-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid. Methyl acid hydrochloride was obtained as a white solid. This hydrochloride was suspended in N, N-dimethylformamide (1.0 mL), and 1- (bromomethyl) -4- (trifluoromethyl) benzene (36 mg, 0.15 mmol) and triethylamine (30 mg, 0.30 mmol) were added. After the addition, the mixture was stirred at room temperature for 4 days. Water and ethyl acetate were added to separate the organic layer, which was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack NH 60 μm, developed by Moritex, developing solvent: hexane / ethyl acetate] to obtain the title compound (34 mg, yield 50%) as a colorless oil.

Reference Example 108-3
Reference Example 108 for Production of 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid 3-({2-Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid obtained in step-2 Methyl acid (34 mg, 0.078 mmol) was dissolved in methanol (1.0 mL), 5M aqueous sodium hydroxide solution (0.25 mL) was added, and the mixture was stirred at room temperature for 15 hr. After cooling to 0 ° C., the pH was adjusted to 4 by adding 5M hydrochloric acid. A mixed solvent of chloroform and 2-propanol (10: 1) was added to separate the organic layer, and a mixed solvent of chloroform and 2-propanol (10: 1) was again added to the aqueous layer to separate the organic layer. The obtained organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure to give the title compound 2-propanol hydrate (44 mg).

Example 108
t-butyl 3- [3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of propyl carbamate (Compound No. 108) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] decan-3-yl} methyl) benzoic acid (10 mg, 0.022 mmol), N- (t-butoxycarbonyl) -1,3-diaminopropane (4.7 mg, 0.027 mmol), 1-hydroxy After dissolving benzotriazole (3.6 mg, 0.027 mmol) in chloroform (1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimi Hydrochloride (5.1 mg, 0.027 mmol) was added and stirred at room temperature for 3 days. Triethylamine (2.7 mg, 0.027 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 days. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [Chromatolex NH-PLC05 plate, developed by Fuji Silysia, developing solvent: ethyl acetate 100%] to give the title compound (8.4 mg, yield 63%). Was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.66-1.78 (4H, m), 1.86-1.96 (2H, m), 2.45 -2.59 (4H, m), 3.14 (2H, S), 3.25 (2H, q, J = 6.4 Hz), 3.51 (2H, q, J = 6.4 Hz), 3 .55 (2H, s), 4.47 (2H, s), 4.85-4.89 (1H, brm), 7.33 (1H, brs), 7.38-7.49 (4H, m ), 7.56 (2H, d, J = 8.2 Hz), 7.77 (2H, s).

LC / MS [Condition 2]: Retention time 3.30 minutes; m / z 604.8 [M + H] ⁺ (ESI positive ion mode)

Example 109
N- (1-Benzylpiperidin-4-yl) -3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) benzamide (Compound No. 109) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, obtained in Reference Example 108-3 8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (10 mg, 0.022 mmol), 4-amino-1-benzylpiperidine (4.7 mg, 0.025 mmol), 1-hydroxybenzotriazole ( After dissolving 3.6 mg, 0.027 mmol) in chloroform (1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.1 m , Adding 0.027 mmol), it was stirred at room temperature for 3 days. Triethylamine (2.7 mg, 0.027 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 days. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography [Chromatolex NH-PLC05 plate manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate 100%], and the title compound (14 mg, yield 82%) was colorless. Obtained as an oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.49-1.79 (4H, m), 1.85-1.97 (2H, m), 1.97-2.07 (2H, m) 2.12-2.26 (2H, m), 2.44-2.59 (4H, m), 2.82-2.90 (2H, m), 3.14 (2H, s), 3 .52 (2H, s), 3.55 (2H, s), 3.91-4.08 (1H, m), 4.47 (2H, s), 5.97 (1H, d, J = 7) .5 Hz), 7.23-7.37 (5H, m), 7.38-7.47 (4H, m), 7.53-7.59 (2H, m), 7.62-7.69. (2H, m).

LC / MS [Condition 2]: Retention time 2.84 minutes; m / z 620.9 [M + H] ⁺ (ESI positive ion mode)

Example 110
3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] benzamide (Compound No. 110) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, obtained in Reference Example 108-3 8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (10 mg, 0.022 mmol), tetrahydrofurfurylamine (2.7 mg, 0.027 mmol), 1-hydroxybenzotriazole (3.6 mg, 0 0.027 mmol) in chloroform (1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.1 m , Adding 0.027 mmol), it was stirred at room temperature for 12 hours. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [Chromatolex NH-PLC05 plate manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 10/1], and the title compound (4.0 mg, yield) was obtained. 34%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54-1.80 (3H, m), 1.86-2.12 (5H, m), 2.44-2.62 (4H, m) 3.14 (2H, s), 3.26-3.36 (1H, m), 3.55 (2H, s), 3.71-3.94 (3H, m), 4.01-4 .13 (1H, m), 4.47 (2H, s), 6.48-6.58 (1H, brm), 7.41-7.44 (4H, m), 7.56 (2H, d) , J = 7.8 Hz), 7.67-7.73 (2H, m).

LC / MS [Condition 2]: Retention time 5.42 minutes; m / z 532.2 [M + H] ⁺ (ESI positive ion mode)

Reference Example 111-1
Preparation of t-butyl 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Synthesized according to the method described in JP2008-546820.

Reference Example 111-2
Preparation of ethyl 6- (hydroxymethyl) nicotinate Diethyl pyridine-2,5-dicarboxylate (purchased from Tokyo Chemical Industry Co., Ltd.) (350 mg, 1.6 mmol) was added to tetrahydrofuran (3.3 mL) and ethanol (6.7 mL). ) And then cooled to 0 ° C. After adding calcium chloride (690 mg, 6.25 mmol), sodium borohydride (150 mg, 4.0 mmol) was gradually added and stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added, and the mixture was stirred at 0 ° C. for 40 minutes. After adding chloroform and water, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain the title compound (230 mg, yield 81%) as a white solid.

Reference Example 111-3
Reference Example for Production of t-Butyl 3-{[5- (Ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate The ethyl 6- (hydroxymethyl) nicotinate (100 mg, 0.55 mmol) obtained in 111-2 was dissolved in tetrahydrofuran (4.0 mL), cooled to 0 ° C., and then methanesulfonyl chloride (75 mg, 0.66 mmol). ) And triethylamine (73 mg, 0.72 mmol) were added and stirred for 30 minutes. Furthermore, methanesulfonyl chloride (38 mg, 0.33 mmol) and triethylamine (37 mg, 0.36 mmol) were added and stirred for 30 minutes. After adding ethyl acetate and water, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain ethyl 6-((methylsulfonyloxy) methyl) nicotinate (180 mg). T-butyl 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (100 mg, 0.39 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (1.0 mL) dissolved in sodium hydride (> 55%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (19 mg, 0.43 mmol) at 0 ° C., and stirred at the same temperature for 20 minutes It was. A solution of ethyl 6-[(methylsulfonyloxy) methyl] nicotinate (110 mg) in N, N-dimethylformamide (1.0 mL) was added to the resulting reaction mixture, and the mixture was stirred overnight at room temperature. Further, sodium hydride (> 55%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (9 mg, 0.22 mmol) was added, followed by stirring at room temperature for 1 hour. After adding water and ethyl acetate, the organic layer was separated and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was recrystallized from ethyl acetate / hexane, and the title compound (86 mg) was combined with t-butyl 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate. As a mixture of

Reference Example 111-4
Reference Example for Production of Ethyl 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinate 3-{[5- (Ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid obtained from 111-3 t-Butyl (86 mg) was dissolved in 1,4-dioxane (0.50 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. Ethanol (0.20 mL) was added to the reaction suspension, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and further azeotroped with methanol three times to give 6-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] nicotine. Ethyl acid hydrochloride was obtained as a white solid. This hydrochloride was suspended in N, N-dimethylformamide (1.0 mL), 4- (trifluoromethyl) benzyl bromide (62 mg, 0.26 mmol) and triethylamine (52 mg, 0.52 mmol) were added, and then room temperature was added. Stir for 24 hours. Water and ethyl acetate were added to separate the organic layer, which was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Molytex Prefpack SI 60 μm, developing solvent: chloroform / methanol] to obtain the title compound (49 mg, yield 26%).

Reference Example 111-5
Preparation of 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinic acid Reference Example 111 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotine obtained in -4 Ethyl acid (49 mg, 0.10 mmol) was dissolved in methanol (1.0 mL), 5M sodium hydroxide solution (0.10 mL, 0.51 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 ° C., and 5 M hydrochloric acid was added to adjust the pH to 5. After adding water, the white solid was collected by filtration and dried under reduced pressure at 50 ° C. for 1 hour to obtain the title compound (12 mg, 27%). After adding a mixed solvent of chloroform / isopropyl alcohol (5/1) to the filtrate, the organic layer was separated, and the aqueous layer was extracted with a mixed solvent of chloroform / isopropyl alcohol (5/1). After adding sodium chloride to the aqueous layer, the mixture was further extracted once with a mixed solvent of chloroform / isopropyl alcohol (5/1). The combined organic layers were dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain the title compound (24 mg, 52%).

Example 111
6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] nicotinamide (Compound No. 111) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3 obtained in Reference Example 111-5 , 8-diazaspiro [4.5] decan-3-yl} methyl) nicotinic acid (10 mg, 0.022 mmol), tetrahydrofurfurylamine (2.7 mg, 0.027 mmol) and 1-hydroxybenzotriazole (3.6 mg, 0.027 mmol) was dissolved in chloroform (1.0 mL), and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5. mg, 0.027 mmol) was added and stirred at room temperature for 15 hr. Water was added to separate the organic layer, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The resulting residue was purified by preparative thin layer chromatography [Merck PLC glass plate silica gel _{60F 254,} developing solvent: chloroform / methanol = 10/1] to give the title compound (8.4 mg, yield 72 %) As a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54-1.67 (2H, m), 1.70-1.86 (2H, m), 1.88-2.12 (4H, m) 2.48-2.61 (4H, m), 3.27-3.37 (1H, m), 3.33 (2H, s), 3.56 (2H, s), 3.73-3 .95 (3H, m), 4.02-4.14 (1H, m), 4.59 (2H, s), 6.47-6.54 (1H, brm), 7.38 (1H, d , J = 7.8 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz), 8.08 (1H, dd, J = 7. 8, 2.4 Hz), 8.93 (1H, d, J = 2.4 Hz).

LC / MS [Condition 2]: Retention time 5.19 minutes; m / z 533.3 [M + H] ⁺ (ESI positive ion mode)

Reference Example 112-1
Preparation of methyl 6- (hydroxymethyl) picolinate Diethyl pyridine-2,6-dicarboxylate (purchased from Tokyo Chemical Industry Co., Ltd.) (1.0 g, 5.1 mmol) in dichloromethane (35 mL) and methanol (15 mL) After dissolution, it was cooled to 0 ° C. Sodium borohydride (195 mg, 5.2 mmol) was gradually added and stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was stirred at 0 ° C. for 40 minutes. After adding chloroform and water, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack SI 60 μm, developed by Moritex, developing solvent: hexane / ethyl acetate] to obtain the title compound (300 mg, yield 36%).

Reference Example 112-2
3-{[6- (methoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t-butyl Methyl 6- (hydroxymethyl) picolinate (100 mg, 0.60 mmol) obtained in 112-1 was dissolved in tetrahydrofuran (4.0 mL) and cooled to 0 ° C., and then methanesulfonyl chloride (75 mg, 0.66 mmol). ) And triethylamine (73 mg, 0.72 mmol) were added and stirred for 30 minutes. Furthermore, methanesulfonyl chloride (38 mg, 0.33 mmol) and triethylamine (37 mg, 0.36 mmol) were added and stirred for 30 minutes. After adding ethyl acetate and water, the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain methyl 6-((methylsulfonyloxy) methyl) picolinate (190 mg). T-butyl 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (100 mg, 0.39 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (1.0 mL) dissolved in sodium hydride (> 55%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (19 mg, 0.43 mmol) at 0 ° C., and stirred at the same temperature for 20 minutes It was. To the resulting reaction mixture was added a solution of methyl 6-[(methylsulfonyloxy) methyl] picolinate (110 mg) in N, N-dimethylformamide (1.0 mL), and the mixture was stirred at room temperature overnight. After adding water and ethyl acetate, the organic layer was separated and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack NH 60 μm, developed by Moritex, developing solvent: hexane / ethyl acetate] to obtain the title compound (93 mg, yield 60%).

Reference Example 112-3
Reference example for production of methyl 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) picolinate 3-{[6- (Methoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid obtained in 112-2 t-Butyl (93 mg) was dissolved in methanol (0.20 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated to dryness under reduced pressure and further azeotroped with methanol three times to give 6-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] picoline. Methyl acid hydrochloride was obtained as a white solid. This hydrochloride was suspended in N, N-dimethylformamide (2.0 mL), 4- (trifluoromethyl) benzyl bromide (60 mg, 0.25 mmol) and triethylamine (51 mg, 0.51 mmol) were added, and then room temperature was added. Stir for 24 hours. Water and ethyl acetate were added to separate the organic layer, which was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack SI 60 μm, developed by Morexex, developing solvent: chloroform / methanol] to obtain the title compound (48 mg, yield 45%).

Reference Example 112-4
Preparation of 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) picolinic acid Reference Example 112 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) picoline obtained in -3 Methyl acid (48 mg, 0.10 mmol) was dissolved in methanol (1.0 mL), 5M sodium hydroxide solution (0.10 mL, 0.51 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0 ° C., and 5 M hydrochloric acid was added to adjust the pH to 5. After adding a mixed solvent of water and chloroform / 2-propanol (5/1), the organic layer was separated, and the aqueous layer was extracted with a mixed solvent of chloroform / 2-propanol (5/1). Sodium chloride was added to the aqueous layer, and the mixture was further extracted once with a mixed solvent of chloroform / 2-propanol (5/1). The combined organic layers were dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to obtain the title compound (42 mg, 91%).

Example 112
6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- 2- (yl) methyl] picolinamide (Compound No. 112) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3 obtained in Reference Example 112-4 , 8-diazaspiro [4.5] decan-3-yl} methyl) picolinic acid (10 mg, 0.022 mmol), tetrahydrofurfurylamine (2.7 mg, 0.027 mmol) and 1-hydroxybenzotriazole (3.6 mg, 0.027 mmol) was dissolved in chloroform (1.0 mL), and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5. mg, 0.027 mmol) was added and stirred at room temperature for 15 hr. Water was added to separate the organic layer, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The resulting residue was purified by preparative thin layer chromatography [Merck PLC glass plate silica gel _{60F 254,} developing solvent: chloroform / methanol = 10/1] to give the title compound (5.9 mg, yield 50 %) As a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.53-1.68 (2H, m), 1.71-2.09 (6H, m), 2.48-2.63 (4H, m) 3.31 (2H, s), 3.33-3.46 (1H, m), 3.57 (2H, s), 3.69-3.80 (2H, m), 3.85-3 .94 (1H, m), 4.02-4.13 (1H, m), 4.60 (2H, s), 7.42 (3H, t, J = 7.0 Hz), 7.57 (2H) , D, J = 7.8 Hz), 7.85 (1H, t, J = 7.7 Hz), 8.13 (1H, d, J = 7.2 Hz), 8.17-8.25 (1H, m).

LC / MS [Condition 2]: Retention time 5.35 minutes; m / z 533.2 [M + H] ⁺ (ESI positive ion mode)

Example 113
t-butyl 3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide Preparation of 4- propylcarbamate (Compound No. 113) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Decan-3-yl} methyl) benzoic acid (10 mg, 0.022 mmol), N- (t-butoxycarbonyl) -1,3-diaminopropane (4.7 mg, 0.027 mmol), 1-hydroxybenzotriazole (3.6 mg, 0.027 mmol) was dissolved in chloroform (1.0 mL) and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Salt (5.1 mg, 0.027 mmol) was added and stirred at room temperature for 3 days. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography [Chromatolex NH-PLC05 plate manufactured by Fuji Silysia Ltd.] to obtain the title compound (12 mg, yield 90%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.65-1.80 (4H, m), 1.85-1.96 (2H, m), 2.44 -2.61 (4H, m), 3.12 (2H, s), 3.25 (2H, q, J = 6.0 Hz), 3.51 (2H, q, J = 6.0 Hz), 3 .55 (2H, s), 4.47 (2H, s), 4.80-4.92 (1H, m), 7.30 (1H, brs), 7.34 (2H, d, J = 8) .3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz).

Example 114
N- (1-Benzylpiperidin-4-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) benzamide (Compound No. 114) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (10 mg, 0.022 mmol), 4-amino-1-benzylpiperidine (5.1 mg, 0.027 mmol), 1-hydroxybenzotriazole (3. 6 mg, 0.027 mmol) was dissolved in chloroform (1.0 mL), and then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.1 mg, 0 027Mmol) was added and stirred at room temperature for 15 hr. Water was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [Chromatolex NH-PLC05 plate, developed by Fuji Silysia, developing solvent: ethyl acetate 100%] to give the title compound (9.9 mg, yield 73%). Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.48-1.78 (4H, m), 1.86-1.95 (2H, m), 1.98-2.07 (2H, m) 2.12-2.21 (2H, m), 2.45-2.59 (4H, m), 2.80-2.91 (2H, m), 3.11 (2H, s), 3 .52 (2H, s), 3.55 (2H, s), 3.93-4.09 (1H, m), 4.46 (2H, s), 5.93-6.01 (1H, m ), 7.23-7.34 (5H, m), 7.32 (2H, d, J = 8.3 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.56 (2H) , D, J = 8.0 Hz), 7.73 (2H, d, J = 8.3 Hz).

LC / MS [Condition 2]: Retention time 4.93 minutes; m / z 621.3 [M + H] ⁺ (ESI positive ion mode)

Reference Example 115-1
Preparation of t-butyl 3- [2-methoxy-4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Reference Example 111-1 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (200 mg, 0.78 mmol) obtained in 1 above was added to N, N-dimethylformamide (1.5 mL). Dissolve in sodium hydride (> 55%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (41 mg, 0.78 mmol) and stir for 30 minutes, then methyl 4- (bromomethyl) -3-methoxybenzoate (Purchased from Transworld Chemicals Inc., trans world chemicals Inc.) (200 mg, 0.78 mmol) It was stirred at room temperature for 17 hours. After stopping the reaction, saturated aqueous ammonium chloride solution (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture. Extraction was performed twice with ethyl acetate (10 mL), and a saturated saline solution (10 mL) was added to the combined organic layer for liquid separation operation. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 1/1] to give 3- [2-methoxy-4- (methoxycarbonyl). ) Benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (240 mg, 71% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.60 (2H, dt, J = 5.1, 13.0 Hz), 1.85 (2H, d, J = 13.6 Hz), 3.16 (2H, s), 3.27 (2H, dt, J = 2.4, 12.3 Hz), 3.81 (2H, d, J = 11.6 Hz), 3. 90 (3H, s), 3.93 (3H, s), 4.50 (2H, s), 7.31 (1H, d, J = 7.8 Hz), 7.55 (1H, d, J = 1.4 Hz), 7.64 (1H, dd, J = 1.4, 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.23 minutes; m / z 434.8 [M + H] ⁺ (ESI positive ion mode), m / z 479.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 115-2
Preparation of 3-methoxy-4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid methyl hydrochloride Obtained in Reference Example 115-1 3- [2-Methoxy-4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (220 mg, 0.50 mmol) Was dissolved in chloroform (1.0 mL), 4M hydrogen chloride-dioxane solution (3 mL) was added, and the mixture was stirred at room temperature for 1 hr. After stopping the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and 3-methoxy-4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid Methyl hydrochloride (180 mg, 97% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.93-2.32 (4H, m), 3.14-3.52 (6H, m), 3.90 (3H, s), 3.93 (3H, s), 4.49 (2H, s), 7.31 (1H, d, J = 7.8 Hz), 7.56 (1H, d, J = 1.4 Hz), 7.63 (1H , Dd, J = 1.4, 7.8 Hz).

Reference Example 115-3
3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate of reference example 115-2 in the obtained 3-methoxy-4 - [(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate hydrochloride (180 mg, 0.48 mmol) was dissolved in chloroform (1.0 mL), and N, N-dimethylformamide (1.0 mL) was added. 4- (Trifluoromethyl) benzyl bromide (130 mg, 0.52 mmol) and triethylamine (0.20 mL, 1.4 mmol) were sequentially added, and the mixture was stirred at room temperature for 16 hours. After the reaction was stopped, the reaction mixture was concentrated under reduced pressure to remove chloroform, and then water (2.0 mL) was added. The precipitated solid was collected by filtration and dried at 50 ° C. under reduced pressure to give 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate (190 mg, 80% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.79-1.66 (2H, m), 1.85-1.96 (2H, m), 2.59-2.48 (4H, brm) 3.16 (2H, s), 3.55 (2H, brs), 3.89 (3H, s), 3.92 (3H, s), 4.50 (2H, s), 7.30 ( 1H, d, J = 7.5 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.51-7.60 (3H, m), 7.63 (1H, dd, J = 7 .8, 1.4 Hz).

LC / MS [Condition 1]: retention time 3.28 minutes; m / z 492.8 [M + H] ⁺ (ESI positive ion mode), m / z 536.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 115-4
Of 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane obtained in Preparation Reference Example 115-3 -3-yl} methyl) methyl benzoate (170 mg, 0.35 mmol) was dissolved in 1,4-dioxane (1.5 mL), 1M aqueous sodium hydroxide solution (1.4 mL) was added, and the mixture was stirred at room temperature. . After 21 hours, 1M hydrochloric acid (1.3 mL) was added to stop the reaction. The reaction mixture was extracted twice with ethyl acetate (10 mL), and the combined organic layers were washed with saturated brine (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The precipitated solid was washed with diisopropyl ether to give 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane. -3-yl} methyl) benzoic acid (140.0 mg, 84% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.94 (4H, m), 2.77 (2H, t, J = 10.2 Hz), 2.98-3.15 (4H, m), 3 .88 (3H, s), 3.90 (2H, s), 4.49 (2H, s), 7.27 (1H, d, J = 7.8 Hz), 7.50-7.65 (6H) , M).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 478.8 [M + H] ⁺ (ESI positive ion mode), m / z 476.9 [MH] ⁻ (ESI negative ion mode)

Example 115
3-Methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N— Production of [(tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 115) 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl ] obtained in Reference Example 115-4 ] -1-Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (30 mg, 0.063 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (24 mg, 0.13 mmol) and 1-hydroxybenzotriazole (17 mg, 0.13 mmol) were dissolved in chloroform (1.0 mL). Furyl amine (purchased from Tokyo Chemical Industry (Ltd.)) (0.013 mL, 0.13 mmol) and added triethylamine (0.018 mL, 0.13 mmol) and was stirred at room temperature for 20 hours. After stopping the reaction, water (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, followed by extraction twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated brine (10 mL). did. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained solid was washed with hexane, dried at 50 ° C. under reduced pressure, and 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran-2-yl) methyl] benzamide (23 mg, 66% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54-1.79 (3H, m), 1.84-1.98 (4H, m), 1.98-2.11 (1H, m) , 2.53 (4H, brs), 3.15 (2H, s), 3.34 (1H, ddd, J = 14.0, 7.2, 5.1 Hz), 3.56 (2H, brs) , 3.73-3.85 (2H, m), 3.85-3.94 (4H, m), 4.07 (1H, dq, J = 3.4, 7.2 Hz), 4.48 ( 2H, s), 6.51 (1H, t, J = 5.5 Hz), 7.22 (1H, dd, J = 7.8, 1.7 Hz), 7.28 (1H, d, J = 7) .8 Hz), 7.39-7.48 (3H, m), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 561.8 [M + H] ⁺ (ESI positive ion mode), m / z 606.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 116
4- [3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamide] Preparation of t-butyl piperidine-1-carboxylate (Compound No. 116) Instead of using tetrahydrofurfurylamine, t-butyl 4-aminopiperidine-1-carboxylate (purchased from Aldrich Corporation) The reaction was carried out substantially as in Example 115 to give the title compound as a white solid (100 mg, 84% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40 (2H, td, J = 12.3, 3.7 Hz), 1.47 (9H, s), 1.64-1.79 (2H, brm), 1.89 (2H, d, J = 13.0 Hz), 2.02 (2H, dd, J = 12.6, 2.7 Hz), 2.41-2.63 (4H, brm), 2.91 (2H, t, J = 13.0 Hz), 3.15 (2H, s), 3.55 (2H, brs), 3.90 (3H, s), 4.01-4.21 ( 3H, m), 4.48 (2H, s), 6.00 (1H, d, J = 8.2 Hz), 7.17 (1H, dd, J = 7.8, 1.7 Hz), 7. 29 (1H, d, J = 7.8 Hz), 7.38-7.47 (3H, m), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.58 minutes; m / z 660.9 [M + H] ⁺ (ESI positive ion mode), m / z 705.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 117
3-Methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N— Preparation of (piperidin-4-yl) benzamide dihydrochloride 4- [3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-] obtained in Example 116 Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine-1-carboxylate (60 mg, 0.090 mmol) in 4M hydrogen chloride-dioxane solution (1.0 mL) And stirred at room temperature for 1 hour. After the reaction was stopped, the reaction mixture was concentrated to dryness under reduced pressure to give 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (63 mg, 100% yield) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 1.40 minutes; m / z 560.8 [M + H] ⁺ (ESI positive ion mode)

Example 117
N- [1- (cyanomethyl) piperidin-4-yl] -3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of Decan-3-yl} methyl) benzamide (Compound No. 117) 3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] obtained in Reference Example 117 ] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (32 mg, 0.050 mmol) was added to N, N— Dissolved in dimethylformamide (1.0 mL), bromoacetonitrile (purchased from Tokyo Chemical Industry Co., Ltd.) (0.0067 mL, 0.10 mmol) and triethylamine (0.021 mL, .15Mmol) added sequentially and stirred at room temperature for 1 day. A saturated aqueous ammonium chloride solution (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, followed by extraction twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated brine (10 mL). . The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [Chromatolex NH-PLC05 plate, developed by Fuji Silysia, developing solvent: ethyl acetate], and N- [1- (cyanomethyl) piperidin-4-yl] -3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide ( 18 mg, 60% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.55-1.79 (4H, m), 1.89 (2H, d, J = 13.3 Hz), 2.10 (2H, dd, J = 13.0, 3.1 Hz), 2.45-2.61 (6H, m), 2.84 (2H, dt, J = 11.6, 3.4 Hz), 3.16 (2H, s), 3.54 (2H, s), 3.55 (2H, brs), 3.89 (3H, s), 3.94-4.11 (1H, m), 4.48 (2H, s), 6 .08 (1H, d, J = 7.8 Hz), 7.19 (1H, dd, J = 7.8, 1.4 Hz), 7.28 (1H, d, J = 7.8 Hz), 7. 39-7.46 (3H, m), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 599.9 [M + H] ⁺ (ESI positive ion mode), m / z 644.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 118
4- [3-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 118) In substantially the same manner as in Example 117, except that methyl chloroformate (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of bromoacetonitrile. To give the title compound as a white solid (20 mg, 64% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (2H, dq, J = 3.4, 11.9 Hz), 1.65-1.78 (2H, m), 1.88 (2H, d, J = 13.6 Hz), 2.04 (2H, dd, J = 12.6, 2.7 Hz), 2.43-2.62 (4H, brm), 2.97 (2H, t, J = 12.3 Hz), 3.16 (2H, s), 3.55 (2H, brs), 3.70 (3H, s), 3.89 (3H, s), 4.04-4.26 ( 3H, m), 4.47 (2H, s), 6.13 (1H, d, J = 7.8 Hz), 7.19 (1H, dd, J = 7.8, 1.4 Hz), 7. 28 (1H, d, J = 7.8 Hz), 7.41 (1 H, d, J = 1.4 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d , J = 8 2Hz).

LC / MS [Condition 1]: Retention time 3.22 min; m / z 618.9 [M + H] ⁺ (ESI positive ion mode), m / z 663.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 119-1
Preparation of t-butyl 4- (1-ethoxy-1-oxopropan-2-yl) -4-hydroxypiperidine-1-carboxylate 1M lithium hexamethyldisilazide tetrahydrofuran solution (purchased from Aldrich Co.) (9 (9 mL, 9.9 mmol) in tetrahydrofuran (25 mL) was slowly added dropwise with ethyl propionate (purchased from Tokyo Chemical Industry Co., Ltd.) (1.1 mL, 9.9 mmol) at −78 ° C. in an argon atmosphere. After stirring for 10 minutes at the same temperature, a tetrahydrofuran solution (5.0 mL) of 1-t-butoxycarbonyl-4-piperidine (purchased from Wako Pure Chemical Industries, Ltd.) (1.8 g, 9.0 mmol) was slowly added. It was. After stirring for one day while gradually warming to room temperature, saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL) were added. The reaction was extracted twice with ethyl acetate (10 mL), and the combined organic layers were washed with saturated brine (20 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and tert-butyl 4- (1-ethoxy-1-oxopropan-2-yl) -4-hydroxypiperidine-1-carboxylate. Was obtained as a yellow oil (2.5 g). The crude product was used in the next reaction without purification.

Reference Example 119-2
Production of 2- [1- (t-butoxycarbonyl) -4-hydroxypiperidin-4-yl] propionic acid 4- (1-ethoxy-1-oxopropan-2-yl) obtained in Reference Example 119-1 To a methanol solution (36 mL) of t-butyl-4-hydroxypiperidine-1-carboxylate was added 1M aqueous sodium hydroxide solution (36 mL), and the mixture was stirred at room temperature for 3 days. After setting the reaction temperature to 0 ° C., 1M hydrochloric acid (30 mL) was added to adjust the pH to about 8, and then ethyl acetate (20 mL) was added to wash the aqueous layer twice. The resulting aqueous layer was adjusted to pH 4 by adding 1 M hydrochloric acid, extracted three times with ethyl acetate (20 mL), and the combined organic layer was washed with saturated brine (40 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 2- [1- (t-butoxycarbonyl) -4-hydroxypiperidin-4-yl] propionic acid as a yellow oil (790 mg). ). The crude product was used in the next reaction without purification.

Reference Example 119-3
Preparation of 4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl 2- [1- (t- Triethylamine (0.45 mL, 3.2 mmol) and diphenylphosphoryl azide (0.81 mL, 3.8 mmol) were added to a toluene solution (15 mL) of butoxycarbonyl) -4-hydroxypiperidin-4-yl] propionic acid at 70 ° C. After stirring for 30 minutes, the reaction solution was heated to reflux. Six hours later, a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to adjust the pH to about 8, and then ethyl acetate (20 mL) was added and extracted five times. The combined organic layers were washed with saturated brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: Yamazen Hi-FLASH column size L (40 μm, 30 g), developing solvent: hexane / ethyl acetate = 1/1 400 mL, and then ethyl acetate 300 mL]. -Methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (310 mg, 13% yield over 3 steps) was obtained as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.19 (3H, d, J = 6.5 Hz), 1.46 (9H, s), 1.61 (2H, ddd, J = 31.0, 13.2, 4.4 Hz), 1.87 (2H, td, J = 13.2, 2.7 Hz), 3.14 (2H, q, J = 13.2 Hz), 3.59 (1H, q , J = 6.5 Hz), 4.02 (2H, brs), 5.04 (1H, brs).

Reference Example 119-4
Preparation of methyl 4- (bromomethyl) benzoate 4- (Bromomethyl) benzoic acid (purchased from Tokyo Chemical Industry Co., Ltd.) (500 mg, 2.3 mmol) was added with a 10% hydrogen chloride-methanol solution (10 mL) at 60 ° C. Stir with. After 2 hours, the reaction was stopped, and saturated aqueous sodium hydrogen carbonate solution (20 mL) was added at room temperature. Ethyl acetate (20 mL) was added and extracted twice, and the combined organic layer was washed with saturated brine (40 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure, and a 2: 3 mixture of methyl 4- (bromomethyl) benzoate and methyl 4- (chloromethyl) benzoate was obtained as a pale yellow solid (390 mg). ). The crude product was used in the next reaction without purification.

4- (Bromomethyl) methyl benzoate
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.92 (3H, s), 4.50 (2H, s), 7.46 (2H, d, J = 8.0 Hz), 8.01 (2H , D, J = 8.0 Hz).

4- (Chloromethyl) methyl benzoate
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.92 (3H, s), 4.62 (2H, s), 7.46 (2H, d, J = 8.0 Hz), 8.04 (2H , D, J = 8.0 Hz).

Reference Example 119-5
Preparation of t-butyl 3- [4- (methoxycarbonyl) benzyl] -4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Reference Example 119-3 4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (200 mg, 0.74 mmol) obtained in 1 above was added to N, N-dimethylformamide ( 4.0 ml), sodium hydride (> 55%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (39 mg, 0.89 mmol) was added and stirred for 30 minutes, and then obtained in Reference Example 119-4. The resulting 2: 3 mixture (180 mg, 0.89 mmol) of methyl 4- (bromomethyl) benzoate and methyl 4- (chloromethyl) benzoate was added and stirred at room temperature. After 28 hours, saturated aqueous ammonium chloride solution (5.0 mL) and ethyl acetate (5.0 mL) were added. The mixture was extracted twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated brine (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: Yamazen Hi-FLASH column size L (40 μm, 30 g), developing solvent: hexane / ethyl acetate = 1/1], and 3- [4- (methoxy Carbonyl) benzyl] -4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (290.0 mg, yield 95%) as a colorless oil Got as.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.09 (3H, d, J = 6.5 Hz), 1.45 (9H, s), 1.47-1.62 (2H, m), 1 .66-1.84 (2H, m), 3.14 (2H, dd, J = 22.8, 10.9 Hz), 3.26 (1H, q, J = 6.5 Hz), 3.92 ( 3H, s), 3.94-4.11 (2H, m), 4.16 (1H, d, J = 15.7 Hz), 4.80 (1H, d, J = 15.7 Hz), 7. 36 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.2 Hz).

Reference Example 119-6
Preparation of 4-[(4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid methyl hydrochloride Obtained in Reference Example 119-5 3- [4- (Methoxycarbonyl) benzyl] -4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (280 mg, 0.67 mmol) To the solution was added 4M hydrogen chloride-dioxane solution (3 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction was terminated, the reaction mixture was concentrated to dryness under reduced pressure, and 4-[(4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid Methyl hydrochloride (260 mg, 100% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.15 (3H, d, J = 6.5 Hz), 1.94 (2H, dd, J = 35.6, 14.3 Hz), 2.09- 2.31 (2H, m), 3.17-3.38 (3H, m), 3.38-3.55 (2H, m), 3.93 (3H, s), 4.14 (1H, d, J = 15.6 Hz), 4.79 (1H, d, J = 15.6 Hz), 7.34 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8) .2 Hz), 9.70 (2H, brs).

Reference Example 119-7
4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate 4 obtained in reference example 119-6 of - [(4-methyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate hydrochloride To (200 mg, 0.56 mmol) was added N, N-dimethylformamide (2.0 mL). 4- (Trifluoromethyl) benzyl bromide (150 mg, 0.61 mmol) and triethylamine (0.23 mL, 1.7 mmol) were sequentially added and stirred at room temperature. After 21 hours, the reaction was stopped and water (3.0 mL) was added. The precipitated solid was collected by filtration and dried at 50 ° C. under reduced pressure to give 4-({4-methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate (240 mg, 88% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.10 (3H, d, J = 6.5 Hz), 1.53-1.87 (4H, m), 2.38-2.55 (2H, m), 2.70 (2H, t, J = 11.5 Hz), 3.27 (1H, q, J = 6.5 Hz), 3.57 (2H, s), 3.92 (3H, s) 4.15 (1H, d, J = 15.6 Hz), 4.79 (1 H, d, J = 15.6 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.43 ( 2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz).

Reference Example 119-8
4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid 4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane obtained in Preparation Reference Example 119-7 -3-yl} methyl) methyl benzoate (240 mg, 0.49 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3.0 mL) and methanol (2.0 mL), and then a 1 M aqueous sodium hydroxide solution (3 0.0 mL) was added and stirred at room temperature. After 2 hours, 1M hydrochloric acid (3.0 mL) was added to stop the reaction. The reaction was extracted twice with ethyl acetate (10 mL), and the combined organic layers were washed with saturated brine (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. 4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid ( 170 mg, 77% yield) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 462.7 [M + H] ⁺ (ESI positive ion mode), m / z 460.9 [MH] ⁻ (ESI negative ion mode)

Example 119
4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N— Production of [(tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 119) 4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl ] obtained in Reference Example 119-8 ] -1-Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (40 mg, 0.086 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (33 mg, 0.17 mmol) and 1-hydroxybenzotriazole (23 mg, 0.17 mmol) were dissolved in chloroform (1.0 mL). Triethanolamine (Tokyo Chemical Industry Co., Ltd. purchased from) (0.018mL, 0.17mmol) and added triethylamine (0.024mL, 0.17mmol) and at room temperature, the mixture was stirred for 3 days. Water (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, followed by extraction twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated brine (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: ethyl acetate / methanol = 10/1], and 4-({4-methyl-2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran-2-yl) methyl] benzamide (43 mg, yield 91 %) As a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.09 (3H, d, J = 6.5 Hz), 1.59-1.85 (5H, m), 1.87-1.98 (2H, m), 1.98-2.10 (1H, m), 2.38-2.54 (2H, m), 2.69 (2H, t, J = 11.9 Hz), 3.24 (1H, q, J = 6.5 Hz), 3.27-3.38 (1H, m), 3.56 (2H, brs), 3.72-3.94 (3H, m), 4.07 (1H, dq, J = 2.9, 7.4 Hz), 4.12 (1H, d, J = 15.6 Hz), 4.79 (1H, d, J = 15.6 Hz), 6.48 (1H, t , J = 4.9 Hz), 7.34 (2H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.0 Hz), 7.56 (2H, d, J = 8. 0 Hz), 7.7 (2H, d, J = 7.8Hz).

LC / MS [Condition 1]: retention time 3.18 minutes; m / z 545.9 [M + H] ⁺ (ESI positive ion mode), m / z 590.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 120
4- [4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamide] Production of t-butyl piperidine-1-carboxylate (Compound No. 120) The reaction was carried out substantially as in Example 119 to give the title compound as a white solid (150 mg, 89% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.09 (3H, d, J = 6.5 Hz), 1.32-1.49 (2H, m), 1.47 (9H, s), 1 .60-1.85 (4H, m), 1.96-2.07 (2H, m), 2.38-2.54 (2H, m), 2.69 (2H, t, J = 12. 7 Hz), 2.91 (2H, t, J = 12.7 Hz), 3.24 (1 H, q, J = 6.5 Hz), 3.56 (2H, s), 4.02-4.21 ( 3H, brm), 4.13 (1H, d, J = 15.6 Hz), 4.79 (1H, d, J = 15.6 Hz), 5.93 (1H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.72 (2H , D, J = .2Hz).

LC / MS [Condition 1]: Retention time 3.62 minutes; m / z 645.0 [M + H] ⁺ (ESI positive ion mode), m / z 643.1 [MH] ⁻ (ESI negative ion mode)

Reference Example 121
4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N— Preparation of (piperidin-4-yl) benzamide dihydrochloride 4- [4-({4-methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-] obtained in Example 120 Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide] piperidine-1-carboxylate (110 mg, 0.18 mmol) in 4M hydrogen chloride-dioxane solution (2.0 mL) And stirred at room temperature for 1 hour. After the reaction was stopped, the reaction mixture was concentrated to dryness under reduced pressure, and 4-({4-methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (130 mg) was obtained as a white solid. The crude product was used in the next reaction without purification.

Example 121
N- [1- (cyanomethyl) piperidin-4-yl] -4-({4-methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of Decan-3-yl} methyl) benzamide (Compound No. 121) 4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] obtained in Reference Example 121 ] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (piperidin-4-yl) benzamide dihydrochloride (54 mg, 0.088 mmol) was added to N, N— Dissolved in dimethylformamide (1.0 mL), bromoacetonitrile (purchased from Tokyo Chemical Industry Co., Ltd.) (0.012 mL, 0.18 mmol) and triethylamine (0.037 mL, 0.2 mmol) was sequentially added and stirred at room temperature for 2 days. Water (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (10 mL). The combined organic layers were saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine. Washed sequentially with (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Hexane / ethyl acetate (4/1, 5.0 mL) was added to the resulting solid and shaken, and then the solid was collected by filtration, dried at 50 ° C. under reduced pressure, and N- [1- (cyanomethyl) piperidine-4 -Yl] -4-({4-methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) Benzamide (35 mg, 68% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.10 (3H, d, J = 6.5 Hz), 1.56-1.86 (6H, m), 2.06-2.16 (2H, m), 2.39-2.58 (2H, brm), 2.53 (2H, td, J = 11.0, 2.5 Hz), 2.62-2.78 (2H, brm), 2. 83 (2H, dt, J = 12.3, 3.3 Hz), 3.26 (1H, q, J = 6.5 Hz), 3.54 (2H, s), 3.58 (2H, brs), 3.96-4.10 (1H, m), 4.13 (1H, d, J = 15.6 Hz), 4.79 (1H, d, J = 15.6 Hz), 5.96 (1H, d , J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.40-7.51 (2H, brm), 7.53-7.63 (2H, brm), .73 (2H, d, J = 8.2Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 583.8 [M + H] ⁺ (ESI positive ion mode), m / z 582.1 [MH] ⁻ (ESI negative ion mode)

Example 122
4- [4-({4-Methyl-2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamide] Production of methyl piperidine-1-carboxylate (Compound No. 122) In substantially the same manner as in Example 121 except that methyl chloroformate (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of bromoacetonitrile. To give the title compound as a white powder (46 mg, 87% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.10 (3H, d, J = 6.5 Hz), 1.34-1.50 (2H, m), 1.63-1.85 (4H, m), 2.05 (2H, dd, J = 12.7, 3.3 Hz), 2.38-2.55 (2H, brm), 2.60-2.78 (2H, brm), 2. 97 (2H, t, J = 12.3 Hz), 3.25 (1H, q, J = 6.5 Hz), 3.57 (2H, brs), 3.70 (3H, s), 4.05- 4.26 (3H, m), 4.13 (1H, d, J = 15.3 Hz), 4.78 (1H, d, J = 15.3 Hz), 5.96 (1H, d, J = 7) .8 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.39-7.49 (2H, brm), 7.52-7.62 (2H, brm), 7.73 ( H, d, J = 7.8Hz).

LC / MS [Condition 1]: retention time 3.22 minutes; m / z 602.9 [M + H] ⁺ (ESI positive ion mode), m / z 601.0 [MH] ⁻ (ESI negative ion mode)

Example 123
3-{[(1r, 4r) -4- (1-benzylpiperidin-4-ylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- Production of t-butyl carboxylate (Compound No. 123) (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3 obtained in Reference Example 2-3 , 8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (0.29 g, 0.73 mmol) was dissolved in chloroform (3.0 mL) and 4-amino-1-benzylpiperidine (0 .21 g, 1.1 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 0.21 g, 1.1 mmol) and the mixture was stirred at room temperature for 4 days. After completion of the reaction, water (5.0 mL) was added to the reaction mixture to separate the organic layer. The organic layer was further washed with water (10 mL) and then concentrated to dryness under reduced pressure. Ethyl acetate (3.0 mL) was added to the residue, and after shaking well, the insoluble material was collected by filtration to give 3-{[(1r, 4r) -4- (1-benzylpiperidin-4-ylcarbamoyl) Cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (0.35 g, 83% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 2.9, 12.7 Hz), 1.33-1.72 (2H, m), 1.46 (9H, s), 1.76 (2H, d, J = 13.1 Hz), 1.82-1.95 (6H, m), 1.97 (1H, tt, J = 12.3, 3.7 Hz), 2.11 (2H, t, J = 12.3 Hz), 2.72-2.87 (2H, m), 3.10 (2H, d, J = 7.4 Hz), 3.20-3.35 (2H, m), 3.25 (2H, s), 3.49 (2H, s), 3.65-3.97 (3H, m), 5.28 (1H, d, J = 8.2 Hz) ), 7.21-7.36 (5H, m).

Example 124
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 124) obtained in Reference Example 6-3, (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (91 mg, 0.20 mmol), 4-amino-1-benzylpiperidine ( 57 mg, 0.30 mmol) and 1-hydroxybenzotriazole (8 mg, 0.060 mol) were dissolved in chloroform (2.0 mL), and then at room temperature, 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (58 mg, 0.30 mmol) and the mixture was stirred at room temperature for 3 days. Thereafter, water (2.0 mL) was added, and the organic layer was separated and concentrated under reduced pressure. Ethyl acetate (3.0 mL) was added to the residue and shaken well, and then the insoluble material was collected by filtration. This was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 10/1], and (1r, 4r) -N- (1-benzylpiperidine-4- Yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (109 mg Yield 87%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.7, 12.3 Hz), 1.33-1.64 (5H, m), 1.69-1. 83 (4H, m), 1.83 to 2.03 (7H, m), 2.11 (2H, t, J = 11.5 Hz), 2.45-2.64 (4H, m), 2. 79 (2H, d, J = 11.9 Hz), 3.09 (2H, d, J = 7.0 Hz), 3.25 (2H, s), 3.48 (2H, s), 3.57 ( 2H, br s), 3.69-3.87 (1H, m), 5.27 (1H, brd, J = 7.8 Hz), 7.21-7.33 (5H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: Retention time 3.16 minutes; m / z 314.2 [M + 2H] ²⁺ , 627.4 [M + H] ⁺ (ESI positive ion mode)

Example 125
t-butyl 3-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) cyclohexanecarboxamido] propyl carbamate (Compound No. 125) Substantially except that N- (t-butoxycarbonyl) -1,3-diaminopropane is used instead of 4-amino-1-benzylpiperidine Was reacted in the same manner as in Example 124 to obtain the title compound (0.23 g, yield 84%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 2.9, 12.7 Hz), 1.34—1.53 (7H, m), 1.53-1. 68 (3H, m), 1.69-1.85 (4H, m), 1.85-1.98 (4H, m), 2.05 (1H, tt, J = 12.7, 3.3 Hz) ), 2.43-2.71 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.15 (2H, dt, J = 6.5, 6.1 Hz), 3 .25 (2H, s), 3.28 (2H, dt, J = 6.1, 6.1 Hz), 3.57 (2H, s), 4.88 (1H, br s), 6.19 ( 1H, br s), 7.44 (2H, d, J = 8.6 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: Retention time 3.64 min; m / z 611.4 [M + H] ⁺ (ESI positive ion mode), m / z 655.8 [M + HCOO] ⁻ (ESI negative ion mode)

Example 126
(1r, 4r) -N-cyclohexyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) cyclohexanecarboxamide (Compound No. 126) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1 obtained in Reference Example 6-3 -Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (0.42 g, 0.93 mmol), cyclohexylamine (0.16 mL, 1.4 mmol), and 1-hydroxy After benzotriazole (38 mg, 0.28 mol) was dissolved in chloroform (8.0 mL), 1-ethyl-3- (3-dimethylaminopropylene was dissolved at room temperature. ) Carbodiimide hydrochloride (0.27 g, 1.4 mmol) and the mixture was stirred at room temperature for 1 day. After adding water (8.0 mL) and shaking well, the organic layer was separated and concentrated to dryness under reduced pressure. After adding water (20 mL) to the residue and shaking well, the insoluble material was collected by filtration and (1r, 4r) -N-cyclohexyl-4-({2-oxo-8- [4- (trifluoro) Methyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (0.45 g, 89% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.89-1.24 (5H, m), 1.26-1.52 (4H, m), 1.52-1.83 (8H, m) , 1.84-2.03 (7H, m), 2.43-2.66 (4H, m), 3.09 (2H, d, J = 7.4Hz), 3.25 (2H, br s ), 3.57 (2H, br s), 3.65-3.83 (1H, m), 5.26 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: retention time 3.62 minutes; m / z 536.2 [M + H] ⁺ (ESI positive ion mode)

Example 127
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Production of N- [1- (pyridin-3-ylmethyl) piperidin-4-yl] cyclohexanecarboxamide (Compound No. 127) (1r, 4r) -4-({2-oxo -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (0.36 g, 0.79 mmol), reference 4-amino-1- (pyridin-3-ylmethyl) piperidine trihydrochloride, triethylamine (0.66 mL, 4.8 mmol) and 1-hydroxybenzotriazole obtained in Example 64 32 mg, 0.24 mol) was dissolved in chloroform (20 mL), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.23 g, 1.2 mmol) was added at room temperature. Stir for 1 day. After adding water (8.0 mL) and shaking well, the organic layer was separated and concentrated to dryness under reduced pressure. After adding ethyl acetate (20 mL) to the residue and shaking well, the insoluble material was collected by filtration to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl]. ] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [1- (pyridin-3-ylmethyl) piperidin-4-yl] cyclohexanecarboxamide (0.44 g, Yield 89%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 12.7 Hz), 1.31-1.64 (5H, m), 1.68-1. 84 (4H, m), 1.84-2.04 (7H, m), 2.13 (2H, dt, J = 1.6, 11.9 Hz), 2.40-2.67 (4H, m ), 2.78 (2H, d, J = 11.9 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.49 (2H, s), 3.57 (2H, s), 3.69-3.88 (1H, m), 5.31 (1H, d, J = 8.6 Hz), 7.25 (1H, dd, J = 4.9) , 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.63 (1H, dt, J = 7.8, 2.0 Hz), 8.5 (1H, dd, J = 4.9,1.6Hz), 8.54 (1H, d, J = 2.5Hz).

LC / MS [Condition 1]: Retention time 1.22 minutes; m / z 628.0 [M + H] ⁺ (ESI positive ion mode), m / z 672.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 128
(1r, 4r) -N- (3-aminopropyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Decan-3-yl} methyl) cyclohexanecarboxamide hydrochloride (Compound No. 128) t-butyl 3-[(1r, 4r) -4-({2-oxo-8- [ 4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamido] propylcarbamate (27 mg, 0.044 mmol) in methanol (1.0 mL 2M hydrogen chloride-methanol solution (0.20 mL, 0.40 mmol) was added at room temperature, and the mixture was allowed to stand at room temperature for 5 hours and at 40 ° C. for 2 hours. The solution was concentrated to dryness under reduced pressure. Ethyl acetate (2.0 mL) was added to the residue, and then concentrated to dryness under reduced pressure to give (1r, 4r) -N- (3-aminopropyl) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide hydrochloride (27 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.89 (2H, q, J = 11.9 Hz), 1.33 (2H, q, J = 12.7 Hz), 1.44-1. 61 (1H, m), 1.59-1.79 (6H, m), 1.96-2.29 (5H, m), 2.63-2.82 (2H, m), 2.89- 3.03 (2H, m), 3.03-3.22 (4H, m), 3.22-3.46 (4H, m), 4.45 (2H, d, J = 3.7 Hz), 7.59-8.09 (8H, m), 11.03-11.47 (1H, m).

LC / MS [Condition 2]: Retention time 0.98 min; m / z 511.3 [M + H] ⁺ (ESI positive ion mode)

Example 129
Methyl 3-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) cyclohexanecarboxamido] propyl carbamate (Compound No. 129) (1r, 4r) -N- (3-aminopropyl) -4-({2-oxo-8- [4 ] obtained in Example 128 -(Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide hydrochloride (10 mg, 0.017 mmol) in ethyl acetate (1.0 mL) And triethylamine (0.012 mL, 0.086 mmol) was added, followed by methyl chloroformate (0.0016 mL, 0.021 mm) at room temperature. ol) in ethyl acetate (0.10 mL) was added. After stirring at room temperature for 40 minutes, water (1.0 mL) was added, the organic layer was separated, concentrated to dryness under reduced pressure, and methyl 3-[(1r, 4r) -4-({2-oxo-8 -[4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamido] propyl carbamate (9.0 mg, 93% yield) Obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 2.9, 12.3 Hz), 1.48 (2H, dq, J = 2.9, 12.3 Hz), 1.54-1.69 (3H, m), 1.69-1.85 (4H, m), 1.85-1.98 (4H, m), 2.04 (1H, tt, J = 11) .5, 3.3 Hz), 2.45-2.65 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.20 (2H, dt, J = 6.1) 5.7 Hz), 3.25 (2H, s), 3.30 (2H, dt, J = 5.7, 6.1 Hz), 3.57 (2H, s), 3.67 (3H, s) 5.18 (1H, br s), 6.07 (1 H, br s), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz) .

LC / MS [Condition 2]: retention time 3.26 min; m / z 569.3 [M + H] ⁺ (ESI positive ion mode), m / z 613.6 [M + HCOO] ⁻ (ESI negative ion mode)

Example 130
(1r, 4r) -N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) cyclohexanecarboxamide (Compound No. 130) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1 obtained in Reference Example 6-3 -Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (20 mg, 0.044 mmol), methylamine hydrochloride (5 mg, 0.066 mmol), triethylamine (0.036 mL, 0.26 mmol) and 1-hydroxybenzotriazole (2 mg, 0.013 mmol) with chloroform (0.40 mL) and N, N-dimethylform Was suspended in a mixed solvent of an amide (0.40 mL), was added at room temperature, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (15 mg, 0.078 mmol). After stirring at room temperature for 1 day, the mixture was concentrated to dryness under reduced pressure, and water (1.0 mL) and ethyl acetate (2.0 mL) were added to the resulting residue to separate the organic layer. This was concentrated to dryness under reduced pressure to give (1r, 4r) -N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro. [4.5] Decan-3-yl} methyl) cyclohexanecarboxamide (21 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.3, 12.3 Hz), 1.48 (2H, dq, J = 2.9, 12.7 Hz), 1.52-1.68 (1H, m), 1.69-1.85 (4H, m), 1.85-1.98 (4H, m), 2.01 (1H, tt, J = 11) .5, 3.7 Hz), 2.44-2.72 (4 H, m), 2.80 (3 H, d, J = 4.9 Hz), 3.09 (2 H, d, J = 7.0 Hz) , 3.25 (2H, s), 3.57 (2H, s), 5.43 (1H, br s), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: Retention time 3.08 minutes; m / z 468.2 [M + H] ⁺ (ESI positive ion mode)

Reference Example 131
Production of 1 -benzyl-N-methylpiperidin-4-amine dihydrochloride 1) 4-amino-1-benzylpiperidine (purchased from Tokyo Chemical Industry Co., Ltd.) (1.0 g, 5.3 mmol) in chloroform (5 In 0 mL) and a solution of t-butyl dicarbonate (1.3 g, 5.8 mmol) in chloroform (5 mL) was added at 0 ° C. The mixture was allowed to stand at room temperature for 5 minutes and then concentrated to dryness under reduced pressure to obtain t-butyl 1-benzylpiperidin-4-ylcarbamate (1.5 g, quantitative yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35 to 1.50 (1H, m), 1.44 (9H, s), 1.90 (2H, d, J = 11.2 Hz), 2 .08 (2H, dt, J = 2.3, 11.2 Hz), 2.70-2.89 (2H, m), 3.48 (2H, s), 4.41 (1H, br s), 7.18-7.37 (5H, m).

2) The obtained t-butyl 1-benzylpiperidin-4-ylcarbamate (0.10 g, 0.34 mmol) was dissolved in N, N-dimethylformamide (1.0 mL), and potassium t-butoxide (43 mg, 0.38 mmol) was added and stirred for 10 minutes at room temperature, methyl iodide (0.024 mL, 0.38 mmol) was added and stirred for 1 day at room temperature for 1 day. Water (2.0 mL), n-hexane (2.0 mL) and ethyl acetate (2.0 mL) were added to separate the organic layer, which was washed with water (2.0 mL × 1) and then concentrated under reduced pressure. Dried to dryness. The residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 10/1], and t-butyl 1-benzylpiperidin-4-yl (methyl ) Carbamate (64 mg, 61% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.53-1.64 (2H, m), 1.72 (2H, dq, J = 3.7, 12. 7 Hz), 2.03 (2H, t, J = 11.1 Hz), 2.73 (3H, s), 2.87-2.98 (2H, m), 3.49 (3H, s), 3 .55-4.21 (1H, br m), 7.37-7.18 (5H, m).

3) The obtained t-butyl 1-benzylpiperidin-4-yl (methyl) carbamate (56 mg, 0.19 mmol) was dissolved in methanol (2.5 mL), and a 2M hydrogen chloride-methanol solution (0.50 mL, 1.0 mmol), left at 50 ° C. for 3 hours, and concentrated to dryness under reduced pressure to give 1-benzyl-N-methylpiperidin-4-amine dihydrochloride (50 mg, quantitative yield). Was obtained as a white solid.

Example 131
(1r, 4r) -N- (1-benzylpiperidin-4-yl) -N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 131) (1r, 4r) -4-({2-oxo-8) obtained in Reference Example 6-3 -[4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (20 mg, 0.044 mmol), obtained in Reference Example 131 1-benzyl-N-methylpiperidin-4-amine dihydrochloride (15 mg, 0.053 mmol), triethylamine (0.018 mL, 0.13 mmol) and 1-hydro Cibenzotriazole (2 mg, 0.013 mol) was dissolved in chloroform (0.40 mL), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13 mg, 0.066 mmol) was then added at room temperature. In addition, the mixture was stirred at room temperature for 10 days. After adding water (1.0 mL) and shaking well, ethyl acetate (2.0 mL) was added to separate the organic layer, which was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 10/1], and (1r, 4r) -N- (1-benzylpiperidine-4 -Yl) -N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) Cyclohexanecarboxamide (24 mg, 86% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.93-1.17 (2H, m), 1.42-2.15 (15H, m), 2.42 (1H, tt, J = 11.1. 9, 2.9 Hz), 2.48-2.65 (4H, m), 2.81 & 2.87 (total 3H, s respectively), 2.87-3.03 (2H, m), 3.10 & 3. 11 (total 2H, d each, J = 7.4 Hz, J = 7.0 Hz), 3.25 (2H, s), 3.49 (1.2 H, s), 3.53 (0.8 H, s), 3.57 (2H, brs), 4.40-4.56 (0.6H, m), 7.22-7.37 (5H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz). (3: 2 mixture of amide rotamers)

LC / MS [Condition 2]: Retention time 3.30 minutes; m / z 321.2 [M + 2H] ²⁺ , 641.4 [M + H] ⁺ (ESI positive ion mode)

Reference Example 132-1
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Production of methyl carboxylate (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl obtained in Reference Example 6-1 Cyclohexanecarboxylic acid methyl hydrochloride (50 mg, 0.14 mmol) was suspended in ethyl acetate (2.5 mL), triethylamine (0.080 mL, 0.58 mmol) was added, and 4- (trifluoromethyl chloride) was added at room temperature. ) Benzoyl (0.024 mL, 0.16 mmol) was added and stirred at room temperature for 20 minutes. After adding water (1 mL) and shaking well, the organic layer was separated and concentrated to dryness under reduced pressure to give (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl). ) Benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methyl cyclohexanecarboxylate (71 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.7 Hz), 1.41 (2H, dq, J = 3.7, 13.5 Hz), 1.50-2.16 (9H, m), 2.26 (1H, tt, J = 12.3, 3.7 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.18 −3.63 (5H, m), 3.66 (3H, s), 4.41−4.67 (1H, br m), 7.52 (2H, d, J = 8.2 Hz), 7. 69 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: Retention time 4.39 minutes; m / z 483.2 [M + H] ⁺ (ESI positive ion mode), m / z 527.6 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 132-2
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Production of carboxylic acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro obtained in Reference Example 132-1 [4.5] decan-3-yl} methyl) methyl cyclohexanecarboxylate (62 mg, 0.13 mmol) was dissolved in 1,4-dioxane (3.0 mL), water (0.60 mL) and 1M sodium hydroxide Aqueous solution (0.19 mL) was added, and the mixture was stirred at room temperature for 4 hr. Water (1 mL) was added, and the mixture was concentrated under reduced pressure to distill off dioxane. Water (1.0 mL) and 1M hydrochloric acid (0.30 mL) were added to the residue to adjust the pH to 2, followed by extraction with ethyl acetate (4.0 mL), and then concentrated to dryness under reduced pressure to give (1r, 4r ) -4-({2-Oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (58 mg Yield 96%) as a white solid.

Example 132
(1r, 4r) -N- (1-Benzylpiperidin-4-yl) -4-({2-oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [ 4.5] Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 132) obtained in Reference Example 132-2, (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (28 mg, 0.060 mmol) and 4-amino-1-benzylpiperidine ( 16 mg, 0.090 mmol) was dissolved in N, N-dimethylformamide (0.30 mL) to give 1-hydroxybenzotriazole (3 mg, 0.018 mmol) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (17 mg, 0.090 mmol) was added and stirred 11 days at room temperature. After adding water (1.0 mL) and ethyl acetate (2.0 mL) and shaking well, the organic layer was separated and concentrated to dryness under reduced pressure. After adding ethyl acetate (1.0 mL) to the residue and shaking well, the insoluble material was collected by filtration to give (1r, 4r) -N- (1-benzylpiperidin-4-yl) -4- ( {2-Oxo-8- [4- (trifluoromethyl) benzoyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (12 mg, 32% yield) Was obtained as a slightly yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 2.5, 12.3 Hz), 1.33-2.05 (3H, m), 1.97 (1H, tt, J = 11.9, 3.3 Hz), 2.11 (2H, dt, J = 2.0, 11.5 Hz), 2.80 (2H, d, J = 11.9 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.18-3.67 (5H, m), 3.49 (2H, s), 3.69-3.88 (1H, m), 4.42 -4.68 (1H, br m), 5.27 (1H, d, J = 7.8 Hz), 7.19-7.37 (5H, m), 7.52 (2H, d, J = 8) .2 Hz), 7.69 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: Retention time 3.48 min; m / z 641.4 [M + H] ⁺ (ESI positive ion mode), m / z 685.6 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 133-1
Preparation of 4-aminocyclohexanecarboxylic acid methyl hydrochloride 4-Aminocyclohexanecarboxylic acid (purchased from Tokyo Chemical Industry Co., Ltd.) (2.0 g, 14 mmol) was dissolved in a 2M hydrogen chloride-methanol solution (50 mL) and brought to room temperature. The mixture was allowed to stand for 1 day and then concentrated to dryness under reduced pressure to give dry 4-methylcyclohexanecarboxylic acid methyl hydrochloride (2.6 g, yield 96%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.38-2.30 (8H, m), 2.33 (0.25H, t, J = 11.5 Hz), 2.49-2.63 (0. 75H, m), 3.03-3.21 (0.25H, br m), 3.21-3.41 (0.75H, br m), 3.67 (0.75H, s), 3. 71 (2.25H, s), 7.87-8.68 (3H, br s). (About 3: 1 mixture of cis-trans form)

Reference Example 133-2
Production of t-butyl 3- [4- (methoxycarbonyl) cyclohexyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 1) Obtained in Reference Example 133-1 4-aminocyclohexanecarboxylic acid methyl hydrochloride (0.25 g, 1.3 mmol), 1-oxa-6-azaspiro [2.5] octane-6-carboxylic acid t obtained in Reference Example 1-1 -Butyl (0.25 g, 1.2 mmol) was suspended in water (2.5 mL), methanol (4.0 mL) and 1 M aqueous sodium hydroxide solution (1.2 mL, 1.2 mmol) were added, and 3 days at room temperature. After stirring, methanol was distilled off under reduced pressure. Water (1.0 mL) and chloroform (5.0 mL) were added to the residue, the organic layer was separated and concentrated to dryness under reduced pressure to give 4-hydroxy-4-{[4- (methoxycarbonyl) cyclohexylamino]. A crude product (0.43 g) of t-butyl methyl} piperidine-1-carboxylate was obtained as a colorless oil.

2) Crude product (0.43 g) of 4-hydroxy-4-{[4- (methoxycarbonyl) cyclohexylamino] methyl} piperidine-1-carboxylate in 1,4-dioxane (7.0 mL) After dissolution, 1,1′-carbonyldiimidazole (0.57 g, 3.6 mmol) was added, and the mixture was stirred at 90 ° C. for 2 days, cooled to room temperature, and concentrated to dryness under reduced pressure. Water (5.0 mL), 1M hydrochloric acid (6.0 mL), ethyl acetate (5.0 mL) and n-hexane (2.0 mL) were added to separate the organic layer, and the mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 1/1] to give 3- [4- (methoxycarbonyl) cyclohexyl] -2-oxo. 1-Oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (68 mg, 14% yield, approximately 1: 1 mixture of cis-trans) was obtained as a colorless oil. It was.

¹ H-NMR (CDCl ₃ ) δ: 1.30-1.75 (8H, m), 1.46 (9H, s), 1.78-1.97 (3H, m), 2.03-2 .14 (1H, m), 2.14-2.30 (1.5H, m), 2.66 (0.5H, br s), 3.20 (1H, s), 3.21 (1H, s), 3.27 (2H, t, J = 11.5 Hz), 3.63-3.94 (3H, m), 3.68 (1.5H, s), 3.70 (1.5H, s). (About 1: 1 mixture of cis-trans form)

Reference Example 133-3
Preparation of methyl 4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxylate 1) Reference example T-butyl 3- [4- (methoxycarbonyl) cyclohexyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate obtained in 133-2 (68 mg, 0.17 mmol, about 1: 1 mixture of cis isomer and trans isomer) was dissolved in methanol (1.0 mL), 2M hydrogen chloride-methanol solution (0.30 mL, 0.60 mmol) was added, and 3 mL at room temperature was added. The mixture was allowed to stand for days and concentrated to dryness under reduced pressure to give methyl 4- (2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) cyclohexanecarboxylate (57 mg To obtain a quantitative yield).

2) The obtained methyl 4- (2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) cyclohexanecarboxylate (57 mg, 0.17 mmol) was mixed with N, N-dimethyl. Dissolved in formamide (1.0 mL), ethyl acetate of triethylamine (0.072 mL, 0.51 mmol) and 4- (trifluoromethyl) benzyl bromide (45 mg, 0.19 mmol, purchased from Tokyo Chemical Industry Co., Ltd.) 0.20 mL) solution was added at room temperature and then stirred at room temperature for 1 day. After adding water (2 mL) to the reaction mixture, the insoluble material was collected by filtration, and 4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Methyl decan-3-yl} cyclohexanecarboxylate (65 mg, 83% yield over 2 steps) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.32-2.00 (10H, m), 2.01-2.14 (0.8H, m), 2.14-2.33 (1.6H, m), 2.43-2.62 (4H, m), 2.62-2.70 (0.6H, m), 3.19 & 3.21 (total 2H, respectively s), 3.56 (2H, br s), 3.65-3.80 (1H, m), 3.67 & 3.71 (total 3H, s), 7.44 (2H, d, J = 7.9 Hz), 7.57 (2H) , D, J = 7.9 Hz). (About 3: 2 mixture of cis-trans form)

LC / MS [Condition 2]: Retention time 3.40 minutes; m / z 455.2 [M + H] ⁺ (ESI positive ion mode)

Reference Example 133-4
Preparation of 4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxylic acid Reference Example 133-3 4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxylate ( 60 mg, 0.13 mmol) was dissolved in 1,4-dioxane (3.0 mL), water (0.50 mL) and 1M aqueous sodium hydroxide solution (0.20 mL, 0.20 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. After stirring for one day, the filtrate was concentrated under reduced pressure to distill off 1,4-dioxane. The residue was adjusted to pH 6 by adding 1M hydrochloric acid (0.25 mL, 0.25 mmol), and the precipitated solid was collected by filtration to give 4- {2-oxo-8- [4- (trifluoromethyl) benzyl]. -1-Oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxylic acid (37 mg, yield 65%) was obtained as a white solid.

Example 133
N- (1-Benzylpiperidin-4-yl) -4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of —yl} cyclohexanecarboxamide (Compound No. 133) 4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-- obtained in Reference Example 133-4 Diazaspiro [4.5] decan-3-yl} cyclohexanecarboxylic acid (19 mg, 0.043 mmol) was suspended in N, N-dimethylformamide (0.40 mL) and 4-amino-1-benzylpiperidine (12 mg, 0 0.065 mmol) in chloroform (0.30 mL) and 1-hydroxybenzotriazole (3 mg, 0.022 mmol) were added, and at room temperature, - ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (12 mg, 0.065 mmol) and the mixture was stirred at room temperature for 8 days. Then, water (2.0 mL) and ethyl acetate (4.0 mL) were added, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 2/1], and N- (1-benzylpiperidin-4-yl) -4- {2-Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxamide (14 mg, 54% yield) on white Obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.33-2.06 (16.2 H, m), 2.11 (2 H, t, J = 11.9 Hz) 2.36 (0.8 H, brs), 2.43-2.66 (4H, m), 2.82 (2H, br d, J = 11.9 Hz), 3.20 (0.4 H, s), 3.23 (1.6 H, s) , 3.49 (2H, s), 3.55 (2H, brs), 3.62-3.89 (2H, m), 5.25 (0.2H, d, J = 8.2 Hz), 5 .33 (0.8H, d, J = 7.8 Hz), 7.19-7.36 (5H, m), 7.43 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz). (Cis isomer-trans isomer about 4: 1 mixture)

LC / MS [Condition 1]: Retention time 3.00 min; m / z 307.1 [M + 2H] ²⁺ , 613.0 [M + H] ⁺ (ESI positive ion mode)

Example 134
t-butyl 3- (4- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} cyclohexanecarboxamido) propyl Preparation of carbamate (Compound No. 134) The reaction was carried out in substantially the same manner as in Example 133, except that N- (t-butoxycarbonyl) -1,3-diaminopropane was used instead of 4-amino-1-benzylpiperidine. Performed to give the title compound (22 mg, 92% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, br s), 1.49-2.20 (14.2 H, m), 2.40-2.49 (0.8 H, br s) , 2.46-2.63 (4H, m), 3.18 (2H, dt, J = 6.1, 6.1 Hz), 3.21 & 3.25 (total 2H, s respectively), 3.30 (2H, dt, J = 6.5, 5.7 Hz), 3.56 (2H, brs), 3.65-3.83 (1H, m), 4.72-4.93 (1H, m ), 6.31-6.57 (1H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz). (Cis isomer-trans isomer about 4: 1 mixture)

LC / MS [Condition 1]: Retention time 3.52 minutes; m / z 596.9 [M + H] ⁺ (ESI positive ion mode), m / z 641.2 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 135
Preparation of methyl 4-aminopiperidine-1-carboxylate Hydrochloride t-butyl piperidin-4-ylcarbamate (790 mg, 3.9 mmol) was dissolved in chloroform (10 mL), and methyl chloroformate (0. 31 mL, 3.9 mmol) and triethylamine (0.55 mL, 3.9 mmol) were added, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, the reaction mixture was diluted with chloroform, water was added, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give methyl 4- (t-butoxycarbonylamino) piperidine-1-carboxylate (880 mg). Methyl 4- (t-butoxycarbonylamino) piperidine-1-carboxylate (880 mg) was dissolved in methanol (2.0 mL) and 4M hydrogen chloride-dioxane solution (8.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure, and the obtained solid was washed with diethyl ether and dried under reduced pressure at room temperature to give the title compound (600 mg, yield 96%) as a white solid.

4- (t-Butoxycarbonylamino) piperidine-1-carboxylate methyl
¹ H-NMR (CDCl ₃ ) δ: 1.19-1.37 (2H, m), 1.44 (9H, s), 1.87-2.01 (2H, m), 2.82-2 .99 (2H, m), 3.49-3.72 (1H, m), 3.69 (3H, s), 3.91-4.19 (2H, m), 4.34-4.52 (1H, brm).

4-Aminopiperidine-1-carboxylic acid methyl hydrochloride
¹ H-NMR (CDCl ₃ ) δ: 1.60-1.91 (2H, m), 1.83 (2H, s), 2.04-2.25 (2H, m), 2.73-3 .03 (2H, m), 3.24-3.47 (1H, m), 3.70 (3H, s), 4.03-4.39 (2H, m), 8.49 (3H, brs) ).

Example 135
4- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinamide] piperidine Preparation of methyl-1-carboxylate (Compound No. 135) Substantially in Examples, except that methyl 4-aminopiperidine-1-carboxylate hydrochloride obtained in Reference Example 135 and triethylamine were used instead of tetrahydrofurfurylamine. The reaction was carried out in the same manner as 111 to give the title compound (14 mg, quantitative) as an amorphous solid.

¹ H-NMR (CDCl ₃ ) δ: 1.37-1.54 (2H, m), 1.69-1.84 (2H, m), 1.89-2.11 (4H, m), 2 .42-2.64 (4H, m), 2.96 (2H, t, J = 12.5 Hz), 3.33 (2H, s), 3.56 (2H, s), 3.69 (3H , S), 4.04-4.27 (3H, m), 4.57 (2H, s), 6.48 (1H, br m), 7.35 (1H, d, J = 8.0 Hz) , 7.43 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz), 8.10 (1H, dd, J = 8.0, 2.2 Hz), 8.93 (1H, d, J = 2.2 Hz).
LC / MS [Condition 1]: Retention time 4.68 minutes; m / z 590.3 [M + H] ⁺ (ESI positive ion mode)

Example 136
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) phenyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarboxamide] Production of methyl piperidine-1-carboxylate (Compound No. 136) Except for using 4-aminopiperidine-1-carboxylic acid methyl hydrochloride and triethylamine obtained in Reference Example 135 instead of cyclohexylamine The reaction was carried out substantially in the same manner as in Example 107 to obtain the title compound (11 mg, yield 83%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) δ: 0.95-1.12 (2H, m), 1.22-1.37 (2H, m), 1.41-1.67 (3H, m), 1 .73-2.08 (11H, m), 2.90 (2H, t, J = 12.1 Hz), 3.12 (2H, d, J = 7.4 Hz), 3.29 (2H, s) 3.31-3.43 (2H, m), 3.53-3.64 (2H, m), 3.69 (3H, s), 3.85-4.00 (1H, m), 4 .00-4.23 (2H, m), 5.35-5.48 (1H, br m), 6.94 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz).

LC / MS [Condition 1]: Retention time 5.8 minutes; m / z 582.4 [M + H] ⁺ (ESI positive ion mode), m / z 625.6 [M + HCOO] ⁻ (ESI negative ion mode)

Example 137
3-{[5- (4-Benzoylpiperidin-1-carbonyl) pyridin-2-yl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Production of decan-2-one (Compound No. 137) The reaction was conducted in substantially the same manner as in Example 111 except that 4-benzoylpiperidine hydrochloride and triethylamine were used instead of tetrahydrofurfurylamine to give the title compound ( 14 mg, 80% yield) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.71-2.10 (8H, m), 2.49-2.62 (4H, m), 3.02-3.32 (2H, m), 3 .35 (2H, s), 3.52-3.65 (1H, m), 3.56 (2H, s), 3.73-3.95 (1H, m), 4.53-4.73 (1H, m), 4.58 (2H, s), 7.34-7.64 (8H, m), 7.76 (1H, dd, J = 7.8, 2.0 Hz), 7.95. (2H, dd, J = 8.4, 1.2 Hz), 8.62 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.35 minutes; m / z 621.0 [M + H] ⁺ (ESI positive ion mode), m / z 655.2 [M + Cl] ⁻ (ESI negative ion mode)

Example 138
1- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) pyridine-3- Yl] -3-[(tetrahydrofuran-2-yl) methyl] urea (Compound No. 138) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] obtained in Reference Example 111-5 instead of 8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinic acid, tetrahydrofurfurylamine is used instead of N- (t-butoxycarbonyl) -1,3-diaminopropane thing Outside by carrying out the reaction using substantially similar to Example 83 to give the title compound (1.9 mg, 5% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.69-1.81 (2H, m), 1.84-2.06 (6H, m), 2.45-2.61 (4H, m), 2 .66-2.85 (1H, m), 3.12-3.23 (1H, m), 3.28 (2H, s), 3.51-3.62 (1H, m), 3.55 (2H, s), 3.73-3.95 (2H, m), 3.99-4.09 (1H, m), 4.47 (2H, s), 5.24-5.37 (1H , Brm), 7.19 (1H, d, J = 8.4 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7 .92 (1H, dd, J = 8.4, 2.6 Hz), 8.39 (1H, d, J = 2.6 Hz).

LC / MS [Condition 1]: Retention time 2.79 minutes; m / z 547.6 [M + H] ⁺ (ESI positive ion mode), m / z 546.1 [MH] ⁻ (ESI negative ion mode)

Reference Example 139-1
Preparation of t-butyl 3- {1- [4- (methoxycarbonyl) phenyl] ethyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 6- (hydroxy The reaction was conducted in substantially the same manner as in Reference Example 111-3 except that methyl 4- (1-hydroxyethyl) benzoate was used instead of methyl) nicotinic acid to give the title compound (22 mg, 27% yield). Was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.60 (3H, d, J = 7.2 Hz), 1.64-1.78 (2H, m), 1.82 -1.94 (2H, m), 2.83 (1H, d, J = 8.5 Hz), 3.19 (1H, d, J = 8.5 Hz), 3.19-3.36 (2H, m), 3.65-3.91 (2H, m), 3.92 (3H, s), 5.28 (1H, q, J = 7.2 Hz), 7.39 (2H, d, J = 8.2 Hz), 8.04 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 4.42 minutes; m / z 441.0 [M + Na] ⁺ (ESI positive ion mode)

Reference Example 139-2
Preparation of methyl 4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} ethyl) benzoate Reference instead of t-butyl 3-{[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 3- {1- [4- (methoxycarbonyl) phenyl] ethyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t obtained in Example 139-1 The reaction was carried out substantially in the same manner as in Reference Example 111-4 except that -butyl was used to give the title compound (26 mg, yield 56%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.59 (3H, d, J = 7.2 Hz), 1.61-1.84 (2H, m), 1.88-1.98 (1H, m) , 2.4-2.60 (4H, m), 2.83 (1H, d, J = 8.5 Hz), 3.19 (1H, d, J = 8.5 Hz), 3.54 (2H, s), 3.92 (3H, s), 5.27 (1H, q, J = 7.2 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.5 Hz), 7.56 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.5 Hz).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 477.0 [M + H] ⁺ (ESI positive ion mode)

Reference Example 139-3
Preparation of 4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} ethyl) benzoic acid 6 Reference example instead of ethyl ({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinate 4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} obtained from 139-2 Ethyl) The reaction was performed in substantially the same manner as in Reference Example 111-5 except that methyl benzoate was used to give the title compound (24 mg, quantitative) as a colorless oil.

Example 139
3- {1- [4- (4-Benzoylpiperidine-1-carbonyl) phenyl] ethyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 139) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-] obtained in Reference Example 139-3 instead of -yl} methyl) nicotinic acid Diazaspiro [4.5] decan-3-yl} ethyl) benzoic acid is substantially the same as Example 111 except that 4-benzoylpiperidine hydrochloride and triethylamine are used in place of tetrahydrofurfurylamine. Performing response, to give the title compound (9.3 mg, 85% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.47-1.71 (5H, m), 1.70-2.09 (6H, m), 2.39-2.63 (4H, m), 2 .87 (1H, d, J = 8.5 Hz), 3.00-3.24 (2H, m), 3.18 (1H, d, J = 8.5 Hz), 3.46-3.63 ( 1H, m), 3.55 (2H, s), 3.70-3.97 (1H, m), 4.54-4.82 (1H, m), 5.24 (1H, q, J = 7.2 Hz), 7.33-7.63 (11H, m), 7.91-7.98 (2H, m).

LC / MS [Condition 1]: retention time 3.54 min; m / z 634.0 [M + H] ⁺ (ESI positive ion mode), m / z 678.3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 140
4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} ethyl) -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 140) The reaction was conducted in substantially the same manner as in Example 139, except that 4-benzoylpiperidine hydrochloride and tetrahydrofurfurylamine were used in place of triethylamine. The compound (6.8 mg, yield 73%) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.53-1.65 (5H, m), 1.72-1.84 (2H, m), 1.88-2.11 (4H, m), 2 41-2.61 (4H, m), 2.82 (1H, d, J = 8.5 Hz), 3.18 (1H, d, J = 8.5 Hz), 3.27-3.39 ( 1H, m), 3.55 (2H, s), 3.72-3.95 (3H, m), 4.01-4.13 (1H, m), 5.26 (1H, q, J = 7.2 Hz), 6.43-6.54 (1 H, brm), 7.38 (2 H, d, J = 8.2 Hz), 7.42 (2 H, d, J = 8.2 Hz), 7. 56 (2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 546.0 [M + H] ⁺ (ESI positive ion mode), m / z 580.2 [M + Cl] ⁻ (ESI negative ion mode)

Example 141
4- [4- (1- {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} ethyl) benzamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 141) Substantially except that 4-aminopiperidine-1-carboxylate methyl hydrochloride obtained in Reference Example 135 was used instead of 4-benzoylpiperidine hydrochloride The reaction was carried out in the same manner as in Example 139 to obtain the title compound (8.6 mg, yield 82%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) δ: 1.33-1.65 (6H, m), 1.71-1.82 (2H, m), 1.88-1.97 (1H, m), 2 .00-2.09 (2H, m), 2.39-2.60 (4H, m), 2.82 (1H, d, J = 8.5 Hz), 2.97 (2H, t, J = 12.3 Hz), 3.19 (1H, d, J = 8.5 Hz), 3.54 (2H, s), 3.70 (3H, s), 4.04-4.26 (3H, m) , 5.25 (1H, q, J = 7.2 Hz), 5.93-6.03 (1H, brm), 7.39 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.2 minutes; m / z 603.0 [M + H] ⁺ (ESI positive ion mode), m / z 637.2 [M + Cl] ⁻ (ESI negative ion mode)

Reference Example 142-1
Preparation of ethyl 5- (chloromethyl) thiazole-2-carboxylate Ethyl 2-amino-2-thioxoacetate (1.0 g, 7.5 mmol) and 1,3-dichloropropan-2-one (1.1 g, 8 0.5 mmol) was dissolved in toluene (15 mL) and stirred at 110 ° C. for 5 and a half hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and saturated aqueous sodium hydrogen carbonate solution was added. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography [Polipack 2L 40 μm, developed by Moritex, developing solvent: hexane / ethyl acetate = 6/1], and the title compound (1.3 g, Yield 82%) was obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.0 Hz), 4.50 (2H, q, J = 7.0 Hz), 4.78 (2H, s), 7 .63 (1H, s).

LC / MS [Condition 1]: Retention time 3.62 minutes; m / z 206.0 [M + H] ⁺ (ESI positive ion mode)

Reference Example 142-2
Preparation of ethyl 5- (azidomethyl) thiazole-2-carboxylate Ethyl 5- (chloromethyl) thiazole-2-carboxylate (1.3 g, 6.1 mmol) obtained in Reference Example 142-1 was replaced with N, N- After dissolving in dimethylformamide (20 mL), sodium azide (440 mg, 6.7 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and water was added. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure until the organic layer solution was about 10 mL, 0.020 mL was collected and concentrated under reduced pressure to obtain the title compound. The remaining solution was used for the next reaction as it was.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 4.63 (2H, s), 7 .55 (1H, s).

Reference Example 142-3
Preparation of ethyl 5- (aminomethyl) thiazole-2-carboxylate Ethanol (10 mL) was added to an ethyl acetate solution (about 10 mL) of ethyl 5- (azidomethyl) thiazole-2-carboxylate obtained in Reference Example 142-2. After the addition, 10 wt% palladium-carbon (300 mg) was added under an argon atmosphere. The reaction system was again filled with argon, replaced with hydrogen, and stirred at room temperature for 1 day. After replacing the inside of the reaction system with argon, the reaction mixture was filtered through celite to remove insoluble matters. The filtrate was concentrated under reduced pressure, and 10 wt% palladium-carbon (600 mg) was added under an argon atmosphere. After the reaction system was again filled with argon, it was replaced with hydrogen and stirred at room temperature for 5 hours. After replacing the inside of the reaction system with argon, the reaction mixture was filtered through celite to remove insoluble matters. After the solvent was distilled off until the solution reached about 15 mL, 0.06 mL was collected and concentrated under reduced pressure to obtain the title compound. The remaining solution was used for the next reaction as it was.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.2 Hz), 4.08 (2H, s), 4.49 (2H, q, J = 7.2 Hz), 7 .42 (1H, s).

Reference Example 142-4
Preparation of ethyl 5-({[1- (t-butoxycarbonyl) -4-hydroxypiperidin-4-yl] methylamino} methyl) thiazole-2-carboxylate 5- (amino Methyl) thiazole-2-carboxylate in ethanol (about 15 mL) in water (10 mL) and 1-oxa-6-azaspiro [2.5] octane-6-carboxylic acid t obtained in Reference Example 1-1 After adding -butyl (1.2 g, 5.4 mmol), the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, diluted with chloroform and water, the organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a mixture (2.5 g) containing mainly the title compound as a yellow oil.

Reference Example 142-5
3 - {[2- (ethoxycarbonyl) thiazol-5-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] manufacturing reference decane-8-carboxylic acid t- butyl Mixture (2.5 g) containing ethyl 5-({[1- (t-butoxycarbonyl) -4-hydroxypiperidin-4-yl] methylamino} methyl) thiazole-2-carboxylate obtained in Example 142-4 ) Was dissolved in tetrahydrofuran (30 mL), 1,1′-carbonyldiimidazole (1.5 g, 9.3 mmol) was added, and the mixture was stirred at 70 ° C. for 2 hours. After stirring at room temperature for 1 day, 1,1′-carbonyldiimidazole (1.5 g, 9.3 mmol) was added to the reaction mixture, and the mixture was stirred again at 70 ° C. for 3 hours. After cooling the reaction mixture, water was added and stirred until foaming subsided. The reaction mixture was diluted with ethyl acetate, and saturated aqueous sodium hydrogen carbonate solution was added. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography [Polipack 2L 40 μm, developed by Moritex, developing solvent: hexane / ethyl acetate] to give the title compound (850 g, yield 30%). Obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.2 Hz), 1.45 (9H, s), 1.55-1.73 (2H, m), 1.80 -1.95 (2H, m), 3.29 (2H, t, J = 11.1 Hz), 3.39 (2H, s), 3.72-3.89 (2H, m), 4.49 (2H, q, J = 7.2 Hz), 4.64 (2H, s), 7.55 (1H, s).

LC / MS [Condition 1]: Retention time 4.02 minutes; m / z 448.0 [M + Na] ⁺ (ESI positive ion mode)

Reference Example 142-6
5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiazole-2-carboxylate Preparation of 3-{[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate instead of t-butyl 3-{[2- (ethoxycarbonyl) thiazol-5-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8 obtained in Reference Example 142-5 Reaction was carried out in substantially the same manner as in Reference Example 111-4 except that t-butyl carboxylate was used to give the title compound (140 mg, yield 63%).

¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.2 Hz), 1.67-1.86 (2H, m), 1.86-2.00 (2H, m) , 2.41-2.63 (4H, m), 3.38 (2H, s), 3.56 (2H, s), 4.48 (2H, q, J = 7.1 Hz), 4.63 (2H, s), 7.43 (2H, d, J = 8.3 Hz), 7.54 (1H, s), 7.57 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 2.36 minutes; m / z 483.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 142-7
5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiazole-2-carboxylic acid Preparation 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) instead of ethyl nicotinate 5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} obtained in Reference Example 142-6 The reaction was carried out in substantially the same manner as in Reference Example 111-5 except that ethyl methyl) thiazole-2-carboxylate was used to give the title compound (110 mg, yield 81%).

¹ H-NMR (DMSO-d ₆ ) δ: 1.71-1.89 (4H, m), 3.33 (2H, s), 3.69 (2H, s), 4.50 (2H, s) ), 7.56 (2H, d, J = 8.2 Hz), 7.70 (2H, d, J = 8.2 Hz), 7.84 (1H, s), piperidine 2H cannot be seen due to overlapping peaks .

LC / MS [Condition 1]: Retention time 2.36 minutes; m / z 455.9 [M + H] ⁺ (ESI positive ion mode), m / z 453.0 [MH] ⁻ (ESI negative ion mode)

Example 142
3-{[2- (4-Benzoylpiperidin-1-carbonyl) thiazol-5-yl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-2-one (Compound No. 142) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane 5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-] obtained in Reference Example 142-7 instead of -3-yl} methyl) nicotinic acid Diazaspiro [4.5] decan-3-yl} methyl) thiazole-2-carboxylic acid is substantially the same except that 4-benzoylpiperidine hydrochloride and triethylamine are used instead of tetrahydrofurfurylamine. The reaction was carried out in the same manner as in Example 111 to give the title compound (14 mg, 73% yield).

¹ H-NMR (CDCl ₃ ) δ: 1.68-2.10 (8H, m), 2.46-2.60 (4H, m), 3.03-3.28 (1H, m), 3 .31 (2H, s), 3.40-3.68 (2H, m), 3.55 (2H, s), 4.51-4.73 (1H, m), 4.56 (2H, d , J = 2.7 Hz), 5.20-5.43 (1H, m), 7.36-7.67 (8H, m), 7.95 (2H, d, J = 7.2 Hz).

LC / MS [Condition 1]: Retention time 3.45 minutes; m / z 627.1 [M + H] ⁺ (ESI positive ion mode), m / z 661.3 [M + Cl] ⁻ (ESI negative ion mode)

Example 143
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) nicotinamide (Compound No. 143) The reaction was conducted in substantially the same manner as in Example 111 except that piperonylamine was used instead of tetrahydrofurfurylamine. 7.1 mg, 68% yield) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.70-1.82 (2H, m), 1.90-2.01 (2H, m), 2.46-2.60 (4H, m), 3 .32 (2H, s), 3.56 (2H, s), 4.55 (2H, d, J = 5.8 Hz), 4.57 (2H, s), 5.96 (2H, s), 6.37 (1H, brs), 6.75-6.86 (3H, m), 7.37 (1H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz) ), 7.56 (2H, d, J = 8.2 Hz), 8.09 (1H, dd, J = 8.2, 2.0 Hz), 8.92 (1H, d, J = 2.0 Hz) .

LC / MS [Condition 1]: Retention time 3.2 minutes; m / z 582.9 [M + H] ⁺ (ESI positive ion mode), m / z 617.1 [M + Cl] ⁻ (ESI negative ion mode)

Example 144
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 Preparation of diazaspiro [4.5] decan-2-one (Compound No. 144) Substantially as in Example 111, except that 4- (4-fluorobenzoyl) piperidine hydrochloride and triethylamine are used instead of tetrahydrofurfurylamine. The reaction was performed in the same manner to obtain the title compound (4.9 mg, yield 43%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.69-2.08 (8H, m), 2.45-2.65 (4H, m), 3.01-3.27 (2H, m), 3 .35 (2H, s), 3.41-3.65 (1H, m), 3.57 (2H, s), 4.47-4.76 (1H, m), 4.57 (2H, s) ), 7.17 (2H, t, J = 8.5 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 7.8, 2.0 Hz), 7.94-8.02 (2H, m), 8.61 (1H, d, J = 2.0 Hz). 1Hinvisible (broad)

LC / MS [Condition 1]: Retention time 3.4 minutes; m / z 639.1 [M + H] ⁺ (ESI positive ion mode), m / z 673.3 [M + Cl] ⁻ (ESI negative ion mode)

Example 145
3-({5- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -8- [4- (trifluoromethyl) benzyl Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 145) 6-Fluoro-3- (piperidin-4-yl) benzo [d The reaction was carried out in substantially the same manner as in Example 111 except that isoxazole was used to give the title compound (7.6 mg, yield 66%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.40-1.60 (1H, m), 1.72-1.87 (2H, m), 1.91-2.31 (6H, m), 2 .46-2.65 (4H, m), 3.09-3.47 (4H, m), 3.35 (2H, s), 3.57 (2H, s), 4.58 (2H, s) ), 7.09 (1H, td, J = 8.9, 2.0 Hz), 7.38 (2H, d, J = 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz) 7.57 (2H, d, J = 8.2 Hz), 7.63 (1H, dd, J = 8.7, 4.9 Hz), 7.78 (1H, dd, J = 8.2, 2) .0Hz), 8.65 (1H, d, J = 1.4 Hz).

LC / MS [Condition 1]: Retention time 3.47 minutes; m / z 652.1 [M + H] ⁺ (ESI positive ion mode), m / z 686.3 [M + Cl] ⁻ (ESI negative ion mode)

Reference Example 146
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Production of decan-2-one The reaction was conducted in substantially the same manner as in Example 16 except that phenyl (piperidin-4-yl) methanone hydrochloride (commercially available) and triethylamine were used instead of piperidine. The title compound (37 mg, 59% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.46-1.71 (4H, m), 1.71-1.87 (7H, m), 1.87-2.00 (4H, m), 2.46 (1H, tt, J = 11.9, 3.3 Hz), 2.56 (4H, br s), 2.81 (1H) , T, J = 11.4 Hz), 3.11 (2H, d, J = 8.2 Hz), 3.13-3.29 (3H, m), 3.51 (1H, tt, J = 1.11. 0, 4.5 Hz), 3.57 (2H, s), 3.98 (1 H, d, J = 13.5 Hz), 4.60 (1 H, d, J = 13.1 Hz), 7.39- 7.62 (7H, m), 7.93 (2H, d, J = 6.5 Hz).

LC / MS [Condition 1]: retention time 3.56 minutes; m / z 626.0 [M + H] ⁺ (ESI positive ion mode), m / z 670.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 146
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one hydrochloride (Compound No. 146) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl obtained in Reference Example 146 } -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (17 mg, 0.028 mmol) dissolved in methanol (1.0 mL) After that, a 4M hydrogen chloride-dioxane solution (commercially available) (0.021 mL, 0.083 mmol) was added at room temperature, and the mixture was stirred at 60 ° C. for 5 hours. Thereafter, the solution was concentrated to dryness under reduced pressure to give 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1 -Oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (19 mg, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.4 Hz), 1.46-1.99 (11H, m), 2.05 (2H, d, J = 13.9 Hz), 2.46 (1H, tt, J = 11.4, 2.9 Hz), 2.64-2.93 (3H, m), 3.02-3.28 (5H, m), 3.30-3.43 (2H, br m), 3.38 (2H, s), 3.52 (1H, tt, J = 11.0, 3.7 Hz), 3.97 (1H, br s) ), 4.17 (2H, d, J = 5.3 Hz), 4.57 (1H, brs), 7.42-7.52 (2H, m), 7.53-7.63 (1H, m), 7.73 (2H, d, J = 8.2 Hz), 7.85 (2H, d, J = 8.2 Hz), 7.89-7.97 (2H, m), 13.26 ( 1H, s .

Example 147
3-({(1r, 4r) -4- [4- (tetrahydrofuran-2-carbonyl) piperazine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa- Preparation of 3,8-diazaspiro [4.5] decan-2-one (Compound No. 147) Substantially except that piperazin-1-yl (tetrahydrofuran-2-yl) methanone (commercially available) is used instead of piperidine Was reacted in the same manner as in Example 16 to obtain the title compound (48 mg, yield 72%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.45-1.70 (3H, m), 1.70-1.86 (6H, m), 1.87-2.11 (5H, m), 2.24-2.51 (2H, m), 2.56 (4H, brs), 3.11 (2H, d, J = 7) .4Hz), 3.26 (2H, s), 3.33-3.63 (7H, m), 3.64-3.98 (5H, m), 4.59 (1H, t, J = 6) .1 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 620.9 [M + H] ⁺ (ESI positive ion mode), m / z 665.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 148
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-ylmethyl) } Cyclohexanecarbonyl] Preparation of t-butyl piperazine-1-carboxylate (Compound No. 148) Substantially the same as Example 16 except that t-butyl piperazine-1-carboxylate (commercially available) was used instead of piperidine. The title compound (137 mg, 92% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.47 (9H, s), 1.51-1.69 (3H, m), 1 .70-1.86 (6H, m), 1.87-2.02 (2H, m), 2.42 (1H, t, J = 11.4 Hz), 2.56 (4H, br s), 3.10 (2H, d, J = 6.1 Hz), 3.26 (2H, s), 3.34-3.46 (4H, m), 3.44 (2H, s), 3.57 ( 4H, s), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.42 minutes; m / z 622.9 [M + H] ⁺ (ESI positive ion mode), m / z 667.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 149
3-{[(1r, 4r) -4- (piperazine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-2-one dihydrochloride 4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-] obtained in Example 148 Oxa-3,8-diazaspiro [4.5] decan-3-ylmethyl)} cyclohexanecarbonyl] piperazine-1-carboxylate (89 mg, 0.14 mmol) was dissolved in methanol (1.0 mL) at room temperature. 4M hydrogen chloride-dioxane solution (commercially available) (0.36 mL, 1.4 mmol) was added and stirred at 60 ° C. for 4 hours. Thereafter, the solution was concentrated to dryness under reduced pressure to give 3-{[(1r, 4r) -4- (piperazine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa- 3,8-Diazaspiro [4.5] decan-2-one dihydrochloride (83 mg, quantitative) was obtained as a white powder.

LC / MS [Condition 1]: Retention time 0.96 minutes; m / z 523.0 [M + H] ⁺ (ESI positive ion mode

Example 149
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Production of methyl) cyclohexanecarbonyl] piperazine-1-carboxylate (Compound No. 149) 3-{[(1r, 4r) -4- (piperazine-1-carbonyl) cyclohexyl] methyl}-obtained in Reference Example 149 8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one dihydrochloride (26 mg, 0.044 mmol) was added to dimethylformamide (0.5 mL). And triethylamine (0.031 mL, 0.22 mmol) and methyl chloroformate (0.007 mL, 0.088 mmol) were added at room temperature. And the mixture was stirred for days. Thereafter, chloroform (3.0 mL) and saturated aqueous sodium hydrogen carbonate solution (3.0 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / methanol = 20/1], and 4-[(1r, 4r) -4-({2 -Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarbonyl] piperazine-1-carboxylate (16 mg Yield 63%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.45-1.69 (3H, m), 1.78 (6H, d, J = 11.4 Hz), 1.94 (2 H, d, J = 13.1 Hz), 2.42 (1 H, tt, J = 11.9, 2.9 Hz), 2.55 (4 H, br s), 3 .10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.47 (6H, br s), 3.53-3.64 (4H, m), 3.72 ( 3H, s), 7.43 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz).
LC / MS [Condition 1]: retention time 3.22 minutes; m / z 580.9 [M + H] ⁺ (ESI positive ion mode), m / z 625.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 150
2- {4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of —yl} methyl) cyclohexanecarbonyl] piperazin-1-yl} acetonitrile (Compound No. 150) Substantially the same as Example 149, except that 2-bromoacetonitrile (commercially available) was used instead of methyl chloroformate. The reaction was performed to give the title compound (7.0 mg, yield 33%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, dq, J = 3.7, 12.3 Hz), 1.46-1.69 (3H, m), 1.79 (6H, d, J = 11.4 Hz), 1.88-2.01 (2 H, m), 2.42 (1 H, tt, J = 10.6, 2.5 Hz), 2.57 (8 H, br s) 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.46-3.72 (8H, m), 7.43 (2H, d, J = 7. 8 Hz), 7.57 (2H, d, J = 8.2 Hz).
LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 562.3 [M + H] ⁺ (ESI positive ion mode), m / z 606.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 151
3-{[(1r, 4r) -4- (4-acetylpiperazine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one (Compound No. 151) The reaction was conducted in substantially the same manner as in Example 149 except that acetyl chloride was used in place of methyl chloroformate to give the title compound (9.0 mg Yield 36%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 12.0 Hz), 1.47-1.70 (3H, m), 1.79 (6H, d, J = 11.0 Hz), 1.94 (2H, d, J = 13.1 Hz), 2.12 (3 H, s), 2.36-2.51 (1 H, m), 2.56 (4 H, br s) ), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.38-3.53 (4H, br m), 3.57 (2H, s), 3 .55-3.69 (4H, br m), 7.43 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 2.98 minutes; m / z 564.9 [M + H] ⁺ (ESI positive ion mode), m / z 609.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 152
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarboxamide] Preparation of ethyl piperidine-1-carboxylate (Compound No. 152) Substantially the same as Example 16 except that ethyl 4-aminopiperidine-1-carboxylate (commercially available) was used instead of piperidine. The title compound (58 mg, 92% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 2.9, 12.3 Hz), 1.18-1.36 (5H, m), 1.38-1. 66 (3H, m), 1.67-2.06 (11H, m), 2.55 (4H, br s), 2.89 (2H, t, J = 11.9 Hz), 3.09 (2H , D, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.82-4.00 (1H, m), 4.01-4.19 (4H M), 5.29 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 7.4 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 608.9 [M + H] ⁺ (ESI positive ion mode), m / z 653.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 153
(1r, 4r) -N-butyl-4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexane Preparation of carboxamide (Compound No. 153) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane (1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3] obtained in Reference Example 17-2 instead of -3-yl} methyl) cyclohexanecarboxylic acid , 8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid, n-butylamine (commercially available) instead of piperidine and dimethylformamide instead of chloroform Outside by performing the same reaction as substantially Example 16 to give the title compound (23 mg, 37% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.92 (3H, t, J = 7.0 Hz), 1.01 (2H, dq, J = 4.1, 12.7 Hz), 1.23- 1.66 (7H, m), 1.68-2.06 (9H, m), 2.58 (4H, brs), 3.09 (2H, d, J = 7.4 Hz), 3.16 -3.30 (4H, m), 3.59 (2H, s), 5.39 (1H, t, J = 6.1 Hz), 7.45 (2H, d, J = 7.8 Hz), 7 .61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 466.9 [M + H] ⁺ (ESI positive ion mode), m / z 511.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 154
4-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] benzonitrile (Compound No. 154) Substantially Example 153 except that phenyl (piperidin-4-yl) methanone hydrochloride (commercially available) and triethylamine were used instead of n-butylamine. The title compound (37 mg, yield 56%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 2.9, 11.9 Hz), 1.43-2.06 (15H, m), 2.47 (1H, tt, J = 11.4, 2.9 Hz), 2.55 (4H, br s), 2.81 (1H, t, J = 11.9 Hz), 3.11 (2H, d, J = 5. 7 Hz), 3.20 (1 H, t, J = 12.7 Hz), 3.26 (2 H, s), 3.44-3.56 (1 H, m), 3.57 (2 H, s), 3 .98 (1H, d, J = 12.7 Hz), 4.59 (1 H, d, J = 12.7 Hz), 7.39-7.53 (4H, m), 7.54-7.65 ( 3H, m), 7.93 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 3.28 minutes; m / z 582.9 [M + H] ⁺ (ESI positive ion mode), m / z 627.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 155
(1r, 4r) -N- (Benzo [d] [1,3] dioxol-5-ylmethyl) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide (Compound No. 155) Instead of n-butylamine, benzo [d] [1,3] dioxol-5-ylmethanamine (commercially available) The reaction was carried out substantially in the same manner as in Example 153, except that the title compound (21 mg, yield 30%) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.7, 12.7 Hz), 1.40-1.68 (3H, m), 1.70-1. 86 (4H, m), 1.87-1.99 (4H, m), 2.04 (1H, tt, J = 11.0, 2.9 Hz), 2.55 (4H, br s), 3 .09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.56 (2H, s), 4.32 (2H, d, J = 5.7 Hz), 5.68 (1H, t, J = 5.5 Hz), 5.93 (2H, s), 6.66-6.78 (3H, m), 7.44 (2H, d, J = 7.8 Hz), 7 .60 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 544.9 [M + H] ⁺ (ESI positive ion mode), m / z 589.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 156
(1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- (2 , 3-Dihydro-1H-inden-2-yl) cyclohexanecarboxamide (Compound No. 156), except that 2,3-dihydro-1H-inden-2-amine (commercially available) was used instead of n-butylamine. The reaction was carried out substantially in the same manner as in Example 153 to obtain the title compound (26 mg, yield 48%) as a yellow powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.98 (2H, dq, J = 3.7, 13.1 Hz), 1.36-1.65 (3H, m), 1.66-2. 01 (9H, m), 2.55 (4H, br s), 2.76 (2H, dd, J = 16.8, 4.5 Hz), 3.07 (2H, d, J = 7.4 Hz) , 3.24 (2H, s), 3.31 (2H, dd, J = 15.9, 7.8 Hz), 3.56 (2H, s), 4.73 (1H, dtt, J = 7. 8, 7.0, 4.1 Hz), 5.64 (1H, d, J = 7.8 Hz), 7.10-7.29 (4H, m), 7.43 (2H, d, J = 8) .2 Hz), 7.60 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 526.9 [M + H] ⁺ (ESI positive ion mode), m / z 571.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 157
(1r, 4r) -N-methoxy-N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane Preparation of -3-yl} methyl) cyclohexanecarboxamide (Compound No. 157) In substantially the same manner as in Example 16, except that N, O-dimethylhydroxylamine hydrochloride (commercially available) and triethylamine were used instead of piperidine. To give the title compound (140 mg, 77% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07 (2H, dq, J = 2.6, 12.6 Hz), 1.41-1.68 (3H, m), 1.69-2. 00 (8H, m), 2.57 (4H, br s), 2.65 (1 H, t, J = 10.6 Hz), 3.11 (2H, d, J = 7.3 Hz), 3.17 (3H, s), 3.26 (2H, s), 3.57 (2H, s), 3.69 (3H, s), 7.44 (2H, d, J = 7.9 Hz), 7. 57 (2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 498.4 [M + H] ⁺ (ESI positive ion mode)

Reference Example 158
Preparation of 4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzoic acid 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-obtained in Example 1 instead of t-butyl carboxylate In addition, methyl 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoate is used. Except for the above, the reaction was carried out in substantially the same manner as in Reference Example 2-3 to give the title compound (900 mg, yield 93%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.55-1.68 (2H, m), 1.87 (2H, d, J = 13.1 Hz), 3 .15 (2H, s), 3.28 (2H, td, J = 12.3, 2.9 Hz), 3.82 (2H, dt, J = 13.5, 4.1 Hz), 4.51 ( 2H, s), 7.37 (2H, d, J = 8.2 Hz), 8.09 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: retention time 3.88 min ;, m / z 389.0 [MH] ⁻ (ESI negative ion mode)

Example 158
3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (Compound No. 158) manufacturing (1r, 4r) -4 - { [8- (t- butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid Instead of 4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzoic acid obtained in Reference Example 158 The acid was reacted in substantially the same manner as in Example 2 except that phenyl (piperidin-4-yl) methanone hydrochloride (commercially available) and triethylamine were used instead of tetrahydrofurfurylamine. Title compound (1.1 g, 88% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.52-1.69 (2H, m), 1.71-2.15 (6H, m), 2.96 -3.22 (2H, m), 3.13 (2H, s), 3.29 (2H, t, J = 12.7 Hz), 3.47-3.64 (1H, m), 3.66 -4.00 (3H, m), 4.45 (2H, s), 4.68 (1H, br s), 7.30 (2H, d, J = 8.2 Hz), 7.36-7. 53 (4H, m), 7.54-7.63 (1H, m), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.39 minutes; m / z 606.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 159
3- [4- (4-oxopiperidin-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of (Compound No. 159) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [3] obtained in Reference Example 21 instead of 3-yl} methyl) cyclohexanecarboxylic acid 4.5] decan-3-yl} methyl) benzoic acid using piperidin-4-one-hydrate-hydrochloride (commercially available) and triethylamine instead of t-butyl 4-aminopiperidine-1-carboxylate thing Outside the title compound by performing the reaction as a substantially Example 6 (240 mg, 99% yield) as a yellow powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74 (2H, dt, J = 13.5, 7.0 Hz), 1.92 (2H, d, J = 13.1 Hz), 2.34- 2.68 (8H, br m), 3.15 (2H, s), 3.56 (2H, s), 3.88 (4H, br s), 4.46 (2H, s), 7.34 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.46 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 529.9 [M + H] ⁺ (ESI positive ion mode), m / z 574.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 160
1- (Benzo [d] [1,3] dioxol-5-ylmethyl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-3-yl} methyl) phenyl] urea (Compound No. 160) Benzo [d] [1, 3] The reaction was carried out in substantially the same manner as in Example 83 except that dioxol-5-ylmethanamine (commercially available) was used to give the title compound (24 mg, yield 20%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.49-1.79 (2H, m), 1.78-1.93 (2H, m), 2.50 (4H, br s), 3. 11 (2H, s), 3.54 (2H, s), 4.26-4.38 (4H, m), 5.23 (1H, t, J = 5.7 Hz), 5.91 (2H, s), 6.66-6.83 (4H, m), 7.13 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.2 Hz), 7.42 ( 2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.64 minutes; m / z 596.9 [M + H] ⁺ (ESI positive ion mode), m / z 641.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 161
4-benzoyl-N- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of phenyl] piperidine-1-carboxamide (Compound No. 161) 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 obtained in Reference Example 93 Diazaspiro [4.5] decan-2-one dihydrochloride (77 mg, 0.16 mmol) was dissolved in chloroform (1.0 mL) and pyridine (0.090 mL, 1.1 mmol) and chloroformate 4 at 0 ° C. -Nitrophenyl (38 mg, 0.19 mmol) was added and stirred at room temperature for 1 day. Thereafter, triethylamine (0.056 mL, 0.40 mmol) and phenyl (piperidin-4-yl) methanone hydrochloride (commercially available) (43 mg, 0.19 mmol) were added, and the mixture was stirred at room temperature for 1 day. Chloroform (3.0 mL) and saturated aqueous sodium hydrogen carbonate solution (3.0 mL) were added to the reaction mixture, and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate] to give 4-benzoyl-N- [4-({2-oxo-8 -[4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] piperidine-1-carboxamide (23 mg, 23% yield) Obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.77 (2H, m), 1.76-2.03 (6H, m), 2.50 (4H, br s), 3. 10 (2H, s), 3.13 (4H, dt, J = 2.9, 12.7 Hz), 3.51 (1H, tt, J = 11.0, 4.1 Hz), 3.54 (2H , Br s), 4.11 (2H, dt, J = 13.2, 3.5 Hz), 4.36 (2H, s), 6.44 (1H, s), 7.18 (2H, d, J = 9.0 Hz), 7.34 (2H, d, J = 8.6 Hz), 7.37-7.63 (7H, m), 7.95 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.82 minutes; m / z 635.0 [M + H] ⁺ (ESI positive ion mode), m / z 633.2 [MH] ⁻ (ESI negative ion mode)

Example 162
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 162) Substantially except that (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) was used instead of 4- (2-aminoethyl) morpholine. The reaction was carried out in the same manner as in Example 44 to obtain the title compound (41 mg, yield 72%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-2.11 (8H, m), 2.54 (4H, br s), 2.98-3.26 (2H, br m), 3 .14 (2H, s), 3.39-3.68 (3H, br m), 3.84 (1H, br s), 4.44 (2H, s), 4.67 (1H, br s) 7.15 (2H, t, J = 8.2 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.35-7.50 (4H, m), 7.50-7. 62 (2H, m), 7.97 (2H, dd, J = 9.0, 5.7 Hz).

LC / MS [Condition 1]: retention time 3.54 minutes; m / z 638.1 [M + H] ⁺ (ESI positive ion mode), m / z 682.3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 163
3- [4- (4-Hydroxy-4-phenylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane Preparation of -2-one (Compound No. 163) The reaction was carried out in substantially the same manner as in Example 44 except that 4-phenylpiperidin-4-ol (commercially available) was used instead of 4- (2-aminoethyl) morpholine. The title compound (41 mg, yield 76%) was obtained as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.48-2.02 (8H, m), 2.15 (1H, br s), 2.57 (4H, br s), 3.14 (2H , S), 3.35 (1H, br s), 3.47-3.73 (4H, br m), 4.44 (2H, s), 4.67 (1H, br s), 7.26 -7.33 (3H, m), 7.33-7.51 (8H, m), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 608.1 [M + H] ⁺ (ESI positive ion mode), m / z 652.3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 164
1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperidine- Preparation of 4-carbonitrile (Compound No. 164) The reaction was carried out in substantially the same manner as in Example 44 except that piperidine-4-carbonitrile (commercially available) was used instead of 4- (2-aminoethyl) morpholine. The title compound (38 mg, yield 79%) was obtained as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.53-2.07 (8H, m), 2.59 (4H, brs), 2.94 (1H, tt, J = 7.0, 4 .5Hz), 3.15 (2H, s), 3.28-4.01 (6H, br m), 4.44 (2H, s), 7.31 (2H, d, J = 8.2 Hz) 7.38 (2H, d, J = 8.6 Hz), 7.41-7.51 (2H, m), 7.58 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 541.0 [M + H] ⁺ (ESI positive ion mode), m / z 585.3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 165
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperazine- Production of t-butyl 1-carboxylate (Compound No. 165) Substantially the same as Example 44, except that t-butyl piperazine-1-carboxylate (commercially available) was used instead of 4- (2-aminoethyl) morpholine. The title compound (37 mg, 66% yield) was obtained as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.64-1.84 (2H, m), 1.92 (2H, d, J = 12.7 Hz), 2 .54 (4H, br s), 3.14 (2H, s), 3.22-3.84 (10H, br m), 4.44 (2H, s), 7.31 (2H, d, J = 7.8 Hz), 7.35-7.49 (4H, m), 7.57 (2H, d, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 617.1 [M + H] ⁺ (ESI positive ion mode), m / z 661.3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 166
3- [4- (4-Methoxypiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of (Compound No. 166) The reaction was conducted in substantially the same manner as in Example 44 except that 4-methoxypiperidine (commercially available) was used instead of 4- (2-aminoethyl) morpholine to give the title compound (33 mg, yield). 68%) was obtained as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41-2.07 (8H, m), 2.55 (4H, br s), 3.13 (2H, s), 3.21 (1H, br s), 3.36 (3H, s), 3.40-3.74 (5H, m), 3.47 (1H, tt, J = 7.4, 3.7 Hz), 3.99 (1H) , Br s), 4.44 (2H, s), 7.29 (2H, d, J = 8.2 Hz), 7.33-7.49 (4H, m), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 546.1 [M + H] ⁺ (ESI positive ion mode), m / z 590.3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 167
N-[(6-chloropyridin-3-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Preparation of decan-3-yl} methyl) benzamide (Compound No. 167) Substantially except that (6-chloropyridin-3-yl) methanamine (commercially available) was used instead of 4- (2-aminoethyl) morpholine The reaction was carried out in the same manner as in Example 44 to obtain the title compound (34 mg, yield 67%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-1.96 (4H, m), 2.54 (4H, br s), 3.12 (2H, s), 3.57 (2H, br s), 4.45 (2H, s), 4.63 (2H, d, J = 6.1 Hz), 6.63 (1H, t, J = 5.7 Hz), 7.30 (1H, d) , J = 8.6 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.37-7.49 (2H, br m), 7.56 (2H, d, J = 7.8 Hz) ), 7.70 (1H, dd, J = 8.2, 2.5 Hz), 7.77 (2H, d, J = 8.2 Hz), 8.37 (1H, d, J = 2.5 Hz) .

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 573.0 [M + H] ⁺ (ESI positive ion mode), m / z 571.2 [MH] ⁻ (ESI negative ion mode)

Reference Example 168-1
Preparation of t-butyl 4- [methoxy (methyl) carbamoyl] piperidine-1-carboxylate 1- (t-butoxycarbonyl) piperidine-4-carboxylic acid (commercially available) (1.0 g, 4.4 mmol) and N, O -Dimethylhydroxylamine hydrochloride (commercially available) (470 mg, 4.8 mmol), 1-hydroxybenzotriazole (600 mg, 4.4 mol), and triethylamine (1.8 mL, 13 mmol) were dissolved in chloroform (10 ml), then at room temperature. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (46 mg, 0.22 mmol) was added thereto, and the mixture was stirred at room temperature for 3 days. Thereafter, chloroform (10 mL) and saturated aqueous sodium hydrogen carbonate solution (5.0 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure to give t-butyl 4- [methoxy (methyl) carbamoyl] piperidine-1-carboxylate (1.2 g, quantitative) as a colorless oil. It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.61-1.77 (4H, m), 2.66-2.89 (3H, br m), 3. 18 (3H, s), 3.71 (3H, s), 4.03-4.24 (2H, br m).

Reference Example 168-2
Production of t-butyl 4-acetylpiperidine-1-carboxylate 1.1 M methylmagnesium bromide-tetrahydrofuran solution (commercially available) (0.68 mL, 0.68 mmol) was dissolved in tetrahydrofuran under nitrogen atmosphere at 0 ° C. 4- [Methoxy (methyl) carbamoyl] piperidine-1-carboxylate t-butyl (93 mg, 0.34 mmol) obtained in Reference Example 168-1 was added, and the mixture was stirred at room temperature for 1 day. Thereafter, ethyl acetate (2.0 mL) and saturated aqueous ammonium chloride solution (2.0 mL) were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 2/1], and tert-butyl 4-acetylpiperidine-1-carboxylate (45 mg). Yield 59%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.42-1.63 (2H, m), 1.83 (2H, dd, J = 13.1, 2. 5 Hz), 2.16 (3 H, s), 2.45 (1 H, tt, J = 11.4, 3.7 Hz), 2.78 (2 H, td, J = 13.1, 2.9 Hz), 4.10 (2H, dt, J = 13.1, 3.3 Hz).

Reference Example 168-3
Preparation of 1- (piperidin-4-yl) ethanone hydrochloride 4-acetylpiperidine-1-carboxylate t-butyl (45 mg, 0.20 mmol) obtained in Reference Example 168-2 was added to methanol (0.50 mL). After dissolution, a 10% hydrogen chloride-methanol solution (commercially available) (0.30 mL, 0.70 mmol) was added at room temperature, and the mixture was stirred at 50 ° C. for 3 hr. Then, it was concentrated to dryness under reduced pressure to give 1- (piperidin-4-yl) ethanone hydrochloride (33 mg, quantitative) as a yellow powder.

LC / MS [Condition 1]: Retention time 0.61 min; m / z 128.0 [M + H] ⁺ (ESI positive ion mode)

Example 168
3- [4- (4-Acetylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of (Compound No. 168) Essentially, Example 44 except that 1- (piperidin-4-yl) ethanone hydrochloride obtained in Reference Example 168-3 was used in place of 4- (2-aminoethyl) morpholine. The title compound (36 mg, yield 73%) was obtained as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-2.09 (8H, m), 2.19 (3H, s), 2.39-2.72 (5H, m), 3.00 (2H, br s), 3.14 (2H, s), 3.58 (2H, br s), 3.78 (1H, br s), 4.44 (2H, s), 4.62 (1H , Br s), 7.29 (2H, d, J = 8.2 Hz), 7.38 (2H, d, J = 8.2 Hz), 7.40-7.50 (2H, br m), 7 .57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 558.0 [M + H] ⁺ (ESI positive ion mode), m / z 602.3 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 169-1
Preparation of t-butyl 4- (thiophene-2-carbonyl) piperidine-1-carboxylate The reaction was carried out substantially in the same manner as in Reference Example 168-2 to give the title compound (92 mg, yield 80%) as a brown oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.66-1.92 (4H, m), 2.87 (2H, td, J = 11.9, 3. 7 Hz), 3.24 (1 H, tt, J = 10.8, 4.0 Hz), 4.17 (2 H, dt, J = 13.1, 2.9 Hz), 7.14 (1 H, t, J = 4.5 Hz), 7.65 (1H, d, J = 4.9 Hz), 7.73 (1H, d, J = 3.9 Hz).

Reference Example 169-2
Preparation of piperidin-4 -yl (thiophen-2-yl) methanone hydrochloride 4- (thiophen-2-carbonyl) piperidine-1-carboxylate instead of t-butyl 4-acetylpiperidine-1-carboxylate The title compound (72 mg, quantitative) was obtained as a brown powder in substantially the same manner as in Reference Example 168-3 except that was used.

LC / MS [Condition 1]: retention time 0.65 min; m / z 196.0 [M + H] ⁺ (ESI positive ion mode)

Example 169
3- {4- [4- (Thiophen-2-carbonyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-2-one (Compound No. 169) Piperidin-4-yl (thiophen-2-yl) methanone hydrochloride obtained in Reference Example 169-2 was used instead of 4- (2-aminoethyl) morpholine. The reaction was carried out substantially in the same manner as in Example 44 except for using, to obtain the title compound (43 mg, yield 76%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-2.19 (8H, m), 2.53 (4H, brs), 2.92-3.23 (2H, m), 3. 13 (2H, s), 3.30-3.47 (1H, m), 3.56 (2H, br s), 3.85 (1H, br s), 4.44 (2H, s), 4 .68 (1H, brs), 7.15 (1H, dd, J = 4.9, 3.7 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.35-7.48 (4H, m), 7.56 (2H, d, J = 7.8 Hz), 7.67 (1H, dd, J = 4.9, 1.2 Hz), 7.75 (1H, dd, J = 3.7, 1.2 Hz).

LC / MS [Condition 1]: retention time 3.44 minutes; m / z 626.1 [M + H] ⁺ (ESI positive ion mode), m / z 670.3 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 170-1
Preparation of 4- (dimethylcarbamoyl) piperidine-1-carboxylate t-butyl Substantially the same as Reference Example 168-1, except that dimethylamine hydrochloride was used instead of N, O-dimethylhydroxylamine hydrochloride The reaction was performed to give the title compound (240 mg, quantitative) as a yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.60-1.80 (4H, m), 2.53-2.84 (3H, m), 2.95 (3H, s), 3.06 (3H, s), 4.15 (2H, d, J = 10.6 Hz).
LC / MS [Condition 1]: Retention time 3.64 minutes; m / z 257.1 [M + H] ⁺ (ESI positive ion mode)

Reference Example 170-2
Preparation of N, N-dimethylpiperidine-4-carboxamide hydrochloride 4- (dimethylcarbamoyl) piperidine-1-carboxylic acid obtained in Reference Example 170-1 instead of t-butyl 4-acetylpiperidine-1-carboxylate The reaction was carried out substantially in the same manner as in Reference Example 168-3 except that t-butyl was used to obtain the title compound (181 mg, quantitative) as a colorless powder.

LC / MS [Condition 1]: Retention time 0.59 minutes; m / z 157.0 [M + H] ⁺ (ESI positive ion mode)

Example 170
N, N-dimethyl-1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzoyl] piperidine-4-carboxamide (Compound No. 170) N, N-dimethylpiperidine-4-carboxamide hydrochloride obtained in Reference Example 170-2 was used instead of 4- (2-aminoethyl) morpholine. The reaction was carried out substantially in the same manner as in Example 44 except for using, to obtain the title compound (35 mg, yield 68%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-2.00 (8H, m), 2.53 (4H, br s), 2.72-2.85 (1H, m), 2. 87-3.03 (2H, br m), 2.96 (3H, s), 3.08 (3H, s), 3.13 (2H, s), 3.56 (2H, br s), 3 .80 (1H, br s), 4.44 (2H, s), 4.68 (1H, br s), 7.28 (2H, d, J = 7.8 Hz), 7.34-7.50 (2H, br m), 7.39 (2H, d, J = 8.2 Hz), 7.57 (2H, br d, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 587.1 [M + H] ⁺ (ESI positive ion mode), m / z 631.4 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 171-1
Preparation of methyl 4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzoate 4- (trifluoromethyl ) The title compound (820 mg, 95% yield) was obtained in the same manner as in Example 1 except that 4-cyanobenzyl bromide (commercially available) was used instead of benzyl bromide.

LC / MS [Condition 1]: Retention time 1.36 minutes; m / z 420.0 [M + H] ⁺ (ESI positive ion mode

Reference Example 171-2
Preparation of 4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzoic acid 4-({2-oxo -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) obtained in Reference Example 171-1 instead of methyl benzoate 4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} substantially except using methyl benzoate The reaction was carried out in the same manner as in Reference Example 21 to give the title compound (730 mg, yield 92%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74-1.98 (4H, br m), 2.54-2.79 (4H, br m), 3.11 (2H, s), 3 .68 (2H, s), 4.48 (2H, s), 7.34 (2H, d, J = 8.2 Hz), 7.46 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.6 Hz), 8.05 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 1.14 minutes; m / z 405.9 [M + H] ⁺ (ESI positive ion mode), m / z 404.1 [MH] ⁻ (ESI negative ion mode)

Example 171
4-[(3- {4- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-8-yl) methyl] benzonitrile (Compound No. 171) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) 4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3, obtained in Reference Example 171-2 instead of benzoic acid, 8-Diazaspiro [4.5] decan-3-yl] methyl} benzoic acid is replaced with 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole instead of 4- (2-aminoethyl) morpholine (Commercially available) and birds Except using ethylamine is carried out the same reaction as substantially Example 44 to give the title compound (36 mg, 60% yield) as a colorless amorphous substance.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.82 (2H, m), 1.83-2.36 (6H, m), 2.52 (4H, br s), 3. 01-3.30 (2H, br m), 3.14 (2H, s), 3.37 (1H, tt, J = 10.6, 4.1 Hz), 3.55 (2H, s), 3 .91 (1H, br s), 4.45 (2H, s), 4.72 (1H, br s), 7.08 (1 H, td, J = 8.2, 2.5 Hz), 7.26 -7.35 (3H, m), 7.36-7.48 (4H, m), 7.53-7.67 (3H, m).

LC / MS [Condition 1]: Retention time 3.34 minutes; m / z 608.1 [M + H] ⁺ (ESI positive ion mode)

Example 172
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] Decan-3-yl] methyl} benzamide (Compound No. 172) Preparation of 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole instead of benzo [d] [1,3] dioxol-5 The reaction was carried out substantially in the same manner as in Example 171 except that ylmethanamine (commercially available) was used to give the title compound (24 mg, yield 45%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.79 (2H, m), 1.84-1.97 (2H, m), 2.49-2.52 (4H, br m ), 3.11 (2H, s), 3.54 (2H, s), 4.45 (2H, s), 4.54 (2H, d, J = 5.7 Hz), 5.95 (2H, s), 6.30 (1H, t, J = 5.1 Hz), 6.77 (1H, d, J = 7.4 Hz), 6.81 (1H, dd, J = 8.0, 1.4 Hz) ), 6.84 (1H, d, J = 1.6 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 7.8 Hz), 7.59 (2H, d, J = 7.4 Hz), 7.76 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 539.0 [M + H] ⁺ (ESI positive ion mode)

Example 173
4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[(tetrahydrofuran-2-yl) Preparation of methyl] benzamide (Compound No. 173) Substantially the same as Example 171 except that tetrahydrofurfurylamine (commercially available) was used instead of 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole. The reaction was performed in the same manner to obtain the title compound (22 mg, yield 46%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.51-1.80 (3H, m), 1.82-2.12 (5H, m), 2.39-2.66 (4H, br m ), 3.11 (2H, s), 3.31 (1H, ddd, J = 13.8, 7.7, 4.8 Hz), 3.55 (2H, br s), 3.72-3. 95 (3H, m), 4.06 (1H, dq, J = 3.3, 7.4 Hz), 4.46 (2H, s), 6.47 (1H, brt, J = 4.5 Hz) , 7.32 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 7.0 Hz), 7.59 (2H, d, J = 7.8 Hz), 7.76 ( 2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 0.61 min; m / z 489.0 [M + H] ⁺ (ESI positive ion mode)

Example 174
4- (4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzamido) piperidine-1-carboxylic acid Preparation of methyl (Compound No. 174) Instead of 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole, 4-aminopiperidine-1-carboxylic acid methyl hydrochloride obtained in Reference Example 135 was used. The reaction was carried out substantially in the same manner as in Example 171 except for using, to give the title compound (29 mg, yield 54%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42 (2H, dq, J = 4.1, 11.9 Hz), 1.63-1.80 (2H, m), 1.91 (2H, br d, J = 12.3 Hz), 2.05 (2H, br dd, J = 2.9, 11.9 Hz), 2.51 (4H, br s), 2.97 (2H, t, J = 11.4 Hz), 3.12 (2H, s), 3.55 (2H, s), 3.70 (3H, s), 4.04-4.26 (3H, m), 4.46 (2H , S), 5.95 (1H, d, J = 7.8 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 6.5 Hz), 7 .59 (2H, d, J = 7.8 Hz), 7.73 (2H, d, J = 8.2 Hz).
LC / MS [Condition 1]: Retention time 2.15 minutes; m / z 546.1 [M + H] ⁺ (ESI positive ion mode)

Example 175
4-({3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl} methyl) benzonitrile Preparation of (Compound No. 175) Substantially except that phenyl (piperidin-4-yl) methanone hydrochloride (commercially available) is used instead of 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole Was reacted in the same manner as in Example 171 to obtain the title compound (34 mg, yield 60%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-2.09 (8H, m), 2.55 (4H, br s), 2.99-3.26 (2H, br m), 3 .13 (2H, s), 3.42-3.68 (3H, m), 3.84 (1H, br s), 4.44 (2H, s), 4.67 (1H, br s), 7.30 (2H, d, J = 8.2 Hz), 7.36-7.52 (6H, m), 7.53-7.63 (3H, m), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.24 minutes; m / z 577.1 [M + H] ⁺ (ESI positive ion mode), m / z 611.3 [M + Cl] ⁻ (ESI negative ion mode)

Example 176
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (2,2 , 3,3,3-pentafluoropropyl) benzamide (Compound No. 176) 2,2,3,3,3-pentafluoropropan-1-amine (commercially available instead of 4- (2-aminoethyl) morpholine The title compound (10 mg, yield 20%) was obtained as a white powder in substantially the same manner as in Example 44, except that

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65 to 1.82 (2H, m), 1.85 to 2.01 (2H, m), 2.53 (4H, br s), 3. 14 (2H, s), 3.56 (2H, br s), 4.19 (2H, td, J = 14.6, 6.4 Hz), 4.47 (2H, s), 6.29 (1H , T, J = 6.1 Hz), 7.35-7.47 (2H, m), 7.36 (2H, d, J = 8.2 Hz), 7.50-7.62 (2H, m) , 7.78 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: retention time 3.42 minutes; m / z 580.0 [M + H] ⁺ (ESI positive ion mode), m / z 578.2 [MH] ⁻ (ESI negative ion mode)

Example 177
N-methoxy-N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) Preparation of benzamide (Compound No. 177) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8] obtained in Reference Example 21 instead of (decan-3-yl} methyl) cyclohexanecarboxylic acid The reaction was carried out in substantially the same manner as in Example 157 except that diazaspiro [4.5] decan-3-yl} methyl) benzoic acid was used to give the title compound (240 mg, 85% yield) as colorless amorphous Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64 to 1.81 (2H, m), 1.92 (2H, br d, J = 13.5 Hz), 2.53 (4H, br s) , 3.13 (2H, s), 3.36 (3H, s), 3.54 (5H, s), 4.45 (2H, s), 7.29 (2H, d, J = 8.6 Hz) ), 7.42 (2H, d, J = 7.4 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.66 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 492.0 [M + H] ⁺ (ESI positive ion mode)

Example 178
1- (2-Chloroethyl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3- Ill} methyl) phenyl] urea hydrochloride (Compound No. 178) 3- (4-aminobenzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3 obtained in Reference Example 93 , 8-diazaspiro [4.5] decan-2-one dihydrochloride (44 mg, 0.090 mmol) dissolved in toluene (1.0 mL) and 1-chloro-2-isocyanatoethane (commercially available) at room temperature (0.024 mL, 0.30 mmol) was added and stirred at 100 ° C. for 3 hours. Hexane (1.0 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, dried at room temperature under reduced pressure, and 1- (2-chloroethyl) -3- [4-({2-oxo-8- [ 4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] urea hydrochloride (48 mg, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.04 (4H, br s), 2.99-3.37 (6H, m), 3.40 (2H, q, J = 6.0 Hz) ), 3.64 (2H, t, J = 6.1 Hz), 4.25 (2H, s), 4.33-4.52 (2H, m), 6.46 (1H, t, J = 6) .1 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.37 (2H, d, J = 8.2 Hz), 7.72-7.89 (4H, m), 8.77 (1H, s), 10.77 (1H, br s).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 524.9 [M + H] ⁺ (ESI positive ion mode), m / z 559.2 [M + Cl] ⁻ (ESI negative ion mode)

Example 179
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (2,2 , 2-Trifluoroethyl) benzamide (Compound No. 179) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 obtained in Reference Example 21 -Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (50 mg, 0.11 mmol) dissolved in dichloromethane (1.0 mL) and 2,2,2-trifluoroethanamine (commercially available) at room temperature ) (0.013 mL, 0.17 mmol) and O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (63 mg, 0.17 mmol), Added triethylamine (0.030 mL, 0.22 mmol) and was stirred at room temperature for 1 day. Ethyl acetate (2.0 mL) and saturated aqueous sodium hydrogen carbonate solution (2.0 mL) were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm, manufactured by Yamazen Co., Ltd., developing solvent: ethyl acetate / methanol = 10/1], and 4-({2- Oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (2,2,2-trifluoroethyl ) Benzamide (41 mg, 70% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-1.85 (2H, m), 1.86-1.97 (2H, m), 2.55 (4H, br s), 3. 13 (2H, s), 3.57 (2H, br s), 4.13 (2H, dq, J = 6.5, 8.6 Hz), 4.47 (2H, s), 6.35 (1H) , T, J = 6.1 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 530.0 [M + H] ⁺ (ESI positive ion mode), m / z 528.1 [MH] ⁻ (ESI negative ion mode)

Example 180
N- (4-cyanobenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 180) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4] obtained in Reference Example 21 .5] decan-3-yl} methyl) benzoic acid (47 mg, 0.10 mmol), 4- (aminomethyl) benzonitrile hydrochloride (commercially available) (19 mg, 0.11 mmol), 1-hydroxybenzotriazole (7 0.0 mg, 0.050 mol) and triethylamine (0.042 mL, 0.30 mmol) were dissolved in chloroform (1.0 mL) and 1-ethyl-3- (3- Methyl aminopropyl) carbodiimide hydrochloride (21 mg, 0.11 mmol) and the mixture was stirred at room temperature for 1 day. Thereafter, ethyl acetate (2.0 mL) and water (2.0 mL) were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilicagel 40 μm, manufactured by Yamazen Co., Ltd., developing solvent: ethyl acetate / methanol = 10/1], and N- (4-cyano Benzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (41 mg, Yield 73%) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-1.82 (2H, m), 1.85-1.98 (2H, m), 2.52 (4H, br s), 3. 13 (2H, s), 3.56 (2H, br s), 4.46 (2H, s), 4.71 (2H, d, J = 6.1 Hz), 6.54 (1H, t, J = 5.7 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.37-7.49 (2H, m), 7.45 (2H, d, J = 8.6 Hz), 7 .52-7.63 (2H, m), 7.63 (2H, d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: retention time 3.41 min; m / z 562.8 [M + H] ⁺ (ESI positive ion mode)

Example 181
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [4- ( Preparation of ( trifluoromethyl) benzyl] benzamide (Compound No. 181) Substantially carried out except that [4- (trifluoromethyl) phenyl] methanamine (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in the same manner as in Example 180 to obtain the title compound (47 mg, yield 76%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.80 (2H, m), 1.84-1.96 (2H, m), 2.51 (4H, br s), 3. 12 (2H, s), 3.55 (2H, br s), 4.46 (2H, s), 4.70 (2H, d, J = 5.7 Hz), 6.50 (1H, t, J = 5.3 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 15.1 Hz), 7.45 (2H, d, J = 15.5 Hz) 7.56 (2H, d, J = 13.5 Hz), 7.59 (2H, d, J = 13.5 Hz), 7.78 (2H, d, J = 7.8 Hz).

LC / MS [Condition 2]: Retention time 3.96 minutes; m / z 605.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 182-1
Preparation of t-butyl (tetrahydrofuran-2-yl) methylcarbamate Tetrahydrofurfurylamine (0.86 g, 8.5 mmol) was dissolved in chloroform (9 mL) and di-t-butyl dicarbonate (2.04 g, 9.3 mmol). And stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to give the title compound (1.9 g, quantitative yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.51-1.67 (1H, m), 1.83 to 2.02 (3H, m), 3.06 (1H, ddd, J = 13.5, 5.7, 5.7 Hz), 3.38 (1H, ddd, J = 13.5, 6.1, 3.7 Hz), 3.74 (1H, dt , J = 8.2, 6.5 Hz), 3.85 (1H, dt, J = 8.2, 6.5 Hz), 3.90-4.00 (1H, m), 4.88 (1H, br s).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 101.78 [M-Boc] ⁺ (ESI positive ion mode)

Reference Example 182-2
Preparation of t-butyl methyl [(tetrahydrofuran-2-yl) methyl] carbamate t-butyl (tetrahydrofuran-2-yl) methylcarbamate (132 mg, 0.66 mmol) obtained in Reference Example 182-1 was converted to N, N -Dissolved in dimethylformamide (2 mL), potassium t-butoxide (81 mg, 0.72 mmol) and methyl iodide (0.045 mL, 0.72 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Thereafter, potassium t-butoxide (81 mg, 0.72 mmol) and methyl iodide (0.045 mL, 0.72 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Thereafter, water (5.0 mL) and ethyl acetate (5.0 mL) were added to the reaction mixture for liquid separation, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 10/1]. The compound (90 mg, yield 64%) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.48-1.70 (1H, m), 1.78-2.01 (3H, m), 2.93 (3H, s), 3.01-3.60 (2H, m), 3.74 (1H, q, J = 7.4 Hz), 3.85 (1H, q, J = 7.2 Hz), 3 .96-4.11 (1H, m).

LC / MS [Condition 1]: Retention time 3.78 minutes; m / z 115.91 [M-Boc] ⁺ (ESI positive ion mode)

Reference Example 182-2
Production of N-methyl-1- (tetrahydrofuran-2-yl) methanamine hydrochloride t-butyl methyl [(tetrahydrofuran-2-yl) methyl] carbamate obtained in Reference Example 182-2 (90 mg, 0.66 mmol) Was dissolved in methanol (1.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was then concentrated to give the title compound (63 mg, quantitative yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.55-1.69 (1H, m), 2.21-1.81 (3H, m), 2.80 (3H, t, J = 5. 3 Hz), 2.84-2.98 (1 H, m), 3.07-3.20 (1 H, m), 3.80 (1 H, dt, J = 7.8, 7.0 Hz), 3. 96 (1H, dt, J = 8.2, 7.0 Hz), 4.36-4.47 (1H, m), 9.29 (1H, brs), 9.53 (1H, brs).

Example 182
(1r, 4r) -N-methyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 182) Instead of tetrahydrofurfurylamine, N-methyl-1- (tetrahydrofuran-) obtained in Reference Example 182-2 The reaction was carried out in substantially the same manner as in Example 10 except that 2-yl) methanamine hydrochloride was used to give the title compound (68 mg, yield 85%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.95-1.14 (2H, m), 1.42-2.03 (15H, m), 2.47 (1H, tt, J = 1.11. 9, 3.1 Hz), 2.49-2.65 (4H, m), 2.97 (1.05 H, s), 3.05-3.17 (4.6 H, m), 3.25 ( 2H, s), 3.29 (0.35H, dd, J = 14.6, 3.7 Hz), 3.43 (0.35H, dd, J = 15.0, 7.5 Hz), 3.57 (2H, s), 3.89-3.68 (2.65H, m), 4.09-3.95 (1H, m), 7.43 (2H, d, J = 7.8 Hz), 7 .56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 551.9 [M + H] ⁺ (ESI positive ion mode), m / z 596.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 183
1-methyl-3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of phenyl] -1-[(tetrahydrofuran-2-yl) methyl] urea (Compound No. 183) Obtained in Reference Example 182-2 instead of N- (t-butoxycarbonyl) -1,3-diaminopropane The reaction was conducted in substantially the same manner as in Example 83 except that N-methyl-1- (tetrahydrofuran-2-yl) methanamine hydrochloride was used to give the title compound (24 mg, yield 39%) as a white solid. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.76 (3H, m), 1.89 (2H, br d, J = 13.1), 1.94-2.09 (3H , M), 2.42-2.59 (4H, m), 3.02 (3H, s), 3.09 (2H, s), 3.34 (1H, dd, J = 16.0, 6 .5 Hz), 3.55 (2 H, s), 3.58 (1 H, dd, J = 16.0, 1.6 Hz), 3.90 (1 H, dt, J = 8.2, 6.1 Hz) , 3.98 (1H, dt, J = 8.2, 7.0 Hz), 4.08-4.18 (1H, m), 4.35 (2H, s), 7.15 (2H, d, J = 8.6 Hz), 7.31 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz) ), 8.54 (1H, r s).

LC / MS [Condition 1]: Retention time 3.35 minutes; m / z 560.9 [M + H] ⁺ (ESI positive ion mode), m / z 559.1 [MH] ⁻ (ESI negative ion mode)

Example 184
3-{[(1r, 4r) -4- (4-morpholinopiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one (Compound No. 184) The reaction was conducted in substantially the same manner as in Example 10 except that 4-morpholinopiperidine was used instead of tetrahydrofurfurylamine to give the title compound (23 mg Yield 53%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.3 Hz), 1.31-1.68 (5H, m), 1.71-2.00 (10H, m), 2.30-2.65 (11H, m), 3.02 (1H, t, J = 12.3 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.25 ( 2H, s), 3.57 (2H, s), 3.68-3.75 (4H, m), 3.93 (1H, d, J = 13.5 Hz), 4.63 (1H, d, J = 13.9 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 1.34 minutes; m / z 606.7 [M + H] ⁺ (ESI positive ion mode), m / z 651.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 185
3-({(1r, 4r) -4-[(1,1,1 -dioxo-thiomorpholin-4-yl) carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa Preparation of -3,8-diazaspiro [4.5] decan-2-one (Compound No. 185) Substantially the same as Example 10, except that thiomorpholine 1,1-dioxide was used instead of tetrahydrofurfurylamine. The title compound (23 mg, 48% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06 (2H, qd, J = 12.7, 2.5 Hz), 1.48-1.71 (3H, m), 1.72-1. 87 (6H, m), 1.94 (2H, d, J = 12.7 Hz), 2.46 (1H, tt, J = 11.9, 3.3 Hz), 2.49-2.66 (4H M), 2.99-3.07 (4H, m), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.57 (2H, s), 3.91-4.18 (4H, br m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.03 minutes; m / z 571.8 [M + H] ⁺ (ESI positive ion mode), m / z 616.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 186-1
Preparation of 2-[(tetrahydrofuran-3-yl) methyl] isoindoline-1,3-dione (tetrahydrofuran-3-yl) methanol (950 mg, 9.3 mmol), phthalimide (1.37 g, 9.3 mmol) and tri Phenylphosphine (2.7 g, 10 mmol) was dissolved in tetrahydrofuran (9.0 mL), and diisopropyl azodicarboxylate (2.0 mL, 10 mmol) was added dropwise under ice cooling. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. To the obtained residue, 2-propanol (24 mL) was added, and the solid was collected by filtration. The resulting solid was further washed with 2-propanol (10 mL), and the solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (1.3 g, yield 62%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72 (1H, ddt, J = 13.9, 6.5, 6.5 Hz), 2.01 (1H, dtd, J = 12.7, 7 .8, 5.3 Hz), 2.73 (1H, tt, J = 7.4, 7.4 Hz), 3.61 (1H, dd, J = 9.0, 5.7 Hz), 3.69 ( 1H, dd, J = 13.5, 7.0 Hz), 3.80-3.72 (2H, m), 3.83 (1H, dd, J = 9.0, 7.2 Hz), 3.94 (1H, ddd, J = 8.2, 8.2, 5.7 Hz), 7.70-7.77 (2H, m), 7.83-7.90 (2H, m).

Reference Example 186-2
Production of (tetrahydrofuran-3-yl) methanamine 2-[(tetrahydrofuran-3-yl) methyl] isoindoline-1,3-dione (1.3 g, 5.8 mmol) obtained in Reference Example 186-1 was added to ethanol. (13 mL), hydrazine monohydrate (0.4 mL) was added, and the mixture was stirred at 85 ° C. for 2 hr. The reaction mixture was then concentrated to give the title compound (63 mg, quantitative yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58 (1H, ddt, J = 11.9, 7.3, 7.3 Hz), 2.04 (1H, dtd, J = 12.9, 7 .9, 5.3 Hz), 2.29 (1H, ttt, J = 7.3, 7.3, 7.3 Hz), 2.72 (2H, d, J = 6.9 Hz), 3.51 ( 1H, dd, J = 8.6, 5.9 Hz), 3.74 (1H, dt, J = 8.3, 7.6 Hz), 3.84 (1H, dd, J = 8.3, 5. 3 Hz), 3.87 (1H, dt, J = 8.6, 7.3 Hz).

Example 186
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Production of N-[(tetrahydrofuran-3-yl) methyl] cyclohexanecarboxamide (Compound No. 186) Instead of using tetrahydrofurfurylamine, (tetrahydrofuran-3-yl) methanamine obtained in Reference Example 186-2 was used. The reaction was carried out substantially in the same manner as in Example 10 to obtain the title compound (44 mg, yield 75%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, qd, J = 12.9, 3.0 Hz), 1.39-1.68 (4H, m), 1.71-1. 85 (4H, m), 1.85 to 2.09 (6H, m), 2.39-2.61 (5H, m), 3.09 (2H, d, J = 7.3 Hz), 3. 20-3.34 (4H, m), 3.52 (1H, dd, J = 8.9, 5.3z), 3.57 (2H, s), 3.73 (1H, dd, J = 15 .9, 8.3 Hz), 3.80 (1H, dd, J = 8.9, 7.3 Hz), 3.88 (1H, ddd, J = 8.3, 8.3, 5.3 Hz), 5.69 (1H, t, J = 5.6 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: Retention time 2.99 minutes; m / z 537.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 187
(1r, 4r) -N-[(2,2-Dimethyl-1,3-dioxolan-4-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl]- Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 187) 2,2-dimethyl-1,3-dioxolane- in place of tetrahydrofurfurylamine The reaction was carried out substantially in the same manner as in Example 10 except for using 4-methanamine to obtain the title compound (28 mg, yield 69%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 12.9 Hz), 1.35 (3H, s), 1.43 (3H, s), 1.45-1 .64 (3H, m), 1.72-1.85 (4H, m), 1.88-1.99 (4H, m), 2.06 (1H, tt, J = 12.2,3. 3Hz), 2.49-2.61 (4H, m), 3.10 (2H, d, J = 7.3 Hz), 3.26 (2H, s), 3.32 (1H, ddd, J = 13.9, 5.9, 5.9 Hz), 3.53 (1H, ddd, J = 14.2, 5.9, 3.6 Hz), 3.57 (2H, s), 3.61 (1H , Dd, J = 8.3, 6.3 Hz), 4.03 (1H, dd, J = 8.4, 6.4 Hz), 4.26-4.18 (1H, qd, J = 6.3) , 3.3 Hz), 5 79 (1H, t, J = 5.8Hz), 7.44 (2H, d, J = 7.9Hz), 7.57 (2H, d, J = 7.9Hz).

LC / MS [Condition 1]: retention time 3.19 min; m / z 567.8 [M + H] ⁺ (ESI positive ion mode), m / z 612.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 188
N-methyl-1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) cyclohexanecarbonyl] piperidine-4-carboxamide (Compound No. 188) In substantially the same manner as in Example 10, except that piperidine-4-carboxylic acid methylamide was used instead of tetrahydrofurfurylamine. To give the title compound (22 mg, 57% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.6 Hz), 1.46-1.71 (5H, m), 1.72-1.99 (10H, m), 2.31 (1H, tt, J = 11.2, 3.6 Hz), 2.38-2.67 (6H, m), 2.82 (3H, d, J = 5.0 Hz), 3.04 (1H, t, J = 11.9 Hz), 3.10 (2H, d, J = 6.9 Hz), 3.26 (2H, s), 3.57 (2H, s), 3. 94 (1H, d, J = 12.9 Hz), 4.62 (1 H, d, J = 12.2 Hz), 5.43-5.52 (1 H, m), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 578.9 [M + H] ⁺ (ESI positive ion mode), m / z 623.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 189
1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarbonyl] piperidine-4-carbonitrile (Compound No. 189) The title compound was reacted in substantially the same manner as in Example 10 except that 4-cyanopiperidine was used instead of tetrahydrofurfurylamine. (27 mg, 71% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.9 Hz), 1.45 to 1.68 (3H, m), 1.71 to 2.00 (12H, m), 2.42 (1H, tt, J = 11.7, 3.0 Hz), 2.48-2.65 (4H, m), 2.89 (1H, tt, J = 7.3, 4) .6 Hz), 3.11 (2H, d, J = 7.3 Hz), 3.26 (2H, s), 3.38-3.87 (4H, m), 3.57 (2H, s), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 7.9 Hz).

LC / MS [condition 1]: retention time 3.19 minutes; m / z 546.8 [M + H] ⁺ (ESI positive ion mode), m / z 591.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 190
3-{[(1r, 4r) -4- (4-oxopiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one (Compound No. 190) The reaction was substantially the same as Example 10 except that piperidin-4-one monohydrate monohydrochloride was used instead of tetrahydrofurfurylamine. To give the title compound (39 mg, 99% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07 (2H, qd, J = 12.6, 5.3 Hz), 1.50-1.70 (3H, m), 1.72-1. 88 (6H, m), 1.95 (2H, d, J = 13.2 Hz), 2.41-2.66 (9H, m), 3.12 (2H, d, J = 7.3 Hz), 3.27 (2H, s), 3.58 (2H, s), 3.95-3.72 (4H, m), 7.44 (2H, d, J = 7.9 Hz), 7.57 ( 2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: Retention time 3.05 minutes; m / z 535.87 [M + H] ⁺ (ESI positive ion mode), m / z 580.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 191
3-{[(1r, 4r) -4- (4-benzylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Production of decan-2-one (Compound No. 191) The reaction was conducted in substantially the same manner as in Example 10 except that 4-benzylpiperidine was used instead of tetrahydrofurfurylamine to give the title compound (35 mg Yield 78%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.92-1.23 (4H, m), 1.43-1.86 (12H, m), 1.94 (2H, d, J = 13. 1 Hz), 2.37-2.65 (8 H, m), 2.93 (1 H, t, J = 12.3 Hz), 3.10 (2 H, d, J = 7.4 Hz), 3.25 ( 2H, s), 3.57 (2H, s), 3.85 (1H, d, J = 12.3 Hz), 4.60 (1H, d, J = 13.1 Hz), 7.09-7. 33 (5H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.83 minutes; m / z 612.0 [M + H] ⁺ (ESI positive ion mode), m / z 656.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 192
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- (tetrahydro-2H-pyran-4-yl) cyclohexanecarbothioamide (Compound No. 192) (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (tetrahydro-2H-pyran-4-yl) cyclohexanecarboxamide (16 mg, 0 0.030 mmol) was dissolved in toluene (2.0 mL), Lawesson's reagent (25 mg, 0.061 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. After cooling, ethyl acetate (5.0 mL) and saturated aqueous sodium hydrogen carbonate solution (3.0 mL) were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (5.0 mL), and the combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1/1] to give the title compound (9.3 mg, yield 55). %) As a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06 (2H, q, J = 11.9 Hz), 1.54 (2H, qd, J = 12.3, 4.5 Hz), 1.62- 2.00 (11H, m), 2.08 (2H, d, J = 10.6 Hz), 2.36 (1H, tt, J = 11.9, 4.1 Hz), 2.45-2.66 (4H, m), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.51 (2H, ddd, J = 11.5, 11.5, 2.. 0 Hz), 3.57 (2H, s), 3.92-4.04 (2H, m), 4.65 (1H, dtt, J = 15.1, 7.4, 4.1 Hz), 7. 21-7.28 (1H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.39 minutes; m / z 553.8 [M + H] ⁺ (ESI positive ion mode), m / z 588.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 193
3-({(1r, 4r) -4- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl ) Preparation of benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 193) Instead of tetrahydrofurfurylamine, 6-fluoro-3- (4-piperidinyl) -1 , 2-benzisoxazole (purchased from Wako Pure Chemical Industries, Ltd.) was used, and the reaction was carried out in substantially the same manner as in Example 10 to obtain the title compound (26 mg, yield 70%) as a white solid. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07 (2H, q, J = 12.3 Hz), 1.49-1.71 (3H, m), 1.72 to 2.03 (10H, m), 2.07-2.25 (2H, m), 2.50 (1H, tt, J = 11.9, 3.3 Hz), 2.50-2.64 (4H, m), 2. 88 (1H, t, J = 12.7 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.20-3.41 (1H, m), 3.27 (2H, s), 3.33 (1H, tt, J = 11.1, 3.7 Hz), 3.58 (2H, s), 4.05 (1H, d, J = 13.5 Hz), 4.67 (1H, d , J = 13.1 Hz), 7.08 (1H, td, J = 8.8, 2.0 Hz), 7.26 (1H, dd, J = 8.2, 2.0 Hz), 7.44 ( 2H, d, = 7.8Hz), 7.57 (2H, d, J = 8.2Hz), 7.62 (1H, dd, J = 8.6,4.9Hz).

LC / MS [condition 1]: retention time 3.81 minutes; m / z 657.0 [M + H] ⁺ (ESI positive ion mode), m / z 701.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 194
(1r, 4r) -N- [1- (isoxazol-5-yl) ethyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 194) In place of tetrahydrofurfurylamine, 1- (isoxazol-5-yl) ethylamine (PCT / JP2008 / 070621) The title compound (7.1 mg, 34% yield) was obtained as a pale yellow oil in substantially the same manner as in Example 10 except that was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 12.3 Hz), 1.40-1.64 (3H, m), 1.54 (3H, d, J = 7.0 Hz), 1.71-1.99 (8H, m), 2.05 (1H, tt, J = 12.3, 3.3 Hz), 2.50-2.63 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.58 (2H, s), 5.36 (1H, qd, J = 7.4, 7.4 Hz) ), 5.84 (1H, d, J = 8.2 Hz), 6.11 (1H, d, J = 1.6 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz), 8.17 (1H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 3.33 minutes; m / z 548.8 [M + H] ⁺ (ESI positive ion mode), m / z 593.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 195
Preparation of 3-isopropyl-5- (piperidin-4-yl) -1,2,4-oxadiazole hydrochloride The compound was synthesized using the method described in Journal of Medicinal Chemistry (2008, 51, 5172-5175).

Example 195
3-({(1r, 4r) -4- [4- (3-isopropyl-1,2,4-oxadiazol-5-yl) piperidin-1-carbonyl] cyclohexyl} methyl) -8- [4- Preparation of (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 195) Instead of tetrahydrofurfurylamine, the 3- The reaction was carried out in substantially the same manner as in Example 10 except that isopropyl-5- (piperidin-4-yl) -1,2,4-oxadiazole hydrochloride was used, and the title compound (39 mg, yield 73) was obtained. %) As a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.33 (6H, d, J = 6.9 Hz), 1.46-1.70 ( 3H, m), 1.71-2.00 (10H, m), 2.03-2.21 (2H, m), 2.46 (1H, tt, J = 11.9, 3.0 Hz), 2.49-2.62 (4H, m), 2.88 (1H, t, J = 11.9 Hz), 3.01-3.28 (5H, m), 3.26 (2H, s), 3.57 (2H, s), 3.94 (1H, d, J = 13.2 Hz), 4.52 (1H, d, J = 12.9 Hz), 7.44 (2H, d, J = 8) .3 Hz), 7.58 (2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: retention time 3.64 minutes; m / z 631.9 [M + H] ⁺ (ESI positive ion mode), m / z 676.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 196
3-{[(1r, 4r) -4- (4-methoxypiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Production of decan-2-one (Compound No. 196) The reaction was conducted in substantially the same manner as in Example 10 except that 4-methoxypiperidine was used instead of tetrahydrofurfurylamine to give the title compound (34 mg Yield 87%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.3 Hz), 1.43-2.00 (15H, m), 2.45 (1H, tt, J = 11.5, 2.9 Hz), 2.51-2.63 (4 H, m), 3.10 (2 H, d, J = 7.4 Hz), 3.18-3.33 (4 H, m), 3.36 (3H, s), 3.43 (1H, tt, J = 7.4, 3.7 Hz), 3.57 (2H, s), 3.62-3.74 (1H, m), 3.84-3.99 (1H, m), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [condition 1]: retention time 3.23 minutes; m / z 551.8 [M + H] ⁺ (ESI positive ion mode), m / z 596.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 197
3-{[(1r, 4r) -4- (4-methoxypiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one hydrochloride (Compound No. 197) 3-{[(1r, 4r) -4- (4-methoxypiperidine-1-carbonyl) cyclohexyl] obtained in Example 196 Methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (2.3 mg, 0.0042 mmol) in methanol (1.0 mL) 10 wt% hydrogen chloride-methanol solution was added and stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to give the title compound (2.3 mg, 92%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 11.5 Hz), 1.43-1.92 (11H, m), 2.05 (2H, d, J = 13.5 Hz), 2.44 (1 H, t, J = 11.9 Hz), 2.75 (2 H, t, J = 12.7 Hz), 3.01-3.50 (14 H, m), 3. 55-3.97 (2H, m), 4.18 (2H, s), 7.73 (2H, d, J = 7.8 Hz), 7.85 (2H, d, J = 7.8 Hz), 13.18 (1H, br s).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 551.9 [M + H] ⁺ (ESI positive ion mode), m / z 586.2 [M + Cl] ⁻ (ESI negative ion mode)

Reference Example 198-1
Preparation of methyl 4-methyl-3- (trifluoromethyl) benzoate 4-Methyl-3- (trifluoromethyl) benzoic acid (commercially available) (1.3 g, 6.2 mmol) dissolved in methanol (6.0 mL) Concentrated sulfuric acid (0.5 mL) was added and stirred at 60 ° C. for 10 hours. After the reaction mixture was cooled to room temperature, water (15 mL) and ethyl acetate (15 mL) were added, and the organic layer was separated. The obtained organic layer was washed once with a saturated aqueous sodium hydrogen carbonate solution, saturated brine and water. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.4 g, quantitative yield) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.56-2.53 (3H, m), 3.94 (3H, s), 7.37 (1H, d, J = 7.8 Hz), 8 .09 (1H, d, J = 7.8 Hz), 8.28 (1H, s).

Reference Example 198-2
Reference for production of t-butyl 3- [4- (methoxycarbonyl) -2- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Methyl 4-methyl-3- (trifluoromethyl) benzoate (110 mg, 0.50 mmol) obtained in Example 198-1 was dissolved in chloroform (2.0 mL), heated to 80 ° C., and then N-bromo Succinimide (179 mg, 1.0 mmol) and azobisisobutyronitrile (17 mg, 0.10 mmol) were added, and the mixture was stirred at 80 ° C. for 3 hours. After the reaction mixture was cooled to room temperature, water (5.0 mL) and chloroform (5.0 mL) were added, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 10/1], and pale yellow oily substance (156 mg) was obtained.
2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (130 mg, 0.50 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (2.0 mL), sodium t-butoxide (53 mg, 0.55 mmol) was added, and the mixture was stirred for 30 minutes, and then the pale yellow oil (156 mg) obtained above, N, N-dimethylformamide (2. 0 mL) solution was added and stirred for 3 hours. Thereafter, water (10 mL) and ethyl acetate (10 mL) were added, and then the organic layer was separated. The obtained organic layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 3/1] to give the title compound (120 mg, 49% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.52-1.70 (2H, m), 1.81-1.93 (2H, m), 3.16 (2H, s), 3.22-3.35 (2H, m), 3.75-3.89 (2H, m), 3.96 (3H, s), 4.69 (2H, s), 7.61 (1H, d, J = 8.2 Hz), 8.23 (1H, d, J = 8.2 Hz), 8.35 (1H, s).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 494.8 [M + Na] ⁺ (ESI positive ion mode)

Reference Example 198-3
4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -3- (trifluoromethyl) benzoic acid methyl hydrochloride Reference Example 198-2 3- [4- (methoxycarbonyl) -2- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t- Butyl (120 mg, 0.025 mmol) was dissolved in 1,4-dioxane (2.0 mL) and methanol (0.50 mL), 4M hydrogen chloride-dioxane solution (1.0 mL) was added, and the mixture was stirred at room temperature for 12 hr. . The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was concentrated again to dryness under reduced pressure to give the title compound (100 mg, yield 99%) as a white solid.

LC / MS [Condition 1]: Retention time 2.33 minutes; m / z 373.0 [M + H] ⁺ (ESI positive ion mode)

Reference Example 198-4
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -3- (trifluoromethyl ) Preparation of methyl benzoate 4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -3- (tri Fluoromethyl) benzoic acid methyl hydrochloride (100 mg, 0.24 mmol) was suspended in N, N-dimethylformamide (2.0 mL), triethylamine (0.10 mL, 0.73 mmol) and 4- (trifluoromethyl) benzyl Bromide (64 mg, 0.27 mmol) was added and stirred at room temperature for 7 hours. Thereafter, water (10 mL) and ethyl acetate (10 mL) were added to the reaction mixture, and then the organic layer was separated and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 3/1] to give the title compound (100 mg, yield 85%). Was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-1.85 (2H, m), 1.89-2.00 (2H, m), 2.47-2.66 (4H, m) 3.17 (2H, s), 3.58 (2H, s), 3.96 (3H, s), 4.68 (2H, s), 7.69-7.39 (5H, m), 8.21 (1H, d, J = 7.8 Hz), 8.35 (1H, s).

LC / MS [Condition 1]: Retention time 3.56 minutes; m / z 530.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 198-5
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -3- (trifluoromethyl ) Preparation of benzoic acid 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane obtained in Reference Example 198-4 Methyl-3-yl} methyl) -3- (trifluoromethyl) benzoate (71 mg, 0.13 mmol) was suspended in methanol (2.0 mL), dissolved by heating to 50 ° C., and then 1M sodium hydroxide Aqueous solution (0.68 mL, 0.68 mmol) was added, and the mixture was stirred at 50 ° C. for 1 hr. After completion of the reaction, the reaction mixture was cooled to room temperature, and methanol was distilled off under reduced pressure. Water was added to the obtained residue, and 1M hydrochloric acid (0.68 mL, 0.68 mmol) was added dropwise. The precipitated white solid was filtered and then dried under reduced pressure to obtain the title compound (60 mg, yield 86%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.60-2.08 (4H, m), 2.67-2.81 (2H, m), 2.94-3.07 (4H, m) 3.88 (2H, s), 4.67 (2H, s), 7.48-7.55 (3H, m), 7.62 (2H, d, J = 8.2 Hz), 8.21. (1H, d, J = 8.2 Hz), 8.37 (1H, s).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 516.9 [M + H] ⁺ (ESI positive ion mode), m / z 515.1 [MH] ⁻ (ESI negative ion mode)

Example 198
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -3- ( 4-({2-oxo-8- [4- (trifluoromethyl) benzyl]-] obtained in Reference Example 198-5 of Preparation of Methyl (trifluoromethyl) benzamide] piperidine-1-carboxylate (Compound No. 198) 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -3- (trifluoromethyl) benzoic acid (25 mg, 0.048 mmol), 4-amino obtained in Reference Example 135 Piperidine-1-carboxylic acid methyl hydrochloride (11 mg, 0.073 mmol), triethylamine (9.9 μL, 0.073 mmol) and 1-hydroxybenzotriazole (6.4 mg) Was dissolved 0.048 mmol) in chloroform (1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (14 mg, 0.073 mmol) was added and stirred at room temperature for 60 hours. Thereafter, water (2.0 mL) was added to the reaction mixture, the organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1/1] to give the title compound (25 mg, yield 80%). Obtained as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37-1.52 (2H, m), 1.68-1.81 (2H, m), 1.87-1.98 (2H, m) , 2.00-2.11 (2H, m), 2.48-2.59 (4H, m), 2.97 (2H, t, J = 12.6 Hz), 3.15 (2H, s) 3.56 (2H, s), 3.71 (3H, s), 4.07-4.25 (3H, m), 4.67 (2H, s), 6.09 (1H, d, J = 7.6 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.54-7.62 (3H, m), 7.91 (1H, d, J = 8.3 Hz), 8 .08 (1H, s).

LC / MS [Condition 1]: Retention time 3.41 min; m / z 657.1 [M + H] ⁺ (ESI positive ion mode), m / z 655.3 [MH] ⁻ (ESI negative ion mode)

Example 199
3- [4- (4-Benzoylpiperidine-1-carbonyl) -2- (trifluoromethyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Production of decan-2-one (Compound No. 199) Substantially the same as Example 198, except that 4-benzoylpiperidine hydrochloride was used in place of methyl 4-aminopiperidine-1-carboxylate The title compound (9.0 mg, 84% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-2.13 (8H, m), 2.42-2.64 (4H, m), 3.03-3.26 (2H, m) 3.17 (2H, s), 3.43-3.88 (4H, m), 4.52-4.72 (1H, m), 4.65 (2H, s), 7.38-7 .53 (4H, m), 7.53-7.64 (5H, m), 7.74 (1H, s), 7.98-7.91 (2H, m).

LC / MS [Condition 1]: Retention time 3.71 min; m / z 688.0 [M + H] ⁺ (ESI positive ion mode), m / z 732.3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 200
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) -3- (trifluoromethyl) benzamide (Compound No. 200) Use piperonylamine instead of methyl 4-aminopiperidine-1-carboxylate and triethylamine Except for the above, the reaction was carried out in substantially the same manner as in Example 198 to give the title compound (9.5 mg, yield 93%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.80 (2H, m), 1.87-1.98 (2H, m), 2.48-2.65 (4H, m) 3.14 (2H, s), 3.56 (2H, s), 4.56 (2H, d, J = 5.3 Hz), 4.66 (2H, s), 5.96 (2H, s) ), 6.38 (1H, t, J = 5.3 Hz), 6.72-6.97 (3H, m), 7.42 (2H, d, J = 8.2 Hz), 7.54-7 .65 (3H, m), 7.93 (1H, d, J = 8.2 Hz), 8.11 (1H, s).

LC / MS [Condition 1]: Retention time 3.61 min; m / z 650.0 [M + H] ⁺ (ESI positive ion mode), m / z 648.2 [MH] ⁻ (ESI negative ion mode)

Example 201
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] -3- (trifluoromethyl) benzamide (Compound No. 201) Was reacted in the same manner as in Example 198 to give the title compound (2.6 mg, yield 28%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.51-1.81 (3H, m), 1.87-2.13 (5H, m), 2.46-2.64 (4H, m) , 3.14 (2H, s), 3.31 (1H, ddd, J = 13.9, 7.9, 4.6 Hz), 3.56 (2H, s), 3.74-3.97 ( 3H, m), 4.07 (1H, qd, J = 7.3, 3.0 Hz), 4.67 (2H, s), 6.55 (1H, t, J = 5.3 Hz), 7. 43 (2H, d, J = 7.9 Hz), 7.54-7.62 (3H, m), 7.93 (1H, dd, J = 7.9, 2.0 Hz), 8.11 (1H , D, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.37 minutes; m / z 600.0 [M + H] ⁺ (ESI positive ion mode), m / z 598.2 [MH] ⁻ (ESI negative ion mode)

Example 202
4- [3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide) piperidine- Production of methyl 1-carboxylate (Compound No. 202) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (28 mg, 0.062 mmol), 4-aminopiperidine-1-carboxylic acid methyl hydrochloride obtained in Reference Example 135 (15 mg, 0.075 mmol) , Triethylamine (13 μL, 0.094 mmol) and 1-hydroxybenzotriazole (8.4 mg, 0.062 mmol) were dissolved in chloroform (1.0 mL). After 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (18 mg, 0.094 mmol) was added and stirred at room temperature for 36 hours. After completion of the reaction, water (3.0 mL) was added to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1/1] to give the title compound (31 mg, yield 83%). Obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.36-1.53 (2H, m), 1.67-1.81 (2H, m), 1.86-1.99 (2H, m) 1.99-2.12 (2H, m), 2.47-2.61 (4H, m), 2.97 (2H, t, J = 11.9 Hz), 3.14 (2H, s) , 3.55 (2H, s), 3.71 (3H, s), 4.08-4.24 (3H, m), 4.46 (2H, s), 6.03 (1H, d, J = 7.0 Hz), 7.39-7.48 (4H, m), 7.56 (2H, d, J = 8.2 Hz), 7.72-7.64 (2H, m).

LC / MS [Condition 1]: Retention time 3.01 minutes; m / z 589.1 [M + H] ⁺ (ESI positive ion mode), m / z 623.2 [M + Cl] ⁻ (ESI negative ion mode)

Example 203
3- [3- (4-Benzoylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of (Compound No. 203) The title compound was obtained by carrying out the reaction in substantially the same manner as in Example 202 except that 4-benzoylpiperidine hydrochloride was used instead of 4-aminopiperidine-1-carboxylic acid methyl hydrochloride. (4.8 mg, 17% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-2.05 (8H, m), 2.42-2.65 (4H, m), 3.00-3.29 (4H, m) , 3.49-3.62 (3H, m), 3.75-4.01 (1H, br m), 4.44 (2H, s), 4.58-4.77 (1H, br m) , 7.28-7.63 (11H, m), 7.88-8.01 (2H, m).

LC / MS [condition 1]: retention time 3.51 minutes; m / z 620.2 [M + H] ⁺ (ESI positive ion mode), m / z 654.4 [M + Cl] ⁻ (ESI negative ion mode)

Example 204
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) benzamide (Compound No. 204) Substantially Example 202 except that 4-aminopiperidine-1-carboxylic acid methyl hydrochloride and triethylamine were used instead of piperonylamine. The title compound (17 mg, yield 65%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-1.78 (2H, m), 1.85-1.95 (2H, m), 2.45-2.58 (4H, m) 3.14 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.54 (2H, d, J = 5.7 Hz), 5.94 (2H, s) ), 6.40 (1H, t, J = 5.7 Hz), 6.73-6.87 (3H, m), 7.38-7.46 (4H, m), 7.56 (2H, d) , J = 8.2 Hz), 7.73-7.65 (2H, m).

LC / MS [Condition 1]: Retention time 3.37 minutes; m / z 582.0 [M + H] ⁺ (ESI positive ion mode), m / z 616.3 [M + Cl] ⁻ (ESI negative ion mode)

Reference Example 205-1
Preparation of t-butyl 3- [3-methoxy-4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 2-methoxy-4 -Methyl methyl benzoate (commercially available) (120 mg, 0.64 mmol) was dissolved in chloroform (2.0 mL) and heated to 80 ° C., and then N-bromosuccinimide (172 mg, 0.96 mmol) and azobisisobutyro Nitrile (21 mg, 0.13 mmol) was added and stirred at 80 ° C. for 1.5 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution (5.0 mL) and chloroform (5.0 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 4/1], and colorless oil ( 199 mg) was obtained.
2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (164 mg, 0.64 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (2.0 mL), sodium t-butoxide (68 mg, 0.70 mmol) was added, and the mixture was stirred for 30 minutes, and then the pale yellow oil (199 mg) obtained above, N, N-dimethylformamide (2. 0 mL) solution was added and stirred for 2 hours. Thereafter, water and ethyl acetate were added to separate the organic layer, and the organic layer was washed twice with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / Purification by ethyl acetate = 1/1] gave the title compound (120 mg, 45%) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.54-1.68 (2H, m), 1.79-1.90 (2H, m), 3.13 (2H, s), 3.22-3.36 (2H, m), 3.70-3.86 (2H, m), 3.89 (3H, s), 3.90 (3H, s), 4.44 (2H, s), 6.81-6.92 (2H, m), 7.77 (1H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.03 min; m / z 457.0 [M + Na] ⁺ (ESI positive ion mode)

Reference Example 205-2
Preparation of 2-methoxy-4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid methyl hydrochloride Obtained in Reference Example 205-1 3- [3-Methoxy-4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (120 mg, 0.029 mmol) Was dissolved in methanol (1.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. Thereafter, the mixture was concentrated to dryness under reduced pressure to obtain the title compound (110 mg, quantitative yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 2.20-1.94 (4H, m), 3.39-3.23 (4H, m), 3.38 (2H, s), 3. 85 (3H, s), 3.88 (3H, s), 4.48 (2H, s), 6.95 (1H, dd, J = 8.2, 1.4 Hz), 7.04-7. 06 (1H, m), 7.72-7.78 (1H, m).

LC / MS [Condition 1]: Retention time 0.58 minutes; m / z 335.1 [M + H] ⁺ (ESI positive ion mode)

Reference Example 205-3
2-Methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate of reference example 205-2 obtained in 2-methoxy-4 - [(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate hydrochloride (110 mg, 0.29 mmol) was suspended in N, N-dimethylformamide (2.0 mL) and triethylamine (0.12 mL, 0.85 mmol) and 4- (trifluoromethyl) benzyl bromide (82 mg, 0.34 mmol) And stirred at room temperature for 1.5 hours. Water and ethyl acetate were added, the organic layer was separated, and washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1/1], and the title compound (88 mg, yield 63%). Was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65-1.79 (2H, m), 1.85-1.96 (2H, m), 2.46-2.60 (4H, m) , 3.13 (2H, s), 3.55 (2H, s), 3.89 (6H, s), 4.43 (2H, s), 6.82-6.90 (2H, m), 7.42 (2H, d, J = 7.9 Hz), 7.56 (2H, d, J = 8.3 Hz), 7.77 (1H, d, J = 7.6 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 492.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 205-4
2-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid 2-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] obtained in Production Reference Example 205-3) Decan-3-yl} methyl) methyl benzoate (88 mg, 0.18 mmol) was suspended in methanol (2.0 mL), dissolved by heating to 50 ° C., and then 1M aqueous sodium hydroxide solution (0.36 mL, 0 mL). .36 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was then cooled to room temperature and 1M hydrochloric acid (0.36 mL, 0.36 mmol) was added dropwise. After adding ethyl acetate (5.0 mL) and water (5.0 mL), the organic layer was separated and concentrated under reduced pressure to give the title compound (78 mg, 91% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.82 (2H, m), 1.85-1.98 (2H, m), 2.46-2.64 (4H, m) 3.17 (2H, s), 3.57 (2H, s), 4.03 (3H, s), 4.45 (2H, s), 6.93-7.02 (2H, m), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 8.12 (1H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 2.42 minutes; m / z 479.1 [M + H] ⁺ (ESI positive ion mode), m / z 477.1 [MH] ⁻ (ESI negative ion mode)

Example 205
3- [4- [4-Benzoylpiperidine-1-carbonyl) -3-methoxybenzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane Preparation of 2-one (Compound No. 205) 2-Methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3 obtained in Reference Example 205-4 , 8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (8.3 mg, 0.017 mmol), 4-benzoylpiperidine hydrochloride (4.7 mg, 0.021 mmol), triethylamine (3.6 μL) 0.026 mmol) and 1-hydroxybenzotriazole (2.3 mg, 0.027 mmol) were dissolved in chloroform (1.0 mL), and then 1-ethyl-3- 3-dimethylaminopropyl) carbodiimide hydrochloride (5.1 mg, 0.017 mmol) was added and stirred at room temperature for 3 days. Thereafter, water (2.0 mL) was added to the reaction mixture, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [Chromatolex NH-PLC05 plate, developed by Fuji Silysia, developing solvent: ethyl acetate 100%] to give the title compound (8.4 mg, yield 75%). Was obtained as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.69-2.08 (8H, m), 2.47-2.62 (4H, m), 2.99-3.25 (4H, m) 3.45-3.65 (4H, m), 3.81-3.87 (3H, m), 4.28-4.56 (2H, m), 4.70-4.80 (1H, m), 6.79-6.91 (2H, m), 7.19-7.26 (1H, m), 7.43 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 7.8 Hz), 7.40-7.63 (3H, m), 7.95 (2H, d, J = 7.4 Hz).

LC / MS [Condition 1]: retention time 3.31 minutes; m / z 650.2 [M + H] ⁺ (ESI positive ion mode), m / z 684.3 [M + Cl] ⁻ (ESI negative ion mode)

Example 206
4- [2-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Benzamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 206) Instead of 4-benzoylpiperidine hydrochloride, the methyl 4-aminopiperidine-1-carboxylate obtained in Reference Example 135 was used. The reaction was carried out substantially in the same manner as in Example 205 to give the title compound (8.7 mg, yield 81%) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.37-1.61 (2H, m), 1.63-1.79 (2H, m), 1.82-1.96 (2H, m) 1.96-2.08 (2H, m), 2.43-2.60 (4H, m), 2.97-3.13 (2H, m), 3.14 (2H, s), 3 .55 (2H, s), 3.71 (3H, s), 3.94 (3H, s), 3.96-4.25 (3H, m), 4.43 (2H, s), 6. 90 (1H, s), 6.95 (1H, d, J = 7.8 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz) ), 7.75 (1H, d, J = 7.8 Hz), 8.17 (1H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.07 minutes; m / z 619.2 [M + H] ⁺ (ESI positive ion mode), m / z 653.4 [M + Cl] ⁻ (ESI negative ion mode)

Example 207
2-methoxy-4-({-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [ Preparation of (tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 207) The reaction was carried out in substantially the same manner as in Example 205 except that tetrahydrofurfurylamine was used instead of 4-benzoylpiperidine hydrochloride and triethylamine. The title compound (6.5 mg, 67% yield) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.80-1.60 (3H, m), 2.08-1.85 (5H, m), 2.45-2.66 (4H, m) , 3.13 (2H, s), 3.45 (1H, ddd, J = 13.9, 6.8, 5.5 Hz), 3.55 (2H, s), 3.74 (1H, ddd, J = 13.5, 5.7, 3.3 Hz), 3.79 (1H, dt, J = 8.2, 6.5 Hz), 3.90 (1H, dt, J = 8.2, 6. 5 Hz), 3.95 (3H, s), 4.08 (1H, qd, J = 7.0, 3.7 Hz), 4.43 (2H, s), 6.87-6.98 (2H, m), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 8.09 (1H, t, J = 5.7 Hz), 8. 17 (1H, d, J = 8 2Hz).

LC / MS [Condition 1]: Retention time 2.99 minutes; m / z 562.0 [M + H] ⁺ (ESI positive ion mode), m / z 596.1 [M + Cl] ⁻ (ESI negative ion mode)

Example 208
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -2-methoxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (Compound No. 208) Substantially the same as Example 205, except that piperonylamine was used instead of 4-benzoylpiperidine hydrochloride and triethylamine. The title compound (9.1 mg, yield 86%) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-1.80 (2H, m), 1.85-1.98 (2H, m), 2.44-2.61 (4H, m) 3.14 (2H, s), 3.55 (2H, s), 3.91 (3H, s), 4.43 (2H, s), 4.57 (2H, d, J = 5.7 Hz) ), 5.94 (2H, s), 6.71-7.01 (5H, m), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8) 0.2 Hz), 8.05 (1 H, t, J = 6.1 Hz), 8.21 (1 H, d, J = 7.8 Hz).

LC / MS [condition 1]: retention time 3.23 minutes; m / z 612.0 [M + H] ⁺ (ESI positive ion mode), m / z 646.2 [M + Cl] ⁻ (ESI negative ion mode)

Example 209
4- (4-Fluorobenzoyl) -N- [3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of -yl} methyl) phenyl] piperidine-1-carboxamide (Compound No. 209) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1 obtained in Reference Example 108-3 -Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (50 mg, 0.11 mmol) was suspended in toluene (1.0 mL) and triethylamine (0.023 mL, 0.22 mmol). ) And diphenylphosphoryl azide (0.014 mL, 0.13 mmol) were added and stirred at room temperature for 4 days. After adding water (3.0) mL to the reaction mixture, the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a pale yellow oil (74 mg). This oil (37 mg) was dissolved in toluene (3.0 mL) and stirred at 110 ° C. for 2 hours. Thereafter, a solution of 4- (4-fluorobenzoyl) piperidine hydrochloride (27 mg, 0.11 mmol) and triethylamine (0.015 mL, 0.11 mmol) in toluene (1.0 mL) was added to the reaction mixture, and the mixture was stirred for 5 hours. The reaction mixture was cooled to room temperature, ethyl acetate (3.0 mL) and water (3.0 mL) were added to separate the organic layer, and the aqueous layer was extracted with ethyl acetate (3 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate] to give the title compound (2.3 mg, yield 7%) as a colorless oil. Got as.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-2.00 (8H, m), 2.47-2.60 (4H, m), 3.12 (2H, ddd, J = 13. 5, 11.5, 2.9 Hz), 3.16 (2 H, s), 3.47 (1 H, tt, J = 11.1, 4.1 Hz), 3.55 (2 H, s), 4. 07-4.16 (2H, m), 4.38 (2H, s), 6.44 (1H, s), 6.91-6.96 (1H, m), 7.17 (2H, t, J = 8.6 Hz), 7.22-7.37 (3H, m), 7.43 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.95-8.03 (2H, dd, J = 9.0, 5.3 Hz).

LC / MS [Condition 1]: retention time 3.43 minutes; m / z 653.1 [M + H] ⁺ (ESI positive ion mode), m / z 651.1 [MH] ⁻ (ESI negative ion mode)

Example 210
1- [3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] -3 Production of — [(tetrahydrofuran-2-yl) methyl] urea (Compound No. 210) 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1 obtained in Reference Example 108-3 -Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (50 mg, 0.11 mmol) was suspended in toluene (1.0 mL) and triethylamine (0.023 mL, 0.22 mmol). ) And diphenylphosphoryl azide (0.014 mL, 0.13 mmol) were added and stirred at room temperature for 4 days. Water (3.0 mL) was added to separate the organic layer, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a pale yellow oil (74 mg). This oil (37 mg) was dissolved in toluene (3.0 mL) and stirred at 110 ° C. for 2 hours. Thereafter, tetrahydrofurfurylamine (0.012 mL, 0.11 mmol) was added to the reaction solution, and the mixture was stirred for 5 hours. The reaction mixture was cooled to room temperature, ethyl acetate (3.0 mL) and water (3.0 mL) were added to separate the organic layer, and then the aqueous layer was extracted with ethyl acetate (3.0 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate], and further subjected to preparative thin layer chromatography [chromatolex NH manufactured by Fuji Silysia Ltd. -The product was purified by -PLC05 plate, developing solvent: ethyl acetate 100%] to give the title compound (11 mg, yield 35%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-1.79 (3H, m), 1.85-2.05 (5H, m), 2.45-2.62 (4H, m) , 3.15 (2H, s), 3.15 (1H, ddd, J = 14.3, 6.5, 5.3 Hz), 3.55 (2H, s), 3.57 (1H, ddd, J = 14.3, 6.5, 2.9 Hz), 3.78 (1H, dt, J = 8.2, 7.0 Hz), 3.88 (1H, dt, J = 8.2, 6. 5 Hz), 4.02 (1H, qd, J = 7.0, 3.3 Hz), 4.38 (2H, s), 5.07 (1H, t, J = 5.7 Hz), 6.90- 6.96 (1H, m), 7.27-7.31 (4H, m), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz) ).

LC / MS [Condition 1]: Retention time 2.99 minutes; m / z 547.0 [M + H] ⁺ (ESI positive ion mode), m / z 545.1 [MH] ⁻ (ESI negative ion mode)

Reference Example 211-1
Preparation of methyl (1s, 4s) -4- (hydroxymethyl) cyclohexanecarboxylate cis-4- (hydroxymethyl) cyclohexanecarboxylic acid (purchased from Tokyo Chemical Industry Co., Ltd.) (500 mg, 3.2 mmol) in methanol (10 mL) After dissolution, concentrated sulfuric acid (17 μL) was added, and the mixture was stirred with heating at 80 ° C. for 2 hr. A saturated aqueous sodium hydrogen carbonate solution (5.0 mL) and ethyl acetate (5.0 mL) were added to the reaction mixture and shaken, and then the organic layer was separated. The aqueous layer was then extracted twice with ethyl acetate (10 mL), and the combined organic layers were washed with a saturated aqueous sodium chloride solution (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give methyl (1s, 4s) -4- (hydroxymethyl) cyclohexanecarboxylate (522 mg, yield 96%) as a colorless oil. Obtained. The obtained oil was used for the next reaction without purification.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.19-1.73 (1H, brs), 1.22-1.38 (2H, m), 1.50-1.70 (5H, m ), 1.94-2.09 (2H, m), 2.58 (1H, tt, J = 4.9, 4.1 Hz), 3.50 (2H, d, J = 5.9 Hz), 3 .69 (3H, s).

Reference Example 211-2
Production of methyl (1s, 4s) -4-[(trifluoromethylsulfonyloxy) methyl] cyclohexanecarboxylate Methyl (1s, 4s) -4- (hydroxymethyl) cyclohexanecarboxylate obtained in Reference Example 211-1. 200 mg, 1.16 mmol) and pyridine (187 μL, 2.32 mmol) were dissolved in dichloromethane (10 mL), the reaction solution was cooled to −78 ° C., and then trifluoromethanesulfonic anhydride (Tokyo Chemical Industry Co., Ltd.). Purchased more) (343 μL, 2.1 mmol) was added slowly. After stirring at the same temperature for 1.5 hours, water (5 mL) and ethyl acetate (5 mL) were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate (10 mL), and the combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Upon drying, methyl (1s, 4s) -4-[(trifluoromethylsulfonyloxy) methyl] cyclohexanecarboxylate (266 mg, yield 75%) was obtained as a colorless oil. The obtained product was used in the next reaction without further purification.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.22-1.42 (2H, m), 1.51-1.75 (4H, m), 1.84-2.14 (3H, m) , 2.64 (1H, tt, J = 4.5, 4.5 Hz), 3.70 (3H, s), 4.35 (2H, d, J = 7.4 Hz).

Reference Example 211-3
Preparation of t-butyl 3-{[(1s, 4s) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate T-butyl 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (0.11 g, 0.43 mmol) obtained in Reference Example 111-1 was added to tetrahydrofuran (1. (0 mL), sodium hydride (> 55 wt%, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (23 mg, 0.52 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Next, a tetrahydrofuran solution (1) of methyl (1s, 4s) -4-[(trifluoromethylsulfonyloxy) methyl] cyclohexanecarboxylate (0.28 g, 0.85 mmol) obtained in Reference Example 211-2 was added to the reaction mixture. 0.0 mL) and sodium iodide (purchased from Kanto Chemical Co., Inc.) (6.5 mg, 0.04 mmol) were added, followed by stirring at 80 ° C. for 1 hour. Thereafter, water (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture and shaken to separate the organic layer, and then the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained colorless oil was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 2/1] to give 3-{[(1s, 4s) -4- (Methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (0.10 g, 57% yield) as a white solid Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.20-1.35 (2H, m), 1.46 (9H, s), 1.49-1.73 (7H, m), 1.88 (2H, d, J = 12.9 Hz), 1.98-2.11 (2H, m), 2.52-2.61 (1H, m), 3.13 (2H, d, J = 7. 6 Hz), 3.20-3.34 (4H, m), 3.68 (3H, s), 3.77-3.92 (2H, br m).

Reference Example 211-4
(1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Preparation of methyl carboxylate 3-{[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t- 3-{[(1s, 4s) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro obtained in Reference Example 211-3 instead of butyl [4. 5] The reaction was carried out in substantially the same manner as in Reference Example 111-4 except that t-butyl decane-8-carboxylate (12 mg, 0.035 mmol) was used. %).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.18-1.34 (2H, m), 1.46-1.62 (4H, m), 1.67-1.83 (3H, m) 1.93 (2H, d, J = 13.5 Hz), 1.98-2.10 (2H, m), 2.49-2.61 (5H, m), 3.12 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.56 (2H, br s), 3.67 (3H, s), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

Reference Example 211-5
(1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane Preparation of carboxylic acid (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) (1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-] obtained in Reference Example 211-4 instead of methyl cyclohexanecarboxylate 3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylate (13 mg, 0.027 mmol) was used, except that the reaction was carried out in substantially the same manner as in Reference Example 6-3. The title compound is converted to a white solid (1 mg, was obtained as 90% yield).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 454.8 [M + H] ⁺ (ESI positive ion mode), m / z 453.0 [MH] ⁻ (ESI negative ion mode)

Example 211
(1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 211) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1- (1s, 4s) -4-({2-oxo-8) obtained in Reference Example 211-5 in place of oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid -[4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (11 mg, 0.024 mmol) is used except that Conducted 10 by performing the same reaction as the title compound was obtained as a colorless oil (7.3 mg, 57% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40-1.69 (7H, m), 1.70-2.04 (10H, m), 2.30 (1H, tt, J = 7. 8, 3.7 Hz), 2.55 (4 H, br s), 3.12 (1 H, ddd, J = 13.5, 7.4, 4.5 Hz), 3.20 (2 H, d, J = 8.2 Hz), 3.27 (2H, s), 3.57 (2H, s), 3.59 (1H, ddd, J = 13.5, 6.5, 3.3 Hz), 3.75 ( 1H, dt, J = 8.2, 7.0 Hz), 3.85 (1H, dt, J = 8.2, 7.0 Hz), 3.94 (1H, dq, J = 3.3, 7.). 0 Hz), 6.00 (1H, t, J = 4.5 Hz), 7.44 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 3.15 minutes; m / z 537.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 212
4-[(1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarboxamide] Production of t-butyl piperidine-1-carboxylate (Compound No. 212) Instead of using tetrahydrofurfurylamine, 4-amino-1-t-butoxycarbonylpiperidine (purchased from Aldrich) was used. The reaction was carried out substantially as in Example 211 to obtain the title compound as a white solid (48 mg, yield 69%).

¹ H-NMR (CDCl ₃ ) δ: 1.27 (2H, dq, J = 4.1, 11.5 Hz), 1.41-1.69 (6H, m), 1.46 (9H, s) , 1.71-1.99 (9H, m), 2.25 (1H, tt, J = 7.4, 4.1 Hz), 2.47-2.64 (4H, br m), 2.84. (2H, t, J = 12.7 Hz), 3.19 (2H, d, J = 7.8 Hz), 3.27 (2H, s), 3.57 (2H, s), 3.91 (1H , Dtt, J = 7.4, 11.5, 3.7 Hz), 3.93-4.15 (2H, m), 5.39 (1H, d, J = 7.8 Hz), 7.44 ( 2H, d, J = 8.4 Hz), 7.57 (2H, d, J = 8.4 Hz).

LC / MS [Condition 1]: retention time 3.62 minutes; m / z 636.9 [M + H] ⁺ (ESI positive ion mode), m / z 681.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 213
(1s, 4s) -N- [1- (cyanomethyl) piperidin-4-yl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 213) 4-[(1s, 4s) -4-({2-oxo-8- [ 4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide] piperidine-1-carboxylate (16 mg, 0.025 mmol ) Was dissolved in 4M hydrogen chloride-dioxane solution (1 mL) and stirred at room temperature for 1 hour, and then the reaction mixture was concentrated to dryness under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (1.0 mL), and bromoacetonitrile (purchased from Tokyo Chemical Industry Co., Ltd.) (6.7 μL, 0.10 mmol) and triethylamine (21 μL, 0.15 mmol) were sequentially added. In addition, the mixture was stirred at room temperature for 1 day. A saturated aqueous ammonium chloride solution (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture, and the mixture was shaken. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate / methanol = 5/1], and the title compound was purified as a white solid (6.8 mg, yield 47 %).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40-1.70 (8H, m), 1.70-2.03 (9H, m), 2.26 (1H, tt, J = 7. 8, 4.1 Hz), 2.46 (2H, td, J = 11.1, 2.5 Hz), 2.50-2.63 (4H, br m), 2.77 (2H, dt, J = 11.9, 4.1 Hz), 3.19 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.51 (2H, s), 3.57 (2H, br s) ), 3.82 (1H, dtt, J = 7.8, 10.4, 4.0 Hz), 5.37 (1H, d, J = 7.4 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

Example 214
4-[(1s, 4s) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarboxamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 214) Example 213 was substantially the same as Example 213 except that methyl chloroformate (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of bromoacetonitrile. The same reaction was performed to obtain the title compound as a white solid (10 mg, yield 68%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (2H, dq, J = 4.9, 11.8 Hz), 1.41-1.72 (6H, m), 1.72-1. 99 (9H, m), 2.25 (1 H, tt, J = 7.8, 3.7 Hz), 2.46-2.64 (4H, br m), 2.90 (2H, t, J = 12.7 Hz), 3.19 (2H, d, J = 7.8 Hz), 3.27 (2H, s), 3.57 (2H, br s), 3.69 (3H, s), 3. 93 (1H, dtt, J = 7.4, 11.5, 3.7 Hz), 4.00-4.13 (2H, br m), 5.38 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

Example 215
3- (4- {4-[(methoxyimino) (phenyl) methyl] piperidine-1-carbonyl} benzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-2-one (Compound No. 215) 3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) obtained in Example 55 ) Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (30 mg, 0.049 mmol), methoxyamine hydrochloride (purchased from Aldrich Co.) (8.2 mg, 0.8). 098 mmol) and sodium acetate (purchased from Junsei Co., Ltd.) (8.0 mg, 0.098 mmol) were dissolved in ethanol (1.0 mL) and stirred at 100 ° C. for 28 hours. Thereafter, water (5.0 mL) and ethyl acetate (5.0 mL) were added to the reaction mixture and shaken, the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate / methanol = 20/1], and 3- (4- {4-[(methoxyimino) (Phenyl) methyl] piperidine-1-carbonyl} benzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (14 mg, yield) 44%) as a colorless oil.

¹ H-NMR (DMSO-d ₆ ) δ: 1.41 (1H, br q, J = 11.9 Hz), 1.54-1.89 (7H, br m), 2.34-2.47 ( 4H, br m), 1.71-2.89 & 3.34-3.48 (1H, each m), 2.71-3.15 (2H, br m), 3.22 (2H, br s), 3.57 (2H, s), 3.58 (1H, br s), 3.70 & 3.87 (3H, eaches), 4.38 (2H, s), 4.48 (1H, br s), 7.21-7.44 (9H, m), 7.53 (2H, d, J = 8.6 Hz), 7.68 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.82 minutes; m / z 649.0 [M + H] ⁺ (ESI positive ion mode), m / z 693.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 216
3- [4- (4-Benzoylpiperidine-1-carbonyl) -2-methoxybenzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane Preparation of -2-one (Compound No. 216) The reaction was conducted in substantially the same manner as in Example 115 except that 4-benzoylpiperidine hydrochloride (purchased from Acros) and triethylamine were used instead of tetrahydrofurfurylamine. The compound was obtained as a colorless oil (16 mg, 54% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58-2.06 (8H, m), 2.44-2.63 (4H, m), 2.99-3.26 (2H, m) 3.16 (2H, s), 3.50-3.63 (1H, m), 3.56 (2H, s), 3.86 (3H, s), 3.89 (1H, br s) 4.47 (2H, s), 4.69 (1H, br s), 6.90-7.03 (2H, m), 7.26 (1H, d, J = 7.0 Hz), 7. 36-7.65 (7H, m), 7.95 (2H, d, J = 7.4 Hz).

LC / MS [Condition 1]: retention time 3.54 minutes; m / z 650.2 [M + H] ⁺ (ESI positive ion mode), m / z 694.3 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 217-1
Preparation of t-butyl 4- (cyanomethyl) -4-hydroxypiperidine-1-carboxylate To a tetrahydrofuran solution (50 mL) of acetonitrile (purchased from Kanto Chemical Co., Ltd.) (1.4 mL, 25 mmol), lithium hexamethyldisilazide 1.0M tetrahydrofuran solution (purchased from Aldrich) (28 mL, 28 mmol) was slowly added dropwise at −78 ° C., followed by stirring at the same temperature for 30 minutes. Next, 15 mL of a tetrahydrofuran solution of N- (t-butoxycarbonyl) piperidin-4-one (purchased from Wako Pure Chemical Industries, Ltd.) was added, and the reaction solution was stirred for 12 hours while gradually warming to room temperature. Thereafter, water (30 mL) and ethyl acetate (30 mL) were added to the reaction mixture and shaken to separate the organic layer, and then the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The obtained orange oil was subjected to silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1. / 1] to give the title compound as a yellow oil (2.0 g, 32% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.55-1.79 (4H, m), 1.99 (1H, br s), 2.53 (2H, s), 3.15 (2H, t, J = 12.3 Hz), 3.90 (2H, d, J = 14.3 Hz).

Reference Example 217-2
Production of t-butyl 2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylate 4- (cyanomethyl) -4-hydroxypiperidine-1 obtained in Reference Example 217-1 -To a methanol solution (20 ml) of t-butyl carboxylate (0.50 g, 2.1 mmol) and cobalt (II) chloride hexahydrate (purchased from Aldrich) (0.99 g, 4.2 mmol) at 0 ° C The sodium borohydride (purchased from Pure Chemical Co., Ltd.) (0.79 g, 21 mmol) was added in three portions. After confirming the disappearance of foaming, the reaction mixture was warmed to room temperature and further stirred for 120 hours. Thereafter, the reaction mixture was cooled to 0 ° C., 1M hydrochloric acid (15 mL) was added, and the mixture was stirred at the same temperature for 10 minutes. Next, diethyl ether (50 mL) was added and shaken to separate the organic layer. 28 wt% aqueous ammonia (6.0 mL) was added to the aqueous layer, and the mixture was extracted 3 times with ethyl acetate (50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure.
The obtained residue was dissolved in 1,4-dioxane (10 mL), carbonyldiimidazole (purchased from Tokyo Chemical Industry Co., Ltd.) (0.36 g, 2.2 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Thereafter, a saturated aqueous ammonium chloride solution (5.0 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Diisopropyl ether (10 mL) was added to the obtained yellow oil and allowed to stand at room temperature, and the precipitated crystals were collected by filtration to give the title compound as a yellow solid (124.4 mg, yield 22%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 1.59 (2H, td, J = 13.3, 4.7 Hz), 1.80-1.95 (4H, m), 3.29 (2H, t, J = 13.1 Hz), 3.41 (2H, td, J = 6.4, 2.4 Hz), 3.74-3.95 (2H, m), 5.27 (1H, br s).

Reference Example 217-3
Preparation of t-butyl 3- [4- (methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylate Obtained in Reference Example 217-2 To a solution of t-butyl 2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylate (0.12 g, 0.46 mmol) in N, N-dimethylformamide (1.5 mL) Sodium hydride (55% by weight, dispersed in liquid paraffin) (purchased from Kanto Chemical Co., Inc.) (24 mg, 0.55 mmol) was added and stirred at room temperature for 1 hour, and then methyl 4- (bromomethyl) benzoate (Tokyo Chemical Industry (Purchased from Kogyo Co., Ltd.) (0.13 g, 0.55 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water (1.0 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The precipitated crystals were collected by filtration to give the title compound as a colorless solid (0.14 g, yield 71%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.49-1.62 (2H, m), 1.75-1.88 (2H, m), 1.86 (2H, t, J = 6.4 Hz), 3.22 (2H, t, J = 6.4 Hz), 3.32 (2H, t, J = 12.3 Hz), 3.76-3.91 ( 2H, m), 3.92 (3H, s), 4.62 (2H, s), 7.36 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8. 2 Hz).

LC / MS [Condition 1]: Retention time 4.23 minutes; m / z 418.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 217-4
Preparation of methyl 4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) benzoate 4- 3- [4- (methoxycarbonyl) 3-methyl-4-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 3- [4- (methoxycarbonyl) obtained in Reference Example 217-3 Benzyl] -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylate t-butyl (44 mg, 0.11 mmol) substantially except Reference Example 119-5 The title compound was obtained as a yellow oil (48 mg, yield 95%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.60-1.91 (6H, m), 2.49-2.70 (4H, br m), 3.13-3.24 (2H, m ), 3.60 (2H, s), 3.91 (3H, s), 4.61 (2H, s), 7.35 (2H, d, J = 8.2 Hz), 7.45 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.99 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.50 minutes; m / z 476.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 217-5
Preparation of 4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) benzoic acid 4- ( {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Reference Example 217-instead of methyl benzoate 4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) benzoic acid obtained in 4 The reaction was carried out in substantially the same manner as in Reference Example 21 except that methyl (47 mg, 0.10 mmol) was used to give the title compound as a colorless solid (32 mg, yield 69%).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 462.9 [M + H] + (ESI positive ion mode), m / z 461.1 [MH] − (ESI negative ion mode)

Example 217
3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-2-one Preparation of (Compound No. 217) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) 4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecane obtained in Reference Example 217-5 instead of benzoic acid The reaction was carried out in substantially the same manner as in Example 55 except that -3-yl} methyl) benzoic acid (5.4 mg, 0.012 mmol) was used to give the title compound as a colorless oil (2.7 mg, yield). 36%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.95 (10H, m), 2.49-2.69 (4H, br m), 3.00-3.25 (2H, m ), 3.20 (2H, t, J = 6.4 Hz), 3.48-3.62 (1H, br m), 3.59 (2H, s), 3.85 (1H, br s), 4.59 (2H, s), 4.62 (1H, br s), 7.32 (2H, d, J = 8.4 Hz), 7.36-7.63 (9H, m), 7.95 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.78 minutes; m / z 634.0 [M + H] ⁺ (ESI positive ion mode), m / z 678.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 218
4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] benzamide (Compound No. 218) Reaction was substantially the same as Example 217 except that tetrahydrofurfurylamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of 4-benzoylpiperidine hydrochloride. To give the title compound as a yellow solid (11 mg, 75% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58-1.75 (3H, m), 1.76-2.08 (7H, m), 2.49-2.66 (4H, br m ), 3.18 (2H, t, J = 6.1 Hz), 3.32 (1H, ddd, J = 13.9, 7.8, 4.9 Hz), 3.58 (2H, s), 3 .72-3.96 (3H, m), 4.02-4.13 (1H, m), 4.60 (2H, s), 6.44-6.48 (1H, br m), 7. 35 (2H, d, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.75 (2H, d , J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.42 minutes; m / z 545.9 [M + H] ⁺ (ESI positive ion mode)

Example 219
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [ 5.5] Preparation of undecan -3-yl} methyl) benzamide (Compound No. 219) Example 217 was substantially used except that piperonylamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of 4-benzoylpiperidine hydrochloride. The title compound was obtained as a colorless solid (5.3 mg, yield 33%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58-1.73 (2H, m), 1.78-1.91 (4H, m), 2.52-2.64 (4H, br m ), 3.18 (2H, t, J = 7.0 Hz), 3.58 (2H, s), 4.54 (2H, d, J = 5.3 Hz), 4.60 (2H, s), 5.95 (2H, s), 6.31 (1H, t, J = 4.9 Hz), 6.77 (1H, d, J = 8.0 Hz), 6.81 (1H, dd, J = 8) 0.0, 1.2 Hz), 6.85 (1H, d, J = 1.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8. 2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.68 minutes; m / z 596.0 [M + H] ⁺ (ESI positive ion mode), m / z 594.2 [MH] ⁻ (ESI negative ion mode)

Example 220
4- [4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) benzamide] piperidine- Preparation of methyl 1-carboxylate (Compound No. 220) Substantially the Example except that 4-aminopiperidine-1-carboxylate methyl hydrochloride synthesized in Reference Example 135 was used instead of 4-benzoylpiperidine hydrochloride The reaction was carried out in the same manner as 217 to give the title compound as a yellow oil (9.4 mg, 61% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.34 to 1.52 (2H, m), 1.57-1.75 (2H, m), 1.77 to 1.89 (4H, m) 1.98-2.10 (2H, m), 2.49-2.64 (4H, br m), 2.97 (2H, t, J = 12.3 Hz), 3.18 (2H, t , J = 5.7 Hz), 3.59 (2H, s), 3.70 (3H, s), 4.00-4.31 (3H, br m), 4.60 (2H, s), 6 .12 (1H, d, J = 8.2 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.73 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 603.0 [M + H] ⁺ (ESI positive ion mode), m / z 601.2 [MH] ⁻ (ESI negative ion mode)

Example 221
3- {4- [4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperidin-1-carbonyl] benzyl} -9- [4- (trifluoromethyl) benzyl] -1 Preparation of Oxa-3,9-diazaspiro [5.5] undecan-2-one (Compound No. 221) 3-isopropyl-5- (piperidin-4-yl) -1 instead of 4-benzoylpiperidine hydrochloride The reaction was carried out in substantially the same manner as in Example 217 except that 2,4-oxadiazole hydrochloride was used to give the title compound as a colorless oil (19 mg, yield 42%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.34 (6H, d, J = 6.8 Hz), 1.61-1.77 (2H, m), 1.77-1.99 (6H, m), 2.01-2.28 (2H, br m), 2.49-2.69 (4H, br m), 3.08 (1H, sep, J = 6.8 Hz), 3.10- 3.26 (5H, m), 3.59 (2H, s), 3.85 (1H, br s), 4.59 (1H, br s), 4.60 (2H, s), 7.33 (2H, d, J = 7.8 Hz), 7.38 (2H, d, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.22 minutes; m / z 640.1 [M + H] ⁺ (ESI positive ion mode), m / z 684.2 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 222-1
Preparation of t-butyl 3-{[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylate 2-Oxo-1-oxa-3,9-diazaspiro obtained in Reference Example 217-2 instead of t-butyl oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate [5.5] The reaction was carried out in substantially the same manner as in Reference Example 111-3 except that t-butyl undecane-9-carboxylate (0.21 g, 0.78 mmol) was used. (80 mg, 24% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (3H, t, J = 7.4 Hz), 1.46 (9H, s), 1.52-1.67 (2H, m), 1 .84-1.99 (4H, m), 3.31 (2H, t, J = 12.7 Hz), 3.47 (2H, t, J = 6.1 Hz), 3.74-3.98 ( 2H, m), 4.41 (2H, q, J = 7.4 Hz), 4.71 (2H, s), 7.42 (1H, d, J = 7.8 Hz), 8.27 (1H, dd, J = 8.2, 1.6 Hz), 9.13 (1H, s).

Reference Example 222-2
Preparation of ethyl 6-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) nicotinate 3- {[5- (Ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate instead of t-butyl Reference Example 222 3-{[5- (ethoxycarbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylic acid t The reaction was carried out substantially in the same manner as in Reference Example 111-4 except that -butyl (77.0 mg, 0.18 mmol) was used to give the title compound as a colorless oil (36.0 mg, yield 41%). It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.40 (3H, t, J = 7.4 Hz), 1.64-1.80 (2H, m), 1.84-2.00 (4H, m), 2.50-2.66 (4H, m), 3.43 (2H, t, J = 6.1 Hz), 3.59 (2H, s), 4.40 (2H, q, J = 7.0 Hz), 4.71 (2H, s), 7.41 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 8.26 (1H, dd, J = 8.2, 2.0 Hz), 9.12 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.98 min; m / z 491.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 222-3
Preparation of 6-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) nicotinic acid 6- ( {2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Reference Example 222- in place of ethyl nicotinate 6-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-3-yl} methyl) nicotinic acid obtained in 2 The reaction was performed in substantially the same manner as in Reference Example 111-5 except that ethyl (36 mg, 0.070 mmol) was used to give the title compound as a colorless solid (31 mg, yield 91%).

¹ H-NMR (300 MHz, CD ₃ OD) δ: 1.80-1.93 (2H, m), 1.96-2.08 (4H, m), 2.70 (2H, t, J = 11) .6 Hz), 2.77-2.90 (2H, m), 3.45 (2H, t, J = 6.3 Hz), 3.83 (2H, s), 4.67 (2H, s), 7.36 (1H, d, J = 7.9 Hz), 7.60 (2H, d, J = 8.3 Hz), 7.66 (2H, d, J = 8.3 Hz), 8.27 (1H , Dd, J = 8.3, 2.0 Hz), 9.01 (1H, s).

LC / MS [Condition 1]: Retention time 1.00 min; m / z 463.9 [M + H] ⁺ (ESI positive ion mode), m / z 462.0 [MH] ⁻ (ESI negative ion mode)

Example 222
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9 Preparation of diazaspiro [5.5] undecan-2-one (Compound No. 222) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Decan-3-yl} methyl) 6-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa obtained in Reference Example 222-3 instead of nicotinic acid -3,9-diazaspiro [5.5] undecan-3-yl} methyl) nicotinic acid (14 mg, 0.030 mmol), 4- (4-fluorobenzoyl) piperidine hydrochloride instead of tetrahydrofurfurylamine and triethyla But using down by performing the same reaction as substantially Example 111, the title compound was obtained as a colorless oil (13 mg, 66% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.60-2.01 (10H, m), 2.50-2.68 (4H, m), 2.98-3.31 (2H, br m ), 3.43 (2H, t, J = 6.1 Hz), 3.47-3.62 (1H, m), 3.59 (2H, s), 3.84 (1H, br s), 4 .66 (1H, br s), 4.68 (2H, s), 7.17 (2H, t, J = 8.2 Hz), 7.39 (1H, d, J = 8.2 Hz), 7. 44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.73 (1H, dd, J = 8.2, 2.0 Hz), 7.98 (2H, dd, J = 8.2, 5.3 Hz), 8.59 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 653.1 [M + H] ⁺ (ESI positive ion mode), m / z 697.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 223
3-({5- [4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -9- [4- (tri Preparation of fluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5] undecan-2-one (Compound No. 223) 3-isopropyl instead of 4- (4-fluorobenzoyl) piperidine hydrochloride The reaction was carried out in substantially the same manner as in Example 222 except that -5- (piperidin-4-yl) -1,2,4-oxadiazole hydrochloride was used, and the title compound was purified as a colorless oil (14 mg, Yield 68%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.34 (6H, d, J = 7.2 Hz), 1.60-1.82 (2H, m), 1.82-2.01 (6H, m), 2.05-2.29 (2H, m), 2.49-2.68 (4H, m), 3.08 (1H, sep, J = 7.2 Hz), 3.14-3. 31 (3H, m), 3.43 (2H, t, J = 6.5 Hz), 3.59 (2H, s), 3.81 (1H, br s), 4.58 (1H, br s) , 4.68 (2H, s), 7.40 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.72 (1H, dd, J = 8.2, 2.1 Hz), 8.59 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 641.2 [M + H] ⁺ (ESI positive ion mode), m / z 685.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 224
(1r, 4r) -4-{[8- (2-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 224) Substantially examples except using 2-cyanobenzyl bromide (commercially available) instead of 3- (bromomethyl) pyridine hydrobromide The reaction was carried out in the same manner as in Example 4 to obtain the title compound (21.7 mg, yield 63%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.7, 13.1 Hz), 1.38-1.69 (4H, m), 1.69-1. 85 (4H, m), 1.85-2.13 (8H, m), 2.49-2.76 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3 .11 (1H, ddd, J = 13.9, 7.4, 4.5 Hz), 3.25 (2H, s), 3.58 (1H, ddd, J = 13.9, 6.5, 3 .3 Hz), 3.71 (2H, s), 3.74 (1 H, dt, J = 8.2, 6.5 Hz), 3.85 (1 H, dt, J = 8.2, 6.5 Hz) 3.94 (1H, dq, J = 3.3, 7.1 Hz), 5.80 (1H, br t, J = 5.3 Hz), 7.36 (1H, t, J = 7.4 Hz) , 7.48 (1 H, d, J = 7.4 Hz), 7.55 (1H, t, J = 7.4 Hz), 7.66 (1H, d, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 1.48 minutes; m / z 495.0 [M + H] ⁺ (ESI positive ion mode), m / z 493.0 [M−H] ⁻ , 529.1 [M + Cl] ⁻ 539.3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 225
(1r, 4r) -4-{[8- (3-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 225) Substantially examples except using 3-cyanobenzyl bromide (commercially available) instead of 3- (bromomethyl) pyridine hydrobromide The reaction was carried out in the same manner as in 4 to give the title compound (23.9 mg, yield 69%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.0, 12.7 Hz), 1.40-1.69 (4H, m), 1.71-1. 84 (4H, m), 1.84-2.11 (8H, m), 2.42-2.70 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3 .11 (1H, ddd, J = 13.9, 7.6, 4.5 Hz), 3.26 (2H, s), 3.55 (2H, s), 3.58 (1H, ddd, J = 13.9, 6.5, 3.3 Hz), 3.74 (1H, dt, J = 8.2, 7.0 Hz), 3.85 (1H, dt, J = 8.2, 6.5 Hz) , 3.94 (1H, dq, J = 3.3, 7.1 Hz), 5.82 (1H, br t, J = 5.3 Hz), 7.42 (1H, t, J = 7.8 Hz) 7.55 (2 H, br d, J = 7.8 Hz), 7.67 (1H, s).

LC / MS [Condition 1]: Retention time 1.62 minutes; m / z 494.9 [M + H] ⁺ (ESI positive ion mode), m / z 493.2 [M−H] ⁻ , 539.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 226
(1r, 4r) -4-{[8- (Cyclohexylmethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] cyclohexanecarboxamide (Compound No. 226) Substantially the same as Example 4 except that (bromomethyl) cyclohexane (commercially available) was used instead of 3- (bromomethyl) pyridine hydrobromide The title compound (32.7 mg, 98% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.86 (2H, br q, J = 11.9 Hz), 1.02 (2H, dq, J = 3.3, 12.9 Hz), 1.10 -1.35 (3H, m), 1.37-2.11 (22H, m), 2.08-2.24 (2H, br m), 2.33-2.68 (4H, br m) 3.09 (2H, d, J = 7.6 Hz), 3.11 (1H, ddd, J = 13.9, 7.6, 4.5 Hz), 3.24 (2H, s), 3. 59 (1H, dddd, J = 13.9, 6.5, 3.3 Hz), 3.75 (1H, dt, J = 8.2, 6.9 Hz), 3.86 (1H, dt, J = 8.2, 6.5 Hz), 3.94 (1H, dq, J = 3.3, 6.9 Hz), 5.80 (1H, br t, J = 5.3 Hz).

LC / MS [Condition 1]: Retention time 2.77 minutes; m / z 476.0 [M + H] ⁺ (ESI positive ion mode), m / z 474.3 [MH] ⁻ , 510.1 [M + Cl] ⁻ , 520.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 227
(1r, 4r) -4-{[8- (4-Methylbenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 227) Substantially examples except using 4-methylbenzyl bromide (commercially available) instead of 3- (bromomethyl) pyridine hydrobromide The reaction was carried out in the same manner as in Example 4 to obtain the title compound (15.8 mg, yield 65%) as a colorless oil.

LC / MS [Condition 1]: Retention time 2.78 minutes; m / z 483.9 [M + H] ⁺ (ESI positive ion mode), m / z 482.0 [M−H] ⁻ , 518.1 [M + Cl] ⁻ 528.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 228
(1r, 4r) -4-[(8-Benzyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N-[(tetrahydrofuran-2-yl ) Preparation of methyl] cyclohexanecarboxamide (Compound No. 228) The reaction was carried out in substantially the same manner as in Example 4 except that benzyl bromide (commercially available) was used instead of 3- (bromomethyl) pyridine hydrobromide. The title compound (5.6 mg, 24% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 2.9, 12.7 Hz), 1.38-1.66 (4H, m), 1.66-2. 12 (12H, m), 2.44-2.79 (4H, br m), 3.08 (2H, d, J = 7.4 Hz), 3.11 (1H, ddd, J = 13.5, 7.4, 4.9 Hz), 3.25 (2 H, s), 3.58 (2 H, br s), 3.58 (1 H, ddd, J = 13.5, 7.0, 3.3 Hz) 3.74 (1H, dt, J = 8.6, 6.5 Hz), 3.85 (1H, dt, J = 8.6, 6.5 Hz), 3.94 (1H, dq, J = 3) .3, 7.0 Hz), 5.79 (1 H, br t, J = 5.3 Hz), 7.25-7.39 (5 H, m).

Example 229
(1r, 4r) -4-{[8- (3-Methoxybenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 229) Substantially Examples except using 3-methoxybenzyl chloride (commercially available) instead of 3- (bromomethyl) pyridine hydrobromide The reaction was carried out in the same manner as in 4 to give the title compound (5.6 mg, yield 22%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 12.3 Hz), 1.39-1.67 (4H, m), 1.70-1. 84 (4H, m), 1.84-2.11 (8H, m), 2.43-2.71 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3 .11 (1H, ddd, J = 13.9, 7.4, 4.9 Hz), 3.25 (2H, s), 3.52 (2H, br s), 3.58 (1H, ddd, J = 13.9, 6.5, 3.3 Hz), 3.75 (1H, dt, J = 8.2, 6.5 Hz), 3.81 (3H, s), 3.85 (1H, dt, J = 8.2, 6.5 Hz), 3.94 (1H, dq, J = 3.3, 7.1 Hz), 5.80 (1H, br t, J = 5.7 Hz), 6.81 ( 1H, dd, = 8.2, 2.5 Hz), 6.89 (1H, d, J = 2.5 Hz), 6.89 (1H, d, J = 8.2 Hz), 7.23 (1H, t, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.75 minutes; m / z 499.9 [M + H] ⁺ (ESI positive ion mode), m / z 498.0 [M−H] ⁻ , 534.3 [M + Cl] ⁻ 544.3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 230
(1r, 4r) -4-({8- [3-Fluoro-5- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 230) 3-Fluoro-5- (trifluoromethyl) instead of 3- (bromomethyl) pyridine hydrobromide ) The reaction was carried out in substantially the same manner as in Example 4 except that benzyl bromide (commercially available) was used to obtain the title compound (24.9 mg, yield 90%) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 2.8, 12.7 Hz), 1.39-1.68 (4H, m), 1.68-2. 15 (12H, m), 2.44-2.76 (4H, br m), 3.09 (2H, d, J = 7.8 Hz), 3.10 (1H, ddd, J = 13.9, 7.6, 4.5 Hz), 3.26 (2H, s), 3.58 (1H, ddd, J = 13.9, 6.5, 3.3 Hz), 3.58 (2H, s), 3.74 (1H, dt, J = 8.2, 6.5 Hz), 3.85 (1H, dt, J = 8.2, 6.5 Hz), 3.93 (1H, dq, J = 3. 3, 7.1 Hz), 5.80 (1 H, brt, J = 5.3 Hz), 7.22 (1 H, d, J = 8.6 Hz), 7.29 (1 H, d, J = 8. 4 Hz), 7. 39 (1H, s).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 555.8 [M + H] ⁺ (ESI positive ion mode)

Example 231
(1r, 4r) -4-{[8- (4-t-butylbenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- Preparation of [(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 231) Substantially except that 4-t-butylbenzyl bromide (commercially available) was used instead of 3- (bromomethyl) pyridine hydrobromide Specifically, the reaction was carried out in the same manner as in Example 4 to obtain the title compound (26.3 mg, yield 61%) as a pale yellow powder.

LC / MS [Condition 1]: retention time 3.34 minutes; m / z 525.9 [M + H] ⁺ (ESI positive ion mode), m / z 560.1 [M + Cl] ⁻ , 570.2 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 232
(1r, 4r) -4-{[8- (4-Fluorophenethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 232) Substantially examples except using 4-fluorophenethyl bromide (commercially available) instead of 3- (bromomethyl) pyridine hydrobromide The reaction was carried out in the same manner as in Example 4 to obtain the title compound (13.6 mg, yield 54%) as a pale yellow oil.

LC / MS [Condition 1]: retention time 3.12 minutes; m / z 502.0 [M + H] ⁺ (ESI positive ion mode), m / z 536.2 [M + Cl] ⁻ , 546.2 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 233
(1r, 4r) -4-{[8- (4-Fluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-[( Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 233)

The reaction was conducted in substantially the same manner as in Example 4 except that 4-fluorobenzylbromide (commercially available) was used instead of 3- (bromomethyl) pyridine hydrobromide to give the title compound (14.6 mg, yield). 60%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 13.1 Hz), 1.39-1.67 (4H, m), 1.67-1. 83 (4H, m), 1.83-2.09 (8H, m), 2.40-2.70 (4H, br m), 3.08 (2H, d, J = 7.8 Hz), 3 .10 (1H, ddd, J = 13.9, 7.6, 4.5 Hz), 3.24 (2H, s), 3.49 (2H, s), 3.58 (1H, ddd, J = 13.9, 6.5, 3.3 Hz), 3.74 (1H, dt, J = 8.2, 6.5 Hz), 3.85 (1H, dt, J = 8.2, 6.5 Hz) 3.93 (1H, dq, J = 3.3, 7.1 Hz), 5.79 (1H, br t, J = 5.3 Hz), 6.99 (2H, t, J = 8.6 Hz) , 7.27 (4 H, dd, J = 8.6, 4.8 Hz).

LC / MS [Condition 1]: Retention time 1.26 minutes; m / z 487.9 [M + H] ⁺ (ESI positive ion mode)

Example 234
(1r, 4r) -4-({8- [4- (methylthio) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- Preparation of [(Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 234) Substantially except that 4- (methylthio) benzyl bromide (commercially available) was used instead of 3- (bromomethyl) pyridine hydrobromide Specifically, the reaction was carried out in the same manner as in Example 4 to obtain the title compound (16.1 mg, yield 62%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, br q, J = 12.2 Hz), 1.38-2.11 (16H, m), 2.43-2.71 (4H , Br m), 2.48 (3H, s), 3.08 (2H, d, J = 6.9 Hz), 3.11 (2H, ddd, J = 13.5, 7.5, 4.6 Hz) ), 3.24 (2H, s), 3.49 (2H, s), 3.58 (1H, ddd, J = 13.5, 6.8, 3.3 Hz), 3.74 (1H, dt) , J = 8.3, 6.6 Hz), 3.85 (1H, dt, J = 8.3, 6.6 Hz), 3.94 (1H, dq, J = 3.3, 6.9 Hz), 5.81 (1H, br t, J = 4.6 Hz), 7.22 (4H, s).

LC / MS [Condition 1]: retention time 2.96 min; m / z 516.0 [M + H] ⁺ (ESI positive ion mode), m / z 514.1 [MH] ⁻ (ESI negative ion mode) 550. 3 [M + Cl] ⁻ (ESI negative ion mode)

Example 235
(1r, 4r) -4-({8- [3,5-bis (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 235)

(1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N-[(tetrahydrofuran) obtained in Example 3 -2-yl) methyl] cyclohexanecarboxamide monohydrochloride (20.8 mg, 0.05 mmol) was dissolved in a mixed solvent of methanol / acetic acid (10/1) (2.0 mL) and 3,5-bis at room temperature. (Trifluoromethyl) benzaldehyde (commercially available) (11.5 μL, 0.07 mmol) and borane-2-picoline complex (purchased from Junsei Kagaku) (7.5 mg, 0.07 mmol) were added, and the mixture was stirred at room temperature for 1 day. It was. After completion of the reaction, the reaction solution was distilled off under reduced pressure, and the resulting reaction residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / methanol = 20/1] ( 1r, 4r) -4-({8- [3,5-bis (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) -N-[(Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (23.3 mg, 77% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.0, 12.6 Hz), 1.36-1.69 (4H, m), 1.69-2. 15 (12H, m), 2.53-2.68 (4H, br m), 3.10 (2H, d, J = 7.3 Hz), 3.11 (1H, ddd, J = 13.9, 7.3, 4.6 Hz), 3.27 (2H, s), 3.58 (1 H, ddd, J = 13.9, 6.9, 3.3 Hz), 3.63 (2H, s), 3.75 (1H, dt, J = 8.3, 6.8 Hz), 3.85 (1H, dt, J = 8.3, 6.6 Hz), 3.94 (1H, dq, J = 3. 3, 7.1 Hz), 5.82 (1 H, br t, J = 5.6 Hz), 7.78 (1 H, br s), 7.80 (2 H, br s).

LC / MS [condition 1]: retention time 3.60 minutes; m / z 606.0 [M + H] ⁺ (ESI positive ion mode), m / z 640.2 [M + Cl] ⁻ , 650.2 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 236
(1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 236) Instead of 3,5-bis (trifluoromethyl) benzaldehyde, 6- (trifluoromethyl) The reaction was carried out substantially in the same manner as in Example 235 except that pyridine-3-pyridinecarboxaldehyde (commercially available) was used to obtain the title compound (11.7 mg, yield 43%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.7, 12.8 Hz), 1.39-1.65 (4H, m), 1.69-1. 84 (4H, m), 1.84-2.12 (8H, m), 2.46-2.70 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3 .11 (1H, ddd, J = 13.9, 7.4, 4.5 Hz), 3.26 (2H, s), 3.58 (1H, ddd, J = 13.9, 6.5, 3 .3 Hz), 3.61 (2H, s), 3.74 (1 H, dt, J = 8.2, 6.5 Hz), 3.85 (1 H, dt, J = 8.2, 6.5 Hz) 3.94 (1H, dq, J = 3.3, 7.1 Hz), 5.80 (1H, br t, J = 5.3 Hz), 7.65 (1H, d, J = 7.8 Hz) , 7.85 (1 H, br d, J = 7.8 Hz), 8.68 (1H, s).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 538.9 [M + H] ⁺ (ESI positive ion mode), m / z 573.1 [M + Cl] ⁻ , 583.2 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 237
Preparation of 3- [4- (4-benzoylpiperidine-1-carbonyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 2-oxo-3-[(( 1r, 4r) -4-{[(Tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3,8-diazaspiro [4.5] decan-8-carboxylate instead of t-butyl 3- [4- (4-benzoylpiperidine-1-carbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone obtained in Example 158 The reaction was carried out substantially in the same manner as in Example 3 except for using t-butyl acid to obtain the title compound (1.1 g, quantitative) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.70-2.14 (6H, m), 2.25 (2H, t, J = 9.8 Hz), 2.92-4.02 (10H, m), 4.44 (2H, s), 4.67 (1H, br s), 7.30 (2H, d, J = 7.4 Hz), 7.36-7.54 (4H, m), 7.59 (1H, t, J = 7.4 Hz), 7.94 (2H, d, J = 7.0 Hz), 9.70 (1H, s).
LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 461.9 [M + H] ⁺ (ESI positive ion mode)

Example 237
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (4-nitro-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane-2- Preparation of ON (Compound No. 237) 3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -1-oxa-3,8-diaza-spiro [4.5] obtained in Reference Example 237 Decan-2-one hydrochloride (24.9 mg, 0.05 mmol) was dissolved in N, N-dimethylformamide (1.0 mL) and 4-nitrobenzyl bromide (commercially available) (15.1 mg, 0.1 mL) at room temperature. 07 mmol) and triethylamine (20.9 μL, 0.15 mmol) were added, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, ethyl acetate was added, washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate / methanol = 20/1], and 3- [4- (4-benzoyl-piperidine-1] was obtained. -Carbonyl) -benzyl] -8- (4-nitro-benzyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one (20.4 mg, 68% yield) as a pale yellow oil Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-2.17 (8H, m), 2.40-2.66 (4H, br m), 2.95-3.29 (2H, br m), 3.14 (2H, s), 3.48-3.62 (1H, m), 3.60 (2H, s), 3.65-4.07 (1H, br m), 4. 44 (2H, s), 4.49-4.85 (1H, br m), 7.30 (2H, d, J = 8.0 Hz), 7.41 (2H, d, J = 8.0 Hz) , 7.49 (2H, t, J = 8.0 Hz), 7.49 (2H, d, J = 8.6 Hz), 7.59 (1H, tt, J = 7.4, 1.2 Hz), 7.94 (2H, d, J = 8.0 Hz), 8.17 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 597.1 [M + H] ⁺ (ESI positive ion mode), m / z 595.4 [MH] ⁻ , 631.3 [M + Cl] ⁻ (ESI negative ion mode)

Example 238
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (4-trifluoromethoxy-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane- Preparation of 2-one (Compound No. 238) The reaction was carried out in substantially the same manner as in Example 237 except that 4- (trifluoromethoxy) benzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide. The title compound (27.8 mg, 87% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-2.13 (8H, m), 2.38-2.63 (4H, br m), 2.95-3.25 (2H, br m), 3.12 (2H, s), 3.49 (2H, s), 3.49-3.61 (1H, m), 3.65-4.05 (1H, br m), 4. 44 (2H, s), 4.47-4.83 (1H, br m), 7.14 (2H, d, J = 7.8 Hz), 7.30 (2H, d, J = 8.2 Hz) , 7.32 (2H, d, J = 7.8 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.48 (1H, t, J = 7.8 Hz), 7.58 ( 1H, tt, J = 7.4, 1.2 Hz), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.50 min; m / z 636.2 [M + H] ⁺ (ESI positive ion mode), m / z 670.2 [M + Cl] ⁻ , 680.3 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 239
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (4-bromo-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane-2- Preparation of ON (Compound No. 239) The reaction was conducted in substantially the same manner as in Example 237 except that 4-bromobenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide to give the title compound (149.8 mg Yield 95%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-2.18 (8H, m), 2.36-2.61 (4H, br m), 2.94-3.27 (2H, br m), 3.12 (2H, s), 3.45 (2H, s), 3.48-3.63 (1H, m), 3.64-4.05 (1H, br m), 4. 44 (2H, br s), 4.48-4.92 (1H, br m), 7.17 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.2 Hz) ), 7.41 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.4 Hz), 7.49 (2H, t, J = 7.8 Hz), 7.59 (1H, tt, J = 7.4, 1.6 Hz), 7.94 (2H, d, J = 8.2 Hz).
LC / MS [Condition 1]: Retention time 3.40 minutes; m / z 630.1 [M + H] ⁺ (ESI positive ion mode), m / z 664.3 [M + Cl] ⁻ (ESI negative ion mode)

Example 240
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (4-chloro-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane-2- Preparation of ON (Compound No. 240) The reaction was conducted in substantially the same manner as in Example 237 except that 4-chlorobenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide to give the title compound (9.5 mg Yield 31%) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-2.20 (8H, m), 2.37-2.65 (4H, br m), 2.97-3.29 (2H, br m), 3.12 (2H, s), 3.46 (2H, s), 3.48-3.65 (1H, m), 3.65-4.07 (1H, br m), 4. 44 (2H, s), 4.46-4.84 (1H, br m), 7.22 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz) 7.30 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 ( 1H, tt, J = 7.4, 1.6 Hz), 7.94 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 586.1 [M + H] ⁺ (ESI positive ion mode), m / z 620.2 [M + Cl] ⁻ (ESI negative ion mode), m / z 630 .3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 241
2- {3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] dec-8-ylmethyl}- Preparation of benzonitrile (Compound No. 241) The reaction was conducted in substantially the same manner as in Example 237 except that 2-cyanobenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide to give the title compound (26. 5 mg, 92% yield) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-2.17 (8H, m), 2.44-2.72 (4H, m), 2.95-3.26 (2H, br m ), 3.13 (2H, s), 3.46-3.63 (1H, m), 3.67-4.12 (1H, br m), 3.69 (2H, s), 4.44 (2H, s), 4.47-4.88 (1H, br m), 7.30 (2H, d, J = 8.2 Hz), 7.35 (1H, dt, J = 1.2, 7 .8 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.44-7.61 (5H, m), 7.63 (1H, d, J = 7.8 Hz), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.28 minutes; m / z 576.7 [M + H] ⁺ (ESI positive ion mode)

Example 242
3- {3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] dec-8-ylmethyl}- Preparation of benzonitrile (Compound No. 242) The reaction was conducted in substantially the same manner as in Example 237 except that 3-cyanobenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide to give the title compound (21. 3 mg, 74% yield) was obtained as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-2.17 (8H, m), 2.40-2.65 (4H, br m), 2.96-3.30 (2H, br m), 3.13 (2H, s), 3.47-3.62 (1H, m), 3.53 (2H, s), 3.63-4.05 (1H, br m), 4. 45 (2H, s), 4.51-4.87 (1H, br m), 7.30 (2H, d, J = 8.2 Hz), 7.40 (1H, t, J = 7.4 Hz) , 7.41 (2H, d, J = 8.2 Hz), 7.48 (2H, t, J = 7.4 Hz), 7.50-7.57 (2H, m), 7.59 (1H, tt, J = 7.4, 1.2 Hz), 7.64 (1H, brs), 7.94 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.28 min; m / z 577.1 [M + H] ⁺ (ESI positive ion mode), m / z 611.3 [M + Cl] ⁻ , 621.4 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 243
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] decane-8-thiocarboxylic acid (4-cyano -Phenyl) -amide (Compound No. 243) The reaction was conducted in substantially the same manner as in Example 237 except that 4-cyanophenyl isothiocyanate (commercially available) was used instead of 4-nitrobenzyl bromide. The compound (27.2 mg, 87% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74-2.11 (8H, m), 2.95-3.26 (2H, br m), 3.18 (2H, s), 3. 54 (2H, t, J = 11.9 Hz), 3.55-3.63 (1H, m), 3.64-3.99 (1H, br m), 4.46 (2H, s), 4 .48 (1H, br d, J = 14.3 Hz), 4.54-4.78 (1 H, br m), 7.30 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.5 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.56 (2H, d, J = 8) .5 Hz), 7.60 (1H, tt, J = 7.0, 1.2 Hz), 7.94 (2H, d, J = 8.2 Hz), 7.97 (1H, br s).

LC / MS [Condition 1]: Retention time 4.33 minutes; m / z 622.2 [M + H] ⁺ (ESI positive ion mode), m / z 620.3 [M−H] ⁻ , 656.2 [M + Cl] ⁻ (ESI negative ion mode)

Example 244
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] decane-8-carboxylic acid (4-cyano -Phenyl) -amide (Compound No. 244) The title compound was reacted in substantially the same manner as in Example 237 except that 4-cyanophenyl isocyanate (commercially available) was used instead of 4-nitrobenzyl bromide. (27.4 mg, 90% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65-2.14 (8H, m), 2.93-3.28 (2H, br m), 3.16 (2H, s), 3. 36 (2H, t, J = 12.7 Hz), 3.50-3.65 (1H, m), 3.69-3.95 (1H, br m), 3.92 (2H, br d, J = 13.9 Hz), 4.45 (2H, s), 4.48-4.80 (1 H, br m), 7.30 (2 H, d, J = 8.2 Hz), 7.34 (1 H, br s), 7.40 (2H, d, J = 8.2 Hz), 7.49 (2H, t, J = 7.8 Hz), 7.50 (4H, s), 7.59 (1H, tt) , J = 7.8, 1.2 Hz), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.03 min; m / z 606.1 [M + H] ⁺ (ESI positive ion mode), m / z 604.2 [M−H] ⁻ , 640.2 [M + Cl] ⁻ (ESI negative ion mode)

Example 245
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] decane-8-carboxylic acid (3-cyano -Phenyl) -amide (Compound No. 245) The title compound was reacted in substantially the same manner as in Example 237 except that 3-cyanophenyl isocyanate (commercially available) was used instead of 4-nitrobenzyl bromide. (38.1 mg, 100% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-2.11 (8H, m), 2.98-3.30 (2H, br m), 3.16 (2H, s), 3. 36 (2H, br t, J = 12.7 Hz), 3.49-3.65 (1H, m), 3.73-4.05 (1H, br m), 3.90 (2H, br d, J = 13.9 Hz), 4.46 (2H, s), 4.51-4.81 (1H, br m), 7.18 (1 H, br s), 7.26 (1 H, ddd, J = 7.4, 1.6, 1.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.34 (1H, t, J = 7.8 Hz), 7.41 (2H, d , J = 8.2 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, tt, J = 7.4, 1.2 Hz), 7.63 (2H, ddd, J = .8,2.0,1.2Hz), 7.70 (1H, t, J = 1.6Hz), 7.94 (2H, d, J = 8.2Hz).

LC / MS [Condition 1]: Retention time 4.01 min; m / z 606.2 [M + H] ⁺ (ESI positive ion mode), m / z 604.2 [MH] ⁻ (ESI negative ion mode)

Example 246
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (2,5-dimethoxy-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane- Preparation of 2-one (Compound No. 246) The title compound was prepared by carrying out the reaction substantially in the same manner as in Example 237 except that 2,5-dimethoxybenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide. (7.7 mg, 25% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.67-2.06 (8H, m), 2.41-2.72 (4H, m), 2.97-3.25 (2H, br m ), 3.12 (2H, s), 3.48-3.63 (1H, m), 3.54 (1H, s), 3.71-3.99 (1H, br m), 3.77. (6H, s), 4.44 (2H, s), 4.51-4.84 (1H, br m), 6.74 (1H, dd, J = 9.0, 2.9 Hz), 6. 78 (1H, d, J = 9.0 Hz), 6.93 (1H, d, J = 2.9 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.41 (2H, d , J = 8.2 Hz), 7.48 (2H, t, J = 8.2 Hz), 7.58 (1H, tt, J = 7.4, 1.2 Hz), 7.94 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.01 min; m / z 606.2 [M + H] ⁺ (ESI positive ion mode), m / z 604.2 [MH] ⁻ (ESI negative ion mode)

Example 247
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (2-trifluoromethyl-benzyl) -1-oxa-3,8-diaza-spiro [4.5] decane- Preparation of 2-one (Compound No. 247) The title compound was reacted in substantially the same manner as in Example 237 except that 2-trifluoromethylbenzyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide. (20.5 mg, 66% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.70-2.13 (8H, m), 2.40-2.55 (2H, br m), 2.63 (2H, br t, J = 9.0 Hz), 3.01-3.35 (2H, br m), 3.15 (2H, s), 3.47-3.64 (1H, m), 3.65-4.07 (1H , Br m), 3.66 (2H, s), 4.45 (2H, s), 4.47-4.90 (1H, br m), 7.27-7.37 (3H, m), 7.41 (2H, d, J = 8.2 Hz), 7.44-7.54 (3H, m), 7.59 (1H, tt, J = 7.4, 1.6 Hz), 7.61 (1H, br d, J = 7.8 Hz), 7.73 (2H, br d, J = 8.2 Hz), 7.94 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.40 minutes; m / z 620.2 [M + H] ⁺ (ESI positive ion mode), m / z 654.1 [M + Cl] ⁻ , 664.3 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 248
3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- [2- (4-trifluoromethyl-phenyl) -ethyl] -1-oxa-3,8-diaza-spiro [ 4.5] Preparation of decan-2-one (Compound No. 248) Reaction substantially in the same manner as in Example 237, except that 4-trifluoromethylphenethyl bromide (commercially available) was used instead of 4-nitrobenzyl bromide. To give the title compound (20.5 mg, 65% yield) as a pale yellow oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.71-2.11 (6H, br m), 2.13-2.39 (2H, br m), 2.82-3.02 (4H, br m), 3.02-3.25 (6H, br m), 3.22 (2H, s), 3.57 (1H, tt, J = 9.8, 4.1 Hz), 3.65- 4.05 (1H, brm), 4.45 (2H, s), 4.49-4.87 (1H, brm), 7.31 (2H, d, J = 8.2 Hz), 7. 35 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.56 (2H, d , J = 8.2 Hz), 7.59 (1H, tt, J = 7.4, 1.2 Hz), 7.95 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.34 minutes; m / z 634.3 [M + H] ⁺ (ESI positive ion mode), m / z 668.4 [M + Cl] ⁻ , 678.4 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 249
8- (4-Acetyl-benzyl) -3- [4- (4-benzoyl-piperidine-1-carbonyl) -benzyl] -1-oxa-3,8-diaza-spiro [4.5] decane-2- Preparation of ON (Compound No. 249) 3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -8- (4-bromo-benzyl) -1-oxa- obtained in Example 239 3,8-diazaspiro [4.5] decan-2-one (102.3 mg, 0.2 mmol) was dissolved in tetrahydrofuran (2.0 mL) and tributyl (1-ethoxyvinyl) tin (from Aldrich) at room temperature. Purchase) (135.1 μL, 0.4 mmol) and bis (triphenylphosphine) palladium (II) chloride (7.9 mg, 0.01 mmol) were added, and the mixture was heated under reflux for 15 And the mixture was stirred between. After cooling, 0.1 M hydrochloric acid (2.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, ethyl acetate was added, washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: ethyl acetate → ethyl acetate / methanol = 20/1], and 8- (4-acetyl-benzyl)- 3- [4- (4-Benzoyl-piperidine-1-carbonyl) -benzyl] -1-oxa-3,8-diaza-spiro [4.5] decan-2-one (28.3 mg, 24% yield) ) Was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-2.21 (8H, m), 2.35-2.65 (4H, br m), 2.58 (3H, s), 2. 93-3.28 (2H, br m), 3.13 (2H, s), 3.49-3.61 (1H, m), 3.56 (2H, s), 3.70-4.04 (1H, br m), 4.44 (2H, s), 4.49-4.86 (1 H, br m), 7.30 (2H, d, J = 7.8 Hz), 7.40 (2H , D, J = 8.2 Hz), 7.41 (2H, d, J = 7.8 Hz), 7.49 (2H, t, J = 7.8 Hz), 7.59 (1H, tt, J = 7.4, 1.4 Hz), 7.90 (2H, d, J = 8.2 Hz), 7.94 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 594.1 [M + H] ⁺ (ESI positive ion mode), m / z 592.1 [M−H] ⁻ , 628.2 [M + Cl] ⁻ , 638.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 250
3- {4-[(Benzo [1.3] dioxol-5-ylmethyl) -carbamoyl] -benzyl} -2-oxo-1-oxa-3,8-diaza-spiro [4.5] decane-8- Preparation of t-butyl carboxylate (Compound No. 250) The reaction was conducted in substantially the same manner as in Example 158 except that piperonylamine was used instead of 4-benzoylpiperidine hydrochloride to give the title compound (905.2 mg, yield). 70%) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.43 (9H, s), 1.52-1.66 (2H, m), 1.83 (2H, br d, J = 13.9 Hz), 3.10 (2H, s), 3.26 (2H, ddd, J = 13.9, 11.5, 2.5 Hz), 3.78 (2H, br d, J = 13.5 Hz), 4. 45 (2H, s), 4.54 (2H, d, J = 5.7 Hz), 5.94 (2H, s), 6.42 (1H, br s), 6.77 (1H, d, J = 7.8 Hz), 6.81 (1H, dd, J = 7.8, 1.6 Hz), 6.84 (1H, d, J = 1.6 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.77 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.10 minutes; m / z 424.1 [M-isobutene-CO2 + H] ⁺ , 468.1 [M-isobutene + H] ⁺ , 524.2 [M + H] ⁺ (ESI positive ion Mode), m / z 522.2 [M−H] ⁻ , 568.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 251
3- (4- {4- [Hydroxy (phenyl) methyl] piperidine-1-carbonyl} benzyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-2-one (Compound No. 251) 3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl obtained in Example 55 ] -1-Oxa-3,8-diazaspiro [4.5] decan-2-one (20 mg, 0.032 mmol) in methanol (1.0 mL) in sodium borohydride (2.0 mg, 0.048 mmol) After stirring at room temperature for 30 minutes, acetic acid (5 μL, 0.09 mmol) was added, and the mixture was concentrated to dryness under reduced pressure. Water (1 mL) and ethyl acetate (2 mL) were added to the residue, the organic layer was separated and concentrated to dryness under reduced pressure to give the title compound (18 mg, yield 90%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.10-1.52 (3H, br m), 1.72 (2H, ddd, J = 13.9, 7.8, 6.1 Hz), 1 80-2.21 (5H, br m), 2.42-2.60 (4H, br m), 2.60-2.82 (1H, br m), 2.82-3.07 (1H , Br m), 3.11 (2H, s), 3.55 (2H, s), 3.55-3.90 (1H, br m), 4.36-4.52 (3H, m), 4.52-4.92 (1H, br m), 7.24-7.40 (9H, m), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.66 minutes; m / z 622.0 [M + H] ⁺ (ESI positive ion mode), m / z 666.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 252
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone Preparation of t-butyl acid (Compound No. 252) (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3, obtained in Reference Example 2-3 8-Diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (1.63 g, 4.11 mmol), 1-hydroxybenzotriazole (0.17 g, 1.2 mmol) and 4-benzoylpiperidine hydrochloride (Commercially available) (1.0 g, 4.5 mmol) in chloroform (50 mL) was added to triethylamine (1.1 mL, 82 mmol) and 1-ethyl-3- (3-di It added Chill aminopropyl) carbodiimide hydrochloride (1.2 g, 6.2 mmol), then was allowed to stand 2 days at room temperature, add water (50 mL) 2 hours stirring vigorously. The organic layer was separated, washed with a solution of citric acid (0.80 g) in water (50 mL), and concentrated to dryness under reduced pressure to give the title compound (2.5 g, quantitative yield) as a colorless amorphous product. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, br q, J = 12.7 Hz), 1.46 (9H, s), 1.49-1.99 (15H, m), 2.47 (1H, tt, J = 11.9, 2.9 Hz), 2.82 (1H, br t, J = 12.7 Hz), 3.12 (2H, d, J = 7.4 Hz), 3.21 (1H, br t, J = 13.1 Hz), 3.26 (2H, s), 3.28 (2H, br t, J = 13.0 Hz), 3.51 (1 H, tt, J = 10.6, 4.1 Hz), 3.85 (2H, br d, J = 13.0 Hz), 3.98 (1 H, br d, J = 13.5 Hz), 4.59 (1 H, br d , J = 13.1 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.94 (2H, , J = 7.4Hz).

LC / MS [Condition 1]: Retention time 4.47 minutes; m / z 590.1 [M + Na] ⁺ (ESI positive ion mode), m / z 612.4 [M + HCOO] ⁻ (ESI negative ion mode)

Example 253
3- [4- (4-Benzylpiperidine-1-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Preparation of (Compound No. 253) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 21 Decan-3-yl} methyl) benzoic acid (22 mg, 0.049 mmol), 1-hydroxybenzotriazole (2 mg, 0.01 mmol) and 4-benzylpiperidine (commercially available) (11 μL, 0.064 mmol) in chloroform (1 mL) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (14 mg, 0.074 mmol) was added and dissolved at room temperature for 7 days. After standing, water was added (2 mL) solution of citric acid (3 mg). The organic layer was separated and concentrated to dryness under reduced pressure to give the title compound (33 mg, quantitative yield) as a light orange amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02-1.42 (2H, br m), 1.63-1.87 (5H, m), 1.91 (2H, br d, J = 13.5 Hz), 2.44-2.64 (4 H, br m), 2.54 (2 H, d, J = 7.4 Hz), 2.60-2.85 (1 H, br m), 2. 80-3.05 (1H, br m), 3.12 (2H, s), 3.53-3.83 (1H, br m), 3.56 (2H, s), 4.43 (2H, s), 4.52-4.84 (1H, br m), 7.13 (2H, dd, J = 7.4, 1.6 Hz), 7.20 (1H, tt, J = 7.4) 1.6 Hz), 7.25-7.34 (4 H, m), 7.37 (2 H, d, J = 7.8 Hz), 7.42 (2 H, d, J = 8.2 Hz), 7. 56 (2H, , J = 8.2Hz).

LC / MS [Condition 1]: Retention time 3.52 minutes; m / z 606.2 [M + H] ⁺ (ESI positive ion mode), m / z 650.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 254
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamido] piperidine- Preparation of ethyl 1-carboxylate (Compound No. 254) The reaction was carried out in substantially the same manner as in Example 253, except that ethyl 4-aminopiperidine-1-carboxylate (commercially available) was used instead of 4-benzylpiperidine. To give the title compound (29 mg, quantitative yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.4 Hz), 1.43 (2H, dq, J = 4.1, 11.5 Hz), 1.71 ( 2H, ddd, J = 14.3, 8.2, 6.1 Hz), 1.90 (2H, br d, J = 12.7 Hz), 2.05 (2H, br d, J = 12.7 Hz) , 2.42-2.64 (4H, br m), 2.96 (2H, br t, J = 12.7 Hz), 3.11 (2H, s), 3.55 (2H, s), 4 .01-4.29 (3H, br m), 4.14 (2H, q, J = 7.4 Hz), 4.46 (2H, s), 5.96 (1H, br d, J = 7. 8 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7. 4 (2H, d, J = 8.2Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 603.2 [M + H] ⁺ (ESI positive ion mode), m / z 601.3 [MH] ⁻ (ESI negative ion mode)

Reference Example 255
3-{[(1r, 4r) -4- (4-Benzoylpiperidin-1-carbonyl) cyclohexyl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 2-oxo-3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3,8-diazaspiro [4.5] decane- 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1 obtained in Example 252 instead of t-butyl 8-carboxylate The title compound (20 g, quantitative) was prepared by carrying out the reaction in substantially the same manner as in Example 3 except that t-butyl oxa-3,8-diazaspiro [4.5] decane-8-carboxylate was used. It was obtained as a white powder.

¹ H-NMR (CD ₃ OD) δ: 1.10 (2H, q, J = 11.2 Hz), 1.36-2.22 (15H, m), 2.68 (1H, t, J = 11) .2 Hz), 2.88 (1 H, t, J = 13.2 Hz), 3.11 (2 H, d, J = 8.1 Hz), 3.28-3.38 (1 H, m), 3.48 (2H, s), 3.67-3.80 (1H, m), 4.11 (1H, d, J = 11.9 Hz), 4.53 (1H, d, J = 13.9 Hz), 7 .52 (1H, t, J = 7.9 Hz), 7.62 (1H, t, J = 7.9 Hz), 8.01 (2H, d, J = 7.9 Hz).

LC / MS [Condition 1]: Retention time 2.82 minutes; m / z 467.9 [M + H] ⁺ (ESI positive ion mode), m / z 502.1 [M + Cl] ⁻ (ESI negative ion mode)

Example 255
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [2,4-bis (trifluoromethyl) benzyl] -1-oxa-3,8 Preparation of diazaspiro [4.5] decan-2-one (Compound No. 255) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3 3-{[(1r, 4r) -4- (4-benzoyl) obtained in Reference Example 255 instead of -yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride Using piperidine-1-carbonyl) cyclohexyl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride and 3- (bromomethyl) pyridine bromide The reaction was conducted in substantially the same manner as in Example 4 except that 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene (commercially available) was used instead of the acid salt to give the title compound (14 mg Yield 25%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 12.7 Hz), 1.44 to 2.02 (15H, m), 2.47 (1H, t, J = 11.1. 9 Hz), 2.50-2.71 (4 H, br m), 2.82 (1 H, t, J = 11.5 Hz), 3.11 (2 H, d, J = 6.5 Hz), 3.20 (1H, t, J = 13.0 Hz), 3.28 (2H, s), 3.43-3.59 (1H, m), 3.73 (2H, s), 3.98 (1H, d , J = 13.1 Hz), 4.60 (1H, d, J = 12.7 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7. 4 Hz), 7.78 (1 H, d, J = 7.8 Hz), 7.88 (1 H, br s), 7.94 (2 H, d, J = 7.4 Hz), 7.97 (1 H, d , J = 7.8H z).

LC / MS [Condition 1]: Retention time 4.01 min; m / z 694.0 [M + H] ⁺ (ESI positive ion mode), m / z 738.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 256
4-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] -3-fluorobenzonitrile (Compound No. 256) 4- (Bromomethyl) -3-fluoro instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene The reaction was carried out substantially in the same manner as in Example 255 except that benzonitrile (commercially available) was used, and the title compound (23 mg, yield 55%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.39-2.02 (15H, m), 2.47 (1H, t, J = 10. 9 Hz), 2.54-2.69 (4H, br m), 2.81 (1H, t, J = 12.5 Hz), 3.11 (2H, d, J = 5.9 Hz), 3.20 (1H, t, J = 12.2 Hz), 3.26 (2H, s), 3.45-3.58 (1H, m), 3.64 (2H, s), 3.98 (1H, d , J = 11.9 Hz), 4.60 (1H, d, J = 12.9 Hz), 7.34 (1H, d, J = 9.2 Hz), 7.44 (1H, d, J = 9. 2 Hz), 7.49 (2H, t, J = 7.3 Hz), 7.51-7.58 (1H, m), 7.59 (1H, t, J = 7.3 Hz), 7.95 ( 2H, d, J = 7 3Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 601.0 [M + H] ⁺ (ESI positive ion mode), m / z 645.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 257
3-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of —8-yl) methyl] benzonitrile (Compound No. 257) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} obtained in Reference Example 255 To a suspension of -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (16 mg, 0.032 mmol) in N, N-dimethylformamide (0.50 mL) triethylamine (11 μL, 0 0.079 mmol) and 3- (bromomethyl) benzonitrile (commercially available) (7 mg, 0.035 mmol) were added. After standing at room temperature for 2 days, water (0.5 mL) was added. The resulting solid was collected by filtration to give the title compound (17 mg, yield 94%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 4.1, 12.3 Hz), 1.49-1.71 (4H, br m), 1.71-1 .87 (7H, br m), 1.87-2.01 (4H, br m), 2.47 (1H, tt, J = 11.5, 2.9 Hz), 2.49-2.65 ( 4H, m), 2.82 (1H, br t, J = 11.5 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.21 (1H, br t, J = 13.9 Hz) ), 3.27 (2H, s), 3.51 (1H, tt, J = 10.6, 3.7 Hz), 3.55 (2H, s), 3.98 (1H, br d, J = 12.7 Hz), 4.59 (1 H, br d, J = 13.1 Hz), 7.36-7.63 (6 H, m), 7.66 (1 H, br s), 7.94 ( 2H, d, J = 7.8 Hz).

LC / MS [Condition 2]: retention time 3.58 min; m / z 583.6 [M + H] ⁺ (ESI positive ion mode), m / z 627.6 [M + HCOO] ⁻ (ESI negative ion mode)

Example 258
2-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of —8-yl) methyl] benzonitrile (Compound No. 258) Substantially the same as Example 257, except that 2- (bromomethyl) benzonitrile (commercially available) was used instead of 3- (bromomethyl) benzonitrile. The title compound (19 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 4.1, 11.9 Hz), 1.48-1.70 (4H, br m), 1.70-1 .87 (7H, br m), 1.87-2.01 (4H, br m), 2.46 (1H, tt, J = 11.5, 2.9 Hz), 2.54-2.74 ( 4H, br m), 2.82 (1H, br t, J = 11.9 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.20 (1H, br t, J = 1.11. 9 Hz), 3.26 (2 H, s), 3.51 (1 H, tt, J = 10.2, 3.7 Hz), 3.72 (2 H, s), 3.97 (1 H, br d, J = 14.3 Hz), 4.59 (1H, br d, J = 13.9 Hz), 7.36 (1H, dt, J = 1.2, 7.4 Hz), 7.41-7.6. 2 (5H, m), 7.65 (1H, d, J = 7.8 Hz), 7.94 (2H, d, J = 8.6 Hz).

LC / MS [Condition 2]: retention time 3.56 min; m / z 583.6 [M + H] ⁺ (ESI positive ion mode), m / z 627.6 [M + HCOO] ⁻ (ESI negative ion mode)

Example 259
4- {3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] ureido } Production of ethyl piperidine-1-carboxylate (Compound No. 259) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 obtained in Reference Example 21 -Diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (100 mg, 0.22 mmol) in chloroform (2 mL) was added triethylamine (62 μL, 0.45 mmol) and diphenylphosphoryl azide (72 μL, 0.33 mmol). ) And allowed to stand at room temperature for 18 hours, and then water (2 mL) was added to separate the organic layer. The organic layer was concentrated under reduced pressure to 1/3 volume, toluene (2 mL) was added and stirred at 110 ° C. for 2 hours, and then ethyl 4-aminopiperidine-1-carboxylate (commercially available) (57 μL, 0. 33 mmol) was added and allowed to cool to room temperature. After adding water (2 mL) to the reaction mixture, the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / 2-propanol = 10/1] to obtain the title compound (64 mg, yield 47%) as a white solid. It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.31 (2H, dq, J = 4.1, 11.5 Hz), 1.71 ( 2H, dt, J = 13.5, 7.4 Hz), 1.83 to 2.04 (4H, br m), 2.41-2.61 (4H, br m), 2.95 (2H, br t, J = 12.3 Hz), 3.15 (2H, s), 3.54 (2H, s), 3.77-3.95 (1H, m), 3.98-4.13 (2H, br m), 4.12 (2H, q, J = 7.0 Hz), 4.35 (2H, s), 4.89 (1H, br d, J = 7.8 Hz), 6.72 (1H, br s), 7.15 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7 .56 2H, d, J = 8.2Hz).

LC / MS [condition 2]: retention time 3.52 minutes; m / z 618.5 [M + H] ⁺ (ESI positive ion mode), m / z 616.6 [MH] ⁻ (ESI negative ion mode)

Reference Example 260-1
Preparation of 2- (4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} phenyl) acetic acid Reference Example 111 -1,2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (20 mg, 0.078 mmol), N, N-dimethylformamide (0 .60 mL) solution was added sodium t-butoxide (19 mg, 0.20 mmol) and stirred at room temperature for 30 minutes. 2- {4- (Bromomethyl) phenyl} acetic acid (commercially available) (18 mg, 0.078 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 days, and then water (2 mL), 1M hydrochloric acid (0.12 mL) and ethyl acetate were added. (2 mL) was added and the organic layer was separated. A solution of sodium bicarbonate (33 mg) in water (2.4 mL) was added to the organic layer, and the aqueous layer was separated. After adding 1M hydrochloric acid (0.50 mL) and ethyl acetate (3 mL) to the aqueous layer, the organic layer was separated and concentrated to dryness under reduced pressure to give the title compound (24 mg, 75% yield) as colorless amorphous. Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 (9H, s), 1.59 (2H, ddd, J = 13.1, 10.2, 4.9 Hz), 1.85 (2H, brd, J = 13.1 Hz), 3.12 (2H, s), 3.28 (2H, br t, J = 11.9 Hz), 3.65 (2H, s), 3.79 (2H, br d, J = 11.9 Hz), 4.41 (2H, s), 7.22 (2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.2 Hz).

LC / MS [Condition 2]: Retention time 4.02 min; m / z 427.3 [M + Na] ⁺ , 349.3 [M-isobutene + H] ⁺ , 305.3 [M-isobutene-CO2 + H] ⁺ (ESI positive ion mode)

Reference Example 260-2
2-Oxo-3- (4- {2-oxo-2-[(tetrahydrofuran-2-yl) methylamino] ethyl} benzyl) -1-oxa-3,8-diazaspiro [4.5] decane-8- Preparation of t-butyl carboxylate 2- (4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 260-1. ] Decan-3-yl] methyl} phenyl) acetic acid (24 mg, 0.059 mmol), 1-hydroxybenzotriazole (3 mg, 0.02 mmol) and tetrahydrofurfurylamine (commercially available) (12 μL, 0.12 mmol) in chloroform (1 mL ) To the solution was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (17 mg, 0.089 mmol) at room temperature. After standing days, and the organic layer was separated by adding water (1 mL). The organic layer was washed with a solution of citric acid (3 mg) in water (2 mL) and then concentrated to dryness under reduced pressure to give the title compound (26 mg, yield 90%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41-1.53 (1H, m), 1.45 (9H, s), 1.53-1.68 (2H, m), 1.74 -2.01 (5H, m), 3.13 (2H, s), 3.14 (1H, ddd, J = 13.5, 7.4, 5.3 Hz), 3.28 (2H, ddd, J = 13.9, 11.0, 2.9 Hz), 3.54 (1H, ddd, J = 13.5, 6.5, 3.3 Hz), 3.56 (2H, s), 3.63 −3.80 (2H, m), 3.80 (2H, br d, J = 12.3 Hz), 3.91 (1H, dq, J = 3.3, 7.0 Hz), 4.42 (2H , S), 5.67-5.88 (1H, br m), 7.23 (2H, d, J = 8.2 Hz), 7.27 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.99 minutes; m / z 510.0 [M + Na] ⁺ (ESI positive ion mode), m / z 486.3 [MH] ⁻ (ESI negative ion mode)

Example 260
2- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] -N Production of — [(tetrahydrofuran-2-yl) methyl] acetamide (Compound No. 260) 2-oxo-3- (4- {2-oxo-2-[(tetrahydrofuran-2 ) obtained in Reference Example 260-2 -Yl) methylamino] ethyl} benzyl) -1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (26 mg, 0.053 mmol) of 1,4-dioxane (1. (3 mL) was added a 10 mass% hydrogen chloride methanol solution (0.13 mL), allowed to stand at room temperature for 16 hours, and then concentrated to dryness under reduced pressure. The residue was dissolved in N, N-dimethylformamide (1 mL), triethylamine (22 μL) and 4- (trifluoromethyl) benzyl bromide (9 μL) were added, and the mixture was allowed to stand at room temperature for 4 days. Water (3 mL) and ethyl acetate (4 mL) were added to the reaction mixture, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / acetone = 3/1] to obtain the title compound (12 mg, yield 52%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.42-1.56 (1 H, m), 1.65 to 2.01 (7 H, m), 2.43-2.61 (4 H, br m ), 3.13 (2H, s), 3.14 (1H, ddd, J = 13.5, 7.4, 4.9 Hz), 3.53 (1H, ddd, J = 13.9, 6. 5, 3.3 Hz), 3.55 (4H, s), 3.63-3.78 (2H, m), 3.91 (1H, dq, J = 3.7, 7.0 Hz), 4. 41 (2H, s), 5.78 (1H, br m), 7.23 (2H, d, J = 8.2 Hz), 7.26 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 546.0 [M + H] ⁺ (ESI positive ion mode), m / z 590.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 261
4-({3-[((1r, 4r) -4- {4- [Hydroxy (phenyl) methyl] piperidine-1-carbonyl} cyclohexyl) methyl] -2-oxo-1-oxa-3,8-diazaspiro Preparation of [4.5] decan-8-yl} methyl) benzonitrile (Compound No. 261) 4-[(3-{[(1r, 4r) -4- (4-Benzoyl) obtained in Example 154 Piperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl) methyl] benzonitrile (30 mg, 0.051 mmol) in methanol (1 0.0 mL) -tetrahydrofuran (0.5 mL) solution, sodium borohydride (2.0 mg, 0.051 mmol) was added and stirred at room temperature for 30 minutes. By adding an acid (6 [mu] L), concentrated to dryness under reduced pressure. Methanol (1 mL) was added to the residue, and the mixture was concentrated to dryness under reduced pressure. Cyclopentyl methyl ether (2 mL) and water (1 mL) were added to the residue, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: chloroform / ethyl acetate = 1/1], and the title compound (21 mg, yield 70%) was colorless and amorphous. Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.87-1.40 (5H, m), 1.40-2.13 (13H, m), 2.27-2.51 (2H, m) 2.47-2.65 (4H, br m), 2.89 (0.5 H, br t, J = 12.7 Hz), 2.96 (0.5 H, br t, J = 13.5 Hz) , 3.03-3.14 (2H, m), 3.25 (2H, s), 3.57 (2H, s), 3.82 (0.5H, br d, J = 13.5 Hz), 3.93 (0.5 H, br d, J = 13.1 Hz), 4.39 (1 H, d, J = 7.4 Hz), 4.58 (0.5 H, br d, J = 13.5 Hz) 4.69 (0.5 H, br d, J = 13.1 Hz), 7.26-7.40 (5 H, m), 7.44 (2 H, d, J = 8.2 Hz), 7.61 ( H, d, J = 8.2Hz).

LC / MS [Condition 1]: Retention time 2.98 min; m / z 585.0 [M + H] ⁺ (ESI positive ion mode), m / z 629.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 262
(1r, 4r) -N- (4-cyanobenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 262) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) obtained in Reference Example 6-3 ) Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (20 mg, 0.044 mmol), 1-hydroxybenzotriazole (2 mg, 0.01 mmol) and 4- (Aminomethyl) benzonitrile hydrochloride (commercially available) (9.0 mg, 0.053 mmol) was dissolved in chloroform (1 mL) and triethylamine (12 μL) was dissolved. 0.088 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13 mg, 0.066 mmol) was added and allowed to stand at room temperature for 8 days. Water (1 mL) was added to the reaction mixture, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / acetone = 2/1] to obtain the title compound (23 mg, yield 92%) as a colorless amorphous product. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 2.9, 12.7 Hz), 1.44-1.66 (3H, m), 1.70-1. 85 (4H, m), 1.86-2.00 (4H, m), 2.09 (1H, tt, J = 12.3, 2.9 Hz), 2.46-2.63 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 4.49 (2H, d, J = 6.1 Hz) , 5.87 (1H, br t, J = 5.7 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 569.1 [M + H] ⁺ (ESI positive ion mode), m / z 603.2 [M + Cl] ⁻ (ESI negative ion mode)

Example 263
(1r, 4r) -N- (4-cyanobenzyl) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- Preparation of (yl) methyl} cyclohexanecarboxamide (Compound No. 263) (1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-] obtained in Reference Example 17-2 To a suspension of 3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (0.10 g, 0.24 mmol) in N, N-dimethylformamide (2 mL) was added triethylamine (0.10 mL). , 0.72 mmol), 1-hydroxybenzotriazole (10 mg, 0.072 mmol), 4- (aminomethyl) benzonitrile hydrochloride (commercially available) (48 mg, 0.29 m ol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (69 mg, 0.36 mmol) was added and stirred at room temperature for 5 days. Water (4 mL) and chloroform (6 mL) were added to the reaction mixture, and the organic layer was washed with water (5 mL × 2) and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / acetone = 2/1] to obtain the title compound (26 mg, yield 20%) as a colorless amorphous product. It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.5 Hz), 1.52 (2H, dq, J = 3.3, 12.5 Hz), 1.56-1.66 (1H, m), 1.69-1.85 (4H, m), 1.86-2.00 (4H, m), 2.10 (1H, tt, J = 11 .9, 3.3 Hz), 2.44-2.64 (4H, br m), 3.09 (2H, d, J = 7.8 Hz), 3.26 (2H, s), 3.57 ( 2H, s), 4.48 (2H, d, J = 6.0 Hz), 6.02 (1H, brt, J = 6.0 Hz), 7.36 (2H, d, J = 8.2 Hz) 7.44 (2H, d, J = 7.8 Hz), 7.61 (4H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 2.61 minutes; m / z 526.1 [M + H] ⁺ (ESI positive ion mode), m / z 524.2 [MH] ⁻ (ESI negative ion mode)

Reference Example 264-1
Preparation of t-butyl 4- (4-cyanophenoxy) piperidine-1-carboxylate Synthesized using the method described in WO2007 / 106705.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.64-1.86 (2H, m), 1.86-2.01 (2H, m), 3.36 (2H, ddd, J = 13.5, 8.0, 4.0 Hz), 3.69 (2H, ddd, J = 13.5, 7.6, 3.6 Hz), 4.55 (1H, tt , J = 7.4, 3.3 Hz), 6.95 (2H, d, J = 9.0 Hz), 7.58 (2H, d, J = 9.0 Hz).

LC / MS [Condition 1]: Retention time 4.49 minutes; m / z 247.2 [M-isobutene + H] ⁺ , 203.2 [M-isobutene-CO2 + H] ⁺ (ESI positive ion mode)

Reference Example 264-2
Preparation of 4- (piperidin-4-yloxy) benzonitrile hydrochloride The compound was synthesized using the method described in WO2007 / 106705.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.06-2.25 (2H, br m), 2.26-2.48 (2H, br m), 3.18-3.52 (4H, br m), 4.68-4.81 (1H, br m), 6.96 (2H, d, J = 9.0 Hz), 7.62 (2H, d, J = 9.0 Hz), 9. 74 (2H, brs).

LC / MS [Condition 1]: Retention time 0.49 minutes; m / z 203.2 [M + H] ⁺ (ESI positive ion mode)

Example 264
4- {1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl Preparation of piperidin-4-yloxy} benzonitrile (Compound No. 264) Other than using 4- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in Reference Example 264-2 instead of 4-benzylpiperidine Was carried out in substantially the same manner as in Example 253 to obtain the title compound (20 mg, yield 68%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.73 (2H, ddd, J = 13.5, 8.6, 6.1 Hz), 1.74-2.13 (4H, br m), 1 .92 (2H, br d, J = 13.5 Hz), 2.40-2.65 (4H, br m), 3.14 (2H, s), 3.26-4.03 (4H, br m ), 3.55 (2H, s), 4.45 (2H, s), 4.67 (1H, tt, J = 6.1, 3.3 Hz), 6.96 (2H, d, J = 8) .6 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.6 Hz), 7 .55 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 633.1 [M + H] ⁺ (ESI positive ion mode), m / z 677.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 265
4- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of —yl} methyl) cyclohexanecarbonyl] piperidin-4-yloxy} benzonitrile (Compound No. 265) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 4- (piperidine obtained in Reference Example 264-2 The reaction was carried out in substantially the same manner as in Example 262, except that -4-yloxy) benzonitrile hydrochloride was used, and the title compound (15 mg, yield 54%) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 2.9, 11.9 Hz), 1.46-1.68 (3H, br m), 1.69-1 .87 (8H, br m), 1.87-2.02 (4H, br m), 2.46 (1H, tt, J = 11.5, 3.3 Hz), 2.52-2.67 ( 4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.37-3.53 (1H, br m), 3.59 (2H, s), 3.60-3.83 (3H, br m), 4.62 (1H, tt, J = 6.1, 3.3 Hz), 6.95 (2H, d, J = 8.6 Hz) , 7.44 (2H, d, J = 8.2 Hz), 7.52-7.63 (4H, m).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 639.2 [M + H] ⁺ (ESI positive ion mode), m / z 683.3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 266
4- [1-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of cyclohexanecarbonyl) piperidin-4-yloxy] benzonitrile (Compound No. 266) 4- (Piperidin-4-yloxy) obtained in Reference Example 264-2 instead of 4- (aminomethyl) benzonitrile hydrochloride ) The reaction was carried out in substantially the same manner as in Example 263 except that benzonitrile hydrochloride was used to obtain the title compound (31 mg, yield 43%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 3.3, 12.3 Hz), 1.50-1.67 (3H, br m), 1.70-1 .87 (8H, br m), 1.87-2.01 (4H, br m), 2.47 (1H, tt, J = 11.5, 2.9 Hz), 2.49-2.64 ( 4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.38-3.53 (1H, br m), 3.57 (2H, s), 3.58-3.85 (3H, br m), 4.63 (1H, tt, J = 6.5, 3.3 Hz), 6.95 (2H, d, J = 8.6 Hz) 7.44 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.6 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 596.1 [M + H] ⁺ (ESI positive ion mode), m / z 640.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 267
4-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] -3,5-difluorobenzonitrile (Compound No. 267) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl] obtained in Reference Example 255 ) Cyclohexyl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (20 mg, 0.040 mmol) and 3,5-difluoro-4-formylbenzonitrile (commercially available) Acetic acid (80 μL) and borane-2-picoline complex (5 mg, 0.05 mmol) were added to a methanol (1 mL) solution of (8.0 mg, 0.046 mmol) at room temperature. After stirring for 3 days, it added borane-2-picoline complex (2 mg, 0.02 mmol), and stirred for an additional 26 days. Thereafter, the reaction mixture was concentrated to dryness under reduced pressure, and the resulting residue was dissolved in methanol (1 mL) and concentrated to dryness under reduced pressure. After adding chloroform (1 mL) and water (1 mL) to the residue, the organic layer was separated and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / acetone = 4/1], and the title compound (18 mg, yield 72%) was colorless and amorphous. Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, br q, J = 12.3 Hz), 1.43-1.68 (4H, br m), 1.68-1.86 ( 7H, br m), 1.86-2.00 (4H, br m), 2.46 (1H, tt, J = 11.9, 2.5 Hz), 2.53-2.72 (4H, br m), 2.81 (1H, br t, J = 12.3 Hz), 3.09 (2 H, d, J = 1.4 Hz), 3.20 (1 H, br t, J = 12.3 Hz), 3.22 (2H, s), 3.51 (1H, tt, J = 10.6, 3.7 Hz), 3.75 (2H, s), 3.98 (1H, br d, J = 13. 5 Hz), 4.60 (1H, br d, J = 13.1 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.49 (2H, dd, J = 8. , 7.4Hz), 7.59 (1H, t, J = 7.4Hz), 7.94 (2H, d, J = 8.2Hz).

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 619.0 [M + H] ⁺ (ESI positive ion mode), m / z 663.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 268
3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] Preparation of t-butyl decane-8-carboxylate (Compound No. 268) Instead of 4-benzoylpiperidine hydrochloride, 4- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in Reference Example 264-2 was used. Except for the above, the reaction was carried out in substantially the same manner as in Example 252 to obtain the title compound (58 mg, quantitative yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 12.7 Hz), 1.46 (9H, s), 1.47-1.73 (5H, m), 1.73 -2.09 (10H, m), 2.47 (1H, br t, J = 11.1 Hz), 3.07-3.18 (2H, m), 3.26 (2H, s), 3. 28 (2H, br t, J = 11.5 Hz), 3.40-3.57 (1H, br m), 3.56-4.04 (5H, br m), 4.63 (1H, tt, J = 6.1, 3.3 Hz), 6.96 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz).

LC / MS [Condition 1]: Retention time 4.33 min; m / z 603.0 [M + Na] ⁺ (ESI positive ion mode), m / z 625.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 269
3-{[(1r, 4r) -4- (4-cyanobenzylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t- Preparation of butyl (Compound No. 269) The reaction was carried out in substantially the same manner as in Example 252, except that 4- (aminomethyl) benzonitrile hydrochloride (commercially available) was used instead of 4-benzoylpiperidine hydrochloride. The title compound (55 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, dq, J = 3.3, 12.3 Hz), 1.46 (9H, s), 1.49-1.73 (5H, m) , 1.73-2.02 (6H, m), 2.10 (1H, tt, J = 12.3, 3.3 Hz), 3.11 (2H, d, J = 7.8 Hz), 3. 26 (2H, s), 3.27 (2H, br t, J = 12.0 Hz), 3.86 (2H, br d, J = 12.0 Hz), 4.49 (2H, d, J = 6) .1 Hz), 5.88 (1H, br t, J = 6.1 Hz), 7.36 (2H, d, J = 7.8 Hz), 7.62 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 4.03 minutes; m / z 532.9 [M + Na] ⁺ (ESI positive ion mode), m / z 509.1 [M−H] ⁻ , 555.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 270
1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexanecarbonyl] -4-phenylpiperidine-4-carbonitrile (Compound No. 270) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 4-phenylpiperidine-4-carbonitrile hydrochloride (commercially available) The title compound (26 mg, yield 96%) was obtained as a colorless amorphous product in substantially the same manner as in Example 262 except that was used.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 12.3 Hz), 1.44-1.69 (3H, m), 1.72-2.04 (10H, m) 2.19 (2H, br t, J = 12.3 Hz), 2.46-2.68 (4 H, br m), 2.49 (1 H, br t, J = 11.9 Hz), 3.02 (1H, br t, J = 13.1 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.55 (1H, br t, J = 13. 5 Hz), 3.58 (2H, s), 4.05 (1 H, br d, J = 14.7 Hz), 4.85 (1 H, br d, J = 14.3 Hz), 7.32-7. 51 (7H, m), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.40 minutes; m / z 623.1 [M + H] ⁺ (ESI positive ion mode), m / z 667.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 271
1-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarbonyl ) Preparation of 4-phenylpiperidine-4-carbonitrile (Compound No. 271) Other than using 4-phenylpiperidine-4-carbonitrile hydrochloride (commercially available) instead of 4- (aminomethyl) benzonitrile hydrochloride Was carried out in substantially the same manner as in Example 263 to obtain the title compound (52 mg, yield 93%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 11.9 Hz), 1.46-1.70 (3H, m), 1.71-2.01 (10H, m) 2.19 (2H, br t, J = 11.9 Hz), 2.44-2.68 (4 H, br m), 2.48 (1 H, br t, J = 11.9 Hz), 3.02 (1H, br t, J = 13.1 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.55 (1H, br t, J = 13. 9 Hz), 3.57 (2H, s), 4.05 (1 H, d, J = 14.3 Hz), 4.86 (1 H, br d, J = 13.5 Hz), 7.31-7.50. (7H, m), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [condition 1]: retention time 3.18 minutes; m / z 580.0 [M + H] ⁺ (ESI positive ion mode), m / z 624.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 272-1
Production of t-butyl 4-[(cyclohexylmethylamino) methyl] -4-hydroxypiperidine-1-carboxylate 1-oxa-6-azaspiro [2.5] octane-6 obtained in Reference Example 1-1 -To a solution of t-butyl carboxylate (0.70 g, 0.33 mmol) in methanol (1.5 mL) was added cyclohexylmethylamine (commercially available) (85 μL, 0.66 mmol) and water (1.5 mL), and at room temperature 8 Stir for days. The reaction solution was concentrated under reduced pressure to remove methanol, and then chloroform (3 mL) was added to separate the organic layer, followed by concentration to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / 2-propanol = 10/1] to give the title compound (25 mg, yield 23%) as a colorless oil. Obtained.

¹ H-NMR (CDCl ₃ ) δ: 0.90 (2H, q, J = 11.5 Hz), 1.09-1.61 (7H, m), 1.45 (9H, s), 1.61 -1.81 (6H, m), 2.48 (2H, d, J = 6.5 Hz), 2.49 (2H, s), 3.16 (2H, brt, J = 11.9 Hz), 3.75-3.97 (2H, br m).

Reference Example 272-2
Production of t-butyl 3- (cyclohexylmethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 4-[( Cyclohexylmethylamino) methyl] -4-hydroxypiperidine-1-carboxylate t-butyl (86 mg, 0.26 mmol) in 1,4-dioxane (3 mL) in 1,1′-carbonyldiimidazole (0.13 g, 0.78 mmol) was added, and the reaction mixture was allowed to stand at 90 ° C. for 15 hours, and then concentrated to dryness under reduced pressure. Water (2 mL), n-hexane (2 mL) and ethyl acetate (2 mL) were added to the residue, and the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by recrystallization (n-hexane-ethyl acetate) to give the title compound (62 mg, 67% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (2H, q, J = 11.5 Hz), 1.11-1.32 (3H, m), 1.54-1.80 (8H, m) , 1.88 (2H, br d, J = 13.5 Hz), 3.08 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.28 (2H, t, J = 11.9 Hz), 3.85 (2H, br d, J = 12.7 Hz).

Reference Example 272-3
Production of 3- (cyclohexylmethyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 3- (cyclohexylmethyl) -2-oxo obtained in Reference Example 272-2 1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (59 mg, 0.17 mmol) in methanol (3 mL) in 10% by weight hydrogen chloride in methanol (0.40 mL) ) Was added, and the reaction mixture was allowed to stand at room temperature for 42 hours and at 40 ° C. for 6 hours. The reaction mixture was then concentrated to dryness under reduced pressure to give the title compound (53 mg, quantitative yield) as a yellow solid.

LC / MS [Condition 2]: Retention time 0.82 minutes; m / z 253.1 [M + H] ⁺ (ESI positive ion mode)

Example 272
3- {4- [3- (cyclohexylmethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-carbonyl] benzyl} -8- [4- (trifluoromethyl) Preparation of benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 272) 3- (cyclohexyl) obtained in Reference Example 272-3 instead of 4-benzylpiperidine The reaction was carried out in substantially the same manner as in Example 253 except that methyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride was used, and the title compound (19 mg, yield) was obtained. 90%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 0.96 (2H, q, J = 11.5 Hz), 1.08-1.35 (3H, m), 1.50-2.15 (13H, m) 2.39-2.68 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.14 (2H, s), 3.22-3.76 (3H, br m), 3.29 (2H, s), 3.56 (2H, s), 4.36-4.65 (1H, br m), 4.45 (2H, br s), 7.31 (2H) , D, J = 8.2 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.42 min; m / z 683.2 [M + H] ⁺ (ESI positive ion mode), m / z 727.2 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 273-1
Production of 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 2-oxo- 1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 111-1. After adding a 10% by mass hydrogen chloride methanol solution (1 mL) to a methanol (2 mL) solution of decane-8-carboxylate t-butyl (95 mg, 0.37 mmol), the reaction mixture was allowed to stand at room temperature for 3 days. . The reaction mixture was then concentrated to dryness under reduced pressure to give the title compound (75 mg, quantitative yield) as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.85-2.06 (4H, m), 2.98-3.13 (2H, m), 3.13-3.24 (2H, m) , 3.32 (2H, s), 7.65 (1H, br s), 8.82 (2H, br s).

Reference Example 273-2
3- [4- (2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa- Production of 3,8-diazaspiro [4.5] decan-2-one 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1- oxa-) obtained in Reference Example 21 3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (51 mg, 0.11 mmol), 1-hydroxybenzotriazole (5 mg, 0.03 mmol) and obtained in Reference Example 273-1 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (24 mg, 0.12 mmol) was suspended in chloroform (1 mL) and triethylamine (63 μL, 0.45 mmol) was suspended. And 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (33 mg, 0.17 mmol) was added and stirred at room temperature for 21 days. After adding water (2 mL) to the reaction mixture, the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / 2-propanol = 5/1] to give the title compound (54 mg, yield 82%) as a colorless amorphous product. Got as.

¹ H-NMR (CDCl ₃ ) δ: 1.54-2.22 (4H, br m), 1.73 (2H, dt, J = 13.5, 7.0 Hz), 1.92 (2H, d , J = 13.1 Hz), 2.41-2.65 (4H, br m), 3.14 (2H, s), 3.26-3.80 (3H, br m), 3.39 (2H , Br s), 3.55 (2H, s), 4.33-4.62 (1H, br m), 4.45 (2H, br s), 5.10 (1H, br s), 7. 32 (2H, d, J = 7.8 Hz), 7.40 (2H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d , J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 1.9 to 2.4 minutes; m / z 587.0 [M + H] ⁺ (ESI positive ion mode), m / z 631.0 [M + HCOO] ⁻ , 585.1 [M -H] ^- (ESI negative ion mode)

Example 273
3- [4- (3-Ethyl-2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl]- Production of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 273) 3- [4- (2-oxo-1-oxa- ) obtained in Reference Example 273-2 3,8-diazaspiro [4.5] decane-8-carbonyl) benzyl] -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-2- To a solution of ON (20 mg, 0.034 mmol) in N, N-dimethylformamide (1 mL) was added potassium t-butoxide (5 mg, 0.05 mmol), and the mixture was stirred at room temperature for 1.5 hours. Then, ethyl iodide (4 μL) was added and stirred at room temperature for 4 hours. Acetic acid (6 μL), water (2 mL) and chloroform (4 mL) were added, and the organic layer was separated and concentrated to dryness under reduced pressure. Water (1 mL) and ethyl acetate (2 mL) were added to the residue, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: chloroform / ethyl acetate = 2/1] to give the title compound (10 mg, 48% yield) as a white solid. Obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.73 (2H, dt, J = 13.1, 7.0 Hz), 1.74-2.16 (4H, br m), 1.92 (2H, br d, J = 13.1 Hz), 2.43-2.65 (4H, br m), 3.14 (2H, s), 3.26-3.76 (3H, br m), 3.30 ( 2H, s), 3.34 (2H, q, J = 7.4 Hz), 3.56 (2H, s), 4.33-4.62 (1H, br m), 4.45 (2H, br s), 7.32 (2H, d, J = 8.2 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7. 57 (2H, d, J = 8.2 Hz)

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 615.0 [M + H] ⁺ (ESI positive ion mode), m / z 659.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 274
4- (3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 8-yl) -3-nitrobenzonitrile (Compound No. 274) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} obtained in Reference Example 255 1,4-Oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (20 mg, 0.040 mmol) and 4-chloro-3-nitrobenzonitrile (7 mg, 0.040 mmol) After adding N, N-diisopropylethylamine (21 μL, 0.12 mmol) to a suspension of dioxane (1 mL), the reaction mixture was stirred at 100 ° C. for 20 hours, Was solidified pressure concentrated to dryness. After adding ethyl acetate (2 mL) and water (2 mL) to the residue, the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / acetone = 3/1] to obtain the title compound (23 mg, yield 96%) as a yellow solid.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 12.7 Hz), 1.51-1.72 (3H, m), 1.73-2.11 (12H, m) 2.48 (1H, br t, J = 11.1 Hz), 2.82 (1 H, br t, J = 11.9 Hz), 3.14 (2H, d, J = 7.4 Hz), 3. 19-3.31 (3H, m), 3.35 (2H, s), 3.36-3.47 (2H, m), 3.52 (1H, tt, J = 10.6, 3.7 Hz) ), 3.99 (1H, brd, J = 13.5 Hz), 4.61 (1H, brd, J = 13.1 Hz), 7.14 (1H, d, J = 9.0 Hz), 7 .49 (2H, t, J = 7.4 Hz), 7.59 (1H, tt, J = 7.4, 1.2 Hz), 7.68 (1H, dd, J = 8.6, 2.0 Hz) ), 7. 5 (2H, d, J = 7.4Hz), 8.12 (1H, d, J = 2.0Hz).

LC / MS [Condition 1]: Retention time 4.31 min; m / z 614.1 [M + H] ⁺ (ESI positive ion mode), m / z 658.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 275
3- (4- {2- [4- (4-Cyanophenoxy) piperidin-1-yl] -2-oxoethyl} benzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of t-butyl -8-carboxylate (Compound No. 275) 2- (4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3] obtained in Reference Example 260-1 , 8-diazaspiro [4.5] decan-3-yl] methyl} phenyl) acetic acid (60 mg, 0.15 mmol), 1-hydroxybenzotriazole (6 mg, 0.05 mmol) and Reference Example 264-2. , 4- (piperidin-4-yloxy) benzonitrile hydrochloride (35 mg, 0.15 mmol) in chloroform suspension was added triethylamine (62 μL, 0.45 mmol) and 1- Chill-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (43 mg, 0.22 mmol) was added and stirred for 19 days at room temperature. Then, after adding water (2 mL), the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / acetone = 5/1] to obtain the title compound (55 mg, yield 63%) as a colorless amorphous product. .

¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.59-1.99 (8H, m), 3.13 (2H, s), 3.27 (2H, t, J = 12.3 Hz), 3.40-3.52 (1H, m), 3.67 (1H, ddd, J = 13.9, 7.8, 4.1 Hz), 3.70-3.91 ( 4H, m), 3.75 (2H, s), 4.41 (2H, s), 4.59 (1H, tt, J = 6.1, 3.3 Hz), 6.93 (2H, d, J = 9.0 Hz), 7.22 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 8.6 Hz), 7.58 (2H, d, J = 9.0 Hz) ).

LC / MS [Condition 1]: Retention time 4.27 min; m / z 610.8 [M + Na] ⁺ , 532.9 [M-isobutene + H] ⁺ , 488.9 [M-isobutene-CO2 + H] ⁺ (ESI positive ion Mode), m / z 633.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 276
(1r, 4r) -N- (Benzo [d] [1,3] dioxol-5-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa- Preparation of 3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 276) Instead of 4- (aminomethyl) benzonitrile hydrochloride, benzo [d] [1,3] The reaction was carried out substantially in the same manner as in Example 262 except that dioxol-5-ylmethanamine (commercially available) was used to give the title compound (17 mg, yield 65%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (2H, br q, J = 12.9 Hz), 1.41-1.67 (3H, m), 1.69-1.87 (4H, m ), 1.87-2.14 (5H, m), 2.43-2.66 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s) ), 3.57 (2H, s), 4.33 (2H, d, J = 5.7 Hz), 5.65 (1H, br t, J = 5.3 Hz), 5.95 (2H, s) 6.67-6.81 (3H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [condition 1]: retention time 3.18 minutes; m / z 587.9 [M + H] ⁺ (ESI positive ion mode), m / z 632.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 277-1
Preparation of 4-hydroxy-4-({[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methylamino} methyl) piperidine-1-carboxylate obtained in Reference Example 2-1 ( 1r, 4r) -4- (aminomethyl) cyclohexanecarboxylic acid methyl hydrochloride (0.10 g, 0.48 mmol) and 1-oxa-6-azaspiro [2.5] octane obtained in Reference Example 1-1 To a solution of tert-butyl-6-carboxylate (0.10 g, 0.48 mmol) in methanol (1.5 mL) -water (1.0 mL) was added 1M aqueous sodium hydroxide solution (0.48 mL), and the reaction mixture was Stir at room temperature for 5 days. After removing insolubles by filtration, the filtrate was concentrated under reduced pressure to remove methanol. Chloroform was added to the residue, the organic layer was separated, and the aqueous layer was extracted with chloroform. The combined organic layers were concentrated to dryness under reduced pressure to give the title compound (0.12 g, yield 63%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 0.95 (2H, dq, J = 3.3, 12.3 Hz), 1.32-1.56 (3H, m), 1.46 (9H, s) , 1.86 (2H, br d, J = 12.7 Hz), 1.92-2.15 (6H, m), 2.24 (1H, tt, J = 12.3, 3.3 Hz), 2 .44-2.56 (4H, m), 3.16 (2H, br t, J = 11.9 Hz), 3.67 (3H, s), 3.75-3.99 (2H, br m) .

Reference Example 277-2
Preparation of t-butyl 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-thioxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 4-hydroxy-4-({[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methylamino} methyl) piperidine-1-carboxylate t-butyl (0. 0) obtained in Reference Example 277-1. 10 g, 0.26 mmol) in 1,4-dioxane (2 mL) was added 1,1′-thiocarbonyldiimidazole (0.12 g, 0.68 mmol) and the reaction mixture was allowed to stand at 90 ° C. for 43 hours. After that, it was concentrated to dryness under reduced pressure. Hexane (2 mL), ethyl acetate (2 mL) and water (2 mL) were added to the residue, and the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / ethyl acetate = 6/1] to obtain the title compound (68 mg, 61% yield) as a white solid. .

¹ H-NMR (CDCl ₃ ) δ: 1.12 (2H, dq, J = 3.3, 12.3 Hz), 1.42 (2H, dq, J = 3.7, 13.1 Hz), 1. 46 (9H, s), 1.63-1.85 (5H, m), 1.95 (2H, br d, J = 13.1 Hz), 2.04 (2H, br d, J = 13.5 Hz) ), 2.27 (1H, tt, J = 11.9, 3.7 Hz), 3.37 (2H, br t, J = 11.9 Hz), 3.46 (2H, s), 3.51 ( 2H, d, J = 7.0 Hz), 3.67 (3H, s), 3.82 (2H, br d, J = 11.9 Hz).

LC / MS [Condition 2]: Retention time 4.61 min; m / z 449.2 [M + Na] ⁺ , 427.2 [M + H] ⁺ , 371.1 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 277-3
Preparation of (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-thioxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-thioxo-1-oxa-3,8-diazaspiro [4.5] decane obtained in Reference Example 277-2 To a solution of tert-butyl -8-carboxylate (68 mg, 0.16 mmol) in 1,4-dioxane (1.4 mL) was added water (0.50 mL) and 1M aqueous sodium hydroxide solution (0.18 mL). Stir at room temperature for 1 day. Acetic acid (10 μL) was added to adjust the pH to 7, and then the reaction mixture was concentrated to dryness under reduced pressure. Water (2 mL), chloroform (4 mL) and citric acid (61 mg) were added to the residue, the organic layer was separated and concentrated to dryness under reduced pressure to give the title compound (65 mg, 98% yield) as a white solid. Obtained.

LC / MS [Condition 1]: Retention time 5.56 minutes; m / z 435.0 [M + Na] ⁺ (ESI positive ion mode), m / z 411.0 [MH] ⁻ (ESI negative ion mode)

Example 277
3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-thioxo-1-oxa-3,8-diazaspiro [4.5] Production of t-butyl decane-8-carboxylate (Compound No. 277) (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-thioxo-1 obtained in Reference Example 277-3 -Oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (65 mg, 0.16 mmol), 1-hydroxybenzotriazole (6 mg, 0.05 mmol) and Reference Example 264-2 To a chloroform suspension of 4- (piperidin-4-yloxy) benzonitrile hydrochloride (41 mg, 0.17 mmol) obtained in 1 above, triethylamine ( 6 [mu] L, 0.47 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (45 mg, 0.24 mmol) was added and allowed to stand 26 days at room temperature. Then, after adding water (3 mL), the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / acetone = 5/1] to obtain the title compound (96 mg, quantitative yield) as a colorless amorphous product. .

¹ H-NMR (CDCl ₃ ) δ: 1.18 (2H, q, J = 12.7 Hz), 1.46 (9H, s), 1.49-2.10 (15H, m), 2.50 (1H, br t, J = 11.9 Hz), 3.28-3.54 (3H, m), 3.45 (2H, s), 3.55 (2H, d, J = 7.0 Hz), 3.59-3.95 (5H, m), 4.57-4.69 (1H, m), 6.96 (2H, d, J = 8.6 Hz), 7.60 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 4.51 min; m / z 597.0 [M + H] ⁺ , 619.1 [M + Na] ⁺ (ESI positive ion mode), m / z 641.1 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 278-1
Preparation of 4- (quinolin-4-yl) piperazine-1-carboxylate t-butyl 4-chloroquinoline (0.20 g, 1.2 mmol), t-butyl piperazine-1-carboxylate (0.34 g, 1. 8 mmol) in N, N-dimethylformamide (2 mL) was added N, N-diisopropylethylamine (0.43 mL, 2.4 mmol), and the reaction mixture was allowed to stand at 100 ° C. for 22 hours, and then concentrated to dryness under reduced pressure. did. Ethyl acetate (2 mL) and water (2 mL) were added to the residue, and the organic layer was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 2/3] to give the title compound (0.27 g, yield 71%) as an amber oily substance. Got as.

¹ H-NMR (CDCl ₃ ) δ: 1.51 (9H, s), 3.13-3.25 (4H, m), 3.68-3.78 (4H, m), 6.85 (1H , D, J = 4.9 Hz), 7.51 (1H, ddd, J = 8.2, 7.0, 1.2 Hz), 7.68 (1H, ddd, J = 8.2, 7.0). , 1.6 Hz), 8.02 (1H, dd, J = 8.2, 1.2 Hz), 8.07 (1H, d, J = 8.2 Hz), 8.75 (1H, d, J = 4.9 Hz).

Reference Example 278-2
Production of 4- (piperazin-1-yl) quinoline dihydrochloride t-butyl 4- (quinolin-4-yl) piperazin-1-carboxylate (0.27 g, 0.4 g) obtained in Reference Example 278-1. After adding 10 mass% hydrogen chloride methanol solution (2 mL) to a solution of 86 mmol) in methanol (6 mL), the reaction mixture was allowed to stand at 55 ° C. for 3 hours and concentrated to dryness under reduced pressure to give the title compound (0. 25 g, quantitative yield) was obtained as a white solid.

LC / MS [Condition 1]: Retention time 0.45 minutes; m / z 214.1 [M + H] ⁺ (ESI positive ion mode)

Example 278
4-{[2-oxo-3-({(1r, 4r) -4- [4- (quinolin-4-yl) piperazin-1-carbonyl) cyclohexyl] methyl} -1-oxa-3,8-diazaspiro Preparation of [4.5] decan-8-yl) methyl] benzonitrile (Compound No. 278) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 4- (piperazine-) obtained in Reference Example 278-2 The reaction was carried out in substantially the same manner as in Example 263 except that 1-yl) quinoline dihydrochloride was used to give the title compound (25 mg, yield 86%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.08 (2H, q, J = 12.3 Hz), 1.53-1.65 (1H, m), 1.61 (2H, q, J = 13. 1 Hz), 1.71-1.90 (6H, m), 1.95 (2H, br d, J = 13.5 Hz), 2.43-2.69 (5H, m), 3.12 (2H) , D, J = 7.4 Hz), 3.15-3.32 (6H, m), 3.27 (2H, s), 3.57 (2H, s), 3.72-3.85 (2H) M), 3.85-3.99 (2H, m), 6.85 (1H, d, J = 4.9 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.53 (1H, t, J = 7.0 Hz), 7.61 (2H, d, J = 8.2 Hz), 7.69 (1H, dt, J = 1.2, 7.6 Hz), 8.03 ( 1H, d, J = 8.2Hz) 8.08 (1H, d, J = 8.2Hz), 8.77 (1H, d, J = 4.9Hz).

LC / MS [Condition 1]: retention time 0.51 min; m / z 606.9 [M + H] ⁺ (ESI positive ion mode), m / z 651.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 279
3- {4- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 279) Instead of 4-benzylpiperidine, 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole (commercially available) The reaction was carried out in substantially the same manner as in Example 253 except for using, to give the title compound (30 mg, quantitative yield) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.73 (2H, dt, J = 13.6, 7.0 Hz), 1.92 (2H, br d, J = 13.5 Hz), 1.96-2 .35 (4H, br m), 2.37-2.69 (4H, br m), 3.03-3.32 (2H, br m), 3.14 (2H, s), 3.38 ( 1H, tt, J = 11.1, 4.1 Hz), 3.56 (2H, s), 3.71-4.13 (1H, br m), 4.46 (2H, s), 4.55 -4.94 (1H, br m), 7.09 (1H, dt, J = 2.0, 8.6 Hz), 7.27 (2H, dd, J = 2.0, 8.6 Hz), 7 .33 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 z), 7.64 (1H, dd, J = 8.6,5.3Hz).

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 650.9 [M + H] ⁺ (ESI positive ion mode), m / z 695.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 280
4-{[3-({(1r, 4r) -4- [4- (6-Fluorobenzo [d] isoxazol-3-yl) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1- Preparation of Oxa-3,8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 280) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 6-fluoro-3- ( The title compound (41 mg, yield 91%) was obtained as a colorless amorphous product in substantially the same manner as in Example 263 except that piperidin-4-yl) benzo [d] isoxazole (commercially available) was used. It was.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 11.9 Hz), 1.49-1.69 (3H, m), 1.71-2.04 (10H, m) , 2.08-2.25 (2H, br m), 2.47-2.68 (4H, br m), 2.50 (1H, br t, J = 11.5 Hz), 2.88 (1H , Br t, J = 11.5 Hz), 3.11 (2H, d, J = 7.8 Hz), 3.18-3.31 (1H, br m), 3.27 (2H, s), 3 .33 (1H, tt, J = 11.5, 3.7 Hz), 3.57 (2H, s), 4.05 (1H, d, J = 13.9 Hz), 4.67 (1H, br d , J = 13.9 Hz), 7.08 (1H, dt, J = 2.0, 8.6 Hz), 7.27 (1H, dd, J = 8.2, 2.5 Hz), 7.45 ( 2H, , J = 8.2Hz), 7.61 (2H, d, J = 8.2Hz), 7.63 (1H, d, J = 8.6Hz).

LC / MS [Condition 1]: retention time 3.24 minutes; m / z 614.0 [M + H] ⁺ (ESI positive ion mode), m / z 658.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 281-1
Preparation of t-butyl 4- (3-cyanophenoxy) piperidine-1-carboxylate Synthesized using the method described in WO2007 / 106705.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.67-1.81 (2H, m), 1.87-1.99 (2H, m), 3.35 (2H , Ddd, J = 13.5, 7.8, 3.7 Hz), 3.70 (2H, ddd, J = 13.5, 7.0, 3.7 Hz), 4.49 (1H, tt, J = 7.4, 3.3 Hz), 7.10-7.18 (2H, m), 7.24 (1H, dt, J = 7.4, 0.8 Hz), 7.38 (1H, td, J = 7.8, 0.8 Hz).

LC / MS [Condition 1]: Retention time 4.59 minutes; m / z 247.0 [M-isobutene + H] ⁺ , 203.0 [M-isobutene-CO2 + H] ⁺ (ESI positive ion mode)

Reference Example 281-2
Preparation of 3- (piperidin-4-yloxy) benzonitrile hydrochloride The compound was synthesized using the method described in WO2007 / 106705.

¹ H-NMR (DMSO-d ₆ ) δ: 1.74-1.91 (2H, m), 2.03-2.19 (2H, m), 2.97-3.14 (2H, m) 3.16-3.32 (2H, m), 4.74 (1H, tt, J = 7.8, 3.7 Hz), 7.35 (1H, d, J = 7.8 Hz), 7. 43 (1H, d, J = 7.8 Hz), 7.51 (1H, t, J = 7.8 Hz), 7.54-7.56 (1H, m), 8.88 (2H, br s) .

LC / MS [Condition 1]: retention time 0.55 min; m / z 203.1 [M + H] ⁺ (ESI positive ion mode)

Example 281
3- {1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl Preparation of piperidin-4-yloxy} benzonitrile (Compound No. 281) Other than using 4- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in Reference Example 281-2 instead of 4-benzylpiperidine Was carried out in substantially the same manner as in Example 253 to obtain the title compound (30 mg, quantitative yield) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.65-2.17 (8H, m), 2.39-2.64 (4H, m), 3.14 (2H, s), 3.29-3 .52 (1H, m), 3.56 (2H, s), 3.58-4.06 (3H, m), 4.45 (2H, s), 4.56-4.66 (1H, m ), 7.11-7.18 (2H, m), 7.22-7.29 (1H, m, overlappedbyCHCl3), 7.32 (2H, d, J = 8.2 Hz), 7.39 (1H , T, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.42 min; m / z 633.0 [M + H] ⁺ (ESI positive ion mode), m / z 677.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 282
3- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of —yl} methyl) cyclohexanecarbonyl] piperidin-4-yloxy} benzonitrile (Compound No. 282) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 3- (piperidine obtained in Reference Example 281-2 The reaction was carried out in substantially the same manner as in Example 262 except that -4-yloxy) benzonitrile hydrochloride was used to give the title compound (32 mg, quantitative yield) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, br q, J = 12.7 Hz), 1.47-1.69 (2H, m, overlappedby H 2 O), 1.69-1.87 (8H) M), 1.87-2.06 (4H, m), 2.47 (1H, tt, J = 11.9, 2.9 Hz), 2.49-2.65 (4H, m), 3 .11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.38-3.51 (1H, m), 3.52-3.89 (3H, m), 3 .57 (2H, s), 4.50-4.62 (1H, m), 7.10-7.18 (2H, m), 7.23-7.29 (1H, m, overlappedbyCHCl3), 7 .39 (1H, t, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8) 2Hz).

LC / MS [Condition 1]: retention time 3.42 minutes; m / z 639.0 [M + H] ⁺ (ESI positive ion mode), m / z 683.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 283
6- (3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 8-yl) nicotinonitrile (Compound No. 283) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -1-- obtained in Reference Example 255 Suspension of oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride (20 mg, 0.040 mmol) and 6-chloronicotinonitrile (commercially available) (7 mg, 0.05 mmol) in ethanol (1 mL) After adding triethylamine (22 μL, 0.16 mmol) to the solution, the reaction mixture was stirred at 70 ° C. for 33 hours and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / acetone = 3/1] to obtain the title compound (16 mg, yield 70%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 12.3 Hz), 1.49-1.68 (3H, m), 1.68-1.88 (8H, m) 1.94 (2H, br d, J = 14.3 Hz), 2.02 (2 H, br d, J = 13.9 Hz), 2.48 (1 H, br t, J = 11.9 Hz), 2 .82 (1H, br t, J = 11.9 Hz), 3.13 (2H, d, J = 17.0 Hz), 3.21 (1 H, br t, J = 12.4 Hz), 3.29 ( 2H, s), 3.42-3.61 (3H, m), 3.99 (1H, br d, J = 13.9 Hz), 4.25 (2H, br d, J = 13.5 Hz), 4.61 (1H, br d, J = 13.9 Hz), 6.65 (1H, d, J = 9.0 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.6 0 (1H, t, J = 7.4 Hz), 7.62 (1H, dd, J = 9.0, 2.5 Hz), 7.95 (2H, d, J = 7.8 Hz), 8.41 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 4.11 min; m / z 569.9 [M + H] ⁺ (ESI positive ion mode), m / z 614.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 284
Production of (1r, 4r) -N- (4-cyanobenzyl) -4- [2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxamide hydrochloride 3-{[(1r, 4r) -4- (4-cyanobenzylcarbamoyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane obtained in Example 269 To a solution of -8-carboxylate t-butyl (51 mg, 0.10 mmol) in dioxane (1 mL) -acetonitrile (1 mL) was added 10% by mass hydrogen chloride methanol solution (0.20 mL), and left at room temperature for 1 day. Then, it was concentrated to dryness under reduced pressure to give the title compound (55 mg, quantitative yield) as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 0.91 (2H, q, J = 12.3 Hz), 1.37 (2H, q, J = 13.1 Hz), 1.46-1.61 ( 1H, m), 1.69 (2H, br d, J = 12.3 Hz), 1.79 (2H, br d, J = 13.5H), 1.89-2.07 (4H, m), 2.16 (1H, tt, J = 11.9, 2.9 Hz), 2.99 (2H, d, J = 7.4 Hz), 3.02-3.24 (4H, br m), 3. 40 (2H, s), 4.32 (2H, d, J = 5.7 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz) ), 8.42 (1H, t, J = 5.7 Hz), 8.92 (2H, br s).

LC / MS [Condition 1]: retention time 0.5 to 1.1 minutes; m / z 410.9 [M + H] ⁺ (ESI positive ion mode), m / z 454.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 284
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } -N- (4-Cyanobenzyl) cyclohexanecarboxamide (Compound No. 284) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -1-oxa- Instead of 3,8-diazaspiro [4.5] decan-2-one hydrochloride, (1r, 4r) -N- (4-cyanobenzyl) -4-[(2-oxo) obtained in Reference Example 284 was used. The reaction was conducted in substantially the same manner as in Example 267 except that 1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxamide hydrochloride was used. The (3 mg, 13% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (2H, dq, J = 2.9, 12.3 Hz), 1.52 (2H, dq, J = 2.9, 13.5 Hz), 1. 57-1.66 (1H, m), 1.69-1.84 (4H, m), 1.85-2.01 (4H, m), 2.09 (1H, tt, J = 12.3) , 2.9 Hz), 2.50-2.74 (4 H, m), 3.08 (2 H, d, J = 7.8 Hz), 3.22 (2 H, s), 3.75 (2 H, s) ), 4.49 (2H, d, J = 6.1 Hz), 5.87 (1H, brt, J = 6.1 Hz), 7.22 (2H, d, J = 6.1 Hz), 7. 36 (2H, d, J = 8.2 Hz), 7.62 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 561.9 [M + H] ⁺ (ESI positive ion mode), m / zm / z 560.0 [M−H] ⁻ , 606.1 [M + HCOO] ] ^- (ESI negative ion mode)

Reference Example 285
4- (1-{(1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy ) Preparation of benzonitrile hydrochloride 3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo obtained in Example 268 1-Oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (54 mg, 0.093 mmol) in acetonitrile (2 mL) in 10% by weight hydrogen chloride in methanol (0.20 mL) ) And left at room temperature for 1 day, and then concentrated to dryness under reduced pressure. The residue was washed with ethyl acetate (2 mL) to give the title compound (56 mg, quantitative yield) as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 0.99 (2H, q, J = 11.9 Hz), 1.36 (2H, q, J = 11.5 Hz), 1.44-1.75 ( 7H, m), 1.85-2.07 (6H, m), 2.58 (1H, br t, J = 12.3 Hz), 2.98-3.28 (6H, m), 2.98 (2H, d, J = 7.0 Hz), 3.40 (2H, s), 3.71-3.96 (2H, m), 4.72-4.84 (1H, m), 7.16 (2H, d, J = 8.6 Hz), 7.77 (2H, d, J = 8.6 Hz), 8.98 (2H, br s).

LC / MS [Condition 1]: Retention time 2.88 min; m / z 480.9 [M + H] ⁺ (ESI positive ion mode), m / z 525.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 285
4-{[3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl) methyl] -3,5-difluorobenzonitrile (Compound No. 285) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl ] Instead of methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride, 4- (1-{(1r, 4r) -4-] obtained in Reference Example 285 was used. Except for using [(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy) benzonitrile hydrochloride To perform the reaction in the same manner as in Example 267 to give the title compound (14 mg, 58% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, q, J = 12.7 Hz), 1.45 to 1.67 (3H, m), 1.67 to 2.02 (12H, m) , 2.46 (1H, br t, J = 11.5 Hz), 2.54-2.78 (4H, m), 3.09 (2H, d, J = 7.0 Hz), 3.23 (2H , S), 3.37-3.55 (1H, br m), 3.56-3.86 (3H, m), 3.76 (2H, s), 4.56-4.69 (1H, m), 6.96 (2H, d, J = 8.6 Hz), 7.23 (2H, d, J = 6.1 Hz), 7.59 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 632.0 [M + H] ⁺ (ESI positive ion mode), m / z 676.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 286-1
Preparation of t-butyl 4- (2-chlorophenylamino) piperidine-1-carboxylate A solution of t-butyl 4-oxopiperidine-1-carboxylate (0.38 g, 1.9 mmol) in 1,2-dichloroethane (4 mL) 2-chloroaniline (0.10 mL, 0.95 mmol), acetic acid (0.16 mL, 2.8 mmol) and sodium triacetoxyborohydride (0.60 g, 2.8 mmol) were added to the reaction mixture at room temperature. Stir for 1 day. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, and the mixture was further stirred for 30 minutes and allowed to stand. The organic layer was separated and concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 3/1] (0.29 g, quantitative yield) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.35 to 1.51 (2H, m), 1.46 (9H, s), 1.96-2.11 (2H, m), 2.97 (2H , T, J = 11.9 Hz), 3.38-3.55 (1H, m), 3.91-4.13 (2H, br m), 4.20 (1H, br d, J = 6. 9 Hz), 6.62 (1H, td, J = 7.3, 1.3 Hz), 6.68 (1H, d, J = 7.9 Hz), 7.12 (1H, ddd, J = 7.9) , 7.3, 1.3 Hz), 7.25 (1H, dd, J = 7.6, 1.7 Hz).

LC / MS [Condition 2]: Retention time 4.83 minutes; m / z 310.9 [M + H] ⁺ , 254.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 286-2
Preparation of N- (2-chlorophenyl) piperidin-4-amine dihydrochloride 4- (quinolin-4-yl) piperazine-1-carboxylate obtained in Reference Example 286-1 in place of t-butyl The reaction was carried out substantially in the same manner as in Reference Example 278-2 except that t-butyl (2-chlorophenylamino) piperidine-1-carboxylate was used to give the title compound (0.27 g, quantitative yield) as white Obtained as a solid.

LC / MS [Condition 2]: Retention time 1.74 minutes; m / z 211.0 [M + H] ⁺ (ESI positive ion mode)

Example 286
4-{[3-({(1r, 4r) -4- [4- (2-chlorophenylamino) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} benzonitrile (Compound No. 286) In place of 4- (aminomethyl) benzonitrile hydrochloride, N- (2- The reaction was carried out substantially in the same manner as in Example 263, except that (chlorophenyl) piperidin-4-amine dihydrochloride was used, and the title compound (24 mg, yield 83%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.5 Hz), 1.32-1.69 (5H, m), 1.70-1.87 (6H, m) 1.94 (2H, d, J = 12.7 Hz), 2.03-2.21 (2H, m), 2.47-2.66 (4H, br m), 2.47 (1H, tt , J = 11.9, 2.9 Hz), 2.92 (1H, br t, J = 11.9 Hz), 3.11 (2H, d, J = 7.8 Hz), 3.22 (1H, br t, J = 12.3 Hz), 3.26 (2H, s), 3.47-3.63 (1H, m), 3.57 (2H, s), 3.88 (1H, br d, J = 13.5 Hz), 4.21 (1 H, d, J = 7.8 Hz), 4.46 (1 H, br d, J = 13.5 Hz), 6.64 (1 H, dt, J = 1.2) , 7.8H z), 6.68 (1H, d, J = 8.6 Hz), 7.14 (1H, dt, J = 1.2, 7.8 Hz), 7.26 (1H, dd, J = 1.6) , 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 603.8 [M + H] ⁺ (ESI positive ion mode), m / z 648.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 287-1
Preparation of t-butyl 4- (6-chloropyrimidine-4-yl) piperazine-1-carboxylate Piperazine-1-carboxylate in a solution of 4,6-dichloropyrimidine (0.50 g, 3.4 mmol) in acetonitrile (25 mL) T-Butyl acid (0.63 g, 3.4 mmol) and triethylamine (1.4 mL, 10.1 mmol) were added, and the reaction mixture was stirred at 80 ° C. for 4 hours, and then concentrated to dryness under reduced pressure. After adding ethyl acetate (5 mL) and water (5 mL) to the residue and separating the organic layer, the organic layer is washed with water (5 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL), and concentrated to dryness under reduced pressure. To give the title compound (0.64 g, 64% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 3.48-3.59 (4H, m), 3.59-3.70 (4H, m), 6.50 (1H , S), 8.39 (1H, s).

Reference Example 287-2
Production of t-butyl 4- (pyrimidin-4-yl) piperazine-1-carboxylate 4- (6-chloropyrimidine-4-yl) piperazine-1-carboxylic acid t-obtained in Reference Example 287-1 To a solution of butyl (0.30 g, 1.0 mmol) in ethanol (15 mL) under nitrogen atmosphere, 10% by mass palladium on carbon (60 mg), triethylamine (2.1 mL, 15 mmol) and formic acid (0.28 mL, 7.5 mmol) After stirring at room temperature for 1 day, the catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. Ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added to the residue, the organic layer was separated, and the organic layer was concentrated to dryness under reduced pressure to give the title compound (0.25 g, yield 6491%). ) Was obtained as a white solid.

Reference Example 287-3
Preparation of 4- (piperazin-1-yl) pyrimidine dihydrochloride 4- (pyrimidine obtained in Reference Example 287-2 instead of t-butyl 4- (quinolin-4-yl) piperazine-1-carboxylate The reaction was carried out in substantially the same manner as in Reference Example 278-2 except that t-butyl-4-yl) piperazine-1-carboxylate was used to give the title compound (76 mg, quantitative yield) as a white solid. It was.

¹ H-NMR (DMSO-d ₆ ) δ: 3.18-3.30 (4H, br m), 3.99-4.19 (4H, m), 7.27 (1H, d, J = 7) .6 Hz), 8.44 (1 H, d, J = 7.3 Hz), 8.90 (1 H, s), 9.65 (2 H, br s).

Example 287
3-({(1r, 4r) -4- [4- (pyrimidin-4-yl) piperazine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa- Preparation of 3,8-diazaspiro [4.5] decan-2-one (Compound No. 287) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 4- (piperazine-) obtained in Reference Example 287-3 The reaction was carried out in substantially the same manner as in Example 263 except that 1-yl) pyrimidine dihydrochloride was used to obtain the title compound (19 mg, yield 87%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 12.7 Hz), 1.49-1.70 (3H, m), 1.70-1.88 (6H, m) 1.94 (2H, br d, J = 13.1 Hz), 2.47 (1 H, tt, J = 11.9, 2.9 Hz), 2.48-2.68 (4H, br m), 3.12 (2H, d, J = 7.8 Hz), 3.27 (2H, s), 3.55 to 3.67 (4H, br m), 3.57 (2H, s), 3.66 -3.82 (4H, br m), 6.52 (1H, dd, J = 6.1, 1.5 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H , D, J = 7.8 Hz), 8.25 (1H, d, J = 6.1 Hz), 8.63 (1H, br s).

LC / MS [Condition 1]: Retention time 0.92 min; m / z 600.8 [M + H] ⁺ (ESI positive ion mode), m / z 645.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 288
Preparation of 4-chloro-6- (piperazin-1-yl) pyrimidine dihydrochloride obtained in Reference Example 287-1 instead of t-butyl 4- (quinolin-4-yl) piperazine-1-carboxylate The reaction was carried out in substantially the same manner as in Reference Example 278-2 except that t-butyl 4- (6-chloropyrimidine-4-yl) piperazine-1-carboxylate was used, and the title compound (0.21 g, yield) was obtained. Was obtained as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 3.08-3.21 (4H, m), 3.84-3.95 (4H, m), 7.09 (1H, s), 8.42 (1H, s), 9.33 (2H, s).

Example 288
3-({(1r, 4r) -4- [4- (6-chloropyrimidin-4-yl) piperazine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1 Preparation of Oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 288) 4-Chloro- obtained in Reference Example 288 instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out substantially in the same manner as in Example 263 except that 6- (piperazin-1-yl) pyrimidine dihydrochloride was used to give the title compound (20 mg, yield 91%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.07 (2H, q, J = 11.5 Hz), 1.52-1.70 (3H, m), 1.70-1.88 (6H, m) 1.95 (2H, br d, J = 13.1 Hz), 2.46 (1 H, br t, J = 12.7 Hz), 2.48-2.68 (4H, br m), 3.12. (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.49-3.71 (4H, br m), 3.58 (2H, s), 3.64-3. 87 (4H, br m), 6.52 (1H, s), 7.44 (2H, d, J = 7.4 Hz), 7.57 (2H, d, J = 7.4 Hz), 8.41 (1H, s).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 634.8 [M + H] ⁺ (ESI positive ion mode), m / z 678.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 289
4- [1- (2- {4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] phenyl} acetyl) piperidin-4-yloxy] benzo Preparation of nitrile hydrochloride 3- (4- {2- [4- (4-cyanophenoxy) piperidin-1-yl] -2-oxoethyl} benzyl) -2-oxo-1- obtained in Example 275 After adding 10 mass% hydrogen chloride methanol solution (95 μL) to a solution of t-butyl oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (28 mg, 0.048 mmol) in methanol (1 mL). The reaction mixture was allowed to stand at room temperature for 10 days and concentrated to dryness under reduced pressure to give the title compound (24 mg, quantitative yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.65-2.39 (8H, br m), 2.99-4.00 (12H, br m), 4.42 (2H, br s), 4. 50-4.69 (1H, br m), 6.94 (2H, d, J = 8.0 Hz), 7.18-7.31 (4H, m), 7.59 (2H, d, J = 8.0 Hz), 9.43-9.99 (2H, br m).

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 488.7 [M + H] ⁺ (ESI positive ion mode), m / z 532.9 [M + HCOO] ⁻ , 487.0 [M−H] ⁻ (ESI negative ion mode)

Example 289
3- (4- {2- [4- (4-Cyanophenoxy) piperidin-1-yl] -2-oxoethyl} benzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of ethyl -8-carboxylate (Compound No. 289) 4- [1- (2- {4-[(2-oxo-1-oxa-3,8-diazaspiro [4. 5] Decan-3-yl) methyl] phenyl} acetyl) piperidin-4-yloxy] benzonitrile hydrochloride (24 mg, 0.046 mmol) in chloroform (1 mL) was added triethylamine (32 μL, 0.23 mmol), At 0 ° C. ethyl chloroformate (5 μL, 0.05 mmol) was added. After removing the ice bath and allowing to stand for 3 days, a solution of citric acid (44 mg) in water (1 mL) was added, the organic layer was separated, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia Ltd., developing solvent: chloroform / acetone = 4/1] to obtain the title compound (16 mg, yield 62%) as a colorless amorphous product. It was.

¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.53-2.01 (8H, m), 3.14 (2H, s), 3.31 (1H, br t, J = 11.9 Hz), 3.46 (1H, ddd, J = 13.5, 6.1, 4.1 Hz), 3.67 (1H, ddd, J = 13.5, 8.2, 3.7 Hz), 3.70-3.80 (2H, m), 3.75 (2H, s), 3.78-4.01 (2H, br m), 4.13 (2H , Q, J = 7.0 Hz), 4.42 (2H, s), 4.59 (1H, tt, J = 6.5, 4.1 Hz), 6.93 (2H, d, J = 9. 0 Hz), 7.22 (2H, d, J = 9.0 Hz), 7.26 (2H, d, J = 9.0 Hz), 7.58 (2H, d, J = 9.0 Hz).

LC / MS [Condition 1]: Retention time 4.01 min; m / z 560.8 [M + H] ⁺ (ESI positive ion mode), m / z 605.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 290
4- (1-{(1r, 4r) -4-[(2-Thioxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy ) Preparation of benzonitrile hydrochloride 3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-thioxo obtained in Example 277 1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (82 mg, 0.14 mmol) in methanol (2 mL) -chloroform (0.5 mL) After adding hydrogen methanol solution (0.3 mL), the reaction mixture was allowed to stand at room temperature for 3 days and concentrated to dryness under reduced pressure to give the title compound (79 mg, quantitative yield) as a white solid It was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.08-1.29 (2H, m), 1.48-1.68 (2H, m), 1.68-2.05 (9H, m), 2 .16 (2H, br d, J = 12.7 Hz), 2.29-2.58 (3H, m), 3.23-3.84 (12H, m), 4.59-4.69 (1H M), 6.96 (2H, d, J = 9.0 Hz), 7.60 (2H, d, J = 9.0 Hz), 9.64-10.16 (2H, br m).

LC / MS [Condition 1]: retention time minutes 3.12; m / z 496.8 [M + H] ⁺ (ESI positive ion mode), m / z 540.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 290
3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-thioxo-1-oxa-3,8-diazaspiro [4.5] Preparation of ethyl decane-8-carboxylate (Compound No. 290) 4- (1-{(1r, 4r) -4-[(2-thioxo-1-oxa-3,8- To a suspension of diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy) benzonitrile hydrochloride (20 mg, 0.038 mmol) in chloroform (1 mL) is triethylamine (26 μL, 0.19 mmol). ) And ethyl chloroformate (4 μL, 0.04 mmol) was added at 0 ° C. The ice bath was removed and the mixture was allowed to stand for 3 days. A solution of citric acid (37 mg) in water (1 mL) was added, the organic layer was separated, and concentrated to dryness under reduced pressure to give the title compound (22 mg, quantitative yield). Was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.18 (2H, q, J = 12.3 Hz), 1.27 (3H, t, J = 7.0 Hz), 1.45 to 1.66 (3H, m), 1.66-1.89 (8H, m), 1.97 (2H, br d, J = 14.0 Hz), 2.41-2.58 (1H, m), 3.37-3 .52 (1H, br m), 3.41 (2H, t, J = 11.1 Hz), 3.46 (2H, s), 3.56 (2H, d, J = 7.4 Hz), 3. 59-3.83 (3H, m), 3.81-4.01 (2H, br m), 4.15 (2H, q, J = 7.0 Hz), 4.63 (1H, tt, J = 6.1, 3.3 Hz), 6.96 (2H, d, J = 8.6 Hz), 7.59 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 4.23 minutes; m / z 568.8 [M + H] ⁺ (ESI positive ion mode), m / z 612.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 291
4- [1-((1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-thioxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Cyclohexanecarbonyl) piperidin-4-yloxy] benzonitrile (Compound No. 291) 4- (1-{(1r, 4r) -4-[(2-thioxo-1-oxa) obtained in Reference Example 290 −3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy) benzonitrile hydrochloride (20 mg, 0.038 mmol) in N, N-dimethylformamide (0.60 mL) ) To the suspension, triethylamine (16 μL, 0.11 mmol) and 4- (bromomethyl) benzonitrile (commercially available) (8 mg, 0.041 mmol) were added. I was painting. After stirring at room temperature for 3 days, water (1 mL) was added. The resulting solid was collected by filtration to give the title compound (17 mg, yield 74%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.17 (2H, q, J = 12.7 Hz), 1.47-1.67 (2H, m), 1.66-2.11 (13H, m) , 2.41-2.74 (5H, m), 3.39-3.83 (4H, br m), 3.45 (2H, s), 3.54 (2H, d, J = 7.4 Hz) ), 3.58 (2H, s), 4.56-4.68 (1H, m), 6.95 (2H, d, J = 8.6 Hz), 7.44 (2H, d, J = 7) .8 Hz), 7.60 (2H, d, J = 8.6 Hz), 7.62 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.34 minutes; m / z 611.9 [M + H] ⁺ (ESI positive ion mode), m / z 656.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 292-1
Preparation of 4- (2-methoxyphenylamino) piperidine-1-carboxylate t-butyl 4-oxopiperidine-1-carboxylate t-butyl (0.38 g, 1.9 mmol) 1,2-dichloroethane (4 mL) To the solution was added 2-methoxyaniline (0.11 mL, 0.95 mmol), acetic acid (0.16 mL, 2.8 mmol) and sodium triacetoxyborohydride (0.60 g, 2.8 mmol) and the reaction mixture was allowed to cool to room temperature. For 2 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, and the mixture was further stirred for 30 minutes and allowed to stand. The organic layer was separated and concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: n-hexane / ethyl acetate = 3/1] to give the title compound (0.31 g, quantitative yield) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.36 (2H, ddd, J = 13.0, 10.9, 4.3 Hz), 1.47 (9H, s), 2.04 (2H, br dd , J = 12.6, 3.3 Hz), 2.95 (2H, t, J = 12.6 Hz), 3.36-3.50 (1H, m), 3.84 (3H, s), 3 .94-4.12 (2H, br m), 4.11-4.17 (1 H, br m), 6.63 (1 H, td, J = 7.9, 1.5 Hz), 6.67 ( 1H, dd, J = 7.6, 1.5 Hz), 6.78 (1H, dd, J = 7.9, 1.5 Hz), 6.86 (1H, td, J = 7.6, 1. 5 Hz).

LC / MS [Condition 2]: Retention time 2.81 minutes; m / z 307.0 [M + H] ⁺ , 251.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 292-2
Preparation of N- (2-methoxyphenyl) piperidin-4-amine dihydrochloride 4 obtained in Reference Example 292-1 instead of t-butyl 4- (quinolin-4-yl) piperazine-1-carboxylate The reaction was carried out in substantially the same manner as in Reference Example 278-2 except that t-butyl 2- (2-methoxyphenylamino) piperidine-1-carboxylate was used to give the title compound (0.29 g, quantitative yield). Was obtained as a gray solid.

LC / MS [Condition 2]: retention time 0.55 min; m / z 207.0 [M + H] ⁺ (ESI positive ion mode)

Example 292
4-{[3-({(1r, 4r) -4- [4- (2-methoxyphenylamino) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro Preparation of [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 292) N- (2) obtained in Reference Example 292-2 instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 263 except that -methoxyphenyl) piperidin-4-amine dihydrochloride was used to obtain the title compound (29 mg, quantitative yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 12.7 Hz), 1.31-1.47 (2H, br m), 1.47-1.69 (3H, m ), 1.69-1.87 (6H, m), 1.94 (2H, br d, J = 13.9 Hz), 2.00-2.22 (2H, m), 2.47 (1H, t, J = 11.1 Hz), 2.48-2.66 (4H, m), 2.89 (2H, br t, J = 12.3 Hz), 3.11 (2H, d, J = 7. 4 Hz), 3.20 (2 H, br t, J = 12.3 Hz), 3.26 (2 H, s), 3.43-3.62 (1 H, br m), 3.57 (2 H, s) 3.83 (3H, s), 3.87 (1H, br d, J = 13.5 Hz), 4.09-4.19 (1H, br m), 4.46 (1 H, br d, J = 13. 5 Hz), 6.63 (1H, dd, J = 7.8, 1.2 Hz), 6.67 (1H, dt, J = 1.2, 7.8 Hz), 6.78 (1H, dd, J = 7.8, 1.2 Hz), 6.86 (1H, dt, J = 1.2, 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 599.8 [M + H] ⁺ (ESI positive ion mode), m / z 644.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 293-1
Preparation of 4- (5-cyanopyridin-2-yloxy) piperidine-1-carboxylate t-butyl 4-hydroxypiperidine-1-carboxylate (commercially available) (0.20 g, 0.99 mmol) in tetrahydrofuran (0.20 g, 0.99 mmol) 2.0 mL) solution was added sodium hydride (55 mass%, liquid paraffin dispersion) (44 mg, 0.99 mmol) at room temperature over 13 minutes. After stirring at room temperature for 20 minutes, a solution of 6-chloronicotinonitrile (commercially available) (0.11 g, 0.79 mmol) in tetrahydrofuran (2.0 mL) was added and stirred for 3 hours. Acetic acid (23 μL) was added and concentrated to dryness under reduced pressure. After adding ethyl acetate (2 mL) and water (1 mL) to the residue, the organic layer was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / ethyl acetate = 10/1] to obtain the title compound (0.27 g, quantitative yield) as a white solid. It was.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.75 (2H, dddd, J = 13.1, 8.6, 8.2, 3.7 Hz), 1.92- 2.04 (2H, m), 3.28 (2H, ddd, J = 13.9, 8.6, 3.7 Hz), 3.70-3.85 (2H, m), 5.29 (1H , Tt, J = 8.2, 4.1 Hz), 6.79 (1H, d, J = 9.0 Hz), 7.78 (1H, dd, J = 9.0, 2.5 Hz), 8. 45 (1H, d, J = 2.5 Hz).

Reference Example 293-2
Production of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride t-butyl 4- (5-cyanopyridin-2-yloxy) piperidine-1-carboxylate obtained in Reference Example 293-1 (0. 26 g, 0.86 mmol) was dissolved in methanol (2 mL), 10 mass% hydrogen chloride methanol solution (2 mL) was added, and the mixture was allowed to stand at 50 ° C. for 4 hours. The reaction solution was concentrated to dryness under reduced pressure, The title compound (0.22 g, quantitative yield) was obtained as a white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 1.79-1.98 (2H, m), 2.06-2.22 (2H, m), 3.11 (2H, ddd, J = 12. 7, 9.0, 3.7 Hz), 3.25 (2H, ddd, J = 12.7, 6.5, 3.7 Hz), 5.32 (1H, tt, J = 7.8, 3. 7 Hz), 7.03 (1 H, d, J = 9.0 Hz), 8.19 (1 H, dd, J = 9.0, 2.5 Hz), 8.70 (1 H, d, J = 2.5 Hz) ), 8.77 (2H, br s).

LC / MS [Condition 1]: Retention time 0.54 minutes; m / z 204.1 [M + H] ⁺ (ESI positive ion mode)

Example 293
6- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of -yl} methyl) cyclohexanecarbonyl] piperidin-4-yloxy} nicotinonitrile (Compound No. 293) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 6- ( The reaction was carried out in substantially the same manner as in Example 263 except that piperidin-4-yloxy) nicotinonitrile hydrochloride was used to obtain the title compound (26 mg, yield 93%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 11.9 Hz), 1.46-1.68 (3H, m), 1.68-1.87 (8H, m) 1.92-2.13 (2H, br m), 1.94 (2H, br d, J = 13.5 Hz), 2.45-2.69 (4H, br m), 2.47 (1H , Tt, J = 11.9, 2.9 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.32-3.52 (2H, br m ), 3.57 (2H, s), 3.67-3.83 (1H, br m), 3.89-4.05 (1H, br m), 5.36 (1 H, tt, J = 7) .8, 3.7 Hz), 6.80 (1H, d, J = 9.0 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8. 2Hz), 7.79 1H, dd, J = 8.8,2.5Hz), 8.46 (1H, d, J = 2.5Hz).

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 639.9 [M + H] ⁺ (ESI positive ion mode), m / z 684.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 294
6- {1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl Preparation of piperidin-4-yloxy} nicotinonitrile (Compound No. 294) Instead of 4-benzylpiperidine, 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride and triethylamine obtained in Reference Example 293-2 The title compound (29 mg, quantitative yield) was obtained as a colorless amorphous substance by carrying out the reaction substantially in the same manner as in Example 253 except that was used.

¹ H-NMR (CDCl ₃ ) δ: 1.72-2.29 (4H, br m), 1.73 (2H, dt, J = 13.5, 7.0 Hz), 1.92 (2H, br d, J = 13.5 Hz), 2.39-2.64 (4H, br m), 3.14 (2H, s), 3.24-3.51 (1 H, br m), 3.48- 3.85 (2H, br m), 3.56 (2H, s), 3.88-4.22 (1 H, br m), 4.45 (2H, s), 5.40 (1 H, tt, J = 7.0, 3.7 Hz), 6.81 (1H, d, J = 9.0 Hz), 7.32 (2H, d, J = 7.8 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.80 (1H, dd, J = 9.0, 2.0 Hz), 8. 5 (1H, d, J = 2.0Hz).

LC / MS [condition 1]: retention time 3.26 minutes; m / z 633.9 [M + H] ⁺ (ESI positive ion mode), m / z 677.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 295
3- [1-((1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of cyclohexanecarbonyl) piperidin-4-yloxy] benzonitrile (Compound No. 295) Instead of 4- (aminomethyl) benzonitrile hydrochloride, 3- (piperidin-4-yloxy) obtained in Reference Example 281-2 ) The reaction was carried out in substantially the same manner as in Example 263 except that benzonitrile hydrochloride was used to obtain the title compound (23 mg, yield 79%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 13.1 Hz), 1.45 to 1.68 (3H, m), 1.70-1.87 (8H, m) , 1.87-2.03 (4H, m), 2.47 (1H, br t, J = 11.1 Hz), 2.49-2.62 (4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.37-3.51 (1H, m), 3.52-3.86 (3H, m), 3.57 (2H, s), 4.56 (1H, tt, J = 6.5, 3.3 Hz), 7.10-7.19 (2H, m), 7.22-7.28 (1H, m), 7. 39 (1H, t, J = 7.8 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.18 min; m / z 595.9 [M + H] ⁺ (ESI positive ion mode), m / z 640.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 296
4-{[3-({(1r, 4r) -4- [4- (4-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-thioxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 296) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl ] 4- (1-{(1r, 4r) -4-] obtained in Reference Example 290 instead of methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride Other than using [(2-Thioxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-yloxy) benzonitrile hydrochloride By performing the same reaction as substantially Example 267 to give the title compound (23 mg, 94% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.07-1.28 (2H, m), 1.40-2.09 (15 H, m), 2.49 (1 H, t, J = 11.5 Hz) , 2.53-2.82 (4H, m), 3.40-3.59 (1H, br m), 3.41 (2H, s), 3.52 (2H, d, J = 7.0 Hz) ), 3.59-3.90 (3H, br m), 3.75 (2H, s), 4.56-4.69 (1H, m), 6.95 (2H, d, J = 8. 6 Hz), 7.23 (2H, d, J = 5.7 Hz), 7.60 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: retention time 3.56 minutes; m / z 647.9 [M + H] ⁺ (ESI positive ion mode), m / z 692.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 297
3-({5- [4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -8- [4- (tri Preparation of (fluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 297) 3-isopropyl-5 obtained in Reference Example 195 instead of tetrahydrofurfurylamine The reaction was conducted in substantially the same manner as in Example 111 except that-(piperidin-4-yl) -1,2,4-oxadiazole hydrochloride and triethylamine were used to give the title compound (25 mg, quantitative). Obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d, J = 6.0 Hz), 1.66-1.85 (2H, m), 1.88-2.03 (4H, m) , 2.06-2.26 (2H, m), 2.45-2.64 (4H, m), 3.01-3.15 (1H, septet, J = 6.0 Hz), 3.17- 3.30 (3H, m), 3.35 (2H, s), 3.57 (2H, s), 3.69-3.88 (1H, brm), 4.50-4.61 (1H, brm), 4.58 (2H, s), 7.37 (1H, d, J = 7.8 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 7.8, 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [condition 1]: retention time 3.19 minutes; m / z 627.0 [M + H] ⁺ (ESI positive ion mode), m / z 671.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 298
N- (4-cyanobenzyl) -6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) nicotinamide (Compound No. 298) The title compound was reacted in substantially the same manner as in Example 111 except that 4- (aminomethyl) benzonitrile hydrochloride and triethylamine were used instead of tetrahydrofurfurylamine. (25 mg, quantitative) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.69-1.83 (2H, m), 1.90-2.01 (2H, m), 2.47-2.59 (4H, m), 3 .34 (2H, s), 3.56 (2H, s), 4.57 (2H, s), 4.72 (2H, d, J = 6.1 Hz), 6.79-6.98 (1H , Brm), 7.37 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.5 Hz), 7 .57 (2H, d, J = 8.2 Hz), 7.64 (2H, d, J = 8.5 Hz), 8.13 (1H, dd, J = 7.8, 2.4 Hz), 8. 96 (1H, d, J = 2.4 Hz).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 563.9 [M + H] ⁺ (ESI positive ion mode), m / z 562.1 [MH] ⁻ (ESI negative ion mode)

Example 299
4- [5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiazole-2- Carboxamide] Preparation of piperidine-1-carboxylate methyl (Compound No. 299) Substantially except that 4-aminopiperidine-1-carboxylate methyl hydrochloride obtained in Reference Example 135 was used instead of 4-benzoylpiperidine hydrochloride The reaction was carried out in the same manner as in Example 142 to obtain the title compound (9.1 mg, yield 69%) as an oil.

¹ H-NMR (CDCl ₃ ) δ: 1.43-1.54 (2H, m), 1.70-1.84 (2H, m), 1.88-2.10 (4H, m), 2 49-2.64 (4H, m), 2.98 (2H, t, J = 12.1 Hz), 3.28 (2H, s), 3.57 (2H, s), 3.71 (3H) , S), 4.01-4.27 (3H, m), 4.56 (2H, s), 7.07 (1H, d, J = 8.0 Hz), 7.42 (1H, s), 7.44 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 595.9 [M + H] ⁺ (ESI positive ion mode), m / z 594.0 [MH] ⁻ (ESI negative ion mode)

Example 300
N- (4-cyanobenzyl) -5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) thiazole-2-carboxamide (Compound No. 300) The reaction was carried out in substantially the same manner as in Example 142, except that 4- (aminomethyl) benzonitrile hydrochloride was used instead of 4-benzoylpiperidine hydrochloride. To give the title compound (7.9 mg, 64% yield) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.68-1.81 (2H, m), 1.87-1.98 (2H, m), 2.45-2.62 (4H, m), 3 .25 (2H, s), 3.56 (2H, s), 4.56 (2H, s), 4.69 (2H, d, J = 6.3 Hz), 7.43 (2H, d, J = 8.3 Hz), 7.46 (1H, s), 7.46 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.3 Hz), 7.61-7 .68 (1H, m), 7.64 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 3.19 minutes; m / z 569.8 [M + H] ⁺ (ESI positive ion mode), m / z 568.0 [MH] ⁻ (ESI negative ion mode)

Example 301
5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] thiazole-2-carboxamide (Compound No. 301) The reaction was carried out in substantially the same manner as in Example 142 except that tetrahydrofurfurylamine was used instead of 4-benzoylpiperidine hydrochloride and triethylamine. The title compound (8.0 mg, 68% yield) was obtained as an oil.

¹ H-NMR (CDCl ₃ ) δ: 1.60-1.67 (1H, m), 1.70-1.83 (2H, m), 1.86-2.10 (5H, m), 2 .48-2.60 (4H, m), 3.32 (2H, s), 3.34-3.43 (1H, m), 3.57 (2H, s), 3.68-3.80 (2H, m), 3.83-3.93 (1H, m), 4.01-4.12 (1H, m), 4.56 (2H, s), 7.40-7.52 (1H M), 7.42 (1H, s), 7.43 (2H, d, J = 8.0 Hz), 7.57 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 2.91 minutes; m / z 538.9 [M + H] ⁺ (ESI positive ion mode), m / z 537.0 [MH] ⁻ (ESI negative ion mode)

Example 302
4- {1- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinoyl Preparation of piperidin-4-yloxy} benzonitrile (Compound No. 302) Substantially the same as Example 111, except that 4- (piperidin-4-yloxy) benzonitrile hydrochloride and triethylamine were used in place of tetrahydrofurfurylamine. The title compound (14 mg, 96%) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.71-2.13 (8H, brm), 2.45-2.66 (4H, m), 3.29-4.00 (4H, brm), 3 .35 (2H, s), 3.57 (2H, s), 4.58 (2H, s), 4.66-4.77 (1H, m), 6.97 (2H, d, J = 8) .9 Hz), 7.37 (1H, d, J = 7.8 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7 .60 (2H, d, J = 8.9 Hz), 7.76 (1H, dd, J = 7.8, 2.0 Hz), 8.62 (1H, d, J = 2.0 Hz).

LC / MS [condition 1]: retention time 3.26 minutes; m / z 634.0 [M + H] ⁺ (ESI positive ion mode), m / z 678.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 303
4- {1- [5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiazole Preparation of -2-carbonyl] piperidin-4-yloxy} benzonitrile (Compound No. 303) Substantially except that 4- (piperidin-4-yloxy) benzonitrile hydrochloride is used in place of 4-benzoylpiperidine hydrochloride The reaction was carried out in the same manner as in Example 142 to obtain the title compound (5.8 mg, yield 41%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.69-1.82 (2H, m), 1.86-2.13 (6H, m), 2.44-2.59 (4H, m), 3 .28 (2H, s), 3.55 (2H, s), 3.83-3.95 (2H, brm), 4.33-4.49 (2H, brm), 4.56 (2H, s) ), 4.67-4.75 (1H, m), 6.97 (2H, d, J = 8.9 Hz), 7.39 (1H, s), 7.43 (2H, d, J = 8) .2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.9 Hz).

LC / MS [Condition 1]: Retention time 3.39 minutes; m / z 640.0 [M + H] ⁺ (ESI positive ion mode), m / z 684.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 304-1
Production of methyl 4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate 3- [4- (Methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (160 mg, 0.40 mmol) dissolved in methanol (0.40 mL) 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated to dryness under reduced pressure, and then the resulting solid was dissolved in chloroform and neutralized with an aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained solid was dissolved in ethyl acetate and precipitated again with hexane to obtain the title compound (93 mg, yield 76%) as a white solid.

Reference Example 304-2
Preparation of 1- [4- (trifluoromethyl) phenyl] ethanol 1- [4- (Trifluoromethyl) phenyl] ethanone (commercial reagent) (190 mg, 1.0 mmol) was dissolved in methanol (5.0 mL), Sodium borohydride (38 mg, 1.0 mmol) was added and stirred at room temperature for 30 minutes. Water and ammonium chloride were added to the reaction mixture, and then ethyl acetate was added. The organic layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (180 mg, yield 92%) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.51 (3H, d, J = 6.8 Hz), 1.91 (1H, brs), 4.97 (1H, q, J = 6.8 Hz), 7 .49 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz).

Reference Example 304-3
4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid Production of methyl 1- [4- (trifluoromethyl) phenyl] ethanol (30 mg, 0.16 mmol) obtained in Reference Example 304-2 was dissolved in tetrahydrofuran (2.0 mL), and methanesulfonyl chloride was cooled with ice. (0.014 mL, 0.17 mmol) and triethylamine (0.024 mL, 0.17 mmol) were added, followed by stirring for 30 minutes. After further stirring at room temperature for 15 minutes, the reaction mixture was ice-cooled, ethyl acetate and water were added, and the organic layer was separated. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1- [4- (trifluoromethyl) phenyl] ethyl methanesulfonate as a pale yellow oil. Methyl 4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate (52 mg, 0.17 mmol) obtained in Reference Example 304-1 was used. After being dissolved in N, N-dimethylformamide (1.0 mL), 1- [4- (trifluoromethyl) phenyl] ethyl methanesulfonate and triethylamine (17 mg, 0.17 mmol) obtained above under ice cooling were used. And stirred at room temperature for 1 day. Water was added to the reaction mixture, and the precipitated white solid was collected by filtration and dried at 50 ° C. for 1 hour under reduced pressure to obtain the title compound (27 mg, yield 34%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, d, J = 6.5 Hz), 1.49-1.95 (4H, m), 2.38-2.63 (4H, m) 3.10 (2H, s), 3.49 (1H, q, J = 6.5 Hz), 3.92 (3H, s), 4.47 (2H, s), 7.33 (2H, d) , J = 8.3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.3 Hz), 8.02 (2H, d, J = 8. 3 Hz).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 476.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 304-4
4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid Preparation of 3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methylbenzoate 4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 304-3. Reaction was carried out in substantially the same manner as in Reference Example 108-3, except that methyl (decan-3-yl) methyl] benzoate was used, to give the title compound (19 mg, yield 73%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.77 (3H, d, J = 6.1 Hz), 1.86-2.05 (2H, m), 2.27-2.59 (2H, m) , 2.76-2.96 (2H, m), 3.00-3.14 (1H, m), 3.17 (2H, s), 3.41-3.59 (1H, m), 4 .06 (1H, q, J = 6.1 Hz), 4.42 (1H, d, J = 15.1 Hz), 4.50 (1H, d, J = 15.1 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.61-7.72 (4H, m), 8.03 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.84 minutes; m / z 462.8 [M + H] ⁺ (ESI positive ion mode), m / z 461.0 [MH] ⁻ (ESI negative ion mode)

Example 304
3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 304) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3 obtained in Reference Example 304-4 instead of -yl} methyl) nicotinic acid , 8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid is substantially as described in Example 11 except that 4-benzoylpiperidine hydrochloride and triethylamine are used in place of tetrahydrofurfurylamine. The reaction was carried out similarly to give the title compound (6.0 mg, 50% yield).

¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, d, J = 6.8 Hz), 1.62-2.07 (8H, m), 2.34-2.64 (4H, m) 3.00-3.22 (2H, brm), 3.10 (2H, s), 3.44-3.62 (1H, brm), 3.50 (1H, q, J = 6.8 Hz) , 3.73-3.96 (1H, brm), 4.44 (2H, s), 4.58-4.77 (1H, brm), 7.30 (2H, d, J = 8.2 Hz) 7.37-7.45 (4H, m), 7.46-7.63 (5H, m), 7.95 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.39 minutes; m / z 633.7 [M + H] ⁺ (ESI positive ion mode), m / z 678.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 305
4- (1- {4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] ethyl} -1-oxa-3,8-diazaspiro [4.5] decane-3- Yl) methyl] benzoyl} piperidin-4-yloxy) benzonitrile (Compound No. 305) 6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- 4-[(2-oxo-8- {1- [4- (trifluoromethyl) phenyl] obtained in Example 304-4 instead of diazaspiro [4.5] decan-3-yl} methyl) nicotinic acid ] Ethyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid with 4- (piperidin-4-yloxy) benzonitrile hydrochloride instead of tetrahydrofurfurylamine Except using triethylamine is carried out the same reaction as substantially Example 111 to give the title compound (7.5 mg, 61% yield).

¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, d, J = 6.5 Hz), 1.62-2.07 (8H, m), 2.35-2.63 (4H, m) , 3.11 (2H, s), 3.36-3.92 (4H, br m), 3.50 (1H, q, J = 6.5 Hz), 4.44 (2H, s), 4. 63-4.73 (1H, m), 6.96 (2H, d, J = 8.9 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.9 Hz) .

LC / MS [Condition 1]: Retention time 3.44 minutes; m / z 647.0 [M + H] ⁺ (ESI positive ion mode), m / z 691.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 306-1
Production of t-butyl 4-[(4-bromophenethylamino) methyl] -4-hydroxypiperidine-1-carboxylate 1-oxa-6-azaspiro [2.5] octane-obtained in Reference Example 1-1 After suspending t-butyl 6-carboxylate (1 g, 4.7 mmol) in methanol (10 mL) and water (10 mL), 4-bromophenethylamine (commercially available) (940 mg, 4.7 mmol) was added, and Stir for hours. After adding chloroform to the reaction mixture, the organic layer was separated and washed with saturated aqueous ammonium chloride solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in a small amount of ethyl acetate, and hexane was added for crystallization. The resulting white solid was dried at 50 degrees under reduced pressure to give the title compound (1.6 g, yield 81%).

¹ H-NMR (CDCl ₃ ) δ: 1.28-1.52 (4H, m), 1.45 (9H, s), 2.52 (2H, s), 2.73 (2H, t, J = 7.0 Hz), 2.90 (2H, t, J = 7.0 Hz), 3.03-3.34 (2H, m), 3.69-4.02 (2H, m), 7.06 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz).
(NH, OH invisible)

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 412.9, 414.8 [M + H] ⁺ (ESI positive ion mode), retention time 3.81 minutes; m / z 446.9, 449. 2 [M + HCOO] ^- (ESI negative ion mode)

Reference Example 306-2
Preparation of 3- (4-bromophenethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 4- [4-] obtained in Reference Example 306-1 (4-Bromophenethylamino) methyl] -4-hydroxypiperidine-1-carboxylate t-butyl (1.5 g, 3.6 mmol) was dissolved in tetrahydrofuran (20 mL), and 1,1′-carbonyldiimidazole ( 1.2 g, 7.3 mmol) was added and stirred at room temperature for 48 hours. Water was added to the reaction mixture, and the mixture was stirred for 1 hour until foaming stopped. After adding ethyl acetate to the reaction mixture, the organic layer was separated and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in a small amount of ethyl acetate and crystallized by adding hexane. The resulting white solid was collected and dried at 50 ° C. under reduced pressure to give the title compound (970 mg, 61% yield).

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.50-1.63 (2H, m), 1.70-1.84 (2H, m), 2.84 (2H , T, J = 7.2 Hz), 3.09 (2H, s), 3.17-3.32 (2H, m), 3.50 (2H, t, J = 7.2 Hz), 3.67 -3.87 (2H, m), 7.09 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz).

LC / MS [Condition 1]: Retention time 4.65 minutes; m / z 460.7, 462.7 [M + Na] ⁺ (ESI positive ion mode)

Reference Example 306-3
Preparation of 2-oxo-3- (4-vinylphenethyl) -1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 3- (obtained in Reference Example 306-2 4-Bromophenethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (100 mg, 0.23 mmol), tributyl (vinyl) tin (87 mg, 0 .27 mmol) and tetrakis (triphenylphosphine) palladium complex (27 mg, 0.023 mmol) were suspended in toluene, and then stirred at 110 degrees for 3 hours. The reaction mixture was cooled to room temperature, 5% aqueous potassium fluoride solution was added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate was added to the reaction mixture, followed by filtration through celite to remove insolubles. The organic layer of the filtrate was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to dryness under reduced pressure, and the obtained residue was purified by silica gel column chromatography [Prefpack SI 60 μm, manufactured by Shoko Scientific Co., Ltd., developing solvent: hexane-ethyl acetate] to give the title compound (54 mg, Yield 62%) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.50-1.59 (2H, m), 1.72-1.81 (2H, m), 2.88 (2H , T, J = 7.2 Hz), 3.07 (2H, s), 3.17-3.31 (2H, m), 3.52 (2H, t, J = 7.2 Hz), 3.66 −3.84 (2H, br m), 5.24 (1H, d, J = 10.9 Hz), 5.73 (1H, d, J = 17.4 Hz), 6.69 (1H, dd, J = 17.4, 10.9 Hz), 7.18 (2H, d, J = 8.2 Hz), 7.36 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.47 minutes; m / z 408.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 306-4
Production of t-butyl 3- (4-formylphenethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 2-oxo obtained in Reference Example 306-3 -3- (4-Vinylphenethyl) -1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (50 mg, 0.13 mmol) was dissolved in tetrahydrofuran (2.0 mL). Later, osmium tetroxide (microencapsulation, content 10% by weight, purchased from Wako Pure Chemical Industries, Ltd.) (46 mg, 0.10 mmol), water (1.0 mL) and sodium periodate (83 mg, 0.39 mmol) And stirred at room temperature. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. After adding ethyl acetate, insoluble matters were removed, and the organic layer of the filtrate was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title compound (60 mg) as a white solid. The obtained solid was used for the next reaction without purification.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.50-1.61 (2H, m), 1.70-1.83 (2H, m), 2.98 (2H , T, J = 7.2 Hz), 3.11 (2H, s), 3.17-3.29 (2H, m), 3.58 (2H, t, J = 7.2 Hz), 3.72. -3.89 (2H, m), 7.40 (2H, d, J = 8.2 Hz), 7.85 (2H, d, J = 8.2 Hz), 10.00 (1H, s).

LC / MS [Condition 1]: Retention time 4.02 minutes; m / z 410.9 [M + Na] ⁺ (ESI positive ion mode)

Reference Example 306-5
Preparation of 4- {2- [8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] ethyl} benzoic acid Reference Example 306-4 3- (4-Formylphenethyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (60 mg) obtained in 1 above was converted to t-butyl alcohol (1 0.5 mL) and water (1.0 mL), 2-methyl-2-butene (0.14 mL, 1.3 mmol), sodium dihydrogen phosphate (78 mg, 0.65 mmol) and sodium perchlorate (35 mg). , 0.39 mmol) was added and stirred at room temperature for 24 hours. Dimethyl sulfoxide (0.50 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 24 hours. To the reaction mixture was added sodium perchlorate (35 mg, 0.39 mmol), sodium dihydrogen phosphate (78 mg, 0.65 mmol) and 2-methyl-2-butene (0.14 mL, 1.3 mmol), followed by chloroform. (1.5 mL) was added and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, chloroform and water were added and shaken, the organic layer was separated, and the aqueous layer was extracted twice with chloroform. The combined organic layers were washed with saturated brine, and the separated aqueous layer was extracted once again with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. Diethyl ether was added to the residue, and the precipitated white solid was collected, and dried under reduced pressure at 30 ° C. for 1 hour to obtain the title compound (28 mg, yield 53% (2 steps)).

LC / MS [Condition 1]: Retention time 3.81 minutes; m / z 403.0 [MH] ⁻ (ESI negative ion mode)

Reference Example 306-6
3- {4- [4- (4-Cyanophenoxy) piperidine-1-carbonyl] phenethyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl obtained in the reference example 306-5 4- {2- [8- (t- butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] Ethyl} benzoic acid (25 mg, 0.062 mmol), 4- (piperidin-4-yloxy) benzonitrile hydrochloride (15 mg, 0.062 mmol) obtained in Reference Example 264-2 and 1-hydroxybenzotriazole (2. 5 mg, 0.019 mmol) was dissolved in chloroform (2.0 mL), and then triethylamine (0.0090 mL, 0.062 mmol) and 1-ethyl-3- (3 Dimethylaminopropyl) carbodiimide hydrochloride (12 mg, 0.062 mmol) and the mixture was stirred at room temperature for 20 hours. After adding water, it was shaken and the organic layer was separated. The organic layer was washed with aqueous citric acid solution, 1.0 M aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by preparative thin-layer chromatography [Merck PLC glass plate silica gel _{60F 254,} developing solvent: chloroform / methanol = 10/1] to give the title compound (22 mg, 60% yield) as a white solid Got as.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.53-1.62 (2H, m), 1.73-2.11 (6H, m), 2.92 (2H , T, J = 7.2 Hz), 3.13 (2H, s), 3.17-3.30 (2H, m), 3.48-3.96 (6H, m), 3.53 (2H , T, J = 7.2 Hz), 4.62-4.72 (1H, m), 6.96 (2H, d, J = 9.2 Hz), 7.27 (2H, d, J = 8. 0 Hz), 7.38 (2H, d, J = 8.0 Hz), 7.59 (2H, d, J = 9.2 Hz).

LC / MS [Condition 1]: Retention time 4.34 minutes; m / z 610.8 [M + Na] ⁺ (ESI positive ion mode), m / z 633.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 306-7
Preparation of 4- (1- {4- [2- (2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) ethyl] benzoyl} piperidin-4-yloxy) benzonitrile 3- {4- [4- (4-Cyanophenoxy) piperidine-1-carbonyl] phenethyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 306-6 After immersing decane-8-carboxylate t-butyl (22 mg, 0.037 mmol) in dioxane (1.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction solution was further stirred at 50 ° C. for 4 hours, cooled to room temperature, methanol (0.10 mL) was added, and the mixture was stirred at room temperature for 12 hours. Thereafter, a 4M hydrogen chloride-dioxane solution (0.020 mL) was added to the reaction solution, and the mixture was stirred at 50 ° C. for 4 hours. After concentration to dryness under reduced pressure, chloroform and saturated aqueous sodium hydrogen carbonate solution were added and shaken. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. Concentration to dryness under reduced pressure gave a white solid containing the title compound (15 mg) as the main component. The obtained white solid was used for the next reaction without purification.

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 488.8 [M + H] ⁺ (ESI positive ion mode), m / z 532.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 306
4-[(3- {4- [4- (4-Cyanophenoxy) piperidine-1-carbonyl] phenethyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl ) Preparation of methyl] -3,5-difluorobenzonitrile (Compound No. 306) 4- (1- {4- [2- (2-oxo-1-oxa-3,8 ) obtained in Example 306-7 -Diazaspiro [4.5] decan-3-yl) ethyl] benzoyl} piperidin-4-yloxy) benzonitrile (15 mg) and 3,5-difluoro-4-formylbenzonitrile (5.5 mg, 0.033 mmol) It melt | dissolved in the dichloromethane (1.0 mL), sodium triacetoxyborohydride (9.5 mg, 0.045 mmol) was added, and it stirred at room temperature for 10 minutes. Analytical thin-layer chromatography [Merck TLC glass plate silica gel 60F ₂₅₄ , developing solvent: chloroform / methanol = 10/1], until the raw materials disappeared, sodium triacetoxyborohydride and 3,5-difluoro-4- Formylbenzonitrile was added and stirred at room temperature. After confirming disappearance of the raw materials, a saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, chloroform was added, and the mixture was shaken vigorously. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to dryness under reduced pressure, the resulting residue by preparative thin layer chromatography [Merck PLC glass plate silica gel 60F _254, developing solvent: chloroform / methanol = 10/1] to give the A crude product (27 mg) mainly containing the title compound was obtained. The crude product was recrystallized from diethyl ether, and the precipitated solid was collected and dried at room temperature under reduced pressure for 3 hours to obtain the title compound (9.7 mg, yield 40%, 2 steps) as a white solid. It was.

¹ H-NMR (CDCl ₃ ) δ: 1.59-2.09 (8H, m), 2.50-2.67 (4H, m), 2.89 (2H, t, J = 7.0 Hz) , 3.12 (2H, s), 3.36-3.98 (4H, m), 3.50 (2H, t, J = 7.0 Hz), 3.71 (2H, s), 4.60 -4.73 (1H, m), 6.96 (2H, d, J = 8.8 Hz), 7.18-7.28 (4H, m), 7.36 (2H, d, J = 7. 7 Hz), 7.60 (2H, d, J = 8.8 Hz)

LC / MS [Condition 1]: Retention time 3.29 minutes; m / z 640.0 [M + H] ⁺ (ESI positive ion mode), m / z 684.2 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 307
Preparation of 1,2,5-oxadiazepan-5-carboxylic acid methyl hydrochloride 1,2,5-oxadiazepan-2-carboxylic acid t-purchased from Watanabe Chemical Co. instead of t-butyl piperidin-4-ylcarbamate The reaction was carried out in substantially the same manner as in Reference Example 135 except that butyl hydrochloride (230 mg, 0.97 mmol) was used to give the title compound (100 mg, yield 54%) as a pale yellow amorphous solid.
¹ H-NMR (CDCl ₃ ) δ: 3.57-3.68 (2H, br m), 3.78 (3H, s), 3.80-4.02 (4H, br m), 4.48 -4.61 (2H, br m), 12.56 (2H, brs).
LC / MS [Condition 1]: Retention time 0.59 minutes; m / z 160.9 [M + H] ⁺ (ESI positive ion mode)

Example 307
2-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarbonyl] -1,2,5-oxadiazepane-5 Preparation of methyl 5-carboxylate (Compound No. 307) The reaction was carried out in substantially the same manner as in Example 10 except that acid methyl hydrochloride and triethylamine were used to obtain the title compound (8.3 mg, yield 21%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, dq, J = 3.3, 12.3 Hz), 1.36-2.41 (12H, br m), 2.51-3.04 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.29 (2H, s), 3.54-3.96 (8H, m), 3.72 (3H, s), 3.95-4.08 (2H, br m), 7.51-7.67 (4H, br m).
LC / MS [Condition 1]: Retention time 3.09 minutes; m / z 596.9 [M + H] ⁺ (ESI positive ion mode), m / z 641.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 308
5-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarbonyl] -1,2,5-oxadiazepane-2- Preparation of t-butyl carboxylate (Compound No. 308) 1,2,5-oxadiazepan-2- purchased from Watanabe Chemical Co. instead of tetrahydrofurfurylamine The reaction was carried out substantially in the same manner as in Example 10 except for using t-butyl carboxylate and triethylamine to obtain the title compound (89 mg, yield 94%) as a colorless solid.

¹ H-NMR (CDCl ₃ ) δ: 0.95-1.14 (2H, br m), 1.48 (9 H, s), 1.37-2.03 (11 H, br m), 2.31 -2.49 (1H, m), 2.49-2.78 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3. 53-3.82 (8H, m), 3.94-4.05 (2H, m), 7.48 (2H, br d, J = 7.8 Hz), 7.59 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 639.0 [M + H] ⁺ (ESI positive ion mode), m / z 683.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 309
3- {4- [4- (3-Isopropyl-1,2,4-oxadiazol-5-yl) piperidin-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1 Preparation of Oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 309) 3-Isopropyl-5 obtained in Reference Example 195 instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 180 except that-(piperidin-4-yl) -1,2,4-oxadiazole hydrochloride was used to give the title compound (14 mg, yield 19%). Obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.34 (6H, d, J = 7.0 Hz), 1.65 to 1.80 (2H, br m), 1.82-1.99 (4H , Br m), 2.13 (2H, br s), 2.52 (4H, br s), 2.99-3.28 (4H, m), 3.13 (2H, s), 3.55 (2H, s), 3.79 (1H, br s), 4.45 (2H, s), 4.57 (1H, br s), 7.31 (2H, d, J = 8.2 Hz), 7.36-7.46 (4H, m), 7.56 (2H, d, J = 8.4 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 626.0 [M + H] ⁺ (ESI positive ion mode), m / z 670.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 310
1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperidine-4- Preparation of carboxylic acid 1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane obtained in Example 76 -3-yl} methyl) benzoyl] piperidine-4-carboxylate (0.13 g, 0.23 mmol) was dissolved in 1,4-dioxane (1.5 ml), and then 1M aqueous sodium hydroxide solution (0.35 mL) was dissolved. 0.35 mmol), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to distill off 1,4-dioxane, and then 1M hydrochloric acid (0.30 mL) and chloroform (3 mL) were added to the residual reaction mixture to separate the organic layer. The obtained organic layer was concentrated to dryness under reduced pressure to give the title compound (0.15 g, quantitative) as a colorless amorphous product.

LC / MS [Condition 1]: Retention time 2.78 minutes; m / z 560.0 [M + H] ⁺ (ESI positive ion mode), m / z 558.1 [MH] ⁻ (ESI negative ion mode)

Example 310
3- {4- [4- (piperidine-1-carbonyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-2-one (Compound No. 310) 1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, obtained in Reference Example 310 8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperidine-4-carboxylic acid (29 mg, 0.052 mmol) and piperidine (0.010 mL, 0.10 mmol), 1-hydroxybenzotriazole (7 0.0 mg, 0.052 mmol) and triethylamine (0.022 mL, 0.16 mmol) in chloroform (1.0 mL), The Te 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (20 mg, 0.10 mmol) was added and stirred at room temperature for 1 day. Thereafter, chloroform (2.0 mL) and water (2.0 mL) were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm, manufactured by Yamazen Co., Ltd., developing solvent: ethyl acetate / methanol = 10/1] to give the title compound (6.4 mg Yield 19%) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47-1.97 (14H, m), 2.53 (4H, br s), 2.71-2.84 (1H, m), 2. 96 (2H, br s), 3.13 (2H, s), 3.38-3.49 (2H, br m), 3.56 (4H, s), 3.79 (1H, br s), 4.44 (2H, s), 4.68 (1H, br s), 7.29 (2H, d, J = 8.2 Hz), 7.35-7.46 (4H, m), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 2.84 minutes; m / z 627.0 [M + H] ⁺ (ESI positive ion mode), m / z 671.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 311
3- {4- [4- (1-Methyl-1H-imidazol-5-yl) piperidin-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 Preparation of diazaspiro [4.5] decan-2-one (Compound No. 311) 4- (1-methyl-1H-imidazol-5-yl) piperidine (commercially available) instead of 4- (aminomethyl) benzonitrile hydrochloride The title compound (27 mg, 52% yield) was obtained as a colorless oil substantially in the same manner as in Example 180, except that

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.43 to 2.09 (8H, m), 2.60 (4H, br s), 2.78 (1H, tt, J = 11.9, 2 .5Hz), 2.88-3.17 (2H, br m), 3.15 (2H, s), 3.61 (5H, s), 3.85 (1H, br s), 4.45 ( 2H, s), 4.80 (1H, br s), 6.81 (1H, s), 7.31 (2H, d, J = 7.8 Hz), 7.37-7.49 (5H, m ), 7.57 (2H, d, J = 7.4 Hz).

LC / MS [Condition 1]: retention time 0.51 min; m / z 298.6 [M + 2H] ²⁺ , 595.9 [M + H] ⁺ (ESI positive ion mode), m / z 640.1 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 312
N- (4-nitrobenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 312) The reaction was substantially the same as Example 180 except that (4-nitrophenyl) methanamine hydrochloride (commercially available) was used instead of 4- (aminomethyl) benzonitrile hydrochloride. To give the title compound (27 mg, 52% yield) as a yellow amorphous.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-1.80 (2H, br m), 1.84-1.96 (2H, br m), 2.52 (4H, br s), 3.13 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.75 (2H, d, J = 5.7 Hz), 6.73 (1H, t, J = 6.1 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.37-7.60 (6H, m), 7.81 (2H, d, J = 8.6 Hz), 8.19 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 582.9 [M + H] ⁺ (ESI positive ion mode), m / z 581.0 [M−H] ⁻ , 627.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 313
N- [4- (methylsulfonyl) benzyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) Preparation of benzamide (Compound No. 313) Substantially carried out except that [4- (methylsulfonyl) phenyl] methanamine hydrochloride (commercially available) was used instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in the same manner as in Example 180 to obtain the title compound (33 mg, yield 59%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74 (2H, br s), 1.84-1.96 (2H, br m), 2.55 (4H, br s), 3.04 ( 3H, s), 3.13 (2H, s), 3.58 (2H, s), 4.46 (2H, s), 4.74 (2H, d, J = 5.7 Hz), 6.64 (1H, t, J = 6.1 Hz), 7.35 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 7.4 Hz), 7.51-7.60 ( 4H, m), 7.80 (2H, dt, J = 8.2, 1.6 Hz), 7.91 (2H, dt, J = 8.6, 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.65 minutes; m / z 616.0 [M + H] ⁺ (ESI positive ion mode), m / z 614.1 [MH] ⁻ , 660.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 314
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [3- ( Preparation of ( trifluoromethyl) benzyl] benzamide (Compound No. 314) Substantially carried out except that [3- (trifluoromethyl) phenyl] methanamine (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in the same manner as in Example 180 to obtain the title compound (28 mg, yield 51%) as a yellow amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72-1.96 (4H, br m), 2.51-2.72 (4H, br m), 3.13 (2H, s), 3 .63 (2H, s), 4.46 (2H, s), 4.71 (2H, d, J = 6.1 Hz), 6.52 (1H, t, J = 5.9 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.40-7.50 (3H, m), 7.52-7.62 (5H, m), 7.79 (2H, d, J = 8. 6 Hz).

LC / MS [Condition 1]: retention time 3.22 minutes; m / z 605.9 [M + H] ⁺ (ESI positive ion mode), m / z 604.1 [M−H] ⁻ , 650.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 315
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [2- ( Preparation of ( trifluoromethyl) benzyl] benzamide (Compound No. 315) Substantially carried out except that [2- (trifluoromethyl) phenyl] methanamine (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in the same manner as in Example 180 to obtain the title compound (32 mg, yield 59%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72-1.98 (4H, br m), 2.62 (4H, br s), 3.12 (2H, s), 3.63 (2H , S), 4.45 (2H, s), 4.82 (2H, d, J = 6.1 Hz), 6.46 (1H, t, J = 5.9 Hz), 7.32 (2H, d) , J = 8.2 Hz), 7.36-7.48 (3H, m), 7.49-7.61 (3H, m), 7.66 (2H, t, J = 8.0 Hz), 7 .75 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 3.22 minutes; m / z 605.9 [M + H] ⁺ (ESI positive ion mode), m / z 604.1 [M−H] ⁻ , 650.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 316
N- (4-t-butylbenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3- Il} methyl) Preparation of benzamide (Compound No. 316) Substantially the same as Example 180, except that (4-tert-butylphenyl) methanamine (commercially available) was used instead of 4- (aminomethyl) benzonitrile hydrochloride. The title compound (37 mg, 69% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.31 (9H, s), 1.63-1.77 (2H, br m), 1.85-1.95 (2H, br m), 2 .51 (4H, br s), 3.11 (2H, s), 3.55 (2H, s), 4.45 (2H, s), 4.61 (2H, d, J = 5.3 Hz) , 6.31 (1H, t, J = 5.1 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 7.4 Hz), 7.38 ( 2H, dt, J = 8.2, 2.0 Hz), 7.41 (2H, d, J = 7.0 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.76 (2H , D, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 594.0 [M + H] ⁺ (ESI positive ion mode), m / z 592.2 [M−H] ⁻ , 638.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 317
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- [4- ( Preparation of ( trifluoromethoxy) benzyl] benzamide (Compound No. 317) Substantially except that [4- (trifluoromethoxy) phenyl] methanamine (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride and triethylamine. Was reacted in the same manner as in Example 180 to obtain the title compound (28 mg, yield 52%) as a yellow powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65-1.98 (4H, br m), 2.57 (4H, br s), 3.12 (2H, s), 3.60 (2H , S), 4.46 (2H, s), 4.65 (2H, d, J = 5.7 Hz), 6.45 (1H, t, J = 5.5 Hz), 7.19 (2H, d). , J = 8.6 Hz), 7.30-7.50 (6H, m), 7.57 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.2 Hz) .

LC / MS [Condition 1]: Retention time 3.28 minutes; m / z 621.9 [M + H] ⁺ (ESI positive ion mode), m / z 620.1 [M−H] ⁻ , 666.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 318
N- [3,5-bis (trifluoromethyl) benzyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Preparation of decan-3-yl} methyl) benzamide (Compound No. 318) [3,5-bis (trifluoromethyl) phenyl] methanamine (commercially available) instead of 4- (aminomethyl) benzonitrile hydrochloride and triethylamine The reaction was carried out substantially in the same manner as in Example 180 except for using, and the title compound (30 mg, yield 50%) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72-1.97 (4H, br m), 2.62 (4H, br s), 3.14 (2H, s), 3.63 (2H , S), 4.46 (2H, s), 4.77 (2H, d, J = 6.1 Hz), 6.68 (1H, t, J = 5.9 Hz), 7.35 (2H, d) , J = 8.6 Hz), 7.45 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.77-7.83 (5H, m) .

LC / MS [Condition 1]: Retention time 3.52 minutes; m / z 674.0 [M + H] ⁺ (ESI positive ion mode), m / z 672.0 [M−H] ⁻ , 718.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 319
N- (4-chlorobenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 319) The reaction was carried out in substantially the same manner as in Example 180 except that (4-chlorophenyl) methanamine (commercially available) was used instead of 4- (aminomethyl) benzonitrile hydrochloride and triethylamine. Performed to give the title compound (31 mg, 61% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.79 (2H, br m), 1.82-1.98 (2H, br m), 2.51 (4H, br s), 3.11 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.61 (2H, d, J = 5.7 Hz), 6.41 (1H, t, J = 5.1 Hz), 7.22-7.36 (6H, m), 7.41 (2H, d, J = 7.4 Hz), 7.56 (2H, d, J = 7.8 Hz), 7.77 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 571.9 [M + H] ⁺ (ESI positive ion mode), m / z 570.1 [M−H] ⁻ , 616.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 320
N- (4-methylbenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 320) The reaction was carried out in substantially the same manner as in Example 180, except that 4- (aminomethyl) benzonitrile hydrochloride and p-tolylmethanamine (commercially available) were used instead of triethylamine. The title compound (31 mg, 63% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.77 (2H, br m), 1.83-1.96 (2H, br m), 2.35 (3H, s), 2 .51 (4H, br s), 3.10 (2H, s), 3.54 (2H, s), 4.45 (2H, s), 4.60 (2H, d, J = 5.7 Hz) 6.29 (1H, t, J = 4.5 Hz), 7.16 (2H, d, J = 7.8 Hz), 7.24 (2H, d, J = 7.0 Hz), 7.32 ( 2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 7.8 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.76 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 552.0 [M + H] ⁺ (ESI positive ion mode), m / z 550.1 [M−H] ⁻ , 596.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 321
N- (4-methoxybenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 321) Reaction substantially in the same manner as in Example 180 except that 4- (aminomethyl) benzonitrile hydrochloride and (4-methoxyphenyl) methanamine (commercially available) were used instead of triethylamine. To give the title compound (24 mg, 47% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.79 (2H, br m), 1.83-1.97 (2H, br m), 2.51 (4H, br s), 3.11 (2H, s), 3.54 (2H, s), 3.80 (3H, s), 4.45 (2H, s), 4.57 (2H, d, J = 5.7 Hz) 6.29 (1H, t, J = 4.9 Hz), 6.88 (2H, dt, J = 8.6, 2.5 Hz), 7.23-7.35 (4H, m), 7. 41 (2H, d, J = 7.8 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.76 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 568.0 [M + H] ⁺ (ESI positive ion mode), m / z 566.1 [M−H] ⁻ , 612.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 322
N- (3,4-dimethoxybenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3- Il} methyl) benzamide (Compound No. 322) Example 180 substantially except that (3,4-dimethoxyphenyl) methanamine (commercially available) was used instead of 4- (aminomethyl) benzonitrile hydrochloride and triethylamine. The title compound (16 mg, yield 30%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.78 (2H, br m), 1.83-1.97 (2H, br m), 2.51 (4H, br s), 3.11 (2H, s), 3.54 (2H, s), 3.88 (6H, s), 4.45 (2H, s), 4.58 (2H, d, J = 5.3 Hz) , 6.31 (1H, t, J = 4.9 Hz), 6.78-6.94 (3H, m), 7.32 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 7.4 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.76 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.71 minutes; m / z 597.9 [M + H] ⁺ (ESI positive ion mode), m / z 596.1 [M−H] ⁻ , 642.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 323
N-[(2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1- Preparation of Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzamide (Compound No. 323) Instead of 4- (aminomethyl) benzonitrile hydrochloride and triethylamine, (2,3-dihydrobenzo [B] [1,4] dioxin-6-yl) methanamine (commercially available) was used substantially in the same manner as in Example 180 to give the title compound (16 mg, yield 29%) as a white powder Got as.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-1.79 (2H, br m), 1.84-1.97 (2H, br m), 2.51 (4H, br s), 3.10 (2H, s), 3.55 (2H, s), 4.25 (4H, s), 4.45 (2H, s), 4.53 (2H, d, J = 5.7 Hz) , 6.27 (1H, t, J = 4.9 Hz), 6.76-6.88 (3H, m), 7.31 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 7.8 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.76 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 2.80 minutes; m / z 595.9 [M + H] ⁺ (ESI positive ion mode), m / z 594.1 [M−H] ⁻ , 640.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 324
N- (furan-2-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Preparation of methyl) benzamide (Compound No. 324) Substantially the same as Example 180, except that 4- (aminomethyl) benzonitrile hydrochloride and furan-2-ylmethanamine (commercially available) were used instead of triethylamine. Reaction was performed to obtain the title compound (20 mg, yield 41%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-1.79 (2H, br m), 1.84-1.97 (2H, br m), 2.51 (4H, br s), 3.11 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.64 (2H, d, J = 5.3 Hz), 6.27-6.36 ( 2H, m), 6.36 (1H, t, J = 4.9 Hz), 7.32 (2H, d, J = 8.6 Hz), 7.36-7.39 (1H, m), 7. 41 (2H, d, J = 7.0 Hz), 7.55 (2H, d, J = 7.8 Hz), 7.77 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 2.63 minutes; m / z 527.8 [M + H] ⁺ (ESI positive ion mode), m / z 526.0 [M−H] ⁻ , 571.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 325
4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N- (tetrahydro-2H Preparation of -pyran-4-yl) benzamide (Compound No. 325) Substantially except that tetrahydro-2H-pyran-4-amine hydrochloride (commercially available) was used instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was conducted in the same manner as in Example 180 to obtain the title compound (28 mg, yield 59%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.48-1.80 (4H, br m), 1.83 to 2.08 (4H, br m), 2.52 (4H, br s), 3.12 (2H, s), 3.45-3.62 (4H, m), 3.94-4.05 (2H, br m), 4.11-4.28 (1H, m), 4 .46 (2H, s), 5.95 (1H, d, J = 7.0 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8. 6 Hz), 7.56 (2H, d, J = 7.4 Hz), 7.74 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.37 minutes; m / z 531.9 [M + H] ⁺ (ESI positive ion mode), m / z 530.1 [M−H] ⁻ , 576.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 326
3- {4- [3- (4-Chlorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 326) Substantially except that (4-chlorophenyl) (piperidin-3-yl) methanone hydrochloride (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride Was reacted in the same manner as in Example 180 to obtain the title compound (49 mg, 84% yield) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.39-2.21 (8H, br m), 2.53 (4H, br s), 2.81-3.19 (2H, br m), 3.14 (2H, s), 3.31 (1H, br s), 3.56 (2H, s), 3.67-3.93 (1H, br m), 4.45 (2H, s) , 4.55-4.92 (1H, br m), 7.31 (2H, d, J = 6.5 Hz), 7.35-7.51 (6H, m), 7.56 (2H, d , J = 8.2 Hz), 7.61-8.06 (2H, br m).

LC / MS [Condition 1]: Retention time 3.50 minutes; m / z 653.9 [M + H] ⁺ (ESI positive ion mode), m / z 652.1 [M−H] ⁻ , 698.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 327
1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] -4 -Preparation of phenylpiperidine-4-carbonitrile (Compound No. 327) Substantially except that 4-phenylpiperidine-4-carbonitrile hydrochloride (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride The reaction was carried out in the same manner as in Example 180 to obtain the title compound (41 mg, yield 75%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.63-2.34 (8H, br m), 2.53 (4H, br s), 3.14 (2H, s), 3.28 (1H , Br s), 3.55 (3H, s), 3.91 (1H, br s), 4.45 (2H, s), 4.93 (1H, br s), 7.28-7.50. (11H, m), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.42 minutes; m / z 617.0 [M + H] ⁺ (ESI positive ion mode), m / z 661.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 328
3- {4- [4- (3,5-Dimethyl-1H-pyrazol-1-yl) piperidin-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3 , 8-Diazaspiro [4.5] decan-2-one (Compound No. 328) 4- (3,5-dimethyl-1H-pyrazole-1 instead of 4- (aminomethyl) benzonitrile hydrochloride and triethylamine -Ill) The reaction was carried out in substantially the same manner as in Example 180 except that piperidine (commercially available) was used to give the title compound (42 mg, yield 76%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64 to 1.81 (2H, br m), 1.83 to 2.00 (4H, br m), 2.14 to 2.31 (2H, m), 2.22 (3H, s), 2.25 (3H, s), 2.53 (4H, br s), 2.80-3.15 (2H, br m), 3.13 (2H) , S), 3.55 (2H, s), 3.91 (1H, br s), 4.13 (1H, tt, J = 11.4, 4.1 Hz), 4.44 (2H, s) 4.84 (1 H, br s), 5.79 (1 H, s), 7.29 (2 H, d, J = 7.8 Hz), 7.36-7.47 (4 H, m), 7. 56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 305.6 [M + 2H] ²⁺ , 610.0 [M + H] ⁺ (ESI positive ion mode), m / z 654.1 [M + HCOO] ^— (ESI Negative ion mode)

Example 329
3- {4- [4- (morpholine-4-carbonyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Preparation of decan-2-one (Compound No. 329) The reaction was conducted in substantially the same manner as in Example 310 except that morpholine (commercially available) was used instead of piperidine to give the title compound (20 mg, yield 59%). Was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-2.00 (8H, br m), 2.53 (4H, br s), 2.66-2.83 (1H, br m), 2.83-3.15 (2H, br m), 3.13 (2H, s), 3.44-3.75 (10H, m), 3.81 (1H, br s), 4.44 ( 2H, s), 4.68 (1H, br s), 7.29 (2H, d, J = 8.2 Hz), 7.34-7.47 (4H, m), 7.56 (2H, d , J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 629.1 [M + H] ⁺ (ESI positive ion mode), m / z 673.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 330
N-cyclohexyl-1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of benzoyl] piperidine-4-carboxamide (Compound No. 330) The reaction was conducted in substantially the same manner as in Example 310 except that cyclohexaneamine (commercially available) was used instead of piperidine to give the title compound (21 mg, yield 59 %) As a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.10 (2H, dq, J = 2.5, 11.4 Hz), 1.20-1.46 (2H, m), 1.49-1. 99 (14H, br m), 2.30 (1H, tt, J = 11.4, 3.7 Hz), 2.52 (4H, br s), 2.76-3.11 (2H, br m) 3.13 (2H, s), 3.55 (2H, s), 3.67-3.87 (2H, m), 4.44 (2H, s), 4.67 (1H, br s) , 5.29 (1H, d, J = 7.8 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.33-7.47 (4H, m), 7.56 (2H, d, J = 7.4 Hz).

LC / MS [Condition 1]: retention time 3.22 minutes; m / z 641.0 [M + H] ⁺ (ESI positive ion mode), m / z 685.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 331
Nt-butyl-1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzoyl] piperidine-4-carboxamide (Compound No. 331) The reaction was carried out in substantially the same manner as in Example 310 except that 2-methylpropan-2-amine (commercially available) was used instead of piperidine. The title compound (21 mg, 62% yield) was obtained as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35 (9H, s), 1.61-1.99 (8H, br m), 2.24 (1H, tt, J = 11.0, 3 .7Hz), 2.52 (4H, br s), 2.78-3.07 (2H, br m), 3.13 (2H, s), 3.55 (2H, s), 3.76 ( 1H, brs), 4.44 (2H, s), 4.67 (1H, brs), 5.25 (1H, s), 7.29 (2H, d, J = 8.2 Hz), 7 .33-7.48 (4H, m), 7.56 (2H, d, J = 8.0 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 615.1 [M + H] ⁺ (ESI positive ion mode), m / z 659.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 332
N- (furan-3-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Preparation of methyl) benzamide (Compound No. 332) Substantially the same as Example 180, except that 4- (aminomethyl) benzonitrile hydrochloride and triethylamine were replaced with furan-3-ylmethanamine (commercially available). The reaction was performed to give the title compound (37 mg, yield 78%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.61-1.79 (2H, br m), 1.82-1.98 (2H, br m), 2.51 (4H, br s), 3.11 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.49 (2H, d, J = 5.3 Hz), 6.21 (1H, t, J = 4.5 Hz), 6.42 (1H, s), 7.32 (2H, d, J = 8.2 Hz), 7.36-7.46 (4H, m), 7.56 (2H, d, J = 7.8 Hz), 7.75 (2H, dt, J = 8.6, 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 527.8 [M + H] ⁺ (ESI positive ion mode), m / z 526.0 [M−H] ⁻ , 572.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 333-1
Preparation of t-butyl 4- (4-t-butylbenzoyl) piperidine-1-carboxylate The reaction was carried out substantially in the same manner as in Reference Example 168-2 except that a solution (commercially available) was used, and the title compound (81 mg, yield 71%) was obtained as a colorless oil.

LC / MS [Condition 1]: Retention time 5.38 minutes; m / z 290.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 333-2
Preparation of (4-t-butylphenyl) (piperidin-4-yl) methanone hydrochloride 4- (4-t) obtained in Reference Example 333-1 instead of t-butyl 4-acetylpiperidine-1-carboxylate The reaction was carried out in substantially the same manner as in Reference Example 168-3 except that t-butyl-butylbenzoyl) piperidine-1-carboxylate was used to give the title compound (61 mg, quantitative) as a purple powder.

LC / MS [Condition 1]: Retention time 2.82 minutes; m / z 246.1 [M + H] ⁺ (ESI positive ion mode)

Example 333
3- {4- [4- (4-t-butylbenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-2-one (Compound No. 333) Instead of 4- (aminomethyl) benzonitrile hydrochloride, (4-t-butylphenyl) (piperidin-4-yl) obtained in Reference Example 333-2 ) The reaction was carried out in substantially the same manner as in Example 180 except that methanone hydrochloride was used to obtain the title compound (57 mg, yield 95%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.35 (9H, s), 1.63 to 2.08 (8H, br m), 2.52 (4H, br s), 2.96-3 .25 (2H, br m), 3.13 (2H, s), 3.46-3.61 (1H, br m), 3.55 (2H, s), 3.82 (1H, br s) 4.44 (2H, s), 4.66 (1H, brs), 7.30 (2H, d, J = 8.2 Hz), 7.36-7.45 (4H, m), 7. 49 (2H, dt, J = 8.6, 1.6 Hz), 7.56 (2H, d, J = 7.4 Hz), 7.89 (2H, dt, J = 8.6, 1.6 Hz) .

LC / MS [Condition 1]: Retention time 3.70 minutes; m / z 338.6 [M + 2H] ²⁺ , 676.1 [M + H] ⁺ (ESI positive ion mode), m / z 720.3 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 334-1
Preparation of t-butyl 4- (cyclohexanecarbonyl) piperidine-1-carboxylate The reaction was performed in the same manner as in Reference Example 168-2 to give the title compound (17 mg, yield 15%) as a colorless oil.

LC / MS [Condition 1]: Retention time 4.87 min; m / z 240.1 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 334-2
Preparation of cyclohexyl (piperidin-4-yl) methanone hydrochloride 4- (cyclohexanecarbonyl) piperidine-1-carboxylic acid t obtained in Reference Example 334-1 in place of t-butyl 4-acetylpiperidine-1-carboxylate The reaction was carried out substantially in the same manner as in Reference Example 168-3 except that -butyl was used to give the title compound (13 mg, quantitative) as a white powder.

LC / MS [Condition 1]: retention time 0.74 minutes; m / z 196.1 [M + H] ⁺ (ESI positive ion mode)

Example 334
3- {4- [4- (Cyclohexanecarbonyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 2-one (Compound No. 334) Substantially except that cyclohexyl (piperidin-4-yl) methanone hydrochloride obtained in Reference Example 334-2 was used instead of 4- (aminomethyl) benzonitrile hydrochloride Was reacted in the same manner as in Example 180 to obtain the title compound (22 mg, yield: 80%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.11-1.42 (6H, br m), 1.47-2.00 (12H, br m), 2.40-2.64 (5H, br m), 2.68-2.83 (1H, m), 2.96 (2H, br s), 3.13 (2H, s), 3.57 (2H, s), 3.74 (1H) , Br s), 4.44 (2H, s), 4.65 (1H, br s), 7.29 (2H, d, J = 7.8 Hz), 7.38 (2H, d, J = 7). .8 Hz), 7.43 (2H, d, J = 7.0 Hz), 7.56 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.48 minutes; m / z 626.0 [M + H] ⁺ (ESI positive ion mode), m / z 670.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 335
3- {4- [4- (4-Chlorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 335) Substantially except that (4-chlorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) is used instead of 4- (aminomethyl) benzonitrile hydrochloride Was reacted in the same manner as in Example 180 to give the title compound (52 mg, yield 89%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-2.08 (8H, br m), 2.52 (4H, br s), 2.96-3.28 (2H, br m), 3.13 (2H, s), 3.42-3.57 (1H, m), 3.55 (2H, s), 3.83 (1H, br s), 4.44 (2H, s), 4.67 (1H, br s), 7.30 (2H, d, J = 8.2 Hz), 7.35-7.50 (6H, m), 7.56 (2H, d, J = 8. 6 Hz), 7.88 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.50 minutes; m / z 653.9 [M + H] ⁺ (ESI positive ion mode), m / z 698.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 336-1
Preparation of t-butyl 4- (4-methoxybenzoyl) piperidine-1-carboxylate The reaction was carried out in substantially the same manner as in Reference Example 168-2 except that the title compound (113 mg, yield 88%) was obtained as a colorless oil.

LC / MS [Condition 1]: Retention time 4.45 minutes; m / z 264.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 336-2
Preparation of (4-methoxyphenyl) (piperidin-4-yl) methanone hydrochloride 4- (4-methoxybenzoyl) obtained in Reference Example 336-1 instead of t-butyl 4-acetylpiperidine-1-carboxylate The reaction was carried out substantially in the same manner as in Reference Example 168-3 except that t-butyl piperidine-1-carboxylate was used to give the title compound (83 mg, quantitative) as a blue amorphous product.

LC / MS [Condition 1]: Retention time 0.53 minutes; m / z 220.0 [M + H] ⁺ (ESI positive ion mode)

Example 336
3- {4- [4- (4-Methoxybenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of Decan-2-one (Compound No. 336) (4-Methoxyphenyl) (piperidin-4-yl) methanone hydrochloride obtained in Reference Example 336-2 instead of 4- (aminomethyl) benzonitrile hydrochloride The title compound (59 mg, yield 70%) was obtained as a colorless amorphous product in substantially the same manner as in Example 180 except that was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.64-2.10 (8H, br m), 2.52 (4H, br s), 2.95-3.25 (2H, br m), 3.13 (2H, s), 3.43-3.57 (1H, m), 3.55 (2H, s), 3.84 (1H, br s), 3.88 (3H, s), 4.44 (2H, s), 4.68 (1H, br s), 6.95 (2H, dt, J = 9.0, 2.0 Hz), 7.30 (2H, d, J = 8. 2 Hz), 7.36-7.46 (4 H, m), 7.56 (2 H, d, J = 7.8 Hz), 7.94 (2 H, dt, J = 9.0, 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 649.9 [M + H] ⁺ (ESI positive ion mode), m / z 694.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 337-1
Preparation of t-butyl 4- (2-methylbenzoyl) piperidine-1-carboxylate A 1.0 Mo-tolylmagnesium bromide-tetrahydrofuran solution (commercially available) was used in place of the 1.1 M methylmagnesium bromide-tetrahydrofuran solution. The reaction was carried out substantially in the same manner as in Reference Example 168-2 to give the title compound (20 mg, yield 27%) as a colorless oil.

LC / MS [Condition 1]: Retention time 4.63 minutes; m / z 248.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 337-2
Preparation of piperidin-4-yl (o-tolyl) methanone hydrochloride 4- (2-methylbenzoyl) piperidine-1 obtained in Reference Example 337-1 in place of t-butyl 4-acetylpiperidine-1-carboxylate Reaction was carried out in substantially the same manner as in Reference Example 168-3 except that t-butyl carboxylate was used to give the title compound (16 mg, quantitative) as a white powder.

LC / MS [Condition 1]: Retention time 0.68 min; m / z 204.1 [M + H] ⁺ (ESI positive ion mode)

Example 337
3- {4- [4- (2-Methylbenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 337) Instead of 4- (aminomethyl) benzonitrile hydrochloride, use piperidin-4-yl (o-tolyl) methanone hydrochloride obtained in Reference Example 337-2. The title compound (26 mg, yield 69%) was obtained as a colorless amorphous product in substantially the same manner as in Example 180 except for the above.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.62-2.09 (8H, br m), 2.43 (3H, s), 2.52 (4H, br s), 2.89-3 .20 (2H, br m), 3.13 (2H, s), 3.26-3.43 (1H, m), 3.55 (2H, s), 3.81 (1H, br s), 4.44 (2H, s), 4.64 (1H, br s), 7.21-7.32 (4H, m), 7.33-7.46 (5H, m), 7.48-7 .59 (3H, m).

LC / MS [condition 1]: retention time 3.42 minutes; m / z 634.0 [M + H] ⁺ (ESI positive ion mode), m / z 678.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 338-1
Preparation of piperazine- 1,4-dicarboxylic acid (1-t-butyl) 4-methyl Piperazine-1-carboxylate t-butyl (4.1 g, 22 mmol) was dissolved in chloroform (12 mL) and triethylamine at 0 ° C. (9.2 mL, 66 mmol) was added, methyl chloroformate (3.4 mL, 66 mmol) dissolved in chloroform (8.0 mL) was slowly added dropwise at 0 ° C., and the mixture was warmed to room temperature, then 12 hours. Stir. Thereafter, water (40 mL) and chloroform (40 mL) were added, the organic layer was separated, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure to give the title compound (5.3 g, yield 98%). Obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 3.35-3.48 (8H, br m), 3.71 (3H, s).

LC / MS [Condition 1]: Retention time 3.66 minutes; m / z 145.0 [M-isobutene-CO ₂ + H] ⁺ (ESI positive ion mode)

Reference Example 338-2
Preparation of piperazine-1-carboxylic acid methyl hydrochloride Piperazine-1,4-dicarboxylic acid (1-t-butyl) obtained in Reference Example 338-1 instead of t-butyl 4-acetylpiperidine-1-carboxylate The reaction was carried out substantially in the same manner as in Reference Example 168-3, except that 4-methyl was used, to give the title compound (3.9 g, quantitative) as a white powder.

LC / MS [Condition 1]: Retention time 0.51 min; m / z 145.0 [M + H] ⁺ (ESI positive ion mode)

Example 338
4- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl] piperazine- Preparation of methyl 1-carboxylate (Compound No. 338) Substantially except that piperazine-1-carboxylic acid methyl hydrochloride obtained in Reference Example 338-2 was used in place of 4- (aminomethyl) benzonitrile hydrochloride Was reacted in the same manner as in Example 180 to obtain the title compound (49 mg, yield 57%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.65 to 1.81 (2H, br m), 1.85 to 2.00 (2H, br m), 2.52 (4H, br s), 3.13 (2H, s), 3.29-3.86 (8H, br m), 3.55 (2H, s), 3.73 (3H, s), 4.45 (2H, s), 7.31 (2H, d, J = 8.2 Hz), 7.39 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 6.5 Hz), 7.56 (2H , D, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 574.9 [M + H] ⁺ (ESI positive ion mode), m / z 619.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 339
4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarbonyl ) Preparation of methyl piperazine-1-carboxylate (Compound No. 339) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] (1r, 4r) -4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3] obtained in Reference Example 17-2 instead of (decan-3-yl} methyl) benzoic acid , 8-Diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid instead of 4- (aminomethyl) benzonitrile hydrochloride, piperazine-1-carboxylic acid obtained in Reference Example 338-2 Methyl salt Except using salt The reaction was carried out in the same manner as substantially Example 180 to give the title compound (14 mg, 34% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.4 Hz), 1.45 to 1.68 (3H, br m), 1.69 to 1.86 (6H) , Br m), 1.87-2.00 (2H, br m), 2.43 (1H, t, J = 11.7 Hz), 2.56 (4H, br s), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.40-3.64 (8H, br m), 3.57 (2H, s), 3.72 (3H, s), 7.44 (2H, d, J = 8.2 Hz), 7.61 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 1.40 minutes; m / z 537.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 340
4- (4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzamido) piperidine-1-carboxylic acid Preparation of ethyl (Compound No. 340) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl ) 4-{[8- (4-Cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- obtained in Reference Example 171-2 instead of benzoic acid Yl] methyl} benzoic acid in substantially the same manner as in Example 180 except that ethyl 4-aminopiperidine-1-carboxylate (commercially available) was used instead of 4- (aminomethyl) benzonitrile hydrochloride. Go to the title compound The (24 mg, 57% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.27 (3H, t, J = 7.2 Hz), 1.42 (2H, dq, J = 3.3, 12.1 Hz), 1.63- 1.78 (2H, br m), 1.83-1.96 (2H, br m), 1.98-2.10 (2H, br m), 2.40-60 (4H, br m), 2.96 (2H, t, J = 12.5 Hz), 3.11 (2H, s), 3.55 (2H, s), 4.04-4.26 (3H, br m), 4.14 (2H, q, J = 7.1 Hz), 4.46 (2H, s), 5.96 (1H, d, J = 7.8 Hz), 7.33 (2H, d, J = 8.2 Hz) 7.42 (2H, d, J = 8.2 Hz), 7.59 (2H, d, J = 8.2 Hz), 7.73 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.78 minutes; m / z 559.9 [M + H] ⁺ (ESI positive ion mode), m / z 558.1 [M−H] ⁻ , 604.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 341
4-((1r, 4r) -4-{[8- (4-cyanobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxamide ) Preparation of Piperidine-1-Carboxylate (Compound No. 341) Substantially Examples except that ethyl 4-aminopiperidine-1-carboxylate (commercially available) was used in place of piperazine-1-carboxylate methyl hydrochloride The reaction was conducted in the same manner as in 339 to give the title compound (30 mg, yield 63%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 2.9, 12.7 Hz), 1.25 (3H, t, J = 7.0 Hz), 1.28 ( 2H, dq, J = 4.1, 11.9 Hz), 1.48 (2H, dq, J = 2.9, 12.3 Hz), 1.48-1.65 (1H, br m), 1. 70-2.05 (11H, br m), 2.55 (4H, br s), 2.89 (2H, t, J = 12.3 Hz), 3.09 (2H, d, J = 7.4 Hz) ), 3.25 (2H, s), 3.56 (3H, s), 3.84-3.98 (1H, m), 4.01-4.20 (2H, br m), 4.12 (2H, q, J = 7.1 Hz), 5.29 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.60 (2H, t, J = 4 1Hz).

LC / MS [Condition 1]: Retention time 2.82 minutes; m / z 565.9 [M + H] ⁺ (ESI positive ion mode), m / z 564.1 [M−H] ⁻ , 610.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 342
3-{[(1r, 4r) -4- (3,5-dimethylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-2-one (Compound No. 342) 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Decan-3-yl} methyl) benzoic acid instead of (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] obtained in Reference Example 6-3 ] 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid is converted to 3,5-dimethylpiperidine (commercially available) instead of 4- (aminomethyl) benzonitrile hydrochloride ) It except by performing the reaction as a substantially Example 180 to give the title compound (22 mg, 61% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.84-0.94 (6H, m), 1.05 (2H, q, J = 12.4 Hz), 1.40-1.65 (6H, br m), 1.69-1.87 (7H, br m), 1.88-2.00 (3H, br m), 2.38-2.56 (1.85 H, m), 2.56 (4H, br s), 3.10 (2H, d, J = 7.8 Hz), 3.17 (0.15H, dd, J = 13.1, 7.4 Hz), 3.26 (2H, s ), 3.42 (0.15H, dd, J = 13.1, 3.7 Hz), 3.57 (2H, s), 3.64 (0.15H, dd, J = 13.9, 3. 7 Hz), 3.73 (0.85 H, d, J = 12.7 Hz), 4.58 (0.85 H, d, J = 12.7 Hz), 7.43 (2 H, d, J = 7.8 H) ), 7.57 (2H, d, J = 7.6Hz).

LC / MS [Condition 1]: Retention time 3.40 minutes; m / z 549.8 [M + H] ⁺ (ESI positive ion mode), m / z 593.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 343
3-{[(1r, 4r) -4- (4-Isopropylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Production of decan-2-one (Compound No. 343) The reaction was carried out in substantially the same manner as in Example 342 except that 4-isopropylpiperidine (commercially available) was used instead of 3,5-dimethylpiperidine. The title compound (27 mg, 73% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.88 (6H, d, J = 6.5 Hz), 0.94-1.33 (6H, m), 1.36-1.85 (11H, br m), 1.86-2.00 (2H, br m), 2.37-2.51 (2H, m), 2.55 (4H, br s), 2.94 (1H, t, J = 11.7 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 3.89 (1H, d, J = 13) .1 Hz), 4.66 (1H, d, J = 13.1 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.6 Hz).

LC / MS [Condition 1]: Retention time 3.54 minutes; m / z 563.9 [M + H] ⁺ (ESI positive ion mode), m / z 608.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 344
3-{[(1r, 4r) -4- (decahydroisoquinoline-2-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-2-one (Compound No. 344) The reaction was conducted in substantially the same manner as in Example 342 except that decahydroisoquinoline (commercially available) was used instead of 3,5-dimethylpiperidine. The compound (26 mg, yield 68%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.92-1.16 (3H, br m), 1.19-2.15 (22H, br m), 2.36-2.55 (1H, br m), 2.56 (4H, s), 2.81-3.28 (2H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s) 3.48-4.74 (2H, br m), 3.57 (2H, s), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7) .6 Hz).

LC / MS [Condition 1]: Retention time 3.52 minutes; m / z 575.9 [M + H] ⁺ (ESI positive ion mode), m / z 620.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 345
8- [4- (trifluoromethyl) benzyl] -3-({(1r, 4r) -4- [4- (trifluoromethyl) piperidine-1-carbonyl] cyclohexyl} methyl) -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 345) Substantially except that 4- (trifluoromethyl) piperidine hydrochloride (commercially available) is used instead of 3,5-dimethylpiperidine. The reaction was conducted in the same manner as in Example 342 to give the title compound (30 mg, yield 77%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.0 Hz), 1.35 to 1.68 (5H, br m), 1.69-1.85 (6H , Br m), 1.85-2.01 (4H, br m), 2.15-2.35 (1 H, m), 2.36-2.54 (2H, br m), 2.55 ( 4H, br s), 3.02 (1H, t, J = 12.9 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.57 (2H) , S), 3.99 (1H, d, J = 13.1 Hz), 4.75 (1H, d, J = 13.1 Hz), 7.43 (2H, d, J = 8.2 Hz), 7 .57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 589.8 [M + H] ⁺ (ESI positive ion mode), m / z 634.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 346
3-({(1r, 4r) -4- [4- (2-hydroxypropan-2-yl) piperidin-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1 Preparation of oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 346) 2- (piperidin-4-yl) propan-2-ol instead of 3,5-dimethylpiperidine (commercially available) ) Was used substantially in the same manner as in Example 342 to give the title compound (30 mg, yield 78%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.3 Hz), 1.17 (3H, s), 1.19 (3H, s), 1.20-1 .68 (6H, br m), 1.68-2.00 (10H, br m), 2.36-2.52 (2H, m), 2.55 (4H, br s), 2.96 ( 1H, t, J = 12.1 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.57 (2H, s), 3.96 (1H, d, J = 12.3 Hz), 4.74 (1H, d, J = 13.9 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8) .2 Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 579.9 [M + H] ⁺ (ESI positive ion mode), m / z 624.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 347
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of ethyl methyl) cyclohexanecarbonyl] piperazine-1-carboxylate (Compound No. 347) Substantially the same as Example 342 except that ethyl piperazine-1-carboxylate (commercially available) was used instead of 3,5-dimethylpiperidine. The reaction was performed in the same manner to obtain the title compound (32 mg, yield 81%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.7 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.46-1.68 ( 3H, br m), 1.70-1.86 (6H, br m), 1.87-2.00 (2H, br m), 2.42 (1 H, t, J = 11.7 Hz), 2 .55 (4H, br s), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.47 (6H, br s), 3.57 (4H, br) s), 4.16 (2H, q, J = 7.4 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 7.2 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 594.7 [M + H] ⁺ (ESI positive ion mode), m / z 639.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 348
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of t-butyl methyl) cyclohexanecarbonyl] -1,4-diazepane-1-carboxylate (Compound No. 348) t-butyl 1,4-diazepane-1-carboxylate instead of 3,5-dimethylpiperidine (commercially available) The title compound (37 mg, yield 89%) was obtained as a white powder in substantially the same manner as in Example 342 except that was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.3 Hz), 1.38-1.48 (9H, m), 1.48-1.68 (3H, br m), 1.68-1.88 (8H, br m), 1.87-2.01 (2H, br m), 2.40 (1 H, t, J = 12.3 Hz), 2.55 (4H, br s), 3.05-3.14 (2H, br m), 3.25 (2H, s), 3.28-3.66 (8H, br m), 3.57 (2H, s), 7.43 (2H, d, J = 7.4 Hz), 7.57 (2H, d, J = 7.6 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 636.8 [M + H] ⁺ (ESI positive ion mode), m / z 681.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 349
Preparation of methyl 1,4-diazepan-1-carboxylate hydrochloride t-butyl 1,4-diazepan-1-carboxylate (503 mg, 2.51 mmol) instead of t-butyl piperidin-4-ylcarbamate The title compound (524 mg, quantitative) was obtained as a pale yellow solid substantially in the same manner as in Reference Example 135 except that was used.

¹ H-NMR (CDCl ₃ ) δ: 2.17-2.37 (2H, br m), 3.16-3.37 (4H, br m), 3.57-3.69 (2H, m) 3.74-3.86 (2H, m), 3.74 (3H, s), 9.81 (2H, br s).
LC / MS [Condition 1]: Retention time 0.49 min; m / z 159.0 [M + H] ⁺ (ESI positive ion mode)

Example 349
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexanecarbonyl] -1,4-diazepane-1-carboxylate (Compound No. 349) 1,4-diazepane-1-carboxylic acid obtained in Reference Example 349 instead of 3,5-dimethylpiperidine The reaction was carried out substantially in the same manner as in Example 342 except for using acid methyl hydrochloride to obtain the title compound (17 mg, yield 43%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.7 Hz), 1.46-1.69 (3H, br m), 1.69-2.00 (10H , Br m), 2.41 (1H, t, J = 11.7 Hz), 2.58 (4H, br s), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H , S), 3.34-3.65 (8H, m), 3.58 (2H, s), 3.66-3.72 (3H, m), 7.44 (2H, d, J = 8) .2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 594.7 [M + H] ⁺ (ESI positive ion mode), m / z 638.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 350
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of 2-methoxyethyl methyl) cyclohexanecarbonyl] piperazine-1-carboxylate (Compound No. 350) Substantially the same as Example 149, except that 2-methoxyethyl chloroformate (commercially available) was used instead of methyl chloroformate. The title compound (6.4 mg, 22% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.0 Hz), 1.46-1.69 (3H, br m), 1.71-1.87 (6H , Br m), 1.88-2.00 (2H, br m), 2.42 (1H, t, J = 11.9 Hz), 2.56 (4H, br s), 3.10 (2H, d, J = 8.2 Hz), 3.26 (2H, s), 3.38 (3H, s), 3.41-3.54 (6H, br m), 3.53-3.66 (6H) M), 4.22-4.31 (2H, m), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 624.9 [M + H] ⁺ (ESI positive ion mode), m / z 669.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 351
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarbonyl] piperazine-1-carboxylate (Compound No. 351) was prepared. The reaction was carried out in substantially the same manner as in Example 149 except that isopropyl chloroformate (commercially available) was used instead of methyl chloroformate. The title compound (7.3 mg, 27% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.25 (6H, d, J = 6.1 Hz), 1.43-1.67 ( 3H, br m), 1.70-1.86 (6H, br m), 1.87-2.02 (2H, br m), 2.43 (1 H, t, J = 12.1 Hz), 2 .56 (4H, br s), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.47 (6H, br s), 3.57 (4H, br) s), 4.94 (1H, qq, J = 6.1, 6.1 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz) ).

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 608.8 [M + H] ⁺ (ESI positive ion mode), m / z 653.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 352
3-({(1r, 4r) -4- [4- (methylsulfonyl) piperazine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-2-one (Compound No. 352) The reaction was conducted in substantially the same manner as in Example 149 except that methanesulfonyl chloride (commercially available) was used instead of methyl chloroformate. The title compound (18 mg, 70% yield) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.47-1.68 (3H, br m), 1.71-1.85 (6H , Br m), 1.87-2.01 (2H, br m), 2.42 (1 H, t, J = 11.9 Hz), 2.56 (4 H, br s), 2.79 (3H, s), 3.11 (2H, d, J = 7.4 Hz), 3.22 (4H, br s), 3.26 (2H, s), 3.57 (2H, s), 3.60 ( 2H, br s), 3.73 (2H, br s), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 9.4 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 600.8 [M + H] ⁺ (ESI positive ion mode), m / z 645.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 353
3-oxo-3- {4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) cyclohexanecarbonyl] piperazin-1-yl} propanenitrile (Compound No. 353) 3-{[(1r, 4r) -4- (piperazine-1) obtained in Reference Example 149 -Carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one dihydrochloride (28 mg, 0.047 mmol) 2-cyanoacetic acid (commercially available) (6.0 mg, 0.071 mmol), 1-hydroxybenzotriazole (3.0 mg, 0.024 mol), and triethylamine (0. 33 mL, 0.24 mmol) was dissolved in chloroform (1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (14 mg, 0.071 mmol) was added at room temperature, and one day at room temperature. Stir. Thereafter, chloroform (2.0 mL) and water (2.0 mL) were added to the reaction mixture to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm, manufactured by Yamazen Co., Ltd., developing solvent: ethyl acetate / methanol = 10/1], and the title compound (20 mg, 71%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.57 (2H, q, J = 12.7 Hz), 1.56-1.71 ( 1H, br m), 1.72-1.86 (6H, br m), 1.88-2.00 (2H, br m), 2.44 (1 H, t, J = 10.0 Hz), 2 .57 (4H, br s), 3.11 (2H, d, J = 7.0 Hz), 3.26 (2H, s), 3.38-3.77 (12 H, br m), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.75 minutes; m / z 589.8 [M + H] ⁺ (ESI positive ion mode), m / z 587.9 [MH] ⁻ (ESI negative ion mode)

Example 354
1- {4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of —yl} methyl) cyclohexanecarbonyl] piperazine-1-carbonyl} cyclopropanecarbonitrile (Compound No. 354) Substantially except that 1-cyanocyclopropanecarboxylic acid (commercially available) was used instead of 2-cyanoacetic acid. Was reacted in the same manner as in Example 353 to give the title compound (18 mg, 61% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.48-1.68 (7H, m), 1.71-1.86 (6H, br m), 1.86-2.02 (2H, br m), 2.44 (1H, t, J = 11.9 Hz), 2.56 (4H, br s), 3.11 (2H, d , J = 7.4 Hz), 3.26 (2H, s), 3.43-3.93 (8H, br m), 3.57 (2H, s), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 615.8 [M + H] ⁺ (ESI positive ion mode), m / z 659.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 355-1
Preparation of methyl 5- (hydroxymethyl) thiophene-2-carboxylate 5- (methoxycarbonyl) thiophene-2-carboxylic acid (synthesized using the method described in US26094694) (120 mg, 0.62 mmol) in tetrahydrofuran (2.0 mL) 1 M borane tetrahydrofuran solution (1.2 mL, 1.2 mmol) was added under ice cooling, and the mixture was stirred at 60 ° C. for 3 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture, and the organic layer was separated. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 2/1], and the title compound ( 110 mg, 98% yield) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.00 (1H, t, J = 6.1 Hz), 3.88 (3H, s), 4.86 (2H, d, J = 5.7 Hz) , 6.99 (1H, dt, J = 3.7, 0.8 Hz), 7.68 (1H, d, J = 3.7 Hz).

Reference Example 355-2
Preparation of methyl 5- (chloromethyl) thiophene-2-carboxylate Methyl 5- (hydroxymethyl) thiophene-2-carboxylate obtained in Reference Example 355-1 was dissolved in dichloromethane (1.0 mL), and the mixture was cooled on ice. , Triethylamine (0.066 mL, 0.48 mmol) and methanesulfonyl chloride (0.042 mL, 0.52 mmol) were added, and the mixture was stirred at room temperature for 2.5 hours. Further, triethylamine (0.066 mL, 0.48 mmol) and methanesulfonyl chloride (0.042 mL, 0.52 mmol) were added under ice cooling, and the mixture was stirred overnight at room temperature. Water and chloroform were added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 4/1], and the title compound (35 mg Yield 47%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.88 (3H, s), 4.76 (2H, s), 7.07 (1H, d, J = 3.7 Hz), 7.65 (1H , D, J = 4.1 Hz).

Reference Example 355-3
Reference example for the preparation of t-butyl 3-{[5- (methoxycarbonyl) thiophen-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate 2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (71 mg, 0.28 mmol) obtained in 111-1 was converted to N, N-dimethylformamide (2 0.05), sodium t-butoxide (30 mg, 0.31 mmol) was added, and the mixture was stirred for 30 minutes, and then methyl 5- (chloromethyl) thiophene-2-carboxylate (35 mg) obtained in Reference Example 355-2. 0.19 mmol) in N, N-dimethylformamide (2.0 mL) was added and stirred for 3 hours. Thereafter, water and ethyl acetate were added to separate the organic layer, and the organic layer was washed twice with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) from Merck GMBH, developing solvent: hexane / Purification by ethyl acetate = 1/1] gave the title compound (20 mg, yield 26%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.58-1.70 (2H, m), 1.88 (2H, d, J = 13.1 Hz), 3 .24 (2H, s), 3.29 (2H, d, J = 10.6 Hz), 3.83 (2H, d, J = 14.3 Hz), 3.88 (3H, s), 4.62 (2H, s), 6.99 (1H, d, J = 3.7 Hz), 7.68 (1H, d, J = 3.7 Hz).

LC / MS [Condition 1]: Retention time 4.11 min; m / z 432.9 [M + Na] ⁺ (ESI positive ion mode)

Reference Example 355-4
Preparation of methyl 5-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] thiophene-2-carboxylate [(tetrahydrofuran-2-yl) methyl ] Instead of t-butyl carbamate, 3-{[5- (methoxycarbonyl) thiophen-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8- The reaction was carried out substantially in the same manner as in Reference Example 182-2 except that t-butyl carbamate was used to give the title compound (17 mg, quantitative yield) as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 2.05-1.91 (3H, m), 2.15 (2H, d, J = 14.3 Hz), 3.44 (2H, s), 3.86 (3H, s), 4.66 (2H, s), 7.11 (1H, d, J = 3.7 Hz), 7.70 (1H, d, J = 3.7 Hz).

LC / MS [Condition 1]: Retention time 0.59 minutes; m / z 311.0 [M + H] ⁺ (ESI positive ion mode)

Reference Example 355-5
5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiophene-2-carboxylate methyl 5 obtained in reference example 355-4 of - [(2-oxo-1-oxa-3,8-diazaspiro [4.5] decane - yl) methyl] thiophene-2-carboxylic acid methyl hydrochloride (17 mg , 0.049 mmol) was suspended in N, N-dimethylformamide (2.0 mL), and triethylamine (0.020 mL, 0.15 mmol) and 4- (trifluoromethyl) benzyl bromide (14 mg, 0.058 mmol) were added. Stir at room temperature for 1 hour. Water and ethyl acetate were added to separate the organic layer, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Ltd., developing solvent: hexane / ethyl acetate = 1/1], and the title compound (25 mg, quantitative yield). Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.69-1.84 (2H, m), 1.93 (2H, d, J = 12.9 Hz), 2.61-2.49 (4H, brm), 3.24 (2H, s), 3.56 (2H, s), 3.88 (3H, s), 4.61 (2H, s), 6.98 (1H, d, J = 4). .0Hz), 7.43 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz), 7.68 (1H, d, J = 3.6 Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 468.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 355-6
Of 5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiophene-2-carboxylic acid 5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl obtained in Preparation Reference Example 355-5 } Methyl) methyl thiophene-2-carboxylate (25 mg, 0.052 mmol) was suspended in methanol (2.0 mL), dissolved by heating to 60 ° C., and then 1M aqueous sodium hydroxide solution (0.26 mL, 0.2 mL). 26 mmol) was added, and the mixture was stirred at 60 ° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 1M hydrochloric acid (0.26 mL, 0.26 mmol) was added dropwise. Further, saturated brine and ethyl acetate were added to separate the organic layer, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated to dryness under reduced pressure to give the title compound (20 mg, 83% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.88-2.03 (4H, m), 2.65-3.23 (6H, m), 3.93 (2H, s), 4.57 (2H, s), 6.93 (1H, brs), 7.69-7.44 (6H, m).
LC / MS [Condition 1]: Retention time 2.53 minutes; m / z 454.8 [M + H] ⁺ (ESI positive ion mode), m / z 453.0 [MH] ⁻ (ESI negative ion mode)

Example 355
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] thiophen-2-yl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 355) 5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1 obtained in Reference Example 355-6 -Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiophene-2-carboxylic acid (4.0 mg, 0.0088 mmol), 4- (4-fluorobenzoyl) piperidine hydrochloride (3 0.2 mg, 0.013 mmol), triethylamine (1.8 μL, 0.013 mmol) and 1-hydroxybenzotriazole (1.2 mg, 0.0088 mmol) in chloroform Was dissolved in 1.0 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.5 mg, 0.013 mmol) was added and stirred for 84 hours at room temperature. After completion of the reaction, water was added to the reaction mixture to separate the organic layer, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by thin layer chromatography [PLC05 Plate NH, manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate] to obtain the title compound (4.1 mg, yield 73%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-2.00 (8H, m), 2.47-2.58 (4H, brm), 3.12-3.28 (4H, m) , 3.46-3.59 (3H, m), 4.44 (2H, d, J = 13.3 Hz), 4.60 (2H, s), 6.93 (1H, d, J = 3. 7 Hz), 7.11-7.24 (3H, m), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 8.02- 7.94 (2H, m).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 644.0 [M + H] ⁺ (ESI positive ion mode), m / z 642.1 [MH] ⁻ (ESI negative ion mode)

Example 356
4- [5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) thiophene-2- Carboxamide] Preparation of methyl piperidine-1-carboxylate (Compound No. 356) In place of 4- (4-fluorobenzoyl) piperidine hydrochloride, 4-aminopiperidine-1-carboxylate methyl hydrochloride obtained in Reference Example 135 was used. The reaction was carried out substantially in the same manner as in Example 355, except that the title compound (3.6 mg, yield 69%) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (2H, qd, J = 12.3, 3.3 Hz), 1.74 (2H, dt, J = 13.5, 7.2 Hz), 1.92 (2H, d, J = 13.1 Hz), 2.02 (2H, d, J = 13.9 Hz), 2.49-2.57 (4H, m), 2.94 (2H, t , J = 12.7 Hz), 3.24 (2H, s), 3.56 (2H, s), 3.70 (3H, s), 4.25-4.00 (3H, m), 4. 59 (2H, s), 5.76 (1H, d, J = 7.4 Hz), 6.96 (1H, d, J = 3.7 Hz), 7.36 (1H, d, J = 3.7 Hz) ), 7.42 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.31 min; m / z 594.9 [M + H] ⁺ (ESI positive ion mode), m / z 593.0 [MH] ⁻ (ESI negative ion mode)

Example 357
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-3-yl} methyl) thiophene-2-carboxamide (Compound No. 357) substantially except that piperonylamine is used in place of 4- (4-fluorobenzoyl) piperidine hydrochloride. The title compound (3.8 mg, yield 74%) was obtained as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74 (2H, dt, J = 14.1, 6.9 Hz), 1.92 (2H, dt, J = 13.5, 3.3 Hz), 2.47-2.57 (4H, m), 3.23 (2H, s), 3.56 (2H, s), 4.50 (2H, d, J = 5.7 Hz), 4.59 ( 2H, s), 5.95 (2H, s), 6.12 (1H, t, J = 5.7 Hz), 6.73-6.85 (3H, m), 6.96 (1H, d, J = 4.1 Hz), 7.36 (1H, d, J = 3.7 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz) ).

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 587.9 [M + H] ⁺ (ESI positive ion mode), m / z 586.0 [MH] ⁻ (ESI negative ion mode)

Example 358
5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N-[(tetrahydrofuran- Preparation of 2-yl) methyl] thiophene-2-carboxamide (Compound No. 358) Reaction substantially as in Example 355 except that tetrahydrofurfurylamine was used in place of 4- (4-fluorobenzoyl) piperidine hydrochloride. To give the title compound (2.9 mg, 60% yield) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.75 (2H, dt, J = 13.5, 7.5 Hz), 1.85-2.09 (6H, m), 2.46-2. 60 (4H, m), 3.24 (2H, s), 3.29 (1H, ddd, J = 13.9, 7.8, 4.9 Hz), 3.56 (2H, s), 3. 70-3.83 (2H, m), 3.89 (1H, dt, J = 8.2, 7.0 Hz), 4.05 (1H, qd, J = 7.4, 3.3 Hz), 4 .59 (2H, s), 6.30 (1H, t, J = 5.7 Hz), 6.96 (1H, d, J = 3.7 Hz), 7.37 (1H, d, J = 3. 7 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 537.8 [M + H] ⁺ (ESI positive ion mode), m / z 536.1 [MH] ⁻ (ESI negative ion mode)

Example 359
N- (4-cyanobenzyl) -5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) thiophene-2-carboxamide (Compound No. 359) Reaction substantially as in Example 355 except that 4-cyanobenzylamine hydrochloride was used instead of 4- (4-fluorobenzoyl) piperidine hydrochloride To give the title compound (2.4 mg, 48% yield) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.53-1.87 (2H, m), 1.93 (2H, d, J = 13.1 Hz), 2.48-2.69 (4H, m), 3.25 (2H, s), 3.59 (2H, s), 4.60 (2H, s), 4.66 (2H, d, J = 6.1 Hz), 6.36 (1H) , T, J = 5.9 Hz), 6.98 (1H, d, J = 3.7 Hz), 7.42 (1H, d, J = 3.7 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.64 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.20 minutes; m / z 568.9 [M + H] ⁺ (ESI positive ion mode), m / z 567.0 [MH] ⁻ (ESI negative ion mode)

Example 360
N- (4-cyanobenzyl) -3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) benzamide (Compound No. 360) The reaction was carried out in substantially the same manner as in Example 202 except that 4-cyanobenzylamine hydrochloride was used instead of methyl 4-aminopiperidine-1-carboxylate. To give the title compound (23 mg, 91% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72 (2H, dt, J = 13.8, 6.9 Hz), 1.91 (2H, dt, J = 13.1, 3.3 Hz), 2.44-2.60 (4H, m), 3.15 (2H, s), 3.55 (2H, s), 4.46 (2H, s), 4.71 (2H, d, J = 6.1 Hz), 6.67 (1H, t, J = 5.7 Hz), 7.38-7.50 (6H, m), 7.56 (2H, d, J = 8.2 Hz), 7. 64 (2H, d, J = 8.2 Hz), 7.70-7.78 (2H, m).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 562.9 [M + H] ⁺ (ESI positive ion mode), m / z 561.0 [MH] ⁻ (ESI negative ion mode)

Example 361
4- {1- [3-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl Preparation of piperidin-4-yloxy} benzonitrile (Compound No. 361) 4- (piperidin-4-yloxy) obtained by Reference Example 264-2 instead of 4-aminopiperidine-1-carboxylic acid methyl hydrochloride The reaction was carried out substantially in the same manner as in Example 202 except for using benzonitrile hydrochloride to obtain the title compound (31 mg, quantitative yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.66-2.11 (8H, m), 2.44-2.60 (4H, m), 3.15 (2H, s), 3.28 -3.96 (4H, brm), 3.55 (2H, s), 4.45 (2H, s), 4.68 (1H, tt, J = 6.1, 3.7 Hz), 6.96 (2H, d, J = 9.3 Hz), 7.29-7.38 (3H, m), 7.40 (1H, d, J = 7.9 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.60 (2H, d, J = 9.0 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 633.0 [M + H] ⁺ (ESI positive ion mode), m / z 677.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 362
1- (4-Cyanobenzyl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) phenyl] urea (Compound No. 362) Preparation of 4-cyanobenzylamine (commercially available 4-cyanobenzylamine hydrochloride instead of N- (t-butoxycarbonyl) -1,3-diaminopropane The reaction was carried out in substantially the same manner as in Example 83 except that the iron was used to give the title compound (24 mg, yield 46%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.72 (2H, dt, J = 13.2, 7.5 Hz), 1.89 (2H, dt, J = 13.5, 4.1 Hz), 2.44-2.58 (4H, m), 3.16 (2H, s), 3.54 (2H, s), 4.35 (2H, s), 4.51 (2H, d, J = 5.7 Hz), 5.43 (1H, t, J = 6.1 Hz), 6.78 (1H, s), 7.15 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8) .2 Hz), 7.61 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 577.9 M + H] ⁺ (ESI positive ion mode), m / z 576.0 [MH] ⁻ (ESI negative ion mode)

Example 363
1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) phenyl] -3 Preparation of — [(tetrahydro-2H-pyran-4-yl) methyl] urea (Compound No. 363) 4-aminomethyltetrahydropyran is used in place of N- (t-butoxycarbonyl) -1,3-diaminopropane Except for the above, the reaction was carried out in substantially the same manner as in Example 83 to obtain the title compound (31 mg, yield: 63%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.32 (2H, qd, J = 12.7, 4.5 Hz), 1.60-1.84 (5H, m), 1.90 (2H, dt, J = 13.1, 3.7 Hz), 2.44-2.61 (4H, m), 3.15 (2H, s), 3.16 (2H, t, J = 6.1 Hz), 3.37 (2H, td, J = 11.7, 1.9 Hz), 3.55 (2H, s), 3.97 (2H, dd, J = 11.3, 3.1 Hz), 4.36 (2H, s), 4.99 (1H, t, J = 5.7 Hz), 6.58 (1H, s), 7.16 (2H, d, J = 8.6 Hz), 7.28 (2H , D, J = 9.4 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 560.9 [M + H] ⁺ (ESI positive ion mode), m / z 559.0 [MH] ⁻ (ESI negative ion mode)

Example 364
1- (furan-2-ylmethyl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) phenyl] urea (Compound No. 364) Substantially the same as Example 83 except for using furfurylamine instead of N- (t-butoxycarbonyl) -1,3-diaminopropane The title compound (21 mg, 43% yield) was obtained as a yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.70 (2H, dt, J = 14.4, 6.9 Hz), 1.89 (2H, d, J = 13.1 Hz), 2.44— 2.59 (4H, m), 3.12 (2H, s), 3.54 (2H, s), 4.36 (2H, s), 4.44 (2H, d, J = 5.7 Hz) , 5.06 (1H, t, J = 5.3 Hz), 6.25 (1H, d, J = 3.3 Hz), 6.32 (1H, dd, J = 3.3, 1.6 Hz), 6.46 (1H, s), 7.17 (2H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.33-7.36 (1H, m ), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 542.9 [M + H] ⁺ (ESI positive ion mode), m / z 541.1 [MH] ⁻ (ESI negative ion mode)

Example 365
1- (furan-3-ylmethyl) -3- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3-yl} methyl) phenyl] urea (Compound No. 365) Substantially Examples except that 3-furylmethylamine was used instead of N- (t-butoxycarbonyl) -1,3-diaminopropane The reaction was conducted in the same manner as in 83 to give the title compound (21 mg, yield 43%) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.71 (2H, dt, J = 13.8, 7.2 Hz), 1.89 (2H, dt, J = 13.1, 4.1 Hz), 2.45-2.58 (4H, m), 3.13 (2H, s), 3.55 (2H, s), 4.30 (2H, d, J = 5.3 Hz), 4.36 ( 2H, s), 4.87-4.98 (1H, m),
6.40 (1H, s), 6.48 (1H, brs), 7.17 (2H, d, J = 8.6 Hz), 7.28 (2H, d, J = 8.6 Hz), 7. 36-7.42 (2H, m), 7.42 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 542.9 [M + H] ⁺ (ESI positive ion mode), m / z 541.1 [MH] ⁻ (ESI negative ion mode)

Example 366
(1r, 4r) -N- (3-cyanobenzyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 366) Substantially except that 3- (aminomethyl) benzonitrile hydrochloride (produced by the method described in WO2007 / 002313) is used in place of tetrahydrofurfurylamine. Specifically, the reaction was carried out in the same manner as in Example 10 to obtain the title compound (19 mg, yield 73%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, qd, J = 11.9, 2.9 Hz), 1.53 (2H, qd, J = 12.7, 2.9 Hz), 1.62-1.69 (1H, m), 1.79 (4H, d, J = 10.6 Hz), 1.95 (4H, d, J = 15.1 Hz), 2.10 (1H, tt , J = 11.9, 3.7 Hz), 2.51-2.61 (4H, m), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3 .58 (2H, s), 4.47 (2H, d, J = 6.1 Hz), 5.91 (1H, t, J = 5.7 Hz), 7.39-7.62 (8H, m) .

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 568.7 [M + H] ⁺ (ESI positive ion mode), m / z 612.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 367-1
Preparation of t-butyl 4- [4- (methylsulfonyl) benzoyl] piperidine-1-carboxylate Synthesized using the method described in WO2005 / 059107.

Reference Example 367-2
Production of 4- [4- (methylsulfonyl) benzoyl] piperidine hydrochloride t-butyl 4- [4- (methylsulfonyl) benzoyl] piperidine-1-carboxylate obtained in Reference Example 367-1 (68 mg, 0. 18 mmol) was dissolved in methanol (2.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 30 hr. The reaction mixture was filtered, and the resulting solid was washed with 1,4-dioxane and dried under reduced pressure to give the title compound (30 mg, yield 53%) as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 1.90 (2H, dtd, J = 15.1, 11.1, 4.1 Hz), 2.14 (2H, dd, J = 14.9, 2.7 Hz), 3.15 (1 H, dd, J = 7.4, 4.1 Hz), 3.17 (3 H, s), 3.21 (1 H, dd, J = 12.3, 3.3 Hz) ), 3.47 (2H, dt, J = 13.1, 4.2 Hz), 3.82 (1H, tt, J = 11.1, 3.7 Hz), 8.12 (2H, d, J = 8.6 Hz), 8.24 (2H, d, J = 9.0 Hz).

Example 367
3-[((1r, 4r) -4- {4- [4- (methylsulfonyl) benzoyl] piperidine-1-carbonyl} cyclohexyl) methyl] -8- [4- (trifluoromethyl) benzyl] -1- Preparation of Oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 367) 4- [4- (methylsulfonyl) benzoyl obtained in Reference Example 367-2 instead of tetrahydrofurfurylamine The reaction was performed in substantially the same manner as in Example 10 except that piperidine hydrochloride was used to obtain the title compound (30 mg, yield 97%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 12.7 Hz), 1.56 (2H, q, J = 13.1 Hz), 1.56-1.69 ( 2H, m), 1.72-1.87 (7H, m), 1.88-2.00 (4H, m), 2.46 (1H, tt, J = 12.3, 3.3 Hz), 2.53-2.63 (4H, m), 2.84 (1H, t, J = 11.9 Hz), 3.09 (3H, s), 3.11 (2H, d, J = 8.2 Hz) ), 3.22 (1H, t, J = 13.5 Hz), 3.26 (2H, s), 3.51 (1H, tt, J = 10.6, 3.7 Hz), 3.57 (2H , S), 3.99 (1H, d, J = 13.5 Hz), 4.60 (1H, d, J = 13.1 Hz), 7.44 (2H, d, J = 7.8 Hz), 7 .57 ( H, d, J = 8.2Hz), 8.07 (2H, d, J = 8.6Hz), 8.11 (2H, d, J = 9.0Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 703.8 [M + H] ⁺ (ESI positive ion mode), m / z 747.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 368
3- {4- [4- (4-Fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid t- Preparation of Butyl (Compound No. 368) 4- (Bromomethyl) benzenesulfonyl chloride (530 mg, 2.0 mmol) was dissolved in chloroform (5.0 mL), and 4- (4-fluorobenzoyl) piperidine hydrochloride ( 480 mg, 2.0 mmol) and triethylamine (0.55 mL, 4.0 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After adding water (10 mL) and chloroform (10 mL) to the reaction mixture, the organic layer was separated, and the solution obtained by filtration was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: chloroform / ethyl acetate = 10/1] to give a colorless oil ( 60 mg) was obtained.
2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (35 mg, 0.14 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (1.0 mL), sodium t-butoxide (16 mg, 0.16 mmol) was added, and the mixture was stirred for 30 minutes, and then the colorless oil (60 mg) obtained above, N, N-dimethylformamide (2.0 mL) was added. ) The solution was added and stirred for 5 hours. Thereafter, water and ethyl acetate were added to separate the organic layer. The obtained organic layer was washed twice with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [filler: silica gel 60 (0.040- from Merck GMBH). 0.063 mm), developing solvent: ethyl acetate = 1] to give the title compound (75 mg, 6%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.59-1.72 (2H, m), 1.78-1.99 (6H, m), 2.61 (2H, td, J = 10.6, 3.7 Hz), 3.20 (1H, tt, J = 10.2, 4.5 Hz), 3.21 (2H, s), 3.29 (2H, t, J = 11.5 Hz), 3.78 (2H, dt, J = 12.3, 3.3 Hz), 3.79-3.92 (2H, m), 4.53 (2H, s), 7.12 (2H, t, J = 8.6 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.79 (2H, d, J = 8.2 Hz), 7.89 (2H , Dd, J = 8.8, 5.5 Hz).

LC / MS [Condition 1]: Retention time 4.59 minutes; m / z 615.8 [M + H] ⁺ (ESI positive ion mode), m / z 659.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 369
3- {4- [4- (4-Fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride Preparation Example 368 3- {4- [4- (4-Fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- T-butyl carboxylate (69 mg, 0.11 mmol) was dissolved in 1,4-dioxane (2.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (61 mg, yield 98%) as a white solid.

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 515.8 [M + H] ⁺ (ESI positive ion mode), m / z 513.8 [MH] ⁻ (ESI negative ion mode)

Example 369
3,5-difluoro-4-[(3- {4- [4- (4-fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Production of decan-8-yl) methyl] benzonitrile (Compound No. 369) 3- {4- [4- (4-fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl}-obtained in Reference Example 369 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride is desalted to give 3- {4- [4- (4-fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl}- 1-oxa-3,8-diazaspiro [4.5] decan-2-one was obtained.
The resulting 3- {4- [4- (4-fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one and 3,5 -Difluoro-4-formylbenzonitrile (6.9 mg, 0.041 mmol) was dissolved in dichloromethane (2.0 mL), sodium triacetoxyborohydride (12 mg, 0.057 mmol) was added, and the mixture was stirred at room temperature for 1 hour. . Water and chloroform were added to the reaction mixture, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography [PLC05 Plate NH, manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate] to obtain the title compound (3.0 mg, yield 12%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.70-1.82 (2H, m), 1.82-1.99 (6H, m), 2.54-2.67 (6H, m) 3.17 (2H, s), 3.19 (1H, tt, J = 9.6, 5.0 Hz), 3.74 (2H, s), 3.77 (2H, dt, J = 12. 6, 3.3 Hz), 4.51 (2H, s), 7.12 (2H, t, J = 8.6 Hz), 7.22 (2H, d, J = 6.3 Hz), 7.43 ( 2H, d, J = 8.3 Hz), 7.77 (2H, d, J = 8.3 Hz), 7.89 (2H, dd, J = 8.9, 5.6 Hz).

LC / MS [Condition 1]: retention time 3.58 minutes; m / z 666.7 [M + H] ⁺ (ESI positive ion mode), m / z 711.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 370
4-[(3- {4- [4- (4-Fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- Yl) methyl] benzonitrile (Compound No. 370) (1r, 4r) -N- (1-benzylpiperidin-4-yl) -4-[(2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Decan-3-yl) methyl] cyclohexanecarboxamide hydrochloride instead of 3- {4- [4- (4- (4-fluorobenzoyl) piperidin-1-ylsulfonyl] benzyl}-obtained in Reference Example 369 Example 9 substantially except that 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride is used instead of 4-cyanobenzyl bromide instead of benzyl bromide. The reaction was carried out similarly to give the title compound (12 mg, 66% yield) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.73-2.01 (8H, m), 2.50-2.67 (6H, m), 3.19 (1H, tt, J = 9. 8, 5.3 Hz), 3.20 (2H, s), 3.58 (2H, s), 3.77 (2H, dt, J = 12.3, 3.7 Hz), 4.52 (2H, s), 7.11 (2H, t, J = 8.6 Hz), 7.44 (4H, d, J = 8.2 Hz), 7.61 (2H, d, J = 8.2 Hz), 7. 78 (2H, d, J = 8.2 Hz), 7.89 (2H, dd, J = 8.6, 5.3 Hz).

LC / MS [Condition 1]: Retention time 3.29 minutes; m / z 630.9 [M + H] ⁺ (ESI positive ion mode), m / z 629.2 [MH] ⁻ (ESI negative ion mode)

Reference Example 371-1
Preparation of methyl 2- (methoxymethoxy) -4-methylbenzoate Methyl 4-methylsalicylate (426 mg, 2.6 mmol) was dissolved in N, N-dimethylformamide (5.0 mL), and sodium hydride was cooled with ice. (55 wt%, liquid paraffin dispersion) (170 mg, 3.9 mmol) was added and stirred for 20 minutes, chloromethyl methyl ether (0.25 mL, 3.3 mmol) was added, and the mixture was stirred at room temperature for 15 hours. A saturated aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL) were added to the reaction mixture, and the organic layer was separated and washed with saturated brine three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 10/1], and the title compound was colorless. Obtained as an oil (480 mg, 89% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.37 (3H, s), 3.53 (3H, s), 3.87 (3H, s), 5.25 (2H, s), 6. 85 (1H, d, J = 8.2 Hz), 7.00 (1H, s), 7.71 (1H, d, J = 7.8 Hz).

Reference Example 371-2
Reference example for production of t-butyl 3- [4- (methoxycarbonyl) -3- (methoxymethoxy) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Methyl 2- (methoxymethoxy) -4-methylbenzoate (480 mg, 2.3 mmol) obtained in 371-1 was dissolved in chloroform (5.0 mL), heated to 80 ° C., and then N-bromosuccinimide ( 534 mg, 3.0 mmol) and azobisisobutyronitrile (75 mg, 0.46 mmol) were added, and the mixture was stirred at 80 ° C. for 3 hours. After cooling to room temperature, saturated aqueous sodium hydrogen carbonate solution (10 mL) and chloroform (10 mL) were added, the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 5/1], and colorless oil ( 694 mg) was obtained.
2-Oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (591 mg, 2.3 mmol) obtained in Reference Example 111-1 was replaced with N, N-dimethylformamide. (6.0 mL), sodium t-butoxide (222 mg, 2.3 mmol) was added, and the mixture was stirred for 30 minutes. The colorless oil (694 mg) obtained above was then added to N, N-dimethylformamide (4.0 mL) And dissolved for 2 hours. Thereafter, water and ethyl acetate were added to separate the organic layer, washed with saturated brine three times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography [filler Was purified by silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: hexane / ethyl acetate = 1/1] to give the title compound (542 mg, 51%) as a colorless oil. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.58-1.69 (2H, m), 1.88 (2H, d, J = 13.5 Hz), 3 .15 (2H, s), 3.29 (2H, t, J = 11.1 Hz), 3.51 (3H, s), 3.81 (2H, d, J = 12.3 Hz), 3.90 (3H, s), 4.45 (2H, s), 5.25 (2H, s), 6.94 (1H, dd, J = 7.8, 1.6 Hz), 7.07 (1H, d , J = 1.2 Hz), 7.77 (1H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.09 minutes; m / z 486.8 [M + Na] ⁺ (ESI positive ion mode)

Reference Example 371-3
Preparation of 2-hydroxy-4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoic acid hydrochloride Obtained in Reference Example 371-2 3- [4- (methoxycarbonyl) -3- (methoxymethoxy) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (542 mg, 0 0.029 mmol) was dissolved in methanol (5.0 mL), 4M hydrogen chloride-dioxane solution (2.0 mL) was added, and the mixture was stirred at room temperature for 2 hr. Thereafter, the solid obtained by filtration was washed with 1,4-dioxane three times and dried under reduced pressure to obtain the title compound (225 mg, yield 54%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.06 (2H, d, J = 13.5 Hz), 2.17-2.31 (2H, m), 3.23 (2H, s), 3 .28 (2H, t, J = 10.2 Hz), 3.45 (2H, d, J = 11.9 Hz), 3.96 (3H, s), 4.40 (2H, s), 6.77 (1H, dd, J = 8.2, 1.6 Hz), 6.84 (1H, d, J = 1.2 Hz), 7.83 (1H, d, J = 8.2 Hz), 9.76 ( 2H, brs), 10.82 (1H, s).

LC / MS [Condition 1]: Retention time 0.74 minutes; m / z 321.0 [M + H] ⁺ (ESI positive ion mode)

Reference Example 371-4
2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) methyl benzoate of reference example 2-hydroxy obtained in 371-3 4 - [(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] benzoate hydrochloride (110 mg, 0.36 mmol) was suspended in N, N-dimethylformamide (3.0 mL), triethylamine (0.15 mL, 1.1 mmol) and 4- (trifluoromethyl) benzyl bromide (100 mg, 0.43 mmol). And stirred at room temperature for 2 hours. Water and ethyl acetate were added to separate the organic layer, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: amine silica NH-DM1020 manufactured by Fuji Silysia Co., developing solvent: hexane / ethyl acetate = 1/1] to give the title compound (142 mg, yield 82%). Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.68-1.80 (2H, m), 1.93 (2H, d, J = 13.1 Hz), 2.48-2.62 (4H, m), 3.15 (2H, s), 3.56 (2H, s), 3.95 (3H, s), 4.40 (2H, s), 6.80 (1H, dd, J = 8) .2, 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.56 (2H, d, J = 7. 8 Hz), 7.82 (1 H, d, J = 8.2 Hz), 10.81 (1 H, s).

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 478.8 [M + H] ⁺ (ESI positive ion mode), m / z 477.0 [MH] ⁻ (ESI negative ion mode)

Reference Example 371-5
Of 2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid 2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane obtained in Preparation Reference Example 371-4 -3-yl} methyl) methyl benzoate (88 mg, 0.18 mmol) was suspended in methanol (5.0 mL), dissolved by heating to 50 ° C., and then 1M aqueous sodium hydroxide solution (1.5 mL, 1.. 5 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hours, at 60 ° C. for 15 hours, and at room temperature for 16 hours. Thereafter, 1M hydrochloric acid (1.5 mL, 1.5 mmol) and water (4.0 mL) were added, and the solid obtained by filtration was dried under reduced pressure to give the title compound (122 mg, 90% yield) as a white solid. Obtained.

¹ H-NMR (300 MHz, CD ₃ OD) δ: 1.82-1.96 (2H, m), 2.03 (2H, d, J = 14.3 Hz), 2.82-2.98 (4H M), 3.98 (2H, s), 4.38 (2H, s), 6.74 (2H, d, J = 9.4 Hz), 7.61 (2H, d, J = 8.6 Hz). ), 7.70 (2H, d, J = 8.6 Hz), 7.83 (1H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 2.88 minutes; m / z 464.8 [M + H] ⁺ (ESI positive ion mode), m / z 462.9 [MH] ⁻ (ESI negative ion mode)

Example 371
4- [2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of ethyl benzoyl] piperazine-1-carboxylate (Compound No. 371) 2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl]-obtained in Reference Example 371-5 1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (20 mg, 0.043 mmol), 1-piperazinecarboxylic acid ethyl ester (0.0075 mL, 0.052 mmol) and 1 -Hydroxybenzotriazole (1.7 mg, 0.031 mmol) was dissolved in chloroform (1.0 mL), and then 1-ethyl-3- (3-dimethylaminopropyl) was dissolved. Pills) carbodiimide hydrochloride (13 mg, 0.068 mmol) was added and stirred for 84 hours at room temperature. After completion of the reaction, water and citric acid (6 mg, 0.031 mmol) were added to separate the organic layer. After concentration under reduced pressure, ethyl acetate, water and sodium bicarbonate were added to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography [PLC05 Plate NH, manufactured by Fuji Silysia Ltd., developing solvent: ethyl acetate / methanol = 25/1], and the title compound (8.5 mg, yield 33%) was white. Obtained as a solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.29 (3H, t, J = 6.9 Hz), 1.75 (2H, dt, J = 11.1, 6.6 Hz), 1.94 ( 2H, d, J = 13.9 Hz), 2.47-2.64 (4H, m), 3.18 (2H, s), 3.51-3.62 (6H, m), 3.67- 3.77 (4H, m), 4.18 (2H, q, J = 6.9 Hz), 4.39 (2H, s), 6.79 (1H, dd, J = 7.9, 1.3 Hz) ), 6.90 (1H, d, J = 1.3 Hz), 7.22 (1H, d, J = 7.9 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 8.1 Hz), 9.65 (1H, brs).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 604.6 [M + H] ⁺ (ESI positive ion mode), m / z 602.9 [MH] ⁻ (ESI negative ion mode)

Example 372
3- {4- [4- (6-chloropyrimidin-4-yl) piperazine-1-carbonyl] -3-hydroxybenzyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 372) 4-Chloro-6- (piperazin-1-yl) obtained in Reference Example 288 instead of 1-piperazinecarboxylic acid ethyl ester The reaction was carried out substantially in the same manner as in Example 371 except that pyrimidine dihydrochloride was used to obtain the title compound (11 mg, yield 41%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.76 (2H, dt, J = 13.2, 6.9 Hz), 1.94 (2H, d, J = 12.9 Hz), 2.50− 2.61 (4H, m), 3.19 (2H, s), 3.57 (2H, s), 3.73-3.81 (4H, m), 3.81-3.90 (4H, m), 4.41 (2H, s), 6.54 (1H, d, J = 0.7 Hz), 6.81 (1H, dd, J = 7.9, 1.7 Hz), 6.91 ( 1H, d, J = 1.7 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 7.9 Hz), 8.42 (1H, d, J = 0.7 Hz), 9.68 (1H, brs).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 644.9 [M + H] ⁺ (ESI positive ion mode), m / z 642.9 [MH] ⁻ (ESI negative ion mode)

Example 373
2-Hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) -N— Preparation of [(tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 373) The reaction was carried out in substantially the same manner as in Example 371 except that tetrahydrofurfurylamine was used instead of 1-piperazinecarboxylic acid ethyl ester. The title compound (25 mg, quantitative yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.73 (2H, dt, J = 13.5, 6.9 Hz), 1.67-1.80 (2H, m), 1.87-2. 12 (5H, m), 2.47-2.61 (4H, m), 3.15 (2H, s), 3.31 (1H, ddd, J = 13.9, 7.9, 4.6 Hz) ), 3.56 (2H, s), 3.74-3.84 (2H, m), 3.90 (1H, dt, J = 8.6, 6.6 Hz), 4.07 (1H, dq) , J = 3.0, 7.3 Hz), 4.38 (2H, s), 6.66 (1H, t, J = 5.9 Hz), 6.77 (1H, dd, J = 8.3). 1.7 Hz), 6.84 (1H, d, J = 1.3 Hz), 7.37 (1H, d, J = 8.3 Hz), 7.43 (2H, d, J = 7.9 Hz), 7.56 (2H, d, = 8.3Hz), 12.45 (1H, s).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 547.7 [M + H] ⁺ (ESI positive ion mode), m / z 545.9 [MH] ⁻ (ESI negative ion mode)

Example 374
4- [2-hydroxy-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Preparation of methyl benzoyl] -1,4-diazepane-1-carboxylate (Compound No. 374) 1,4-diazepane-1-carboxylate methyl hydrochloride obtained in Reference Example 349 instead of 1-piperazinecarboxylic acid ethyl ester The reaction was carried out in substantially the same manner as in Example 371 except that the salt was used to give the title compound (9.9 mg, yield 38%) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.71-2.03 (6H, m), 2.50-2.64 (4H, m), 3.18 (2H, s), 3.47 -3.85 (13H, m), 4.38 (2H, s), 6.78 (1H, d, J = 7.6 Hz), 6.88 (1H, s), 7.25-7.32. (1H, m), 7.43 (2H, d, J = 7.6 Hz), 7.57 (2H, d, J = 8.9 Hz), 9.47 (1H, brs).

LC / MS [Condition 1]: Retention time 2.88 minutes; m / z 604.7 [M + H] ⁺ (ESI positive ion mode), m / z 603.0 [MH] ⁻ (ESI negative ion mode)

Reference Example 375-1
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl manufacturing (1r, 4r) -4 - { [8- (t- butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid Instead of 4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} benzoic acid obtained in Reference Example 158 Substantially conducted except using acid and (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) and triethylamine instead of tetrahydrofurfurylamine The title compound by performing the reaction as in 2 (1.5 g, 92% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.54-1.67 (2H, m), 1.71-2.09 (6H, br m), 2.97- 3.22 (2H, m), 3.14 (2H, s), 3.28 (2H, t, J = 11.1 Hz), 3.43-3.60 (1H, m), 3.74- 3.94 (1H, br m), 3.81 (2H, d, J = 11.5 Hz), 4.46 (2H, s), 4.52-4.78 (1 H, br m), 7. 16 (2H, t, J = 8.6 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.99 (2H, dd) , J = 8.6, 5.3 Hz).

LC / MS [Condition 1]: Retention time 4.37 minutes; m / z 579.7 [M + H] ⁺ , 523.7 [M-isobutene + H] ⁺ (ESI positive ion mode), m / z 624.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 375-2
Preparation of 3- {4- [4- (4-fluorobenzoyl) piperidine-1-carbonyl] benzyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 2-oxo- 3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid Instead of t-butyl, 3- {4- [4- (4-fluorobenzoyl) piperidine-1-carbonyl] benzyl} -2-oxo-1-oxa-3,8 obtained in Reference Example 375-1 Reaction was carried out in substantially the same manner as in Example 3 except that t-butyl diazaspiro [4.5] decane-8-carboxylate was used to obtain the title compound (1.5 g, quantitative) as a white powder. .

LC / MS [Condition 1]: Retention time 2.73 minutes; m / z 480.0 [M + H] ⁺ (ESI positive ion mode), m / z 514.0 [M + Cl] ⁻ , 524.0 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 375
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethylthio) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 375) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N 3- [4- [4- (4- (4-fluorobenzoyl) piperidine-1-carbonyl] benzyl} obtained in Reference Example 375-2 instead of [(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride} 1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride is used, and instead of 3- (bromomethyl) pyridine hydrobromide, [4- (bromo The reaction was carried out in substantially the same manner as in Example 4 except that (methyl) phenyl] (trifluoromethyl) sulfane (commercially available) was used to give the title compound (35 mg, yield 99%) as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 1.51 (2H, dq, J = 2.9, 11.9 Hz), 1.67-1.95 (6H, m), 2.32-2. 49 (4H, br m), 2.88-3.10 (1H, br m), 3.12-3.32 (2H, br m), 3.23 (2H, s), 3.55 (2H , S), 3.58-3.69 (1H, br m), 3.76 (1H, tt, J = 11.5, 3.3 Hz), 4.39 (2H, s), 4.42- 4.61 (1H, br m), 7.32 (2H, d, J = 8.2 Hz), 7.37 (2H, t, J = 8.6 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.46 (2H, d, J = 8.2 Hz), 7.67 (2H, d, J = 8.2 Hz), 8.10 (2H, dd, J = 8.6, 4 .9 Hz).

LC / MS [Condition 1]: Retention time 3.48 minutes; m / z 669.9 [M + H] ⁺ (ESI positive ion mode), m / z 704.0 [M + Cl] ⁻ , 714.1 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 376
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethyl) phenethyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 376) Instead of [4- (bromomethyl) phenyl] (trifluoromethyl) sulfane, 1- (2-bromoethyl) -4- (trifluoromethyl) benzene (commercially available) The reaction was carried out substantially in the same manner as in Example 375 except for using, to give the title compound (14 mg, yield 42%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.64-2.06 (8H, m), 2.49-2.71 (6H, m), 2.75-2.91 (2H, m), 2 .98-3.23 (2H, m), 3.15 (2H, s), 3.44-3.60 (1H, m), 3.72-3.98 (1H, br m), 4. 46 (2H, s), 4.57-4.82 (1H, br m), 7.17 (2H, t, J = 9.0 Hz), 7.30 (2H, d, J = 7.8 Hz) , 7.32 (2H, d, J = 8.2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.53 (2H, d, J = 7.8 Hz), 7.99 ( 2H, dd, J = 9.0, 5.3 Hz).

LC / MS [Condition 1]: retention time 3.40 minutes; m / z 651.8 [M + H] ⁺ (ESI positive ion mode), m / z 686.1 [M + Cl] ⁻ , 696.0 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 377
3- [2- (3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8 Preparation of -yl) acetyl] benzonitrile (Compound No. 377) except that 3- (2-bromoacetyl) benzonitrile (commercially available) was used instead of [4- (bromomethyl) phenyl] (trifluoromethyl) sulfane The reaction was carried out substantially in the same manner as in Example 375 to give the title compound (2.2 mg, yield 2.0%) as a pale yellow amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.71-2.09 (8H, m), 2.57-2.81 (4H, br m), 2.99-3.22 (2H, m), 3.16 (2H, s), 3.44-3.60 (1H, m), 3.75-3.96 (1H, br m), 3.81 (2H, s), 4.46 (2H , S), 4.55-4.81 (1H, br m), 7.17 (2H, t, J = 8.6 Hz), 7.32 (2H, d, J = 8.2 Hz), 7. 42 (2H, d, J = 8.2 Hz), 7.61 (1H, t, J = 7.8 Hz), 7.85 (1H, d, J = 7.8 Hz), 7.99 (2H, dd) , J = 8.6, 5.3 Hz), 8.22 (1H, d, J = 7.8 Hz), 8.31 (1H, s).

LC / MS [Condition 1]: Retention time 3.20 minutes; m / z 622.9 [M + H] ⁺ (ESI positive ion mode), m / z 621.1 [MH] ⁻ (ESI negative ion mode)

Reference Example 378
Preparation of 1- (bromomethyl) -4- (trifluoromethylsulfinyl) benzene and 1- (bromomethyl) -4- (trifluoromethylsulfonyl) benzene [4- (bromomethyl) phenyl] (trifluoromethyl) sulfane (commercially available) (0.27 g, 1.0 mmol) dissolved in acetonitrile (5.0 mL), hexamolybdate hexaammonium tetrahydrate (0.12 g, 0.10 mmol) and 30% aqueous hydrogen peroxide (0.041 mL, 4.0 mmol) was added, and the mixture was stirred at room temperature for 7 hours 30 minutes. After completion of the reaction, an aqueous sodium thiosulfate solution (4.0 mL) and ethyl acetate (10 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and then subjected to silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: hexane / ethyl acetate = 10/1 → 2/1]. 1- (bromomethyl) -4- (trifluoromethylsulfinyl) benzene (30 mg, 10% yield) as a colorless oil, 1- (bromomethyl) -4- (trifluoromethylsulfonyl) benzene ( 42 mg, 14% yield) was obtained as a colorless oil.

Data for 1- (bromomethyl) -4- (trifluoromethylsulfinyl) benzene

¹ H-NMR (CDCl ₃ ) δ: 4.53 (2H, s), 7.64 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.07 minutes; m / z 286.8 [M + H] ⁺ (ESI positive ion mode)

1- (Bromomethyl) -4- (trifluoromethylsulfonyl) benzene data

¹ H-NMR (CDCl ₃ ) δ: 4.53 (2H, s), 7.70 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz).

Example 378
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethylsulfinyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Production of decan-2-one (Compound No. 378)

Substantially the Example, except that 1- (bromomethyl) -4- (trifluoromethylsulfinyl) benzene obtained in Reference Example 378 was used instead of [4- (bromomethyl) phenyl] (trifluoromethyl) sulfane. The reaction was conducted in the same manner as in 375 to give the title compound (12 mg, yield 34%) as a pale orange amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.66-2.08 (8H, m), 2.48-2.64 (4H, br m), 2.98-3.22 (2H, br m) 3.14 (2H, s), 3.44-3.58 (1H, m), 3.60 (2H, s), 3.73-3.96 (1H, br m), 4.45 ( 2H, s), 4.54-4.79 (1H, br m), 7.16 (2H, t, J = 8.6 Hz), 7.31 (2H, d, J = 8.2 Hz), 7 .42 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.74 (2H, d, J = 8.2 Hz), 7.99 (2H, dd, J = 8.6, 5.3 Hz).

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 686.0 [M + H] ⁺ (ESI positive ion mode), m / z 720.2 [M + Cl], 730.1 [M + HCOO] ⁻ (ESI negative Ion mode) ^- (ESI negative ion mode)

Example 379
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8- [4- (trifluoromethylsulfonyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 Production of decan-2-one (Compound No. 379)

Substantially the Example, except that 1- (bromomethyl) -4- (trifluoromethylsulfonyl) benzene obtained in Reference Example 378 was used instead of [4- (bromomethyl) phenyl] (trifluoromethyl) sulfane. The reaction was conducted in the same manner as in 375 to give the title compound (24 mg, yield 69%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.48-2.10 (8H, m), 2.44-2.67 (4H, br m), 2.89-3.28 (2H, br m) , 3.15 (2H, s), 3.52 (1H, tt, J = 7.3, 7.3 Hz), 3.64 (2H, s), 3.71-4.01 (1H, br m ), 4.46 (2H, s), 4.55-4.80 (1H, br m), 7.17 (2H, t, J = 8.6 Hz), 7.32 (2H, d, J = 7.8 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.64 (2H, d, J = 8.2 Hz), 7.98 (2H, d, J = 8.6 Hz), 8.00 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.48 min; m / z 702.0 [M + H] ⁺ (ESI positive ion mode), m / z 700.1 [M−H] ⁻ , 746.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 380
Preparation of 1- (methoxymethylene) -4- (trifluoromethyl) cyclohexane (Methoxymethyl) triphenylphosphonium chloride (commercially available) (1.4 g, 4.2 mmol) was dissolved in tetrahydrofuran (8.0 mL) and ice-cooled. N-Butyllithium (about 15% hexane solution, 2.6 mL, 4.0 mmol) was added thereto, and the mixture was stirred for 20 minutes under ice cooling, and then 4- (trifluoromethyl) cyclohexanone (commercially available) (0.0. 40 g, 2.4 mmol) was added, and the mixture was stirred for 90 minutes under ice cooling. After completion of the reaction, the reaction was quenched with a saturated aqueous ammonium chloride solution (15 mL), and then ethyl acetate (30 mL) was added to separate the organic layer. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, followed by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm manufactured by Yamazen Co., Ltd., developing solvent: hexane / ethyl acetate = 4 / 1 → 1/1] to give the title compound (0.31 g, yield 67%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.28 (2H, dq, J = 4.5, 12.3 Hz), 1.65 (1H, dt, J = 5.7, 15.1 Hz), 1. 82-2.03 (3H, m), 2.04-2.28 (2H, m), 2.87 (1H, d, J = 13.9 Hz), 3.56 (3H, s), 5. 80 (1H, s).

Example 380
3- {4- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] benzyl} -8-{[4- (trifluoromethyl) cyclohexyl] methyl} -1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-2-one (Compound No. 380) 1- (methoxymethylene) -4- (trifluoromethyl) cyclohexane (0.12 g, 0.62 mmol) obtained in Reference Example 380 was added to acetone (0.12 g, 0.62 mmol). 2.0M), 1M hydrochloric acid (0.19mL, 0.19mmol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, methanol was distilled off under reduced pressure, and chloroform (20 mL) was added to the residue to separate the organic layer. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain a colorless oil (60 mg).
This oil and 3- {4- [4- (4-fluorobenzoyl) piperidine-1-carbonyl] benzyl} -1-oxa-3,8-diazaspiro [4.5] obtained in Reference Example 375-2. ] Decan-2-one hydrochloride (26 mg, 0.050 mmol) was dissolved in methanol / acetic acid (10/1) (2 mL) and borane-2-picoline complex (purchased from Junsei Co., Ltd.) at room temperature ( 11 mg, 0.10 mmol) was added and stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the resulting reaction residue was purified by silica gel column chromatography [filler: NH-DM1020 manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 20/1], The title compound (24 mg, 73% yield) was obtained as a pale yellow amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.38-2.06 (18H, m), 2.27 (1H, d, J = 7.0 Hz), 2.36-2.59 (4H, br m ), 3.00-3.24 (2H, m), 3.12 (2H, s), 3.45-3.58 (1H, m), 3.70-3.99 (1H, br m) 4.45 (2H, s), 4.54-4.79 (1H, br m), 7.17 (2H, t, J = 8.6 Hz), 7.31 (2H, d, J = 8) .2 Hz), 7.42 (2H, d, J = 8.2 Hz), 7.99 (2H, dd, J = 8.6, 5.3 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 643.9 [M + H] ⁺ (ESI positive ion mode), m / z 688.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 381-1
3- (5-Cyanopyridin-2-yloxy) azetidine-1-carboxylate t-butyl
Preparation of 3-hydroxyazetidine-1-carboxylate t-butyl (commercially available) (0.87 g, 5.0 mmol) dissolved in tetrahydrofuran (8.0 mL) and sodium hydride (> 55%, flowing) at room temperature After adding paraffin dispersion (purchased from Kanto Chemical Co., Inc.) (0.19 g, 5.0 mmol), stirring at the same temperature for 30 minutes, 6-chloronicotinonitrile (0.66 g, 4.8 mmol) added. After stirring at room temperature for 150 minutes, water (25 mL) and ethyl acetate (50 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, followed by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm manufactured by Yamazen Co., Ltd., developing solvent: hexane / ethyl acetate = 4 / 1 → 1/1] to give the title compound (1.5 g, quantitative yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 3.98 (2H, dd, J = 10.6, 4.1 Hz), 4.34 (2H, dd, J = 10. 6, 6.7 Hz), 5.36 (1 H, tt, J = 6.5, 4.1 Hz), 6.89 (1 H, d, J = 8.8 Hz), 7.83 (1 H, dd, J = 8.8, 2.0 Hz), 8.44 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 4.17 minutes; m / z 276.0 [M + H] ⁺ , 220.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 381-2
Production of 6- (azetidin-3-yloxy) nicotinonitrile t-butyl 3- (5-cyanopyridin-2-yloxy) azetidine-1-carboxylate (0.36 g, obtained in Reference Example 381-1) 1.3 mmol) was dissolved in chloroform (2.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution (30 mL), and chloroform (60 mL) was added to separate the organic layer. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain the title compound (0.10 g, yield 44%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 3.76 (2H, dd, J = 10.2, 6.5 Hz), 3.98 (2H, dd, J = 10.2, 6.1 Hz), 5. 50-5.52 (1H, m), 6.84 (1H, d, J = 8.6 Hz), 7.80 (1H, dd, J = 8.6, 2.5 Hz), 8.43 (1H , D, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 0.49 min; m / z 176.0 [M + H] ⁺ (ESI positive ion mode)

Example 381
6- {1- [4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoyl Preparation of azetidin-3-yloxy} nicotinonitrile (Compound No. 381) 6- (azetidin-3-yloxy) nicotinonitrile obtained in Reference Example 381-2 instead of 4- (2-aminoethyl) morpholine The title compound (19 mg, 61% yield) was obtained as a colorless amorphous product by substantially reacting in the same manner as in Example 44 except that was used.

¹ H-NMR (CDCl ₃ ) δ: 1.66-1.79 (2H, m), 1.81-1.98 (2H, m), 2.41-2.64 (4H, br m), 3.13 (2H, s), 3.55 (2H, s), 4.29 (2H, dd, J = 10.7, 3.5 Hz), 4.45 (2H, s), 4.56- 4.76 (0H, br m), 5.47 (1H, tt, J = 6.6, 3.9 Hz), 6.91 (1H, d, J = 8.6 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.3 Hz), 7.64 (2H, d, J = 8) .3 Hz), 7.85 (1H, dd, J = 8.6, 2.3 Hz), 8.43 (1H, d, J = 2.3 Hz).

LC / MS [Condition 1]: Retention time 3.16 min; m / z 605.9 [M + H] ⁺ (ESI positive ion mode), m / z 640.0 [M + Cl] ⁻ , 650.0 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 382
6- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 Preparation of —yl} methyl) cyclohexanecarbonyl] azetidin-3-yloxy} nicotinonitrile (Compound No. 382) Instead of piperidine, 6- (azetidin-3-yloxy) nicotinonitrile obtained in Reference Example 381-2 The title compound (20 mg, yield 66%) was obtained as a white powder in substantially the same manner as in Example 16 except that was used.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (2H, q, J = 12.8 Hz), 1.39-2.00 (2H, m), 2.12 (1H, tt, J = 13. 0, 3.3 Hz), 2.40-2.68 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H) , S), 4.05 (1H, dd, J = 11.3, 4.1 Hz), 4.14 (1H, dd, J = 13.9, 4.1 Hz), 4.40 (1H, dd, J = 11.3, 7.2 Hz), 4.56 (1H, dd, J = 9.2, 7.2 Hz), 5.42 (1H, tt, J = 6.1, 4.5 Hz), 6 .90 (1H, d, J = 8.6 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.85 (1H, dd, J = 8.6 .0Hz), 8.45 (1H, d, J = 2.0Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 611.9 [M + H] ⁺ (ESI positive ion mode), m / z 645.9 [M + Cl] ⁻ , 656.0 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 383-1
Preparation of t-butyl 3- (4-cyanophenoxy) azetidine-1-carboxylate Substantially Reference Example 381-1 except that 4-fluorobenzonitrile (commercially available) was used instead of 6-chloronicotinonitrile. The title compound (1.1 g, yield 77%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 4.01 (2H, dd, J = 9.8, 4.1 Hz), 4.33 (2H, dd, J = 9. 8, 6.5 Hz), 4.93 (1H, tt, J = 6.5, 4.1 Hz), 6.81 (2H, d, J = 9.4 Hz), 7.60 (2H, d, J = 9.4 Hz).

LC / MS [Condition 1]: Retention time 4.29 minutes; m / z 219.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 383-2
Preparation of 4- (azetidin-3-yloxy) benzonitrile 3- (5-cyanopyridin-2-yloxy) azetidine-1-carboxylate obtained in Reference Example 383-1 in place of t-butyl The reaction was carried out in substantially the same manner as in Reference Example 381-2 except that t-butyl (4-cyanophenoxy) azetidine-1-carboxylate was used to give the title compound (0.10 g, yield 31%) as white Obtained as a powder.

¹ H-NMR (DMSO-d ₆ ) δ: 3.20 (1H, dd, J = 6.1, 4.9 Hz), 3.61 (1H, t, J = 6.1 Hz), 4.87 ( 1H, tt, J = 6.1, 4.9 Hz), 7.01 (2H, d, J = 8.6 Hz), 7.75 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 0.51 min; m / z 175.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

Example 383
4- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) cyclohexanecarbonyl] azetidin-3-yloxy} benzonitrile (Compound No. 383)

The reaction was conducted in substantially the same manner as in Example 16 except that 4- (azetidin-3-yloxy) benzonitrile obtained in Reference Example 383-2 was used instead of piperidine to give the title compound (6.0 mg Yield 20%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (2H, q, J = 12.6 Hz), 1.46-1.62 (3H, m), 1.74-1.83 (6H, m) 1.94 (2H, d, J = 13.1 Hz), 2.13 (1H, tt, J = 12.1, 3.1 Hz), 2.42-2.68 (4H, br m), 3 .10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 4.05 (1H, dd, J = 10.8, 3.9 Hz) 4.20 (1H, dd, J = 9.2, 3.5 Hz), 4.40 (1H, dd, J = 10.8, 6.3 Hz), 4.55 (1H, dd, J = 9) .2, 6.5 Hz), 4.96-5.03 (1 H, m), 6.82 (2 H, d, J = 9.0 Hz), 7.44 (2 H, d, J = 8.2 Hz) 7.57 (2H, d J = 8.2Hz), 7.62 (2H, d, J = 9.0Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 611.0 [M + H] ⁺ (ESI positive ion mode), m / z 644.9 [M + Cl] ⁻ , 655.2 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 384
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa Preparation of -3,8-diazaspiro [4.5] decan-2-one (Compound No. 384) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5 ] Instead of 3-decane-3-yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride, 3-{[(1r, 4r) -4- Using (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride, and 3,5-bis (trif The reaction was carried out in substantially the same manner as in Example 235 except that 6- (trifluoromethyl) nicotinaldehyde (commercially available) was used instead of olomethyl) benzaldehyde to give the title compound (14 mg, yield 28%) as colorless Obtained as an amorphous material.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.5 Hz), 1.46-2.04 (15H, m), 2.47 (1H, t, J = 16. 0 Hz), 2.52-2.71 (4H, br m), 2.82 (1H, t, J = 11.5 Hz), 3.11 (2H, d, J = 6.1 Hz), 3.20 (1H, t, J = 12.7 Hz), 3.27 (2H, s), 3.52 (1H, tt, J = 11.5, 3.7 Hz), 3.62 (2H, s), 3 .98 (1H, d, J = 13.1 Hz), 4.60 (1 H, d, J = 12.7 Hz), 7.49 (1 H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.65 (1H, d, J = 8.2 Hz), 7.85 (1H, d, J = 8.2 Hz), 7.94 (2H, d, J = 7) .4Hz), 8 68 (1H, s).

LC / MS [Condition 1]: retention time 3.28 minutes; m / z 626.9 [M + H] ⁺ (ESI positive ion mode), m / z 661.4 [M + Cl] ⁻ , 671.0 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 385
3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [2-fluoro-4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 385) 1- (Bromomethyl) -2-fluoro instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene The reaction was carried out in substantially the same manner as in Example 255 except that -4- (trifluoromethyl) benzene (commercially available) was used to give the title compound (34 mg, yield 67%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.3 Hz), 1.45-2.02 (15H, m), 2.46 (1H, t, J = 11.1. 5 Hz), 2.53-2.69 (4 H, br m), 2.82 (1 H, t, J = 12.7 Hz), 3.10 (2 H, d, J = 5.7 Hz), 3.20 (1H, t, J = 13.5 Hz), 3.25 (2H, s), 3.44-3.58 (1H, m), 3.64 (2H, s), 3.98 (1H, d , J = 12.7 Hz), 4.60 (1H, d, J = 14.3 Hz), 7.30 (2H, d, J = 10.2 Hz), 7.39 (1H, d, J = 8. 2 Hz), 7.49 (2H, t, J = 7.6 Hz), 7.52-7.57 (1 H, m), 7.59 (1 H, t, J = 7.6 Hz), 7.94 ( 2H, d, J = .6Hz).

LC / MS [Condition 1]: retention time 3.42 minutes; m / z 643.8 [M + H] ⁺ (ESI positive ion mode), m / z 677.9 [M + Cl] ⁻ , 687.9 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 386
Preparation of 6- (bromomethyl) nicotinonitrile 6-Methylnicotinonitrile (commercially available) (0.30 g, 2.5 mmol) was dissolved in carbon tetrachloride (6.0 mL), and N-bromosuccinimide (0.50 g) was dissolved. 2.8 mmol) and azobisisobutyronitrile (41 mg, 0.25 mmol) were added, followed by stirring at 60 ° C. for 2 days. After completion of the reaction, an aqueous sodium thiosulfate solution (8.0 mL) and ethyl acetate (20 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, followed by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm manufactured by Yamazen Co., Ltd., developing solvent: ethyl acetate / methanol. = 1/0 → 1/1] to give the title compound (50 mg, yield 10%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 4.57 (2H, s), 7.60 (1H, d, J = 8.2 Hz), 7.99 (1H, dd, J = 8.2, 2. 0 Hz), 8.85 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.35 minutes; m / z 196.8 [M + H] ⁺ (ESI positive ion mode)

Example 386
6-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] nicotinonitrile (Compound No. 386) 6- (Bromomethyl) obtained in Reference Example 386 instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene ) The reaction was carried out in substantially the same manner as in Example 255 except that nicotinonitrile was used to obtain the title compound (42 mg, yield 90%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 12.1 Hz), 1.47-2.02 (11H, m), 2.47 (1H, tt, J = 1.11. 6, 3.6 Hz), 2.54-2.74 (4H, br m), 2.81 (1 H, td, J = 13.2, 2.3 Hz), 3.11 (2H, d, J = 7.6 Hz), 3.20 (1 H, t, J = 13.0 Hz), 3.28 (2 H, s), 3.52 (1 H, tt, J = 10.6, 3.9 Hz), 3. 76 (2H, s), 3.98 (1H, d, J = 13.2 Hz), 4.60 (1H, d, J = 13.2 Hz), 7.49 (2H, t, J = 7.4 Hz) ), 7.58 (1H, d, J = 7.9 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.90-7.98 (1H, m), 7.94 (1H , Dd, J = .3,1.6Hz), 8.84 (1H, d, J = 1.6Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 583.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.1 [M−H] ⁻ , 627.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 387
Production of 5- (bromomethyl) picolinonitrile The reaction was conducted in substantially the same manner as in Reference Example 386 except that 5-methylpicolinonitrile (commercially available) was used instead of 6-methylnicotinonitrile. (0.59 g, 71% yield) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 4.52 (2H, s), 7.72 (1H, d, J = 8.2 Hz), 7.91 (1H, dd, J = 8.2, 2. 5 Hz), 8.74 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 196.9 [M + H] ⁺ (ESI positive ion mode)

Example 387
5-[(3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of —8-yl) methyl] picolinonitrile (Compound No. 387) 5- (bromomethyl) obtained in Reference Example 387 instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene ) The reaction was carried out in substantially the same manner as in Example 255 except that picolinonitrile was used to obtain the title compound (25 mg, yield 53%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.45-2.01 (4H, m), 2.47 (1H, t, J = 1.11. 9 Hz), 2.52-2.64 (4 H, br m), 2.81 (1 H, t, J = 12.9 Hz), 3.11 (2 H, d, J = 6.5 Hz), 3.20 (1H, t, J = 12.5 Hz), 3.27 (2H, s), 3.52 (1H, t, J = 11.1 Hz), 3.61 (2H, s), 3.98 (1H , D, J = 13.5 Hz), 4.60 (1H, d, J = 13.5 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.66 (1H, d, J = 7.8 Hz), 7.81 (1H, d, J = 7.8 Hz), 7.94 (2H, d, J = 7.4 Hz), 8.68 (1H s).

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 583.9 [M + H] ⁺ (ESI positive ion mode), m / z 618.0 [M + Cl] ⁻ , 627.9 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 388
3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [2-methoxy-4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-2-one (Compound No. 388) 2-methoxy-4- (trifluoromethyl) benzaldehyde (commercially available) is used instead of 6- (trifluoromethyl) nicotinaldehyde. In substantially the same manner as in Example 384, the title compound (13 mg, yield 24%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.45-2.03 (15H, m), 2.47 (1H, t, J = 1.11. 7 Hz), 2.54-2.73 (4H, br m), 2.81 (1H, t, J = 12.2 Hz), 3.11 (2H, d, J = 7.3 Hz), 3.20 (1H, t, J = 11.9 Hz), 3.26 (2H, s), 3.52 (1H, tt, J = 10.9, 3.3 Hz), 3.61 (2H, s), 3 .87 (3H, s), 3.98 (1H, d, J = 14.2 Hz), 4.60 (1H, d, J = 13.2 Hz), 7.06 (1H, s), 7.20 (1H, d, J = 7.6 Hz), 7.49 (3H, t, J = 7.6 Hz), 7.59 (1H, t, J = 7.6 Hz), 7.94 (2H, d, J = 7.6 Hz .

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 655.8 [M + H] ⁺ (ESI positive ion mode), m / z 690.2 [M + Cl] ⁻ , 699.6 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 389
Preparation of 5- (trifluoromethyl) picolinaldehyde Methyl 5- (trifluoromethyl) picolinate (commercially available) (1.0 g, 4.9 mmol) was dissolved in dichloromethane (30 mL), and diisobutyl hydride at −78 ° C. Aluminum (17% toluene solution, about 1.0 mol / L) (15 mL, 15 mmol) was added, and the mixture was stirred at −78 ° C. for 20 minutes. After completion of the reaction, saturated aqueous potassium sodium tartrate solution (50 mL) and chloroform (25 mL) were added, and the mixture was stirred vigorously for 1 hour, and then the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, followed by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm manufactured by Yamazen Co., Ltd., developing solvent: hexane / ethyl acetate = 9. / 1/1/1] to give the title compound (0.24 g, 28% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 8.10 (1H, d, J = 8.2 Hz), 8.17 (1H, dd, J = 8.2, 1.2 Hz), 9.07 (1H, d, J = 1.2 Hz), 10.15 (1H, s).

LC / MS [Condition 1]: Retention time 2.69 minutes; m / z 175.9 [M + H] ⁺ (ESI positive ion mode)

Example 389
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8-{[5- (trifluoromethyl) pyridin-2-yl] methyl} -1-oxa Preparation of 3,8-diazaspiro [4.5] decan-2-one (Compound No. 389) 5- (trifluoromethyl) obtained in Reference Example 389 instead of 6- (trifluoromethyl) nicotinaldehyde ) The reaction was carried out in substantially the same manner as in Example 384 except that picolinaldehyde was used to obtain the title compound (12 mg, yield 19%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.4 Hz), 1.40-2.03 (11H, m), 2.47 (1H, t, J = 1.11. 7 Hz), 2.55-2.73 (4 H, br m), 2.82 (1 H, t, J = 11.4 Hz), 3.11 (2 H, d, J = 6.6 Hz), 3.21 (1H, t, J = 12.9 Hz), 3.28 (2H, s), 3.52 (1H, tt, J = 10.5, 3.6 Hz), 3.76 (2H, s), 3 .99 (1H, d, J = 12.9 Hz), 4.60 (1H, d, J = 13.2 Hz), 7.49 (4H, t, J = 7.6 Hz), 7.56 (1H, d, J = 8.3 Hz), 7.59 (1H, t, J = 7.6 Hz), 7.90 (1H, dd, J = 8.3, 2.3 Hz), 7.95 (2H, d , J = 7.6 z), 8.83 (1H, s).

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 626.8 [M + H] ⁺ (ESI positive ion mode), m / z 660.8 [M + Cl] ⁻ , 671.0 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 390-1
Preparation of t-butyl 3- (3-cyanophenoxy) azetidine-1-carboxylate Substantially Reference Example 381-1 except that 3-fluorobenzonitrile (commercially available) was used instead of 6-chloronicotinonitrile. The title compound (0.66 g, yield 83%) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 4.00 (2H, dd, J = 9.8, 4.1 Hz), 4.34 (2H, dd, J = 9. 8, 6.5 Hz), 4.90 (1 H, tt, J = 6.5, 4.1 Hz), 6.99 (1 H, br s), 7.00 (1 H, dd, J = 8.0, 2.0 Hz), 7.30 (1H, dd, J = 7.4, 2.0 Hz), 7.40 (1H, t, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 4.27 minutes; m / z 274.9 [M + H] ⁺ , 218.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 390-2
Preparation of 3- (azetidin-3-yloxy) benzonitrile hydrochloride 2-oxo-3-[((1r, 4r) -4-{[(tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1 3- (3-Cyanophenoxy) azetidine-1-carboxylic acid obtained in Reference Example 390-1 instead of t-butyl oxa-3,8-diazaspiro [4.5] decane-8-carboxylate The reaction was carried out substantially in the same manner as in Example 3 except for using t-butyl to obtain the title compound (0.47 g, yield 92%) as a white powder.

¹ H-NMR (CD ₃ OD) δ: 4.16 (2H, dd, J = 12.7, 4.5 Hz), 4.58 (2H, dd, J = 12.7, 6.1 Hz), 5 .21 (1H, tt, J = 6.1, 4.5 Hz), 7.21 (1H, ddd, J = 8.2, 2.5, 1.2 Hz), 7.25 (1H, dd, J = 2.5, 1.2 Hz), 7.41 (1H, dt, J = 7.7, 1.2 Hz), 7.52 (1H, t, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 0.51 min; m / z 175.0 [M + H] ⁺ (ESI positive ion mode)

Example 390
3- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) cyclohexanecarbonyl] azetidin-3-yloxy} benzonitrile (Compound No. 390)

The reaction was conducted in substantially the same manner as in Example 16 except that 3- (azetidin-3-yloxy) benzonitrile hydrochloride obtained in Reference Example 390-2 was used instead of piperidine to give the title compound (36 mg Yield 73%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (2H, dq, J = 4.5, 11.9 Hz), 1.53 (2H, dq, J = 2.5, 11.5 Hz), 1. 58-2.00 (9H, m), 2.14 (1H, tt, J = 11.9, 3.3 Hz), 2.43-2.65 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 4.04 (1H, dd, J = 11.3, 3.9 Hz), 4.19 ( 1H, dd, J = 9.4, 3.9 Hz), 4.39 (1H, dd, J = 10.6, 6.5 Hz), 4.55 (1H, dd, J = 8.6, 6. 5 Hz), 4.96 (1H, tt, J = 6.5, 3.9 Hz), 6.99 (1H, d, J = 1.2 Hz), 7.01 (1H, ddd, J = 9.0) , 2.9, 0.8H ), 7.32 (1H, dt, J = 7.8, 1.2 Hz), 7.42 (1H, t, J = 8.6 Hz), 7.44 (2H, d, J = 8.2 Hz) 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.30 minutes; m / z 610.7 [M + H] ⁺ (ESI positive ion mode), m / z 654.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 391-1
Preparation of t-butyl 4- [4- (trifluoromethyl) phenylamino] piperidine-1-carboxylate 1- (t-butoxycarbonyl) -4-piperidone (1.0 g, 5.0 mmol) was converted to 1,2- After dissolving in dichloroethane (10 mL), 4- (trifluoromethyl) aniline (0.97 g, 6.0 mmol) and acetic acid (1.2 mL, 20 mmol) were added at room temperature, and the mixture was stirred at 80 ° C. for 9 hours. . The reaction mixture was allowed to cool to room temperature, sodium triacetoxyborohydride (1.3 g, 6.0 mmol) was added, and the mixture was stirred at room temperature for 12 hr. After completion of the reaction, water (10 mL), saturated aqueous sodium hydrogen carbonate solution (20 mL) and chloroform (60 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, then acetone (10 mL) was added and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.1 g, yield 62%). Was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, dq, J = 4.9, 12.7 Hz), 1.47 (9H, s), 2.04 (2H, dd, J = 12. 7, 3.3 Hz), 2.94 (2H, t, J = 11.7 Hz), 3.39-3.54 (1 H, m), 3.87 (1 H, d, J = 7.4 Hz), 4.07 (2H, d, J = 11.9 Hz), 6.59 (2H, d, J = 8.6 Hz), 7.39 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 4.85 minutes; m / z 288.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 391-2
Production of N- [4- (trifluoromethyl) phenyl] piperidin-4-amine dihydrochloride 4- [4- (trifluoromethyl) phenylamino] piperidine-1-carboxylic acid obtained in Reference Example 391-1 T-Butyl acid (1.1 g, 3.1 mmol) was dissolved in acetonitrile (20 mL), 10% hydrogen chloride-methanol solution (6.2 mL) was added at room temperature, and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, acetone (10 mL) was added, and the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (0.94 g, yield 95%) as a white powder.

¹ H-NMR (CD ₃ OD) δ: 1.65 to 1.81 (2H, m), 2.23 (2H, dd, J = 14.3, 3.7 Hz), 3.15 (2H, td , J = 11.9, 2.9 Hz), 3.46 (2H, dt, J = 13.0, 3.7 Hz), 3.72 (1H, tt, J = 10.2, 4.0 Hz), 6.84 (2H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 1.92 minutes; m / z 244.9 [M + H] ⁺ (ESI positive ion mode)

Example 391
8- [4- (trifluoromethyl) benzyl] -3-[((1r, 4r) -4- {4- [4- (trifluoromethyl) phenylamino] piperidine-1-carbonyl} cyclohexyl) methyl]- Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 391) Instead of piperidine, N- [4- (trifluoromethyl) obtained in Reference Example 391-2 The reaction was carried out in substantially the same manner as in Example 16 except that phenyl] piperidin-4-amine dihydrochloride and triethylamine were used to obtain the title compound (41 mg, yield 73%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 12.2 Hz), 1.36 (2H, q, J = 12.6 Hz), 1.46-1.90 (9H, m), 1.94 (2H, d, J = 13.2 Hz), 2.14 (2H, d, J = 12.9 Hz), 2.47 (1 H, t, J = 11.7 Hz), 2. 51-2.70 (4H, br m), 2.85 (1H, t, J = 11.6 Hz), 3.11 (2H, d, J = 7.6 Hz), 3.20 (1H, t, J = 12.9 Hz), 3.26 (2H, s), 3.51-3.68 (1H, br m), 3.57 (2H, s), 3.80-4.01 (2H, m ), 4.52 (1H, d, J = 13.5 Hz), 6.60 (2H, d, J = 8.6 Hz), 7.40 (2H, d, J = 8.6 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz).
LC / MS [Condition 1]: Retention time 3.68 minutes; m / z 680.9 [M + H] ⁺ (ESI positive ion mode), m / z 725.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 392-1
Preparation of ethyl 6-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} nicotinate 3-[{5- (Ethoxycarbonyl) pyridin-2-yl} methyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8- obtained in Reference Example 111-3 A 4M hydrogen chloride-dioxane solution (10 mL) was added to t-butyl carboxylate (0.84 g, 2.0 mmol), and the mixture was stirred at room temperature for 10 minutes. After the reaction, the reaction mixture was concentrated, and dichloromethane and saturated aqueous ammonia were added to the obtained residue. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The obtained white solid and 3,5-difluoro-4-formylbenzonitrile (0.40 g, 2.40 mmol) were dissolved in dichloromethane (6.0 mL), and sodium triacetoxyborohydride (0.64 g, 3. 0 mmol) was added and stirred at room temperature for 10 minutes. After the reaction, water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Prefpack SI 60 μm, Shoko Scientific Co., Ltd., developing solvent: ethyl acetate] to obtain the title compound (0.80 g, yield 85%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.41 (3H, t, J = 7.2 Hz), 1.68-1.80 (2H, m), 1.89-2.00 (2H, m), 2.62 (4H, brs), 3.31 (2H, s), 3.74 (2H, s), 4.41 (2H, q, J = 7.1 Hz), 4.58 (2H) , S), 7.22 (2H, d, J = 6.1 Hz), 7.36 (1H, d, J = 8.0 Hz), 8.28 (1H, dd, J = 8.0, 1.). 8 Hz), 9.14 (1H, d, J = 1.8 Hz).

LC / MS [Condition 1]: Retention time 1.96 minutes; m / z 470.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 392-2
Reference for production of 6-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} nicotinic acid 6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl obtained in Example 392-1 ] To a tetrahydrofuran solution (20 mL) of methyl} ethyl nicotinate (0.97 g, 2.05 mmol) was added potassium trimethylsilanolate (0.53 g, 4.1 mmol), and the mixture was stirred at room temperature for 3 hours. After the reaction, 4M hydrogen chloride-dioxane solution (1.0 mL) was added, and then the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography [Prefpack SI 60 μm, manufactured by Shoko Scientific Co., Ltd., developing solvent: chloroform / methanol = 10/1 → 2/1], and the title compound (0.53 g, yield 60%). ) Was obtained as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 1.68-1.86 (4H, m), 2.20-2.45 (4H, m), 3.29 (2H, s), 3 .63 (2H, s), 4.47 (2H, s), 7.34 (1H, d, J = 8.2 Hz), 7.78 (2H, d, J = 6.3 Hz), 8.20 (1H, d, J = 8.2 Hz), 8.97 (1H, s).

LC / MS [Condition 1]: Retention time 0.53 minutes; m / z 442.7 [M + H] ⁺ (ESI positive ion mode), m / z 440.8 [MH] ⁻ (ESI negative ion mode)

Example 392
3,5-difluoro-4-{[3-({5- [4- (4-fluorobenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 392) 6-{[8- (4-cyano-2,6-- ) obtained in Reference Example 392-2 Difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} nicotinic acid (20 mg, 0.045 mmol), 1-hydroxybenzotriazole (2 mg, .0. 01 mmol) and (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) (13 mg, 0.054 mmol) in chloroform (1 mL) Amine (26 [mu] L, 0.19 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13 mg, 0.068 mmol) was added and the reaction mixture was stirred at room temperature for 5 days. After adding a solution of citric acid (26 mg) in water (1 mL), the organic layer was separated and concentrated to dryness under reduced pressure. To the residue was added ethyl acetate (1 mL) and a solution of sodium hydrogen carbonate (3 mg) in water (1 mL), the organic layer was separated and concentrated to dryness under reduced pressure to give the title compound (21 mg, yield 72%). Was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.66-2.09 (8H, m), 2.45-2.80 (4H, m), 2.97-3.36 (2H, m), 3 .31 (2H, s), 3.45-3.61 (1H, m), 3.69-3.97 (1H, br m), 3.74 (2H, s), 4.55-4. 78 (1H, br m), 4.56 (2H, s), 7.17 (2H, t, J = 8.6 Hz), 7.22 (2H, d, J = 6.5 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 7.8, 2.5 Hz), 7.99 (2H, dd, J = 8.6, 5.7 Hz), 8.61 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 3.12 minutes; m / z 631.9 [M + H] ⁺ (ESI positive ion mode), m / z 675.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 393-1
Preparation of t-butyl 4- (methylsulfonyloxy) piperidine-1-carboxylate 1- (t-butoxycarbonyl) -4-hydroxypiperidine (purchased from Tokyo Chemical Industry Co., Ltd.) (4.0 g, 20 mmol) in tetrahydrofuran (20 ml) ), Triethylamine (2.4 g, 24 mmol) and methanesulfonyl chloride (2.7 g, 24 mmol) were added, and the mixture was vigorously stirred at 0 ° C. for 3 hours. After completion of the reaction, ethyl acetate and 1M hydrochloric acid were added and shaken to separate the organic layer. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give t-butyl 4- (methylsulfonyloxy) piperidine-1-carboxylate (5 0.0 g, 90% yield) was obtained as a colorless solid.

LC / MS [Condition 1]: Retention time 3.70 minutes; m / z 280.0 [M + H] ⁺ , 223.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 393-2
Production of t-butyl 4- [4- (trifluoromethyl) phenylthio] piperidine-1-carboxylate 4- (methylsulfonyloxy) piperidine-1-carboxylate t-butyl (0. 60 g, 2.2 mmol) was dissolved in N, N-dimethylformamide, and 4- (trifluoromethyl) benzenethiol (0.50 g, 2.8 mmol) and potassium carbonate (0.38 g, 2.8 mmol) were added. , Vigorously stirred at 70 ° C. for 3 hours. After completion of the reaction, ethyl acetate and 0.5M aqueous sodium hydroxide solution were added and shaken. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: ethyl acetate / hexane = 1/19], and 4- [4 -(Trifluoromethyl) phenylthio] piperidine-1-carboxylate t-butyl (0.55 g, yield 70%) was obtained as a colorless liquid.

LC / MS [Condition 1]: Retention time 5.17 minutes; m / z 305.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 393-3
Preparation of t-butyl 4- (3-fluorophenylthio) piperidine-1-carboxylate Substantially Reference Example 393 except that 3-fluorobenzenethiol was used instead of 4- (trifluoromethyl) benzenethiol The reaction was carried out in the same manner as 2 to give the title compound (0.62 g, yield 93%) as a colorless liquid.

LC / MS [Condition 1]: Retention time 4.94 minutes; m / z 255.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 393-4
Production of t-butyl 4- (3-fluorophenylsulfonyl) piperidine-1-carboxylate t-butyl 4- (3-fluorophenylthio) piperidine-1-carboxylate synthesized in Reference Example 393-3 (0.31 g , 0.99 mmol) in methanol, 30% aqueous hydrogen peroxide (0.45 ml, 4.0 mmol) and hexaammonium heptamolybdate tetrahydrate (0.12 g, 0.10 mmol) were added, and room temperature was added. Under vigorous stirring for 4 days. After completion of the reaction, sodium thiosulfate (0.63 g, 4.0 mmol), water and chloroform were added to the reaction mixture under ice cooling, and the mixture was shaken to separate the organic layer. The aqueous layer was extracted three times with chloroform. . The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give t-butyl 4- (3-fluorophenylsulfonyl) piperidine-1-carboxylate (0.29 g, yield 86%) as colorless. Obtained as a solid.

LC / MS [Condition 1]: Retention time 4.26 minutes; m / z 343.9 [M + H] ⁺ , 287.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 393-5
Production of t-butyl 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine-1-carboxylate 4- [4- (trifluoromethyl) phenylthio] piperidine-1-carboxylic acid synthesized in Reference Example 393-2 t-Butyl (0.32 g, 0.88 mmol) was dissolved in methanol and 30% aqueous hydrogen peroxide (0.40 ml, 3.5 mmol) and hexaammonium heptamolybdate tetrahydrate (0.11 g, .0. 10 mmol) was added and stirred vigorously at room temperature overnight. After completion of the reaction, sodium thiosulfate (0.56 g, 3.52 mmol) and water were added to the reaction mixture under ice cooling and stirred. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure. The filtrate after the solid was collected by filtration was extracted three times with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. Combined with the previously obtained solid, t-butyl 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine-1-carboxylate (0.31 g, yield 90%) was obtained as a colorless solid.

LC / MS [Condition 1]: Retention time 4.54 minutes; m / z 337.9 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 393-6
Production of 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine hydrochloride 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine-1-carboxylate t-butyl (0) synthesized in Reference Example 393-5 .18 g, 0.50 mmol) was dissolved in 4M hydrogen chloride-dioxane solution and stirred vigorously for 1 hour. After completion of the reaction, the precipitated solid was collected by filtration and washed with 1,4-dioxane. The obtained solid was dried under reduced pressure to obtain 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine hydrochloride (0.20 g, yield 100%) as a colorless solid.

LC / MS [Condition 1]: Retention time 0.81 min; m / z 293.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 393-7
Preparation of 4- (3-fluorophenylsulfonyl) piperidine hydrochloride 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine-1-carboxylate synthesized in Reference Example 393-4 instead of t-butyl 4- The reaction was carried out in substantially the same manner as in Reference Example 393-6, except that t-butyl (3-fluorophenylsulfonyl) piperidine-1-carboxylate was used, and the title compound (0.11 g, yield 80%) was obtained. Obtained as a colorless solid.

LC / MS [Condition 1]: Retention time 0.54 minutes; m / z 243.9 [M + H] ⁺ (ESI positive ion mode)

Example 393
3-({(1r, 4r) -4- [4- (3-fluorophenylsulfonyl) piperidine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa- Preparation of 3,8-diazaspiro [4.5] decan-2-one (Compound No. 393) (1r, 4r) -4-({2-oxo-8- [4- (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid (40 mg, 0.090 mmol) was dissolved in N, N-dimethylformamide. 4- (3-fluorophenylsulfonyl) piperidine hydrochloride (25 mg, 0.088 mmol) obtained in Reference Example 393-7, diisopropylethylamine (30 μl, 0 18 mmol) and 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (40 mg, 0.11 mmol) were added at room temperature overnight. Stir vigorously. After completion of the reaction, citric acid (42 mg, 0.22 mmol), water and chloroform were added and shaken. The organic layer was separated, washed with a saturated aqueous sodium bicarbonate solution, and concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: ethyl acetate / methanol = 9/1], and 3-({ (1r, 4r) -4- [4- (3-Fluorophenylsulfonyl) pipaidin-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Diazaspiro [4.5] decan-2-one (3.1 mg, 5.0% yield) was obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 12.3 Hz), 1.44-2.20 (15H, m), 2.34-2.55 (2H, m), 2.58 (4H, br m), 2.93-3.21 (4H, m), 3.26 (2H, s), 3.59 (2H, s), 4.04 (1H, d, J = 12.6 Hz), 4.76 (1H, d, J = 12.6 Hz), 7.36-7.48 (3H, m), 7.55-7.70 (5H, m).

LC / MS [Condition 1]: Retention time 3.29 minutes; m / z 679.9 [M + H] ⁺ (ESI positive ion mode)

Example 394
8- [4- (trifluoromethyl) benzyl] -3-[((1r, 4r) -4- {4- [4- (trifluoromethyl) phenylsulfonyl] piperidine-1-carbonyl} cyclohexyl) methyl]- Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 394) Obtained in Reference Example 393-6 instead of 4- (3-fluorophenylsulfonyl) piperidine hydrochloride The reaction was carried out substantially in the same manner as in Example 393 except that 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine hydrochloride was used to obtain the title compound (15 mg, yield 23%) as a colorless liquid. It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.43-1.88 (11H, m), 1.89-2.19 (3H, m), 2.34-2.60 (2H, m), 2.56-2.59 (4H, br m), 2.95-3.23 (4H, m), 3.26 (2H, s) ), 3.59 (2H, s), 4.05 (1H, d, J = 14.0 Hz), 4.77 (1H, d, J = 13.6 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.88 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.2 Hz) .

LC / MS [Condition 1]: Retention time 3.47 minutes; m / z 729.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 395-1
Preparation of 5- (bromomethyl) isoxazole 5-Methylisoxazole (5.0 g, 60 mmol) and N-bromosuccinimide (12 g, 66 mmol) were dissolved in 1,2-dichloroethane (150 ml) and benzoyl peroxide (0. 73 g, 3.0 mmol) was added and stirred vigorously at 85 ° C. for 4 hours. After completion of the reaction, the reaction solution was washed with 1M sodium hydroxide aqueous solution, sodium thiosulfate aqueous solution, ammonium chloride aqueous solution and saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography, developing solvent: ethyl acetate / hexane = 1/19]. Concentration under reduced pressure gave 5- (bromomethyl) isoxazole (5.2 g, 53% yield) as a yellow liquid.

Reference Example 395-2
Production of 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione 5- (bromomethyl) isoxazole (3.2 g, 20 mmol) synthesized in Reference Example 395-1 and potassium phthalimide (4.5 g, 24 mmol) was dissolved in N, N-dimethylformamide (32 ml) and stirred vigorously at 90 ° C. for 2 hours. After completion of the reaction, water (200 ml) was added and the precipitated solid was collected by filtration to give 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione (2.7 g, yield 60%) as a brown solid Got as.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 5.03 (2H, s), 6.25-6.29 (1H, m), 7.72-7.80 (2H, m), 7.86 -7.93 (2H, m), 8.67-8.68 (1H, m).

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 229.0 [M + H] ⁺ (ESI positive ion mode)

Reference Example 395-3
Production of isoxazol-5-ylmethanamine 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione (91 mg, 0.40 mmol) synthesized in Reference Example 395-2 and hydrazine monohydrate ( 0.10 g, 2.0 mmol) was dissolved in ethanol (4 ml) and heated to reflux for 3 hours. After completion of the reaction, the mixture was filtered with ethanol, and the filtrate was concentrated to dryness under reduced pressure. The obtained residue was filtered through chloroform, and the filtrate was concentrated under reduced pressure to give isoxazol-5-ylmethanamine (67 mg, yield 85%) as a colorless liquid.

Reference Example 395-4
Preparation of 2-[(2-fluoropyridin-4-yl) methyl] isoindoline-1,3-dione Synthesized according to the method described in WO2009057827.

LC / MS [Condition 1]: Retention time 3.62 minutes; m / z 256.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 395-5
Preparation of (2-fluoropyridin-4-yl) methanamine 2-[(2-fluoro) obtained in Reference Example 395-4 instead of 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione Pyridin-4-yl) methyl] isoindoline-1,3-dione was used in substantially the same manner as in Reference Example 395-3 to give the title compound (55 mg, yield 73%) as a colorless solid Got as.

LC / MS [Condition 1]: Retention time 0.49 min; m / z 126.9 [M + H] ⁺ (ESI positive ion mode)

Example 395
(1r, 4r) -N-[(2-Fluoropyridin-4-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 395) (2-fluoropyridin-4-yl) methanamine (11 mg, 0.090 mmol) obtained in Reference Example 395-5 ) And Reference Example 6-3 (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Decan-3-yl} methyl) cyclohexanecarboxylic acid (40 mg, 0.090 mmol) dissolved in chloroform, diisopropylethylamine (15 μl, 0.090 mmol) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (17 mg, 0.090 mmol) was stirred vigorously at room temperature for 3 hours. After completion of the reaction, water was added and shaken to separate the organic layer, and then the aqueous layer was extracted three times with chloroform. The combined organic layers were concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: ethyl acetate / methanol = 9/1] (1r, 4r ) -N-[(2-fluoropyridin-4-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4 .5] decan-3-yl} methyl) cyclohexanecarboxamide (24 mg, 48% yield) was obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.7 Hz), 1.45-1.68 (3H, m), 1.73-1. 87 (4H, m), 1.87-2.02 (4H, m), 2.19 (1H, tt, J = 11.9, 3.3 Hz), 2.53-2.56 (4H, br m), 3.10 (2H, d, J = 7.0 Hz), 3.28 (2H, s), 3.58 (2H, s), 4.47 (2H, d, J = 6.5 Hz) , 6.76 (1H, t, J = 6.1 Hz), 6.82 (1H, s), 7.08 (1H, d, J = 4.9 Hz), 7.45 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 7.8 Hz), 8.14 (1H, d, J = 5.7 Hz).

LC / MS [Condition 1]: Retention time 3.11 min; m / z 563.1 [M + H] ⁺ (ESI positive ion mode)

Example 396
(1r, 4r) -N- (isoxazol-5-ylmethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 396) Instead of (2-fluoropyridin-4-yl) methanamine, isoxazol-5-ylmethane obtained in Reference Example 395-3 The reaction was carried out substantially in the same manner as in Example 395 except that amine was used, and the title compound (19 mg, yield 41%) was obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 2.5, 12.7 Hz), 1.41-1.66 (3H, m), 1.71-1. 86 (4H, m), 1.88-2.00 (4H, m), 2.12 (1H, tt, J = 3.3, 11.9 Hz), 2.54-2.57 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.58 (2H, s), 3.95 (3H, s), 4.44 (2H) , D, J = 5.7 Hz), 5.80 (1H, s), 6.30-6.41 (1H, br m), 7.45 (2H, d, J = 7.8 Hz), 7. 58 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 2.81 minutes; m / z 534.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 397-1
Preparation of 4 -cyanophenethyl methanesulfonate 4- (2-hydroxyethyl) benzonitrile (0.50 g, 3.4 mmol) and triethylamine (0.60 ml, 4.1 mmol) were dissolved in tetrahydrofuran, and methanesulfonyl chloride (0 .30 ml, 4.1 mmol) was added dropwise and stirred vigorously for 2 hours under ice cooling. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with water, 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4-cyanophenethyl methanesulfonate (0.70 g, yield 93%) as a colorless liquid.

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 225.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 397-1
Preparation of 4- [2- (1,3-dioxoisoindoline-2-yl) ethyl] benzonitrile Instead of 5- (bromomethyl) isoxazole, methanesulfonic acid 4-phenyl ester obtained in Reference Example 397-1 The reaction was carried out substantially in the same manner as in Reference Example 395-2 except that cyanophenethyl was used to give the title compound (0.20 g, yield 54%) as a colorless solid.

LC / MS [Condition 1]: Retention time 4.04 minutes; m / z 276.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 397-3
Preparation of 4- (2-aminoethyl) benzonitrile 4- [2- (1) obtained in Reference Example 397-2 instead of 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione , 3-Dioxoisoindoline-2-yl) ethyl] benzonitrile was used to carry out the reaction in substantially the same manner as in Reference Example 395-3, to give the title compound (80 mg, yield 78%) as a yellow solid Got as.

LC / MS [Condition 1]: Retention time 0.52 minutes; m / z 147.0 [M + H] ⁺ (ESI positive ion mode)

Example 397
(1r, 4r) -N- (4-Cyanophenethyl) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 397) 4- (2-aminoethyl) benzoate obtained in Reference Example 397-3 instead of (2-fluoropyridin-4-yl) methanamine The reaction was carried out in substantially the same manner as in Example 395 except that nitrile was used to give the title compound (21 mg, yield 42%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, q, J = 12.7 Hz), 1.45 (2H, dq, J = 3.3, 12.7 Hz), 1.54- 1.67 (1H, m), 1.71-2.05 (9H, m), 2.55-2.58 (4H, br m), 2.90 (2H, t, J = 7.0 Hz) 3.09 (2H, d, J = 7.0 Hz), 3.27 (2H, s), 3.52 (2H, q, J = 6.5 Hz), 3.58 (2H, s), 5 .69 (1H, brs), 7.31 (2H, d, J = 8.2 Hz), 7.45 (2H, d, J = 8.6 Hz), 7.54-7.64 (4H, m) .

LC / MS [condition 1]: retention time 3.21 minutes; m / z 582.8 [M + H] ⁺ (ESI positive ion mode), m / z 627.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 398-1
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Production of methyl cyclohexanecarboxylate 3-[{5- (Ethoxycarbonyl) pyridin-2-yl} methyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylic acid 3-[{(1r, 4r) -4- (methoxycarbonyl) cyclohexyl} methyl] -2-oxo-1-oxa-3,8-diazaspiro obtained in Reference Example 2-2 instead of t-butyl [4.5] The reaction was carried out in substantially the same manner as in Reference Example 392-1 except that t-butyl decane-8-carboxylate (2.05 g, 5.0 mmol) was used, and the title compound (2. 13 g, yield 92%) It was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, qd, J = 13.0, 3.3 Hz), 1.40 (2H, qd, J = 13.0, 3.3 Hz), 1.51-1.61 (1H, m), 1.69-1.81 (4H, m), 1.90-2.03 (4H, m), 2.24 (1H, tt, J = 12 .3, 3.6 Hz), 2.54-2.68 (4H, m), 3.07 (2H, d, J = 7.5 Hz), 3.22 (2H, s), 3.66 (3H) , S), 3.74 (2H, s), 7.21 (2H, d, J = 6.5 Hz).

LC / MS [Condition 1]: Retention time 2.76 minutes; m / z 461.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 398-2
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Production of cyclohexanecarboxylic acid (1r, 4r) -4-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3, obtained in Reference Example 398-1 To a tetrahydrofuran solution (20 mL) of 8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylate (2.13 g, 4.60 mmol) was added potassium trimethylsilanolate (1.77 g, 13.80 mmol). And stirred at room temperature for 3 hours. After the reaction, a saturated aqueous ammonium chloride solution was added, followed by extraction with chloroform. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Prefpack SI 60 μm, manufactured by Shoko Scientific Co., Ltd., developing solvent: chloroform / methanol = 10/1] to give the title compound (1.36 g, 66% yield) as a white solid Got as.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 0.90 (2H, q, J = 9.9 Hz), 1.26 (2H, q, J = 9.9 Hz), 1.40-1. 55 (1H, m), 1.63 (2H, d, J = 12.2 Hz), 1.73-1.74 (4H, m), 1.88 (2H, d, J = 10.6 Hz), 2.12 (1H, t, J = 12.1 Hz), 2.40-2.50 (4H, m), 2.95 (2H, d, J = 7.3 Hz), 3.26 (2H, s ), 3.65 (2H, s), 7.81 (2H, dd, J = 12.4, 5.4 Hz), 12.02 (1H, brs).

LC / MS [Condition 1]: Retention time 0.70 min; m / z 447.8 [M + H] ⁺ (ESI positive ion mode)

Example 398
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N- (4-cyanophenethyl) cyclohexanecarboxamide (Compound No. 398) 4- (2-aminoethyl) obtained in Reference Example 397-3 instead of (2-fluoropyridin-4-yl) methanamine ) Benzonitrile and (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane (1r, 4r) -4-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo obtained in Reference Example 398-2 instead of -3-yl} methyl) cyclohexanecarboxylic acid - The reaction was carried out in substantially the same manner as in Example 395 except that -oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid was used to give the title compound (27 mg, yield). 53%) was obtained as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.99 (2H, dq, J = 3.3, 13.1 Hz), 1.44 (2H, dq, J = 2.9, 13.1 Hz), 1.52-1.64 (1H, m), 1.65-2.05 (9H, m), 2.54-2.71 (4H, m), 2.90 (2H, t, J = 7) .4 Hz), 3.07 (2H, d, J = 7.8 Hz), 3.23 (2H, s), 3.52 (2H, q, J = 6.5 Hz), 3.75 (2H, s) ), 5.50-5.69 (1H, m), 7.23 (2H, d, J = 6.1 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.60 (2H) , D, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 575.9 [M + H] ⁺ (ESI positive ion mode), m / z 620.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 399
Preparation of (2-chlorothiazol-4-yl) methanamine hydrochloride The compound was synthesized according to the method described in WO2009057827.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 4.10 (2H, dd, J = 11.9, 5.7 Hz), 7.81 (1H, s), 8.55 (3H, br s ).

LC / MS [Condition 1]: retention time 0.50 min; m / z 148.8 [M + H] ⁺ (ESI positive ion mode)

Example 399
(1r, 4r) -N-[(2-chlorothiazol-4-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 399) Instead of (2-fluoropyridin-4-yl) methanamine, it was obtained in Reference Example 399 (2-chloro The reaction was carried out in substantially the same manner as in Example 395 except that thiazol-4-yl) methanamine hydrochloride was used to give the title compound (20 mg, yield 38%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, dq, J = 2.9, 12.7 Hz), 1.41-1.67 (3H, m), 1.70-1. 87 (4H, m), 1.89-2.01 (4H, m), 2.10 (1H, tt, J = 11.9, 3.3 Hz), 2.55 to 2.59 (4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.59 (2H, s), 4.46 (2H, d, J = 5.7 Hz) 6.17 (1H, t, J = 5.3 Hz), 7.06 (1H, s), 7.45 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.11 min; m / z 584.6 [M + H] ⁺ (ESI positive ion mode)

Reference Example 400
Preparation of (S) -2- (4-fluorophenyl) pyrrolidine Org. Chem. , 2010, 75, 2236.

LC / MS [Condition 1]: Retention time 0.56 minutes; m / z 166.1 [M + H] ⁺ (ESI positive ion mode)

Example 400
3-({(1r, 4r) -4-[(S) -2- (4-fluorophenyl) pyrrolidine-1-carbonyl] cyclohexyl} methyl) -8- [4- (trifluoromethyl) benzyl] -1 Preparation of —oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 400) Instead of 4- (3-fluorophenylsulfonyl) piperidine hydrochloride, it was obtained in Reference Example 400 (S The reaction was carried out in substantially the same manner as in Example 393 except that 2- (4-fluorophenyl) pyrrolidine was used to give the title compound (32.8 mg, yield 62%) as a yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.57 (0.6 H, q, J = 12.3 Hz), 0.90 (0.6 H, q, J = 12.3 Hz), 0.99- 1.17 (0.8H, m), 1.16-1.29 (0.8H, m), 1.36-2.12 (14.2H, m), 2.16-2.45 (1H) M), 2.46-2.65 (4H, br m), 2.89-3.17 (2H, m), 3.21 (1.2H, s), 3.26 (0.8H, s), 3.57 (2H, br s), 3.61-3.81 (2H, m), 4.96 (0.6 H, d, J = 7.2 Hz), 5.15 (0.4 H) , Dd, J = 2.7, 7.8 Hz), 6.91-7.16 (4H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.44 minutes; m / z 601.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 401-1
Preparation of methyl 4-methylbenzenesulfonate (3-methoxyisoxazol-5-yl ) To a suspension of methyl 3-hydroxyisoxazole-5-carboxylate (commercially available) (6.0 g, 42 mmol) in tetrahydrofuran (60 mL) At room temperature, potassium carbonate (6.4 g, 46 mmol) and dimethyl sulfate (4.3 g, 46 mmol) were added and stirred at 75 ° C. for 21 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were concentrated to dryness under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain methyl 3-methoxyisoxazole-5-carboxylate (1.7 g, yield 26%) as a solid. Got as.
Sodium borohydride (0.19 g, 4.9 mmol) was added to a solution of the obtained methyl 3-methoxyisoxazole-5-carboxylate (0.50 g, 3.2 mmol) in ethanol (10 mL) at room temperature. Then, the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated to dryness under reduced pressure. A saturated aqueous ammonium chloride solution was added to the obtained residue, followed by extraction twice with ethyl acetate, and the combined organic layers were concentrated to dryness under reduced pressure. The residue (0.47 g) was dissolved in tetrahydrofuran (5.0 mL), and triethylamine (0.80 mL, 5.8 mmol) and 4-methylbenzenesulfonic acid chloride (0.82 g, 4.3 mmol) were added. For 15 hours. A saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution were added to the reaction mixture, followed by extraction twice with ethyl acetate, and the organic layer was concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solvent: hexane / ethyl acetate = 3/1] to give 4-methylbenzenesulfonic acid (3-methoxyisoxazol-5-yl) methyl (0.51 g). Yield 57%) as a white solid.

Reference Example 401-2
Production of 2-[(3-methoxyisoxazol-5-yl) methyl] isoindoline-1,3-dione 4-methylbenzenesulfonic acid (3-methoxyisoxazole-5 obtained in Reference Example 401-1 -Yl) methyl (0.50 g, 1.8 mmol) was dissolved in N, N-dimethylformamide (5.0 mL), and potassium phthalimido (commercially available) (0.39 g, 2.1 mmol) was added at 90 ° C. Stir for 1 hour. The reaction mixture was allowed to cool to room temperature, and water (20 mL) was added. The precipitated solid was collected by filtration and washed with water to give 2-[(3-methoxyisoxazol-5-yl) methyl] isoindoline-1,3-dione (0.43 g, yield 93%) as white. Obtained as a solid.

Reference Example 401-3
Preparation of (3-methoxyisoxazol-5-yl) methanamine Instead of 2- (isoxazol-5-ylmethyl) isoindoline-1,3-dione, 2-[(3- The reaction was conducted in substantially the same manner as in Reference Example 395-3 except that methoxyisoxazol-5-yl) methyl] isoindoline-1,3-dione was used to give the title compound (46 mg, yield 90%). Obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.86 (2H, s), 3.96 (3H, s), 5.77 (1H, s).

Example 401
(1r, 4r) -N-[(3-methoxyisoxazol-5-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 401) Obtained in Reference Example 401-3 instead of (2-fluoropyridin-4-yl) methanamine ( The reaction was carried out in substantially the same manner as in Example 395 except that 3-methoxyisoxazol-5-yl) methanamine was used to give the title compound (18 mg, yield 37%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 2.9, 12.3 Hz), 1.41-1.66 (3H, m), 1.72-1. 86 (4H, m), 1.88-2.00 (4H, m), 2.14 (1H, tt, J = 11.4, 3.3 Hz), 2.54-2.57 (4H, br m), 3.10 (2H, d, J = 7.0 Hz), 3.28 (2H, s), 3.59 (2H, s), 4.58 (2H, d, J = 5.7 Hz) 6.18 (1H, d, J = 1.2 Hz), 6.45-6.53 (1H, brm), 7.45 (2H, d, J = 8.6 Hz), 7.58 (2H, d, J = 7.8 Hz), 8.18 (1H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 3.01 minutes; m / z 564.9 [M + H] ⁺ (ESI positive ion mode)

Example 402
6- [1-((1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -3-yl] methyl} cyclohexanecarbonyl) piperidin-4-yloxy] nicotinonitrile (Compound No. 402)

Reference example instead of 4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) benzoic acid (1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] obtained in 398-2 Decan-3-yl] methyl} cyclohexanecarboxylic acid was obtained by replacing 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride obtained in Reference Example 293-2 with 4- (aminomethyl) benzonitrile hydrochloride. The reaction was carried out substantially in the same manner as in Example 180 except for using, and the title compound (28 mg, yield 66%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, dq, J = 3.7, 11.9 Hz), 1.46-1.66 (3H, br m), 1.69-1 .85 (8H, br m), 1.86-2.11 (4H, br m), 2.47 (1H, tt, J = 11.9, 2.9 Hz), 2.63 (4H, br s ), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.31-3.53 (2H, br m), 3.66-3.80 (1H, br m), 3.75 (2H, s), 3.88-4.05 (1 H, br m), 5.35 (1 H, tt, J = 7.8, 3.7 Hz), 6.79 ( 1H, d, J = 8.6 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.78 (1H, dd, J = 8.6, 2.0 Hz), 8.45 (1H , D, = 2.5Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 632.8 [M + H] ⁺ (ESI positive ion mode), m / z 676.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 403
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } -N-[(Tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 403)

The reaction was conducted in substantially the same manner as in Example 402 except that tetrahydrofurfurylamine (commercially available) was used instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride to give the title compound (26 mg, yield). 72%) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, q, J = 12.3 Hz), 1.36-1.66 (3H, m), 1.67-1.82 (4H, br m), 1.82-2.10 (9H, m), 2.63 (4H, br s), 3.01-3.18 (1H, m), 3.07 (2H, d, J = 7.8 Hz), 3.22 (2H, s), 3.52-3.63 (1H, m), 3.67-4.01 (3H, m), 3.75 (2H, s), 5 79 (1H, t, J = 5.3 Hz), 7.22 (2H, d, J = 5.7 Hz).

LC / MS [Condition 1]: Retention time 1.38 minutes; m / z 530.8 [M + H] ⁺ (ESI positive ion mode), m / z 575.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 404
4-{[3-({(1r, 4r) -4- [4- (6-chloropyrimidin-4-yl) piperazine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 404) Reference example instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was conducted in substantially the same manner as in Example 402 except that 4-chloro-6- (piperazin-1-yl) pyrimidine dihydrochloride obtained in 288 was used to give the title compound (26 mg, yield 72%) Was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 4.5, 11.4 Hz), 1.47-1.67 (3H, br m), 1.68-1 .86 (6H, br m), 1.86-1.98 (2H, br m), 2.46 (1H, tt, J = 11.7, 2.5 Hz), 2.63 (4H, br s ), 3.10 (2H, d, J = 7.4 Hz), 3.23 (2H, s), 3.61 (4H, br s), 3.75 (6H, br s), 6.51 ( 1H, s), 7.22 (2H, d, J = 6.1 Hz), 8.40 (1H, s).

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 314.6 [M + 2H] ²⁺ , 627.8 [M + H] ⁺ (ESI positive ion mode), m / z 671.9 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 405
3,5-difluoro-4-{[2-oxo-3-({(1r, 4r) -4- [4- (quinolin-4-yl) piperazine-1-carbonyl] cyclohexyl} methyl) -1-oxa Preparation of -3,8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 405) Reference Example 278-2 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The title compound (38 mg, 87% yield) was obtained as a colorless amorphous substance by carrying out the reaction substantially in the same manner as in Example 402 except that 4- (piperazin-1-yl) quinoline dihydrochloride obtained in the above was used. Obtained as a thing.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06 (2H, q, J = 13.1 Hz), 1.55-1.70 (1H, m), 1.60 (2H, q, J = 12.7 Hz), 1.70-1.98 (8 H, br m), 2.51 (1 H, tt, J = 12.3, 3.3 Hz), 2.57-2.71 (4 H, br m ), 3.10 (2H, d, J = 7.4 Hz), 3.15-3.32 (4H, br m), 3.23 (2H, s), 3.75 (2H, s), 3 79 (2H, br s), 3.91 (2H, br s), 6.85 (1H, d, J = 4.9 Hz), 7.22 (2H, d, J = 7.0 Hz), 7 .53 (1H, t, J = 7.8 Hz), 7.70 (1H, t, J = 7.8 Hz), 8.02 (1H, dd, J = 8.2, 1.2 Hz), 8. 11 (1H , D, J = 8.2 Hz), 8.75 (1H, d, J = 4.9 Hz).

LC / MS [Condition 1]: Retention time 0.84 min; m / z 322.0 [M + 2H] ²⁺ , 642.8 [M + H] ⁺ (ESI positive ion mode), m / z 686.9 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 406
3,5-difluoro-4-{[3-({(1r, 4r) -4- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] cyclohexyl} methyl) Preparation of -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 406) 6- (Piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 402 except that 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole (commercially available) was used in place of the title compound (19 mg, yield). 43%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 12.3 Hz), 1.46-1.68 (3H, br m), 1.70-2.06 (10H , Br m), 2.07-2.25 (2H, br m), 2.49 (1H, t, J = 12.3 Hz), 2.63 (4H, br s), 2.87 (1H, t, J = 11.4 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.16-3.41 (2H, m), 3.23 (2H, s), 3.75 ( 2H, s), 4.04 (1H, d, J = 13.1 Hz), 4.67 (1H, d, J = 12.7 Hz), 7.07 (1H, td, J = 8.9, 2) .2 Hz), 7.16-7.29 (3 H, m), 7.61 (1 H, dd, J = 8.6, 4.9 Hz).

LC / MS [Condition 1]: Retention time 3.40 minutes; m / z 649.9 [M + H] ⁺ (ESI positive ion mode), m / z 694.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 407
4-[(3-{[(1r, 4r) -4- (4-benzylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] -3,5-difluorobenzonitrile (Compound No. 407) Other than using 4-benzylpiperidine (commercially available) instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride Reacted substantially as in Example 402 to give the title compound (35 mg, 86% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.89-1.11 (2H, br m), 1.12 (2H, dq, J = 3.3, 13.5 Hz), 1.40-1 .64 (3H, br m), 1.64-1.84 (9H, br m), 1.85-1.99 (2H, br m), 2.33-2.72 (8H, br m) 2.93 (1H, t, J = 12.9 Hz), 3.08 (2H, d, J = 7.4 Hz), 3.21 (2H, s), 3.74 (2H, s), 3 .84 (1H, d, J = 12.7 Hz), 4.60 (1 H, d, J = 14.3 Hz), 7.08-7.15 (2H, m), 7.15-7.33 ( 5H, m).

LC / MS [Condition 1]: Retention time 3.56 minutes; m / z 604.9 [M + H] ⁺ (ESI positive ion mode), m / z 649.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 408
4-((1r, 4r) -4-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- Yl] methyl} cyclohexanecarboxamide) Preparation of ethyl piperidine-1-carboxylate (Compound No. 408) 6- (Piperidin-4-yloxy) nicotinonitrile hydrochloride instead of ethyl 4-aminopiperidine-1-carboxylate (commercially available) ) Was used substantially in the same manner as in Example 402 to obtain the title compound (33 mg, yield 81%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, dq, J = 2.9, 12.3 Hz), 1.25 (3H, t, J = 7.0 Hz), 1.27 ( 2H, dq, J = 4.1, 11.0 Hz), 1.46-1.65 (1H, br m), 1.47 (2H, dq, J = 2.9, 11.9 Hz), 1. 65-1.82 (4H, br m), 1.82-2.06 (7H, br m), 2.63 (4H, br s), 2.89 (2H, t, J = 11.9 Hz) 3.07 (2H, d, J = 7.0 Hz), 3.22 (2H, s), 3.75 (2H, s), 3.82-3.98 (1H, m), 4.00 -4.21 (2H, br m), 4.12 (2H, q, J = 7.2 Hz), 5.34 (1H, d, J = 7.8 Hz), 7.22 (2H, d, J = 5.7 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 601.8 [M + H] ⁺ (ESI positive ion mode), m / z 646.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 409
1-((1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- Yl] methyl} cyclohexanecarbonyl) piperidine-4-carbonitrile (compound no. 409) Reacted substantially as in Example 402 to give the title compound (33 mg, 91% yield) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.94-1.14 (2H, br m), 1.44-1.68 (3H, br m), 1.68-2.02 (12H, br m), 2.42 (1H, t, J = 10.2 Hz), 2.64 (4H, br s), 2.83-2.97 (1H, m), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.37-3.91 (4H, br m), 3.77 (2H, s), 7.16-7.31 (2H, m ).

LC / MS [Condition 1]: Retention time 1.48 minutes; m / z 539.8 [M + H] ⁺ (ESI positive ion mode), m / z 583.8 [M + HCOO] ⁻ (ESI negative ion mode)

Example 410
3,5-difluoro-4-({3-[((1r, 4r) -4-{[-(2-methoxyphenylamino) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa Preparation of 3,8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 410) Reference Example 292-2 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 402 except that N- (2-methoxyphenyl) piperidin-4-amine dihydrochloride obtained in the above was used to give the title compound (32 mg, yield 74%). Obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 13.1 Hz), 1.27-1.47 (2H, br m), 1.47-1.66 (3H , Br m), 1.67-1.84 (6H, br m), 1.86-1.97 (2H, br m), 2.11 (2H, t, J = 13.5 Hz), 2. 46 (1H, tt, J = 11.9, 2.9 Hz), 2.53-2.71 (4H, br m), 2.89 (1H, t, J = 11.4 Hz), 3.08 ( 2H, d, J = 7.4 Hz), 3.13-3.26 (1H, br m), 3.22 (2H, s), 3.51 (1 H, br s), 3.74 (2H, s), 3.79-3.92 (1H, br m), 3.84 (3H, s), 4.13 (1H, br s), 4.46 (1H, d, J = 14.3 Hz) 6.59-6.71 (2H, m), 6.78 (1H, dd, J = 7.4, 1.6 Hz), 6.86 (1H, td, J = 7.0, 1.6 Hz) ), 7.22 (2H, d, J = 5.7 Hz).

LC / MS [Condition 1]: Retention time 2.98 min; m / z 318.5 [M + 2H] ²⁺ , 636.0 [M + H] ⁺ (ESI positive ion mode), m / z 680.0 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 411
4-((1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- Preparation of methyl [yl] methyl} cyclohexanecarbonyl) piperazine-1-carboxylate (Compound No. 411) Piperazine-1 obtained in Reference Example 338-2 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride Reaction was carried out in substantially the same manner as in Example 402 except that methyl carboxylate was used to obtain the title compound (23 mg, yield 59%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 12.7 Hz), 1.45 to 1.65 (3H, br m), 1.69-1.83 (6H , Br m), 1.84-1.97 (2H, br m), 2.42 (1H, t, J = 11.0 Hz), 2.63 (4H, br s), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.46 (6H, br s), 3.58 (2H, br s), 3.67-3.78 (2H, br m ), 3.72 (3H, s), 7.22 (2H, d, J = 5.7 Hz).

LC / MS [Condition 1]: Retention time 2.49 minutes; m / z 573.8 [M + H] ⁺ (ESI positive ion mode), m / z 618.3 [M + HCOO] ⁻ (ESI negative ion mode)

Example 412
3-{[(1r, 4r) -4- (4,4-difluoropiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8- Preparation of diazaspiro [4.5] decan-2-one (Compound No. 412) Substantially the same as Example 342, except that 4,4-difluoropiperidine hydrochloride (commercially available) was used instead of 3,5-dimethylpiperidine. The reaction was performed in the same manner to obtain the title compound (28 mg, yield 76%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.45 to 1.68 (3H, br m), 1.71-1.85 (6H) , Br m), 1.85-2.08 (6H, br m), 2.45 (1H, tt, J = 11.9, 2.9 Hz), 2.55 (4H, br s), 3. 11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.59 (4H, br s), 3.72 (2H, br s), 7.43 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 557.8 [M + H] ⁺ (ESI positive ion mode), m / z 601.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 413
3-{[(1r, 4r) -4- (4-nicotinoylpiperidine-1-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] Preparation of decan-2-one (Compound No. 413) Substantially except that piperidin-4-yl (pyridin-3-yl) methanone hydrochloride (commercially available) is used instead of 3,5-dimethylpiperidine Specifically, the reaction was carried out in the same manner as in Example 342 to obtain the title compound (35 mg, yield 86%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.47-1.70 (4H, br m), 1.72-1.87 (7H , Br m), 1.88-2.02 (2H, br m), 2.46 (1H, tt, J = 11.9, 2.5 Hz), 2.56 (4H, br s), 2. 83 (1H, t, J = 12.1 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.22 (1H, t, J = 12.7 Hz), 3.26 (2H, s ), 3.48 (1H, tt, J = 10.6, 3.7 Hz), 3.57 (2H, s), 3.99 (1H, d, J = 13.5 Hz), 4.61 (1H , D, J = 12.7 Hz), 7.38-7.49 (3H, m), 7.57 (2H, d, J = 8.2 Hz), 8.22 (1H, dt, J = 7. 8 2.0Hz), 8.75-8.84 (1H, m), 9.16 (1H, s).

LC / MS [Condition 1]: Retention time 3.06 minutes; m / z 313.9 [M + 2H] ²⁺ , 626.8 [M + H] ⁺ (ESI positive ion mode), m / z 670.9 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 414
4-{[3-({(1r, 4r) -4- [4- (2,4-difluorobenzoyl) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8- Preparation of diazaspiro [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (compound no. 414) 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride instead of (2,4 The reaction was carried out in substantially the same manner as in Example 402 except that -difluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) was used to give the title compound (24 mg, 51% yield) as a yellow powder. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 12.3 Hz), 1.44 to 1.65 (3H, br m), 1.65 to 1.84 (6H) , Br m), 1.85-2.03 (4H, br m), 2.45 (1H, t, J = 11.7 Hz), 2.51-2.69 (4H, br m), 2. 77 (1H, t, J = 11.9 Hz), 3.06-3.23 (1H, br m), 3.08 (2H, d, J = 7.4 Hz), 3.22 (2H, s) 3.33 (1H, tt, J = 10.4, 3.3 Hz), 3.74 (2H, s), 3.94 (1H, d, J = 13.1 Hz), 4.56 (1H, d, J = 13.1 Hz), 6.82-6.93 (1H, m), 6.98 (1H, td, J = 8.2, 2.5 Hz), 7.16-7.26 (2H) , m), 7.86 (1H, td, J = 8.6, 6.5 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 654.8 [M + H] ⁺ (ESI positive ion mode), m / z 698.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 415-1
Preparation of 4- [2- (pyridin-2-yl) hydrazinecarbonyl] piperidine-1-carboxylate t-butyl 2-hydrazinopiperidine (520 mg, 4.8 mmol, commercially available), 1- (t-butoxycarbonyl) piperidine -4-carboxylic acid (1.0 g, 4.4 mmol) and 1-hydroxybenzotriazole (180 mg, 1.3 mmol) were dissolved in chloroform (10 mL), and then 1-ethyl-3- (3-dimethylaminopropyl) was dissolved. Carbodiimide hydrochloride (920 mg, 4.8 mmol) was added and stirred at room temperature for 27 hours. Water was added to separate the organic layer, and the aqueous layer was extracted with chloroform. The combined organic layers were washed with a saturated aqueous sodium hydrogen carbonate solution, a 1.0 M aqueous sodium hydroxide solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure. The obtained yellow residue was dissolved in diethyl ether (5.0 mL), and hexane was added. Thereafter, the precipitated white solid was collected and dried under reduced pressure at 30 ° C. for 1 hour to obtain the title compound (920 mg, yield 66%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.57-1.82 (2H, m), 1.82-1.95 (2H, m), 2.33-2 .46 (1H, m), 2.68-1.86 (2H, m), 4.05-4.26 (2H, brm), 6.65 (1H, d, J = 8.5 Hz), 6 .80 (1H, dd, J = 6.8, 4.4 Hz), 7.53 (1H, ddd, J = 8.5, 6.8, 2.0 Hz), 8.16 (1H, dd, J = 4.4, 2.0 Hz).

LC / MS [Condition 1]: Retention time 1.12 minutes; m / z 320.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 415-2
4-([1,2,4] Triazolo [4,3-a] pyridin-3-yl) piperidine-1-carboxylate 4- [2- (obtained in Reference Example 415-1 Pyrridin-2-yl) hydrazinecarbonyl] piperidine-1-carboxylate t-butyl (700 mg, 2.2 mmol) was dissolved in tetrahydrofuran (20 mL), and then Burgess reagent (for details, see J. Am. Chem. Soc. 126, 2004, 6234.) (570 mg, 2.4 mmol) was added, and the mixture was heated to reflux for 4 hours and further stirred at room temperature for 60 hours. Thereafter, the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and water was added. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After concentrating to dryness under reduced pressure, the obtained residue was purified by silica gel column chromatography [Prepack Pak SI 60 μm, developed by Shoko Scientific Co., developing solvent: chloroform-methanol] to give the title compound (420 mg, yield 64%). Was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 1.99-2.14 (4H, m), 2.94-3.09 (2H, m), 3.17-3 .29 (1H, m), 4.19-4.32 (2H, m), 6.85 (1H, dd, J = 6.6, 7.2 Hz), 7.24 (1H, dd, J = 9.2, 6.6 Hz), 7.77 (1H, d, J = 9.2 Hz), 7.94 (1H, d, J = 7.2 Hz).

LC / MS [Condition 1]: Retention time 3.11 min; m / z 302.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 415-3
Production of 3- (piperidin-4-yl)-[1,2,4] triazolo [4,3-a] pyridine dihydrochloride 4-([1,2,4] obtained in Reference Example 415-2 Triazolo [4,3-a] pyridin-3-yl) piperidine-1-carboxylate t-butyl (420 mg, 1.4 mmol) was dissolved in methanol (2.0 mL), and then 4M hydrogen chloride-dioxane solution (6 0.0 mL) and stirred at room temperature for 3 hours. The precipitated white solid was collected and dried under reduced pressure at 30 ° C. for 2 hours to obtain the title compound (320 mg, yield 84%).

¹ H-NMR (DMSO-d ₆ ) δ: 2.02-2.32 (4H, m), 3.00-3.20 (2H, m), 3.34-3.47 (2H, m) , 3.74-3.94 (1H, m), 6.07 (1H, brs), 7.47 (1H, dd, J = 6.7, 6.9 Hz), 7.94 (1H, dd) , J = 9.1, 6.7 Hz), 8.05 (1H, d, J = 9.1 Hz), 9.03 (1H, d, J = 6.9 Hz), 9.22-9.53 ( 2H, m).

LC / MS [Condition 1]: Retention time 0.47 minutes; m / z 203.0 [M + H] ⁺ (ESI positive ion mode)

Example 415
3-({(1r, 4r) -4- [4-([1,2,4] triazolo [4,3-a] pyridin-3-yl) piperidin-1-carbonyl] cyclohexyl} methyl) -8- Preparation of [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 415)
Use 3- (piperidin-4-yl)-[1,2,4] triazolo [4,3-a] pyridine dihydrochloride obtained in Reference Example 415-3 instead of 3,5-dimethylpiperidine. Except for the above, the reaction was carried out in substantially the same manner as in Example 342 to give the title compound (13 mg, yield 34%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.07 (2H, q, J = 13.1 Hz), 1.47-1.71 (3H, br m), 1.71-2.01 (9H , Br m), 2.04-2.30 (3H, br m), 2.50 (1H, tt, J = 11.9, 4.1 Hz), 2.56 (4H, br s), 2. 99 (1H, t, J = 11.9 Hz), 3.07-3.16 (2H, m), 3.24-3.40 (2H, m), 3.26 (2H, s), 3. 58 (2H, s), 4.12 (1H, d, J = 7.4 Hz), 4.59 (1H, d, J = 13.5 Hz), 6.86 (1H, t, J = 6.5 Hz) ), 7.19-7.30 (1H, m), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.78 (1H , D, J 9.4Hz), 7.92 (1H, d, J = 7.0Hz).

LC / MS [Condition 1]: Retention time 2.86 min; m / z 320.0 [M + 2H] ²⁺ , 638.9 [M + H] ⁺ (ESI positive ion mode), m / z 682.9 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 416-1
Production of t-butyl isopropyl [(tetrahydrofuran-2-yl) methyl] carbamate t-butyl (tetrahydrofuran-2-yl) methylcarbamate (0.10 g, 0.50 mmol) obtained in Reference Example 182-1 , N-dimethylformamide (1.0 mL), sodium hydride (> 63 wt%, liquid paraffin dispersion) (36 mg, 1.5 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. . Thereafter, 2-iodopropane (0.25 mL, 2.5 mmol) was added, and the mixture was stirred overnight at room temperature. After adding water (2.0 mL) and ethyl acetate (2.0 mL), the organic layer was separated and washed with water (2.0 mL). The organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [Polipack SI 60 μm, developed by Mortex, developing solvent: ethyl acetate / hexane] to give the title compound (35 mg, yield 29%) as a colorless oil.

LC / MS [Condition 1]: Retention time 4.31 min; m / z 143.9 [M-isobutene-CO ₂ + H] ⁺ (ESI positive ion mode)

Reference Example 416-2
Production of N-[(tetrahydrofuran-2-yl) methyl] propan-2-amine hydrochloride t-butyl isopropyl [(tetrahydrofuran-2-yl) methyl] carbamate obtained in Reference Example 416-1 (35 mg, 0 .14 mmol) was dissolved in methanol (1.0 mL), 10% hydrogen chloride-methanol (0.7 mL) was added at room temperature, and the mixture was stirred at 50 ° C. for 3 hr. The reaction solution was then concentrated to dryness under reduced pressure to give the title compound (25 mg, quantitative) as a colorless oil.

LC / MS [Condition 1]: Retention time 0.49 min; m / z 144.0 [M + H] ⁺ (ESI positive ion mode)

Example 416
(1r, 4r) -N-isopropyl-4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 416) N-[(tetrahydrofuran-2) obtained in Reference Example 416-2 instead of 3,5-dimethylpiperidine Reaction was carried out in substantially the same manner as in Example 342 except that -yl) methyl] propan-2-amine hydrochloride was used to give the title compound (11 mg, yield 28%) as a colorless oil.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 3.7, 13.1 Hz), 1.11-1.21 (3.9 H, m), 1.26 ( 2.1H, d, J = 6.5 Hz), 1.41-1.67 (3H, br m), 1.65-1.86 (7H, br m), 1.85-2.10 (5H) , Br m), 2.47 (1H, tt, J = 11.4, 2.9 Hz), 2.55 (4H, br s), 2.97 (0.65H, dd, J = 13.9, 7.0 Hz), 3.10 (2H, d, J = 7.4 Hz), 3.11-3.39 (1H, m), 3.25 (2H, s), 3.49-3.62 ( 0.65H, m), 3.57 (2H, s), 3.63-3.88 (2H, m), 3.86-3.98 (0.35H, m), 3.98-4. 14 (1H, m 4.51 (0.35H, tt, J = 7.4, 7.4 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz) ).

LC / MS [Condition 1]: retention time 3.24 minutes; m / z 579.9 [M + H] ⁺ (ESI positive ion mode), m / z 624.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 417
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N- (furan-2-ylmethyl) cyclohexanecarboxamide (Compound No. 417) Using furan-2-ylmethanamine (commercially available) instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The title compound (19 mg, yield 55%) was obtained as a white powder in substantially the same manner as in Example 402 except for the above.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, dq, J = 3.3, 12.7 Hz), 1.49 (2H, dq, J = 2.9, 13.1 Hz), 1.50-1.64 (1H, br m), 1.67-1.84 (4H, br m), 1.85-1.98 (4H, br m), 2.03 (1 H, tt, J = 11.9, 3.3 Hz), 2.62 (4H, brs), 3.07 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.75 (2H) , S), 4.42 (2H, d, J = 5.3 Hz), 5.71 (1H, t, J = 4.9 Hz), 6.21 (1H, d, J = 2.5 Hz), 6 .31 (1H, dd, J = 3.3, 2.0 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.34 (1H, dd, J = 1.6, 0.8 Hz) ).

LC / MS [Condition 1]: Retention time 2.55 minutes; m / z 527.0 [M + H] ⁺ (ESI positive ion mode), m / z 571.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 418
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N- (furan-3-ylmethyl) cyclohexanecarboxamide (Compound No. 418) Substituting furan-3-ylmethanamine (commercially available) for 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride Except for the above, the reaction was carried out in substantially the same manner as in Example 402 to give the title compound (17 mg, yield 48%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, dq, J = 3.3, 13.1 Hz), 1.49 (2H, dq, J = 2.5, 12.3 Hz), 1.51-1.63 (1H, br m), 1.68-1.83 (4H, br m), 1.85-1.99 (4H, br m), 2.02 (1 H, tt, J = 11.9, 3.3 Hz), 2.62 (4H, brs), 3.07 (2H, d, J = 7.4 Hz), 3.22 (1H, s), 3.75 (2H) , S), 4.27 (2H, d, J = 5.3 Hz), 5.57 (1H, t, J = 4.9 Hz), 6.33 (1H, s), 7.22 (2H, d) , J = 5.7 Hz), 7.33-7.38 (2H, m).

LC / MS [Condition 1]: Retention time 2.27 minutes; m / z 526.9 [M + H] ⁺ (ESI positive ion mode), m / z 571.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 419
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N-[(3-methoxyisoxazol-5-yl) methyl] cyclohexanecarboxamide (Compound No. 419) Reference Example 401-3 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was conducted in substantially the same manner as in Example 402 except that (3-methoxyisoxazol-5-yl) methanamine obtained in 1 was used to give the title compound (26 mg, yield 70%) as a white powder. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, dq, J = 2.9, 13.1 Hz), 1.48 (2H, dq, J = 2.5, 13.1 Hz), 1.50-1.63 (1H, br m), 1.67-1.82 (4H, br m), 1.84-1.98 (4H, br m), 2.07 (1 H, tt, J = 11.9, 3.3 Hz), 2.63 (4H, brs), 3.07 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.75 (2H) , S), 3.94 (3H, s), 4.43 (2H, d, J = 5.7 Hz), 5.78 (1H, s), 5.92 (1H, t, J = 5.7 Hz) ), 7.22 (2H, d, J = 6.1 Hz).

LC / MS [Condition 1]: Retention time 1.50 minutes; m / z 558.0 [M + H] ⁺ (ESI positive ion mode), m / z 556.1 [M−H] ⁻ , 602.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 420
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N-[(2-fluoropyridin-4-yl) methyl] cyclohexanecarboxamide (Compound No. 420) Obtained in Reference Example 395-5 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was performed in substantially the same manner as in Example 402 except that the obtained (2-fluoropyridin-4-yl) methanamine was used to obtain the title compound (18 mg, yield 47%) as a white powder.
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, dq, J = 3.3, 12.7 Hz), 1.42-1.66 (3H, br m), 1.68-1 .84 (4H, br m), 1.85-2.03 (4H, br m), 2.12 (1H, tt, J = 11.0, 4.1 Hz), 2.62 (4H, br s ), 3.09 (2H, d, J = 7.4 Hz), 3.23 (2H, s), 3.74 (2H, s), 4.47 (2H, d, J = 6.1 Hz), 5.95 (1H, t, J = 6.1 Hz), 6.79 (1H, s), 7.05 (1H, d, J = 4.9 Hz), 7.22 (2H, d, J = 5) .3 Hz), 8.15 (1H, d, J = 4.9 Hz).

LC / MS [Condition 1]: Retention time 1.40 minutes; m / z 278.6 [M + 2H] ²⁺ , 555.9 [M + H] ⁺ (ESI positive ion mode), m / z 554.2 [M−H] ⁻ , 600.0 [M + HCOO] ^- (ESI negative ion mode)

Example 421
4-[(3-{[(1r, 4r) -4- (4,4-difluoropiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5 ] Decan-8-yl) methyl] -3,5-difluorobenzonitrile (Compound No. 421) Preparation of 4- (piperidin-4-yloxy) nicotinonitrile hydrochloride instead of 4,4-difluoropiperidine hydrochloride ( The reaction was carried out in substantially the same manner as in Example 402 except that (commercially available) was used to obtain the title compound (46 mg, quantitative) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.46-1.67 (3H, br m), 1.67-1.85 (6H , Br m), 1.85-2.07 (6H, br m), 2.45 (1H, tt, J = 12.7, 2.5 Hz), 2.51-2.74 (4H, br m ), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.57 (2H, br s), 3.71 (2H, br s), 3.75 ( 2H, s), 7.22 (2H, d, J = 6.1 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 551.0 [M + H] ⁺ (ESI positive ion mode), m / z 595.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 422
3,5-difluoro-4-{[2-oxo-3-({(1r, 4r) -4- [4- (trifluoromethyl) piperidine-1-carbonyl] cyclohexyl} methyl) -1-oxa-3 , 8-Diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 422) 4- (Trifluoromethyl) instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was performed in substantially the same manner as in Example 402 except that piperidine hydrochloride (commercially available) was used, and the title compound (53 mg, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 13.1 Hz), 1.36-1.65 (5H, br m), 1.67-1.84 (6H , Br m), 1.85-2.01 (4H, br m), 2.16-2.34 (1H, m), 2.35-2.51 (2H, m), 2.52-2 .73 (4H, br m), 3.01 (1H, t, J = 12.7 Hz), 3.09 (2H, d, J = 7.0 Hz), 3.22 (2H, s), 3. 75 (2H, s), 3.98 (1H, d, J = 12.3 Hz), 4.75 (1H, d, J = 13.5 Hz), 7.22 (2H, d, J = 6.1 Hz) ).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 583.1 [M + H] ⁺ (ESI positive ion mode), m / z 627.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 423
4-((1r, 4r) -4-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- [Ill] methyl} cyclohexanecarbonyl) Preparation of ethyl piperazine-1-carboxylate (Compound No. 423) Using ethyl piperazine-1-carboxylate (commercially available) instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride In substantially the same manner as in Example 402, the title compound (48 mg, quantitative) was obtained as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 12.3 Hz), 1.27 (3H, t, J = 7.4 Hz), 1.44 to 1.65 ( 3H, br m), 1.68-1.84 (6H, br m), 1.84-1.97 (2H, br m), 2.42 (1 H, t, J = 11.9 Hz), 2 50-2.72 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.47 (6H, br s), 3.59 (2H, br s), 3.75 (2H, s), 4.16 (2H, q, J = 6.5 Hz), 7.22 (2H, d, J = 5.9 Hz).

LC / MS [Condition 1]: Retention time 2.88 minutes; m / z 588.1 [M + H] ⁺ (ESI positive ion mode), m / z 632.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 424
4-((1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- [Ill] methyl} cyclohexanecarbonyl) -1,4-diazepane-1-carboxylate methyl ester (Compound No. 424) Obtained in Reference Example 349 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was carried out substantially in the same manner as in Example 402 except for using 1,4-diazepane-1-carboxylic acid methyl hydrochloride to obtain the title compound (42 mg, quantitative) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 11.6 Hz), 1.42-1.68 (3H, br m), 1.67-1.98 (10H , Br m), 2.40 (1H, t, J = 11.4 Hz), 2.50-2.73 (4H, br m), 3.08 (2H, d, J = 7.4 Hz), 3 .22 (2H, s), 3.36-3.61 (8H, m), 3.64-3.79 (5H, m), 7.14-7.28 (2H, m).

LC / MS [Condition 1]: Retention time 2.55 minutes; m / z 588.1 [M + H] ⁺ (ESI positive ion mode), m / z 632.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 425
2-((1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- Preparation of methyl [yl] methyl} cyclohexanecarbonyl) -1,2,5-oxadiazepan-5-carboxylate (Compound No. 425) Obtained in Reference Example 307 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 402 except that the obtained 1,2,5-oxadiazepan-5-carboxylic acid methyl hydrochloride was used to give the title compound (19 mg, yield 48%) as a white powder. Obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) ¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.9 Hz), 1.38-1.66 (4H, br m), 1.68 -2.04 (8H, br m), 2.63 (4H, br s), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.56-3 .89 (8H, m), 3.72 (3H, s), 3.96-4.08 (2H, m), 7.17-7.26 (2H, m).

LC / MS [Condition 1]: Retention time 2.69 minutes; m / z 590.0 [M + H] ⁺ (ESI positive ion mode), m / z 634.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 426
3,5-difluoro-4-[(3-{[(1r, 4r) -4- (4-nicotinoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8- Preparation of diazaspiro [4.5] decan-8-yl) methyl] benzonitrile (compound no. 426) 6- (Piperidin-4-yloxy) nicotinonitrile hydrochloride instead of piperidin-4-yl (pyridin-3- Yl) The reaction was carried out in substantially the same manner as in Example 402 except that methanone hydrochloride (commercially available) was used to give the title compound (36 mg, yield 87%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.6 Hz), 1.45 to 1.67 (4H, br m), 1.68-1.85 (7H , Br m), 1.86-2.01 (4H, br m), 2.46 (1 H, t, J = 11.9 Hz), 2.63 (4 H, br s), 2.82 (1 H, t, J = 11.4 Hz), 3.09 (2H, d, J = 7.4 Hz), 3.13-3.28 (1H, br m), 3.22 (2H, s), 3.48 (1H, tt, J = 10.6, 4.1 Hz), 3.75 (2H, s), 3.99 (1H, d, J = 13.9 Hz), 4.61 (1H, d, J = 14.3 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.45 (1H, dd, J = 8.2, 4.5 Hz), 8.22 (1H, dt, J = 7) . 9, 1.9 Hz), 8.80 (1 H, dd, J = 4.9, 1.6 Hz), 9.15 (1 H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 2.65 minutes; m / z 310.6 [M + 2H] ²⁺ , 619.9 [M + H] ⁺ (ESI positive ion mode), m / z 664.2 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 427
4- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) nicotinoyl] piperazine- Production of t-butyl 1-carboxylate (Compound No. 427) The reaction was carried out in substantially the same manner as in Example 111 except that piperazine-1-carboxylate t-butyl (commercially available) and triethylamine were used instead of tetrahydrofurfurylamine. Performed to give the title compound (20 mg, 81% yield) as a yellow amorphous.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 1.67-1.87 (2H, br m), 1.91-2.05 (2H, br m), 2 .55 (4H, br s), 3.29-3.61 (6H, br m), 3.35 (2H, s), 3.57 (2H, s), 3.74 (2H, br s) , 4.57 (2H, s), 7.37 (1H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.56 (2H, d, J = 8.2 Hz), 7.74 (1H, dd, J = 8.0, 2.2 Hz), 8.59 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 561.9 [M-isobutene + H] ⁺ , 618.0 [M + H] ⁺ (ESI positive ion mode), m / z 662.2 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 428
3-{[(1r, 4r) -4- (1,2,5-oxadiazepan-5-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Diazaspiro [4.5] decan-2-one Preparation of ditrifluoroacetate 5-[(1r, 4r) -4-({2-oxo-8- [4- (tri Fluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarbonyl] -1,2,5-oxadiazepan-2-carboxylate (49 mg, 0.077 mmol) was dissolved in trifluoroacetic acid (1.0 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure to give the title compound (59 mg, quantitative) as a yellow oil.

LC / MS [Condition 1]: Retention time 2.21 minutes; m / z 538.9 [M + H] ⁺ (ESI positive ion mode), m / z 582.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 428
5-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexanecarbonyl] -1,2,5-oxadiazepan-2-carboxylic acid methyl trifluoroacetate (Compound No. 428) 3-{[(1r, 4r) -4- ( 1,2,5-oxadiazepan-5-carbonyl) cyclohexyl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one Trifluoroacetate (59 mg, 0.077 mmol) was dissolved in chloroform (3.0 mL), and triethylamine (0.054 mL, 0.39 mmol) and chloroformate were dissolved at 0 ° C. Chill (0.012 mL, 0.012 mL) was added and stirred at room temperature for 1 hour. To the obtained reaction mixture, chloroform (2.0 mL), 1.0 M aqueous citric acid solution (0.38 mL) and water (2.0 mL) were added, and the organic layer was separated. The obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the title compound (39 mg, yield 84%) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.90-1.13 (2H, br m), 1.46-1.68 (3H, br m), 1.69-1.88 (4H, br m), 1.96-2.11 (2H, br m), 2.26-2.50 (3H, br m), 2.98-3.16 (2H, br m), 3.10 ( 2H, d, J = 7.4 Hz), 3.36 (2H, s), 3.42 (2H, br s), 3.67 (2H, q, J = 4.5 Hz), 3.70-3 .85 (7H, m), 3.96-4.07 (2H, br m), 4.18 (2H, br s), 7.57 (2H, d, J = 8.2 Hz), 7.71 (2H, d, J = 7.8 Hz). 13.87 (1H, br s).

LC / MS [Condition 1]: Retention time 2.88 minutes; m / z 597.0 [M + H] ⁺ (ESI positive ion mode), m / z 641.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 429
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N- (3-cyanobenzyl) cyclohexanecarboxamide (Compound No. 429) Instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride, 3- (aminomethyl) benzonitrile hydrochloride (WO2007 / The title compound (13 mg, 50% yield) was obtained as a white solid in substantially the same manner as in Example 402 except that the above compound was used.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, qd, J = 12.3, 2.9 Hz), 1.52 (2H, qd, J = 13.1, 3.3 Hz), 1.59-1.64 (1H, m), 1.69-1.84 (4H, m), 1.86-1.99 (4H, m), 2.09 (1H, tt, J = 12 .3, 3.7 Hz), 2.54-2.67 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.75 (2H , S), 4.47 (2H, d, J = 6.1 Hz), 5.87 (1H, t, J = 5.7 Hz), 7.22 (2H, d, J = 5.9 Hz), 7 .39-7.60 (4H, m).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 561.8 [M + H] ⁺ (ESI positive ion mode), m / z 560.0 [MH] ⁻ (ESI negative ion mode)

Example 430
3,5-difluoro-4-({3-[((1r, 4r) -4- {4- [4- (methylsulfonyl) benzoyl] piperidine-1-carbonyl} cyclohexyl) methyl] -2-oxo-1 Preparation of —oxa-3,8-diazaspiro [4.5] decan-8-yl} methyl) benzonitrile (Compound No. 430) Reference Example instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was conducted in substantially the same manner as in Example 402 except that 4- [4- (methylsulfonyl) benzoyl] piperidine hydrochloride obtained in 367-2 was used, and the title compound (20 mg, yield 95%) Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.47-1.70 (4H, m), 1.70-1.87 (7H, m), 1.88-1.99 (4H, m), 2.46 (1H, tt, J = 10.0, 3.3 Hz), 2.54-2.71 (4H, m), 2. 83 (1H, t, J = 11.9 Hz), 3.09 (2H, d, J = 4.6 Hz), 3.10 (3H, s), 3.22 (1H, t, J = 12.2 Hz) ), 3.23 (2H, s), 3.51 (1H, tt, J = 11.1, 3.6 Hz), 3.75 (2H, s), 3.99 (1H, d, J = 14) .5Hz), 4.60 (1H, d, J = 13.5 Hz), 7.23 (2H, d, J = 6.3 Hz), 8.07 (2H, d, J = 8.9 Hz), 8 .11 (2 , D, J = 8.9Hz).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 696.8 [M + H] ⁺ (ESI positive ion mode), m / z 740.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 431-1
Preparation of ethyl 6-[(1,3-dioxoisoindoline-2-yl) methyl] nicotinate Ethyl 6- (hydroxymethyl) nicotinate (3.62 g, 20 mmol) obtained in Reference Example 111-2, To a tetrahydrofuran solution (100 mL) of triphenylphosphine (6.30 g, 24 mmol) and phthalimide (3.53 g, 24 mmol) at 0 ° C. was added dropwise a toluene solution of diisopropyl azodicarboxylate (1.9 M, 12.70 mL, 24 mmol). And stirred at room temperature for 30 minutes. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solvent: hexane / ethyl acetate = 2/1], and the obtained solid was recrystallized from ethanol to give the title compound (4.82 g, yield). 78%) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.38 (3H, t, J = 7.2 Hz), 4.38 (2H, q, J = 7.1 Hz), 5.07 (2H, s) , 7.35 (1H, d, J = 8.3 Hz), 7.73-7.79 (2H, m), 7.87-7.92 (2H, m), 8.25 (1H, dd, J = 8.3, 2.2 Hz), 9.12 (1H, d, J = 1.4 Hz).

LC / MS [Condition 1]: retention time 3.97 minutes; m / z 310.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 431-2
Preparation of ethyl 6-[(t-butoxycarbonylamino) methyl] nicotinate Ethyl 6-[(1,3-dioxoisoindoline-2-yl) methyl] nicotinate obtained above (2.58 g, 8 Hydrazine monohydrate (807.50 μL, 16.65 mmol) was added to an ethanol solution (30 mL) of .32 mmol), and the mixture was refluxed for 1 hour. After allowing to cool, dichloromethane was added to the reaction solution, insolubles were filtered off, and the filtrate was distilled off under reduced pressure. Dichloromethane was added to the resulting residue, the insoluble material was filtered off again, and the filtrate was distilled off under reduced pressure to obtain a white solid. Di-t-butyl dicarbonate (2.18 g, 9.99 mmol) was added to a dichloromethane solution (10 mL) of the obtained white solid, and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [developing solvent: hexane / ethyl acetate = 2/1] to give the title compound (2.20 g, yield 94). %) As a white solid.

LC / MS [Condition 1]: Retention time 3.87 minutes; m / z 280.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 431-3
Preparation of t-butyl [5- (hydroxymethyl) pyridin-2-yl] methylcarbamate of ethyl 6-[(t-butoxycarbonylamino) methyl] nicotinate (0.28 g, 1.0 mmol) obtained above Sodium borohydride (0.19 g, 4.0 mmol) was added to an ethanol solution (4.0 mL) and refluxed for 30 minutes. After completion of the reaction, water and 1M hydrochloric acid were added to make it acidic. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solvent: ethyl acetate} to give the title compound (0.17 g, yield 73%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 4.36 (2H, brs), 4.67 (2H, brs), 5.69 (1H, brs), 7. 24 (1H, d, J = 8.0 Hz), 7.67 (1H, d, J = 6.6 Hz), 8.38 (1H, s).

LC / MS [Condition 1]: Retention time 0.61 min; m / z 239.0 [M + H] ⁺ (ESI positive ion mode)

Reference Example 431-4
Preparation of (5-cyanopyridin-2-yl) methylcarbamate t-butyl [5- (hydroxymethyl) pyridin-2-yl] methylcarbamate t-butyl (94.70 mg, 0.40 mmol) obtained above Manganese dioxide (0.17 g, 2.0 mmol) was added to the chloroform solution (2.0 mL), and the mixture was refluxed for 30 minutes. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated. Hydroxylamine hydrochloride (138.98 mg, 2.0 mmol) and pyridine (321.90 μL, 4.0 mmol) were added to the obtained liquid ethanol solution (3.0 mL), and the mixture was refluxed for 10 minutes. After allowing to cool, the solvent was distilled off, water and ethyl acetate were added, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and then evaporated under reduced pressure to obtain a white solid. Methanesulfonyl chloride (61.90 μL, 0.80 mmol) was slowly added to a dichloromethane solution (3.0 mL) of the obtained white solid and triethylamine (116.20 μL, 1.2 mmol) at 0 ° C. and then refluxed for 2 hours. did. After the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [developing solvent: hexane / ethyl acetate = 1/1] to give the title compound (71.30 mg, yield 76). %) As a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.46 (9H, s), 4.51 (2H, d, J = 5.8 Hz), 5.47 (1H, s), 7.43 (1H , Dd, J = 8.2, 0.7 Hz), 7.93 (1H, dd, J = 8.2, 2.1 Hz), 8.82 (1H, d, J = 0.7 Hz).

LC / MS [Condition 1]: retention time 3.44 minutes; m / z 234.0 [M + H] ⁺ (ESI positive ion mode)

Reference Example 431-5
Preparation of 6- (aminomethyl) nicotinonitrile dihydrochloride t-butyl (5-cyanopyridin-2-yl) methylcarbamate (71.30 mg, 0.30 mmol) obtained above, 1,4-dioxane To the solution (1.0 mL) was added 4M hydrogen chloride-dioxane solution (1.0 mL), and the mixture was stirred at room temperature for 1 hr. After the reaction, the precipitated solid was collected by filtration to give the title compound (37.50 mg, yield 59%) as a white solid.

LC / MS [Condition 1]: Retention time 0.47 minutes; m / z 134.0 [M + H] ⁺ (ESI positive ion mode)

Example 431
(1r, 4r) -N-[(5-Cyanopyridin-2-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 431) Instead of (2-fluoropyridin-4-yl) methanamine 6- The reaction was carried out substantially in the same manner as in Example 395 except that (aminomethyl) nicotinonitrile dihydrochloride was used to give the title compound (23 mg, yield 47%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, dq, J = 2.9, 12.7 Hz), 1.43-1.68 (3H, m), 1.72-1. 86 (4H, m), 1.88-2.03 (4H, m), 2.18 (1H, tt, J = 12.3, 3.3 Hz), 2.53-2.56 (4H, br m), 3.10 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.58 (2H, s), 4.61 (2H, d, J = 5.3 Hz) 6.71 (1H, t, J = 5.3 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 ( 2H, d, J = 8.2 Hz), 7.92 (1H, dd, J = 8.2, 2.0 Hz), 8.80 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 569.7 [M + H] ⁺ (ESI positive ion mode)

Reference Example 432-1
Preparation of 4- [1- (1,3-dioxoisoindoline-2-yl) ethyl] benzonitrile 4- (1-hydroxyethyl) benzonitrile (735) instead of ethyl 6- (hydroxymethyl) nicotinate The compound was reacted in substantially the same manner as in Reference Example 431-1 except that 90 mg, 5.0 mmol, synthesized by the method described in WO2006060461), and the title compound (977.70 mg, 71% yield) was obtained. Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.93 (3H, d, J = 7.4 Hz), 5.59 (1H, q, J = 7.4 Hz), 7.60 (2H, d, J = 8.6 Hz), 7.64 (2H, d, J = 8.6 Hz), 7.72-7.73 (2H, m), 7.82-7.84 (2H, m).

LC / MS [Condition 1]: Retention time 3.89 minutes; m / z 276.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 432-2
Preparation of 4- (1-aminoethyl) benzonitrile of 4- [1- (1,3-dioxoisoindoline-2-yl) ethyl] benzonitrile (276.30 mg, 1.0 mmol) obtained above. Hydrazine monohydrate (48.50 μL, 1.0 mmol) was added to an ethanol solution (5.0 mL), and the mixture was refluxed for 1 hour. After allowing to cool, chloroform was added to the reaction solution, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. 1M Hydrochloric acid (5.0 mL) was added to the residue, and the aqueous layer was washed twice with diethyl ether (5.0 mL). Saturated aqueous ammonia was added to the aqueous layer to make the solution basic (pH> 9), and then extracted twice with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (81.90 mg, yield 59%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.38 (3H, dd, J = 6.6, 1.2 Hz), 4.19 (1H, q, J = 6.6 Hz), 7.47 ( 2H, d, J = 7.8 Hz), 7.62 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 0.50 min; m / z 146.9 [M + H] ⁺ (ESI positive ion mode)

Example 432
(1r, 4r) -N- [1- (4-Cyanophenyl) ethyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro Preparation of [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 432) Instead of (2-fluoropyridin-4-yl) methanamine 4- (1) obtained in Reference Example 432-2 The reaction was carried out in substantially the same manner as in Example 395 except that -aminoethyl) benzonitrile was used to give the title compound (11 mg, yield 21%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, dd, J = 24.1, 12.3 Hz), 1.35 to 1.64 (3H, m), 1.47 (3H, d, J = 7.0 Hz), 1.66-2.00 (8H, m), 2.10 (1H, tt, J = 11.9, 3.3 Hz), 2.54-2.57 (4H) , Br m), 3.10 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.58 (2H, s), 5.03-5.17 (1H, quin, J = 7.0 Hz), 6.14 (1H, d, J = 7.4 Hz), 7.37-7.48 (4H, m), 7.53-7.65 (4H, m).

LC / MS [Condition 1]: Retention time 3.22 minutes; m / z 582.8 [M + H] ⁺ (ESI positive ion mode), m / z 627.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 433-1
Preparation of ethyl 5-[(1,3-dioxoisoindoline-2-yl) methyl] pyrazine-2-carboxylate ethyl 5- (bromomethyl) pyrazine-2-carboxylate (2.45 g, 10 mmol, described in WO2005018557 And a solution of potassium phthalimide (1.85 g, 10 mmol) in N, N-dimethylformamide (15 ml) was heated and stirred at 80 ° C. for 20 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Ethanol (50 mL) was added to the obtained residue, and the mixture was heated to 60 ° C., cooled to 0 ° C., and the precipitated solid was collected by filtration to give the title compound (2.40 g, yield 77%) as white. Obtained as a solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.43 (4H, t, J = 7.2 Hz), 4.49 (2H, q, J = 7.2 Hz), 5.13 (2H, s) , 7.76-7.78 (2H, m), 7.90-7.92 (2H, m), 8.76 (1H, s), 9.17 (1H, s).

LC / MS [Condition 1]: Retention time 3.64 minutes; m / z 311.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 433-2
Preparation of ethyl 5- (aminomethyl) pyrazine-2-carboxylate ethyl 5-[(1,3-dioxoisoindoline-2-yl) methyl] pyrazine-2-carboxylate obtained above (1.56 g , 5.0 mmol) in ethanol solution (20 mL) was added hydrazine monohydrate (485 μL, 10.0 mmol) and refluxed for 1 hour. After allowing to cool, dichloromethane was added to the reaction solution, insolubles were filtered off, and the filtrate was distilled off under reduced pressure. Dichloromethane was added to the residue, the insoluble material was filtered off again, and the filtrate was evaporated under reduced pressure to give the title compound (716.70 mg, yield 80%) as a brown liquid.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (3H, t, J = 7.1 Hz), 4.14 (2H, s), 4.51 (2H, q, J = 7.1 Hz), 8 .73 (1H, d, J = 1.4 Hz), 9.24 (1H, d, J = 1.4 Hz).

Example 433
5-{[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) cyclohexanecarboxamide] Preparation of ethyl methyl} pyrazine-2-carboxylate (Compound No. 433) Instead of (2-fluoropyridin-4-yl) methanamine, 5- (amino The reaction was carried out in substantially the same manner as in Example 395 except that ethyl methyl) pyrazine-2-carboxylate was used to give the title compound (11 mg, yield 21%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06 (2H, dq, J = 3.7, 12.3 Hz), 1.47 (3H, t, J = 7.4 Hz), 1.51- 1.72 (3H, m), 1.73-1.87 (4H, m), 1.90-2.04 (4H, m), 2.19 (1H, tt, J = 11.9, 3 .7 Hz), 2.58 (4 H, br m), 3.12 (2 H, d, J = 6.5 Hz), 3.28 (2 H, s), 3.59 (2 H, s), 4.52 (2H, q, J = 7.8 Hz), 4.70 (2H, d, J = 5.3 Hz), 6.58 (1H, brs), 7.45 (2H, d, J = 8.2 Hz) 7.58 (2H, d, J = 7.8 Hz), 8.70 (1H, s), 9.23 (1H, s).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 617.7 [M + H] ⁺ (ESI positive ion mode)

Reference Example 434-1
Preparation of 1,1,1-trifluoro-2- (4-fluorophenyl) -3-nitropropan-2-ol To a tetrahydrofuran solution (50 mL) of 1-bromo-4-fluorobenzene (5.25 g, 30 mmol) A hexane solution of n-butyllithium (2.66 M, 12.4 mL, 33 mmol) was slowly added dropwise at −78 ° C. After stirring at −78 ° C. for 30 minutes, ethyl trifluoroacetate (4.64 mL, 45 mmol) was added at −78 ° C., and the temperature was raised to room temperature. Nitromethane (3.25 mL, 60 mmol) was added to the reaction mixture at room temperature, and then stirred for 30 minutes. The reaction solution was poured into 1M hydrochloric acid (75 mL) and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solvent: hexane / ethyl acetate = 5/1] to give the title compound (6.07 g, yield 80%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.66 (1H, brs), 5.04 (2H, dd, J = 23.1, 13.8 Hz), 7.15 (2H, dd, J = 8.9, 8.5 Hz), 7.59 (2H, dd, J = 8.5, 5.1 Hz).

Reference Example 434-2
Preparation of 3-amino-1,1,1-trifluoro-2- (4-fluorophenyl) propan-2-ol 1,1,1-trifluoro-2- (4-fluorophenyl) obtained above To an ethanol solution (25 mL) of -3-nitropropan-2-ol (6.07 g, 24 mmol) was added 10 wt% palladium-carbon (1.0 g), and the mixture was stirred at room temperature for 16 hours in a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (4.52 g, yield 84%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 2.97 (1H, d, J = 13.0 Hz), 3.57 (1H, d, J = 13.0 Hz), 7.08 (2H, dd, J = 8.9, 8.5 Hz), 7.55 (2H, dd, J = 8.5, 5.2 Hz).

LC / MS [Condition 1]: Retention time 0.54 minutes; m / z 224.0 [M + H] ⁺ (ESI positive ion mode)

Example 434
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of —N- [3,3,3-trifluoro-2- (4-fluorophenyl) -2-hydroxypropyl] cyclohexanecarboxamide (Compound No. 434) instead of (2-fluoropyridin-4-yl) methanamine And 3-amino-1,1,1-trifluoro-2- (4-fluorophenyl) propan-2-ol obtained in Reference Example 434-2, and (1r, 4r) -4- ({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) Reference instead of cyclohexanecarboxylic acid (1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] obtained in 398-2 The reaction was carried out in substantially the same manner as in Example 395 except that decan-3-yl] methyl} cyclohexanecarboxylic acid was used to give the title compound (32 mg, yield 54%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.81-1.02 (2H, m), 1.24-2.07 (12H, m), 2.53-2.71 (4H, br m ), 3.03 (2H, d, J = 6.1 Hz), 3.23 (2H, s), 3.75 (2H, s), 3.78 (1H, dd, J = 13.5, 5) .7 Hz), 4.00 (1 H, dt, J = 13.5, 4.1 Hz), 6.13-6.66 (2 H, brm), 7.06 (2 H, t, J = 8.6 Hz) , 7.23 (2H, d, J = 6.1 Hz), 7.57 (2H, dd, J = 9.0, 4.9 Hz).

LC / MS [Condition 1]: Retention time 3.39 minutes; m / z 652.9 [M + H] ⁺ (ESI positive ion mode), m / z 650.9 [MH] ⁻ (ESI negative ion mode)

Example 435
4-{[3-({(1r, 4r) -4- [3- (4-cyanophenoxy) azetidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 435) Obtained instead of (2-fluoropyridin-4-yl) methanamine in Reference Example 383-2 4- (azetidin-3-yloxy) benzonitrile and (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3, (1r, 4r) -4-{[8- (4-cyano-2,8) obtained in Reference Example 398-2 instead of 8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid 6- Fluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid was used for the reaction in substantially the same manner as in Example 395. The title compound (1.2 mg, yield 3.0%) was obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 12.7 Hz), 1.43-1.66 (3H, m), 1.70-1.87 (6H, m), 1.87-1.98 (2H, m), 2.14 (1H, tt, J = 11.4, 2.9 Hz), 2.61-2.64 (4H, br m), 3 .09 (2H, d, J = 6.5 Hz), 3.22 (2H, s), 3.76 (2H, s), 4.06 (1H, dd, J = 4.1, 11.0 Hz) 4.21 (1H, dd, J = 9.0, 3.3 Hz), 4.41 (1H, dd, J = 11.4, 6.1 Hz), 4.55 (1H, dd, J = 9) 0.0, 6.5 Hz), 4.94-5.05 (1 H, m), 6.82 (2 H, d, J = 9.4 Hz), 7.23 (2 H, d, J = 6.5 Hz) , 7.62 (2 , D, J = 8.6Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 603.9 [M + H] ⁺ (ESI positive ion mode), m / z 648.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 436
4-{[3-({(1r, 4r) -4- [3- (3-cyanophenoxy) azetidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 436) Obtained in Reference Example 390-2 instead of (2-fluoropyridin-4-yl) methanamine Using 3- (azetidin-3-yloxy) benzonitrile hydrochloride, and (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa- (1r, 4r) -4-{[8- (4-cyano-) obtained in Reference Example 398-2 instead of 3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid 2 6-Difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid, but using substantially the same reaction as in Example 395 To give the title compound (31 mg, 72% yield) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, q, J = 11.9 Hz), 1.43-1.66 (3H, m), 1.70-1.87 (6H, m), 1.87-1.99 (2H, m), 2.07-3.19 (4H, br m), 2.15 (1H, tt, J = 11.9, 3.3 Hz), 3 .10 (2H, d, J = 7.4 Hz), 3.23 (2H, s), 3.76 (2H, s), 4.05 (1H, dd, J = 3.7, 11.0 Hz) , 4.20 (1H, dd, J = 8.6, 3.3 Hz), 4.41 (1H, dd, J = 10.6, 6.1 Hz), 4.57 (1H, dd, J = 9) 0.0, 6.1 Hz), 4.91-5.03 (1H, m), 6.98-7.05 (2H, m), 7.24 (2H, d, J = 6.1 Hz), 7 .33 (1H, d J = 7.4Hz), 7.43 (1H, t, J = 7.8Hz).

LC / MS [Condition 1]: Retention time 3.21 minutes; m / z 603.9 [M + H] ⁺ (ESI positive ion mode), m / z 648.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 437-1
Preparation of 1,1,1-trifluoro-2- (6-methoxypyridin-3-yl) -3-nitropropan-2-ol Instead of 1-bromo-4-fluorobenzene, 5-bromo-2- The reaction was carried out substantially in the same manner as in Reference Example 434-1 except that methoxypyridine was used to give the title compound (2.03 g, yield 91%) as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.96 (3H, s), 5.04 (2H, dd, J = 21.3, 13.2 Hz), 6.82 (1H, d, J = 9.0 Hz), 7.78 (1H, dd, J = 9.0, 3.0 Hz), 8.38 (1H, d, J = 3.0 Hz).

Reference Example 437-2
Preparation of 3-amino-1,1,1-trifluoro-2- (6-methoxypyridin-3-yl) propan-2-ol 1,1,1-trifluoro-2- (4-fluorophenyl)- Use 1,1,1-trifluoro-2- (6-methoxypyridin-3-yl) -3-nitropropan-2-ol obtained above in place of 3-nitropropan-2-ol The title compound (1.52 g, yield 84%) was obtained as a colorless liquid in substantially the same manner as in Reference Example 434-2 except for the above.

LC / MS [Condition 1]: Retention time 0.54 minutes; m / z 237.0 [M + H] ⁺ (ESI positive ion mode)

Example 437
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- [3,3,3-trifluoro-2-hydroxy-2- (6-methoxypyridin-3-yl) propyl] cyclohexanecarboxamide (Compound No. 437) 4- (3-Fluorophenylsulfonyl) piperidine hydrochloride Substantially other than using 3-amino-1,1,1-trifluoro-2- (6-methoxypyridin-3-yl) propan-2-ol obtained in Reference Example 437-2 instead of the salt Specifically, the reaction was carried out in the same manner as in Example 393 to obtain the title compound (5.1 mg, yield 9.0%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.81-1.00 (2H, m), 1.23-1.88 (9H, m), 1.90-2.11 (3H, m) 2.47-2.66 (4H, m), 3.03 (2H, d, J = 7.2 Hz), 3.28 (2H, s), 3.58 (2H, s), 3.80 (1H, dd, J = 14.6, 6.5 Hz), 3.93 (3H, s), 4.00 (1H, dd, J = 14.6, 5.4 Hz), 6.74 (1H, d, J = 8.5 Hz), 7.03 (1H, t, J = 6.1 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.58 (2H, d, J = 7) .8 Hz), 7.81 (1H, dd, J = 8.5, 2.7 Hz), 8.34 (1H, d, J = 2.7 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 672.8 [M + H] ⁺ (ESI positive ion mode)

Example 438
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- [3,3,3-trifluoro-2- (4-fluorophenyl) -2-hydroxypropyl] cyclohexanecarboxamide (Compound No. 438) Instead of 4- (3-fluorophenylsulfonyl) piperidine hydrochloride Substantially the same as Example 393 except that 3-amino-1,1,1-trifluoro-2- (4-fluorophenyl) propan-2-ol obtained in Reference Example 434-2 was used. Reaction was performed to obtain the title compound (28 mg, yield 48%) as a yellow liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.80-1.01 (2H, m), 1.24-1.46 (2H, m), 1.46-1.87 (7H, m) , 1.87-2.07 (3H, m), 2.54-2.57 (4H, br m), 3.03 (2H, d, J = 7.5 Hz), 3.25 (2H, s ), 3.56 (2H, s), 3.78 (1H, dd, J = 6.5, 14.7 Hz), 4.00 (1H, dd, J = 5.8, 14.7 Hz), 6 .27 (1H, br s), 6.59 (1H, br s), 7.06 (2H, t, J = 8.5 Hz), 7.44 (2H, d, J = 8.2 Hz), 7 51-7.62 (4H, m).

LC / MS [Condition 1]: Retention time 3.51 minutes; m / z 659.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 439-1
Preparation of 2- (6-chloropyridin-3-yl) -1,1,1-trifluoro-3-nitropropan-2-ol Instead of 1-bromo-4-fluorobenzene, 5-bromo-2- The reaction was carried out substantially in the same manner as in Reference Example 434-1 except that chloropyridine (5.2 g, 27 mmol) was used to give the title compound (4.93 g, yield 67%) as a yellow liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.96 (1H, brs), 5.06 (2H, s), 7.45 (1H, d, J = 8.4 Hz), 7.92 (1H , Dd, J = 8.4, 2.8 Hz), 8.62 (1H, d, J = 2.8 Hz).

LC / MS [Condition 1]: Retention time 3.60 minutes; m / z 270.9, 272.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 439-2
Preparation of 3-amino-1,1,1-trifluoro-2- (pyridin-3-yl) propan-2-ol 2- (6-chloropyridin-3-yl) -1,1 obtained above , 1-trifluoro-3-nitropropan-2-ol (2.53 g, 9.39 mmol) in tetrahydrofuran (20 mL) was added triethylamine (2.60 mL, 18.8 mmol) and 10 wt% palladium-carbon (0 .60 g) was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Prefpack SI 60 μm, manufactured by Shoko Scientific Co., Ltd., developing solvent: ethyl acetate / methanol / triethylamine = 9/1/1], and the title compound (0.91 g, yield 47) was obtained. %) As a white amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.01 (1H, d, J = 13.5 Hz), 3.62 (1H, d, J = 13.5 Hz), 5.84 (1H, brs) , 7.34 (1H, dd, J = 8.1, 4.8 Hz), 7.95 (1H, d, J = 8.1 Hz), 8.61 (1H, d, J = 4.8 Hz), 8.79 (1H, s).

Example 439
(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl)- Preparation of N- [3,3,3-trifluoro-2-hydroxy-2- (pyridin-3-yl) propyl] cyclohexanecarboxamide (Compound No. 439) Instead of 4- (3-fluorophenylsulfonyl) piperidine hydrochloride In Example 393, except that 3-amino-1,1,1-trifluoro-2- (pyridin-3-yl) propan-2-ol obtained in Reference Example 439-2 was used. The reaction was performed in the same manner to obtain the title compound (22 mg, yield 38%) as a colorless solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 0.79-1.00 (2H, m), 1.22-1.42 (2H, m), 1.45-1.61 (1H, m) , 1.61-1.87 (6H, m), 1.89-2.08 (3H, m), 2.54-2.57 (4H, br m), 3.02 (2H, d, J = 7.2 Hz), 3.26 (2H, s), 3.58 (2H, s), 3.84 (1H, dd, J = 15.0, 6.5 Hz), 4.08 (1H, dd) , J = 15.7, 5.8 Hz), 6.66-6.90 (1H, m), 7.36 (1H, dd, J = 4.8, 7.5 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.58 (2H, d, J = 8.2 Hz), 8.04 (1H, d, J = 7.5 Hz), 8.54-8.60 (1H, m ), 8.71 (1H, ).

LC / MS [Condition 1]: Retention time 2.97 minutes; m / z 642.7 [M + H] ⁺ (ESI positive ion mode)

Reference Example 440-1
Preparation of 5-[(1,3-dioxoisoindoline-2-yl) methyl] picolinonitrile 5- (bromoethyl) pyrazine-2-carboxylate obtained in Reference Example 387 instead of 5- The reaction was carried out substantially in the same manner as in Reference Example 433-1 except that (bromomethyl) picolinonitrile was used to give the title compound (0.17 g, yield 63%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 4.92 (2H, s), 7.66 (1H, d, J = 8.6 Hz), 7.76 (2H, dd, J = 5.3, 2. 9 Hz), 7.88 (2H, dd, J = 5.3, 2.9 Hz), 7.91 (1H, dd, J = 8.6, 2.0 Hz), 8.81 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.58 minutes; m / z 263.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 440-2
Preparation of 5- (aminomethyl) picolinonitrile Obtained in Reference Example 440-1 instead of ethyl 5-[(1,3-dioxoisoindoline-2-yl) methyl] pyrazine-2-carboxylate , 5-[(1,3-dioxoisoindoline-2-yl) methyl] picolinonitrile was reacted in substantially the same manner as in Reference Example 433-2 to give the title compound (10 mg, yield). 12%) as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 4.02 (2H, s), 7.68 (1H, d, J = 8.0 Hz), 7.86 (1H, dd, J = 8.0, 2. 0 Hz), 8.68 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 0.49 min; m / z 133.8 [M + H] ⁺ (ESI positive ion mode)

Example 440
(1r, 4r) -N-[(6-Cyanopyridin-3-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 440) Using 5- (aminomethyl) picolinonitrile obtained in Reference Example 440-2 instead of piperidine Except for the above, the reaction was carried out in substantially the same manner as in Example 16 to obtain the title compound (11 mg, yield 26%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.0, 13.0 Hz), 1.51 (2H, dq, J = 3.0, 12.5 Hz), 1. 59-1.87 (5H, m), 1.93 (4H, d, J = 13.0 Hz), 2.12 (1H, tt, J = 12.2, 3.3 Hz), 2.44-2 .64 (4H, br m), 3.09 (2H, d, J = 7.3 Hz), 3.26 (2H, s), 3.58 (2H, s), 4.50 (2H, d, J = 5.9 Hz), 6.37 (1H, t, J = 5.9 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz) ), 7.65 (1H, d, J = 7.9 Hz), 7.76 (1H, dd, J = 7.9, 2.1 Hz), 8.62 (1H, d, J = 2.1 Hz) .

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 569.7 [M + H] ⁺ (ESI positive ion mode), m / z 604.0 [M + Cl] ⁻ , 613.9 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 441-1
Preparation of t-butyl 4- (4-cyanophenylamino) piperidine-1-carboxylate Substantially Reference Example 391-1 except that 4-aminobenzonitrile was used instead of 4- (trifluoromethyl) aniline The title compound (0.84 g, yield 56%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.37 (2H, q, J = 11.5 Hz), 1.47 (9H, s), 2.02 (2H, d, J = 11.9 Hz), 2 .93 (2H, t, J = 11.5 Hz), 3.39-3.55 (1H, m), 3.96-4.22 (0H, m), 6.55 (2H, d, J = 8.6 Hz), 7.42 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: retention time 4.29 minutes; m / z 246.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 441-2
Preparation of 4- (piperidin-4-ylamino) benzonitrile dihydrochloride Obtained in Reference Example 441-1 instead of t-butyl 4- [4- (trifluoromethyl) phenylamino] piperidine-1-carboxylate The reaction was conducted in substantially the same manner as in Reference Example 391-2 except that t-butyl 4- (4-cyanophenylamino) piperidine-1-carboxylate was used. The title compound (0.73 g, yield) 96%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.56 (2H, dt, J = 27.0, 12.5 Hz), 1.93 (2H, d, J = 111.2 Hz), 2.89 (2H, q, J = 9.6 Hz), 3.20 (2H, d, J = 11.2 Hz), 3.55 (1H, tt, J = 10.2, 3.6 Hz), 6.63 (2H, d) , J = 8.3 Hz), 7.38 (2H, d, J = 8.3 Hz), 8.92-9.16 (2H, br m).

LC / MS [Condition 1]: Retention time 0.52 minutes; m / z 202.1 [M + H] ⁺ (ESI positive ion mode)

Example 441
4- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane-3 -Il} methyl) cyclohexanecarbonyl] piperidin-4-ylamino} benzonitrile (Compound No. 441)

The reaction was conducted in substantially the same manner as in Example 16 except that 4- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Reference Example 441-2 was used instead of piperidine to give the title compound ( 26 mg, yield 51%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.5 Hz), 1.37 (2H, q, J = 11.3 Hz), 1.46-1.69 (3H, m), 1.71-1.86 (6H, m), 1.94 (2H, d, J = 13.1 Hz), 2.13 (2H, d, J = 13.9 Hz), 2.46 ( 1H, tt, J = 11.9, 3.3 Hz), 2.52-2.64 (4H, br m), 2.83 (1H, t, J = 11.9 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.19 (1H, t, J = 12.7 Hz), 3.26 (2H, s), 3.48-3.65 (1H, m), 3.57 ( 2H, s), 3.90 (1H, d, J = 13.9 Hz), 4.12 (1H, d, J = 7.0 Hz), 4.53 (1H, d, J = 13.1 Hz), 6.56 (2 , D, J = 9.0 Hz), 7.43 (2H, d, J = 9.0 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 637.8 [M + H] ⁺ (ESI positive ion mode), m / z 672.2 [M + Cl] ⁻ , 682.0 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 442-1
Preparation of t-butyl 4- (3-cyano-4-fluorophenylamino) piperidine-1-carboxylate Other than using 5-amino-2-fluorobenzonitrile instead of 4- (trifluoromethyl) aniline The reaction was carried out substantially in the same manner as in Reference Example 391-1 to give the title compound (0.73 g, yield 96%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.22-1.42 (2H, m), 1.47 (9H, s), 2.01 (2H, dd, J = 12.6, 3.7 Hz) , 2.93 (2H, t, J = 11.7 Hz), 3.26-3.43 (1H, br m), 3.76-3.92 (1H, br m), 4.06 (2H, d, J = 12.3 Hz), 6.71 (1H, dd, J = 4.9, 3.3 Hz), 6.77 (1H, ddd, J = 9.0, 4.5, 3.3 Hz) , 7.00 (1H, t, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 4.43 minutes; m / z 319.9 [M + H] ⁺ , 263.9 [M-isobutene + H] ⁺ (ESI positive ion mode), m / z 363.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 442-2
Preparation of 2-fluoro-5- (piperidin-4-ylamino) benzonitrile dihydrochloride Reference example 442 instead of t-butyl 4- [4- (trifluoromethyl) phenylamino] piperidine-1-carboxylate The reaction was performed in substantially the same manner as in Reference Example 391-2 except that t-butyl 4- (3-cyano-4-fluorophenylamino) piperidine-1-carboxylate obtained in 1 was used to obtain the title. The compound (0.63 g, yield 50%) was obtained as a white powder.

¹ H-NMR (DMSO-d ₆ ) δ: 1.54 (2H, dq, J = 4.1, 11.9 Hz), 2.02 (2H, br d, J = 13.9 Hz), 2.96 (2H, q, J = 11.1 Hz), 3.28 (2H, br d, J = 12.3 Hz), 3.41-3.66 (2H, br m), 6.92-7.00 ( 2H, m), 7.23 (1H, t, J = 9.8 Hz), 8.79 (2H, br s).

LC / MS [Condition 1]: Retention time 0.67 minutes; m / z 220.0 [M + H] ⁺ (ESI positive ion mode)

Example 442
2-Fluoro-5- {1-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) cyclohexanecarbonyl] piperidin-4-ylamino} benzonitrile (Compound No. 442) Instead of piperidine, 2-fluoro-5- (piperidine--) obtained in Reference Example 442-2 The reaction was carried out in substantially the same manner as in Example 16 except that 4-ylamino) benzonitrile dihydrochloride and triethylamine were used to give the title compound (36 mg, yield 69%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.5 Hz), 1.33 (2H, q, J = 11.1 Hz), 1.45-1.88 (9H, m), 1.94 (2H, d, J = 13.1 Hz), 2.11 (2H, d, J = 16.0 Hz), 2.46 (1 H, tt, J = 11.5, 2.9 Hz) ), 2.52-2.63 (4H, br m), 2.83 (1H, t, J = 11.5 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.19 ( 1H, t, J = 12.7 Hz), 3.26 (2H, s), 3.36-3.52 (1H, m), 3.58 (2H, s), 3.72 (1H, d, J = 7.8 Hz), 3.90 (1 H, d, J = 13.5 Hz), 4.52 (1 H, d, J = 13.1 Hz), 6.72 (1 H, dd, J = 4.9). 2.9Hz 6.76 (1H, ddd, J = 8.8, 4.1, 2.9 Hz), 7.01 (1H, t, J = 8.8 Hz), 7.44 (2H, d, J = 7) .8 Hz), 7.57 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.44 minutes; m / z 655.8 [M + H] ⁺ (ESI positive ion mode), m / z 690.2 [M + Cl] ⁻ , 700.0 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 443-1
Preparation of (6-fluoropyridin-3-yl) methanol Substantially Reference Example 431 except that 6-fluoronicotinaldehyde was used instead of ethyl 6-[(t-butoxycarbonylamino) methyl] nicotinate The reaction was conducted in the same manner as for -3 to give the title compound (0.26 g, yield 50%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 4.71 (2H, s), 6.93 (1H, dd, J = 8.2, 2.5 Hz), 7.83 (1H, td, J = 8. 2, 2.5 Hz), 8.15 (1H, br s).

LC / MS [Condition 1]: Retention time 0.74 minutes; m / z 127.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 443-2
Preparation of 2-[(6-fluoropyridin-3-yl) methyl] isoindoline-1,3-dione Instead of ethyl 6- (hydroxymethyl) nicotinate, it was obtained in Reference Example 443-1 (6 The reaction was carried out in substantially the same manner as in Reference Example 431-1 except that -fluoropyridin-3-yl) methanol was used to obtain the title compound (0.36 g, yield 69%) as a white powder. .

¹ H-NMR (CDCl ₃ ) δ: 4.84 (2H, s), 6.89 (1H, dd, J = 8.6, 2.9 Hz), 7.71-7.78 (2H, m) 7.83-7.90 (3H, m), 8.33 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 3.64 minutes; m / z 256.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 443-3
Preparation of (6-fluoropyridin-3-yl) methanamine Obtained in Reference Example 443-2 instead of ethyl 5-[(1,3-dioxoisoindoline-2-yl) methyl] pyrazine-2-carboxylate The reaction was conducted in substantially the same manner as in Reference Example 433-2 except that 2-[(6-fluoropyridin-3-yl) methyl] isoindoline-1,3-dione was used to give the title compound ( 24 mg, 24% yield) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 3.89 (2H, s), 6.90 (1H, dd, J = 8.2, 2.9 Hz), 7.79 (1H, td, J = 8. 2, 2.9 Hz), 8.13 (1H, br s).

LC / MS [Condition 1]: Retention time 0.49 min; m / z 126.9 [M + H] ⁺ (ESI positive ion mode)

Example 443
(1r, 4r) -N-[(6-Fluoropyridin-3-yl) methyl] -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxamide (Compound No. 443) Instead of piperidine, (6-fluoropyridin-3-yl) methanamine obtained in Reference Example 443-3 was used. The reaction was carried out substantially in the same manner as in Example 16 except for using, and the title compound (24 mg, yield 53%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.3, 13.0 Hz), 1.50 (2H, dq, J = 3.3, 12.3 Hz), 1. 58-1.66 (1H, m), 1.70-1.84 (4H, m), 1.87-1.98 (4H, m), 2.08 (1H, tt, J = 12.1) , 3.3 Hz), 2.47-2.62 (4H, br m), 3.08 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.57 (2H, s), 4.43 (2H, d, J = 6.1 Hz), 6.09 (1H, t, J = 6.1 Hz), 6.89 (1H, dd, J = 8.6, 2.9 Hz) ), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.74 (1H, td, J = 8.6, 2.5 Hz) , 8.11 (1H, d, J 2.5Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 562.7 [M + H] ⁺ (ESI positive ion mode), m / z 560.8 [M−H] ⁻ , 606.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 444-1
Reference Example for Production of t-Butyl 3-{[5- (Ethoxycarbonyl) pyrazin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate Tetrahydrofuran solution (4.0 mL) of 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate t-butyl (256.30 mg, 1.0 mmol) obtained in 111-1. ) Was added at 0 ° C. with sodium hydride (> 55% by weight, liquid paraffin dispersion, purchased from Kanto Chemical Co., Inc.) (43.60 mg, 1.0 mmol), Ethyl acid (245.07 mg, 1.0 mmol, synthesized by the method described in WO2005018557) was added, and the mixture was heated to reflux for 1 hour. After completion of the reaction, a saturated aqueous ammonium chloride solution and water were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Prefpack NH 60 μm, manufactured by Shoko Scientific Co., Ltd., developing solvent: hexane / ethyl acetate = 1: 3], and the title compound (20.96 mg, yield 48%) was white. Obtained as a solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.44 to 1.54 (4H, m), 1.46 (3H, t, J = 7.1 Hz), 1.46 (9H, s), 1 .62-1.72 (3H, m), 1.91-1.96 (2H, m), 3.28-3.32 (2H, m), 3.40 (2H, s), 3.82 -3.86 (2H, m), 4.52 (2H, q, J = 7.1 Hz), 4.69 (2H, s), 8.72 (1H, s), 9.26 (1H, s ).

LC / MS [Condition 1]: Retention time 3.89 minutes; m / z 442.8 [M + Na] ⁺ (ESI positive ion mode), m / z 418.8 [MH] ⁻ (ESI negative ion mode)

Reference Example 444-2
Preparation of 5-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} pyrazine-2-carboxylic acid 3- { Instead of [(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate instead of t-butyl 3-{[5- (Ethoxycarbonyl) pyrazin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-obtained in Example 444-1 The reaction was carried out substantially in the same manner as in Reference Example 2-3 except that t-butyl carboxylate was used to give the title compound (0.24 g, yield 79%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.70 (2H, ddd, J = 13.6, 11.5, 4.5 Hz), 1.95 (2H, d, J = 13.6 Hz), 3.30 (2H, t, J = 11.3 Hz), 3.45 (2H, s), 3.78-3.94 (2H, m), 4.72 (2H, s), 6.11 (1H, br s), 8.72 (1H, s), 9.34 (1H, s).

LC / MS [Condition 1]: Retention time 3.52 minutes; m / z 392.9 [M + H] ⁺ , 336.8 [M-isobutene + H] ⁺ (ESI positive ion mode), m / z 390.9 [M−H ] ^- (ESI negative ion mode)

Reference Example 444-3
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- Preparation of t-butyl 8-carboxylate (1r, 4r) -4-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-3- Yl] methyl} cyclohexanecarboxylic acid instead of 5-{[8- (t-butoxycarbonyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Use of decan-3-yl] methyl} pyrazine-2-carboxylic acid and (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) instead of tetrahydrofurfurylamine Except isosamples performing the reaction as a substantially Example 2 to give the title compound (54 mg, 62% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.61-1.74 (2H, m), 1.76-1.98 (6H, m), 3.14 (1H , Dt, J = 2.4, 12.3 Hz), 3.22-3.38 (3H, m), 3.42 (2H, s), 3.47-3.61 (1H, m), 3 71-3.92 (2H, br m), 4.04-4.14 (2H, m), 4.63 (2H, s), 4.69 (1H, d, J = 13.5 Hz), 7.17 (2H, t, J = 8.6 Hz), 7.99 (2H, dd, J = 8.6, 5.3 Hz), 8.55 (1H, d, J = 1.5 Hz), 8 .89 (1H, d, J = 1.5 Hz).

LC / MS [Condition 1]: Retention time 4.17 minutes; m / z 580.1 [M−H] ⁻ , 626.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 444-4
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one 3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl] methyl} -2-oxo-1-oxa-3 obtained in Production Reference Example 444-3 , 8-diazaspiro [4.5] decane-8-carboxylate t-butyl (54 mg, 0.093 mmol) was dissolved in methanol (2 mL), and a 10 mass% hydrogen chloride methanol solution (0.23 mL) was added at room temperature. In addition, the mixture was stirred for 1 hour at 40 ° C. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and chloroform (20 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added to the residue. The organic layer concentrated to dryness under reduced pressure to give the title compound (46 mg, yield quantitative) as a colorless amorphous substance.

¹ H-NMR (CDCl ₃ ) δ: 1.72 (2H, ddd, J = 13.2, 9.2, 4.0 Hz), 1.79-2.13 (6H, m), 2.84 ( 2H, dt, J = 12.9, 5.0 Hz), 3.07 (2H, ddd, J = 12.6, 9.6, 3.3 Hz), 3.08-3.20 (1H, m) 3.32 (1H, ddd, J = 14.5, 9.9, 5.0 Hz), 3.42 (2H, s), 3.56 (1H, tt, J = 9.9, 4.6 Hz) ), 4.06-4.14 (1H, m), 4.63 (2H, s), 4.66-4.74 (1H, m), 7.17 (2H, t, J = 8.6 Hz) ), 7.9 (2H, dd, J = 8.9, 5.6 Hz), 8.56 (1H, d, J = 1.3 Hz), 8.89 (1H, d, J = 1.3 Hz) .

LC / MS [Condition 1]: retention time 1.56 minutes; m / z 481.7 [M + H] ⁺ (ESI positive ion mode), m / z 479.9 [M−H] ⁻ , 525.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 444
3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-2-one (compound no. 444)

(1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexane Instead of carboxamide hydrochloride, 3-({5- [4- (4-fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -1-oxa- obtained in Reference Example 444-4 Using 3,8-diazaspiro [4.5] decan-2-one and instead of 3- (bromomethyl) pyridine hydrobromide, 1- (bromomethyl) -4- (trifluoromethyl) benzene ( The reaction was carried out in substantially the same manner as in Example 4 except that the commercially available product was used to give the title compound (7.6 mg, yield 24%) as a pale red powder.

¹ H-NMR (CDCl ₃ ) δ: 1.73-2.11 (8H, m), 2.41-2.68 (4H, br m), 3.14 (1H, dt, J = 3.0 , 12.8 Hz), 3.32 (1 H, tt, J = 4.9, 8.9 Hz), 3.41 (2 H, s), 3.48-3.64 (1 H, m), 3.57 (2H, s), 4.09 (1H, d, J = 12.8 Hz), 4.63 (2H, s), 4.69 (1H, d, J = 13.9 Hz), 7.17 (2H , T, J = 8.8 Hz), 7.44 (2H, d, J = 7.9 Hz), 7.57 (2H, d, J = 7.9 Hz), 7.9 (2H, dd, J = 8.8, 5.4 Hz), 8.55 (1H, d, J = 1.0 Hz), 8.88 (1H, d, J = 1.0 Hz).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 639.8 [M + H] ⁺ (ESI positive ion mode), m / z 637.9 [M−H] ⁻ , 683.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 445
3,5-difluoro-4-{[3-({5- [4- (4-fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 445) 3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl } -1-Oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride instead of 3-({5- [4- (4-fluorobenzoyl) obtained in Reference Example 444-4 ) Piperidin-1-carbonyl] pyrazin-2-yl} methyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one and 6- (trifluoromethyl) nicotine alde The reaction was conducted in substantially the same manner as in Example 384, except that 3,5-difluoro-4-formylbenzonitrile (commercially available) was used instead of 3, and the title compound (14 mg, yield 56%) was converted to white Obtained as a powder.

¹ H-NMR (CDCl ₃ ) δ: 1.70-2.11 (8H, m), 2.53-2.71 (4H, br m), 3.13 (1H, td, J = 12.3 , 3.3 Hz), 3.24-3.35 (1 H, m), 3.37 (2 H, s), 3.55 (1 H, tt, J = 9.2, 4.6 Hz), 3.74. (2H, s), 4.09 (1H, d, J = 14.5 Hz), 4.61 (2H, s), 4.69 (1H, d, J = 13.5 Hz), 7.17 (2H , T, J = 8.8 Hz), 7.22 (2H, d, J = 5.9 Hz), 7.99 (2H, dd, J = 8.8, 5.4 Hz), 8.54 (1H, d, J = 1.3 Hz), 8.88 (1H, d, J = 1.3 Hz).

LC / MS [Condition 1]: Retention time 3.10 minutes; m / z 632.8 [M + H] ⁺ (ESI positive ion mode), m / z 630.9 [M−H] ⁻ , 676.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 446
3-({5- [4- (4-Cyanophenylamino) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Production of t-butyl -8-carboxylate (Compound No. 446)

Other than using 4- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Reference Example 441-2 and triethylamine instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out substantially in the same manner as in Reference Example 444-3 to give the title compound (76 mg, yield 44%) as a colorless amorphous product. As a by-product, t-butyl 3-[(5-carbamoylpyrazin-2-yl) methyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (43 mg, 37% yield) was obtained as a white powder.

3-({5- [4- (4-Cyanophenylamino) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Data for t-butyl 8-carboxylate (Compound No. 446)

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.57 (2H, dq, J = 4.0, 13.5 Hz), 1.61-1.76 (4H, m) 1.93 (2H, d, J = 13.5 Hz), 2.10 (1 H, d, J = 13.9 Hz), 2.21 (1 H, d, J = 11.1 Hz), 3.12 ( 1H, dt, J = 2.5, 12.6 Hz), 3.29 (3H, t, J = 11.3 Hz), 3.43 (2H, s), 3.56-3.72 (2H, m ), 3.83 (2H, d, J = 12.7 Hz), 4.05 (1H, d, J = 13.1 Hz), 4.26 (1H, d, J = 7.8 Hz), 4.63 (2H, s), 4.65 (1H, d, J = 11.1 Hz), 6.58 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz) , 8.55 ( H, d, J = 1.6Hz), 8.89 (1H, d, J = 1.6Hz).

LC / MS [Condition 1]: Retention time 4.05 min; m / z 575.9 [M + H] ⁺ , 475.7 [M-isobutene + H] ⁺ , 431.9 [M-isobutene-CO2 + H] ⁺ (ESI positive ion Mode), m / z 573.9 [M−H] ⁻ , 619.9 [M + HCOO] ⁻ (ESI negative ion mode)

Data for t-butyl 3-[(5-carbamoylpyrazin-2-yl) methyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate (byproduct)

¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.62-1.74 (2H, m), 1.92 (2H, d, J = 12.3 Hz), 3.30 (2H, t, J = 11.5 Hz), 3.42 (2H, br s), 3.83 (2H, d, J = 13.1 Hz), 4.67 (2H, s), 5.72 ( 1H, br s), 7.60 (1H, br s), 8.58 (1H, s), 9.34 (1H, s).

LC / MS [Condition 1]: Retention time 3.41 minutes; m / z 335.9 [M-isobutene + H] ⁺ (ESI positive ion mode), m / z 390.1 [MH] ⁻ (ESI negative ion mode)

Reference Example 447
4- (1- {5-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] pyrazin-2-carbonyl} piperidin-4-ylamino) benzonitrile obtained in example 446, 3 - ({5- [4- (4-cyanophenyl) piperidine-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa -3 , 8-diazaspiro [4.5] decane-8-carboxylate t-butyl (75 mg, 0.13 mmol) was dissolved in methanol (2 mL), and a 10 mass% hydrogen chloride methanol solution (0.32 mL) was added at room temperature. In addition, the mixture was stirred at 40 ° C for 1 hour. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and chloroform (20 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added to the residue. The organic layer was concentrated to dryness under reduced pressure to give the title compound (60 mg, yield 98%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.48-1.79 (4H, m), 1.92 (2H, dt, J = 13.5, 3.6 Hz), 2.10 (1H, d, J = 13.9 Hz), 2.21 (1H, d, J = 13.1 Hz), 2.84 (2H, dt, J = 13.1, 4.5 Hz), 2.99-3.19 (3H M), 3.29 (1H, dt, J = 2.9, 12.9 Hz), 3.42 (2H, s), 3.56-3.72 (1H, m), 4.05 (1H , D, J = 12.3 Hz), 4.19 (1H, d, J = 7.8 Hz), 4.63-4.72 (1H, m), 4.63 (2H, s), 6.58. (2H, d, J = 9.0 Hz), 7.43 (2H, d, J = 9.0 Hz), 8.55 (1H, d, J = 1.6 Hz), 8.89 (1H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 1.04 minutes; m / z 475.8 [M + H] ⁺ (ESI positive ion mode), m / z 473.9 [M−H] ⁻ , 520.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 447
4-{[3-({5- [4- (4-Cyanophenylamino) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-8-yl] methyl} -3,5-difluoro-benzonitrile (Compound No. 447) 3-({5- [4- (4-Fluorobenzoyl) piperidine-1-carbonyl] pyrazine- 4- (1- {5-[(2-oxo) obtained in Reference Example 447 instead of 2-yl} methyl) -1-oxa-3,8-diazaspiro [4.5] decan-2-one 1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] pyrazin-2-carbonyl} piperidin-4-ylamino) benzonitrile, but substantially the same as Example 445 React to Conducted to give the title compound (14 mg, 45% yield) as a colorless amorphous substance.

¹ H-NMR (CDCl ₃ ) δ: 1.56 (2H, dq, J = 4.1, 12.1 Hz), 1.70-1.85 (2H, m), 1.96 (2H, d, J = 13.1 Hz), 2.05-2.15 (1 H, m), 2.22 (1 H, d, J = 11.5 Hz), 2.51-2.72 (4 H, br m), 3 .12 (1H, td, J = 12.5, 2.9 Hz), 3.29 (1H, td, J = 12.9, 2.9 Hz), 3.37 (2H, s), 3.56- 3.71 (1H, m), 3.74 (2H, s), 4.04 (1H, d, J = 13.5 Hz), 4.19 (1H, d, J = 7.4 Hz), 4. 61 (2H, s), 4.65 (1H, d, J = 12.3 Hz), 6.58 (2H, d, J = 9.0 Hz), 7.23 (2H, d, J = 6.1 Hz) ), 7.43 (2 , D, J = 9.0Hz), 8.53 (1H, d, J = 1.5Hz), 8.88 (1H, d, J = 1.5Hz).


LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 626.9 [M + H] ⁺ (ESI positive ion mode), m / z 624.7 [M−H] ⁻ , 671.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 448
4-{[3-({(1r, 4r) -4- [4- (4-cyanophenylamino) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro Production of [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 448)

Substantially the Example, except that 4- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Reference Example 441-2 was used instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was conducted in the same manner as in 402 to give the title compound (33 mg, yield 78%) as a white powder.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.03 (2H, q, J = 13.1 Hz), 1.24 to 1.67 (5H, br m), 1.66 to 1.84 (6H , Br m), 1.83 to 2.01 (2H, br m), 2.01-2.23 (2H, br m), 2.45 (1 H, t, J = 11.9 Hz), 2. 52-2.73 (4H, br m), 2.83 (1 H, t, J = 11.7 Hz), 3.05-3.25 (1 H, br m), 3.08 (2H, d, J = 6.5 Hz), 3.22 (2H, s), 3.47-3.63 (1H, br m), 3.75 (2H, s), 3.83-3.97 (1 H, br m ), 4.07 (1H, d, J = 7.4 Hz), 4.46-4.60 (1H, br m), 6.55 (2H, d, J = 8.6 Hz), 7.22 ( 2 , D, J = 6.1Hz), 7.42 (2H, d, J = 9.0Hz).

LC / MS [condition 1]: retention time 3.20 minutes; m / z 631.1 [M + H] ⁺ (ESI positive ion mode), m / z 629.2 [M−H] ⁻ , 675.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 449
4- [2- (3-{[(1r, 4r) -4- (4-benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5 Production of decane-8-yl) ethyl] benzonitrile (Compound No. 449)

Example 255 is substantially the same as Example 255 except that 4-cyanophenethyl methanesulfonate obtained in Reference Example 397-1 is used in place of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene. The reaction was conducted in the same manner to obtain the title compound (3.5 mg, yield 7.0%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 13.1 Hz), 1.49-1.71 (4H, m), 1.71-1.87 (7H, m) 1.87-2.02 (4H, m), 2.47 (1H, tt, J = 11.9, 3.3 Hz), 2.53-2.73 (6H, m), 2.74- 2.90 (3H, m), 3.11 (2H, d, J = 7.4 Hz), 3.21 (1H, br t, J = 12.3 Hz), 3.26 (2H, s), 3 .52 (1H, tt, J = 10.6, 3.7 Hz), 3.98 (1H, br d, J = 13.5 Hz), 4.60 (1 H, br d, J = 13.5 Hz), 7.31 (2H, d, J = 7.8 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.59 (1H , T, J = 7 4Hz), 7.94 (2H, d, J = 7.4Hz).

LC / MS [Condition 1]: Retention time 3.18 min; m / z 597.0 [M + H] ⁺ (ESI positive ion mode), m / z 641.2 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 450-1
Preparation of 1H-imidazole-1-carboxylic acid (1,1,1-trifluoro-2-methylpropan-2-yl) 1,1,1-trifluoro-2-methylpropan-2-ol (commercially available) 1.3 g, 10 mmol) was dissolved in chloroform (10 mL), 1,1′-carbonyldiimidazole (3.2 g, 20 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, water (10 mL) and chloroform (20 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain the title compound (2.7 g, quantitative yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.84 (6H, s), 7.08 (1H, br s), 7.37 (1H, br s), 8.09 (1H, br s).

LC / MS [Condition 1]: Retention time 3.46 minutes; m / z 222.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 450-2
Production of 3-methyl-1-[(1,1,1-trifluoro-2-methylpropan-2-yloxy) carbonyl] -1H-imidazole-3-ium iodide The 1H— obtained in Reference Example 450-1 Imidazole-1-carboxylic acid (1,1,1-trifluoro-2-methylpropan-2-yl) (1.1 g, 4.8 mmol) was dissolved in acetonitrile (10 mL), and iodine methane (10 mL) was dissolved at room temperature. 1.2 mL, 19 mmol) was added, and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure to give the title compound (1.2 g, quantitative yield) as a yellow oil.

Example 450
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone Preparation of acid 1,1,1-trifluoro-2-methylpropan-2-yl (compound no. 450)

Instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene, 3-methyl-1-[(1,1,1-trifluoro-2-) obtained in Reference Example 450-2 was used. (Methylpropan-2-yloxy) carbonyl] -1H-imidazol-3-ium iodide was used to carry out the reaction substantially in the same manner as in Example 255 to obtain the title compound (32 mg, quantitative) as a white powder. .

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 11.9 Hz), 1.47-1.87 (11H, m), 1.93 (4H, br d, J = 13) .9 Hz), 2.48 (1H, tt, J = 11.9, 3.3 Hz), 2.82 (1H, br t, J = 12.3 Hz), 3.12 (2H, d, J = 7) .4 Hz), 3.13-3.43 (3H, br m), 3.28 (2H, s), 3.52 (1H, tt, J = 10.6, 3.3 Hz), 3.75- 4.05 (3H, br m), 4.60 (1H, br d, J = 13.9 Hz), 7.49 (2H, t, J = 7.8 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.95 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 4.43 min; m / z 621.9 [M + H] ⁺ (ESI positive ion mode), m / z 666.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 451
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Methyl) cyclohexanecarbonyl] piperazine-1-carboxylic acid 1,1,1-trifluoro-2-methylpropan-2-yl (Compound No. 451)

Instead of methyl chloroformate, 3-methyl-1-[(1,1,1-trifluoro-2-methylpropan-2-yloxy) carbonyl] -1H-imidazole-obtained in Reference Example 450-2 The reaction was carried out substantially in the same manner as in Example 149 except that 3-ium iodide was used to give the title compound (28 mg, yield 52%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, q, J = 11.5 Hz), 1.50-1.69 (3H, m), 1.70 (6H, s), 1.72 -1.85 (6H, m), 1.94 (2H, d, J = 13.1 Hz), 2.41 (1H, t, J = 11.5 Hz), 2.49-2.65 (4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.25 (2H, s), 3.36-3.53 (6H, br m), 3.54-3.65 ( 2H, m), 3.57 (2H, s), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 677.1 [M + H] ⁺ (ESI positive ion mode), m / z 721.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 452-1
Preparation of 1H-imidazol-1-carboxylic acid (2-cyanopropan-2-yl) Instead of 1,1,1-trifluoro-2-methylpropan-2-ol, 2-hydroxy-2-methyl The reaction was carried out substantially in the same manner as in Reference Example 450-1 except that propanenitrile (commercially available) was used, and the title compound (2.0 g, quantitative) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.96 (6H, s), 7.08 (1H, br s), 7.41 (1H, br s), 8.12 (1H, br s).

LC / MS [Condition 1]: Retention time 1.18 minutes; m / z 179.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 452-2
Preparation of 1-[(2-cyanopropan-2-yloxy) carbonyl] -3-methyl-1H-imidazole-3-ium iodide 1H-imidazole- 1-carboxylic acid (1,1,1-trifluoro-2-methyl) Reference Example substantially except that 1H-imidazole-1-carboxylic acid (2-cyanopropan-2-yl) obtained in Reference Example 452-1 was used in place of Propan-2-yl) The reaction was conducted in the same manner as in 450-2 to give the title compound (2.1 g, quantitative) as a yellow oil.

LC / MS [Condition 1]: Retention time 0.51 min; m / z 194.1 M ⁺ (ESI positive ion mode)

Example 452
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone Preparation of 2-cyanopropan-2-yl acid (Compound No. 452) Instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene, 1- [ The reaction was carried out in substantially the same manner as in Example 255 except that (2-cyanopropan-2-yloxy) carbonyl] -3-methyl-1H-imidazol-3-ium iodide was used to give the title compound (28 mg, yield). 60%) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 11.9 Hz), 1.47-2.00 (13H, m), 1.78 (6H, s), 2.48 (1H, tt, J = 11.9, 3.3 Hz), 2.82 (1H, t, J = 11.7 Hz), 3.13 (2H, d, J = 7.4 Hz), 3.26− 3.30 (4H, m), 3.28 (2H, s), 3.52 (1H, tt, J = 10.6, 3.7 Hz), 3.83 (1H, d, J = 10.6 Hz) ), 3.92-4.10 (2H, m), 4.60 (1H, d, J = 13.1 Hz), 7.49 (2H, t, J = 7.0 Hz), 7.59 (1H , T, J = 7.0 Hz), 7.94 (2H, d, J = 7.0 Hz).

LC / MS [Condition 1]: Retention time 4.13 minutes; m / z 579.0 [M + H] ⁺ (ESI positive ion mode), m / z 612.9 [M + Cl] ⁻ , 623.1 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 453
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of methyl) cyclohexanecarbonyl] piperazine-1-carboxylate 2- cyanopropan -2-yl (Compound No. 453) In place of methyl chloroformate, 1-[(2-cyano Propan-2-yloxy) carbonyl] -3-methyl-1H-imidazol-3-ium iodide was used to carry out the reaction substantially in the same manner as in Example 149, to give the title compound (19 mg, yield 39%). Obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.6 Hz), 1.42-1.87 (9H, m), 1.79 (6H, s), 1.94 (2H, d, J = 13.1 Hz), 2.43 (1H, t, J = 11.5 Hz), 2.49-2.61 (4H, br m), 3.11 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.35-3.66 (8 H, m), 3.57 (2H, s), 7.44 (2H, d, J = 8.2 Hz) ), 7.57 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 634.0 [M + H] ⁺ (ESI positive ion mode), m / z 668.2 [M + Cl] ⁻ , 678.0 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 454-1
Preparation of 1H-imidazole-1-carboxylic acid (2,2,2-trifluoroethyl) 2,2,2- in place of 1,1,1-trifluoro-2-methylpropan-2-ol The reaction was carried out substantially in the same manner as in Reference Example 450-1 except that trifluoroethanol (commercially available) was used, and the title compound (2.2 g, quantitative) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 4.79 (2H, q, J = 7.9 Hz), 7.09-7.14 (1H, m), 7.44-7.47 (1H, m) , 8.18 (1H, br s).

LC / MS [Condition 1]: Retention time 1.67 minutes; m / z 194.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 454-2
Preparation of 3-methyl-1-[(2,2,2-trifluoroethoxy) carbonyl] -1H-imidazole-3-ium iodide 1H-imidazole-1-carboxylic acid (1,1,1-trifluoro-2- Substantially other than using 1H-imidazole-1-carboxylic acid (2,2,2-trifluoroethyl) obtained in Reference Example 454-1 instead of methylpropan-2-yl) The reaction was carried out in the same manner as in Reference Example 450-2 to obtain the title compound (2.2 g, quantitative) as a yellow oil.

¹ H-NMR (CD ₃ OD) δ: 4.00 (3H, s), 4.64 (1H, q, J = 7.4 Hz), 4.80-5.02 (1H, m), 7. 56-7.59 (1H, m), 7.61-7.64 (1H, m), 8.96 (1H, s).

LC / MS [Condition 1]: Retention time 0.51 min; m / z 208.9 M ⁺ (ESI positive ion mode)

Example 454
4-[(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} Preparation of 2,2,2-trifluoroethyl (methyl) cyclohexanecarbonyl] piperazine-1-carboxylate (Compound No. 454) In place of methyl chloroformate, 3-methyl-1- The reaction was carried out in substantially the same manner as in Example 149 except that [(2,2,2-trifluoroethoxy) carbonyl] -1H-imidazol-3-ium iodide was used, and the title compound (27 mg, yield 84%) was obtained. ) Was obtained as a pale yellow powder.

¹ H-NMR (CDCl ₃ ) δ: 1.05 (2H, q, J = 11.7 Hz), 1.4-1.87 (9H, m), 1.88-1.99 (2H, m) , 2.43 (1H, t, J = 11.7 Hz), 2.50-2.65 (4H, br m), 3.11 (2H, d, J = 7.3 Hz), 3.26 (2H , S), 3.45-3.69 (8H, m), 3.58 (2H, s), 4.51 (2H, q, J = 8.3 Hz), 7.44 (2H, d, J = 8.3 Hz), 7.57 (2H, d, J = 8.3 Hz).

LC / MS [Condition 1]: retention time 3.24 minutes; m / z 649.0 [M + H] ⁺ (ESI positive ion mode), m / z 683.1 [M + Cl] ⁻ , 693.1 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 455
3-{[(1r, 4r) -4- (4-Benzoylpiperidine-1-carbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone Preparation of acid 2,2,2-trifluoroethyl (Compound No. 455)

3-methyl-1-[(2,2,2-trifluoroethoxy) carbonyl obtained in Reference Example 454-2 instead of 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene ] The reaction was carried out in substantially the same manner as in Example 255 except that 1H-imidazole-3-ium iodide was used to give the title compound (25 mg, yield 53%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 12.3 Hz), 1.47-2.00 (4H, m), 2.48 (1H, tt, J = 1.11. 7, 3.1 Hz), 2.82 (1H, t, J = 11.7 Hz), 3.12 (2H, d, J = 7.2 Hz), 3.21 (1H, t, J = 13.5 Hz) ), 3.28 (2H, s), 3.35 (2H, q, J = 11.9 Hz), 3.52 (1H, tt, J = 10.8, 3.9 Hz), 3.86-4 .09 (3H, m), 4.34-4.66 (3H, m), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7.4 Hz) , 7.94 (2H, d, J = 7.4 Hz).

LC / MS [Condition 1]: Retention time 4.23 minutes; m / z 593.8 [M + H] ⁺ (ESI positive ion mode), m / z 628.0 [M + Cl] ⁻ , 637.9 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 456
6- [1-((1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -3-yl] methyl} cyclohexanecarbonyl) azetidin-3-yloxy] nicotinonitrile (Compound No. 456) Obtained in Reference Example 381-2 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was conducted in substantially the same manner as in Example 402 except that 6- (azetidin-3-yloxy) nicotinonitrile was used to give the title compound (16 mg, yield 33%) as a white powder. .

¹ H-NMR (CDCl ₃ ) δ: 0.91-1.10 (2H, m), 1.41-1.85 (9H, m), 1.91 (2H, br d, J = 12.7 Hz) ), 2.12 (1H, tt, J = 11.9, 3.3 Hz), 2.52-2.71 (4H, m), 3.07 (2H, d, J = 7.8 Hz), 3 .21 (2H, s), 3.75 (2H, s), 4.05 (1H, dd, J = 11.1, 4.1 Hz), 4.14 (1H, dd, J = 9.8, 4.1 Hz), 4.40 (1 H, dd, J = 11.1, 7.0 Hz), 4.56 (1 H, dd, J = 9.8, 7.0 Hz), 5.42 (1 H, tt) , J = 7.0, 4.1 Hz), 6.90 (1H, d, J = 8.6 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.85 (1H, dd, J = 8.6, 2.5H ), 8.45 (1H, d, J = 2.5Hz).

LC / MS [Condition 1]: Retention time 2.98 min; m / z 604.9 [M + H] ⁺ (ESI positive ion mode), m / z 649.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 457-1
Production of 5-[(trifluoromethyl) pyridin-2-yl] methanol 5- (trifluoromethyl) picolinaldehyde (0.24 g, 1.4 mmol) obtained in Reference Example 389 was added to chloroform (6. 0 mL), sodium triacetoxyborohydride (0.51 g, 2.4 mmol) was added at room temperature, and the mixture was stirred at room temperature for 70 minutes. After completion of the reaction, water (10 mL), saturated aqueous sodium hydrogen carbonate solution (20 mL) and chloroform (60 mL) were added, and the organic layer was separated. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure, followed by silica gel column chromatography [filler: HI-FLASH (registered trademark) COLUMNsilica gel 40 μm manufactured by Yamazen Co., Ltd., developing solvent: hexane / ethyl acetate = 9. / 1 → 0/1] to give the title compound (0.24 g, 100% yield) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 3.48 (1H, br s), 4.86 (2H, s), 7.44 (1H, d, J = 8.3 Hz), 7.94 (1H, d, J = 8.3 Hz), 8.85 (1H, s).

LC / MS [Condition 1]: Retention time 2.03 minutes; m / z 177.9 [M + H] ⁺ (ESI positive ion mode)

Reference Example 457-2
Preparation of 2-{[5- (trifluoromethyl) pyridin-2-yl] methyl} isoindoline-1,3-dione Obtained in Reference Example 457-1 instead of ethyl 6- (hydroxymethyl) nicotinate The reaction was carried out in substantially the same manner as in Reference Example 431-1 except that 5-[(trifluoromethyl) pyridin-2-yl] methanol was used, and the title compound (0.31 g, yield 73) was obtained. %) As a white powder.

¹ H-NMR (CDCl ₃ ) δ: 5.08 (2H, s), 7.42 (1H, d, J = 8.2 Hz), 7.67-8.00 (5H, m), 8.77 (1H, s).

LC / MS [Condition 1]: Retention time 4.13 minutes; m / z 306.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 457-3
Preparation of [5- (trifluoromethyl) pyridin-2-yl] methanamine Reference Example 457 instead of ethyl 5-[(1,3-dioxoisoindoline-2-yl) methyl] pyrazine-2-carboxylate -2, substantially the same as Reference Example 433-2, except that 2-{[5- (trifluoromethyl) pyridin-2-yl] methyl} isoindoline-1,3-dione was used. The reaction was performed to give the title compound (0.10 g, yield 57%) as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ: 4.07 (2H, s), 7.45 (1H, d, J = 8.2 Hz), 7.89 (1H, dd, J = 8.2, 1. 8 Hz), 8.83 (1 H, br s).

LC / MS [Condition 1]: Retention time 0.51 min; m / z 177.0 [M + H] ⁺ (ESI positive ion mode)

Example 457
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } -N-{[5- (Trifluoromethyl) pyridin-2-yl] methyl} cyclohexanecarboxamide (Compound No. 457) Reference Example 457 instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride The reaction was conducted in substantially the same manner as in Example 402 except that [5- (trifluoromethyl) pyridin-2-yl] methanamine obtained in -3 was used to give the title compound (11 mg, yield 23% ) Was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, dq, J = 2.9, 13.1 Hz), 1.41-1.85 (7H, m), 1.86-2.04 ( 4H, m), 2.17 (1H, tt, J = 11.9, 3.7 Hz), 2.52-2.74 (4H, m), 3.09 (2H, d, J = 7.4 Hz) ), 3.22 (2H, s), 3.75 (2H, s), 4.62 (2H, d, J = 5.7 Hz), 6.70 (1H, br t, J = 4.9 Hz) , 7.22 (2H, d, J = 6.1 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.90 (1H, d, J = 8.2 Hz), 8.81 ( 1H, s).

LC / MS [Condition 1]: Retention time 3.02 minutes; m / z 605.6 [M + H] ⁺ (ESI positive ion mode), m / z 650.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 458
(1r, 4r) -4-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } -N-[(6-Fluoropyridin-3-yl) methyl] cyclohexanecarboxamide) (Compound No. 458)

Example 402 is substantially the same as Example 402 except that (6-fluoropyridin-3-yl) methanamine obtained in Reference Example 443-3 is used instead of 6- (piperidin-4-yloxy) nicotinonitrile hydrochloride. The reaction was performed in the same manner to obtain the title compound (15 mg, yield 34%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 0.99 (2H, dq, J = 3.3, 12.6 Hz), 1.40-1.63 (3H, m), 1.64-1.83 ( 4H, m), 1.91 (4H, d, J = 12.7 Hz), 2.07 (1H, tt, J = 12.1, 3.5 Hz), 2.50-2.69 (4H, m ), 3.06 (2H, d, J = 7.4 Hz), 3.22 (2H, s), 3.74 (2H, s), 4.41 (2H, d, J = 5.7 Hz), 6.14 (1H, t, J = 5.9 Hz), 6.88 (1H, dd, J = 8.2, 2.9 Hz), 7.22 (2H, d, J = 6.1 Hz), 7 .73 (1H, td, J = 8.1, 2.6 Hz), 8.09 (1H, s).

LC / MS [Condition 1]: Retention time 2.45 minutes; m / z 555.9 [M + H] ⁺ (ESI positive ion mode), m / z 554.1 [MH] ⁻ , m / z 600.1 [M + HCOO ] ^- (ESI negative ion mode)

Example 459
4- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [4.5] decan-3-yl} methyl) nicotinoyl] piperazine- Preparation of ethyl 1-carboxylate (Compound No. 459) The reaction was conducted in substantially the same manner as in Example 111 except that ethyl piperazine-1-carboxylate (commercially available) was used instead of tetrahydrofurfurylamine to give the title compound ( 18 mg, 78% yield) was obtained as a pale orange amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 6.7 Hz), 1.71-1.89 (2H, m), 1.97 (2H, d, J = 13. 5Hz), 2.46-2.62 (4H, br m), 3.35 (2H, s), 3.38-3.61 (6H, br m), 3.57 (2H, s), 3 .62-3.88 (2H, br m), 4.17 (2H, q, J = 7.2 Hz), 4.57 (2H, s), 7.38 (1H, d, J = 7.8 Hz) ), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 7.8, 2.0 Hz) , 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.88 minutes; m / z 590.0 [M + H] ⁺ (ESI positive ion mode), m / z 634.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 460
1- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [4.5] decan-3-yl} methyl) nicotinoyl] piperidine- Preparation of 4-carbonitrile (Compound No. 460) The reaction was conducted in substantially the same manner as in Example 111 except that piperidine-4-carbonitrile (commercially available) was used instead of tetrahydrofurfurylamine to give the title compound (25 mg, Quantitative) was obtained as a pale orange amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.64-2.03 (8H, m), 2.45-2.63 (4H, br m), 2.92-3.02 (1H, m), 3.36 (2H, s), 3.39-4.02 (4H, m), 3.57 (3H, s), 4.58 (2H, s), 7.37 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.57 (2H, d, J = 7.8 Hz), 7.74 (1H, dd, J = 8.2, 2) .0Hz), 8.59 (1H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 1.90 minutes; m / z 541.9 [M + H] ⁺ (ESI positive ion mode), m / z 540.0 [M−H] ⁻ , 586.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 461
4- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [4.5] decan-3-yl} methyl) nicotinamide] piperidine Preparation of ethyl-1-carboxylate (Compound No. 461) The reaction was carried out in substantially the same manner as in Example 111 except that ethyl 4-aminopiperidine-1-carboxylate (commercially available) was used instead of tetrahydrofurfurylamine. The title compound (26 mg, quantitative) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.45 (2H, dq, J = 4.0, 12.7 Hz), 1.70-1. 84 (2H, m), 1.88-2.10 (4H, m), 2.40-2.64 (0H, br m), 2.95 (2H, t, J = 11.9 Hz), 3 .33 (2H, s), 3.56 (2H, s), 3.99-4.24 (5H, m), 4.58 (2H, s), 6.29 (1H, d, J = 7) .8 Hz), 7.36 (1 H, d, J = 7.8 Hz), 7.43 (2 H, d, J = 7.8 Hz), 7.57 (2 H, d, J = 8.2 Hz), 8 .09 (1H, dd, J = 8.2, 2.0 Hz), 8.91 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 604.0 [M + H] ⁺ (ESI positive ion mode), m / z 602.1 [M−H] ⁻ , 648.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 462
N- (furan-2-ylmethyl) -6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [4.5] decan-3-yl } Preparation of methyl) nicotinamide (Compound No. 462) The reaction was conducted in substantially the same manner as in Example 111 except that furan-2-ylmethanamine (commercially available) was used instead of tetrahydrofurfurylamine. 23 mg, quantitative) was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.76 (2H, dt, J = 12.7, 7.0 Hz), 1.96 (2H, d, J = 12.7 Hz), 2.40-2. 62 (4H, br m), 3.32 (2H, s), 3.56 (2H, s), 4.58 (2H, s), 4.66 (2H, d, J = 5.3 Hz), 6.32 (1H, d, J = 3.3 Hz), 6.36 (1H, dd, J = 3.3, 2.0 Hz), 6.42-6.53 (1H, m), 7.37 (1H, d, J = 8.2 Hz), 7.39 (1H, dd, J = 1.6, 0.8 Hz), 7.43 (2H, d, J = 7.8 Hz), 7.57 ( 2H, d, J = 7.8 Hz), 8.09 (1H, dd, J = 8.2, 2.0 Hz), 8.93 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.82 minutes; m / z 528.9 [M + H] ⁺ (ESI positive ion mode), m / z 527.0 [MH] ⁻ (ESI negative ion mode)

Example 463
3-{[5- (4,4-Difluoropiperidin-1-carbonyl) pyridin-2-yl] methyl} -8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [ 4.5] Preparation of decan-2-one (Compound No. 463) Reaction substantially in the same manner as in Example 111 except that 4,4-difluoropiperidine hydrochloride (commercially available) and triethylamine were used instead of tetrahydrofurfurylamine. To give the title compound (26 mg, quantitative) as a pale yellow amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.80 (2H, td, J = 13.8, 6.7 Hz), 1.84-2.23 (4H, br m), 1.98 (2H, d , J = 13.8 Hz), 2.44-2.64 (4H, m), 3.36 (2H, s), 3.43-3.98 (4H, m), 3.57 (2H, s) ), 4.58 (2H, s), 7.38 (1H, d, J = 8.2 Hz), 7.44 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.76 (1H, dd, J = 8.2, 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.92 minutes; m / z 552.9 [M + H] ⁺ (ESI positive ion mode), m / z 551.1 [M−H] ⁻ , 597.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 464
6- {1- [6-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-dizaspiro [4.5] decan-3-yl} methyl) nicotinoyl Preparation of azetidin-3-yloxy} nicotinonitrile (Compound No. 464) Instead of using tetrahydrofurfurylamine, 6- (azetidin-3-yloxy) nicotinonitrile obtained in Reference Example 381-2 was used. Reacted essentially as in Example 111 to give the title compound (17 mg, 69%) as a pale orange amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.77 (2H, dt, J = 13.5, 6.5 Hz), 1.97 (2H, d, J = 13.5 Hz), 2.41-2. 67 (4H, br m), 3.34 (2H, s), 3.56 (2H, s), 4.23-4.39 (2H, br m), 4.58 (2H, s), 4 61-4.79 (2H, br m), 5.49 (1H, tt, J = 7.0, 2.5 Hz), 6.92 (1H, d, J = 9.0 Hz), 7.37 (1H, d, J = 8.2 Hz), 7.43 (2H, d, J = 8.2 Hz), 7.57 (2H, d, J = 8.2 Hz), 7.86 (1H, dd, J = 9.0, 2.5 Hz), 7.98 (1H, dd, J = 8.2, 2.0 Hz), 8.44 (1H, d, J = 2.5 Hz), 8.80 (1H , D, J = 2.0 Hz .

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 607.0 [M + H] ⁺ (ESI positive ion mode), m / z 651.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 465
5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl}} methyl) pyrazine-2-carboxamide ( Preparation of Compound No. 465) 3-[(5-Carbamoylpyrazin-2-yl) methyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-obtained in Example 446 Dissolve t-butyl 8-carboxylate (43 mg, 0.11 mmol) in methanol (2.0 mL), add a 10% hydrogen chloride-methanol solution (0.28 mL) at room temperature, and at room temperature for 1 day. Stir. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The obtained white solid was dissolved in N, N-dimethylformamide (1.0 mL), and triethylamine (0.037 mL, 0.26 mmol) and 4- (trifluoromethyl) benzyl bromide (29 mg, 0.11 mmol) at room temperature. ) And stirred at room temperature for 1 day. After completion of the reaction, ethyl acetate and water were added, and the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The obtained reaction residue was purified by silica gel column chromatography [filler: FL100D manufactured by Fuji Silysia, developing solvent: chloroform / methanol = 30/1] to give the title compound (2.9 mg, yield 6.0%). Obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.79 (3H, ddd, J = 13.9, 12.7, 6.5 Hz), 1.97 (2H, d, J = 12.7 Hz), 2. 42-2.68 (4H, br m), 3.41 (2H, s), 3.57 (2H, s), 4.66 (2H, s), 5.64 (1H, br s), 7 .43 (2H, d, J = 8.2 Hz), 7.52-7.64 (1H, br m), 7.57 (2H, d, J = 8.2 Hz), 8.58 (1H, d , J = 1.3 Hz), 9.34 (1H, d, J = 1.3 Hz).

LC / MS [Condition 1]: Retention time 0.80 min; m / z 449.9 [M + H] ⁺ (ESI positive ion mode), m / z 448.0 [M−H] ⁻ , 493.7 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 466
Preparation of 3- [4- (4-benzoylpiperidine-1-carbonyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one hydrochloride 2-oxo-3-[(( 1r, 4r) -4-{[(Tetrahydrofuran-2-yl) methyl] carbamoyl} cyclohexyl) methyl] -1-oxa-3,8-diazaspiro [4.5] decan-8-carboxylate instead of t-butyl 3- [4- (4-benzoylpiperidine-1-carbonyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carvone obtained in Example 158 The reaction was carried out substantially in the same manner as in Example 3 except for using t-butyl acid to obtain the title compound (1.1 g, quantitative) as a colorless amorphous product.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.70-2.14 (6H, m), 2.25 (2H, t, J = 9.8 Hz), 2.92-4.02 (10H, m), 4.44 (2H, s), 4.67 (1H, br s), 7.30 (2H, d, J = 7.4 Hz), 7.36-7.54 (4H, m), 7.59 (1H, t, J = 7.4 Hz), 7.94 (2H, d, J = 7.0 Hz), 9.70 (1H, s).
LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 461.9 [M + H] ⁺ (ESI positive ion mode)

Example 466
4-({3- [4- (4-Benzoylpiperidine-1-carbonyl) benzyl] -2-oxo-1-oxa-3,8-diaza-spiro [4.5] decan-8-yl} methyl) Preparation of -3,5-difluorobenzonitrile (Compound No. 466) (1r, 4r) -4-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl ] -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide hydrochloride instead of 3- [4- (4-benzoylpiperidine-1-carbonyl) benzyl] -1- obtained in Reference Example 466 Using oxa-3,8-diaza-spiro [4.5] decan-2-one hydrochloride and 3,5-difluoro instead of 3,5-bis (trifluoromethyl) benzaldehyde Except using 4-formyl-benzonitrile (commercially available) is carried out the same reaction as substantially Example 235 to give the title compound (21.4 mg, 70% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.54-2.03 (8H, m), 2.44-2.70 (4H, br m), 3.03-3.26 (2H, m), 3.10 (2H, s), 3.49-3.61 (1H, m), 3.73 (2H, s), 3.76-3.97 (1H, br m), 4.43 (2H , S), 4.50-4.82 (1H, br m), 7.21 (2H, d, J = 5.7 Hz), 7.29 (2H, d, J = 7.8 Hz), 7. 41 (2H, d, J = 7.8 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.95 (2H, d , J = 7.4 Hz).

LC / MS [Condition 1]: retention time 3.30 minutes; m / z 613.0 [M + H] ⁺ (ESI positive ion mode), m / z 647.0 [M + Cl] ⁻ , 657.1 [M + HCOO] ⁻ (ESI Negative ion mode)

Reference Example 467-1
(1r, 4r) -4-({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl ]} Production of methyl) cyclohexanecarboxylate Substantially Reference Example except that 2-methoxy-4- (trifluoromethyl) benzaldehyde (commercially available) is used instead of 3,5-difluoro-4-formylbenzonitrile The reaction was carried out in the same manner as 398-1 to obtain the title compound (0.68 g, yield 84%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.3, 12.7 Hz), 1.41 (2H, dq, J = 3.3, 13.1 Hz), 1. 50-2.09 (9H, m), 2.25 (1H, tt, J = 12.3, 3.3 Hz), 2.48-2.76 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.60 (2H, s), 3.66 (3H, s), 3.86 (3H, s), 7.05 (1H) , Br s), 7.20 (1H, d, J = 7.8 Hz), 7.46 (1H, d, J = 7.8 Hz).

LC / MS [Condition 1]: retention time 3.14 minutes; m / z 499.0 [M + H] ⁺ (ESI positive ion mode)

Reference Example 467-2
(1r, 4r) -4-({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) Production of cyclohexanecarboxylic acid (1r, 4r) -4-({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1--) obtained in Reference Example 467-1 Oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylate methyl (0.65 g, 1.3 mmol) was dissolved in 1,4-dioxane and 1.0 M aqueous sodium hydroxide solution was dissolved. (1.9 mL) was added and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to distill off 1,4-dioxane, and water (2.0 mL) was added. 1.0M hydrochloric acid was added until the pH reached 6, and the precipitated solid was collected by filtration to give the title compound (0.59 g, yield 94%) as a white powder.

LC / MS [Condition 1]: Retention time 2.82 minutes; m / z 484.8 [M + H] ⁺ (ESI positive ion mode), m / z 483.0 [MH] ⁻ (ESI negative ion mode)

Example 467
4- {1-[(1r, 4r) -4-({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl} methyl) cyclohexanecarbonyl] azetidin-3-yloxy} benzonitrile (Compound No. 467) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) )] Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanic acid (1r, 4r) -4- obtained in Reference Example 467-2 ({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid The reaction was conducted in substantially the same manner as in Example 10 except that 4- (azetidin-3-yloxy) benzonitrile hydrochloride obtained in Reference Example 383-2 was used instead of tetrahydrofurfurylamine. 33 mg, 84% yield) was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, q, J = 11.9 Hz), 1.53 (2H, q, J = 13.5 Hz), 1.62-1.87 ( 7H, m), 1.94 (2H, d, J = 12.9 Hz), 2.13 (1H, tt, J = 12.2, 3.3 Hz), 2.52-2.68 (4H, m ), 3.10 (2H, d, J = 7.3 Hz), 3.25 (2H, s), 3.60 (2H, s), 3.86 (3H, s), 4.05 (1H, dd, J = 10.9, 4.3 Hz), 4.20 (1H, dd, J = 9.2, 3.3 Hz), 4.39 (1H, dd, J = 10.9, 6.6 Hz) , 4.55 (1H, dd, J = 9.6, 6.9 Hz), 4.99 (1H, tt, J = 6.3, 3.3 Hz), 6.81 (2H, d, J = 8) .6Hz), .06 (1H, s), 7.20 (1H, d, J = 7.9 Hz), 7.47 (1H, d, J = 7.9 Hz), 7.62 (2H, d, J = 8. 3 Hz).

LC / MS [condition 1]: retention time 3.26 minutes; m / z 641.1 [M + H] ⁺ (ESI positive ion mode), m / z 685.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 468
(1r, 4r) -4-({8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 468) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl ) -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid, (1r, 4r) -4-({ 8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid It except by performing the same reaction as substantially Example 10 to give the title compound (31 mg, 89% yield) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.02 (2H, qd, J = 11.5, 2.9 Hz), 1.48 (2H, qd, J = 13.5, 3.3 Hz), 1.58-1.67 (1H, m), 1.72-2.03 (12H, m), 2.04 (1H, tt, J = 11.5, 4.1 Hz), 2.54-2 .67 (4H, m), 3.09 (2H, d, J = 7.4 Hz), 3.11 (1H, ddd, J = 13.9, 7.0, 4.5 Hz), 3.25 ( 2H, s), 3.58 (1H, ddd, J = 13.5, 6.5, 3.3 Hz), 3.60 (2H, s), 3.75 (1H, dt, J = 8.2) 7.0 Hz), 3.85 (1H, dt, J = 8.2, 6.1 Hz), 3.87 (3H, s), 3.94 (1H, qd, J = 7.0, 2. 9 Hz), 5. 9 (1H, t, J = 5.7 Hz), 7.06 (1H, s), 7.20 (1H, d, J = 8.2 Hz), 7.47 (1H, d, J = 7.4 Hz) ).

LC / MS [Condition 1]: Retention time 2.90 minutes; m / z 567.9 [M + H] ⁺ (ESI positive ion mode), m / z 612.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 469
8- [2-methoxy-4- (trifluoromethyl) benzyl] -3-({(1r, 4r) -4- [4- (quinolin-4-yl) piperazin-1-carbonyl] cyclohexyl} methyl)- Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 469) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) (1r, 4r) -4- () obtained in Reference Example 467-2 instead of [benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid {8- [2-methoxy-4- (trifluoromethyl) benzyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid is converted to tetrahydro F The reaction was conducted in substantially the same manner as in Example 10 except that 4- (piperazin-1-yl) quinoline dihydrochloride obtained in Reference Example 278-2 was used instead of furylamine to give the title compound (22 mg Yield 51%) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.08 (2H, q, J = 11.5 Hz), 1.61 (2H, q, J = 13.5 Hz), 1.61-1.70 ( 1H, m), 1.74-1.90 (6H, m), 1.91-2.01 (2H, m), 2.52 (1H, tt, J = 12.3, 3.7 Hz), 2.54-2.67 (4H, m), 3.12 (2H, d, J = 7.4 Hz), 3.16-3.27 (4H, m), 3.27 (2H, s), 3.60 (2H, s), 3.73-3.95 (4H, m), 3.86 (3H, s), 6.85 (1H, d, J = 4.9 Hz), 7.06 ( 1H, s), 7.20 (1H, d, J = 7.4 Hz), 7.47 (1H, d, J = 7.8 Hz), 7.52 (1H, ddd, J = 8.2, 7) .0, 1.2 Hz), .69 (1H, ddd, J = 8.2, 6.5, 1.6 Hz), 8.03 (1H, d, J = 8.6 Hz), 8.08 (1H, d, J = 8.2 Hz) ), 8.77 (1H, d, J = 4.9 Hz).

LC / MS [Condition 1]: Retention time 2.07 minutes; m / z 679.9 [M + H] ⁺ (ESI positive ion mode), m / z 724.3 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 470-1
(1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of methyl 3-yl) methyl] cyclohexanecarboxylate Substantially Reference Example 398 except that 6- (trifluoromethyl) nicotinaldehyde (commercially available) was used instead of 3,5-difluoro-4-formylbenzonitrile. The reaction was conducted in the same manner as for -1 to give the title compound (1.1 g, yield 87%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.02 (2H, dq, J = 3.3, 12.9 Hz), 1.41 (2H, dq, J = 3.3, 13.1 Hz), 1. 51-1.66 (1H, m), 1.68-1.86 (4H, m), 1.88-2.08 (4H, m), 2.25 (1H, tt, J = 12.3) , 3.6 Hz), 2.49-2.65 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.26 (2H, s), 3.61 (2H, s), 3.66 (3H, s), 7.65 (1H, d, J = 7.8 Hz), 7.83 (1H, d, J = 7.8 Hz), 8.68 (1H, br s) ).

LC / MS [Condition 1]: Retention time 2.75 minutes; m / z 469.7 [M + H] ⁺ (ESI positive ion mode), m / z 467.8 [M−H] ⁻ , m / z 503.7 [M + Cl ] ⁻ 513.8 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 470-2
(1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decane- Preparation of 3 -yl) methyl] cyclohexanecarboxylic acid 3-{[(1r, 4r) -4- (methoxycarbonyl) cyclohexyl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] Instead of t-butyl decane-8-carboxylate, (1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridine] obtained in Reference Example 470-1 was used. [3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] reacts in substantially the same manner as in Reference Example 2-3 except that methyl cyclohexanecarboxylate is used. And title it Things a (0.51 g, 100% yield) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, dq, J = 3.7, 12.3 Hz), 1.42 (2H, dq, J = 3.3, 13.0 Hz), 1. 51-1.67 (1H, m), 1.80 (4H, dd, J = 13.9, 9.0 Hz), 1.94 (2H, d, J = 13.0 Hz), 2.06 (2H , D, J = 13.0 Hz), 2.28 (1H, tt, J = 12.3, 3.7 Hz), 2.50-2.67 (4H, br m), 3.10 (2H, d , J = 7.4 Hz), 3.27 (2H, s), 3.62 (2H, s), 7.64 (1H, d, J = 8.2 Hz), 7.83 (1H, d, J = 8.2 Hz), 8.67 (1H, s).

LC / MS [Condition 1]: Retention time 0.94 minutes; m / z 456.0 [M + H] ⁺ (ESI positive ion mode), m / z 454.1 [MH] ⁻ (ESI negative ion mode)

Example 470
3-{[(1r, 4r) -4- (4,4-difluoropiperidine-1-carbonyl) cyclohexyl] methyl} -8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1 Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 470) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl ) -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid, (1r, 4r) -4-[( 2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylic acid Tetrahydr The reaction was carried out substantially in the same manner as in Example 10 except that 4,4-difluoropiperidine hydrochloride and triethylamine were used instead of furfurylamine to obtain the title compound (33 mg, yield 90%) as a white solid. .

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.06 (2H, q, J = 11.4 Hz), 1.56 (2H, q, J = 12.9 Hz), 1.60-1.67 ( 1H, m), 1.79 (6H, d, J = 12.2 Hz), 1.95 (6H, d, J = 12.9 Hz), 2.46 (1H, tt, J = 11.9, 3) .3 Hz), 2.48-2.67 (4 H, m), 3.11 (2 H, d, J = 7.3 Hz), 3.27 (2 H, s), 3.59 (2 H, brt, J = 7.3 Hz), 3.61 (2H, s), 3.72 (2H, brt, J = 5.6 Hz), 7.65 (1H, d, J = 7.9 Hz), 7.84 (1H) , D, J = 6.9 Hz), 8.68 (1H, s).

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 558.9 [M + H] ⁺ (ESI positive ion mode), m / z 603.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 471
3-({(1r, 4r) -4- [4- (trifluoromethyl) piperidine-1-carbonyl] cyclohexyl} methyl) -8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} Preparation of 1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 471) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl ) Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanic acid (1r, 4r) -4- obtained in Reference Example 470-2 [(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylic Acid The reaction was carried out in substantially the same manner as in Example 10 except that 4- (trifluoromethyl) piperidine hydrochloride and triethylamine were used in place of lahydrofurfurylamine to give the title compound (36 mg, 94% yield) in white Obtained as a solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 12.2 Hz), 1.37-1.67 (5H, m), 1.72-1.86 (6H, m), 1.87-2.02 (4H, m), 2.15-2.35 (1H, m), 2.38-2.53 (2H, m), 2.54-2.64 ( 4H, m), 3.02 (1H, t, J = 13.2 Hz), 3.11 (2H, d, J = 7.3 Hz), 3.27 (2H, s), 3.62 (2H, s), 3.99 (1H, d, J = 11.6 Hz), 4.76 (1H, d, J = 12.6 Hz), 7.65 (1H, d, J = 7.9 Hz), 7. 84 (1H, d, J = 7.6 Hz), 8.68 (1H, s).

LC / MS [Condition 1]: retention time 3.16 minutes; m / z 590.9 [M + H] ⁺ (ESI positive ion mode), m / z 635.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 472
4- (1-{(1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [ 4.5] Preparation of Decan-3-yl) methyl] cyclohexanecarbonyl} piperidin-4-ylamino) benzonitrile (Compound No. 472) (1r, 4r) -4-({2-oxo-8- [4- ( (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid, instead of (1r, 4r) obtained in Reference Example 470-2 -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl ] Cyclohexane The rubonic acid was reacted in the same manner as in Example 10 except that 4- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Reference Example 441-2 and triethylamine were used in place of tetrahydrofurfurylamine. To give the title compound (30 mg, 71% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.3 Hz), 1.37 (2H, q, J = 11.9 Hz), 1.47-1.67 ( 3H, m), 1.71-1.86 (6H, m), 1.94 (2H, d, J = 13.1 Hz), 2.10 (2H, brt, J = 13.1 Hz), 2. 46 (1H, tt, J = 11.9, 3.3 Hz), 2.52-2.65 (4H, m), 2.83 (1H, t, J = 11.5 Hz), 3.11 (2H , D, J = 7.4 Hz), 3.19 (1H, t, J = 11.9 Hz), 3.27 (2H, s), 3.50-3.64 (1H, m), 3.61 (2H, s), 3.90 (1H, d, J = 14.3 Hz), 4.09 (1H, d, J = 7.4 Hz), 4.54 (1H, d, J = 13.5 Hz) 6.56 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.65 (1H, d, J = 7.8 Hz), 7.84 (1H , D, J = 8.2 Hz), 8.68 (1H, s).

LC / MS [Condition 1]: Retention time 3.14 minutes; m / z 639.0 [M + H] ⁺ (ESI positive ion mode), m / z 683.2 [M + HCOO] ⁻ (ESI negative ion mode)

Example 473
1-{(1r, 4r) -4-[(2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5 ] Decan-3-yl) methyl] cyclohexanecarbonyl} piperidine-4-carbonitrile (Compound No. 473) (1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] ) -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid, (1r, 4r) -4-[( 2-oxo-8-{[6- (trifluoromethyl) pyridin-3-yl] methyl} -1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] cyclohexanecarboxylic acid , Tet Except using 4-cyano-piperidine instead of tetrahydrofurfuryl amine is carried out the same reaction as substantially Example 10 to give the title compound (35 mg, 96% yield) as a pale yellow solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.05 (2H, q, J = 11.5 Hz), 1.55 (2H, q, J = 11.9 Hz), 1.57-1.67 ( 1H, m), 1.70-2.00 (12H, m), 2.43 (1H, tt, J = 11.9, 3.3 Hz), 2.49-2.66 (4H, m), 2.90 (1H, dtt, J = 7.4, 4.1, 4.1 Hz), 3.11 (2H, d, J = 7.4 Hz), 3.27 (2H, s), 3.38 −3.87 (4H, m), 3.62 (2H, s), 7.65 (1H, d, J = 7.8 Hz), 7.84 (1H, d, J = 7.4 Hz), 8 .68 (1H, s).

LC / MS [Condition 1]: Retention time 2.12 minutes; m / z 547.8 [M + H] ⁺ (ESI positive ion mode), m / z 592.1 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 474-1
Production of methyl 4-[(2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl) methyl] benzoate 3- [4- ( Methoxycarbonyl) benzyl] -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-9-carboxylate t-butyl (0.35 g, 0.84 mmol) in methanol (0.5 mL) 4M hydrogen chloride-dioxane solution (5.0 mL) was added thereto, and the mixture was stirred for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. Chloroform (10 mL) and saturated aqueous sodium hydrogen carbonate solution (5.0 mL) were added to the obtained yellow oil and shaken to separate the organic layer. The aqueous layer was extracted three times with chloroform (10 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give the title compound as a yellow oil (0.30 g). The obtained oil was used in the next reaction without purification.

Reference Example 474-2
4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl} Production of methyl benzoate A solution of methyl 4-[(2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl) methyl] benzoate (0.30 g) obtained in Reference Example 474-1 (2.0 mL) with 3,5-difluoro-4-formylbenzonitrile (purchased from Aldrich) (0.15 g, 0.92 mmol) and sodium triacetoxyborohydride (purchased from Aldrich) (0. 27 g, 1.3 mmol) was added and stirred for 2 hours. To the reaction mixture, an aqueous sodium hydrogen carbonate solution (5.0 mL) and ethyl acetate (5.0 mL) were added and shaken to separate the organic layer, and then the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure. Diethyl ether was added to the obtained yellow oil, and the precipitated solid was collected by filtration to give the title compound as a yellow solid (0.28 g, yield 71%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58-1.71 (2H, m), 1.76-1.90 (2H, m), 1.82 (2H, t, J = 6. 1 Hz), 2.58-2.70 (4H, m), 3.18 (2H, t, J = 6.3 Hz), 3.73 (2H, s), 3.92 (3H, s), 4 .61 (2H, s), 7.22 (2H, d, J = 6.1 Hz), 7.35 (2H, d, J = 7.8 Hz), 8.01 (2H, d, J = 8. 2 Hz).

LC / MS [Condition 1]: Retention time 1.71 minutes; m / z 469.8 [M + H] ⁺ (ESI positive ion mode)

Reference Example 474-3
4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl} benzoic acid production reference 4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl obtained in Example 474-2 ] To a tetrahydrofuran solution (1.0 mL) of methyl} methyl benzoate (82 mg, 0.17 mmol), potassium trimethylsilanolate (purchased from Aldrich) (37 mg, 0.26 mmol) was added and stirred for 4 hours. A 4M hydrogen chloride-dioxane solution (0.13 mL) was added to the reaction mixture, ethyl acetate (5.0 mL) and a saturated aqueous sodium hydrogen carbonate solution (5.0 mL) were added, and the mixture was shaken to separate the aqueous layer. To the obtained aqueous layer, 1 M hydrochloric acid (5.0 mL) and ethyl acetate were added and shaken to separate the organic layer, and then the aqueous layer was extracted twice with ethyl acetate (10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give the title compound as a yellow solid (32 mg, 41% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.74-1.94 (6H, m), 2.68-1.90 (4H, br m), 3.21 (2H, t, J = 6 .5Hz), 3.85 (2H, s), 4.62 (2H, s), 7.22 (2H, d, J = 6.5 Hz), 7.36 (2H, d, J = 8.6 Hz) ), 8.03 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: retention time 0.70 min; m / z 455.8 [M + H] ⁺ (ESI positive ion mode), m / z 453.9 [MH] ⁻ (ESI negative ion mode)

Example 474
4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl} -N-[( Preparation of Tetrahydrofuran-2-yl) methyl] benzamide (Compound No. 474) 4-({2-oxo-9- [4- (trifluoromethyl) benzyl] -1-oxa-3,9-diazaspiro [5.5 ] Undecan-3-yl} methyl) 4-{[9- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-] obtained in Reference Example 474-3 instead of benzoic acid The reaction was carried out in substantially the same manner as in Example 218 except that 3,9-diazaspiro [5.5] undecan-3-yl] methyl} benzoic acid was used to give the title compound as a yellow oil (14 mg, yield). 47%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.54-1.75 (3H, m), 1.77-2.10 (7H, m), 2.60-2.78 (4H, m) 3.17 (2H, t, J = 6.1 Hz), 3.32 (1H, ddd, J = 13.9, 7.4, 4.5 Hz), 3.72-3.94 (3H, m ), 3.75 (2H, s), 4.07 (1H, dq, J = 3.3, 7.4 Hz), 4.59 (2H, s), 6.54 (1H, t, J = 4) .9 Hz), 7.20 (2H, d, J = 6.1 Hz), 7.34 (2H, d, J = 8.6 Hz), 7.75 (2H, d, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 0.94 minutes; m / z 538.9 [M + H] ⁺ (ESI positive ion mode), m / z 536.9 [MH] ⁻ (ESI negative ion mode)

Example 475
6- [1- (4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl } Preparation of Benzoyl) azetidin-3-yloxy] nicotinonitrile (Compound No. 475) Except for using 6- (azetidin-3-yloxy) nicotinonitrile synthesized in Reference Example 381-2 instead of tetrahydrofurfurylamine Was carried out in substantially the same manner as in Example 474 to give the title compound as a colorless oil (14 mg, yield 70%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.58-1.73 (2H, m), 1.77-1.92 (2H, m), 1.82 (2H, t, J = 6. 2 Hz), 2.56-2.72 (4H, m), 3.19 (2H, t, J = 6.5 Hz), 3.74 (2H, s), 4.22-4.33 (2H, m), 4.51-4.73 (2H, br m), 4.58 (2H, s), 5.42-5.52 (1H, m), 6.91 (1H, d, J = 8) .6 Hz), 7.22 (2H, d, J = 6.5 Hz), 7.33 (2H, d, J = 7.8 Hz), 7.62 (2H, d, J = 8.2 Hz), 7 .85 (1H, dd, J = 8.6, 2.5 Hz), 8.44 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 2.86 minutes; m / z 612.9 [M + H] ⁺ (ESI positive ion mode), m / z 657.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 476
4-[(3- {4- [4- (3-Cyanophenoxy) piperidine-1-carbonyl] benzyl} -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-9-yl ) Preparation of methyl] -3,5-difluorobenzonitrile (Compound No. 476) Instead of tetrahydrofurfurylamine, 3- (piperidin-4-yloxy) benzonitrile hydrochloride and triethylamine synthesized in Reference Example 281-2 were used. Except for the above, the reaction was carried out in substantially the same manner as in Example 474 to give the title compound as a colorless oil (18 mg, yield 86%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.59-1.73 (2H, m), 1.75-2.13 (8H, m), 2.60-2.70 (4H, m) 3.19 (2H, t, J = 6.2 Hz), 3.31-3.51 (1H, br m), 3.55-4.02 (3H, br m), 3.74 (2H, s), 4.52-4.67 (1H, m), 4.58 (2H, s), 7.12-7.18 (2H, m), 7.22 (2H, d, J = 5. 6 Hz), 7.26 (1 H, d, J = 7.4 Hz), 7.33 (2 H, d, J = 8.0 Hz), 7.39 (1 H, t, J = 7.4 Hz), 7. 39 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 3.18 minutes; m / z 640.0 [M + H] ⁺ (ESI positive ion mode), m / z 684.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 477
4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl} -N- (furan Preparation of -2-ylmethyl) benzamide (Compound No. 477) The reaction was conducted in substantially the same manner as in Example 474 except that furfurylamine (purchased from Tokyo Chemical Industry Co., Ltd.) was used instead of tetrahydrofurfurylamine. The compound was obtained as a colorless oil (22 mg, 92% yield).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.57-1.87 (6H, m), 2.56-2.68 (4H, m), 3.16 (2H, t, J = 6. 5Hz), 3.73 (2H, s), 4.58 (2H, s), 4.63 (2H, d, J = 5.7 Hz), 6.30 (1H, d, J = 3.0 Hz) , 6.32-6.36 (1H, m), 6.57 (1H, t, J = 5.3 Hz), 7.21 (2H, d, J = 6.1 Hz), 7.33 (2H, d, J = 8.6 Hz), 7.38 (1H, d, J = 1.2 Hz), 7.76 (2H, d, J = 8.6 Hz).

LC / MS [Condition 1]: Retention time 1.69 minutes; m / z 534.9 [M + H] ⁺ (ESI positive ion mode), m / z 533.0 [M−H] ⁻ (ESI negative ion mode)

Reference Example 478-1
3-({5- [4- (4-Cyanophenoxy) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- Production of t-butyl 8-carboxylate

Substantially except that 4- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in Reference Example 264-2 was used instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out in the same manner as in Reference Example 444-3 to give the title compound (46 mg, yield 53%) as a yellow powder.

LC / MS [Condition 1]: Retention time 4.13 minutes; m / z 520.7 [M-isobutene + H] ⁺ , 476.8 [M-isobutene-CO ₂ + H] ⁺ (ESI positive ion mode), m / z 575 0.0 [M−H] ⁻ , 621.0 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 478-1
4- (1- {5-[(2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] pyrazin-2-carbonyl} piperidin-4-yloxy) benzonitrile Production of hydrochloride

3-({5- [4- (4-Fluorobenzoyl) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane- 3-({5- [4- (4-Cyanophenoxy) piperidin-1-carbonyl] pyrazin-2-yl} methyl) obtained in Reference Example 478-1 instead of t-butyl 8-carboxylate The reaction was conducted in substantially the same manner as in Reference Example 444-4 except that t-butyl 2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8-carboxylate was used. The compound (45 mg, quantitative) was obtained as a yellow oil.

LC / MS [Condition 1]: retention time 1.54 minutes; m / z 476.8 [M + H] ⁺ (ESI positive ion mode), m / z 474.9 [MH] ⁻ (ESI negative ion mode)

Example 478
4- {1- [5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) pyrazine Preparation of -2-carbonyl] piperidin-4-yloxy} benzonitrile (Compound No. 478) 4- (1- {5-[(2-oxo-1-oxa-3,8 ) obtained in Reference Example 478-2 -Diazaspiro [4.5] decan-3-yl) methyl] pyrazin-2-carbonyl} piperidin-4-yloxy) benzonitrile hydrochloride (20 mg, 0.040 mmol) and 1- (bromomethyl) -4- (trifluoro Methyl) benzene (commercially available) (10.20 mg, 0.040 mmol) was dissolved in N, N-dimethylformamide, and triethylamine (13 μl, 0.090 mmol) was added. It was vigorously stirred for 3 hours at room temperature Te. After completion of the reaction, water was added to the reaction mixture, followed by extraction three times with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: ethyl acetate / methanol = 9/1], and 4- {1 -[5-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) pyrazine-2-carbonyl Piperidin-4-yloxy} benzonitrile (6.6 mg, yield 26%) was obtained as a colorless liquid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.83-2.16 (6H, m), 2.19-2.48 (2H, brm), 2.78-3.00 (2H, m) , 3.01-3.25 (2H, br m), 3.48 (2H, s), 3.63 (1H, ddd, J = 13.5, 6.5, 4.9 Hz), 3.74. -4.09 (5H, m), 4.63 (2H, s), 4.73 (1H, tt, J = 5.3, 2.9 Hz), 6.98 (2H, d, J = 8. 6 Hz), 7.56-7.71 (6 H, m), 8.53 (1 H, d, J = 1.6 Hz), 8.88 (1 H, d, J = 1.6 Hz).

LC / MS [condition 1]: retention time 3.32 minutes; m / z 634.8 [M + H] ⁺ (ESI positive ion mode), m / z 632.9 [MH] ⁻ (ESI negative ion mode)

Example 479
4-{[3-({5- [4- (4-Cyanophenoxy) piperidin-1-carbonyl] pyrazin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 479) 4- (1- {5-[(2-oxo-1- ) obtained in Reference Example 478-2 To the oxa-3,8-diazaspiro [4.5] decan-3-yl) methyl] pyrazin-2-carbonyl} piperidin-4-yloxy) benzonitrile hydrochloride (15 mg, 0.030 mmol) was added an aqueous sodium bicarbonate solution. And extracted three times with chloroform. After the combined organic layers were concentrated under reduced pressure, 3,5-difluoro-4-formylbenzonitrile (5.8 mg, 0.040 mmol) was added to the resulting residue, and then dissolved in dichloromethane. Sodium triacetoxyborohydride (9.5 mg, 0.050 mmol) was added to the reaction mixture, and the mixture was vigorously stirred at room temperature for 10 minutes. After completion of the reaction, water was added and extracted twice with chloroform. The combined organic layers were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [filler: silica gel 60 (0.040-0.063 mm) manufactured by Merck GMBH, developing solvent: ethyl acetate / methanol = 9/1]. After concentration under reduced pressure, hexane was added to the residue, concentrated to dryness under reduced pressure, and 4-{[3-({5- [4- (4-cyanophenoxy) piperidin-1-carbonyl] pyrazin-2-yl} Methyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (14 mg, 75% yield) was obtained as a colorless liquid. It was.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.79 (2H, dt, J = 13.5, 6.5 Hz), 1.87-2.17 (6H, m), 2.64 (4H, br m), 3.39 (3H, s), 3.63 (1H, ddd, J = 13.1, 5.7, 4.5 Hz), 3.76 (2H, s), 3.82 (1H) , Ddd, J = 13.1, 8.2, 3.7 Hz), 3.88 (1H, ddd, J = 13.1, 8.2, 3.7 Hz), 3.99 (1H, ddd, J = 13.1, 6.5, 4.9 Hz), 4.62 (2H, s), 4.73 (1H, tt, J = 5.7, 2.9 Hz), 6.98 (2H, d, J = 9.0 Hz), 7.23 (2H, d, J = 5.7 Hz), 7.61 (2H, d, J = 8.6 Hz), 8.55 (1H, d, J = 1.6 Hz) ), 8.9 (1H, d, J = 1.6Hz).

LC / MS [Condition 1]: Retention time 3.11 min; m / z 627.8 [M + H] ⁺ (ESI positive ion mode), m / z 625.9 [MH] ⁻ (ESI negative ion mode)

Example 480
3,5-difluoro-4-{[3-({5- [4- (6-fluorobenzo [d] isoxazol-3-yl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2- Preparation of Oxo-1-oxa-3,8-diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 480) (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Instead, the reaction was carried out in substantially the same manner as in Example 392 except that 6-fluoro-3- (piperidin-4-yl) benzo [d] isoxazole (commercially available) was used, and the title compound (24 mg, yield) 83%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.76 (2H, dt, J = 13.5, 7.4 Hz), 1.96 (2H, br d, J = 13.1 Hz), 1.97-2 .37 (4H, br m), 2.48-1.75 (4H, br m), 3.03-3.43 (2H, br m), 3.32 (2H, s), 3.40 ( 1H, tt, J = 11.1, 3.7 Hz), 3.74 (2H, s), 3.75-4.03 (1H, br m), 4.56-4.86 (1 H, br m ), 4.57 (2H, s), 7.10 (1H, dt, J = 2.5, 8.8 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.28 (1H , Dd, J = 8.8, 2.5 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.63 (1H, dd, J = 8.6, 4.9 Hz), 7. 78 (1H, dd J = 8.2,2.0Hz), 8.64 (1H, d, J = 2.0Hz).

LC / MS [Condition 1]: Retention time 3.20 minutes; m / z 644.8 [M + H] ⁺ (ESI positive ion mode), m / z 688.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 481
N- (benzo [d] [1,3] dioxol-5-ylmethyl) -6-{[8- (4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8- Preparation of diazaspiro [4.5] decan-3-yl] methyl} nicotinamide (Compound No. 481)

Example 392 substantially except that benzo [d] [1,3] dioxol-5-ylmethanamine (commercially available) was used instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride. The title compound (20 mg, yield 77%) was obtained as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.74 (2H, dt, J = 13.5, 7.4 Hz), 1.94 (2H, br d, J = 13.1 Hz,), 2.50− 2.70 (4H, br m), 3.29 (2H, s), 3.73 (2H, s), 4.55 (2H, d, J = 5.3 Hz), 4.55 (2H, s) ), 5.96 (2H, s), 6.46 (1H, br t, J = 5.0 Hz), 6.78 (3H, d, J = 7.8 Hz), 6.82 (1H, dd, J = 7.8, 1.6 Hz), 6.85 (1H, d, J = 1.6 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.34 (1H, d, J = 8.2 Hz), 8.08 (1H, dd, J = 8.2, 2.0 Hz), 8.91 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.71 minutes; m / z 575.8 [M + H] ⁺ (ESI positive ion mode), m / z 573.8 [MH] ⁻ (ESI negative ion mode)

Example 482
4-{[3-({5- [4- (4-Cyanophenoxy) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 482) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, Reference Example 264-2 The reaction was conducted in substantially the same manner as in Example 392 except that 4- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in 1 above was used to give the title compound (25 mg, yield 89%) as a white solid Obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.74-2.14 (4H, br m), 1.76 (2H, dt, J = 12.7, 7.8 Hz), 1.96 (2H, br d, J = 12.7 Hz), 2.51-2.72 (4H, m), 3.29-4.03 (4H, br m), 3.31 (2H, s), 3.74 (2H) , S), 4.56 (2H, s), 4.65-4.75 (1H, m), 6.97 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.60 (2H, d, J = 8.6 Hz), 7.76 (1H, dd, J = 8.2) 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.08 minutes; m / z 626.8 [M + H] ⁺ (ESI positive ion mode), m / z 670.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 483
6- [1- (6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Nicotinoyl) piperidin-4-yloxy] Production of nicotinonitrile (Compound No. 483) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, the 6- product obtained in Reference Example 293-2 The reaction was carried out substantially in the same manner as in Example 392 except that (piperidin-4-yloxy) nicotinonitrile hydrochloride was used to give the title compound (24 mg, yield 86%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.71-2.22 (4H, br m), 1.76 (2H, dt, J = 13.9, 6.5 Hz), 1.95 (2H, d , J = 13.5 Hz), 2.49-2.72 (4H, br m), 3.30-3.52 (1H, br m), 3.31 (2H, s), 3.55-3 .84 (2H, br m), 3.74 (2H, s), 3.95-4.18 (1H, br m), 4.56 (2H, s), 5.43 (1H, tt, J = 7.4, 3.7 Hz), 6.82 (1H, d, J = 9.0 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.76 (2H, dd, J = 8.2, 2.5 Hz), 7.81 (2H, dd, J = 8.6, 2.5 Hz), 8.46 (1H, d , J = 2.5 Hz), 8.62 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 2.96 minutes; m / z 627.8 [M + H] ⁺ (ESI positive ion mode), m / z 671.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 484
6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- (4 -Cyanobenzyl) Preparation of nicotinamide (Compound No. 484) except that 4- (aminomethyl) benzonitrile hydrochloride (commercially available) is used instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Was carried out in substantially the same manner as in Example 392 to give the title compound (23 mg, yield 92%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.74 (2H, dt, J = 13.9, 7.4 Hz), 1.93 (2H, br d, J = 13.1 Hz), 2.49-2 .69 (4H, br m), 3.31 (2H, s), 3.73 (2H, s), 4.55 (2H, s), 4.71 (2H, d, J = 5.7 Hz) 6.86 (1H, br t, J = 5.7 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.2 Hz), 7.65 (2H, d, J = 8.2 Hz), 8.12 (1H, dd, J = 8.2, 2.0 Hz), 8.95 ( 1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.53 minutes; m / z 556.7 [M + H] ⁺ (ESI positive ion mode), m / z 554.8 [MH] ⁻ (ESI negative ion mode)

Example 485
3,5-difluoro-4-{[2-oxo-3-({5- [4- (quinolin-4-yl) piperazin-1-carbonyl] pyridin-2-yl} methyl) -1-oxa-3 , 8-Diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 485) instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Reference Example 278- The reaction was carried out in substantially the same manner as in Example 392 except that 4- (piperazin-1-yl) quinoline dihydrochloride obtained in 2 was used, and the title compound (25 mg, yield 88%) was cream-colored. Obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.77 (2H, dt, J = 13.1, 7.0 Hz), 1.96 (2H, br d, J = 13.5 Hz), 2.51-2 .73 (4H, br m), 3.10-3.45 (4H, br m), 3.32 (2H, s), 3.57-3.89 (2H, br m), 3.75 ( 2H, s), 3.91-4.27 (2H, br m), 4.58 (2H, s), 6.87 (1H, d, J = 4.9 Hz), 7.22 (2H, d , J = 6.1 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.53 (1H, t, J = 7.8 Hz), 7.70 (1H, t, J = 7. 4 Hz), 7.82 (1 H, dd, J = 7.8, 2.0 Hz), 8.02 (1 H, d, J = 8.2 Hz), 8.09 (1 H, d, J = 8.6 Hz) ), 8.67 (1H , D, J = 2.0 Hz), 8.78 (1H, d, J = 4.9 Hz).

LC / MS [Condition 1]: retention time 0.53 min; m / z 638.0 [M + H] ⁺ , 319.5 [M + 2H] ²⁺ (ESI positive ion mode), m / z 681.8 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 486
4-{[3-({5- [4- (2-chlorophenylamino) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 486) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, Reference Example 286-2 The title compound (29 mg, quantitative yield) was purified in substantially the same manner as in Example 392 except that the N- (2-chlorophenyl) piperidin-4-amine dihydrochloride obtained in 1 was used. Obtained as an amorphous material.

¹ H-NMR (CDCl ₃ ) δ: 1.38-1.72 (2H, br m), 1.78 (2H, dt, J = 13.9, 7.4 Hz), 1.98 (2H, br d, J = 13.9 Hz), 2.03-2.36 (2H, br m), 2.50-2.78 (4H, br m), 3.11-3.34 (2H, br m) 3.33 (2H, s), 3.55-3.77 (2H, br m), 3.76 (2H, s), 4.27 (1 H, d, J = 7.8 Hz), 4. 47-4.67 (1H, br m), 4.58 (2H, s), 6.68 (1H, t, J = 7.4 Hz), 6.70 (1H, d, J = 7.8 Hz) 7.16 (1H, t, J = 7.8 Hz), 7.24 (2H, d, J = 5.7 Hz), 7.29 (1H, d, J = 7.4 Hz), 7.37 ( 1H, br d, J = 8.6 Hz), 7.78 (1 H, d, J = 7.9 Hz), 8.63 (1 H, br s).

LC / MS [Condition 1]: Retention time 3.32 minutes; m / z 634.8 [M + H] ⁺ (ESI positive ion mode), m / z 679.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 487
4-{[3-({5- [4- (2,4-difluorobenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 487) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, (2, The reaction was carried out in substantially the same manner as in Example 392 except that 4-difluorophenyl) (piperidin-4-yl) methanone hydrochloride (commercially available) was used, and the title compound (27 mg, yield 92%) was cream colored Obtained as an amorphous material.

¹ H-NMR (CDCl ₃ ) δ: 1.64-1.83 (4H, m), 1.83-2.13 (2H, m), 1.95 (2H, br d, J = 13.1 Hz) ), 2.42-2.77 (4H, br m), 2.95-3.30 (2H, br m), 3.31 (2H, s), 3.34-3.50 (1H, m ), 3.57-3.94 (1H, br m), 3.74 (2H, s), 4.42-4.80 (1H, br m), 4.56 (2H, s), 6. 90 (1H, dt, J = 2.5, 10.0 Hz), 7.00 (1H, t, J = 9.0 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.34 (1H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.6 Hz), 7.89 (1H, q, J = 8.2 Hz), 8.59 (1H, br s ).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 649.8 [M + H] ⁺ (ESI positive ion mode), m / z 693.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 488
4-{[3-({5- [4- (3-Cyanophenoxy) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 488) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, Reference Example 281-2 The title compound (29 mg, quantitative yield) was obtained as a colorless amorphous substance by carrying out the reaction substantially in the same manner as in Example 392 except that 3- (piperidin-4-yloxy) benzonitrile hydrochloride obtained in 1 above was used. Obtained as a thing.

¹ H-NMR (CDCl ₃ ) δ: 1.68-2.13 (4H, br m), 1.76 (2H, dt, J = 13.1, 7.4 Hz), 1.95 (2H, br d, J = 13.5 Hz), 2.50-2.72 (4H, br m), 3.31 (2H, s), 3.33-3.56 (1H, br m), 3.57- 3.78 (1H, br m), 3.74 (2H, s), 3.78-3.99 (2H, br m), 4.56 (2H, s), 4.59-4.69 ( 1H, m), 7.15 (1H, d, J = 7.8 Hz), 7.17 (1H, brs), 7.22 (2H, d, J = 6.5 Hz), 7.27 (1H , D, J = 7.8 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.76 (1H, dd, J = 8.2, 2.0H ), 8.61 (1H, d, J = 2.0Hz).

LC / MS [Condition 1]: Retention time 3.14 min; m / z 626.8 [M + H] ⁺ (ESI positive ion mode), m / z 670.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 489
4-{[3-({5- [4- (4-Chlorobenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 489) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride (4-chlorophenyl) The reaction was carried out substantially in the same manner as in Example 392 except that (piperidin-4-yl) methanone hydrochloride (commercially available) was used to give the title compound (27 mg, yield 92%) as a colorless amorphous product. .

¹ H-NMR (CDCl ₃ ) δ: 1.72-2.00 (4H, m), 1.76 (2H, dt, J = 12.7, 8.2 Hz), 1.96 (2H, br d , J = 13.9 Hz), 2.51-2.72 (4H, br m), 3.00-3.36 (2H, br m), 3.31 (2H, s), 3.45-3-3 .59 (1H, m), 3.67-3.94 (1H, br m), 3.74 (2H, s), 4.52-4.77 (1H, br m), 4.56 (2H) , S), 7.22 (2H, d, J = 5.7 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.47 (2H, d, J = 9.0 Hz), 7 .76 (1H, dd, J = 8.2, 2.5 Hz), 7.90 (2H, d, J = 9.0 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: retention time 3.24 minutes; m / z 647.8 [M + H] ⁺ (ESI positive ion mode), m / z 691.8 [M + HCOO] ⁻ (ESI negative ion mode)

Example 490
6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- (furan Preparation of -2-ylmethyl) nicotinamide (Compound No. 490) Substantially except that furan-2-ylmethanamine (commercially available) is used instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Specifically, the reaction was carried out in the same manner as in Example 392 to obtain the title compound (18 mg, yield 76%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.74 (2H, dt, J = 13.5, 7.4 Hz), 1.94 (2H, br d, J = 13.1 Hz), 2.51-2 .72 (4H, br m), 3.29 (2H, s), 3.73 (2H, s), 4.56 (2H, s), 4.66 (2H, d, J = 5.7 Hz) , 6.29-6.39 (2H, m), 6.39-6.51 (1H, br m), 7.22 (2H, d, J = 5.7 Hz), 7.36 (1H, d , J = 8.2 Hz), 7.39 (1 H, br s), 8.09 (1 H, dd, J = 8.2, 2.0 Hz), 8.92 (1 H, d, J = 2.0 Hz) ).

LC / MS [Condition 1]: Retention time 1.30 minutes; m / z 521.7 [M + H] ⁺ (ESI positive ion mode), m / z 519.9 [MH] ⁻ (ESI negative ion mode)

Example 491
4-{[3-({5- [3- (3-Cyanophenoxy) azetidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 491) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, Reference Example 390-2 The reaction was conducted in substantially the same manner as in Example 392 except that 3- (azetidin-3-yloxy) benzonitrile hydrochloride obtained in 1 above was used to give the title compound (16 mg, yield 59%) as a white solid Obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.75 (2H, dt, J = 13.5, 7.0 Hz), 1.95 (2H, br d, J = 13.1 Hz), 2.51-2 .73 (4H, br m), 3.31 (2H, s), 3.74 (2H, s), 4.22-4.44 (2H, br m), 4.56 (2H, s), 4.59-4.77 (2H, br m), 5.05 (1H, tt, J = 6.1, 3.7 Hz), 6.96-7.05 (2H, m), 7.22 ( 2H, d, J = 6.0 Hz), 7.33 (1H, dt, J = 7.8, 1.2 Hz), 7.37 (1H, d, J = 8.2 Hz), 7.42 (1H , T, J = 7.8 Hz), 7.98 (1H, dd, J = 8.2, 2.0 Hz), 8.72-8.84 (1H, m).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 598.8 [M + H] ⁺ (ESI positive ion mode), m / z 642.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 492
3,5-difluoro-4-({2-oxo-3-[(5- {4- [4- (trifluoromethyl) phenylamino] piperidin-1-carbonyl} pyridin-2-yl) methyl] -1 Preparation of -oxa-3,8-diazaspiro [4.5] decan-8-yl} methyl) benzonitrile (Compound No. 492) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The title compound was reacted in substantially the same manner as in Example 392 except that N- [4- (trifluoromethyl) phenyl] piperidin-4-amine dihydrochloride obtained in Reference Example 391-2 was used. (25 mg, 85% yield) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.29-1.69 (2H, br m), 1.75 (2H, dt, J = 13.5, 7.0 Hz), 1.95 (2H, d , J = 13.5 Hz), 1.99-2.35 (2H, br m), 2.48-2.74 (4H, m), 3.00-3.36 (2H, br m), 3 .30 (2H, s), 3.53-3.69 (1H, m), 3.65-3.88 (1H, br m), 3.74 (2H, s), 3.91 (1H, d, J = 7.8 Hz), 4.44-4.77 (3H, m), 4.54-4.57 (3H, m), 6.61 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 5.7 Hz), 7.35 (1H, d, J = 8.2 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.75 (1H , Dd, J = 7.8, 2 0Hz), 8.60 (1H, br s).

LC / MS [Condition 1]: retention time 3.50 min; m / z 669.0 [M + H] ⁺ (ESI positive ion mode), m / z 712.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 493
4-{[3-({5- [4- (3-cyano-4-fluorophenylamino) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8 -Preparation of diazaspiro [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 493) instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out in the same manner as in Example 392 except that 2-fluoro-5- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Reference Example 442-2 was used, and the title compound (25 mg Yield 86%) was obtained as a cream-colored amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.27-1.59 (2H, br m), 1.76 (2H, dt, J = 13.9, 7.4 Hz), 1.96 (2H, d , J = 13.5 Hz), 2.00-2.31 (2H, br m), 2.45-2.78 (4H, br m), 2.96-3.32 (2H, br m), 3.31 (2H, s), 3.41-3.57 (1H, m), 3.58-3.92 (1H, br m), 3.69 (1H, d, J = 8.2 Hz) 3.74 (2H, s), 4.42-4.81 (1H, br m), 4.47-4.75 (3H, m), 4.55 (2H, s), 6.67- 6.84 (2H, m), 7.02 (1H, t, J = 9.0 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.35 (1H, d, J = 8) .2 Hz), 7.75 ( H, dd, J = 8.2,2.0Hz), 8.60 (1H, d, J = 1.6Hz).

LC / MS [Condition 1]: Retention time 3.16 minutes; m / z 643.8 [M + H] ⁺ (ESI positive ion mode), m / z 688.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 494
3,5-difluoro-4-({2-oxo-3-[(5- {4- [4- (trifluoromethyl) phenylsulfonyl] piperidin-1-carbonyl} pyridin-2-yl) methyl] -1 Preparation of -oxa-3,8-diazaspiro [4.5] decan-8-yl} methyl) benzonitrile (Compound No. 494) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out in substantially the same manner as in Example 392 except that 4- [4- (trifluoromethyl) phenylsulfonyl] piperidine hydrochloride obtained in Reference Example 393-6 was used, and the title compound (27 mg, yield) was obtained. 84%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.66-1.88 (4H, m), 1.96 (2H, d, J = 13.1 Hz), 2.01-2.17 (2H, m) , 2.44-2.72 (4H, br m), 2.70-3.16 (2H, br m), 3.12-3.27 (1H, m), 3.31 (2H, s) 3.71-4.09 (1H, br m), 3.74 (2H, s), 4.55 (2H, br s), 4.58-5.00 (1H, br m), 7. 22 (2H, d, J = 5.7 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.71 (1H, dd, J = 7.8, 1.6 Hz), 7.88 (2H, d, J = 8.2 Hz), 8.03 (2H, d, J = 8.2 Hz), 8.55 (1H, s).

LC / MS [Condition 1]: Retention time 3.26 minutes; m / z 717.9 [M + H] ⁺ (ESI positive ion mode), m / z 761.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 495
6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- [3 , 3,3-trifluoro-2- (4-fluorophenyl) -2-hydroxypropyl] nicotinamide (Compound No. 495) instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Substantially the same as Example 392 except that 3-amino-1,1,1-trifluoro-2- (4-fluorophenyl) propan-2-ol obtained in Reference Example 434-2 was used. The reaction was performed to give the title compound (20 mg, yield 68%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.67-1.83 (2H, m), 1.93 (2H, br d, J = 13.5 Hz), 2.43-2.71 (4H, br m), 3.30 (2H, s), 3.72 (2H, s), 4.05 (1H, dd, J = 15.1, 7.0 Hz), 4.21 (1H, dd, J = 15.1, 6.1 Hz), 4.45 (2H, s), 5.88 (1 H, s), 7.07 (1 H, t, J = 8.6 Hz), 7.14-7.25 ( 3H, m), 7.36 (1H, t, J = 5.3 Hz), 7.63 (2H, dd, J = 8.2, 5.7 Hz), 7.98 (1H, dd, J = 8) .2, 2.0 Hz), 8.80 (1H, d, J = 2.0 Hz).

LC / MS [condition 1]: retention time 3.24 minutes; m / z 647.8 [M + H] ⁺ (ESI positive ion mode), m / z 645.9 [MH] ⁻ (ESI negative ion mode)

Reference Example 496-1
Preparation of 4- [2- (trifluoromethyl) quinolin-4-yl] piperazine-1-carboxylate t-butyl 4-chloro-2- (trifluoromethyl) quinoline (0.20 g, 0.86 mmol), piperazine N, N-Diisopropylethylamine (0.30 mL, 1.7 mmol) was added to a solution of t-butyl-1-carboxylate (0.24 g, 1.3 mmol) in N-methyl-2-pyrrolidone (2 mL), and the reaction mixture was added. Was allowed to stand at 120 ° C. for 5 hours, and then ethyl acetate (8 mL) and water (4 mL) were added. The organic layer was washed with water (4 mL × 2), concentrated to dryness under reduced pressure, and the residue was purified by recrystallization (n-hexane-ethyl acetate) to give the title compound (0.19 g, yield 57%). ) Was obtained as an amber solid.

LC / MS [Condition 2]: Retention time 3.77 minutes; m / z 382.0 [M + H] ⁺ , 326.0 [M-isobutene + H] ⁺ (ESI positive ion mode)

Reference Example 496-2
Preparation of 4- (piperazin-1-yl) -2- (trifluoromethyl) quinoline dihydrochloride Reference Example 496-1 instead of t-butyl 4- (quinolin-4-yl) piperazine-1-carboxylate The reaction was carried out in substantially the same manner as in Reference Example 278-2, except that t-butyl 4- [2- (trifluoromethyl) quinolin-4-yl] piperazine-1-carboxylate obtained in The title compound (0.30 g, quantitative yield) was obtained as a cream solid.

¹ H-NMR (DMSO-d ₆ ) δ: 3.36-3.48 (4H, m), 3.48-3.60 (4H, m), 7.37 (1H, s), 7.73 (1H, ddd, J = 8.2, 7.0, 1.2 Hz), 7.88 (1H, ddd, J = 8.6, 7.0, 1.2 Hz), 8.12 (1H, d , J = 8.6 Hz), 8.17 (1H, d, J = 8.2 Hz), 9.39 (2H, brs).

Example 496
3,5-difluoro-4-({2-oxo-3-[(5- {4- [2- (trifluoromethyl) quinolin-4-yl] piperazin-1-carbonyl} pyridin-2-yl) methyl ] -1-Oxa-3,8-diazaspiro [4.5] decan-8-yl} methyl) benzonitrile (Compound No. 496) (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Instead, the reaction was carried out in substantially the same manner as in Example 392 except that 4- (piperazin-1-yl) -2- (trifluoromethyl) quinoline dihydrochloride obtained in Reference Example 496-2 was used. The title compound (27 mg, 84% yield) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.79 (2H, dt, J = 13.5, 7.0 Hz), 1.97 (2H, d, J = 13.1 Hz), 2.51-2. 76 (4H, br m), 3.12-3.57 (2H, br m), 3.33 (2H, s), 3.63-4.25 (4H, br m), 3.76 (2H , S), 4.58 (2H, s), 7.17 (1H, s), 7.23 (2H, d, J = 6.1 Hz), 7.39 (1H, d, J = 8.2 Hz) ), 7.64 (1H, t, J = 7.4 Hz), 7.79 (1H, t, J = 7.8 Hz), 7.82 (1H, dd, J = 7.8, 1.6 Hz) , 8.05 (1H, d, J = 8.6 Hz), 8.20 (1H, d, J = 8.6 Hz), 8.67 (1H, d, J = 1.6 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 705.9 [M + H] ⁺ , 353.5 [M + 2H] ²⁺ (ESI positive ion mode), m / z 749.9 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 497
6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N- [3 , 3,3-Trifluoro-2-hydroxy-2- (6-methoxypyridin-3-yl) propyl] nicotinamide (Compound No. 497) (4-Fluorophenyl) (piperidin-4-yl) methanone hydrochloride Substantially other than using 3-amino-1,1,1-trifluoro-2- (6-methoxypyridin-3-yl) propan-2-ol obtained in Reference Example 437-2 instead of the salt Specifically, the reaction was carried out in the same manner as in Example 392 to obtain the title compound (17 mg, yield 57%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.75 (2H, dt, J = 12.3, 7.4 Hz), 1.94 (2H, br d, J = 13.9 Hz), 2.41-2 .73 (4H, br m), 3.31 (2H, s), 3.72 (2H, s), 3.92 (2H, s), 4.05 (1H, dd, J = 15.1, 7.0 Hz), 4.21 (1H, dd, J = 15.1, 5.7 Hz), 4.46 (2H, s), 6.03 (1H, s), 6.74 (1H, d, J = 9.0 Hz), 7.14-7.25 (3H, m), 7.56 (1H, br t, J = 4.9 Hz), 7.86 (1H, dd, J = 8.6) 2.5 Hz), 8.00 (1H, dd, J = 8.2, 2.0 Hz), 8.37 (1H, s), 8.83 (1H, s).

LC / MS [Condition 1]: Retention time 3.04 minutes; m / z 660.7 [M + H] ⁺ , 330.9 [M + 2H] ²⁺ (ESI positive ion mode), m / z 658.9 [M−H] ⁻ (ESI negative ion mode)

Example 498
4-{[3-({5- [4- (4-t-butylbenzoyl) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 498) Reference Example 333 instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out in substantially the same manner as in Example 392 except that (4-t-butylphenyl) (piperidin-4-yl) methanone hydrochloride obtained in -2 was used, and the title compound (30 mg, yield) (Quantitative) was obtained as a colorless amorphous.

¹ H-NMR (CDCl ₃ ) δ: 1.35 (9H, s), 1.73-2.15 (4H, br m), 1.76 (2H, dt, J = 13.5, 7.4 Hz) ), 1.96 (2H, br d, J = 13.5 Hz), 2.49-2.72 (4H, br m), 3.00-3.36 (2H, br m), 3.30 ( 2H, s), 3.48-3.65 (1H, m), 3.68-3.92 (1H, br m), 3.74 (2H, s), 4.53-4.75 (1H , Br m), 4.56 (2H, s), 7.22 (2H, d, J = 6.1 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.76 (1H, dd, J = 8.2, 2.0 Hz), 7.89 (2H, d, J = 8.4 Hz), 8.61 (1H, d , J = 2.0Hz)

LC / MS [Condition 1]: retention time 3.60 minutes; m / z 669.9 [M + H] ⁺ , 335.5 [M + 2H] ²⁺ (ESI positive ion mode), m / z 714.1 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 499
3,5-difluoro-4-{[3-({5- [4- (2-methoxyphenylamino) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3 , 8-Diazaspiro [4.5] decan-8-yl] methyl} benzonitrile (Compound No. 499) instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Reference Example 292 The reaction was conducted in substantially the same manner as in Example 392 except that N- (2-methoxyphenyl) piperidin-4-amine dihydrochloride obtained in 2 was used to give the title compound (23 mg, yield 81%) Was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.37-1.64 (2H, br m), 1.75 (2H, dt, J = 13.5, 6.9 Hz), 1.95 (2H, br d, J = 13.5 Hz), 2.01-2.28 (2H, br m), 2.54-2.70 (4H, br m), 3.07-3.32 (2H, br m) 3.30 (2H, s), 3.51-3.65 (1H, br m), 3.65-3.80 (1 H, br m), 3.74 (2H, s), 3.85 (3H, s), 4.12-4.25 (1H, br m), 4.49-4.64 (1H, br m), 4.56 (2H, s), 6.63 (1H, dd , J = 1.7, 7.6 Hz), 6.69 (1H, dt, J = 1.7, 7.9 Hz), 6.79 (1H, dd, J = 1.7, 7.9 Hz), 6.86 (1H dt, J = 1.7, 7.6 Hz), 7.22 (2H, d, J = 6.3 Hz), 7.35 (1H, d, J = 7.9 Hz), 7.75 (1H, dd) , J = 7.9, 2.3 Hz), 8.60 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.71 minutes; m / z 630.8 [M + H] ⁺ (ESI positive ion mode), m / z 675.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 500
4-[(3-{[5- (4-Benzylpiperidin-1-carbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane-8 -Il) methyl] -3,5-difluorobenzonitrile (Compound No. 500) Preparation (4-Fluorophenyl) (piperidin-4-yl) methanone hydrochloride instead of 4-benzylpiperidine (commercially available) The title compound (22 mg, yield 82%) was obtained as a cream amorphous product in substantially the same manner as in Example 392 except for the above.

¹ H-NMR (CDCl ₃ ) δ: 1.07-1.42 (2H, br m), 1.66-1.88 (4H, m), 1.94 (2H, br d, J = 13. 1 Hz), 2.43-2.70 (6H, br m), 2.65-2.85 (1 H, br m), 2.87-3.11 (1 H, br m), 3.28 (2H) , S), 3.56-3.76 (1H, br m), 3.74 (2H, s), 4.54 (2H, s), 4.58-4.78 (1H, br m), 7.14 (2H, d, J = 7.8 Hz), 7.17-7.25 (1 H, m), 7.22 (2H, d, J = 7.0 Hz), 7.27-7.37 (3H, m), 7.72 (1H, dd, J = 7.8, 2.0 Hz), 8.57 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.38 minutes; m / z 599.9 [M + H] ⁺ (ESI positive ion mode), m / z 644.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 501
4-{[3-({(1r, 4r) -4- [4- (3-cyanophenoxy) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [ 4.5] Production of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 501) (1r, 4r) -4-{[8- ( 4-cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} cyclohexanecarboxylic acid (20 mg, 0.045 mmol), 1 -Hydroxybenzotriazole (2 mg, 0.01 mmol) and 3- (piperidin-4-yloxy) benzonitrile hydrochloride (12 mg, 0.049) obtained in Reference Example 281-2 mol) in chloroform (1 mL) was added triethylamine (25 μL, 0.18 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (13 mg, 0.067 mmol) and the reaction mixture was allowed to cool to room temperature. Left for 5 days. After adding a solution of citric acid (26 mg) in water (1 mL), the organic layer was separated, washed with a solution of sodium bicarbonate (3 mg) in water (1 mL), concentrated to dryness under reduced pressure, and the title compound (27 mg , Yield 96%) was obtained as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, q, J = 12.7 Hz), 1.46-1.67 (3H, m), 1.68-2.03 (12H, m) 2.39-2.52 (1H, m), 2.52-2.73 (4H, br m), 3.09 (2H, d, J = 7.4 Hz), 3.22 (2H, s ), 3.37-3.53 (1H, m), 3.54-3.88 (3H, m), 3.75 (2H, s), 4.51-4.62 (1H, m), 7.10-7.18 (2H, m), 7.19-7.29 (3H, m), 7.39 (1H, t, J = 7.8 Hz).

LC / MS [Condition 1]: Retention time 3.36 minutes; m / z 631.8 [M + H] ⁺ (ESI positive ion mode), m / z 675.9 [M + HCOO] ⁻ (ESI negative ion mode)

Example 502
4-{[3-({(1r, 4r) -4- [4- (3-cyano-4-fluorophenylamino) piperidine-1-carbonyl] cyclohexyl} methyl) -2-oxo-1-oxa-3 , 8-Diazaspiro [4.5] decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 502) Reference instead of 3- (piperidin-4-yloxy) benzonitrile hydrochloride The reaction was carried out in substantially the same manner as in Example 501 except that 2-fluoro-5- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in Example 442-2 was used, and the title compound (29 mg, Yield quantitative) was obtained as a cream colored solid.

¹ H-NMR (CDCl ₃ ) δ: 1.04 (2H, q, J = 11.9 Hz), 1.32 (2H, q, J = 11.9 Hz), 1.47-1.67 (3H, m), 1.69-1.86 (4H, m), 1.92 (2H, br d, J = 13.5 Hz), 2.00-2.18 (3H, m), 2.46 (1H) , Tt, J = 11.6, 2.6 Hz), 2.53-2.72 (4H, m), 2.82 (1H, t, J = 11.6 Hz), 3.09 (2H, d, J = 7.6 Hz), 3.18 (1H, t, J = 12.9 Hz), 3.22 (2H, s), 3.36-3.51 (1H, m), 3.63 (1H, d, J = 8.3 Hz), 3.75 (2H, s), 3.89 (1H, br d, J = 13.9 Hz), 4.53 (1 H, br d, J = 13.2 Hz), 6.68- .80 (2H, m), 7.01 (1H, t, J = 8.6Hz), 7.22 (2H, d, J = 5.9Hz).

LC / MS [Condition 1]: retention time 3.34 min; m / z 648.8 [M + H] ⁺ (ESI positive ion mode), m / z 692.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 503-1
(1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Preparation of methyl decan-3-yl} methyl) cyclohexanecarboxylate Instead of 4- (trifluoromethyl) benzyl bromide, 1- (bromomethyl) -2,3,5,6-tetrafluoro-4- (tri The reaction was carried out substantially in the same manner as in Reference Example 6-2, except that fluoromethyl) benzene was used, to give the title compound (0.18 g, yield 52%) as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (2H, dq, J = 3.7, 13.1 Hz), 1.41 (2H, dq, J = 3.7, 13.1 Hz), 1. 50-1.64 (4H, m), 1.66-1.84 (4H, m), 1.98 (4H, dt, J = 22.2, 9.3 Hz), 2.25 (1 H, tt , J = 12.1, 3.5 Hz), 2.51-2.75 (4H, br m), 3.08 (2H, d, J = 7.4 Hz), 3.23 (2H, s), 3.66 (3H, s), 3.83 (2H, s).

LC / MS [Condition 1]: retention time 3.87 minutes; m / z 540.6 [M + H] ⁺ (ESI positive ion mode), m / z 539.0 [M−H] ⁻ , 584.9 [M + HCOO] ⁻ (ESI negative ion mode)

Reference Example 503-2
(1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Production of decan-3-yl} methyl) cyclohexanecarboxylic acid (1r, 4r) -4-({2-oxo-8- [2,3,5,6-) obtained in Reference Example 503-1 1 of methyl tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylate (0.16 g, 0.30 mmol) Water (0.30 mL) and 1M aqueous sodium hydroxide solution (0.33 mL) were added to a suspension of 1,4-dioxane (4 mL), and the mixture was stirred at room temperature for 1 day. Thereafter, water (1.0 mL) was added and the mixture was further stirred for 5 days. After concentration under reduced pressure and 1,4-dioxane was distilled off from the reaction mixture, 1M hydrochloric acid (0.33 mL) and chloroform (5 mL) were added to the residue to separate the organic layer. The organic layer was concentrated to dryness under reduced pressure to give the title compound (0.14 g, yield 87%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.03 (2H, q, J = 12.6 Hz), 1.42 (2H, q, J = 13.0 Hz), 1.51-1.65 (1H, m), 1.70-1.86 (4H, m), 1.94 (2H, br d, J = 13.9 Hz), 2.07 (2H, br d, J = 12.9 Hz), 2. 28 (1H, tt, J = 12.2, 3.0 Hz), 2.53-2.76 (4H, br m), 3.09 (2H, d, J = 7.9 Hz), 3.24 ( 2H, s), 3.84 (2H, s).

LC / MS [Condition 1]: Retention time 3.46 min; m / z 526.6 [M + H] ⁺ (ESI positive ion mode), m / z 524.8 [MH] ⁻ (ESI negative ion mode)

Example 503
3-({(1r, 4r) -4- [4- (pyrimidin-4-yl) piperazine-1-carbonyl] cyclohexyl} methyl) -8- [2,3,5,6-tetrafluoro-4- ( (Trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-2-one (Compound No. 503) (1r, 4r) -4 obtained in Reference Example 503-2 -({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl } Methyl) cyclohexanecarboxylic acid (20 mg, 0.038 mmol), 4- (piperazin-1-yl) pyrimidine dihydrochloride (10 mg, 0.042 mmol) and 1-hydroxybenzoic acid obtained in Reference Example 287-3 To a solution of triazole (2 mg, 0.01 mmol) in chloroform (1 mL) was added triethylamine (26 μL, 0.19 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (11 mg, 0.057 mmol). After standing at room temperature for 2 days, a solution of citric acid (22 mg) in water (1 mL) was added. The organic layer was separated, washed with a solution of sodium hydrogen carbonate (3 mg) in water (1 mL), and concentrated to dryness under reduced pressure to give the title compound (20 mg, yield 77%) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 1.06 (2H, q, J = 12.3 Hz), 1.49-1.69 (3H, m), 1.70-1.87 (6H, m) 1.93 (2H, br d, J = 13.5 Hz), 2.47 (1 H, br t, J = 11.5 Hz), 2.53-2.76 (4 H, m), 3.11 ( 2H, d, J = 7.4 Hz), 3.24 (2H, s), 3.55 to 3.68 (4H, br m), 3.66-3.80 (4H, br m), 3. 83 (2H, s), 6.52 (1H, d, J = 6.1 Hz), 8.26 (1H, d, J = 6.1 Hz), 8.63 (1H, s).

LC / MS [Condition 1]: Retention time 2.65 minutes; m / z 673.2 [M + H] ⁺ , 337.0 [M + 2H] ²⁺ (ESI positive ion mode), m / z 717.2 [M + HCOO] ⁻ (ESI Negative ion mode)

Example 504
4-{[3-({5- [3- (4-Cyanophenoxy) azetidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 504) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, Reference Example 383-2 The title compound (27 mg, quantitative yield) was obtained in the form of a cream-colored amorphous substance by substantially the same reaction as in Example 392 except that 4- (azetidin-3-yloxy) benzonitrile obtained in 1 was used. Got as.

¹ H-NMR (CDCl ₃ ) δ: 1.75 (2H, dt, J = 13.1, 7.8 Hz), 1.95 (2H, br d, J = 13.1 Hz), 2.50-2 .72 (4H, br m), 3.31 (2H, s), 3.74 (2H, s), 4.20-4.47 (2H, br m), 4.56 (2H, s), 4.59-4.76 (2H, br m), 5.08 (1H, tt, J = 6.5, 4.1 Hz), 6.82 (2H, d, J = 8.6 Hz), 7. 22 (2H, d, J = 5.7 Hz), 7.36 (1 H, d, J = 8.2 Hz), 7.62 (2H, d, J = 8.6 Hz), 7.98 (1H, dd) , J = 8.2, 2.5 Hz), 8.79 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 2.94 minutes; m / z 598.9 [M + H] ⁺ (ESI positive ion mode), m / z 643.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 505
6- [1- (6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl } Preparation of Nicotinoyl) azetidin-3-yloxy] nicotinonitrile (Compound No. 505) Instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride, the 6-obtained in Reference Example 381-2 The reaction was carried out substantially in the same manner as in Example 392 except that (azetidin-3-yloxy) nicotinonitrile was used to give the title compound (9 mg, yield 33%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.75 (2H, dt, J = 13.5, 7.4 Hz), 1.95 (2H, br d, J = 13.5 Hz), 2.47-2 .78 (4H, br m), 3.31 (2H, s), 3.74 (2H, s), 4.25-4.45 (2H, br m), 4.56 (2H, s), 4.56-4.86 (2H, br m), 5.43-5.58 (1H, m), 6.92 (1H, d, J = 8.2 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.86 (1H, dd, J = 8.2, 2.0 Hz), 7.98 (1H, dd, J = 8.2, 2.0 Hz), 8.44 (1H, d, J = 2.0 Hz), 8.80 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 2.73 minutes; m / z 600.0 [M + H] ⁺ (ESI positive ion mode), m / z 644.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 506
4-{[3-({5- [4- (4-Cyanophenylamino) piperidin-1-carbonyl] pyridin-2-yl} methyl) -2-oxo-1-oxa-3,8-diazaspiro [4 .5] Preparation of decan-8-yl] methyl} -3,5-difluorobenzonitrile (Compound No. 506) Reference Example 441 instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was conducted in substantially the same manner as in Example 392 except that 4- (piperidin-4-ylamino) benzonitrile dihydrochloride obtained in 2 was used to give the title compound (25 mg, yield 89%) as white Obtained as a solid.

¹ H-NMR (CDCl ₃ ) δ: 1.32-1.62 (2H, br m), 1.76 (2H, dt, J = 13.1, 7.4 Hz), 1.95 (2H, br d, J = 13.1 Hz), 2.01-2.32 (2H, br m), 2.49-2.72 (4H, br m), 2.99-3.39 (2H, br m) 3.30 (2H, s), 3.54-3.69 (1H, m), 3.62-3.94 (1H, br m), 3.74 (2H, s), 4.01- 4.16 (1H, br m), 4.50-4.78 (1 H, br m), 4.55 (2H, s), 6.57 (2H, d, J = 8.6 Hz), 7. 22 (2H, d, J = 6.1 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.75 (1H, dd) , J = 7.8, 2.0 Hz), 8.60 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 3.00 minutes; m / z 626.0 [M + H] ⁺ (ESI positive ion mode), m / z 670.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 507
4-[(3-{[5- (4,4-Difluoropiperidin-1-carbonyl) pyridin-2-yl] methyl} -2-oxo-1-oxa-3,8-diazaspiro [4.5] decane Preparation of -8-yl) methyl] -3,5-difluorobenzonitrile (Compound No. 507) 4,4-Difluoropiperidine hydrochloride instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out substantially in the same manner as in Example 392 except that (commercially available) was used, and the title compound (23 mg, yield 92%) was obtained as a cream-colored amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.76 (2H, dt, J = 13.1, 7.8 Hz), 1.95-2.22 (4H, br m), 1.96 (2H, d , J = 13.1 Hz), 2.51-2.74 (4H, br m), 3.31 (2H, s), 3.44-4.04 (4H, br m), 3.74 (2H) , S), 4.56 (2H, s), 7.22 (2H, d, J = 5.7 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.75 (1H, dd) , J = 7.8, 2.0 Hz), 8.61 (1H, d, J = 2.0 Hz).

LC / MS [Condition 1]: Retention time 1.52 minutes; m / z 545.9 [M + H] ⁺ (ESI positive ion mode), m / z 590.0 [M + HCOO] ⁻ (ESI negative ion mode)

Example 508
4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecan-3-yl] methyl} -N-[( Preparation of 3-methoxyisoxazol-5-yl) methyl] benzamide (Compound No. 508) 6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3, Instead of 8-diazaspiro [4.5] decan-3-yl] methyl} nicotinic acid,
4-{[9- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,9-diazaspiro [5.5] undecane-3 obtained in Reference Example 474-3 -Yl] methyl} benzoic acid and (3-methoxyisoxazole-5--5) obtained in Reference Example 401-3 instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride Yl) The reaction was carried out in substantially the same manner as in Example 392 except that methanamine was used to give the title compound (11 mg, yield 76%) as a colorless amorphous product.

¹ H-NMR (CDCl ₃ ) δ: 1.60-1.71 (2H, m), 1.73-1.92 (4H, m), 2.50-2.73 (4H, br m), 3.18 (2H, t, J = 6.5 Hz), 3.72 (2H, s), 3.96 (3H, s), 4.59 (2H, s), 4.64 (2H, d, J = 5.7 Hz), 5.89 (1 H, s), 6.70 (1 H, t, J = 6.1 Hz), 7.21 (2 H, d, J = 6.1 Hz), 7.36 ( 2H, d, J = 8.2 Hz), 7.76 (2H, d, J = 8.2 Hz).

LC / MS [Condition 1]: Retention time 1.42 minutes; m / z 565.8 [M + H] ⁺ (ESI positive ion mode), m / z 564.0 [MH] ⁻ (ESI negative ion mode)

Example 509
6-{[8- (4-Cyano-2,6-difluorobenzyl) -2-oxo-1-oxa-3,8-diazaspiro [4.5] decan-3-yl] methyl} -N-{[ Preparation of 5- (trifluoromethyl) pyridin-2-yl] methyl} nicotinamide) (Compound No. 509) Reference Example 457-3 instead of (4-fluorophenyl) (piperidin-4-yl) methanone hydrochloride The reaction was carried out in substantially the same manner as in Example 392 except that [5- (trifluoromethyl) pyridin-2-yl] methanamine was used to give the title compound (4.9 mg, yield 18%) Was obtained as a white powder.

¹ H-NMR (CDCl ₃ ) δ: 1.75 (2H, dt, J = 12.7, 6.1 Hz), 1.95 (2H, d, J = 12.7 Hz), 2.54-2. 65 (4H, br m), 3.31 (2H, s), 3.74 (2H, s), 4.59 (2H, s), 4.85 (2H, d, J = 4.9 Hz), 7.22 (2H, d, J = 6.1 Hz), 7.40 (1H, d, J = 8.2 Hz), 7.48 (1H, d, J = 8.2 Hz), 7.59 (1H , T, J = 4.9 Hz), 7.96 (1H, dd, J = 8.2, 2.0 Hz), 8.17 (1H, dd, J = 8.2, 2.0 Hz), 8. 84 (1H, s), 9.02 (1H, d, J = 2.5 Hz).

LC / MS [Condition 1]: Retention time 2.88 min; m / z 600.9 [M + H] ⁺ (ESI positive ion mode), m / z 599.0 [MH] ⁻ (ESI negative ion mode)

Example 510
(1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4. 5] Preparation of decan-3-yl} methyl) -N-[(tetrahydrofuran-2-yl) methyl] cyclohexanecarboxamide (Compound No. 510) (1r, 4r) -4-({2-oxo-8- [4 Instead of-(trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid, it was obtained in Reference Example 503-2 (1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decane -3-Ile} But using Le) cyclohexanecarboxylic acid by performing the same reaction as substantially Example 10 to give the title compound (27 mg, 78% yield) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.01 (2H, qd, J = 12.9, 3.3 Hz), 1.39-1.64 (4H, m), 1.69-1. 83 (4H, m), 1.84 to 2.00 (7H, m), 2.03 (1H, tt, J = 11.9, 3.6 Hz), 2.52-2.74 (4H, m ), 3.08 (2H, d, J = 7.3 Hz), 3.11 (3H, ddd, J = 10.0, 7.6, 4.3 Hz), 3.23 (2H, s), 3 .58 (1H, ddd, J = 13.5, 6.3, 3.0 Hz), 3.75 (1H, dt, J = 7.6, 6.9 Hz), 3.79-3.89 (1H M), 3.83 (2H, s), 3.94 (1H, qd, J = 7.3, 3.0 Hz), 5.80 (1H, t, J = 5.3 Hz).

LC / MS [condition 1]: retention time 3.46 minutes; m / z 610.0 [M + H] ⁺ (ESI positive ion mode), m / z 654.1 [M + HCOO] ⁻ (ESI negative ion mode)

Example 511
4- {1-[(1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) benzyl] -1-oxa-3, Preparation of 8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarbonyl] azetidin-3-yloxy} benzonitrile (Compound No. 511)

(1r, 4r) -4-({2-oxo-8- [4- (trifluoromethyl) benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexane (1r, 4r) -4-({2-oxo-8- [2,3,5,6-tetrafluoro-4- (trifluoromethyl) obtained in Reference Example 503-2 instead of carboxylic acid] [Benzyl] -1-oxa-3,8-diazaspiro [4.5] decan-3-yl} methyl) cyclohexanecarboxylic acid instead of tetrahydrofurfurylamine 4- (azetidine-) obtained in Reference Example 383-2 The reaction was carried out in substantially the same manner as in Example 10 except that 3-yloxy) benzonitrile was used to give the title compound (31 mg, yield 81%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.00 (2H, q, J = 12.6 Hz), 1.52 (2H, q, J = 12.3 Hz), 1.59-1.68 ( 1H, m), 1.69-1.86 (6H, m), 1.93 (2H, d, J = 14.2 Hz), 2.12 (1H, tt, J = 12.2, 3.6 Hz) ), 2.53-2.75 (4H, m), 3.08 (2H, d, J = 7.3 Hz), 3.22 (2H, s), 3.83 (2H, s), 4. 05 (1H, dd, J = 10.6, 4.0 Hz), 4.20 (1H, dd, J = 9.4, 3.8 Hz), 4.39 (1H, dd, J = 10.7, 6.8 Hz), 4.55 (1H, dd, J = 8.3, 7.3 Hz), 4.99 (1H, tt, J = 6.3, 3.6 Hz), 6.81 (2H, d , J = 8. Hz), 7.62 (2H, d, J = 8.3Hz).

LC / MS [Condition 1]: Retention time 3.87 minutes; m / z 683.0 [M + H] ⁺ (ESI positive ion mode), m / z 727.2 [M + HCOO] ⁻ (ESI negative ion mode)

In the present invention, in order to evaluate and select the target compound, it is desirable that the direct action on the adiponectin receptor can be verified. Examples of such an evaluation system include an evaluation system using cells in which adiponectin receptor is stably expressed, and an evaluation system using genetically modified animals (so-called knockout mice, etc.). Moreover, an invention compound can be evaluated efficiently by using these evaluation systems appropriately.

Test Example: Measurement of ACC Phosphorylation in Human AdipoR1 Stable Expression CHO Cell Line The ACC phosphorylation ability of the compound of the present invention, which is a compound of the present invention, was measured by constructing a human AdipoR1 stable expression CHO cell line (CHOR1). In the description of activity, a Rigel compound (WO2008 / 083124 Compound 94) reported as a low molecular weight compound exhibiting an adiponectin receptor agonist-like action was used as an index.

(1) Cells and culture The human AdipoR1 stable expression CHO cell line (CHOR1) stably expresses human AdipoR1. In addition, the CHO cell which is the parent strain is less responsive to the Rigel compound (Compound 94) than CHOR1. The above two types of cells were subcultured in a F-12 medium containing 10% bovine serum using a CO ₂ incubator (5% CO ₂ , 37 ° C.).
(2) Measurement of ACC phosphorylation ability The subcultured cells were suspended in F-12 medium containing 10% bovine serum, and this suspension was transferred to a 96-well plate for tissue culture. This cell suspension was cultured in a CO ₂ incubator for 1 day.
The compound of Rigel (Compound 94) or a compound of the synthesis example separately dissolved in dimethyl sulfoxide was diluted with a medium without serum, added after removing the culture supernatant of the 96-well plate, and then added in a CO ₂ incubator. Incubated for 30 minutes.
ACC phosphorylation was measured according to the following procedure using a time fluorescence decomposition method (PerkinElmer DELFIA assay). Specifically, cells were immobilized on a 96-well plate using 4% paraformaldehyde, washed, blocked with an albumin-containing buffer (purchased from Sigma), and primary antibody (ACC phosphorylated antibody) (Cell Signaling) And purchased at 4 ° C. for 12 to 15 hours. After washing, a europium-labeled secondary antibody (purchased from PerkinElmer) was added and incubated at room temperature for 1 hour. After washing with PBST (mixed solution of 0.1% by weight of Tween 20 added to phosphate buffer (pH 7.4)), enhancer (registered trademark) (purchased from PerkinElmer) was added, and time-resolved fluorescence was added. Measurement was performed with a detector (ARVO-HTS manufactured by PerkinElmer).
As the active concentration of the compound of the synthesis example, the compound concentration (ECR50) that gives 50% phosphorylation rate when the ACC phosphorylation rate of human AdipoR1 stably expressing CHO cells in Rigel compound (Compound 94) is defined as 100% is Rigel. It was expressed as a specific activity value divided by the compound concentration (EC ₅₀ ) giving a 50% phosphorylation rate of the company compound (Compound 94). The results are shown below.
―――――――――――――――
Compound number Specific activity value ―――――――――――――――
1 0.57
2> 5
3> 5
4> 5
5> 5
6 0.21
7> 4
8 0.88
9 1.36
10 0.61
11 0.64
12 0.86
13 2.45
14> 4.5
16 0.16
17 0.44
18 3.44
19> 5
20 2.29
21 0.47
22 0.55
23 0.60
24 5.56
25 2.12
26 0.64
27 0.48
28 0.52
29 3.29
30 0.35
31 2.68
32 0.10
33 0.78
34 0.21
35 0.29
36 0.24
37 0.29
38 0.41
39 0.45
40 0.30
41 4.51
42 0.79
43 1.30
44 0.68
45 1.37
46 0.70
47 0.28
48 0.48
49 1.16
50 4.77
51 0.24
52 0.70
53 0.65
54> 5
55 0.41
56 0.44
57 1.16
58 1.43
59 0.31
60 0.85
61 1.85
62 0.45
63 2.06
64 0.42
65> 5
66 0.99
67 2.29
68 2.04
69 0.30
70 0.57
71 0.34
72 0.39
73 1.51
74 0.71
75 0.12
76 1.40
77 0.73
78 0.54
79 0.32
80 0.46
81 0.50
82 0.30
83 0.68
84 1.20
85 0.72
86 0.80
87 1.54
88 0.71
89 0.96
90 1.02
91 1.62
92 0.28
93 0.27
94 0.74
95 0.23
96 1.07
97 0.24
98 1.18
99 0.88
100 0.48
101> 5
102 1.13
103 1.05
104> 5
105> 5
106 0.48
107 5.77
108 0.46
109 1.28
110 1.25
111 1.58
112 1.72
113 0.53
114 0.71
115 0.80
116 0.39
117 0.71
118 0.61
119 0.85
120 0.22
121 1.37
122 0.43
123 1.12
124 0.19
125 0.42
126 0.08
127 0.47
128 8.76
129 4.50
130 3.54
131 0.10
132 3.82
133 1.40
134 0.82
135 1.73
136 0.43
137 0.72
138 8.10
139 0.60
140 0.69
141 0.27
142 0.66
143 1.03
144 0.85
145 0.46
146 0.24
147 1.99
149 0.32
150 1.46
151 2.76
152 0.29
153 0.89
154 0.16
155 1.13
156 1.15
157 0.84
158 2.19
159 2.87
160 0.51
161 0.15
162 0.32
163 1.70
164 2.43
165 0.75
166 1.44
167 0.62
169 0.55
170 5.84
171 0.48
172 3.36
173 8.64
174 5.32
175 1.00
176 0.88
177 1.64
178 2.52
179 2.00
180 0.18
181 0.37
182 0.13
183 0.56
184 0.87
185 4.61
186 0.52
187 0.38
188> 5
189 0.27
190 0.92
191 0.20
192 0.09
193 0.13
194 1.03
195 0.11
197 0.54
198 0.27
199 0.89
200 2.12
201 0.56
202 0.54
203 0.52
204 0.88
205 1.08
206 0.48
207 0.88
208 0.48
209 0.36
210 1.24
211 0.34
212 0.33
213 1.28
214 0.22
215 1.21
216 0.73
217 0.36
218 2.98
219 1.29
220 0.89
221 0.32
222 0.64
223 0.60
224> 5
225 5.77
226> 5
227 3.34
228> 5
229 7.11
230 0.50
231 0.42
232 6.29
233 10.02
234 1.36
235 8.84
236 5.38
237 0.61
238 0.57
239 0.74
240 0.98
241 1.52
242 1.48
243 9.88
244 6.64
245> 5
246 7.68
247 0.84
248 0.44
249 1.24
250 6.84
251 0.62
252 1.05
253 0.44
254 0.28
255 0.46
256 0.23
257 0.36
258 0.56
259 1.08
260 0.96
261 0.92
262 0.04
263 0.61
264 0.20
265 0.04
266 0.12
267 0.34
268 0.50
269 2.62
270 0.17
271 0.65
272 0.44
273 3.76
274 0.20
275 0.39
276 0.06
277 0.25
278 0.31
279 0.26
280 0.10
281 0.27
282 0.07
283 0.54
284 2.62
285 0.30
286 0.18
287 0.41
288 0.21
289 0.92
290 0.58
291 0.05
292 0.20
293 0.04
294 0.17
295 0.21
296 0.10
297 0.56
298 0.40
299 0.64
300 0.24
301 0.72
302 0.15
303 0.12
304 1.68
305 0.52
306 0.37
307 0.25
308 0.20
309 0.68
310 2.30
311 5.26
312 0.16
313 1.90
314 0.35
315 0.44
316 0.57
317 0.35
318 3.40
319 0.71
320 0.96
321 0.84
322 1.15
323 0.73
324> 5
325 0.99
326 0.23
327 0.83
328 2.00
329 7.70
330 1.88
331 4.77
332 1.00
333 0.19
334 0.79
335 0.13
336 0.31
337 0.47
338 2.41
339 3.12
340 1.53
341 1.69
342 0.22
343 0.23
344 0.09
345 0.22
346 0.68
347 0.16
348 0.20
349 0.42
350 0.61
351 0.17
352 3.50
353> 5
354 1.56
355 0.24
356 0.25
357 0.64
358 0.29
359 0.14
360 0.41
361 0.10
362 0.23
363 2.01
364 1.84
365 1.64
366 0.14
367 0.42
368 2.09
369 0.76
370 0.52
371 2.10
372 0.75
373 0.58
374 2.93
375 0.38
376 0.20
377 4.51
378 0.73
379 0.27
380 0.86
381 0.40
382 0.26
383 0.08
384 0.28
385 0.08
386 1.18
387 1.03
388 0.73
389 0.29
390 0.13
391 0.09
392 0.65
393 0.48
394 0.36
395 0.25
396 1.19
397 0.09
398 1.36
399 0.40
400 0.76
401 0.38
402 0.18
403 0.09
404 2.25
405 0.68
406 0.26
407 0.16
408 2.94
409 4.36
410 0.71
411 1.93
412 0.20
413 0.31
414 0.27
415 2.70
416 0.66
417 5.44
418 5.90
419> 5
420 9.07
421 1.29
422 1.59
423 6.28
424> 5
425 6.37
426 3.09
427 1.45
428 1.02
429 2.67
430 2.96
431 0.54
432 0.18
433 0.48
434 0.59
435 0.55
436 1.07
437 0.45
438 0.22
439 1.00
440 0.31
441 0.09
442 0.15
443 0.29
444 0.48
445 1.42
446 3.11
447 3.26
448 0.44
449 0.33
450 0.90
451 0.14
452 2.85
453 0.76
454 0.10
455 0.99
456 0.87
457 2.42
458> 5
459 3.97
460 7.83
461 1.20
462 3.07
463 2.72
464 1.21
465 7.94
466 1.30
467 0.94
468 5.38
469 0.40
470 1.46
471 0.89
472 0.59
473 7.49
474> 5
475 2.75
476 0.56
477 13.68
478 0.21
479 0.58
480 1.12
481 8.92
482 0.85
483 2.11.
484 6.39
485 2.46
486 1.15
487 0.25
488 7.73
489 0.75
490 0.56
491 5.40
492 0.32
493 5.95
494 7.57
495 3.99
496 4.77
497 8.49
498 0.10
499 2.56
500 0.90
501 0.36
502 0.52
503 0.73
504 3.41
505 5.37
506 6.75
507> 5
508> 5
509 9.95
510 1.29
511 0.26

Formulation Example 1
A granule containing the following ingredients is produced.
Component Compound represented by formula (I) 10 mg
Lactose 700mg
Corn starch 274mg
HPC-L 16mg
----------------------------
1000mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded and granulated (extruded granulated pore diameter: 0.5 to 1 mm), and then dried. The obtained dried granules are sieved with a vibrating sieve (12/60 mesh) to obtain granules.

Formulation Example 2
A powder for capsule filling containing the following components is produced.
Component Compound represented by formula (I) 10 mg
Lactose 79mg
Corn starch 10mg
Magnesium stearate 1mg
----------------------------
100mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These and magnesium stearate are mixed in a V-type mixer. 100 mg of 10 times powder is filled into a No. 5 hard gelatin capsule.

Formulation Example 3
A capsule filling granule containing the following ingredients is produced.
Component Compound represented by formula (I) 15 mg
Lactose 90mg
Corn starch 42mg
HPC-L 3mg
----------------------------
150mg total
The compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass corn starch through a 120 mesh sieve. These are mixed in a V-type mixer. A low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution is added to the mixed powder, kneaded, granulated, and dried. The obtained dried granules are sieved with a vibrating sieve (12/60 mesh) and sized, and 150 mg thereof is filled into a No. 4 hard gelatin capsule.

Formulation Example 4
A tablet containing the following ingredients is produced.
Component Compound represented by formula (I) 10 mg
Lactose 90mg
Microcrystalline cellulose 30mg
Magnesium stearate 5mg
CMC-Na 15mg
----------------------------
150mg total
The compound represented by the formula (I), lactose, microcrystalline cellulose, and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for preparation. The mixed powder is directly hit to obtain a 150 mg tablet.

Formulation Example 5
The intravenous formulation is produced as follows.
Compound represented by formula (I) 100 mg
Saturated fatty acid glyceride 1000mL
The solution of the above components is usually administered intravenously to the patient at a rate of 1 mL per minute.

Since the compound of the present invention has an affinity and / or agonist action for adiponectin receptor, it is a prophylactic / therapeutic / ameliorating agent for diseases in which adiponectin receptor activation action is effective, particularly metabolic syndrome, particularly metabolic syndrome associated with obesity and diabetes It can be used for the prevention or treatment of syndrome and arteriosclerosis, and is useful as a pharmaceutical.
The entire contents of the specification, claims, and abstract of Japanese Patent Application No. 2010-108491 filed on May 10, 2010 are incorporated herein as the disclosure of the specification of the present invention. Is.

Claims (35)

1. Formula (I)
   

   

   [In the formula (I),
   E means an oxygen atom or a sulfur atom,
   L 1 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
   L 2 represents a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
   X represents a C 3-11 cycloalkylene group, a C 3-11 cycloalkenylene group (the C 3-11 cycloalkylene group and the C 3-11 cycloalkenylene group are unsubstituted or a C 1-3 alkyl group) Substituted with one or more substituents independently selected from the group consisting of C 2-3 alkenyl groups, —OR 16 and cyano groups.), C 6-10 arylene groups or 5- to 10-membered heteroarylenes A group (the C 6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted or a halogen atom, a nitro group, a cyano group, a C 1-3 alkyl group (the C 1-3 alkyl group is or an unsubstituted, substituted by one or more substituents independently selected from the group consisting of a halogen atom and -OR 16.), C 2-3 alkenyl, C 2-3 Rukiniru group, -OR 16, -O (C 2-3 alkenyl group), - O (C 3-4 cycloalkyl group), - N (R 16) C (= O) OR 17, -N (R 16) C (═O) R 17 , —N (R 16 ) C (═O) H, —N (R 16 ) R 17 , —NH 2 , —N (R 16 ) S (═O) 2 R 17 , — C (═O) NR 16 R 17 , —C (═O) NH 2 , —C (═O) R 16 , —S (═O) 2 R 17 , —S (═O) 2 NR 16 R 17 , Substituted with one or more substituents independently selected from the group consisting of —S (═O) 2 NH 2 ;
   Z 1 represents the formulas (II-1) to (II-8)
   

   

   (Where
   J ¹ each independently represents an oxygen atom or a sulfur atom;
   G ¹ means a single bond, an oxygen atom or a sulfur atom,
   R ¹ and R ³ are
   R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or one selected independently from substituent group A ₃ ) Substituted with the above substituents), a C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5-10 membered heteroaryl (wherein the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or independently of the group consisting of substituent groups A ₂ and C _4-6 alkyl groups) The C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group may be unsubstituted or substituted with one or more selected substituents). Substituent Which is substituted by one or more substituents independently selected from the group consisting of A ₁ and C _4-6 alkyl groups.) Means, R ³ means a hydrogen atom or a C _1-3 alkyl group Or
   Or R ¹ and R ³ together with the nitrogen atom to which they are attached are 4- to 11-membered heterocycloalkyl groups (the 4- to 11-membered heterocycloalkyl groups are unsubstituted or substituted) Substituted with one or more substituents independently selected from the group consisting of group A ₁ and a C _4-6 alkyl group;
   R ² represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₃ ). A C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( The C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups. The C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group may be unsubstituted or substituted with the substituent groups A ₁ and C _4-6 alkyl. A group of groups Substituted by one or more substituents independently selected),
   R ⁴ and R ⁵ each independently represents a hydrogen atom or a C _1-3 alkyl group. )
   Means either
   m means an integer of 1 or 2,
   R ⁶ independently represents a hydrogen atom, a C _1-3 alkyl group or a cyclopropyl group, or two R ⁶ existing on the same carbon atom are bonded to the carbon atom to which they are bonded. Together with C to form a C _3-6 cycloalkane,
   n means an integer of 0 to 4,
   Each R ⁷ independently represents a C _1-3 alkyl group;
   T represents the formulas (VI-1) to (VI-3)
   

   

   (Where
   L ⁴ represents a C _1-3 alkylene group,
   L ⁵ represents a single bond, an oxygen atom, a sulfur atom, S (═O), S (═O) ₂ , C═O or C═NOR ¹² ;
   R ⁸ represents a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or substituted with the substituent groups A ₂ and C _4. Substituted with one or more substituents independently selected from the group consisting of _-6 alkyl groups).
   J ² means an oxygen atom or a sulfur atom,
   G ² means an oxygen atom, a sulfur atom or NR ¹¹ ,
   R ⁹ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₄ ). , A C _6-10 aryl group (the C _6-10 aryl group is one or more substituents which are unsubstituted or independently selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups) A C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is a C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered) Heteroaryl is unsubstituted or substituted by one or more substituents independently selected from the group consisting of substituent groups A ₂ and C _4-6 alkyl groups. well, and the _{C 3-11} cycloalkyl Group is substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted.), Or, a C _1-3 alkyl group (the C _1-3 alkyl group Is a C _6-10 aryl group or a C _3-11 cycloalkyl group (the C _6-10 aryl group and the C _3-11 cycloalkyl group are unsubstituted or substituted with the substituent groups A ₂ and C _4-6. Substituted with one or more substituents independently selected from the group consisting of alkyl groups).
   R ¹⁰ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ ). A C _6-10 aryl group, a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or substituted with the substituent groups A ₂ and C _4-6 alkyl, Substituted with one or more substituents independently selected from the group consisting of groups), a C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5- 10-membered heteroaryl (wherein the C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups independently Substituted by substituents It is.) And may be a condensed ring, and the C _3-11 cycloalkyl group, optionally substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted Or a C _1-3 alkyl group (the C _1-3 alkyl group is a C _3-11 cycloalkyl group (the C _3-11 cycloalkyl group is unsubstituted or substituted by the substituent group A ₂₎ . Substituted with one or more independently selected substituents)). )
   Means either
   Substituent group A ₁ is a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₃ ). .) and means a substituent group consisting of substituent group a _3,
   Substituent group A ₃ is
   A C _3-11 cycloalkyl group, a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of substituent groups A ₂ and C _4-6 alkyl groups The C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group may be unsubstituted or substituted with the substituent group A ₂ and the C _4-6 alkyl group. which is substituted by one or more substituents independently selected from the group consisting _{of.), C 6-10} aryl group, 5-10-membered heteroaryl group (the _{C 6-10} aryl group and 5 to 1 Membered heteroaryl group, 4-11-membered heterocycloalkyl alkane (said 4-11 membered heterocycloalkyl cycloalkane is substituted by one or more substituents selected as or independently from Substituent group A ₂ unsubstituted And the C _6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or a group consisting of the substituent group A ₂ and the C _4-6 alkyl group. Substituted with one or more substituents selected more independently.), —C (═O) OR ¹³ , —C (═O) NR ¹² R ¹³ , —C (═O) R ¹³ , — C (= NOR ¹² ) R ¹³ , —S (═O) R ¹³ , —S (═O) ₂ R ¹³ , —OR ¹³ , —SR ¹³ , —N (R ¹² ) C (═O) OR ¹³ , ^{-N (R 12) C (=} O) R 13, -N (R 12) R 13, C Gen atom, a cyano group, a nitro group, means a formyl ^{group, -C (= NOR 12) H} , -N (R 12) C (= O) H, or a substituent group consisting of a hydroxyl group,
   Substituent group A ₂ is
   Means a substituent group composed of a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms) and a substituent group A ₄ ,
   Substituent group A ₄ is
   Halogen atom, nitro group, cyano group, —OR ¹⁴ , —SR ¹⁴ , —C (═O) OR ¹⁴ , —C (═O) NR ¹⁴ R ¹⁵ , —C (═O) R ¹⁵ , —C (= NOR ¹⁵ ) R ¹⁴ , -C (= NOR ¹⁵ ) H, -S (= O) R ¹⁴ , -S (= O) ₂ R ¹⁴ , -N (R ¹⁵ ) C (= O) OR ¹⁴ , -N (R ¹⁵ ) C (═O) R ¹⁴ , or —N (R ¹⁵ ) C (═O) H means a substituent group composed of,
   Each of R ¹¹ independently represents a hydrogen atom or a C _1-6 alkyl group;
   Each R ¹² independently represents a hydrogen atom or a C _1-3 alkyl group;
   Each R ¹³ is independently
   A C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ ),
   C _3-11 cycloalkyl group, _4-11 membered heterocycloalkyl group, C _6-10 aryl group, or 5-10 membered heteroaryl group (the C _3-11 cycloalkyl group, _4-11 membered heterocycloalkyl group) , The C _6-10 aryl group and the 5- to 10-membered heteroaryl group are one or more substituents which are unsubstituted or independently selected from the group consisting of the substituent groups A ₂ and C _4-6 alkyl groups Is replaced by
   R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
   R ¹⁵ represents a hydrogen atom or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
   R ¹⁶ represents a hydrogen atom or a C _1-3 alkyl group,
   R ¹⁷ means a C _1-3 alkyl group. ]
   Or a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
2. Formula (I)
   

   

   [In the formula (I),
   E means an oxygen atom or a sulfur atom,
   L 1 is a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
   L 2 represents a single bond, a C 1-3 alkylene group, a C 2-3 alkenylene group or a C 2-3 alkynylene group (the C 1-3 alkylene group, C 2-3 alkenylene group and C 2-3 alkynylene group are , Unsubstituted or substituted by a cyclopropyl group)
   X represents a C 3-11 cycloalkylene group, a C 3-11 cycloalkenylene group (the C 3-11 cycloalkylene group and the C 3-11 cycloalkenylene group are unsubstituted or a C 1-3 alkyl group) Substituted with one or more substituents independently selected from the group consisting of C 2-3 alkenyl groups, —OR 16 and cyano groups.), C 6-10 arylene groups or 5- to 10-membered heteroarylenes A group (the C 6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted or a halogen atom, a nitro group, a cyano group, a C 1-3 alkyl group (the C 1-3 alkyl group is or an unsubstituted, substituted by one or more substituents independently selected from the group consisting of a halogen atom and -OR 16.), C 2-3 alkenyl, C 2-3 Rukiniru group, -OR 16, -O (C 2-3 alkenyl group), - O (C 3-4 cycloalkyl group), - N (R 16) C (= O) OR 17, -N (R 16) C (═O) R 17 , —N (R 16 ) C (═O) H, —N (R 16 ) R 17 , —NH 2 , —N (R 16 ) S (═O) 2 R 17 , — C (═O) NR 16 R 17 , —C (═O) NH 2 , —C (═O) R 16 , —S (═O) 2 R 17 , —S (═O) 2 NR 16 R 17 , Substituted with one or more substituents independently selected from the group consisting of —S (═O) 2 NH 2 ;
   Z 1 represents the formulas (II-1) to (II-8)
   

   

   (Where
   J ¹ each independently represents an oxygen atom or a sulfur atom;
   G ¹ means a single bond, an oxygen atom or a sulfur atom,
   R ¹ and R ³ are
   R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or one selected independently from substituent group A ₃ ) Substituted with the above substituents), a C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5- to 10-membered heteroaryl (the C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ The C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group may be unsubstituted or independently selected from the substituent group A ₁ One or more Which is substituted by substituents.) I mean, or R ³ means a hydrogen atom or a C _1-3 alkyl group,
   Or R ¹ and R ³ together with the nitrogen atom to which they are attached are 4- to 11-membered heterocycloalkyl groups (the 4- to 11-membered heterocycloalkyl groups are unsubstituted or substituted) which is substituted by one or more substituents independently selected from the group a _1.) means,
   R ² represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₃ ). A C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( The C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ). And the C _3-11 cycloalkyl group and the _4- to 11-membered heterocycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₁ ) And,
   R ⁴ and R ⁵ each independently represents a hydrogen atom or a C _1-3 alkyl group. )
   Means either
   m means an integer of 1 or 2,
   R ⁶ independently represents a hydrogen atom, a C _1-3 alkyl group or a cyclopropyl group, or two R ⁶ existing on the same carbon atom are bonded to the carbon atom to which they are bonded. Together with C to form a C _3-6 cycloalkane,
   n means an integer of 0 to 4,
   Each R ⁷ independently represents a C _1-3 alkyl group;
   T represents the formulas (VI-1) to (VI-3)
   

   

   (Where
   L ⁴ represents a C _1-3 alkylene group,
   L ⁵ represents a single bond, an oxygen atom, a sulfur atom, S (═O), S (═O) ₂ , C═O or C═NOR ¹² ;
   R ⁸ represents a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or independently of the substituent group A ₂₎ Substituted with one or more substituents selected from
   J ² means an oxygen atom or a sulfur atom,
   G ² means an oxygen atom, a sulfur atom or NR ¹¹ ,
   R ⁹ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₄ ). A C _6-10 aryl group (the C _6-10 aryl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ), C _{3 -11} cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5- to 10-membered heteroaryl (the C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted) Substituted with one or more substituents independently selected from group A ₂ ) and the C _3-11 cycloalkyl group may be unsubstituted or substituted. one or more independently selected from the group & A ₂ Which is substituted by a substituent.), _{Or, a C 1-3} alkyl group (the _{C 1-3} alkyl _{group, C 6-10} aryl group or _{C 3-11} cycloalkyl group (the _{C 6-10} aryl The group and the C _3-11 cycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ). And
   R ¹⁰ represents a C _1-9 alkyl group (the C _1-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ ). , C _6-10 aryl group, 5- to 10-membered heteroaryl group (the C _6-10 aryl group and 5- to 10-membered heteroaryl group are unsubstituted or independently selected from substituent group A ₂ Substituted with one or more substituents), a C _3-11 cycloalkyl group (wherein the C _3-11 cycloalkyl group is C _6-10 aryl or 5- to 10-membered heteroaryl (the C _6-10 Aryl and 5- to 10-membered heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from substituent group A ₂ ) and The C _3-11 cycloalkyl group is , Unsubstituted or substituted with one or more substituents independently selected from substituent group A ₂ ), or a C _1-3 alkyl group (the C _1-3 alkyl group is C ₃ Substituted with an _-11 cycloalkyl group (the C _3-11 cycloalkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ). Means). )
   Means either
   Substituent group A ₁ is a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₃ ). .) and means a substituent group consisting of substituent group a _3,
   Substituent group A ₃ is
   A C _3-11 cycloalkyl group, a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl (the C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ . And the C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group are unsubstituted or substituted by one or more substituents independently selected from substituent group A _{2 .), C 6-10} aryl group, 5-10-membered heteroaryl group (the _{C 6-10} aryl and 5-10 membered heteroaryl group, 4-11-membered heterocycloalkyl alkane (said 4-11 Heterocycloalkane may be condensed with unsubstituted or substituted with or independently from the substituent group A ₂ is substituted by one or more substituents selected.), And the C _6-10 aryl The group and the 5- to 10-membered heteroaryl group are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ )), —C (═O) OR ¹³ , -C (= O) NR ¹² R ¹³ , -C (= O) R ¹³ , -C (= NOR ¹² ) R ¹³ , -S (= O) R ¹³ , -S (= O) ₂ R ¹³ ,- OR ¹³ , —SR ¹³ , —N (R ¹² ) C (═O) OR ¹³ , —N (R ¹² ) C (═O) R ¹³ , —N (R ¹² ) R ¹³ , halogen atom, cyano group, A nitro group, a formyl group, —C (═NOR ¹² ) H, —N (R ¹² ) C (═O) H, Or a group of substituents composed of hydroxyl groups,
   Substituent group A ₂ is
   Means a substituent group composed of a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms) and a substituent group A ₄ ,
   Substituent group A ₄ is
   Halogen atom, nitro group, cyano group, —OR ¹⁴ , —SR ¹⁴ , —C (═O) OR ¹⁴ , —C (═O) NR ¹⁴ R ¹⁵ , —C (═O) R ¹⁵ , —C (= NOR ¹⁵ ) R ¹⁴ , -C (= NOR ¹⁵ ) H, -S (= O) R ¹⁴ , -S (= O) ₂ R ¹⁴ , -N (R ¹⁵ ) C (= O) OR ¹⁴ , -N (R ¹⁵ ) C (═O) R ¹⁴ , or —N (R ¹⁵ ) C (═O) H means a substituent group composed of,
   Each of R ¹¹ independently represents a hydrogen atom or a C _1-6 alkyl group;
   Each R ¹² independently represents a hydrogen atom or a C _1-3 alkyl group;
   Each R ¹³ is independently
   A C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₄ ),
   C _3-11 cycloalkyl group, _4-11 membered heterocycloalkyl group, C _6-10 aryl group, or 5-10 membered heteroaryl group (the C _3-11 cycloalkyl group, _4-11 membered heterocycloalkyl group) , C _6-10 aryl and 5-10-membered heteroaryl group is substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted.) means ,
   R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
   R ¹⁵ represents a hydrogen atom or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
   R ¹⁶ represents a hydrogen atom or a C _1-3 alkyl group,
   R ¹⁷ means a C _1-3 alkyl group. ]
   The spiro compound of Claim 1 represented by this, the tautomer of this compound, or its pharmaceutically acceptable salt.
3. X is a C _3-11 cycloalkylene group or a C _3-11 cycloalkenylene group (the C _3-11 cycloalkylene group and the C _3-11 cycloalkenylene group are unsubstituted or a C _1-3 alkyl group) Substituted with one or more substituents independently selected from the group consisting of C ₂ , C _2-3 alkenyl groups, —OR ¹⁶ and cyano groups.)
   The spiro compound according to claim 2, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
4. X is a C _6-10 arylene group or a 5- to 10-membered heteroarylene group (the C _6-10 arylene group and the 5- to 10-membered heteroarylene group are unsubstituted, halogen atoms, nitro groups, cyano groups, A C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of a halogen atom and —OR ¹⁶ ). ), C _2-3 alkenyl group, C _2-3 alkynyl group, —OR ¹⁶ , —O (C _2-3 alkenyl group), —O (C _3-4 cycloalkyl group), —N (R ¹⁶ ) C (═O) OR ¹⁷ , —N (R ¹⁶ ) C (═O) R ¹⁷ , —N (R ¹⁶ ) C (═O) H, —N (R ¹⁶ ) R ¹⁷ , —NH ₂ , —N ( ^{_{R 16) S (= O)}} 2 R 17, -C (= O) NR 16 R 1 ^{_{, -C (= O) NH 2}} , -C (= O) R 16, -S (= O) 2 R 17, -S (= O) 2 NR 16 R 17, -S (= O) 2 NH 2 Substituted with one or more substituents independently selected from the group consisting of
   The spiro compound according to claim 2, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
5. L ¹ is a C _1-3 alkylene group, C _2-3 alkenylene group or C _2-3 alkynylene group (the C _1-3 alkylene group, C _2-3 alkenylene group and C _2-3 alkynylene group are unsubstituted) Or substituted by a cyclopropyl group.)
   The spiro compound according to claim 4, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
6. Z ¹ is represented by formulas (II-1) to (II-8)
   

   

   (Where
   J ¹ each independently represents an oxygen atom or a sulfur atom;
   G ¹ means a single bond, an oxygen atom or a sulfur atom,
   R ¹ and R ³ are
   R ¹ is a hydrogen atom, OR ¹¹ , NR ¹¹ R ¹² , C _1-5 alkyl group (wherein the C _1-5 alkyl group is unsubstituted or independently selected from Substituent Group A ₃ Substituted by the above substituents, provided that when m is 1 and both R ⁶ are hydrogen atoms, the C _1-5 alkyl group is independently selected from the substituent group A ₃ A C _6-9 alkyl group (wherein the C _6-9 alkyl group is unsubstituted or independently selected from Substituent Group A ₃ ). Substituted with the above substituents), a C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _{6 -10} aryl or 5-10 membered hetero ants (Wherein the C _6-10 aryl and 5- to 10-membered heteroaryl are unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂ ) and fused rings And the C _3-11 cycloalkyl group and the _4-11 membered heterocycloalkyl group may be unsubstituted or substituted by one or more substituents independently selected from the substituent group A ₁ Substituted, and R ³ represents a hydrogen atom or a C _1-3 alkyl group,
   Or R ¹ and R ³ together with the nitrogen atom to which they are attached are 4- to 11-membered heterocycloalkyl groups (the 4- to 11-membered heterocycloalkyl groups are unsubstituted or substituted) which is substituted by one or more substituents independently selected from the group a _1.) means,
   R ² represents a C _1-5 alkyl group (the C _1-5 alkyl group is unsubstituted or substituted by one or more substituents independently selected from substituent group A _3, provided that , M means 1 and two R ⁶ both represent a hydrogen atom, the C _1-5 alkyl group is substituted with one or more substituents independently selected from the substituent group A _3. A C _6-9 alkyl group (the C _6-9 alkyl group is unsubstituted or substituted by one or more substituents independently selected from Substituent Group A ₃ ). A C _3-11 cycloalkyl group or a _4-11 membered heterocycloalkyl group (the C _3-11 cycloalkyl group and _4-11 membered heterocycloalkyl group are C _6-10 aryl or 5-10 membered heteroaryl ( the _{C 6-10} aryl and 5-10 Heteroaryl may be condensed one or more are replaced by a substituent.) And selected as or independently from Substituent group A ₂ unsubstituted, and the C _3-11 cycloalkyl groups and 4-11 membered heterocycloalkyl group is substituted by one or more substituents selected as or independently from substituent group a ₁ unsubstituted.) I mean,
   R ⁴ and R ⁵ each independently represents a hydrogen atom or a C _1-3 alkyl group. )
   The spiro compound according to claim 5, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
7. L ¹ is a C _1-3 alkylene group,
   L ² is a single bond,
   Z ¹ represents the formula (II-1), (II-4) or (II-7)
   

   

   The spiro according to claim 2 or 3, wherein R ¹ , R ² , R ³ , R ⁴ , J ¹ and G ¹ have the same meaning as defined in claim 2. A compound, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
8. L ¹ is a C _1-3 alkylene group,
   L ² is a single bond,
   Z ¹ represents the formula (II-1), (II-4) or (II-7)
   

   

   (Wherein R ¹ , R ² , R ³ , R ⁴ , J ¹ and G ¹ have the same meaning as defined in claim 6), the spiro compound according to claim 6, A tautomer of the compound, or a pharmaceutically acceptable salt thereof.
9. E is an oxygen atom, m is 1, and n is 0. The spiro compound according to any one of claims 2 to 8, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. salt.
10. E is an oxygen atom, m is 2, and n is 0. The spiro compound according to any one of claims 2 to 8, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. salt.
11. T is the formula (VI-1) or (VI-2)
    

    

    (Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ have the same meaning as defined in claim 2). The spiro compound according to any one of claims 2 to 10, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
12. Z ¹ is
    Formula (II-1), (II-4) or (II-7)
    

    

    (Wherein R ¹ and R ³ are
    R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)) Or R ³ represents a hydrogen atom,
    R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and a 5- to 10-membered heteroaryl group) is 4-11 membered heterocycloalkyl alkanes (the 4-11 membered heterocycloalkyl alkanes are substituted by one or more substituents selected as or independently from substituent group a ₂ unsubstituted.) and The C _6-10 aryl group and the 5- to 10-membered heteroaryl group may be condensed or substituted with one or more substituents independently selected from substituent group A ₂ And the C _1-6 alkyl group is substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group. means may be.), ^{R 3} Means a hydrogen atom,
    R ¹ is a 4- to 11-membered nitrogen-containing heterocycloalkyl group (the 4- to 11-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Unsubstituted or independently from the group consisting of —C (═O) OCH ₃ , cyano group, nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , chlorine atom, —CF ₃ and —CH ₃ Substituted with one or more selected substituents) or substituted with either a cyano group) or substituted with either —C (═O) O (C _1-6 alkyl). R ³ represents a hydrogen atom, or
    R ¹ and R ³ together with the nitrogen atom to which they are bonded are 4- to 11-membered nitrogen-containing heterocycloalkyl groups (the 4- to 11-membered nitrogen-containing heterocycloalkyl groups are represented by substituent group A ₁ Substituted with one or more independently selected substituents),
    R ² is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is substituted with a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). .)
    R ⁴ represents a hydrogen atom,
    J ¹ means an oxygen atom,
    G ¹ means a single bond or an oxygen atom. )
    The spiro compound according to any one of claims 2 to 11, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
13. Z ¹ is
    Formula (II-1), (II-4) or (II-7)
    

    

    (Wherein R ¹ and R ³ are
    R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)) Or R ³ represents a hydrogen atom,
    R ¹ is a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group (the phenyl group is Unsubstituted or independently from the group consisting of —C (═O) OCH ₃ , a cyano group, a nitro group, —SCH ₃ , —OCF ₃ , —OCH ₃ , a chlorine atom, —CF ₃ and —CH ₃ Substituted with one or more selected substituents)), substituted with), and R ³ represents a hydrogen atom, or R ¹ and R ³ are , 1 they are bonded to together with the nitrogen atom a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is independently selected from substituent group a ₁ Substituted with one or more substituents.
    R ² is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is substituted with a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)). .)
    R ⁴ represents a hydrogen atom,
    J ¹ means an oxygen atom,
    G ¹ means a single bond or an oxygen atom. )
    The spiro compound according to any one of claims 2 to 12, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
14. Z ¹ is
    Formula (II-1) or (II-4)
    

    

    (Wherein R ¹ and R ³ are
    R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and a 5- to 10-membered heteroaryl group) Is a 4- to 7-membered oxygenated heterocycloalkane (the 4- to 7-membered oxygenated heterocycloalkane is unsubstituted or substituted by one or more substituents independently selected from substituent group A ₂₎ And the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or independently selected from substituent group A ₂ The C _1-6 alkyl group is substituted with one or more substituents independently selected from the group consisting of a hydroxyl group, a halogen atom and a cyano group. Meaning R) ³ means a hydrogen atom,
    R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ represents a hydrogen atom, or R ¹ and R ³ together with the nitrogen atom to which they are bonded are an azetidinyl group (the azetidinyl group is independently of the substituent group A ₁ Substituted with one or more selected substituents),
    R ⁴ represents a hydrogen atom,
    J ¹ is, means an oxygen atom. )
    The spiro compound according to any one of claims 2 to 12, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
15. T is the formula (VI-1) or (VI-2)
    

    

    (Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ each independently represents a C _6-10 aryl group or a 5-10 membered nitrogen-containing group) Heteroaryl group (C _6-10 aryl group and 5-10 membered nitrogen-containing heteroaryl group are unsubstituted or a fluorine atom, a C _1-3 alkyl group (the C _1-3 alkyl group is one or more Or a substituent selected from the group consisting of a cyano group and one or more substituents independently selected from the group consisting of a cyano group. The spiro compound according to any one of 1 to 14, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
16. T is the formula (VI-1) or (VI-2)
    

    

    (Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ are each independently a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are , Unsubstituted or independently selected from the group consisting of a fluorine atom, a C _1-3 alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group 16. The spiro compound according to any one of claims 2 to 15, a tautomer of the compound, or a pharmaceutical thereof, which is substituted by one or more substituents Acceptable salt.
17. T is the formula (VI-1) or (VI-2)
    

    

    (Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ are each independently a phenyl group (the phenyl group represents one or two Or a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms) or a cyano group). The spiro compound according to any one of claims 2 to 16, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
18. T is the formula (VI-1) or (VI-2)
    

    

    (Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ each independently represents a phenyl group (the phenyl group represents one or more fluorine atoms) Substituted by an atom, and the phenyl group is substituted by either a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms) or a cyano group The spiro compound according to any one of claims 2 to 16, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
19. Z ¹ is
    Formula (II-1) or (II-4)
    

    

    (Wherein R ¹ and R ³ are
    R ¹ and R ³ together with the nitrogen atom to which they are attached are 5- to 7-membered nitrogen-containing heterocycloalkyl group (the 5- to 7-membered nitrogen-containing heterocycloalkyl group is a phenyl group, 5-10 A member heteroaryl group (the phenyl group and the 5-10 membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or one or more Substituted with one or more substituents independently selected from the group consisting of halogen atoms and cyano groups), —C (═O) OR ¹³ , —C ( ═O) substituted with one or more substituents independently selected from the group consisting of R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , a halogen atom and a cyano group.
    R ¹² represents a hydrogen atom,
    R ¹³ represents a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a C _6-10 aryl group, or 5 to 10 members. A heteroaryl group (the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or Substituted with one or more substituents independently selected from the group consisting of a halogen atom, a cyano group, and —OR ¹⁴ ),
    R ¹⁴ represents a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more halogen atoms);
    R ⁴ represents a hydrogen atom,
    J ¹ is, means an oxygen atom. )
    The spiro compound according to any one of claims 2 to 13 or any one of claims 15 to 18, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
20. Z ¹ is
    Formula (II-1) or (II-4)
    

    

    (Wherein R ¹ and R ³ are
    R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group, a pyridyl group, a furyl group or an isoxazolyl group (the phenyl group, the pyridyl group, the furyl group and the isoxazolyl group are 4 to 7-membered). It may be condensed with an oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group, furyl group and isoxazolyl group may be unsubstituted, halogen atom, cyano group, C _1-3 alkyl group (the C _{1-3 1-3} alkyl groups are substituted by one or more fluorine atoms.) And one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl). And R ³ is a hydrogen atom, or R ¹ is a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group). , Pyridyl group or furyl group (the phenyl group, pyridyl group and furyl group may be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the phenyl group, pyridyl group and furyl group are unsubstituted. Or one or more independently selected from the group consisting of a halogen atom, a cyano group and a C _1-3 alkyl group (wherein the C _1-3 alkyl group is substituted by one or more fluorine atoms) And the C _1-3 alkyl group is one or more independently selected from the group consisting of a hydroxyl group, a halogen atom, and a cyano group. Substituted with a substituent group), R ³ represents a hydrogen atom,
    R ⁴ represents a hydrogen atom,
    J ¹ is, means an oxygen atom. )
    The spiro compound according to any one of claims 2 to 12 or any one of claims 14 to 18, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
21. Z ¹ is
    Formula (II-1) or (II-4)
    

    

    (Wherein R ¹ and R ³ are
    R ¹ and R ³ together with the nitrogen atom to which they are attached are piperidyl, piperazinyl, homopiperidyl or homopiperazinyl (the piperidyl, piperazinyl, homopiperidyl and homopiperazinyl groups are -C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , substituted by one or more substituents independently selected from the group consisting of a halogen atom and a cyano group Means)
    R ¹² represents a hydrogen atom,
    R ¹³ is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a phenyl group or a pyridyl group (the phenyl group and pyridyl group). The group may be unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom, a cyano group, and Substituted with one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl).
    R ⁴ represents a hydrogen atom,
    J ¹ is, means an oxygen atom. )
    The spiro compound according to claim 19, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
    
22. Z ¹ is
    Formula (II-1) or (II-4)
    

    

    (Wherein R ¹ and R ³ are
    R ¹ and R ³ together with the nitrogen atom to which they are attached are piperidyl, piperazinyl, homopiperidyl or homopiperazinyl (the piperidyl, piperazinyl, homopiperidyl and homopiperazinyl groups are phenyl groups , Pyridyl group, oxadiazolyl group, benzimidazolyl group, benzisoxazolyl group or quinolyl group (the phenyl group, pyridyl group, oxadiazolyl group, benzimidazolyl group, benzisoxazolyl group and quinolyl group are unsubstituted) Or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), independently selected from the group consisting of a halogen atom and a cyano group Substituted with one or more substituents). Taste,
    R ⁴ represents a hydrogen atom,
    J ¹ is, means an oxygen atom. )
    The spiro compound according to claim 19, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
23. Z ¹ is
    Formula (II-1) or (II-4)
    

    

    (Wherein R ¹ and R ³ are
    R ¹ and R ³ together with the nitrogen atom to which they are attached are azetidinyl groups (the azetidinyl group is unsubstituted or —C (═O) OR ¹³ , —C (═O) Substituted with one or more substituents independently selected from the group consisting of R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , a halogen atom and a cyano group.
    R ¹² represents a hydrogen atom,
    R ¹³ represents a C _1-6 alkyl group, a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted). Or substituted with one or more substituents independently selected from the group consisting of a halogen atom, a cyano group, and —O (C _1-3 alkyl). Means either)
    R ⁴ represents a hydrogen atom,
    J ¹ is, means an oxygen atom. )
    The spiro compound according to any one of claims 2 to 12 and 14, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
24. L ¹ is a C _1-3 alkylene group,
    L ² is a single bond,
    E is an oxygen atom,
    m is an integer of 1 or 2,
    R ⁶ is a hydrogen atom,
    n is 0,
    T is the formula (VI-1) or (VI-2)
    

    

    (Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ have the same meaning as defined in claim 1). The spiro compound according to claim 1, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
25. Z ¹ is
    Formula (II-1) or (II-4)
    

    

    (Wherein R ¹ and R ³ are
    R ¹ is either a C _1-3 alkyl group (the C _1-3 alkyl group is a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are substituted with a C _4-6 alkyl group)). Or R ³ represents a hydrogen atom, or
    R ¹ represents a piperidyl group (the piperidyl group is substituted by a C _4-6 alkyl group), R ³ represents a hydrogen atom, or R ¹ and R ³ are bonded to each other. A piperidyl group together with the nitrogen atom in which the piperidyl group is independently selected from the group consisting of —C (═O) R ¹³ , —OR ¹³ and —NR ¹² R ¹³ Substituted by a group)
    R ¹² represents a hydrogen atom,
    R ¹³ represents either a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are unsubstituted or substituted by a C _4-6 alkyl group);
    R ⁴ represents a hydrogen atom,
    J ¹ is, means an oxygen atom. )
    The spiro compound according to claim 1 or 24, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
26. Z ¹ is
    Formula (II-1) or (II-4)
    

    

    (Wherein R ¹ and R ³ are
    R ¹ is substituted with a C _1-6 alkyl group (the C _1-6 alkyl group is a 4- to 7-membered oxygen-containing heterocycloalkyl group or —NHC (═O) O (C _1-6 alkyl)) Or R ³ represents a hydrogen atom,
    R ¹ is a C _1-6 alkyl group (the C _1-6 alkyl group is a C _6-10 aryl group or a 5- to 10-membered heteroaryl group (the C _6-10 aryl group and a 5- to 10-membered heteroaryl group) May be condensed with a 4- to 7-membered oxygen-containing heterocycloalkane, and the C _6-10 aryl group and the 5- to 10-membered heteroaryl group are unsubstituted or a halogen atom, a cyano group, C _1-3 alkyl groups (the C _1-3 alkyl groups are unsubstituted or substituted by one or more fluorine atoms), —O (C _1-3 alkyl) and C _4-6 alkyl groups And the C _1-6 alkyl group is substituted with a hydroxyl group, a halogen atom or a cyano group, and is substituted with one or more substituents independently selected from the group consisting of Chosen independently from the group May be substituted with one or more substituents.) Means, or R ³ means a hydrogen atom,
    R ¹ represents a 4-11 membered nitrogen-containing heterocycloalkyl group (the 4-11 membered nitrogen-containing heterocycloalkyl group is substituted by —C (═O) O (C _1-6 alkyl)). R ³ represents a hydrogen atom, or R ¹ and R ³ together with the nitrogen atom to which they are bonded are an azetidinyl group or a 5- to 7-membered nitrogen-containing heterocycloalkyl group (the azetidinyl group). And a 5- to 7-membered nitrogen-containing heterocycloalkyl group is a phenyl group, a 5-10-membered heteroaryl group (the phenyl group and the 5-10-membered heteroaryl group are unsubstituted or a C _1-3 alkyl group) (The C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), by one or more substituents independently selected from the group consisting of halogen atoms and cyano groups Replaced One or more independently selected from the group consisting of —C (═O) OR ¹³ , —C (═O) R ¹³ , —OR ¹³ , —NR ¹² R ¹³ , a halogen atom and a cyano group. Substituted with a substituent of
    R ¹² represents a hydrogen atom,
    R ¹³ is a C _1-6 alkyl group (the C _1-6 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a phenyl group or a pyridyl group (the phenyl group and pyridyl group). The group may be unsubstituted or a C _1-3 alkyl group (the C _1-3 alkyl group is unsubstituted or substituted by one or more fluorine atoms), a halogen atom, a cyano group, and Substituted with one or more substituents independently selected from the group consisting of —O (C _1-3 alkyl).
    R ⁴ represents a hydrogen atom,
    J ¹ is, means an oxygen atom. The spiro compound according to claim 1 or 24, a tautomer of the compound, or a pharmaceutically acceptable salt thereof.
27. T is the formula (VI-1) or (VI-2)
    

    

    (Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, and R ⁸ and R ¹⁰ are each independently a phenyl group or a pyridyl group (the phenyl group and the pyridyl group are , Unsubstituted or independently selected from the group consisting of a fluorine atom, a C _1-3 alkyl group (the C _1-3 alkyl group is substituted by one or more fluorine atoms) and a cyano group 27. A spiro compound according to any one of claims 1, 24 to 26, a tautomer of the compound, or Its pharmaceutically acceptable salt.
28. T is the formula (VI-1) or (VI-2)
    

    

    (Wherein L ⁴ represents a C _1-3 alkylene group, L ⁵ represents a single bond, R ⁸ and R ¹⁰ are each independently a phenyl group (the phenyl group is a C _4-6 alkyl group) 27. The spiro compound according to any one of claims 1, 24 to 26, a tautomer of the compound, or a pharmaceutically acceptable salt thereof. Salt that can be done.
29. The spiro compound according to any one of claims 2 to 23, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a hydrogen atom.
30. 30. The spiro compound according to any one of claims 1 to 3, 7, and 9 to 29, a tautomer of the compound, or a pharmaceutically acceptable salt thereof, wherein X is cyclohexylene.
31. 30. The spiro compound according to any one of claims 1 or 2, 4 to 6, and 8 to 29, wherein X is a phenylene group, a pyridinediyl group, a pyrazinediyl group, a thiophenediyl group, or a thiazolediyl group. Sex or a pharmaceutically acceptable salt thereof.
32. 32. An adiponectin receptor activator comprising the spiro compound according to any one of claims 1 to 31, a tautomer of the compound, or a pharmaceutically acceptable salt thereof as an active ingredient.
33. A prophylactic / therapeutic / ameliorating agent for a disease effective for activating the adiponectin receptor, comprising the adiponectin receptor activating agent according to claim 32 as an active ingredient.
34. A metabolic syndrome and a prophylactic or therapeutic agent for arteriosclerosis comprising the adiponectin receptor activator according to claim 32 as an active ingredient.
35. A medicament comprising the spiro compound according to any one of claims 1 to 31, a tautomer of the compound, or a pharmaceutically acceptable salt thereof as an active ingredient.